A physicochemical basis for the extensive intestinal lymphatic transport of a poorly lipid soluble antimalarial, halofantrine hydrochloride, after postprandial administration to dogs

The highly lipid soluble, free-base form of halofantrine (Hf base; ∼ 50 mg/mL in triglyceride lipids), a highly lipophilic (calculated log P ∼ 8.5) antimalarial, has recently been shown to undergo significant intestinal lymphatic transport (54% of administered dose) after postprandial administration to dogs. In contrast, the clinically available hydrochloride salt of Hf (Hf · HCl), was not considered to be a likely substrate for lymphatic transport because its solubility in long-chain triglyceride lipids is low (< 1 mg/mL). This paper reports the lymphatic transport of Hf after postprandial administration of Hf · HCl, which was surprisingly high at 47% of the administered dose, and not significantly different from that of Hf base. It was postulated that partial conversion of solubilized Hf · HCl to the highly lipid soluble Hf base within the intestinal lumen might account for the extensive lymphatic transport. However, as Hf is a tertiary amine with an expected pKa of > 10, at gastrointestinal pH, the fraction of Hf present as the free base form is likely to be extremely low. Physicochemical studies exploring the solubility and pKa of Hf suggest that Hf · HCl was extensively solubilized following fed administration. When solubilized in representative fed state mixed micellar solutions, its apparent pKa was 6.92 and considerably lower than anticipated for a tertiary amine. It appears that the extensive lymphatic transport of Hf observed after postprandial administration of Hf · HCl was likely to be due to the conversion of solubilized Hf · HCl to the free base. Therefore, in addition to indicators such as log P and triglyceride solubility, factors such as drug solubilization in representative fed state intestinal conditions and the possible conversion to the un-ionized form should be considered when predicting the potential lymphatic transport of salts of poorly water soluble acids and bases. © 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91:647–659, 2002