C ARVEDILOL PHOSPHATE
Cross Reference to Related Applications
This-application claims the benefits of U.S. Provisional Patent Applications Nos. 60/817,634, filed 28 June 2006; 60/837,878, filed 14 August 2006; 60/843,818, filed 11 September 2006; 60/845,632, filed 18 September 2006; 60/845,879, filed 19 September 2006; 60/846.699, filed 21 September 2006; 60/847,587, filed 26 September 2006; 60/848,514, filed 28 September 2006; 60/851,366, filed 12 October 2006; 60/853,505, filed 19 October 2006; 60/857,716, filed 07 November 2006; 60/859,764, filed 16 November 2006; 60/878,914, filed 4 January 2007; 60/897,083, filed 23 January 2007; 60/899,815, filed 5 February 2007; 60/903,696, filed 26 February 2007; 60/927,098, filed 30 April 2007; 60/927,099, filed 30 April 2007; the contents of all of which are incorporated herein by reference.
Field of the Invention
The invention encompasses caryedilol phosphate and solid states thereof
Background of the Invention
Caryedilol, (+)-l -{Carbazol-4-yloxy)-3-[[2-(o-methoxyphenoxy)ethyl3amino]-2-propanol, is a nonselective ß-adrenergic blocker with α1-blocking activity. Caryedilol is a racemic mixture having the following structural formula:
(Formula Removed)
Caryedilol is the active ingredient in COREG®, which is indicated for the treatment of congestive heart failure and for the management of hypertension. Since caryedilol is a multiple-action drug, its beta-blocking activity affects the response to certain nerye impulses in parts of the body. As a result, beta-blockers decrease the heart's need for blood and oxygen
by reducing its workload. Caryedilol is also known to be a vasodilator resulting primarily from alpha-adrenoceptor blockade. The multiple actions of caryedilol are responsible for the antihypertensive efficacy of the drug and for its effectiveness in managing congestive heart failure.
U.S. patent No. 4,503,067 C"067 patent") discloses a class of carbazolyl-(4)-oxypropanolamine compounds, including caryedilol. See '067 patent, col. 1,1. 15 to col. 2,1. 3. The '067 patent also discloses the conversion of the compounds to their pharmacologically acceptable salts, by reacting the compoimd with "an equivalent amoimt of an inorganic or organic acid," such as phosphoric acid. See id. at col. 4,11. 23-29.
U.S. publication No. 2005/0240027 ("'027 publication") and U.S- publication No. 2005/0277689 ("'689 publication") each disclose that caryedilol has "relatively low solubility" (<1 ng/mL) in alkaline media, and that its solubility increases with decreasing pH, up to about 100 (xg/mL. See '027 publication, p. 1, 7; '689 publication, p. 1, 7. These publications also disclose solid and crystalline forms of caryedilol salts, as well as solvates thereof. See. e.g., '027 publication, p. 3, 51; '689 publication, p. 5, 169.
The discovery of new salt forms of caryedilol is needed in order to have greater aqueous solubility and also greater chemical stability.
Solid state phj^ical properties of a pharmaceutical compound can be influenced by controlling the conditions tmder which the compound is obtained in solid form. Solid state physical properties include, for example, the flowability of the milled solid. Flowability affects the ease with which the material is handled during processing into a pharmaceutical product. When particles of the powdered compound do not flow past each other easily, a formulation specialist must take that fact into account in developing a tablet or capsule formulation, which may necessitate the use of glidants such as colloidal silicon dioxide, talc, starch or tribasic calcium phosphate.
Another important solid state property of a pharmaceutical compound is its rate of dissolution in aqueous fluid. The rate of dissolution of an active ingredient in a patient's stomach fluid can have therapeutic consequences since it imposes an upper limit on the rate at which an orally-administered active ingredient can reach the patient's bloodstream. The rate of dissolution is also a consideration in formulating symps, elixirs and other liquid medicaments. The solid state form of a compound may also affect its behavior on compaction and its storage stability.
These practical physical characteristics are influenced by the conformation and orientation of molecules in the unit cell, which defines a particular polymorphic form of a

substance. The polymorphic form may give rise to thermal behavior different from that of the amorphous material or another polymorphic form. Thermal behavior is measured in the laboratory by such techniques as capillary melting point, thermograAometric analysis (TGA) and differential scaiming calorimetric (DSC) and can be used to distinguish some polymorphic forms from others. A particular polymorphic form may also give rise to distinct sectroscopic properties that may be detectable by powder X-ray crystallography, solid state 13C NMR spectrometry or infrared spectrometry.
One of the most important physical properties of a pharmaceutical compound, which can form polymorphs or solvates, is its solubility in aqueous solution, particularly the solubility in gastric juices of a patient. Other important properties relate to the ease of processing the form into pharmaceutical dosages, as the tendency of a powdered or granulated form to flow and the surface properties determine whether crystals of the form will adhere to each other when compacted into a tablet.
The discovery of new solid states of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product It enlarges the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic.
Summary of the Invention Caryedilol phosphate
In one embodiment, the invention encompasses caryedilol phosphate in an amorphous form. The invention also encompasses pharmaceutical compositions comprising amorphous caryedilol phosphate as well as methods of treatment using such pharmaceutical compositions. X-ray dif&actogram is substantially shown in Figure 1.
In another embodiment, the invention encompasses a process for preparing caryedilol pho^hate in an amorphous form comprising: (a) providing a solution of caryedilol, phosphoric acid, and ethanol; (b) optionally adding water to the solution to accelerate precipitation of the caryedilol phosphate; and (c) recovering the caryedilol phosphate in amorphous form.
Caryedilol hydrogen phosphate

In one embodiment, the invention encompasses a crystalline form of caryedilol hydrogen phosphate, referred to herein as Form G, and characterized by data selected from the group consisting of: X-ray powder diffraction reflections at about: 6.5,9.7,13.0, 16.0 and 17.8 degrees two theta ± 0.2 degrees two theta; a solid-state 13C- NMR spectrum having chemical shift resonances at about: 145.8,141.7 and 110.8 ± 0.2 ppm; and a solid-state 13C NMR spectrum having chemical shift differences between the lowest ppm resonance in the chanical shift area of 100 to 180 ppm and another in the chemical shift area of 100 to 180 ppm of about: 43.8, 39.7 and 8.8 ± 0.1 ppm; any five peaks selected fix)m the following hst of PXRD peaks at about: 6.5, 9.7, 13.0,13.5,16.0, 17.8, 22.8 and 23.2 ± 0.2 degrees two theta; X-ray powder diffraction reflections at about: 6.5,9.7,13.5,16.0 and 17.8 degrees two theta ± 0.2 degrees two theta; X-ray powder diffraction reflections at about: 6.5, 9.7,16.0, 18.4 and 23.2 degrees two theta ± 0.2 degrees two -theta; X-ray difSractogram substantially shown in Figure 2; the solid-state 13C- NMR substantially shown in Figure 3 or 3a.
In another embodiment, the invention encompasses a crystalline form of caryedilol hydrogen phosphate, referred to herein as Form H, and characterized by data selected from the group consisting of: X-ray powder diffraction reflections at about: 6.4,6.6,9.4, 14.5 and 15.4 degrees two theta ± 0.2 degrees two theta; X-ray powder diffraction reflections at about: 6.6, 9.7,13.0, 13.8 and 15.6 degrees two theta± 0.2 degrees two thetei; any five peaks selected from the following list of PXRD peaks at about: 6.5, 6.8, 9.6, 13.0,13.6,15.6, 17.5 and 28.7 ± 0.2 degrees two theta; X-ray powder diffraction reflections at about: 6.5,9.6,13.0,13.6 and 18.7 degrees two theta ± 0.2 degrees two theta; X-ray powder diffraction reflections at about: 6.5, 9.6, 13.6, 18.7 and 20.2 degrees two thetai 0.2 degrees two theta; a solid-state 13C- NMR spectrum having chemical shift resonances at about: 146.3,142.6 and 139.1 ± 0.2 ppm; and a solid-state 13C NMR spectrum having chemical shift di:Serences between the lowest ppm resonance in the chemical shift area of 100 to 180 ppm and another in the chemical shift area of 100 to 180 ppm of about 34,30.3 and 26.8 ± 0.1 ppm; X-ray dif&actogram substantially shown in Figure 4 or 5; solid-state 13C- NMR substantially shown in Figure 6 or 6a.
In another embodiment, the inv»ition encompasses a crystalline form of caryedilol hydrogen phosphate, referred to herein as Form K, and characterized by data selected from the group consisting of: X-ray powder diflSraction reflections at about: 6.3,9.8,12.7,13.2 and 16.9 degrees two theta ± 0.2 degrees two theta; X-ray diffractogram substantially shown in Figure 7; any five peaks selected from the following list of PXRD peaks at about: 6.3,9.8, 12.7, 13.2, 16.3,16.9,18.3 and 19.0 ± 0.2 degrees two theta;
X-ray powder dif&action reflections at about: 6.3, 9.8, 16.9,183 and 23 J2 degrees two theta ± 0.2 degrees two theta; X-ray powder dif&action reflections at about: 6.3,9.8, 14.9, 20.1 and
28.2 degrees two theta ± 0.2 degrees two theta.
In another embodiment, the invention encompasses a crystalline form of caryedilol dihydrogen phosphate, referred to herein as Form Q, characterized by data selected from the group consisting of: X-ray powder dif&action reflections at about: 6.2, 7.3,14.5, 17.5 and
21.3 degrees two theta ± 0.2 degrees two theta; X-ray dif&actogram substantially shown in
Figure 8.
In another embodimoit, the invention encompasses an amorphous form of caryedilol hydrogen phosphate. This amorphous forai is substantially depicted in XRD difBractograms shown in Figures 9 or 10
The invention also encompasses pharmaceutical compositions comprising the crystalline forms and the amorphous form of caryedilol hydrogen phosphate as well as methods of treatment using such pharmaceutical compositions.
In another embodiment, the invention encompasses processes for preparing the crystalline forms and the amorphous form of caryedilol hydrogen phosphate.
Caryedilol dihydrogai phosphate
In one embodiment, the invention encompasses a process for preparing crystalline caryedilol dihydrogen phosphate Form I, characterized by data selected &om the group consisting of: X-ray powder dif&action reflections at about: 7.0, 8.0, 9.2, 11.4 and 16.0 degrees two theta ± 0.2 degrees two theta; a solid-state 13C- NMR spectrum having chemical shift resonances at about 154.5, 146.5,139.7 and 122.1 ± 0.2 ppm; and a solid-state 13CNMR spectrum having chemical shift differences between the lowest ppm resonance in the chemical shift area of 100 to 180 ppm and another in the chemical shift area of 100 to 180 ppm of about 50.7,42.7, 35.9 and 18.3 ± 0.1 ppm, comprising: combining caryedilol, phosphoric acid and a solvent selected from the gjcaap consisting of C1-C8 alcohols, C5-C10 aliphatic hydrocarbons, C6-12 aromatic hydrocarbons, C3-C7 ketones, C4-C8 ethers, C3-C7 esters and acetonitrile and precipitating caryedilol dihydrogen phosphate Form I from the reaction mixture. X-ray dififractogram substantially shown in Figure 11; solid-state 13C-NMR substantially shown in Figure 12.
In another embodiment, the invention encompasses a crystalline form of caryedilol dihydrogen phosphate, referred to herein as Form L, characterized by data selected from the
group consisting of: X-ray powder diffraction reflections at about: 4.6, 7.5,8.7, 11.6 and 15.6 degrees two theta± 0.2 degrees two theta; a solid-state 13C-NMR spectrum having chemical shift resonances at about 156.6,150.3 and 102.5 ± 0.2 ppm; and a solid-state 13C NMR spectrum having chemical shift difTerences between the lowest ppm resonance in the chemical shift area of 100 to 180 ppm and another in the chemical shift area of 100 to 180 ppm of about 54.1 and 47.8and 0.0 ± 0.1 ppm.; X-ray dif&actogram shown in Figure 13; solid-state 13C- NMR shown in Figure 14 and/or 14a; any five peaks selected from the following list of PXRD peaks at about: 4.6, 7.5, 8.7,11.6 13.4, 15.6 and 19.4 ± 0.2 degrees two theta; X-ray powder dif&action reflections at about: 4.6, 7.5, 8.7, 11.6 and 15.0 degrees two theta ± 0.2 degrees two theta.; X-ray powder diffraction reflections at about: 4.6, 7.5, 8.7, 15.0 and 22.9 degrees two theta ± 0.2 degrees two theta.
Bi another embodiment, the invention encompasses a crystalline form of caryedilol dihydrogen pho^hate, referred to herein as Form LI, characterized by data selected from the group consisting of: X-ray powder dif&action reflections at about: 4.6, 8.7,11.6,14.6 and
15.3 degrees two theta ± 0.2 degrees two theta; a solid-state "°C-NMR spectrum having
chemical shift resonances at about 156.6, 150.3 and 148.4 ± 0.2 ppm; and a solid-state 13C NMR spectrum having chemical shift differences between the lowest ppm resonance in the
chemical shift area of 100 to 180 ppm and another in the chemical shift area of 100 to 180
ppm of about 53.2,46.9 and 45.0 ±0.1 ppm.; X-ray dif&actogram substantially shown in
Figure 15; solid-state 13C-NMR substantially shown in Figure 16 and/or 16a; PXRD peaks at
about: 4.6, 7.4, 8.7,11.6 14.6, 15.3 and 19.4 ± 0.2 degrees two theta; PXRD peaks at about
4.6, 7.4, 8.7,13.6 and 15.3 degrees two theta ± 0.2 degrees two theta; PXRD peaks at about
4.6, 7.4, 8.7,11.6 and 17.4; PXRD peaks at about 4.6,7.4, 8.7,15.3 and 17.4 degrees two
theta db 0.2 degrees two theta.
In another embodiment, the invention encompasses a crystalline form of caryedilol dihydrogen phosphate, referred to herein as Form N, characterized by data selected from the group consisting of: X-ray powder dif&action reflections at about: 6.0, 6.9,15.2,16.3 and
17.4 degrees two theta ± 0.2 degrees two theta; a solid-state 13C- NMR spectrum having
chemical shift resonances at about 154.4,146.9 and 138.4 ± 0.2 ppm; and a solid-state 13C NMR spectrum having chemical shift differences between the lowest ppm resonance in the
chemical shift area of 100 to 180 ppm and another in the chemical shift area of 100 to 180
ppm of about 52.9,45.4 and 36.9 ± 0.1 ppm.; a solid-state '°C-NMR spectrum having
chemical shift resonances at about 154.4,146.9, 138.4 and 110.9 ± 0.2 ppm; a solid-state 13C NMR spectrum having chemical shift differences between the lowest ppm resonaiK;e in the
chemical shift area of 100 to 180 ppm and another in the chemical shift area of 100 to 180 ppm of about 52.9,45.4,36.9 and 9.4 ± 0.1 ppm; X-ray diffractogram substantially shown in Figure 17 and 18; solid-state 13C-NMR substantially shown in Figure 19 and/or 19a; X-ray powdfer diffraction reflections at about: 6.0,6.9,13.7 15.2 and 18.1 degrees two theta± 0.2 degrees two theta; X-ray powder diffraction reflections at about: 6.0,6.9,13.7,15.2 and 17.4 ± 0.2 degrees two theta.
In another embodiment, the invention encompasses a crystaUine form of caryedilol dihydrogen phosphate, referred to herein as Form O, characterized by data selected fi-om the group consisting of:X-ray powder diffraction reflections at about: 6.1,12.2, 12.9, 16.2 and 18.0 degrees two theta ± 0.2 degrees two theta; X-ray diffractogram shown in Figure 20.
hi another embodiment, the invention encompasses a crystalline form of caryedilol dihydrogen phosphate, referred to herein as Form P, characterized by data selected fix>m the group consisting of: X-ray powder diffraction reflections at about: 5.3,10.4,16.8, 26.0 and 31.8 degrees two theta ± 0.2 degrees two theta; a solid-state 13C- NMR spectrum haAong chemical shift resonances at about 154.7,146.6 and 122.2 ± 0.2 ppm; and a solid-state 13C NMR ^ectrum having chemical shifi: differences between the lowest ppm resonance in the chemical shift area of 100 to 180 ppm and another in the chemical shift area of 100 to 180 ppm of about 54.7,46.6 and 22.2 ± 0.1 ppm; X-ray diffractogram shown in Figure 21; solid-state 13C- NMR shown in Figure 22 and/or 22a; any five peaks selected from the following Ust of PXRD peaks at about: 5.3,10.4,14.5,16.8,17.8,26.0 and 31.8 ± 0.2 degrees two theta; X-ray powder diffraction reflections at about: 5.3,10.4,15.2,17.8.and 22.5 degrees two theta± 0.2 degrees two theta; Form P can also be characterized by X-ray powder diffraction refiectioiis at about: 5.3, 14.5,15.2, 16.8 and 17.3 degrees two theta ± 0.2 degrees two theta; Form P can also be characterized by X-ray powder diffraction reflections at about: 5.3,10.4, 14.5,15.2 and 17.8 degrees two theta ± 0.2 degrees two theta; Form P can also be characterized by X-ray powder diffraction reflections at about: 5.3,14.5, 15.2,17.8 and 20.1 degrees two theta ± 0.2 degrees two theta.
Li another embodiment, the invention encompasses a crystalUne form of caryedilol dihydrogen phosphate, referred to herein as Form F, characterized by data selected from: X-ray powder diffraction reflections at about: 7.7, 8.7,16.8 and 22.8 degrees two theta ± 0.2 degrees two theta; X-ray powder diffraction reflections at about: 7.6, 8.6, 16.7 and 22.8 degrees two theta ± 0.2 degrees two theta; X-ray powder diffraction reflections at about: 7.7, 8.7,16.8, 22.8 and 26.5 degrees two theta ± 0.2 degrees two theta; X-ray powder diffraction reflections at about: 7.6,8.6,16.7,22.8 and 26.5 degrees two theta ± 0.2 degrees two theta; a
solid-state 13C- NMR spectrum having chemical shift resonances at about 149.8, 145.4 and 140.7 ± 0.2 ppm; and a solid-state 13C NMR spectrum having chemical shift differences between the lowest ppm resonance in the chemical shift area of 100 to 180 ppm and another in the chemical shift area of 100 to 180 ppm of about 50.6,46.2 and 41.5 ± 0.1 ppm.; a solid-state 13C- NMR spectrum having chemical shift resonances at about 149.8,145.4,138.5 and 140.7 ± 0.2 ppm; and a solid-state C NMR spectrum having ch^nical shift dififerences between the lowest ppm resonance in the chemical shift area of 100 to 180 ppm and another in the chemical shift area of 100 to 180 ppm of about 50.6,46.2, 39.3 and 41.5 ± 0.1 ppm; X-ray diffractogram shown in Figures 23 or 24; solid-state 13C-NMR shown in Figure 25 and/or 25a; X-ray powder dif&action reflections at about: 7.7, 8.7,13.5,15.2 and 22.9 degrees two theta ± 0.2 degrees two theta; X-ray powder dif&action reflections at about: 7.6, 8.6,13.4, 15.1 and 22.8 degrees two theta ± 0.2 degrees two theta; X-ray powder difBraction reflections at about: 7.7,13.5,15.2,18.3 and 18,9 degrees two theta± 0.2 degrees two theta; X-ray powder diffiaction reflections at about: 7.6, 13.4, 15.1, 18.2 and 18.8 degrees two theta ± 0.2 degrees two theta; X-ray powder diffraction reflections at about: 7.7,13,5,15.2,17.2 and 21.5 degrees two theta ± 0.2 degrees two theta; X-ray powder diffraction reflections at about: 7.6,13.4, 15.1,17.1 and 21.4 degrees two theta ± 0.2 degrees two theta.
hi another embodiment, the invention encompasses a crystalline form of caryedilol dihydrogen phosphate, referred to herein as Form Fl, characterized by X-ray powder diffraction reflections at about: 7.6, 9.8,10.9,21.2 and 25.0 degrees two theta ± 0.2 degrees two theta; a solid-state 13C-NMR qjectrum having chemical shift resonances at about 155,3, 145.3 and 127.7 ± 0.2 ppm; and a solid-state 13C NMR spectrum having chemical shift differences between the lowest ppm resonance in the chemical shift area of 100 to 180 ppm and another in the chemical shift area of 100 to 180 ppm of about 52.6,42.6 and 25 ± 0.1 ppm; X-ray diffractogram shown in Figures 26 or 27; solid-state 13C- NMR shown in Figures 28 and/or 28a; X-ray powder diffraction reflections at about: 7.6, 10.9,13.3,15.2 and 18.8 degrees two theta ± 0.2 degrees two theta; X-ray powder diffraction reflections at about: 7.6, 8.5,9,8,15.2 and 16.9 ± 0..2 degrees two theta; X-ray powder diffraction reflections at about: 7.6, 9.8, 10.9, 14.7,15.2 and 22.8 ± 0.2 degrees two theta; X-ray powder dif&action reflections at about: 7.6, 8.5,9.8, 13.3 and 15.2 ± 0.2 degrees two theta.
In another «nbodiment, the invention encompasses a crystalline form of caryedilol dihydrogen phosphate, referred to herein as Form R, characterized by X-ray powder diffraction reflections at about: 5.8, 11.8, 16.8, 18.6 and 23.2 degrees two theta ± 0.2 degrees two theta; a solid-state 13C- NMR spectrum having chemical shift resonances at about 153.7,
147.9 and 122.8 ± 0.2 ppm; and a solid-state 13C NMR spectrum having chemical shift differences between the lowest ppm resonance in the ch^nical shift area of 100 to 180 ppm and another in the chemical shift area of 100 to 180 ppm of about 51.0,45.2 and 20.1 ± 0.1 ppm.; X-ray dif&actogram shown in Figure 29; solid-state 13C- NMR shown in Figure 30 and/or 30a; X-ray powder difl&action reflections at about: 5.8,11.8,15.5, 16.2 and 18.6 degrees two theta ± 0.2 degrees two theta; X-ray powder diffraction reflections at about: 5.8, 16.2,18.6,23.2 and 27.0 degrees two theta ± 0.2 degrees two theta; X-ray powder diffraction reflections at about: 5.8,16.2,16.8,19.9 and 25.4 degrees two theta ± 0.2 degrees two theta.
In another onbodiment, the invention encompasses a crystalline form of caryedilol dihydrogen phosphate, refaxed to herein as Form Y, characterized by X-ray powder diffraction reflections at about: 7.7, 7.9,9.1,16.6 and 19.5 degrees two theta ± 0.2 degrees two theta; X-ray powder diffraction reflections at about:7.7,8.5, 16.6, 19.5 and 20.3 degrees two theta; X-ray diffractogram as substantially shown in Figure 31.
In another embodiment, the invention encompasses a crystalline form of caryedilol dihydrogen phosphate, referred to herein as Form W, characterized by data selected fi-om the group consisting of: X-ray powder diffraction reflections at about: 6.6, 9.7, 13.8,15.7 and 17.1 degrees two theta ± 0.2 degrees two theta; X-ray dififractogram is shown in Figure 32.
In another embodiment, the invention encompasses an essentially amorphous form of caryedilol dihydrogen phosphate characterized by data selected from the group consisting of: a solid-state 13C-NMR spectrum having chemical shift resonances at about 154.6,146.7 and 140.3 ± 0.2 ppm; and a solid-state 13C NMR spectrum having chemical shift differences between the lowest ppm resonance in the chemical shift area of 100 to 180 ppm and another in the ch^ical shift area of-100 to 180 ppm of about 54.2,46.3 and 39.9 ± 0.1 ppm.; solid-state 13C-NMR spectrum having broad chemical shift resonances at about 154.6,146.7,140.3 and 100.4 ±0.2 ppm; and a solid-state 13C- NMR spectrum having chemical shift differences between the lowest ppm resonance in the chemical shift area of 100 to 180 ppm and another in the chemical shift area of 100 to 180 ppm of about 54.2,46.3,39.9 and 0.0 ± 0.1 ppm; X-ray dififractogram as substantially shown in Figure 33; solid-state 13C- NMR spectrum as substantially shown in figure 34 and/or 34a.
In another embodiment the present invention provides a crystalline form of Caryedilol phosphate salt, referred to herein as Form F2. Form F2 is characterized by an X-Ray powder diffraction pattern with peaks at about 7.4,7.9, 8.5, 8.9 and 11.1 ± 0.2 degrees two theta. The Calculated X-ray powder dif&action pattern of Caryedilol phosphate salt Form F2 is substantially depicted in Figure 35. The structure was solved by direct methods for trichnic
P-1 group with the unit cell parameters: a= 13.281(3), b = 14.315(3), c = 16.406(4) A, α = 66.85(2), ß = 85.94(2) l = 65.44(4) [deg], andcell volume 2592.4(12) Å3.
The invention also encompasses pharmaceutical compositions comprising the crystalline forms and the amorphous form of caryedilol dihydrogen phosphate as well as methods of treatment using such pharmaceutical compositions.
In another embodiment, the invention encompasses processes for preparing the crystalline forms and the amorphous form of caryedilol dihydrogen phosphate.
Brief Description of the. Figures
Figure 1 is a PXRD for caryedilol phosphate amorphous form.
Figure 2 is a powder X-ray diffractogram for caryedilol hydrogen phosphate Form G.
Figure 3 illustrate a solid-state 13C- NMR spectmm of caryedilol hydrogen phosphate Form G.
Figure 3a illustrate a solid-state 13C-NMR spectrum of caryedilol dihydrogen phosphate Form G in the chemical shift area of 100 to 180 ppm.
Figures 4 and 5 are powder X-ray diffractograms for caryedilol hydrogen phosphate Form H.
Figure 6 illustrate a solid-state 13C- NMR spectrum of caryedilol hydrogen phosphate Form H.
Figure 6a illustrate a solid-state 13C-NMR spectrum of caryedilol dihydrogen phosphate Form H in the chemical shift area of 100 to 180 ppm.
Figure 7 is a powder X-ray diffractogram for caryedilol hydrogen phosphate Form K.
Figure 8 is a powder X-ray diffractogram for caryedilol hydrogen phosphate Form Q.
Figure 9 is a powder X-ray diffractogram for the amorphous form of caryedilol hydrogen phosphate (according to Example 12).
Figure 10 is a powder X-ray diffractogram for the amorphous form of caryedilol hydrogen phosphate (according to Example 13).
Figure 11 illustrates a characteristic powder X-ray diffractogram for caryedilol dihydrogen phosphate Form I.
Figure 12 illustrates a solid-state 13C-NMR spectrum of caryedilol dihydrogMi phosphate Form I.
Figure 13 illustrates a characteristic powder X-ray diffiactogram for caryedilol dihydrogen phosphate Form L.
Figure 14 illustrates a solid-state 13C- NMR spectrum of caryedilol dihydrogen phosphate Form L.
Figure 14a illustrate a solid-state 13C-NMR spectrum of caryedilol dihydrogen phosphate Form L in the chemical shift area of 100 to 180 ppm.
Figure 15 illustrates a characteristic powder X-ray diffractogram for caryedilol dihydrogen phosphate Form LI.
Figure 16 illustrates a solid-state 13C- NMR specttum of caryedilol dihydrogen phosphate Form LI.
Figure 16a illustrates a solid-state 13C- NMR spectrum of caryedilol dihydrogen phosphate Form LI in the chemical shift area of 100 to 180 ppm.
Figures 17 and 18 illustrate a characteristic powder X-ray diffractogram for caryedilol dihydrogen phosphate Form N.
Figure 19 illustrates a solid-state 13C- NMR spectrum of caryedilol dihydrogen phosphate Form N.
Figure 19a illustrates a solid-state 13C- NMR spectrum of caryedilol dihydrogen phosphate Form N in the chemical shift area of 100 to 180 ppm.
Figure 20 illustrates a characteristic powder X-ray diffractogram for caryedilol dihydrogen phosphate Form O.
Figure 21 illustrates a characteristic powder X-ray diffractogram for caryedilol dihydrogen phosphate Form P.
Figure 22 illustrates a solid-state 13C- NMR spectrum of caryedilol dihydrogen phosphate Form P.
Figure 22a illustrates a solid-state 13C-NMR spectrum of caryedilol dihydrogen phosphate Form P in the chemical shift area of 100 to 180 ppm.
Figure 23 illustrates a characteristic powder X-ray diffractogram for caryedilol dihydrogen phosphate Form F obtained in Example 49.
Figure 24 illustrates a characteristic powder X-ray dififractogram for caryedilol dihydrogen phosphate Form F obtained in Example 50.
Figure 25 illustrates a solid-state 13C- NMR spectrum of caryedilol dihydrogen phosphate Form F.
Figure 25a illustrate a solid-state 13C- NMR spectrum of caryedilol dihydrogen phosphate Form F in the chemical shift area of 100 to 180 ppm.
Figure 26 illustrates a characteristic powder X-ray diffractogram for caryedilol dihydrogen phosphate Form Fl obtained in Example 52.

Figure 27 illustrates a characteristic powder X-ray diffractogram for caryedilol dihydrogen phosphate Form Fl obtained in Example 86.
Figure 28 illustrate a solid-state 13C- NMR spectrum of caryedilol dihydrogen phosphate Form Fl.
Figure 28a illustrates a sohd-state 13C-NMR spectrum of caryedilol dihydrogen phosphate Form Fl in the chemical shift area of 100 to 180 ppm.
Figure 29 illustrates a characteristic powder X-ray diffractogram for caryedilol dihydrogen phosphate Form R.
Figure 30 illustrate a sohd-state 13C- NMR- spectrum of caryedilol dihydrogen phosphate Form R.
Figure 30a illustrate a solid-state 13C-NMR spectrum of caryedilol dihydrogen phosphate Form R in the chemical shift area of 100 to 180 ppm.
Figure 31 illustrates a characteristic powder X-ray diffractogram for phosphate salt of caryedilol Form Y.
Figure 32 illustrates a characteristic powder X-ray diffractogram for caryedilol dihydrogen phosphate Form W.
Figure 33 illustrates a characteristic powder X-ray diffractogram for the amorphous form of caryedilol dihydrogen phosphate.
Figure 34 illustrates a solid-state 13C- NMR spectrum of the amorphous form of caryedilol dihydrogen phosphate.
Figure 34a illustrate a solid-state 13C-NMR spectrum of the amorphous form of caryedilol dihydrogen phosphate in the chemical shift area of 100 to 180 ppm.
Figure 35 illustrates a characteristic powder X-ray diffractogram for the caryedilol hydrogen phosphate Form F2.
Figure 36 is an SEM image of the Form I.
Figure 37 is an SEM images of the Form IV.
Figure 38 is a Microscope image of the Form I.
Figure 39 illustrates the % Crystallinity of Form L.
Figure 40 illustrates the % Crystallinity of Form LI.
Figure 41 illustrates the % Crystallinity of Form I.
Figure 42 is a Microscope image of the Form N.
Figure 43 illustrates the % Crystallinity of Form N.
Figure 44 is a Microscope image of the Form IV.
Figure 45 is a Microscope image of Form F.
Figure 46 illustrates the % Crystallinity of Form F.
Figure 47 is a Microscope image of Form Fl.
Figure 48 illustrates the % Crystallinity of Form Fl.
Figure 49 is a Microscope image of Form R.
Figure 50 illustrates the % crystallinity of R.
Figure 51 is a Microscope image of Form Y.
Figure 52 is an SEM images of amorphous form 1:1.
Figure 53 is the % crystallinity of Form P.
Detailed Description of the Invention
There is a need in the art for solid forms of caryedilol phosphate, caryedilol hydrogen phosphate, and caryedilol dihydrogen phosphate with increased solubility over the caryedilol free base. Increased solubility leads to improved bioavailability when the drug is administered to a patient, and thus allows for a reduction in the dosages required. The invention addresses this need by providiag amorphous forms and crystalline forms of caryedilol phosphate, caryedilol hydrogen phosphate and caryedilol dihydrogen phosphate, which are more readily soluble than caryedilol free base. Also provided are processes for preparing the amorphous forms and crystalline forms of caryedilol phosphate, caryedilol hydrogen phosphate and caryedilol dihydrogen phosphate.
As used herein, unless otherwise defined, the term "caryedilol phosphate" refers to a tricaryedilol phosphate complex, in which caryedilol and phosphate are present in a molar ratio of about 3:1.
As used herein, the term "caryedilol hydrogen phosphate" refers to a caryedilol phosphate salt, in which caryedilol and phosphoric acid are present in a molar ratio of about 2:1.
As used herein, the term "caryedilol dihydrogen phosphate" refers to a caryedilol phosphate salt, in which caryedilol and phosphate are present in a molar ratio of about 1:1.
"Therapeutically effective amount" means'the amount of a crystalline form that, when administered to a patient for treating a disease or other undesirable medical condition, is sufficient to have a beneficial effect with respect to that disease or condition. The "therapeutically effective amount" may vary depending on the crystalline form, the disease or condition and its severity, and the age, weight, etc., of the patient to be treated. Determining the therapeutically effective amount of a given crystalline form is within the ordinary skill of the art and requires no more than routine experimentation.
'Tharmaceutically acceptable" means a substance which is not biologically or otherwise undesirable, i.e., the substance can be administered to an individual -without causing significant undesirable effects.
As used herein, the term "water content" refers to the content of water based upon the Loss on Drying method (the "LOD" method) as described in UPS 29-NF 24, official August 1,2006, Physical Test and Determinations, <731> LOSS ON DRYING or in Pharmacopeial Forum, Vol. 24, No. 1, p. 5438 (Jan - Feb 1998), the Karl Fisher assay for determining water content or thermogravimetric analysis (TGA). All percentages herein are by weight unless otherwise indicated. Those skilled in the art will also understand that the term "dihydrate" when used in reference to caryedilol dihydrogen phosphate describes caryedilol dihydrogen phosphate having a water content of between about 4.7-6.9% w/w. Those skilled in the art will also understand that the term "hemihydrate" when used in reference to caryedilol dihydrogen phosphate describes caryedilol dihydrogen phosphate having a water content of about 1.7-2.0% w/w.
As used herein, the term "GC measurement of residual solvent" refers to an automatic headspace gas-chromatographic system.
As used herein, "solvate" is meant to include any crystalline form which incorporates solvent in a level of more than about 1%.
Those skilled in the art will imderstand that the term "hemimethanolate" when used in reference to caryedilol dihydrogen phosphate describes caryedilol dihydrogen phosphate having a methanol content of between about 2.7-3.2% w/w.
Those skilled in the art will understand that the term "hemiethanolate" when used in reference to caryedilol dihydrogen phosphate describes caryedilol dihydrogen phosphate having an ethanol content of between about 4.4-4.7% wAv.
Those skilled in the art wdll understand that the term "isopropanol solvate" when used in reference to caryedilol dihydrogen phosphate describes caryedilol dihydrogen phosphate having an isopropanol content of between about 7.5-10.3% w/w.
Spray drying broadly refers to processes involving breaking up liquid mixtures into small droplets (atomization) and rapidly removing solvent from the mixture, hi a typical spray drying apparatus, there is a strong driving force for evaporation of solvent Scora the droplets, which may be provided by providing a drying gas. Spray drying processes and equipment are described in Perry's Chemical Engineer's Handbook, pp. 20-54 to 20-57 (6th ed. 1984) and Remington: The Science and Practice of Pharmacy, 19th ed., vol. n, pg. 1627, which are herein incorporated by reference.
By way of non-limiting example only, the typical spray drying apparatus comprises a drying chamber, atomizing means for atomizing a solvent-containing feed into the drying chamber, a somrce of drying gas that flows into the drying chamber to remove solvent from the atomized-solvent-containing feed, an outlet for the products of drying, and product collection means located downstream of the drying chamber. Examples of such apparatuses include Niro Models PSD-1, PSD-2 and PSD-4 (Niro A/S, Soeborg, Denmark). Typically, the product collection means includes a cyclone connected to the drying apparatus, in the cyclone, the particles produced during spray drying are separated from the drying gas and evaporated solvent, allowing the particles to be collected. A filter may also be used to separate and collect the particles produced by spray drying.
As used herein, the term chemical shift difference refers to the difference in chemical shift resonance between a reference chemical shift resonance and another chemical shift resonance in the same NMR spectrum. In the present patent application, the chemical shift differences were calculated by subtracting the lowest ppm resonance (reference chemical shift resonance) in the NMR spectrum of chemical shifts in the area of 100 to 180 ppm from another (obseryed) ppm resonance in the same NMR spectrum of chemical shifts in the area of 100 to 180 ppm. These chemical shift differences provide a measurement for a substance, for example caryedilol phosphate, of the present invention that compensates for a phenomenon in NMR spectroscopy wherein, depending on the instrumentation and calibration method used, a shift in the SS-NMR "footprint" is obseryed. This shift in the SS-NMR "footprint", having chemical shift resonances at a certain positions, is such that although the individual chemical shift resonances have altered, the distance between each chemical shift resonance and the next is retained.
Caryedilol phosphate
In one embodiment, the invention provides an amorphous form of caryedilol phosphate. The amorphous form of ceiryedilol phosphate may be firee of any crystalline form.
In anotiier embodiment, the invention encompasses a process for preparing the amoiphous form of caryedilol phosphate. The amorphous form of caryedilol phosphate can be prepared by precipitation from ethanol. Preferably, the caryedilol phosphate is prepared by precipitation from a mixture of ethanol and water.
Accordingly, the invention provides a method for preijaring amorphous caryedilol phosphate comprising:
(a) precipitating amorphous caryedilol phosphate from a solution of caryedilol and phosphoric acid in a mixture of ethanol and water; and
(b) recovering the amorphous caryedilol phosphate.
In one preferred embodiment, the process comprises: (a) providing a solution of caryedilol, phosphoric acid, and ethanol; (b) optionally adding water to the solution to accelerate precipitation of the caryedilol phosphate; and (c) recovering the caryedilol phosphate in amorphous form.
The caryedilol and phosphoric acid in step (a) can be present in a molar ratio of about 5:1 to about 1:1, preferably about 4:1 to about 2:1, more preferably about 2.5:1 to about 3.5:1, and even more preferably about 3:1. The solution of step (a) may be prepared by combining caryedilol and ethanol to form a mixture and then slowly adding phosphoric acid to the mixture. The solution of step (a) may also be prepared by combining phosphoric acid and ethanol and then adding caryedilol or by adding caryedilol and phosphoric acid more or less simultaneously to ethanol.
The ingredients in step (a) may be heated in order to achieve dissolution. Stirring may also be employed to promote dissolution. In one embodiment, heating is carried out to about 60°C to about reflux temperature, followed by cooling to a temperature of about 0°C to about 30°C. Preferably, the ingredients in step (a) are heated to reflux (about TS°C to 82°C) and maintained at reflux for a period of time. More preferably, the ingredients in step (a) are maintained at reflux for about 5 to about 10 minutes, or for about 5 to about 100 minutes, optionally, with stirring.
If the solution of step (a) is heated, the solution is preferably cooled to about 20°C to about 35°C, preferably to about room temperature (about 20-23°C), before adding the water of step (b). Preferably, after water is added to the solution of step (a), the resulting mixture is stirred at about 20°C to about 35°C, preferably at about room temperature (about 20-23°C). More preferably, the mixture is stirred at about 20°C to about 35°C for about 4 to about 16 hours, or about 6 to about 12 hours, or about 8 to about 10 hours, or overnight.
In certain embodiments, the ratio of water to ethanol is about 3:1 to about 1:3, preferably about 2:1 to about 1:2, and more preferably about 1:1 (v/v).
In certain embodiments, the ratio of caryedilol to ethanol is about 1:5 to about 1:30, preferably about 1:10 to about 1:20, and more preferably about 1:15 (g/ml).
Tn certain embodiments, the ratio of caryedilol to water is about 1:5 to about 1:30, preferably about 1:10 to about 1:20, and more preferably about 1:15 (g/ml).
The precipitated caryedilol phosphate may be recovered by any method known to the skilled artisan. Preferably, the caryedilol phosphate is recovered firom the mixture by filtration, and then dried imder reduced pressure (< 1 atmosphere). Preferably, the drying can be at elevated temperature, e.g., in an oven at about 40'°C to about 60°C, preferably about 50°C.
Amorphous solids, in contrast to crystalline forms, do not possess a distinguishable crystal lattice and do not have an orderly arrangement of structural units. Amorphous forms are generally more soluble, and thus they are desirable for pharmaceutical purposes because the bioavailability of amorphous compounds may be greater than their crystalline counterparts.
Amorphous caryedilol phosphate may be analyzed to detennine the amorphous nature of the product. The powder X-ray diffraction ("PXRD") pattern of amorphous caryedilol phosphate would show no peaks characteristic of crystalline forms of caryedilol phosphate, thus demonstrating the amorphous nature of the product. The presence of peaks characteristic of crystalline forms would indicate presence of crystalline caryedilol phosphate. A representative PXRD pattern for amorphous caryedilol phosphate is depicted in Figure 1.
Preferably, the amorphous caryedilol phosphate comprises less than about 20% crystalline caryedilol and or caryedilol phosphate salts by weight, more preferably less than about 10% by weight, and even more preferably less than about 5% by weight, more preferably less than 1% by weight. The presence of a particular crystalline caryedilol can be determined by the presence of PXRD peaks characteristic of crystalline forms of caryedilol phosphate salts. The amoimt of crystallinity is quantified by methods known in the art like "crystallinity index" available to most XRD softwares.
In certain embodiments, the amorphous caryedilol phosphate comprises less than about 20% of Form I crystalline caryedilol by weight, more preferably less than about 10% by weight, and even more preferably less than about 5% by weight of Form I, as judged by the presence of PXRD peaks characteristic of Form I crystalline caryedilol. Form I is disclosed in European Patent Application EP 0893440.
Caryedilol hydrogen phosphate
The invention provides crystalline forms and an amorphous form of caryedilol hydrogen phosphate, which are more readily soluble than caryedilol free base. The amorphous caryedilol hydrogensulfate of the present invention has an XRD spectrum as substantially depicted in Figures 9 and 10.
Also provided is a process for preparing amorphous caryedilol hydrogen phosphate comprising dissolving caryedilol hydrogen phosphate in C1-C8 alcohols or in a mixture of C3-7 ketones with water, followed by solvent removal. Preferably the caryedilol hydrogen phosphate is dissolved in acetone and the ratio of acetone/water is about 2:1 (v/v).
Preferably the solvent is removed by fast evaporation, more preferably by spray drying.. Spray drying can be carried out with an inlet temperature of about 80°C to about 120'°C and an outlet temperature of below about 100°C. In one embodiment the spray drying is carried out with an inlet temperature of about 95°C to about 105°C and an outlet temperature of below about 40'°C.
In one embodiment, the invention encompasses a crystalline form of caryedilol hydrogen phosphate, referred to herein as Form G, characterized by data selected fix)m the group consisting of: X-ray powder diffraction reflections at about: 6.5, 9.7,13.0,16.0 and 17.8 degrees two thetadb 0.2 degrees two theta; a solid-state 13C- NMR spectrum having chemical shift resonances at about 145.8,141.7 and 110.8 ± 0.2 ppm; and a solid-state 13C NMR spectrum having chemical shift differences between the lowest ppm resonance in the chemical shift area of 100 to 180 ppm and another in the chemical shift area of 100 to 180 ppm of about 43.8,39.7 and 8.8 ± 0.1 ppm. The lowest ppm resonance in the chemical shift area of 100 to 180 ppm is typically at about 102.0 ± 1 ppm. The X-ray powder dififractogram of Form G is substantially shown in Figure 2. The solid-state 13C NMR spectrum of Form G is substantially shown in Figure 3 and/or 3a..
Form G can also be characterized by any five peaks selected from the following list of PXRD peaks at about: 6.5, 9.7,13.0,13.5,16.0, 17.8, 22.8 and 23.2 ± 0.2 degrees two theta. hi another embodiment Form G is characterized by data selected fixim: X-ray powder diffraction reflections at about: 6.5,9.7, 16.0, 18.4 and 23.2 degrees two theta ± 0.2 degrees two theta.
Form G, and can be ftirther characterized by data selected fi'om the group consisting of: X-ray powder diffraction reflections at about 18.5, 19.5,20.9,23.1 and 24.7 degrees two-theta, ± 0.2 degrees two-theta; a solid-state 13C- NMR spectrum having chemical shift resonances at about 154.5, 146.5 and 138.8 db 0.2 ppm; and a solid-state 13C NMR spectnnn having chemical shift differences between the lowest ppm resonance in the chemical shift
area of 100 to 180 ppm and another in the chemical shift area of 100 to 180 ppm of 52.5,44.5 and 36.8 ± 0.1 ppm. The lowest ppm resonance in the chemical shift area of 100 to 180 ppm is typically at about 102.0 ± 1 ppm.
Form G has a weight loss, as measured by TGA, of between about 4.5-11.0% by weight.
In another embodiment, the invention encompasses a process for preparing caryedilol hydrogen phosphate Form G comprising: (a) combining caryedilol, phosphoric acid, and methanol to obtain a solution; (b) combining the solution with water to obtain a solid; and (c) recovering caryedilol hydrogen phosphate Form G.
The caryedilol and phosphoric acid in step (a) are preferably combined in a molar ratio of about 2:1. The solution of step (a) may be prepared by combining caryedilol and methanol to form a mixture and then slowly adding phosphoric acid to the mixture. Alternatively, the caryedilol and phosphoric acid may be added more or less simultaneously to the methanol.
The ratio of caryedilol to water can be about 1:8 (g/ml) to about 1:12 (g/ml). Preferably, the ratio of caryedilol to water is about 1:10 (g/ml).
The ingredients in step (a) may be heated to in order to achieve dissolution. Stirring niay also be employed to promote dissolution. Preferably, the ingredients in step (a) are heated to reflux.
If the solution of step (a) is heated, the solution is preferably cooled to about 20°C to about 35°C before combining the solution with water in step (b).
The precipitated caryedilol hydrogen phosphate Form G may be recovered by any method known to the skilled artisan. Preferably, the caryedilol hydrogen phosphate Form G is recovered from the mixture by filtration, and then dried imder reduced pressure (< 1 atmosphere).
In another embodiment, the invention encompasses a process for preparing caryedilol hydrogen phosphate Form G comprising: (a) combining caryedilol, phosphoric acid, and acetone/water to obtain a mixture; (b) maintaining the mixture to obtain a solid; and (c) recovering caryedilol hydrogen phosphate Form G.
The caryedilol and phosphoric acid in step (a) are preferably combined in a molar ratio of about 2:1. In some embodiments, the molar ratio of phosphoric acid to caryedilol is about 0.8:1 to about 2.5:1. The mixture of step (a) may be prepared by first combining caryedilol and acetone/water and then slowly adding phosphoric acid to the mixture.
Alternatively, the and phosphoric acid may be added more or less simultaneously to the acetone/water mixture.
Preferably, the acetone/water in step (a) is in a ratio of jfrom about 4:1 to about 2:1 (v/v), and most preferably at about 3:1 (y/v).
Preferably, in step (b), the mixture is maintained, while stirring, at a temperature of about 20'°C to about SS°C, preferably at about room temperature (about 20'°C to about 23*»C) for about 12 hours.
The precipitated caryedilol hydrogen phosphate Form G may be recovered by any method known to the skilled artisan. Preferably, the caryedilol hydrogen phosphate Form G is recovered from the mixture by filtration, and then dried under reduced pressure (< 1 atmosphere). ^
Form G can also be prepared by slurrying Form R, Fl or I in water. The slurry may be carried out for about 6 hotirs to about 3 days. The product is recovered and may be dried, such as at about 40°C to about 60°C.
In another embodiment, the invention encompasses a process for preparing a phosphate salt of caryedilol, characterized by data selected from the group consisting of: X-ray powder diffraction reflections at about: 6.5,9.7,13.0,16.0 and 17.8 degrees two theta± 0.2 degrees two theta; a solid-state 13C-NMR spectrum having chemical shift resonances at about 145.8,141.7 and 110.8 ± 0.2 ppm; and a solid-state 13C NMR spectrum having chemical shift differences between the lowest ppm resonance in the chemical shift area of 100 to 180 ppm and another in the chemical shift area of 100 to 180 ppm of about 43.8, 39.7 and 8.8 ±0.1 ppm. The lowest ppm resonance in the chemical shift area of 100 to 180 ppm is typically at about 102.0 ± 1 ppm. The X-ray powder diffractogram of Form G is substantially shown in Figure 2. The solid-state 13C NMR spectrum of Form G is substantially shown in Figure 3 and/or 3 a.
Form G can also be characterized by any five peaks selected from the following list of PXRD peaks at about: 6.5, 9.7, 13.0, 13.5,16.0,17.8, 22.8 and 23.2 ± 0.2 degrees two theta. In one embodiment. Form G is characterized by data selected from: X-ray powder diffraction reflections at about: 6.5, 9.7,13.5,16.0 and 17.8 degrees two theta ± 0.2 degrees two theta. In another embodiment Form G is characterized by data selected from: X-ray powder diffraction reflections at about: 6.5, 9.7,16.0, 18.4 and 23.2 degrees two theta ± 0.2 degrees two theta.
In another embodiment the present invention provides a method for preparing Form G comprising: (a) providing a suspension of amorphous caryedilol dihydrogen phosphate iij
phosphoric acid and water at a pH of about 3.5-7; (b) maintaining tiie mixture for at least 15 hours; and (c) recovering the phosphate salt of caryedilol.
Typically, in step (a) an aqueous solution of phosphoric acid is combined with the amorphous caryedilol dihydrogen phosphate.
Preferably, in step (b), the suspension is maintained, while stirring, at a temperature of about 20°C to about 35°C, preferably at about 25°C, for about 19-21 hours.
The precipitated Form G may be recovered by any method known to the skilled artisan. Preferably, the caryedilol hydrogen phosphate Form G is recovered from the mixture by filtration, and then dried under reduced pressure (< 1 atmosphere),
hi another embodiment, the invention encompasses a process for preparing caryedilol hydrogen phosphate Form G comprising slurrying caryedilol dihydrogen phosphate Form R in water.
The ingredients are preferably maintained, while stirring, at a temperature of about 20°C to about 35°C, preferably about room temperature (about 20°C to about 23'°C), for about 12 hours to about 24 hours.
The obtained caryedilol hydrogen phosphate may be further recovered by any method known to the skilled artisan. Preferably, the caryedilol dihydrogen phosphate is recovered by filtration, and then dried imder reduced pressure (< 1 atmosphere).
In another embodiment, the invention encompasses a process for preparing caryedilol hydrogen phosphate Form G comprising slxurying caryedilol dihydrogen phosphate Form Fl in water.
The ingredients are preferably maintained, while stirring, at a temperature of about 20'°C to about 35'°C, preferably about room temperature (about 20»°C to about 23°C), for about 12 hours to about 24 hours.
The obtained caryedilol hydrogen phosphate may be fiirther recovered by any metihod known to the skilled artisan. Preferably, the caryedilol dihydrogen phosphate is recovered by filtration, and then dried under reduced pressure (<1 atmosphere).
In one embodiment, the invention encompasses a crystalline form of caryedilol hydrogen phosphate, referred to herein as Form H, characterized by data selected from the group consisting of: X-ray powder diffraction reflections at about: 6.4, 6.6, 9.4,14.5 and 15.4 degrees two theta ± 0.2 degrees two theta; X-ray powder diffraction reflections at about: 6.6, 9.7,13.0,13.8 and 15.6 degrees two theta ± 0.2 degrees two theta;; any five peaks selected from the following list of PXRD peaks at about: 6.5, 6.8,9.6,13.0,13.6, 15.6,17.5 and 28.7 ± 0.2 degrees two theta; X-ray powder diffraction reflections at about: 6.5, 9.6,13.0,13.6 and
18.7 degrees two theta ± 0.2 degrees two theta; X-ray powder diffraction reflections at about: 6.5,9.6,13.6,18.7 and 20.2 degrees two theta ± 0.2 degrees two theta; a solid-state 13C-NMR spectrum having chemical shift resonances at about 146.3,142.6 and 139.1 ± 0.2 ppm; and a solid-state 13C NMR spectrum having chemical shift differences between the lowest ppm resonance in the chemical shift area of 100 to 180 ppm and another in the chemical shift area of 100 to 180 ppm of about 34, 30.3 and 26.8 ± 0.1 ppm. The lowest ppm resonance in the chemical shift area of 100 to 180 ppm is typically at about 112.3 ± 1 ppm.
The X-ray powder diffractogram of Form H is substantially shown in Figure 4 or 5. The solid-state '°C NMR spectrum of Form H is substantially shown in Figure 6 and/or 6a.
Form H, and can be further characterized by data selected from the group consisting of: X-ray powder diffraction reflections at about 18.4,19.3,20.4,22.4 and 25.3 degrees two-theta, ± 0.2 degrees two-theta; X-ray powder diffraction reflections at about 18.6, 19.5, 20.6, 22.6 and 25.0 degrees two-theta, ± 0.2 degrees two-theta; a solid-state 13C- NMR spectrum having chemical shift resonances at about 155.3,122.2 and 112.3 ± 0.2 ppm; and a solid-state 13C NMR spectrum having chemical shift differences between the lowest ppm resonance in the chemical shift area of 100 to 180 ppm and another in the chemical shift area of 100 to 180 ppm of 43,9.9 and.O ±0.1 ppm. The lowest ppm resonance in the chemical shift area of 100 to 180 ppm is typically at about 112.3 ± 1 ppm.
Form H has a weight loss, as measvured by TGA, of between about 2-9-7.1% by weight.
In another embodiment, the invention encompasses a process for preparing caryedilol hydrogaa phosphate Form H comprising: (a) combining caryedilol, phosphoric acid, and ethanol/water to obtain a mixture; (b) maintaining the mixture for at least 6 hours to obtain a solid; and (c) recovering caryedilol hydrogen phosphate Form H.
The caryedilol and phosphoric acid in step (a) are preferably combined in a molar ratio of about 2.5:1 to about 0.8:1, more preferably about 2:1. The mixtmre of step (a) maybe prepared by first combining caryedilol and ethanol, then slowly adding phosphoric acid to the mixture, heating to reflux and finally adding water.
Preferably, the ethanol/water in step (a) is in a ratio of from about 1:1 to about 7:1, most preferably about 5:1.
If the solution of step (a) is heated, the solution is cooled to about 20°C to about 35°C, preferably to about room temperature (about 20°C to about 23°C), prior to step (b).
Preferably, in step (b), the mixture is maintained, while stirring, at a temperature of about 20°C to about 35°C, preferably about room temperature (about 20°C to about 23°C), for about 12 hours.
The precipitated caryedilol hydrogen phosphate Fonn H may be recovered by any method known to the skilled artisan. Preferably, the caryedilol hydrogen phosphate Form H is recovered from the mixture by filtration, and then dried imder reduced pressure (< 1 atmosphere).
In another embodiment, the invention encompasses a crystalline form of caryedilol hydrogen phosphate, referred to herein as Form K, characterized by X-ray powder diffraction reflections at about: 6.3, 9.8,12.7,13.2 and 16.9 degrees two theta ± 0.2 degrees two theta;
Form K has an X-ray powder diffractogram as substantially shown in Figure 7.
Form K can also be characterized by any five peaks selected from the following list of PXRD peaks at about: 6.3, 9.8,12.7, 13.2,16.3,16.9,18.3 and 19.0 ± 0.2 degrees two theta.
Form K can also be characterized by data selected from: X-ray powder diffraction reflections at about: 6.3, 9.8,16.9,18.3 and 23.2 degrees two theta ± 0.2 degrees two theta.
Form K can also be characterized by data selected from: X-ray powder diffraction reflections at about: 6.3, 9.8,14.9,20.1 and 28.2 degrees two theta ± 0.2 degrees two theta.
Form K can be ftirther characterized by X-ray powder diffraction reflections at about 16.3,20.1,20.7,24.1 and 24.8 degrees two-theta, db 0.2 degrees two-theta
Form K has a weight loss, as measured by TGA, of between about 9.1-13.0% by weight.
In another embodiment, the invention encompasses a process for preparing caryedilol hydrogen phosphate Form K comprising exposing caryedilol hydrogen phosphate Form H to more than about 80% relative humidity for at least about 7 days.
Fork K can also be prepared by combining caryedilol in acetone/water, preferably (3:1) solution higher than 50 ml and adding phosphoric acid, preferably about 85% concentration. The resulting reaction mixture can then be stirred and maintained to obtain a precipitate. The product can be recovered and dried, imder a pressure of less than one atmosphere.
In another embodiment, the invention encompasses a process for preparing an amorphous form of caryedilol hydrogen phosphate. This process comprises dissolving caryedilol hydrogen phosphate in C1-C8 alcohols or in a mixture of C3-7 ketones with water, followed by solvent removal.
Preferably, the solvent in which carvcdilol hydrogen phosphate is dissolved is methanol or acetone.
Whenever acetone is used, the ratio of acetone/water is preferably from about 3:1 to about 1:1 (v/v), and more preferably about 2:1 (v/v).
Preferably, removing the solvent is performed using spray drying.
The processes of the present invention may preferably employ spray drying with an inlet temperature of about 80'°C to about 120°C, and an outlet temperature of less than about 100°C.
The processes of the present invention may preferably employ spray drying with an inlet temperature of about 9S'°C to about 105°C, preferably about 100°C.
The spray drying may preferably be conducted with an outlet temperature of below the inlet temperature, preferably below about 35°C to about 45°C, and more preferably below about 40°C.
The drying gas used in the process of the present invention may be any suitable gas, although inert gases such as nitrogen, nitrogen-enriched air, and argon are preferred.
The caivedilol dihydrogen phosphate product produced by spray drying may be recovered by techniques commonly used in the art, such as using a cyclone or a filter.
The carvcdilol hydrogen phosphate starting material used for the processes of the presCTit invention maybe any crystalline form of carvcdilol hydrogen phosphate, including any solvates and hydrates. With processes where caryedilol hydrogen phosphate goes into solution, the form of the starting material is of minimal relevance since any solid state structure is lost in solution.
In another embodiment, the invention encompasses a phosphate salt of caryedilol, referred to herein as Form Q, characterized by X-ray powder diffraction reflections at about: 6.2,7.3,14.5,17.5 and 21.3 degrees two theta ± 0.2 degrees two theta.
In another embodiment. Form Q having X-ray powder diffractogram as substantially shown in Figure 8.
Form Q has a weight loss, as measured by TGA, of about 3.8% by weight.
Form Q Caryedilol hydrogen phosphate can be prepared by exposing Form K to a relative humidity of less than about 20%, preferably about 0% relative humidity (RH). Exposure is preferably from about 1 day to about 10 days, more preferably about 7 days. The process can be carried out at room temperature(about 20-23 °C) .
Each of Forms G, H, K and Q contain less than comprises less than about 20% crystalline caryedilol phosphate salts by weight, more preferably less than about 10% by

weight, and even more preferably less than about 5% by weight add: less than 1%. The presence of a particular crystalline caryedilol can be determined by the presence of PXKD peaks characteristic of crystalline caryedilol phosphate salts.
In certain embodiments. Each of Forms G, H, K and Q contain less than 50%, less than 25%, less than 10%, less than 5%, or less than 1% by weight of caryedilol dihydrogen phosphate Form I. In certain embodiments. Each of Form G, H, K and Q is provided as a solid material in which Each of Form G, H, K and Q represents 50%, 75%, 90%, 95%, or 99% by weight of the solid material..
In another embodiment, the invention encompasses an amorphous form of caryedilol hydrogen phosphate. A typical powder x-ray diffraction diagram for the amorphous form is shown in Figures 9 and 10.
Amoiphous caryedilol hydrogen phosphate may be analyzed to determine the amorphous nature of the product. The powder X-ray diffraction ("PXRD") pattern of amorphous caryedilol hydrogen phosphate would show no peaks characteristic of crystalline forms of caryedilol hydrogen phosphate, thus demonstrating the amorphous nature of the product. The presence of peaks characteristic of crystalline forms would indicate presence of crystalline caryedilol hydrogen phosphate.
Preferably, the amorphous caryedilol hydrogen phosphate comprises less than about 20% crystalline caryedilol and or caryedilol phosphate salts by weight, more preferably less than about 10% by weight, and even more preferably less than about 5% by weight, and even more preferably less than about 1% by weight. The presence of crystalline caryedilol hydrogen phosphate can be determined by the presence of PXRD peaks characteristic of crystalline caryedilol phosphate salts.
In certain embodiments, the amorphous caryedilol hydrogen phosphate comprises less than about 20% of Form I crystalline caryedilol by weight, more preferably less than about 10% by weigbt, and even more preferably less than about 5% by weight of Form I, as judged by the presence of PXRD peaks characteristic of Form I crystalline caryedilol. Form I is disclosed in European Patent Application EP 0893440.
Caryedilol dihydrogen phosphate
The invention provides crystalline forms of caryedilol dihydrogen phosphate as well as processes for obtaining crystalline forms of caryedilol dihydrogen phosphate, which are more readily soluble than caryedilol jfree base.
In one embodiment the present invention provides processes for preparing caryedilol dihydrogen phosphate Form I. Form I is characterized by data selected from the group consisting of: X-ray powder diffraction reflections at about: 7.0,8.0,9.2,11.4 and 16.0 degrees two theta ± 0.2 degrees two theta; a solid-state 13C-NMR spectrum having chemical shift resonances at about 154.5,146.5, 139.7 and 122.1 db 0.2 ppm; and a solid-state 13C NMR spectram having chemical shift differences between the lowest ppm resonance in the chemical shift area of 100 to 180 ppm and another in the chemical shift area of 100 to 180 ppm of about 50.7,42.7 and 18.3 ± 0.1 ppm. X-ray diffractogram substantially shown in Figure 11; solid-state 13C-NMR substantially shown in Figure 12.
I can be prepared by exposing Form F to about 100% humidity at elevated temperature, preferably about 30°C to about 80°C, more preferably about 60°C. Preferably the exposure is carried out for about 1 to about 10 days, more preferably for about 7 days.
In one embodiment, the invention encompasses a process for preparing crystalline caryedilol dihydrogen phosphate Form I, comprising: combining caryedilol, phosphoric acid and a solvent selected from the group consisting of C4-C8 alcohols, C5-C10 aliphatic hydrocarbons, C6-12 aromatic hydrocarbons, C3-C7 ketones C4-C8 ethers, C3-C7 esters and acetonitnle and precipitating caryedilol dihydrogen phosphate Form I from the reaction mixture.
Preferably, the solvent is selected from the group consisting of:, butanol, 2-butanol, n-butanol, tert-butanol, heptane, acetone, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), propylene glycol monomethyl ether (PGME), THF, methyl tert-butyl ether (MTBE>, methyl acetate, isobutyl acetate, ethyl acetate and acetonitnle. More preferably, the solvent is selected from the group consisting of: methanol, cthanol, isopropyl alcohol (EPA), and THF. Acetone is not used in a mixture with another solvent.
C1-C4 alcohols can be used, but the process with methanol and ethanol is carried out at about room temperature (about 20-23°C). Recovery from methanol and ethanol is carried out rapidly, preferably less than about 4 hours. The process with isopropyl alcohol is carried out at a temperature higher than about 55°C.
The caryedilol and phosphoric acid are preferably present in a molar ratio of about 1:1. Precipitation may be obtained from a solution or a slurry of caryedilol, phosphoric acid and the solvent.
The ingredients may be heated in order to achieve dissolution. Stirring may also be employed to promote dissolution. Preferably, the ingredients are heated to reflux. Whether
the ingredients are heated, the process may further comprise cooling, to induce crystallization.
Whenever precipitation occurs from a slurry of caryedilol, phosphoric acid and the solvent, the ingredients are preferably maintained, while stirring, at a temperature of about 20°C to about 35°C for about 12 hours to about 24 hours. When precipitation occurs from a slurry in ethanol, stirring is anployed for about 1 hour.
Precipitation may occur with or without the presence of water, except when acetone is used water is absent and when methanol is used water is present. The precipitated caryedilol dihydrogen phosphate Form I may be recovered by any method known to the skilled artisan. Preferably, the caryedilol dihydrogen phosphate Form I is recovCTed by filtration, and then dried under reduced pressure (< 1 atmosphere).
In another embodiment, the invention encompasses a process for preparing crystalline caryedilol dihydrogen phosphate Form I, is characterized by data selected from the group consisting of: X-ray powder diffraction reflections at about: 7.0,8.0,9.2,11.4 and 16.0 degrees two theta db 0,2 degrees two theta; a solid-state °C-MMR spectrum having chemical shift resonances at about 154.5,146,5,139.7 and 122,1 ± 0,2 ppm; and a solid-state 13C NMR spectrum having chemical shift differences between the lowest ppm resonance in the chemical shift area of 100 to 180 ppm and another in the chemical shift area of 100 to 180 ppm of about 50.7,42.7 and 18.3 ± 0,1 ppm. X-ray diffractogram substantially shown in Figure 11; solid-state 13C- NMR substantially shown in Figure 12 comprising slurrying caryedilol dihydrogen phosphate Form R in ethanol.
The caryedilol dihydrogen phosphate Form R starting material may be obtained as described below.
The ingredients are preferably maintained, while stirring, at a temperature of about 20'°C to about 35°C for about 12 hours to about 24 hours.
Preferably, absolute ethanol is used, "Absolute" or "technical grade" or "anhydrous" are common terms used in the art to refer to alcohols having less than about 2% water by volume.
The obtained caryedilol dihydrogen phosphate Form I may be further recovered by any method known to the skilled artisan. Preferably, the caryedilol dihydrogen phosphate Form I is recovered by filtration, and then dried under reduced pressure (<1 atmosphere).
From I can be prepared by heating Form, N, P caryedilol dihydrogen phosphate, preferably to about 60°C to about 140°C, more preferably about 80'°C-120°C; Preferably the
heating is carried out for about 10 minutes to about 3 hours, more preferably about 30 minutes.
From I can be prepared by heating Form LI, R and amorphous caryedilol dihydrogen phosphate, preferably to about 110°C to about 150°C, more preferably about 120°C-140°C. Preferably the heating is carried out for about 10 minutes to about 3 hours, more preferably about 30 minutes.
Fomi I can also be prepared by slurrying Form Fl, amoiphous caryedilol dihydrogen phosphate. Form R, or Form N in acetone. The slurry can be maintained until obtaining the transformation. The slurry maybe maintained for about 12 hours to about 5 days, preferably for about 1 day. The crystals can then be recovered by conventional techniques, and can also be dried such as at a temperature of about 50°C to about 90°C, and a pressure of below one atmosphere.
Fomi I can also be prepared by putting Form P or Form N under pressure, such as pressure of about 1 ton to about 3 ton, preferably about 2 ton.
Form I can also be prepared by grinding Forms F and P, such as for about 1 to about 3 minutes.
Form I can also be prepared by placing amorphous caryedilol dihydrogen phosphate in an atmosphere of n-propanol, iso-propanol, butanol, acetone and ethyl acetate.
Form I can be prepared by slurrying Form N in water. The slurry can be carried out for about 12 hours to about 5 days, preferably about 12 hours. The product can then be recovered by conventional techniques, such as filtration, and then dried, such as at about 40'°C to about eO°C, imder pressure below one atmosphere.
In another embodiment, the invention encompasses a crystalline fonn of caryedilol dihydrogen phosphate, referred to herein as Form F, characterized by data selected from: X-ray powder diffraction reflections at about: 7.7, 8.7,16.8 and 22.8 degrees two theta ± 0.2 degrees two theta; X-ray powder diffraction reflections at about: 7.6, 8.6,16.7 and 22.8 degrees two theta ± 0.2 degrees two theta; X-ray powder diffraction reflections at about: 7.7, 8.7,16.8,22.8 and 26,5 degrees two theta ± 0.2 degrees two theta; and X-ray powder diffraction reflections at about:. 7.6, 8.6,16.7,22.8 and 26.5 degrees two theta ± 0.2 degrees two theta; a solid-state 13C-NMR spectrum having chemical shift resonances at about 149.8, 145.4 and 140.7 ± 0.2 ppm; and a solid-state 13C NMR spectrum having chemical shift differences between the lowest ppm resonance in the chemical shift area of 100 to 180 ppm and another in the chemical shift area of 100 to 180 ppm of about 50.6,46.2 and 41.5 ± 0.1 ppm. The lowest ppm resonance in the chemical shift area of 100 to 180 ppm is typically at about 99.2 ± 1 ppm; a solid-state 13C- NMR spectrum having chemical shift resonances at about 149.8, 145.4, 138.5 and 140.7 ± 0.2 ppm; and a solid-state 13C NMR spectrum having chemical shift differences between the lowest ppm resonance in the chemical shift area of 100 to 180 ppm and another in the chemical shift area of 100 to 180 ppm of about 50.6,46.2,
39.3 and 41.5 ± 0.1 ppm. The lowest ppm resonance in the chemical shift area of 100 to 180
ppm is typically at about 99.2 ± 1 ppm.
Form F has an X-ray powder diffractogram as substantially shown in Figure 23 or 24. Form F has a solid-state 13C NMR spectrum as substantially shown in Figure 25 and or 25a.
In another embodiment, the invention encompasses a crystalline form of caryedilol • dihydrogen phosphate, referred to herein as Form F, characterized by data selected from: X-ray powder diffraction reflections at about: 7.7, 8.7, 13.5,15.2 and 22.9 degrees two theta ± 0.2 degrees two theta; X-ray powder diffraction reflections at about: 7.6, 8.6,13.4,15.1 and 22.8 degrees two theta ± 0.2 degrees two theta.
In another embodiment, the invention encompasses a crystalline form of caryedilol dihydrogen phosphate, referred to herein as Form F, characterized by data selected from: X-ray powder diffraction reflections at about: 7.7, 13.5,15.2,18.3 and 18.9 degrees two theta ± 0.2 degrees two theta; X-ray powder diffraction reflections at about: 7.6,13.4,15.1,18.2 and 18.8 degrees two theta ± 0.2 degrees two theta.
In another embodiment, the invention encompasses a crystalline form of caryedilol dihydrogen phosphate, referred to herein as Form F, characterized by data selected from: X-ray powder diffraction reflections at about: 7.7,13.5,15,2,17.2 and 21.5 degrees two theta± 0.2 degrees two theta; X-ray powder diffraction reflections at about: 7.6,13.4,15.1,17.1 and
21.4 degrees two theta ± 0.2 degrees two theta.
Form F can be further characterized by data selected from: X-ray powder diffraction reflections at about 10.0,11.6,13.6,15.2 and 27.1 degrees two-theta, ± 0.2 degrees two-theta; and X-ray powder diffraction reflections at about 9.9,11.5,13.4,15.1 and 27.0 degrees two-theta, ± 0.2 degrees two-theta; a solid-state 13C-NMR spectrum having chemical shift resonances at about 146.7,138.5 and 111.8 ± 0.2 ppm; and a solid-state 13C NMR spectrum having chemical shift differences between the lowest ppm resonance in the chemical shift area of 100 to 180 ppm and another in the chemical shift area of 100 to 180 ppm of about 47.5, 39.3 and 12.6 ± 0.1 ppm. The lowest ppm resonance in the chemical shift area of 100 to 180 ppm is typically at about 99.2 ± 1 ppm. Typical powder x-ray diffractograms for Form F are shown in Figures 23 and 24. A typical solid-state 13C-NMR spectrum of Form F is shown in Figure 25 and/or 25a.
Form F has a weight loss, as measured by TGA, of about 2.9% by weight, while it has water content, as measured by KF, of about 0.2% by weight. This corresponds to caryedilol dihydrogen phosphate hemimethanolate, GC measurement of residual solvents gives about 30,800-32,300 ppm of methanol confirming presence of hemimethanolate solvate of caryedilol dihydrogen phosphate.
In another embodiment, the invention encompasses a process for crystallizing caryedilol dihydrogen phosphate Form F from a solution of caryedilol, phosphoric acid and methanol.
The caryedilol and phosphoric acid are preferably present in a molar ratio of about 0,8:1 to about 1.2:1, more preferably about 1:1.
The ingredients may be heated in order to achieve dissolution. Stirring may also be employed to promote dissolution. Preferably, the ingredients are heated to reflux. Whether the ingredients are heated, the process may further comprise cooling, to induce crystallization.
Crystallization occurs without addition of water; a minimal amoimt of water may be present from the phosphoric acid. Preferably, the methanol is anhydrous, i.e., contains less than 2% water by volume.
Crystallization may be carried out for about 5 minutes to about 30 minutes or for about 5 minutes to about 300 minutes.
The caryedilol dihydrogen phosphate may be recovered by any method known to the skilled artisan. Preferably, the caryedilol dihydrogen phosphate is recovered from the mixture by filtration, and then dried under reduced pressure (< 1 atmosphere).
In another embodiment, the invention encompasses a process for crystallizing caryedilol dihydrogen phosphate Form F from a solution of caryedilol dihydrogen phosphate and methanol.
The starting material used for the processes for obtaining caryedilol dihydrogen phosphate Form F may be any crystalline or amorphous form of caryedilol dihydrogen phosphate, including various solvates and hydrates. With crystallization processes, the crystalline form of the starting material does not usually affect the final result.
Preferably, the caryedilol dihydrogen phosphate starting material is caryedilol dihydrogen phosphate Form I.
The ingredients may be heated in order to achieve dissolution. Stirring may also be employed to promote dissolution. Preferably, the ingredients are heated to reflux. Whether
the ingredients are heated, the process may further comprise cooling, to induce crystallization.
Crystallization occurs without addition of water; a minimal amount of water maybe present from the phosphoric acid.
The caryedilol dihydrogen phosphate may be recovered by any method known to the skilled artisan. Preferably, the caryedilol dihydrogen phosphate is recovered from the mixture by filtration, and then dried under reduced pressure (< 1 atmosphere).
In another embodiment, the invention encompasses a crystalline form of caryedilol dihydrogen phosphate, referred to herein as Form Fl, characterized by data selected from: X-ray powder diffraction reflections at about: 7.6, 9.8, 10.9, 21.2 and 25.0 degrees two theta ± 0.2 degrees two theta; a splid-state 13C-NMR spectrum having chamical shift resonances at about 155.3,145.3 and 127.7 ± 0.2 ppm; and a solid-state 13C NMR spectrum having chemical shifl differences between the lowest ppm resonance in the chemical shift area of 100 to 180 ppm and another in the chemical shift area of 100 to 180 ppm of about 52.6,42.6 and 25 ± 0.1 ppm. The lowest ppm resonance in the chemical shift area of 100 to 180 ppm is typically at about 102.7 ± 1 ppm.
In another embodiment, Form Fl having X-ray powder diffractogram as substantially shown in Figure 26 and 27.
In anottier embodiment. Form Fl having solid-state 13C NMR spectrum as substantially shown in Figure 28 and 28 a.
Form Fl can also be characterized by X-ray powder diffraction reflections at about: 7.6, 10.9,13.3,15.2 and 18.8 degrees two theta± 0.2 degrees two theta.
Form Fl can also be characterized by X-ray powder diffraction reflections at about: 7.6, 8.5, 9.8, 15.2 and 16.9 ± 0.2 degrees two theta.
Form Fl can also be characterized by X-ray powder diffraction reflections at about: 7.6, 9.8, 10.9,14.7,15.2 and 22.8 ± 0.2 degrees two theta.
Form Fl can also be characterized by X-ray powder diffiaction reflections at about: 7.6, 8.5, 9.8,13.3 and 15.2 ± 0.2 degrees two theta.
Form Fl can be further characterized by X-ray powder diffraction reflections at about 15.7 and 28.0 degrees two-theta, ± 0.2 degrees two-theta. A typical powder x-ray diffractogram for Form Fl is shown in Figure 26 and 27.
Form Fl can be distinguished from Form F by having four diffraction peaks in the area of about 19-20.7 degrees two-theta, whereas Form F has only three; further. Form Fl has four diffraction peaks in the area of about 24.8-26.0 degrees two-theta, whereas Form F has
two; lastly. Form Fl has three difjBracted peaks in the area of about 27.8-29.3 degrees two-theta, whereas Fonn F has two.
Form Fl has a weight loss, as measured by GC measurement of residual solvents between about 42,500-47,000 ppm of ethanol. Hence, Form Fl is heriiiethanolate solvate of caryedilol dihydrogen phosphate.
In another embodiment, the invention encompasses a process for preparing caryedilol dihydrogen phosphate Form Fl comprising precipitation from a slurry of caryedilol, phosphoric acid and ethanol, wherein the slurry is stirred for at least about 4 hours.
The caryedilol and phosphoric acid are preferably present in a molar ratio of about 0.8:1 to about 1.2:1, and more preferably about 1:1.
Preferably, absolute ethanol is used.
Preferably, the ingredients are heated to reflux. Whether the ingredients are heated, the process may further comprise cooling, to induce precipitation.
The caryedilol dihydrogen phosphate may be recovered by any metiiod known to the skilled artisan. Preferably, the caryedilol dihydrogen phosphate is recovered from the mixture by filtration, and then dried under reduced pressure (< 1 atmosphere).
In another embodiment, the invention encompasses a process for preparing caryedilol dihydrogen phosphate Form Fl comprising precipitation from a slurry of caryedilol dihydrogen phosphate and ethanol, wherein the slurry is maintained for at least about 4 hours.
Preferably, the caryedilol dihydrogen phosphate starting material is caryedilol dihydrogen phosphate Form I, Form N or Form R.
Preferably, absolute ethanol is used.
Preferably, the ingredients are heated to reflux. Whether the ingredients are heated, the process may further comprise cooling, to induce precipitation.
The caryedilol dihydrogen phosphate may be recovered by any method known to the skilled artisan. Preferably, the caryedilol dihydrogen phosphate is recovered from the mixture by filtration, and then dried under reduced pressure (< 1 atmosphere).
In one embodiment, caryedilol base is combined with ethanol and heated to obtain a solution. Heating is preferably carried out of about 65°C to about 82°C (reflux temperature),, preferably about 78-82°C. Phosphoric acid and optionally an additional amount of ethanol are added to the solution. The solution is cooled, preferably to about 10°C to about 20°C. The product is then recovered as described above.
In another embodiment the present invention provides a crystalline form of Caryedilol phosphate salt, referred to herein as Form F2. Form F2 is characterized by an X-Ray powder diffraction pattern with peaks at about 7.4, 7.9, 8.5, 8.9 and 11.1 ± 0.2 degrees two theta. The Calculated X-ray powder diffraction pattern of Caryedilol phosphate salt Form F2 is substantially depicted in Figure 35. The structure' was solved by direct methods for triclinic P-1 group with the unit cell parameters: a = 13.281(3), b = 14.315(3), c = 16.406(4) A, a = 66.85(2), p « 85.94(2) y = 65.44(4) [deg], and cell volume 2592.4(12) Å3 Form F2 is caryedilol dihydrogen phosphate hemietiianolate.
Form F2 is prepared by dissolution of Caryedilol dihydrogen phosphate in ethanol at elevated temperature, of about 25°C to about reflux temperature, preferably about 70°C, followed by cooling. Caryedilol dihydrogen phosphate Form I can be used as starting material. Cooling is preferably carried out in about one to about 10 days, preferably about 6 days. A final temperature can be about 10°C to about 30°C, preferably about 20°C. The crystal form can then be recovered by conventional techniques.
In another embodiment, the invention encompasses a crystalline form of caryedilol dihydrogen phosphate, denominated Form L, characterized by data selected from the group consisting of: X-ray powder diffraction reflections at about: 4.6, 7.5, 8.7,11.6 and 15.6 degrees two theta ±0.2 degrees two theta; a solid-state 13C-NMR spectrum having chemical shift resonances at about 156.6,150.3 and 102.5 ± 0.2 ppm; and a solid-state 13CNMR spectrum having chemical shift differences between the lowest ppm resonance in the chemical shift area of 100 to 180 ppm and another in the chemical shift area of 100 to 180 ppm of about 54.1,47.8 and 0.0 ±0.1 ppm. The lowest ppm resonance in the chemical shift area of 100 to 180 ppm is typically at about 102.5 ± 1 ppm.
A typical powder x-ray diffractogram for Form L is shown in Figure 13. A typical solid-state 13C- NMR spectrum of Form L is shown in Figure 14 and or 14a.
Form L can also be characterized by any five peaks selected from the following list of PXRD peaks at about: 4.6, 7.5, 8.7,11.6 13.4,15.6 and 19.4 ± 0.2 degrees two theta.
Form L can also be characterized by data selected from: X-ray powder diffraction reflections at about: 4.6, 7.5, 8.7,11.6 and 15.0 degrees two theta ± 0.2 degrees two theta.
Form L can also be characterized by data selected from: X-ray powder diffraction reflections at about: 4.6, 7.5, 8.7,15,0 and 22.9 degrees two theta ± 0.2 degrees two theta.
Form L can be further characterized by data selected from the group consisting of: X-ray powder diffraction reflections at about 13.4, 19.4, 22.3, 22.9 and 23.3 degrees two-theta, ± 0.2 degrees two-theta; a solid-state 13C- NMR spectrum having chemical shift resonances at

about 148,3,139,2 and 112,4 ± 0.2 ppm; and a solid-state 13C NMR spectrum having chemical shift differences between the lowest ppm resonance in the chemical shift area of 100 to 180 ppm and another in the chemical shift area of 100 to 180 ppm of 45.8, 36.7 and 9.9 ±0,1 ppm. The lowest ppm resonance in the chemical shift area of 100 to 180 ppm is typically at about 102,5 ± 1 ppm,
GC measurement of residual solvents of Fonn L gives about 137500 ppm of dioxane. Form L is a dioxane solvate of caryedilol dihydrogen phosphate
In another embodiment, the invention encompasses a process for preparing caryedilol dihydrogen phosphate Form L comprising: combining caryedilol, phoqjhoric acid and dioxane and precipitating caryedilol dihydrogen phosphate Form L from the reaction mixture. In this embodiment less than about 30 g of caryedilol dihydrogen phosphate and less than about 300 ml dioxane are used.
Precipitation may also be obtained from a slurry of caryedilol dihydrogen phosphate and dioxane.
Whenever precipitation occurs from a slurry of caryedilol, phosphoric acid and dioxane, the caryedilol and phosphoric acid are preferably present in a molar ratio of about 1:1.
The ingredients are preferably heated to reflux, and fiuther maintained for about 12 hours.
The caryedilol dihydrogen phosphate may be recovered by any method known to the skilled artisan. Preferably, the caryedilol dihydrogen phosphate is recovered from the mixture by filtration, and then dried under reduced pressure (< 1 atmosphere).
In anotiier embodiment, the invention encompasses a crystalline form of caryedilol dihydrogen phosphate, referred to herein as Form L1, characterized by data selected from the group consisting of: X-ray powder diffraction reflections at about: 4.6, 8.7, 11.6,14.6 and 15.3 degrees two theta± 0,2 degrees two theta; a solid-state 13C- NMR spectrum having chemical shift resonances at about 156.6,150,3 and 148,4 ± 0.2 ppm; and a solid-state 13C NMR spectrum having chemical shift differences between the lowest ppm resonance in the chemical shift area of 100 to 180 ppm and another in the chemical shift area of 100 to 180 ppm of about 53.2,46.9 and 45,0 ±0.1 ppm. The lowest ppm resonance in the chemical shift area of 100 to 180 ppm is typically at about 103,4 ± 1 ppm.
Form LI has an X-ray powder diffractogram as substantially shown in Figure 15. Form LI has a solid-state 13C NMR spectrum as substantially shown in Figure 16 and or 16a,
Form LI can also be characterized by PXRD peaks at about: 4,6, 7.4,8.7,11.6 14.6, 15.3 and 19.4 ± 0.2 degrees two theta.
Form LI can also be characterized by PXRD peaks at about 4,6, 7.4, 8,7,13.6 and
15.3 degrees two theta ± 0.2 degrees two theta.
Form LI can also be characterized by PXRD peaks at about 4.6, 7.4,8.7,11.6 and 17.4,
Form LI can also be characterized by PXRD peaks at about 4.6, 7.4, 8,7,15.3 and
17.4 degrees two theta ± 0.2 degrees two theta.
Form LI can be further characterized by data selected from the group consisting of: X-ray powder diffraction reflections-at about 7.4,13.6,21.3 and 28.4 degrees two-theta, ± 0.2 degrees two-theta; a solid-state 13C-NMR spectrum having chemical shift resonances at about 140.3,139.1, 123.5 and 112.5 ± 0.2 ppm; and a solid-state 13C NMR spectrum having chemical shift differences between the lowest ppm resonance in the chemical shift area of 100 to 180 ppm and another in the chemical shift area of 100 to 180 ppm of 36.9,35.7 20.1 and 9,1 ±0.1 ppm. The lowest ppm resonance in the chemical shift area of 100 to 180 ppm is typically at about 103,4 ± 1 ppm,
A typical powder x-ray dif&actogram for Form LI is shown in Figure 15. A typical solid-state 13C- NMR spectrum of Form LI is shown in Figure 16 and or 16a.
Form LI has a weight loss, as measured by TGA, of about 9.7% by weight, while it has water content, as measured by KF, of about 0,4% by weight. Form LI is a dioxane solvate of caryedilol dihydrogen phosphate.
Form LI can be obtained by a scaled up version of the process for producing Form L, Accordingly, the invention also encompasses a process for preparing caryedilol dihydrogen phosphate Form LI comprising slurrying at least about 30 g caryedilol dihydrogen phosphate, preferably Form I, in at least about 300 ml dioxane. Preferably, the slurry is heated to reflux.
The caryedilol dihydrogen phosphate may be recovered by any method known to the skilled artisan. Preferably, the caryedilol dihydrogen phosphate is recovered from the mixture by filtration, and then dried, preferably at about 55°C, under reduced pressure (< 1 atmosphere).
In another embodiment, the invention encompasses a crystalline form of caryedilol dihydrogen phosphate, denominated Form N, characterized by data selected from the group consisting of: X-ray powder diffraction reflections at about: 6,0, 6.9,15.2,16.3 and 17.4 degrees two theta ± 0.2 degrees two theta; a solid-state 13C-NMR spectrum having chemical shift resonances at about 154.4,146.9 and 138,4 ± 0.2 ppm; and a solid-state 13C NMR
spectrum having chemical shift diflFerences between the lowest ppm resonance in the chemical shift area of 100 to 180 ppm and another in the chemical shift area of 100 to 180 ppm of about 52.9*, 45.4 and 36.9 ± 0.1 ppm. The lowest ppm resonance in the chanical shift area of 100 to 180 ppm is typically at about 101.5 ± 1 ppm; a solid-state 13C- NMR spectrum having chemical shift resonances at about 154.4,146.9, 138.4 and 110.9 ± 0.2 ppm; and a solid-state 13C NMR spectrum having chemical shift differences between the lowest ppm resonance in the chemical shift area of 100 to 180 ppm and another in the chemical shift area of 100 to 180 ppm of about 52.9, 45.4, 36.9 and 9.4 ± 0.1 ppm. The lowest ppm resonance in the chemical shift area of 100 to 180 ppm is typically at about 101.5 ± 1 ppm.
Form N has an X-ray powder diffractogram as substantially shown in Figure 17 and 18. Form N also has a solid-state 13C NMR spectrum as substantially shown in Figure 19 and or 19a.
In another embodiment, the invention encompasses a crystalline form of caryedilol dihydrogen phosphate, referred to herein as Form N, characterized by data selected fixim: X-ray powder diffraction reflections at about: 6,0, 6.9,13.7 15.2 and 18.1 degrees two theta ± 0.2 degrees two theta.
In another embodiment, the invention encompasses a crystalline form of caryedilol dihydrogen phosphate, referred to herein as Form N, characterized by data selected from: X-ray powder dififractionreflections at about: 6.0, 6.9, 13.7, 15.2 and 17.4 ± 0.2 degrees two theta.
Form N can be fiirther characterized by data selected from the group consisting of: X-ray powder diffraction reflections at about 18.1,20.6, 24.6 and 26.3 degrees two-theta, ± 0.2 degrees two-theta; a solid-state 13C-NMR spectrum having chemical shift resonances at about 141.3, 122.0 and 110.9 ± 0.2 ppm; and a solid-state 13C NMR spectrum having chemical shift differences betweei the lowest ppm resonance in the chemical shift area of 100 to 180 ppm and another in the chemical shift area of 100 to 180 ppm of about 39.8, 20.5 and 9.4 ± 0.1 ppm. The lowest ppm resonance in the chemical shift area of 100 to 180 ppm is typically at about 101.5 ± I ppm, or substantially as depicted in Figure 19a.
A typical powder x-ray diffractogram for Form N is shown in Figures 17 and 18. A typical solid-state 13C-NMR spectrum of Form N is shown in Figure 19 and 19a.
Form N has a weight loss, as measured by TGA, of about 5.0-6.6% by weight, while it has water content, as measured by KF, between 4.7-6.9% by weight. This corresponds to caryedilol dihydrogen phosphate dihydrate.
In another embodiment, the invention encompasses a process for preparing caryedilol dihydrogen phosphate Form N comprising exposing caryedilol dihydrogen phosphate Form L to high relative humidity (e.g., greater than about 80%, greater than about 90%, greater than about 95% or about 100% relative humidity), preferably for at least about 7 days.
In another embodiment, the invention encompasses a process for prqjaring caryedilol dihydrogen phosphate Form N comprising exposing caryedilol dihydrogen phosphate Form Fl, LI or R to high relative humidity (e.g., greater than about 80%, greater than about 90%, greater than about 95% or about 100% relative humidity), preferably for at least about 7 days.
In another embodiment, the invention encompasses a process for preparing caryedilol dihydrogen phosphate Form N comprising exposing amorphous caryedilol dihydrogen phosphate to high relative hximidity (e.g., greater than 80%, greater than 90%, greater than 95% or about 100% relative humidity), preferably for about 7 days.
In another embodiment, the invention encompasses a process for prq>aring caryedilol dihydrogen phosphate Form N comprising drying caryedilol dihydrogen phosphate Form O. Preferably, caryedilol dihydrogen phosphate Form O is heated to a temperature of from about 30°C to about 70°C, more preferably to about 35*°C, for a time sufficient to obtain caryedilol dihydrogen phosphate Form N. Caryedilol dihydrogen phosphate Form O may be prepared as described below. As one skilled in the art will appreciate, the time required to obtain caryedilol dihydrogen phosphate Form N will vary depending upon, among other factors, the amount of wet caryedilol dihydrogen phosphate Form O to be dried and the drying temperature, and can be determined by taking periodic XRDs.
In another embodiment, the invention encompasses a crystalline form of caryedilol dihydrogen phosphate, denominated Form O, characteri;2ed by X-ray powder diffraction reflections at about: 6.1,12.2,12.9,16.2 and 18.0 degrees two theta ± 0.2 degrees two theta. Form O can be further characterized by X-ray powder diffraction reflections at about 20.1, 23.0, 23.7, 24.5 and 26.5 degrees two-theta, ± 0.2 degrees two-theta. A typical powder x-ray dif&actogram for Form O is shown in Figure 20.
X-ray powder difi&actogram of Form O is substantially shown in Figure 20.
In another embodiment, the invention encompasses a process for preparing caryedilol dihydrogen phosphate Form O comprising grinding the amorphous form of caryedilol dihydrogen phosphate in the presence of water, for about 1-2 minutes.
Preferably, the amorphous form is ground in the presence of 2-3 drops of water. Preferably, about 2-3 drops of water per 200 mg of amorphous form is used.
in another embodiment, the invention encompasses a Crystalline form of caryedilol dihydrogen phosphate, referred to herein as Form P, characterized by data selected from the group consisting of: X-ray powder diffraction reflections at about: 5.3,10.4,16.8,26.0 and 31.8 degrees two theta ± 0.2 degrees two theta; a solid-state "C-MMR spectrum having chemical shift resonances at about 154.7,146.6 and 122.2 ± 0.2 ppm; and a solid-state 13C NMR spectrum having chemical shift differences between the lowest ppm resonance in the chemical shift area of 100 to 180 ppm and another in the chemical shift area of 100 to 180 ppm of about 54.7,46.6 and 22.2 ±0.1 ppm. The lowest ppm resonance in the chemical shift area of 100 to 180 ppm is typically at about 100.0 ± 1 ppm.
Form P has a X-ray powder diffractogram as substantially shown in Figure 21. Form P has a solid-state 13C NMR spectrum as substantially shown in Figure 22 and 22a.
Form P can also be characterized by any five peaks selected from the following list of PXRD peaks at about: 5.3.10.4,14.5,16.8, 17.8, 26.0 and 31.8 ± 0.2 degrees two theta.
Form P can also be characterized by X-ray powder diffraction reflections at about: 5.3,10.4,15,2,17.8 and 22.5 degrees two theta ± 0.2 degrees two theta.
Form P can also be characterized by X-ray powder diffraction reflections at about: 5.3,14.5,15.2,16.8 and 17.3 degrees two theta ± 0.2 degrees two theta.
Form P can also be characterized by X-ray powder diffraction reflections at about: 5.3,10.4,14,5,15.2 and 17.8 degrees two theta ± 0.2 degrees two theta.
Form P can also be characterized by X-ray powder diffraction reflections at about: 5.3,14.5,15.2,17.8 and 20,1 degrees two theta ± 0,2 degrees two theta.
Form P can be fimher characterized by data selected from the group consisting of: X-ray powder diffraction reflections at about 14.5 and 17.8 degrees two-theta, ± 0.2 degrees two-theta; a solid-state 13C-NMR spectrum having chemical shift resonances at about 141.4, 139.9 and 111.9 ± 0.2 ppm; and a solid-state 13C-NMR spectrum having chemical shift differences between the lowest ppm resonance in the chemical shift area of 100 to 180 ppm and another in the chemical shift area of 100 to 180 ppm of about 41.4, 39.9 and 11.9 ± 0.1 ppm. The lowest ppm resonance in the chemical shift area of 100 to 180 ppm is typically at about 100.0 ± 1 ppm. A typical powder x-ray diffractogram for Form P is shown in Figure 21. A typical solid-state 13C-NMR spectrum of Form P is shown in Figure 22 and or 22a.
Form P has a weight loss, as measured by TGA, of about 2.0% by weight, while it has water content, as measured by KF, of about 1.7% by weight. Form P is caryedilol dihydrogen phosphate hemihydrate.
In another embodiment, the invention encompasses a process for preparing caryedilol dihydrogen phosphate Form P comprising slurrying amorphous caryedilol dihydrogen phosphate in ethanol. Preferably, the reaction occurs at room temperature.
The caryedilol dihydrogen phosphate may be recovered by any method known to the skilled artisan. Preferably, the caryedilol dihydrogen phosphate is recovered from the mixture by filtration, and then dried under reduced pressure (< 1 atmosphere).
In another embodiment, the invention encompasses a crystalline form of caryedilol dihydrogen phosphate, referred to herein as Form R, characterized by data selected from: X-ray powder dif&action reflections at about: 5.8,11.8,16.8,18.6 and 23.2 degrees two theta ± 0.2 degrees two theta; a solid-state '°C-NMR spectrum having chemical shift resonances at about 153.7, 147.9 and 122.8 ± 0.2 ppm; and t solid-state 13C NMR spectrum having chemical shift differences between the lowest ppm resonance in the chemical shift area of 100 to 180 ppm and another in the chemical shift area of 100 to 180 ppm of about 51.0,45.2 and 20.1 ±0.1 ppm. The lowest ppm resonance in the chemical shift area of 100 to 180 ppm is typically at about 102.7 ± 1 ppm.
Form R has an X-ray powder diffractogram as substantially shown in Figure 29. Form R has a solid-state 13C NMR spectrum as substantially shown in Figure 30 and or 30a.
Form R is also characterized by an X-ray powder diffraction reflections at about: 5.8, 11.8, 15.5,16.2 and 18.6 degrees two theta ± 0.2 degrees two theta.
Form R is also characterized by X-ray powder diffraction reflections at about: 5.8, 16.2,18.6,23.2 and 27.0 degrees two theta ± 0.2 degrees two theta,
Fonn R is also characterized by X-ray powder diffraction reflections at about: 5.8, 16.2, 16.8, 19.9 and 25.4 degrees two theta ± 0.2 degrees two theta.
Form R can be further characterized by X-ray powder diffraction reflections at about 8.5,23.5,24.7 and 27.0 degrees two-theta, ± 0.2 degrees two-theta; a solid-state 13C- NMR spectrum having chemical shift resonances at about 137.8 and 116.5 ± 0.2 ppm; and a solid-state 13C NMR spectrum having chemical shift differences between the lowest ppm resonance in the chemical shift area of 100 to 180 ppm and another in the chemical shift area of 100 to 180 ppm of about 35.1 and 13,8 ± 0.1 ppm. The lowest ppm resonance in the chemical shift area of 100 to 180 ppm is typically at about 102.7 ± 1 ppm. A typical powder x-ray diffractogram for Form R is shown in Figure 29. A typical solid-state 13C- NMR spectrum of Form R is shown in Figure 30 and or 30a,
Form R has a weight loss, as measirred by GC measurement of residual solvents between about 75,000-100,300 ppm of isopropanol. Hence, Form R is isopropanol solvate of caryedilol dihydrogen phosphate.
Form R can be prepared by combining caryedilol base, isopropyl alcohol, and phosphoric acid to obtain a reaction mixture, followed by precipitation and recovery of Form R. Caryedilol base and phosphoric acid may be present in a molar ratio of about 0.8:1 to about 1.2:1, preferably 1:1. The reaction mixture can be heated or left at room temperature. Heating can be carried out of about 40'°C to about 60°C, such as about 55°C. The reaction mixture can be cooled to accelerate the precipitation process. Cooling can be carried at about 0°C to about 20°C.
The product can be recovered by conventional techniques such as filtration. The crystals can be dried at elevated temperature, and a pressure of less than about 1 atmosphere.
Form R can also be prepared by slurrying caryedilol dihydrogen phosphate, such as amorphous. Form Fl, Form N, in isopropanol. The slurry can be maintained to obtain Form R, such as a bout of about 6 hours to about 3 days. The product can be recovered and dried as above.
The present invention also provides crystalline form of Caryedilol phosphate salt, referred to herein as Form W. The X-ray powder diffraction pattern of Caryedilol phosphate salt Form W is substantially depicted in Figure -32. Form W may be identified by characteristic X-Ray dif&action peaks at 6.6,9.7,13.8,15.7 and 17.1 ± 0.2,
Form W can be prepared firom Caryedilol dihydrogen phosphate form Fl, by adding Form Fl to KH2PO4. followed by adjustion with a base, such as an alkali or alkaline metal base, including sodium and potassium hydroxide to obtain a suspension. A suspension is obtained when the pH reaches about 7. The suspension can be stirred at room temperature for a sufficient time, such as about 12 hours to about 2 days. Form W can be recovered by conventional techniques.
In another embodiment, the invention encompasses a crystalline form of caryedilol dihydrogen phosphate, referred to herein as Form Y, characterized by X-ray powder difflaction reflections at about: 7.7, 7.9, 9.1, 16.6 and 19.5 degrees two theta± 0.2 degrees two theta; X-ray powder dif&action reflections at about: 7.7, 8.5,16.6,19.5 and 20.3 degrees two theta ± 0.2 degrees two theta. Form Y can be further characterized by X-ray powder dif&action reflections at about 8,5 and 15.5 degrees tivo-theta, i 0.2 decrees two-theta. A typical powder x-ray diffractogram for Form Y is shown in Figure 31.
In another emhodiment, the invention encompasses a process for preparing caryedilol dihydrogen phosphate Form Y comprising precipitation from a slurry of caryedilol, phosphoric acid and ethanol, wherein the slurry is maintained for about 2 to 3 hours.
The caryedilol and phosphoric acid are preferably present in a molar ratio of about 1:1.
Preferably, absolute ethanol is used.
Preferably, the ingredients are heated to reflux. Whether the ingredients are heated, the process may further comprise cooling, to induce precipitation.
The caryedilol dihydrogen phosphate may be recovered by any method known to the skilled artisan. Preferably, the caryedilol dihydrogen phosphate is recovered from the mixture by filtration.
Each of Forms L, LI, N, P, O, F, Fl, F2, R, Y and W contain less than comprises less than about 20% crystalline caryedilol phosphate salts by weight, more preferably less than about 10% by weight, and even more preferably less than about 5% by weight, and even more preferably less than 1% by weight. The presence of a particular crystalline caryedilol can be detennined by the presence of PXRD peaks characteristic of crystalline caryedilol phosphate salts.
In certain embodiments, each of Form L, LI, N, P, O, F, Fl, F2, R, Y and W contains less than about 20%, less than about 10%, less than about 5% or less than about 1% by weight of Form I of caryedilol dihydrogen phosphate. In certain embodiments, each of Form L, LI, N, P, O, F, Fl, F2, R, Y and W is provided as a solid material in which Form L, LI, N, P, O, F, Fl, F2, R, Y and W represents about 80%, about 90%, about 95%, or about 99% by weight of the solid material.
In another embodiment, the invention encompasses essentially amorphous form of caryedilol dihydrogen phosphate characterized by data selected from the group consisting of: a solid-state 13C- NMR spectrum having broad chemical shift resonances at about 154.6, 146.7 and 140.3 ± 0.2 ppm; and a solid-state 13C- NMR spectrum having chemical shift differences between the lowest ppm resonance in the chemical shift area of 100 to 180 ppm and another in the chemical shift area of 100 to 180 ppm of about 54.2,46.3 and 39.9 db 0.1 ppm; a solid-state 13C- NMR spectrum havmg broad chemical shift resonances at about 154.6, 146.7,140.3 and 100.4 ± 0.2 ppm; and a solid-state 13C- NMR spectrum having chemical shift differences between the lowest ppm resonance in the chemical shift area of 100 to 180 ppm and another in the chemical shift area of 100 to 180 ppm of about 54.2,46.3, 39.9 and 0.0 ± 0.1 ppm. The lowest ppm resonance in the chemical shift area of 100 to 180 ppm is typically
at about 100.4 ± 1 ppm. X-ray diffractogram shown in figure S3, solid state 13C-NMR spectrum shown in figure 34 and or 34a.
The essentially amorphous form of caryedilol dihydrogen phosphate can be further characterized by data selected fi-om the group consisting of: a solid-state 13C- NMR spectrum having chemical shift resonances, which are broader than chemical shift resonances of a crystalline material, at about 121.9 and 111.5 ± 0.2 ppm; and a solid-state 13C NMR spectrum having chemical shift differences between the lowest ppm resonance in the chemical shift area of 100 to 180 ppm and another in the chemical shift area of 100 to 180 ppm of about 21.5 and 11.1 ± 0.1 ppm. The lowest ppm resonance in the chemical shift area of 100 to 180 ppm is typically at about 100.4 ± 1 ppm. A typical powder x-ray diffractogram for the amorphous form is shown in Figure 33. A typical solid-state 13C- NMR spectrum of amorphous form of caryedilol dihydrogen phosphate is shown in Figure 34 and or 34a.
The above amorphous form of caryedilol dihydrogen phosphate is substantially fi-ee of crystalline and is herein referred to as "caryedilol dihydrogen phosphate purely amorphous." Figure 33 or 34 illustrates an XRPD pattern for this fonn, where the halo shape of the pattern illustrates the substantial absence of crystalline structure, by the absraice of sharp peaks.
The caryedilol dihydrogen phosphate essentially amorphous contains not less than about 50% by weight of amorphous caryedilol dihydrogen phosphate, preferably not less than about 60%, more preferably not less than about 70%, even more preferably not less than about 80% and most preferably not less than about 90% or 95% by weight of amorphous caryedilol dihydrogen phosphate! In a certain embodiment, the caryedilol dihydrogen phosphate pxu^ly amorphous contains not more than about 20% by weight of Form I of caryedilol dihydrogen phosphate, preferably not more than about 10%, more preferably not more than about 5%, even more preferably not more than about 1% by weight of Form I of caryedilol dihydrogen phosphate.
The amoimt of crystallinity is quantified by methods known in the art like "crystallinity index" available to most XRD softwares.
Generally, the detection of peaks of Form I in amorphous caryedilol dihydrogen phosphate can be done by any method known to the skilled artisan.
For example, a person skilled in the art would know, when using XRD as a method for detecting or quantifying peaks of Form I in amorphous caryedilol dihydrogen phosphate, to select a peak or a number of peaks fi-om the following Hst of peaks at about 7.0, 8.0, 9.2, 11.4,16.0 and 20.7 ± 0.2 degrees two theta. The absence or presence or intensity of a peak or
a number of peaks from the following Hst of peaks at about 7.0, 8.0,9,2, 11.4, 16,0 and 20.7 ± 0.2 degrees two theta may be monitored at a scan rate slow enough, according to the common knowledge of the skilled in the art. The scan rate used may vary from instrument to instrument, and sample preparation. A skilled artisan will know to use other accepted analytical methods such as solid-state NMR, Raman, IR to detect Form I in amorphous caryedilol dihydrogen phosphate.
The caryedilol dihydrogen phosphate purely amorphous of the present invention is a solid material in which the caryedilol dihydrogen phosphate purely amorphous represents about 80% by weight of the solid material, ,more preferably about 90%, even more preferably about 95% and most preferably 99% by weight of the solid material, wherein the detection of crystalline percMitage and/or amorphous percentage material can be calculated according to the common knowledge of the skilled in the art, for example by XRPD, in which the detection of crystalline percentage and/or amorphous percentage material is calculated by the ratio of the integrated area under the crystalline peaks to the total integrated area.
In another embodiment, the invention encompasses a process for preparing an amorphous form of caryedilol dihydrogen phosphate comprising dissolving cairyedilol dihydrogen phosphate in a solvent selected from the group consisting of C1-C8 alcohols and mixtures of C3.7 ketones with water, followed by solvent removal.
Preferably, a caryedilol dihydrogen phosphate purely amorphous is obtained.
Preferably, the solvent is methanol or acetone, "Whenever acetone is used as the solvent, a ratio of acetone/water of 2:1 is preferably used and the solvent is preferably removed by spray drying.
Removing the solvent can be performed using vacuum drying or spray drying.
Vacuum drying broadly refers to processes involving removal of liquid material from a solution or mixture under air pressure below atmospheric pressure. The process of the present invention may preferably employ vacuum drying at a pressure of less than one atmosphere, such as less than about 100 mm Hg, more preferably less than about 40 mm Hg.
Alternatively, the solution maybe spray dried.
The processes of the present invention may preferably employ spray drying with an inlet temperature of above about 80°C, preferably from about 80°C to about leO°C.
The spray drjdng may preferably be conducted with an outlet temperature of below the inlet temperature, preferably from about 30°C to about IIO°C, more preferably below about 40°C.
The drying gas used in the process of the present invention may be any suitable gas, although inert gases such as nitrogen, nitrogen-enriched air, and argon are preferred.
The caryedilol dihydrogen phosphate product produced by spray drying may be recovered by techniques commonly used in the art, such as using a cyclone or a filter.
The caryedilol hydrogen phosphate starting material used for the processes of the present invention may be any crystalline or amorphous form of caryedilol hydrogen phosphate, including any solvates and hydrates. With processes where caryedilol hydrogen phosphate goes into solution, the form of the starting material is of minimal relevance since any solid state structure is lost in solution.
Amorphous Caryedilol Dihydrogen phosphate can also be prepared by heating another crystalline form of Caryedilol Dihydrogen phosphate. Particularly, heating of crystalline forms Form N or R results in Amorphous Caryedilol Dihydrogen. Heating is carried out at a temperature of about 80°C to about 110°C preferably about 80°C to about 100°C. Heating can be carried out until the amorphous form obtained, such as from about 10 minutes to about 1 hours, preferably about 30 minutes.
Amoiphous Caryedilol Dihydrogen phosphate can also be prepared by heating another crystalline form of Caryedilol Dihydrogen phosphate. Particularly, heating of crystalline Form N results in Amorphous Caryedilol Dihydrogen. Heating is preferably carried out at a temperature of about 20°C to about 150°C, preferably about 140°C. Heating can be carried out until the amorphous form obtained, such as from about 10 minutes to about 4 hours, preferably about 30 minutes. In another embodiment, the invention encompasses a process for preparing a mixture of caryedilol dihydrogen phosphate Form N and caryedilol dihydrogen phosphate Form I comprising dissolving caryedilol dihydrogen phosphate in a mixture of C3.7 ketones with water, followed by vacuum drying.
Preferably, the solvent is acetone. Whenever acetone is used as the solvent, a ratio of acetone/water of 2:1 is preferably used.
The invention further encompasses pharmaceutical compositions comprising the crystalline caryedilol phosphate, caryedilol hydrogen phosphate and caryedilol dihydrogen phosphate of the invention and, optionally, amorphous caryedilol dihydrogen phosphate of the invention, and at least one pharmaceutically acceptable excipient.
Pharmaceutical compositions of the invention contain the caryedilol dihydrogen forms of the invention, optionally in mixture with other crystalline or amorphous forms of caryedilol and/or other active ingredients such as hydrochlorothiazide.
la certain embodiments, the pharmaceutical compositions of the invention comprise Form LI Form N, Form P, Form F, Form Fl, Form F2, Fonn R, Form Y, Fonn L. Form LI, Forai G, Form H, Form K, Form Q, Form Y or Form W and less than about 50%, less than about 25%, less than about 10%, less than about 5%, or less than about 1% (by weight of Form I of caryedilol dihydrogen phosphate present).
In certain embodiments, the pharmaceutical compositions of the invention comprise amorphous caryedilol phosphate and less than about 50%, less than about 25%, less than about 10%, less than about 5%, or less than about 1% (by weight of Form I of caryedilol dihydrogen phosphate present).
In certain embodiments, the pharmaceutical compositions of the invention comprise amorphous caryedilol hydrogen phosphate and less than about 50%, less than about 25%, less tiian about 10%, less than about 5%, or less than about 1% (by weight of Form I of caryedilol dihydrogen phosphate present).
In certain embodiments, the pharmaceutical compositions of the invention comprise amorphous caryedilol dihydrogen phosphate and less than about 50%, less than-about 25%, less than about 10%, less than about 5%, or less than about 1% (by weight of Form I of caryedilol dihydrogen phosphate present).
In certain embodiments, the pharmaceutical compositions of the invention comprise a therapeutically effective amount of caryedilol phosphate, caryedilol hydrogen phosphate and caryedilol dihydrogen phosphate crystalline forms G, H, K, Q, L, LI, N, O, P, F, Fl, F2, R, Y, W and amorphous forms (1:1,2:1, 3:l)or mixtures thereof.
The purity of caryedilol phosphate, caryedilol hydrogen phosphate and caryedilol dihydrogen phosphate crystalline forms G, H, K, Q, L, LI, N, O, P, F, Fl, F2, R, Y, W and amorphous form can be measured by any person skilled in the art, by PXRD using at least one peak of Form I when measuring the content of Form I. The peak or peaks may be selected from the following list of peaks at about: 7.0, 8.0, 9.2,11.4,14.0,14.8,15.5,16.0, 18.3,18.9,19.7, 22.3,22.9 and 25.4 ± 0.2 degrees two theta.
Alternatively, the purity of the above crystalline forms can be measured by solid-state 13C NMR using at list one signal of Fonn I when measuring the content of Form I. The signal or signals maybe selected from the following list of signals at about: 154.5,146.5,141.1, 139.7,125.3,122.1,120.7,118.3,113.6,110.2,109.4 and 103.8 ± 0.2 ppm.
In another embodiment, the present invention provides a pharmaceutical composition comprising by at least about 95% by weight at least one of the following crystal forms: crystalline Form G of caryedilol hydrogen phosphate, crystalline Form H of caryedilol
hydrogen phosphate, crystalline Fdrm K of caryedilol hydrogen phosphate, crystalline Form Q of caryedilol hydrogen phosphate crystalline Form L of caryedilol dihydrogen phosphate, crystalline Form LI of caryedilol dihydrogen phosphate, crystalline Form N of caryedilol dihydrogen phosphate, crystalline Form O of caryedilol dihydrogen phosphate, crystalline Form P of caryedilol dihydrogen phosphate, crystalline Fonn F of caryedilol dihydrogen phosphate, crystalline Form Fl of caryedilol dihydrogen phosphate, crystalline Form F2 of caryedilol dihydrogen phosphate, crystalline Form R of caryedilol dihydrogen phosphate, crystalline Form Y of caryedilol dihydrogen phosphate,-and a pharmaceutically acceptable excipient, crystalline Form W of caryedilol dihydrogen phosphate.
In another embodiment, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of crystalline Form G of caryedilol hydrogen phosphate, crystalline Form H of caryedilol hydrogen phosphate, crystalline Form K of caryedilol hydrogen phosphate, crystalline Form Q of caryedilol hydrogen phosphate crystalline Form L of caryedilol dihydrogen phosphate, crystalline Form LI of caryedilol dihydrogen phosphate, crystalline Form N of caryedilol dihydrogen phosphate, crystalline Form O of caryedilol dihydrogen phosphate, crystalline Form P of caryedilol dihydrogen phosphate, crystalline Form F of caryedilol dihydrogen phosphate, crystalline Form Fl of caryedilol dihydrogen phosphate, crystalline Form F2 of caryedilol dihydrogen phosphate, crystalline Form R of caryedilol dihydrogen phosphate, crystalHne Form Y of caryedilol dihydrogen phosphate,-and a pharmaceutically acceptable excipient, crystalline Form W of caryedilol dihydrogen phosphate, amorphous caryedilol phosphate and amorphous caryedilol dihydrogen phosphate, and a pharmaceutically acceptable excipient.
In another embodiment, the present invention provides a method of treatment of congestive heart failure or hypertension comprising administering the above pharmaceutical composition to a mammal in need thereof.
Another embodiment of the invention provides a process of preparing a pharmaceutical composition comprising combining any of the caryedilol dihydrogen phosphate, caryedilol hydrogen phosphate and caryedilol phosphate forms of the invention, or a solution prepared using the caryedilol dihydrogen phosphate forms of the invention, with at least one pharmaceutically acceptable excipient.
Pharmaceutical compositions of the invention can contain the amorphous forms and/or crystalline forms of caryedilol phosphate, caryedilol hydrogen phosphate, or caryedilol dihydrogen phosphate described herein, optionally in mixture with other active ingredients such as hydrochlorothiazide. In addition to the active ingredient(s), the pharmaceutical
compositions of the present invention can contain one or more excipients. Excipients are added to the composition for a variety of purposes.
Diluents increase the bulk of a solid pharmaceutical composition and can make a pharmaceutical dosage form containing the composition easier for the patient and caregiver to handle. Diluents for solid compositions include, for example, microcrystalline cellulose (e.g. AVICEL®), microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g. EUDRAGIT®), potassium chloride, powdered cellulose, sodium chloride, sorbitol and talc.
Solid pharmaceutical compositions that are compacted into a dosage form like a tablet can include excipients whose functions include helping to bind the active ingredient and other excipients together aiter compression. Binders for solid pharmaceutical compositions include at least one of acacia, alginic acid, carbomer (e.g. carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. KLUCEL®), hydroxypropyl methyl cellulose (e.g. METHOCEL®), liquid glucose, magnesiimi aliuninum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g. KOLLIDON®, PLASDONE®), pregelatinized starch, sodium alginate, or starch.
The dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach can be increased by the addition of a disintegrant to the composition. Disintegrants include, but are not limited to, alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g. AC-DI-SOL ©PRIMELLOSE®), colloidal silicon dioxide, croscannellose sodium, crospovidone (e.g. KOLLIDON®, POLYPLASDONE®), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium', powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g. EXPLOTAB®) or starch.
Glidants can be added to improve the flow properties of non-compacted solid composition and improve the accuracy of dosing. Excipients that can function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, and/or tribasic calcium phosphate.
When a dosage fomi such as a tablet is made by compaction of a powdered composition, the composition is subjected to pressure JGrom a punch and dye. Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which
can cause the product to have pitting and other surface irregularities. A lubricant can be added to the composition to reduce adhesion and ease release of the product form the dye. Lubricants include, but are not limited to, magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl ftunarate, stearic acid, talc, and/or zinc stearate.
Flavoring agents and flavor enhancers make the dosage form more palatable to the patient. Common flavoring agents and flavor enhancers for pharmaceutical products that can be included in the composition of the present invention include, but are not limited to, maltol, vanillin, ethyl vanillin, menthol, citric acid, iumaric acid, ethyl maltol, or tartaric acid.
Solid and liquid compositions can also be dyed using any pharmaceutically acceptable colorant to improve their appearance and/or facilitate patient identification of the product and unit dosage level.
In liquid pharmaceutical compositions of the present invention, one or more of the caryedilol forms described above and any other solid excipients are dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerin. .
Liquid pharmaceutical compositions can contain emulsifying agents to disperse uniformly throughout the composition an active ingredient or other excipient that is not soluble in the liquid carrier. Emulsifying agents that can be useful in liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol, or cetyl alcohol.
Liquid pharmaceutica] compositions of the present invention can also contain a viscosity-enhancing agent to improve the mouth-feel of the product and/or coat the lining of the gastrointestinal tract. Such agents include acacia, alginic acid bentonite, carbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methyl cellulose, etihylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch, tragacanth or xanthan gum.
Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fiiictose, mannitol and/or invert sugar can be added to improve the taste.
Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxy toluene, butylated hydroxyanisole and ethylenediamine tetraacetic acid can be added at levels safe for ingestion to improve storage stabihty.
A liquid composition according to the invention can also contain a buffer such as gluconic acid, lactic acid, citric acid or acetic acid, sodium gluconate, sodium lactate, sodium citrate or sodium acetate.
Selection of excipients and the amounts to use can be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference wor|k:s in the field.
The sohd compositions of the invention include powders, granulates, aggregates and compacted compositions.
The amorphous forms and/or crystalline forms of caryedilol phosphate, caryedilol hydrogen phosphate, or caryedilol dihydrogen phosphate of the invention can be administered for treatment of congestive heart failure and hypertension (by any means that delivers the active ingredients) to the site of the body where beta-blocking activity exerts a therapeutic effect on the patient. For example, administration can be oral, buccal, parenteral (including subcutaneous, intramuscular, and intravenous) rectal, inhalant or ophthalmic. Although the most suitable route in any given case will depend on the nature and severity of the condition being treated, the most preferred route of the invention is oral. Amorphous caryedilol phosphate of the invention can be conveniently administered to a patient in oral unit dosage form and prepared by any of the methods well-known in the pharmaceutical arts. Dosage forms include solid dosage forms like tablets, powders, capsules, sachets, troches, or lozenges as well as liquid syrups, suspensions, or elixirs.
The active ingredient(s) and excipients can be formulated into compositions and dosage forms according to methods known in the art.
A composition for tableting or capsule filling can be prepared by wet granulation. In wet granulation some or all of the active ingredients and excipients in powder form are blended and then fimher mixed in the presence of a hquid, typically water that causes the powders to clump up into granules. The granulate is screened and/or milled, dried and then screened and/or milled to the desired particle size. The granulate can then be tabletted or other excipients can be added prior to tableting such as a glidant and or lubricant.
A tableting composition can be prepared conventionally by dry blending. For instance, the blended composition of the actives and excipients can be compacted into a slug
or a sheet and then conuninuted into compacted granules. The compacted granules can be compressed subsequently into a tablet.
As an alternative to dry granulation, a blended composition can be compressed directly into a compacted dosage form using direct compression techniques. Direct compression produces a more xmifotm tablet without granules. Excipients that are particularly well suited to direct compression tableting include microcrystalline cellulose, spray dried lactose, dicalciiun phosphate dihydrate and/or colloidal silica. The proper use of these and other excipients in direct compression tableting is known to those in the art with experience and skill in particular formulation challenges of direct compression tableting.
A capsule filling of the invention can comprise any of the aforementioned blends and granulates that were described with reference to tableting, only they are not subjected to a final tableting step.
Yet more particularly, a tablet can, for example, be formulated by blending and directly compressing the composition in a tablet machine.
A capsule can, for example, be prepared by filling half of a gelatin capsule with the above tablet composition and capping it with the other half of the gelatin capsule.
A simple parenteral solution for injection can, for example, be prepared by combining amorphous caryedilol phosphate of the invention, sterile propylene glycol, and sterile water and sealing the composition in a sterile vial under sterile conditions.
Capsules, tablets and lozenges and other unit dosage forms preferably contain a dosage level of about 1 mgto about 100 mg of amorphous forms and/or crystalline forms of caryedilol phosphate, caryedilol hydrogen phosphate, or caryedilol dihydrogen phosphate described herein.
Another embodiment of the present invention provides a method for treating a patient sufiFering from hypertension, congestive heart failure, or another condition that would benefit fi-om treatment with amorphous forms and/or crystalline forms of caryedilol phosphate, caryedilol hydrogen phosphate, or caryedilol dihydrogen phosphate, comprising the step of administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of the amorphous forms and/or crystalline forms of caryedilol phosphate, caryedilol hydrogen phosphate, or caryedilol dihydrogen phosphate of the invention described herein.
The amorphous form (1:1) of the present invention has higher solubility with compared to Form I at pH = 7 and 25 °C:

(Table Removed)
Such higher solubility contributes to better bioavailability and can. lead to greater efficacy. Furthermore, the amorphous form has very homogenous spherical habit (Figure 52) directly obtained firom manufacture process with compared to Form I (Figure 36) or Form IV (Figure 37). Pharmaceutical particles are rarely spherical. Such spherical habit has many advantages such as: higher compressibility. The compressibility and homogeneity of the powder also affect the uniformity of the solid dosage form (poor content uniformity would result if a drug powder were not dispersed evenly throughout a mixture with excipients) and its size.
Using spherical powders, flowability of the powder may be improved. Processing of powders strongly depends on powder flowability. Powder flowability is defined as the time required for a specific quantity of powder to flow through an orifice or a die cavity. Flowability of a powder is important in high-volume manufacturing, which depends on rapid, uniform, consistent filling of die cavity. Poor flow characteristics cause slow and nonuniform press feeding and difficulty in ensuring a fill of the die cavity. Free-flowing powder refers to powders that readily flow in the die cavity [ASM Handbook, vol. 7: Powder Metallurgy].
Forms F, Fl, L, LI, N, P and R of the present invention have more crystaUinity than Form I (about 86% for Form R, about 87% for Form F, about 86% for Fl, about 88% for L and about 85% for LI compared to about 68% of I, about 86% for Form N, about 85% for Form P) as can be seen fi-om the % crystallinity calculation preformed using the WinXRD 2.0 program (Figures 46, 48, 39, 40, 43, 53, 50, 41). Less crystallinity powder means that the % of the amorphous ratio of the powder is greater, which can mean less stable material (amorphous materials are chemically and physically less stable than crystalline materials, such as when exposed to pressure, grinding, heat, long term shelf-hfe, humidity, etc.)
Forms F, Fl, L, LI and R are more stable for formulation than Form IV. Under extreme heat conditions (80°C for 30 min in oven) which may be used during formulation processes. Forms F, Fl, L, LI and R are stable upon heating when compared to Form FV (it transforms to amorphous form under these conditions).
Forms F, Fl, N and Y of the present invention have bigger particle size dimensions (Form N has particle size dimensions ~ 200-400 pm) (Form Y has bigger particle size dimensions~ 20-100 |LUn), (Form Fl has particle size dimensions ~ 50-150 pm) (Form F has bigger particle size dimensions ~ 50-200 [ua) compared to Form I (less than 20 \xm), as can be seen from the microscope images of figures 45, 47, 42, 51, 38. It has the advantage of being able to reduce the particle size to a range of smaller dimensions (according to the requirements of the formulator who prepare the capsule or tablet), while when starting in advance with a smaller size of powder (Form I) limits this option. In addition, small particles^ reduce flowability.
Form P has higher melting point (about 158 °C) with compared to Form IV (about 90 "C) as was measured by DSC (Differential Scanning Calorimetry) measurement which is a thermal analysis technique to detect heat changes of a material as a function of temperature change.
Form Y has a more homogenous habit (Figure 51) directly obtained from manufacture process when compared to that of Form IV (Figure 44). This has many advantages such as: higher compressibility which is very important for handling the powder, storage, safety, etc. The compressibility and homogeneity of the powder also affect the imifbrmity of the solid dosage form (poor content uniformity would result if a dmg powder were not dispersed evenly throughout a mixture vsdth excipients) and its size.
Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples describing in detail the preparation of the composition and methods of use of the invention. It will be appar^it to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.
The following examples are given for the purpose of illustrating the invention and shall not be construed as limiting the scope or spirit of the invention.
Examples
Instruments
Powder X-rav difEraction
Powder X-ray difSBraction data were obtained by using conventional methods employing a SCINTAG powder X-Ray diffractometer model X'TRA equipped with a solid-state detector. Copper radiation of 1.5418 A was vised to analyze the samples, which were in round alrnniniun sample holders with zero backgroimd. All peak positions reported are within ±0.2 degrees two theta.
TQA analysis
TGA analysis was preformed using Mettler 3M with Mettler TG 50 thermobalance. The weight of the samples was about 10 mg; the samples were scanned at a rate of 10°C/min fi-om 25°C to 200 or 250'°C. The oven was constantly pvurged with nitrogen gas at a flow rate of 40 ml/min. Standard alumina crucibles covered by lids with 1 hole were used.
Water content
Water content was determined by Karl Fisher analysis using Mettler Toledo DL 38 Karl Fisher Titrator.
13C NMR spectroscopy
The cp/mas 13C NMR investigations were preformed at 125.76 MHz at ambient temperature on a Bruker DMX-500 digital FT-NMR spectrometer equipped with a BL-4 cp/mas probehead and Higb Resolution/High Performance (HPHP) IH and X-channel preamplifiers for solids. Samples were placed in 4 mm zirconia rotors fitted with 'Kel-F' plastic caps, and spun with dry air at 5.0 kHz.
Example 1: Preparation of amorphous caryedilol phosphate

To a mixture of 3 g of caryedilol in 45 ml ethanol was slowly added 0.14 ml of phosphoric acid. The mixture was heated to reflux until complete dissolution. The resulting solution was stirred for an additional 10 minutes, and cooled to room temperature. 45 ml of water were then added to the solution and it was stirred overnight, upon which a precipitate formed. The precipitate was filtered and dried in a vacuum oven to give 2.7 g of a white solid. The resulting solid was analyzed by PXRD and was determined to be amorphous caryedilol phosphate.
Example 2: Preparation of caryedilol hydroeen phosphate Form G
To a mixture of 5 g of caryedilol in 50 ml methyl alcohol was slowly added 0.84 ml of phosphoric acid and the mixture heated to reflux to obtain a clear solution. After cooling to room temperature, 50 ml of water were added and the resulting solid was filtered and dried in . a vacuum oven to give 2.85 g of a white solid. The resulting solid was analyzed by XRD and shown to be caryedilol hydrogen phosphate Form G.
Example 3: Preparation of caryedilol hydrogen phosphate Form G
To a mixture of 3 g of caryedilol in 45 ml acetone/water (3:1) was slowly added 0.22 ml of phosphoric acid and the mixture was stirred overnight at room temperature. The resulting solid was filtered and analyzed by XRD and shown to be caryedilol hydrogen phosphate Form G.
Example 4: Preparation of phosphate salt of caryedilol hydroeen phosphate Form G
lOg of dry amorphous caryedilol dihydrogen phosphate were charged into 1 liter glass
reactor equipped with mechanical stirrer, and controlled heating/cooling system. 250 ml of
O.IM (buffer phosphoric pH=3.5) aqueous solution were charged into the reactor. The
agitator was turned on, and suspension was obtained. The suspension was stirred at 25°C for
19 hours and filtered.
The cake product was dried in a vacuum oven under a reduced pressure (under 100
mniHg) at 50°C until a dried product was obtained.
The resulting solid was analyzed by XRD and showed phosphate salt of caryedilol
hydrogen phosphate Fonn G.
Example 5: Preparation of phosphate salt of caryedilol hydroeen phosphate Form G
lOg of dry amorphous caryedilol dihydrogen phosphate were charged into 1 liter glass reactor equipped with mechanical stirrer, and controlled heating/cooling system. 250 ml of O.IM (buffer phosphoric pH=7) aqueous solution were charged into the reactor. The agitator was turned on, and suspension was obtained. The suspension was stirred at 25'°C for 21 hours and filtered.
The cake product was dried in a Vacuum oven imder a reduced pressure (under 100 mmHg) at 50°C until a dried product was obtained.
The resulting solid was analyzed by XRD and showed phosphate salt of caryedilol hydrogen phosphate Form G.
Example 6: Preparation of caryedilol hydrogen phosphate Form G
A 50 ml flask is charged with 1 g of Caryedilol dihydrogen phosphate Form R and 10 ml water. The mixture is stirred at room temperature for 24 hours until the crystals are converted to Form G. The crystals are collected by filtration under reduced pressure.and dried at SO°C under reduced pressure (under 100 mmHg).
The resulting solid was analyzed by XRD and showed Caryedilol hydrogen phosphate FormG.
Example 7: Preparation of caryedilol hydrogen phosT>hate Form G
A 50 ml flask is charged with 1 g of Caryedilol dihydrogen phosphate Form Fl and 10 ml water. The mixture is stirred at room temperature for 24 hours until the crystals are converted to Form G. The crystals are collected by filtration under reduced pressure and dried at SO^°C under reduced pressure (under 100 mmHg).
The resulting solid was analyzed by XRD and showed Caryedilol hydrogen phosphate FormG.
Example 8: Preparation of caryedilol hydrogen phosphate Form H
To a mixture of 3 g of caryedilol in 45 ml ethyl alcohol was slowly added 0.22 ml of phosphoric acid and the mixture heated to reflux and 150 ml of ethyl alcohol followed by 30 ml of water were added. After cooling to room temperature, the mixture was stirred overnight. The resulting solid was filtered and dried in a vacuum oven to give 2.37 g of a white solid. The resulting solid was analyzed by XRD and shown to be caryedilol hydrogen phosphate Form H.
Example 9: Preparation of caryedilol hydrogen phosphate Form K
Caryedilol hydrogen phosphate Form H was exposed to 80% and 100% relative humidity (RH) for 16 days at room temperature. According to XRD, the exposed samples contain caryedilol hydrogen phosphate Foim K.
Example 10: Preparation of caryedilol hydrogen phosphate Form K
A mixture of 10 g of caryedilol in 150 ml acetone/water (3:1) was stirred at room temperature for 30 minutes and 0.56 ml. of phosphoric acid 85% were added and stirred for overnight. The resulting mixture was filtered and dried in vacuum oven for over night at 50°C. The product was analyzed by XRD and found to be caryedilol hydrogen phosphate Form K.
Example 11: Preparation of a mixture of caryedilol hydrogen phosphate Forms K and H A mixture of 10 g of caryedilol in 150 ml acetone/water (3:1) was stirred at room temperature for 30 minutes and filtrated (to remove foreign objects). To the filtrated solution was added 0.56 ml. of phosphoric acid 85% and stirred for overnight. The resulting mixture was filtered and dried in vacuum oven for over night at 50°C. The product was analyzed by XRD and foimd to be a ncdxture of caryedilol hydrogen phosphate Forms K and H.
Example 12: Preparation of caryedilol hydrogen phosphate Form O
Caryedilol hydrogen phosphate Form K was exposed to 0% relative humidity (RH) for 7 days at room temperature. According to XRD, the exposed sample is caryedilol hydrogen phosphate Form Q.
Example 13: Preparation of amorphous caryedilol hydrogen phosphate
10 g of caryedilol hydrogen phosphate was dissolved in 200 ml of methanol at reflux. The solution was sprayed (72[ml/h3) into the chamber with ambient nitrogen (38m'/h, 100°C) at co-current flow. The atomizing flow (660 [1/h]) of nitrogen produced droplets, which led to a high evaporation rate. The temperature of the outlet solids was 29-30°C. The obtained sample was analyzed by XRD and found to be amorphous caryedilol hydrogen phosphate.
Example 14: Preparation of amorphous caryedilol hydrogen phosphate
10 g of carvedilol hydrogen phosphate was dissolved in 200 ml of acetone/water (2:1) at reflux. The solution was sprayed (72[ml/h3) into the chamber with ambient nitrogen (38m'/h, lOCC) at co-current flow. The atomizing flow (660[iyh]) of nitrogen produced droplets, which led to a high evaporation rate. The temperature of the outlet solids was 40°C. The obtained sample was analyzed by XRD and found to be amorphous.
Example 15: Preparation of carvedilol dihydrogen phosphate Form I
To a mixture of 5 g of Carvedilol in 100 ml acetone was slowly added 0.84 ml of phosphoric acid and the mixture stirred at the same temperature overnight. The resulting solid was filtered and dried in a vacuum oven to give 2.46 g of a white solid. The resulting solid was analyzed by XRD and showed Carvedilol dihydrogen phosphate Form I.
Example 16: Preparation of carvedilol dihydroeen phosphate Form I
To a mixture of 5 g of Carvedilol in 75 ml ethanol was slowly added 0.84 ml of phosphoric acid and the mixture was heated to reflux. The mixture was cooled to room temperature and kept at the same temperature overnight. The resulting solid was filtered and dried in a vacuum oven to give 5.22 g of a white solid. The resulting solid was analyzed by XRD and showed Carvedilol dihydrogen phosphate Form I.
Example 17: Preparation of carvedilol dihydrogen phosphate Form I
To a mixture of 5 g of Carvedilol in 120 ml IPA was slowly added 0.84 ml of phosphoric acid and the mixture was heated to reflux. After 1 hour, the mixture was cooled to room temperature and stirred overnight. The resulting solid was filtered and dried in a vacuum oven to give 5.12 g of a white solid. The resulting solid was analyzed by XRD and showed Carvedilol dihydrogen phosphate Form I.
Example 18: Preparation of carvedilol dihydroeen phosphate Form I
To a mixture of 3 g of Carvedilol in 45 ml ethanol was slowly added 0.53 ml of phosphoric acid and the mixture was heated to reflux. To the reflux mixture were added an additional 150 ml of ethanol and 30 ml of water (till complete dissolution). After cooling to room temperature, the mixture was stirred overnight. The resulting solid was filtered and dried in a vacuum oven to give 2.32 g of a white solid. The resulting solid was analyzed by XRD and showed Carvedilol dihydrogen phosphate Form I.
Example 19: Preparation of carvedilol dihydrogen phosphate Form I
To a mixture of 5 g of Carvedilol in 50 ml methanol was slowly added 0.84 ml of phosphoric acid and the mixture was heated to reflux (till complete dissolution). After cooling to room temperature, 20 ml of water were added and the mixture stirred at the same temperature overnight. The resulting solid was filtered and dried in a vacuum oven to give 4.06 g of a white solid. The resulting solid was analyzed by XRD and showed Carvedilol dihydrogen phosphate Form I.
Example 20: Preparation of carvedilol dihydrogen phosphate Form I
To a mixture of 5 g of Carvedilol in 75 ml ethanol was slowly added 0.84 ml of phosphoric acid and the mixture was heated to reflux and 75 ml of water was added (till complete dissolution). The solution was cooled to room temperature and stirred at the same temperature overnight The resulting solid was filtered and dried in a vacuum oven to give 4 g of a white solid. The resulting solid was analyzed by XRD and showed Carvedilol dihydrogen phosphate Form I.
Example 21: Preparation of carvedilol dihydrogen phosphate Form I
To a mixture of 5 g of Carvedilol in 25 ml THF was slowly added 0.84 ml of phosphoric acid and stirred at room temperature overnight. The resulting solid was filtered and dried in a vacuum oven to give 6 g of a white solid. The resulting solid was analyzed by XRD and showed Carvedilol dihydrogen phosphate Form I.
Example 22: Preparation of carvedilol dihydrogen phosphate Form I A slurry of 1 g of a mixture of Carvedilol hydrogen phosphate and Carvedilol base in 10 ml acetone was stirred overnight. The resulting solid was filtered and dried in a vacuum oven to give 0.27 g of a white solid. The resulting solid was analyzed by XRD and showed Carvedilol dihydrogen phosphate Form I content.
Example 23: Preparation of carvedilol dihydrogen phosphate Form I To a mixture of 10 g of Carvedilol in 200 ml absolute ethanol was slowly added 1.7 ml of phosphoric acid and 100 ml of ethanol were slowly distilled out. The solution was cooled to room temperature and stirred at the same temperature overnight. The resulting solid was filtered and dried in a vacuum oven to give 7 g of a white solid. The resulting solid was analyzed by XRD to yield Carvedilol dihydrogen phosphate Form I.
Example 24: Preparation of carvedilol dihydrogen phosphate Form I To a mixture of 5 g of Carvedilol in 50 ml acetonitrile was slowly added 0.84 ml of phosphoric acid and the mixture was heated to reflux. The solution was cooled to room temperature and stirred at the same temperature for overnight. The resulting solid was filtered and dried in a vacuum oven to give 3.36 g of a white solid. The resulting solid was analyzed by XRD to yield Carvedilol dihydrogen phosphate Form L
Example 25: Preparation of carvedilol dihydrogen phosphate Form I
To a mixture of 5 g of Carvedilol in 100 ml heptane was slowly added 0.84 ml of phosphoric acid and the mixture was heated to reflux. The mixture was cooled to room temperature and stirred at the same temperature overnight. The resulting solid was filtered and dried in a vacuum oven to give 2.12 g of a white solid. The resulting solid was analyzed by XRD to yield Carvedilol dihydrogen phosphate Form I.
Example 26: Preparation of carvedilol dihydrogen phosphate Form I To a mixture of 5 g of Carvedilol in 50 ml PGME was slowly added 0.84 ml of phosphoric acid and the mixture was heated to reflux. The solution was cooled to room temperature and stirred at the same temperature overnight. The resulting solid was filtered and dried in a vacuum oven to give 5.17 g of a white solid. The resulting solid was analyzed by XRD to yield Carvedilol dihydrogen phosphate Form I.
Example 27: Preparatioin of carvedilol dihydrogen phosphate Form I To a mixture of 5 g of Carvedilol in 100 ml MIBK was slowly added 0.84 ml of phosphoric acid and the mixture was heated to reflux. The mixture was cooled to room temperature and stirred at the same temperature overnight. The resulting solid was filtered and dried in a vacuum oven to give 0.66 g of a white solid. The resulting solid was analyzed by XRD to yield Carvedilol dihydrogen phosphate Form I.
Example 28: Preparation of carvedilol dihydrogen phosphate Form I To a mixture of 5 g of Carvedilol in 100 ml MEK was slowly added 0.84 ml of phosphoric acid and the mixture was heated to reflux. The mixture was cooled to room temperature and stirred at the same temperature overnight. The resulting solid was filtered and dried in a
vacuum oven to give 5.65 g of a white solid. The resulting solid was analyzed by XRD to yield Carvedilol dihydrogen phosphate Form I.
Example 29: Preparation of carvedilol dihydrogen phosphate Form I To a mixture of 5 g of Carvedilol in 50 ml 2-BuOH was slowly added 0.84 ml of phosphoric acid and the mixture was heated to reflux. The solution was cooled to room temperature and stirred at the same temperature overnight. The resulting solid was filtered and dried in a vacuum oven to give 3.89 g of a white solid. The resulting solid was analyzed by XRD to yield Carvedilol dihydrogen phosphate Fonn I.
Example 30: Preparation of carvedilol dihydrogen phosphate Form I
To a mixture of 5 g of Carvedilol in 50 ml n-BuOH was slowly added 0.84 ml of phosphoric acid and the mixture was heated to reflux. The solution was cooled to room temperature and stirred at the same temperature for 5 hours. The resulting solid was filtered and dried in a vacuum oven to give 0.30 g of a white solid. The resulting solid was analyzed by XRD to yield Carvedilol dihydrogen phosphate Form I.
Example 31: Preparation of carvedilol dihydrogen phosphate Form I
To a mixture of 5 g of Carvedilol in 150 ml tert-BuOH was slowly added 0.84 ml of phosphoric acid and the mixture was heated to reflux. The mixture was cooled to room temperature and stirred at the same temperature over the weekend. The resulting solid was filtered and dried in a vacuum oven to give 2.74 g of a white solid. The resulting solid was analyzed by XRD to yield Carvedilol dihydrogen phosphate Form I.
Example 32: Preparation of carvedilol dihydrogen phosphate Form I To a mixture of 8 g of Carvedilol in 80 ml n-propanol was slowly added 1.34 ml of phosphoric acid and the mixture stirred at room temperature overnight. The resulting solid was filtered and dried in a vacuum oven to give 5.67 g of a white solid. The resulting solid was analyzed by XRD and showed Carvedilol dihydrogen phosphate Form I.
Example 33: Preparation of carvedilol dihydrogen phosphate Form I
To a mixture of 8 g of Carvedilol in 80 ml of methyl acetate was slowly added 1.34 ml of
phosphoric acid and the mixture stirred at room temperature overnight. The resulting solid
was filtered and dried in a vacuum oven to give 5.13 g of a white solid. The resulting solid was analyzed by XRD and showed Carvedilol dihydrogen phosphate Form I.
Example 34: Preparation of carvedilol dihydrogen phosphate Form I To a mixture of 8 g of Carvedilol in 80 mi isobutyl acetate was slowly added 1.34 ml of phosphoric acid and the mixture was heated to reflux. After 2 hour, the mixture was cooled to room temperature and stirred overnight. The resulting solid was filtered and dried in a vacuum oven to give 7.5 g of a white solid. The resulting solid was analyzed by XRD and showed Carvedilol dihydrogen phosphate Form I.
Examtile 35: Preparation of carvedilol dihydrogen phosphate Form I To a mixture of 8 g of Carvedilol in 80 ml ethyl acetate was slowly added 1.34 ml of phosphoric acid and the mixture was heated to reflux. After 2 hour, the mixture was cooled to room temperature and stirred overnight. The resulting solid was filtered and dried in a vacuxim oven to give 7.2 g of a white solid. The resulting solid was analyzed by XRD and showed Carvedilol dihydrogen phosphate Form I.
T?.Yamplfl 36: Preparation of carvedilol dihydrogen phosphate Form I To a mixture of 8 g of Carvedilol in 80 ml MTBE was slowly added 1.34 ml of phosphoric acid and the mixture was heated to reflux. After 2 hour, the mixture was cooled to room temperature and stirred overnight. The resulting solid was filtered and dried in a vacuum oven to give 7.7 g of a white solid. The resulting solid was analyzed by XRD and showed Carvedilol dihydrogen phosphate Form I.
Example 37: Preparation of carvedilol dihydrogen phosphate Form I A 50 ml flask was charged with 1 g of Carvedilol dihydrogen phosphate Form R and 10 ml EtOH abs. The mixture was stirred at room temperature for 24 hours xmtil the crystals were converted to Form I. The crystals were collected by filtration under reduced pressure and dried at 50°C under reduced pressure (under 100 mmHg). The resulting solid was analyzed by XRD and showed Carvedilol dihydrogen phosphate Form I.
Example 38: Preparation of carvedilol dihydrogen phosphate Form L
A mixture of 4 g of Carvedilol dihydrogen phosphate in 40 ml of dioxane was heated to
reflux overnight. After cooling to room temperature, the resulting solid was filtered and dried
in a vacuum oven at 45°C to give 3.88 g of a white solid. The resuJting solid was analyzed by XRD and showed Carvedilol dihydrogen phosphate Form L.
Example 39: Preparation of carvedilol dihydrogen phosphate Form L
To a solution of 4 g of Carvedilol in 60 ml dioxane was slowly added 0.67 ml of phosphoric acid and the resulting mixture was heated to reflux (an additional 20 ml of dioxane were added). Aiier overnight the mixture was cooled to room temperature, and stirred for overnight. The resulting solid was filtered and dried in a vacuum oven to give 3.45 g (64.32% chemical yield) of a white solid. The resulting solid was analyzed by XRD to yield Carvedilol dihydrogen phosphate Form L.
Example 40: Preparation of carvedilol dihydrogen phosphate Form LI A mixture of 30 g of Carvedilol dihydrogen phosphate in 300 ml of dioxane was heated to reflux overnight. After cooling to room temperature, the resulting solid was filtered and dried in a vacuum oven at SS°C to give 29 g of a white solid. The resulting solid was analyzed by XRD and showed Carvedilol dihydrogen phosphate Form LI.
Example 41: Preparation of carvedilol dihydrogen phosphate Form O
Form O was prepared by grinding about 200 mg of amorphous form with 2-3 drops of water
for about 1-2 min (using mortar and pestle).
Example 42: Preparation of carvedilol dihydrogen phosphate Form P
A mixture of 5 g of amorphous Carvedilol dihydrogen phosphate in 50 ml of ethanol was stirred at room temperature overnight. The resulting solid was filtered and dried in a vacuum oven at 55°C to give 3.4 g of a white solid. The resulting solid was analyzed by XRD and showed Carvedilol dihydrogen phosphate Form P.
Example 43: Preparation of amorphous carvedilol dihydrogen phosphate 10 g of Carvedilol dihydrogen phosphate was dissolved in 200 ml of methanol at reflux. The solution was sprayed (72[ml/h]) into the chamber of a spray drying apparatus with ambient nitrogen (38m'/h, 100°C) at co-current flow. The atomizing flow (660[l/h]) of nitrogen produced droplets, which led to a high evaporation rate. The temperature of the outlet solids was SyC. The obtained sample was analyzed by XRD and found to be amorphous.
Example 44: Preparation of amorphous carvedilol dihydroeen phosphate
10 g of carvedilol dihydrogen phosphate was dissolved in 200 ml of acetone/water (2:1) at
reflux. The solution was sprayed (72[ml/h}) into the chamber of a spray drying apparatus
with ambient nitrogen (38m'/h, 100 °C) at co-current flow. The atomizing flow (660[l/h]) of
nitrogen produced droplets, which led to a high evaporation rate. The temperature of the
outlet solids was SS-SS°C. The obtained sample was analyzed by XRD and found to be
amorphous.
Example 45: Preparation of amorphous carvedilol dihydroeen phosphate
5 g of Carvedilol dihydrogen phosphate was dissolved in 100 ml of methanol at reflux.
The solution was sprayed (72[ml/h3) into the chamber of a spray drying apparatus with
ambient nitrogen (38m'/h, 80 *°C) at co-current flow. The atomizing flow (660[l/h]) of
nitrogen produced droplets, which led to a high evaporation rate. The temperature of the
outlet solids was 19°C. The obtained sample was analyzed by XRD and found to be
amorphous.
Example 46: Preparation of amorphous carvedilol dihydroeen phosphate
5 g of Carvedilol dihydrogen phosphate was dissolved in 100 ml of methanol.
The solution was sprayed (72[m]/h]) into the chamber of a spray drying apparatus with
ambient nitrogen (38m'/h, 100 °C) at co-current flow. The atomizing flow (660[l/h]) of
nitrogen produced droplets, which led to a high evaporation rate. The temperature of the
outlet solids was 40°C. The obtained sample was analyzed by XRD and found to be
amorphous.
Example 47: Preparation of amorphous carvedilol dihydrogen phosphate
lOOg of dry Carvedilol were charged into a 5 hter stainless steel lab dryer equipped with a
mechanical siirrer, and a controlled heating/cooling system, 1000 ml of methanol were
charged and 17 ml of 85% phosphoric acid was introduced into the dryer. The agitator was
turned on, and suspension was obtained. The jacket temperature was adjusted to 70°C and at
58*°C clear solution was obtained. The solution was heated to reflux and was mixed for 15
minutes.
The solution was dried imder reduced pressure (the pressure was reduced gradually firom
atmospheric pressure down to 40 mmHg) at 70°C until a dried product was obtained.
20g of the product were further dried at 50°C, under reduced pressure (under 100 mmHg). 16g of white solid were obtained. The resulting solid was analyzed by XRD and showed Amorphous Carvedilol dihydrogen phosphate.
Example 48: Preparation of carvedilol dihydrogen phosphate Form N Carvedilol dihydrogen phosphate Form L, LI and amorphous carvedilol dihydrogen phosphate were exposed to 100% relative humidity (RH) for 7 days at room temperature. According to XRD, the exposed samples are carvedilol dihydrogen phosphate Form N.
Example 49: Preparation of a mixture of carvedilol dihydrogen phosphate Form I and Form N lOOg of dry Carvedilol were charged into a 5 liter stainless steel lab dryer equipped with a mechanical stirrer and a controlled heating/cooling system. 350 ml of acetone and 150 ml of water were charged and 17 ml of 85% phosphoric acid was introduced into the dryer. The agitator was turned on and suspension was obtained. The jacket temperature was adjusted to TO°C and at about 60'°C a clear solution was obtained.
The solution was dried under reduced pressure (the pressure was reduced gradually from atmospheric pressure down to 40 mmHg) at a jacket temp of 70'°C until a dried product was obtained.
The resulting solid was analyzed by XRD and showed a Carvedilol dihydrogen phosphate mixture of Form I and Form N.
Example 50: Preparation of carvedilol dihydrogen phosphate Form F
40g of dry Carvedilol were charged into a 1 liter glass lab reactor equipped with a mechanical stirrer and a controlled heating/cooling system. 400 ml of methanol were charged. The agitator was turned on and a suspension was obtained. The temperature was adjusted to 50°C and 6.8 ml of 85% phosphoric acid was introduced into the reactor. The solution was heated to reflux and was mixed for 3 hours until Carvedilol dihydrogen phosphate precipitated. The precipitated product was slurried for 1 hr and then the product was isolated by filtration under reduced pressure. The filtered cake was washed with 40 ml of methanol. 10g of the wet product were dried in a tray oven at 50°C, under reduced pressure. 8g of white solid were obtained. The resulting solid was analyzed by XRD and showed Carvedilol dihydrogffla phosphate Form F.
Example 51: Preparation of carvedilol dihydrogen phosphate Form F

20g of dry Carvedilol base were charged into 0.5 liter glass reactor equipped with mechanical stiirer, and controlled heating/cooling system. 300 ml of Methanol were charged. The agitator was turned on, the solution was heated to 50°C and partial dissolution was obtained, 3.4 ml of 85% phosphoric acid were introduced into the reactor.
The jacket temperature was adjusted to 75°C (at 54°C a full dissolution was obtained). The solution was heated and stirred for 16 hoxirs during which the product precipitated. Itie product was filtered and the cake product was dried in a Vacuum oven under reduced pressure (under 100 mmHg) at 55°C until a dried product was obtained. The dry sample was analyzed by 'XKD and found to be carvedilol dihydrogen phosphate Form F.
Example 52: Preparation of carvedilol dihydrogen phosphate Form F
A 100 ml flask was charged with Carvedilol dihydrogen phoqahate Form I (2g) and methanol
(20 ml). The suspension was heated to reflux and stirred for 30 min to obtain a clear solution.
The solution was further stirred at reflux until precipitation was observed and then cooled to
room temperature and stirred for an additional hour.
The crystals were collected by filtration imder reduced pressure and dried at 50'°C under
reduced pressure to obtain Carvedilol dihydrogen phosphate. (1.7 g)
The dry sample was analyzed by XRD and found to be carvedilol dihydrogen phosphate
FoimF.
Example S3: Preparation of carvedilol dihydrogen phosphate Form Fl
50g of dry Carvedilol base were charged into 1 liter glass reactor equipped with mechanical
stirrer, and controlled heating/cooling system, 750 ml of EtOH abs (Ethanol absolute) were
charged and 8.5 ml of 85% phosphoric acid was introduced into the reactor. The agitator was
turned on, and suspension was obtained. The jacket temperature was adjusted to 80 °C. The
suspension was heated and stirred for 4 hours, cooled to 15'°C and stirred for 2 hours, filtered
and washed with 50 ml EtOH abs.
The cake product was dried in a Vacuum oven under a reduced pressure firom amt under 100
mmHg) at 55°C until a dried product was obtained.
The dry sample was analyzed by XRD and found to be carvedilol dihydrogen phosphate
FormFl.'
Example 54: Preparation of carvedilol dihydrogen phosphate Form Fl
20g of dry Carvedilol dihydrogen Phosphate Form I were charged into 1 liter glass reactor equipped with mechanical stirrer, and controlled heating/cooling system. 300 ml of EtOH abs (Ethanol absolute) were charged into the reactor, The agitator was turned on, and suspension was obtained. The jacket temperature was adjusted to 80°C. The suspension was heated and stirred for 15.5 hours, cooled to 15°C and stirred for 2 hours and filtered.
The cake product was dried in a vacuum oven under a reduced pressure from atm (xmder 100 mmHg) at SO°C imtil a dried product was obtained.
The resulting solid was analyzed by XRD and showed Carvedilol dihydrogen phosphate FormFl.
Example 55: Preparation of carvedilol dihydrogen phosphate Form Fl
20g of dry Carvedilol dihydrogen Phosphate Form R were charged into a 1 liter glass reactor equipped with mechanical stirrer, and controlled heating/cooling system. 300 ml of EtOH abs (Ethanol absolute) were charged into the reactor. The agitator was turned on, and suspension was obtained. The jacket temperature was adjusted to 80°C. The suspension was heated and stirred for 15.5 hours, cooled to 15°C, and stirred for 2 hours and filtered.
The cake product was dried in a vacuum oven under a reduced pressure from atm (under 100 mmHg) at 80°C until a dried product was obtained.
The resulting solid was analyzed by XRD and showed Carvedilol dihydrogen phosphate FormFl.
Example 56: Preparation of carvedilol dihydrogen phosphate Form R
50g of dry Carvedilol base were charged into 1 liter glass reactor equipped with mechanical
stirrer, and controlled heating/cooling system. 750 ml of IPA (isopropyl alcohol) were
charged and 8.5 ml of 85% phosphoric acid was introduced into the reactor. The agitator was
turned on, and suspension was obtained. The jacket temperature was adjusted to 25 °C. The
suspension was stirred for 4 hours at 25°C, cooled to 15'°C, stirred for 2 hours, filtered and
washed with 50 ml IPA.
The cake product was dried in a Vacuum oven vuider a reduced pressure from (under 100
nmiHg) at 55'°C until a dried product was obtained.
The dry sample was analyzed by XRD and fovmd to be carvedilol dihydrogen phosphate
FormR.
Example 57: Preparation of carvedilol dihydrogen phosphate Form R
50g of dry Carvedilol base were charged into 1 liter glass reactor equipped with mechanical
stirrer, and controlled heating/cooling system. 250 ml of IPA (isopropyl alcohol) were
charged and 8.5 ml of 85% phosphoric acid was introduced into the reactor. The agitator was
turned on, and suspension was obtained. The jacket temperature was adjusted to 52.5 °C. The
suspension was heated and stirred for 2 hours, cooled to 15°C, stirred for 2 hours, filtered and
washed with 50 ml IPA.
The cake product was dried in a Vacuum oven under a reduced pressure from (under 100
mmHg) at 55°C until a dried product was obtained.
The dry sample was analyzed by XRD and found to be carvedilol dihydrogen phosphate
Form R including traces of Form I.
Example 58: Preparation of carvedilol dihydrogen phosphate Form R
A 50 ml flask was charged with 1 g of Carvedilol dihydrogen phosphate amorphous and 10
ml IPA. The mixture was stirred at room temperature for 24 hours until the crystals were
converted to Form R. The crystals were collected by filtration imder reduced pressure and
dried at SO°C under reduced pressure (under 100 mmHg).
The resulting solid was analyzed by XRD and showed Carvedilol dihydrogen phosphate
FormR.
Example 59: Preparation of carvedilol dihydrogen phosphate Form R
A 50 ml flask was charged with 1 g of Carvedilol dihydrogen phosphate Fomi Fl and 10 ml
IPA. The mixture was stirred at room temperature for 24 hours until the crystals were
converted to Form R. The crystals were collected by filtration under reduced pressure and
dried at 50°C under reduced pressure (under 100 mmHg).
The resulting solid was analyzed by XRD and showed Carvedilol dihydrogen phosphate
FormR.
Example 60: Preparation of carvedilol dihydrogen phosphate Form Y
450g of dry Carvedilol were charged into a 10 liter glass reactor equipped with mechanical stirrer, aad controlled heating/cooling system. 6,750 mJ of EtOH abs (Ethanol absolute) were charged and 768.5 ml of 85% phosphoric acid was introduced into the reactor. The agitator was turned on and suspension was obtained. The jacket temperature was adjusted to 80°C.
The suspension was heated and stirred. A sample from the suspension was taken after 3 hours
and then was filtered.
The wet sample was analyzed by XRD and found to be carvedilol dihydrogen pho^hate
FormY.
Examples to obtain essentially Form I: Example 61:
Carvedilol dihydrogen phosphate Foini F was exposed to 100 % relative humidity (RH) for 7 days at 60 "C. According to XRD, the resulting exposed sample is carvedilol dihydrogen phosphate Form I.
Example 62:
Carvedilol dihydrogen phosphate Form N was placed in oven at a temperature of 120 "C for 30 min. The resulting solid was analyzed by XRD and showed a Carvedilol dihydrogen phosphate Form I.
Example 63:
A 50 ml flask is charged with 1 gr of Carvedilol dihydrogen phosphate Form Fl and 10 ml Acetone. The mixture is stirred at room temperature for 1 day while which the crystals are converted to Form I. The crystals are collected by filtration under reduced pressure and dried at 80°C xmder reduced pressure (imder 100 mmHg).
The resulting solid was analyzed by XRD and showed Carvedilol dihydrogen phosphate FORM I.
Example 64:
A 50 ml flask is charged with 1 gr of Amorphous Carvedilol dihydrogen phosphate and 10 inl
Acetone. The mixtiure is stirred at room temperature for 1 day until the crystals are converted
to Form L The crystals are collected by filtration imder reduced pressure and dried at 80°C
under reduced pressure (under 100 mmHg).
The resulting sohd was analyzed by XRD and showed Carvedilol dihydrogen phosphate
Fomil.
Example 65:
A 50 ml flask is charged with 1 gr of Carvedilol dihydrogen phosphate Form R and 10 ml
Acetone. The mixture is stirred at room temperature for 1 day until the crystals are converted
to Form I. The crystals are collected by filtration under reduced pressure and dried at 80°C
under reduced pressure (under 100 mmHg).
The resulting solid was analyzed by XRD and showed Carvedilol dihydrogen phosphate
FORM I.
Example 66:
A 100 ml flask is charged with 7 gr of Carvedilol dihydrogen phosphate Form N and 70 ml Acetone. The mixture is stirred at room temperature for 1 day while which the crystals are converted to Form I. The crystals are collected by filtration under reduced pressure and dried at 50°C under reduced pressure (imder 100 mmHg).
The resulting solid was analyzed by XRD and showed Carvedilol dihydrogen phosphate FORM I.
Example 67:
Carvedilol dihydrogen phosphate Form LI was placed in oven at a temperature of about between 80-120 "C for 30 min. The resulting solid was analyzed by XRD and showed a Carvedilol dihydrogen phosphate Form I.
Example 68:
Amorphous Carvedilol dihydrogen phosphate was placed in oven at a temperature of 120 °C for 30 min. The resulting solid was analyzed by XRD and showed a Carvedilol dihydrogen phosphate Form I.
Example 69:
40 ml of water was added to 4gr Carvedilol dihydrogen phosphate Form I (MAB-1449). The mixture was slurred at room temperature over night.
The suspension was vacuum filtered and dried in vacuum at 50 °C in oven over night to obtain 3.13 gr (78%yield). The resulting solid was analyzed by XRD and showed a mixture of carvedilol dihydrogen phosphate Form I and carvedilol hydrogen phosphate Form G.
Example 70:
Carvedilol dihydrogen phosphate Form P was placed in oven at a temperature of about between 80-120 *°C for about 30 min. The resulting solid was analyzed by XRD and showed a Carvedilol dihydrogen phosphate Form I.
Example 71:
Carvedilol dihydrogen phosphate Form R was placed in oven at a temperature of about 120 °C for about 30 min. The resulting solid was analyzed by XRD and showed a Carvedilol dihydrogen phosphate Form I.
Example 72:
Carvedilol dihydrogen phosphate Form N was pressed by pressure of 2 ton by a laboratory press for about 1 min. The resulting solid was analyzed by XRD and showed a Carvedilol dihydrogen phosphate mixture of Form N and Form I.
Example 73:
Carvedilol dihydrogen phosphate Fonn P was pressed by pressure of 2 ton by a laboratory press for about 1 min. The resulting solid was analyzed by XRD and showed a Carvedilol dihydrogen phosphate Form I.
Example 74:
Carvedilol dihydrogen phosphate Form P was groimd by mortal and pestle for about 1 min. The resulting solid was analyzed by XRD and showed a Carvedilol dihydrogen phosphate Form I.
Example 75:
Carvedilol dihydrogen phosphate Form F was ground by mortal and pestle with 2-3 drops of butanol for about 1 min. The resulting solid was analyzed by XRD and showed a Carvedilol dihydrogen phosphate mixture of Form F and Form I.
Example 76:
Amorphous Carvedilol dihydrogen phosphate was placed in an atmosphere of the following solvents for 7 days: n-propanol, iso-propanol, butanol, acetone and ethyl acetate. The resulting solids were analyzed by XRD and showed a Carvedilol dihydrogen phosphate
mixture of amorphous form and Form I for n-propanol, iso-propanol, butanol, acetone and ethyl acetate.
Example 77:
A 50 ml flask is charged with 0.6 gr of Carvedilol dihydrogen phosphate Form N and 6 ml
water. The mixture is stirred at room temperature for 3 days until part of the crystals are
converted to Form I. The crystals are collected by filtration under reduced pressure and dried
at 50°C xmder reduced pressure (imder 100 mmHg).
The resulting solid was analyzed by XRD and showed a mixture of Carvedilol dihydrogen
phosphate FORM N and Form I.
Examples to obtain essentially amorphons form (1:1): Example 78:
Carvedilol dihydrogen phosphate Form F was placed in oven at a temperature of about 140 °C for about 30 min. The resulting solid was analyzed by XRD and showed an amorphous form of Carvedilol dihydrogen phosphate.
Example 79:
Carvedilol dihydrogen phosphate Form R was placed in oven at a temperature of about 100 "C for about 30 min. The resulting solid was analyzed by XRD and showed a mixture of Carvedilol dihydrogen phosphate Form R and amorphous form.
Example 80:
Solid pharmaceutical compositions of amorphous fonn and the following excipients: lactose monohydrate, sucrose and avicel were compacted into a dosage form like a tablet.
Examples to obtain Form N (1:1): Example 81:
Carvedilol dihydrogen phosphate Form Fl was exposed to 100 % relative humidity (RH) for 7 days at room temperature. The resulting solid was analyzed by XRD and showed a Carvedilol dihydrogen phosphate mixture of Foim N and Form Fl.
Example 82:
Carvedilol dihydrogen phosphate Form R was exposed to 100 % relative humidity (RH) for 7 days at room temperature. According to XRD, the exposed sample is Carvedilol dihydrogen phosphate Form N.
Example 83:
Carvedilol dihydrogen phosphate Fonn Fl was exposed to 100 % relative humidity (RH) for 7 days at room temperature. The resulting solid was analyzed by XEU> and showed a Carvedilol dihydrogen phosphate mixture of Form Fl and Form N.
Example 84:
Carvedilol dihydrogen phosphate Form N was placed in oven at a temperature of 80 °C for 30 min. The resulting solid was analyzed by XRD and showed a Carvedilol dihydrogen phosphate mixture of amorphous form and Form N.
Example 85:
Solid pharmaceutical compositions of Form N and the following excipients: lactose monohydrate, sucrose and avicel were compacted into a dosage form like a tablet.
Examples to obtain Form Fl (1:1): Example 86:
A 50 ml flask is charged with 0.6 gr of Carvedilol dihydrogen phosphate Form N and 6 ml
EtOH. The mixture is stirred at room temperature for 3 days until the crystals are converted
to Form Fl. The crystals are collected by filtration under reduced pressure and dried at SO°C
under reduced pressure (under 100 mmHg).
The resulting solid was analyzed by XRD and showed Carvedilol dihydrogen phosphate
FORMFl.
Example 87:
30 gr (on dry basis) of wet Carvedilol base were charged into 1 liter glass reactor equipped with mechanical stirrer, and controlled heating/cooling system. 810 ml of EtOH abs (Ethanol absolute) were charged, the agitator was turned on and the reactor content was heated to reflux (78-82 "C), during the heating full dissolution was achieved,
5.6 ml of 85% phosphoric acid and 90 ml of EtOH abs. were introduced into the reactor. Seeding was preformed with 0.15 gr Carvedilol dihydrogen phosphate FORM Fl slurried in 8
ml EtOH abs. The reactor content was stirred for 4 hr, cooled to 15 °C stirred for another 2
hr, filtered and washed with 60 ml ETOH abs.
The cake product was dried in a vacuum oven under a reduced pressure (under 100 mmHg) at
50 °C imtil a dried product was obtained.
The resulting solid was analyzed by XRD and showed Carvedilol dihydrogen phosphate
Carvedilol dihydrogen phosphate FOJRM Fl.
ExampIeSS:
Solid pharmaceutical compositions of Form Fl and the following excipients: lactose monohydrate, sucrose and avicel were compacted into a dosage form like a tablet.
Examples to obtain Form R (1:1): Example 89:
A 50 ml flask is charged with 0.6 gr of Carvedilol dihydrogen phosphate Form N and 6 ml IPA. The mixture is stiired at room temperature for 3 days while which the crystals are converted to Form R. The crystals are collected by filtration under reduced pressure and dried at SCC under reduced pressure (under 100 mmHg). The resulting solid was analyzed by XRD and showed Carvedilol dihydrogen phosphate FORM R. Example 90:
Sohd pharmaceutical compositions of Form R and the following excipients: lactose monohydrate, sucrose and avicel were compacted into a dosage form like a tablet.
Example 91: Process for the preparation of Carvedilol dihydrogen phosphate Form F2:
Carvedilol dihydrogen phosphate Form I was used for crystallization. Sample (40 mg) was dissolved in ethanol (4 ml, Merck l.l 1727.25t)0) at 70 °C. The flask was placed at the thermos flask at 50 °C and was allowed to cool slowly to 20 "C within 6 days. Data collection was preformed at 150 K.
Process for the preparation of Form Q. Example 92:
Carvedilol hydrogen phosphate Form K was exposed to 0% relative humidity (RH) for 7 days at room temperature. The resulting solid was analyzed by XRD and showed Form Q content. Example 93:
Process for the preparation of Carvedilol phosphate salt phosphate Form W:
Carvedilol dihydrogen phosphate form FT, sample LI-11193, was added to 30 ml of 0.1 M KH2PO4 (pH = 7.0 adjusted with IM KOH) until a suspension was obtained. The suspension was stirred at was stirred at 25*°C for 24 hr and filtered under vacuum. XRD analysis showed that it was a new crystal form (designated Form W),

We Claims :-
1. Amorphous carvedilol phosphate.
2. The amorphous carvedilol phosphate of claim 1 comprising at least one of less than fabout 20%, preferably less than about 10%, more preferably less than about 5%, and even more preferably less than about 1% crystalline carvedilol or phosphate salt by weight.
3- The amorphous carvedilol phosphate of claim 1-2 comprising less than about 20%,
preferably less than about 10%, more preferably less than about 5%, and even more preferably less than about 1% crystalline carvedilol dihydrogen phosphate Form 1 by weight.
4. The amorphous carvedilol phosphate of claim 1-3 characterized by an X-ray powder diffraction pattern substantially as depicted in Figure 1.
5. Pure amorphous carvedilol phosphate free of any crystalline form.
6. A procces for preparing amorphous carvedilol phosphate of any of the preceding claims comprising:

(a) combining carvedilol, phosphoric acid, and ethanol; and
(b) recovering the carvedilol phosphate as a precipitate in amorphous form.

7. The process of claim 6, further comprising adding water to accelerate the precipitation.
8. The process of claim 6-7 where the carvedilol and phosphoric acid in step (a) are present in a molar ratio of about 2.5:1 to about3.5:l.
9. The process of claim 6-8 where the solution in step (a) is heated to about 60°C to about reflux temperature.
10. The process of claim 6-9 wherein the solution is heated to about 7B°C to 82°C and maintained at about 78°C to 82°C for about 5 to about 100 minutes.

11. The process of claim 6-10 where the solution of step (a) is cooled to about 0°C to about 30°C.
12. The process of claim 6-11, wherein the temperature of the solution is cooled to about 20'C to about 23 °C before adding the water.
13. The process of claim 6-12 where, after water is added to the solution, the resulting mixture is stirred at about 20°C to about 23°C for about 4 to about 16 hours.
14. Amorphous carvedilol hydrogen phosphate.
15. The amorphous carvedilol hydrogen phosphate of claim 14 comprising at least one of less than about 20%, preferably less than about 10%, more preferably less than about 5%, and even more preferably less than about 1% crystalline carvedilol or phosphate salt by weight.
16. The amorphous carvedilol hydrogen phosphate of claim 14-15 comprising less than about 20%, preferably less than about 10%, more preferably less than about 5%, and even more preferably less than about 1% crystalline carvedilol dihydrogen phosphate Form I by weight.
17. The amorphous carvedilol hydrogen phosphate of claim 14-16 characterized by an X-ray powder diffiraction pattern substantially as depicted in Figure 10 or Figure 11.
18. A process for preparing amorphous carvedilol hydrogen phosphate of claim 14-17 comprising dissolving carvedilol hydrogen phosphate in C1 -C8 alcohols or m a mixture of C3.7 ketones with water, followed by solvent removal.
19. The process of claim 18 where the solvent is removed by fast evaporation.
20. The process of claim 18-19 where the solvent is removed by spray drying.
21. The process of claim 18-20 where carvedilol hydrogen phosphate is dissolved in acetone and the ratio of acetone/water is about 2:1 (v/v).
22. The process of claim 20-21 where spray drying is carried out with an inlet temperature of about 80°C to about 120°C and an outlet temperature of below about 100°C.
23. The process of claim 20-22 where spray drying is carried out with an inlet temperature of about 95°C to about 105°C and an outlet temperature of below about 40°C.
24. Pure amorphous carvedilol hydrogen phosphate.
25. Essentially amorphous carvedilol dihydrogen phosphate.
26. The essentially amorphous carvedilol dihydrogen phosphate of claim 25 characterized by data selected from the group consisting of;

(a) a solid-state 13C-NMR spectrum having broad chemical shift resonances at about 154-6, 146.7 and 140.3 ± 0.2 ppm; and
(b) a solid-state 13C-NMR spectrum having chemical shift differences between the lowest ppm resonance in the chemical shift area of 100 to 180 ppm and another in the chemical shift area of 100 to 180 ppm of about 54.2, 46.3 and 39.9 ±0.1 ppm; and
(c ) a solid-state 13C-NMR spectrum having broad chemical shift resonances at about 154.6, 146.7,140.3 and 100.4 ± 0.2 ppm.
27- The essentially amorphous carvedilol dihydrogen phosphate of claim 25-26 further characterized by data selected from the group consisting of: a solid-state 13C-NMR spectrum having chemical shift resonances, which are broader than chemical shift resonances of a crystalline material, at about 121.9 and 111.5 ± 0.2 ppm; and a solid-state 13C NMR spectrum having chemical shift differences between the lowest ppm resonance in the chemical shift area of 100 to 180 ppm and another in the chemical shift area of 100 to 180 ppm of about 21.5 and 11.1 ± 0.1 ppm.
28. The essentially amorphous carvedilol dihydrogen phosphate of claim 25-27 comprising at least one of less than about 20%, at least one of less than about 20%, preferably less than about 10%, more preferably less than about 5%, and even more preferably less than about 1% crystalline carvedilol or phosphate salt by wei^t.
29. The essfflatially amorphous carvedilol dihydrogen phosphate of claim 25-28 comprising less than about 20%, preferably less than about 10%, more preferably less than about 5%, and even more preferably less than about 1% crystalline carvedilol dihydrogen phosphate Form I by weight.
30. Pure amorphous carvedilol dihydrogen phosphate.
31. A process for preparing the essentially amoiphous carvedilol dihydrogen phosphate of claim 25-30 comprising dissolving carvedilol dihydrogen phosphate in a solvent selected from the group consisting of Ci-Cg alcohols and mixtures of C3-7 ketones with water, followed by solvent removal.
32. The process of claim 31 where the solvent is removed by fast evaporation.
33. The process of claim 31 -32 where the solvent is removed by drying under a pressure of less than one atmosphere or spray drying.
34. The process of claim 31-33 where carvedilol dihydrogen phosphate is dissolved in acetone and liie ratio of acetone/water is about 2:1 (v/v) and the solvent is removed by sray drying.
35. The process of claim 31-34 where the solvent is removed by spray drying and the sqpray drying is cairial out with an inlet temperature of above about 80°C to about 160°C and an outlet temperature of about 30°C to about 110°C.
36. A crystaliine form carvedilol dihydrogen phosphate (Form N) characterized by data selected fiom the group consisting of:

(a) X-ray powdediffraction reflections at about: 6.0, 6.9,15.2, 16.3 and 17.4 degrees two theta ± 0.2 degrees two theta;
(b) X-ray powder diffiraction reflections at about: 6.0, 6.9, 13.7 15.2 and 18.1 degrees two theta ± 0.2 degrees two theta;
(c) X-ray powdear diffraction reflections at about: 6.0, 6.9, 13.7, 15.2 and 17.4± 0.2 degrees two theta ±0.2 degrees two theta;
(d) a solid-state 13C-NMR spectrum having chemical shift resonances at about 154.4, 146.9,138.4, and 110.9 ± 0.2 ppm;
(e) a solid-state 13C NMR spectrum having chemical shift differences between the lowest ppm resonance in the chemical shift area of 100 to 180 ppm and another in the chemical shift area of 100 to 180 ppm of about 52.9, 45.4,36.9, and 9.4 ±0.1 ppm. it) SL solid-state 13C-NMR spectrum substantially as depicted in Figure 6; and
(g) an X-ray powder diffraction pattern substantially as depicted in Figure 4 or Figure 5.
37. The crystalline form carvedilol dihydrogen phosphate (Form N) of claim 36 characterized by X-ray powder diffraction reflections at about: 6.0, 6.9, 15.2, 16.3 and 17.4 degrees two theta ± 0.2 degrees two theta.
38. The crystalline form carvedilol dihydrogen phosphate (Form N) of claim 36-37 further characterized by X-ray powder diffraction reflections at about 18.1,20.6, 24.6 and 26.3 degrees two-theta, ± 0.2 degrees two-theta.
39. The crystalline form carvedilol dihydrogen phosphate (Form N) of claim 36-38 characterized by a solid-state 13C-NMR spectrum having chemical diift resonances at about 154.4, 146.9 and 138.4 ± 0.2 ppm.
40. The crystalline form carvedilol dihydrogen phosphate (Form N) of claim 36-39 fiirther characterized by a solid-state 13C-NMR spectrum having chemical shift resonances at about 141.3, and 122.0 ± 0.2 ppm.
41. The crtalline form carvedilol dihydrogen phosphate (Form N) of claim 36-40
characterized by a solid-state 13C NMR spectrum having chemical diift differences between the lowest ppm resonance in the chemical shift area of 100 to 180 ppm and another in the chemical shift area of 100 to 180 ppm of about 52.9,45.4 and 36.9 ± 0.1 ppm.
42. The crystalline form carvedilol dihydrogen phosphate (Form N) of claim 36-41 fiirther characterized by a solid-state 13C NMR spectrum having chemical shift differences between the lowest ppm resonance in the chemical shift area of 100 to 180 ppm and another in the chemical shift area of 100 to 180 ppm of about 39.8, and 20.5 ±0-1 ppm.
43. The crj^talline form carvedilol dihydrogen phosphate (Form N) of claim 36-42 characterized by a solid-state 13C NMR spectrum substantially as depicted in Figure 6.
44. The crystalline form carvedilol dihydrogen phosphate (Form N) of claim 36-43 characterized by an X-ray powder diffraction pattern substantially as depicted in Figure 4 or Figure 5.
45. The crystalline form carvedilol dihydrogen phosphate (Form N) of claim 36-44 containing less than about 25%, preferably less than about 10%, more preferably less than about 5%, and even more preferably less than about 1% by weight of amorphous forms of carvedilol and carvedilol phosphate salts or other crystalline forms of carvedilol and carvedilol phosphate salts.
46. The crystalline form carvedilol dihydrogen phosphate (Form N) of claim 36-45 containing less than about 25%, preferably less than about 10%, more preferably less thaa about 5%, and even more preferably less than about 1% by weight of crystalline carvedilol dihydrogen phosphate Form I.
47. A process for preparing the carvedilol dihydrogen phosphate of claim 36-46 comprising exposing carvedilol dihydrogen phosphate Form L, carvedilol dihydrogen phosphate Form LI, or amorphous carvedilol dihydrogen phosphate to relative humidity of greater than about 80%.
48. The process of claim 47 where the carvedilol dihydrogen phosphate Form L, carvedilol dihydrogen phosphate Form LI, or amorphous carvedilol dihydrogen phosphate is exposed to relative humidity of greater than about 80% preferably for at least about 7 days.

49. A process for prqparing the carvedilol dihydrogen phosphate of claim 36-48 comprising dryiag carvedilol dihydrogen phosphate Form O.
50. The process of claim 49 where carvedilol dihydrogen phosphate Form O is heated to a temperature of from about 30°C to about 70°C to obtain carvedilol dihydrogen phosphate Form N.
51. A crystalline form of carvedilol dihydrogen phosphate (Form Fl) characterized by data selected from the group consisting of:
(a) X-ray powder dif&action reflections at about: 7.6, 9.8, 10.9, 21.2 and 25.0 degrees two theta ±0.2 degrees two theta;
(b) any five peaks selected from the following list of PXRD peaks at about: 7.6, 8.5, 9.8,10.9,12.0,13.3, 15.2 and 16.9 ± 0.2 degrees two theta;
(c) X-ray powder diffraction reflections at about: 7.6, 10.9, 13.3, 15.2 and 18.8 degrees two theta ± 0.2 degrees two theta;
d) X-ray powder diffraction reflections at about: 7.6, 8.5, 9.8, 15.2 and 16.9 ± 0.2 degrees two theta;
(e) X-ray powder diffraction reflections at about: 7.6, 9,8, 10.9, 14.7,15.2 and 22.8 ± 0.2 degrees two theta;
(f) X-ray powder diffraction reflections at about: 7.6, 8.5, 9.8, 13.3 and 15.2± 0.2 degrees two theta;
(g) a solid-state 13C-NMR spectrum having chemical shift resonances at about 155.3,
145.3 and 127.7 ± 0.2 ppm;
(h) a solid-state 13C NMR spectrum having chemical shift differences between the
lowest ppm resonance in the chemical shift area of 100 to 180 ppm and another in the
chemical shift area of 100 to 180 ppm of about 52.6, 42.6 and 25 ± 0.1 ppm;
(i) an X-ray powder diffraction pattern substantially as depicted in Figure 27, Figure
28, or Figure 38; and
(j) a solid-state 13C NMR spectrum substantially as depicted in Figure 29, Figure 29a,
or Figure 39.
52. The crystalline form carvedilol dihydrogen phosphate (Form Fl) of claim 51 characterized by X-ray powder diffraction reflections at about: 7.6, 9.8,10.9, 21.2 and 25.0 degrees two theta ± 0.2 degrees two theta.
53. The crystalline fonn carvedilol dihydrogen phosphate (Form Fl) of claim 51-52 characterized by any five peaks selected from the following list of PXRD peaks at about: 7.6, 8.5, 9.8, 10.9, 12.0, 13.3, 15.2 and 16.9 ± 0.2 degrees two theta.
54. The crystalline form carvedilol dihydrogen phosphate (Form Fl) of claim 51-53 characterized by X-ray powder diffraction reflections at about: 7.6, 10.9, 13.3, 15.2 and 18.8 degrees two theta i 0.2 degrees two theta.
55. The crystalline form carvedilol dihydrogen phosphate (Form Fl) of claim 51-54 characterized by X-ray powder diffraction reflections at about: 7.6, 8.5, 9.8, 15.2 and 16.9 ± 0.2 degrees two theta.
56. The crystalline form carvedilol dihydrogen phosphate (Form Fl) of claim 51-55 characterized by X-ray powder diffiraction reflections at about: 7.6, 9.8,10.9, 14.7, 15.2 and 22.8 ± 0.2 degrees two theta.
57. The crystalline form carvedilol dihydrogen phosphate (Form Fl) of claim 51-56 charactaized by X-ray powder diffraction reflections at about: 7.6, 8.5, 9.8, 13.3 and 15.2 ± 0.2 degrees two theta.
58. The crystalline form carvedilol dihydrogen phosphate (Form Fl) of claim 51-57 characterized by a solid-state 13C-NMR spectrum having chemical shift resonances at about 155.3, 145.3 and 127.7 ± 0.2 ppm.
59. The crystalline form carvedilol dihydrogen phosphate (Form Fl) of claim 51-58 characterized by a solid-state 13C NMR spectnmi having chemical shift differences between the lowest ppm resonance in the chemical shift area of 100 to 180 ppm and another in the chemical shift area of 100 to 180 ppm of about 52.6, 42.6 and 25 ±
0.1 ppm.
60. The crystalline form carvedilol dihydrogen phosphate (Form Fl) of claim 51 -59 characterized by an X-ray powder diffraction pattern substantially as depicted in Figure 27, Figure 28, or Figure 38.
61. The crystalline form carvedilol dihydrogen phosphate (Form F1) of claim 51-60 characterized by a solid-state 13C NMR spectrum substantially as depicted in Figure 29, Figure 29a, or Figure 39.
62. The crystalline form carvedilol dihydrogen phosphate (Form Fl) of claim 51-61 containing less than about 25%, preferably less than about 10%, more preferably less than about 5%, and even more preferably less than about 1% by weight of amorphous forms of carvedilol and carvedilol phosphate salts or other crystalline forms of carvedilol and carvedilol phosphate salts.
63. The crystalline form carvedilol dihydrogen phosphate (Form Fl) of claim 51 -62 containing less than about 25%, preferably less than about 10%, more preferably less than about 5%, and even more preferably less than about 1% by weight of crystalline carvedilol dihydrogen phosphate Form I.
64. Crystalline carvedilol dihydrogen phosphate Form Fl of claim 51-63 ethanol solvate.
65. The crystalline carvedilol dihydrogen phosphate Form Fl of claim 64 that is a hemiethanol solvate.
66. A process for preparing carvedilol dihydrogen phosphate of claim 51-65 comprising combining carvedilol dihydrogen phosphate and ethanol to obtain a slurry; and m^ntaning the slurry for at least about 4 hours to obtain the crystal form.
67. The process of claim 66 where carvedilol and phosphoric acid are present in a molar ratio of about 0.8:1 to about 1.2:1.
68. The process of claim 66-67 where absolute ethanol is used.
69. The process of claim 66-68 where the carvedilol, phosphoric acid and ethanol are heated to reflux.
70. The process of claim 66-69 where cooling is used to induce precipitation of the carvedilol dihydrogen phosphate.
71. The process of claim 66-70 where the carvedilol that is combined with ethanol is carvedilol dihydrogen phosphate in any crystalline fomi.
72. The process of claim 66-71 where the carvedilol that is combined with ethanol is carvedilol dihydrogen phosphate Form I or Form R.
73. A crystalline form of carvedilol dihydrogen phosphate (Form F) characterized by data selected from the group consisting of:

(a) X-ray powder diffraction reflections at about: 7.7, 8.7, 16.8 and 22.8 degrees two theta ± 0.2 degrees two theta;
(b) X-ray powder diffraction reflections at about: 7.6, 8.6, 16.7 and 22.8 degrees two theta ± 0.2 degrees two theta;
(c) X-ray powder diffraction reflections at about: 7.7, 8.7,16.8, 22.8 and 26.5 degrees two theta ± 0.2 degrees two theta;
(d) X-ray powder diffraction reflections at about: 7.6, 8.6, 16.7, 22.8 and 26.5 degrees two theta ±0.2 degrees two theta;
(e) X-ray powder diffraction reflections at about: 7.7, 8.7, 13,5, 15,2 and 22.9 degrees two theta ± 0.2 degrees two theta;
(f) X-ray powder diifraction reflections at about: 7.6, 8.6, 13.4, 15.1 and 22.8 degrees two theta ± 0.2 degrees two theta;
(g) X-ray powder diffraction reflections at about: 7.7, 13.5,15,2,18.3 and 18.9 degrees two theta ± 0.2 degrees two theta;
(h) X-ray powder diffiraction reflections at about: 7.6, 13,4, 15.1,18.2 and 18.8 degrees two theta ± 0.2 degrees two theta;
(i) X-ray powder diffraction reflections at about: 7.7,13.5,15.2,17.2 and 21.5 degrees two theta ±0.2 degrees two theta;
(j) X-ray powder diffraction reflections at about: 7.6,13.4, 15.1, 17.1 and 21.4 degrees two theta + 0.2 degrees two theta;
(k) a solid-state 13C-NMR spectrum having chemical shift resonances at about 149.8, 145.4, 140.7, and 138.5 i 0.2 ppm;
(1) a solid-state 13C NMR spectnmi having chemical shifl differences between the lowest ppm resonance in the chemical shift area of 100 to 180 ppm and another in the chendcal shift area of 100 to 180 ppm of about 50.6, 46.2, 41.5, and 39.3 ± 0.1 ppm; (m) an X-ray powder dif&action pattern substantially as depicted in Figure 24 or Figure 25; and
(n) a solid-state 13C NMR spectrum substantially as depicted in Figure 26 or Figure 26a.
74. The crystalline form carvediloi dihydrogen phosphate (Form F) of claim 73 characterized by X-ray powder diffraction reflections at about: 7.7, 8.7,16.8 and 22.8 degrees two theta ± 0.2 degrees two theta.
75. The crystalline form carvediioi dihydrogen phosphate (Form F) of claim 73-74 characterized by X-ray powder diffraction reflections at about; 7.6, 8.6, 16.7 and 22.8 degrees two theta i 0.2 degrees two theta.
76. The crystalline form carvediloi dihydrogen phosphate (Form F) of claim 73-75 characterized by X-ray powder diffraction reflections at about: 7.7, 8.7, 16.8, 22.8 . and 26.5 degrees two theta ± 0.2 degrees two theta.
77. The crystalline form carvedilol dihydrogen phosphate (Form F) of claim 73-76 characterized by X-ray powder diffraction reflections at about: 7.6, 8.6, 16.7, 22.8 and 26.5 degrees two theta ±0.2 degrees two theta.
78. The crystalline foim carvedilol dihydrogen phosphate (Form F) of claim 73-77 characterized by X-ray powder diffraction reflections at about: 7.7, 8.7, 13.5, 15.2 and 22.9 degrees two theta ± 0.2 degrees two theta.
79. The crystalline form carvedilol dihydrogen phosphate (Form F) of claim 73-78 characterized by X-ray powder diffraction reflections at about: 7.6,8.6, 13.4, 15.1 and 22.8 degrees two theta ±0.2 degrees two theta.
80. The crystalline form carvedilol dihydrogen phosphate (Form F) of claim 73-79 characterized by X-ray powder diffraction reflections at about: 7.7, 13.5,15.2, 18.3 and 18.9 degrees two theta ± 0.2 degrees two theta.
81. The crystalline form carvedilol dihydrogen phosphate (Form F) of claim 73-80 characterized by X-ray powder diffraction reflections at about: 7.6, 13.4,15.1,18.2 and 18.8 degrees two theta ±0.2 degrees two theta.

82. The crystalline form carvedilol dihydrogen phosphate (Form F) of claim 73-81characterized by X-raypowder diffraction reflections at about: 7.7, 13.5, 15.2, 17.2 and 21.5 degrees two theta ± 0.2 degrees two theta.
83. The crystalline form carvedilol dihydrogen phosphate (Form F) of claim 73-82characterized by X-ray powder diffraction reflections at about: 7.6,13.4, 15.1, 17.1 and 21.4 degrees two theta ± 0.2 degrees two theta.
84. The crystalline form carvedilol dihydrogen phosphate (Form F) of claim 73-83 characterized by a solid-state 13C-NMR spectrum having chemical shift resonances at about 149.8, 145.4 and 140.7 ± 0.2 ppm.
85. The crystalline form carvedilol dihydrogen phosphate (Form F) of claim 73-84 fiirthar characterized by a solid-state 13C-NMR spectrum having chemical shift resonances at about 146.7, 138.5 and 111.8 ± 0.2 ppm.
86. The crystalline form carvediloi dihydrogen phosphate (Form F) of claim 73-85 characterized by a solid-state 13C NMR spectrum having chemical shift differences between the lowest ppm resonance in the chemical shift area of 100 to 180 ppm and another in the chemical shift area of 100 to 180 ppm of about 50.6,46.2 and 41.5 ± 0.1 ppm.
87. The crystalhne form carvediloi dihydrogen phosphate (Form F) of claim 73-86 fijriher characterized by a solid-state 13C NMR spectrum having chemical shift differences between the lowest ppm resonance in the chemical shift area of 100 to 180 ppm and another in the chemical shift area of 100 to 180 ppm of 47.5,39,3 and 12.6 ±0.1 ppm.
88. The crystalline form carvediloi dihydrogen phosphate (Form F) of claim 73-87 characterized by an X-ray powder diffraction pattern substantially as depicted in Figure 24 or Figure 25.
89. The crystalline form carvediloi dihydrogen phosphate (Form F) of claim 7'3-8S characterized by a solid-state 13C NMR spectrum substantially as depicted in Figure 26 or Figure 26a.
90. The crystalline form carvediloi dihydrogen phosphate (Form F) of claim 73-89 containing less than about 25%, preferably less than about 10%, more preferably less than about 5%, and even more preferably less than about 1 % by weight of amorphous forms of carvediloi and carvediloi phosphate salts or other crystalline forms of carvediloi and carvediloi phosphate salts.
91. The crystalline form carvediloi dihydrogen phosphate (Form F) of claim 73-90 containing less than about 25%, preferably less than about 10%, more preferably less than about 5%, and even more preferably less than about 1% by weight of crystalline carvediloi dihydrogen phosphate Form I.
92. A process for pr^aring carvediloi dihydrogen phosphate of claim 73-91 comprising combining carvediloi, phosphoric acid and methanol to obtain a solution and crystallizing carvediloi dihydrogen phosphate from the solution.
93. The process of claim 92 where carvedilol and phosphoric acid are present in a molar ratio of about 0.8.1 to about 1.2:1.
94. The process of claim 92-93 where carvedilol, phosphoric acid and methanol are heated to reflux.
95. The process of claim 92-94 wherein the methanol contains less than 2% water by
volume.
96. The process of claim 92-95 where crystallization is carried out for about 5 minutes to about 300 minutes.
97. A crystalline form carvedilol dihydrogen phosphate (Form R) characsterized by data selected from the group consisting of:

(a) X-ray powder diffraction reflections at about: 5.8, 11.8, 16.8, 18.6 and 23.2 degrees two theta ± 0.2 degrees two theta;
(b) X-ray powder diffraction reflections at about: 5.8, 11.8, 15.5, 16.2 and 18.6 degrees two theta ± 0.2 degrees two theta;
(c) X-ray powder diffraction reflections at about: 5.8, 16.2, 18.6,23.2 and 27.0 degrees two ttieta ± 0.2 degrees two theta;
(d) X-ray powder diffraction reflections at about: 5.8, 16.2, 16.8, 19.9 and 25.4 degrees two theta ± 0.2 degrees two theta;
(e) a solid-state 13C-NMIR spectrum having chemical shift resonances at about 153.7, 147.9 and 122.8 ± 0.2 ppm;
(f) a solid-state 13C NMR spectrum having chemical shift differences between the lowest ppm resonance in the chemical shift area of 100 to 180 ppm and another in the chemical shift area of 100 to 180 ppm of about 51.0, 45.2 and 20.1 ±0.1 ppm;
(g) an X-ray powder diffraction pattem substantially as depicted in Figure 30; and (h) a solid-state 13C NMR spectrum substantially as depicted in Figure 31, Figure 31a, or Figure 40.
98. The crystalline form carvedilol dihydrogen phosphate (Form R) of claim 97
charactraized by X-ray powdei- diffraction reflections at about: 5.8, 11.8, 16.8, 18.6
and 23.2 degrees two theta ± 0.2 degrees two theta.
99. The crystalline form carvedilol dihydrogen phosphate (Form R) of claim 97-98 characterized by X-ray powder diffraction reflections at about: 5.8,11.8, 15.5, 16.2 and 18.6 degrees two theta ± 0.2 degrees two theta.
100. The crystalline form carvedilol dihydrogen phosphate (Form R) of claim 97-99 characterized by X-ray pwjwder difBraction reflections at about: 5.8,16.2, 18.6, 23.2 and 27.0 degrees two theta ± 0.2 degrees two theta.
101. The crystalline form carvedilol dihydrogen phosphate (Form R) of claim 97-100 characterized by X-ray powder diffraction reflections at about: 5.8,16.2,16.8,19.9 and 25.4 degrees two theta ±0.2 degrees two theta.

102. The crystalline form carvedilol dihydrogen phosphate (Form R) of claim 97-101 characterized by a solid-state 13C-NMR spectrum having chemical shift resonances at about 153.7,147.9 and 122,8 ± 0.2 ppm.
103. The crystalline form carvedilol dihydrogen phosphate (Form R) of claim 97-102 characterized by a solid-state 13C NMR spectrum having chemical shift differences between the lowest ppm resonance in the chemical shift area of 100 to 180 ppm and another in the chemical shift area of 100 to 180 ppm of about 51.0,45.2 and 20.1 ± 0.1 ppm.
104. The crystalline form carvedilol dihydrogen phosphate (Form R) of claim 97-103 characterized by an X-ray powder diffraction pattern substantially as depicted in Figure 30.
105. The crystalline form carvedilol dihydrogen phosphate (Form R) of claim 97-104 characterized by a solid-state 13C NMR spectrum substantially as depicted in Figure 31. Figure 3la, or Figure 40.
106. The crystalline ft)rm carvedilol dihydrogen pho^hate (Form R) of claim 97-105 containing less than about 25%, preferably less than about 10%, more preferably less than about 5%, and even more preferably less than about 1% by weight of amorphous forms of carvedilol and carvedilol phosphate salts or other crystalline forms of carvedilol and carvedilol phosphate salts.
107. The crystalline form carvedilol dihydrogea phosphate (Form R) of claim 97-106 containing less than about 25%, preferably less than about 10%, more preferably less than about 5%, and even more preferably less than about 1% by weight of crystalline carvedilol dihydrogen phosphate Form I.
108. Crystalline carvedilol dihydrogen phosphate Form R isopropanol solvate.
109. Pure Crystalline carvedilol dihydrogen phosphate Form R.
110. A process for preparing carvedilol dihydrogen phosphate of claim 97-109 comprising combining carvedilol, phosphoric acid and isopropyl alcohol to obtain a slurry, and maintaining the slurry at a temperature below the reflux temperature to obtain the crystalline form..
111. The process of claim 110 where carvedilol and phosphoric acid are present in a molar ratio of about 0.8:1 to about 1.2:1.
112. The process of claim 110-111 where the slurry of carvedilol, phosphoric acid and isopropyl alcohol is heated to a temperature of from about room temperature to about 50°C.
113. A process for preparing crystalline carvedilol dihydrogen phosphate of claim 97-
109 comprising slurrying amorphous carvedilol dihydrogen phosphate or carvedilol dihydrogen phosphate Form Fl or Form N in isopropyl alcohol.
114. The procMS of claim 113 where the slurry is maintained, while stirring, at a temperature of about 20°C to about 35°C for about 12 hours to about 24 hours.
115. A crystalline form carvedilol hydrogen phosphate (Form G) characterized by data selected from the group consisting of:

(a) X-ray powder diffraction reflections at about: 6.5, 9.7, 13.0, 16.0 and 17.8 degrees two theta ± 0.2 degrees two theta;
(b) any five peaks selected from the following list of PXRD peaks at about: 6.5, 9.7, 13.0, 13.5, 16.0, 17.8, 22.8 and 23.2 ± 0.2 degrees two theta;
(c) X-ray powder difEraction reflections at about: 6.5, 9.7, 13,5, 16.0 and 17,8 degrees two theta ± 0.2 degrees two theta;
(d) X-ray powder difjfraction reflections at about: 6.5, 9.7, 16.0,18.4 and 23.2 degrees two theta ± 0.2 degrees two theta;
(e) a solid-state 13C-NMR spectrum having chemical shift resonances at about 145.8, 141.7 and 110.8± 0.2 ppm;
(f) a solid-state 13C NMR spectrum having chemical shift differences between the lowest ppm resonance in the chemical shift area of 100 to 180 ppm and another in the chemical shift area of 100 to 180 ppm of about 43.8, 39.7 and 8.8 =b 0.1 ppm;
(g) an X-ray powdca: diffraction pattern substantially as depicted in Figure 2; (h) a solid-state 13C-NMR spectrum substantially as depicted in Figure 3; and
(i) any five X-ray powder difiBraction reflections selected from the following list: 6.5, 9.7, 13.0,13.5,16.0, 17.8,22.8 and 23.2 ± 0,2 degrees two theta.
116. The crystalline form carvedilol hydrogen phosphate (Form G) of claim 115 characterized by X-ray powder diffraction reflections at about: 6.5,9.7,13.0, 16.0 and 17.8 degrees two theta ± 0.2 degrees two theta.
117. The crystalline form carvedilol hydrogen phosphate (Form G) of claim 115-116 characterized by any five peaks selected from the following list of PXRD peaks at about: 6.5, 9.7, 13.0,13.5, 16.0, 17.8, 22.8 and 23.2 ± 0.2 degrees two theta.
118. The crystalline form carvedilol hydrogen phosphate (Form G) of claim 115-117 characterized by X-ray powder diffraction reflections at about: 6.5, 9.7, 13.5,16.0 and 17.8 degrees two theta db 0.2 degrees two theta.
119. The crystalline form carvedilol hydrogen phosphate (Form G) of claim 115-118 characterized by X-ray powder diffraction reflections at about: 6.5,9.7, 16.0,18.4 and 23.2 degrees two theta ±0.2 degrees two theta.
120. The crystalline form carvedilol hydrogen phosphate (Form G) of claim 115-119 characterized by a solid-state 13C-NMR spectrum having chemical shift resonances at about 145,8, 141.7 and 110.8 ±0.2 ppm.
121. The crj^talline form carvedilol hydrogen phosphate (Form G) of claim 115-120 characterized by a solid-state 13C NMR spectrum having chemical shift differences between flae lowest ppm resonance in the chemical shift area of 100 to 180 ppm and
another in the chemical shift area of 100 to 180 ppm of about 43.8, 39.7 and 8.8 ±
0.1 ppm.
122. The crystalline form Carvedilol hydrogen phosphate (Form G) of claim: 115-121 characterized by an X-ray powder diffraction pattem sixbstantially as depicted in Figure 2.
123. The crystalline form carvedilol hydrogen phosphate (Form G) of claim 115-122 characterized by a solid-state 13C NMR spectrum substantially as depicted in Figure
3.
124. The crystalline form carvedilol hydrogen phosphate (Fomi G) of claim 115-123 characterized by any five X-ray powder diffraction reflections selected firom the foUowing list: 6.5,9.7, 13.0, 13.5, 16.0,17.8,22.8 and 23.2 ± 0.2 degrees two theta.
125. The crystaUine form carvedilol hydrogen phosphate (Form G) of claim 115-124 containing less than about 25%, preferably less than about 10%, more preferably less tihan about 5%, and even more preferably less than about 1% by weight of amorphous forms of carvedilol and carvedilol phosphate salts or oths- crystalline forms of carvedilol and carvedilol phosphate salts.
126. The cr>^talline form carvedilol hydrogen phosphate (Form G) of claim 115-125 containing less than about 25%, preferably less than about 10%, more preferably less than about 5%, amd evsn more preferably less than about 1% by weight of crystalline carvedilol dihydrogen phosphate Form I.
127. A process for preparing carvedilol hydrogen phosphate of claim 115-126 comprising:

(a) combining carvedilol, phosphoric acid, and methanol to obtain a solution;
(b) combuiing the jwjlution with water; and
(c) recovering carvedilol hydrogen phosphate Form G;
where the molar ratio of phosphoric acid to carvedilol in step (a) is about 0.8:1 to about 2.5:1 .
128. A process for preparing carvedilol hydrogen phosphate of claim 115-126
comprising:
(a) combining carvedilol, phosphoric acid, and acetone/water to obtain a mixture;
(b) maintaining the mixture to obtain a solid; and
(c) recovering carvedilol hydrogen phosphate;
where the molar ratio of phosphoric acid to carvedilol in step (a) is about 0.8:1 to about 2.5:1 .
129. A process for pr^aring carvedilol hydrogen phosphate of claim 115-126
comprising:
(a) providing a suspension of amorphous carvedilol dihydrogcn phosphate in phosphoric acid and water at a pH of about 3.5-7;
(b) maintaining the mixture for at least 15 hours; and
(c) recovering the phosphate salt of carvedilol.

130. A process for preparing carvedilol hydrogen phosphate of claim 115-126 comprising slurrying carvedilol dihydrogen phosphate Form R or carvedilol dihydrogen phosphate Form Fl or Form I in water.
131. A crystalline form carvedilol hydrogen phosphate (Form H) characterized by data selected from the group consisting of:

(a) X-ray powder diffraction reflections at about: 6.4, 6.6, 9.4, 14.5 and 15.4 degrees two thetadb 0.2 degrees two theta;
(b) X-ray powder diffraction reflections at about: 6.6, 9.7, 13.0, 13.8 and 15.6 degrees two theta ± 0.2 degrees two theta;
(c) X-ray powder diffraction reflections at about: 6.5, 9.6, 13.0, 13.6 and 18.7 degrees two theta ± 0.2 degrees two theta;
(d) X-ray powder diffraction reflections at about: 6.5, 9.6, 13.6, 18.7 and 20.2 degrees two theta ± 0.2 degrees two theta;
(e) any five X-ray powder diffiaction reflections selected from the following list of at about: 6.5, 6.8, 9.6,13.0, 13.6,15.6,17.5 and 28.7 ± 0.2 degrees two theta;
(f) a solid-state 13C-NMR spectrum having chemical shift resonances at about 146.3, 142.6 and 139.1 + 0.2 ppm;
(g) a solid-state 13C NMR spectrum having chemical shift differences between the lowest ppm resonance in the chemical shift area of 100 to 180 ppm and another in the chemical shift area of 100 to 180 ppm of about 34, 30.3 and 26.8 ± 0.1 ppm;
(h) an X-ray powder diffi-action pattern substantially as depicted in Figure 4 or Figure
5; and
(i) a solid-state 13C-NMR spectrum substantially as depicted in Figure 6.
132. The crystalline form carvedilol hydrogen phosphate (Form H) of claim 131 characterized by X-ray powder diffraction reflections at about: 6.4, 6.6, 9.4, 14.5 and 15.4 degrees two theta ± 0.2 degrees two theta.
133. The crystalline form carvedilol hydrogen phosphate (Form H) of claim 131-132 fiirther characterized by X-ray powder diffraction reflections at about 18.4, 19.3, 20.4, 22.4 and 25.3 degrees two-theta, ± 0.2 degrees two-theta.
134. The crystalline form carvedilol hydrogen phosphate (Form H) of cteim 131-133 fttrther characterized by X-ray powder diffraction reflections at about 18.6, 19.5, 20.6, 22.6 and 25.0 degrees two-theta, ± 0.2 degrees two-theta.
135. The crystalline form carvedilol hydrogen phosphate (Form H) of claim 131-134 characterizedby X-ray powder dif&action reflections at about: 6.6, 9.7, 13.0,13.8 and 15.6 degrees two theta ± 0.2 degrees two theta.
136. The crystalline form carvedilol hydrogen phosphate (Form H) of claim 131-135 fiariher characterized by X-ray powder diffraction reflections at about 18.4, 19.3, 20.4, 22.4 and 25.3 degrees two-theta, ± 0.2 degrees two-theta.
137. The crystalline form carvedilol hydrogen phosphate (Form H) of claim 131-136 fiirther characterized by X-ray powder diffraction reflections at about 18.6, 19.5, 20.6, 22.6 and 25.0 degrees two-theta, ± 0.2 degrees two-theta.
138. The crystalline form carvedilol hydrogen phosphate (Form H) of claim 131-137 characterized by X-ray powder diffraction reflections at about: 6.5, 9.6, 13.0, 13.6 and 18.7 degrees two theta ± 0.2 degrees two theta.
139. The crystalline form carvedilol hydro gen phosphate (Form H) of claim 131-138 characterized by X-ray powder difiraction reflections at about: 6.5, 9.6, 13.6,18.7 and 20.2 degrees two theta ± 0.2 degrees two theta.
140. The crystalline form carvedilol hydrogen phosphate (Form H) of claim 131-139 characterized by any five X-ray powder diffraction reflections selected from the following hst of al about: 6.5, 6.8, 9.6, 13.0, 13.6,15.6,17.5 and 28.7 rf 0.2 degrees two theta.
141. The crj^talline form carvedilol hydro gen phosphate (Form H) of claim 131 -140 characterized by a solid-state 13C-NMR spectrum having chemical shift resonances at about 146.3,142.6 and 139.1 ± 0.2 ppm.
142. The crystalline form carvedilol hydrogen phosphate (Form H) of claim 130-141 further characterized by a solid-state 13C-NMR spectrum having chemical shift resonances at about 155.3, 122.2 and 112.3 ± 0.2 ppm.
143. The crystalline form carvedilol hydrogen phosphate (Form H) of claim 131-142 characterized by a solid-state 13C NMR spectrum having chemical shift differences between the lowest ppm resonance in the chemical shift area of 100 to 180 ppm and another in the chemical shift area of 100 to 180 ppm of about 34, 30.3 and 26.8 ± 0.1 ppm.
144. The crystalline form carvedilol hydrogen phosphate (Form H) of claim 131-143 characterized by a solid-state 13C NMR spectrum having chemical shift differences between the lowest ppm resonance in the chemical shift area of 100 to 180 ppm and another in the chemical shift area of 100 to 180 ppm of about 43, 9.9 and 0 ± 0.1 ppm.
145. The crystalline form carv edilol hydro gen phosphate (Form H) of claim 131 -144 charactCTized by an X-ray powder diffraction pattern substantially as depicted in Figure 4 or Figure 5.
146. The crystalline form carvedilol hydrogen phosphate (Form H) of claim 131-145
characterized by a sohd-state 13C-NMR spectnun substantially as dq)icted in Figure
6.
147. The crystalline form carvedilol hydrogen phosphate (Form H) of claim 131 -146 containing less than about 25%, preferably less than about 10%, more preferably less than about 5%, and even more preferably less than about 1 % by weight of amorphous fonns of carvedilol and carvedilol phosphate salts or other crystalline forms of carvedilol and carvedilol phosphate salts.
148. The crystalline form carvedilol hydrogen phosphate (Form H) of claim 131 -147 containing less than about 25%, preferably less than about 10%, more preferably less than about 5%, and even more preferably less than about 1% by weight of crystalline carvedilol dihydrogen phosphate Form I.
149. A process for pr^aring carvedilol hydrogen phosphate of claim 131-148 comprising:

(a) combining carvedilol, phosphoric acid, and ethanol/water to obtain a mixture;
(b) maintaining the mixture for at least about 6 hours; and
(c) recovering carvedilol hydrogen phosphate Form H.

150. The process of claim 149 where the carvedilol and phosphoric acid in step (a) arc combined in a molar ratio of about 2.5:1 to about 0.8:1.
151. The process of claim 149-150 where the mixture of step (a) is heated and then cooled to about ICC to about 35°C prior to step (b).
152. A crystalline form carvedilol hydrogen phosphate (Form K) characterized by data selected from the group consisting of:

(a) X-ray powder diffraction reflections at about: 6.3, 9.8,12.7, 13.2 and 16.9 degrees two theta ± 0.2 degrees two theta;
(b) X-ray powder diffraction reflections at about: 6.3, 9.8, 16.9, 18 3 and 23.2) degrees two theta ± 0.2 degrees two theta,
(c) X-ray powder diffimction reflections at about: 6.3, 9.8, 14.9,20.1 and 28.2 degrees two theta ± 0.2 degrees two theta;
(d) any five X-ray powder diffraction reflections selected from the following list at about: 6.3, 9.8,12.7,13.2,16.3, 16.9, 18.3 and 19.0 =k 0.2 degrees two theta;
(e) an X-ray powder diffiaction pattern substantially as depicted in Figure 7; and
(f) a solid-state 13C-NMR spectmm substantially as depicted in Figure 8.
153. A crystalline form carvedilol hydrogen phosphate (Form Q) characterized by data
selected from the group consisting of:
(a) X-ray powder diffraction reflections at about: 6.2, 7.3,14.5, 17.5 and 21.3 degrees two theta ± 0.2 degrees two theta; and
(b) an X-ray powder diffraction pattern substantially as depicted in Figure 9 or Figvsre 41.
154. A crystalline form carvedilol dihydrogen phosphate (Form L) characterized by data
selected from the group consisting of:
(a) X-ray powder diffraction reflections at about: 4,6, 7.5,8.7,11.6 and 15.6 degrees two theta ± 0,2 degrees two theta;
(b) X-ray powder diffraction reflections at about: 4.6, 7.5, 8.7, 11.6 and 15,0 degrees two theta ± 0.2 degrees two theta;
(c) X-ray powder diffraction reflections at about: 4.6, 7.5, 8.7, 15.0 and 22.9 degrees two theta ± 0.2 degrees two theta;
(d) any five X-ray powder diffraction reflections selected from the following list of at about: 4.6, 7.5, 8.7, 11.6 13.4, 1 5.6 and 19.4 ± 0.2 degrees two theta;
(e) a solid-state ^^C-NMR spectrum having chemical shift resonances at about 156.6, 150.3 and 102.5 ± 0.2 ppm;
(f) a sohd-state ^'C NMR spectrum having chemical shift differences between the lowest ppm resonance in the chemical shift area of 100 to 180 ppm and another in the chemical shift area of 100 to 180 ppm of about 54.1 and 47.8 ± 0.1 ppm;
(g) an X-ray powder diffraction pattern substantially as depicted in Figure 14; and (h) a solid-state 13C-NMR spectrum substantially as depicted in Figure 15 or Figure 15a.
155. A crystalline form carvedilol dihydrogen phosphate (Form LI) characterized by
data selected from the group consisting of;
(a) X-ray powder diffraction reflections at about: 4.6, 8.7, 11.6, 14.6 and 15.3 degrees two theta* 0.2 degrees two theta;
(b) X-ray powder diffraction reflections at about: 4.6, 7.4, 8.7, 11.6 14.6,15.3 and 19.4 ± 0.2 degrees two theta ± 0.2 degrees two theta;
(c) X-ray powder diffraction reflections at about: 4.6, 7.4, 8.7, 13.6 and 15.3 degrees two theta ±0.2 degrees two theta;
(d) X-ray powder dif&action reflections at about: 4.6, 7.4, 8.7, 11.6 and 17.4 degrees two theta ± 0.2 degrees two theta;
(e) X-ray powder diffraction reflections at about: 4.6, 7.4, 8.7, 15.3 and 17.4 degrees two theta ±0.2 degrees two theta;
(f) a solid-state 13C-NMR spectrum having chemical shift resonances at about 156.6, 130.3 and 148.4 ± 0.2 ppm;
(g) a solid-state 13C NMR spectrum having chemical shift differences between the lowest ppm resonance in the chemical shift area of 100 to 180 ppm and another in the chemical shift area of 100 to 180 ppm of about 53.2, 46.9 and 45.0 ± 0.1 ppm;
(h) an X-ray powder diffraction pattern substantially as depicted in Figure 16; and (i) a solid-state 13C-NMR spectrum substantially as depicted in Figure 17 or Figure 17a.
156. A crystalline form carvedilol dihydrogen phosphate (Form O) characterized by data
selected from the group consisting of:
(a) X-ray powder dif&action reflections at about: 6.1, 12.2, 12.9, 16.2 and 18.0
degrees two theta ± 0.2 degrees two theta; and
(e) an X-ray powder diffraction pattern substantially as depicted in Figure 21.
157. A crystalline form carvedilol dihydrogen phosphate (Form P) characterized by data
selected from the group consisting of:
(a) X-ray powder dif&action reflections at about: 5.3,10.4, 16.8, 26.0 and 31.8 aegrees two theta ± 0.2 degrees two theta;
(b) X-ray powder dif&action reflections at about: 5.3, 10.4, 15.2, 17.8 and 22.5 degrees two theta ± 0.2 degrees two theta;
(c) X-ray powder diffiraction reflections at about: 5.3, 14.5,15.2, 16.8 and 17.3 degrees two theta ± 0.2 degrees two theta;
(d) X-ray powder dif&action reflections at about: 5.3,10.4,14.5,15.2 and 17.8 degrees two theta ± 0.2 degrees two theta;
(e) X-ray powder diffraction reflections at about: 5.3, 14.5, 15.2, 17.8 and 20.1 degrees two theta ±0.2 degrees two theta;
(f) any five X-ray powder diffraction reflections selected from the following list at about: 5.3, 10.4, 14.5, 16.8, 17.8, 26.0 and 31.8 ± 0.2 degrees two theta;
(g) a solid-state 13C-1>JMR spectrmn having chemical shift resonances at about 154.7, 146.6 and 122.2 ±0.2 ppm;
(h) a solid-state 13C NMR spectrum having chemical shift differences between the lowest ppm resonance in the chemical shift area of 100 to 180 ppm and another in the chemical shift area of 100 to 180 ppm of about 54.7, 46.6 and 22.2 ± 0.1 opm; (i) an X-xay powder dif&action pattern substantially as depicted in Figure 22; and (j) a solid-state 13C-NMR spectrum substantially as depicted in Figure 23 or Figure 23a.
158. A crystalline fonn carvedilol dihydrogen phosphate (Form Y) characterized by data
selected from the group consisting of
(a) X-raypowder diffraction reflections at about: 7.7, 7.9, 9.1, 16.6 and 19,5 degrees two theta ± 0.2 degrees two theta;
(b) X-ray powder diffraction reflections at about:7.7, 8.5, 16.6, 19.5 and 20.3 degrees two theta; and
(c) an X-ray powder dif&action pattern substantially as depicted in Figure 32.
159. A crystalline form carvedilol dihydrogen phosphate (Form W) characterized by data
selected from the group consisting of;
(a) X-ray powder diffraction reflections at about: 6.6, 9.7, 13.8, 15.7 and 17.1 degrees two theta ± 0.2 degrees two theta; and
(b) an X-ray powder diffraction pattern substantially as depicted in Figure 33

160. Crystalline carvedilol etbanol solvate.
161. Crystalline carvedilol hemiethanol solvate.
162. A pharmaceutical composition comprising the crystalline or amorphous form of any of the preceding product claims, including any of the claims to F2 below, and at least one pharmaceutically acceptable excipient.
163. Us of the composition of claim 162 for manufacture of a medicament in treatment of congestive heart failure or management..
164. A process for preparing crystalline carvedilol dihydrogen phosphate Form I, characterized by data selected from the group consisting of: X-ray powder diffraction reflections at about: 7.0, 8.0, 9.2,11.4 and 16.0 degrees two theta ± 0.2 degrees two theta; a solid-state 13C-NMR spectrum having chemical shift resonances at about 154.5,146.5, 139.7 and 122.1 ± 0.2 ppm; and a solid-state °C NMR spectrum having chemical shift differences between the lowest ppm resonance in the chemical shift area of 100 to 180 ppm and another in the chemical shift area of 100 to 180 ppm of about 50.7, 42.7 and 18.3 ±0.1 ppm, comprising: combining carvedilol, phosphoric acid and a solvent selected from the group consisting of C4-C8 alcohols, n-propanol, C5-C10 ahphatic hydrocarbons, C6-12 aromatic hydrocarbons, C3-C7 ketones C4-C8 ethers, C3-C7 esters, water and acetonitriie and precipitating carvedilol dihydrogen phosphate Form I from the reaction mixture.
165. The process of claim 164, wherein the solvent is selected from the group consisting of: n-propanol, butanol, 2-butanol, n-butanol, tert-butancl, heptane, methyl isobutyl ketone (MIBK),-methyl ethyl ketone (MEK), propylene glycol monomethyl ether (PGME), THF, methyl tert-butyl ether (MTBE), methyl acetate, isobutyl acetate, ethyl acetate and acetonitriie and mixtures thereof.
166. The process of claim 165, wherein the solvent is THF.
167. A process for preparing crystalline carvedilol dihydrogen phosphate Form I, characterized by data selected from the group consisting of: X-ray powder diffraction reflections at about: 7.0, 8.0, 9.2, 11.4 and 16.0 degrees two theta ± 0.2 degrees two theta; a solid-state 13C-NMR spectrum having chemical shift resonances at about 154.5, 146.5, 139,7 and 127.1 + 0.2 ppm; and a soiid-staie 13C NMR spectrum having chemical shift differences between the lowest ppm resonance in the chemical shift area of 100 to 180 ppm and another in the chemical
shift area of 100 to 180 ppm of about 50.7, 42.7 and 18.3 ± 0.1 ppm, comprising slixrrying carvedilol dihydrogen phosphate Form R in ethanol.
168. Crystalline carvedilol dihydrogen phosphate isopropanol solvate.
169. A crystalline form carvedilol dihydrogen phosphate (Form F2) characterized by data
selected from the group consisting of:
(a) X-ray powder diffraction reflections at about: 7.4, 7.9, 8.5, 8.9 and 11.1 ± 0.2
degrees two theta; and
(b ) a calculated X-ray powder diffraction pattern substantially as depicted in Figure 35.
170. The crystalline form carvedilol dihydrogen phosphate (Form F2) of claim 169 characterized by X-ray powder diffraction reflections at about: 7.4, 7.9, 8.5, 8.9 and 11.1 ± 0.2 degrees two theta.
171. The crystalline form carvedilol dihydrogen phosphate (Form F2) of claim 169-170 characterized by a calculated X-ray powder diffraction pattern substantially as depicted in Figure 35.
172. The crystalline form carvedilol dihydrogen phosphate (Form F2) of claim 168-171 that is a hemiethanolate.
173. A process for preparing carvedilol dihydrogen phosphate (Form F2) of claim 168-172 comprising:
174. (a) dissolving carvedilol dihydrogen phosphate in ethanol to form a solution at a
temperature of about 25°C to about reflxix temperature;
(b) cooling the solution; and
(c ) recovering carvedilol dihydrogen phosphate Form F2.
175. The process of claim 174 where the temperature of step (a) is about 70°C.
176. The process of claim 174-175 where the carvedilol dihydrogen phosphate of stqj (a) is carvedilol dihydrogen phosphate Fomi I.
177. The process of claim 174-176 where cooling is carried out in about one to about 10 days.
178. The process of claim 174-177 where coollng is carried out to a temperature of about 10°C to about 30°C
179. A process for preparing carvedilol hydrogen phosphate (Form K) of any one of the above claims characterizing Form K comprising exposing carvedilol hydrogen phosphate Form H to more than about 80% relative humidity preferably for at least about 7 days.
180. A process for preparing carvedilol hydrogen phosphate (Form K) of of any one of the above claims characterizing Form K comprising combining carvedilol with more than about 50ml of acetone/water, preferably (3:1), and adding phosphoric acid, preferably about 85% concentration.
181. A process for prejjaring carvedilol hydro gen phosphate (Form Q) of of any one of the above claims characterizing Form Q comprising exposing Form K to a relative humidity of less than about 20% for about 1 day to about 10 days.
182. A process for preparing carvedilol dihydrogen phosphate (Form L) of of any one of the above claims characterizing Form L comprising:

(a) combining carvedilol, phosphoric acid and dioxane to form a reaction mixture; and
(b) precipitating carvedilol dihydrogen phosphate Form L from the itsaction mixture.

183. A process for preparing carvedilol dihydrogen phosphate (Form LI) of any one of the above claims characterizing Form Ll comprising slurrying at least about 30 g carvedilol dihydrogen phosphate in at least about 300 ml dioxane.
184. A process for preparing carvedilol dihydrogen phosphate (Form P) of any one of the above claims characterizing Form P comprising slurrying amorphous carvedilol dihydrogen phosphate in ethanol.
185. A process for preparing carvedilol dihydrogen phosphate (Form' Y) of any one of the above claims characterizing Form Y comprising:
(a) combining carvedilol, phosphoric acid and ethanol to obtain a slurry;
(b) maintaining the slurry for about 2 to 3 hours to obtain the crytal form.
186. A process for preparing carvedilol dihydrogen phosphate (Form W) of any one of the above claims characterizing Form W comprising:
(a) adding carvedilol dihydrogen phosphate Form Fl to a solution of KH2PO4;
(b) adding a base to the solution to obtain a suspension;
(c) stirring the suspension at preferably room temperahire for about 12 hours to about 2 days; and
(d) recovering carvedilol dihydiogen phosphate Form W.
186. A process for preapring Form I comprising exposing Form F to about 100% hmnidity
at elevated temperature
187. A process for preapring Form I comprising slurrying carvedilol dihydrogen phosphate Form R in ethanol,
188. A process for preapring Form I comprising heating Form N, L1, amorphous carvedilol hydrogen sulfate or Form P.
189. A process for preapring Form I comprising slurrying Form Fl, amorphous carvedilol dihydrogen phophate. Form R, or Form N in acetone.
190. A process for preapring Form I comprising grinding Forms F and P.
191. A process for preapring Form I comprising placing amoiphous carvedilol dihydrogen phosphate in an atmosphere of n-propanol, iso-propanol, butanol, acetone and ethyl acetate.
192. A process for preapring Form I comprising slurryiag Form N in water.