ENHANCING PIPERINE SOLUBILITY THROUGH MULTICOMPONENT CRYSTALS WITH CINNAMIC ACID: CHARACTERIZATION AND EVALUATION
DOI:
https://doi.org/10.22159/ijap.2025.v17s1.22Keywords:
Piperine, Cinnamic acid, Multicomponent crystalAbstract
Objective: Piperine, an active alkaloid in Piper nigrum and Piper retrofractum, is known for its anti-inflammatory, antioxidant, and bioavailability-enhancing properties. However, its low water solubility limits its therapeutic potential.
Methods: This study addresses that limitation by enhancing piperine's solubility through forming multicomponent crystals using cinnamic acid as a coformer in a molar ratio of 4.5:5.5 via Liquid-Assisted Grinding (LAG). Various techniques, including X-ray Diffraction (XRD), Differential Scanning Calorimetry (DSC), Fourier Transform Infrared Spectroscopy (FT-IR), and Scanning Electron Microscopy (SEM), were used to characterize these crystals. Solubility tests were conducted in CO2-free distilled water using sonication and analyzed with high-performance liquid chromatography (HPLC).
Results: The DSC results revealed an endothermic peak at 79.91 °C, and XRD analysis showed no new peaks, indicating that the crystal structure of piperine remained unchanged. FT-IR analysis revealed hydrogen bond formation, and SEM showed smaller particle sizes in the modified crystals. Most importantly, the solubility of the multicomponent crystals increased 1.785-fold compared to intact piperine.
Conclusion: These findings suggest that piperine-cinnamic acid multicomponent crystals, forming a eutectic mixture, significantly improve piperine’s solubility, with statistical analysis confirming the results (p<0.05).
References
Tiwari A, Mahadik KR, Gabhe SY. Piperine: a comprehensive review of methods of isolation, purification, and biological properties. Medicine in Drug Discovery. 2020 Sep;7:100027. doi: 10.1016/j.medidd.2020.100027.
Chopra B, Dhingra AK, Kapoor RP, Prasad DN. Piperine and its various physicochemical and biological aspects: a review. Chem. 2016;3(1):75-96. doi: 10.2174/1874842201603010075.
Jessica A, Naura R, Hasanah U, Zaini E, Fitriani L. Pembentukan multikomponen kristal piperin dan kuersetin. JOPS. 2021;4(2):1-11. doi: 10.36341/jops.v4i2.1881.
Fitriani L, Tirtania S, Umar S, Zaini E. Enhancing the solubility and dissolution rate of piperine via preparation of piperine-hydroxypropyl methylcellulose 2910 solid dispersion system using freeze-drying method. J Pharm Pharmacogn Res. 2024 Jan 1;12(1):175-83. doi: 10.56499/jppres23.1734_12.1.175.
DN CP, AS. A solubility enhancement of aceclofenac by new crystallization technique. Asian J Pharm Clin Res. 2022 Feb 7:113-8.
Munde MK, Shinde AM, Kulkarni NS, Tambe VS, Alhat HP. Comprehensive review on nanocrystal technology in pharmaceutical formulation. Int J Pharm Pharm Sci. 2023 Apr 1:1-7. doi: 10.22159/ijpps.2023v15i4.47317.
Qiao N, Li M, Schlindwein W, Malek N, Davies A, Trappit G. Pharmaceutical cocrystals: an overview. Indian J Pharm Sci. 2017;79(6):858-71.
Sonita H, Zaini E, Umar S. Preparation and characterization phisicochemical properties of multi-component ketoprofen with co-former glutamine. MS. 2023;8(2):849-60. doi: 10.37874/ms.v8i2.799.
Umar S, Farnandi R, Salsabila H, Zaini E. Multicomponent crystal of trimethoprim and citric acid: solid state characterization and dissolution rate studies. Open Access Maced J Med Sci. 2022;10(A):141-5. doi: 10.3889/oamjms.2022.7920.
Anggraini D, Salsabila H, Umar S, Aldi Y, Zaini E. Preparation and characterization of a eutectic mixture of fenofibric acid and nicotinic acid and evaluation of in vivo antihyperlipidemic activity. Sci Technol Indones. 2022 Oct 31;7(4):514-21. doi: 10.26554/sti.2022.7.4.514-521.
Izadihari R, Rosaini H, Zaini E, Yuliandra Y. Multicomponent crystals of mefenamic acid-tromethamine with improved dissolution rate. Sanat. 2019;23(6):988-96. doi: 10.35333/jrp.2019.63.
Zaini E, Evert A, Dona Octavia MD. Increase in dissolution rate of simvastatin by amorphous solid dispersion system with hydroxypropylmethylcellulose polymer. Orient J Chem. 2017;33(4):2080-4. doi: 10.13005/ojc/330457.
Putri D. Review: multi-component crystals: cinnamic acid as a co-former. Int J Pharm Sci Med. 2021 Jan 21;6(1):92-8. doi: 10.47760/ijpsm.2021.v06i01.008.
Octavia MD, Hasmiwati H, Revilla G, Zaini E. Multicomponent crystals of piperine-nicotinic acid: the physicochemical and dissolution rate properties. Trop J Nat Prod Res. 2023 Aug 31;7(8):3701-5.
Yamashita H, Hirakura Y, Yuda M, Teramura T, Terada K. Detection of cocrystal formation based on binary phase diagrams using thermal analysis. Pharm Res. 2013 Aug 21;30(1):70-80. doi: 10.1007/s11095-012-0850-1, PMID 22907418.
Sunil Dhoot A, Naha A, JuhiPriya J J, NehaXalxo N N. Phase diagrams for three-component mixtures in pharmaceuticals and its applications. J. 2018;10(2):132-7. doi: 10.5530/jyp.2018.10.31.
Hasanah U, Badriyya E, Safitri R, Yuliza S, Ihsan I, Saafrida RH. Ketoprofen-tromethamine: binary phase diagram of multicomponent crystal, dissolution rate, and analgesic activity evaluation. Sci Technol Indones. 2024 Jun 30;9(3):726-34. doi: 10.26554/sti.2024.9.3.726-734.
Dwichandra Putra O, Yonemochi E, Uekusa H. Isostructural multicomponent gliclazide crystals with improved solubility. Cryst Growth Des. 2016 Nov 2;16(11):6568-73. doi: 10.1021/acs.cgd.6b01279.
Sari YN, Zaini E, Ismed F. Peningkatan laju disolusi piperine dengan pembentukan multikomponen kristal menggunakan asam nikotinat. J Sains Farm Klin. 2019 Aug 28;6(2):180. doi: 10.25077/jsfk.6.2.180-185.2019.
Pena Pereira F, de la Calle I. Solvents and eutectic solvents. In: Worsfold P, Poole C, Townshend A, Miro M, editors. Encyclopedia of analytical science. 3rd ed. Cambridge: Academic Press; 2019. p. 184-90.
Zaini E, Afriyani FL, Fitriani L, Ismed F, Horikawa A, Uekusa H. Improved solubility and dissolution rates in novel multicomponent crystals of piperine with succinic acid. Sci Pharm. 2020;88(2). doi: 10.3390/scipharm88020021.
Hasanah U, Wahyuni L, Zaini E. Micronized eutectic mixture of fenofibric acid-saccharin formation for solubility and disoolution enhancement. Int J Appl Pharm. 2023 Feb 7;15 Special Issue 1:56-60.
Rabiej S. A comparison of two X-ray diffraction procedures for crystallinity determination. Eur Polym J. 1991 Jan 1;27(9):947-54. doi: 10.1016/0014-3057(91)90038-P.
Ainurofiq A, Mauludin R, Mudhakir D, Setianto AB, Soewandhi SN. The effect of compression force on alteration of desloratadine and its multicomponent crystal crystallinities using X-ray diffraction and ATR-FTIR techniques. KEM. 2018;787:43-51. doi: 10.4028/www.scientific.net/KEM.787.43.
Salsabila H, Fitriani L, Zaini E. Recent strategies for improving solubility and oral bioavailability of piperine. Int J Appl Pharm. 2021;13(4):31-9. doi: 10.22159/ijap.2021v13i4.41596.
Garrido B, Gonzalez S, Hermosilla J, Millao S, Quilaqueo M, Guineo J. Carbonate-β-cyclodextrin-based nanosponge as a nanoencapsulation system for piperine: physicochemical characterization. J Soil Sci Plant Nutr. 2019 Sep 1;19(3):620-30. doi: 10.1007/s42729-019-00062-7.
Fitriani L, Fitriandi AD, Hasanah U, Zaini E. Nano-cocrystals of piperine-succinic acid: physicochemical characterization and dissolution rate studies. Chemistry Select. 2022 Apr 12;7(14):e202104196. doi: 10.1002/slct.202104196.
Mannava MK, Gunnam A, Lodagekar A, Shastri NR, Nangia AK, Solomon KA. Enhanced solubility, permeability, and tabletability of nicorandil by salt and cocrystal formation. Cryst Eng Comm. 2021;23(1):227-37. doi: 10.1039/D0CE01316A.
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