Multicomponent Crystal of Trimethoprim and Citric Acid: Solid State Characterization and Dissolution Rate Studies

Salman Umar; Rido Farnandi; Hulwa Salsabila; Erizal Zaini

doi:10.3889/oamjms.2022.7920

Authors

Salman Umar Department of Pharmaceutics, Faculty of Pharmacy, Universitas Andalas, Padang, Indonesia
Rido Farnandi Department of Pharmaceutics, Faculty of Pharmacy, Universitas Andalas, Padang, Indonesia
Hulwa Salsabila Department of Pharmaceutics, Faculty of Pharmacy, Universitas Andalas, Padang, Indonesia
Erizal Zaini Department of Pharmaceutics, Faculty of Pharmacy, Universitas Andalas, Padang, Indonesia

DOI:

https://doi.org/10.3889/oamjms.2022.7920

Keywords:

Trimethoprim, Citric acid, Multicomponent crystals, Solvent evaporation, Solubility, Dissolution rate

Abstract

BACKGROUND: Trimethoprim is a broad spectrum antimicrobial agent with low solubility in water which causes low bioavailability in systemic circulation.

AIM: The purpose of this study was to prepare multicomponent crystals of trimethoprim and citric acid to increase the solubility and dissolution rate of trimethoprim.

MATERIALS AND METHODS: Multicomponent crystals were prepared by solvent evaporation method. Characterizations of multicomponent crystalline solid phase properties were carried out by powder X-ray diffraction (PXRD) analysis, differential scanning calorimetry (DSC), FT-IR spectroscopy, scanning electron microscopy (SEM). Solubility and dissolution rate tests were carried out in aqueous medium.

RESULTS: The PXRD characterization results showed a new X-ray diffraction pattern in the multicomponent crystal phase. DSC analysis showed the formation of a new endothermic peak. This indicates the formation of a multicomponent crystal phase between trimethoprim and citric acid. The results of the SEM analysis indicate the formation of a new crystal habit. Solubility of multi-component crystal phase of trimethoprim increased 7 times compared to intact trimethoprim. The dissolution of trimethoprim and multicomponent crystals in 0.1 N HCl medium at 60 minutes was 56.36% and 95.57% and CO₂-free distilled water medium was 43.03% and 88.26%, respectively.

CONCLUSIONS: From the results of the study, it can be concluded that the multicomponent phase of trimethoprim crystals with citric acid successfully increase the solubility and dissolution rate of trimethoprim significantly.

Downloads

Download data is not yet available.

Metrics

Metrics Loading ...

Plum Analytics Artifact Widget Block

References

Kawabata Y, Wada K, Nakatani M, Yamada S, Onoue S. Formulation design for poorly water-soluble drugs based on biopharmaceutics classification system: Basic approaches and practical applications. Int J Pharm. 2011;420(1):1-10. https://doi.org/10.1016/j.ijpharm.2011.08.032 PMid:21884771 DOI: https://doi.org/10.1016/j.ijpharm.2011.08.032

Li N, Zhang YH, Wu YN, Xiong XL, Zhang YH. Inclusion complex of trimethoprim with beta-cyclodextrin. J Pharm Biomed Anal. 2005;39(3-4):824-9. https://doi.org/10.1016/j.jpba.2005.05.011 PMid:16011886 DOI: https://doi.org/10.1016/j.jpba.2005.05.011

Hawser S, Lociuro S, Islam K. Dihydrofolate reductase inhibitors as antibacterial agents. Biochem Pharmacol. 2006;71(7):941-8. https://doi.org/10.1016/j.bcp.2005.10.052 PMid:16359642 DOI: https://doi.org/10.1016/j.bcp.2005.10.052

Guptat RL, Kumar R, Singla AK. Enhanced dissolution and absorption of trimethoprim from coprecipitates with polyethylene glycols and polyvinylpyrrolidone. Drug Dev Ind Pharm. 1991;17(3):463-8. DOI: https://doi.org/10.3109/03639049109043840

Pawar PH, Pawar AP, Mahadik KR, Paradkar AR. Evaluation of tableting properties of agglomerates obtained by spherical crystallisation of trimethroprim. Indian J Pharm Sci. 1998;60(1):24-8.

Nugrahani I, Fisandra F, Horikawa A, Uekusa H. New sodium mefenamate-nicotinamide multicomponent crystal development to modulate solubility and dissolution: Preparation, structural, and performance study. J Pharm Sci. 2021;110(9):324-60. https://doi.org/10.1016/j.xphs.2021.05.022 PMid:34090898 DOI: https://doi.org/10.1016/j.xphs.2021.05.022

Zaini E, Afriyani A, 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):21. DOI: https://doi.org/10.3390/scipharm88020021

Yuliandra Y, Izadihari R, Rosaini H, Zaini E. Multicomponent crystals of mefenamic acid–tromethamine with improved dissolution rate. J Res Pharm. 2019;23(6):988-96. DOI: https://doi.org/10.35333/jrp.2019.63

Thakur TS, Thakuria R. Crystalline multicomponent solids: An alternative for addressing the hygroscopicity issue in pharmaceutical materials. Cryst Growth Des. 2020;20(9):6245-65. DOI: https://doi.org/10.1021/acs.cgd.0c00654

Ainurofiq A, Mauludin R, Mudhakir D, Umeda D, Soewandhi SN, Putra OD, et al. Improving mechanical properties of desloratadine via multicomponent crystal formation. Eur J Pharm Sci. 2018;111:65-72. https://doi.org/10.1016/j.ejps.2017.09.035 PMid:28958892 DOI: https://doi.org/10.1016/j.ejps.2017.09.035

Putra OD, Uekusa H. Pharmaceutical multicomponent crystals: Structure, design, and properties. In: Advances in Organic Crystal Chemistry. Singapore: Springer; 2020. p. 153-84. DOI: https://doi.org/10.1007/978-981-15-5085-0_9

Zaini E. Formation and characterization of sulfamethoxazole-trimethoprim cocrystal by milling process. J Appl Pharm Sci. 2018;7(12):169-73. https://doi.org/10.7324/ JAPS.2017.71224

Muthiah PT, Francis S, Rychlewska U, Warzajtis B. Crystal engineering of analogous and homologous organic compounds: Hydrogen bonding patterns in trimethoprim hydrogen phthalate and trimethoprim hydrogen adipate. Beilstein J Org Chem. 2006;2:8. https://doi.org/10.1186/1860-5397-2-8 PMid:16603061 DOI: https://doi.org/10.1186/1860-5397-2-8

Bryan RF, Haltiwanger RC, Woode MK. Trimethoprim acetate. Acta Crystallogr Sect C. 1987;43(12):2412-5. DOI: https://doi.org/10.1107/S0108270187087584

Umadevi B, Prabakaran P, Muthiah PT. A pseudo-quadruple hydrogen-bonding motif consisting of six N-H.O hydrogen bonds in trimethoprim formate. Acta Crystallogr C. 2002;58(8):o510-2. https://doi.org/10.1107/s0108270102011150 PMid:12154314 DOI: https://doi.org/10.1107/S0108270102011150

Prabakaran P, Robert J, Muthiah P, Bocelli G, Righi L. Aminopyrimidine-carboxyl(ate) interactions in trimethoprim maleate, an antifolate drug. Acta Crystallogr C. 2001;57(4):459-61. https://doi.org/10.1107/s0108270101000269 PMid:11313594 DOI: https://doi.org/10.1107/S0108270101000269

Bhattacharya B, Das S, Lal G, Soni S, Ghosh A, Reddy C, et al. Screening, crystal structures and solubility studies of a series of multidrug salt hydrates and cocrystals of fenamic acids with trimethoprim and sulfamethazine. J Mol Struct. 2019;1199:127028. DOI: https://doi.org/10.1016/j.molstruc.2019.127028

Al Rahal O, Williams PA, Hughes CE, Kariuki BM, Harris KD. Structure determination of multicomponent crystalline phases of (S)-ibuprofen and l-proline from powder X-ray diffraction data, augmented by complementary experimental and computational techniques. Cryst Growth Des. 2021;21(4):2498-507. DOI: https://doi.org/10.1021/acs.cgd.1c00160

Zaini E, Fitriani L, Sari RY, Rosaini H, Horikawa A, Uekusa H. Multicomponent crystal of mefenamic acid and n-methyl-d-glucamine: Crystal structures and dissolution study. J Pharm Sci. 2019;108(7):2341-8. https://doi.org/10.1016/j.xphs.2019.02.003 PMid:30779887 DOI: https://doi.org/10.1016/j.xphs.2019.02.003

Ma D, Pei T, Bai Y, Zhou L, Bao Y, Yin Q, et al. Salts formation between ibuprofen and pyridine derivatives: Effect of amino group on supramolecular packing and proton transfer. J Mol Struct. 2019;1179:487-94. DOI: https://doi.org/10.1016/j.molstruc.2018.11.033

Martins F, Guimarães F, Honorato S, Ayala A, Ellena J. Vibrational and thermal analyses of multicomponent crystal forms of the anti-HIV drugs lamivudine and zalcitabine. J Pharm Biomed Anal. 2015;110:76-82. https://doi.org/10.1016/j.jpba.2015.03.004 PMid:25808817 DOI: https://doi.org/10.1016/j.jpba.2015.03.004

Ishihara S, Hattori Y, Otsuka M, Sasaki T. Cocrystal formation through solid-state reaction between ibuprofen and nicotinamide revealed using THz and IR spectroscopy with multivariate analysis. Crystals. 2020;10(9):760. DOI: https://doi.org/10.3390/cryst10090760

Dwichandra Putra O, Umeda D, Fujita E, Haraguchi T, Uchida T, Yonemochi E, et al. Solubility improvement of benexate through salt formation using artificial sweetener. Pharmaceutics. 2018;10(2):64. https://doi.org/10.3390/pharmaceutics10020064 PMid:29861459 DOI: https://doi.org/10.3390/pharmaceutics10020064

Yuliandra Y, Hutabarat LJ, Ardila R, Octavia MD, Zaini E. Enhancing solubility and antibacterial activity using multicomponent crystals of trimethoprim and malic acid. Pharm Educ. 2021;21(2):296-304. DOI: https://doi.org/10.46542/pe.2021.212.296304