Specification
SOLID FORMS OF LINEZOLID AND PROCESSES FOR PREPARATION THEREOF
Cross-reference to Related Applications
This application claims the benefit of provisional applications Serial Numbers 60/584,371, filed June 29,2004; 60/584,283, filed June 30,2004; 60/601,086, filed August 12,2004; 60/602,227, filed August 17,2004; 60/633,887, filed December 7, 2004; 60/678,440, filed May 5,2005; and 60/684,410, filed May 24,2005; which are incorporated herein by reference.
Field of the Invention
The present invention relates to the solid state chemistry of Linezolid and provides novel crystalline and amorphous forms of Linezolid.
Background of the Invention
F
Linezolid [(S)-N-[[3 -(3-Fluoro-4-morpholmyl)phenyl]-2-oxo-5-oxazolidinyljmethyl] acetamide] is an antimicrobial agent. Linezolid is an oxazolidinone, having the following structure:
(Figure Remove)(
Linezolid is described in the Merck index (13th edition, Monograph number: 05526, CAS Registry Number: 165800-03-3) as wMte crystals, mp 181.5-182,5°. Linezolid, as well as a process for its preparation, is disclosed in U.S. Patent No. 5,688,792 (example 5). Linezolid produced had a m.p. of 181.5-182.5°.
U.S. Patent No. 6,559,305 and U.S. Patent No. 6,444,813 disclose a new crystal form (Form H) of Linezolid. According to U.S. Patent No. 6,559,305, Form U differs from Form I in its DR. spectrum, X-ray powder diffraction spectrum and
melting point. According to U.S. Patent No. 6,559,305, at column 3, line 37: "Crystal Form n is the most stable form below about 85°."
The present invention relates to the solid state physical properties of Linezolid. These properties can be influenced by controlling the conditions under which Linezolid 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 hi a patient's stomach fluid can have therapeutic consequences since it imposes an upper limit on the rate at which an oraUy-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 hi the unit cell, which defines a particular polymorphic form of a substance. These conformational and orientation factors in turn result in particular intramolecular interactions such that different polymorphic forms may give rise to distinct spectroscopic properties that may be detectable by powder X-ray diffraction, solid state 13C NMR spectrometry and infrared spectrometry. A particular 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, thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) and can be used to distinguish some polymorphic forms from others.
The discovery of new polymorphic forms of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials mat 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 Linezolid.
Summary of the Invention
The present invention discloses solid crystalline and amorphous forms of (S)-N-[[3-[3-Fluoro-4-(4-moipholmyl)phenyl]-2-oxo~5-oxazo-lidmyl]methyl]-acetamide and aracemic mixture of solid crystal form (S) and (R) -N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazo-lidinyl]methyl3-acetamide.
One embodiment of the present invention is crystalline Linezolid racemate. Another embodiment of the present invention is Linezolid hydrate.
The present invention relates to novel solid crystal forms of (S)-N-[[3-[3-Fluoro-4-(4-morpholinyi)phenyl]-2-oxo-5-oxazo-lidinyl]me1:hyl]-acetamide (Linezolid), referred to herein as Form Tin, Form V, Form VI, Form DC, Form X, Form Xn, Form XTV, Form XVH, and Form XVm. The crystalline forms of Linezolid described herein have the powder X-ray diffraction (PXRD), Fourier transform infrared spectroscopy (FTIR), FTRaman, or differential scanning calorimetry (DSC) characteristics described herein.
A particular embodiment of the present invention is crystalline Linezolid Form Till, characterized by a PXRD pattern with peaks at about 13.5,16.8,21.1, 21.7, and 22.2 ±0.2 degrees 2 theta.
Another embodiment of the present invention is crystalline Linezolid Form V, characterized by a PXRD pattern with peaks at about 12.3,17.6,22.2,24.6, and 31.8 ±0.2 degrees 2 theta.
Another embodiment of the present invention is crystalline Linezolid Form VI, characterized a PXRD pattern with peaks at about 12.3,21.3,24.7,25.2, and 27.7 ±0.2 degrees 2 theta.
Another embodiment of the present invention is crystalline Linezolid Form IX, characterized by a PXRD pattern with peaks at about 13.4,17.9,21.4,22.3, and 25.6 ±0.2 degrees 2 theta. This form is a racemate.
Another embodiment of the present invention is crystalline Linezolid Form X, characterized by a PXRD pattern with peaks at about 4.7,15.7, and 21.7 ±0.2 degrees 2 theta.
Another embodiment of the present invention is crystalline Linezolid Form XH, characterized by a PXRD pattern with peaks at about 10.4,10.7,17.1, and 22.7 ±0.2 degrees 2 theta.
Another embodiment of the present invention is crystalline Linezolid Form
XIV, characterized by a PXRD pattern with peaks at about 3.7,5.0,15.8, and 16.7
±0.2 degrees 2 theta. .
Another embodiment of the present invention is crystalline Linezolid Form
XVII, characterized by a PXRD pattern with peaks at about 6.1,12.3,18.4,and21.2
±0.2 degrees 2 theta.
Another embodiment of the present invention is crystalline Linezolid Form
XVIII, characterized by a PXRD pattern with peaks at about 6.0,11.8,17.2,18.2, and
24.9 ±0.2 degrees 2 theta.
The PXRD peaks in degrees 2 theta of the novel crystalline forms are shown in Table 1, with the most characteristic peaks indicated in bold.
TABLE 1
4
(Table Remove)The characteristic FTIR peaks of Form H (listed in U.S. Patent No. 6,444,813), Form TDI, Form V, Form VI, Form DC, Form X and Form XII in cm"1 are shown in Table 2a. This data was obtained using a Perkin Elmer SPECTRUM ONE FT-IR spectrometer in DRIFT mode. The samples in the 4000-400 cm"1 interval were scanned 16 times with 4.0 cm"1 resolution.
(Table Remove)
The characteristic FTIR peaks of Form n (listed in U.S. Patent No. 6,444,813), Form Till, Form V, Form VI, Form IX, Form X and Form XII in cm"1 are shown in Table 2b. This data was obtained using a Perkin Elmer SPECTRUM ONE FT-ffi. spectrometer using mineral oil mull technique. The samples in the 4000-400 cm"1 interval were scanned 16 times with 4.0 cm"1 resolution.
TABLE 2b
10
(Table Remove)
The characteristic FTRaman peaks of Form n, Form Tin, Form V, Form VI, and Form X in cm"1 are shown in Table 3.
TABLES
(Table Remove)
The present invention provides methods of preparing the novel crystalline Form THI, Form V, Form VE, Form DC, Form X, Form XH, Form XIV, Form XVII, and Form XVHI of Linezolid.
One embodiment of the present invention is crystalline Linezolid racemate. Crystalline Linezolid racemate is a mixture of the (S) and (R) enantiomers of N-[[3-(3-Fluoro-4-morpholinyl)phenyl]-2-oxo-5-oxazoliduiyl]methyl] acetamide.
Yet another embodiment of the present invention is an amorphous form of Linezolid and a method for preparing thereof.
A further embodiment of the present invention is pharmaceutical formulations comprising any one of the novel crystalline Form TIE, Form V, Form VI, Form DC, Form X, Form XH, Form XIV, Form XVH, and Form XV3H, as well as the amorphous form of Linezolid, and apharmaceutically acceptable excipient.
Also provided is the method of treating gram positive bacterial infections using said pharmaceutical formulations.
The crystalline forms of the present invention may exist in anhydrous forms as well as in hydrated and solvated forms. The present invention encompasses solvates, particularly hydrates, of the novel crystalline forms of Linezolid described herein where those solvates or hydrates have the powder X-ray diffraction (PXRD), Fourier transform infrared spectroscopy (FTIR), FTRaman, or digital scanning calorimetry (DSC) characteristics described herein.
Figures
Figure 1 is a powder X-Ray diffractogram of crystalline Linezolid Form Tin.
Figure 2a-2c is an FTIR spectrum of crystalline Linezolid Form Tin, obtained using
mineral oil mull technique.
Figure 2d-2f is an FTIR spectrum of crystalline Linezolid Form Tin, obtained using
DRIFT technique.
Figure 3 is a DSC thermogram of crystalline Linezolid Form THI.
Figure 4a-4d is an FTRaman spectrum of crystalline Linezolid Form Tin.
Figure 5 is a powder X-Ray diffractogram of crystalline Linezolid Form V.
Figure 6a-6c is an FTIR spectrum of crystalline Linezolid Form V, obtained using
mineral oil mull technique.
Figure 6d-6f is an FTIR spectrum of crystalline Linezolid Form V, obtained using
DRIFT technique.
Figure 7a-7d is an FTRaman spectrum of crystalline Linezolid Form V.
Figure 8 is a powder X-Ray diffractograrn of crystalline Linezolid Form VI.
Figure 9a-9c is an FTIR spectrum of crystalline Linezolid Form VI, obtained using
mineral oil mull technique.
Figure 9d-9f is an FTIR spectrum of crystalline Linezolid Form VI, obtained using
DRIFT technique..
figure lOa-lOd is an FTRaman spectrum of crystalline Linezolid Form VI.
N-[2-(acetyloxy)-3-chloropropyl]acetamide (obtained in example lOb) in 20 ml THF was added. The solution was stirred at RT for 15 hr. 60 ml water, 60 ml methylene chloride, and 6 ml acetic acid were added to the solution and stirred at RT for 30 min. The phases were separated. The aqueous phase was washed with 100 ml methylene chloride. The combined organic phase was concentrated in vacuum to dryness. The resulting oil was slurried with 20 ml hexane at RT. The obtained crystals were filtered and dried under nitrogen to obtain 0.52 g of (±) Linezolid Form IX.
Example 6 - preparation of Linezolid FormX by Ivophilization of Linezolid
2.0 g of Linezolid Form II was dissolved in 800 ml water, frozen at -50°C, and placed in a laboratory lyophilizer. The vacuum was set to 0.2 mm Hg. The water was evaporated during 5 days at a temperature of 10°C. The resulting material was analyzed by PXRD and showed a novel form of Linezolid (Form X).
Example 7 - preparation of Linezolid Form XII
A flask charged with a mixture containing 2.8 g of (S)-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl amine in 40 ml ethyl acetate was stirred at 0°C. Methyl amine (2 equivalents) was added followed by acetic anhydride (2.5 equivalents). The reaction mixture was maintained at 0°C overnight. Linezolid precipitated and was filtered and dried in an oven at 50°C. The crystals were analyzed by PXRD and showed a novel form of Linezolid (Form XII).
Example 8 - preparation of Linezolid Form XIV
To a solution of 5.6 g crude (S)-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl amine in 300 ml ethyl acetate was added 10 ml triethyl amine. The reaction mixture was stirred at 25°C. Acetic anhydride (10 ml) was added dropwise. The reaction mixture was stirred overnight at room temperature. Petroleum ether was added and a gelatinous precipitation was observed. The reaction mixture was stirred overnight at room temperature. Linezolid precipitated and the crystals were filtered. The wet crystals were analyzed by PXRD and showed a novel form of Linezolid (Form XIV).
Example 9 - preparation of Linezolid Form XVII
A flask charged with a solution containing 1.5 g of (S)-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl amine in 60 ml toluene was cooled to 3°C and acetic anhydride (2 equivalents) was added dropwise. The reaction mixture was brought to RT. Linezolid was precipitated from the reaction mixture and filtered. The wet crystals were analyzed by PXRD and showed a novel form of Linezolid (Form XVIT).
Example 10 - preparation of Linezolid Form XVIII
To a flask charged with a mixture containing 1.5 g of (S)-N-(4-morpholinyl~3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl amine in 60 ml toluene at 25°C, triethyl amine (5.2 ml) was added. The mixture was cooled to 3°C and acetic anhydride (2.5 equivalents) was added dropwise. The reaction mixture was brought to RT. Linezolid that precipitated from the reaction mixture was filtered. The wet crystals were analyzed by PXRD showing a novel form of Linezolid (Form XVEDT).
Example 11 -preparation of amorphous Linezolid bv melting of Linezolid
Linezolid Form II (2.0 g) was heated in a test tube until melting occurred. The liquefied material was transferred to a cooled reservoir. The solid form obtained was analyzed by PXRD and showed a novel form of Linezolid, the amorphous form.
Example 12 -preparation of amorphous Linezolid by heating of Linezolid
Linezolid Form X (0.5 g) was heated in a conventional oven at a temperature of 60°C for 1.5-2 hours. The amorphous form obtained was analyzed by PXRD.
WHAT IS CLAIMED IS:
Linezolid hydrate.
Crystalline Linezolid and solvates thereof characterized by data selected from the
group consisting of: an X-ray powder diffraction pattern having peaks at about
12.3,17.6,22.2,24.6, and 31.8 ±0.2 degrees 2 theta, an FTIR spectrum having
peaks at about 3336,2497,1742,1662,1546,1516,1425,1229, and 1038 cm'1
and an FTRaman spectrum having peaks at about 2933,2978,1082 and 1036cm"1.
The crystalline linezolid of Claim 2, characterized by an X-ray powder diffraction
pattern having peaks at about 12.3,17.6,22.2,24.6, and 31.8 ±0.2 degrees 2 theta.
The crystalline linezolid of Claim 3, further characterized by an X-ray powder
diffraction pattern having peaks at about 7.5,13.5,21.1,25.5, and 27.8 ±0.2
i degrees 2 theta.
The crystalline linezolid of Claim 4, characterized by an X-ray powder diffraction
pattern substantially as depicted in Figure 5.
The crystalline linezolid of Claim 2, characterized an FTIR spectrum having peaks
at about 3336,2497, 1742,1662,1546,1516,1425,1229, and 1038 cm'1.
The crystalline linezolid of Claim 6, characterized by an FTIR spectrum
substantially as depicted in Figures 6a-6c.
The crystalline linezolid of Claim 2, characterized an FTRaman spectrum having
peaks at about 2933,2978,1082 and 1036 cm"1.
The crystalline linezolid of Claim 8, farther characterized by an FTRaman
spectrum having peaks at about 1660,1428,1465,904, 661,462,424,339 and
127 cm"1.
10. The crystalline linezolid of Claim 9, characterized by an FTRaman spectrum
substantially as depicted in Figures 7a-7d.
11. The crystalline linezolid of any one of Claims 2-10, having plate-shaped crystals.
12. The crystalline linezolid of any one of Claims 2-11, containing less than about
10% of linezolid Form II.
13. A process for the preparation of the crystalline linezolid of Claim 2 comprising:
a) dissolving R-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl
amine in a solution of ethyl acetate and a base; b). cooling the solution;
adding an acetylating agent to the solution and maintaining the solution for at
least one hour;
adding an anti-solvent so as to precipitate the Linezolid; and
recovering the precipitated Linezolid of Claim 2.
The process of Claim 13, wherein the base in step a) is triethyl amine.
The process of any one of Claims 13 and 14, wherein the acetylating agent in step
c) is acetyl chloride or acetic anhydride.
The process of any one of Claims 13-15, wherein the anti-solvent in step d) is
petroleum ether.
Crystalline Linezolid and solvates thereof characterized by data selected from the
group consisting of: an X-ray powder diffraction pattern having peaks at about
4.7,15.7, and 21.7 ±0.2 degrees 2 theta, an FTER. spectrum having peaks at about
3090,1524,1335,1195,1115,1081, 940, 927, 802, and 752 cm'1 and an
FTRaman spectrum having peaks at about 2957,2859, 880,752 and 715 cm"1.
The crystalline linezolid of Claim 17, characterized by an X-ray powder
diffraction pattern having peaks at about 4.7,15.7, and 21.7 ±0.2 degrees 2 theta.
19. The crystalline linezolid of Claim 18, further characterized by an X-ray powder
diffraction pattern having peaks at about 3.5,10.3, and 20.2 degrees 2 theta.
The crystalline linezolid of Claim 19, characterized by an X-ray powder
diffraction pattern substantially as depicted in Figure 13.
The crystalline linezolid of Claim 17, characterized an FTIR spectrum having
peaks at about 3090,1524,1335,1195,1115,1081, 940, 927, 802, and 752 cm"1.
The crystalline linezolid of Claim 21, characterized by an FTIR spectrum
substantially as depicted in Figures 14a-14c.
The crystalline linezolid of Claim 17, characterized an FTRaman spectrum having
peaks at about 2957,2859, 880,752 and 715 cm"1.
The crystalline linezolid of Claim 23, further characterized by an FTRaman
spectrum having a peak at about 975 cm"1.
The crystalline linezolid of Claim 24, characterized by an FTRaman spectrum
substantially as depicted hi Figures 16a-16d.
The crystalline linezolid of any one of Claims 17-25, containing less than about
10% of linezolid Form H.
A process for the preparation of the crystalline linezolid of Claim 17 comprising:
dissolving linezolid in water; and
lyopbilizing the dissolved linezolid to form the crystalline Linezolid of Claim
17.
28. Crystalline Linezolid forms and hydrates thereof characterized by having peaks at
X-ray powder diffraction patterns selected from the group consisting of:
13.5,16.8,21.1,21.7, and 22.2 ±0.2 degrees 2 theta;
12.3,21.3,24.7, 25.2, and 27.7 ±0.2 degrees 2 13.4,17.9,2L4,22.3, and 25.6 ±0.2 degrees 2 theta; ' 10.4,10.7,17.1, and 22.7 ±0.2 degrees 2 theta; 3.7, 5.0,15.8, and 16.7 ±0.2 degrees 2 theta; 6.1, 12.3,18.4, and 21.2 ±0.2 degrees 2 theta; or 6.0,11.8,17.2,18.2, and 24.9 ±0.2 degrees 2 theta.
The crystalline linezolid forms and hydrates of Claim 28, containing less than
about 10% of linezolid Form H
A pharmaceutical composition prepared by combining at least one
pharmaceutically-acceptable excipient with at least one of the crystalline forms,
and hydrates of Linezolid of any one of Claims 2-12,17-26,28, and 29.
31. Amorphous Linezolid characterized by data selected from the group consisting of:
an X-ray powder diffraction pattern that is substantially free of visible
diffraction peaks;
an X-ray powder diffraction pattern substantially as shown in Figure 22;c) an
FTIR spectrum having peaks at about 1741, 1662, 1547, 1516, 1335, 1257, 1228,
1214, 1149, 1080,1059, 1050, 903, 824, and 755 cm"1;
an FTIR spectrum substantially as shown in Figure 23a-23c;
a DSC thermogram having a broad exothermic peak around 70°C, followed by
an endothermic peak at around 180°C; and
a DSC thermogram substantially as shown in Figure 24.
The amorphous Linezolid of claim 1 containing less than 20% by weight
Linezolid Form II.
The amorphous Linezolid of claim 1 containing less than 10% by weight.
The amorphous Linezolid of claim 1 containing less than 5% by weight Linezolid
Form II.
A pharmaceutical formulation comprising a therapeutically effective amount of
the amorphous Linezolid of claim 1 and a pharmaceutically acceptable excipient.