Ritonavir-PEG 8000 amorphous solid dispersions: in vitro and in vivo evaluations.

Ritonavir is a large, lipophilic molecule that is practically insoluble in aqueous media and exhibits an exceedingly slow intrinsic dissolution rate. Although it has favorable lipophilicity, in vitro permeability studies have shown that ritonavir is a substrate of P-glycoprotein. Thus, the oral absorption of ritonavir could be limited by both dissolution and permeability, thereby making it a Class IV compound in the Biopharmaceutics Classification System. Because formulations rarely exert direct influence on local intestinal permeability, the effect of enhanced dissolution rate on oral absorption was explored. More specifically, poly(ethylene glycol) (PEG)-amorphous ritonavir solid dispersions were prepared with different drug loadings, and the in vitro and in vivo performances of the dispersions were evaluated. In vitro dissolution was conducted in 0.1N HCl with a USP Apparatus I. A crossover design was used to evaluate the oral bioavailability of amorphous dispersions relative to crystalline drug in beagle dogs. Intrinsic dissolution measurements of the two solid phases indicated a 10-fold improvement in intrinsic dissolution rate for amorphous ritonavir compared with the crystalline counterpart. In vitro dissolution of ritonavir depended on the solid phase as well as drug loading of the dispersion. In vivo study results indicate that amorphous solid dispersions containing 10-30% drug exhibited significant increases in area under the curve of concentration versus time (AUC) and maximum concentration (C(max)) over crystalline drug. For example, 10% amorphous dispersion exhibited increases of 22- and 13.7-fold in AUC and C(max), respectively. However, both in vitro dissolution and bioavailability decreased with increasing drug load, which led to the construction of a multiple Level C in vitro-in vivo relationship for this Class IV compound. The established relationship between in vitro dissolution and in vivo absorption can help guide formulation development.

Properties of rapidly dissolving eutectic mixtures of poly(ethylene glycol) and fenofibrate: the eutectic microstructure.

Poly(ethylene glycol) or PEG is an ideal inactive component for preparing simple binary eutectic mixtures because of its low entropy of fusion ( approximately 0.0076 J/mol-K), lower melting point (approximately 62 degrees C) compared to most pharmaceuticals, miscibility with drugs at elevated temperatures, and its covalent crystalline lattice. Implication of these physicochemical properties on eutectic crystallization and size reduction of the drug is discussed. Enhancement of the dissolution rate of a poorly soluble compound through the formation of PEG-drug eutectics was investigated using fenofibrate. Solid dispersions of PEG-fenofibrate when characterized, revealed that PEG and fenofibrate form a simple eutectic mixture containing 20-25%(w/w) fenofibrate at the eutectic point. Eutectic crystallization led to the formation of an irregular microstructure in which fenofibrate crystals were found to be less than 10 microm in size. Dissolution rate improvement of fenofibrate correlated with the phase diagram, and the amount of fenofibrate released from the dispersions that contained fenofibrate as a eutectic mixture was at least 10-fold higher compared to untreated fenofibrate. On aging, the dissolution rate of the dispersion containing 15%(w/w) fenofibrate in PEG remained unaltered. The results indicate that PEG-drug eutectic formation is a valuable option for particle size reduction and subsequent dissolution rate improvement.

Effect of physicochemical and formulation variables on the in vivo absorption of ABT-761.

ABT-761 is a 5-lipoxygenase inhibitor developed for the treatment of asthma. The present study was undertaken to evaluate different crystal forms of ABT-761 and their impact on in vitro and in vivo performance in capsule formulations. Two crystal forms of ABT-761, hemihydrate and non-solvate from different sources, were characterized by thermal analysis, x-ray powder diffraction, moisture sorption, and intrinsic dissolution studies. An in vitro test was performed to assess the effect of formulation and drug from different sources on drug release. Crossover design was also used to evaluate oral bioavailability of ABT-761 hemihydrate formulations in beagle dogs. Plasma concentrations of ABT-761 were analyzed using a reverse-phase high-performance liquid chromatography (HPLC) assay. It was found that in vivo oral absorption as well as in vitro dissolution of ABT-761 were influenced by different formulations. Capsule formulations of ABT-761 hemihydrate are bioequivalent to the solution formulation in terms of extent of absorption, butformulation and the method of granulation preparation can have a major impact on the absorption rate. In conclusion, a single crystal form of ABT-761, i.e., hemihydrate, is preferred for subsequent product development. However, exposure of the drug to conditions that may facilitate phase transformation should be avoided.