Dissolution Performance of High Drug Loading Celecoxib Amorphous Solid Dispersions Formulated with Polymer Combinations
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The aims of this study were twofold. First, to evaluate the effectiveness of selected polymers in inhibiting solution crystallization of celecoxib. Second, to compare the release rate and crystallization tendency of celecoxib amorphous solid dispersions (ASDs) formulated with a single polymer, or binary polymer combinations.
The effectiveness of polymers, polyvinylpyrrolidone (PVP), hydroxypropylmethyl cellulose (HPMC) or HPMC acetate succinate (HPMCAS), in maintaining supersaturation of celecoxib solutions was evaluated by performing nucleation induction time measurements. Crystallization kinetics of ASD suspensions were monitored using Raman spectroscopy. Dissolution experiments were carried out under non-sink conditions.
Pure amorphous celecoxib crystallized rapidly through both matrix and solution pathways. Matrix and solution crystallization was inhibited when celecoxib was molecularly mixed with a polymer, resulting in release of the drug to form supersaturated solutions. Cellulosic polymers were more effective than PVP in maintaining supersaturation. Combining a cellulosic polymer and PVP enabled improved drug release and stability to crystallization.
Inclusion of an effective solution crystallization inhibitor as a minor component in ternary dispersions resulted in prolonged supersaturation following dissolution. This study shows the feasibility of formulation strategies for ASDs where a major polymer component is used to achieve one key property e.g. release, while a minor polymer component is added to prevent crystallization.
KEY WORDSamorphous solid dispersion crystallization dissolution supersaturation
Amorphous solid dispersion
High performance liquid chromatography
Hydroxypropylmethyl cellulose acetate succinate
Sodium phosphate buffer
ACKNOWLEDGMENTS AND DISCLOSURES
The Dane O. Kildsig Center for Pharmaceutical Processing Research is acknowledged for providing funding for this project.
- 3.Baird JA, Van Eerdenbrugh B, Taylor LS. A classification system to assess the crystallization tendency of organic molecules from undercooled melts. J Pharm Sci. 2010;99(9):3787–806.Google Scholar
- 8.Alonzo DE, Zhang GGZ, Zhou DL, Gao Y, Taylor LS. Understanding the behavior of amorphous pharmaceutical systems during dissolution. Pharm Res. 2010;27(4):608–18.Google Scholar
- 17.Rumondor ACF, Stanford LA, Taylor LS. Effects of polymer type and storage relative humidity on the kinetics of felodipine crystallization from amorphous solid dispersions. Pharm Res. 2009;26(12):2599–606.Google Scholar
- 20.Janssens S, De Armas HN, Roberts CJ, Van Den Mooter G. Characterization of ternary solid dispersions of itraconazole, PEG 6000, and HPMC 2910 E5. J Pharm Sci. 2008;97(6):2110–20.Google Scholar
- 23.Mullin JW. Crystallization: Butterworth-Heinemann; 2001.Google Scholar
- 24.Myerson A. Handbook of industrial crystallization: Butterworth-Heinemann; 2002.Google Scholar