Solubility enhancement and structural insights into pipemidic acid via salt formation with benzoic acid

Shwetha Jayapura Chandrashekar; Rajalakshmanan Eswaramoorthy; Kamalakaran Anand Solomon

doi:10.5155/eurjchem.16.2.104-116.2631

PDF CIF FILE

Published: Jun 30, 2025

DOI: https://doi.org/10.5155/eurjchem.16.2.104-116.2631

Keywords:

Solubility, Benzoic acid, Pipimedic acid, Dissolution rate, Hirshfeld surface analysis, Single-crystal X-ray diffraction

Section

Research Article

Issue

Vol. 16 No. 2 (2025): June 2025

Dates

Received 2025-01-06
Accepted 2025-04-23
Published 2025-06-30

Shwetha Jayapura Chandrashekar

Department of Physical and Chemical Science, Sri Sathya Sai University for Human Excellence, Navanihal, Kalaburagi, 585313, Karnataka, India

https://orcid.org/0000-0002-3262-7583

Rajalakshmanan Eswaramoorthy

Centre of Molecular Medicine and Diagnostics, Department of Biochemistry, Saveetha Dental College and Hospital, Saveetha Institute of Medical and Technical Sciences, 600077, Chennai, India

https://orcid.org/0000-0002-8331-2100

Kamalakaran Anand Solomon

Department of Chemistry, School of Engineering, Dayananda Sagar University, Devarakaggalahalli, Harohalli, Kanakapura Road, Dt, Ramanagara, 562112, Karnataka, India

https://orcid.org/0000-0003-4677-2340

Abstract

Pipemidic acid (PMA) is an active pharmaceutical ingredient (API) belonging to the quinolone class of antibacterial agents, primarily used to treat urinary tract infections. This study investigated improving the dissolution properties of poorly soluble PMA by forming a 1:1 stoichiometry molecular salt (4BA) with benzoic acid (BA). Liquid-assisted grinding and slow evaporation techniques were used to prepare the solid form of the salt. The salt was then characterized using differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), and single-crystal X-ray diffraction (SC-XRD). The DSC analysis provided information on the changes in thermal behavior associated with the formation of the salt. FTIR spectroscopy helped identify the functional groups present and potential interactions between PMA and benzoic acid. SC-XRD determined the definitive three-dimensional arrangement of atoms within the salt structure, revealing a wave-like hydrogen bonding network directing a 3D layered packing of molecules. This improved packing is believed to be responsible for the improved solubility of PMA in the salt form. The Hirshfeld surface analysis, along with its associated 2D fingerprint plots, further elucidated the intermolecular interactions within the crystal lattice. This analysis showed that, in addition to the strong N-H···O and O-H···O hydrogen bonds, weaker H···H, C···H, and H···C interactions also play a significant role in stabilizing the molecular packing. Finally, cumulative drug release (CDR) showed that the formation of the molecular salt significantly improved the dissolution behavior of PMA, potentially leading to sustained drug release.

This Abstract was viewed 9 times |

Article PDF downloaded 1 times

Article CIF FILE downloaded 0 times

How to Cite

(1)

Chandrashekar, S. J.; Eswaramoorthy, R.; Solomon, K. A. Solubility Enhancement and Structural Insights into Pipemidic Acid via Salt Formation With Benzoic Acid. Eur. J. Chem. 2025, 16, 104-116.

Links for Article

Crossref - Scopus - Google - European PMC

References

[1]. Shimizu, M.; Takase, Y.; Nakamura, S.; Katae, H.; Minami, A.; Nakata, K.; Inoue, S.; Ishiyama, M.; Kubo, Y. Pipemidic Acid, a New Antibacterial Agent Active Against Pseudomonas aeruginosa In Vitro Properties. Antimicrob Agents Chemother 1975, 8 (2), 132-138.
https://doi.org/10.1128/AAC.8.2.132

[2]. Fernandes, P. B. Mode of Action, and In Vitro and In Vivo Activities of the Fluoroquinolones. The Journal of Clinical Pharma 1988, 28 (2), 156-168.
https://doi.org/10.1002/j.1552-4604.1988.tb05967.x

[3]. Zhang, Y.; Duan, Y.; Su, J.; Liu, L.; Feng, Y.; Wu, L.; Zhang, L.; Zhang, Y.; Zou, D.; Liu, Y. Inspiration for revival of old drugs: improving solubility and avoiding hygroscopicity of pipemidic acid by forming two pharmaceutical salts based on charge-assisted hydrogen bond recognitions. New J. Chem. 2021, 45 (42), 19704-19713.
https://doi.org/10.1039/D1NJ03314J

[4]. Zhang, X.; Chen, J.; Hu, J.; Liu, M.; Cai, Z.; Xu, Y.; Sun, B. The solubilities of benzoic acid and its nitro-derivatives, 3-nitro and 3,5-dinitrobenzoic acids. J. Chem. Res. 2021, 45 (11-12), 1100-1106.
https://doi.org/10.1177/17475198211058617

[5]. Jouyban, A.; Rahimpour, E.; E. Acree Jr., W. Further Analysis on Solubility Measurement and Thermodynamic Modeling of Benzoic Acid in Monosolvents and Binary Mixtures. Pharm. Sci. 2019, 25 (2), 165-170.
https://doi.org/10.15171/PS.2019.24

[6]. Sopyan, I.; Layyareza, R. T.; Megantara, S.; Marvita, S. S. Carvedilol solubility enhancement by multicomponent crystallization with coformers of benzoic acid, isonicotinamide, and saccharin. Pharmacia 2023, 70 (2), 283-290.
https://doi.org/10.3897/pharmacia.70.e98177

[7]. Mannava, M. K.; Garai, A.; Bommaka, M. K.; Solomon, K. A.; Nangia, A. K. Solubility and permeability enhancement of BCS class IV drug ribociclib through cocrystallization. CrystEngComm 2022, 24 (45), 7915-7923.
https://doi.org/10.1039/D2CE01288J

[8]. Florindo, C.; Costa, A.; Matos, C.; Nunes, S. L.; Matias, A. N.; Duarte, C. M.; Rebelo, L. P.; Branco, L. C.; Marrucho, I. M. Novel organic salts based on fluoroquinolone drugs: Synthesis, bioavailability and toxicological profiles. Int. J. Pharm. 2014, 469 (1), 179-189.
https://doi.org/10.1016/j.ijpharm.2014.04.034

[9]. Khadka, P.; Ro, J.; Kim, H.; Kim, I.; Kim, J. T.; Kim, H.; Cho, J. M.; Yun, G.; Lee, J. Pharmaceutical particle technologies: An approach to improve drug solubility, dissolution and bioavailability. Asian J. Pharm. Sci. 2014, 9 (6), 304-316.
https://doi.org/10.1016/j.ajps.2014.05.005

[10]. Yang, J.; Yin, L.; Gong, X.; Sinditskii, V. P.; Zhang, J. Origins of Salt Formation and Cocrystallization: A Combined Experimental and Theoretical Study. Cryst. Growth amp; Des. 2020, 20 (9), 5834-5842.
https://doi.org/10.1021/acs.cgd.0c00459

[11]. Berry, D. J.; Steed, J. W. Pharmaceutical cocrystals, salts and multicomponent systems; intermolecular interactions and property based design. Adv. Drug Deliv. Rev. 2017, 117, 3-24.
https://doi.org/10.1016/j.addr.2017.03.003

[12]. Gupta, D.; Bhatia, D.; Dave, V.; Sutariya, V.; Varghese Gupta, S. Salts of Therapeutic Agents: Chemical, Physicochemical, and Biological Considerations. Molecules 2018, 23 (7), 1719.
https://doi.org/10.3390/molecules23071719

[13]. Del Olmo, A.; Calzada, J.; Nuñez, M. Benzoic acid and its derivatives as naturally occurring compounds in foods and as additives: Uses, exposure, and controversy. Crit. Rev. Food Sci. Nutr. 2017, 57, 3084-3103.
https://doi.org/10.1080/10408398.2015.1087964

[14]. Cerreia Vioglio, P.; Chierotti, M. R.; Gobetto, R. Pharmaceutical aspects of salt and cocrystal forms of APIs and characterization challenges. Adv. Drug Deliv. Rev. 2017, 117, 86-110.
https://doi.org/10.1016/j.addr.2017.07.001

[15]. Rajkumar, M.; Chandramohan, A. Synthesis, growth, structural characterization and biological investigation of hydrogen bonded organic molecular salt: N, N-diethylanilinium-5-sulphosalicylate. J. Mol. Struct. 2019, 1192, 122-131.
https://doi.org/10.1016/j.molstruc.2019.04.120

[16]. Karthammaiah, G. N.; Rao Amaraneni, S.; Solomon, A. K. Co-crystal of nadifloxacin with oxalic acid. Acta Crystallogr E. Cryst Commun 2023, 79 (4), 319-322.
https://doi.org/10.1107/S2056989023002244

[17]. Mashhadi, S. M.; Yufit, D.; Liu, H.; Hodgkinson, P.; Yunus, U. Synthesis and structural characterization of cocrystals of isoniazid and cinnamic acid derivatives. J. Mol. Struct. 2020, 1219, 128621.
https://doi.org/10.1016/j.molstruc.2020.128621

[18]. Chaves Júnior, J. V.; dos Santos, J. A.; Lins, T. B.; de Araújo Batista, R. S.; de Lima Neto, S. A.; de Santana Oliveira, A.; Nogueira, F. H.; Gomes, A. P.; de Sousa, D. P.; de Souza, F. S.; Aragão, C. F. A New Ferulic Acid-Nicotinamide Cocrystal With Improved Solubility and Dissolution Performance. J. Pharm. Sci. 2020, 109 (3), 1330-1337.
https://doi.org/10.1016/j.xphs.2019.12.002

[19]. Anand Solomon, K. Molecular modelling and drug design; Mjp Publisher, 2023.

[20]. Karki, S.; Friščić, T.; Fábián, L.; Laity, P. R.; Day, G. M.; Jones, W. Improving Mechanical Properties of Crystalline Solids by Cocrystal Formation: New Compressible Forms of Paracetamol. Adv. Mater. 2009, 21 (38-39), 3905-3909.
https://doi.org/10.1002/adma.200900533

[21]. Champa, R.; Vishnumurthy, K.; Bodke, Y. D.; Bhojya Naik, H.; Pushpavathi, I.; Meghana, P.; Kadam, P. R. Synthesis, characterization, and biological investigations of potentially bioactive heterocyclic compounds containing benzimidazole nucleus. Results Chem. 2023, 6, 101018.
https://doi.org/10.1016/j.rechem.2023.101018

[22]. Mannava, M. K.; Garai, A.; Bommaka, M. K.; Solomon, K. A.; Nangia, A. K. Solubility and permeability enhancement of BCS class IV drug ribociclib through cocrystallization. CrystEngComm 2022, 24 (45), 7915-7923.
https://doi.org/10.1039/D2CE01288J

[23]. Dolomanov, O. V.; Bourhis, L. J.; Gildea, R. J.; Howard, J. A.; Puschmann, H. OLEX2: a complete structure solution, refinement and analysis program. J. Appl Crystallogr 2009, 42 (2), 339-341.
https://doi.org/10.1107/S0021889808042726

[24]. Spackman, P. R.; Turner, M. J.; McKinnon, J. J.; Wolff, S. K.; Grimwood, D. J.; Jayatilaka, D.; Spackman, M. A. CrystalExplorer: a program for Hirshfeld surface analysis, visualization and quantitative analysis of molecular crystals. J. Appl Crystallogr 2021, 54 (3), 1006-1011.
https://doi.org/10.1107/S1600576721002910

[25]. Puchkov, S. V.; Nepomnyashchikh, Y. V. Evaluation of the Reactivity of Cyclohexanone СН Bonds in Reactions with tert-Butylperoxy Radical by Quantum Chemical Methods. Kinet Catal 2021, 62 (4), 479-487.
https://doi.org/10.1134/S0023158421040108

[26]. Srikanth, K. E.; Veeraiah, A.; Pooventhiran, T.; Thomas, R.; Solomon, K. A.; Soma Raju, C.; Latha, J. N. Detailed molecular structure (XRD), conformational search, spectroscopic characterization (IR, Raman, UV, fluorescence), quantum mechanical properties and bioactivity prediction of a pyrrole analogue. Heliyon 2020, 6 (6), e04106.
https://doi.org/10.1016/j.heliyon.2020.e04106

[27]. Stuart, J. G.; Jebaraj, J. W. Synthesis, characterisation, in silico molecular docking and DFT studies of 2,6-bis(4-hydroxy-3-methoxyphenyl)-3,5-dimethylpiperidin-4-one. Indian J. Chem. 2023, 62, 1061-1080
https://doi.org/10.56042/ijc.v62i10.6186

[28]. Mišura, O.; Kodrin, I.; Borovina, M.; Pisačić, M.; De Silva, V.; Aakeröy, C. B.; Đaković, M. Exploring the Co-Crystallization Landscape of One-Dimensional Coordination Polymers Using a Molecular Electrostatic Potential-Driven Approach. Cryst. Growth amp; Des. 2023, 23 (10), 7198-7206.
https://doi.org/10.1021/acs.cgd.3c00615

[29]. Manin, A. N.; Drozd, K. V.; Churakov, A. V.; Perlovich, G. L. Hydrogen Bond Donor/Acceptor Ratios of the Coformers: Do They Really Matter for the Prediction of Molecular Packing in Cocrystals? The Case of Benzamide Derivatives with Dicarboxylic Acids. Cryst. Growth amp; Des. 2018, 18 (9), 5254-5269.
https://doi.org/10.1021/acs.cgd.8b00711

[30]. Yang, L.; Tao, D.; Yang, X.; Li, Y.; Guo, Y. Synthesis, characterization, and antibacterial activities of some rare Earth metal complexes of pipemidic acid. Chem. Pharm. Bull. (Tokyo) 2003, 51, 494-498.
https://doi.org/10.1248/cpb.51.494

[31]. Siddiqi, A. Z.; Mirza, A. Z. Synthesis, characterization, and antibacterial studies of pipemidic acid metal complexes. Futur J. Pharm Sci 2021, 7 (1).
https://doi.org/10.1186/s43094-021-00301-8

[32]. Rodríguez-Rodríguez, W. A.; Colón, J.; Guzmán, R.; Rivera, H.; Santiago-Berríos, M. B. Synthesis, characterization and electrochemical characterization of lead selenide sub-micron particles capped with a benzoate ligand and prepared at different temperatures. Mater. Res. Express 2014, 1 (3), 035906.
https://doi.org/10.1088/2053-1591/1/3/035906

[33]. Hariprasad, V. M.; Nechipadappu, S. K.; Trivedi, D. R. Cocrystals of Ethenzamide: Study of Structural and Physicochemical Properties. Cryst. Growth amp; Des. 2016, 16 (8), 4473-4481.
https://doi.org/10.1021/acs.cgd.6b00606

[34]. Solomon, K. A.; Blacque, O.; Venkatnarayan, R. Molecular salts of 2,6-dihydroxybenzoic acid (2,6-DHB) with N-heterocycles: Crystal structures, spectral properties and Hirshfeld surface analysis. J. Mol. Struct. 2017, 1134, 190-198.
https://doi.org/10.1016/j.molstruc.2016.12.055

[35]. Cruz-Cabeza, A. J. Acid-base crystalline complexes and the pKa rule. CrystEngComm 2012, 14 (20), 6362-6365.
https://doi.org/10.1039/c2ce26055g

[36]. Seaton, C. C.; Parkin, A. Making benzamide cocrystals with benzoic acids: The influence of chemical structure. Cryst. Growth Des. 2011, 11, 1502-1511.
https://doi.org/10.1021/cg101403j

[37]. Desiraju, G. R. Supramolecular Synthons in Crystal Engineering-A New Organic Synthesis. Angew. Chem. Int. Ed. Engl. 1995, 34 (21), 2311-2327.
https://doi.org/10.1002/anie.199523111

[38]. Braga, D.; Grepioni, F.; Maini, L. ChemInform Abstract: The Growing World of Crystal Forms. ChemInform 2010, 41 (47), 6232-6242.
https://doi.org/10.1002/chin.201047264

[39]. Luo, Y.; Sun, B. Pharmaceutical Co-Crystals of Pyrazinecarboxamide (PZA) with Various Carboxylic Acids: Crystallography, Hirshfeld Surfaces, and Dissolution Study. Cryst. Growth amp; Des. 2013, 13 (5), 2098-2106.
https://doi.org/10.1021/cg400167w

[40]. MacGillivray, L. R. Organic Synthesis in the Solid State via Hydrogen-Bond-Driven Self-Assembly. J. Org. Chem. 2008, 73 (9), 3311-3317.
https://doi.org/10.1021/jo8001563

[41]. Siegfried, A. M.; Arman, H. D.; Kobra, K.; Liu, K.; Peloquin, A. J.; McMillen, C. D.; Hanks, T.; Pennington, W. T. Phosphorus···Iodine Halogen Bonding in Cocrystals of Bis(diphenylphosphino)ethane (dppe) and p-Diiodotetrafluorobenzene (p-F4DIB). Cryst. Growth amp; Des. 2020, 20 (11), 7460-7469.
https://doi.org/10.1021/acs.cgd.0c01129

[42]. Amarne, H.; Helal, W.; Taher, D.; Korb, M.; Al-Hunaiti, A. Crystal structure, Hirshfeld surface analysis and contact enrichment ratios of 5,5-dimethyl-2-(2,4,6-tris(trifluoromethyl)phenyl)-1,3,2-dioxaborinane. Mol. Cryst. Liq. Cryst. 2022, 743, 77-88.
https://doi.org/10.1080/15421406.2022.2050981

[43]. Irrou, E.; Elmachkouri, Y. A.; Oubella, A.; Ouchtak, H.; Dalbouha, S.; Mague, J. T.; Hökelek, T.; El Ghayati, L.; Sebbar, N. K.; Taha, M. L. Crystal structure determination, Hirshfeld surface, crystal void, intermolecular interaction energy analyses, as well as DFT and energy framework calculations of 2-(4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acetic acid. Acta Crystallogr E. Cryst Commun 2022, 78 (9), 953-960.
https://doi.org/10.1107/S2056989022008489

[44]. Sangeetha, M.; Mathammal, R. Establishment of the structural and enhanced physicochemical properties of the cocrystal-2-benzyl amino pyridine with oxalic acid. J. Mol. Struct. 2017, 1143, 192-203.
https://doi.org/10.1016/j.molstruc.2017.04.085

[45]. Üstün, E.; Şahin, N. Density Functional Theory and Molecular Docking Analysis of Newly Synthesized and Characterized Benzimidazolium Salts. Ordu Universitesi Bilim ve Teknol. Derg. 2022, 12 (1), 52-63.
https://doi.org/10.54370/ordubtd.1117826

[46]. Phetmung, H.; Musikapong, K.; Srichana, T. Thermal analysis, structure, spectroscopy and DFT calculations of a pharmaceutical cocrystal of salicylic acid and salicylamide. J. Therm Anal Calorim 2019, 138 (2), 1207-1220.
https://doi.org/10.1007/s10973-019-08794-5

[47]. Pandey, J.; Prajapati, P.; Shimpi, M. R.; Tandon, P.; Velaga, S. P.; Srivastava, A.; Sinha, K. Studies of molecular structure, hydrogen bonding and chemical activity of a nitrofurantoin-l-proline cocrystal: a combined spectroscopic and quantum chemical approach. RSC. Adv. 2016, 6 (78), 74135-74154.
https://doi.org/10.1039/C6RA13035F

[48]. Abbas, F.; Mohammadi, M. D.; Louis, H.; Amodu, I. O.; Charlie, D. E.; Gber, T. E. Design of new bithieno thiophene (BTTI) central core-based small molecules as efficient hole transport materials for perovskite solar cells and donor materials for organic solar cells. Mater. Sci. Eng.: B 2023, 291, 116392.
https://doi.org/10.1016/j.mseb.2023.116392

[49]. Bakheit, A. H.; Alkahtani, H. M. Integrated Structural, Functional, and ADMET Analysis of 2-Methoxy-4,6-diphenylnicotinonitrile: The Convergence of X-ray Diffraction, Molecular Docking, Dynamic Simulations, and Advanced Computational Insights. Molecules 2023, 28 (19), 6859.
https://doi.org/10.3390/molecules28196859

[50]. Bouallag, S.; Mougari, A.; Zabat, M.; Belayadi, A. Computational study of transition metal coordinated polyaniline: A first principle investigation into tuning the electronic properties of the resulting hybrid material. Phys. B: Condens. Matter 2024, 695, 416597.
https://doi.org/10.1016/j.physb.2024.416597

[51]. Agwamba, E. C.; Benjamin, I.; Louis, H.; Udoikono, A. D.; Igbalagh, A. T.; Egemonye, T. C.; Adeyinka, A. S. Antitubercolusic Potential of Amino-(formylphenyl) Diazenyl-Hydroxyl and Nitro-Substituted Naphthalene-Sulfonic Acid Derivatives: Experimental and Theoretical Investigations. Chem. Afr. 2022, 5 (5), 1451-1467.
https://doi.org/10.1007/s42250-022-00423-3

[52]. Yan, Y.; Wang, X.; Zhang, Y.; Wang, P.; Zhang, J. Theoretical evaluation of inhibition performance of purine corrosion inhibitors. Mol. Simul. 2013, 39 (13), 1034-1041.
https://doi.org/10.1080/08927022.2013.792928

[53]. Phetmung, H.; Musikapong, K.; Srichana, T. Thermal analysis, structure, spectroscopy and DFT calculations of a pharmaceutical cocrystal of salicylic acid and salicylamide. J. Therm. Anal. Calorim. 2019, 138, 1207-1220.
https://doi.org/10.1007/s10973-019-08794-5

[54]. Shwetha, J. C.; Sharma, A.; Solomon, K. A. Molecular salts of pipemedic acid and crystal structure, spectral properties, and Hirshfeld surface analysis. J. Iran Chem. Soc. 2023, 20 (12), 3161-3176.
https://doi.org/10.1007/s13738-023-02905-8

[55]. Nyamba, I.; Sombié, C. B.; Yabré, M.; Zimé-Diawara, H.; Yaméogo, J.; Ouédraogo, S.; Lechanteur, A.; Semdé, R.; Evrard, B. Pharmaceutical approaches for enhancing solubility and oral bioavailability of poorly soluble drugs. Eur. J. Pharm. Biopharm. 2024, 204, 114513.
https://doi.org/10.1016/j.ejpb.2024.114513

[56]. Lekhan, A.; Fiore, C.; Shemchuk, O.; Grepioni, F.; Braga, D.; Turner, R. J. Comparison of Antimicrobial and Antibiofilm Activity of Proflavine Co-crystallized with Silver, Copper, Zinc, and Gallium Salts. ACS. Appl. Bio Mater. 2022, 5 (9), 4203-4212.
https://doi.org/10.1021/acsabm.2c00404

Most read articles by the same author(s)

TrendMD

Dimensions - Altmetric - scite_ - PlumX

Downloads and views

Downloads

Download data is not yet available.

Metrics

Metrics Loading ...

License Terms

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

License Terms

by-nc

Copyright © 2025 by Authors. This work is published and licensed by Atlanta Publishing House LLC, Atlanta, GA, USA. The full terms of this license are available at https://www.eurjchem.com/index.php/eurjchem/terms and incorporate the Creative Commons Attribution-Non Commercial (CC BY NC) (International, v4.0) License (http://creativecommons.org/licenses/by-nc/4.0). By accessing the work, you hereby accept the Terms. This is an open access article distributed under the terms and conditions of the CC BY NC License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited without any further permission from Atlanta Publishing House LLC (European Journal of Chemistry). No use, distribution, or reproduction is permitted which does not comply with these terms. Permissions for commercial use of this work beyond the scope of the License (https://www.eurjchem.com/index.php/eurjchem/terms) are administered by Atlanta Publishing House LLC (European Journal of Chemistry).

Article Sidebar

Main Article Content

Abstract

Article Details

Downloads

Metrics