Chiajen Lai

Enhancement of oral bioavailability of an HIV-attachment inhibitor by nanosizing and amorphous formulation approaches

BMS-488043 is an HIV-attachment inhibitor that exhibited suboptimal oral bioavailability upon using conventional dosage forms prepared utilizing micronized crystalline drug substance. BMS-488043 is classified as a Biopharmaceutics Classification System (BCS) Class-II compound with a poor aqueous solubility of 0.04mg/mL and an acceptable permeability of 178nm/s in the Caco2 cell-line model. Two strategies were evaluated to potentially enhance the oral bioavailability of BMS-488043. The first strategy targeted particle size reduction through nanosizing the crystalline drug substance. The second strategy aimed at altering the drugs physical form by producing an amorphous drug. Both strategies provided an enhancement in oral bioavailability in dogs as compared to a conventional formulation containing the micronized crystalline drug substance. BMS-488043 oral bioavailability enhancement was approximately 5- and 9-folds for nanosizing and amorphous formulation approaches, respectively. The stability of the amorphous coprecipitated drug prepared at different compositions of BMS-488043/polyvinylpyrrolidone (PVP) was evaluated upon exposure to stressed stability conditions of temperature and humidity. The drastic effect of exposure to humidity on conversion of the amorphous drug to crystalline form was observed. Additionally, the dissolution behavior of coprecipitated drug was evaluated under discriminatory conditions of different pH values to optimize the BMS-488043/PVP composition and produce a stabilized, amorphous BMS-488043/PVP (40/60, w/w) spray-dried intermediate (SDI), which was formulated into an oral dosage form for further development and evaluation.

Introduction of a new scaling approach for particle size reduction in toothed rotor-stator wet mills.

A new scaling approach has been demonstrated for particle size reduction of an active pharmaceutical ingredient (API) in toothed rotor-stator wet mills for a wide range of wet milling conditions and scales. Compound A was crystallized by a cooling crystallization protocol in ethanol and wet milled with 2 types of lab scale mills and 1 pilot plant mill. The particle size was analyzed by FBRM (focused beam reflectance measurement), static light scattering and optical microscopy. The correlation between particle size and the energy input calculations, tailored for the toothed rotor-stator wet mill, had R(2)=0.90 on a logarithmic plot. The new scaling approach forms the basis to correlate API particle size to energy input in toothed rotor-stator wet mills by accounting for wet mill tooth configuration and geometry, rotor tip speed and the probabilistic effects of collision such as shear frequency and slurry residence time.