Salts of weakly basic active pharmaceutical ingredients are widely used to improve aqueous solubility and/or dissolution rate. However, these compounds are prone to precipitation due to the lower solubility of the un-ionized species at the higher pH in the intestinal region, and this can result in poor and/or variable absorption. The goal of this study was to investigate the degree of supersaturation achieved following dissolution of different amounts of pazopanib hydrochloride at low pH, followed by rapid pH increase. Using pH solubility profiles, phase boundaries were defined for crystalline and amorphous free base forms. The resultant phase diagram was used to rationalize the observed supersaturation and phase behavior of pazopanib following pH adjustment. In the presence of a crystallization inhibitor, hydroxypropylmethyl cellulose (HPMC), the degree of supersaturation was found to be very high, approximately 600-fold, at pH 6.5. At a dose equivalent to the clinical dose, the maximum free drug concentration observed at pH 6.5 was dictated by the amorphous solubility. Solutions that exceeded the amorphous solubility upon pH increase were found to undergo glass-liquid phase separations (GLPS) with the formation of amorphous colloidal drug-rich particles. Microscopic observations confirmed that HPMC delayed the appearance of pazopanib free base crystals. The phase behavior upon pH change is thus well predicted by the phase diagram, after taking into consideration the initial dose, the extent of supersaturation generated upon pH change, and the presence or absence of a crystallization inhibitor.

Conclusions

In this study, the phase behavior and supersaturation profile was evaluated for pazopanib following dissolution of the HCl salt at low pH with subsequent transfer to a higher pH environment. The maximum potential supersaturation was evaluated by creating a pH-solubility phase diagram showing the crystalline and amorphous phase boundaries as a function of pH. In the presence of a crystallization inhibitor, pazopanib was found to  undergo extensive supersaturation, with the amorphous solubility being approximately 500 times higher than the crystalline solubility. Phase behavior following pH shift experiments with different initial doses of the pazopanib HCl salt could be readily explained by considering the pH-solubility phase diagram as well as the kinetics of crystallization. Such in vitro evaluations are likely to be helpful in optimization of formulations of poorly soluble weakly basic compounds, as well as understanding potential origins of absorption variability.

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From: Mol Pharm. 2018 Mar 9. doi: 10.1021/acs.molpharmaceut.8b00081