Thermokinetic characterization of amorphous carbamazepine was performed utilizing non-isothermal differential scanning calorimetry (DSC) and thermogravimetry (TGA). Structural relaxation of the amorphous matrix was described in terms of the Tool-Narayanaswamy-Moynihan model with the following parameters: Δh* ≈ 200-300 kJ·mol-1, β = 0.57, x = 0.44. The crystallization of the amorphous phase was modeled using complex Šesták-Berggren kinetics, which incorporates temperature-dependent activation energy and degree of autocatalysis. The activation energy of the crystal growth was determined to be >320 kJ·mol-1 at the glass transition temperature (Tg). Owing to such a high value, the amorphous carbamazepine is stable at Tg, allowing for extensive processing of the amorphous phase (e.g., self-healing of the quench-induced mechanical defects or internal stress). A discussion was conducted regarding the converse relation between the activation energies of relaxation and crystal growth, which is possibly responsible for the absence of sub-Tg crystal growth modes. The high-temperature thermal decomposition of carbamazepine proceeds via multistep kinetics, identically in both an inert and an oxidizing atmosphere. A complex reaction mechanism, consisting of a series of consecutive and competing reactions, was proposed to explain the second decomposition step, which exhibited a temporary mass increase. Whereas a negligible degree of carbamazepine degradation was predicted for the temperature characteristic of the pharmaceutical hot-melt extrusion (~150 °C), the degradation risk during the pharmaceutical 3D printing was calculated to be considerably higher (1-2% mass loss at temperatures 190-200 °C).

Department of Physical Chemistry Faculty of Chemical Technology University of Pardubice Studentská 573 532 10 Pardubice Czech Republic

Zobrazit více v PubMed

Yan R., Tuo J., Tai Z., Zhang H., Yang J., Yu C., Xu Z. Management of anti-seizure medications in lactating women with epilepsy. Front. Neurol. 2022;13:1005890. doi: 10.3389/fneur.2022.1005890. PubMed DOI PMC

Hakami T. Efficacy and tolerability of antiseizure drugs. Ther. Adv. Neurol. Disord. 2021;14:17562864211037430. doi: 10.1177/17562864211037430. PubMed DOI PMC

Cornett E.M., Amarasinghe S.N., Angelette A., Abubakar T., Kaye A.M., Kaye A.D., Neuchat E.E., Urits I., Viswanath O. Valtoco® (Diazepam nasal spray) for the acute treatment of intermittent stereotypic episodes of frequent seizure activity. Neurol. Int. 2021;13:64–78. doi: 10.3390/neurolint13010007. PubMed DOI PMC

Mirza N., Stevelink R., Taweel B., Koeleman B.P., Marson A.G. Using common genetic variants to find drugs for common epilepsies. Brain Commun. 2021;3:fcab287. doi: 10.1093/braincomms/fcab287. PubMed DOI PMC

Nierenberg A.A., Agustini B., Köhler-Forsberg O., Cusin C., Katz D., Sylvia L.G., Peters A., Berk M. Diagnosis and treatment of bipolar disorder: A review. JAMA. 2023;330:1370–1380. doi: 10.1001/jama.2023.18588. PubMed DOI

Lochana P., Banerjee M., Bansal N., Patel J.A., Varghese R. Carbamazepine and Bipolar Disorder: Pharmacodynamics, Pharmacokinetics, Pharmacogenomics, and Adverse Drug Reactions—A Comprehensive Review. Asian J. Pharm. Pharmacol. 2023;9:189–195. doi: 10.31024/ajpp.2023.9.6.3. DOI

Grunze A., Amann B.L., Grunze H. Efficacy of carbamazepine and its derivatives in the treatment of bipolar disorder. Medicina. 2021;57:433. doi: 10.3390/medicina57050433. PubMed DOI PMC

Ali S.F.B., Rahman Z., Dharani S., Afrooz H., Khan M.A. Chemometric models for quantification of carbamazepine anhydrous and dihydrate forms in the formulation. J. Pharm. Sci. 2019;108:1211–1219. doi: 10.1016/j.xphs.2018.10.023. PubMed DOI

Kobayashi Y., Ito S., Itai S., Yamamoto K. Physicochemical properties and bioavailability of carbamazepine polymorphs and dihydrate. Int. J. Pharm. 2000;193:137–146. doi: 10.1016/S0378-5173(99)00315-4. PubMed DOI

Lindenberg M., Kopp S., Dressman J.B. Classification of orally administered drugs on the World Health Organization Model list of Essential Medicines according to the biopharmaceutics classification system. Eur. J. Pharm. Biopharm. 2004;58:265–278. doi: 10.1016/j.ejpb.2004.03.001. PubMed DOI

Xu X., Grohganz H., Knapik-Kowalczuk J., Paluch M., Rades T. Mechanistic Investigation into Crystallization of Hydrated Co-Amorphous Systems of Flurbiprofen and Lidocaine. Pharmaceutics. 2025;17:175. doi: 10.3390/pharmaceutics17020175. PubMed DOI PMC

Shen S., Wang X., Dong C., Zhao W., Wang Y., Zhu L. Solution-Mediated Phase Transformation Processes of Amorphous Iohexol: Mechanisms and Its Applications. Cryst. Growth Des. 2025;25:519–532. doi: 10.1021/acs.cgd.4c01155. DOI

Budiman A., Lailasari E., Nurani N.V., Yunita E.N., Anastasya G., Aulia R.N., Lestari I.N., Subra L., Aulifa D.L. Ternary solid dispersions: A review of the preparation, characterization, mechanism of drug release, and physical stability. Pharmaceutics. 2023;15:2116. doi: 10.3390/pharmaceutics15082116. PubMed DOI PMC

Baird J.A., van Eerdenbrugh B., Taylor L.S. A classification system to assess the crystallization tendency of organic molecules from undercooled melts. J. Pharm. Sci. 2010;99:3787–3806. doi: 10.1002/jps.22197. PubMed DOI

Schneider-Rauber G., Arhangelskis M., Bond A.D., Ho R., Nere N., Bordawekar S., Sheikh A.Y., Jones W. Polymorphism and surface diversity arising from stress-induced transformations—The case of multicomponent forms of carbamazepine. Struct. Sci. 2021;77:54–67. doi: 10.1107/S2052520620015437. DOI

Dołęga A., Juszyńska-Gałązka E., Deptuch A., Baran S., Zieliński P.M. Cold-crystallization and physical stability of glassy carbamazepine. Thermochim. Acta. 2022;707:179100. doi: 10.1016/j.tca.2021.179100. DOI

Chakravarty P., Pandya K., Nagapudi K. Determination of fragility in organic small molecular glass forming liquids: Comparison of calorimetric and spectroscopic data and commentary on pharmaceutical importance. Mol. Pharm. 2018;15:1248–1257. doi: 10.1021/acs.molpharmaceut.7b01068. PubMed DOI

Angell C.A., Ngai K.L., McKenna G.B., McMillan P.F., Martin S.W. Relaxation in glassforming liquids and amorphous solids. J. Appl. Phys. 2000;88:3113–3157. doi: 10.1063/1.1286035. DOI

Kohlrausch F. Beiträge zur Kenntniss der elastischen Nachwirkung. Ann. Der Phys. 1866;204:1–20. doi: 10.1002/andp.18662040502. DOI

Williams G., Watts D.C. Non-symmetrical dielectric relaxation behaviour arising from a simple empirical decay function. Trans. Faraday Soc. 1970;66:80–85. doi: 10.1039/tf9706600080. DOI

Dołęga A., Zieliński P.M. Kinetics of non-isothermal cold-crystallization of carbamazepine in the glassy state studied by DSC. J. Non-Cryst. Solids. 2022;575:121198. doi: 10.1016/j.jnoncrysol.2021.121198. DOI

Avrami M. Kinetics of phase change. I—General theory. J. Chem. Phys. 1939;7:1103–1112. doi: 10.1063/1.1750380. DOI

Avrami M. Kinetics of phase change. II—Transformation-time relations for random distribution of nuclei. J. Chem. Phys. 1940;8:212–224. doi: 10.1063/1.1750631. DOI

Avrami M. Granulation, phase change, and microstructure kinetics of phase change III. J. Chem. Phys. 1941;9:177–184. doi: 10.1063/1.1750872. DOI

Luo M., Chen A., Shan S., Guo M., Cai T. Molar Ratio-Dependent Crystallization in Coamorphous Celecoxib–Carbamazepine Systems: The Interplay of Thermodynamics and Kinetics. Mol. Pharm. 2025;22:3401–3413. doi: 10.1021/acs.molpharmaceut.5c00278. PubMed DOI

Pinto M.A.L., Ambrozini B., Ferreira A.P.G., Cavalheiro É.T.G. Thermoanalytical studies of carbamazepine: Hydration/dehydration, thermal decomposition, and solid phase transitions. Braz. J. Pharm. Sci. 2014;50:877–884. doi: 10.1590/S1984-82502014000400023. DOI

Bordawekar M.S., Pudipeddi M., Ruegger C.E., Dhareshwar S.S. Formulation Intervention to Overcome Decreased Kinetic Solubility of a Low Tg Amorphous Drug. AAPS PharmSciTech. 2023;24:149. doi: 10.1208/s12249-023-02601-z. PubMed DOI

Kushwah V., Gomes Lopes D., Saraf I., Koutsamanis I., Werner B., Zangger K., Roy M.C., Bartlett J.A., Schmidt H.F., Shamblin S.L., et al. Phase behavior of drug–lipid–surfactant ternary systems toward understanding the annealing-induced change. Mol. Pharm. 2021;19:532–546. doi: 10.1021/acs.molpharmaceut.1c00651. PubMed DOI

Luo M., Chen A., Huang C., Guo M., Cai T. Effects of Polymers on Cocrystal Growth in a Drug–Drug Coamorphous System: Relations between Glass-to-Crystal Growth and Surface-Enhanced Crystal Growth. Mol. Pharm. 2024;21:3591–3602. doi: 10.1021/acs.molpharmaceut.4c00315. PubMed DOI

Cai T., Zhu L., Yu L. Crystallization of organic glasses: Effects of polymer additives on bulk and surface crystal growth in amorphous nifedipine. Pharm. Res. 2011;28:2458–2466. doi: 10.1007/s11095-011-0472-z. PubMed DOI

Sun Y., Zhu L., Wu T., Cai T., Gunn E.M., Yu L. Stability of amorphous pharmaceutical solids: Crystal growth mechanisms and effect of polymer additives. AAPS J. 2012;14:380–388. doi: 10.1208/s12248-012-9345-6. PubMed DOI PMC

Scherer G.W. Theories of relaxation. J. Non-Cryst. Sol. 1990;123:75–89. doi: 10.1016/0022-3093(90)90775-H. DOI

Richert R. Physical aging and heterogeneous dynamics. Phys. Rev. Lett. 2010;104:085702. doi: 10.1103/PhysRevLett.104.085702. PubMed DOI

Svoboda R., Pakosta M., Doležel P. How the Presence of Crystalline Phase Affects Structural Relaxation in Molecular Liquids: The Case of Amorphous Indomethacin. Int. J. Mol. Sci. 2023;24:16275. doi: 10.3390/ijms242216275. PubMed DOI PMC

Awad A., Gaisford S., Basit A.W. Fused deposition modelling: Advances in engineering and medicine. 3D Print. Pharm. 2018;31:107–132. doi: 10.1007/978-3-319-90755-0_6. DOI

Mohapatra S., Kar R.K., Biswal P.K., Bindhani S. Approaches of 3D printing in current drug delivery. Sens. Int. 2022;3:100146. doi: 10.1016/j.sintl.2021.100146. DOI

Li N., Qiao D., Zhao S., Lin Q., Zhang B., Xie F. 3D printing to innovate biopolymer materials for demanding applications: A review. Mater. Today Chem. 2021;20:100459. doi: 10.1016/j.mtchem.2021.100459. DOI

Liu J., Sun L., Xu W., Wang Q., Yu S., Sun J. Current advances and future perspectives of 3D printing natural-derived biopolymers. Carbohydr. Polym. 2019;207:297–316. doi: 10.1016/j.carbpol.2018.11.077. PubMed DOI

Patel N.G., Serajuddin A.T. Development of FDM 3D-printed tablets with rapid drug release, high drug-polymer miscibility and reduced printing temperature by applying the acid-base supersolubilization (ABS) principle. Int. J. Pharm. 2021;600:120524. doi: 10.1016/j.ijpharm.2021.120524. PubMed DOI

Svoboda R. Thermally Induced Phenomena in Amorphous Nifedipine: The Correlation Between the Structural Relaxation and Crystal Growth Kinetics. Molecules. 2025;30:175. doi: 10.3390/molecules30010175. PubMed DOI PMC

Svoboda R., Kozlová K. Thermo-Structural Characterization of Phase Transitions in Amorphous Griseofulvin: From sub-Tg Relaxation and Crystal Growth to High-Temperature Decomposition. Molecules. 2024;29:1516. doi: 10.3390/molecules29071516. PubMed DOI PMC

Svoboda R., Košťálová D., Krbal M., Komersová A. Indomethacin: The interplay between structural relaxation, viscous flow and crystal growth. Molecules. 2022;27:5668. doi: 10.3390/molecules27175668. PubMed DOI PMC

Svoboda R., Macháčková J., Nevyhoštěná M., Komersová A. Thermal stability of amorphous nimesulide: From glass formation to crystal growth and thermal degradation. Phys. Chem. Chem. Phys. 2024;26:856–872. doi: 10.1039/D3CP02260A. PubMed DOI

Grzesiak A.L., Lang M., Kim K., Matzger A.J. Comparison of the four anhydrous polymorphs of carbamazepine and the crystal structure of form I. J. Pharm. Sci. 2003;92:2260–2271. doi: 10.1002/jps.10455. PubMed DOI

Tian F., Zeitler J.A., Strachan C.J., Saville D.J., Gordon K.C., Rades T. Characterizing the conversion kinetics of carbamazepine polymorphs to the dihydrate in aqueous suspension using Raman spectroscopy. J. Pharm. Biomed. Anal. 2006;40:271–280. doi: 10.1016/j.jpba.2005.07.030. PubMed DOI

Šesták J. Science of Heat and Thermophysical Studies: A Generalized Approach to Thermal Analysis. Elsevier; Amsterdam, The Netherlands: 2005.

Svoboda R., Málek J. Description of enthalpy relaxation dynamics in terms of TNM model. J. Non-Cryst. Solids. 2013;378:186–195. doi: 10.1016/j.jnoncrysol.2013.07.008. DOI

Ediger M. Lecture: Unusual liquids prepared by vapor deposition; Proceedings of the Viscous Liquids and the Glass Transition XXI; Roskilde, Denmark. 14–16 May 2025.

Dołęga A., Juszyńska-Gałązka E., Osiecka-Drewniak N., Natkański P., Kuśtrowski P., Krupa A., Zieliński P.M. Study on the thermal performance of carbamazepine at different temperatures, pressures and atmosphere conditions. Thermochim. Acta. 2021;703:178990. doi: 10.1016/j.tca.2021.178990. DOI

Dołęga A., Krupa A., Zieliński P.M. Enhanced thermal stability of carbamazepine obtained by fast heating, hydration and recrystallization from organic solvent solutions: A DSC and HPLC study. Thermochim. Acta. 2020;690:178691. doi: 10.1016/j.tca.2020.178691. DOI

Guinet Y., Paccou L., Danède F., Willart J.F., Derollez P., Hédoux A. Comparison of amorphous states prepared by melt-quenching and cryomilling polymorphs of carbamazepine. Int. J. Pharm. 2016;509:305–313. doi: 10.1016/j.ijpharm.2016.05.050. PubMed DOI

O’Brien L.E., Timmins P., Williams A.C., York P. Use of in situ FT-Raman spectroscopy to study the kinetics of the transformation of carbamazepine polymorphs. J. Pharm. Biomed. Anal. 2004;36:335–340. doi: 10.1016/j.jpba.2004.06.024. PubMed DOI

Tool A.Q. Relation between inelastic deformability and thermal expansion of glass in its annealing range. J. Am. Ceram. Soc. 1946;29:240–253. doi: 10.1111/j.1151-2916.1946.tb11592.x. DOI

Narayanaswamy O. A model of structural relaxation in glass. J. Am. Ceram. Soc. 1971;54:491–498. doi: 10.1111/j.1151-2916.1971.tb12186.x. DOI

Moynihan C.T., Easteal A.J., De Bolt M.A., Tucker J. Dependence of the fictive temperature of glass on cooling rate. J. Am. Ceram. Soc. 1976;59:12–16. doi: 10.1111/j.1151-2916.1976.tb09376.x. DOI

Svoboda R. Novel equation to determine activation energy of enthalpy relaxation. J. Therm. Anal. Calorim. 2015;121:895–899. doi: 10.1007/s10973-015-4619-8. DOI

Hodge I.M., Berens A.R. Effects of annealing and prior history on enthalpy relaxation in glassy polymers. 2. Mathematical modeling. Macromolecules. 1982;15:762–770. doi: 10.1021/ma00231a016. DOI

Holba P., Šesták J. Heat inertia and its role in thermal analysis. J. Therm. Anal. Calorim. 2015;121:303–307. doi: 10.1007/s10973-015-4486-3. DOI

Svoboda R., Málek J. Enthalpy relaxation in Ge–Se glassy system. J. Therm. Anal. 2012;113:831–842. doi: 10.1007/s10973-012-2829-x. DOI

Šesták J. Thermophysical Properties of Solids, Their Measurements and Theoretical Analysis. Elsevier; Amsterdam, The Netherlands: 1984.

Kissinger H.E. Reaction kinetics in differential thermal analysis. Anal. Chem. 1957;29:1702–1706. doi: 10.1021/ac60131a045. DOI

Augis J.A., Bennett J.E. Calculation of the Avrami parameters for heterogeneous solid state reactions using a modification of the Kissinger method. J. Therm. Anal. 1978;13:283–292. doi: 10.1007/BF01912301. DOI

Svoboda R., Chovanec J., Slang S., Beneš L., Konrad P. Single-curve multivariate kinetic analysis: Application to the crystallization of commercial Fe-Si-Cr-B amorphous alloys. J. Alloys Compd. 2021;889:161672. doi: 10.1016/j.jallcom.2021.161672. DOI

Opfermann J. Kinetic analysis using multivariate non-linear regression. J. Therm. Anal. Calorim. 2000;60:641–658. doi: 10.1023/A:1010167626551. DOI

Svoboda R., Romanová J., Šlang S., Obadalová I., Komersová A. Influence of particle size and manufacturing conditions on the recrystallization of amorphous Enzalutamide. Eur. J. Pharm. Sci. 2020;153:105468. doi: 10.1016/j.ejps.2020.105468. PubMed DOI

Patil H., Tiwari R.V., Repka M.A. Hot-Melt Extrusion: From Theory to Application in Pharmaceutical Formulation. AAPS PharmSciTech. 2016;17:20–42. doi: 10.1208/s12249-015-0360-7. PubMed DOI PMC

Huang S., O’Donnell K.P., Keen J.M., Rickard M.A., McGinity J.W., Williams R.O., III A New Extrudable Form of Hypromellose: AFFINISOL™ HPMC HME. AAPS PharmSciTech. 2016;17:106–119. doi: 10.1208/s12249-015-0395-9. PubMed DOI PMC

Svoboda R., Nevyhoštěná M., Macháčková J., Vaculík J., Knotková K., Chromčíková M., Komersová A. Thermal degradation of Affinisol HPMC: Optimum processing temperatures for hot melt extrusion and 3D printing. Pharm. Res. 2023;40:2253–2268. doi: 10.1007/s11095-023-03592-z. PubMed DOI PMC

Cohen M.H., Turnbull D. Molecular Transport in Liquids and Glasses. J. Chem. Phys. 1959;31:1164–1169. doi: 10.1063/1.1730566. DOI