PURPOSE: Amorphous active pharmaceutical ingredients (APIs) are generally considered to have significantly higher bioavailability, compared to their crystalline counterpart, due to the enhanced solubility of the disordered phase. However, an akin functionality can be also adopted by the particle size of the powdered API. In this case study, a detailed investigation of the particle-size-influenced properties of amorphous griseofulvin powders will be introduced. METHODS: The crystallization of amorphous griseofulvin powders in the range 20 - 1000 μm (+ 2 - 10 μm only for crystalline form) was studied calorimetrically, spectroscopically, and microscopically. Dissolution profiles of pharmaceutical tablets with incorporated either amorphous or crystalline griseofulvin were obtained under conditions simulating the path through the gastrointestinal tract. RESULTS: Standard crystal growth regime was accompanied by the rapid diffusionless growth mode, which was detected at low heating rates for the finest griseofulvin powders. The dissolution profiles of the pharmaceutical tablets with incorporated individual griseofulvin powder fractions were described in terms of the Korsmeyer-Peppas model (indicating the release by super case II transport). CONCLUSION: Particle size was found to play dominant role in the dissolution kinetics, whereas the difference in the dissolution rates of the crystalline and amorphous particles was rather negligible. This is a beneficial finding, considering the very low stability of finely powdered amorphous griseofulvin, but at the same time, it negates the primary purpose of amorphization. Main benefit is thus that of the coarse amorphous griseofulvin powder, which can be utilized to fine-tune the dissolution profile due to its delayed dissolution.

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

Zobrazit více v PubMed

Rathinasamy K, Jindal B, Asthana J, Singh P, Balaji PV, Panda D. Griseofulvin stabilizes microtubule dynamics, activates p53 and inhibits the proliferation of MCF-7 cells synergistically with vinblastine. BMC Cancer. 2010;10(1): 213. PubMed DOI PMC

Paguigan ND, Al-Huniti MH, Raja HA, Czarnecki A, Burdette JE, González-Medina M, et al. Chemoselective fluorination and chemoinformatic analysis of griseofulvin: natural vs fluorinated fungal metabolites. Bioorg Med Chem. 2017;25(20):5238–46. PubMed DOI PMC

Rebacz B, Larsen TO, Clausen MH, Rønnest MH, Löffler H, Ho AD, et al. Identification of griseofulvin as an inhibitor of centrosomal clustering in a phenotype-based screen. Cancer Res. 2007;67(13):6342–50. PubMed DOI

Berthier J. Chapter 9 - Cell manipulations in EWD. In: Berthier J, editor. Micro-drops and digital microfluidics (2nd edn). William Andrew Publishing; 2013. p. 367–86.

Diniz MO, Spoletti E, Ghosh P, Lusi M, Svärd M, Rasmuson Å, et al. New solid forms of griseofulvin: a solvate and a relict polymorph related to reported solvates. Cryst Growth Des. 2023;23(12):8953–61. PubMed DOI PMC

Su Y, Xu J, Shi Q, Yu L, Cai T. Polymorphism of griseofulvin: concomitant crystallization from the melt and a single crystal structure of a metastable polymorph with anomalously large thermal expansion. Chem Commun (Camb). 2018;54(4):358–61. PubMed DOI

Zhao S, Ma Y, Gong J, Hou B, Tang W. Solid-liquid phase equilibrium and thermodynamic analysis of griseofulvin in twelve mono-solvents. J Mol Liq. 2019;296:111861. DOI

Menczel JD, Judovits L, Prime RB, Bair HE, Reading M, Swier S, et al. Differential Scanning Calorimetry (DSC). Therm Anal Polym. 2009;7–239. https://doi.org/10.1002/9780470423837.ch2 .

Svoboda R, Málek J. Interpretation of crystallization kinetics results provided by DSC. Thermochim Acta. 2011;526(1):237–51. DOI

Brown M. Introduction to thermal analysis: techniques and applications. 2001.

Nickerson B, Kong A, Gerst P, Kao S. Correlation of dissolution and disintegration results for an immediate-release tablet. J Pharm Biomed Anal. 2018;150:333–40. PubMed DOI

Komersová A, Lochař V, Myslíková K, Mužíková J, Bartoš M. Formulation and dissolution kinetics study of hydrophilic matrix tablets with tramadol hydrochloride and different co-processed dry binders. Eur J Pharm Sci. 2016;95:36–45. PubMed DOI

Muselík J, Komersová A, Kubová K, Matzick K, Skalická B. A critical overview of FDA and EMA statistical methods to compare in vitro drug dissolution profiles of pharmaceutical products. Pharmaceutics. 2021;13(10): 1703. PubMed DOI PMC

Zheng K, Lin Z, Capece M, Kunnath K, Chen L, Davé RN. Effect of particle size and polymer loading on dissolution behavior of amorphous griseofulvin powder. J Pharm Sci. 2019;108(1):234–42. PubMed DOI

Rahman M, Ahmad S, Tarabokija J, Parker N, Bilgili E. Spray-dried amorphous solid dispersions of Griseofulvin in HPC/Soluplus/SDS: elucidating the multifaceted impact of SDS as a minor component. Pharmaceutics. 2020. https://doi.org/10.3390/pharmaceutics12030197 . PubMed DOI PMC

Briese L, Arvidson RS, Luttge A. The effect of crystal size variation on the rate of dissolution – a kinetic Monte Carlo study. Geochim Cosmochim Acta. 2017;212:167–75. DOI

Greco K, Bogner R. Crystallization of amorphous Indomethacin during dissolution: effect of processing and annealing. Mol Pharm. 2010;7(5):1406–18. PubMed DOI

Europe ECo. European pharmacopoeia. 11th ed. Strasbourg: EDQM Council of Europe; 2023.

Phillips DJ, Pygall SR, Cooper VB, Mann JC. Overcoming sink limitations in dissolution testing: a review of traditional methods and the potential utility of biphasic systems. J Pharm Pharmacol. 2012;64(11):1549–59. PubMed DOI

Temkin DE. The theory of diffusionless crystal growth. J Cryst Growth. 1969;5(3):193–202. DOI

Sun Y, Xi H, Ediger MD, Yu L. Diffusionless crystal growth from glass has precursor in equilibrium liquid. J Phys Chem B. 2008;112(3):661–4. PubMed DOI

Huang C, Ruan S, Cai T, Yu L. Fast surface diffusion and crystallization of amorphous griseofulvin. J Phys Chem B. 2017;121(40):9463–8. PubMed DOI

Mahieu A, Willart J-f, Dudognon E, Eddleston MD, Jones W, Danède F, et al. On the polymorphism of griseofulvin: identification of two additional polymorphs. J Pharm Sci. 2013;102(2):462–8. PubMed DOI

Kim S-M, Jeon H, Shin S-H, Park S-A, Jegal J, Hwang SY, et al. Superior toughness and fast self-healing at room temperature engineered by transparent elastomers. Adv Mater. 2018;30(1):1705145. DOI

Ratwani CR, Kamali AR, Abdelkader AM. Self-healing by Diels-Alder cycloaddition in advanced functional polymers: a review. Prog Mater Sci. 2023;131: 101001. DOI

Chen X, Dam MA, Ono K, Mal A, Shen H, Nutt SR, et al. A thermally re-mendable cross-linked polymeric material. Science. 2002;295(5560):1698–702. PubMed DOI

Irzhak VI, Uflyand IE, Dzhardimalieva GI. Self-healing of polymers and polymer composites. Polymers. 2022. https://doi.org/10.3390/polym14245404 . PubMed DOI PMC

Yanagisawa Y, Nan Y, Okuro K, Aida T. Mechanically robust, readily repairable polymers via tailored noncovalent cross-linking. Science. 2018;359(6371):72–6. PubMed DOI

Šesták J. Thermophysical properties of solids: their measurements and theoretical thermal analysis. Elsevier; 2021.

Šesták J. Chapter 11 - Non-isothermal kinetic by thermal analysis. In: Šesták J, editor. Science of heat and thermophysical studies. Amsterdam: Elsevier Science; 2005. p. 318–43. DOI

Avrami M. Kinetics of phase change. I general theory. J Chem Phys. 1939;7(12):1103–12. DOI

Avrami M. Kinetics of phase change. II transformation‐time relations for random distribution of nuclei. J Chem Phys. 1940;8(2):212–24. DOI

Avrami M. Granulation, phase change, and microstructure kinetics of phase change. III The Journal of Chemical Physics. 1941;9(2):177–84. DOI

Svoboda R. Crystallization of glasses – when to use the Johnson-Mehl-Avrami kinetics? J Eur Ceram Soc. 2021;41(15):7862–7. DOI

Kissinger HE. Reaction kinetics in differential thermal analysis. Anal Chem. 1957;29(11):1702–6. DOI

Friedman HL. Kinetics of thermal degradation of char-forming plastics from thermogravimetry. Application to a phenolic plastic. J Polym Sci C Polym Symp. 1964;6(1):183–95. DOI

Starink MJ. The determination of activation energy from linear heating rate experiments: a comparison of the accuracy of isoconversion methods. Thermochim Acta. 2003;404(1):163–76. DOI

Luciano G, Svoboda R. Activation energy determination in case of independent complex kinetic processes. Processes. 2019. https://doi.org/10.3390/pr7100738 . DOI

Svoboda R, Luciano G. Complex process activation energy evaluated by combined utilization of differential and integral isoconversional methods. J Non-Cryst Solids. 2020;535: 120003. DOI

Svoboda R, Málek J. Is the original Kissinger equation obsolete today? J Therm Anal Calorim. 2014;115(2):1961–7. DOI

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. https://doi.org/10.3390/pharmaceutics11050202 . PubMed DOI PMC

Musumeci D, Hasebe M, Yu L. Crystallization of organic glasses: how does liquid flow damage surface crystal growth? Cryst Growth Des. 2016;16(5):2931–6. DOI

Svoboda R, Koutná N, Košťálová D, Krbal M, Komersová A. Indomethacin: effect of diffusionless crystal growth on thermal stability during long-term storage. Molecules. 2023. https://doi.org/10.3390/molecules28041568 . 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(2):856–72. PubMed 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

Gibaldi M, Feldman S. Establishment of sink conditions in dissolution rate determinations. Theoretical considerations and application to nondisintegrating dosage forms. J Pharm Sci. 1967;56(10):1238–42. PubMed DOI

Fosca M, Rau JV, Uskoković V. Factors influencing the drug release from calcium phosphate cements. Bioact Mater. 2022;7:341–63. PubMed

Berthier J. Chapter 7 - Electrowetting on Curved Surfaces. In: Berthier J, editor. Micro-Drops and Digital Microfluidics. 2nd ed. William Andrew Publishing; 2013. p. 325–37. DOI

Berthier J. Chapter 14 - Introduction to droplet microfluidics and multiphase microflows. In: Berthier J, eds. Micro-Drops and Digital Microfluidics (2nd edn): William Andrew Publishing; 2013. p. 493–532.