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. 2004 Mar 12;5(2):9–16. doi: 10.1208/pt050226

Effects of water vapor absorption on the physical and chemical stability of amorphous sodium indomethacin

Ping Tong 1, George Zografi 2,✉
PMCID: PMC2750461  PMID: 15760084

Abstract

This study reports on the effects that water absorbed into amorphous sodium indomethacin (NaIMC) can have on simultaneous tendencies to crystallize to its trihydrate form and to undergo base-catalyzed hydrolysis because of the plasticizing effects of water on molecular mobility. Measurement of water vapor absorption at 30°C and powder x-ray diffraction patterns as a function of relative humidity (RH) reveal that upon exposure to 21% RH, NaIMC does not crystallize over a 2-month period. Measurements of the glass transition temperature as a function of such exposure reveals a change in Tg from 121°C, dry, to 53°C at 21% RH, such that Tg at 21% RH is ≈13°C above the highest storage temperature of 40°C used in the study. At 56% RH and higher, however, crystallization to the trihydrate occurs rapidly; although over the 2-month period, crystallization was never complete. Assessment of chemical degradation by high-performance liquid chromatography analysis revealed significant instability at 21% RH; whereas at higher RH, the extent of chemical degradation was reduced, reflecting the greater crystallization to the more chemically stable crystalline form. It is concluded that when amorphous forms of salts occur in solid dosage forms, the simultaneous effects of enhanced water vapor sorption on crystallization and chemical degradation must be considered, particularly when assessing solid-state chemical degradation at higher temperatures and RH (eg, 40°C 75% RH).

Keywords: water vapor sorption, amorphous, sodium indomethacin, chemical degradation, crystallization

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References

  • 1.Saleki-Gerhardt A, Ahlneck C, Zografi G. Assessment of disorder in crystalline solids. Int J Pharm. 1994;101:237–247. doi: 10.1016/0378-5173(94)90219-4. [DOI] [Google Scholar]
  • 2.Hancock BC, Zografi G. Characterization and significance of the amorphous state in pharmaceutical systems. J Pharm Sci. 1997;86:1–12. doi: 10.1021/js9601896. [DOI] [PubMed] [Google Scholar]
  • 3.Oberholtzer ER, Brenner GS. Cefoxitin: Solution and solid-state stability studies. J Pharm Sci. 1979;68:863–866. doi: 10.1002/jps.2600680720. [DOI] [PubMed] [Google Scholar]
  • 4.Pikal MJ, Lukes AL, Lang JE, Gaines K. Quantitative crystallinity determinations for β-lactam antibiotics by solution calorimetry: Correlations with stability. J Pharm Sci. 1978;67:767–772. doi: 10.1002/jps.2600670609. [DOI] [PubMed] [Google Scholar]
  • 5.Huttenrauch R. Fundamentals of pharmaceutical technology. Acta Pharm Technol. 1988;34(suppl):1–10. [Google Scholar]
  • 6.Kitamura S, Miyame A, Koda S, Morimoto Y. Effect of grinding on the solid-state stability of cefixime trihydrate. Int J Pharm. 1989;56:125–134. doi: 10.1016/0378-5173(89)90005-7. [DOI] [Google Scholar]
  • 7.Ahlneck C, Zografi G. The molecular basis of moisture effects on the physical and chemical stability of drugs in the solid state. Int J Pharm. 1990;62:87–95. doi: 10.1016/0378-5173(90)90221-O. [DOI] [Google Scholar]
  • 8.Hancock BC, Zografi G. The relationship between the glass transition temperature and the water coutent of amorphous pharmaceutical solids. Pharm Res. 1994;11:471–477. doi: 10.1023/A:1018941810744. [DOI] [PubMed] [Google Scholar]
  • 9.Tong P, Zografi G. Solid-state characterization of amorphous sodium indomethacin relative to its free acid. Pharm Res. 1999;16:1186–1192. doi: 10.1023/A:1018985110956. [DOI] [PubMed] [Google Scholar]
  • 10.Tong P, Zografi G. A study of amorphous molecular dispersions of indomethacin and its sodium salt. J Pharm Sci. 2001;90:1991–2004. doi: 10.1002/jps.1150. [DOI] [PubMed] [Google Scholar]
  • 11.Carstensen JT, Morris T. Chernical stability of indomethacin in solid amorphous and molten states. J Pharm Sci. 1993;82:657–659. doi: 10.1002/jps.2600820622. [DOI] [PubMed] [Google Scholar]
  • 12.Cipiciani A, Ebert C, Linda P, Rubeasa F, Savelli G. Kinetics and mechanism of the basic hydrolysis of indomethacin and related compounds: A reevaluation. J Pharm Sci. 1983;72:1075–1076. doi: 10.1002/jps.2600720928. [DOI] [PubMed] [Google Scholar]
  • 13.Byrn SR, Pfeiffer RR, Stowell JG. Loss of solvent of crystallization. In: Byrn SR, Pfeiffer RR, Stowell JG, editors. Solid-State Chemistry of Drugs. 2nd ed. West Lafayette, IN: SSCI, Inc; 1999. pp. 279–303. [Google Scholar]

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