Introduction
Enalapril (ENA) suffers degradation in the solid state as a consequence of its interaction with excipients, a fact that causes an important stability problem when considering its formulation1.
A strategy used to increase the stability of drugs is the formation of complexes with macromolecules, of which molecular encapsulation with B-cyclodextrin (B-CD) constitutes an alternative for the development of new pharmaceutical dosage forms2.
Previously, we have reported the preparation and partial characterization of the ENA:B-CD complex3. In this work we have employed powder x-ray diffraction, scanning electron microscopy (SEM) and solid state nuclear magnetic resonance in order to complete the characterization of the complex in solid state. Also we evaluated the chemical stability of the complex in the presence of excipients.
Results and Discussion
SEM studies:
SEM studies reveal change in the morphology of particles and homogeneity of the product obtained by complexation. The drastic change of the particle shape and aspect in ENA:B-CD complex, was indicative of the presence of a new solid phase.
Powder x-ray Diffraction Studies:
The X-ray diffraction pattern of ENA and B-CD revealed several high intensity reflections, which are indicative of their crystalline character. Comparing the diffraction patterns of pure components with those of physical mixture (PM), we observed the superposition of the pure components. Furthermore, for ENA:B-CD complex prepared by liophilization the obtained patterns were diffused, indicating the amorphous state reached by the lyophilization technique.
Solid State Nuclear Magnetic Resonance Studies:
The spectrum of B-CD in the uncomplexed state shows multiple resolved resonances between 50-110 ppm, and in the case of ENA the resonance appears between 10-70 and 120-180 ppm. The characteristic resonances of ENA and B-CD were clearly distinguishable in the PM. The changes observed in the spectrum for the complex may be attributed to its amorphous state.
Stability studies
The stability of the free drug and complexes with B-CD was studied by thermogravimetric analysis (TA) and high pressure liquid chromatography (HPLC), in presence and absence of excipients (magnesium stearate (MS) and microcrystalline cellulose (MC)).
Because TA studies demonstrated only incompatibility with MS, the studies at 40 ºC and 75% RH for 6 months were carried out using this excipient.
This study showed a recovery rate of 82.1± 0.5 for the pure drug and 95 ± 1 for drug complexed with B-CD. The results demonstrated that complexation of ENA with B-CD stabilizes the drug in solid state.
Conclusion
The complexation with B-CD was shown to be a good strategy to enhance the stability of ENA, suggesting that the formulation of this drug with B-CD could overcome its stability problems.
Acknowledgements
The authors thanks the Agencia Nacional de Promoción Científica y Tecnológica (FONCYT), the Secretaría de Ciencia y Técnica de la Universidad Nacional de Córdoba (SECyT), and the Consejo Nacional de Investigaciones Científicas y Tecnológicas de la Nación (CONICET) for financial support.
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[1] Al-Omari M.M.; Abdelah M.K.; Badwan A.A.; Jaber A.M.Y. J. Pharm.Biomed. Anal. 2001, 25, 893-902.
2 Loftsson T.; Brewster M.E. J. Pharm. Sci. 1996, 85, 1017-1025.
3 Zoppi, A., Quevedo, M.A., Longhi, M.R. Bioorg. Med. Chem. 2008, 16 (18), 8403-8412.