Polymorphism of pharmaceutical substances has a significant impact on their physicochemical properties, durability, bioavailability and consequently on their pharmacological activity. Solid dosage forms may exist in both crystalline and amorphous forms. Amorphous varieties are characterized by higher solubility and dissolution rates, while crystalline forms show greater purity and storage stability. The choice between the crystalline or amorphous form of a drug is extremely important to ensure effective and safe pharmacotherapy. Statins − the most commonly used group of drugs in the treatment of lipid disorders − are an example of drugs that occur in many crystalline and amorphous forms. Statins belong to class II in the biopharmaceutical classification system (BCS), which means that they are poorly soluble, but permeate biological membranes well. The bioavailability of statins shows considerable variation, which is associated with the first-pass effect in the liver and the accumulation of the drug in the hepatocytes. The improvement of bioavailability after oral administration of poorly soluble medicinal substances remains one of the most challenging aspects of the drug development process. A specific polymorphic form is obtained by applying appropriate conditions during the process of its preparation under industrial conditions, including the use of a suitable solvent, a specific temperature or rate of crystallization. The article provides a comprehensive update on the current knowledge of the influence of polymorphic form on statin solubility and bioavailability. Research is still being carried out to obtain new polymorphic varieties of statins that are characterized by better physicochemical and pharmacokinetic parameters.
Background: Atorvastatin (AT) belongs to cholesterol-lowering agents, commonly used in patients with an increased risk of cardiovascular disease. The drug, as well as its hydroxyl metabolites, exhibit pharmacological activity, and their plasma levels may be helpful in the assessment of the therapeutic effectiveness. Objective: Development and validation of a fast and reproducible RP-HPLC method with UV detection for the simultaneous determination of atorvastatin and its active metabolites, para-hydroxy-atorvastatin (p-OH-AT) and ortho-hydroxy-atorvastatin (o-OH-AT) in human plasma. Methods: Optimal conditions of chromatographic separation of the analytes, as well as rosuvastatin, chosen as an internal standard, were studied. The absorbance of the compounds was measured at λ=248 nm. Validation of the method was performed. The usefulness of the method was confirmed for determination of the analytes in plasma of patients treated with the drug. Results: Total peak separation was achieved at LiChrospher 100 RP-18 column with a mobile phase composed of methanol and water (1:1,v:v) and a flow rate of 1.2 ml/min. The method was linear in the ranges of 0.025 - 1.0 μg/ml for AT, o-OH-AT and p-OH-AT. Intra- and inter-assay precision expressed as relative standard deviation was ≤13% for AT, ≤12% for p-OH-AT and ≤11% for o-OH-AT. Intraand inter-day accuracy of the method, expressed as a relative error, was ≤15%. Conclusion: The elaborated HPLC method is specific, repeatable, reproducible, adequately accurate and precise and fulfills the validation requirements for the bioanalytical method. The method was successfully applied for analysis of atorvastatin and its o-hydroxy metabolite in plasma of patients treated with the drug.
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