Polymorphic quantification of dexketoprofen trometamol by differential scanning calorimetry

Abstract

The check of the solid phase in which the active principles crystallize is an activity of primary importance, both in the preformulation studies and in the quality control of pharmaceutical products. Indeed, it is necessary to ensure that only the polymorph of interest is present in the dosage form, as well as in the various stages leading to its preparation. The regulatory agencies underline the importance of limiting the presence, in the pharmaceutical solids, of polymorphic impurities which, having different physico-chemical, technological and pharmaceutical properties, could compromise the efficacy, the stability and the safety of the product. The present work fits into this problem and is configured as a response to the industrial need to identify the presence of an unwanted polymorph in batches of powder of an active ingredient, also in systems in which these determinations show serious problems. In particular, the studies here performed respond to the need to develop a method that allows to detect and quantify the presence of polymorphic impurity in dexketoprofen trometamol samples by the DSC technique. The main critical points of this system are constituted by the fact that the melting enthalpies of the two polymorphs (A and B) are very similar and the difference between the onset temperatures of their melting is just 2 °C. This second point makes it impossible to obtain an adequate resolution of the melting peaks, even when the experimental conditions are appropriately selected. A system characterized by this thermal behavior, in the scientific literature, is considered "impossible". The success of the method developed in this work is to be attributed, on the one side, to the methods adopted in the preparation of the physical mixtures of the two polymorphs, which need to have the composition as homogeneous as possible, and on the other side, to the idea of performing a conditioning of the samples that makes the low-melting temperature polymorph thermally inert. The polymorphic mixtures treated in this way show only the fusion of the high-melting temperature polymorph whose enthalpy decreases linearly with the increase of impurity present in the mixture. The method proposed here allows to detect the polymorphic impurity even when it is present in a very low percentage, equal to 0.3, while it is possible to quantify it reliably for contents higher than 2%.