JP2009526068A - Ciclesonide crystal form - Google Patents

Abstract

  The present invention encompasses ciclesonide crystal forms characterized by XRD patterns having peaks at about 11.0, 14.8, 15.7, 16.5 and 22.8 ° 2θ ± 0.2 ° 2θ, methods for their preparation and pharmaceutical compositions thereof.

Description

Field of Invention :
The present invention includes novel ciclesonide crystal forms and methods for their preparation. The invention also encompasses pharmaceutical compositions comprising the novel ciclesonide crystal forms and methods for their preparation.

Background of the invention :
Following formula:

-Pregna-1,4-diene-3,20-dione, 16,17-[[(R) -cyclohexylmethylene] bis (oxy)]-11-hydroxy-21- (2-methyl-1- Oxopropoxy)-(11β, 16α)-(9CI), or ciclesonide, is an unhalogenated glucocorticoid with high local anti-inflammatory properties that is inhaled in the treatment of asthma. Ciclesonide is an ester prodrug substantially lacking oral bioavailability that is activated on the basis of degradation by endogenous esterases.

The preparation of ciclesonide is disclosed in EP Patent No. 929566, PCT Publication No. WO2004 / 085460, and US Pat. No. 5,482,934.
The occurrence of different crystal forms, ie polymorphism, is a property of several molecules and molecular complexes. A single molecule, such as ciclesonide, can give rise to various crystal forms with well-defined crystal structures and properties such as melting points, X-ray diffraction patterns, infrared absorption fingerprints, and solid state NMR spectra. One crystal form results in a thermal behavior that is different from the thermal behavior of the other crystal form. Thermal behavior is measured experimentally by techniques such as capillary melting point, thermogravimetric analysis (“TGA”) and differential scanning calorimetry (“DSC”) and can be used to characterize crystalline forms.

  The difference in physical properties of different crystal forms is due to the orientation of adjacent molecules or complexes in the mass solid and intermolecular interactions. Thus, polymorphs are distinct crystal forms that have distinct advantageous and / or unfavorable physical properties as compared to other crystal forms of the same compound or complex.

  One of the most important physical properties of pharmaceutical polymorphs is their solubility in aqueous solutions, particularly their solubility in the gastric juices of patients. For example, if absorption through the gastrointestinal tract is slow, a drug that dissolves slowly is often desired so that it does not accumulate in a harmful environment. This is especially true when the drug is unstable to conditions in the patient's stomach or intestine. Different crystal forms or polymorphs of the same pharmaceutical compound have been reported to have different aqueous solubility.

  The crystal structure and crystal shape (morphology) and size also have a significant practical and commercial influence on the active substance, in particular for formulations for inhalation. Ideal particles for inhalation delivery are low density spheres and small sizes with a narrow size distribution. In principle, the size can be adjusted by direct crystallization or micronization. Ultrafine milling methods can lead to partial crystal form dislocations, or in some cases, the generation of amorphous regions. These amorphous regions are more reactive and increase the instability of the active substance. This is because the region can be recrystallized and causes cross-linking of the particles. Particle cross-linking increases particle size. Therefore, when using a micronization method, it is important to produce small size particles by a crystallization process to avoid particle enlargement and to make sure that no amorphous form is found in the active material.

  The discovery of new polymorphic forms of pharmaceutically useful compounds provides new opportunities to improve the performance characteristics of pharmaceutical formulations. Formulation scientists expand the repertoire of materials that can be utilized, for example, for the planning of pharmaceutical dosage forms having targeted open profiles or other desired properties. Due to limited selection, there is a need in the art for new ciclesonide polymorphic forms, such as those shown below.

Summary of invention :
One embodiment of the present invention includes ciclesonide crystal forms characterized by an XRD pattern having peaks at about 11.0, 14.8, 15.7, 16.5 and 22.8 ° 2θ ± 0.2 ° 2θ.
Another embodiment of the present invention is a therapeutically effective amount of ciclesonide crystalline form characterized by an XRD pattern having peaks at about 11.0, 14.8, 15.7, 16.5 and 22.8 ° 2θ ± 0.2 ° 2θ, and at least one pharmaceutical agent A pharmaceutical composition comprising a pharmaceutically acceptable excipient.

  Yet another embodiment of the present invention provides a therapeutically effective amount of ciclesonide crystal form characterized by an XRD pattern having peaks at about 11.0, 14.8, 15.7, 16.5 and 22.8 ° 2θ ± 0.2 ° 2θ, and at least one Pharmaceutical composition of ciclesonide crystal form characterized by XRD pattern having peaks at about 11.0, 14.8, 15.7, 16.5 and 22.8 ° 2θ ± 0.2 ° 2θ, comprising mixing with pharmaceutically acceptable excipients The preparation method of the product is included.

  One embodiment of the present invention involves the use of ciclesonide crystal forms characterized by XRD patterns having peaks at about 11.0, 14.8, 15.7, 16.5 and 22.8 ° 2θ ± 0.2 ° 2θ for the manufacture of pharmaceutical compositions. Include.

Specific description of the invention :
The present invention encompasses novel ciclesonide crystal forms that are solvated forms of ciclesonide. Purification of ciclesonide through the solvated form provides substantially pure ciclesonide.

  The present invention encompasses novel ciclesonide crystal forms characterized by XRD patterns having peaks at about 11.0, 14.8, 15.7, 16.5 and 22.8 ° 2θ ± 0.2 ° 2θ. The crystalline form is further characterized by an XRD pattern having peaks at about 5.6, 18.3, 19.5, 20.7 and 22.0 ° 2θ ± 0.2 ° 2θ. The crystal form is also characterized by the XRD pattern substantially shown in FIG. The crystalline form is also characterized by a weight loss of about 10% by weight when measured by thermogravimetric analysis (“TGA”) at a temperature of about 25 ° C. to about 130 ° C. The ciclesonide crystal form of the present invention is further characterized by a melting temperature of about 207 ° C. The crystalline form can be a solvate. Preferably, the crystalline form is a solvation of tert-butanol in a 1: 1 ratio of ciclesonide: tert-butanol (about 12 wt% tert-butanol). The crystalline form can be characterized by any other method known to those skilled in the art, such as solid state NMR and FTIR.

  Preferably, the ciclesonide crystal form exists in the form of spherical and irregular shapes. Typically, as used herein, the term “irregular” refers to a crystal having a form that is not spherical or flat. The crystalline form can also be substantially identified by the micrograph shown in FIG. This micrograph shows that some crystals have a spherical shape and some have an irregular morphology. The ciclesonide crystal form can have a form suitable for inhalation delivery.

  The present invention is characterized by an XRD pattern having peaks at about 11.0, 14.8, 15.7, 16.5 and 22.8 ° 2θ ± 0.2 ° 2θ, and other cyclosonide forms of up to about 5% by weight as determined by XRD. Includes ciclesonide crystal forms having Preferably, the crystalline ciclesonide has no more than about 2% by weight of other cyclosonide forms as determined by XRD. The ciclesonide form is about ciclesonide crystalline form characterized by a PXRD pattern with peaks at about 7.0, 15.0, 17.0, 17.5 and 18.4 ° 2θ and additional peaks at about 5.6, 12.7, 14.5, 19.3 and 20.2 ° 2θ. 5 wt% or less. Preferably, the ciclesonide form is characterized by a ciclesonide characterized by a PXRD pattern having peaks at about 7.0, 15.0, 17.0, 17.5 and 18.4 ° 2θ and additional peaks at about 5.6, 12.7, 14.5, 19.3 and 20.2 ° 2θ. It has a crystal form of about 2% by weight or less.

The present invention provides for the preparation of a ciclesonide crystal form characterized by an XRD pattern having peaks at about 11.0, 14.8, 15.7, 16.5 and 22.8 ° 2θ ± 0.2 ° 2θ, comprising crystallizing ciclesonide from Tert-butanol. Includes methods.
A method for producing ciclesonide crystal forms characterized by XRD patterns having peaks at about 11.0, 14.8, 15.7, 16.5 and 22.8 ° 2θ ± 0.2 ° 2θ, wherein ciclesonide is added to a sufficient amount of tert-butanol at about 50 ° C. to Dissolving at a temperature of about 70 ° C. to form a solution; cooling the solution to a temperature of about 25 ° C. to about 35 ° C. to induce crystallization of ciclesonide; and isolating the crystalline ciclesonide It consists of

Ciclesonide used as starting material is prepared by conventional techniques such as those described in PCT Publication Nos. WO98 / 09982 and WO2004 / 085460 and US Pat. No. 5,482,934, which are incorporated herein by reference. obtain. Preferably, the ciclesonide has a purity of at least 99% area by HPLC. For example, ciclesonide is a C _6-8 linear or branched aliphatic hydrocarbon, branched aliphatic hydrocarbon, C ₂ , as described in US patent application Ser. No. 11 / 592,475, filed Nov. 2, 2006. Obtained by crystallization from a non-hydroxyl organic solvent selected from the group consisting of _-5 ethers and mixtures thereof.

  One method for preparing the starting ciclesonide of the present invention involves crystallization of ciclesonide from a water-immiscible organic solvent. The method comprises dissolving ciclesonide in at least one water immiscible organic solvent to form a solution; crystallizing ciclesonide from the solution; and recovering the crystallized ciclesonide. After the initial crystallization, a solid is obtained that can be recrystallized to further increase its epimeric purity. Preferably, the water immiscible organic solvent is a non-hydroxyl organic solvent.

  Starting cyclosonides are disclosed in methods known in the art, such as US Pat. Nos. 2,990,401; 3,929,768; 4,695,625; 4,925,933; 5,482,934 and 5,728,826, and PCT Publication No. WO 98/0982. And WO2004 / 085460 (incorporated herein by reference). Preferably, the starting ciclesonide contains no more than about 15% 22S-epimer as determined by HPLC. More preferably, the starting ciclesonide contains no more than about 12% 22S-epimer as determined by HPLC.

A water-immiscible organic solvent is a non-hydroxyl organic solvent. A non-hydroxyl organic solvent is an organic solvent that lacks a hydroxyl group in the compound. Typically, non-hydroxyl organic solvents include C ₁ -C ₁₂ linear, branched or cyclic alkanes and C ₂ -C ₁₂ linear, branched or cyclic ethers. Preferably, the C ₁ -C ₁₂ straight chain, branched chain or cyclic alkane is a C ₆ -C ₁₂ straight chain, branched chain or cyclic alkane, and more preferably a C ₆ -C ₈ straight chain, branched chain or cyclic alkane. It is. Preferably, the C ₂ -C ₁₂ straight chain, branched chain or cyclic ether is a C ₅ -C ₁₂ straight chain, branched chain or cyclic ether, and more preferably a C ₅ -C ₆ straight chain, branched chain or cyclic ether. It is. Specific examples of C ₁ -C ₁₂ straight chain, branched chain or cyclic alkanes include heptane, hexane and isooctane. Particular examples of C ₂ -C ₁₂ straight chain, branched chain or cyclic ethers include tert-butyl methyl ether and diisopropyl ether. Preferably, the non-hydroxyl organic solvent is isooctane.

The crystallization step can further use a second organic solvent, where the term second organic solvent refers to an organic solvent having a lower boiling point than the non-hydroxyl organic solvent. The low boiling organic solvent can be any solvent that can dissolve the starting mixture of ciclesonide 22R / 22S epimers. Preferably, low boiling point organic solvents include C ₁ -C ₈ alcohols, C ₂ -C ₈ ketones and C ₁ -C ₆ aliphatic halogen-containing carbon compounds. Preferably, the C ₁ -C ₈ alcohol is a C ₁ -C ₅ alcohol, and more preferably a C ₁ -C ₄ alcohol. Preferably, the C ₂ -C ₈ ketone is a C ₂ -C ₅ ketone and more preferably a C ₂ -C ₃ ketone.

Preferably, the C ₁ -C ₆ aliphatic halogen-containing carbon compound is a C ₁ -C ₄ aliphatic halogen-containing carbon compound, and more preferably a C ₁ -C ₂ aliphatic halogen-containing carbon compound. Specific examples of C ₁ -C ₈ alcohols include methanol, ethanol and tert-butanol. Particular examples of C ₂ -C ₈ ketones include acetone. Particular examples of C ₁ -C ₆ aliphatic halogen-containing carbon compounds include dichloromethane. More preferably, the low boiling organic solvent is either acetone or didichloromethane, and most preferably dichloromethane. The co-solvent is preferably of a technical variety, i.e. comprises about 2 wt% or less of water, preferably 1 wt% or less, and more preferably 0.5 wt% or less of water.

  Typically, when a mixture of a water-immiscible organic solvent and a low boiling organic solvent is used, the solvent ratio is 20: 1 (by weight) each. Preferably the ratio is 10: 1 and more preferably 5: 1 (by weight). Optionally, the low boiling organic solvent can be removed by evaporation prior to inducing precipitation of the crystalline ciclesonide.

  Preferably, the crystallization involves dissolving the starting ciclesonide, the water-immiscible organic solvent, at a temperature ranging from ambient temperature to the boiling point of the water-immiscible organic solvent to form a solution, concentrating the solution, and A suspension is obtained and the suspension is cooled to the ciclesonide precipitation. In embodiments in which a second low boiling organic solvent is used, the process preferably takes the starting ciclesonide to a second low boiling organic solvent from ambient temperature to the boiling point of the second low boiling organic solvent. And adding a water-miscible organic solvent. The mixture is then concentrated to remove most or all of the second low boiling organic solvent, which typically results in a suspension.

  Typically, the suspension obtained with or without the second solvent is cooled to a temperature of about 80 ° C to about 10 ° C. Preferably, the concentration step is carried out by removing the water-immiscible organic solvent by distillation. The precipitate can be separated or recovered using methods commonly known to those skilled in the art. For example, crystalline ciclesonide can be removed by filtration. Optionally, the recovered crystalline ciclesonide is washed and dried.

  In the method of the present invention, the temperature for dissolving ciclesonide should be sufficient to dissolve ciclesonide in tert-butanol. Preferably, the temperature for dissolving ciclesonide in tert-butanol is from about 55 ° C to about 65 ° C, and more preferably the temperature is about 60 ° C. In nature, the cooling temperature should be lower than the dissolution temperature and sufficient to induce crystallization of ciclesonide. Preferably, the solution is cooled at a temperature of about 30 ° C. to about 25 ° C., and more preferably the temperature is about 27 ° C. to about 26 ° C. Optionally, the solution can be stirred during the cooling phase.

  Any method known in the art can be used to isolate the crystalline ciclesonide. For example, ciclesonide crystal forms can be isolated by filtration of the precipitate. Filtration can be performed by methods including (but not limited to) suction and subsequent washing of the precipitate. The precipitate can be washed with 2,2,4-trimethylpentane and subsequently dried in a vacuum oven for about 8 hours. Preferably, the vacuum is about 5-10 mmHg. Preferably, the drying step is performed at a temperature of about 80 ° C.

  The ciclesonide crystal form obtained by the above crystallization method typically comprises no more than about 5% by weight of other ciclesonide crystal forms as determined by XRD. Preferably, the cyclosonide crystal form has no more than 2 weights of other ciclesonide crystal forms as determined by XRD.

  The present invention also dissolves ciclesonide having a first R / S epimer ratio in a sufficient amount of acetone to form a solution and heat the solution to reflux; add isooctane to the heated solution; And heating the solution to about 90 ° C; cooling the suspension to about 70 ° C for about 30 minutes; cooling the solution to about 25 ° C to about 28 ° C; and then collecting the crystalline ciclesonide Comprising a method for increasing the R / S epimer ratio of ciclesonide, wherein the crystalline ciclesonide has a second R / S epimer ratio, and the second R / S epimer ratio is the first R / S epimer ratio. Higher than S epimer ratio. Optionally, the method further comprises drying the collected crystalline ciclesonide at a temperature of about 80 ° C. under vacuum.

  Typically, the acetone: isooctane ratio is about 1: 1-40 (by volume). Preferably, the acetone: isooctane ratio is about 1: 2-30 (by volume), and more preferably the acetone: isooctane ratio is about 1: 5-20 (by volume). Typically, the second R / S epimer ratio is about 96.5: 3.5, preferably about 98: 2, and more preferably 99: 1, and most preferably 99.75: 0.25, as determined by HPLC region.

  The invention also provides a therapeutically effective amount of ciclesonide crystalline form characterized by an XRD pattern having peaks at about 11.0, 14.8, 15.7, 16.5 and 22.8 ° 2θ ± 0.2 ° 2θ, and at least one pharmaceutically acceptable Also included are pharmaceutical compositions comprising excipients. The present invention also includes a therapeutically effective amount of ciclesonide crystalline form characterized by an XRD pattern having peaks at about 11.0, 14.8, 15.7, 16.5 and 22.8 ° 2θ ± 0.2 ° 2θ, and at least one pharmaceutically acceptable A method of preparing a pharmaceutical composition of ciclesonide crystalline form characterized by an XRD pattern having peaks at about 11.0, 14.8, 15.7, 16.5 and 22.8 ° 2θ ± 0.2 ° 2θ, comprising mixing with excipients Include.

  As used herein, unless otherwise indicated, the term “therapeutically effective amount” refers to an amount of ciclesonide sufficient to achieve the desired biological effect. Preferably, the amount of ciclesonide is sufficient to act as a bronchodilator when administered to a patient having a respiratory disorder such as asthma. The amount will depend on the method of use, the age, sex and condition of the patient and can be readily determined by one skilled in the art with little or no experimentation.

  The amount of ciclesonide crystal form in a pharmaceutical composition for treating atherosclerosis or hypercholesterolemia should be sufficient to treat or ameliorate atherosclerosis or hypercholesterolemia.

  The present invention also includes a ciclesonide crystal form characterized by an XRD pattern having peaks at about 11.0, 14.8, 15.7, 16.5 and 22.8 ° 2θ ± 0.2 ° 2θ, the crystal form for the manufacture of a pharmaceutical composition comprising Includes the use of

  A pharmaceutical composition comprising a ciclesonide crystal form characterized by an XRD pattern having peaks at about 11.0, 14.8, 15.7, 16.5 and 22.8 ° 2θ ± 0.2 ° 2θ comprises said crystal form and at least one diluent or excipient. Can be prepared by mixing with a dosage form, wherein the diluent or excipient is a carrier, filler, filler, binder, wetting agent, disintegrant, disintegration inhibitor, absorption enhancer, adsorption Including, but not limited to, agents, surfactants or lubricants. The pharmaceutical composition of the present invention should maintain a novel crystalline form of ciclesonide (not a solution formulation), however, the process for producing the pharmaceutical composition of the present invention can include a solution. Additional ingredients such as solubilizers, buffers, and analgesics can be added. If necessary, colorants, preservatives, flavorings, seasonings, sweeteners, and other agents can also be added to the desired preparation. The pharmaceutical composition can be in various forms for administration of the pharmaceutical composition, for example, but not limited to tablets, pills, powders, suspensions, emulsions, granules, suppositories or injectable preparations. Can be

  Any excipient commonly known and widely used in the art can be used in the pharmaceutical composition. Carriers used include, but are not limited to, lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid and the like. Binders used include water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone and the like, except that It is not limited to only. Disintegrants used are buffered precipitate, sodium alginate, agar powder, laminaria powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, monoglyceride of stearic acid, starch, lactose And the like, but is not limited thereto.

  Disintegration inhibitors used include, but are not limited to, sucrose, stearin, coconut butter, hydrogenated oils and the like. Absorption enhancers used include, but are not limited to, quaternary ammonium bases, sodium lauryl sulfate and the like. Wetting agents used include, but are not limited to glycerin, starch and the like. Adsorbents used include but are not limited to starch, lactose, kaolin, bentonite, colloidal silicic acid and the like. Lubricants used include, but are not limited to, purified talc, stearate, boric acid powder, polyethylene glycol and the like.

  Optionally, the tablet is a commonly known coating material such as a sugar coated tablet, a gelatin film coated tablet, a tablet coated with an enteric coating, a film coated tablet, a bilayered Can be coated with tablets, and those used for multilayered tablets.

  When shaping the pharmaceutical composition into a pill form, any known excipient known in the art can be used. For example, when making pills, carriers include, but are not limited to, lactose, starch, coconut butter, hardened vegetable oil, kaolin, talc, and the like. The binders used include, but are not limited to, gum arabic powder, gum tragacanth, gelatin, ethanol and the like when making pills. The disintegrants used include but are not limited to agar, laminaria and the like.

  Any of the known excipients used in the art can be used to shape the pharmaceutical composition into the form of suppositories. For example, excipients include, but are not limited to, polyethylene glycol, coconut butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthesized glycerides and the like.

  In preparing injectable pharmaceutical compositions, solutions and suspensions are sterilized and are preferably isotonic with blood. Injectable preparations contain carriers commonly known in the art such as water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and fatty acid esters of polyoxyethyl sorbitan. Can be used, but is not limited thereto. One skilled in the art can readily determine the amount of sodium chloride, glucose or glycerin with little experimentation to make the injectable formulation isotonic.

  The pharmaceutical composition of the present invention can be administered in various ways depending on the age, sex and symptoms of the patient. For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules can be administered orally. Injectable preparations can be administered individually or can be mixed and injected intravenously with injectable infusions such as glucose and amino acid solutions. If necessary, the injectable preparation can be administered intramuscularly, intradermally, subcutaneously or intraperitoneally. Suppositories can be administered rectally.

  Although the invention has been described with respect to certain preferred embodiments, other embodiments will become apparent to those skilled in the art from consideration of the specification. The invention is further defined by the following examples describing in detail the synthesis of ciclesonide and its fractional crystallization. It will be apparent to those skilled in the art that many modifications to the materials and methods can be made within the scope of the invention.

  X-ray powder diffraction data was obtained using methods known in the art using a SCINTAG powder X-ray diffractometer model X'TRA equipped with a solid state detector. 1.5418mm of copper radiation was used. A round aluminum sample holder with zero background was used. Scan parameters included: Range: 2-40 ° 2θ; Scan Mode: Continuous scan; Step size: 0.05 °; and 5 ° / min speed. All peak positions are within ± 0.2 ° 2θ.

Comparative Example 1: Repeat of Example 1 of EP929566 :
Ciclesonide (> 99% according to HPLC) was dissolved in 3.37 parts absolute ethanol under reflux; and 1.96 parts water was added to the boiling mixture. The mixture is then cooled to RT under vigorous stirring and the precipitate is filtered off with suction, washed with 1.58 parts absolute ethanol / water (2/1, v / v) and 50 ° C. under vacuum. For 5 hours to obtain crystalline ciclesonide. The crystalline material was analyzed by PXRD and peaks at about 7.0, 15.0, 17.0, 17.5 and 18.4 ° 2θ ± 0.2 ° 2θ, and addition at 5.6, 12.7, 14.5, 19.3 and 20.2 ° 2θ ± 0.2 ° 2θ The pattern with the following peaks was shown.

Example 2: Preparation of a ciclesonide crystal form characterized by a PXRD pattern with peaks at about 11.0, 14.8, 15.7, 16.5 and 22.8 ° 2θ ± 0.2 ° 2θ :
Ciclesonide (greater than 99% according to HPLC) was dissolved at 70 ° C. in 6.25 parts tert-butanol and 10.0 parts water. The solvent was distilled under vacuum and 5.0 parts water was added. The mixture was cooled to RT under vigorous stirring and the precipitate was filtered off with suction and washed with 5.0 parts of water.

Example 3: Preparation of a ciclesonide crystal form characterized by a PXRD pattern with peaks at about 11.0, 14.8, 15.7, 16.5 and 22.8 ° 2θ ± 0.2 ° 2θ :
Ciclesonide (99% or higher according to HPLC) was dissolved in 3.0 parts (w / w) of tert-butanol at 60 ° C. The solution is cooled to 26-27 ° C. with stirring and the precipitate is filtered off with suction, washed with 2.0 parts (w / w) of 2,2,4-trimethylpentane and evacuated to 80 ° C. For 8 hours. Its melting point was 206.9 ° C. The dried precipitate was analyzed by XRD and showed ciclesonide crystal forms characterized by XRD patterns with peaks at about 11.0, 14.8, 15.7, 16.5 and 22.8 ° 2θ ± 0.2 ° 2θ, and about 7.0, 15.0, 17.0 5% by weight of ciclesonide crystal form with XRD showing patterns with peaks at 17.5 and 18.4 ° 2θ ± 0.2 ° 2θ and additional peaks at 5.6, 12.7, 14.5, 19.3 and 20.2 ° 2θ ± 0.2 ° 2θ It has the following.

Example 4: Preparation of starting ciclesonide :
Example 4a: Preparation of ciclesonide :
Desonide 21-isobutyrate (70 g, 144 mmol) is added in portions to 73% hydrofluoric acid (350 g) at about −20 ° C. and 18.4 g (164 mmol) is added to the resulting solution for about 5 minutes. Of cyclohexanecarboxaldehyde was added. The reaction mixture is maintained at −10 ° C. to −15 ° C. for 1 hour, then at about −30 ° C. for 2 hours, and then 26% ammonium hydroxide solution (87.5 g) and water (2625 g) in ice. Poured into the cooled mixture. The suspension was stirred for 1 hour, then the precipitate was collected by a filter and rinsed with water.

  In order to confirm the absence of acidity, the wet precipitate was partitioned between 1000 g dichloromethane and 1000 g water (adjusted to pH 8 with ammonium hydroxide solution). The organic phase was concentrated under atmospheric pressure to give an oily residue (crude product) having an R / S epimer ratio of about 90/10.

Example 4b: First crystallization :
The oil of Example 4a is dissolved in 280 g of acetone under reflux, and the solution is diluted with 1400 g of isooctane while maintaining at reflux and until the temperature of the suspension reaches 90 ° C. Concentrated under atmospheric pressure. The suspension was cooled with stirring to about 70 ° C. for 30 minutes and the precipitate was collected by filtration and rinsed with isooctane. The crystals were dried under vacuum at 80 ° C. to obtain 64 g of ciclesonide having an R / S epimer ratio of 96.5 / 3.5.

Example 4c: Second crystallization :
The product of Example 4b was recrystallized using 96 g of acetone and 1400 g of isooctane in the same manner as disclosed in Example 4b to give 56.8 g of ciclesonide with an R / S epimer ratio of 98.3 / 1.7. .

Example 4d: Third crystallization :
The product of Example 4c was recrystallized using 85 g of acetone and 1400 g of isooctane in the same manner as disclosed in Example 4b to give 50.5 g of ciclesonide with an R / S epimer ratio of 99.3 / 0.7. .

Example 4e: Fourth crystallization :
The product of Example 4d was recrystallized using 76 g of acetone and 1400 g of isooctane in the same manner as disclosed in Example 4b to give 45.9 g of ciclesonide with an R / S epimer ratio of 99.75 / 0.25. .

FIG. 1 shows the powder X-ray diffraction pattern of the ciclesonide crystal form obtained by repeating Example 1 of EP Patent No. 929566. FIG. 2 shows a powder X-ray diffraction pattern of the ciclesonide crystal form of the present invention. FIG. 3 shows a photomicrograph of the ciclesonide crystal form obtained by repeating Example 1 of EP Patent No. 929566. FIG. 4 shows a photomicrograph of the ciclesonide crystal form of the present invention.

Claims (19)

  Ciclesonide crystal form characterized by an XRD pattern with peaks at about 11.0, 14.8, 15.7, 16.5 and 22.8 ° 2θ ± 0.2 ° 2θ.   The ciclesonide crystal form of claim 1, further characterized by an XRD pattern having peaks at about 5.6, 18.3, 19.5, 20.7 and 22.0 ° 2θ ± 0.2 ° 2θ.   3. The ciclesonide crystal form according to any one of claims 1-2, characterized by a PXRD pattern substantially as shown in FIG.   The ciclesonide crystal form according to any one of claims 1 to 3, wherein the crystal form has a weight loss of about 10% by weight when measured by thermogravimetric analysis at a temperature of about 25C to about 130C.   The ciclesonide crystal form according to any one of claims 1 to 4, wherein the ciclesonide crystal form has a melting point at about 207 ° C.   The ciclesonide crystal form according to any one of claims 1 to 5, wherein the crystal form is a solvent compound of tert-butanol.   The ciclesonide crystal form according to any one of claims 1 to 6, wherein the crystal form has a spherical shape and an irregular shape.   8. The ciclesonide crystal form according to any one of claims 1 to 7, further characterized by a micrograph substantially as shown in FIG.   9. The ciclesonide crystal form according to any one of claims 1 to 8, wherein the ciclesonide crystal form has no more than about 5% by weight of other cyclosonide forms as determined by PXRD.   Certsonide crystal form characterized by an XRD pattern having peaks at about 11.0, 14.8, 15.7, 16.5 and 22.8 ° 2θ ± 0.2 ° 2θ, comprising crystallizing ciclesonide from Tert-butanol. The crystallization is
Ciclesonide is dissolved in a sufficient amount of tert-butanol at a temperature of about 50 ° C. to about 70 ° C. to form a solution; and the solution is cooled to a temperature of about 25 ° C. to about 35 ° C. 11. The method of claim 10, comprising inducing precipitation of ciclesonide.   12. The method for producing a ciclesonide crystal form according to claim 11, wherein the temperature of the dissolution step is about 55 ° C. to about 65 ° C.   The method for producing a ciclesonide crystal form according to any one of claims 10 to 12, further comprising isolating the crystal form.   A pharmaceutical composition comprising a therapeutically effective amount of the ciclesonide crystal form of any one of claims 1 to 9 and at least one pharmaceutically acceptable excipient.   10. A method according to any of claims 1 to 9, comprising mixing a therapeutically effective amount of the ciclesonide crystal form of any one of claims 1 to 9 and at least one pharmaceutically acceptable excipient. A method for preparing a crystalline pharmaceutical composition according to claim 1.   10. A crystalline form according to any one of claims 1 to 9 for use as a medicament.   Use of the crystalline form according to any one of claims 1 to 9 for the manufacture of a pharmaceutical composition.   18. Use according to claim 17, wherein the pharmaceutical composition is for the treatment of inflammation, asthma, atherosclerosis or hypercholesterolemia.   18. Use according to claim 17, wherein the pharmaceutical composition is for the treatment of asthma.

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