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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 vitropermeability 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 vitroand in vivoperformances of the dispersions were evaluated. In vitrodissolution was conducted in 0.1NHCl 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 vitrodissolution of ritonavir depended on the solid phase as well as drug loading of the dispersion. In vivostudy 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 (Cmax) over crystalline drug. For example, 10% amorphous dispersion exhibited increases of 22- and 13.7-fold in AUC and Cmax, respectively. However, both in vitrodissolution and bioavailability decreased with increasing drug load, which led to the construction of a multiple Level C in vitro–in vivorelationship for this Class IV compound. The established relationship between in vitrodissolution and in vivoabsorption can help guide formulation development. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association

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 (Cmax) over crystalline drug. For example, 10% amorphous dispersion exhibited increases of 22- and 13.7-fold in AUC and Cmax, 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. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93:563–570, 2004

Poly(ethylene glycol) or PEG is an ideal inactive component for preparing simple binary eutectic mixtures because of its low entropy of fusion (~0.0076 J/mol-K), lower melting point (~62°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 μm 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 least10-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. © 2003 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 92:505–515, 2003

A systematic study of the properties of ritonavir and the influence of polyethylene glycol 8000 (PEG) on ritonavir revealed that amorphous ritonavir dispersions in PEG would have an improved dissolution profile and could exhibit long-term stability. Ritonavir, a human immunodeficiency virus (HIV) protease inhibitor, is highly lipophilic [distribution coefficient (log D)= 4.3, 25°C, pH 6.8], poorly water soluble (400 μg/mL in 0.1 N HCl, 1 μg/mL at pH 6.8, 37°C), and exhibits an exceedingly slow dissolution rate (0.03 mg/cm²-min in 0.1 N HCl at 37°C). These properties indicated that a solid dispersion containing ritonavir might be useful for overcoming problems associated with slow dissolution. In addition, ritonavir is a good glass former [glass-transition temperature (Tg)/melting point (Tm) > 0.7]. Amorphous ritonavir has an apparent solubility of 4 mg/mL in 0.1 N HCl at 37°C and shows reasonable stability at 25°C. Amorphous ritonavir, therefore, has properties desirable for preparing a solid dispersion containing this phase. Since PEG, a commonly used polymer, improved the aqueous solubility of crystalline ritonavir, it was expected to have a positive influence on the dissolution rate of ritonavir. Moreover, PEG was found to have negligible plasticizing effect on amorphous ritonavir, which was beneficial for the stability of the dispersion. Finally, solid dispersions of amorphous ritonavir in PEG were prepared, and these dispersions had improved in vitro dissolution rate and were physically stable for > 1.5 years at 25°C when protected from moisture. The performance of this solid dispersion has been attributed to the physicochemical properties of amorphous ritonavir. © 2001 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:1015–1025, 2001