Ketoprofen-Tromethamine: Binary Phase Diagram of Multicomponent Crystal, Dissolution Rate, and Analgesic Activity Evaluation

Uswatul Hasanah, Elsa Badriyya, Reza Safitri, Sukma Yuliza, Ikhwanul Ihsan, Saafrida, Henni Rosaini, Adhitya Jessica, Erizal Zaini

Abstract

Ketoprofen is a non-steroidal anti-inflammatory drug (NSAID) whose formulation options are limited due to its low dissolution rate in aqueous media. This research aimed to enhance the solubility of ketoprofen in distilled water and to compare the anti-inflammatory and analgesic effects of its resulting multicomponent crystal with tromethamine. The binary phase diagram of ketoprofen-tromethamine was created across molar ratios ranging from 1:9 to 9:1. The multicomponent crystal comprising ketoprofen and tromethamine in the selected ratio was synthesized using a solvent drop grinding method and subjected to further characterization for thermal properties, crystallinity, chemical groups, and morphology. The dissolution rate assessments were evaluated in CO2-free distilled water. Pharmacological analyses examined the anti-inflammatory and analgesic effects of the multicomponent crystal. The binary phase analysis identified the 5:5 (1:1) molar ratio as optimal in forming a multicomponent crystal. Thermograms and diffractograms revealed crystalline alterations attributed to a new crystalline phase. The new multicomponent crystal exhibited approximately 2.7 times higher dissolution rate after 30 minutes, outperforming pure ketoprofen. Pharmacological assessments demonstrated superior analgesic effects of the multicomponent crystal. In summary, the ketoprofen-tromethamine cocrystal in 1:1 molar ratio offers enhanced dissolution rate and provides better analgesic activity than ketoprofen alone.

References

Amdekar, S., P. Roy, V. Singh, A. Kumar, R. Singh, and P. Sharma (2012). Anti-Inflammatory Activity of Lactobacillus on Carrageenan-Induced Paw Edema in Male Wistar Rats. International Journal of Inflammation, 2012; 752015.

Beliatskaya, A. V., I. I. Krasnyuk, I. I. Krasnyuk, O. I. Stepanova, Z. A. Abgaryan, T. P. Kudinova, and I. S. Nesterenko (2019). Study on the Solubility of Ketoprofen from Solid Dispersions with Polyvinylpyrrolidone. Moscow University Chemistry Bulletin, 74(2); 93–99.

Belkacem, N., M. Salem, and H. S. Alkhatib (2015). Effect of Ultrasound on the Physico-Chemical Properties of Poorly Soluble Drugs: Antisolvent Sonocrystallization of Ketoprofen. Powder Technology, 285; 16–24.

Bookwala, M., P. Thipsay, S. Ross, F. Zhang, S. Bandari, and M. A. Repka (2018). Preparation of a Crystalline Salt of Indomethacin and Tromethamine by Hot Melt Extrusion Technology. European Journal of Pharmaceutics and Biopharmaceutics, 131; 109–119.

Browne, E., Z. A. Worku, and A. M. Healy (2020). Physicochemical Properties of Poly-Vinyl Polymers and Their Influence on Ketoprofen Amorphous Solid Dispersion Performance: A Polymer Selection Case Study. Pharmaceutics, 12(5); 433.

Chatzizaharia, K. A. and D. T. Hatziavramidis (2015). Dissolution Efficiency and Design Space for an Oral Pharmaceutical Product in Tablet Form. Industrial & Engineering Chemistry Research, 54(24); 6305–6310.

Das, S. K., S. Chakraborty, A. Bose, R. Rajabalaya, and J. Khanam (2021). Effects of the Preparation Technique on the Physicochemical Characteristics and Dissolution Improvement of Ketoprofen-SBE7-β-CD Binary Inclusion Complexes. Colloids and Surfaces A: Physicochemical and Engineering Aspects, 611; 125775.

Devi, S., S. Kumar, V. Verma, D. Kaushik, R. Verma, and M. Bhatia (2022). Enhancement of Ketoprofen Dissolution Rate by the Liquisolid Technique: Optimization and In Vitro and In Vivo Investigations. Drug Delivery and Translational Research, 12(11); 2693–2707.

Dudek, M. K., J. Śniechowska, A. Wróblewska, S. Kaźmierski, and M. J. Potrzebowski (2020). Cocrystals “Divorce and Marriage”: When a Binary System Meets an Active Multifunctional Synthon in a Ball Mill. Chemistry – A European Journal, 26(58); 13264–13273.

Dzoyem, J. P., L. J. McGaw, V. Kuete, and U. Bakowsky (2017). Anti-Inflammatory and Anti-Nociceptive Activities of African Medicinal Spices and Vegetables. Academic Press, pages 239–270.

Fulias, A., G. Vlase, I. Ledeti, and L. M. Suta (2015). Ketoprofen-Cysteine Equimolar Salt: Synthesis, Thermal Analysis, PXRD and FTIR Spectroscopy Investigation. Journal of Thermal Analysis and Calorimetry, 121(3); 1087–1091.

Gobbo, D., P. Ballone, S. Decherchi, and A. Cavalli (2020). Solubility Advantage of Amorphous Ketoprofen: Thermodynamic and Kinetic Aspects by Molecular Dynamics and Free Energy Approaches. Journal of Chemical Theory and Computation, 16(7); 4126–4140.

Goyal, M., M. Ghosh, B. P. Nagori, and D. Sasmal (2013). Analgesic and Anti-Inflammatory Studies of Cyclopeptide Alkaloid Fraction of Leaves of Ziziyphus Nummularia. Saudi Journal of Biological Sciences, 20(4); 365–371.

Green, B. G. and C. Akirav (2010). Threshold and Rate Sensitivity of Low-Threshold Thermal Nociception. The European Journal of Neuroscience, 31(9); 1637–1645.

Gregory, N. S., A. L. Harris, C. R. Robinson, P. M. Dougherty, P. N. Fuchs, and K. A. Sluka (2013). An Overview of Animal Models of Pain: Disease Models and Outcome Measures. The Journal of Pain, 14(11); 1255–1269.

Grothe, E., H. Meekes, E. Vlieg, J. H. Ter Horst, and R. De Gelder (2016). Solvates, Salts, and Cocrystals: A Proposal for a Feasible Classification System. Crystal Growth & Design, 16(6); 3237–3243.

Gyawali, R., S. Aryal, Y. Regmi, and S. Rajarajan (2021). Cocrystallization: An Approach to Improve Bioavailability by Altering Physicochemical Properties of Poorly Soluble APIs. International Journal of Pharmacy & Pharmaceutical Research, 20(4); 381–397.

Kuczyńska, J. and B. Nieradko-Iwanicka (2021). Future Prospects of Ketoprofen in Improving the Safety of the Gastric Mucosa. Biomedicine & Pharmacotherapy, 139; 111608.

Lutfiyah, D. S., L. Fitriani, M. Taher, and E. Zaini (2022). Crystal Engineering Approach in Physicochemical Properties Modifications of Phytochemical. Science and Technology Indonesia, 7(3); 353–371.

Mahat, M. A. and B. M. Patil (2007). Evaluation of Anti-Inflammatory Activity of Methanol Extract of Phyllanthus Amarus in Experimental Animal Models. Indian Journal of Pharmaceutical Sciences, 69(1); 33–36.

Patel, V. D., V. Rathod, R. V. Haware, and W. C. Stagner (2023). Optimized L-SNEDDS and Spray-Dried S-SNEDDS Using a Linked QbD-DM3 Rational Design for Model Compound Ketoprofen. International Journal of Pharmaceutics, 631; 122494.

Pereira-Leite, C., C. Nunes, S. K. Jamal, I. M. Cuccovia, and S. Reis (2017). Nonsteroidal Anti-Inflammatory Therapy: A Journey Toward Safety. Medicinal Research Reviews, 37(4); 802–859.

Raja, S. N., D. B. Carr, M. Cohen, N. B. Finnerup, H. Flor, S. Gibson, and K. Vader (2020). The Revised International Association for the Study of Pain Definition of Pain: Concepts, Challenges, and Compromises. Pain, 161(9); 1976–1982.

Sanas, M. N. and T. S. Pachpute (2023). Exploring the Potential of Ketoprofen Nanosuspension: In Vitro and In Vivo Insights into Drug Release and Bioavailability. Journal of Drug Delivery and Therapeutics, 13(6); 152–158.

Santenna, C., S. Kumar, S. Balakrishnan, R. Jhaj, and S. N. Ahmed (2019). A Comparative Experimental Study of Analgesic Activity of a Novel Non-Steroidal Anti-Inflammatory Molecule - Zaltoprofen, and a Standard Drug - Piroxicam, Using Murine Models. Journal of Experimental Pharmacology, 11; 85–91.

Sarzi-Puttini, P., F. Atzeni, L. Lanata, and M. Bagnasco (2013). Efficacy of Ketoprofen vs. Ibuprofen and Diclofenac: A Systematic Review of the Literature and Meta-Analysis. Clinical and Experimental Rheumatology, 31(5); 731–738.

Singh, T. and A. B. Newman (2011). Inflammatory Markers in Population Studies of Aging. Ageing Research Reviews, 10(3); 319–329.

Swieboda, P., R. Filip, A. Prystupa, and M. Drozd (2013). Assessment of Pain: Types, Mechanism and Treatment. Retrieved from https://www.medrevivals.com/assessment-pain-types-mechanism-treatment.

Wais, F. M. H., A. N. Abood, and H. K. Abbas (2017). Preparation and Evaluation of Ketoprofen Nanosuspension Using Solvent Evaporation Technique. Iraqi Journal of Pharmaceutical Sciences, 26(2); 41–55.

Wicaksono, Y., D. Setyawan, and S. Siswandono (2018). Multicomponent Crystallization of Ketoprofen-Nicotinamide for Improving the Solubility and Dissolution Rate. Chemistry Journal of Moldova, 13(2); 74–81.

Yadav, P. S., V. Kumar, U. P. Singh, H. R. Bhat, and B. Mazumder (2013). Physicochemical Characterization and In Vitro Dissolution Studies of Solid Dispersions of Ketoprofen with PVP K30 and D-Mannitol. Saudi Pharmaceutical Journal, 21(1); 77–84.

Yamashita, H., Y. Hirakura, M. Yuda, T. Teramura, and K. Terada (2013). Detection of Cocrystal Formation Based on Binary Phase Diagrams Using Thermal Analysis. Pharmaceutical Research, 30(1); 70–80.

Yuliandra, Y., R. Izadihari, H. Rosaini, and E. Zaini (2019). Multicomponent Crystals of Mefenamic Acid-Tromethamine with Improved Dissolution Rate. Journal of Research in Pharmacy, 23(6); 988–996.

Zaini, E., L. Fitriani, R. Y. Sari, H. Rosaini, A. Horikawa, and H. Uekusa (2019). Multicomponent Crystal of Mefenamic Acid and N-Methyl-D-Glucamine: Crystal Structures and Dissolution Study. Journal of Pharmaceutical Sciences, 108(7); 2341–2348.

Zaini, E., Y. C. Sumirtapura, S. N. Soewandhi, and A. Halim (2010). Identification of Physical Interaction Between Trimethoprim and Sulfamethoxazole by Contact Method Kofler and Crystallization Reaction. Indonesian Journal of Pharmacy, 21(1); 32–39.

Zayed, G. (2014). Dissolution Rate Enhancement of Ketoprofen by Surface Solid Dispersion with Colloidal Silicon Dioxide. Unique Journal of Pharmaceutical and Biological Sciences, 2(1); 33–38.

Authors

Uswatul Hasanah
Elsa Badriyya
Reza Safitri
Sukma Yuliza
Ikhwanul Ihsan
Saafrida
Henni Rosaini
Adhitya Jessica
Erizal Zaini
erizal@phar.unand.ac.id (Primary Contact)
Hasanah, U., Badriyya, E., Safitri, R., Yuliza, S., Ihsan, I. ., Saafrida, Rosaini, H., Jessica, A., & Zaini, E. (2024). Ketoprofen-Tromethamine: Binary Phase Diagram of Multicomponent Crystal, Dissolution Rate, and Analgesic Activity Evaluation. Science and Technology Indonesia, 9(3), 726–734. https://doi.org/10.26554/sti.2024.9.3.726-734

Article Details