Crystallization and Polymorphism-Scalable Process for Celecoxib and It’s Polymorph From-3 (Non- Steroidal Anti-Inflammatory Drug (NSAID)

The present process provides an improved process for the preparation of 4-[5-(4-methylphenyl)-3(trifluoromethyl)-1Hpyrazol-1-yl] benzene sulfonamide (Celecoxib) and its purification and crystallization to produce polymorph. The present process, which describes the manufacturing process of Celecoxib, which is a nonsteroidal anti-inflammatory drug (NSAID), has the advantage of scaling up to the industrial level of production. The process uses safe reagents in the process which makes it for industrial scale operations. The yields in the process are high, which makes it a cost-effective process. Formation of isomers are less compared with the all existing process, which makes it effective to make it to the pharmacopoeia grade. Residual solvents play a very important role in the impurity profile of APIs as per the ICH Guidelines ICH Q3C (R4). In this process by carrying out the final step of condensation in the aqueous medium followed by crystallization, the residual solvents limits are well taken care of.


LOJ Med Sci
Copyrights@ Krishna Sarma Pathy, et al. makes prostaglandins, resulting in lowering the concentrations of prostaglandins. As a consequence, reduction in inflammation and its accompanying pain, fever, swelling and tenderness. The manufacture of Celecoxib has been described in various patents and to cite a few references, G. D. Searl & Co. has disclosed method for preparation of Celecoxib [2][3] (Figure 3).

Description of the Process
The present procedure describes the preparation of Celecoxib by a novel process and its crystallization to polymorphic form. The present process for the preparation of Celecoxib by a process involving condensation of 4,4,4-trifluoro-1-[4-(methyl) phenyl]butane-1,3-dione [1] with sulphonamido phenyl hydrazine hydrochloride [2] in an aqueous medium to give Celecoxib [3]. This is followed by crystallization from a mixture of solvents [4][5][6][7][8] containing Aromatic hydrocarbon and aliphatic ketone. In the condensation reaction the reactants are added in water and reactions done at ambient temperature. The crude Celecoxib is isolated by filtration. In the for purification of Celecoxib and its crystallization to polymorphic FORM Preparing a solution of Crude Celecoxib in a solvent mixture comprising of an aliphatic ketone (Acetone) and an aromatic hydrocarbon (Toluene)at reflux temperature followed by cooling crystallization to give crystals of Celecoxib polymorph [8][9][10][11][12] (Figure 4). In this process by carrying out the final step of condensation in the aqueous medium followed by crystallization, the residual solvents limits are well taken care of. The yields in the process are higher compared to the prior art, which makes it a cost-effective process. Formation of isomers are less compared with the prior art, which makes it effective to make it to the pharmacopoeia grade. Residual solvents play a very important role in the impurity profile of APIs as per the ICH Guidelines ICH Q3C (R4). In this process   by carrying out the final step of condensation in the aqueous medium followed by crystallization, the residual solvents limits are well taken care of [13,14]. The crystallization conditions are well established to give crystalline polymorph. The powder X-Ray diffraction pattern of the Celecoxib is given in Figure 1 and 2θ values are given in Table 1

a) Purification and Crystallization to Give Polymorph:
Celecoxib wet-cake obtained in the process described above was taken into 20 liter 3-necked flask, equipped with stirrer, thermometer and reflux condenser, mixture of acetone (0.54liter) and toluene (10.8liter) was added and the reaction mixture was heated to 80˚C to 85˚C for 30 minutes. Activated carbon (0.3Kg) was added and the reaction mixture was further heated to 80C to 85˚C. The reaction mixture was cooled to 25˚C -30˚C. The slurry was filtered, washed with toluene and then dried at 70C to yield

a) Purification and crystallization to give Polymorph:
Celecoxib wet-cake obtained in the process described above was taken into 20liter 3-necked flask, equipped with stirrer, thermometer and reflux condenser, mixture of acetone (0.54liter) and toluene (10.8liter) was added and the reaction mixture was heated to 80˚C to 85˚C for 30 minutes. Activated carbon (0.3Kg) was added and the reaction mixture was further heated to 80˚C to 85˚C. The reaction mixture was cooled to 25˚C -30˚C. The separated solid was filtered, washed with toluene and then dried at 70˚C to yield the Celecoxib polymorph compound1.24 kg (HPLC purity-99.3% & molar yield; 47%) (Figures 8-11c).

Conclusion
The distinct advantage of the present method of preparation over the prior art can be summarized as per below: The present process, which describes the manufacturing process of Celecoxib, which is a non-steroidal anti-inflammatory drug (NSAID), has the advantage of scaling up to the industrial level of production. The process uses safe reagents in the process which makes it for industrial scale operations. The present process provides an improved process for the preparation of 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1yl] benzene sulfonamide (Celecoxib) and its purification and crystallization to produce polymorph. The yields in the process are high compared to existing process which makes it a cost-effective process. Formation of isomers are less compared with the prior art, which makes it effective to make it to the pharmacopoeia grade. In this process by carrying out the final step of condensation in the aqueous medium followed by crystallization, the residual solvents limits are well taken care of. The yields in the process are higher compared to the prior art, which makes it a cost-effective process.
Residual solvents play a very important role in the impurity profile of APIs as per the ICH Guidelines ICH Q3C (R4).