The majority of NCEs are weakly basic drugs. Consequently, their solubility is highly pH-dependent, with higher solubility in the acidic stomach and poor solubility in the neutral intestinal environment. The gastric emptying of dissolved drug can lead to the intestinal precipitation of the drug. One option of reducing this process is to formulate the drug together with a precipitation inhibitor (PI). The aim of this study was to investigate the effects of different PIs on the intestinal concentrations of ketoconazole and five orally administered kinase inhibitors (i.e. pazopanib, gefitinib, lapatinib, vemurafenib, and a Merck KGaA research compound, MSC-A) with the aid of a predictive small-scale in vitro transfer model. This screening revealed that HPMCAS and Soluplus® were the most effective PIs. Whereas all other drugs precipitated within several minutes, gefitinib expressed highly variable amorphous precipitation which was confirmed by PXRD. During the transfer model experiments, this intermediate supersaturated state was stabilized using HPMCAS and Soluplus®. The PI screening protocol described herein allows to study the effect of PIs for solubility and potential bioavailability improvement of poorly soluble drugs to support formulation development already in early stages.
Keywords: Biorelevant; Polymers; Precipitation; Precipitation inhibitors; Solid-state; Supersaturation; Transfer model.
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