The effect of crystal size on the bioavailability of benoxaprofen: studies utilizing deuterium labeled drug

A study of the effect of crystal size on the bioavailability of benoxaprofen, 2-[4-chlorophenyl]-alpha-methyl-5-benzoxazoleacetic acid, in man is reported. The technique utilized comparison of either the plasma concentrations or urine levels, resulting from administration of deuterium labeled (2H7) drug in solution coadministered with a test capsule formulation. Drug concentrations were determined by gas chromatography, and the ratio of labeled to unlabeled drug was obtained by gas chromatography mass spectrometry. Measurements following coadministration of labeled and unlabeled drug in solution established the absence of an isotope effect due to the presence of deuterium. The dry formulations consisted of either a 3.17--100 micron fraction (mean = 18.5 microns) or a 32--1000 micron fraction (mean = 610 microns) formulated with starch powder. The results in three subjects indicate an almost complete availability (0.95--0.98) of the small crystals as measured by comparison of either area under the plasma level curves or urine excretion (0.94--0.97) of labeled versus unlabeled drug measured to 168 hours. The larger crystals exhibited a lower availability as shown by plasma levels (0.41--0.46) or urine recovery (0.39--0.43). A higher dose of the large crystal formulation resulted in decreased relative availability with a fourfold dose dropping availability to 0.22 in a single subject.