Dissolution Enhancement of Ketoconazole by Melt Granulation Co-Processing

Abstract

Background: Melt granulation (MG) is a simple operation involving a uniform mixture of active ingredients with a melted polymeric carrier. However, this process can also enhance a drug's biopharmaceutical properties by augmenting its dissolution rate and, thus, its absorption.

Purpose: By applying MG technology, current research focuses on developing co-processed ketoconazole with a higher aqueous dissolution rate than its pure form.

Methods: A measure of how the type and proportion of polymeric carriers affect the crystallinity and dissolution rate of co-processed ketoconazole materials was performed. MG prepared materials in a high-shear mixer using co-povidone (Kollidon®) VA 64, HPMCAS HF as polymeric carriers, PEG 1450 (Kollisolv®) and triethyl citrate as plasticizers.

Results: The co-processed ketoconazole materials exhibited miscibility in the polymeric systems, as indicated by the reduction in the enthalpy of fusion. Drug crystallinity was significantly reduced in the HPMCAS HF polymeric system, confirmed by XRPD and ATR-FTIR studies. The dissolution rate was enhanced by using a higher drug concentration in a co-povidone VA 64 environment; contrarily, for HPMCAS HF, a higher drug dilution was observed to favor the dissolution rate.

Conclusions: MG is a handy, low-cost technology that develops dissolution-enhanced co-processed active pharmaceutical ingredients, spotting specific carrier-drug interactions. MG yields scalable, proven processes, raising interest in its applications in optimizing drug therapeutic efficacy. Ultimately, this technology for dissolution enhancement could bring lower-cost, high-efficiency drugs to improve patients' quality of life.

  • Page Number : 1–14
  • Published Date : 2024-11-20
  • Keywords
    Melt granulation, Dissolution rate, High-shear mixer, Co-processed ketoconazole
  • DOI Number
    10.15415/jprtm.2024.122001
  • Authors
    Abigail Garcia-Radilla, Mariana Ortiz-Reynoso , Gabriel Cuevas , Edna T. Alcantara-Fierro , and Jonnathan G. Santillán-Benitez

References

  • Auch, C., Jede, C., Harms, M., Wagner, C., & Mäder, K. (2020). Impact of amorphization and GI physiology on supersaturation and precipitation of poorly soluble weakly basic drugs using a small-scale in vitro transfer model. International Journal of Pharmaceutics, 574, 118917. https://doi.org/10.1016/j.ijpharm.2019.118917
  • Bouffard, J., Bertrand, F., & Chaouki, J. (2012). A multiscale model for the simulation of granulation in rotor-based equipment. Chemical engineering science, 81, 106-117. https://doi.org/10.1016/j.ces.2012.06.025
  • Chan, S. Y., Chung, Y. Y., Cheah, X. Z., Tan, E. Y. L., & Quah, J. (2015). The characterization and dissolution performances of spray dried solid dispersion of ketoprofen in hydrophilic carriers. Asian journal of pharmaceutical sciences, 10(5), 372-385. https://doi.org/10.1016/j.ajps.2015.04.003
  • Coksu, I., Bozkurt, Y., Akmayan, I., Demirci, H., Ozbek, T., & Acar, S. (2023). Ketoconazole-loading strategy to improve antifungal activity and overcome cytotoxicity on human renal proximal tubular epithelial cells. Nanotechnology, 35(11), 115702. https://doi.org/10.1088/1361-6528/ad1444
  • Crowley, K. J., Forbes, R. T., York, P., Nyqvist, H., & Camber, O. (2000). Drug-fatty acid salt with wax-like properties employed as binder in melt granulation. International journal of pharmaceutics, 211(1-2), 9-17. https://doi.org/10.1016/S0378-5173(00)00577-9
  • De Almeida, R. F., Santos, F. C., Marycz, K., Alicka, M., Krasowska, A., Suchodolski, Panek, J.J., Jezierska, A., & Starosta, R. (2019). New diphenylphosphane derivatives of ketoconazole are promising antifungal agents. Scientific reports, 9(1), 16214. https://doi.org/10.1038/s41598-019-52525-7
  • Duarte Alaniz, V., Rocha‐Rinza, T., & Cuevas, G. (2015). Assessment of hydrophobic interactions and their contributions through the analysis of the methane dimer. Journal of Computational Chemistry, 36(6), 361-375. https://doi.org/10.1002/jcc.23798
  • European Medicines Agency (EMA). Committee for Medicinal Products for Human Use (CHMP). (2014). Public Assessment Report Ketoconazole HRA EMA/CHMP/534845/2014. Public Assessment Report, 44(September), 1–115. https://www.ema.europa.eu/en/documents/assessment-report/ketoconazole-hra-epar-public-assessment-report_en.pdf
  • Freichel, O. L., & Lippold, B. C. (2001). An easy producible new oral hydrocolloid drug delivery system with a late burst in the release profile. International journal of pharmaceutics, 216(1-2), 165-169. https://doi.org/10.1016/S0378-5173(01)00586-5
  • Garcia, A., Ortiz, M., Alcantara, E., Santillan, J., & Hernández, F. (2024). Accelerating the development of solubility-enhanced solid dispersions: use of multiscale and mathematical prediction of drug-polymer miscibility. European Journal of Pharmaceutical and Medical Research, 11(2), 184–196.
  • Garcia-Radilla, A., Ortiz-Reynoso, M., Santillán-Benítez, J. G., & Alcantara-Fierro, E. T. (2023). Dispersiones sólidas de solubilidad mejorada fabricadas en mezcladores de alto corte: una oportunidad para la industria farmacéutica local mexicana. Revista Colombiana de Ciencias Químico-Farmacéuticas, 52(1). https://doi.org/10.15446/rcciquifa.v52n1.102588
  • Jadav, N. B., & Paradkar, A. (2020). Solid dispersions: technologies used and future outlook. Nanopharmaceuticals, 91-120. https://doi.org/10.1016/B978-0-12-817778-5.00005-1
  • Jaspers, M., Roelofs, T. P., Janssen, P. H., Meier, R., & Dickhoff, B. H. (2022). A novel approach to minimize loss of compactibility in a dry granulation process using superdisintegrants. Powder Technology, 408, 117773. https://doi.org/10.1016/j.powtec.2022.117773
  • Lee, J. H., Jeong, H. S., Jeong, J. W., Koo, T. S., Kim, D. K., Cho, Y. H., & Lee, G. W. (2021). The development and optimization of hot-melt extruded amorphous solid dispersions containing Rivaroxaban in combination with polymers. Pharmaceutics, 13(3), 344. https://doi.org/10.3390/pharmaceutics13030344
  • Medarević, D., Djuriš, J., Barmpalexis, P., Kachrimanis, K., & Ibrić, S. (2019). Analytical and computational methods for the estimation of drug-polymer solubility and miscibility in solid dispersions development. Pharmaceutics, 11(8), 372. https://doi.org/10.3390/pharmaceutics11080372
  • Nair, A. R., Lakshman, Y. D., Anand, V. S. K., Sree, K. N., Bhat, K., & Dengale, S. J. (2020). Overview of extensively employed polymeric carriers in solid dispersion technology. AAPS PharmSciTech, 21, 1-20. https://doi.org/10.1208/s12249-020-01849-z
  • Perissutti, B., Rubessa, F., Moneghini, M., & Voinovich, D. (2003). Formulation design of carbamazepine fast-release tablets prepared by melt granulation technique. International journal of pharmaceutics, 256(1-2), 53-63. https://doi.org/10.1016/S0378-5173(03)00062-0
  • Ramirez-Gualito, K., Alonso-Rios, R., Quiroz-Garcia, B., Rojas-Aguilar, A., Diaz, D., Jimenez-Barbero, J., & Cuevas, G. (2009). Enthalpic nature of the CH/π interaction involved in the recognition of carbohydrates by aromatic compounds, confirmed by a novel interplay of NMR, calorimetry, and theoretical calculations. Journal of the American Chemical Society, 131(50), 18129-18138. https://doi.org/10.1021/ja903950t
  • Rask, M. B., Knopp, M. M., Olesen, N. E., Holm, R., & Rades, T. (2016). Influence of PVP/VA copolymer composition on drug–polymer solubility. European journal of pharmaceutical sciences, 85, 10-17. https://doi.org/10.1016/j.ejps.2016.01.026
  • Sarpal, K., Tower, C. W., & Munson, E. J. (2019). Investigation into intermolecular interactions and phase behavior of binary and ternary amorphous solid dispersions of ketoconazole. Molecular Pharmaceutics, 17(3), 787-801. https://doi.org/10.1021/acs.molpharmaceut.9b00970
  • Singh, M., Shirazian, S., Ranade, V., Walker, G. M., & Kumar, A. (2022). Challenges and opportunities in modelling wet granulation in pharmaceutical industry–a critical review. Powder Technology, 403, 117380. https://doi.org/10.1016/j.powtec.2022.117380
  • Steffens, K. E., Brenner, M. B., Hartig, M. U., Monschke, M., & Wagner, K. G. (2020). Melt granulation: a comparison of granules produced via high-shear mixing and twin-screw granulation. International Journal of Pharmaceutics, 591, 119941. https://doi.org/10.1016/j.ijpharm.2020.119941
  • Tamez-Fernández, J. F., Soto-Suárez, F. M., Estrada-Chavarría, Y. D., Quijano-Quiñones, R. F., Toscano, R. A., Cuétara-Guadarrama, F., & Cuevas, G. (2021). Effect of the nO→ π* C═ O Interaction on the Conformational Preference of 1, 3-Diketones: A Case Study of Riolozatrione Derivatives. The Journal of Organic Chemistry, 86(14), 9540-9551. https://doi.org/10.1021/acs.joc.1c00847
  • Vaka, S. R. K., Bommana, M. M., Desai, D., Djordjevic, J., Phuapradit, W., & Shah, N. (2014). Excipients for amorphous solid dispersions. Amorphous solid dispersions: Theory and practice, 123-161. https://doi.org/10.1007/978-1-4939-1598-9_4
  • Yazdani, A., Höhne, G. W., Misture, S. T., & Graeve, O. A. (2020). A method to quantify crystallinity in amorphous metal alloys: A differential scanning calorimetry study. PloS one, 15(6), e0234774. https://doi.org/10.1371/JOURNAL.PONE.0234774
  • Ye, G., Wang, S., Heng, P. W. S., Chen, L., & Wang, C. (2007). Development and optimization of solid dispersion containing pellets of itraconazole prepared by high shear pelletization. International journal of pharmaceutics, 337(1-2), 80-87. https://doi.org/10.1016/j.ijpharm.2006.12.028