WO2005066196A1

WO2005066196A1 - Amorphous form of finasteride and processes for its preparation

Info

Publication number: WO2005066196A1
Application number: PCT/IB2004/004270
Authority: WO
Inventors: Yatendra Kumar; Saridi Madhava Dileep Kumar; Rakesh Singh; Swargam Sathyanarayana
Original assignee: Ranbaxy Laboratories Ltd
Current assignee: Ranbaxy Laboratories Ltd
Priority date: 2003-12-30
Filing date: 2004-12-23
Publication date: 2005-07-21
Anticipated expiration: 2006-06-30

Abstract

The present invention relates to an amorphous form of finasteride and processes for its preparation. Also provided are pharmaceutical compositions that include the amorphous finasteride.

Description

AMORPHOUS FORM OF FINASTERIDE AND PROCESSES FOR ITS PREPARATION Field of Invention The present invention relates to an amorphous form of finasteride and processes for its preparation. The present invention also relates to pharmaceutical compositions that include amorphous finasteride. Background of the Invention Chemically, finasteride is 17β -N- (tert-butylcarbamoyl)-4-aza-5α-androst-l-ene-3- one of structural Formula I

Formula I and is lαiown from U.S. Patent No. 4,760,071. It is a testosterone 5α-reductase inhibitor and is used in the treatment of hyperandro genie conditions, such as acne vulgaris, seborrhea, female hirsutism and benign prostatic hypertrophy. Finasteride has been reported to exist in two crystalline polymorphic forms, I and II, in U.S. Patent Nos. 5,652,365 and 5,886,184 respectively. Another polymorphic form, form III, is disclosed in PCT application WO 02/20553. Summary of the Invention In one general aspect there is provided an amorphous form of finasteride. The amorphous form of finasteride is characterized by the X-ray diffraction pattern as shown in figure 1. In another general aspect there is provided a process for the preparation of an amorphous form of finasteride. The process includes obtaining a solution of finasteride in one or more solvents and recovering the pure amorphous form of finasteride by the removal of the solvent. Embodiments of the process may include one or more of the following features. For example, the solution of finasteride may be obtained directly from a reaction mixture or it may be obtained by dissolving crystalline finasteride in a solvent. The solvent may include one or more of alcohols, ketones, ethers, chlorinated hydrocarbons, esters, nitriles, dipolar aprotic solvents, cyclic ethers and mixtures thereof. The alcohols may include one or more of methanol, ethanol, isopropanol and mixtures thereof. The chlorinated hydrocarbons may include one or more of dichloromethane, dichloroethane and mixtures thereof. The nitriles may include one or more of acetonitrile and benzonitrile. The cyclic ethers may include one or more of tetrahydrofuran, dioxane and mixtures thereof. The ethers may include one or more of diethyl ether, diisopropylether, tertiary butylethylether and mixtures thereof. The solvent may be removed by one or more of distillation, distillation under vacuum, evaporation, spray drying, freeze-drying, lyophilization, filtration, filtration under vacuum, decantation and centrifugation. For example, the amorphous form of finasteride may be recovered from the solution by spray drying. The gas inlet temperature of the spray drier may range from about 40°C to about 100°C and the gas outlet temperature of the spray drier may range from about 20°C to about 80°C. The process may further include adding one or more additional solvents before removing the solvent. The one or more additional solvents may include organic solvents in which finasteride is insoluble, poorly soluble, practically insoluble or partially soluble. The amorphous form of finasteride may be recovered from the solution by distillation.

The distillation may be carried out under vacuum. The amorphous form of finasteride may also be recovered from the solution by filtration. The process may further include drying of the product obtamed. The amorphous finasteride obtained may have the X-ray diffraction pattern of Figure 1. In another general aspect there is provided a process for the preparation of an amorphous form of finasteride. The process includes subjecting crystalline finasteride to milling until the crystalline form is converted to the amorphous form. Embodiments of the process may include one or more of the features described above. In yet another general aspect there is provided a pharmaceutical composition comprising an amorphous form of finasteride and one or more pharmaceutically acceptable excipients. Embodiments of the pharmaceutical composition may include one or more of the following features or those described above. For example, the pharmaceutical composition may further include one or more additional therapeutic ingredients. The amorphous form of finasteride has the X-ray diffraction pattern as shown in figure 1. In yet another general aspect there is provided a method of treating and preventing hyperandrogenic conditions including acne vulgaris, seborrhea, androgenetic alopecia, female hirsutism, and benign prostatic hypertrophy. The method mcludes administering a pharmaceutical composition of finasteride to a patient in need thereof, wherein the pharmaceutical composition includes an amorphous form of finasteride and one or more pharmaceutically acceptable excipients. The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the description and claims. Description of the Drawings Fig. 1 is an X-ray diffraction spectrum of the amorphous form of finasteride. Fig. 2 is an IR spectrum of the amorphous form of finasteride using potassium bromide pellets. Fig. 3 is a DSC graph of the amorphous form of finasteride.

Detailed Description of the Invention The amorphous form of finasteride is characterized by its non-crystalline nature. It may be characterized by X-ray powder diffraction spectrum, IR spectrum or DSC graph as shown in Figures 1, 2 and 3, respectively. The inventors have developed a process for the preparation of the amorphous form of finasteride. The process includes obtaining a solution of finasteride in one or more of solvents and recovering the amorphous form of finesteride by the removal of the solvent. The inventors also have developed pharmaceutical compositions that include the amorphous form of finesteride and one or more pharmaceutically acceptable excipients. The solution of finasteride may be obtained by dissolving crystalline finasteride in one or more suitable solvents. This solution of finasteride may be obtained directly from the last step of a reaction in which finasteride is formed. The solution of crystalline finasteride may be obtamed by heating the solvent which includes crystalline finasteride. It may be heated from about 40°C to about 200°C, or from about 50°C to about 150°C. It may be heated for about 10 minutes to about 24 hours and, in particular, it may be heated for about 2 hours to about 3 hours. The solution may then be filtered to remove any undissolved foreign particulate matter. The crystalline finasteride used as the starting material includes polymorphic forms I to III lαiown in the prior art, solvates, hydrates and mixtures thereof. Finasteride may be obtained by methods known in the art, such as the processes reported in U.S. Patent Nos.

4,377,584; 4,760,071; 5,084,574; 5,237,061; 5,120,847; 5,670,643; 5,021,575; 6,509,466; and WO 02/46207; J. Med. Chem., 1986, 29, 2298-2315; J. Med. Chem., 1984, 27, 1690-1701; and Heterocycles, 1998,47, 703. The solvent may be removed by one or more of distillation, distillation under vacuum, evaporation, spray drying, freeze-drying, lyophilization, filtration, filtration under vacuum, decantation and centrifugation. The amorphous form of finasteride maybe recovered, for example, from the solution by the spray drying technique. The spray drying may be accomplished using a spray dryer that operates on the principle of nozzle spraying in a parallel flow, i.e., the sprayed product and the drying gas flow in the same direction. The drying gas may be air or inert gases, such as nitrogen, argon and carbon dioxide. For example, the drying gas may be nitrogen. The gas inlet temperature to the spray drier may range from about 40°C to about 100°C and the outlet temperature may range from about 20°C to about 80°C. Suitable solvents include any solvent or solvent mixture in which finasteride is soluble. This mcludes one or more of alcohols, ethers, esters, ketones, chlorinated hydrocarbons, nitriles, polar aprotic solvents, cyclic ethers, and mixtures thereof. Suitable alcohols include one or more of methanol, ethanol, n-propanol, and isopropanol. Suitable ketones include one or more of acetone, ethyl methyl ketone, methyl isobutyl ketone and diisobutyl ketone. Suitable esters include one or more of ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, n-propyl acetate, isobutyl acetate, butyl acetate and amyl acetate. Suitable ethers include one or more of diethylether, diisopropylether and tertiary butylethylether. Suitable chlorinated hydrocarbons include methylene chloride and ethylenedichloride. Suitable cyclic ethers include tetrahydrofuran and 1,4-dioxane. Suitable polar aprotic solvents include one or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, acetonitrile and N-methylpyrrolidone. Suitable nitriles include acetonitrile and benzonitrile. The amorphous finasteride also can be recovered from the solution by freeze-drying. The amorphous form of finasteride also can be recovered from the solution by adding a suitable second solvent resulting in the precipitation of the amorphous form. The second solvent is then removed by filtration, filtration under vacuum, decantation or centrifugation. The second solvent may include organic solvents in which finasteride is insoluble, poorly soluble, practically insoluble or partially soluble and would be known to a person of ordinary skills in the art. Suitable second solvents include one or more of cyclopentane, cyclohexane, cycloheptane, hexane, heptane, petroleum ether, water and mixtures thereof. The process may further include drying the product obtained to achieve the desired moisture values. For example, the product may be dried in a tray drier, under vacuum or in a fluid bed dryer. Also provided is a process for the preparation of the amorphous form of finasteride.

The process includes subjecting crystalline finasteride or a slurry of finasteride in a solvent to milling until the crystalline form is converted to the amorphous form. The slurry of the crystalline form in a solvent can be from about 30% to 85% w/v. The milling may be carried out using a traditional technique of compounding, using a pestle and mortar, or by milling machines known in the art. Suitable milling machines include various makes of ball mills, roller mills, gyratory mills, and the like. Also provided is a pharmaceutical composition that includes the amorphous form of finasteride and one or more pharmaceutically acceptable excipients. This pharmaceutical composition also may include one or more additional therapeutic ingredients. The amorphous form of finasteride may be conventionally formulated into tablets, capsules, suspensions, dispersions, injectables, creams, ointments, gels, solutions, transdermal patches, aerosols and other pharmaceutical forms. Any suitable route of administration may be employed including topical, peroral and parental. Also provided is a method for treating or preventing hyperandrogenic conditions, such as acne vulgaris, seborrhea, androgenetic alopecia, female hirsutism, and benign prostatic hypertrophy. The method includes administering a pharmaceutical composition that includes the amorphous form of finasteride and one or more pharmaceutically acceptable excipients. The following example is intended to illustrate the invention should not be construed as limiting the scope of the invention in any way.

METHODS Powder XRD X-Ray Difractometer, Rigaku Coorperation, RU-H3R Goniometer CN2155A3 X-Ray tube with Cu target anode Divergence slits 1 0, Receiving slit 0.15mm, Scatter slit 1° Power: 40 KV, 100 mA Scanning speed: 2 deg/min step: 0.02 deg Wave length: 1.5406 A

FT-IR Instrument: Perkin Elmer, 16 PC SCAN: lόscans, 4.0 cm.-l according to the USP 25, general test methods page 1920, infrared absorption spectrum by potassium bromide pellet method.

DSC DSC821 e, Mettler Toledo Sample weight: 3-5 mg Temperature range: 50-350° C Heating rate: 20° C/min Nitrogen: 80.0 mL/min Number of holes in the crucible: 1 Example 1 Crystalline finasteride (20 g) was dissolved in methanol (100 ml) at 25°C to 30°C. The clear solution obtained was subjected to spray drying in a mini spray dryer (Buchi Model 190). The spray drier had a nitrogen gas flow rate of 600 NL/hour. The inlet temperature was kept at 50°C and the outlet temperature was 30°C. The finasteride was charged in the spray drier for 30 minutes and 12.5 g of white fluffy powder was collected and dried under reduced pressure at 50°C to 55°C. The moisture content was measured and the material subjected to powder XRD, IR, and DSC. The results of these measurements are provided below:

Moisture content: 0.2% w/w (by KF)

Powder XRD, IR and DSC were similar to those shown in Figures 1, 2, and 3 respectively. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are included within the scope of the present invention.

Claims

We Claim: 1. An amorphous form of finasteride.

2. An amorphous form of finasteride characterized by X-ray diffraction pattern of Figure 1.

3. A process for the preparation of an amorphous form of finasteride, the process comprising obtaining a solution of finasteride in one or more solvents and recovering the pure amorphous form of finasteride by the removal of the solvent.

4. The process according to claim 3, wherein the solution of finasteride is obtained directly from a reaction mixture.

5. The process according to claim 3, wherein the solution of finasteride is obtained by dissolving crystalline finasteride in a solvent.

6. The process according to claim 3, wherein the solvent comprises one or more of alcohols, ketones, ethers, chlorinated hydrocarbons, esters, nitriles, dipolar aprotic solvents, cyclic ethers and mixtures thereof.

7. The process according to claim 6, wherein the alcohol comprises one or more of methanol, ethanol, isopropanol and mixtures thereof.

8. The process according to claim 6, wherein the chlorinated hydrocarbons comprise one or more of dichloromethane, dichloroethane and mixtures thereof.

9. The process according to claim 6, wherein the nitriles comprise one or more of acetonitrile and benzonitrile.

10. The process according to claim 6, wherein the cyclic ethers comprise one or more of tetrahydrofuran, dioxane and mixtures thereof.

11. The process according to claim 6, wherein the ether comprises one or more of diethylether, diisopropylether, tertiary butylethylether and mixtures thereof.

12. The process according to claim 3, wherein removing the solvent comprises one or more of distillation, distillation under vacuum, evaporation, spray drying, freeze-drying, lyophilization, filtration, filtration under vacuum, decantation and centrifugation.

13. The process according to claim 12, wherein the amorphous form of finasteride is recovered from the solution by spray drying.

14. The process according to claim 13, wherein the gas inlet temperature of the spray drier ranges from about 40°C to about 100°C.

15. The process according to claim 13, wherein the gas outlet temperature of the spray drier ranges from about 20°C to about 80°C.

16. The process according to claim 12, further comprising adding one or more additional solvents before removing the solvent.

17. The process according to claim 16, wherein the one or more additional solvents comprise organic solvents in which finasteride is insoluble, poorly soluble, practically insoluble or partially soluble.

18. The process according to claim 3, wherein the finasteride in an amorphous form is recovered from the solution by distillation.

19. The process according to claim 18, wherein the distillation is caπied out under vacuum.

20. The process according to claim 3, wherein the finasteride in an amorphous form is recovered from the solution by filtration.

21. The process according to claim 3, further comprising additional drying of the product obtained.

22. The process according to claim 3, further comprising forming the product obtained into a finished dosage form.

23. The process according to claim 3, wherein the finasteride has the X-ray diffraction pattern of Figure 1.

24. A process for the preparation of an amorphous form of finasteride, the process comprising subjecting crystalline finasteride to milling until said crystalline form is converted to the amorphous form.

25. A pharmaceutical composition comprising an amorphous form of finasteride and one or more pharmaceutically acceptable excipients.

26. The pharmaceutical composition according to claim 25, further comprising one or more additional therapeutic ingredients.

27. The pharmaceutical composition according to claim 25, wherein the amorphous form of finasteride has the X-ray diffraction pattern of Figure 1.

28. A method of treating and preventing hyperandrogenic conditions comprising acne vulgaris, seborrhea, androgenetic alopecia, female hirsutism, and benign prostatic hypertrophy, the method comprising administering a pharmaceutical composition of finasteride, wherein the pharmaceutical composition comprises an amorphous form of finasteride and one or more pharmaceutically acceptable excipients.