AU2014233577B2

AU2014233577B2 - Enzymatic process for obtaining 17 alpha-monoesters of cortexolone and/or its 9,11-dehydroderivatives

Info

Publication number: AU2014233577B2
Application number: AU2014233577A
Authority: AU
Inventors: Mauro Ajani; Luigi Moro
Original assignee: Cassiopea SpA
Current assignee: Cassiopea SpA
Priority date: 2007-08-03
Filing date: 2014-09-24
Publication date: 2016-03-03
Anticipated expiration: 2028-07-24
Also published as: AU2014233572B2; AU2014233577A1; AU2014233572A1

Abstract

The present invention refers to an enzymatic process for obtaining 17alpha-monoesters of cortexolone and/or its 9, 5 11-dehydroderivatives starting from the corresponding 17alpha, 21-diesters which comprises an enzymatic alcoholysis reaction. Furthermore, the present invention refers to crystalline forms of cortexolone 17alpha propionate and 9,11-dehydro-cortexolone 17alpha-butanoate. 5779166_1 (GHMatters) P82876.AU.2 PETERS 17109114

Description

1 TITLE Enzymatic process for obtaining 17 alpha-monoesters of cortexolone and/or its 9,11 -dehydroderivatives. The present patent application is a divisional patent application of Australian patent application no. 2008285784, the entirety of which is incorporated herein by reference. DESCRIPTION Cortexolone derivatives in which the hydroxyl group at position C-17a is esterified with short chain aliphatic or aromatic acids, and the derivatives of the corresponding 9,11-dehydro derivative, are known to have an antiandrogenic effect. EP1421099 describes cortexolone 17a-propionate and 9,11-dehydro-cortexolone 17-a-butanoate regarding a high antiandrogenic biological activity demonstrated both "in vitro" and "in vivo" on the animal. A method for obtaining the above mentioned derivatives is described by Gardi et al. (Gazz. Chim. It. 63, 43 1,1963) and in the United States patent US3152154 providing for the transformation of cortexolone, or transformation of 9,11 dehydrocortexolone, in the intenrediate orthoester using orthoesters available in the market as a mixture of aprotic solvents such as cyclohexane and DMF, in presence of acid catalysis (ex. PTSA.H 2 0). The intermediate orthoester thus obtained can be used as is or upon purification by suspension in a solvent capable of solubilising impurities, preferably in alcohols. The subsequent hydrolysis in a hydroalcoholic solution, buffered to pH 4-5 preferably in acetate buffer, provides the desired monoester. Such synthesis is indicated in the diagram 1 below 2 Diagram 1 OH OR OH ,OH R O R 0 R= CH 3, CH 3CH 2 , CH 3CH 2 CH 2, CH 3CH 2 CH 2CH 2 R=CH 3 , CH 3CH 2 However, the monoesters thus obtained were, in the reaction conditions, unstable and, consequently hard to manipulate and isolate (R. Gardi et al Tetrahedron Letters, 448, 1961). The instability is above all due to the secondary reaction of migration of the esterifying acyl group from position 17 to position 21 It is thus known that in order to obtain the above mentioned monoesters with a chemical purity in such a manner to be able to proceed to the biological tests, it is necessary to use, at the end of the synthesis, a purification process which is generally performed by means of column chromatography. Furthermore, US3152154 describes how the hydrolysis of the diester in a basic environment is not convenient due to the formation of a mixture of 170,21-diol, of 17- and 21 -monoesters, alongside the initial non-reacted product. Now, it has been surprisingly discovered that an alcoholysis reaction using a lipase from Candida as a biocatalyst can be usefully applied during the preparation of 17a monoesters of cortexolone, or its 9,11-dehydroderivatives. As a matter of fact, it has been discovered that such enzymatic alcoholysis of the 17,21-diester of the cortexolone, or of its derivative 9,11-dehydro, selectively occurs in position 21 moving to the corresponding monoester in position 17, as shown in diagram 2 below: Diagram 2 3 OH 0 'O R 0 upasi + ROH - -- + ROCOR 0 06 The chemoselectivity of the special enzymatic reaction in alcoholysis conditions, according to the present invention, opens new perspectives for preparation, at industrial level with higher 5 yields, of 1 7a-monoesters with respect to the methods already indicated in literature. The diesters serving as a substrate for the reaction of the invention can be prepared according to the prior art, for example following the one described in B.Turner, (Journal of American Chemical Society, 75, 3489, 1953) which provides for the esterification of corticosteroids with a linear carboxylic acid in presence of its anhydride and PTSA monohydrate. 10 The present invention as claimed herein is described in the following items 1 to 32: 1. Hydrate crystalline form IV of cortexolone-17a-propionate characterized by a DRX as represented in Figure 28. 2. A pharmaceutical composition comprising hydrate crystalline form IV according to item 1 in association with at least one physiologically acceptable excipient. 15 3. The pharmaceutical composition according to item 2 in solid, semisolid, or pasty form. 4. The pharmaceutical composition according to item 2 or 3 in the form of a tablet, capsule, powder, pellet, suspension, emulsion, cream, gel, ointment, lotion, or paste. 5. A process for preparing hydrate crystalline form IV according to item 1, said process comprising crystallizing cortexolone-17a-propionate from a mixture of propylene 20 glycol/water; or a mixture of polyethylenglycol/water, wherein the cortexolone- 1 7a propionate is prepared by by reacting a compound of formula II 7296227_1 (GHMatters) P82876.AU.2 JESSIEL 3a 0 R O R "11110 with a compound of formula III 5 R'OH (III) in an organic solvent in the presence of a lipase from Candida, wherein R is CH 3

CH

2 and R' is a linear aliphatic chain containing 1 - 10 carbon atoms.. 6. The process of item 5, wherein the mixture of propylene glycol/water orthe mixture of polyethylenglycol/water is in a ratio of about 1/2 to 2/1. 10 7. The process of item 6, wherein the mixture of propylene glycol/water or the mixture of polyethylenglycol/water is in a ratio of about 1/1. 8. The process according to item 5 wherein R' is an aliphatic chain containing 1 - 8 carbon atoms. 9. The process according to item 5 wherein the organic solvent is aprotic. 15 10. The process according to item 9 wherein the solvent is selected from the group consisting of toluene, acetonitrile, tetrahydrofuran, dichloromethane, chloroform, and combinations thereof. 11. The process according to item 5 wherein said compound of formula II is present at an amount in the range of about 0.01 to 0.15 molar. 20 12. The process according to item 5 wherein said compound of formula II is present at an amount of about 0.025 molar. 13. The process according to item 5 wherein said compound of formula III is selected from the group consisting of methanol, ethanol, butanol, octanol, and combinations thereof. 6875787_1 (GHMatters) P82876.AU.2 PETERB 28/10/15 3b 14. The process according to item 5 wherein said compound of formula III is present at an amount varying from about 0.5 to about 50 moles per mole of compound of formula II. 15. The process according to item 5 wherein said compound of formula III is present at 5 moles per mole of compound of formula II. 5 16. The process according to item 5 wherein said lipase from Candida is Candida cylindracea ("CCL") or Candida antarctica of type B ("CALB"). 17. The process according to claim 5 wherein said lipase from Candida is present at an amount varying from about 100 to 1,000,000 U/mmol. 18. The process according to item 17 wherein said lipase from Candida is present at an 10 amount ranging from about 1,000 to 1,000,000 U/mmol when the lipase from Candida is from CCL, and ranges from about 100 to 100,000 U/mmol when the lipase from Candida is from CALB. 19. The process according to any one of items 5 to 18 wherein the reaction takes place at a temperature in the range of 10 to 48'C. 15 20. The process according to item 19, wherein the reaction takes place at a temperature in the range of 20 to 32'C. 21. Cortexolone-17a-propionate in hydrate crystalline form IV according to item 1 for use in the treatment of pathologies affecting the urogenital system, the endocrine system, the skin, and/or the cutaneous appendages. 20 22. Cortexolone-17a-propionate in hydrate crystalline form IV according to item 1 for use in the treatment of acne, seborrhoeic dermatitis, androgenetic alopecia, hirsutism, benign prostatic hyperplasia, forms of prostate cancer, polycystic ovary syndrome, precocious puberty, and control of aggressive or aberrant sexual behaviors. 23. Cortexolone-17a-propionate in hydrate crystalline form IV according to item 1 for use 25 in the treatment of acne. 24. Cortexolone-17a-propionate in hydrate crystalline form IV according to item 1 for use in the treatment of androgenetic alopecia. 25. A method for the treatment of acne, seborrhoeic dermatitis, androgenetic alopecia, hirsutism, benign prostatic hyperplasia, forms of prostate cancer, polycystic ovary syndrome, 30 precocious puberty, and control of aggressive or aberrant sexual behaviors, comprising administering cortexolone-17a.-propionate in hydrate crystalline form IV according to item 1. 26. A method for the treatment of acne, comprising administering cortexolone-17a propionate in hydrate crystalline form IV according to item 1. 27. A method for the treatment of androgenetic alopecia comprising administering 35 cortexolone- 1 7a.-propionate in hydrate crystalline form IV according to item 1. 7296227_1 (GHMatters) P82876.AU.2 JESSIEL 3c 28. Use of cortexolone-17a.-propionate in hydrate crystalline form IV according to item 1 in the manufacture of a medicament for the treatment of acne, seborrhoeic dermatitis, androgenetic alopecia, hirsutism, benign prostatic hyperplasia, forms of prostate cancer, polycystic ovary syndrome, precocious puberty, and control of aggressive or aberrant sexual 5 behaviors. 29. Use of cortexolone-17a.-propionate in hydrate crystalline form IV according to item 1 in the manufacture of a medicament for the treatment of acne. 30. Use of cortexolone-17a.-propionate in hydrate crystalline form IV according to item 1 in the manufacture of a medicament for the treatment of androgenetic alopecia. 10 31. A process for the manufacture of a pharmaceutical composition according to item 2 or 3 or 4, which comprises the dissolution of cortexolone-17a-propionate in an organic solvent, followed by the addition of water in a ratio of 1/3 to 3/1 with respect to the organic solvent, wherein the organic solvent is selected from propylene glycol or polyethylene glycol, wherein the cortexolone- 1 7a-propionate is prepared by reacting a compound of formula II 0 R O R "111110 15 with a compound of formula III R'OH (III) in an organic solvent in the presence of a lipase from Candida, wherein R is CH 3

CH

2 and R' is a 20 linear aliphatic chain containing 1 - 10 carbon atoms. 7296227_1 (GHMatters) P82876.AU.2 JESSIEL 3d 32. A pharmaceutical composition comprising the hydrate crystalline form IV of cortexolone-17a-propionate according to item 1, and: a. a crystalline form I of cortexolone-17a-propionate characterised by a DRX as represented in Fig. 1, 16, 19, 22 or 25 and/or a DSC as represented in Fig. 2, 5 17, 20, 23 or 26 and/or an IR as shown in Fig. 3, 18, 21, 24 or 27; and/or b. a crystalline form III of cortexolone-17a-propionate characterized by a DRX as represented in Fig. 7, 10 or 13 and/or a DSC as represented in Fig. 8, 11 or 14 and/or an IR as represented in Fig. 9, 12 or 15, in association with at least one physiologically acceptable excipient. 10 Described herein is a process for the preparation of 17 a monoesters of cortexolone, and its 9,11 -dehydroderivatives, of formula I OH 0 R 0 15 wherein R is a linear or branched aliphatic or aromatic chain containing 1 to 10 carbon atoms, characterised in that a compound of formula 11. 7296227 1 (GHMatters) P82876.AU.2 JESSIEL 4 R 0 O R 0 wherein R bears the same meaning indicated above, is reacted with a compound having the formula R'OH, wherein R' is a linear chain containing 1 to 10 carbon atoms, preferably a C 1

-C

8 alkyl , in presence of a lipase from Candida. According to the present invention R is preferably a Ci-C 4 alkyl , even more preferably it is selected from among CH 3 , CH 3

CH

2 , CH 3

(CH

2

)

2 or CH 3

(CH

2

)

3 . The dashed symbol in position 9,11 inside the abovementioned formulas I and II means that the double bond can be present (9,11 -dehydroderivative) or not present in such position, as shown in the formulas indicated hereinafter OH OH R 0 0 laO O O R R O 01ab 5 The lipase from Candida used to catalyse the process of the present invention is preferably selected between the lipase from Candida cylindracea (CCL) and lipase from Candida antarctica of type B (CALB). Lipase from Candida, and in particular the ones from Candida cylindracea and Candida antarctica are proved to be capable of selectively hydrolysing the ester function in position 21, contrary to the porcine pancreatic lipase (PPL) and to one from Pseudoinonasfluorescens (PFL), which are proved to be almost inactive. The amount of said enzyme, calculated with respect to the initial substrate, may vary depending on the type of enzyme used. In particular, said enzyme is preferably used in an amount in the range of 100 to 1,000,000 U/mmol; more preferably in the range of 1,000 to 1,000,000 U/mmol in case of CCL and in the range of 100 to 100,000 U/mnol in case of CALB. Even more preferably, said enzyme is present at an amount of about 60,000 U/mmol in case of CCL and about 5,000 U/mrnmol in case CALB. Furthermore, from an economical/industrial point of view, the possibility to reutilise such enzymes in several cycles without losing the catalytic activity was proved. The concentration of the initial diesters of formula II is preferably in the range of about 0.01 to 0.15 molar, more preferably about 0.025 molar. The process of the invention preferably occurs in the presence of an organic solvent, more preferably an aprotic organic solvent. Said solvent is then preferably selected from among toluene, acetonitrile, tetrahydrofuran, dichloromethane and/or chloroform. The R'OH alcohol according to the invention is preferably selected from among methanol, ethanol, butanol and/or octanol. Said alcohol is preferably present at a quantity in the range of about 0.5 to about 50 moles per mole of initial substrate, more preferably 5 moles per mole of substrate. The process according to the present invention preferably occurs under constant stirring until the initial diester of formula II is dissolved. Subsequently the enzyme used is removed for filtration, preferably filtration on Celite and the monoester of formula I is obtained through evaporation of the solvent under low pressure.

6 When the compound of formula II is a 17u.,21-diester of cortexolone, the reaction time of the process is usually in the range of 20 to 150 hours, preferably in the range of 24 to 72 hours and the reaction temperature is preferably in the range of about 10 to 48'C, more preferably in the range of 20 to 32'C. 5 Table 1 below summarises the reaction conditions and the results of the enzymatic alcoholysis according to the present invention. TABLE 1 Enzynatic alcoholysis reaction of ] 7a, 21 -diesters of cortexolone to produce the corresponding 17a -monoester Compound of Enzyme Alcohol Solvent Reaction time Yield of the Formula 11 (hours) monoester of (diester) formula J* Diacetate CCL Octanol Toluene 51 97% CALB Ethanol Toluene 96 67% CALB Octanol Acetonitrile 51 88% Dipropionate CCL Ethanol Toluene 120 73% CCL Butanol Toluene 24 100% CCL Octanol Toluene 28 100% CCL Butanol Acetonitrile 96 91% CCL Butanol Tetrahydrofuran 96 86% CCL Butanol Chloroform 96 10% PPL Octanol Toluene 120 13% PFL Methanol Chloroform 24 0% CALB Octanol acetonitrile 76 91% Dibutanoate CCL Butanol Toluene 74 98% CCL Octanol Toluene 24 98% Divalerate CCL Butanol Toluene 74 81% CCL Octanol Toluene 48 97% 10 *the conversion percentages were evaluated from the 'H-NMR spectra from the integrations of signals due to the hydrogens in position 21 of the corresponding diesters and monoesters. The enzymatic method according to the present invention also proved useful not only for converting 17a.2 1 -diesters of cortexolone or of 9,11 -dehydro-cortexolone: in particular the 15 17abutanoate of 9,11 -dehydrocortexolone was obtained starting from the corresponding dibutanoate preferably using the CCL enzyme and methanol as an 6875787_1 (GHMatters) P82876.AU.2 PETERB 28/10/15 7 acceptor alcohol of the acyl group. The concentration of the initial 9,11 -dehydro derivatives is preferably in the range of 0.01 to 0.15 molar, more preferably 0.025 molar. In this case, the reaction time is preferably in the range of 45 to 55 hours, preferably 53 hours. Also in this case the reaction temperature is preferably in the range of 10 to 48'C, more preferably in the range of 20 to 32*C': Table 2 below shows the reaction conditions of the enzymatic alcoholysis of 17a,21-dibutanoate of 9,11-dehydrocortexolone and the related final yield of the respective monoester. TABLE 2 Enzymatic alcoholysis reaction of 17a,21-diesters of 9,11-dehydro-cortexolone to produce the corresponding 17a -monoester. Compound Enzyme Alcohol Solvent Reaction Yield in of formula II time compound (diester) (hours) of formula I* Dibutanoate CCL Methanol Toluene 53 79% Diabutanoate CCL Ethanol Toluene 53 28% Dibutanoate CCL Butanol Toluene 53 100% Dibutanoate CCL Octanol Toluene 53 100% *the conversion percentages were evaluated from the 'H-NMR spectra from the integrations of signals due to the hydrogens in position 21 of the corresponding diesters and monoesters. Furthermore, the process according to the present invention may optionally comprise a final step of crystallisation from an organic solvent, water, buffered aqueous solutions and/or or their mixture. The organic solvent of said step of crystallisation is preferably selected from among diisopropylether, terbutylmethylether, dichloromethane, ethyl acetate, hexane, acetone, ethanol, water or their mixture at any proportion. Thus, further object of the present invention are crystalline forms of 17a monoesters of cortexolone, and their corresponding 9,11 -dehydro derivatives. In particular, an object of the present invention are the crystalline forms of 8 cortexolone 17a-propionate and of 9,11-cortexolone-17a-butanoate. The crystalline form I of 17u-propionate is preferably obtained through crystallisation from tert-butylmethylether. The concentration of 17u-propionate in said solvent is in the range of 0.9 to 1.1 g in 9-11 ml of tert-butylmethylether preferably 1 g in 10 ml. Said crystalline form I is characterised by a melting point in the range of about 133 to 135'C and/or a DRX as in Fig. 1 and/or a DSC as shown in Fig. 2 and/or an IR as shown in Fig. 3. The crystalline form II of 17a-propionate is preferably obtained through crystallisation from diisopropylether. The concentration in said solvent is preferably in the range of 0.9 to 1.1 g in 54-66 ml of diisopropylether. Said crystalline form II is characterised by a melting point in the range of about 114 to 116 0 C and/or a DRX as in Fig. 4 and/or a DSC as shown in Fig. 5 and/or an IR as shown in Fig. 6. The crystalline form III of 17a-propionate is preferably obtained through crystallisation from a mixture of dichloromethane/n-hexane preferably in a ratio of about 1/30, acetone/n-hexane preferably in a ratio of about 1/8, or ethanol/water mixture preferably in a ratio of about 1/2. The melting point of said crystalline forms III could not be determined. The crystalline form III obtained from dichloromethane/n-hexane has a DRX as shown in Fig. 7 and/or a DSC as shown in Fig. 8 and/or an IR as shown in Fig. 9. The crystalline form III obtained from acetone/n-hexane has a DRX as shown in Fig. 10 and/or a DSC as shown in Fig, II and/or an IR as shown in Fig. 12. The crystalline form III obtained from ethanol/water has a DRX as shown in Fig. 13 and/or a DSC as shown in Fig. 14 and/or an IR as shown in Fig. 15. The crystalline form I of 9,11-dehydro-17a-cortexolone is preferably obtained from tert-butylmethylether, diisopropylether, a dichloromethanc/n-hexane mixture preferably in a ratio of 1/15 , or an acetone/n-hexane mixture preferably in a ratio of 1/5. The crystalline form I obtained from tert-butylmethylether has a DRX as shown in Fig. 16 and/or a DSC as shown in Fig. 17 and/or an IR as shown in Fig. 18. The crystalline form I obtained from diisopropylether has a DRX as shown in Fig. 19 and/or a DSC as shown in Fig. 20 and/or an JR as shown in Fig. 21.

9 The crystalline form I obtained from dichloromethane/n-hexane has a DRX as shown in Fig. 22 and/or a DSC as shown in Fig. 23 and/or an IR as shown in Fig. 24. The crystalline form I obtained from acetone/n-hexane has a DRX as shown in Fig. 25 and/or a DSC as shown in Fig. 26 and/or an IR as shown in Fig. 27. The differences observable in the DRX diagrams regarding the form III of 17a propionate and regarding the form I of 9,11 -dehydro derivative are to be deemed irrelevant in that they are due to the phenomena of crystal disorientation. Likewise, the differences observed in IR and DSC are to be deemed irrelevant in that they are due to variations when preparing the sample and/or when performing the analysis. Table 3 shows some identification parameters and conditions for obtaining the abovementioned crystalline forms. TABLE 3 Compound Solid Solvents Concentrations Melti DRX DSC IR of formula I form (g compound/ml ng (monoester) solvent) point (OC) Cortexolone Crystallin Tert- Ig/10mi 133- Fig. 134.90'C Fig. 17a- e form I butymethylet her 135 1 (AH=40.6 3 propionate 8 J/g) Fig. 2 Crystallin diisopropylether lg/60ml 114- Fig. 4 115.85C Fig. e form II 116 (AI-1=46.6 6 1 J/g) Fig.5 Crystallin Dichloromethane lg/15.5ml n.d. Fig. 134.90C Fig, e form Ill /n-hexane (dichloronethan 7 (AH=42.4 9 e/n-hexane 1/30) 5 J/g) Fig. 8 Crystallin Acetone/n- 1g/9ml n.d. Fig. 134,18 C Fig. c form III hexane (acetone/n- 10 (AH=43.8 12 hexane 1/8) 3 J/g) Fig. _______________________ _______________ _______________ ______ ______ 11 __11 10 TABLE 3 Compound Solid Solvents Concentrations Melti DRX DSC IR of formula I form (g compound/mi ng (monoester) solvent) point

(

0 C) Crystallin Ethanol/water lg/24nl n.d Fig. 134.29'C Fig. e form III (ethanol/water 13 (AH=43.3 15 1/2) 4 J/g) Fig. 14 9,11 -dehydro Crystallin Tert 1g/24ml n.d. Fig. 137.45'C Fig. 17cf- e forn I butylmethylether 16 (AH=62.6 18 cortexolone 3 J/g) Fig. 17 Crystallin diisopropylether 1g/96ml 136 Fig. 136.76'C Fig. e form I 19 (AH=60.4 21 8 J/g) Fig.20 Crystallin Dichloromethane 1g/16nl n.d. Fig. 136.65'C Fig. e form I /n-hexane (dichloromethan 22 (AH=66.6 24 e/n-hexane 1/15) 6 J/g) Fig. 23 Crystallin Acetone/n- lg/21ml n.d. Fig. 136.491C Fig. e form I hexane (acetone/n- 25 (AH=67.6 27 hexane 1/5) 4 J/g) Fig 26 The existence of a pseudo polymorph crystalline form of 17a-propionate, characterised by the presence of a crystallization water molecule and defined as solvate form IV was determined. The solvate crystalline form IV of 17o-propionate is preferably obtained through crystallisation from an organic/water solvent mixture in a ratio generally in the range of 1/2 to 2/1, preferably from propylene glycol/water in a ratio of 1/1 or polyethylenglyco I/water in a ratio of 1/1.

11 The crystallisation of 17ua-propionate in solvate form may occur during the formulation processes of the final pharmaceutical form, where the manufacturing process of the pharmaceutical form provides for the dissolution of the active ingredient in an organic solvent, such as for example, propylene glycol, polyethylene glycol or short-chained aliphatic alcohols, followed by the addition of water in a ratio of 1/3 to 3/1 with respect to the organic solvents used for the dissolution of the active ingredient. Furthermore, an object of the present invention is a pharmaceutical composition containing at least one of the crystalline forms described above in association with at least one physiologically acceptable excipient. The compositions of the present invention can be of solid, semi-solid, pasty or liquid form and they are preferably selected from among tablets, capsules, powders, pellets, suspensions, emulsions, solutions, creams, gel, ointment, lotions or pastes both ready to use or to be reconstituted before use. Lastly, object of the present invention is the use, preferably for human beings, of at least one of the crystalline forms and/or solvates described above for the preparation of a medication for treating pathologies affecting the urogenital system, the endocrine system, the skin and/or the cutaneous appendages. In particular, an object of the present invention is the use of a liquid or semi-liquid formulation for topical administration, such as for example, cream, gel, ointment, emulsion or dispersion containing cortexolone-17u-propionate in the range of 0.1 to 2% by weight, preferably in the range of 0.2 to 1%, in a crystalline form selected from among solvate forms I, II, III or IV, preferably in solvate form IV, both in solution and crystalline dispersion states, the latter being possibly obtained also in an extemporaneous manner by precipitation of the crystalline active ingredient upon addition of water or aqueous solution to a solution containing the same active ingredient in an organic solvent or a mixture of organic solvents, for the preparation of a medication for treating pathologies affecting the urogenital system, the endocrine system, the skin and/or or skin appendages. Additionally, an object of the present invention is the use of a liquid or solid formulation for oral or systemic administration, such as for example, a tablet, capsule, granule or powder containing 9,11-dehydro-cortexolone-17a-butanoate 12 in the dosage in the range of 4 to 65% by weight, preferably in the range of 5 to 50%, with respect to the total formulation when said total formulation has a final weight of 200 mg or in the range of 1 to 25% by weight, preferably in the range of 2 to 20%, when the total formulation has a final weight of 500 mg in a crystalline form selected between solvate forms I, or IV, for treating pathologies affecting the urogenital system, the endocrine system, the skin and/or or skin appendages. Said pathologies according to the invention are preferably selected from among acne, seborrhoeic dermatitis, androgenetic alopecia, hirsutism, benign prostatic hyperplasia, forms of prostate cancer, male contraception, polycystic ovary syndrome, control of aggressive or aberrant sexual behaviours and syndrome of precocious puberty. The following examples are included to enhance the understanding of the present invention without restricting it in any way whatsoever. EXAMPLES Example 1 Alcoholysis with CCL of cortexolone 17a. 21-dipropionate Add butanol (0.4g, 5.45 mmoles) and CCL (17.4g, 3.86 U/mg, FLUKA) to a solution of cortexolone-17a,21-dipropionate (0.5g, 1.09 mmoles) in toluene (50ml). Maintain the mixture under stirring, at 30 'C, following the progress of the reaction in TLC (Toluene/ethyl acetate 6/4) until the initial material is dissolved (24h). Remove the enzyme by means of filtration using a Celite layer. Recover the cortexolone 17a-propionate (0.43 7, 99%) after evaporation under low pressure. Through crystallisation, from diisopropyl ether you obtain a product with a purity >99% in HPLC. ' H-NMR (500MHz, CDC13) relevant signals 6 (ppm) 5.78 (br s, I H, H-4), 4.32 (dd, 1 H, H-21), 4.25 (dd, 1H, H-21), 1.22 (s, 3H, CH 3 -19), 1.17 (t, 3H, CH 3 ), 0.72 (s, 3H, CH 3 -18). P.f. 114 'C Example 2 According to the method described in example I prepare cortexolone-17a butanoate. 1 H-NMR relevant signals 6 (ppm) 5.78 (br s, lH, H-4), 4.32 (dd, IH, H-21), 4.26 (dd, 1H, H-21), 1.23 (s, 3H, CH 3 -19), 0.97 (t, 3H, CH 3 ), 0.73 (s, 3H, CH 3 -18). P.F.

13 134-136 C Example 3 According to the method described in the example prepare cortexolone- 1 7a.

valerate. 'H-NMR relevant signals 6 (ppm) 5.77 (br s, IH, H-4), 4.32 (dd, IH, H-21), 4.26 (dd, IH, H-21), 1,22 (s, 3H, CH 3 -19), 0.95 (t, 3H, CH3), 0.72 (s, 3H, CH 3 -18). P.f. 114 'C (diisopropyl ether). Example 4 According to the method described in the example prepare 9,1 1-dehydro cortexolone- 1 7a-butanoate. H-NMR relevant signals 6 (ppm) 5.77 (br s, IH, H-4), 5.54 (m, IH, H-9), 4.29 (dd, 1H, H-21), 4.24 (dd, 1H, H-21), 1.32 (s, 3H, CH 3 -19), 0.94(t, 3H, CH 3 ), 0.68 (s, 3H, CH 3 -18). P.f. 135-136 'C (acetone/hexane). Example 5 Alcoholysis with CALB of cortexolone-17a, 21-dipropionate Dissolve cortexolone, 17a, 2-dipropionate (0.5g, 1 .09 mmoles) in acetonitrile (40ml), add CALB (2.3g, 2.5 U/mg Fluka) and octanol (0.875ml). Leave the mixture under stirring, at 30 'C, for 76 hrs. Remove the enzyme by means of filtration using a paper filter. Once the solvents evaporate, recover a solid (0.4758) which upon analysis 1 H-NMR shall appear made up of cortexolone-17a propionate at 91%. Example 6 Crystallisation Add the solvent (t-butylmethylether or diisopropylether) to the sample according to the ratios indicated in Table 3. Heat the mixture to the boiling temperature of the solvent, under stirring, until the sample dissolves completely. Cool to room temperature and leave it at this temperature, under stirring, for 6 hours. Filter using a buchner finnel and maintain the solid obtained, under low pressure, at a room temperature for 15 hours and then, at 40'C, for 5 hours. Example 7 Precipitation 14 Disslove the sample in the suitable solvent (dichloromethane, acetone, ethyl acetate or ethanol) according to the ratios indicated in table 3 and then add the solvent, hexane or water, according to the ratios indicated in table 3, maintaining the mixture, under stirring, at room temperature. Recover the precipitate by filtration using a buchner funnel and desiccate as in example 6. Example 8. Obtaining a pharmaceutical form containing the medication in a defined crystalline form. Prepare a fluid cream containing 2 % cetylic alcohol, 16% glyceryl monostearate, 10% vaseline oil, 13 % propylene glycol, 10% polyethylenglycol with low polymerization 1.5% polysorbate 80 and 47.5 % purified water. Add I g of cortexolone 17a-propionate of crystalline form III to 100 g of this cream and subject the mixture to homogenisation by means of a turbine agitator until you obtain homogeneity. You obtain a cream containing a fraction of an active ingredient dissolved in the formulation vehicle and a non-dissolved fraction of an active ingredient, present as a crystal of crystalline form IlII This preparation is suitable for use as a formulation vehicle for skin penetration tests on Franz cells, where a coefficient of penetration in the range of 0.04 to 0.03 cm/h is observed on the preparation. Example 9. Obtaining the pharmaceutical form containing the medication in solvate form IV for replacing the solvent during the galenic formulation procedure Dissolve 100g of cortexolone 17a-propionate of crystalline form III in 2500 g of propylene glycol under stirring at room temperature. Separately prepare, by using a turboemulsifier raising the temperature up to about 70'C, an emulsion with 250 g of Cetylic alcohol, 1500 g of glyceryl monostearate, 1000 g of liquid paraffin, 5 g of mixed tocopherols, 100 g of polysorbate 80 and 4650 g of water. After cooling the emulsion up to about 30'C, add - under stirring and under negative pressure - the cortexolone 17o-propionate solution in propylene glycol. Maintain the emulsioned cream under stirring until you obtain homogeneity, making sure the temperature remains low by means the circulation of a coolant. The cream contains a dispersed crystalline fraction, made up of an active 15 ingredient in solvate crystalline form IV, formed due to the precipitation of the active ingredient itself from the glycolic solution which contained it when the latter was added to the predominantly aqueous formulation. The DPX spectra of the crystalline form present in the cream are indicated in Fig. 28. In the claims which follow and in the preceding description of the invention, except where the context requires otherwise due to express language or necessary implication, the word "comprise" or variations such as "comprises" or "comprising" is used in an inclusive sense, i.e. to specify the presence of the stated features but not to preclude the presence or addition of further features in various embodiments of the invention. It is to be understood that, if any prior art publication is referred to herein, such reference does not constitute an admission that the publication forms a part of the common general knowledge in the art, in Australia or any other country.

Claims

1. Hydrate crystalline form IV of cortexolone-17a-propionate characterized by a DRX as represented in Figure 28.

2. A pharmaceutical composition comprising hydrate crystalline form IV according to 5 claim 1 in association with at least one physiologically acceptable excipient.

3. The pharmaceutical composition according to claim 2 in solid, semisolid, or pasty form.

4. The pharmaceutical composition according to claim 2 or 3 in the form of a tablet, capsule, powder, pellet, suspension, emulsion, cream, gel, ointment, lotion, or paste.

5. A process for preparing hydrate crystalline form IV according to claim 1, said process 10 comprising crystallizing cortexolone-17a-propionate from a mixture of propylene glycol/water; or a mixture of polyethylenglycol/water, wherein the cortexolone-1 7a-propionate is prepared by reacting a compound of formula II 0 R 0 O R 1111O1 II 15 with a compound of formula III R'OH (III) 6875787_1 (GHMatters) P82876.AU.2 PETERB 28/10/15 17 in an organic solvent in the presence of a lipase from Candida, wherein R is CH 3 CH 2 and R' is a linear aliphatic chain containing 1 - 10 carbon atoms.

6. The process of claim 5, wherein the mixture of propylene glycol/water or-the mixture of polyethylenglycol/water is in a ratio of about 1/2 to 2/1. 5

7. The process of claim 6, wherein the mixture of propylene glycol/water or the mixture of polyethylenglycol/water is in a ratio of about 1/1.

8. The process according to claim 5 wherein R' is an aliphatic chain containing 1 - 8 carbon atoms.

9. The process according to claim 5 wherein the organic solvent is aprotic.

10 10. The process according to claim 9 wherein the solvent is selected from the group consisting of toluene, acetonitrile, tetrahydrofuran, dichloromethane, chloroform, and combinations thereof.

11. The process according to claim 5 wherein said compound of formula II is present at an amount in the range of about 0.01 to 0.15 molar. 15

12. The process according to claim 5 wherein said compound of formula II is present at an amount of about 0.025 molar.

13. The process according to claim 5 wherein said compound of formula III is selected from the group consisting of methanol, ethanol, butanol, octanol, and combinations thereof.

14. The process according to claim 5 wherein said compound of formula III is present at an 20 amount varying from about 0.5 to about 50 moles per mole of compound of formula II.

15. The process according to claim 5 wherein said compound of formula III is present at 5 moles per mole of compound of formula II.

16. The process according to claim 5 wherein said lipase from Candida is Candida cylindracea ("CCL") or Candida antarctica of type B ("CALB"). 6875787_1 (GHMatters) P82876.AU.2 PETERB 28/10/15 18

17. The process according to claim 5 wherein said lipase from Candida is present at an amount varying from about 100 to 1,000,000 U/mmol.

18. The process according to claim 17 wherein said lipase from Candida is present at an amount ranging from about 1,000 to 1,000,000 U/mmol when the lipase from Candida is from 5 CCL, and ranges from about 100 to 100,000 U/mmol when the lipase from Candida is from CALB.

19. The process according to any one of claims 5 to 18 wherein the reaction takes place at a temperature in the range of 10 to 48'C.

20. The process according to claim 19, wherein the reaction takes place at a temperature in 10 the range of 20 to 32'C.

21. Cortexolone- 1 7a-propionate in hydrate crystalline form IV according to claim 1 for use in the treatment of pathologies affecting the urogenital system, the endocrine system, the skin, and/or the cutaneous appendages.

22. Cortexolone-1 7a-propionate in hydrate crystalline form IV according to claim 1 for use 15 in the treatment of acne, seborrhoeic dermatitis, androgenetic alopecia, hirsutism, benign prostatic hyperplasia, forms of prostate cancer, polycystic ovary syndrome, precocious puberty, and control of aggressive or aberrant sexual behaviors.

23. Cortexolone-1 7a-propionate in hydrate crystalline form IV according to claim 1 for use in the treatment of acne. 20

24. Cortexolone-1 7a-propionate in hydrate crystalline form IV according to claim 1 for use in the treatment of androgenetic alopecia.

25. A method for the treatment of acne, seborrhoeic dermatitis, androgenetic alopecia, hirsutism, benign prostatic hyperplasia, forms of prostate cancer, polycystic ovary syndrome, precocious puberty, and control of aggressive or aberrant sexual behaviors, comprising 25 administering cortexolone-17a.-propionate in hydrate crystalline form IV according to claim 1. 7296227_1 (GHMatters) P82876.AU.2 JESSIEL 19

26. A method for the treatment of acne, comprising administering cortexolone-17a propionate in hydrate crystalline form IV according to claim 1.

27. A method for the treatment of androgenetic alopecia comprising administering cortexolone- 1 7a.-propionate in hydrate crystalline form IV according to claim 1. 5

28. Use of cortexolone-17a.-propionate in hydrate crystalline form IV according to claim 1 in the manufacture of a medicament for the treatment of acne, seborrhoeic dermatitis, androgenetic alopecia, hirsutism, benign prostatic hyperplasia, forms of prostate cancer, polycystic ovary syndrome, precocious puberty, and control of aggressive or aberrant sexual behaviors. 10

29. Use of cortexolone-17a.-propionate in hydrate crystalline form IV according to claim 1 in the manufacture of a medicament for the treatment of acne.

30. Use of cortexolone-17a.-propionate in hydrate crystalline form IV according to claim 1 in the manufacture of a medicament for the treatment of androgenetic alopecia.

31. A process for the manufacture of a pharmaceutical composition according to claim 2 or 15 3 or 4, which comprises the dissolution of cortexolone-17a-propionate in an organic solvent, followed by the addition of water in a ratio of 1/3 to 3/1 with respect to the organic solvent, wherein the organic solvent is selected from propylene glycol or polyethylene glycol, wherein the cortexolone- 1 7a-propionate is prepared by reacting a compound of formula II 7296227_1 (GHMatters) P82876.AU.2 JESSIEL 20 0 R O R 1 1 1 1 1 1 0 -111 with a compound of formula III R'OH (III) 5 in an organic solvent in the presence of a lipase from Candida, wherein R is CH 3 CH 2 and R' is a linear aliphatic chain containing 1 - 10 carbon atoms.

32. A pharmaceutical composition comprising the hydrate crystalline form IV of cortexolone-1 7a-propionate according to claim 1, and: a. a crystalline form I of cortexolone-17a-propionate characterised by a DRX as 10 represented in Fig. 1, 16, 19, 22 or 25 and/or a DSC as represented in Fig. 2, 17, 20, 23 or 26 and/or an IR as shown in Fig. 3, 18, 21, 24 or 27; and/or b. a crystalline form III of cortexolone-1 7a-propionate characterized by a DRX as represented in Fig. 7, 10 or 13 and/or a DSC as represented in Fig. 8, 11 or 14 and/or an IR as represented in Fig. 9, 12 or 15, 15 in association with at least one physiologically acceptable excipient. 7296227_1 (GHMatters) P82876.AU.2 JESSIEL