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.


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Figure 4: Differential scanning calorimetry thermograms of (a) lovastatin, (b) hydroxypropyl-β-cyclodextrin, (c) the physical mixture, and complexes prepared by (d) the coevaporation method and (e) the kneading method.
DSC analysis. DSC is a method that confirms the formation of a complex in the solid state. The disappearance of thermal events of guest molecules when they are examined as CD complexes is generally taken as a proof of real inclusion (27, 28). The DSC scans for pure LVS, HPβ-CD, the physical mixture, and complexes prepared by the coevaporation and the kneading methods are presented in Figure 4. The LVS showed a melting endotherm at 173.7 C with enthalpy of fusion (ΔH) 104.282 J/g. In the thermogram of the HPβ-CD, the endothermic peak near 100 C was caused by loss of water from HPβ-CD molecules. In the thermogram of the physical mixture, a sharp endotherm was observed at the same position as that of LVS, thus indicating the presence of untrapped LVS. A characteristic sharp endothermic peak of LVS in the range of 171 C to 176 C was absent in the thermograms of complexes prepared by the coevaporation and the kneading methods, indicating partial amorphization of the drug and trapping of LVS inside the HPβ-CD cavity.


Figure 5: X-ray diffractograms of (a) lovastatin, (b) hydroxypropyl-β-cyclodextrin, (c) the physical mixture, and complexes prepared by (d) the coevaporation method (e) and the kneading method.
PXRD analysis. PXRD can provide useful information about the inclusion complex of CDs and other polymers. Their structure can be classified as cage-type or column-type (29). The PXRD patterns of pure LVS, the physical mixture, and complexes prepared by the coevaporation and the kneading methods are presented in Figure 5. The PXRD patterns of pure LVS showed numerous sharp peaks, which are the characteristic of a crystalline compound. In contrast, PXRD patterns of HPβ-CD lacked crystalline peaks, which is the characteristic of an amorphous compound. Some drug crystallinity peaks were still detectable in the physical mixture shown in Figure 5c. The PXRD pattern consisted mostly of the HPβ-CD character, but some of the LVS characteristics remained. Compared with the PXRD patterns of pure LVS and HPβ-CD, the PXRD patterns of complexes prepared by the coevaporation and the kneading methods (Figures 5d and 5e) were more related to that of amorphous HPβ-CD (Figure 5b). Moreover, no other peaks than those that could be assigned to the pure HPβ-CD and LVS were detected in the complexes, thus indicating the absence of chemical interactions in the solid state between the two entities. These results confirm that LVS is no longer present as a crystalline material and its HPβ-CD solid complexes exhibit amorphous nature.

Wettability and dissolution studies. The solubility of LVS in water was 40 g (0.544)/100 mL. The kneading method, the coevaporation method, and the physical mixture improved the solubility of LVS to 720 g (36.01)/100 mL, 569 g (24.49)/100 mL, and 374 g (11.155)/100 mL, respectively. Thus, upon complexation of LVS with HPβ-CD by kneading, coevaporation, and physical mixing, the solubility of LVS improved 18-fold, 14.23-fold, and 9.35-fold, respectively.


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