Development of a general strategy for the quantification of pseudopolymorphs: analysis of cefadroxil monohydrate in commercial products

Abstract

Purpose: The presence of different polymorphic or pseudo-polymorphic forms in active pharmaceutical ingredients may affect the performance of the formulated products. Pseudo-polymorphs, especially hydrates, present a differential dissolution rate. In such a scenario, pseudo-polymorphism should be strictly controlled due to its impact on the bio-availability of formulates products. Methods: In order to determine solid forms of cefadroxil present in commercial capsules, anhydrous and monohydrate pure the solid forms were prepared and fully characterized by optical microscopy, vibrational spectroscopy (middle and near infrared), calorimetric techniques (differential scanning calorimetry and thermogravimetry). Nuclear magnetic resonance was used to corroborate structural integrity. Two sets of synthetic samples for calibration (N = 12) and validation (N = 12) were prepared following a binary-mixtures design of monohydrate/anhydrous cefadroxil in the presence of the excipient matrix. NIR spectra were acquired and used as input of partial least squares (PLS) model. Results: Three PLS-factors, mean scattering correction and MIN–MAX normalization demonstrated to be the optimal parameters on full range spectra (750–2500 nm). The method was validated for linearity/range, accuracy and precision by evaluation of validation set recovery. Once method validated, a commercial lot of capsules was analyzed and acceptable recovery results and low deviations were obtained. Conclusion: Near infrared spectroscopy (NIR) emerged as the technique of choice to determine pseudopolymorphic-purity. Cefadroxil monohydrate was determined in a fast and accurate way in presentence of cefadroxil anhydrous and excipients by NIR–PLS methodology. The developed analytical methodology, arise as a general strategy for hydrates determination, making a direct determination of pseudopolymorphic form.