Development of an abiraterone acetate formulation with improved oral bioavailability guided by absorption modeling based on in vitro dissolution and permeability measurements.

Particle size reduction of drug crystals in the presence of surfactants (often called "top-down" production methods) is a standard approach used in the pharmaceutical industry to improve bioavailability of poorly soluble drugs. Based on the mathematical model used to predict the fraction dose absorbed this formulation approach is successful when dissolution rate is the main rate limiting factor of oral absorption. In case compound solubility is also a major factor this approach might not result in an adequate improvement in bioavailability. Abiraterone acetate is poorly water soluble which is believed to be responsible for its very low bioavailability in the fasted state and its significant positive food effect. In this work, we have successfully used in vitro dissolution, solubility and permeability measurements in biorelevant media to describe the dissolution characteristics of different abiraterone acetate formulations. Mathematical modeling of fraction dose absorbed indicated that reducing the particle size of the drug cannot be expected to result in significant improvement in bioavailability in the fasted state. In the fed state, the same formulation approach can result in a nearly complete absorption of the dose; thereby, further increasing the food effect. Using a "bottom-up" formulation method we improved both the dissolution rate and the apparent solubility of the compound. In beagle dog studies, this resulted in a ≫>10-fold increase in bioavailability in the fasted state when compared to the marketed drug and the elimination of the food effect. Calculated values of fraction dose absorbed were in agreement with the observed relative bioavailability values in beagle dogs.

Effect of ultrasound-assisted crystallization in the diastereomeric salt resolution of tetramisole enantiomers in ternary system with O,O'-dibenzoyl-(2R,3R)-tartaric acid.

The diastereomeric salt resolution of racemic tetramisole was studied using ultrasound irradiation. We examined the effect of power and duration of ultrasonic irradiation on the properties of the crystalline phase formed by ultrasound-assisted crystallization and the result of the whole optical resolution. The results were compared with reference experiment without using ultrasound. The US time (5-30min) caused higher enantiomeric excess. Although yield was lower continuously high resolving efficiency could have been reached through ultrasound. We had the best results with 4.3W ultrasound power when resolvability was even higher than the best of reference. Furthermore, we accomplished a deep and thorough examination of the salts that possibly could form in this resolution. One of the four diastereomeric salts, which have been identified by powder X-ray diffraction, FTIR-spectroscopy, and differential scanning calorimetry (DSC) in the ternary system of the two tetramisole enantiomers and the resolving agent, namely the bis[(S)-tetramisole]-dibenzoyl-(R,R)-tartrate salt have been proven the key compound in the resolution process, and presented the highest melting point of 166°C (dec.) among the four salts. The originally expected diastereomeric bitartrate salts with 1:1M base:acid ratio [(S)-tetramisole-dibenzoyl-(R,R)-hydrogen-tartrate salt and (R)-tetramisole-dibenzoyl-(R,R)-hydrogen-tartrate salt] and their 'racemic' co-crystal [(RS)-tetramisole-dibenzoyl-(R,R)-hydrogen-tartrate salt] showed somewhat lower melting points (152, 145, and 150°C, respectively) and their crystallization was also prevented by application of ultrasound. Based on the melting points and enthalpies of fusion measured by DSC, all the binary and ternary phase diagrams have been newly established and calculated in the system with help of classical modelling equations of liquidus curves.

Selecting Resolving Agents with Respect to Their Eutectic Compositions.

In order to develop a resolution procedure for a given racemic compound, the first and the most important step is finding the most suitable resolving agent. We studied 18 individual resolutions that were carried out with resolving agents having high eutectic composition. We found that very high enantiomeric excess values were obtained in all cases. We assume that the eutectic composition of a given resolving agent is one of the most important properties that should always be considered during the search for the most efficient resolving agent.