Preformulation study of etoposide: identification of physicochemical characteristics responsible for the low and erratic oral bioavailability of etoposide.
Preformulation studies of etoposide, including pH-solubility profile, partition coefficient, pH-stability profile, and in vitro dissolution kinetics, were conducted to identify the responsible factor(s) for the low and erratic oral bioavailability of etoposide. A stability-indicating high-performance liquid chromatographic (HPLC) assay was used for drug monitoring. The equilibrium aqueous solubility of etoposide at 37 degrees C was low, 148.5-167.25 micrograms/ml, and did not vary over the pH range of 2 to 6. The pH-stability profile indicated rapid degradation of etoposide at pH 1.3 and 10, with degradation half-lives of 2.88 and 3.83 hr, respectively, at 25 degrees C. The half-life at pH 7.30 was 27.72 days. Maximum stability at 25 degrees C was reached at pH 5 to 6.15, with half-lives of 63 and 49.5 days, respectively. The intrinsic dissolution rate, determined on a Wood's apparatus, was slow, 0.0094 mg/min/cm2, while the etoposide partition coefficient between n-octanol and water was 9.94. Therefore, etoposide absorption appears to be dissolution rate limited rather than permeation rate limited. The low equilibrium aqueous solubility, slow intrinsic dissolution rate, and chemical instability at pH 1.3 could account for the low oral bioavailability.
Shah
J C
JC
Department of Pharmaceutics, College of Pharmacy, University of Houston, Texas 77030.
Chen
J R
JR
Chow
D
D
D001682:Biological Availability; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002851:Chromatography, High Pressure Liquid; D005047:Etoposide / Q000032:analysis / Q000493:pharmacokinetics* / Q000494:pharmacology; D006207:Half-Life; D006863:Hydrogen-Ion Concentration; D012995:Solubility
D005047:Etoposide