Research On The Quantitative Analysis Method Of Nateglinide Polymorph Based On PXRD, DSC And NIR Technology

Nateglinide is a drug used to lower sugar levers in patients with type 2 diabetes by stimulating release of insulin that can exist in four polymorphs(H,B,S and X2).In the case of nateglinide,the form B suffers from problems of instability,especially when subjected to the mechanical grinding.So it is not ideal for use in medicine.Form H is pharmaceutically preferred because they have better stability.It is desirable in general that a medicinal product containing a crystalline active ingredient has a composition which is well defined and stable in terms of the crystalline form of the active ingredient.Conversion of one crystalline form into unknown amounts of different,or amorphous,forms during processing or storage is undesirable and in many cases would be regarded as analogous to the appearance of unquantified amounts of impurities in the product.Occasionally in our work we detect unquantified amounts of form B in the tested nateglinide form H.Thus,there is a strong demand to develop a simple,rapid and accurate quantitative method for the analysis of nateglinide polymorphs.In this study we develop and validate three methods including powder X-ray diffraction(PXRD),differential scanning calorimetry(DSC)and near infrared(NIR)spectroscopy,coupled with univariate and multivariate analysis,to quantify the nateglinide polymorphs and evaluate its application by studying an unquantified commercial raw material sample.The results show that PXRD is the most suitable for quantification of polymorphic impurity for nateglinide low-content form B in the binary mixtures while NIR spectroscopy is the least accurate technique for the system studied.Though a good linear calibration curve for DSC is successfully obtained,it could not be a practical way for low-content quantification in nateglinide polymorphic mixtures.To futher evaluate the application of PXRD method,we revalidate the PXRD models(peak height,peak area and PLS analysis)with three unqualified nateglinide samples.The results show that PXRD(with PLS regression)is the best choice for quantification in neteglinide polymorphic mixtures in practice due to the high predicted accuracy and good stability of the model.The results of the study would be of great significance to further study for quantification of nateglinide polymorphic mixtures in the dosage form.And the proposed method provides some basis for other polymorphic drugs.