Preparation and Characterization of a Eutectic Mixture of Fenofibric Acid and Nicotinic Acid and Evaluatuion of In Vivo Antihyperlipidemic Activity
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Keywords:
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Fenofibric Acid, Nicotinic Acid, Eutectic Mixture, Dissolution Rate, Solubility
Abstract
Fenofibric Acid (FA) is classified under Biopharmaceutical Classification System (BCS) class II due to its poorly soluble in water and high permeability. The present study aimed to prepare the eutectic mixture of FA with nicotinic acid (NA) and characterize its solid state properties and in vitro dissolution rate, along with its in vivo antihyperlipidemic activity. Solvent drop grinding was the method chosen to prepare the eutectic mixture of FA and NA. Solid-state properties were evaluated using thermal analysis Differential Scanning Calorimetry (DSC), crystallographic analysis Powder X-Ray Diffraction (PXRD), FT-IR spectroscopic analysis, and Scanning Electron Microscopy (SEM). To examine in vivo antihyperlipidemic activity, 16 male Swiss Webster rats were injected with 1% hyperlipidemia-inducing solution, followed by the oral administration of 9.45 mg/kg FA and NA (equivalent to 9.45 mg/kg FA), after which the decrease in cholesterol levels was measured. Two-way ANOVA was used to evaluate the data, followed by Duncan’s multiple range test (95% confidence interval). The results proved that FA formed the eutectic mixture with NA at a molar ratio of 6:4. The eutectic mixture of FA-NA had a better solubility and in vitro dissolution rate compared to intact FA, which also led to notably improved antihyperlipidemic activity.
References
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Bazzo, G. C., B. R. Pezzini, and H. K. Stulzer (2020). Eutectic Mixtures as an Approach to Enhance Solubility, Dissolution Rate and Oral Bioavailability of Poorly Water-soluble Drugs. International Journal of Pharmaceutics, 588; 119741
Chadha, K., M. Karan, R. Chadha, Y. Bhalla, and K. Vasisht (2017). Is Failure of Cocrystallization Actually A Failure? Eutectic Formation in Cocrystal Screening of Hesperetin. Journal of Pharmaceutical Sciences, 106(8); 2026–2036
Chaturvedi, K., H. S. Shah, K. Nahar, R. Dave, and K. R. Morris (2020). Contribution of Crystal Lattice Energy on the Dissolution Behavior of Eutectic Solid Dispersions. ACS Omega, 5(17); 9690–9701
Cink, R. D., J. B. Paterson Jr, Y. Gao, G. G. Zhang, M. A. Long, J. B. Morris, and J. Rosenberg (2013). Salts of Fenofibric Acid and Pharmaceutical Formulations Thereof. US Patent App. 13/619,165
Dalal, N., I. S. Buckner, and P. L. Wildfong (2017). Experimental Determination and Theoretical Calculation of the Eutectic Composition of Cefuroxime Axetil Diastereomers. AAPS PharmSciTech, 18(7); 2570–2578
Davis, R. E., K. A. Lorimer, M. A. Wilkowski, J. H. Rivers, K. A. Wheeler, and J. Bowers (2004). Studies of Phase Relationships in Cocrystal Systems. Crystals in Supramolecular Chemistry, 39; 41À61
Dressman, J., M. Vertzoni, K. Goumas, and C. Reppas (2007). Estimating Drug Solubility in the Gastrointestinal Tract. Advanced Drug Delivery Reviews, 59(7); 591–602
Dwichandra Putra, O., E. Yonemochi, and H. Uekusa (2016). Isostructural Multicomponent Gliclazide Crystals with Improved Solubility. Crystal Growth & Design, 16(11); 6568–6573
Erizal, E., S. Cahyati, S. Nurono, et al. (2008). Effect of Milling on Solid State Transformation of Sulfamethoxazole. International Journal of Pharmaceutics, 4; 140–144
Fernandes, R. P., A. C. S. de Carvalho, B. Ekawa, A. L. S. C. do Nascimento, A. M. Pironi, M. Chorilli, and F. J. Caires (2020). Synthesis and Characterization of Meloxicam Eutectics with Mandelic Acid and Saccharin for Enhanced Solubility. Drug Development and Industrial Pharmacy, 46(7);1092–1099
Ferreira, P. O., A. C. de Almeida, É. C. dos Santos, R. D. Junior, F. F. Ferreira, A. C. Kogawa, and F. J. Caires (2020).A Noroxacin-nicotinic Acid Cocrystal: Mechanochemical Synthesis, Thermal and Structural Characterization and Solubility Assays. Thermochimica Acta, 694; 178782
Ghosh, T., T. Juturu, S. N. Nagar, and S. Kamath (2021). Cocrystals of Modanil-Nicotinic Acid: A Novel Cocrystal for Enhanced Bioavailability. Multidisciplinary Digital Publishing Institute Proceedings, 62(1); 12
Goud, N. R., K. Suresh, P. Sanphui, and A. Nangia (2012). Fast Dissolving Eutectic Compositions of Curcumin. International Journal of Pharmaceutics, 439(1-2); 63–72
Haneef, J., S. Ali, and R. Chadha (2021). Emerging MultiDrug Eutectics: Opportunities and Challenges. AAPS PharmSciTech, 22(2); 1–17
Haneef, J. and R. Chadha (2018). Antioxidant-based Eutectics of Irbesartan: Viable Multicomponent Forms for the Management of Hypertension. AAPS PharmSciTech, 19(3); 1191–1204
Hyun, S.-M., B. J. Lee, S. M. Abuzar, S. Lee, Y. Joo, S.-H. Hong, H. Kang, K.-A. Kwon, S. Velaga, and S.-J. Hwang
(2019). Preparation, Characterization and Evaluation of Celecoxib Eutectic Mixtures with Adipic Acid/saccharin for Improvement of Wettability and Dissolution Rate. International Journal of Pharmaceutics, 554; 61–71
Kalepu, S. and V. Nekkanti (2015). Insoluble Drug Delivery Strategies: Review of Recent Advances and Business Prospects. Acta Pharmaceutica Sinica B, 5(5); 442–453
Kim, K. S., J. H. Kim, S. G. Jin, D. W. Kim, D. S. Kim, J. O. Kim, C. S. Yong, K. H. Cho, D. X. Li, J. S. Woo, et al.
(2016). Effect of Magnesium Carbonate on The Solubility, Dissolution and Oral Bioavailability of Fenobric Acid
Powder as An Alkalising Solubilizer. Archives of Pharmacal Research, 39(4); 531–538
Narwal, S., A. Kumar, M. Chaudhary, V. Budhwar, et al. (2021). Formulation of Eutectic Mixture of Curcumin with Salicylic Acid for Improving Its Dissolution Profile. Research Journal of Pharmacy and Technology, 14(4); 1875–1879
Pereira-da Silva, M. d. A. and F. A. Ferri (2017). Scanning Electron Microscopy. Nanocharacterization Techniques, 2017; 1–35
Putra, O. D., D. Umeda, Y. P. Nugraha, K. Nango, E. Yonemochi, and H. Uekusa (2018). Simultaneous Improvement of Epalrestat Photostability and Solubility Via Cocrystallization: A Case Study. Crystal Growth & Design, 18(1); 373–379
Sanphui, P., V. K. Devi, D. Clara, N. Malviya, S. Ganguly, and G. R. Desiraju (2015). Cocrystals of Hydrochlorothiazide: Solubility and Diffusion/permeability Enhancements Through Drug–coformer Interactions. Molecular Pharmaceutics, 12(5); 1615–1622
Sekiguchi, K. and N. Obi (1961). Studies on Absorption of Eutectic Mixture. I. A Comparison of the Behavior of Eutectic Mixture of Sulfathiazole and that of Ordinary Sulfathiazole in Man. Chemical and Pharmaceutical Bulletin, 9(11); 866–872
Suhery, W. N., Y. C. Sumirtapura, J. S. Pamudji, and D. Mudhakir (2020). Development and Characterization of Self nanoemulsifying Drug Delivery System (snedds) Formulation for Enhancing Dissolution of Fenobric Acid. Journal of Pharmacy Research, 24(5); 738–47
Tommasini, S., D. Raneri, R. Ficarra, M. L. Calabrò, R. Stancanelli, and P. Ficarra (2004). Improvement in Solubility and Dissolution Rate of Flavonoids by Complexation With ???? -cyclodextrin. Journal of Pharmaceutical and Biomedical Analysis, 35(2); 379–387
Vogel, H. G., W. H. Vogel, H. G. Vogel, G. Müller, J. Sandow, and B. A. Schölkens (1997). Drug Discovery and Evaluation: Pharmacological Assays, volume 2. Springer
Windriyati, Y. N., Y. C. Sumirtapura, and J. S. Pamudji (2019). Dissolution Enhancement and Physicochemical Characterization of Fenobric Acid in Surface Solid Dispersion with Croscarmellose Sodium. Journal of Pharmacy Research, 23(2); 315–325
Zaini, E., D. Azhari, and L. Fitriani (2016). Identification and Characterization of Solid Binary System of Quercetin-nicotinamide. Oriental Journal of Chemistry, 32(3); 1545–1550
Zaini, E., R. K. Nisak, R. D. Utami, L. Fitriani, F. Ismed, et al. (2017). Effect of Milling on Physicochemical Properties of Usnic Acid Isolated From Usnea Sp. Oriental Journal of Chemistry, 33(6); 3031–3036
Zaini, E., Y. C. Sumirtapura, S. N. Soewandhi, A. Halim, H. Uekusa, and K. Fujii (2010). Cocrystalline Phase Transformation of Binary Mixture of Trimethoprim and Sulfamethoxazole By Slurry Technique. Asian Journal of Pharmaceutical and Clinical Research, 3(4); 26–9
Zaini, E., Y. S. Wahyuni, A. Halim, and Y. Yuliandra (2015). Preparation of Eutectic Mixture of Ketoprofen and Nicotinamide for Enhanced Dissolution Rate. International Journal Pharmacy and Pharmaceutical Sciences, 35(1); 161–4
Authors
Anggraini, D., Salsabila, H., Umar, S., Aldi, Y., & Zaini, E. (2022). Preparation and Characterization of a Eutectic Mixture of Fenofibric Acid and Nicotinic Acid and Evaluatuion of In Vivo Antihyperlipidemic Activity. Science and Technology Indonesia, 7(4), 514–521. https://doi.org/10.26554/sti.2022.7.4.514-521
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