Antifibrinolytic Agent: Synthesis and Characterization of Cocrystal and Salts of Tranexamic Acid
4 affiliations
- 1Purdue University , , 575 Stadium Mall Drive , , ,
- 2University of São Paulo , , Av. Professor Lineu Prestes, 580─Cidade Universitária , , ,
- 3Purdue University , , 560 Oval Drive , , ,
- 4Purdue University , , 225 S. University Street , , ,
Abstract
Tranexamic acid (TXA) is a potent antifibrinolytic agent with poor oral bioavailability (∼35–40%) due to its high polarity and zwitterionic nature, while physicochemical factors, including its structural instability, further hinder its absorption. In this study, the crystal engineering concept is applied to enhance the physicochemical properties of TXA through targeted structural modifications, resulting in the synthesis of pharmaceutically stable cocrystal and salt forms. The application of supramolecular synthon design, pKa rule, and structural geometry (molecular mimicry), resulted in the rational design, synthesis, and structural characterization of eight binary multicomponent forms of TXA: a TXA-adipate salt, monoclinic space group P21/n; a TXA-salicylate salt, monoclinic space group P21/n; a TXA-picolinate salt, monoclinic space group P21/c; a TXA-acetaminophen cocrystal hydrate, monoclinic space group P21; a TXA-malonate salt, orthorhombic space group Pbca; a TXA-maleate salt hydrate, monoclinic space group P21/c; a TXA-malate salt, monoclinic space group P21/c; and a TXA-citrate salt, triclinic space group P1̅ These multicomponent forms were obtained via different hydrogen bonding interactions, some of them charge-assisted (N–H···O, N+–H···O–, O–H···O, and O–H···O–) between NH2 and/or −OH groups of TXA and the carboxyl (−C(O−)═O) functional groups of the coformers. In the cocrystals, TXA exists as zwitterions (zero charge), whereas in the salts, it carries a positive charge due to the protonation of its carboxylic (−COOH) and ammonium (−NH3+) groups. The NH3+ to COO– charge-assisted H-bond provides stabilization to both the coformer COO– as well as the TXA’s NH3+. Solid-state characterization using Raman and FT-Raman spectroscopy, thermal techniques (DSC), and X-ray diffraction analysis (powder and single-crystal XRD) supports and confirms the structural novelty. The superior stability profiles of the new TXA cocrystal and salts under standard conditions (40 °C ± 2 °C, 75% ± 5% RH) establish an improved structure–property profile compared to pure TXA.
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BibTeX
@article{owoyemi2026antifibrinolytic,
title = {{Antifibrinolytic Agent: Synthesis and Characterization of Cocrystal and Salts of Tranexamic Acid}},
author = {Bolaji C. Dayo Owoyemi and Adedamola E. Adehinmoye and Matthias Zeller and Gabriel L. B. de Araujo and Stephen R. Byrn and Kari Clase},
journal = {ACS Omega},
year = {2026},
month = oct,
doi = {10.1021/acsomega.6c03598},
url = {https://pubs.acs.org/acsodf/article/doi/10.1021/acsomega.6c03598/5456825/Antifibrinolytic-Agent-Synthesis-and},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Antifibrinolytic Agent: Synthesis and Characterization of Cocrystal and Salts of Tranexamic Acid
AU - Bolaji C. Dayo Owoyemi
AU - Adedamola E. Adehinmoye
AU - Matthias Zeller
AU - Gabriel L. B. de Araujo
AU - Stephen R. Byrn
AU - Kari Clase
PY - 2026
DA - 2026/10/23
JO - ACS Omega
DO - 10.1021/acsomega.6c03598
UR - https://pubs.acs.org/acsodf/article/doi/10.1021/acsomega.6c03598/5456825/Antifibrinolytic-Agent-Synthesis-and
AB - Tranexamic acid (TXA) is a potent antifibrinolytic agent with poor oral bioavailability (∼35–40%) due to its high polarity and zwitterionic nature, while physicochemical factors, including its structural instability, further hinder its absorption. In this study, the crystal engineering concept is applied to enhance the physicochemical properties of TXA through targeted structural modifications, resulting in the synthesis of pharmaceutically stable cocrystal and salt forms. The application of supramolecular synthon design, pKa rule, and structural geometry (molecular mimicry), resulted in the rational design, synthesis, and structural characterization of eight binary multicomponent forms of TXA: a TXA-adipate salt, monoclinic space group P21/n; a TXA-salicylate salt, monoclinic space group P21/n; a TXA-picolinate salt, monoclinic space group P21/c; a TXA-acetaminophen cocrystal hydrate, monoclinic space group P21; a TXA-malonate salt, orthorhombic space group Pbca; a TXA-maleate salt hydrate, monoclinic space group P21/c; a TXA-malate salt, monoclinic space group P21/c; and a TXA-citrate salt, triclinic space group P1̅ These multicomponent forms were obtained via different hydrogen bonding interactions, some of them charge-assisted (N–H···O, N+–H···O–, O–H···O, and O–H···O–) between NH2 and/or −OH groups of TXA and the carboxyl (−C(O−)═O) functional groups of the coformers. In the cocrystals, TXA exists as zwitterions (zero charge), whereas in the salts, it carries a positive charge due to the protonation of its carboxylic (−COOH) and ammonium (−NH3+) groups. The NH3+ to COO– charge-assisted H-bond provides stabilization to both the coformer COO– as well as the TXA’s NH3+. Solid-state characterization using Raman and FT-Raman spectroscopy, thermal techniques (DSC), and X-ray diffraction analysis (powder and single-crystal XRD) supports and confirms the structural novelty. The superior stability profiles of the new TXA cocrystal and salts under standard conditions (40 °C ± 2 °C, 75% ± 5% RH) establish an improved structure–property profile compared to pure TXA.
SN - 2470-1343
ER -