A drug-excipient compatibility screening model was developed by which potential stability problems due to interactions of drug substances with excipients in solid dosage forms can be predicted. The model involved storing drug-excipient blends with 20% added water in closed glass vials at 50 degrees C and analyzing them after 1 and 3 weeks for chemical and physical stability. The total weight of drug-excipient blend in a vial was usually kept at about 200 mg. The amount of drug substance in a blend was determined on the basis of the expected drug-to-excipient ratio in the final formulation. Potential roles of several key factors, such as the chemical nature of the excipient, drug-to-excipient ratio, moisture, microenvironmental pH of the drug-excipient mixture, temperature, and light, on dosage form stability could be identified by using the model. Certain physical changes, such as polymorphic conversion or change from crystalline to amorphous form, that could occur in drug-excipient mixtures were also studied. Selection of dosage form composition by using this model at the outset of a drug development program would lead to reduction of "surprise" problems during long-term stability testing of drug products.
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.
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