Title of Invention	"A PROCESS FOR PRODUCING IMPROVED CELECOXIB CRYSTALS"
Abstract	Celecoxib is a medicinal compound having anti-inflammatory action. The present invention describes a process for producing celecoxib crystals having improved physicotechnical properties e.g. better flow due to improved (lower) aspect ratio. Improved aspect ratio leads to better properties of the crystals and is regarded as pharmaceutically superior than crystals having higher aspect ratio.

Full Text

FIELD OF INVENTION The field of invention pertains to process chemistry. More specifically it relates to a method for preparing improved crystals of an anti-inflammatory medicinal compound, celecoxib. BACKGROUND OF INVENTION Celecoxib {4-(5-(4-methylphenyl)-3-(trifluromethyl)-1H-pyrazol-1-yl) benzene sulfonamide} belonging to substituted pyrazolyl benzenesulfonamides is a selective cyclooxygenase-2 (COX-2) inhibitor possessing 375-fold selectivity for the enzyme. Its discovery paved the way for research in new molecules aiding in treatment of inflammation with diminished side effects. It is an active ingredient of Celebrex marketed by Pharmacia Corporation, USA The compound is useful in the treatment of inflammation and pain. It is used in arthiritic disorders, asthma, bronchitis, menstrual cramps, cytomegalovirus infection, liver diseases including hepatitis, skin diseases, central nervous system disorders and damage including alzheimer's disease, neurodegeneration and stroke, ischemia and trauma. Crystal Habit Crystal habit defines the general shape of the crystals. Substances, with differences only in their outer appearance, without any disparity in their internal crystal lattice and with identical diffraction patterns, are termed as isomorphic crystals/forms. Crystals of a substance may exist in different shapes such as acicular, columnar, flake, needle, lath etc. United States Pharmacopoeia provides a discussion on particle shape where it gives definitions for acicular, columnar, flake, plate, lath, equant types of crystal habit (Optical microscopy, general tests (776), USP 24, The United States Pharmacopoeial Convention, Rockville, MD, 2000, pp 1965-1967). These forms due to differences in their particle orientation differ in surface controlled processes such as drying, dissolution, dispersibility, sedimentation, syringeability, absorption and processability such as flowability, homogeneity, compressibility, bulk density and packing behavior. Crystal habits of a particular drug portray different planes, thus differ not only in their specific surface, but also in their free surface energy, and hence, exhibit different physicotechnical properties. The external structure may have a significant influence in high dose drugs, as they contribute towards the maximum portion of the drug product. Crystal habit can be quantitatively expressed in terms of mean aspect ratio defined as ratio of length (longest dimension from edge to edge of a particle oriented parallel to the ocular scale) to the width (the longest dimension of the particle measured at right angles of the length) (G. Brittain; Particle size distribution, part 1, representations of particle shape, size, and distribution. Pharm Tech 38-45, 2001). According to literature, acicular (needle) crystals are to be avoided and cubic or spherical shapes where the values of aspect ratio approach 1 are desirable. These latter shapes produce enhanced crystalline flow properties and are considered to be pharmaceutical^ good (G. Lloyd. Process for improving flow characteristics of crystalline ibuprofen. Albemarle Corporation US5843863, 1998). Crystallization, a purification step in API synthesis is responsible for different polymorph and/or crystal habit. The process and course of crystallization comprises predominantly of three physical phenomena i.e. supersaturation, nucleation and crystal growth. It is the ratio of rate of nucleation to crystal growth which decides the final outcome in terms of modified habit or polymorphic alteration. Variation in solvent polarity, crystallizing temperature, solute concentration, stirring rate and duration, impurities, etc, can modify the process and course of crystallization to alter the final product. Hence, a comprehensive consideration to the various crystallization factors allows complete elucidation of variety of isomorphs and polymorphs (D. J. W. Grant. Theory and origin of polymorphism. In H. G. Brittain (eds.), Polymorphism in pharmaceutical solids, Marcel Dekker Inc, New York, 1999, pp. 1-33). (reference of a book chapter). Among the various crystallization techniques used, vapor diffusion is the least explored method for crystal habit modificaion. It has been used previously in protein crystallization but sparsely applied in pharmaceuticals. In this process, crystals are generated by slow creation of supersaturation through diffusion of non-solvent vapors (defined as solvent in which the solubility of solute is approximately less than 1 mg/ml) into the drug solution in (good solvent), placed together in equilibrium with each other. Both the good solvent and nonsolvent should be miscible with each other and have similar boiling range (J. K. Guillory. Generation of polymorphs, hydrates, solvates and amorphous solids. In H. G. Brittain (eds.), Polymorphism in pharmaceutical solids, Marcel Dekker Inc, New York, 1999, pp 183-227). This technique lends an ideal ratio of rate of nucleation to crystal growth and hence modifies the crystal habit. Though beneficial in habit modification, which may lead to processability advantage, vapor diffusion suffers from certain limitations like longer duration of crystallization process, limited choice of solvents and the major being its non-scalability. However, using the vapor diffusion crystallization product as seeds in conventional recrystallization technique can help to overcome the limitation of non-scalability of vapor diffusion and give a commercial facet to the process. Use of vapor diffusion technique for recrystallization of pharmaceuticals, at a commercial level, has not been reported earlier. Powder flow can be affected by particle size, size distribution, shape, surface texture, surface energy, chemical composition, moisture content and other properties and it is known that crystallization techniques provide a route towards the control of the characteristics of pharmaceutical raw materials to such an extent that the properties of powders can be optimized to suit particular processing applications. Flow properties are commonly evaluated by bulk density, tap density, Carr's index, Hausner ratio. Values of Carr's index below 15 % generally give rise to good flow characteristics, and readings above 25 % indicate poor flowability. International Patent Application No. WO 0042021 discloses a plate-shaped solvated crystalline form of celecoxib and a method for desolvation of that crystalline form. International Application No. WO 00/32189 discloses specific celecoxib compositions and highlights various problems associated with processing of celecoxib. In this document selective COX-2 inhibitory compounds, incluiding celecoxib, deracoxib, valdecoxib, and rofecoxib are hydrophobic and have low solubility in water. This has presented practical difficulties in formulating such compounds for oral administration, particularly where early onset of therapeutic effect is desired or required. The formulation of celecoxib for effective oral administration to a subject has hitherto been complicated by the unique physical and chemical properties of celecoxib, particularly its low solubility and factors associated with its crystal structure, incluiding cohesiveness, low bulk density, and low compressibility. Celecoxib is unusually insoluble in aqueous media. Unformulated celecoxib is not readily dissolved and dispersed for rapid absorption in the gastrointestinal tract when administration orally, for example in capsule form. In addition, unformulated celecoxib, which has a crystal morphology that tends to form long needles, typically fuses into a monolithic mass upon compression in a tableting die. Even when blended with other substances, the celecoxib crystals tend to separate from the other substances and agglomerate during mixing of the composition resulting in a non-uniformily blended composition containing undesirably large aggregates of celecoxib. Therefore, it is difficult prepare a pharmaceutical composition containing celecoxib that has the desired blend uniformity. Further handling problems are encountered during the preparation of pharmaceutical compositions. Accordingly, there is a need for preparing crystalline celecoxib that has improved physicotechnical properties and can help in overcoming processing problems associated with needle-shaped crystals of celecoxib. OBJECTS OF THE INVENTION The main object of the invention is to provide a process for preparing celecoxib crystals with improved properties. Other aspects and advantages of this invention will become apparent from reading the remaining specifications and the claims which follow. SUMMARY OF THE INVENTION It has been found in conventional crystallization process that when celecoxib is dissolved and crystallized from a solution of a non-polar solvent (chloroform, toluene, carbon tetrachloride) using a specific procedure i.e. temperature of 50-60 °C, of low solute concentration (less than 20% of saturation concentration in each solvent) and absence of stirring without seeding leads to generation of crystalline celecoxib obtained by having lower aspect ratio, as compared to crystalline celecoxib obtained by crystallizing from polar solvents. The invention also provides another method of producing improved crystals of celecoxib by seeding the solution of celecoxib with seeds generated by vapor diffusion or sonocrystallization, the crystals from vapor diffusion or sonocrystallization can be used as seeds in conventional crystallization process using non-polar solvent (chloroform, toluene, carbon tetrachloride) and conducting experiment at room temperature. Crystalline celecoxib is subject to further recrystallization and purification utilizing a different solvent. As a result of the process of the invention, a more cost effective manufacturing process is developed by reducing pharmaceutical production down time, due to flow and compression problems, thereby requiring less formulation time. Thus, using the process of this invention, the crystalline forms of celecoxib having improved physical properties and manufacturability are developed. DESCRIPTION OF ACCOMPANYING DRAWINGS FIG. 1 Chemical structure of celecoxib FIG. 2 Microscopic photograph exhibit of celecoxib crystals prepared by the process of prior art. FIG. 3 is microscopic photographic exhibits of celecoxib crystals prepared by the process by the present invention using chloroform. FIG. 4 is microscopic photographic exhibits of celecoxib crystals prepared by the process of vapor diffusion using chloroform as good and hexane as non-solvent FIG. 5 is microscopic photographic exhibits of celecoxib crystals prepared by the process the present invention using chloroform FIG. 6 is microscopic photographic exhibits of celecoxib crystals prepared by the process the present invention using chloroform FIG. 7 Overlay of PXRD pattern of celecoxib crystals prepared by the process of prior art and that prepared by process of the present invention in chloroform where (1) pattern for acicular crystals and (2) pattern for modified crystals. The pattern clearly shows that the crystals of present invention are only a change in habit with no new peaks. DETAILED DESCRIPTION OF THE INVENTION Accordingly, in one aspect, the invention provides a process for preparing crystalline celecoxib having an improved crystal habit comprising: a) contacting celecoxib with a non-polar solvent to obtain a solution wherein concentration of celecoxib as solute is less than at least 20% w/v of saturation point of solvent; b) separating crystalline celecoxib from the solution and allowing it to grow. The non-polar solvent employed in the process may be selected from carbon tetrachloride, toluene and chloroform. Preferably, the solvent is toluene or chloroform having dielectric constant from 2-5 or 2.20 to 4.80. It is surprisingly found that the crystal habit of celecoxib obtained by the above process has been modified and has an aspect ratio of about 2:1 to 4:1. In the celecoxib manufacturing process used in the prior art, the celecoxib crystals obtained are defined by acicular (needle) crystal habit with an aspect ratio of about 6:1 to 10:1. In contrast, the crystals prepared by the process according to this invention, have a crystal aspect ratio, no greater than about 4:1 and even as low as 2:1. In another aspect, the invention provides a process for preparing celecoxib crystals comprising the steps of: (a) contacting celecoxib with a non-polar solvent and recrystallising therefrom to obtain seed crystals; (b) adding seed crystals to the reaction mixture of step (a); (c) separating celecoxib crystals from the mixture of step (b). The non-polar solvent employed in the above process may be selected from chloroform, carbon tetrachloride and toulene. Preferably, less than 10% w/w crystals of celecoxib may be added as seed crystals in the aforesaid process. More preferably, less than 5% w/w and most preferably 2% w/w crystals are added as seed crystals. Once the process is completed, the crystals obtained are analyzed for their flow behaviour where bulk and tap density are calculated using USP method wherein change in volume of power level in measuring cylinders is recorded after 500, 750-1200 taps. Thereafter, Carr's index and Hausner ratio are calculated. In yet another aspect the invention provides an improved process for preparing crystalline celecoxib comprising the steps of: a) contacting celecoxib with a non-polar solvent to obtain a saturated solution b) subjecting the solution of step (a) to continuous sonication throughout the crystallization process and maintained at temperature range not less than 35 °C. c) Allowing crystals of celecoxib to form and grow and separating the crystals. The non-polar solvent employed in the above process may be selected from chloroform toluene and carbon tetrachloride. Preferably, the frequency of the sonication energy may be 30-40 khz. More preferably, in the process above the concentration of celecoxib as a solute may be less than at least 20% below the saturation point of solvent. The inventions have surprisingly found that use of non-polar solvents assists and supports the growth of crystals. Further, it was found that preparation of a solution consisting of celecoxib as solute to the extent of less than 20% w/v supports the process of crystal growth. In other cases (i.e. prior art) it was found that instead of crystals growing to an appropriate size, nuclei were formed and the crystals were not of appropriate shape and were not of desired aspect ratio. A low aspect ratio was achieved using the process of the present invention, as compared to the prior art wherein the aspect ratio was as high as 6:1 to 10:1. Further, the invention provides a process for preparing crystalline celecoxib having an improved crystal habit comprising: (a) contacting celecoxib with a first solvent in which it has a solubility of 5 to 200 mg/ml; (b) initiating crystallization by vapor diffusion in a second solvent in which celecoxib has a solubility of less than 1 mg/ml; (c) separating the crystals of celecoxib from the mixture of step (b). The invention is now illustrated by the following examples which are provided only for illustration and not intended and limit the scope of invention in any manner. Various embodiments which may be apparent to skilled persons would fall within the scope of the present invention. Examples Example 1 Saturation solubility of celecoxib was determined in carbon tetrachloride at 60 ° C as 10.98 gm/ml. A batch of celecoxib was prepared by dissolving 8.23 mg/ml (25% less than the saturation concentration) in carbon tetrachloride. The solution was filtered and subjected to crystallizing temperature of 60 ° C until the crystals were obtained. Majority of crystals show an aspect ratio of 2:1 to 3:1. Example 2 Saturation solubility of celecoxib was determined in toluene at 60 °C as 15.36 mg/ml. A batch of celecoxib was prepared by dissolving 11.52 mg/ml (25% less than the saturation concentration) in toluene. The solution was filtered and subjected to crystallizing temperature of 60 °C until the crystals were obtained. Majority of crystals show an aspect ratio of 2:1 to 3:1. Example 3 Saturation solubility of celecoxib was determined in chloroform at 60 °C as 21.84 mg/ml. A batch of celecoxib was prepared by dissolving 16.38 mg/ml (25% less than the saturation concentration) in chloroform. The solution was filtered and subjected to crystallizing temperature of 60 °C until the crystals were obtained. Majority of crystals show an aspect ratio of 3:1 to 4:1. Example 4 Saturation solubility of celecoxib was determined in chloroform at 25 ° C as 11.11 mg/ml. A batch of celecoxib was prepared by dissolving 11.11 mg/ml in chloroform. The solution was filtered and placed in the large container containing non solvent as hexane at 25 ° C until the crystals were obtained. The crystals show an average aspect ratio of 8:1. These crystals were sieved from BSS # 18 and 1.2 % (w/w) of it were used for seeding in saturated solution of chloroform. Majority of crystals show an aspect ratio of 2:1 to 3:1 Example 5 Saturation solubility of celecoxib was determined in chloroform at 60 °C as 21.84 mg/ml. A batch of celecoxib was prepared by dissolving 16.38 mg/ml in chloroform. The solution was Table 1. Results of flow studies (Table Removed) "SC: Solvent recrystallization *VD: Vapor diffusion filtered and subjected to sonic energy at crystallizing temperature of 60 °C until the crystals were obtained. Majority of crystals show an aspect ratio of 3:1 to 4:1. Advantages of the invention: 1. Provides a process for preparing crystalline celecoxib which has much smaller aspect ratio and improved flow properties compared to previously known celecoxib. 2. Decreases the problem of content non-uniformity in capsules while handling powder mix containing celecoxib. 3. Avoids the formation of monolithic masses during compression with improved crystalline habit of celecoxib. 4. Decreases the problem of high surface energy and cohesiveness with improved crystalline habit of celecoxib. 5. Ensures crystal habit modification free of complications of polymorphic transformation. 6. Proposes a process of crystal habit modification which is industrially viable. We claim: 1. A process for preparing crystalline celecoxib having an aspect ratio of 2:1 to 4:1, comprising the following steps: a) contacting celecoxib with a non-polar solvent having a dielectric constant of 2-5, such as carbon tetrachloride, chloroform, toluene, to obtain a solution, wherein the concentration of celecoxib is less than 20% w/v of saturation point of the solvent, at a temperature from 50 to 60°C; b) separating crystalline celecoxib from the solution, and c) optionally, introducing in the solution of step (a) seed crystals in range of 2% -10% w/w and thereafter separating crystalline celecoxib from the solution. 2. The process as claimed in 1, wherein the seed crystals are generated by contacting celecoxib with a first solvent in which celecoxib has a solubility of 5 to 200 mg/ml; separating the crystals and introducing the crystals thus obtained by vapour diffusion in to a second solvent in which celecoxib has a solubility of less than 1 mg/ml, and separating the crystals of celecoxib from this mixture for use as seed crystals.

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2709-del-2005-abstract.pdf

2709-del-2005-Claims (20-04-2012).pdf

2709-DEL-2005-Claims-(18-01-2012).pdf

2709-del-2005-Claims-(27-07-2012).pdf

2709-del-2005-claims.pdf

2709-DEL-2005-Correspondence Others-(18-01-2012).pdf

2709-del-2005-Correspondence-others (20-04-2012).pdf

2709-del-2005-Correspondence-Others-(27-07-2012).pdf

2709-del-2005-correspondence-others.pdf

2709-del-2005-description (complete).pdf

2709-del-2005-Drawings-(18-01-2012).pdf

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2709-del-2005-form-1.pdf

2709-del-2005-form-18.pdf

2709-del-2005-form-2.pdf

2709-del-2005-form-3.pdf

2709-del-2005-form-5.pdf

2709-del-2005-GPA-(18-01-2012).pdf