Characterization of the solubility of a poorly soluble hydroxylated metabolite in human urine and its implications for potential renal toxicity.

The solubility, in human urine, of the major hydroxylated metabolite (M1) of an experimental cognition enhancer was characterized through a series of in vitro experiments in an effort to estimate the probability of crystalluria occurring following oral administration of the parent compound. The aim of these experiments was to determine if a safety margin existed between clinically observed urine concentrations and the solubility of M1. The mean urine concentrations of M1 in young and elderly subjects following oral administration of the parent compound at the highest doses tested, were 4865 +/- 2368 ng/mL and 2764 +/- 791 ng/mL, respectively. In vitro solubility experiments with M1 were conducted in drug-free human urine (37 degrees C) from four male and four female healthy subjects under conditions of high and low urine osmolality. Mean concentrations (n = 16) of M1 in human urine to which solid M1 was added, were 3656 +/- 621 ng/mL, 4678 +/- 1169 ng/mL and 5378 +/- 2474 ng/mL after stirring for 24, 48 and 72 h, respectively, indicating that the ex vivo mean solubility of M1 in human urine is no greater then approximately 5 microg/mL. Addition of solid M1 to urine from human subjects dosed with the parent compound resulted in mean urine M1 concentrations 23.5% greater than those observed in vivo. The results from both experiments indicated a significant overlap between urine concentrations of M1 in vivo following the highest oral administration of the parent drug and M1 solubility measured in vitro, suggesting a high potential for in vivo saturation of urine with M1 with subsequent precipitation, crystalluria, and nephrotoxicity. Consequently, the results of these studies have placed restrictions on the dose that could be administered during clinical development of this compound.

A spectroscopic and crystallographic study of polymorphism in an aza-steroid.

The crystal structures of two enantiotropic polymorphs of the aza-steroid finasteride (N-(1-1-di-methylethyl)-3-oxo-4-aza-5 alpha-and rost-1-ene-17 beta-carboxam ide ) have been determined. The solid-state nuclear magnetic resonance spectra, infrared spectra, and physical property data of these two polymorphs are discussed in relation to both their solid-state structures and hydrogen-bonding networks.

Two methods for the measurement of the dissociation pressure of a crystalline hydrate.

Two methods for the measurement of the characteristic dissociation pressures of a system containing water vapor and two different crystalline hydrates of the pharmaceutical compound MK-0677 are described. One method involves the spectroscopic determination of water in gases equilibrated with the solids at controlled temperatures, using an infrared spectrometer. The second method utilized the extrapolated onset temperature of the transition from one hydrate to the other at controlled humidities, as observed by differential scanning calorimetry. The methods give similar results for the system of interest.