Oxeglitazar

Oxeglitazar is a new orally administered poorly water soluble active substance used in the treatment of type II diabetes. The objective of this work was to improve its dissolution kinetics using supercritical antisolvent (SAS) and spray-freezing (SF) techniques. Oxeglitazar was formulated with various excipients, including: Poloxamer 188 and 407, polyethylene glycol (PEG) 8000 and polyvinylpyrrolidone (PVP) K17 in a 1:1 weight ratio. In the SAS technology, pharmaceutical ingredients were dissolved in an appropriate solvent, and the feed solution was dispersed through a capillary nozzle in supercritical CO(2) (SC CO(2)). Dichloromethane (DCM), chloroform (CHCl(3)), and a binary co-solvent system of chloroform-ethanol (EtOH/CHCl(3) 50:50, v/v%) were tested. In the SF process, tert-butanol (tBuOH) was used as solvent. The feed solution was injected into liquid nitrogen through a capillary nozzle located above the surface of the boiling nitrogen. Frozen particles were collected and freeze-dried for 30 h. Formulations were compared in terms of particle morphology, particle size, flow properties, crystallinity, polymorphic purity, residual solvent content, precipitation yield, drug content, specific surface area and dissolution kinetics. SAS and SF processed formulations exhibited enhanced dissolution rates. Within 5 min, the amount of dissolved drug varied from 31.6 to 64.3% for SAS and from 77.9 to 96.9% for freeze-dried formulations while only 30.5% was dissolved from raw drug. Apart from oxeglitazar/PVP K17, SAS prepared solid dispersions were characterized by high crystallinity and acicular shape. Freeze-dried formulations consisted of porous spherical particles with high amorphous content (94.2-100%).

The objective of this work was to improve the dissolution rate and aqueous solubility of oxeglitazar. Solid dispersions of oxeglitazar in PVP K17 (polyvinilpyrrolidone) and poloxamer 407 (polyoxyethylene-polyoxypropylene block copolymer) were prepared by supercritical antisolvent (SAS) and coevaporation (CoE) methods. Drug-carrier formulations were characterized by powder X-ray diffraction, Fourier transform infrared spectroscopy, scanning electron microscopy, gas chromatography, UV/VIS spectroscopy and in vitro dissolution tests. The highest dissolution rate (nearly 3-fold higher than raw drug) was achieved by preparation of drug/PVP K17 coevaporate. Oxeglitazar/PVP K17 solid dispersions were stabilized by hydrogen bonding but contained higher amount of residual dichloromethane (DCM) than poloxamer 407 formulations regardless of the method of preparation. SAS prepared oxeglitazar/poloxamer 407 dissolved more than two times faster than raw drug. However, unlike PVP K17, poloxamer 407 did not form a single phase amorphous solid solution with oxeglitazar which has been manifested in higher degrees of crystallinity, too. Among the two techniques, evaluated in this work, conventional coevaporation resulted in higher amorphous content but SAS reduced residual solvent content more efficiently.