Abstract
Purpose
To correlate the polymer’s degree of precipitation inhibition of indomethacin in solution to the amorphous stabilization in solid state.
Methods
Precipitation of indomethacin (IMC) in presence of polymers was continuously monitored by a UV spectrophotometer. Precipitates were characterized by PXRD, IR and SEM. Solid dispersions with different polymer to drug ratios were prepared using solvent evaporation. Crystallization of the solid dispersion was monitored using PXRD. Modulated differential scanning calorimetry (MDSC), IR, Raman and solid state NMR were used to explore the possible interactions between IMC and polymers.
Results
PVP K90, HPMC and Eudragit E100 showed precipitation inhibitory effects in solution whereas Eudragit L100, Eudragit S100 and PEG 8000 showed no effect on IMC precipitation. The rank order of precipitation inhibitory effect on IMC was found to be PVP K90 > Eudragit E100 > HPMC. In the solid state, polymers showing precipitation inhibitory effect also exhibited amorphous stabilization of IMC with the same rank order of effectiveness. IR, Raman and solid state NMR studies showed that rank order of crystallization inhibition correlates with strength of molecular interaction between IMC and polymers.
Conclusions
Correlation is observed in the polymers ability to inhibit precipitation in solution and amorphous stabilization in the solid state for IMC and can be explained by the strength of drug polymer interactions.
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References
Brouwers J, Brewster ME, Augustijns P. Supersaturating drug delivery systems: The answer to solubility-limited oral bioavailability? J Pharmaceut Sci. 2009;98(8):2549–72.
Curatolo W, Nightingale JA, Herbig SM. Utility of hydroxypropylmethylcellulose acetate succinate (HPMCAS) for initiation and maintenance of drug supersaturation in the GI milieu. Pharm Res. 2009;26(6):1419–31.
Alonzo DE, Zhang GGZ, Zhou D, Gao Y, Taylor LS. Understanding the Behavior of Amorphous Pharmaceutical Systems during Dissolution. Pharmaceutical Research. 2009:1–11.
Chokshi RJ, Shah NH, Sandhu HK, Malick AW, Zia H. Stabilization of low glass transition temperature indomethacin formulations: Impact of polymer-type and its concentration. J Pharm Sci. 2008;97(6):2286–98.
Tao J, Sun Y, Zhang GGZ, Yu L. Solubility of small-molecule crystals in polymers: D-Mannitol in PVP, indomethacin in PVP/VA, and nifedipine in PVP/VA. Pharm Res. 2009;26(4):855–64.
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.
Guzmán HR, Tawa M, Zhang Z, Ratanabanangkoon P, Shaw P, Gardner CR, et al. Combined use of crystalline salt forms and precipitation inhibitors to improve oral absorption of celecoxib from solid oral formulations. J Pharm Sci. 2007;96(10):2686–702.
Savolainen M, Kogermann K, Heinz A, Aaltonen J, Peltonen L, Strachan C, et al. Better understanding of dissolution behaviour of amorphous drugs by in situ solid-state analysis using Raman spectroscopy. Eur J Pharm Biopharm. 2009;71:71–9.
Janssens S, De Zeure A, Paudel A, Van Humbeeck J, Rombaut P, Van Den Mooter G. Influence of preparation methods on solid state supersaturation of amorphous solid dispersions: A case study with itraconazole and eudragit E100. Pharm Res. 2010;27:775–85.
Matsumoto T, Zografi G. Physical properties of solid molecular dispersions of indomethacin with poly(vinylpyrrolidone) and poly(vinylpyrrolidone-co-vinyl-acetate) in relation to indomethacin crystallization. Pharm Res. 1999;16(11):1722–8.
Wu T, Yu L. Surface crystallization of indomethacin below T g. Pharm Res. 2006;23(10):2350–5.
Andronis V, Yoshioka M, Zografi G. Effects of sorbed water on the crystallization of indomethacin from the amorphous state. J Pharm Sci. 1997;86(3):346–57.
Taylor LS, Zografi G. Spectroscopic characterization of interactions between PVP and indomethacin in amorphous molecular dispersions. Pharm Res. 1997;14(12):1691–8.
Marsac PJ, Shamblin SL, Taylor LS. Theoretical and practical approaches for prediction of drug-polymer miscibility and solubility. Pharm Res. 2006;23(10):2417–26.
Marsac PJ, Li T, Taylor LS. Estimation of drug-polymer miscibility and solubility in amorphous solid dispersions using experimentally determined interaction parameters. Pharm Res. 2009;26(1):139–51.
Ilevbare GA, Liu H, Edgar KJ, Taylor LS. Maintaining supersaturation in aqueous drug solutions: Impact of different polymers on induction times. Cryst Growth Des. 2013;13(2):740–51.
Miller DA, DiNunzio JC, Yang W, McGinity JW, Williams RO. Enhanced in vivo absorption of itraconazole via stabilization of supersaturation following acidic-to-neutral pH transition. Drug Develop Indust Pharm. 2008;34:890–902.
Ilevbare GA, Liu H, Edgar KJ, Taylor LS. Impact of polymers on crystal growth rate of structurally diverse compounds from aqueous solution. Mol Pharm. 2013;10(6):2381–93.
Abudiak O, David J, Andrews GP. An investigation into the dissolution properties of celecoxib melt extrudates: Understanding the role of polymer type and concentration in stabilizing supersaturated drug concentrations. Mol Pharm. 2011;8:1362–71.
Vander Leeden MC, Kashchiev D, van Rosmalen GM. Effect of additives on nucleation rate, crystal growth rate and induction time in precipitation. J Cryst Growth. 1993;130(1–2):221–32.
Mullin JW. Crystallization: Elsevier Butterworth-Heinemann; 2004.
Cabrera N, Vermilyea D. Growth and Perfection of Crystals. B. Doremus, B.W. Roberts, Turnbull D, editors. New York: Wiley; 1958
Davey RJ. The effect of impurity adsorption on the kinetics of crystal growth from solution. J Cryst Growth. 1976;34(1):109–19.
Gu CH, Chatterjee K, Young Jr V, Grant DJW. Stabilization of a metastable polymorph of sulfamerazine by structurally related additives. J Cryst Growth. 2002;235(1–4):471–81.
Kubota N, Mullin JW. A kinetic model for crystal growth from aqueous solution in the presence of impurity. J Cryst Growth. 1995;152(3):203–8.
Andrews GP, Hui Z, Simons T, David J. Characterization of the thermal, spectroscopic and drug disssolution properties of Mefenamic acid and Polyoxyethylene-Polyoxypropylene solid dispersions. J Pharm Sci. 2009;98(12):4545–56.
Andrews GP, Osama A, David J. Physicochemical characterization of hot melt extruded Bicalutamide-polyvinylpyrrolidine solid dispersions. J Pharm Sci. 2010;99(3):1322–35.
Andrews GP, Osama A, Febe K, Peter H, Zhai H, David J. Physicochemical characterization and drug release properties of celecoxib hot-melt extruded glass solutions. J Pharm Pharmacol. 2010;62:1580–90.
Andrews GP, Osama A, David J. Understanding the performance of Melt-Extruded Poly(ethylene oxide)-Bicalutamide solid dispersions: Characaterization of Microstructural properties using thermal, spectroscopic and drug release methods. J Pharm Sci. 2012;101(1):200–13.
Bin L, Kim H, Lindsay W, Lynne T, Kevin E. Stability and solubility enhancement of ellagic acid in cellulose ester solid disperisons. Carbohydr Polym. 2013;92:1443–50.
Bin L, Stephanie K, Kim H, Lindsay W, Lynne T, Kevin E. Solid dispersions of Quercetin in cellulose derivatives matrices influences both solubility and stability. Carbohydr Polym. 2013;92:2033–40.
Bin L, Lindsay W, Lynne T, Kevin E. Stability and solution conentration enhancement of resveratrol by solid dispersion in cellulose derivative matrices. Cellulose. 2013;20:1249–60.
Gong K, Rehman IU, Darr JA. Characterization and drug release investigation of amorphous drug-hydroxypropyl methylcellulose composites made via supercritical carbon dioxide assisted impregnation. J Pharm Biomed Anal. 2008;48:1112–9.
Li N, Taylor LS, Ferruzzi MG, Mauer LJ. Kinetic study of catechin stability: Effects of ph, concentration, and temperature. J Agric Food Chem. 2012;60(51):12531–9.
Acknowledgments and Disclosures
Vertex Pharmaceuticals Incorporated (Cambridge, MA) and Massachusetts College of Pharmacy and Health Sciences (Boston, MA) are acknowledged for the use of instruments and funding in completing this project.
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Chauhan, H., Kuldipkumar, A., Barder, T. et al. Correlation of Inhibitory Effects of Polymers on Indomethacin Precipitation in Solution and Amorphous Solid Crystallization Based on Molecular Interaction. Pharm Res 31, 500–515 (2014). https://doi.org/10.1007/s11095-013-1178-1
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DOI: https://doi.org/10.1007/s11095-013-1178-1