Differential scanning calorimetry and Raman spectroscopy were used to study the nonisothermal and isothermal crystallization behavior of amorphous indomethacin powders (with particle sizes ranging from 50 to 1000 µm) and their dependence on long-term storage conditions, either 0-100 days stored freely at laboratory ambient temperatures and humidity or placed in a desiccator at 10 °C. Whereas the γ-form polymorph always dominated, the accelerated formation of the α-form was observed in situations of heightened mobility (higher temperature and heating rate), increased amounts of mechanically induced defects, and prolonged free-surface nucleation. A complex crystallization behavior with two separated crystal growth modes (originating from either the mechanical defects or the free surface) was identified both isothermally and nonisothermally. The diffusionless glass-crystal (GC) crystal growth was found to proceed during the long-term storage at 10 °C and zero humidity, at the rate of ~100 µm of the γ-form surface crystalline layer being formed in 100 days. Storage at the laboratory temperature (still below the glass transition temperature) and humidity led only to a negligible/nondetectable GC growth for the fine indomethacin powders (particle size below ~150 µm), indicating a marked suppression of GC growth by the high density of mechanical defects under these conditions. The freely stored bulk material with no mechanical damage and a smooth surface exhibited zero traces of GC growth (as confirmed by microscopy) after >150 days of storage. The accuracy of the kinetic predictions of the indomethacin crystallization behavior was rather poor due to the combined influences of the mechanical defects, competing nucleation, and crystal growth processes of the two polymorphic phases as well as the GC growth complex dependence on the storage conditions within the vicinity of the glass transition temperature. Performing paired isothermal and nonisothermal kinetic measurements is thus highly recommended in macroscopic crystallization studies of drugs with similarly complicated crystal growth behaviors.

Center of Materials and Nanotechnologies Faculty of Chemical Technology University of Pardubice nam Cs legii 565 530 02 Pardubice Czech Republic

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

Zobrazit více v PubMed

Schittny A., Huwyler J., Puchkov M. Mechanisms of increased bioavailability through amorphous solid dispersions: A review. Drug Deliv. 2020;27:110–127. doi: 10.1080/10717544.2019.1704940. PubMed DOI PMC

Rumondor A.C.F., Dhareshwar S.S., Kesisoglou F. Amorphous solid dispersions of prodrugs: Complementary strategies to increase drug absorption. J. Pharm. Sci. 2016;105:2498–2508. doi: 10.1016/j.xphs.2015.11.004. PubMed DOI

Laitinen R., Lobmann K., Strachan C.J., Grohganz H., Rades T. Emerging trends in the stabilization of amorphous drugs. Int. J. Pharm. 2013;453:65–79. doi: 10.1016/j.ijpharm.2012.04.066. PubMed DOI

Chen L., Okuda T., Lu X.Y., Chan H.K. Amorphous powdrs for inhalation drug delivery. Adv. Drug Deliv. Rev. 2016;100:102–115. doi: 10.1016/j.addr.2016.01.002. PubMed DOI

Tomar D., Singh P.K., Hoque S., Modani S., Sriram A., Kumar R., Madan J., Khatri D., Dua K. Amorphous systems for delivery of nutraceuticals: Challenges opportunities. Crit. Rev. Food Sci. Nutr. 2020;62:1204–1221. doi: 10.1080/10408398.2020.1836607. PubMed DOI

Murdande S.B., Pikal M.J., Shanker R.M., Bogner R.H. Aqueous solubility of crystalline and amorphous drugs: Challenges in measurement. Pharm. Dev. Technol. 2011;16:187–200. doi: 10.3109/10837451003774377. PubMed DOI

Shah N., Sandhu H., Choi D.S., Chokshi H., Malick A.W. Amorphous Solid Dispersions: Theory and Practice. Springer; New York, NY, USA: 2014.

Rams-Baron M., Jachowicz R., Boldyreva E., Zhou D., Jamroz W., Paluch M., Rams-Baron M., Jachowicz R., Boldyreva E., Zhou D., et al. Amorphous Drugs—Benefits and Challenges. Springer; Berlin/Heidelberg, Germany: 2018.

Yu L. Amorphous pharmaceutical solids: Preparation, characterization and stabilization. Adv. Drug Deliv. Rev. 2001;48:27–42. doi: 10.1016/S0169-409X(01)00098-9. PubMed DOI

Kumar N.S.K., Suryanarayanan R. Crystallization Propensity of Amorphous Pharmaceuticals: Kinetics and Thermodynamics. Mol. Pharm. 2022;19:472–483. doi: 10.1021/acs.molpharmaceut.1c00839. PubMed DOI

Bhugra C., Pikal M.J. Role of thermodynamic, molecular, and kinetic factors in crystallization from the amorphous state. J. Pharm. Sci. 2008;97:1329–1349. doi: 10.1002/jps.21138. PubMed DOI

Lucas S. The Pharmacology of Indomethacin. Headache. 2016;56:436–446. doi: 10.1111/head.12769. PubMed DOI

Draper M.P., Martell R.L., Levy S.B. Indomethacin-mediated reversal of multidrug resistance and drug efflux in human and murine cell lines overexpressing MRP, but not P-glycoprotein. Br. J. Cancer. 1997;75:810–815. doi: 10.1038/bjc.1997.145. PubMed DOI PMC

Amici C., La Frazia S., Brunelli C., Balsamo M., Angelini M., Santoro M.G. Inhibition of viral protein translation by indomethacin in vesicular stomatitis virus infection: Role of eIF2α kinase PKR. Cell Microbiol. 2015;17:1391–1404. doi: 10.1111/cmi.12446. PubMed DOI PMC

Yalkowsky S.H., Dannenfelser R.M. Aquasol Database of Aqueous Solubility. College of Pharmacy, University of Arizona; Tucson, AZ, USA: 1992. Version 5.

Wu T., Yu L. Surface crystallization of indomethacin below Tg. Pharm. Res. 2006;23:2350–2355. doi: 10.1007/s11095-006-9023-4. PubMed DOI

Rautaniemi K., Vuorimma-Laukkannen E., Strachan C.J., Laaksonen T. Crystallization Kinetics of an Amorphous Pharmaceutical Compound Using Fluorescence-Lifetime-Imaging Microscopy. Mol. Pharm. 2018;15:1964–1971. doi: 10.1021/acs.molpharmaceut.8b00117. PubMed DOI PMC

Sun Y., Zhu L., Kearns K.L., Ediger M.D., Yu L. Glasses crystallize rapidly at free surfaces by growing crystals upward. Proc. Natl. Acad. Sci. USA. 2011;108:5990–5995. doi: 10.1073/pnas.1017995108. PubMed DOI PMC

Einfalt T., Planinsek O., Hrovat K. Methods of amorphization and investigation of the amorphous state. Acta Pharm. 2013;63:305–334. doi: 10.2478/acph-2013-0026. PubMed DOI

Wu T., Sun Y., Li N., de Villiers M.M., Yu L. Inhibiting Surface Crystallization of Amorphous Indomethacin by Nanocoating. Langmuir. 2007;23:5148–5153. doi: 10.1021/la070050i. PubMed DOI

Van Duong T., Van Humbeeck J., Van den Mooter G. Crystallization kinetics of indomethacin/polyethylene glycol dispersions containing high drug loadings. Mol. Pharmaceutics. 2015;12:2493–2504. doi: 10.1021/acs.molpharmaceut.5b00299. PubMed DOI

Planinsek O., Zadnik J., Kunaver M., Srcic S., Godec A. Structural Evolution of Indomethacin Particles upon Milling: Time-Resolved Quantification and Localization of Disordered Structure Studied by IGC and DSC. J. Pharm. Sci. 2010;99:1968–1981. doi: 10.1002/jps.21986. PubMed DOI

Romanová J., Svoboda R., Obadalová I., Beneš L., Pekárek T., Krejčík L., Komersová A. Amorphous Enzalutamide—non-isothermal recrystallization kinetics and thermal stability. Thermochim. Acta. 2018;655:134–141. doi: 10.1016/j.tca.2018.05.020. 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

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

Kawakami K. Crystallization Tendency of Pharmaceutical Glasses: Relevance to Compound Properties, Impact of Formulation Process, and Implications for Design of Amorphous Solid Dispersions. Pharmaceutics. 2019;11:202. doi: 10.3390/pharmaceutics11050202. PubMed DOI PMC

Kawakami K., Harada T., Yoshihashi Y., Yonemochi E., Terada K., Moriyama H. Correlation between Glass-Forming Ability and Fragility of Pharmaceutical Compounds. J. Phys. Chem. B. 2015;119:4873–4880. doi: 10.1021/jp509646z. PubMed DOI

Van Duong T., Lüdeker D., Van Bockstal P.-J., De Beer T., Van Humbeeck J., Van den Mooter G. Polymorphism of Indomethacin in Semicrystalline Dispersions: Formation, Transformation, and Segregation. Mol. Pharm. 2018;15:1037–1051. doi: 10.1021/acs.molpharmaceut.7b00930. PubMed DOI

Surwase S.A., Boetker J., Saville D., Boyd B., Gordon K., Peltonen L., Strachan C.J. Indomethacin: New Polymorphs of an Old Drug. Mol. Pharm. 2013;10:4472–4480. doi: 10.1021/mp400299a. PubMed DOI

Alonzo D.E., Zhang G.G.Z., Zhou D., Gao Y., Taylor L.S. Understanding the Behavior of Amorphous Pharmaceutical Systems during Dissolution. Pharm. Res. 2010;27:608–618. doi: 10.1007/s11095-009-0021-1. PubMed DOI

Lee A.Y., Erdemir D., Myerson A.S. Crystal Polymorphism in Chemical Process Development. Annu. Rev. Chem. Biomol. Eng. 2011;2:259–280. doi: 10.1146/annurev-chembioeng-061010-114224. PubMed DOI

Musumeci D., Hasebe M., Yu L. Crystallization of Organic Glasses: How Does Liquid Flow Damage Surface Crystal Growth? Cryst. Growth Des. 2016;16:2931–2936. doi: 10.1021/acs.cgd.6b00268. DOI

Hasebe M., Musumeci D., Powell C.T., Cai T., Gunn E., Zhu L., Yu L. Fast Surface Crystal Growth on Molecular Glasses and Its Termination by the Onset of Fluidity. J. Phys. Chem. B. 2014;118:7638–7646. doi: 10.1021/jp503110g. PubMed DOI

Newman A., Zografi G. WhatWe Need to Know about Solid-State Isothermal Crystallization of Organic Molecules from the Amorphous State below the Glass Transition Temperature. Mol. Pharm. 2020;17:1761–1777. doi: 10.1021/acs.molpharmaceut.0c00181. PubMed DOI

Zhang W., Brian C.W., Yu L. Fast Surface Diffusion of Amorphous o-Terphenyl and Its Competition with Viscous Flow in Surface Evolution. J. Phys. Chem. B. 2015;119:5071–5078. doi: 10.1021/jp5127464. PubMed DOI

Andronis V., Zografi G. Crystal nucleation and growth of indomethacin polymorphs from the amorphous state. J. Non-Cryst. Solids. 2000;271:236–248. doi: 10.1016/S0022-3093(00)00107-1. DOI

Ueda H., Ida Y., Kadota K., Tozuka Y. Raman mapping for kinetic analysis of crystallization of amorphous drug based on distributional images. Int. J. Pharm. 2014;462:115–122. doi: 10.1016/j.ijpharm.2013.12.025. PubMed DOI

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

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

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

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

Svoboda R. Crystallization of glasses—When to use the Johnson-Mehl-Avrami kinetics? J. Eur. Ceram. Soc. 2021;41:7862–7867. doi: 10.1016/j.jeurceramsoc.2021.08.026. DOI

Johnson W.A., Mehl K.F. Reaction kinetics in processes of nucleation and growth. Trans. Am. Inst. Min. (Metall) Eng. 1939;135:416–442.

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;7:212–224. doi: 10.1063/1.1750631. DOI

Avrami M. Granulation, phase change, and microstructure—kinetics of phase change III. J. Chem. Phys. 1941;7:177–184. doi: 10.1063/1.1750872. DOI

Svoboda R., Chovanec J., Slang S., Beneš L., Konrád 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

Thermo-Structural Characterization of Phase Transitions in Amorphous Griseofulvin: From Sub-Tg Relaxation and Crystal Growth to High-Temperature Decomposition

How the Presence of Crystalline Phase Affects Structural Relaxation in Molecular Liquids: The Case of Amorphous Indomethacin