Solid-State Characterization and Dissolution Properties of Lovastatin Hydroxypropyl-β-Cyclodextrin Inclusion Complex - Pharmaceutical Technology

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Solid-State Characterization and Dissolution Properties of Lovastatin Hydroxypropyl-β-Cyclodextrin Inclusion Complex
The objectives of this study were to prepare and characterize inclusion complexes of lovastatin with hydroxypropyl-β-cyclodextrin (HPβ-CD) and to study the effect of the complexes on the dissolution rate of lovastatin (LVS). The findings suggest that LVS's poor dissolution profile can be overcome by preparing its inclusion complex with HPβ-CD.


Pharmaceutical Technology


In this study, the authors compare the similarities of in vitro dissolution profiles of LVS from complexes, physical mixture, and pure LVS. Dissolution profiles can be compared by calculating a similarity factor (f2) and the mean dissolution time (MDT). The method for calculating the similarity factor was first reported by Moore and Flanner (14). It also has been adopted by the US Food and Drug Administration's Center for Drug Evaluation and Research (15) and by the Human Medicines Evaluation Unit of the European Medicines Agency (16) as a criterion for assessing the similarity of two dissolution profiles (17, 18). A similarity factor of 100% suggests that the test and reference profiles are identical. Values between 50 and 100 indicate that the dissolution profiles are similar, whereas smaller values imply an increase in dissimilarity between release profiles (14). MDT reflects the time for the drug to dissolve and is the first statistical moment for the cumulative dissolution process that provides an accurate drug-release rate (15). A higher MDT value indicates greater drug-retarding ability (16).

The present study was intended to improve the aqueous solubility and dissolution rate of LVS by preparing its complexes with HPβ-CD using various methods such as kneading, coevaporation, and physical mixing. The study further aimed to characterize the interaction between LVS and HPβ-CD.

Materials and methods

Materials. HPβ-CD was a gift sample from Roquette Frères, (Lestrem, France). LVS was received as a gift sample from Lincoln Pharmaceuticals Ltd. (Ahmedabad, India). The samples of sodium lauryl sulfate (SLS) were purchased from S.D. Fine Chemicals, (Vadodara, India). Directly compressible lactose, maize starch, sodium starch glycolate, colloidal silicon dioxide, and magnesium stearate were received as gift samples from Maan Pharmaceuticals Ltd. (Ahmedabad, India). All chemicals and solvents used in this study were of analytical reagent grade. Freshly distilled water was used throughout the work.

Phase-solubility study. Phase-solubility studies were performed according to the method reported by Higuchi and Connors (19). LVS, in amounts that exceeded its solubility, was transferred to screw-capped vials containing 25 mL of an aqueous solution of HPβ-CD (molecular weight = 1500 g/mol) in various molar concentrations (0, 2.0, 4.0, 6.0, 8.0, 10.0, 12.0, and 14.0 mM/L). The contents were stirred with an electromagnetic stirrer (Remi, Mumbai, India) for 36 h at 37 °C ± 0.1 °C and 350 rpm (this duration was previously tested to be sufficient to reach equilibrium). After reaching equilibrium, samples were filtered through a 0.22-μm membrane filter, suitably diluted, and analyzed spectrophotometrically for drug content at the wavelength of 238.2 nm using a spectrophotometer (Shimadzu-1601, ultraviolet-vis spectrophotometer, Shimadzu Corp., Kyoto, Japan). Solubility studies were performed in triplicate (n = 3). The apparent stability constant (Kc), according to the hypothesis of 1:1 stoichiometric ratio of complexes, was calculated from the phase-solubility diagrams using the following equation:











in which the slope is obtained from the initial straight-line portion of the plot of LVS concentration against HPβ-CD concentration, and S0 is the equilibrium solubility of LVS in water.

Preparation of inclusion complexes. Complexes of HPβ-CD and LVS were prepared in the molar ratio of 1:1 (on the basis of the phase solubility study) by various methods such as physical mixture, coevaporation, and kneading.

Physical mixture. A physical mixture of HPβ-CD and LVS was prepared by mixing the powders with a spatula for 15 minutes.


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