Physicochemical considerations in the preparation of amorphous ritonavir-poly(ethylene glycol) 8000 solid dispersions

A systematic study of the properties of ritonavir and the influence of poly ethylene glycol 8000 (PEG) on ritonavir revealed that amorphous ritonavir d ispersions in PEG would have an improved dissolution profile and could exhi bit long-term stability. Ritonavir, a human immunodeficiency virus (HM prot ease inhibitor, is highly lipophilic [distribution coefficient (log D)= 4.3 , 25 degreesC, pH 6.8], poorly water soluble (400 mug/mL in 0.1 N HCl, 1 mu g/mL at pH 6.8, 37 degreesC), and exhibits an exceedingly slow dissolution rate (0.03 mg/cm(2)-min in 0.1 N HCl at 37 degreesC). These properties indi cated that a solid dispersion containing ritonavir might be useful for over coming problems associated with slow dissolution. In addition, ritonavir is a good glass former [glasstransition temperature (T-g)/melting point (T-m) > 0.7]. Amorphous ritonavir has an apparent solubility of 4 mg/mL in 0.1 N HCl at 37 degreesC and shows reasonable stability at 25 degreesC. Amorphou s ritonavir, therefore, has properties desirable for preparing a solid disp ersion 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 dispersi ons of amorphous ritonavir in PEG were prepared., and these dispersions had improved in vitro dissolution rate and were physically stable for > 1.5 ye ars at 25 degreesC when protected from moisture. The performance of this so lid dispersion has been attributed to the physicochemical properties of amo rphous ritonavir. (C) 2001 Wiley-Liss, Inc. and the American Pharmaceutical Association.