Formation Of Celecoxib Polymorphs Induced By Polymers And Research Of Crystal Growth Mechanisms

Celecoxib(CEL),a selective inhibitor of cyclooxygenase-2(COX-2),is extensively used for the treatment of various diseases including rheumatoid arthritis.As a BCS?compound,the medicinal Form?of CEL has poor water solubility which limits the absorption and bioavailability.Three metastable polymorphs(Form?,Form?,and Form?)and amorphous form of CEL are well reported.Form?has significantly higher bioavailability and dissolution rate than Form?,which exhibit the commercial application value.The preparation of metastable polymorphs and amorphous solid dispersion systems(ASDs),via the addition of polymers,are efficient methods to improve the water solubility of drugs.Thus,it is crucial to explore the interaction between celecoxib and polymers.In present study,the medicinal Form?of CEL was used as the research object.Three CEL polymorphs were screened by polymers,and the differences of crystal growth in amorphous CEL were analyzed by crystal growth model.The main contents were as follows:Firstly,the medicinal Form?of CEL was used as raw material.The CEL polymorphs(Form?,Form?,and Form?)were obtained with the induction of different polymers(PVP K30,HPMC E6,Poloxamer188,etc)based on the conventional crystallization experiments.The factors(i.e.,the viscosity and type of polymers,crystallization method,and temperature)were investigated,and the better preparation methods for three polymorphs of CEL were acquired through the research.The CEL Form?,which was induced by PVP K30,showed better stability in hot and humid environment.It suggested that the induced effect of polymers on the crystallization of CEL metastable polymorphs was multifactorial,including the increase of system viscosity and effect of heterogeneous nucleation,which depended on the polymer concentrations.To further reveal the inherent relationship between amorphous drugs and polymorphs,the crystallization behavior of amorphous CEL in presence of low polymer proportion was investigated.The amorphous samples were performed by melt-quenching,the crystallization was carried out in a vacuum incubator and crystal growth rate was measured by PLM.Some internal connections between the amorphous drug and polymorphs,which were affected by polymers,was found with the analysis of crystal growth rate based on two-dimension nucleation model.On the one hand,the crystallization of amorphous CEL and the crystal growth of three polymorphs were inhibited with the addition of cellulose polymers,which increased the viscosity of the system.On the other hand,the nucleation of CEL polymorphs was induced by polymers to different degrees.With increase in polymer proportion form1%to 5%,the decrease of the energy barrier for nucleation of CEL polymorphs followed the order of Form?(1708.70k _B)>Form?(1094.98k _B)>Form I(704.38k _B),which revealed that the addition of cellulose polymers was more conducive to the nucleation of Form?and Form?instead of Form?.The crystallization of three polymorphs relied on the polymer proportion and the environmental temperature instead of the molecular weight of polymers.Moreover,the cellulose polymers with larger substituents exhibited stronger inhibitory effect during the crystal growth of three polymorphs.The inhibitory effect of HPMCAS was3 times more than MC.The analysis of FT-IR,T_gdetermination,and simulation of molecular migration indicated that there was a steric repulsion from the substituents of polymers,which might hinder the crystallization process of CEL polymorphs.Lastly,based on the crystallization process of amorphous CEL inhibited by cellulose polymers,it was speculated that the stability of ASDs could be rapidly predicted by two-dimensional model of crystal growth.To test the idea,CEL ASDs with different cellulose polymers were prepared by planetary ball milling,and the stability of samples were detected under high temperature and high humidity conditions.The stability of CEL ASDs enhanced with the increase of polymer proportions and substituents,but slightly affected by molecular weight of cellulose polymers.The result was consistent with the growth rate of CEL polymorphs in presence of cellulose polymers,which further confirmed that the rapid prediction method was reliable.In present study,three celecoxib polymorphs were successfully prepared by the induction of polymers in new methods,and the optimized technology was determined.The process of crystal growth and nucleation was thoroughly investigated,which enriched the theory of the crystallization of polymorphs induced by polymers.A novel rapid method for predicting the stability of ASDs was proposed based on the crystal growth model,which might help researchers to reasonably select polymers for the preparation of ASDs.