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Title:
INCREASING AQUEOUS SOLUBILITY OF BECLOMETHASONE DIPROPIONATE BY FORMATION OF CO-CRYSTALS WITH CO-CRYSTAL FORMER
Document Type and Number:
WIPO Patent Application WO/2017/153497
Kind Code:
A1
Abstract:
The invention provides a co-crystal, which co-crystal comprises beclomethasone dipropionate and a co-crystal former, which co-crystal former is adipic acid, maleic acid or isonicotinic acid. The invention also concerns a pharmaceutical composition comprising the co-crystal, various uses of the co-crystal, a process for producing the co-crystal, and a precursor composition for use in preparing the co-crystal.

Inventors:
VELLA-ZARB, Liana (5 Triq Stella Maris, Sliema, SLM 1768, SLM 1768, MT)
BAISCH, Ulrich (5 Triq Stella Maris, Sliema, SLM 1768, SLM 1768, MT)
BONELLO, Antonia (44 Marija Assunta, Parish Street, Mqabba, MT)
Application Number:
EP2017/055489
Publication Date:
September 14, 2017
Filing Date:
March 08, 2017
Export Citation:
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Assignee:
UNIVERSITY OF MALTA (Msida, MSD 2080, MT)
International Classes:
C07J5/00
Domestic Patent References:
2014-10-23
2015-06-18
2008-12-18
Foreign References:
JPH07228525A1995-08-29
Other References:
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; THOMAS, M. ET AL: "Solubilization of steroids in oil-in-water microemulsions", XP002770009, retrieved from STN Database accession no. 1999:800628
MOHANAD SAHIB ET AL: "Solubilization of beclomethasone dipropionate in sterically stabilized phospholipid nanomicelles (SSMs): physicochemical and in vitro evaluations", DRUG DESIGN, DEVELOPMENT AND THERAPY, no. 6, 1 February 2012 (2012-02-01), pages 29 - 42, XP055370206, DOI: 10.2147/DDDT.S28265
SAKAGAMI MASAHIRO ET AL: "Mucoadhesive beclomethasone microspheres for powder inhalation: their pharmacokinetics and pharmacodynamics evaluation", JOURNAL OF CONTROLLED RELEASE, vol. 80, no. 1, 2002, pages 207 - 218, XP029377505, ISSN: 0168-3659, DOI: 10.1016/S0168-3659(02)00034-2
KOJI SHIRAKI ET AL: "Dissolution Improvement and the Mechanism of the Improvement from Cocrystallization of Poorly Water-soluble Compounds", PHARMACEUTICAL RESEARCH, KLUWER ACADEMIC PUBLISHERS-PLENUM PUBLISHERS, NL, vol. 25, no. 11, 24 July 2008 (2008-07-24), pages 2581 - 2592, XP019647928, ISSN: 1573-904X, DOI: 10.1007/S11095-008-9676-2
Attorney, Agent or Firm:
SILCOCK, Peter James (14 South Square, Gray's Inn, London Greater London WC1R 5JJ, WC1R 5JJ, GB)
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Claims:
CLAIMS

1. A co-crystal, which co-crystal comprises beclomethasone dipropionate and a co- crystal former, which co-crystal former is adipic acid, maleic acid or isonicotinic acid.

2. A co-crystal according to claim 1 wherein the co-crystal former is adipic acid.

3. A co-crystal according to claim 2 wherein the molar ratio of the beclomethasone dipropionate to the adipic acid in the co-crystal is from 2:5 to 2:7.

4. A co-crystal according to claim 2 or claim 3 wherein the molar ratio of the beclomethasone dipropionate to the adipic acid in the co-crystal is 1 :3.

5. A co-crystal according to any one of claims 2 to 4 which has a melting point within the temperature range of from 132 °C to 152 °C.

6. A co-crystal according to any one of claims 2 to 5 which has a melting point of 142 °C. 7. A co-crystal according to any one of claims 2 to 6 which is characterized by a powder X-ray diffraction pattern, obtained using copper Kai radiation having a wavelength of 1.54056 A, which comprises peaks at at least five of the following two theta values: 8.3°±0.2°, 12.9°±0.2°, 14.5°±0.2°, 16.8°±0.2°, 18.9°±0.2°, 21.4°±0.2°, 25.2°±0.2°,

25.7°±0.2°, 26.8°±0.2° and 31.1°±0.2°.

8. A co-crystal according to any one of claims 2 to 7 which is characterized by a powder X-ray diffraction pattern, obtained using copper Kai radiation having a wavelength of 1.54056 A, which comprises a peak at each of the following two theta values: 8.3°±0.2°, 12.9°±0.2°, 14.5°±0.2°, 16.8°±0.2°, 18.9°±0.2°, 21.4°±0.2°, 25.2°±0.2°, 25.7°±0.2°,

26.8o±0.2° and 31.1o±0.2°.

9. A co-crystal according to any one of claims 2 to 8 which is characterized by an infrared spectrum which comprises peaks at 3296cm"1±15cm"1, 2982cm"1±15cm"1, 1748cm" ^cm"1, 1632cm-1±15cm-1 and 1 ^Ocm^ilScm"1.

10. A co-crystal according to claim 1 wherein the co-crystal former is maleic acid.

11. A co-crystal according to claim 10 wherein the molar ratio of the beclomethasone dipropionate to the maleic acid in the co-crystal is from 2:3 to 2:5.

12. A co-crystal according to claim 10 or claim 11 wherein the molar ratio of the beclomethasone dipropionate to the maleic acid in the co-crystal is 1 :2. 13. A co-crystal according to any one of claims 10 to 12 which has a melting point within the temperature range of from 115 °C to 136 °C.

14. A co-crystal according to any one of claims 10 to 13 which has a melting point of 125-126 °C.

15. A co-crystal according to any one of claims 10 to 14 which is characterized by a powder X-ray diffraction pattern, obtained using copper Kai radiation having a wavelength of 1.54056 A, which comprises peaks at at least five of the following two theta values: 8.3°±0.2°, 11.0°±0.2°, 12.5°±0.2°, 13.0°±0.2°, 14.4°±0.2°, 17.4°±0.2°, 18.1°±0.2°,

21.8°±0.2°, 27.9°±0.2° and 38.1°±0.2°.

16. A co-crystal according to any one of claims 10 to 15 which is characterized by a powder X-ray diffraction pattern, obtained using copper Kai radiation having a wavelength of 1.54056 A, which comprises a peak at each of the following two theta values: 8.3°±0.2°, 11.0°±0.2°, 12.5°±0.2°, 13.0°±0.2°, 14.4°±0.2°, 17.4°±0.2°, 18.1°±0.2°, 21.8°±0.2°,

27.9o±0.2° and 38.1o±0.2°.

17. A co-crystal according to any one of claims 10 to 16 which is characterized by an infrared spectrum which comprises peaks at 3296cm"1±15cm"1, SOS cm^ilScm"1, 1753cm" ^cm"1, 1620cm-1±15cm-1 and lOSScm^ilScm"1.

18. A co-crystal according to claim 1 wherein the co-crystal former is isonicotinic acid.

19. A co-crystal according to claim 18 wherein the molar ratio of the beclomethasone dipropionate to the isonicotinic acid in the co-crystal is from 2:3 to 2:5.

20. A co-crystal according to claim 18 or claim 19 wherein the molar ratio of the beclomethasone dipropionate to the isonicotinic acid in the co-crystal is 1 :2.

21. A co-crystal according to any one of claims 18 to 20 which has a melting point within the temperature range of from 210 °C to 231 °C. 22. A co-crystal according to any one of claims 18 to 21 which has a melting point of 220-221 °C.

23. A co-crystal according to any one of claims 18 to 22 which is characterized by a powder X-ray diffraction pattern, obtained using copper Kai radiation having a wavelength of 1.54056 A, which comprises peaks at at least five of the following two theta values: 9.1°±0.2°, 11.0°±0.2°, 12.5°±0.2°, 14.5°±0.2°, 15.5°±0.2°, 16.6°±0.2°, 17.4°±0.2°,

18.1°±0.2°, 18.9°±0.2° and 26.1°±0.2°.

24. A co-crystal according to any one of claims 18 to 23 which is characterized by a powder X-ray diffraction pattern, obtained using copper Kai radiation having a wavelength of 1.54056 A, which comprises a peak at each of the following two theta values: 9.1°±0.2°, 11.0°±0.2°, 12.5°±0.2°, 14.5°±0.2°, 15.5°±0.2°, 16.6°±0.2°, 17.4°±0.2°, 18.1°±0.2°,

18.9°±0.2° and 26.1°±0.2°. 25. A co-crystal according to any one of claims 18 to 24 which is characterized by an infrared spectrum which comprises peaks at 3296cm"1±15cm"1, 2982cm"1±15cm"1, 2949cm" ^lScm"1, 2884cm"1±15cm-1, 1721cm-1±15cm-1, ^Scn^i^cm"1, 1632αη 1±15αη 1, 1179cm-1±15cm-1, lOSScm^ilScm"1 and 1026cm-1±15cm-1. 26. A pharmaceutical composition which comprises a co-crystal, which co-crystal comprises beclomethasone dipropionate and a co-crystal former, which co-crystal former is adipic acid, maleic acid or isonicotinic acid.

27. A pharmaceutical composition according to claim 26 wherein the co-crystal is as defined in any one of claims 2 to 25.

28. A pharmaceutical composition according to claim 26 or claim 27 which further comprises a pharmaceutically acceptable diluent, excipient or carrier.

29. A co-crystal as defined in any one of claims 1 to 25, or a pharmaceutical composition as defined in any one of claims 26 to 28, for use in a method of treatment of the human or animal body by therapy.

30. A co-crystal as defined in any one of claims 1 to 25, or a pharmaceutical composition as defined in any one of claims 26 to 28, for use in the treatment or prevention of a respiratory infection, a respiratory disease, an allergic reaction which elicits an inflammatory response in the human or animal body, a gastrointestinal tract disorder, a severe aphthous ulcer, or an inflammatory skin disorder.

31. Use of a co-crystal as defined in any one of claims 1 to 25 or a pharmaceutical composition as defined in any one of claims 26 to 28 in the manufacture of a medicament for use in the treatment or prevention of a respiratory infection, a respiratory disease, an allergic reaction which elicits an inflammatory response in the human or animal body, a gastrointestinal tract disorder, a severe aphthous ulcer, or an inflammatory skin disorder.

32. A method of treating a patient suffering from or susceptible to a respiratory infection, a respiratory disease, an allergic reaction which elicits an inflammatory response, a gastrointestinal tract disorder, a severe aphthous ulcer, or an inflammatory skin disorder, which method comprises administering to said patient an effective amount of a co-crystal as defined in any one of claims 1 to 25 or a pharmaceutical composition as defined in any one of claims 26 to 28. 33. A co-crystal or pharmaceutical composition as claimed in claim 30, the use according to claim 31, or a method according to claim 32, wherein the condition is asthma.

34. A process for producing a co-crystal, which co-crystal comprises beclomethasone dipropionate and a co-crystal former, which co-crystal former is adipic acid, maleic acid or isonicotinic acid, which process comprises:

applying a mechanical force to a sample which comprises solid beclomethasone dipropionate, a solid co-crystal former, and a solvent, wherein the co-crystal former is adipic acid, maleic acid or isonicotinic acid.

35. A process according to claim 34 wherein applying the mechanical force to the sample comprises grinding, milling or crushing the sample.

36. A process according to claim 34 or claim 35 wherein applying the mechanical force to the sample comprises grinding the sample.

37. A process according to any one of claims 34 to 36 wherein the sample is a paste, and wherein applying the mechanical force to the sample produces a powder from the paste.

38. A process according to any one of claims 34 to 37 which comprises:

(iii) preparing the sample which comprises solid beclomethasone dipropionate, the solid co-crystal former, and the solvent, by:

(a) applying a mechanical force to a mixture of solid

beclomethasone dipropionate and the solid co-crystal former, and

(b) adding a solvent to the mixture to form a paste; and

(iv) applying a mechanical force to the paste thus formed, to produce a powder.

39. A process according to any one of claims 34 to 38 wherein the solvent comprises an organic solvent.

40. A process according to claim 39 wherein the solvent comprises a polar aprotic organic solvent.

41. A process according to claim 39 or claim 40 wherein the solvent comprises acetonitrile.

42. A process according to any one of claims 34 to 41 wherein the molar ratio of beclomethasone dipropionate to the co-crystal former in the sample is from 2:3 to 2:7.

43. A process according to claim 42 wherein the co-crystal former is adipic acid and said molar ratio is from 2:5 to 2:7, preferably 1 :3.

44. A process according to claim 42 wherein the co-crystal former is isonicotinic acid or maleic acid and said molar ratio is from 2:3 to 2:5, preferably 1 :2. 45. A process according to any one of claims 34 to 44 wherein the amount of solvent in the sample is from 15 % by weight to 80 % by weight, based on the total weight of the sample.

46. A process according to any one of claims 37 to 45 which further comprises:

(d) adding further solvent to the powder thus produced to form a further paste;

(e) applying a mechanical force to the further paste to produce a powder; and

(f) optionally repeating step (a) and then step (b), once, or more than once.

47. A process according to claim 46 wherein said further solvent is as defined in any one of claims 39 to 41.

48. A process according to any one of claims 34 to 47, which further comprises isolating a co-crystal produced thereby. 49. A composition for forming a co-crystal, which composition comprises

beclomethasone dipropionate and a co-crystal former, which co-crystal former is adipic acid, maleic acid or isonicotinic acid.

50. A composition according to claim 49, which is a mixture of solid beclomethasone dipropionate and the solid co-crystal former.

51. A composition according to claim 49 or claim 50, which further comprises a solvent.

52. A composition according to claim 51 wherein the solvent is as defined in any one of claims 39 to 41.

53. A composition according to claim 51 or claim 52 which is a paste.

54. A composition according to any one of claims 51 to 53 wherein the amount of solvent in the composition is from 15 % by weight to 80 % by weight, based on the total weight of the composition. 55. A composition according to any one of claims 49 to 54 wherein the molar ratio of beclomethasone dipropionate to the co-crystal former in the composition is from 2:3 to 2:7.

56. A composition according to claim 55 wherein the co-crystal former is adipic acid and said molar ratio is from 2:5 to 2:7, preferably 1 :3.

57. A composition according to claim 55 wherein the co-crystal former is isonicotinic acid or maleic acid and said molar ratio is from 2:3 to 2:5, preferably 1 :2.

Description:
INCREASING AQUEOUS SOLUBILITY OF BECLOMETHASONE DIPROPIONATE BY FORMATION OF CO-CRYSTALS WITH CO-CRYSTAL FORMER

FIELD OF THE INVENTION

The invention relates to a co-crystal. The invention also concerns a pharmaceutical composition comprising the co-crystal, various uses of the co-crystal, a process for producing the co-crystal, and a precursor composition for use in preparing the co-crystal.

BACKGROUND TO THE INVENTION

Beclomethasone dipropionate, Fluticasone and Triamcinolone are anti- inflammatory corticosteroids administered for the treatment of various respiratory infections, diseases and other allergic reactions which elicit an inflammatory response in the human body. In the case of inflammation in the bronchial tubes due to chronic asthma, they are generally delivered to the pulmonary tract either orally or by making use of nebulisers, dry powder inhalers and metered dose inhalers (Wu, X.; Adedoyin, O. O.; Mansour, H. M. Pulmonary and Nasal Anti-Inflammatory and Anti- Allergy Inhalation

Aerosol Delivery Systems. Anti-Inflammatory Anti- Allergy Agents Med. Chem. 2011, 10, 215 - 229).

The three steroids are lipophilic in nature. This facilitates the passage of the API through the phospholipid bilayer of the cell membrane but the presence of lipophilic side chains on the D-ring of the steroid molecule slow down the overall dissolution of the API in the aqueous bronchial fluid. Lipophilicity may also change their distribution following systemic absorption. This results in the accumulation of the API in body tissues thus increasing the likelihood of the onset of undesired systemic side effects (Derendorf, H.; Nave, Pv.; Drollmann, A.; Cerasoli, F.; Wurst, W. Relevance of pharmacokinetics and pharmacodynamics of inhaled corticosteroids to asthma. Eur. Respir. J. 2006, 28, 1042- 1050).

Beclomethasone dipropionate (BDP), whose structure is shown in Scheme 1, is a pro-drug which undergoes a hydrolysis reaction in order to become beclomethasone 17- monopropionate (BMP) which is the pharmacologically active form (Wu, X.; Adedoyin, O. O.; Mansour, H. M. Pulmonary and Nasal Anti-Inflammatory and Anti- Allergy

Inhalation Aerosol Delivery Systems. Anti-Inflammatory Anti- Allergy Agents Med.

Chem. 2011, 10, 215 - 229).

Scheme 1. Molecular structure of beclomethasone dipropionate (BDP) BDP has a very low aqueous solubility (< 0.1 μg ml "1 ) and due to this fact crystals of BDP dissolve very slowly in aqueous bronchial fluid. As a result, the rate at which BDP activates BMP in the lungs is slowed down considerably thus affecting pulmonary targeting which becomes poor and inefficient. One solution has been the development of a solution metered dose inhaler (QVAR ® ) that employs ethanol as a co-solvent, which serves to dissolve BDP in a hydrofluoroalkane 134a propellant (Saunders, M.; Buttini, F.;

Grainger, C; Forbes, B.; Royall, P. G.; Lincoln, P.; Jones, S. A. In Characterisation of Particles Emitted from Beclomethasone Dipropionate Solution Metered Dose Inhalers, United Kingdom; Duax, W. L.; Cody, V.; Strong, P. D. Structure of the Asthma Drug Beclomethasone Dipropionate. Acta. Cryst. 1981, 37, 383-387).

However, it remains the case that the low aqueous solubility of BDP places a limitation on bioavailability, and therefore on the effectiveness of the drug. It also adversely impacts on formulation development, in terms of severely limiting the range of formulations of the drug that can be developed. SUMMARY OF THE INVENTION

The invention relates to new solid forms of beclomethasone dipropionate (BDP) which have significantly enhanced aqueous solubilities. Thus, co-crystals comprising BDP and particular co-crystal formers are provided which are readily soluble in water, leading to improved bioavailability of the active pharmaceutical ingredient and, consequently, increased effectiveness. Under the U.S. Food and Drug Administration's Biopharmaceutics Classification System (BCS), the co-crystals would likely be classified under class I ("high permeability, high solubility") whereas the pure API falls under class IV ("low permeability, low solubility"). The enhancement in aqueous solubility is expected to facilitate uptake of BDP in aqueous bronchial fluid, and thereby improve pulmonary targeting, and also eliminate or reduce undesirable accumulation of the drug in body tissues and the consequential systemic side effects. The enhanced solubility and bioavailability should also enable lower concentrations of BDP to be employed in formulations than is currently possible, reducing manufacturing costs. It will also enable the development of purely aqueous formulations of BDP, which should provide various benefits including reduced irritation to the skin, reduced side effects and increased environmental friendliness.

The invention results from the inventors' findings that stable co-crystals comprising beclomethasone dipropionate can be produced, by employing adipic acid, maleic acid or isonicotinic acid as the co-crystal former, and that the resulting co-crystals are readily soluble in water. These findings were unexpected and unique to BDP, similar but unsuccessful studies having been carried out at the same time on the structurally similar steroids, fluticasone and triamcinolone.

Accordingly, the invention provides a co-crystal, which co-crystal comprises beclomethasone dipropionate and a co-crystal former, which co-crystal former is adipic acid, maleic acid or isonicotinic acid.

The invention further provides a pharmaceutical composition which comprises a co-crystal, which co-crystal comprises beclomethasone dipropionate and a co-crystal former, which co-crystal former is adipic acid, maleic acid or isonicotinic acid.

Further provided is a co-crystal of the invention, or a pharmaceutical composition of the invention, for use in a method of treatment of the human or animal body by therapy.

The invention also provides a co-crystal of the invention, or a pharmaceutical composition of the invention, for use in the treatment or prevention of a respiratory infection, a respiratory disease, an allergic reaction which elicits an inflammatory response in the human or animal body, a gastrointestinal tract disorder, a severe aphthous ulcer, or an inflammatory skin disorder.

Also provided is a co-crystal of the invention, or a pharmaceutical composition of the invention, for use in the treatment or prevention of asthma.

The invention further provides the use of a co-crystal of the invention or the use of a pharmaceutical composition of the invention, in the manufacture of a medicament for use in the treatment or prevention of a respiratory infection, a respiratory disease, an allergic reaction which elicits an inflammatory response in the human or animal body, a gastrointestinal tract disorder, a severe aphthous ulcer, or an inflammatory skin disorder.

Further provided is the use of a co-crystal of the invention or the use of a pharmaceutical composition of the invention, in the manufacture of a medicament for use in the treatment or prevention of asthma.

The invention also provides a method of treating a patient suffering from or susceptible to a respiratory infection, a respiratory disease, an allergic reaction which elicits an inflammatory response, a gastrointestinal tract disorder, a severe aphthous ulcer, or an inflammatory skin disorderwhich method comprises administering to said patient an effective amount of a co-crystal of the invention, or an effective amount of a

pharmaceutical composition of the invention.

The invention also provides a method of treating a patient suffering from or susceptible to asthma, which method comprises administering to said patient an effective amount of a co-crystal of the invention, or an effective amount of a pharmaceutical composition of the invention.

In another aspect, the invention provides a process for producing a co-crystal, which co-crystal comprises beclomethasone dipropionate and a co-crystal former, which co-crystal former is adipic acid, maleic acid or isonicotinic acid, which process comprises: applying a mechanical force to a sample which comprises solid beclomethasone dipropionate, a solid co-crystal former, and a solvent, wherein the co-crystal former is adipic acid, maleic acid or isonicotinic acid.

The invention also provides a composition for forming a co-crystal, which composition comprises beclomethasone dipropionate and a co-crystal former, which co- crystal former is adipic acid, maleic acid or isonicotinic acid.

BRIEF DESCRIPTION OF THE FIGURES

Fig. 1 shows the infrared (IR) spectrum of the 1 :3 BDP/adipic acid co-crystal (lower trace) and that of the physical mixture of the API and the co-crystal former (upper trace).

Fig. 2 shows the IR spectrum of the 1 :2 BDP/maleic acid co-crystal (lower trace) and that of the physical mixture of the API and the co-crystal former (upper trace).

Fig. 3 shows the IR spectrum of the 1 :2 BDP/isonicotinic acid cocrystal (lower trace) and that of the physical mixture of the API and the co-crystal former (upper trace). DETAILED DESCRIPTION OF THE INVENTION

The invention relates to a co-crystal.

The term "co-crystal" (or "cocrystal") as used herein means a solid that is a crystalline single phase material comprising two or more different molecular and/or ionic compounds which are neither solvents nor simple salts (S. Aitipamula et al. "Polymorphs, Salts, and Cocrystals: What's in a Name?", Cryst. Growth Des., 2012, 12 (5), pp 2147- 2152). The two or more different molecular and/or ionic compounds in a co-crystal are generally compounds which are themselves solid at room temperature (i.e. solids at 22 °C). They are typically present in the co-crystal in a definite stoichiometric ratio.

In the co-crystals of the present invention, one of the two or more different molecular and/or ionic compounds is an API, and another of the two or more different molecular and/or ionic compounds is a co-crystal former. Indeed, the co-crystals of the present invention are pharmaceutical co-crystals. A pharmaceutical co-crystal is a crystalline single phase material comprising an API and one or more unique co-crystal formers, typically in a stoichiometric ratio.

Each of the one or more co-crystal formers is a molecular or an ionic compound that is a solid at room temperature. Solvates (including hydrates) of an API that do not further comprise a co-crystal former are therefore not considered to be co-crystals. A pharmaceutical co-crystal may however include one or more solvent (e.g. acetonitrile, or water) molecules in the crystal lattice which comprises the API and the one or more unique co-crystal formers.

Co-crystals can be constructed through several types of interaction, including hydrogen bonding (H-bonding), pi stacking, and van der Waals forces. However, co- crystals often rely on hydrogen-bonded assemblies between neutral molecules of an API and another (co-crystal former) component.

In the co-crystals of the present invention, the API is BDP, and the co-crystal former is adipic acid, maleic acid or isonicotinic acid.

Thus, the present invention provides a co-crystal, which co-crystal comprises beclomethasone dipropionate and a co-crystal former, which co-crystal former is adipic acid, maleic acid or isonicotinic acid.

The molecular structure of beclomethasone dipropionate is shown in scheme 1, above.

Adipic acid (hexane-l,6-dioic acid), maleic acid (cz ' s-butenedioic acid) and isonicotinic acid (pyridine -4-carboxylic acid) have the following structures, respectively:

adipic acid maleic acid isonicotinic acid

Usually, the co-crystal of the invention comprises only one co-crystal former which is one of adipic acid, maleic acid and isonicotinic acid.

Thus, typically, the co-crystal comprises only one of adipic acid, maleic acid and isonicotinic acid.

The co-crystal of the present invention may or may not further comprise one or more solvent molecules. When the co-crystal of the invention comprises more than one solvent molecule, the solvent molecules may be molecules of the same solvent (for instance, molecules of acetonitrile) or molecules of two or more different solvents (for instance, one or more molecules of acetonitrile and one or more molecules of water). The stoichiometric ratio of the one or more solvents to BDP in the cocrystal (solvent molecules : BDP molecules) may, for instance be from 10: 1 to 1 :4, for example from 5: 1 to 1 :2, or for instance from 3: 1 to 1 : 1.

The co-crystal of the invention may, for instance, consist of: (i) BDP; (ii) the co- crystal former which is one of adipic acid, maleic acid and isonicotinic acid; and, optionally, (iii) one or more solvents.

The co-crystal may, for instance, consist of: (i) BDP; (ii) the co-crystal former which is one of adipic acid, maleic acid and isonicotinic acid; and (iii) one or more solvents.

The one or more solvents may for instance be selected from polar solvents, e.g. from acetonitrile and water. The one or more solvents may, for instance, be selected from polar aprotic solvents, an example of which is acetonitrile. The one or more solvents may for instance be selected from organic solvents. The organic solvents may for instance comprise, or be, polar aprotic organic solvents. The one or more solvents may for example comprise acetonitrile.

The stoichiometric ratio of the one or more solvents to BDP in the cocrystal (solvent molecules:BDP molecules) may, for example, be from 10: 1 to 1 :4, for example from 5 : 1 to 1 :2, or for instance from 3: 1 to 1 : 1. The one or more solvents may consist of a single solvent. Thus, the co-crystal of the invention may consist of: (i) BDP, (ii) a co-crystal former which is one of adipic acid, maleic acid and isonicotinic acid, and (iii) a solvent.

The solvent may, for example, be a polar solvent, for instance acetonitrile or water. It may, for instance, be a polar aprotic solvent, for instance acetonitrile.

The solvent may be an organic solvent. The solvent may for instance be, a polar aprotic organic solvent. The solvent may for example be acetonitrile.

In some embodiments, the co-crystal of the present invention does not comprise a solvent. Accordingly, the co-crystal of the invention may comprise beclomethasone dipropionate, a co-crystal former which is adipic acid, maleic acid or isonicotinic acid, and no solvent.

The co-crystal of the invention may, for instance, consist of: (i) BDP and (ii) a co- crystal former which is one of adipic acid, maleic acid and isonicotinic acid. Adipic acid as the co-crystal former

In one preferred embodiment of the co-crystal of the invention, the co-crystal former is adipic acid.

Accordingly, in a preferred embodiment, the invention provides a co-crystal, which co-crystal comprises beclomethasone dipropionate and a co-crystal former, which co- crystal former is adipic acid.

Usually, the molar ratio of the beclomethasone dipropionate to the adipic acid in the co-crystal is from 2:5 to 2:7. The molar ratio of the beclomethasone dipropionate to the adipic acid in the co-crystal may, for instance, be 1 :3.

Usually, the co-crystal of the invention in which the co-crystal former is adipic acid has a melting point within the temperature range of from 132 °C to 152 °C. It often, for instance, has a melting point within the temperature range of from 137 °C to 147 °C. More typically, the co-crystal has a melting point within the temperature range of from 139 °C to 145 °C. The melting point may, for instance, be 142 °C.

The term "melting point", as used herein throughout, refers to the melting point as the Clear Point, i.e. the point at which the sample becomes a clear liquid and no solid particles remain, as determined under standard atmoshpheric pressure (1013 mbar) in an open vessel. This can be measured using, for instance, a Stuart SMP40 melting point apparatus which employs optical sensors to detect melting. An open melting point glass capillary filled with the co-crystal sample up to ca. 2cm in height is placed into the analysing chamber of the apparatus and, under standard atmospheric pressure, the sample is heated at a heating rate of 5°C per minute to raise the temperature of the sample from about 25°C to a temperature above the melting point; the clear point is determined by the optical sensors of the apparatus.

The co-crystal of the invention, in which the co-crystal former is adipic acid, may be characterized by a powder X-ray diffraction pattern, obtained using copper Και radiation having a wavelength of 1.54056 A, which comprises a peak at at least one of the following two theta values: 8.3°±0.2°, 12.9°±0.2°, 14.5°±0.2°, 16.8°±0.2°, 18.9°±0.2°, 21.4°±0.2°, 25.2°±0.2°, 25.7°±0.2°, 26.8°±0.2° and 31.1°±0.2°. More typically, it is characterized by a said powder X-ray diffraction pattern comprising peaks at at least two of the aforementioned two theta values, for instance at at least three of the aforementioned two theta values, or for example at at least four of the aforementioned two theta values.

Often, for instance, the co-crystal of the invention, in which the co-crystal former is adipic acid, is characterized by a powder X-ray diffraction pattern, obtained using copper Και radiation having a wavelength of 1.54056 A, which comprises peaks at at least five of the following two theta values: 8.3°±0.2°, 12.9°±0.2°, 14.5°±0.2°, 16.8°±0.2°, 18.9°±0.2°, 21.4°±0.2°, 25.2°±0.2°, 25.7°±0.2°, 26.8°±0.2° and 31.1°±0.2°. More typically, it is characterized by a said powder X-ray diffraction pattern comprising peaks at at least seven of the aforementioned two theta values, for instance at at least eight of the aforementioned two theta values, or for example at at least nine of the aforementioned two theta values.

The co-crystal of the invention, in which the co-crystal former is adipic acid, is typically characterized by a powder X-ray diffraction pattern, obtained using copper Και radiation having a wavelength of 1.54056 A, which comprises a peak at each of the following two theta values: 8.3°±0.2°, 12.9°±0.2°, 14.5°±0.2°, 16.8°±0.2°, 18.9°±0.2°, 21.4°±0.2°, 25.2°±0.2°, 25.7°±0.2°, 26.8°±0.2° and 31.1°±0.2°.

Usually, the co-crystal of the invention in which the co-crystal former is adipic acid is characterized by an infrared spectrum which comprises peaks at 3296cm "1 ±15cm "1 , 2982cm "1 ±15cm- 1 , 1748cm- 1 ±15cm- 1 , 1632αη 1 ±15αη 1 and 1 ^Ocm^ilScm "1 .

Often, for instance, the co-crystal is characterized by an infrared spectrum which comprises peaks at 3296cm "1 ±10cm "1 , 2982cm "1 ±10cm "1 , 1748cm "1 ±10cm "1 , 1632cm " ^lOcm "1 and 1 ^Ocm^ilOcm "1 . Said infrared spectrum is typically recorded by performing infrared spectroscopy on a pellet which comprises, and more typically consists essentially of, or consists of: KBr and the co-crystal. The co-crystal of the invention in which the co-crystal former is adipic acid preferably has a melting point as defined above, and is preferably characterized by a powder X-ray diffraction pattern as defined above and by an infrared spectrum as defined above.

The co-crystal of the invention, in which the co-crystal former is adipic acid, may or may not further comprise one or more solvent molecules.

The co-crystal may, for instance, consist of: (i) BDP; (ii) adipic acid; and, optionally, (iii) one or more solvents.

For instance, the co-crystal may consist of: (i) BDP; (ii) adipic acid; and (iii) one or more solvents.

The one or more solvents may consist of a single solvent. Thus, the co-crystal of the invention may consist of: (i) BDP, (ii) adipic acid; and (iii) a solvent. The one or more solvents, or the (single) solvent, may be as further defined hereinbefore.

In some embodiments, the co-crystal of the invention, in which the co-crystal former is adipic acid, does not comprise a solvent. Accordingly, the co-crystal of the invention may comprise beclomethasone dipropionate, adipic acid and no solvent. The co- crystal of the invention may, for instance, consist of: (i) BDP and (ii) adipic acid.

Usually, the molar ratio of the beclomethasone dipropionate to the adipic acid in the co-crystal is from 2:5 to 2:7. The molar ratio of the beclomethasone dipropionate to the adipic acid in the co-crystal may, for instance, be 1 :3.

Maleic acid as the co-crystal former

In one preferred embodiment of the co-crystal of the invention, the co-crystal former is maleic acid.

Accordingly, in a preferred embodiment, the invention provides a co-crystal, which co-crystal comprises beclomethasone dipropionate and a co-crystal former, which co- crystal former is maleic acid.

Usually, the molar ratio of the beclomethasone dipropionate to the maleic acid in the co-crystal is from 2:3 to 2:5. The molar ratio of the beclomethasone dipropionate to the adipic acid in the co-crystal may, for instance, be 1 :2.

Usually, the co-crystal of the invention in which the co-crystal former is maleic acid has a melting point within the temperature range of from 115 °C to 136 °C. It often, for instance, has a melting point within the temperature range of from 120 °C to 131 °C. More typically, the co-crystal has a melting point within the temperature range of from 122 °C to 129 °C. The melting point may, for instance, be 125-126 °C.

The co-crystal of the invention, in which the co-crystal former is maleic acid, may be characterized by a powder X-ray diffraction pattern, obtained using copper Και radiation having a wavelength of 1.54056 A, which comprises a peak at at least one of the following two theta values: 8.3°±0.2°, 11.0°±0.2°, 12.5°±0.2°, 13.0°±0.2°, 14.4°±0.2°, 17.4°±0.2°, 18.1°±0.2°, 21.8°±0.2°, 27.9°±0.2° and 38.1°±0.2°. More typically, it is characterized by a said powder X-ray diffraction pattern comprising peaks at at least two of the aforementioned two theta values, for instance at at least three of the aforementioned two theta values, or for example at at least four of the aforementioned two theta values.

Often, for instance, the co-crystal of the invention, in which the co-crystal former is maleic acid, is characterized by a powder X-ray diffraction pattern, obtained using copper Και radiation having a wavelength of 1.54056 A, which comprises peaks at at least five of the following two theta values: 8.3°±0.2°, 11.0°±0.2°, 12.5°±0.2°, 13.0°±0.2°, 14.4°±0.2°, 17.4°±0.2°, 18.1°±0.2°, 21.8°±0.2°, 27.9°±0.2° and 38.1°±0.2°. More typically, it is characterized by a said powder X-ray diffraction pattern comprising peaks at at least seven of the aforementioned two theta values, for instance at at least eight of the aforementioned two theta values, or for example at at least nine of the aforementioned two theta values.

The co-crystal of the invention, in which the co-crystal former is maleic acid, is typically characterized by a powder X-ray diffraction pattern, obtained using copper Και radiation having a wavelength of 1.54056 A, which comprises a peak at each of the following two theta values: 8.3°±0.2°, 11.0°±0.2°, 12.5°±0.2°, 13.0°±0.2°, 14.4°±0.2°, 17.4°±0.2°, 18.1°±0.2°, 21.8°±0.2°, 27.9°±0.2° and 38.1°±0.2°.

Usually, the co-crystal of the invention in which the co-crystal former is maleic acid is characterized by an infrared spectrum which comprises peaks at 3296cm "1 ±15cm "1 , 3059cm "1 ±15cm- 1 ,

Often, for instance, the co-crystal is characterized by an infrared spectrum which comprises peaks at 3296cm "1 ±10cm "1 , 3059cm "1 ±10cm "1 , 1620cm " ^lOcm "1 and lOSScm^ilOcm "1 . Said infrared spectrum is typically recorded by performing infrared spectroscopy on a pellet which comprises, and more typically consists essentially of, or consists of: KBr and the co-crystal.

The co-crystal of the invention in which the co-crystal former is maleic acid preferably has a melting point as defined above for that co-crystal, and is preferably characterized by a powder X-ray diffraction pattern as defined above for that co-crystal and by an infrared spectrum as defined above for that co-crystal.

The co-crystal of the invention, in which the co-crystal former is maleic acid, may or may not further comprise one or more solvent molecules.

The co-crystal may, for instance, consist of: (i) BDP; (ii) maleic acid; and, optionally, (iii) one or more solvents.

For instance, the co-crystal may consist of: (i) BDP; (ii) maleic acid; and (iii) one or more solvents.

The one or more solvents may consist of a single solvent. Thus, the co-crystal of the invention may consist of: (i) BDP, (ii) maleic acid; and (iii) a solvent.

The one or more solvents, or the (single) solvent, may be as further defined hereinbefore.

In some embodiments, the co-crystal of the invention, in which the co-crystal former is maleic acid, does not comprise a solvent. Accordingly, the co-crystal of the invention may comprise beclomethasone dipropionate, maleic acid and no solvent. The co- crystal of the invention may, for instance, consist of: (i) BDP and (ii) maleic acid.

Usually, the molar ratio of the beclomethasone dipropionate to the maleic acid in the co-crystal is from 2:3 to 2:5. The molar ratio of the beclomethasone dipropionate to the maleic acid in the co-crystal may, for instance, be 1 :2.

Isonicotinic acid as the co-crystal former

In one preferred embodiment of the co-crystal of the invention, the co-crystal former is isonicotinic acid.

Accordingly, in a preferred embodiment, the invention provides a co-crystal, which co-crystal comprises beclomethasone dipropionate and a co-crystal former, which co- crystal former is isonicotinic acid.

Usually, the molar ratio of the beclomethasone dipropionate to the isonicotinic acid in the co-crystal is from 2:3 to 2:5. The molar ratio of the beclomethasone dipropionate to the isonicotinic acid in the co-crystal may, for instance, be 1 :2.

Usually, the co-crystal of the invention in which the co-crystal former is isonicotinic acid has a melting point within the temperature range of from 210 °C to 231 °C. It often, for instance, has a melting point within the temperature range of from 215 °C to 226 °C. More typically, the co-crystal has a melting point within the temperature range of from 217 °C to 224 °C. The melting point may, for instance, be 220-221 °C. The co-crystal of the invention, in which the co-crystal former is isonicotinic acid, may be characterized by a powder X-ray diffraction pattern, obtained using copper Και radiation having a wavelength of 1.54056 A, which comprises a peak at at least one of the following two theta values: 9.1°±0.2°, 11.0°±0.2°, 12.5°±0.2°, 14.5°±0.2°, 15.5°±0.2°, 16.6°±0.2°, 17.4°±0.2°, 18.1°±0.2°, 18.9°±0.2° and 26.1°±0.2°. More typically, it is characterized by a said powder X-ray diffraction pattern comprising peaks at at least two of the aforementioned two theta values, for instance at at least three of the aforementioned two theta values, or for example at at least four of the aforementioned two theta values.

Often, for instance, the co-crystal of the invention, in which the co-crystal former is isonicotinic acid, is characterized by a powder X-ray diffraction pattern, obtained using copper Και radiation having a wavelength of 1.54056 A, which comprises peaks at at least five of the following two theta values: 9.1°±0.2°, 11.0°±0.2°, 12.5°±0.2°, 14.5°±0.2°, 15.5°±0.2°, 16.6°±0.2°, 17.4°±0.2°, 18.1°±0.2°, 18.9°±0.2° and 26.1°±0.2°. More typically, it is characterized by a said powder X-ray diffraction pattern comprising peaks at at least seven of the aforementioned two theta values, for instance at at least eight of the aforementioned two theta values, or for example at at least nine of the aforementioned two theta values.

The co-crystal of the invention, in which the co-crystal former is isonicotinic acid, is typically characterized by a powder X-ray diffraction pattern, obtained using copper Και radiation having a wavelength of 1.54056 A, which comprises a peak at each of the following two theta values: 9.1°±0.2°, 11.0°±0.2°, 12.5°±0.2°, 14.5°±0.2°, 15.5°±0.2°,

16.6°±0.2°, 17.4°±0.2°, 18.1°±0.2°, 18.9°±0.2° and 26.1°±0.2°.

Usually, the co-crystal of the invention in which the co-crystal former is isonicotinic acid is characterized by an infrared spectrum which comprises peaks at 3296cm "1 ±15cm- 1 , 2982cm "1 ±15cm- 1 , 2949cm "1 ±15cm- 1 , 2884cm "1 ±15cm- 1 , 1721cm "

^lScm "1 , ΙόόΒα ^α 1 , 1632αη 1 ±15αη 1 , 1179cm- 1 ±15cm- 1 , lOSScm^ilScm "1 and

1026cm "1 ±15cm "1 .

Often, for instance, the co-crystal is characterized by an infrared spectrum which comprises peaks at 3296cm "1 ±10cm "1 , 2982cm "1 ±10cm "1 , 2949cm "1 ±10cm "1 , 2884cm " ^lOcm "1 , 1721cm- 1 ±10cm- 1 , ΙόόΒα ^ΙΟα 1 , 1632αη 1 ±10αη 1 , 1179cm 1 ±10cm 1 , lOSScm^ilOcm "1 and 1026cm "1 ±10cm "1 . Said infrared spectrum is typically recorded by performing infrared spectroscopy on a pellet which comprises, and more typically consists essentially of, or consists of: KBr and the co-crystal. The co-crystal of the invention in which the co-crystal former is isonicotinic acid preferably has a melting point as defined above for that co-crystal, and is preferably characterized by a powder X-ray diffraction pattern as defined above for that co-crystal and by an infrared spectrum as defined above for that co-crystal.

The co-crystal of the invention, in which the co-crystal former is isonicotinic acid, may or may not further comprise one or more solvent molecules.

The co-crystal may, for instance, consist of: (i) BDP; (ii) isonicotinic acid; and, optionally, (iii) one or more solvents.

For instance, the co-crystal may consist of: (i) BDP; (ii) isonicotinic acid; and (iii) one or more solvents.

The one or more solvents may consist of a single solvent. Thus, the co-crystal of the invention may consist of: (i) BDP, (ii) isonicotinic acid; and (iii) a solvent.

The one or more solvents, or the (single) solvent, may be as further defined hereinbefore.

In some embodiments, the co-crystal of the invention, in which the co-crystal former is isonicotinic acid, does not comprise a solvent. Accordingly, the co-crystal of the invention may comprise beclomethasone dipropionate, isonicotinic acid and no solvent. The co-crystal of the invention may, for instance, consist of: (i) BDP and (ii) isonicotinic acid.

Usually, the molar ratio of the beclomethasone dipropionate to the isonicotinic acid in the co-crystal is from 2:3 to 2:5. The molar ratio of the beclomethasone dipropionate to the maleic acid in the co-crystal may, for instance, be 1 :2.

Process

The co-crystal of the invention can be produced by applying a mechanical force to a sample comprising solid beclomethasone dipropionate, the solid co-crystal former, and a solvent. An embodiment of this process is referred to as a "solvent-assisted grinding".

Accordingly, the invention provides a process for producing a co-crystal, which co- crystal comprises beclomethasone dipropionate and a co-crystal former, which co-crystal former is adipic acid, maleic acid or isonicotinic acid, which process comprises: applying a mechanical force to a sample which comprises solid beclomethasone dipropionate, a solid co-crystal former, and a solvent, wherein the co-crystal former is adipic acid, maleic acid or isonicotinic acid. Applying the mechanical force to the sample may for instance comprise grinding, milling or crushing the sample. Often, it comprises grinding the sample.

The sample to which the mechanical force is applied is typically a paste, and applying the mechanical force to the sample typically produces a powder from the paste.

The process of the invention may therefore comprise:

(i) preparing said sample which comprises solid beclomethasone dipropionate, the solid co-crystal former, and the solvent, by:

(a) applying a mechanical force to a mixture of solid

beclomethasone dipropionate and the solid co-crystal former, and

(b) adding a solvent to the mixture to form a paste; and

(ii) applying a mechanical force to the paste thus formed, to produce a powder. Typically, the solvent comprises an organic solvent. The solvent may for instance comprise, or be, a polar, aprotic organic solvent. The solvent may for example comprise, or be, acetonitrile.

The amount of solvent in the sample is typically from 15 % by weight (wt%) to 90 % by weight (wt%), based on the total weight of the sample, and is more typically from 15 wt% to 80 wt%. The amount of solvent in the sample may for instance be from 20 wt% to 70 wt%, or for instance from 20 wt% to 60 wt%, for example from 25 wt% to 50 wt%.

The balance of the sample is typically made up of the beclomethasone dipropionate and the co-crystal former.

The molar ratio of beclomethasone dipropionate to the co-crystal former in the sample may be from 2:3 to 2:7. For instance, the co-crystal former may be adipic acid and said molar ratio may be from 2:5 to 2:7, and is preferably 1 :3. Alternatively, for instance, the co-crystal former may be isonicotinic acid or maleic acid and said molar ratio may be from 2:3 to 2:5, and is preferably 1 :2.

The process of the invention typically further comprises:

(a) adding further solvent to the powder thus produced to form a further paste;

(b) applying a mechanical force to the further paste to produce a powder; and

(c) optionally repeating step (a) and then step (b), once, or more than once.

The further solvent may comprise an organic solvent. The further solvent may for instance comprise, or be, a polar, aprotic organic solvent. The further solvent may for example comprise, or be, acetonitrile.

The process may further comprise isolating a co-crystal produced thereby. Precursor composition for producing a co-crystal

The invention also provides a composition for forming a co-crystal, which composition comprises beclomethasone dipropionate and a co-crystal former, which co- crystal former is adipic acid, maleic acid or isonicotinic acid. The composition is usually a mixture of solid beclomethasone dipropionate and the solid co-crystal former.

The composition of the invention may further comprise a solvent. Typically, the solvent comprises an organic solvent. The solvent may for instance comprise, or be, a polar, aprotic organic solvent. The solvent may for example comprise, or be, acetonitrile.

When the composition further comprises a solvent, the composition may be a paste. When the composition further comprises a solvent, the amount of solvent in the composition is typically from 15 % by weight (wt%) to 90 % by weight (wt%), based on the total weight of the composition, and is more typically from 15 wt% to 80 wt%. The amount of solvent in the composition may for instance be from 20 wt% to 70 wt%, or for instance from 20 wt% to 60 wt%, for example from 25 wt% to 50 wt%.

When the composition further comprises a solvent, the balance of the composition is typically made up of the beclomethasone dipropionate and the co-crystal former.

The molar ratio of beclomethasone dipropionate to the co-crystal former in the composition may be from 2:3 to 2:7. For instance, the co-crystal former may be adipic acid and said molar ratio may be from 2:5 to 2:7, and is preferably 1 :3. Alternatively, for instance, the co-crystal former may be isonicotinic acid or maleic acid and said molar ratio may be from 2:3 to 2:5, and is preferably 1 :2.

Therapeutic uses and pharmaceutical compositions

The co-crystals of the present invention are therapeutically useful. The present invention therefore provides a co-crystal, which co-crystal comprises beclomethasone dipropionate and a co-crystal former, which co-crystal former is adipic acid, maleic acid or isonicotinic acid, for use in a method of treatment of the human or animal body by therapy. The co-crystal may be as further defined anywhere herein.

Also provided is a pharmaceutical composition which comprises a co-crystal, which co-crystal comprises beclomethasone dipropionate and a co-crystal former, which co-crystal former is adipic acid, maleic acid or isonicotinic acid. The co-crystal may be as further defined anywhere herein. The pharmaceutical composition typically further comprises a pharmaceutically acceptable diluent, excipient or carrier. In a preferred embodiment, the pharmaceutically acceptable diluent, excipient or carrier does not comprise an organic solvent. Preferably, the pharmaceutically acceptable diluent, excipient or carrier is aqueous.

The pharmaceutical composition of the invention typically contains up to 85 wt% of the co-crystal of the invention. More typically, it contains up to 50 wt% of a co-crystal of the invention, for instance up to 30 wt%, or up to 15 wt% of a co-crystal of the invention. Preferred pharmaceutical compositions are sterile and pyrogen free.

Also provided is a pharmaceutical composition of the invention as defined herein, for use in a method of treatment of the human or animal body by therapy.

The co-crystals of the invention are useful in treating or preventing respiratory infections and respiratory diseases. They are, for instance, useful in treating or preventing respiratory infections and respiratory diseases which elicit an inflammatory response in the human or animal body. The co-crystals of the invention are also useful in treating or preventing allergic reactions which elicit an inflammatory response in the human or animal body. The co-crystals of the invention are, for instance, useful in treating asthma. The co- crystals of the invention are additionally useful for treating gastrointestinal tract disorders, and inflammatory skin disorders, and also in the treatment of unusually severe aphthous ulcers.

The present invention therefore provides a co-crystal of the invention as defined herein, or a pharmaceutical composition of the invention as defined herein, for use in the treatment or prevention of a respiratory infection, a respiratory disease, an allergic reaction which elicits an inflammatory response in the human or animal body, a gastrointestinal tract disorder, a severe aphthous ulcer, or an inflammatory skin disorder.

Also provided is a method for treating a patient suffering from or susceptible to a respiratory infection, a respiratory disease, an allergic reaction which elicits an

inflammatory response in the human or animal body, a gastrointestinal tract disorder, a severe aphthous ulcer, or an inflammatory skin disorder, which method comprises administering to said patient an effective amount of a co-crystal of the invention as defined herein, or a pharmaceutical composition of the invention as defined herein.

Further provided is the use of a co-crystal of the invention as defined herein, or a pharmaceutical composition of the invention as defined herein in the manufacture of a medicament for use in treating or preventing a respiratory infection, a respiratory disease, an allergic reaction which elicits an inflammatory response in the human or animal body, a gastrointestinal tract disorder, a severe aphthous ulcer, or an inflammatory skin disorder. Non-limiting examples of respiratory infections and diseases that can be treated or prevented using the co-crystals and the pharmaceutical compositions of the invention are obstructive diseases of the airways including: asthma, including bronchial, allergic, intrinsic, extrinsic, exercise-induced, drug-induced (including aspirin and NSAID-induced) and dust-induced asthma, both intermittent and persistent and of all severities, and other causes of airway hyper-responsiveness; chronic obstructive pulmonary disease (COPD); bronchitis, including infectious and eosinophilic bronchitis; emphysema; bronchiectasis; cystic fibrosis; sarcoidosis; farmer's lung and related diseases; hypersensitivity

pneumonitis; lung fibrosis, including cryptogenic fibrosing alveolitis, idiopathic interstitial pneumonias, fibrosis complicating anti-neoplastic therapy and chronic infection, including tuberculosis and aspergillosis and other fungal infections; complications of lung transplantation; vasculitic and thrombotic disorders of the lung vasculature, and pulmonary hypertension; antitussive activity including treatment of chronic cough associated with inflammatory and secretory conditions of the airways, and iatrogenic cough; acute and chronic rhinitis including rhinitis medicamentosa, and vasomotor rhinitis; perennial and seasonal allergic rhinitis including rhinitis nervosa (hay fever); sinusitis; nasal polyposis; acute viral infection including the common cold, and infection due to respiratory syncytial virus, influenza, corona virus (including SARS) and adenovirus.

Often, the disease or condition is asthma, allergic asthma, hay fever, allergic rhinitis, sinusitis, bronchitis, emphysema, bronchiectasis, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome (ARDS), steroid resistant asthma, severe asthma, paediatric asthma, cystic fibrosis, lung fibrosis, pulmonary fibrosis, interstitial lung disease, skin disorders, atopic dermatitis, psoriasis, and ocular

inflammation.

Inflammatory skin disorders may also be treated using the co-crystal of the invention, including for instance eczema, atopic dermatitis, contact dermatitis or other eczematous dermatoses, and delayed-type hypersensitivity reactions; phyto- and photodermatitis; seborrhoeic dermatitis, dermatitis herpetiformis, psoriasis, lichen planus, lichen sclerosus et atrophica, pyoderma gangrenosum, skin sarcoid, discoid lupus erythematosus, pemphigus, pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitides, toxic erythemas, cutaneous, eosinophilias, alopecia areata, male-pattern baldness, Sweet's syndrome, Weber-Christian syndrome, erythema multiforme; cellulitis, both infective and non-infective; panniculitis; cutaneous lymphomas, non-melanoma skin cancer and other dysplastic lesions; drug-induced disorders including fixed drug eruptions. The co-crystal of the invention may also be used to treat a gastrointestinal tract disorder, including for instance glossitis, gingivitis, periodontitis; oesophagitis, including reflux; eosinophilic gastro-enteritis, mastocytosis, Crohn's disease, colitis including ulcerative colitis, proctitis, pruritis ani; coeliac disease, irritable bowel syndrome, and food-related allergies which may have effects remote from the gut (for example migraine, rhinitis or eczema). The co-crystal of the invention may for instance be used to treat ulcerative colitis. It may be used in conjunction with 5 -aminosalicylates to treat ulcerative colitis.

The co-crystal of the invention may also be used to treat unusually severe aphthous ulcers.

More typically, the disease or condition is asthma or chronic obstructive pulmonary disease (COPD).

Typically, it is asthma.

Accordingly, the invention also provides a co-crystal of the invention as defined herein, or a pharmaceutical composition of the invention as defined herein, for use in the treatment or prevention of asthma.

Also provided is a method for treating a patient suffering from or susceptible to asthma, which method comprises administering to said patient an effective amount of a co- crystal of the invention as defined herein, or a pharmaceutical composition of the invention as defined herein.

Further provided is the use of a co-crystal of the invention as defined herein, or of a pharmaceutical composition of the invention as defined herein, in the manufacture of a medicament for use in the treatment or prevention of asthma. Administration

Co-crystals of the present invention are typically administered to a subject in the form of a pharmaceutical composition of the invention. Such pharmaceutical compositions may be administered to the subject by any acceptable route of administration including, but not limited to, inhaled, oral, nasal, topical (including transdermal) and parenteral modes of administration. Further, the compositions of the invention may be administered, for example orally, in multiple doses per day, in a single daily dose or a single weekly dose. It will be understood that any form of the active agents used in the composition of the invention, (i.e. free base, pharmaceutically acceptable salt, solvate, etc.) that is suitable for the particular mode of administration can be used in the pharmaceutical compositions discussed herein.

The pharmaceutical compositions of this invention typically contain a

therapeutically effective amount of a co-crystal of the invention. Those skilled in the art will recognize, however, that a pharmaceutical composition may contain more than a therapeutically effective amount, i.e., bulk compositions, or less than a therapeutically effective amount, i.e., individual unit doses designed for multiple administration to achieve a therapeutically effective amount. In one embodiment, the composition will contain from about 0.01-95 wt % of a co-crystal of the invention, including, from about 0.01-30 wt %, such as from about 0.01-10 wt %, with the actual amount depending upon the formulation itself, the route of administration, the frequency of dosing, and so forth. In another embodiment, a composition suitable for inhalation, for example, comprises from about 0.01-30 wt % of a co-crystal of the invention with yet another embodiment comprising from about 0.01-10 wt % active agent.

Any conventional carrier or excipient may be used in the pharmaceutical compositions of the invention. The choice of a particular carrier or excipient, or combinations of carriers or excipients, will depend on the mode of administration being used to treat a particular subject or type of medical condition or disease state. In this regard, the preparation of a suitable composition for a particular mode of administration is well within the scope of those skilled in the pharmaceutical arts. Additionally, carriers or excipients used in such compositions are commercially available. By way of further illustration, conventional formulation techniques are described in Remington: The Science and Practice of Pharmacy, 20 th Edition, Lippincott Williams & White, Baltimore, Md. (2000); and H. C. Ansel et al, Pharmaceutical Dosage Forms and Drug Delivery Systems, 7 th Edition, Lippincott Williams & White, Baltimore, Md. (1999).

Representative examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, the following: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, such as microcrystalline cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; compressed propellant gases, such as

chlorofluorocarbons and hydrofluorocarbons; and other non-toxic compatible substances employed in pharmaceutical compositions.

Pharmaceutical compositions are typically prepared by thoroughly and intimately mixing or blending the co-crystal of the invention with a pharmaceutically acceptable carrier and one or more optional ingredients. The resulting uniformly blended mixture may then be shaped or loaded into tablets, capsules, pills, canisters, cartridges, dispensers and the like using conventional procedures and equipment.

The pharmaceutical compositions of the invention, which comprise a co-crystal of the invention, are often suitable for inhaled administration. The pharmaceutical

composition may be for administration by dry powder inhaler (DPI) or metered-dose inhaler (MDI).

Suitable compositions for inhaled administration will typically be in the form of an aerosol or a powder, for instance a dry powder composition. Such compositions are generally administered using well-known delivery devices, such as a dry powder inhaler, or a metered-dose inhaler, examples of which are described below.

A composition comprising the co-crystal of the invention may be administered by inhalation using a dry powder inhaler (DPI). Such DPIs typically administer the active agent as a free-flowing powder that is dispersed in a subject's air- stream during inspiration. In order to achieve a free flowing powder, the active agent(s) / active ingredient(s) is typically formulated with a suitable excipient such as lactose, starch, mannitol, dextrose, polylactic acid, polylactide-co-glycolide, and combinations thereof. Typically, the co- crystal of the invention is micronized and combined with an excipient to form a blend suitable for inhalation. Accordingly, in one embodiment of the invention, the co-crystal of the invention is in micronized form. For example, a representative composition for use in a DPI comprises dry lactose having a particle size between about 1 μιη and about 100 μιη (e.g., dry milled lactose) and micronized particles of the active agent. Such a dry powder formulation can be made, for example, by combining lactose with the co-crystal of the invention and then dry blending the components. Alternatively, if desired, the co-crystal of the invention can be formulated without an excipient. The composition is then typically loaded into a DPI, or into inhalation cartridges or capsules for use with a DPI. DPIs are well known to those of ordinary skill in the art, and many such devices are commercially available, with representative devices including Aerolizer R ™ (Novartis), Airmax™ (IVAX), ClickHaler R ™ (Innovata Biomed), Diskhaler R ™ (Glaxo SmithKline), Diskus R ™ or Accuhaler (Glaxo SmithKline), Easyhaler R ™ (Orion Pharma), Eclipse™ (Aventis), FlowCaps R ™ (Hovione), Handihaler R ™ (Boehringer Ingelheim), Pulvinal R ™ (Chiesi), Rotahaler R ™ (Glaxo SmithKline), SkyeHaler™ or Certihaler™ (SkyePharma), Twisthaler (Schering-Plough), Turbuhaler R ™ (AstraZeneca), Ultrahaler R ™ (Aventis), and the like.

Alternatively, the composition comprising the co-crystal of the invention may be administered by inhalation using a MDI. Such MDIs typically discharge a measured amount of the active agent using compressed propellant gas. Metered-dose formulations thus typically comprise a solution or suspension of the active agent in a liquefied propellant, such as a chlorofluorocarbon such as CCbF or a hydrofluoroalkane (HFA) such as 1,1,1,2-tetrafluoroethane (HFA 134a) and 1,1, 1,2,3, 3,3-heptafluoro-n-propane (HFA 227), although HFAs are generally preferred due to concerns about chlorofluorocarbons affecting the ozone layer. Additional optional components of HFA formulations include co-solvents, such as water, ethanol or pentane, and surfactants, such as sorbitan trioleate, oleic acid, lecithin, and glycerin. See, for example, U.S. Pat. No. 5,225,183 to Purewal et al, EP 0717987 A2 (Minnesota Mining and Manufacturing Company), and WO 92/22286 (Minnesota Mining and Manufacturing Company). A representative composition for use in an MDI comprises from about 0.01-5 wt % of co-crystal of the invention; from about 0-20 wt % ethanol; and from about 0-5 wt % surfactant; with the remainder being an HFA propellant. Such compositions are typically prepared by adding a chilled or pressurized hydrofluoroalkane to a suitable container containing the co-crystal of the invention, ethanol (if present) and the surfactant (if present). To prepare a suspension, the co-crystal of the invention is micronized and then combined with the propellant. The formulation is then loaded into an aerosol canister, which forms a portion of the MDI. MDIs are well known to those of ordinary skill in the art, and many such devices are commercially available, with representative devices including AeroBid Inhaler System (Forest

Pharmaceuticals), Atrovent Inhalation Aerosol (Boehringer Ingelheim), Flovent R ™ (GlaxoSmithKline), Maxair Inhaler (3M), Proventil R ™ Inhaler (Schering), Serevent R ™ Inhalation Aerosol (GlaxoSmithKline), and the like. Alternatively, a suspension formulation can be prepared by spray drying a coating of surfactant on micronized particles of the active agent. See, for example, WO 99/53901 (Glaxo Group Ltd.) and WO 00/61108 (Glaxo Group Ltd.).

Additional examples of processes of preparing respirable particles, and

formulations and devices suitable for inhalation dosing are described in U.S. Pat. Nos. 5,874,063 to Briggner et al; 5,983,956 to Trofast; 6,221,398 to Jakupovic et al; 6,268,533 to Gao et al; 6,475,524 to Bisrat et al; and 6,613,307 to Cooper.

Alternatively, the pharmaceutical compositions may be suitable for nasal administration, for instance as a nasal spray or as a nasal aerosol.

Alternatively, the pharmaceutical compositions may be suitable for oral administration. Suitable compositions for oral administration may be in the form of capsules, tablets, pills, lozenges, cachets, dragees, powders, granules; suspensions;

emulsions; elixirs or syrups; and the like; each containing a predetermined amount of the co-crystal of the invention.

When intended for oral administration in a solid dosage form (i.e., as capsules, tablets, pills and the like), the composition will typically comprise the co-crystal of the invention and one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate. Solid dosage forms may also comprise: fillers or extenders, such as starches, microcrystalline cellulose, lactose, sucrose, glucose, mannitol, and/or silicic acid; binders, such as carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; humectants, such as glycerol; disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and/or sodium carbonate; solution retarding agents, such as paraffin; absorption accelerators, such as quaternary ammonium compounds; wetting agents, such as cetyl alcohol and/or glycerol monostearate; absorbents, such as kaolin and/or bentonite clay; lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and/or mixtures thereof; coloring agents; and buffering agents.

Release agents, wetting agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants may also be present in the

pharmaceutical compositions. Exemplary coating agents for tablets, capsules, pills and like, include those used for enteric coatings, such as cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, methacrylic acid-methacrylic acid ester copolymers, cellulose acetate trimellitate, carboxymethyl ethyl cellulose, hydroxypropyl methyl cellulose acetate succinate, and the like. Examples of

pharmaceutically acceptable antioxidants include: water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfate sodium sulfite and the like; oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, lecithin, propyl gallate, alpha-tocopherol, and the like; and metal-chelating agents, such as citric acid, ethylenediamine tetraacetic acid, sorbitol, tartaric acid, phosphoric acid, and the like.

Compositions may also be formulated to provide slow or controlled release of the co-crystal of the invention using, by way of example, hydroxypropyl methyl cellulose in varying proportions or other polymer matrices and/or microspheres. In addition, the pharmaceutical compositions of the invention may contain opacifying agents and may be formulated so that they release the active agent only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. The active agent can also be in micro-encapsulated form, if appropriate, with one or more of the above- described excipients.

Suitable liquid dosage forms for oral administration include, by way of illustration, pharmaceutically acceptable emulsions, microemulsions, suspensions, syrups and elixirs. Suspensions may contain the co-crystal of the invention and suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminium metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

When intended for oral administration, the pharmaceutical compositions of the invention may be packaged in a unit dosage form. The term "unit dosage form" refers to a physically discrete unit suitable for dosing a subject, i.e., each unit containing a

predetermined quantity of the active agents calculated to produce the desired therapeutic effect either alone or in combination with one or more additional units. For example, such unit dosage forms may be capsules, tablets, pills, and the like.

Compositions of the invention can also be administered parenterally (e.g., by subcutaneous, intravenous, intramuscular, or intraperitoneal injection). For such administration, the co-crystal of the invention are provided in a sterile suspension, or emulsion. Parenteral formulations may also contain one or more solubilizers, stabilizers, preservatives, wetting agents, emulsifiers, and dispersing agents. These formulations may be rendered sterile by use of a sterile injectable medium, a sterilizing agent, filtration, irradiation, or heat.

Compositions of the invention can also be administered transdermally using known transdermal delivery systems and excipients. For example, the co-crystal of the invention can be admixed with permeation enhancers, such as propylene glycol, polyethylene glycol monolaurate, azacycloalkan-2-ones and the like, and incorporated into a patch or similar delivery system. Additional excipients including gelling agents, emulsifiers and buffers, may be used in such transdermal compositions if desired.

The present invention is further illustrated in the Example which follows: EXAMPLE

Cocrystal syntheses

Cocrystals were prepared in three definite stoichiometries: 1 : 1, 1 :2 and 1 :3 by solvent- assisted grinding. Stoichiometric amounts of the co former and the API were ground together for a short period of time. Two drops of acetonitrile (in total ca. 62.9 mg of acetonitrile*) were pipetted onto the ground mixture, turning into a paste which re-formed a powder upon further grinding due to evaporation of the solvent. Due to the fine nature of BDP particles, another two drops of the solvent were added and the grinding process described above was followed again (repeated). In total, each API and co former mixture was ground for a period of 10 minutes. (*One drop of acetonitrile has a volume of ca. 0.04 mL, and the density of acetonitrile is 0.786 g/mL, meaning that two drops of acetonitrile weigh ca. 62.9 mg.) Co-crystals of BDP and three different co formers respectively were produced by the above method. Thus: (1) co-crystals of Beclomethasone dipropionate and Maleic Acid (in a 1 :2 molar ratio) were produced, as were (2) co-crystals of Beclomethasone dipropionate and Isonicotinic Acid (in a 1 :2 molar ratio), and (3) co-crystals of Beclomethasone

dipropionate and Adipic Acid (in a 1 :3 molar ratio).

The masses of the API (anhydrous beclomethasone dipropionate) and the coformer that were ground together were as follows:

Beclomethasone dipropionate : Maleic Acid (1 :2 molar ratio) = 70.9 mg : 31.3 mg. Thus, the total weight of the sample after adding the first two drops of solvent (but before further grinding) was 165.1 mg, assuming a mass of 62.9 mg for two drops of acetonitrile.

Beclomethasone dipropionate : Isonicotinic Acid (1 :2 molar ratio) = 71.0 mg : 32.8 mg. Thus, the total weight of the sample after adding the first two drops of solvent (but before further grinding) was 166.7 mg, assuming a mass of 62.9 mg for two drops of acetonitrile. Beclomethasone dipropionate : Adipic Acid (1 :3 molar ratio) = 70.0 mg : 58.7 mg. Thus, the total weight of the sample after adding the first two drops of solvent (but before further grinding) was 191.6 mg, assuming a mass of 62.9 mg for two drops of acetonitrile.

Comparative synthesis examples

Co-crystals containing fluticasone or triamcinolone could not be produced using the solvent-drop assisted grinding method described above.

Furthermore, 1 : 1 molar ratio mixtures of each API (BDP, fluticasone, and triamcinolone) and the selected coformer were also prepared, and placed in glass vials (75 x 25 mm) together with 5 ml of solvent. In contrast to solvent-assisted grinding, this conventional method (commonly known as slurry) yielded no co-crystals for any of the three APIs tested, including BDP.

BDP polymorphs

Both the monohydrate and anhydrous form of BDP crystallise in an orthorhombic space group ( 2i2i2i). The monohydrate form is more thermodynamically stable than the anhydrous form (Duax, W. L.; Cody, V.; Strong, P. D. Structure of the Asthma Drug Beclomethasone Dipropionate. Acta. Cryst. 1981 , B37, 383-387). However, the anhydrous form exhibits more intermolecular hydrogen bonds than the monohydrate form and moreover, due to its efficient crystal packing, the anhydrous form gives rise to a more dense crystal (1.362 g cm "3 ) than the monohydrate form (1.287 g cm "3 ) (Millard, J. W.; Myrdal, P. B. Anhydrous beclomethasone dipropionate. Acta, Cryst. 2002, E58, 712 - 714).

Anhydrous beclomethasone dipropionate was employed in the solvent-assisted grinding co-crystal syntheses described in this Example. However, the monohydrate form could readily have been employed successfully, in the same syntheses, instead of the anhydrous form. Indeed, either of the BDP polymorphs (anhydrous or monohydrate) can be used as the starting material because none of the solvents employed in the synthesis method was used in its water-free form, so the presence of small amounts of water do not change the result. Moreover, in the solvent-assisted grinding synthesis methods, the BDP comes out of the solid state (and is thus no longer in an anhydrous or monohydrate form) because it becomes dissolved in the small amount of solvent (acetonitrile) present before it combines with the co-crystal former to form the co-crystal product. The same co-crystal would therefore be produced irrespective of the particular BDP polymorph employed as the starting material.

Characterisation techniques IR spectroscopy

Figure 1 compares the IR spectrum of the 1 :3 BDP/adipic acid cocrystal (lower trace) with that of the physical mixture of the API and coformer (upper trace). Table 1. The labelled peaks of the IR spectra of both the cocrystal and the physical mixture.

Figure 2 compares the IR spectrum of the 1 :2 BDP/maleic acid cocrystal (lower trace) with that of the physical mixture of the API and coformer (upper trace).

Table 2. The peaks labelled on the IR spectra of both the cocrystal and physical mixture. IR peak label Characteristic of Frequency (cm 1 )

Cocrystal Mixture

A O-H stretch 3296.35 3269.34

B C-H stretch 3059.10 3059.10

C C = O stretch 1753.29 1747.15

D C = C stretch 1620.10 1615.82

E C-O stretch 1053.13 1068.32

Figure 3 compares the IR spectrum of the 1 :2 BDP/isonicotinic acid cocrystal (lower trace) with that of the physical mixture of the API and coformer (upper trace).

Table 3. The labelled peaks of the IR spectra of both the cocrystal and physical mixture.

Melting point

Melting points were determined under standard atmoshpheric pressure (1013 mbar) in an open vessel. In particular, the melting point of each co-crystal was determined using a Stuart SMP40 melting point apparatus, which uses optical sensors to detect melting. In terms of sample preparation, open melting point glass capillaries were filled with the co- crystal sample up to ca. 2cm in height and then placed into the analysing chamber of the apparatus. Under standard atmospheric pressure, the sample was heated at a heating rate of 5°C per minute to raise the temperature of the sample from about 25°C to a temperature above the melting point. Thus, melting curves were recorded using a heating rate of 5°C/min. The melting point was determined to be the Clear Point; the point at which the sample becomes a clear liquid and no solid particles remain.

Table 4. The melting point of the synthesized cocrystals compared to the theoretical mpt. of the cocrystal and the individual mpts. of the API and coformer.

PXRD analysis An X-ray powder diffraction pattern of each of the selected cocrystal samples was recorded at room temperature on a STOE Stadi P diffractometer using Cu Και radiation source (λ = 1.5460 A) from a curved germanium (111) monochromator and a

stationary/fixed omega image plate PSD generating 40 kV. The powder diffraction data were collected covering a range of 3 - 50° along 2theta in steps of 0.015 every 300 seconds. In the event of an unknown pattern generated, the program DASH 3.3.3. (David, W. I. F.; Shankland, K.; van de Streek, J.; Pidcock, E.; Motherwell, W. D. S.; Cole, J. C. DASH: a program for Crystal Structure Determination from Powder Diffraction Data. J. Appl. Cryst. 2006, 39, 910 - 915) was utilised for indexing and unit cell refinement. Table 5. Characteristic PXRD peaks of beclomethasone co-crystals with corresponding coformers.

Maleic Acid Isonicotinic Acid Adipic Acid

1 8.266 9.124 8.269

2 11.008 11.022 12.931

3 12.519 12.479 14.479

4 13.034 14.490 16.823

5 14.444 15.485 18.897

6 17.445 16.618 21.429

7 18.101 17.374 25.230 8 21.777 18.096 25.685

9 27.932 18.923 26.807

10 38.122 26.096 31.110

Solubility testing

The aqueous solubilities of the co-crystals produced as described above, namely the co- crystals of beclomethasone dipropionate and Maleic Acid (1 :2 molar ratio), the co-crystals of beclomethasone dipropionate and Isonicotinic Acid (1 :2 molar ratio), and the co-crystals of beclomethasone dipropionate and Adipic Acid (1 :3 molar ratio), were tested. All three co-crystals were found to be readily soluble in water. Solubility tests showed a solubility of ca. 500mg in 250 mL of water. Fast dissolution of 2mg of the cocrystals in 2 mL of pH 7 water was also observed. The results suggested that the co-crystals of the invention would likely fall within class I of the U.S. Food and Drug Administration's Biopharmaceutics Classification System (BCS). This is in contrast to beclomethasone dipropionate itself, which is essentially insoluble in water, having an aqueous solubility of less than 0.1 μg ml " 1 , and falls in class IV of the BCS. Guidance on the BCS can be found on the website of the U.S. Food and Drug Administration, at the following URL:

http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedica lProductsandTobacco/CDE R/ucml28219.htm