Skip to main content
Log in

Kinetics and nucleation mechanism of carbamazepine–saccharin co-crystals in ethanol solution

Journal of Thermal Analysis and Calorimetry Aims and scope Submit manuscript


This study aimed to investigate the metastable zone width (MSZW) and the nucleation order of carbamazepine–saccharin (CBZ–SAC) co-crystals via slow cooling crystallisation, to obtain the kinetic value using Kashchiev–Borissova–Hammond–Roberts (KBHR) technique and to deduce the induction time, the radius of the critical nucleus and the interfacial energy of the CBZ–SAC co-crystals via fast cooling. Slow cooling experiments with cooling/heating rates of 0.8, 0.6, 0.4 and 0.2 °C min−1 were applied to determine the crystallisation and the dissolution temperature of CBZ–SAC co-crystals at SAC:CBZ ratios of (3.5, 3.0, 2.5, 2.0 and 1.0) and CBZ concentrations of 19.14, 17.96, 17.06 and 15.83 mg mL−1. Then, fast cooling experiments were run at CBZ concentration of 17.96 mg mL−1 and SAC:CBZ mole ratio of 2.0. Nucleation kinetics, such as MSZW, nucleation order, nucleation kinetic constant and interfacial energy, was determined and analysed. KBHR method was applied to analyse the kinetics value and compared with isothermal method. The nucleation orders obtained from slow cooling method were in between 1.65 and 4.9, which were within the range for nucleation of organic compounds. The results of KBHR method in determining the kinetic values of CBZ–SAC co-crystals were similar to those of the isothermal method.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5


  1. Zeng G, Li H, Huang S, Wang X, Chen J. Determination of metastable zone width and the primary nucleation kinetics of sodium sulfate. Theor Found Chem Eng. 2015;49:869–76.

    Article  CAS  Google Scholar 

  2. Hazi Mastan T, Lenka M, Sarkar D. Nucleation kinetics from metastable zone widths for sonocrystallization of l-phenylalanine. Ultrason Sonochem. 2017;36:497–506.

    Article  CAS  Google Scholar 

  3. Camacho Corzo DM, Borissova A, Hammond RB, Kashchiev D, Roberts KJ, Lewtas K, et al. Nucleation mechanism and kinetics from the analysis of polythermal crystallisation data: methyl stearate from kerosene solutions. CrystEngComm. 2014;16:974–91.

    Article  CAS  Google Scholar 

  4. Mohammad KA, Rahim SA, Bakar MRA. Effect of seed loading and temperature of seeding on carbamazepine–saccharin co-crystal. Indian J Sci Technol. 2017;10:1–5.

    Article  Google Scholar 

  5. Wang H, Wang Z, Liu L, Gong X, Wang M. Alumina hydrate polymorphism control in Al–water reaction crystallization by seeding to change the metastable zone width. Cryst Growth Des. 2016;16:1056–62.

    Article  CAS  Google Scholar 

  6. Shimono K, Kadota K, Tozuka Y, Shimosaka A, Shirakawa Y, Hidaka J. Kinetics of co-crystal formation with caffeine and citric acid via liquid-assisted grinding analyzed using the distinct element method. Eur J Pharm Sci. 2015;76:217–24.

    Article  CAS  Google Scholar 

  7. Ledeti A, Vlase G, Vlase T, Circioban D, Dehelean C, Ledeti I, et al. Binary adduct formation of desipramine with dicarboxylic acids. J Therm Anal Calorim. 2016. doi:10.1007/s10973-016-5967-8.

  8. Fuliaş A, Vlase G, Vlase T, Şuta LM, Şoica C, Ledeţi I. Screening and characterization of cocrystal formation between carbamazepine and succinic acid. J Therm Anal Calorim. 2015;121:1081–6.

    Article  Google Scholar 

  9. Aitipamula S, Banerjee R, Bansal AK, Biradha K, Cheney ML, Choudhury AR, et al. Polymorphs, salts, and cocrystals: what’s in a name? Cryst Growth Des. 2012;12:2147–52.

    Article  CAS  Google Scholar 

  10. Duggirala NK, Perry ML, Almarsson Ö, Zaworotko MJ. Pharmaceutical cocrystals: along the path to improved medicines. Chem Commun R Soc Chem. 2016;52:640–55.

    Article  CAS  Google Scholar 

  11. Moos W, Miller S, Munk S, Munk B. Managing the drug discovery process: how to make it more efficient and cost-effective. Woodhead Publishing: Elsevier; 2016.

    Google Scholar 

  12. Tiwari RV, Patil H, Repka MA. Contribution of hot-melt extrusion technology to advance drug delivery in the 21st century. Exp Opin Drug Deliv Informa Healthcare. 2016;13:451–64.

    Article  CAS  Google Scholar 

  13. Ledeţi A, Vlase G, Vlase T, Bercean V, Murariu MS, Ledeţi I, et al. Solid-state preformulation studies of amiodarone hydrochloride. J Therm Anal Calorim. 2016;126:181–7.

    Article  Google Scholar 

  14. Zhang X, Yang Z, Chai J, Xu J, Zhang L, Qian G, et al. Nucleation kinetics of lovastatin in different solvents from metastable zone widths. Chem Eng Sci. 2015;133:62–9.

    Article  CAS  Google Scholar 

  15. Turner TD, Corzo DMC, Toroz D, Curtis A, Dos Santos MM, Hammond RB, et al. The influence of solution environment on the nucleation kinetics and crystallisability of para-aminobenzoic acid. Phys Chem Chem Phys R Soc Chem. 2016;18:27507–20.

    Article  CAS  Google Scholar 

  16. Nỳvlt J. Kinetics of nucleation in solutions. J Cryst Growth. 1968;3:377–83.

    Article  Google Scholar 

  17. Sangwal K, Mielniczek-Brzóska E, Barylska S. Solubility of ammonium oxalate in water–acetone mixtures and metastable zone width of their solutions. Chem Eng Res Des. 2014;92:491–9.

    Article  CAS  Google Scholar 

  18. Arunmozhi G, de M Gomes E. Metastability and crystal growth kinetics on l-arginine phosphate. Cryst Res Technol. 2004;39:34–9.

    Article  CAS  Google Scholar 

  19. Mohammad KA, Abd Rahim S, Abu Bakar MR. Nucleation kinetics of carbamazepine–saccharin (CBZ–SAC) co-crystal. In: Hashim AM, editor. ICGSCE 2014. Singapore: Springer Singapore; 2015. p. 263–70.

    Chapter  Google Scholar 

Download references

Author information

Authors and Affiliations


Corresponding author

Correspondence to Syarifah Abd Rahim.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mohammad, K.A., Abd Rahim, S. & Abu Bakar, M.R. Kinetics and nucleation mechanism of carbamazepine–saccharin co-crystals in ethanol solution. J Therm Anal Calorim 130, 1663–1669 (2017).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: