Preformulation Development of a Human Leukocyte Elastase Inhibitor for Oral Dosage

Abstract

WIN 64733 solubility and partition coefficients were determined with a precise and accurate HPLC method. Solubility decreased with increasing pH (140 mg/mL at pH 2.0, 86 mg/mL at pH 3.8, and 48 mg/mL at pH 5.2) but equilibrated within 30 hours. In purified water the maximum concentration was 102 mg/mL with pH 3.6. The maximum solubility in hydroxypropyl-beta-cyclodextrin (HP-β-CD) is only 43 mg/mL. However, unlike the water solution, the cyclodextrin preparation did not precipitate when added to 0.1 N HCl or 0.9% NaCl. The precipitated chloride salt of WIN 64733 is amorphous. Excess compound that was wetted, but not dissolved, formed liquid crystals.

In human gastric fluid (HGF), WIN 64733 did not decompose in the solid or liquid state for 2 hours, or precipitate from solution despite NaCl and HCl in the HGF. WIN 64733 solid is stable to heat (50°C), light (1000 ft-candles), humidity (75% RH), and heat plus humidity for 6 weeks. Solutions of WIN 64733 are unstable, with first-order decomposition rates that are light independent at pH's 2.0 to 6.6. Decomposition was more rapid at higher pH's and increased temperature. This occurred by hydrolysis of the ester linkage forming an N-hydroxymethyl fragment that subsequently decomposed to saccharin and formaldehyde, verified by the Hantzsch reaction.

Since solubility is high in water and HGF, dissolution in the gastric environment would favor absorption of an oral dose.