Search tips
Search criteria 


Logo of aapspharmspringer.comThis journalToc AlertsSubmit OnlineOpen Choice
AAPS PharmSciTech. 2004 March; 5(1): 101.
Published online 2009 November 27. doi:  10.1208/pt050114
PMCID: PMC2784847

Influence of moisture on the crystal forms of niclosamide obtained from acetone and ethyl acetate


The purpose of this study was to elucidate the formation of crystal hydrates of niclosamide and to delineate the effect of relative humidity on the crystal forms obtained from acetone and ethyl acetate. Recrystallization of niclosamide was performed in the presence and absence of moisture. Two hydrates and their corresponding anhydrates were isolated. The hydrates obtained by the process of recrystallization from acetone (Form I) and that obtained from ethyl acetate (Form II) were classified based on differences in their dehydration profile, crystal structure, shape, and morphology. Crystals obtained in the absence of moisture were unstable, and when exposed to the laboratory atmosphere transformed to their corresponding hydrates. Differential scanning calorimetry thermograms indicate that Form I changes to an anhydrate at temperatures below 100°C, while Form II dehydrates in a stepwise manner above, 140°C. This finding was further confirmed by thermogravimetric analysis. Dehydration of Form II was accompanied by a loss of structural integrity, demonstrating that water molecules play an important role in maintaining its crystal structure. Form I, Form II, and the anhydrate of Form II showed no significant moisture sorption over the entire range of relative humidity. Although the anhydrate of Form I did not show any moisture uptake at low humidity, it converted to the monohydrate at elevated relative humidity (>95%). All forms could be interconverted depending on the solvent and humidity conditions.

KeyWords: niclosamide, isomorphic desolvates, polymorphism, hydrate formation, relative humidity, channeltype solvates

Full Text

The Full Text of this article is available as a PDF (697K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
1. Haleblian J, McCrone W. Pharmaceutical applications of polymorphism. J Pharm Sci. 1969;58:911–929. doi: 10.1002/jps.2600580802. [PubMed] [Cross Ref]
2. Berger A, Ramberger R. On the polymorphism of phamaceuticals and other molecular crystals I. Mikrochim Acta. 1979;11:259–271. doi: 10.1007/BF01197379. [Cross Ref]
3. Berger A, Ramberger R. On the polymorphism of pharmaceuticals and other molecular crystals II. Mikrochim Acta. 1979;11:273–316. doi: 10.1007/BF01197380. [Cross Ref]
4. Stahl HP. The problems of drug interactions with excipients. In: Braimar DD, editor. Towards Better Safety of Drugs and Pharmaceutical Products. Amsterdam, The Netherlands: Elsevier; 1980. pp. 265–280.
5. Cambridge Structural Database [computer program]. Version 2.3.7. Cambridge, UK; 1996.
6. Bym SR, Pfeiffer RR, Stowell JG. Solid State Chemistry of Drugs. West Lafayette: SSCI Inc; 1999.
7. Pfeiffer RR, Yang KS, Tucker MA. Crystal pseudopolymorphism of cephaloglycin and cephalexin. J Pharm Sci. 1970;59:1809–1812. doi: 10.1002/jps.2600591222. [PubMed] [Cross Ref]
8. Stephenson GA, Groleau EG, Kleemann RL, Xu W, Rigsbee DR. Formation of isomorphic desolvates: creating a molecular vacuum. J Pharm Sci. 1998;87:536–542. doi: 10.1021/js970449z. [PubMed] [Cross Ref]
9. O'Neil MJ, Smith A, Heckelman PE. Merck Index. 13th ed. Whitehouse Station, NJ: Merck & Co; 2001.
10. van Tonder EC, de Villiers MM, Lotter AP, Caira MR, Liebenberg W. Correlation between hydrate formation and the physical instability of suspensions prepared with different niclosamide crystal forms. Pharm Ind. 1998;60:722–725.
11. Caira MR, van Tonder EC, de Villiers MM, Lotter AP. Diverse modes of solvent inclusion in crystalline pseudopolymorphs of the anthelmintic drug niclosamide. J Inclusion Phenom Mol Recognit Chem. 1983;31:1–16. doi: 10.1023/A:1007931314609. [Cross Ref]
12. Kuhnert-Brandstatter M. Thermomicroscopy in the Analysis of Pharmaceuticals. New York, NY: Pergamon Press; 1971.
13. Byrn SR, Lin CT. The effect of crystal packing and defects on desolvation of hydrated crystals of caffeine and L-(-)-1,4-cyclohexadiene-1-alanine [letter] J Am Chem Soc. 1976;98:4004–4005. doi: 10.1021/ja00429a048. [PubMed] [Cross Ref]
14. Lin CT, Bym SR. Desolvation of solvated organic crystals. Mol Cryst Liq Cryst. 1979;50:99–104. doi: 10.1080/15421407908084418. [Cross Ref]
15. van Tonder EC. Preparation and Characterization of Niclosamide Crystal Modifications. Potchefstroom, South Africa: Potchefstroom University for CHE; 2004.
16. Morris KR. Structural aspects of hydrates and solvates. In: Brittain HG, editor. Polymorphism in Pharmaceutical Solids. New York, NY: Marcel Dekker; 1999. pp. 125–181.
17. Pauling L. The Nature of the Chemical Bond. New York, NY: Comell University Press; 1960.
18. Scheiner S. Hydrogen Bonding: A Theoretical Perspective. New York, NY: Oxford University Press; 1997.
19. United States Pharmacopeial Convention X-Ray Diffraction, General Test <941>.United States Pharmacopeia, 25th ed. Rockville, MD: United States Pharmacopeial Convention, 2002:2088-2089.
20. Kitaigorodskii AI. Molecular Crystals and Molecules. New York, NY: Academic Press; 1973.
21. Gavezzotti A, Filippini G. Polymorphic forms of organic crystals at room conditions: thermodynamics and structural implications. J Am Chem Soc. 1995;117:12299–12305. doi: 10.1021/ja00154a032. [Cross Ref]
22. Gavezzotti A. Calculations on packing energies, packing efficiencies and rotational freedom for molecular crystals. Nouv J Chim. 1982;6:444–450.
23. Bauer JF, Dziki W, Quick JE. Role of isomorphic desolvates in dissolution failures of an erythromycin tablet formulation. J Pharm Sci. 1999;88:1222–12227. doi: 10.1021/js9900102. [PubMed] [Cross Ref]

Articles from AAPS PharmSciTech are provided here courtesy of American Association of Pharmaceutical Scientists