CLIAMS:1. A process for preparation of a Clocortolone of formula (I),

wherein R1, R3 and R5 is CH3, R2 and R4 is OH, R6 is H, X is Cl and Y is F,
comprising the steps of
i) reacting a 9,11-epoxy compound of formula (III)

wherein R1, R3, R5 and R7 is CH3, R6 is H and Y is F, with hydrogen chloride to form a compound formula (II); and

ii) deacetylating the compound of formula (II)

wherein R1, R3, R5 and R7 is CH3, R2 is OH, R6 is H, X is Cl and Y is F, with an alkaline carbonate in the presence of a polar solvent.

2. The process as claimed in claim 1, wherein the hydrogen chloride is selected from any one of a concentrated hydrochoric acid and a gaseous hydrochloride.

3. The process as claimed in claim 1, wherein the polar solvent is selected from methanol, ethanol, n-propanol, dichloromethane, tetrahydrofuran, acetonitrile, acetone and/or mixtures thereof.

4. The process as claimed in claim 1, wherein the polar solvent is a mixture of methanol and dichloromethane in a ratio of 1:1.

5. The process as claimed in claim 1, wherein the 9,11-epoxy compound of formula (III) is prepared by,
a) enolizing a compound of formula (IV)

wherein R1, R3, R5, R7 is CH3 and R6 is H,
by treating with an acylating agent in the presence of a solvent to form a 9ß,11ß-epoxy compound of formula (IVa),

wherein R1, R3, R5, R7 and R8 is CH3 and R6 is H; and

b) treating the 9ß,11ß-epoxy compound of formula (IVa) with a stereoselective fluorinating agent to get the 9,11-epoxy compound of formula (III).

6. The process as claimed in claim 5, wherein the acylating agent is selected from acetic anhydride, acetyl chloride and isopropenyl acetate, preferably isopropenyl acetate.

7. The process as claimed in claim 5, wherein the solvent used in step a) is an inert solvent selected from the group consisting of halogenated solvent, hydrocarbon solvent, ester solvent, nitrile solvent and aprotic polar solvent.

8. The process as claimed in claim 5, wherein the halogenated solvents is selected from dichloromethane, ethylene dichloride and chloroform; the hydrocarbon solvent is selected from toluene, xylene, n-hexane, n-heptane and cyclohexane; the ester solvent is selected from ethyl acetate, isopropyl acetate and tert-butyl aceatate; the nitrile solvent is selected from acetonitrile, propionitrile and butyronitrile; and the aprotic polar solvent selected from dimethyl sulfoxide, N,N-dimethyl formamide, dimethyl acetamide, N-methyl pyrolidinone and mixtures thereof.

9. The process as claimed in claim 5, wherein the stereoselective fluorinating agent is selected from the group consisting of N-fluoro-N-chloromethyl triethylene diamine bis tetrafluoroborate, Octan-di-tetrafluoroborate, 1-fluoro-benzenesulfonamide and perchloryl fluoride and mixture thereof.

10. The process as claimed in claim 5, wherein the fluorinating agent is N-fluoro-N-chloromethyl triethylene diamine bis tetrafluoroborate.

11. The process as claimed in claim 5, wherein the compound of formula (IV) is prepared by acetylation of a 17-desoxy oxide compound of formula (V)

wherein R1, R3, R5 is CH3, R4 is OH and R6 is H..

12. The process as claimed in claim 11, wherein the acylating agent used is selected from acetic anhydride and acetyl chloride.

13. The process as claimed in claim 1, wherein the Clocortolone obtained is converted to Clocortolone pivalate by reaction of Clocortolone with pivaloyl chloride.

14. The process as claimed in claim 13, wherein the reaction is carried out in the presence of a solvent and a weak base.

15. The process as claimed in claim 13, wherein the solvent is selected from ethyl acetate and methylene dichloride.

16. The process as claimed in claim 13, wherein the weak base is selected from pyridine and triethyl amine.

17. A process for preparation of a Clocortolone Pivalate polymorph A, the process comprising the steps of:
a. adding crude Clocortolone Pivalate to toluene;
b. heating the reaction mixture to reflux;
c. cooling the mixture to room temperature;
d. cooling the mixture to 5-10°C;
e. dissolving the toluene purified solid in acetone to get clear solution;
f. adding methanol to the solution and heating to reflux; and
g. cooling filtering and drying.
,TagSPECI:
Field of the invention

The present invention relates to an improved process for preparation of a 17-desoxy corticosteroid and more particularly, to a preparation of a Clocortolone Pivalate and polymorphic form A thereof.

Background of the invention

Clocortolone chemically described as (6a,11a,16a)-9-Chloro-6-fluoro-11,21-dihydroxy-16-methylpregna-1,4-diene-3,20-dione, is a topical corticosteroid and typically used as an anti-inflammatory agent. Clocortolone is 17-desoxy medium-strength corticosteroid and is used to treat a variety of skin conditions for example eczema, dermatitis, allergies, rash and the like. Clocortolone reduces swelling, itching, and redness that occur in these types of conditions. Clocortolone is normally applied in the form of 21-Acetate or Pivalate ester. It is well known in the prior art that Clocortolone pivalate of formula (Ia) in 0.1% cream is effective in relieving the signs and symptoms of corticosteroid-responsive inflammatory dermatoses involving facial skin, including seborrheic dermatitis, contact dermatitis, atopic dermatitis, and psoriasis.

Inclusion of halogen, particularly fluorine, at either C-6 or C-9 positions in the cortisone molecule increases potency. Combination of these potentiating groups in the same molecule leads to an additive influence on potency. Various laboratory scale methods have been reported in the prior art for the synthesis of clocortolone. Reference may be made to PCT application WO2012011106 that teaches a single step procedure for the synthesis of clorcotolone. The process employed is regioselective and removes the hydroxyl group at the 17th position only, without the need to protect the halogen groups present at different position of the steroid ring. However, the procedure disclosed in WO2012011106 involves the use of trimethyl silyl iodide which is a highly inflammable, volatile substance and reacts violently with water {Ref: Material Safety Data Sheet-MSDS-Sigma Aldrich}. This could be a limitation and potential problem during the scale up and large scale production of clocortolone.
Similarly, GB1340769A and US3729495, both disclose the synthesis of clocortolone from ? 9(11) steroids. This procedure needs to be carried out in the presence of solvents having a high dielectric constant like nitromethane, nitroethane and nitrobenzene. However, the use of these solvents could be potentially risky {Ref: Material Safety Data Sheet-MSDS-Sigma Aldrich} and pose problems during large scale production.
Another US patent, US3057886 also describes similar procedures but with the disadvantage that the removal of by products from the reaction mixture being difficult. It has been observed that the processes known in the prior art use either single step or multi step methods for the synthesis of clocortolone, however on a laboratory scale. One or more of the steps involved or reagents used could be potentially problematic when the process is scaled up. The need for a process of clocortolone synthesis that uses reagents that are easier to handle on a larger scale still remains unmet. Moreover the removal of the hydroxyl group at the 17th position requires highly specific reagents that do not disturb the other groups on the steroid ring.
Accordingly, there is a need to provide an improved process for preparation of clocortolone pivalate where the starting material is 17-desoxy steroid and that the process gives a better yield and higher purity of the final product. Also, there is a need of a multi step process for the preparation of polymorph A of clocortolone pivalate.

Summary of the invention

Accordingly the present invention teaches a process for preparation of a Clocortolone of formula (I)

wherein R1, R3 and R5 is CH3, R2 and R4 is OH, R6 is H, X is Cl and Y is F.
The process comprises reacting a 9,11-epoxy compound of formula (III) wherein R1, R3, R5 and R7 is CH3, R6 is H and Y is F,

with hydrogen chloride to form a compound of formula (II) and deacetylating the compound of formula (II) wherein R1, R3, R5 and R7 is CH3, R2 is OH, R6 is H, X is Cl and Y is F with an alkaline carbonate in the presence of a polar solvent.

The hydrogen chloride is selected from any one of a concentrated hydrochoric acid and a gaseous hydrochloride. The polar solvent is selected from methanol, ethanol, n-propanol, dichloromethane, tetrahydrofuran, acetonitrile, acetone and/or mixtures thereof. The process is preferably carried out in a mixture of methanol and dichloromethane in a ratio of 1:1.
The present invention also teaches a process for preparation of the 9,11-epoxy compound of formula (III). The 9,11-epoxy compound of formula (III) is prepared by enolizing a compound of formula (IV) wherein R1, R3, R5, R7 is CH3 and R6 is H,

by treating with an acylating agent in the presence of a solvent to form a 9ß,11ß-epoxy compound of formula (IVa), wherein R1, R3, R5, R7 and R8 is CH3 and R6 is H. The acylating agent is selected from any one of acetic anhydride, acetyl chloride and isopropenyl acetate, preferably isopropenyl acetate. The solvent is an inert solvent selected from the group consisting of halogenated solvent, hydrocarbon solvent, ester solvent, nitrile solvent and aprotic polar solvent. The halogenated solvent is selected from dichloromethane, ethylene dichloride and chloroform, the hydrocarbon solvent is selected from toluene, xylene, n-hexane, n-heptane and cyclohexane, the ester solvent is selected from ethyl acetate, isopropyl acetate and tert-butyl aceatate, the nitrile solvent is selected from acetonitrile, propionitrile and butyronitrile and the aprotic polar solvent is selected from dimethyl sulfoxide, N,N-dimethyl formamide, dimethyl acetamide, N-methyl pyrolidinone and mixtures thereof.

The 9ß,11ß-epoxy compound of formula (IVa) is then treated with a stereoselective fluorinating agent to get the 9,11-epoxy compound of formula (III). The stereoselective fluorinating agent is selected from the group consisting of N-fluoro-N-chloromethyl triethylene diamine bis tetrafluoroborate, Octan-di-tetrafluoroborate, 1-fluoro-benzenesulfonamide and perchloryl fluoride and mixture thereof. The process preferably utilizes N-fluoro-N-chloromethyl triethylene diamine bis tetrafluoroborate as fluorinating agent.
The compound of formula (IV) is prepared by acetylation of a 17-desoxy oxide compound of formula (V) wherein R1, R3, R5 is CH3, R4 is OH and R6 is H. The acylating agent used is selected from acetic anhydride and acetyl chloride.

The Clocortolone of formula (I) thus obtained is converted to Clocortolone pivalate by reaction of Clocortolone with pivaloyl chloride in the presence of a solvent and a weak base. The solvent is selected from ethyl acetate and methylene dichloride. The weak base is selected from pyridine and triethyl amine.
In another aspect, the present invention teaches a process for preparation of a Clocortolone Pivalate polymorph A. The process comprises adding crude Clocortolone Pivalate to toluene to form a reaction mixture and heating the reaction mixture to reflux. Then the mixture is cooled to room temperature and involves further cooling the mixture to 5-10°C. In next step, the toluene purified solid is dissolved in acetone to get clear solution and methanol is added to the solution and heated to reflux. Then the solution is cooled, filtered and dried to get the Clocortolone Pivalate polymorph A.
The process of the present invention is a multi step process where the starting material is 17-desoxy steroid. The process of the present invention gives a better yield and higher purity of the final product. The process of the present invention uses reagents that are easier to handle on a larger scale.

Brief description of the drawing

FIG. 1 is a characteristic X-Ray Powder Diffraction Pattern (XRPD) of a crystalline polymorph A of Clocortolone Pivalate obtained by a process in accordance with the present invention.

Detailed description of the invention

The foregoing objects of the present invention are accomplished and the problems and shortcomings associated with the prior art, techniques and approaches are overcome by the present invention as described below in the preferred embodiments.
In one aspect, the present invention teaches a process for preparation of Clocortolone of formula (I),

wherein R1, R3and R5 is CH3, R2 and R4 is OH, R6 is H, X1 is Cl and X2 is F, by deacetylation of a compound of formula (II) with an alkaline carbonate,

Wherein R1, R3, R5 and R7 is CH3, R2 is OH, R6 is H, X is Cl and Y is F.
The reaction is preferably carried out in a polar solvent. The polar solvent is selected from methanol, ethanol, n-propanol, dichloromethane (MDC), tetrahydrofuran (THF), acetonitrile, acetone and/or mixtures thereof. Preferably solvent used is a mixture of methanol and MDC. Methanol and MDC solvent mixture used is preferably in a ratio of 1:1. The alkaline carbonate is preferably potassium or sodium carbonate and the reaction is carried out at a lower temperature, preferably at -20 to 10°C and more preferably at -10 to 10°C.
After completion of the reaction the solvent is distilled off to obtain a thick mass and water is added to the thick mass obtained. After maintaining the mass at 5 to 10°C for 15 minutes, the mass is filtered and dried well. Clocortolone, thus obtained is purified using acetone. The wet cake is dissolved in acetone and refluxed to get a clear solution. The mass is gradually cooled and the solid obtained is filtered. The precipitate is dried to give pure compound of formula (I).
In another aspect, the compound of formula (II) is prepared by reacting 9,11-epoxy compound of formula (III) with hydrogen chloride,

wherein R1, R3, R5 and R7 is CH3, R6 is H and Y is F.
The reaction is carried out at lower temperature, preferably at -5 to 0°C. In the solution of 9,11-epoxy compound of formula (III) in a suitable solvent selected from methanol and THF, hydrogen chloride is added. Hydrogen chloride used is selected from chilled concentrated HCl solution or hydrogen chloride gas is purged in the reaction mixture. 9,11-epoxy group opens and yields 9-chloro-11-hydroxy steroid. The reaction mass is quenched in chilled potassium carbonate solution after completion of the reaction. The pale yellow solid 9a-chloro-11ß compound of formula (II) obtained is filtered and washed with water.
In yet another aspect, the 9,11-epoxy compound of formula (III) is prepared by, reacting a compound of formula (IV),

wherein R1, R3, R5, R7 is CH3 and R6 is H, with an acylating agent in presence or in absence of solvent, to give a 9ß,11ß-epoxy compound of formula (IVa),

wherein R1, R3, R5, R7 and R8 is CH3 and R6 is H.
The acylating agent is selected from acetic anhydride, acetyl chloride and isopropenyl acetate, preferably isopropenyl acetate. The solvent used is an inert solvent selected from halogenated solvents such as dichloromethane, ethylene dichloride, chloroform, hydrocarbon solvents such as toluene, xylene, n-hexane, n-heptane and cyclohexane, esters such as ethyl acetate, isopropyl acetate and tert-butyl aceatate, nitriles such as acetonitrile, propionitrile, butyronitrile, aprotic polar solvent such as dimethyl sulfoxide, N,N-dimethyl formamide, dimethyl acetamide, N-methyl pyrolidinone and mixtures thereof.
The acetylation reaction is carried out in the temperature range of 10-70°C, preferably at 30-40°C.
The 9ß,11ß-epoxy compound of formula (IVa) with or without isolation is treated with a stereo-selective fluorinating agent. The reaction is carried out in a dipolar aprotic solvent selected from acetonitrile, dimethylformamide (DMF), N,N-dimethyl acetamide and mixtures thereof. The temperature maintained is in the range of -25 to 50°C, preferably at -5 to 30°C.
The stereo-selective fluorinating agents are compounds that fluorinate enolized 21-esters of 9ß,11ß-epoxy-3,20-dione and related compounds in the 6-position to stereoselectively produce a-epimer. These compounds are capable of donating an electrophilic fluorine moiety. The fluorinating agent is selected from N-fluoro-N-chloromethyl triethylene diamine bis tetrafluoroborate (Selectfluor®), Octan-di-tetrafluoroborate (AccufluorTM), 1-fluoro-benzenesulfonamide and mixture thereof .

The compound of formula (IV) is prepared by acetylation of a 17-desoxy oxide compound of formula (V),

R1, R3, R5 is CH3, R4 is OH and R6 is H. The 17-desoxy oxide compound of formula (V) is treated with an acylating agent. The reaction is optionally carried out in presence of a weak base and in a polar solvent.
The acylating agents used is preferably selected from acetic anhydride and acetyl chloride. The weak base used is sodium acetate or potassium acetate, preferably potassium acetate and polar solvent used is preferably dimethyl acetamide or dimethyl formamide. The reaction is carried out at -10 to 30°C, preferably at 10-20°C. After completion of the reaction, water is added slowly, and reaction mass is maintained at 10-25°C, preferably at 15-20°C.
Clocortolone (I) obtained is converted to Pivalate salt. Clocortolone dissolved in a suitable solvent is treated with Pivaloyl chloride. The reaction is preferably carried out in presence of a base selected from triethyl amine and pyridine, preferably pyridine. The solvent used is methylene dichloride or ethyl acetate, preferably methylene dichloride. The reaction is carried out at lower temperature preferably at -15 to 0°C, particularly at -10 to -5°C. The reaction mixture is stirred continuously and after completion of the reaction dilute HCl is added to remove pyridine. Further washing of sodium bicarbonate solution is given to organic layer to remove trances of HCl. The organic layer is dried over sodium sulfate. The organic layer free from any basic or acidic traces is distilled out. Further alcoholic solvent preferably ethanol is added and mixture is heated to reflux. The mixture is cooled gradually to room temperature and further chilled to 5-10°C. The solid obtained is suck dried well to give Clocortolone Pivalate of purity 96-102%.
The Clocortolone pivalate is further purified to get polymorph A. Clocortolone Pivalate is added to toluene and heated to reflux till it dissolves completely and the solution become clear. The solution is gradually cooled to room temperature and then chilled to 5-10°C. The solid is filtered and suck dried. The toluene purified solid is then dissolved in acetone. Methanol is added to the solution and heated to reflux. The solution is cooled to 20°C, filtered and suck dried well to give polymorphic form A.
The polymorph A thus obtained is characterized by X-Ray Powder Diffraction Pattern (XRPD). As shown in figure 1, the X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2? at about 7.01, 8.72, 11.77, 13.99, 16.12, 17.03, 17.41, 17.82, 18.28, 18.57, 21.00, 21.63, 25.05, 28.02, 33.06, 38.68.

The present invention is further illustrated by following exemplary embodiments, which should not be construed as limiting the scope of the invention.

EXAMPLES
Example 1:
Preparation of 21-acyloxy-9ß, 11ß-epoxy-16a-methylpregna-1,4-diene-3,20-dione
Mixture of 21-hydroxy-9ß, 11ß-epoxy-16a-methylpregna-1,4-diene-3,20-dione (4.15 kg) and N,N-dimethyl acetamide (21 l) was cooled to 10-15°C. Acetic anhydride (6.3 lit) was added over a period of 30 minutes by maintaining temperature in a range of 10-15°C. Potassium acetate (4.15 kg) was gradually added in two lots over a period of 30 minutes to the reaction mixture. After completion of the reaction, water (129 l) was added slowly over a period of 90 minutes. The reaction mixture was maintained at 15-20°C for 1 hour. The solid obtained was filtered and washed with demineralised water. 21-acyloxy-9ß, 11ß-epoxy-16a-methylpregna-1,4-diene-3,20-dione (4.20 kg) was obtained as a white solid. (Purity: 98.5%)

Example 2:
Preparation of 21-acyloxy-9ß, 11ß-epoxy-16a-methylpregna-1,4-diene-3,20-dione
Mixture of 21-hydroxy-9ß, 11ß-epoxy-16a-methylpregna-1,4-diene-3,20-dione (10 g) and dimethyl formamide (50 ml) was cooled to 10-15°C. Acetic anhydride (15 ml) was added over a period of 30 minutes by maintaining temperature in the range of 10-15°C. The reaction mixture was maintained to attain room temperature. Potassium acetate (10 g) was gradually added in two lots over a period of 30 minutes to the reaction mixture. After completion of the reaction, water (200 ml) was added slowly over a period 90 minutes. The reaction mixture was maintained at 15-20°C for 1 hour. The solid obtained was filtered and washed with demineralised water. 21-acyloxy-9ß, 11ß-epoxy-16a-methylpregna-1,4-diene-3,20-dione (10.74 g) was obtained as a white solid.

Example 3:
Preparation of 21-acyloxy-6a-fluoro-9ß, 11ß-epoxy-16a-methylpregna-1,4-diene-3,20-dione
Isopropenyl acetate (1 lit) was added to the mixture of concentrated sulfuric acid (2 ml) and acetic anhydride (33 ml). 21-acyloxy-9ß,11ß-epoxy-16a-methylpregna-1,4-diene-3,20-dione(100 g) was charged. The reaction mixture was heated and maintained at 35-38°C for 30 minutes. After completion of the reaction, triethyl amine (9 ml) was added and the reaction mass was stirred for 15 minutes. The solvent was distilled under vacuum below 35°C and acetonitrile (1 l) was added and the reaction mass was cooled to 0–(-5)°C for 3 hours. N-fluoro-N-chloromethyl triethylene diamine bis tetrafluoroborate (SelectfluorTM) (90 g) was added in four lots within 1 hour. The reaction mixture was maintained at -5 to 0°C till the thick mass was observed. Water (1 l) was added and mixture was stirred for 10 minutes at 25-30°C. The water layer was decanted and solid obtained was filtered and washed with water till the pH is neutral. The light yellow solid of 21-acyloxy-6a-fluoro-9ß, 11ß-epoxy-16a-methylpregna-1,4-diene-3,20-dione (8 g) was obtained. (Purity: 74.3%)

Example 4:
Preparation of (6a,11ß,16a)-9-Chloro-6-fluoro-11,21-dihydroxy-16-methylpregna-1,4-diene-3,20-dione 21-acetate
Under nitrogen atmosphere concentrated HCl (900 ml) was charged and chilled to -5-0°C. Solution of 21-acyloxy-6a-fluoro-9ß, 11ß-epoxy-16a-methylpregna-1,4-diene-3,20-dione (50 g) in THF (100 ml) was charged slowly in chilled HCl solution and the reaction mass was maintained for 30 minutes at -5-0°C. The reaction mass was quenched in a separately prepared solution of potassium carbonate (921.5 ml) and water (3 l) and chilled to -5-0°C. The reaction mass was stirred for 30 minutes. The solid obtained was filtered and washed with demineralised water. White to off-white solid obtained was dried at 40°C under vacuum for 6 hours to get (6a,11ß,16a)-9-Chloro-6-fluoro-11,21-dihydroxy-16-methylpregna-1,4-diene-3,20-dione 21-acetate (22 g). (Purity: 96.12%)

Example 5:
Preparation of (6a,11ß,16a)-9-Chloro-6-fluoro-11,21-dihydroxy-16-methylpregna-1,4-diene-3,20-dione (Clocortolone)
(6a,11ß,16a)-9-Chloro-6-fluoro-11,21-dihydroxy-16-methylpregna-1,4-diene-3,20-dione 21-acetate (14 g) was charged in a mixture of methanol (140 ml) and MDC (140 ml). Separately prepared solution of potassium carbonate (15.54 g) in 40.6 ml water was slowly added at -5 to -10°C to the reaction mixture and reaction mass was maintained at -5 to 10°C. After completion of the reaction, solution of acetic acid (28 ml) in methanol (42 ml) was charged at -10 to 0°C and the mixture was stirred for 10 minutes. Solvent was distilled under vacuum below 35°C till thick mass was observed. Water (140 ml) was added and reaction mass was chilled to 5 to 10°C and maintained for 15 minutes. The solid was filtered and acetone (700 ml) was added to the wet cake obtained. The mixture was heated to reflux at 55-60°C to get a clear yellow solution. The reaction mass was refluxed for 10 minutes to get creamish yellow slurry. The reaction mass was cooled to 25-30°C, gradually chilled to 10°C and maintained for 30 minutes. The solid Clocortolone obtained (10.5 g) was filtered and suck dried well (Purity: 99.03%)

Example 6:
Preparation of Clocortolone Pivalate
MDC (220 ml) was added to Clocortolone obtained in example 4 (10 g) and mixture was chilled to -5 to -10°C under stirring. Pyridine (60 ml) was added at -10°C under stirring to the mixture. Pivaloyl Chloride (20 ml) was added to the reaction mixture within 15-20 minutes to get white turbid solution. The reaction mass was stirred at -10 to -5°C. After completion of the reaction, MDC (110 ml) was added in the reaction mass. Dilute HCl solution (32 ml) was added and stirred for 15 minutes. The organic layer was washed with demineralised water (10 ml). The organic layer was then washed with sodium bicarbonate solution and stirred for 15 minutes and layers were separated. Organic layer was dried over sodium sulfate and stirred for 20-30 minutes. The filtrate was distilled under vacuum below 40°C. Ethanol (40 ml) was added and mixture was heated to 40°C for 15-20 minutes with stirring. The solution was gradually cooled to room temperature and further chilled to 5-10°C. The solid was filtered and suck dried well to give Clocortolone Pivalate (16 g) (Purity: 99.7%)

Example 7:
Preparation of Clocortolone Pivalate polymorph A
Clocortolone Pivalate wet cake (16 g) was added to toluene (336 ml). The reaction mixture was heated to 75-80°C to get a clear solution. The solution was gradually cooled to room temperature and then chilled to 5-10°C. The mixture was maintained for at least 15-20°C. The solid obtained was filtered and suck dried. The toluene purified solid was then dissolved in acetone (70 ml) to get clear solution. Methanol (140 ml) was added to the solution and heated to 40-45°C. The solution was cooled to 20°C, filtered and suck dried well to give crystalline polymorphic form A of Clocortolone Pivalate (5 gm).
The foregoing descriptions of specific embodiments of the present invention have been presented for purposes of illustration and description. They are not intended to be exhaustive or to limit the present invention to the precise forms disclosed, and obviously many modifications and variations are possible in light of the above teaching. The embodiments were chosen and described in order to best explain the principles of the present invention and its practical application, and to thereby enable others skilled in the art to best utilize the present invention and various embodiments with various modifications as are suited to the particular use contemplated. It is understood that various omissions and substitutions of equivalents are contemplated as circumstances may suggest or render expedient, but such omissions and substitutions are intended to cover the application or implementation without departing from the spirit or scope of the claims of the present invention.