Hemant N. Joshi

Differentiation of 3-Hydroxy-3-methylglutaryl-coenzyme A Reductase Inhibitors by Their Relative Lipophilicity

Certain pharmacological and clinical effects of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, commonly known as statins, can be differentiated on the basis of their lipophilicity. Unlike lipophilic statins, a hydrophilic statin has been reported to be selective for the liver due to lower uptake and lower inhibition of cholesterol synthesis in non-hepatic cells. We compared the lipophilicity of three newer statins, fluvastatin, atorvastatin and cerivastatin, with those of pravastatin, lovastatin and simvastatin, by determining their apparent octanol-water partition coefficients at pH 2, 5, 7 and 7-4. Under physiological pH conditions of 7-7.4, the relative lipophilicity of various statins currently in clinical use was: simvastatin ≅ cerivastatin > lovastatin ≅ fluvastatin ≅ atorvastatin >> pravastatin, where pravastatin is 70- to 300-times more hydrophilic than the other statins.

Study of Phase Behavior of Poly(ethylene glycol)–Polysorbate 80 and Poly(ethylene glycol)–Polysorbate 80–Water Mixtures

Mixtures of poly(ethylene glycols) (PEGs) with polysorbate 80 are often used to dissolve poorly water-soluble drugs in dosage forms, where polysorbate 80 helps either in enhancing dispersion or in inhibiting precipitation of drugs once the solution is mixed with water. Binary phase diagrams of polysorbate 80 with several low molecular weight PEGs and a ternary phase diagram of polysorbate 80 with PEG 400 and water are presented. Two phases were observed in the binary mixtures when the concentration of PEG 200, PEG 300, PEG 400, or PEG 600 was >55%(w/w). The miscibility of the binary mixtures increases with an increase in temperature; the upper consolute temperatures of PEG 200-polysorbate 80, PEG 300-polysorbate 80, PEG 400-polysorbate 80, and PEG 600-polysorbate 80 mixtures were 100, 85, 75, and 40 degrees C, respectively. The upper consolute temperature of PEG 1000-polysorbate 80 could not be determined because the melting temperature of the mixtures is approximately 40 degrees C and the consolute temperature appeared to be less than this temperature. The decrease in upper consolute temperature with an increase in PEG molecular weight indicated a greater miscibility of the two components. In the ternary system, phase separation of polysorbate 80 was observed when the concentration of PEG 400 was >50-60 % (w/w), possibly because of the high exclusion volume of PEG 400.