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AAPS PharmSciTech. 2003 December; 4(4): 539–548.
Published online 2003 November 7. doi:  10.1208/pt040468
PMCID: PMC2750661

Solid-vapor interactions: Influence of environmental conditions on the dehydration of carbamazepine dihydrate


The goal of this research was a phenomenological study of the effect of environmental factors on the dehydration behavior of carbamazepine dihydrate. Dehydration experiments were performed in an automated vapor sorption apparatus under a variety of conditions, and weight loss was monitored as a function of time. In addition to lattice water, carbamazepine dihydrate contained a significant amount of physically bound water. Based on the kinetics of water loss, it was possible to differentiate between the removal of physically bound water and the lattice water. The activation energy for the 2 processes was 44 and 88 kJ/mol, respectively. As expected, the dehydration rate of carbamazepine dihydrate decreased with an increase in water vapor pressure. While dehydration at 0% relative humidity (RH) resulted in an amorphous anhydrate, the crystallinity of the anhydrate increased as a function of the RH of dehydration. A method was developed for in situ crystallinity determination of the anhydrate formed. Dehydration in the presence of the ethanol vapor was a 2-step process, and the fraction dehydrated at each step was a function of the ethanol vapor pressure. We hypothesize the formation of an intermediate lower hydrate phase with unknown water stoichiometry. An increase in the ethanol vapor pressure first led to a decrease in the dehydration rate followed by an increase. In summary, the dehydration behavior of carbamazepine dihydrate was evaluated at different vapor pressures of water and ethanol. Using the water sorption apparatus, it was possible to (1) differentiate between the removal of physically bound and lattice water, and (2) develop a method for quantifying, in situ, the crystallinity of the product (anhydrate) phase.

Keywords: carbamazepine, dehydration, water vapor, ethanol vapor

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Selected References

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1. Office of the Federal Register . Q6A-Specifications. Test procedures and acceptance criteria for new drug sustances and drug products: Chemical substances. Washington, DC: Office of the Federal Register; 1997. pp. 62889–62910. [PubMed]
2. Han J, Suryanarayanan R. Influence of environmental conditions on the kinetics and mechanism of dehydration of carbamazepine dihydrate. Pharm Dev Technol. 1998;3(4):587–596. doi: 10.3109/10837459809028643. [PubMed] [Cross Ref]
3. Edwards AD, Shekunov BY, Forbes RT, Grossmann JG, York P. Time-resolved x-ray scattering using synchrotron radiation applied to the study of a polymorphic transition in carbamazepine. J. Pharm Sci. 2001;90(8):1106–1114. doi: 10.1002/jps.1064. [PubMed] [Cross Ref]
4. Li Y, Han J, Zhang GGZ, Grant DJW, Suryanarayanan R. In situ dehydration of carbamazepine dihydrate: a novel technique to prepare amorphous anhydrous carbamazepine. Pharm Dev Technol. 2000;5(2):257–266. doi: 10.1081/PDT-100100540. [PubMed] [Cross Ref]
5. McMahon LE, Timmins P, Williams AC, York P. Characterization of dihydrates prepared from carbamazepine polymorphs. J Pharm Sci. 1996;85(10):1064–1069. doi: 10.1021/js960117e. [PubMed] [Cross Ref]
6. Lang M, Kampf JW, Matzger AJ. Form IV of carbamazepine. J Pharm Sci. 2002;91(4):1186–1190. doi: 10.1002/jps.10093. [PubMed] [Cross Ref]
7. Otsuka M, Hasegawa H, Matsuda Y. Effect of polymorphic transformation during the extrusion-granulation process on the pharmaceutical properties of carbamazepine granules. Chem Pharm Bull. 1997;45(5):894–898.
8. Reck G, Dietz G. The order-disorder structure of carbamazepine dihydrate: 5H-dibenz[b,f]azepine-5-carboxamide dihydrate, C15H12N2O·2 H2O. Cryst Res Technol. 1986;21(11):1463–1468. doi: 10.1002/crat.2170211118. [Cross Ref]
9. Nyvlt J. On the kinetics of solid-liquid-solid phase transformation. Cryst Res Technol. 1997;32(5):695–699. doi: 10.1002/crat.2170320513. [Cross Ref]
10. Nordhoff S, Ulrich J. Dehydration of organic and inorganic hydrates by exchange of solvent. Acta Polytechnica Scandinavica, Chemical Technology Series. 1997;244:61–63.
11. Nordhoff S, Ulrich J. Solvent-induced phase transformations of hydrates. J. Therm Anal Calorim. 1999;57(1):181–192. doi: 10.1023/A:1010159222264. [Cross Ref]
12. Cardew PT, Davey RJ. The kinetics of solvent-mediated phase transformations. P Roy Soc Lond A Mat. 1985;398(1815):415–428.
13. Pikal MJ, Lang JE, Shah S. Desolvation kinetics of cefamandole sodium methanolate: effect of water vapor. Int J Pharm. 1983;17(2–3):237–262. doi: 10.1016/0378-5173(83)90036-4. [Cross Ref]
14. Han J, Suryanarayanan R. A method for rapid evaluation of the physical stability of pharmaceutical hydrates. Thermochim Acta. 1999;329(2):163–170. doi: 10.1016/S0040-6031(99)00054-4. [Cross Ref]
15. Pattern numbers 43-1990 (carbamazepine dihydrate), 43-1998 (anhydrous α-carbamazepine), 33-1565 (anhydrous β-carbamazepine), and 43-1988 (anhydrous γ-carbamazepine). In:PDF-2. Newtown Square, PA: International Centre for Diffraction Data 1998.
16. Suryanarayanan R. Determination of the relative amounts of anhydrous carbamazepine (C15H12N2O) and carbamazepine dihydrate (C15H12N2O·2 H2O) in a mixture by powder x-ray diffractometry. Pharm Res. 1989;6(12):1017–1024. doi: 10.1023/A:1015970218980. [PubMed] [Cross Ref]
17. Zografi G. States of water associated with solids. Drug Dev Ind Pharm. 1988;14(14):1905–1926. doi: 10.3109/03639048809151997. [Cross Ref]
18. Suryanarayanan R, Mitchell AG. Evaluation of two concepts of crystallinity using calcium gluceptate as a model compound. Int J Pharm. 1985;24(1):1–17. doi: 10.1016/0378-5173(85)90140-1. [Cross Ref]
19. Saleki-Gerhardt A, Ahlneck C, Zografi G. Assessment of disorder in crystalline solids. Int J Pharm. 1994;101(3):237–247. doi: 10.1016/0378-5173(94)90219-4. [Cross Ref]
20. Surana R, Pyne A, Suryanarayanan R. The influence of water sorption on thermal history of amorphous trehalose.AAPS PharmSci. 2002;4(4). Abstract T2318. Available at:
21. Weast RC (Ed.).CRC Handbook of Chemistry and Physics. 50th ed. Cleveland, OH: The Chemical Rubber Co; 1969–1970.

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