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

Abstract

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.

Effect of micronization on the extent of drug absorption from suspensions in humans

“…8 shows the fraction dose absorbed of benoxaprofen at various pH values with two different Is values (Is=0 and 1). It shows estimated data of F at two different particle sizes (9.25 pm and 305 p.m) of benoxaprofen and the reported values of F in the literature (Wolen et aL, 1979). As expected, estimated F increases with increasing pH, pointing out that the physiological pH should be used to estimate F for weak electrolytes.…”

Desafios ao controle da qualidade de medicamentos no Brasil

“…Embora alguns produtos apresentassem resultados de dissolução aceitáveis para 30 minutos, perfis de dissolução inadequados foram obtidos para a maioria deles 19 . O polimorfismo e o tamanho dos cristais do princípio ativo obtido por diferentes produtores, e mesmo entre diferentes lotes do mesmo produtor, podem ser responsabilizados por diferenças na eficácia ou na segurança de medicamentos genéricos ou similares 20,21 . Adicionalmente, a não exigência de que os ingredientes supostamente inativos nas formulações genéricas sejam idênticos aos das formulações de referência ou, ainda, a presença de diferentes impurezas pode afetar significativamente a segurança, a estabilidade e a eficácia do produto 22 .…”

Population-Based Mechanistic Prediction of Oral Drug Absorption

“…The effect of drug particle size on drug absorption has been demonstrated in humans for many drugs including nitrofurantoin (121), benoxaprofen (122,123), digoxin (124), and griseofulvin (125). Within ADAM, Eq.…”