AAPS PharmSciTech

, Volume 12, Issue 2, pp 693–704 | Cite as

Physico-mechanical and Stability Evaluation of Carbamazepine Cocrystal with Nicotinamide

  • Ziyaur Rahman
  • Cyrus Agarabi
  • Ahmed S. Zidan
  • Saeed R. Khan
  • Mansoor A. Khan
Research Article


The focus of this investigation was to prepare the cocrystal of carbamazepine (CBZ) using nicotinamide as a coformer and to compare its preformulation properties and stability profile with CBZ. The cocrystal was prepared by solution cooling crystallization, solvent evaporation, and melting and cryomilling methods. They were characterized for solubility, intrinsic dissolution rate, chemical identification by Fourier transform infrared spectroscopy, crystallinity by differential scanning calorimetry, powder X-ray diffraction, and morphology by scanning electron microscopy. Additionally, mechanical properties were evaluated by tensile strength and Heckel analysis of compacts. The cocrystal and CBZ were stored at 40°C/94% RH, 40°C/75% RH, 25°C/60% RH, and 60°C to determine their stability behavior. The cocrystals were fluffy, with a needle-shaped crystal, and were less dense than CBZ. The solubility profiles of the cocrystals were similar to CBZ, but its intrinsic dissolution rate was lower due to the high tensile strength of its compacts. Unlike CBZ, the cocrystals were resistant to hydrate transformation, as revealed by the stability studies. Plastic deformation started at a higher compression pressure in the cocrystals than CBZ, as indicated by the high yield pressure. In conclusion, the preformulation profile of the cocrystals was similar to CBZ, except that it had an advantageous resistance to hydrate transformation.

Key words

carbamazepine cocrystal mechanical property nicotinamide stability 



The authors would like to thank the Oak Ridge Institute for Science and Education (ORISE) for supporting the post doctoral research program. The authors also thank Mr. Alan Carlin for helping with the FTIR spectrum.


The views and opinions expressed in this paper are only those of the authors and do not necessarily reflect the views or policies of the FDA.


  1. 1.
    Food and Drug Administration. Drugs@FDA. Label and Approval History of Tegretol. Accessed 02 September 2010.
  2. 2.
    Granger P, Biton B, Faure C, Vige X, Depoortere H, Graham D, et al. Modulation of the gamma-aminobutyric acid type A receptor by the antiepileptic drugs carbamazepine and phenytoin. Mol Pharmacol. 2005;47:1189–96.Google Scholar
  3. 3.
    Kasim NA, Whitehouse M, Ramachandran C, Bermejo M, Lennernäs H, Hussain AS, et al. Molecular properties of WHO essential drugs and provisional biopharmaceutical classification. Mol Pharm. 2003;1:85–96.CrossRefGoogle Scholar
  4. 4.
    Food and Drug Administration. Guidance for Industry, Waiver of in vitro bioavailability and bioequivalence studies for immediate-release solid oral dosage forms based on a biopharmaceutics classification system. 2000.Google Scholar
  5. 5.
    Grzesiak AL, Lang M, Kim K, Matzger AJ. Comparison of the four anhydrous polymorphs of carbamazepine and the crystal structure of form I. J Pharm Sci. 2003;92:2260–71.PubMedCrossRefGoogle Scholar
  6. 6.
    Rustichelli C, Gamberini G, Ferioli V, Gamberinig MC, Ficarra R, Tomasini S. Solid-state study of polymorphic drugs: carbamazepine. J Pharm Biomed Anal. 2000;23:41–54.PubMedCrossRefGoogle Scholar
  7. 7.
    Kobayashi Y, Ito S, Itai S, Yamamoto K. Physicochemical properties and bioavailability of carbamazepine polymorphs and dihydrate. Int J Pharm. 2000;193:137–46.PubMedCrossRefGoogle Scholar
  8. 8.
    Rahman Z, Zidan AS, Khan MA. Risperidone solid dispersion for orally disintegrating tablet: its formulation design and non-destructive methods of evaluation. Int J Pharm. 2010;400:49–58.PubMedCrossRefGoogle Scholar
  9. 9.
    Hoyer H, Schlocker W, Krum K, Bernkop-Schnnrch A. Preparation and evaluation of microparticles from thiolated polymers via air jet milling. Eur J Pharm Biopharm. 2008;69:476–85.PubMedCrossRefGoogle Scholar
  10. 10.
    Hecq J, Deleers M, Fanara D, Vranckx H, Boulanger P, Le Lamer S, et al. Preparation and in vitro/in vivo evaluation of nano-sized crystals for dissolution rate enhancement of ucb-35440-3, a highly dosed poorly water-soluble weak base. Eur J Pharm Biopharm. 2006;64:360–8.PubMedCrossRefGoogle Scholar
  11. 11.
    Khan MA, Karnachi AA, Agarwal V, Vaithiyalingam SR, Nazzal S, Reddy IK. Stability characterization of controlled release coprecipitates and solid dispersions. J Control Release. 2000;63:1–6.PubMedCrossRefGoogle Scholar
  12. 12.
    Rodriguez-Hornedo N, Nehm SJ, Seefeldt KF, Falkiewicz CF. Reaction crystallization of pharmaceutical molecular complexes. Mol Pharm. 2006;3:362–7.PubMedCrossRefGoogle Scholar
  13. 13.
    Weyna DR, Shattock T, Vishweshwar P, Zaworotko MJ. Synthesis and structural characterization of cocrystals and pharmaceutical cocrystals: mechanochemistry vs slow evaporation from solution. Cryst Growth Des. 2009;9:1106–23.CrossRefGoogle Scholar
  14. 14.
    Food and Drug Administration. Database of select committee on GRAS substances (SCOGS) reviews: niacinamide (nicotinamide). Report No. 108. Accessed 02 September 2010.
  15. 15.
    Remenar JF, Peterson ML, Stephens PW, Zhang Z, Zimenkov Y, Hickey MB. Celecoxib:nicotinamide dissociation using excipients to capture the cocrystal’s potential. Mol Pharm. 2007;4:386–400.PubMedCrossRefGoogle Scholar
  16. 16.
    Lu J, Rohani S. Preparation and characterization of theophylline–nicotinamide cocrystal. Org Pro Res Dev. 2009;13:1269–75.CrossRefGoogle Scholar
  17. 17.
    Berry DJ, Seaton CC, Clegg W, Harrington RW, Coles SJ, Horton PN, et al. Applying hot-stage microscopy to co-crystal screening: a study of nicotinamide with seven active pharmaceutical ingredients. Cryst Growth Des. 2008;8:1697–712.CrossRefGoogle Scholar
  18. 18.
    Chieng N, Hubert M, Saville D, Rades T, Aaltonen J. Formation kinetics and stability of carbamazepine–nicotinamide cocrystals prepared by mechanical activation. Cryst Growth Des. 2009;9:2377–86.CrossRefGoogle Scholar
  19. 19.
    Porter W, Elie S, Matzger A. Polymorphism in carbamazepine cocrystals. Cryst Growth Des. 2008;8:14–6.PubMedCrossRefGoogle Scholar
  20. 20.
    Cheney ML, Shan N, Healey ER, Hanna M, Wojtas L, Zaworotko MJ, et al. Effects of crystal form on solubility and pharmacokinetics: a crystal engineering case study of lamotrigine. Cryst Growth Des. 2010;10:394–405.CrossRefGoogle Scholar
  21. 21.
    Trask AV, Motherwell SWD, Jones W. Physical stability enhancement of theophylline via cocrystallization. Int J Pharm. 2006;320:114–23.PubMedCrossRefGoogle Scholar
  22. 22.
    Jayasankar A, Somwangthanaroj A, Shao Z, Rodriguez-Hornedo N. Cocrystal formation during cogrinding and storage is mediated by amorphous phase. Pharm Res. 2006;23:2381–92.PubMedCrossRefGoogle Scholar
  23. 23.
    Seefeldt K, Miller J, Alvarez-Nunez F, Rodriguez-Hornedo N. Crystallization pathways and kinetics of carbamazepine–nicotinamide cocrystals from the amorphous state by in situ thermomicroscopy, spectroscopy and calorimetry studies. J Pharm Sci. 2007;96:1147–58.PubMedCrossRefGoogle Scholar
  24. 24.
    Fleischman SG, Kuduyam SS, McMahon JA, Moulton B, Walsh RDB, Rodriguez-Hornedo N, et al. Crystal engineering of the composition of pharmaceutical phases: multiple-component crystalline solids involving carbamazepine. Cryst Growth Des. 2003;3:909–19.CrossRefGoogle Scholar
  25. 25.
    Bethune SJ, Huang N, Jayasankar A, Rodrıguez-Hornedo N. Understanding and predicting the effect of cocrystal components and pH on cocrystal solubility. Cryst Growth Des. 2009;9:3976–88.CrossRefGoogle Scholar
  26. 26.
    International Conference of Harmonization–Validation of analytical Procedures Q2(R1); 2005.Google Scholar
  27. 27.
    Ito S, Nishimura M, Kobayashi Y, Itai S, Yamamoto K. Characterization of polymorphs and hydrates of GK-128, a serotonin3 receptor antagonist. Int J Pharm. 1997;151:133–43.CrossRefGoogle Scholar
  28. 28.
    Hairian I, Newton JM. Tensile strength of circular flat and convex faced Avicel PH102 tablets. DARU. 1999;7:36–40.Google Scholar
  29. 29.
    Heckel RW. An analysis of powder compaction phenomena. Trans Metall Soc AIME. 1961;221:1001–8.Google Scholar
  30. 30.
    Sun C, Grant DJW. Influence of crystal shape on the tableting performance of l-lysine monohydrochloride dihydrate. J Pharm Sci. 2001;90:569–79.PubMedCrossRefGoogle Scholar
  31. 31.
    Murphy D, Rodríguez-Cintrón F, Langevin B, Kelly RC, Rodríguez-Hornedo N. Solution-mediated phase transformation of anhydrous to dihydrate carbamazepine and the effect of lattice disorder. Int J Pharm. 2002;246:121–34.PubMedCrossRefGoogle Scholar
  32. 32.
    Nair R, Nyamweya N, Gonen S, Martinez-Miranda LJ, Hoag SW. Influence of various drugs on the glass transition temperature of poly(vinylpyrrolidone): a thermodynamic and spectroscopic investigation. Int J Pharm. 2001;225:83–96.PubMedCrossRefGoogle Scholar
  33. 33.
    Bayarıa S, Atac A, Yurdakul S. Coordination behaviour of nicotinamide: an infrared spectroscopic study. J Mol Struct. 2003;655:163–70.CrossRefGoogle Scholar
  34. 34.
    Rahman Z, Zidan AS, Khan MA. Formulation and evaluation of a protein-loaded solid dispersions by non-destructive methods. AAPS J. 2010;12:158–70.PubMedCrossRefGoogle Scholar
  35. 35.
    Adeyemi MO, Pilpel N. The effects of interacting variables on the tensile strength, disintegration and dissolution of oxytetracycline-lactose tablets. Int J Pharm. 1984;20:171–86.CrossRefGoogle Scholar
  36. 36.
    Hendriksen BA, Williams JD. Characterization of calcium fenoprofen 2. Dissolution from formulated tablets and compressed rotating discs. Int J Pharm. 1991;69:175–80.CrossRefGoogle Scholar
  37. 37.
    Jacob JT, Plein EM. Factors affecting the dissolution rate of medicaments from tablets II. Effect of binder concentration, tablet hardness, and storage conditions on the dissolution rate of phenobarbital from tablets. J Pharm Sci. 2006;57:802–5.CrossRefGoogle Scholar
  38. 38.
    Ryshkewitch E. Compression strength of porous sintered alumina and zirconia. J Am Cer Soc. 1953;36:65–8.CrossRefGoogle Scholar
  39. 39.
    Robert RJ, Rowe RC, York P. The relationship between the fracture properties, tensile strength, and critical stress intensity factor of organic solids and their molecular structure. Int J Pharm. 1995;125:157–62.CrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2011

Authors and Affiliations

  • Ziyaur Rahman
    • 1
  • Cyrus Agarabi
    • 1
  • Ahmed S. Zidan
    • 1
    • 2
  • Saeed R. Khan
    • 1
  • Mansoor A. Khan
    • 1
  1. 1.Division of Product Quality and Research, Center of Drug Evaluation and ResearchFood and Drug AdministrationSilver SpringUSA
  2. 2.Faculty of Pharmacy, Zagazig UniversityZagazigEgypt

Personalised recommendations