Abstract

STUDIES ON ENHANCEMENT OF SOLUBILITY AND DISSOLUTION RATE OF RITONAVIR EMPLOYING ?-CYCLODEXTRIN, SOLUPLUS AND PVPK30

K.Ravi Shankar, K. P. R. Chowdary* and A. Sambasiva Rao

ABSTRACT

Ritonavir, a widely prescribed anti retroviral drug belongs to class IΙ under BCS and exhibit low and variable oral bioavailability due to its poor aqueous solubility. Its oral absorption is dissolution rate limited and it requires enhancement in the solubility and dissolution rate for increasing its oral bioavailability. The objective of the study is to enhance the solubility and dissolution rate of ritonavir by cyclodextrin complexation along with Soluplus and PVP K30 and to evaluate the individual main effects and combined (or interaction) effects of β cyclodextrin (βCD), surfactant (Soluplus) and PVP K30 on the solubility and dissolution rate of ritonavir in a series of 23 factorial experiments. The effects of βCD, Soluplus and PVP K30 alone on the solubility of ritonavir were evaluated by phase solubility studies. The solubility of ritonavir in eight selected fluids containing βCD, Soluplus and PVP K30 as per 23 factorial study was determined. Solid inclusion complexes of ritonavir-βCD were prepared with and without Soluplus and PVP K30 by kneading method as per 23-factorial design and were evaluated. The aqueous solubility of ritonavir was increased linearly as a function of the concentration of βCD as well as Soluplus and PVP K30.The phase solubility diagram of ritonavir –β CD complexes is of type AL. Increase in solubility of ritonavir was due to the formation of a 1:1 M complex in solution with βCD with a stability constant (Kc) value of 325.97 M -1.The individual and combined effects of βCD, Soluplus and PVP K30 in enhancing the solubility and dissolution rate of ritonavir were highly significant (P < 0.01). βCD alone gave a 2.24 fold increase in the solubility of ritonavir. Combination of βCD with Soluplus or PVP K30 resulted in a much higher enhancement in the solubility of ritonavir, 3.97 fold with βCD- Soluplus and 3.44 fold with βCD- PVP K30. There was no further increase in the solubility of ritonavir when βCD is combined with both Soluplus and PVP K 30.The dissolution of ritonavir was rapid and higher in the case of ritonavir- βCD complex systems when compared to ritonavir pure drug. βCD alone gave a 1.54 fold increase in the dissolution rate of (K1) of ritonavir. When βCD is combined with Soluplus or PVP K30 the dissolution rate (K1) was significantly enhanced to 7.67 fold and 5.67 fold with β CD –soluplus and β CD – PVP complexes. There was no further increase in the dissolution rate with ritonavir – β CD - Soluplus - PVP K 30 quaternary complexes. Hence complexation of ritonavir with β CD – Soluplus and β CD – PVP K 30 is recommended to enhance the solubility and dissolution rate of ritonavir, a BCS Class II drug.

Keywords: Ritonavir, ? Cyclodextrin, Soluplus, PVP K30, Solubility, Dissolution rate, Factorial Study.