Towards More Accurate Solubility Measurements With Real Time Monitoring: A Carvedilol Case Study

The aim of this study was to draw attention to the challenges of solubility measurement and to present new techniques and detection methods that provide more accurate results. We investigated the effect of crystal structure, pH and buffer composition on thermodynamic equilibrium solubility using two polymorphs of carvedilol (Form I and Form II) as model compounds. Measuring the solubility of carvedilol is challenging, as the literature data show extremely high standard deviation. Therefore standardized measurements were performed in the pH range 3-10, in two solutions at 25 degrees C: Britton-Robinson (BR) and BR with added KCl. Solid phase analysis was performed by X-ray powder diffraction and Raman spectroscopy. The measured S-pH data were compared to the theoretical Henderson-Hasselbalch (HH) curve and a perfect fit was found in the pH range 7-10. The salt formation could be observed in the acidic pH range. The counter-ion and solubility of the salt were found to be different in various buffer solutions. In situ fiber optic UV probes were used to monitor the dissolution of carvedilol polymorphs in real-time. The results showed significantly different dissolution kinetics for the polymorphs depending on the pH and the buffer solution. From the dissolution profile, the time required to reach the equilibrium was determined. In most cases, it was more than 24 hours, therefore using the standard protocol (6 hours agitation, 18 hours sedimentation) would have caused significant inaccuracy in results. In extreme cases the measured concentration after 24 hours was found to be 5 or 6 times higher than the real equilibrium solubility.