POLYMORPHIC FORMS OF ZIPRASIDONE HOI AND PROCESSES FOR
THEIR PREPARATION
Cross Reference To Related Applications;
This application claims the benefit of U.S. provisional application Serial No. 60/475,806, filed June 3, 2003; U.S. provisional application Serial No, 60/487,913, filed July 16, 2003; U.S. provisional application Serial No. 60/494,970, filed August 13, 2003; U.S. provisional application Serial No. 60/528,346. filed December 9, 2003, and U.S. provisional application Serial No. 60/571,997, filed May 17, 2004, the contents of all of which are incorporated herein.
Field of the Invention:
The present invention relates to the solid state chemistry of ziprasidone JiCl.
Background of the Invention;
Ziprasidone is an antipsychotic agent that is chemically unrelated to phenothiazine or butyrophonone antipsychotic agents. Ziprasidone has the following structure:
(Structure Removed)
The preparation of ziprasidone base is disclosed in U.S. patent No. 4,831,031 (example 16). Preparation of ziprasidone base is also disclosed in U.S. patent No. 5,312,925, A process for preparation of ziprasidone HC1 monohydrate having a mean particle size equal to or less than about 85 microns is also disclosed in U.S. Pat. No. 6,150,366 and BP 0965 343 A2.
Ziprasidone has been marketed under the name GEODON as an oral capsule and as an injectable drug. GEODON capsules contain the monohydrate hydrochloride salt of
' ziprasidone, and come in'20,40,60 and 80mg dosage forms. GEODON for injection contains a lyophilized form of ziprasidone mesylate trihydrate, and contains 20mg base equivalent of ziprasidone. The mesylate salts of ziprasidone, including monohydrate and trihydrate, are disclosed in U.S. Pat. Nos. 6,110,918 and 5,245,765.
The present invention relates to the solid state physical properties of ziprasidone HC1. These properties can be influenced by controlling the conditions under which ziprasidone HC1 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 hi 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 syrups, 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. These conformational and orientational factors in turn result in particular intramolecular interactions and intennolecular interactions with adjacent molecules that influence the macroscopic properties of the bulk compound. A particular polymorphic form may give rise to distinct spectroscopic properties that may be detectable by powder X-Ray diffraction, solid state 13C NMR spectrometry and infrared spectrometry. The polymorphic form may also 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, thennogravimetric analysis
(TGA) and differential scanning calorimetry (DSC) and can be 'used to distinguish some polymorphic forms from others.
Ziprasidone HCI hemihydrate is disclosed in U.S. Pat. No. 4,831,031, Example 16 (column 13, line 13). A ziprasidone HCI monohydrate (herein designated Form M) is disclosed in U.S. Pat No. 5,312,925 and EP 0 586181 Al. Form M is characterized by XRD, IR and water content It is reported that the water content of Form M ranges from 3.8 to 4.5% by weight. Ziprasidone HCI Form M is prepared from ziprasidone base anhydrous.
The discovery of new polymorphic forms of apharmaceutically useful compound provides a new opportunity to improve me 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. There is a need in the art for additional polymorphic forms of ziprasidone HCI.
Summary of the Invention
In one aspect, the present invention provides a crystalline form of ziprasidone HCI
(Form E), wherein the crystalline form is characterized by a powder XRD pattern with peaks at 7.4,13.0,20.7,23.4,25.9 ±0.2 degrees 2 theta.
In another aspect, the present invention provides a process for preparing ziprasidone HCI Form E, comprising:
a) combining aqueous HCI with ziprasidone base in the presence of ethyl acetate or
acetonitrile to obtain a slurry;
b) maintaining the slurry to obtain ziprasidone HCI; and
c) recovering the ziprasidone HCI.
In another aspect, the present invention provides a crystalline form of ziprasidone HCI, wherein the crystalline form is a trihydrate.
In another aspect, the present invention provides a process for preparing ziprasidone HCI Form E in a mixture with a crystalline ziprasidone HCI having an X-Ray diffraction pattern having peaks at about 10.9,17.4 and 19.1 ±0.2 degrees 2 theta, comprising:
a) combining aqueous HCl with ziprasidone base in the presence of tetrahydrofuran to
obtain a slurry,
b) maintaining the slurry to obtain ziprasidone HCl; and
c) recovering the ziprasidone HCl mixture.
In another aspect, the present invention provides a crystalline form of ziprasidone HCl (Form F), wherein the crystalline form is characterized by a powder XRD pattern withpeaks at 11.0,18.1,19.5,21.9 ±0.2 degrees 2 theta.
In another aspect, the present invention provides a process for preparing the ziprasidone HCl Form F, comprising:
a) combining aqueous HCl with ziprasidone base in a solvent selected from the group
consisting of methylethylketone, tetrahydrofuran and dimethylacetamide to obtain a
slurry;
b) maintaining the slurry to obtain ziprasidone HCl; and
c) recovering the ziprasidone HCl.
; In another aspect, the present invention provides a process for preparing the
ziprasidone HCl form M, comprising:
a) heating a slurry of ziprasidone HCl in n-butanol or THF, optionally in mixture with
water; and
b) recovering the ziprasidone HCl form M.
In another aspect, the present invention provides a process for preparing the ziprasidone HCl form M comprising:
a) combining aqueous HCl with ziprasidone base at a temperature of at least about 40°C
in a solvent selected from the group consisting of ethanol, methanol, n-butanol, acetone,
ethyl actate, ethyl lactate, dimethyl-carbonate, optionally in a mixtures with water to
obtain a slurry,
b) maintaining the slurry to obtain the ziprasidone HCl form M; and
c) recovering the ziprasidone HCl form M.
In another aspect, the present invention provides a process for preparing the ziprasidone HCl form M comprising:
a) contacting gaseous hydrogen chloride with ziprasidone base in methanol to obtain a
slurry of ziprasidone hydrochloride in methanol;
b) maintaining the slurry to obtain the ziprasidone HCl form M; and
c) recovering the ziprasidone HCl form M.
In another aspect, the present invention provides a process for preparing the ziprasidone HC1 form M substantially free of the crystalline ziprasidone HC1 characterized by a powder XRD pattern with peaks at 10.9,17.4,19.1,25.0,26.0 ±0.2 degrees 2 theta comprising:
a) combining a solution or slurry of ziprasidone base in a solvent with less than one
equivalent HC1 to obtain a reaction mixture containing ziprasidone HC1;
b) stirring or agitating the reaction mixture;
c) adding additional HC1 to obtain additional ziprasidone HC1; and
d) recovering the ziprasidone HC1 form M.
In another aspect, the present invention provides for amorphous form of ziprasidone HC1.
In another aspect, the present invention provides a process for preparing amorphous form comprising slurrying ziprasidone base with methyl ethyl ketone or mono-chloro benzene with gaseous hydrochloride.
In another aspect, the present invention provides a crystalline form of ziprasidone HC1 (Form G), wherein the crystalline form is characterized by a powder XRD pattern with peaks at 9.0,20.6,22.7,25.0,27.0 ±0.2 degrees 2 theta.
In another aspect, the present invention provides a process for preparing ziprasidone HC1 Form G comprising:
a) combining gaseous HC1 with a mixture of ziprasidone base in a solvent selected from
the group consisting of carbon tetrachloride, di-isopropyl-ether, ethyl acetate, ethyl lactate
and mixtures thereof to obtain a slurry of ziprasidone HC1;
b) maintaining the slurry to obtain ziprasidone HC1 Form G; and
c) recovering the ziprasidone HC1.
In another aspect, the present invention provides a process for preparing a mixture of the ziprasidone HC1 of Form F and ziprasidone HC1 Form G comprising:
a) combining gaseous HC1 with a mixture of ziprasidone base in ethyl acetate to obtain a
slurry of ziprasidone HC1;
b) maintaining the slurry to obtain ziprasidone HC1; and
c) recovering the mixture.
In another aspect, the present invention provides a crystalline form of ziprasidone HC1 (Form I), wherein the crystalline form has an XRD pattern with peaks at 15.8,16.2, 18.9,23.8,27.0 ±0.2 degrees 2 theta,
In another aspect, the present invention provides a crystalline form of ziprasidone HC1 (Form J), wherein the crystalline form is characterized by a powder XRD pattern with peaks at 9.1,19.1,25.7, 26.3,26.9 ±0.2 degrees 2 theta.
In another aspect, the present invention provides a process for preparing ziprasidone HC1 Form J comprising:
a) combining ziprasidone base with HC1 to obtain a slurry of ziprasidone HC1 in a C5 to
C12 hydrocarbon;
b) maintaining the slurry to obtain the crystalline ziprasidone HC1; and
c) recovering the ziprasidone HC1.
In another aspect, the present invention provides a crystalline form of ziprasidone HC1, wherein the crystalline form has a water content of about 24% by LOD.
In another aspect, the present invention provides a crystalline from of ziprasidone HC1 (Form El), wherein the crystalline form is characterized a powder XRD pattern with peaks at 7.5,13.0,21.2,23.4 and 26.0 ±0.2 degrees 2 theta. :
In another aspect, the present invention provides a process for preparing ziprasidone HC1 Form El comprising drying the ziprasidone HC1 Form J.
In another aspect, the present invention provides a crystalline form of ziprasidone, wherein the crystalline form has a water content of about 6% to about 8%.
In another aspect, the present invention provides a pharmaceutical composition and method of treating a patient suffering from schizophrenia.
Figures
Figure 1 is an X-Ray powder diffractogram of amorphous ziprasidone HC1.
Figure 2 is a DSC thermogram of amorphous ziprasidone HC1.
Figure 3 is an IR spectrum of ziprasidone HC1 amorphous.
Figure 4 is an X-Ray powder diffractogram of ziprasidone HC1 form E.
Figure 5 is a DSC thermogram of ziprasidone HC1 form E.
Figure 6 is an IR spectrum of ziprasidone HC1 form E.
Figure 7 is an X-Ray powder diffractogram of ziprasidone HC1 form F.
Figure 8 is a DSC thermogram of ziprasidone HC1 form F.
Figure 9 is an IR spectrum of ziprasidone HC1 form F.
Figure 10 is a DSC thermogram of ziprasidone HC1 Form M.
• Figure 11 is an IR spectrum of ziprasidone HC1 Form M. Figure 12 is an X-Ray powder diffractogram of ziprasidone Base. Figure 13 is a DSC thermogram of ziprasidone Base. Figure 14 is an IR spectrum of ziprasidone Base. Figure 15 is an X-Ray powder diffractogram. of ziprasidone HC1 Form G. Figure 16 is an X-Ray powder difiractogram of ziprasidone HC1 Form I. Figure 17 is an X-Ray powder diffractogram of ziprasidone HC1 Form J. Figure 18 is an FTTR spectrum of ziprasidone HC1 Form J, Figure 19 is an FTIR spectrum of ziprasidone HC1 Form J. Figure 20 is an FTJR spectrum of ziprasidone HC1 Form J. Figure 21 is an X-Ray powder diffiractogram of ziprasidone HC1 Form El. Figure 22 is an FTIR spectrum of ziprasidone HC1 Form El. Figure 23 is an FTIR spectrum of ziprasidone HC1 Form El. Figure 24 is an FTIR spectrum of ziprasidone HC1 Form El.
Detailed Description of the Invention:
As used herein, the term slurry refers to a heterogeneous mixture.
As used herein, the term reduced pressure refers to a pressure below about 1 atm, more preferably below about 100 mmHg.
The present invention provides for obtaining ziprasidone HC1 Form M from ziprasidone base, or other forms of ziprasidone hydrochloride. Ziprasidone base, such as form B, but not limited to this form, is combined with aqueous hydrochloric acid and slurried in solvents such as methanol, ethanol, n-butanol, ethyl acetate, ethyl lactate, acetone, dimethyl carbonate, optionally in mixtures with water. Gaseous hydrogen chloride may be used with methanol. The slurry is then allowed to last for a sufficient amount of time (maintained) to obtain the monohydrate, preferably for about half a day. The slurry process is preferably carried out about room temperature to about reflux temperature of the solvents. Preferred combination of starting bases and solvents include Form B and ethyl acetate/ethanol/methanol/n-butanol. In another embodiment, rather than starting with ziprasidone base, another polymorphic form of ziprasidone HC1 is used for the slurry process. Preferred combination of solvents and starting forms include ziprasidone HC1
Form F and THF and ziprasidone HC1 Form E and n-butanol, preferably in mixtures with water. Preferably, the slurry is heated for a sufficient amount of time, more preferably to at least about 40°C.
The present invention also provides a process for preparation of Form M, but in a substantially pure form, by slow crystallization from slurry or solution of ziprasidone base in an organic solvent Preferred solvents are mixtures of THF/AcOH, THF/MeOH, DMA, n-BuOH/AcOH. The temperature of crystallization is more than about 50 °C, preferably of about 55 to about 70°C, more preferably about 55 to about 65 °C, and most preferably 65± 2°C. The mode of HC1 addition is preferably portion-wise. In one embodiment, a first portion of HC1 is added until opalescence is obtained, and the mixture is stirred to induce nucleation, followed by the rest of HC1 addition. Typically, opalescence resulting from formation of ziprasidone HC1 is observed after adding ~1/10 portion of the HCL Seeding of ziprasidone base before the HC1 addition is ideal.
In one embodiment, A process ziprasidone HC1 form M substantially free of the crystalline ziprasidone HC1 characterized by a powder XRD pattern with peaks at 10.9, 17.4,19.1,25.0,26.0 ±0.2 degrees 2 theta is prepared by combining a solution or slurry of ziprasidone base in a solvent with less than one equivalent HC1 to obtain a reaction mixture containing ziprasidone HC1, stirring or agitating the reaction mixture, adding additional HC1 to'obtain additional ziprasidone HC1 and recovering the ziprasidone HC1

form M,
m another aspect, the present invention provides for ziprasidone HC1 Form E. Ziprasidone HC1 Form E is characterized by an X-Ray diffraction pattern (Figure 4) with peaks at 7.4,13.0,20.7,23.4,25.9 ±0.2 degrees 2 theta. Ziprasidone HC1 Form E is further characterized by XRD peaks at 13.7,20.0,21.3,25.2 ±0.2 degrees two-theta. The DSC thermogram of ziprasidone HC1 Form E (Figure 5) shows endothennic peaks of about 22,152 and 11 J/g at about 54,94 and 132°C respectively, which correspond to the desolvation and dehydration of ziprasidone HC1 Form E. According to the thermogram, the melting and decomposition of ziprasidone HC1 Form E starts at about 280°C. The water content of ziprasidone form E, measured by Karl Fisher, ranges about 9.3% to about 9.6% by weight, and the weight loss measured by TGA is about 19% by weight.
This corresponds approximately to a trihydrate, which may contain solvent approximately as 1 K -1 1/3 solvate of acetonitrile, or 2/3-3/4 solvate of ethyl acetate.
The FTIR spectrum of ziprasidone HC1 form E is shown in Figure 6.
Ziprasidone HC1 Form E when exposed to a high relative humidity, such as for about 22 days, transforms to form M. Ziprasidone HC1 form E transforms to amorphous form when exposed to about 10% to about 0%, more preferably about 0% relative humidity, for such as 22 days, or after heating at elevated temperature, preferably at about 80°C overnight. Ziprasidone HC1 Form E transforms to Form A when exposed to a relative humidity of about 20% to about 60% for about 22 days (see table 1 and 2). Form A is characterized by an X-Ray diffraction pattern having peaks at about 10.9,17.4 19,1,25.0 and 26.0 ±0.2 degrees 2 theta.
Ziprasidone HC1 novel form E may be prepared by combining ziprasidone base with aqueous HC1 in acetonitrile or ethyl acetate to obtain a slurry, and allowing the slurry to last for a sufficient time to obtain Form E, The slurry process is preferably carried out . overnight. The combining of HC1 with ziprasidone base is preferably carried out at a temperature of about 40°C to about 60°C, with about 50°C being preferred. The slurrying after the combining is preferably carried out at a temperature of about 20°C to about 30 °C, more preferably at about room temperature. Ziprasidone Form E may also be obtained as a mixture with Form A by a slurry process that uses tetrahydrofuran as a solvent. Slurrying at room temperature results in the mixture, while slurrying at higher temperatures, such as above about 50 °C results substantially in Form A.
Table No. 1
Water uptake (%) and crystal form of ziprasidoue HC1 form E equilibrated at different
relative humidities for 22 days
(Table Removed)
Table No. 2
Crystal form of ziprasidone HCI form E heated at 80-105°C overnight
(Table Removed)
In another aspect, the present invention provides for ziprasidone HCI Form F. Ziprasidone HCI Form F is characterized by an XKD pattern (Figure 7) With, peaks at 11.0,18.1,19.5, 21.9 ±0.2 degrees 2 theta. Ziprasidone HCI Form F is further characterized by XRD peaks at 14.9,24.9,26.1 ±0.2 degrees 2 theta. Ziprasidone HCI Form F has a DSC thermogram (Figure 8) which shows an about a 71 J/g endothermic peak at about 85°C, corresponding to the dehydration of the ziprasidone HCI Form F. At about 280°C, ziprasidone HCI Form F starts to melt and decompose. The water content and the weight loss by TGA of the sample may range of about 2.6% to about 16% by weight. When ziprasidone HCI Form F is equilibrated at relative humidity of about 0% to about 100%, it retains its crystal form. Ziprasidone HCI Form F, after being heated overnight at about 80°C, has very low water content (0.8%), but still retains its original crystal form (see tables 3 and 4). In the range of relative humidity of about 20% to about 60%, the water content equilibrates around about 4.0% to about 4.5%, which indicates that Form F may be a stable monohydrate when kept in the humidity range of about 20% to about 60% RH.
The IR spectrum of ziprasidone HCI form F in Figure 9 is shown.
Ziprasidone HCI novel Form F may be prepared by combining ziprasidone base with aqueous HCI in tetrahydrofuran, methylethlkyetone or dimethylacetamide to obtain a slurry, and allowing the slurry to last for a sufficient tune to obtain Form F. The slurry maybe diluted by addition of water. The combining step is preferably carried out at elevated temperature, more preferably of about 50°C to about 70°C, most preferably at about 60°C. The slurrying after the combining is preferably carried out at a temperature of about 20°C to about 30°C, more preferably at about room temperature. Preferably, when the solvent is dimethylacetamide, a mixture of Form F and Form M is obtained.

Table No. 3
Water uptake (%) and crystal form of ziprasidone HCI form F equilibrated at different
relative humidities for 22 days
(Table Removed)
Table No. 4
Crystal form of ziprasidone HCI form F heated at 80-105°C overnight
(Table Removed)
Form F may be used for the preparation of Form M, by combining ziprasidone HCI Form F, THF and water, heating the slurry to about 50°C, cooling the slurry to room temperature, and maintaining for a sufficient time to obtain Form M.
In another aspect, the present invention provides for amorphous form of ziprasidone HCI. Amorphous ziprasidone HCI has an X-Ray diffraction pattern as substantially depicted in Figure 1, in which reflection peaks are absent (halo-like pattern). Endothermic peaks are absent from the DSC thermogram of amorphous ziprasidone HCI (Figure 2). The FTIR spectrum of amorphous ziprasidone HCI is substantially depicted in Figure 3.
Amorphous form of ziprasidone HCI may be prepared by placing Form E in a dessicator (dry chamber) having low humidity for a sufficient time to obtain amorphous form. In a preferred embodiment, ziprasidone Form E is put in a dessicator having about 0% relative humidity for about 18 days.
Ziprasidone HCI amorphous may be prepared by drying ziprasidone HCI form E at an elevated temperature, preferably of about 80 to about 105 °C, for a sufficient period of time, preferably of about 5 to about 30 hours, more preferably overnight (-15 hours). Ziprasidone HCI amorphous may also be prepared by exposing ziprasidone HCI form E to low relative humidity, preferably about 0%, for a sufficient period, preferably a time of about 1 -3 weeks, more preferably for about 3 weeks.
Ziprasidone hydrochloride amorphous may also be prepared by treating the slurry of ziprasidone base in MEK or mono-chlorobenzene with gaseous HCI.
In another aspect, the present invention provides for ziprasidone HCI Form G. Ziprasidone HCI Form G has an XRPD diffraction pattern with preferred peaks at 9.0, 20.6,22.7,25.0,27.0 ±0.2 degrees 2 theta, and other peaks at 11.3,12.5,13.9,15.6,21.5, 23.5,25.8,28,0,31.5 ±0.2 degrees two-theta.
Ziprasidone HCI Form G may have a water content of about 5% to about 12%. Ziprasidone HCI Form G may be a dihydrate (about 7.4% stochiometric value for the dihydrate) or a trihydrate (about 10.7% stochiometric value for the trihydrate). Ziprasidone HCI Form G is sparingly soluble in methanol, hence the water determination by Karl Fisher is carried out for more than 30 minutes in order to ensure that all the material is dissolved and all the water is analyzed.
Ziprasidone HCI Form G may be prepared by introducing HCI gas into a mixture of ziprasidone base in ethyl acetate, ethyl lactate, carbon tetrachloride, di-isopropyl-ether and mixtures thereof to obtain a slurry of ziprasidone HCI, and allowing the slurry to last for a sufficient time. The slurry is preferably stirred When ethyl acetate is used in the absence of an ether, the result may be a mixture of Form G with Form F. The resulting wet product may be separated by techniques known in the art such as filtration, and may be dried, preferably at a temperature of about 40 °C to about 60° C for about half a day.
Jh another aspect, the present invention provides for ziprasidone HCI Form I. Ziprasidone HCI Form I is characterized by an XRD pattern with peaks at 15.8,16.2, 18.9,23.8,27.0 ±0.2 degrees 2 theta, and other peaks at 10.5,11.3,21.1,24.8,26.0 ±0.2
degrees two-theta. Ziprasidone HCI Form I may be prepared by heating ziprasidone HCI Form G, preferably a ziprasidone Form G obtained from a slurry in di-iso-propyl ether. The heating is preferably carried out at a temperature of about 40°C to about 60°C for about half a day
The polymorphic forms of the present invention are preferably used with particle size up to 100 microns in light of low solubility of ziprasidone HCI in water.
i
Ziprasidone HCI anhydrous may be prepared by drying ziprasidone HCI Form M, for example by exposing the material to low relative humidity, preferably about 0% relative humidity, for a sufficient period, preferably for about 1 -3 weeks, more preferably for about 3 weeks.
The present invention also provides for ziprasidone HCI form J. Ziprasidone HCI Form J is characterized by XRD peaks at 9.1, 19. 1, 25.7, 26.3, 26.9 ±0.2 degrees 2 theta, and other less characteristic peaks at 1 1.9, 21.4, 23.4, 30.7, 32.2 ±0.2 degrees two-theta. Form J has an FTIR spectrum as substantially depicted in figures 18 to 20. The present invention also provides for ziprasidone HCI Form J with a water content of about 24%.
Ziprasidone HCI Form J may be obtained by slurry of ziprasidone base in a C5 toC12 hydrocarbon, preferably toluene. A few hours of slurrying is sufficient after combining of HCI with ziprasidone base to obtain the slurry. Ziprasidone HCI Form J may then be recovered for example by solvent removal.
The present invention also provides for ziprasidone HCI Form El . Ziprasidone HCI Form El is characterized by XRD peaks at 7.5, 13.0, 21.2, 23.4 and 26.0 ±0.2 degrees 2 theta, and other less characteristic peaks at 10.9, 16.2, 20.8, 25.4, 30.3 and 34.8 ±0.2 degrees two-theta, Ziprasidone HCI Form El has an FTIR spectrum as substantially depicted in figures 22 to 24. The present invention also provides for ziprasidone HCI Form El with a water content of about 6% to about 8%.
Ziprasidone HCI Form El may be prepared by removing solvent from ziprasidone HCI Form J. Such removal may be done by drying Form J at elevated temperature, and/or
under ambient or reduced pressure. A dry nitrogen atmosphere is preferred with a temperature of about 30°C to about 50°C, with about 40°C being preferred.
A slurry is most effective when the solids of the heterogeneous mixture are in substantial contact with the solvent. When the solids settle down, the efficiency of the slurry process often decreases due to a decrease in contact. Thus, one of skill in the art would appreciate that if during the slurry process the solids settle down, a force such as stirring, agitating to disperse the solid. Even when the solids have not settled down, bringing of movement in the solvent may even further increase the efficiency of the slurry process.
One of skill in the art would appreciate that as the slurry is allowed to last for a sufficient time to obtain a particular polymorphic form, the slurry may dry up due to for example evaporation of the solvents. As the examples illustrate, additional amounts of a solvent maybe added (same or different solvent), preferably followed by stirring, to obtain a slurry.
The various forms of ziprasidone may be recovered from the slurry .by conventional techniques in the art such as decanting, filtration and centrifugation.
Pharmaceutical formulations of the present invention contain crystalline ziprasidone HC1, such as one of those disclosed herein, or ziprasidone HC1 amorphous, optionally in mixture with other form(s) of ziprasidone. In addition to the active ingredients), the pharmaceutical formulations of the present invention may contain one or more excipients. Excipients are added to the formulation for a variety of purposes.
Diluents increase the bulk of a solid pharmaceutical composition, and may make a pharmaceutical dosage form containing the composition easier for the patient and care giver to handle. Diluents for solid compositions include, for example, macrocrystalline 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, such as a tablet, may include excipients whose functions include helping to bind the active ingredient and other excipients together after compression. Binders for solid pharmaceutical compositions include 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, magnesium aluminum silicate, mattodextrin, methylcellulose, polymethacrylates, povidone (e.g. Kollidon®, Plasdone®), pregelatinized starch, sodium alginate and starch.
The dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach may be increased by the addition of a disintegrant to the composition. Disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g. Ac-Di-Sol®, Primellose*), colloidal silicon dioxide, croscarmellose 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®) and starch.
Glidants can be added to improve the flowability of a non-compacted solid composition and to improve the accuracy of dosing. Excipients that may function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate.
When a dosage form such as a tablet is made by the compaction of a powdered composition, the composition is subjected to pressure from 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 the release of the product from the dye. Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable
oil, mineral oil, polyethylene glycol,- sodium behzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc and 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 may be included in the composition of the present invention include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol and tartaric acid.
Solid and liquid compositions may 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, ziprasidone and any other solid excipients are dissolved or suspended in a liquid canier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerin.
Liquid pharmaceutical compositions may 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 may 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 and cetyl alcohol.
Liquid pharmaceutical compositions of the present invention may 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, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate; propylene glycol alginate, sodium alginate, sodium starch glycolatc, starch tragacanth and xanthan gum.
Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol and invert sugar may be added to improve the taste.
Preservatives and cbelating agents such as alcohol, sodium benzoate, butylated hydroxy toluene, butylated hydroxyanisole and ethylenediamine tetraacetic acid maybe added at levels safe for ingestion to improve storage stability.
According to the present invention, a liquid composition may also contain a buffer such as guconic acid, lactic acid, citric acid or acetic acid, sodium guconate, sodium lactate, sodium citrate or sodium acetate. Selection of excipients and the amounts used may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field.
The solid compositions of the present invention include powders, granulates, aggregates and compacted compositions. The dosages include dosages suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalant and ophthalmic administration. Although the most suitable administration in any given case will depend on the nature and severity of the condition being treated, the most preferred route of the present invention is oral. The dosages may be conveniently presented in 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, suppositories, sachets, troches and losenges, as well as liquid syrups, suspensions and elixirs.
The dosage form of the present invention may be a capsule containing the composition, preferably a powdered or granulated solid composition of the invention, within either a hard or soft shell. The shell may be made from gelatin and optionally contain a plasticizer such as glycerin and sorbitol, and an opacifying agent or colorant.
The active ingredient and excipients may be formulated into compositions and dosage forms according to methods known in the art.
A composition for tableting or capsule filling may be prepared by wet granulation. In wet granulation, some or all of the active ingredients and excipients in powder form are blended and then further mixed hi the presence of a liquid, typically water, that causes the powders to clump into granules. The granulate is screened and/or milled, dried and then screened and/or milled to the desired particle size. The granulate may then be tableted, or other excipients may be added prior to tableting, such as a glidant and/or a lubricant.
A tableting composition may be prepared conventionally by dry blending. For example, the blended composition of the actives and excipients may be compacted into a slug or a sheet and then comminuted into compacted granules. The compacted granules may subsequently be compressed into a tablet.
As an alternative to dry granulation, a blended composition may be compressed directly into a compacted dosage form using direct compression techniques. Direct compression produces a more uniform tablet without granules. Excipients that are particularly well suited for direct compression tableting include microcrystalline cellulose, spray dried lactose, dicalcium phosphate dihydrate and 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 present invention may comprise any of the aforementioned blends and granulates that were described with reference to tableting, however, they are not subjected to a final tableting step.
The solid compositions of the present invention include powders, granulates, aggregates and compacted compositions. The dosages include dosages suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalant and ophthalmic administration. 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 present invention is oral. The dosages can be conveniently presented in unit dosage form and prepared by any of the methods well-known in the pharmaceutical arts.
The dosage of GEODON may be used as a guidance. The oral dosage form of the present invention is preferably in the form of an oral capsule having a dosage of about 10 mg to about 160 mg, more preferably of about 20 mg to about 80 mg, and most preferably capsules of 20,40,60 and 80 mg.
Instrumentation;
X-Ray powder diffraction data were obtained using by method known in the art using a SCINTAG powder X-Ray difrractometer model X'TRA equipped with a solid state detector. Copper radiation of 1.5418 A was used. A round aluminum sample holder with round zero background quartz plate, with cavity of 25(diameter)*0.5(dept) mm.
DSC analysis was done using a Mettler 821 Star*. The weight of the samples was about 5 mg; the samples were scanned at a rate of 10°C/min from 30°C to 320°C. The oven was constantly purged with nitrogen gas at a flow rate of 40 ml/min. Standard 40 pi aluminum crucibles covered by lids with 3 holes were used.
TGA analysis was done using a Mettler M3 meter. The weight of the samples was about 10 mg; the samples were scanned at a rate of 10°C/min from 25°C to 200°C. The oven was constantly purged with nitrogen gas at a flow rate of 40 ml/min. Standard 70 pi alumina crucibles covered by lids with 1 hole were used.
IR analysis was done using a Perkin Elmer SPECTRUM ONE FT-IR spectrometer in DREFTt mode. The samples in the 4000-400 cm"1 interval were scanned 16 times with 4.0 cm"1 resolution.
The water content of ziprasidone HC1 was measured by the methods known in the art like Karl Fisher or thermogravimetric analysis (TGA). In the case of ziprasidone HC1F, the TGA and Karl Fisher analysis matched, while for ziprasidone HC1 form E the TGA analysis exceeded by far that of Karl Fisher, as an indication that a significant quantity of solvent is present.
Ziprasidone base
Ziprasidone free base used for preparations of the crystal forms of ziprasidone HC1 is characterized by X-Ray peaks at 12.1,15.2,16.3,18.4,25.0 degrees 2 theta and is further characterized by XRD peaks at 5.2,10.4,11.3,13.1,21.1,22.1. The ziprasidone free base has a DSC thermogram like the one shown in Figure 13, in which 17 and 120 J/g endothermic peaks can be seen at 92 and 220°C. The first corresponds to dehydration, the second to melting of the ziprasidone free base. The water content of the sample of the base is about 12 % by weight The Loss on Drying by TGA is about 2.1 % by weight. The IR spectrum of ziprasidone free base is substantially depicted in Figure 14. The form of ziprasidone is referred to as Form B. One of skill in the art would appreciate that the processes of the present invention may use other forms of ziprasidone base as starting material.
Examples
Example 1- Preparation of Ziprasidone base
Ziprasidone base for the experiments below was prepared according to the procedure "EXPERIMENT" in US Pat. No. 5,312,925, column 4. The water content of the base was 1.2 % (Karl Fisher).
Example 2- Preparation of Ziprasidone base Form B
Ziprasidone base (50g) and toluene (250ml) were charged into a 0.5 L three necked flask. The obtained slurry was heated at 85°C for 2 hours. The hot slurry was filtrated and the solid was washed with methanol. The solid was dried in air-circulated oven at 50°C to afford the dried Ziprasidone base form B (by XRD) (45.39g).
Example 3- Preparation of Ziprasidone HCI form E from Ziprasidone base form B in acetonitrile and aqueous HC1
Aqueous HCI (37%) (10ml) was added to a slurry of ziprasidone base Form B (lOg) in acetonitrile (200ml) at reflux. After the addition, the slurry was heated over night A solid was filtered and washed with acetonitrile. After drying at 50°C for ~16 hours, ziprasidone HCI Form E was obtained (12.71 g) (The water content was 9.25% by K.F. and the loss on drying by TGA is 18.8%), as confirmed by XRD.
Example 4- Preparation of Ziprasidone HCI form E from Ziprasidone base form B In ethyl acetate and aqueous HC1
A slurry of ziprasidonc base form B (l0g) in ethyl acetate (100ml) was heated at reflux without complete dissolution. The slurry was then cooled. When the temperature was about 50°C, aqueous HC1 (37%) (10ml) was added, and the slurry was diluted by addition of ethyl acetate (100ml). The slurry was stirred for ~16hours. A solid was filtered and washed with ethyl acetate. The wet solid was ziprasidone HC1 Form E, as confirmed by XRD. The wet solid was dried at 50°C. The dried solid had a water content of 9.62% (by K.F.) and a loss on drying of 19% (by TGA). The dried solid was Form E, as confirmed by XRD.
Example 5- Preparation of Ziprasidone HCI form F from Ziprasidone base form B in methylethylketone and aqueous HCI
Aqueous HCI (37%) (10ml) was added drop-wise to a hot slurry of ziprasidone base Form B (lOg) in methylethylketone (MEK) (200ml). The slurry was stirred at room temperature over night. A solid was filtered and washed with MEK. The wet solid was ziprasidone HCI Form F. The wet solid was dried at 50°C for two days. The dried product was ziprasidone HCI Form F (10.62g) (The water content was 3.87% by K.F. and the loss on drying is 4.1% by TGA), as confirmed by XRD.
Example 6- Preparation of Ziprasidone HCI form F from Ziprasidone base form B in THF and aqueous HCI
Aqueous hydrochloric acid (37%) (910ml) was added to a hot slurry of ziprasidone base (l0g) in tetrahydrofuran (THF) (200ml). The slurry was stirred at room temperature for about 16 hours. A solid was filtered, washed with THF and dried in an oven at 50°C for two days. The wet and the dried solid samples were ziprasidone HCI Form F (The water content was 3.63%), as confirmed by XRD.
Example 7- Preparation of a mixture of Ziprasidone HCI form F and form M djmethvlacetamlde/water and aqueous HCI
Ziprasidone base (10g) was dissolved in dimethylacetamide (1 00ml) at ~95°C. The solution was cooled to 70°C and aqueous HCI (37%) (10ml) was added, resulting in precipitation and formation of a slurry. The slurry was then cooled to room temperature,
followed by addition of water (100 ml). Stirring was continued for 1 hour at room temperature, followed by filtration, and washing of a solid material obtained from filtration with water. The wet solid was dried at 50°C for about 16 hours to a dry solid (7.1g). The wet and the dried solid were ziprasidone HCI Form F in mixture with Form M (The water content of the dried solid is 4.17% by K.F.), as confirmed by XRD.
Example 8- Preparation of Ziprasidone HCI amorphous from form E by drying
Ziprasidone hydrochloride Form E (4.05g) was heated at 80-105°C in an oven for about 16 hours. The solid after heating was ziprasidone HCI amorphous (3.33g) (The water content was 1.21% by K.F.), as confirmed by XRD.
Example 9- Preparation of Ziprasidone HCI Form M in dimethylcarbonate/ methanol from Ziprasidone base form B and aqueous HCI
Ziprasidone base (l0g) was taken in dimethylcarbonate (DMC) (100ml) and the mixture . was heated at ~90°C. Aqueous HCI (37%) (10ml) was added, resulting in a sticky material. Additional amount of DMC (100ml), and methanol (50ml), were added, resulting in a slurry. The slurry was stirred at room temperature over night. A solid was filtered and washed with DMC, and subsequently dried at 50°C overnight. The wet and the dried solids were ziprasidone HCI monohydrate, as confirmed by XRD. The water content of the dried solid by K.F. is 4.78%.
In all the above examples except example 8, drying was carried out in an air-circulated oven. In example 8, the pressure was atmospheric pressure.
Example 10- Preparation of Ziprasidone HCI Form G from ethyl-lactate/ether/
Ziprasidone base Form B (l0g) was added to ethyl-lactate (50ml) and the slurry obtained was cooled to 5°C. HCI (g) was bubbled through the above slurry and ether (150ml) was added. The slurry was stirred over night at room temperature, filtrated and washed with ether. The wet material was dried at 5,0°C in an air-circulated oven and ziprasidone HCI Form G was obtained.
Example 11- Preparation of Ziorasldone HCl Form G from carbon-tetrachloride/ HCl (g)
Ziprasidone base Form B (5g) was added to carbon-tetrachloride (50ml) and HCl(g) was bubbled until pH 1 was reached. The temperature rose to ~40°C. The slurry was stirred at room temperature for 3 hours and filtrated. The solid was dried in an air-circulated oven at 50°C for 17 hours. The wet and the dried solid both were ziprasidone HC1 Form G.
Example 12- Preparation of Ziorasidone HC1 form G from di-isopropyl-ether/ HCl(g)
Ziprasidone base Form B (l0g) was added to di-iso-propyl-ether (200ml) and the slurry was stirred at room temperature; through the slurry HCl(g) was bubbled while the temperature rose to ~50°C. The slurry was stirred at room temperature over-night, the solid was filtrated and washed with di-iso-propyl-ether. The wet solid gave ziprasidone HC1 Form G. Drying of the wet solid in an 'air-circulated oven at 50°C for ~16h gave ziprasidone HC1 Form I.
Example 13- Preparation of ziprasidone HCI mixture of form G and F from ethyl-acetate/ HCl(g)
Ziprasidone base Form B (l0g) was added to ethyl-acetate (200ml) and HCl(g) was bubbled through the slurry; the temperature rose to ~35°C. The slurry was stirred at room temperature for 3 hours and the solid was filtrated, washed with ethyl-acetate and dried for ~16h in an air-circulated oven at 45°C. The wet and dried solids both gave a mixture of ziprasidone HC1 Form G and F.
Example 14- Preparation of ziprasidone HCl Form M
A) Preparation of ziprasidone HCl Form M from ziprasidone base in ethyl-
lactate/ aq. HCl
Concentrated HCl (37%) was added to the slurry of ziprasidone base (form B) (l0g) in ethyl-lactate (200 ml) at 60CC. The reaction mixture was stirred at room temperature for about 16 hours, and a solid was filtrated, washed with ethyl-lactate (20ml) and dried at 50oC for two days. The solid was ziprasidone HCl Form M. (K.F. 4.02%).
B) Preparation of ziprasidone HGI Form M from ziprasidone base in ethanol/aq.
HC1
To the slurry of ziprasidone base (Form B) (l0g) in ethanol (200ml) at room temperature was added concentrated hydrochloric acid 37% (~5g); the temperature rose to ~30°C during the HC1 addition. The slurry was than stirred at room temperature for about 16 hours. A solid was filtrated, washed with ethanol and dried in an air-circulated oven at 50 °C. The product was ziprasidone HC1 form M. (K.F. 4.37%).
C) Preparation of ziprasidone Form M from ziprasidone base in
methanol/HCI(g)
To the slurry of ziprasidone base (Form B) (l0g) in methanol (100ml) at ~5°C was bubbled HC1 (g); the obtained slurry was then stirred over night at room temperature. A solid was filtrated, washed with methanol and dried at 50°C for about 16 hours. The product was ziprasidone HC1 Form M (KF. 4.5%).
D) Preparation of ziprasidone HCI Form M from ziprasidone base in
Methanol/aq. HCI
To the slurry of ziprasidone base (Form B) (10g) in methanol (200ml) a.t 60°C was added concentrated HCI (10ml); the slurry was then stirred at room temperature for about 16 hours. A solid was filtrated, washed with methanol (2x 10ml) and dried at 50°C in an air-circulated oven for 2 days. The product was ziprasidone HCI Form M (K.F. 4.26%).
E) Preparation of ziprasidone HCI Form M from ziprasidone base in n-
BnOH/aq. HCI
A slurry of ziprasidone base (Form B) (l0g) in n-butanol (250ml) was heated to 60°C While maintaining the temperature, concentrated HCI was added (10ml). The reaction mixture was than stirred at room temperature for about 16 hours. A solid was filtrated, washed with n-butanol (2X20ml) and dried for about 16 hours at 50°C in an air-circulated oven. The dried solid was ziprasidone HCI Form M (K.F. 4.12%).
F) Preparation of ziprasidone HCI Form M from ziprasidone base in
acetone/aq. HCI
. To the slurry of ziprasidone base (Form B) (l0g) in acetone (200ml) at room temperature was added concentrated HC1 (10ml); the temperature rose to about 30°C. The reaction mixture was stirred at room temperature for about 16 hours. A solid was filtrated, washed with acetone (2xl0ml) and dried for two days in an air-circulated oven at 50°C. The dried solid was ziprasidone HC1 Form M (K.F.4.57%).
G) Preparation of ziprasidone HCl Form M from Form F
A slurry, of ziprasidone HG1 Form F (5g) in THF/ water 95:5 (50ml) was heated at 50°C for two hours. After cooling to room temperature, a solid was filtrated, washed with mixture THF/ water and dried for 18 hours in an air-circulated oven. The dried solid was ziprasidone HCl Form M (K.F. 4.50%).
H) Preparation of ziprasidone HCl Form M from Form E
Ziprasidone HCl Form E (2g) was heated in n-butanol (200ml) and water (40ml) at 85°C; complete dissolution was not obtained. More water was added (20ml) and the slurry was stirred at 90°C for 1.5 hours. A solid Was filtrated from the hot slurry, washed with n- • butanol/water (4 ml 3:1) and dried. From the filtrate a solid was obtained upon cooling to 10°C. This material was filtrated, washed and dried in the same conditions.-Both dried solids were ziprasidone HCl Form M.
Example 15- Preparation of ziprasidone HCl Form J
Aqueous HCl was drop-wise added over 10 minutes, to a slurry of ziprasidone base (5g) in toluene (100ml) at room temperature. The obtained mixture was stirred at room temperature for 3 hours, and then the solvent was evaporated under vacuum. The solid obtained after the toluene evaporation was ziprasidone HCl Form J.
Example 16- Preparation of ziprasidone HCl FormJEl
The above material (ZPR HCl form J form Example 20) was dried by maintaining it at 40oC and under nitrogen atmosphere over night, followed by additional drying with a rotary evaporator. The dried material collected after the two drying stages was ziprasidone HCl Form El (water content by K.F. ~6% and ~8% respectively).

Example 17- Preparation of ZPR HC1 Form M substantially pure of form A A) Preparation of ZPR HC1 FormM from THF: AcOH
In a 250ml three necked flask were charged Ziprasidone base (5g) and a mixture 9:1 THF:acetic acid. The slurry was heated at 60°C and more solvent was added until complete dissolution was obtained. The total volume of the solvents mixture was 175ml. To the solution 4 drops of 10% hydrochloric acid was added; upon HC1 addition a precipitate is formed. The hazy solution was stirred for 1h at 60°C and after this 15 ml 10% HC1 was added over 30 minutes. The slurry was than stirred for 2.5h maintaining the temperature at 60°C. The solid was filtrated from the slurry after cooling to room temperature and washed with solvent. The solid obtained after drying at 50°C is ZPR HC1 Form M substantially pure of form A. (4.58g). (Water content by K.F.4.04%).
B) Preparation of ZPR HC1 Form M from THF:MeOH.
In a 250ml three necked flask were charged Ziprasidone base (5g) and mixture of THF:MeOH 10:3. The mixture was heated at 60°C and diluted with the solvents until the complete dissolution was observed, (the total volume.is 240ml;). Hydrochloric acid 10% (2ml) was added and the reaction mixture was stirred for 30 minutes. After this period of time more hydrochloric acid was added to complete the reaction. The stirring was continued for Ih at 60°C; the mixture was than cooled to room temperature and the solid filtrated and washed with solvent. After drying at 50°C the ZPR HC1 Form M substantially pure of form A was obtained. (Water content by K.F. 4.08%).
C) Preparation of ZPR HCI Form M from n-Butanol:Acetic Acid.
In a 250ml three necked flask were charged Ziprasidone base (5g) and n-BuOH (100ml) and the slurry was heated at 60°C. Acetic acid was added (10ml) and more n-BuOH (100ml). To the slurry 10% hydrochloric acid (2ml) was added and the mixture was stirred for Ih. After this more HCI was added drop-wise over 30', The reaction mixture was stirred for Ih at 60°C to complete the reaction. After cooling to the room temperature the solid was filtrated, washed with solvent and dried at 50°C to give ZPR HCI Form M substantially pure of form A (4.25g). (Water content by K.F.4.33%).
D) Preparation of ZPR HCI Form M from N,N-dimethyl- acetamide.
In a 250ml three necked flask were charged Ziprasidone base (5g) and N,N-dimethyl-acetamide (DMA) (100ml) and the mixture has been heated at 60°C. To the obtained solution 32% HC1 (3ml) was added and the stirring was continued for 4h. After cooling, the solid was filtrated and then dried to afford ziprasidone HC1 Form M substantially pure of form A. (Water content by K.F. 4.15%).
Example 20- Preparation of ziprasidone Form J and Form El
To the slurry of ziprasidone base (5g) in toluene (100ml) at room temperature was drop-wise added aqueous HC1 over 10 minutes. The obtained mixture was stirred at room temperature for 3 hours, then the solvent was distilled under vacuum. The solid obtained after the toluene distillation was ziprasidone HC1 Form J.
The above material (ZPR HC1 form J) was dried by maintaining it at 40°C and under nitrogen over night, followed by an additional drying operation on a rotary evaporator. The dried material collected in the two drying stages was ziprasidone HC1 Form El (water content by K.F. 6% and 7.8% respectively).
Example 21- Preparation of ZPR .HC1 amorphous from ZPR base and HCI in methyl-eftyl-ketone
To the chilled slurry of ZPR base (5g) in methylethyl-ketone (MEK) (l00ml) (~2oC) Was bubbled hydrogen chloride until the pH 1 was reached. The temperature was in the range 2 to 10°C. The slurry was than stirred at the above temperature for 5 hours, the solid was filtrated and washed with MEK (2xl0ml). After drying at 60oC was obtained a solid which is ZPR .HCI amorphous by XRD.
Having thus described the invention with reference to particular preferred embodiments and illustrative examples, those in the art can appreciate modifications to the invention as described and illustrated that do not depart from the spirit and scope of the invention as disclosed in the specification. The Examples are set forth to aid in understanding the invention but are not intended to, and should not be construed to, limit its scope in any way. The examples do not include detailed descriptions of conventional methods. Such methods are well known to those of ordinary skill in the art and are described in
numerous publications. Polymorphism in Pharmaceutical Solids, Drugs and the Pharmaceutical Sciences, Volume 95 may be used for guidance. All references mentioned herein are incorporated in their entirety.

What is claimed is:
1. A crystalline form of ziprasidone HC1 (Form E), wherein the crystalline form is
characterized by a powder XRD pattern with peaks at 7.4,13.0,20.7,23.4,25.9
±0.2 degrees 2 theta.
2. The crystalline form of claim 1, wherein the crystalline form is further
characterized by peaks at 13.7,20.0,21.3,25.2 ±0.2 degrees two-theta.
3. The crystalline form of claim 2, has an XRD pattern as substantially depicted in
Figure 4.
4. A process for preparing ziprasidone HC1 of claim 1, comprising:

a) combining aqueous HC1 with ziprasidone base in the presence of ethyl acetate
or acetonitrile to obtain a slurry;
b) maintaining the slurry to obtain ziprasidone HC1; and
c) recovering the ziprasidone HC1.

5. The process of claim 4, wherein the ziprasidone base is ziprasidone Form B.
6. The process of claim 4, wherein the slurry temperature is at least about 40°C.
7. A crystalline form of ziprasidone HC1, wherein the crystalline form is a trihydrate.
8. The crystalline form of claim 7, wherein the crystalline form is a solvated form of
ethyl acetate.
9. The crystalline form of claim 7, wherein the crystalline form is a solvated form of
acetonitrile.
10. A process for preparing ziprasidone HC1 of claim 1 in a mixture with a crystalline
ziprasidone HC1 having an X-Ray diffraction pattern having peaks at about 10.9,
17.4 and 19.1 ±0.2 degrees 2 theta, comprising:

a) combining aqueous HC1 with ziprasidone base in the presence of
tetrahydrofuran to obtain a shiny;
b) maintaining the slurry to obtain Ziprasidone HC1; and
c) recovering the ziprasidone HC1 mixture.

11. The process of claim 10, wherein the slurry is at about room temperature.
12. Crystalline form of ziprasidone HC1 prepared by the processes of any of claims 4
or 10.
13. A crystalline form of ziprasidone HC1 (Form F), wherein the crystalline form is
characterized by a powder XRD pattern with peaks at 11.0,18.1,19.5,21.9 ±0.2
degrees 2 theta.
14. The crystalline form of claim 113, wherein the crystalline form is further
characterized by peaks at 14,9,24.9,26.1 ±0.2 degrees two-theta.
15. The crystalline form of claim 14, wherein the crystalline form is further
characterized by an XRD pattern as substantially depicted in Figure 7.
16. A process for preparing the ziprasidone HC1 of claim 13, comprising:

a) combining aqueous HC1 with ziprasidone base in a solvent selected from the
group consisting of methylethylketone, tetrahydrofuran and
dimethylacetamide to obtain a slurry,
b) maintaining the slurry to obtain ziprasidone HC1; and
c) recovering the ziprasidone HCL

17. The process of claim 16, wherein the slurry is diluted by addition of water.
18. The process of claim 16, wherein the ziprasidone base is ziprasidone Form B.
19. The process of claim 16, wherein the slurry is carried out at a temperature of at
least about 40°C.
20. Crystalline form of ziprasidone HG1 prepared by the process of claim 16.
21. A process for preparing the ziprasidone.HCl form M, comprising:

a) heating a slurry of ziprasidone HC1 in n-butanol or THF, optionally in mixture
with water; and
b) recovering the ziprasidone HC1 form M.

22. The process of claim 21, wherein the heating is carried out at a temperature of at
least about 40 °C.
23. The process of claim 21, wherein the ziprasidone HC1 of step (a) is ziprasidone
HC1 characterized by a powder XRD pattern with peaks at 11.0,18.1,19.5,21.9
±0.2 degrees 2 theta,
24. The process of claim 21, wherein the ziprasidone HC1 of step (a) is ziprasidone
HC1 characterized by a powder XRD pattern with peaks at 7.4,13.0, 20.7,23.4,
25.9 ±0.2 degrees 2 theta.
25. A process for preparing the ziprasidone HC1 form M comprising:

a) combining aqueous HC1 with ziprasidone base at a temperature of at least
about 40 °C hi a solvent selected from the group consisting of ethanol,
methanol, n-butanol, acetone, ethyl actate, ethyl lactate, dimethyl-carbonate,
optionally in a mixtures with water to obtain a slurry,
b) maintaining the slurry to obtain the ziprasidone HC1 form M; and
c) recovering the ziprasidone HCl form M.
26. A process for preparing the ziprasidone HC1 form M comprising:
a) contacting gaseous hydrogen chloride with ziprasidone base in methanol to
obtain a slurry of ziprasidone hydrochloride in methanol;
b) maintaining the slurry to obtain the ziprasidone HC1 form M; and
c) recovering the ziprasidone HCl form M.
27. A process for preparing the ziprasidone HCl form M substantially free of the
crystalline ziprasidone HC1 characterized by a powder XRD pattern with peaks at
10.9,17.4,19.1,25.0,26.0 i0.2 degrees 2 theta comprising:
a) combining a solution or slurry of ziprasidone base in a solvent with less than
one equivalent HC1 to obtain a reaction mixture containing ziprasidone HC1;
b) stirring or agitating the reaction mixture;
c) adding additional HC1 to obtain additional ziprasidone HC1; and
d) recovering the ziprasidone HC1 form M.

28. The process of claim 27, wherein prior to the addition of HCl in step a, the
temperature of the solution or the slurry is at least 60°C.
29. The process of claim 27, wherein the HCl is added slowly.
30. The process of claim 27, wherein the ratio of HCl is step (a) to step (c) is about
1:10 to about 5:10.
31. The process of claim 30, wherein the ratio of HCl is step (a) to step (c) is about
1:10.
32. The process of claim 27, wherein the solvent is a mixture selected from the group
consisting of THF/acetic acid, THF/methanol, THF/AcOH di-methyl acetamide,
n-butanol/acetic acid and mixtures thereof.
33. The process of claim 27, wherein the precipitation occurs at a temperature of
about 55 to about 70°C.
34. The process of claim 33, wherein the temperature is about 55 to about 65°C
35. The process of claim 34, wherein the temperature is within 2 degrees of 65°C.
36. The process of claim 27, further comprising seeding the solution or slurry of
ziprasidone base with ziprasidone HCl form M.
37. Crystalline form of ziprasidone HCl prepared by the processes of any of claims
21,25,26, or 27.
38. Amorphous form of ziprasidone HCl.
39. The ziprasidone of claim 38, wherein the XRD pattern is that substantially
depicted in Figure 1.
40. A process for preparing amorphous form of claim 39, comprising heating the
ziprasidone HC1 characterized by a powder XRD pattern with peaks at 7.4,13.0,
20.7,23.4,25.9 ±0.2 degrees 2 theta.
41. The process of claim 40, wherein the heating occurs at a temperature of about 80
to about 105 °C.
42. A process for preparing amorphous form of claim 38, comprising exposing the
ziprasidone HC1 characterized by a powder XRD pattern with peaks at 7.4,13.0,
20.7,23.4,25.9 ±0.2 degrees 2 theta to about 10% to about 0% humidity to obtain
amorphous form.
43. The process of claim 42, wherein the humidity is about 0%.
44. A process for preparing amorphous form of claim 38, comprising slurrying
ziprasidone base with methyl ethyl ketone or mono-chloro benzene with gaseous
hydrochloride.
45. Amorphous form of ziprasidone HC1 prepared by the processes of any of claims
42,43 or 44.
46. A crystalline form of ziprasidone HC1 (Form G), wherein the crystalline form is
characterized by a powder XRD pattern with peaks at 9.0,20.6,22.7,25.0,27.0
±0.2 degrees 2 theta.
47. The crystalline form of claim 46, wherein the crystalline form is further
characterized by peaks at 11.3,12.5,13.9,15.6,21.5,23.5,25.8,28.0, 31.5 ±0.2
degrees two-theta.
48. The crystalline form of claim 47, wherein the crystalline form has an XRD pattern
as substantially depicted in Figure 15,
49. A process for preparing ziprasidone HC1 of claim 46 comprising:

a) combining gaseous HC1 with a mixture of ziprasidone base in a solvent
selected from the group consisting of carbon tetrachloride, di-isopropyl-ether,
ethyl acetate, ethyl lactate and mixtures thereof to obtain a slurry of
ziprasidone HC1;
b) maintaining the slurry to obtain ziprasidone HC1 of claim of claim 46; and
c) recovering the ziprasidone HC1.
50. The process of claim 49, wherein combining is carried out by bubbling gaseous
HCI through a slurry of ziprasidone HCI in the solvent.
51. The process of claim 49, wherein the ziprasidone base is ziprasidone base Form B.
52. A process for preparing a mixture of the ziprasidone HCI of claim 13 or the
ziprasidone HCI of claim 46 comprising:

a) combining gaseous HCI with a mixture of ziprasidone base in ethyl acetate to
obtain a slurry of ziprasidone HCI;
b) maintaining the slurry to obtain ziprasidone HCI; and
c) recovering the mixture.

53. The process of claim 52, wherein combining is carried out by bubbling gaseous
HCI through a slurry of ziprasidone HCI in the solvent.
54. The process of claim 52, wherein the ziprasidone base is ziprasidone base Form B.
55. Crystalline form of ziprasidone HCI prepared by the processes of any of claims 49
or 52.
56. A crystalline form of ziprasidone HCI (Form I), wherein the crystalline form has
an XRD pattern with peaks at 15.8,16.2,18.9,23.8,27.0 ±0.2 degrees 2 theta,
57. The crystalline form of claim 56, wherein the crystalline form has peaks at 10.5,
1.1.3,21.1,24.8,26.0 ±0.2 degrees two-theta.
58. The crystalline form of claim 57, wherein the crystalline form has an XRD pattern as substantially depicted in Figure 16.
59. A process for preparing crystalline ziprasidone HCI of claim 56, comprising
heating the crystalline ziprasidone HCI characterized by a powder XRD pattern
with peaks at 9.0,20.6,22.7,25.0,27.0 ±0.2 degrees 2 theta, wherein the
crystalline ziprasidone HCI characterized by a powder XRD pattern with peaks at
9.0,20.6,22.7,25.0,27.0 ±0.2 degrees 2 theta has been obtained from di-iso-
propyl-ether.
60. Crystalline form of ziprasidone HCI prepared by the process of claim 59,
61. A crystalline form of ziprasidone HCI (Form J), wherein the crystalline form is
characterized by a powder XRD pattern with peaks at 9.1,19.1,25.7,26.3,26.9
±0.2 degrees 2 theta.
62. The crystalline form of claim 61, further characterized by peaks at 11.9,21.4,
23.4,30.7,32.2 ±0.2 degrees two-theta.
63. The crystalline form of claim. 62, wherein the crystalline form has an XRD pattern-
as substantially depicted in Figure 17.
64. A process for preparing ziprasidone HC1 of claim 61 comprising:

a) combining ziprasidone base with HC1 to obtain a slurry of ziprasidone HC1 in
a C5 to C12 hydrocarbon;
b) maintaining the slurry to obtain the crystalline ziprasidone HCl; and
c) recovering the ziprasidone HCl of claim 61.
65. The process of claim 64, wherein the hydrocarbon is toluene.
66. A crystalline form of ziprasidone HCl, wherein the crystalline form has a water
content of about 24% by LOD.
67. Crystalline form of ziprasidone HC1 prepared by the process of claim 64.
68. A crystalline from of ziprasidone HC1 (Form El), wherein the crystalline, form is
characterized a powder XRD pattern with peaks at 7.5,13.0,21.2, 23.4 and 26.0
±02 degrees 2 theta,
69. The crystalline form of claim 68, wherein the crystalline form is former
characterized by peaks at 10.9,16.2,20.8,25.4,303 and 34.8 ±0.2 degrees two-
theta,
70. A crystalline form of ziprasidone HC1 (Form Bl), wherein the crystalline form is
characterized by an FTIR spectrum as substantially depicted in Figure 22,23 and
24.
71. A process for preparing ziprasidone HCl of claim 70 comprising drying the
ziprasidone HCl characterized by a powder XRD pattern with peaks at 9.1,19.1,
25.7,26.3,26v9 ±0.2 degrees 2 theta,
72. The process of claim 71, wherein drying, is carried out by evaporation at a
temperature above about 30ºC.
73. Crystalline form of ziprasidone HCl prepared by the process claim 72.
74. A crystalline form of ziprasidone, wherein the crystalline form has a water content
of about 6% to about 8%.
75. A pharmaceutical composition comprising an effective amount of a the
--ziprasidone HCl of any one of claims 1,7,12,13,20,38,46, 56,60,61,67,68,73
or 74, and at least a single pharmaceuticaly acceptable excipient.
76. A method of .treating a patient suffering from schizophrenia comprising
administering to the patient the pharmaceutical composition of claim 75.