Development of immediate-release formulation with reliable absorption of rivaroxaban in various meal regimes.

The bioavailability of rivaroxaban at the higher doses (15 and 20 mg) is considerably reduced when the drug is administered on an empty stomach. This can lead to inadequate anticoagulant effect, and therefore, it is recommended to use the higher doses at fed state. However, proper posology may represent a barrier for some patients. Therefore, the aim of this study was to evaluate innovative rivaroxaban-containing formulations designed to eliminate the food effect to ensure reliable absorption and thus to improve patient adherence with the treatment. Three prototypes (Cocrystal, HPMCP and Kollidon) with rivaroxaban were developed and their bioavailability and food effect in comparison to the reference product was tested in open label, randomized, single oral dose, crossover studies, where test products were administered under fasting and fed conditions and the reference product was administered under fed conditions. Comparable bioavailability for all tested prototypes both under fed and fasting conditions was demonstrated as the 90% confidence intervals of the geometric mean ratios for area under the concentration-time curve remained within the standard acceptance range of 80.00%-125.00%. An innovative immediate release form of rivaroxaban with no food effect on drug bioavailability has been developed, which may represent an important step toward increasing adherence, improving treatment outcome and reducing health care costs.

Influence of particle size and manufacturing conditions on the recrystallization of amorphous Enzalutamide.

Non-isothermal differential scanning calorimetry was used to study the influences of particle size and mechanically induced defects on the recrystallization kinetics of amorphous Enzalutamide. Enzalutamide prepared by hot melt extrusion and spray-drying was used as a model material. The recrystallization rate was primarily accelerated by the presence of the processing-damaged surface of the powder particles. The actual surface/volume ratio associated with decreasing particle size fulfilled only a secondary role. Interestingly, higher quench rate during the extrusion led to a formation of thermally less stable material (with the worse stability being manifested via lower activation energy of crystal growth in the amorphous matrix). This can be the consequence of the formation of looser structure more prone to rearrangements. The recrystallization kinetics of the prepared Enzalutamide amorphous materials was described by the two-parameter autocatalytic kinetic model. The modified single-curve multivariate kinetic analysis (optimized for the data obtained at heating rate 0.5 °C•min-1) was used to calculate the extrapolated kinetic predictions of long-term isothermal crystal growth. The predictions were made for the temperatures from the range of drug shelf-life and processing for each particle size fraction. By the combination of the mass-weighted predictions for the individual powder fractions it was possible to obtain a very reasonable (temperature-extrapolated) prediction of the crystallization rate for the as-prepared unsieved powdered amorphous Enzalutamide.

Synthesis of latanoprost diastereoisomers.

A new synthesis of latanoprost diastereoisomers is described which utilizes a highly stereoselective Michael addition of higher-order cuprate to a chiral cyclopentenone derived from G-lactone in the crucial skeleton-forming step.