Study On Polymorphism Of Fexofenadine Hydrochloride And Phase Transformation Control During Pharmaceutical Process

Drug polymorphism is an important part in the process of drug production quality control and drug development.Polymorphism can influence physical and chemical properties of active pharmaceutical ingredients,such as melting point,solubility,dissolution rate,hygroscopicity,thereby possibly affecting bioavailability and therapeutic efficacy.The conditions of polymorphic transformation involve a broad variety of factors,such as solvent,temperature,additive,and pH value,which contribute to the selection of optimal polymorphs.In addition,during formulation and process development,certain unit operations such as crushing,material mixing,granulation,drying and tablet pressing may present favorable conditions for a change in crystal form.In order to ensure the effectiveness of drugs,it is necessary to comprehensively consider the possibility of polymorphism alteration during formulation and process development.Phase transformation affects the powder properties of the product,such as bulk density,fluidity,compressibility,hardness and so on,and then affects the selection of preparation process parameters.The study of phase transformation is helpful to determine the process parameters of drug production process,improve the stability and uniformity of product quality,and improve the quality of drug production.We employed fexofenadine hydrochloride as model drug to study polymorphs behavior,to considerate phase transformation during process development and manufacture,and to quantify polymorphs.(1)The polycrystalline stability and phase transformation of FexHCl were studied systematically.In this study,the effects of water addition amount and various pH conditions on the solid phase forms of fexofenadine hydrochloride were investigated.The results showed that the addition of water amount had a critical effect on the generation of different solid phase forms of fexofenadine hydrochloride.Monohydrate(Form B)and dihydrate phase(Form C)were obtained successively with an increase of added water.Furthermore,fexofenadine hydrochloride's polymorphism showed obvious pH-dependent characteristics.The Form B was produced at lower pH(pH < 2),while the Form C was obtained at pH range from 2.03 to 3.01.At high pH > 4.92,the dihydrate fexofenadine free base(Form D)was acquired.The properties of the four solid phase forms were investigated,including thermal behavior,stability,solubility and solid-state transition relationship by thermogravimetric analysis(TGA),differential scanning calorimetry(DSC),powder X-ray diffraction(PXRD),and dynamic vapor sorption(DVS).The dissolution experiments results were presented(Form C > Form D > Form A > Form B).From the perspective of patent litigation relating to the crystal polymorphism of marketed products,select the appropriate crystal form is necessary for product development without infringing patents.Form C might be a superior candidate and alternative form for formulations of fexofenadine hydrochloride,especially for innovative product development.(2)The effect of phase transformation of fexofenadine hydrochloride on powder properties and preparation process was investigated.Wet granulation process was used to improve the fluidity of powder.The addition of water induced the wet adhesion property of fexofenadine hydrochloride,but also caused the phase transformation.Water addition was key controlling factor for the polymorphic conversion during the wet granulation process.Phase transition was investigated in two parts: 1)Water–induced phase transformation of fexofenadine hydrochloride without excipients;2)Water–induced phase transformation of fexofenadine hydrochloride with excipients.When fexofenadine hydrochloride was mixed with water,it rapidly converted to Form II,while the conversion was retarded when fexofenadine hydrochloride was formulated with excipients.In addition,the conversion was totally inhibited when the water content was <15% w/w.The relationship between phase transformation and water content was studied at the small scale,and it was also applicable for the scale-up during wet granulation.The relationship between phase transformation and water content was studied at the small scale,and it was also applicable for the scale-up during wet granulation.The high phase transition degree of FXD corresponded to the good flowability of particles.However,it can lead to the incomplete release of the FXD during dissolution.In order to balance the quality attributes and the dissolution of granules,the phase transition of FXD and the water amount added should be controlled during wet granulation.The knowledge gained from this study around the impact of phase transformation on the manufacturing process has reference value for analogous drugs that undergo phase transformation during wet granulation process.(3)In this study,we developed and validate two quantification system including near infrared spectroscopy-NIR(spectroscopic technique)and differential scanning calorimetry-DSC(thermodynamic analysis),coupled with chemometrics,to quantify the polymorphic forms and successfully evaluate phase transformation in pure API and formulation during wet granulation.The models were considered to provide good fitting results and could be successfully used for quantitative analysis of fexofenadine hydrochloride Form I.In addition,the effect of single excipient on water-induced phase transformation of fexofenadine hydrochloride was quantified successfully by NIR,which could provide a reference for screening the proper excipient,filtrating the kinds and ratio of the excipients and optimizing the formulation and preparation.This study would provide some basis for other polymorphic drugs and technical support for pharmaceutical enterprises in production.