CRYSTALLINE POLYMORPHS OF CICLESONIDE

FIELD OF THE INVENTION

The present invention relates to novel crystalline polymorphs of Ciclesonide or its pharmaceutically acceptable salts, solvates and the process for the preparation thereof.

Ciclesonide, which is the generic name for the compound of formula (I), (R)- l lbeta,16alpha,17,21-Tetrahydroxypregna-l,4-diene-3,20-dione cyclic 16,17-acetal with cyclohexanecarboxaldehyde, 21-isobutyrate. The present invention further provides a process for preparing amorphous form of Ciclesonide or its pharmaceutically acceptable salts, solvates. Ciclesonide is a non-halogenated corticosteroid prodrug with anti-inflammatory activity delivered via a metered-dose inhaler (MDI), as a treatment for asthma.

(I)

BACK GROUND OF INVENTION

Ciclesonide is a non-halogenated corticosteroid prodrug with anti-inflammatory activity delivered via a metered-dose inhaler (MDI), as a treatment for asthma. Inhaled synthetic glucocorticosteroids are widely used in the therapy of bronchial asthma, for which they are the most effective agents available, particularly in patients with persistent mild-to-moderate disease. Regular treatment with inhaled glucocorticoids improves asthma control and lung function, and reduces asthma exacerbations. This improvement in asthma control is associated with attenuation of markers of airway inflammation, such as airway responsiveness to provocative stimuli, sputum eosinophilia and exhaled nitric oxide (NO) concentration.

Poor patient compliance is a perennial problem with prophylactic anti-asthma drugs, and inhaled glucocorticoids suffer particularly from this. This has resulted partly from

complicated schedules of repeated dosing and has prompted the development of formulations for twice- or even once-daily use. A further obstacle to the use of inhaled steroids is the occasional occurrence of local side effects, such as dysphonia and oral candidiasis, and of more serious systemic effects, such as suppression of the hypothalamo-pituitary-adrenal (HPA) axis. New drags have, therefore, been developed with the aim of minimizing systemic actions of inhaled steroids by increasing the ratio of local to systemic availability. Drugs that have very low bioavailability but achieve high local concentrations at the site of topical application are most suitable, and the synthesis of steroids that meet this requirement was the subject of the research program at Recordati Elmu SL that produced ciclesonide. Ciclesonide is a non-halogenated inhaled steroid ester prodrug that is metabolized intracellularly to form the active drag, which binds to cytoplasmic glucocorticoid receptors. A chiral center exists in the cyclic aldehyde group: the R stereoisomer is preferred and currently on the market. Ciclesonide exhibits anti-inflammatory actions in vivo that are comparable to those of budesonide, and it has been studied for potential therapeutic efficacy in allergic rhinitis, asthma and chronic obstructive pulmonary disease (COPD).

Ciclesonide was reported first time in United State patent 5,733,901 describing reactions of 16α-hydroxyprednisolone with cyclohexane carboxaldehyde in different reaction conditions to prepare acetal intermediate (Hβ ₅ 16α)-16,17-

[((R)cyclohexylmethylene)bis(oxy)]-1 l,21-dihydroxy-l,4-pregnadiene-3,20-dione, in different isomeric ratios at C-22 position. Further, United State patent 6,787,533 discloses the condensation of isobutyric anhydride with acetal intermediate in presence of a base to afford ciclesonide with a mixture of approximately 90% R-isomer and approximately 10% S-isomer at C-22 position. The mixture further undergoes to repeated fractional crystallization in water/ethanol mixture to enhance the 22-R-isomer more than 99% and to get ciclesonide in pure isomeric form.

Ciclesonide exist in two diastereoisomeric forms as R epimer (I) and S epimer (II) as shown in below formula:

(I) (H)

Ciclesonide is reported to be pharmaceutically acceptable with diastereoisomer containing R-configuration at C-22 position. The enrichment of S-isomer is reported up to 99% by chromatographic method using Cl 8 Lichrosorb column as stationary phase and eluting by ethanol / water mixture. The elution using such aqueous phases as eluent is commercially not viable at large scale.

In order obtain purer form of desired isomer of Ciclesonide, US patent no 5,733,901 discloses the process for preparing pure form of (R) isomer of Ciclesonide by selective crystallization followed by chromatographic purification. The result indicates the purer form achieved by the process in the epimer ratio of R isomer: S isomer is 94.5:5.5

International Patent Application WO95/24416 describes a process for the epimer enrichment of pregna-l,4-diene-3,20-dione 16,17-acetal derivatives by silylation, fractional crystallization and acid hydrolysis.

US Patent No. 6,787,533 discloses a process for obtaining other approach to obtain enriched R isomer of Ciclesonide by repeated fractionally crystallization. The fractional crystallization involves dissolving the R/S-epimer mixture of the Ciclesonide in a suitable, water-miscible organic solvent, expediently at elevated temperature, in particular at the boiling point of the solvent used. The subsequent addition of water is expediently carried out with stirring and whilst maintaining the elevated temperature, in particular at the boiling point; after the water has been added, the mixture is cooled, preferably to room temperature, with vigorous stirring in order to obtain as finely crystalline a product as possible.

Crystallization method as reported in US 6,787,533 accomplished by using repeated crystallization in water/ethanol mixture to enhance the 22-R-isomer up to 99% from 93% by sacrificing 50% of yield. Thus to enhance the 22-R-isomer content by 7 — 8 % there is a substantial loss of approximately 50% of product

The different physical properties exhibited by polymorphs affect important pharmaceutical parameters such as storage, stability, compressibility, density and dissolution rates (important in determining bioavailability). Stability differences may result from changes in chemical reactivity (e.g., differential hydrolysis or oxidation, such that a dosage form discolors more rapidly when comprised of one polymorph than when comprised of another polymorph), mechanical changes (e. g., tablets crumble on storage as a kinetically favored crystalline form converts to thermodynamically more stable crystalline form) or both (e. g., tablets of one polymorph are more susceptible to breakdown at high humidity). Solubility differences between polymorphs may, in extreme situations, result in transitions to crystalline forms that lack potency or are toxic. In addition, the physical properties of the crystalline form may be important in pharmaceutical processing. For example, a particular crystalline form may form solvates more readily or may be more difficult to filter and wash free of impurities than other forms (i.e., particle shape and size distribution might be different between one crystalline form relative to other forms). Thus, an amorphous form can overcome the problems like thermodynamic stability, solubility, storage, compressibility etc important for formulation and product manufacturing. Objects of the Invention

It is an important object of the present invention to provide novel crystalline polymorphs of Ciclesonide of formula (I). Another object of the invention of the invention is to provide a process for preparing novel crystalline polymorphs of Ciclesonide of formula (I). Brief Description of the drawing

Further object of the present invention together with additional features contributing thereto and advantage occurring there from will be apparent from the following description of preferred embodiments of the invention which are shown in the accompanying drawing figures, wherein:

Fig. 1 represents a PXRD of Form I of Ciclesonide

Fig. 2 represents a. PXRD of Form II of Ciclesonide Fig. 3 represents a PXRD of Form III of Ciclesonide

Fig. 4 represents a PXRD of amorphous form of Ciclesonide

Fig. 5 represents DSC of amorphous form of Ciclesonide

DESCRIPTION OF THE INVENTION

The present invention provides the novel crystalline forms of Ciclesonide of formula (I) and its pharmaceutically acceptable salts, solvates and the process for the preparation thereof.

According to the present invention, there is provided a novel crystalline forms of Ciclesonide of formula (I) designated as Form I, Form II and Form III. The present invention further provides the process for the preparation of Form I, Form II and Form III of Ciclesonide.

The process for the preparation of Ciclesonide is known in the art and can be prepared by reacting 16α-hydroxyprednisolone with cyclohexane carboxaldehyde to get acetal intermediate (11 β, 16α)-16,17-[((R)cyclohexylmethylene)bis(oxy)]-l l,21-dihydroxy-l,4- pregnadiene-3,20-dione, which further undergoes condensation with isobutyric anhydride in presence of a base to afford ciclesonide as a mixture of approximately 90% R-isomer and approximately 10% S-isomer at C-22 position. The mixture further undergoes to repeated fractional crystallization in water/ethanol mixture to enhance the 22-R-isomer more than 99% and to get ciclesonide in pure isomeric form. According to aspect of the present invention, there is provided a novel crystalline form of Ciclesonide. The crystalline form of Ciclesonide is herein after designated as "Form I". The Form I of Ciclesonide is characterized by its powder X-ray diffraction pattern having peaks expressed as 2θ at about 8.0, 14.8, 16.4, 17.9 ± 0.2degrees. The form I of Ciclesonide is further characterized by its powder X-ray diffraction pattern having peaks expressed as 2θ at about 5.4, 6.8, 13.2, 19.4, 20.0, 20.7± 0.2degrees. FIG. 1 shows typical x-ray powder diffraction pattern of Form I of Ciclesonide.

The present invention also provides a process for preparing crystalline Form I Ciclesonide. The process for the preparation of crystalline Form I of Ciclesonide, which comprises treating Ciclesonide with the organic solvent selected from ketonic solvent, ester or ethereal solvent.

Another embodiment of the present invention relates to a process for the preparation of Form I of ciclesonide by using solvents selected from methylisobutyl ketone, acetone, methyl ethyl ketone, diethyl ether, diisopropyl ether, tetrahydrofuran, methyl tert-butyl ether, ethyl acetate, isopropyl acetate, isobutyl acetate or mixture thereof. In the preferred embodiment, the organic solvent can be selected from methylisobutyl ketone, acetone, methyl ethyl ketone, diethyl ether, diisopropyl ether, tetrahydrofuran, methyl tert-butyl ether, ethyl acetate, isopropyl acetate, isobutyl acetate or mixture thereof.

According to preferred embodiment, the present invention relates to the process for the preparation of Form I of Ciclesonide by dissolving ciclesonide in organic solvent selected from ketonic solvent, ester, or ethereal solvent to get clear solution, removing solvent and isolating Form I of ciclesonide. According to preferred embodiment, the present invention relates to the process for the preparation of Form I of Ciclesonide by dissolving ciclesonide in organic solvent selected from ketonic solvent, esters, ethereal solvent to get clear solution, adding anti-solvent such as aliphatic hydrocarbon selected from cyclohexane or cycloheptane and isolating Form I of ciclesonide. The Form I of Ciclesonide can be isolated or recovered by any convenient means. For example, the Form I of Ciclesonide can be precipitated out of a solution. The precipitation may be spontaneous depending upon the solvent system or may be on the conditions. Alternatively, the precipitation can be induced by reducing the temperature of the solution, especially if the initial temperature at contact is elevated. The precipitation may also be facilitated by reducing the volume of the solution/solvent. Seed crystals of Form I of Ciclesonide may also be added to help induce precipitation. The precipitated Form I of Ciclesonide compound can be isolated by conventional methods such as filtration or centrifugation, optionally washed and dried, preferably under diminished pressure.

According to aspect of the present invention, there is provided a novel crystalline form of Ciclesonide. The crystalline form of Ciclesonide is herein after designated as "Form II". The Form II of Ciclesonide is characterized by its powder X-ray diffraction pattern having peaks expressed as 2θ at about 6.8, 16.8, 17.3 ± 0.2degrees. The form II of Ciclesonide is further characterized by its powder X-ray diffraction pattern having peaks expressed as 2θ at about 5.4, 8.0, 14.8, 17.9± 0.2degrees. FIG. 2 shows typical x-ray powder diffraction pattern of Form II of Ciclesonide.

The present invention also provides a process for preparing crystalline Form II Ciclesonide. The process for the preparation of crystalline Form II of Ciclesonide, which comprises treating Ciclesonide with aromatic hydrocarbon solvent.

Another embodiment of present invention relates to the process for the preparation of Form II of ciclesonide by using aromatic hydrocarbon solvent selected from toluene, xylene or mixture thereof.

According to preferred embodiment, the present invention relates to the process for the preparation of Form II of Ciclesonide by dissolving ciclesonide in aromatic hydrocarbon solvent to get clear solution and isolating Form II of ciclesonide.

The Form II of Ciclesonide can be isolated or recovered by any convenient means. For example, the Form II of Ciclesonide can be precipitated out of a solution. The precipitation may be spontaneous depending upon the solvent system or may be on the conditions.

Alternatively, the precipitation can be induced by reducing the temperature of the solution, especially if the initial temperature at contact is elevated. The precipitation may also be facilitated by reducing the volume of the solution/solvent. Seed crystals of Form II of Ciclesonide may also be added to help induce precipitation. The precipitated Form II of

Ciclesonide compound can be isolated by conventional methods such as filtration or centrifugation, optionally washed and dried, preferably under diminished pressure.

According to aspect of the present invention, there is provided a novel crystalline form of Ciclesonide. The crystalline form of Ciclesonide is herein after designated as "Form III". The Form III of Ciclesonide is characterized by its powder X-ray diffraction pattern having peaks expressed as 2θ at about 8.0, 13.3, 18. O± 0.2degrees. The form III of Ciclesonide is further characterized by its powder X-ray diffraction pattern having peaks expressed as 2θ at about 5.5, 8.0, 14.9, 15.3, 19.4, 20.1, 20.7± 0.2degrees. FIG. 3 shows typical x-ray powder diffraction pattern of Form III of Ciclesonide. The present invention also provides a process for preparing crystalline Form III of

Ciclesonide. The process for the preparation of crystalline Form III of Ciclesonide, which comprises treating Ciclesonide with halogenated solvent.

Another embodiment of present invention relates to the process for the preparation of Form III of ciclesonide by using halogenated solvent selected from methylene dichloride, ethylene dichloride, chloroform, carbon tetraflouride or mixture thereof.

According to preferred embodiment, the present invention relates to the process for the preparation of Form III of Ciclesonide by dissolving ciclesonide in halogenated solvent to get clear solution and isolating Form III of ciclesonide.

The Form III of Ciclesonide can be isolated or recovered by any convenient means. For example, the Form III of Ciclesonide can be precipitated out of a solution. The precipitation may be spontaneous depending upon the solvent system or may be on the conditions.

Alternatively, the precipitation can be induced by reducing the temperature of the solution,

especially if the initial temperature at contact is elevated. The precipitation may also be facilitated by reducing the volume of the solution/solvent. Seed crystals of Form III of Ciclesonide may also be added to help induce precipitation. The precipitated Form III of Ciclesonide compound can be isolated by conventional methods such as filtration or centrifugation, optionally washed and dried, preferably under diminished pressure.

The present invention further provides a process for preparing crystalline Form III of Ciclesonide, which comprises

(i) dissolving Ciclesonide with methyl isobutyl ketone solvent to obtain solution

(ii) removing the said solvent to obtain residue (iii) slurring the residue with cyclohexane

(iv) isolating Form III of Ciclesonide.

The present invention further provide a process for the preparation of 22-(R)- ciclesonide in amorphous form by reacting 16α-hydroxyprednisolone with cyclohexane carboxaldehyde to get acetal intermediate (Hβ _> 16α)-16,17-

[((R)cyclohexylmethylene)bis(oxy)]- 11 ,21 -dihydroxy- 1 ,4-pregnadiene-3 ,20-dione, which further undergoes condensation with isobutyric anhydride in presence of a base to afford ciclesonide as a mixture of approximately 90% R-isomer and approximately 10% S-isomer at C-22 position, which is further purified to obtain 22-R-isomer more than 99% pure isomeric form. The R- isomer of ciclesonide is further dissolved in a solvent selected from alcohols and / or ketones to get clear solution and solvent then removed to get amorphous form of Ciclesonide.

Thus, present invention relates to the process for the preparation of amorphous ciclesonide by using alcoholic solvents selected from Cl - C8 alcohols, preferably methanol, ethanol and isopropanol.

According to another embodiment, the present invention relates to the process for the preparation of amorphous ciclesonide by dissolving crystalline ciclesonide in alcoholic solvents selected from Cl - C 8 alcohols, preferably methanol and / or ethanol and / or isopropanol to get clear solution, removing solvent and isolating ciclesonide in amorphous form. Another embodiment of present invention relates to the process for the preparation of amorphous ciclesonide by using ketonic solvents selected from C3 - ClO ketones.

Another embodiment of present invention relates to the process for the preparation of amorphous ciclesonide by using ketonic solvents selected from C3 - ClO ketones, preferably acetone and methyl isobutyl ketone.

According to another embodiment, the present invention relates to the process for the preparation of amorphous ciclesonide by dissolving crystalline ciclesonide in ketonic solvents selected from C3 — ClO ketones, preferably acetone and / or methyl isobutyl ketone to get clear solution, removing solvent and isolating ciclesonide in amorphous form.

According to another embodiment, the present invention relates to the process for the preparation of amorphous ciclesonide by dissolving crystalline ciclesonide in a mixture of solvents selected from alcohols and ketones to become clear solution, removing solvent and isolating ciclesonide in pure amorphous form.

As used herein, with respect to a measured quantity, the term "approximately" indicates variations in the measured quantity as would be expected by the skilled artisan making the measurements or determination and exercising a level of care commensurate with the objective of the measurement and the precision of the measuring apparatus being used.

According the preferred embodiment, Ciclesonide is dissolved in methyl isobutyl ketone at ambient to reflux temperature to obtain solution. The said solution is optionally filtered and the solvent is removed through filtrate/solution by evaporated to obtain residue.

The residue is further slurried with cyclohexane and Form III of Ciclesonide is isolated from the said slurry.

The examples mentioned below do not explain all the aspects of the present invention. The examples are given to illustrate the details of the invention and should not be construed to limit the scope of the present invention. Examples: Example - 1

Preparation of Form I of Ciclesonide

In a 100 mL R. B. Flask, Ciclesonide (I) (3.0 g) was stirred in acetone (3 ml) at 25 - 35 ⁰ C to get clear solution. Slowly, cyclohexane (24ml) is added to the solution and stirred for about 1 hours at 0 to 5 ⁰ C, solid product was collected and dried at 50° C for 3 hrs to obtain Form I of Ciclesonide. Yield: 2.40 g.

Example - 2

Preparation of Form I of Ciclesonide

In a 100 mL R. B. Flask, Ciclesonide (I) (3.0 g) was stirred in Methyl tert-butyl ether

(18 ml) at 25 - 35 ⁰ C to get clear solution. Slowly, cyclohexane (72ml) is added to the solution and stirred for about 1 hours at 0 to 5 ⁰ C, solid product was collected and dried at 50° C for 3 hrs to obtain Form I of Ciclesonide. Yield: 2.54 g.

Example - 3

Preparation of Form I of Ciclesonide

In a 100 mL R. B. Flask, Ciclesonide (I) (3.0 g) was stirred in Methyl isobutyl ketone (6 ml) at 60-65 ⁰ C to get clear solution. Slowly, cyclohexane (18ml) is added to the solution and stirred for about 1 hours at 0 to 5 ⁰ C, solid product was collected and dried at 50° C for 3 hrs to obtain Form I of Ciclesonide. Yield: 1.91 g.

Example - 4

Preparation of Form I of Ciclesonide In a 100 mL R. B. Flask, Ciclesonide (I) (3.0 g) was stirred in ethyl acetate (6 ml) at 60-

65 ⁰ C to get clear solution. Slowly, cyclohexane (24ml) is added to the solution and stirred for about 1 hours at 0 to 5 ⁰ C, solid product was collected and dried at 50° C for 3 hrs to obtain

Form I of Ciclesonide. Yield: 2.02g.

Example - 5 Preparation of Form I of Ciclesonide

In a 100 mL R. B. Flask, Ciclesonide (I) (3.0 g) was stirred in acetone (20ml) at about

5O ⁰ C to get clear solution. Solvent (acetone) is removed by high vacuum using rotary evaporator at 50° C. The residue is slurried with 20ml of cylclohexane and stirred for 15 minutes. The solid product was collected by filtration, washed with 10ml cyclohexane and dried at 50° C for 4 hrs to obtain Form I of Ciclesonide. Yield: 2.02g.

Example - 6

Preparation of Form II of Ciclesonide

In a 100 mL R. B. Flask, Ciclesonide (I) (3.0 g) was stirred in toluene (12 ml) at about

5O ⁰ C to get clear solution. Slowly, cyclohexane (24ml) is added to the solution and stirred for about 1 hours at 0 to 5 ⁰ C, solid product was collected and dried at 50° C for 3 hrs to obtain

Form II of Ciclesonide. Yield: 2.44g.

Example - 7

Preparation of Form II of Ciclesonide

In a 100 mL R. B. Flask, Ciclesonide (I) (3.0 g) was stirred in toluene (20ml) at about

5O ⁰ C to get clear solution. Solvent (toluene) is removed by " high vacuum using rotary evaporator at 50° C. The residue is slurried with 20ml of cylclohexane and stirred for 15 minutes. The solid product was collected by filtration, washed with 15ml cyclohexane and dried at 5O ⁰ C for 3 hrs to obtain Form II of Ciclesonide. Yield: 2.Og.

Example — 8

Preparation of Form III of Ciclesonide In a 100 mL R. B. Flask, Ciclesonide (I) (5.0 g) was stirred in methylene dichloride (20 ml) at about 30 to 35 ⁰ C to get clear solution. Slowly, cyclohexane (10ml) is added to the solution. The resulting liquid solution is distilled out under high vacuum. The residue is slurried with 25ml of cylclohexane and stirred for 15 minutes. The solid product was collected by filtration, washed with 15ml cyclohexane and dried at 50° C for 3 hrs to obtain Form III of Ciclesonide. Yield: 4.92g.

Example - 9

Preparation of amorphous Ciclesonide

In a 100 mL R. B. Flask crystalline Ciclesonide (I) (3.0 g) was stirred in acetone (30 mL) at 25 - 35 ⁰ C to get clear solution. The solvent was completely evaporated under vacuum at 50° C, solid product was collected and dried at 50° C for 3 hrs to obtain amorphous

Ciclesonide. Yield: 2.90 g.

Example - 10

Preparation of amorphous Ciclesonide

In a 100 mL R. B. Flask crystalline Ciclesonide (3.0 g) was stirred in ethanol (30 mL) at 25— 35 ⁰ C to get clear solution. The solvent was completely evaporated under vacuum at 50°

C, solid product was collected and dried at 50° C for 3 hrs to obtain amorphous Ciclesonide.

Yield: 2.82g.

Example -11

Preparation of amorphous Ciclesonide In a 100 mL R. B. Flask crystalline Ciclesonide (3.0 g) was stirred in isopropanol (30 mL) at 25 - 35 ⁰ C to get clear solution. The solvent was completely evaporated under vacuum

at 50° C, solid product was collected and dried at 50° C for 3 hrs to obtain amorphous Ciclesonide. Yield: 2.78 g.

Certain modifications and improvements of the disclosed invention will occur to those of skilled in the art without departing from the scope of invention, which is limited only by the appended claims.