Search tips
Search criteria 


Logo of aapspharmspringer.comThis journalToc AlertsSubmit OnlineOpen Choice
AAPS PharmSciTech. 2003 March; 4(1): 33–41.
Published online 2003 January 9. doi:  10.1208/pt040105
PMCID: PMC2750301

Effect of surface modification on hydration kinetics of carbamazepine anhydrate using isothermal microcalorimetry


The purpose of this research was to improve the stability of carbamazepine (CBZ) bulk powder under high humidity by surface modification. The surface-modified anhydrates of CBZ were obtained in a specially designed surface modification apparatus at 60°C via the adsorption of n-butanol, and powder x-ray diffraction, Fourier-Transformed Infrared spectra, and differential scanning calorimetry were used to determine the crystalline characteristics of the samples. The hydration process of intact and surface-modified CBZ anhydrate at 97% relative humidity (RH) and 40±1°C was automatically monitored by using isothermal microcalorimetry (IMC). The dissolution test for surface-modified samples (20 mg) was performed in 900 mL of distilled water at 37±0.5°C with stirring by a paddle at 100 rpm as in the Japanese Pharmacopoeia XIII. The heat flow profiles of hydration of intact and surface-modified CBZ anhydrates at 97% RH by using IMC profiles showed a maximum peak at around 10 hours and 45 hours after 0 and 10 hours of induction, respectively. The result indicated that hydration of CBZ anhydrate was completely inhibited at the initial stage by surface modification of n-butanol and thereafter transformed into dihydrate. The hydration of surface-modified samples followed a 2-dimensional phase boundary process with an induction period (IP). The IP of intact and surface-modified samples decreased with increase of the reaction temperature, and the hydration rate constant (k) increased with increase of the temperature. The crystal growth rate constants of nuclei of the intact sample were significantly larger than the surface-modified samples at each temperature. The activation energy (E) of nuclei formation and crystal growth process for hydration of surface-modified CBZ anhydrate were evaluated to be 20.1 and 32.5 kJ/mol, respectively, from Arrhenius plots, but the Es of intact anhydrate were 56.3 and 26.8 kJ/mol, respectively. The dissolution profiles showed that the surface-modified sample dissolved faster than the intact sample at the initial stage. The dissolution kinetics were analyzed based on the Hixon-Crowell equation, and the dissolution rate constants for intact and surface-modified anhydrates were found to be 0.0102±0.008 mg1/3 min−1 and 0.1442±0.0482 mg1/3·min−1. The surface-modified anhydrate powders were more stable than the nonmodified samples under high humidity and showed resistance against moisture. However, surface modification induced rapid dissolution in water compared to the control.

Keywords: carbamazepine, anhydrate, surface modification, stability, hydration kinetic analysis, dissolution kinetics

Full Text

The Full Text of this article is available as a PDF (124K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
1. FDA papers. Guidelines: manufacturing and controls for INDs and NDAs. Pharm Tech Japan. 1985;1:835–850.
2. Haleblian JK. Characterization of habits and crystalline modification of solids and their pharmaceutical applications. J Pharm Sci. 1975;64:1269–1288. doi: 10.1002/jps.2600640805. [PubMed] [Cross Ref]
3. Otsuka M, Matsuda Y. Polymorphism, pharmaceutical aspects. In: Swarbrick J, Boylan JC, editors. Encyclopedia of Pharmaceutical Technology. Vol 12. New York, NY: Marcel Dekker; 1995. pp. 305–326.
4. Stephenson GA, Stowell JG, Toma PH, Pfeiffer RR, Byrn SR. Solid-state investigations of erythromycin A dihydrate: structure, NMR spectroscopy, and hygroscopicity. J Pharm Sci. 1997;86:1239–1244. doi: 10.1021/js9701667. [PubMed] [Cross Ref]
5. Campen V, Amidon GL, Zografi G. Moisture sorption kinetics for water-soluble substances, III: theoretical and experimental studies in air. J Pharm Sci. 1983;72:1394–1408. doi: 10.1002/jps.2600721206. [PubMed] [Cross Ref]
6. Campen V, Amidon GL, Zografi G. Moisture sorption kinetics for water-soluble substances, II: experimental verification of heat transport control. J Pharm Sci. 1983;72:1388–1393. doi: 10.1002/jps.2600721205. [PubMed] [Cross Ref]
7. Kontny MJ, Zografi G. Moisture sorption kinetics for water-soluble substances, IV: studies with mixtures of solids. J Pharm Sci. 1983;74:124–127. doi: 10.1002/jps.2600740204. [PubMed] [Cross Ref]
8. Vadas EB, Toma P, Zografi G. Solid-state phase-transitions initiated by water vapor sorption of crystalline L-660, 711, a leukotriene D4 receptor antagonist. Pharm Res. 1991;8:148–155. doi: 10.1023/A:1015871415925. [PubMed] [Cross Ref]
9. Nightingale SL. From the Food and Drug Administration. JAMA. 1990;263:1896–1896. doi: 10.1001/jama.263.14.1896. [PubMed] [Cross Ref]
10. Briggner L, Buckton G, Bystrom K, Darcy P. The use of isothermal microcalorimetry in the study of changes in crystallinity induced during the processing of powders. Int J Pharm. 1994;105:125–135. doi: 10.1016/0378-5173(94)90458-8. [Cross Ref]
11. Sebhatu T, Angberg M, Ahlneck C. Assessment of the degree of disorder in crystalline solids by isothermal microcalorimetry. Int J Pharm. 1994;104:135–144. doi: 10.1016/0378-5173(94)90188-0. [Cross Ref]
12. Angberg M, Nyström C, Castensson S. Evaluation of heat-conduction microcalorimetry in pharmaceutical stability studies, V: a new approach for continuous measurements in abundant water vapour. Int J Pharm. 1992;81:153–167. doi: 10.1016/0378-5173(92)90007-O. [Cross Ref]
13. Sheridan PL, Buckton G, Storey DE. Development of a flow microcalorimetry method for the assessment of surface properties of powders. Pharm Res. 1995;12:1025–1030. doi: 10.1023/A:1016262531972. [PubMed] [Cross Ref]
14. Buckton G, Darcy P, Greenleaf D, Holbrook P. The use of isothermal microcalorimetry in the study of changes in crystallinity of spray-dried salbutamol sulphate. Int J Pharm. 1995;116:113–118. doi: 10.1016/0378-5173(94)00322-V. [Cross Ref]
15. Aso Y, Yoshioka S, Otsuka T, Kojima S. The physical stability of amorphous nifedipine determined by isothermal microcalorimetry. Chem Pharm Bull. 1995;43:300–303.
16. Rat M, Guillaume P, Wilker S, Pantel G. Practical application of microcalorimetry to the stability of propellants. Workshop Microcalorim Energ Mater. 1997; V1–V18.
17. Mimura H, Kitamura S, Koda S. Evaluation of drug stability by isothermal microcalorimetry. Netsu Sokutei. 1998;25(4):92–96.
18. Giron D. Thermal analysis, microcalorimetry, and combined techniques for the study of pharmaceuticals. J Therm Anal Calorim. 1999;56(3):1285–1304. doi: 10.1023/A:1010194020563. [Cross Ref]
19. Du W, Li X, Wang B, Zhang Y. A study on the interaction between cisplatin and urease. Thermochim Acta. 1999;333(2):109–114. doi: 10.1016/S0040-6031(99)00115-X. [Cross Ref]
20. Beezer A, Gaisford S, Hills AK, Mitchell JC. Pharmaceutical microcalorimetry: applications to long-term stability studies. Int J Pharm. 1999;179(2):159–165. doi: 10.1016/S0378-5173(98)00336-6. [PubMed] [Cross Ref]
21. Runge FE, Heger R. Use of microcalorimetry in monitoring stability. Example: vitamin A esters. J Agric Food Chem. 2000;48(1):47–55. doi: 10.1021/jf981163y. [PubMed] [Cross Ref]
22. Tompa AS, Bryant WF Jr. Microcalorimetry and DSC study of the compatibility of energetic materials. Workshop Microcalorim Energ Mater. 1999;Q1–Q21.
23. Phipps MA, Mackin LA. Application of isothermal calorimetry in solid state drug development. Pharm Sci Technol Today. 2000;3(1):9–17. doi: 10.1016/S1461-5347(99)00227-8. [PubMed] [Cross Ref]
24. Otsuka M, Ishii M, Matsuda Y. Effect of surface-modification on hydration kinetics of nitrofurantoin anhydrate. Colloids and Surfaces B: Biointerfaces. 2002;23:73–82. doi: 10.1016/S0927-7765(01)00210-7. [Cross Ref]
25. Kaneniwa N, Yamaguchi T, Watari N, Otsuka M. Hygroscopicity of carbamazepine crystalline powders [in Japanese] Yakugaku Zasshi. 1984;104:184–190. [PubMed]
26. Kaneniwa N, Ichikawa J, Yamaguchi T, Hayashi K, Watari N, Sumi M. Dissolution behaviour of carbamazepine polymorphs. Yakugaku Zasshi. 1987;107(10):808–813. [PubMed]
27. Hixon A, Crowell J. Dependent of reaction velocity upon surface and agitation. Ind Eng Chem. 1931;23:923–923. doi: 10.1021/ie50260a018. [Cross Ref]

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