Sains Malaysiana 54(6)(2025): 1593-1604

http://doi.org/10.17576/jsm-2025-5406-14

 

Enhanced Solubility and Dissolution of Ketoconazole through Co-Amorphization with Fumaric and Tartaric Acid via Co-Milling

(Peningkatan Keterlarutan dan PelarutanKetokonazol melalui Amorfisasi Bersama dengan Fumarik dan Acid Tartarik melalui Pengisaran Bersama)

 

INDRA INDRA^1,*, RANI NURANI¹ & WINDA TRISNA WULANDARI²

 

¹Pharmaceutics Group, Faculty of Pharmacy, Universitas Bakti Tunas Husada, Tasikmalaya, 46115, Indonesia

²Pharmacochemistry Group, Faculty of Pharmacy, Universitas Bakti Tunas Husada, Tasikmalaya, 46115, Indonesia

 

Diserahkan: 17 Disember 2024/Diterima: 24 April 2025

 

Abstract

This study investigates the co-amorphization of ketoconazole (KTZ) with fumaric acid (FA) and tartaric acid (TA) through co-milling, aiming to enhance the solubility, stability, and dissolution properties of this poorly water-soluble antifungal. Phase diagrams obtained via Hot Stage Microscopy (HSM) showed eutectic-like behavior at equimolar ratios for both KTZ-FA and KTZ-TA systems, with a more pronounced melting point depression in KTZ-FA, indicative of stronger molecular interactions fostering stable amorphous formation. Solid-state characterization using Powder X-ray Diffraction, Fourier Transform Infrared Spectroscopy, and Differential Scanning Calorimetry confirmed amorphization and showed significant hydrogen bonding in KTZ-FA. Further analyses with Thermogravimetric Analysis and Scanning Electron Microscopy demonstrated reduced thermal stability and particle size, accompanied by homogenous amorphous morphologies. Solubility and dissolution studies highlighted remarkable improvements: solubilities of KTZ-FA and KTZ-TA were 11.652 mg/mL and 8.750 mg/mL, respectively, compared to 0.060 mg/mL for pure KTZ. Dissolution profiles indicated superior performance of KTZ-FA at neutral pH, attributed to enhanced hydrogen bonding. Taken together, these findings position the co-amorphous KTZ–FA and KTZ–TA systems as promising candidates for developing rapid-acting oral antifungal dosage forms with improved bioavailability and patient compliance.

Keywords: Co-amorphization; co-milling; ketoconazole solubility; solid-state characterization

 

Abstrak

Penyelidikan ini mengkaji amorfisasi bersama ketokonazol (KTZ) bersama asid fumarik (FA) dan asid tartarik (TA) melalui proses pengisaran bersama bagi meningkatkan keterlarutan, kestabilan dan kadar pelarutan ubat antikulat yang kurang larut dalam air ini. Rajah fasa yang diperoleh melalui Mikroskop Panas (HSM) menunjukkan tingkah laku seperti eutektoid pada nisbah molar 1:1 dalam kedua-dua sistem KTZ-FA dan KTZ-TA, dengan penurunan titik lebur yang lebih ketara dalam KTZ-FA, mencadangkan interaksi molekul yang lebih kuat yang menyokong pembentukan fasa amorfus yang stabil. Pencirian keadaan pepejal melalui Pembelauan Sinar-X Serbuk (PXRD), Spektroskopi Inframerah Transformasi Fourier (FTIR) dan Kalorimetri Pengimbasan Pembezaan (DSC) mengesahkan pembentukan amorfus serta menonjolkan pembentukan ikatan hidrogen yang signifikan dalam KTZ-FA. Pengesahan lanjut oleh Analisis Termogravimetrik (TGA) dan Mikroskop Imbasan Elektron (SEM) menunjukkan penurunan kestabilan terma dan saiz zarah dengan morfologi amorfus yang homogen. Kajian keterlarutan dan pelarutan menunjukkan peningkatan yang ketara: KTZ-FA dan KTZ-TA mencapai keterlarutan masing-masing sebanyak 11.652 mg/mL dan 8.750 mg/mL berbanding 0.060 mg/mL bagi KTZ tulen. Profil pelarutan menunjukkan prestasi yang lebih unggul bagi KTZ-FA pada pH neutral, mungkin disebabkan oleh ikatan hidrogen yang lebih kuat. Secara keseluruhan, penemuan ini meletakkan sistem ko-amorfus KTZ–FA dan KTZ–TA sebagai calon yang berpotensi untuk pembangunan bentuk dos antikulat oral bertindak pantas dengan bio keterdapatan yang lebih baik dan pematuhan pesakit yang meningkat.

Kata kunci: Keterlarutan ketokonazol; ko-amorfisasi; pencirian keadaan pepejal; pengisaran bersama

 

RUJUKAN

Adachi, M., Hinatsu, Y., Kusamori, K., Katsumi, H., Sakane, T., Nakatani, M., Wada, K. & Yamamoto, A. 2015. Improved dissolution and absorption of ketoconazole in the presence of organic acids as pH-modifiers. European Journal of Pharmaceutical Sciences 76: 225-230. https://doi.org/10.1016/j.ejps.2015.05.015

An, J.H., Lim, C., Kiyonga, A.N., Chung, I.H., Lee, I.K., Mo, K., Park, M., Youn, W., Choi, W.R., Suh, Y.G. & Jung, K. 2018. Co-amorphous screening for the solubility enhancement of poorly water-soluble mirabegron. Pharmaceutics10(3): 149. https://doi.org/10.3390/pharmaceutics10030149

Aysha Aslam, Muhammad Amer Ashraf, Kashif Barkat, Asif Mahmood, Muhammad Ajaz Hussain, Muhammad Farid-ul-Haq, Manar O Lashkar & Heba A. Gad. 2023. Fabrication of stimuli-responsive quince/mucin co-poly (methacrylate) hydrogel matrices for the controlled delivery of acyclovir sodium: Design, characterization and toxicity evaluation. Pharmaceutics 15(2): 650. https://doi.org/10.3390/pharmaceutics15020650

Baghel, S., Cathcart, H. & O’Reilly, N.J. 2016. Polymeric amorphous solid dispersions. Journal of Pharmaceutical Sciences 105(9): 2527-2544. https://doi.org/10.1016/j.xphs.2015.10.008

Baldea, I., Moldovan, R., Nagy, A-L., Bolfa, P., Decea, R., Miclaus, M.O., Lung, I., Gherman, A.M.R., Sevastre-Berghian, A., Martin, F.A., Kacso, I. & Răzniceanu, V. 2024. Ketoconazole-fumaric acid pharmaceutical cocrystal: From formulation design for bioavailability improvement to biocompatibility testing and antifungal efficacy evaluation. International Journal of Molecular Sciences 25(24): 13346. https://doi.org/10.3390/ijms252413346

Budiman, A., Lailasari, E., Nurani, N.V., Yunita, E.N., Anastasya, G., Aulia, R.N., Lestari, I.N., Subra, L. & Aulifa, D.L. 2023. Ternary solid dispersions: A review of the preparation, characterization, mechanism of drug release, and physical stability. Pharmaceutics 15(8): 2116. https://doi.org/10.3390/pharmaceutics15082116

Chen, Y. & Rodríguez-Hornedo, N. 2018. Cocrystals mitigate negative effects of high pH on solubility and dissolution of a basic drug. Crystal Growth & Design 18(3): 1358-1366. https://doi.org/10.1021/acs.cgd.7b01206

Ding, Y., Xu, S., Ding, C.Z., Zhang, Z. & Xu, Z. 2024. Randomly methylated β-cyclodextrin inclusion complex with ketoconazole: Preparation, characterization, and improvement of pharmacological profiles. Molecules 29(9): 1915. https://doi.org/10.3390/molecules29091915

Fael, H. & Demirel, A.L. 2020. Tannic acid as a co-former in co-amorphous systems: Enhancing their physical stability, solubility and dissolution behavior. International Journal of Pharmaceutics 581: 119284. https://doi.org/10.1016/j.ijpharm.2020.119284

Feng, Y., Wang, H., Wu, D., Chen, K., Wang, N., Wang, T., Huang, X., Zhou, L. & Hao, H. 2024. Polymorph transformation of solid drugs and inhibiting strategies. CrystEngComm 26(46): 6510-6544. https://doi.org/10.1039/D4CE00811A

Fung, M., Berzins, K. & Suryanarayanan, R. 2018. Physical stability and dissolution behavior of ketoconazole-organic acid coamorphous systems. Molecular Pharmaceutics 15(5): 1862-1869. https://doi.org/10.1021/acs.molpharmaceut.8b00035

Guinet, Y., Paccou, L. & Hédoux, A. 2023. Mechanism for stabilizing an amorphous drug using amino acids within co-amorphous blends. Pharmaceutics 15(2): 337. https://doi.org/10.3390/pharmaceutics15020337

Hatanaka, Y., Uchiyama, H., Kadota, K. & Tozuka, Y. 2021. Improved solubility and permeability of both nifedipine and ketoconazole based on coamorphous formation with simultaneous dissolution behavior. Journal of Drug Delivery Science and Technology 65: 102715. https://doi.org/10.1016/J.JDDST.2021.102715

Heikkinen, A., Declerck, L., Löbmann, K., Grohganz, H., Rades, T. & Laitinen, R. 2015. Dissolution properties of co-amorphous drug-amino acid formulations. Die Pharmazie 70(7): 452-457.

Hiendrawan, S., Hartanti, A., Veriansyah, B., Widjojokusumo, E. & Tjandrawinata, R. 2015. Solubility enhancement of ketoconazole via salt and cocrystal formation. International Journal of Pharmacy and Pharmaceutical Sciences 7: 160-164.

Hou, J., Zhao, P., Wang, Y., Jiang, X. & Fu, Q. 2024. Co-amorphization of acemetacin with basic amino acids as co-formers for solubility improvement and side effect mitigation. Pharmaceutics 16(6): 745. https://doi.org/10.20944/preprints202405.0123.v1

Indra, I., Wikarsa, S., Nugraha, Y.P., Suendo, V., Uekusa, H. & Soewandhi, S.N. 2023. Utilizing hot-stage polarized microscopy and ATR-FTIR for ramipril co-crystal screening, supported by principal component analysis and cluster analysis. J. Pharm. Pharmacogn. Res. 11(6): 1137-1148. https://doi.org/10.56499/jppres23.1723_11.6.1137

Ishikawa, M. & Hashimoto, Y. 2011. Improvement in aqueous solubility in small molecule drug discovery. Journal of Medicinal Chemistry 54(6): 1539-1554. https://doi.org/10.1021/jm101356p

Jensen, K.T., Löbmann, K., Rades, T. & Grohganz, H. 2014. Improving co-amorphous drug formulations by the addition of the highly water-soluble amino acid, proline. Pharmaceutics 6: 416-435. https://doi.org/10.3390/pharmaceutics6030416

Jermain, S.V., Brough, C. & Williams, R. 2018. Amorphous solid dispersions for poorly water-soluble drugs. International Journal of Pharmaceutics 535: 379-392. https://doi.org/10.1016/j.ijpharm.2017.10.051

Kadri, L., Casali, L., Emmerling, F. & Tajber, L. 2024. Mechanochemical comparison of ball milling processes for levofloxacin amorphous polymeric systems. International Journal of Pharmaceutics 665: 124652. https://doi.org/https://doi.org/10.1016/j.ijpharm.2024.124652

Kanaujia, P., Poovizhi, P., Ng, W. & Tan, R. 2015. Amorphous formulations for bioavailability enhancement. Powder Technology 285: 2-15. https://doi.org/10.1016/J.POWTEC.2015.05.012

Kapoor, D.U., Singh, S., Sharma, P. & Prajapati, B. 2023. Amorphization of low soluble drug with amino acids. AAPS PharmSciTech. 24: 253. https://doi.org/10.1208/s12249-023-02709-2

Karagianni, A., Malamatari, M. & Kachrimanis, K. 2018. Pharmaceutical cocrystals: New solid phase modification approaches for the formulation of APIs. Pharmaceutics 10(1): 18. https://doi.org/10.3390/pharmaceutics10010018

Keramatnia, F., Jouyban, A., Valizadeh, H., Delazar, A. & Shayanfar, A. 2016. Ketoconazole ionic liquids with citric and tartaric acid: Synthesis, characterization and solubility study. Fluid Phase Equilibria 425: 108-113. https://doi.org/10.1016/J.FLUID.2016.05.016

Khatri, V. & Dey, P. 2025. Exploring the dielectric properties of herbal medicine and modern pharmaceuticals: An integrative review. Frontiers in Pharmacology 15: 1536397. https://doi.org/10.3389/fphar.2024.1536397

Liu, J., Grohganz, H. & Rades, T. 2020. Influence of polymer addition on the amorphization, dissolution and physical stability of co-amorphous systems. International Journal of Pharmaceutics 588: 119768. https://doi.org/10.1016/j.ijpharm.2020.119768

Mithu, M.S.H., Ross, S.A., Hurt, A.P. & Douroumis, D. 2021. Effect of mechanochemical grinding conditions on the formation of pharmaceutical cocrystals and co-amorphous solid forms of ketoconazole – Dicarboxylic acid. Journal of Drug Delivery Science and Technology 63: 102508. https://doi.org/10.1016/J.JDDST.2021.102508

Mohan, S., Li, Y., Chu, K., De La Paz, L., Sperger, D., Shi, B., Foti, C., Rucker, V. & Lai, C. 2024. Integrative salt selection and formulation optimization: Perspectives of disproportionation and microenvironmental pH modulation. Molecular Pharmaceutics 21(5): 2590-2605. https://doi.org/10.1021/acs.molpharmaceut.4c00166

Paisana, M.C., Lino, P.R., Nunes, P.D., Pinto, J.F., Henriques, J. & Paiva, A.M. 2021. Laser diffraction as a tool for amorphous solid dispersion screening. European Journal of Pharmaceutical Sciences 163: 105853. https://doi.org/10.1016/j.ejps.2021.105853

Park, J., Cho, W., Cha, K., Ahn, J., Han, K. & Hwang, S. 2013. Solubilization of the poorly water soluble drug, telmisartan, using supercritical anti-solvent process. International Journal of Pharmaceutics 441(1-2): 50-55. https://doi.org/10.1016/j.ijpharm.2012.12.020

Peltonen, L. & Strachan, C.J. 2020. Degrees of order: A comparison of nanocrystal and amorphous solids for poorly soluble drugs. International Journal of Pharmaceutics 586: 119492. https://doi.org/https://doi.org/10.1016/j.ijpharm.2020.119492

Reppas, C., Kuentz, M., Bauer-Brandl, A., Carlert, S., Dallmann, A., Dietrich, S., Dressman, J., Ejskjaer, L., Frechen, S., Guidetti, M., Holm, R., Holzem, F.L., Karlsson, Ε., Kostewicz, E., Panbachi, S., Paulus, F., Senniksen, M.B., Stillhart, C., Turner, D.B., Vertzoni, M., Vrenken, P., Zöller, L., Griffin, B.T. & O'Dwyer, P.J. 2023. Leveraging the use of in vitro and computational methods to support the development of enabling oral drug products: An inpharma commentary. European Journal of Pharmaceutical Sciences 188: 106505. https://doi.org/https://doi.org/10.1016/j.ejps.2023.106505

Saberi, A., Kouhjani, M., Yari, D., Jahani, A. & Salimi, A. 2023. Development, recent advances, and updates in binary, ternary co-amorphous systems, and ternary solid dispersions. Journal of Drug Delivery Science and Technology 86: 104746. https://doi.org/10.1016/j.jddst.2023.104746

Sakaguchi, Y., Takata, S., Kawakita, Y., Fujimura, Y. & Kondo, K. 2023. Direct observation of concentration fluctuations in Au–Si eutectic liquid by small-angle neutron scattering. Journal of Physics Condensed Matter 35(41): 415403. https://doi.org/10.1088/1361-648x/ace577

Shayanfar, A. & Jouyban, A. 2014. Physicochemical characterization of a new cocrystal of ketoconazole. Powder Technology 262: 242-248. https://doi.org/10.1016/J.POWTEC.2014.04.072

Singh, M., Murugan, N.A., Kongsted, J., Zhan, P., Banerjee, U.C. & Poongavanam, V. 2024. Molecular insights from spectral and computational studies on crystalline and amorphous telmisartan. Crystal Growth & Design 24(15): 6354-6363. https://doi.org/10.1021/acs.cgd.4c00608

Trzeciak, K., Wielgus, E., Kaźmierski, S., Pawlak, T. & Potrzebowski, M.J. 2023. Amorphization of ethenzamide and ethenzamide cocrystals - A case study of single and binary systems forming low-melting eutectic phases loaded on/in silica gel. Pharmaceutics 15(4): 1234. https://doi.org/10.3390/pharmaceutics15041234

Tsume, Y., Mudie, D.M., Langguth, P. & Amidon, G. 2014. Biopharmaceutics classification system subclasses. European Journal of Pharmaceutical Sciences 57: 152-163. https://doi.org/10.1016/j.ejps.2014.01.009

van den Bruinhorst, A., Corsini, C., Depraetère, G., Cam, N., Pádua, A. & Costa Gomes, M. 2024. Deep eutectic solvents on a tightrope: Balancing the entropy and enthalpy of mixing. Faraday Discussions 253: 273-288. https://doi.org/10.1039/d4fd00048j

Vijayakumar, V.N., Chakravarty, S., Sundaram, S., Chitravel, T., Balasubramanian, V., Sukanya, R. & Tharani, A. 2024. Hydrogen bond thermotropic ferroelectric liquid crystal of DL-tartaric acid and 4-heptyloxybenzoic acid (1:1): Experimental and density functional theory (DFT) approach. Journal of Molecular Structure 1316: 138819. https://doi.org/https://doi.org/10.1016/j.molstruc.2024.138819

Wilke, S.K., Al-Rubkhi, A., Benmore, C.J., Byrn, S.R. & Wéber, R. 2024. Modeling the structure of ketoprofen-poly(vinylpyrrolidone) amorphous solid dispersions with empirical potential structure refinements of x-ray scattering data. Molecular Pharmaceutics 21(8): 3967-3978. https://doi.org/10.1021/acs.molpharmaceut.4c00313

Wu, H., Ma, J., Qian, S., Jiang, W., Liu, Y., Li, J., Ke, Z. & Feng, K. 2023. Co-amorphization of posaconazole using citric acid as an acidifier and a co-former for solubility improvement. Journal of Drug Delivery Science and Technology 80: 104136. https://www.sciencedirect.com/science/article/pii/S1773224722010474.

Yang, Y., Ke, Y., Xie, W., Li, Z., Tao, L., Shen, W., Chen, Y., Cheng, H., Chen, J., Yan, G., Li, W., Li, M. & Li, J. 2024. Amphiphilic disodium glycyrrhizin as a co-former for ketoconazole co-amorphous systems: Biopharmaceutical properties and underlying molecular mechanisms. International Journal of Pharmaceutics 665: 124673. https://doi.org/https://doi.org/10.1016/j.ijpharm.2024.124673

Yu, H., Zhang, L., Liu, M., Yang, D. & He, G. 2023. Enhancing solubility and dissolution rate of antifungal drug ketoconazole through crystal engineering. Pharmaceuticals 16(10): 1349. https://doi.org/10.3390/ph16101349

 

*Pengarang untuk surat-menyurat; email: indra@universitas-bth.ac.id