Construction And Updating Of Universal Quantitative Models For Testing Azithromycin By Near-infrared Diffuse Reflectance Spectroscopy. Crystalline Water Of Ranolazine Hydrochloride And The Influence On Its Crystallization

The paper consists of two parts:Part1:Construction and updating of universal quantitative models for testing azithromycin by near-infrared diffuse reflectance spectroscopy.Azithromycin is a semi-synthetic macrolide antibiotic with erythromycin as its precursor. It has been prepared as injection powders, tablets, granule and other oral pharmaceutical agents. In China, there are many azithromycin injection powders with different acid radical such as citric acid, phosphoric acid, lactic acid, hydrochloric acid, etc. In addition, there are about150oral azithromycin products with different strengthes, dosage forms and brand names. Firstly, universal model of azithromycin injection powders was constructed by the usually used method. That is measuring all the samples marketed, cluster analyzing the spectra and selecting training set sample spectra to construct the model.Universal models would be updated continuously by using newly measured spectra because all the marketed samples could hardly be collected once. In China, there are many azithromycin injection powders with different acid radical such as citric acid, phosphoric acid, lactic acid, hydrochloric acid, glutamic acid, lactobionic acid, maleic acid, aspartic acid, etc. In this study, all the azithromycin injection powders were grouped by their acid radical. The quantitative model was set up by using one group of samples (such as azithromycin citrate injection powders). Then representative spectra of others groups of samples were selected and added into the model to update and finished construction. The validation results of the model constructed by the updating method and the traditional method are similar. Each group of samples was regarded as homology sample. A set of samples is considered homologous if the samples contain the same API with same acid or basic radical, similar excipients and production process, etc. The NIR spectra of the samples in one homology sample set are therefore highly similar.To test the model construction method mentioned above, the azithromycin tablets were divided into several groups of homology sample. First the quantitative model was set up using one set of homology sample. And then the model was being updated using other groups of homology sample until the universal model was constructed. This time the validation results of the models constructed by two methods were similar too, which proved that construction of a universal quantitative model by the updating method was feasible.The API content of granules is much lower than that of powder injections, tablets, and capsules. In addition, the universal quantitative model of azithromycin granules was constructed for the first time. And the proposed method of determination of azithromycin in granules using the NIR model was evaluated according to ICH guidelines for such characteristics as specificity, linearity, accuracy, and precision.Part2:Crystalline water of ranolazine hydrochloride and the influence on its crystallization.Ranolazine (C24H33N3O4·2HCl·1/2H2O) with molecular weight509.46, contains half molecule crystalline water in its formula. Water content was1.5～5.0%in the specification. The lower limit of water content was85%of the theoretical value (9/509×85%=1.5) However, the water content of ranolazine was quite unstable during producing process. Usually it could decrease to about1.0%during storage, especially in low humidity area. In this research, the crystalline water in the ranolazine molecule was found to be unstable and easily released from the lattice. Nevertheless, the releasing of the crystalline water nearly has no impact on the crystal lattice. On the other hand, high water content could lead to low degree of crystallinity. As a result, the limit of water content needs to be revised.