Equilibrium solubility measurements of two carvedilol polymorphs with saturation shake-flask method and with real-time monitoring

 The study of polymorphism is important in drug research and development, since the different physico-chemical properties of the polymorphs may affect the stability, solubility, dissolution, and therefore the bioavailability of the substance.

In our work we investigated the pH-dependent equilibrium solubility of two carvedilol polymorphs according to a standard protocol, in the pH range of 3-11, using saturation shake-flask method and µDISS device.

Measurements were performed using two solutions: Britton-Robinson (B-R) with standard ionic strength, and B-R buffer where the ionic strength was modified with 0.15 M KCl. Solubility results were compared to the values predicted by the Henderson-Hasselbalch equation.

In two different buffers (pH 6 and 6.5), in-situ UV probes were used to monitor the dissolution in real-time, so it was possible to obtain precise information on the time needed to achieve the equilibrium, and the rate of supersaturation. At the end of the solubility measurements, the solid phase analysis of the samples was performed by X-ray powder diffraction and Raman spectroscopy. Twofold difference was found between the solubility of the two forms. It was proved that the crystalline structure of the two polymorphs does not change during the measurement, and salt formation could be observed in the acidic pH range (pH ≤ 6.5). The counterion and solubility of the salt were found different in various buffer solutions.

Author(s): Dora Csicsak1, Eniko Jaksa-Borbas 2, Gergely Volgyi1 and Krisztina Takacs-Novak1

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