Faculty Publications
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Item Cocrystals of Ethenzamide: Study of Structural and Physicochemical Properties(American Chemical Society service@acs.org, 2016) Hariprasad, V.M.; Nechipadappu, S.K.; Trivedi, D.R.Pharmaceutical cocrystals of an analgesic drug ethenzamide (ETZ) with various coformers, namely, gallic acid (GA), 2-nitrobenzoic acid (2NB), 3-nitrobenzoic acid (3NB), 2,4-dinitrobenzoic acid (DNB), and 3-toluic acid (3TA) were synthesized by the solvent evaporation method. All the cocrystals were characterized by various analytical techniques, and the crystal structures were determined by the single-crystal X-ray diffraction method (SCXRD). SCXRD analysis revealed that all the synthesized cocrystals were formed through a robust supramolecular acid-amide heterosynthon except the ethenzamide/gallic acid cocrystal, where molecules interacted through O-H···O hydrogen bond involving -OH of gallic acid and oxygen of amide group of the ETZ molecule. The physicochemical properties such as stability, hygroscopicity, and solubility studies of the ETZ-GA cocrystal were evaluated. It was found that the ETZ-GA cocrystal has a higher solubility (2-fold) than that of the pure ETZ drug molecule. Hygroscopic study of the ETZ-GA cocrystal revealed that synthesized cocrystal was non-hygroscopic at ?75% RH conditions. The ETZ-GA cocrystal found to be stable for a time period of four months at ambient temperature. © 2016 American Chemical Society.Item Pharmaceutical salts of ethionamide with GRAS counter ion donors to enhance the solubility(Elsevier B.V., 2017) Nechipadappu, S.K.; Trivedi, D.R.Pharmaceutical salts of BCS class II second line anti-tuberculosis drug ethionamide (ETH) with various counter ions namely, 2-chloro-4-nitrobenzoic acid (CNB), 2,6-dihydroxybenzoic acid (2,6HBA), 2,3-dihydroxybenzoic acid (2,3HBA) and 2,4-dinitrobenzoic acid (DNB) were synthesized by crystal engineering approach. All the synthesized salts were characterized by various spectroscopic (NMR, FT-IR,), thermal (DSC & TGA) and PXRD techniques. The crystal structure of the synthesized salts was determined by single-crystal X-ray diffraction techniques. All the reported salts, except ETH-2,3HBA exhibited charge assisted acid pyridine heterosynthon. In ETH-2,3HBA hydoxyl pyridine heterosynthon is observed. In ETH-CNB salt, both ionic and neutral acid pyridine heterosynthon were observed in the asymmetric unit. ETH-DNB salt consists of both partial and complete proton transfer from DNB to ETH in the asymmetric unit. All the synthesized salts were found to be non-hygroscopic at accelerated humid condition (~ 75% RH). Solubility experiment has been performed in purified water and in 0.1 N HCl (pH = 1) solution and found that the solubility of ETH-CNB salt was about eight-fold higher soluble than ETH in purified water. The solubility of synthesized salts follows the order of ETH < ETH-2,3HBA < ETH-2,6HBA < ETH-CNB in purified water. © 2016 Elsevier B.V.Item Pharmaceutical Co-Crystal of Flufenamic Acid: Synthesis and Characterization of Two Novel Drug-Drug Co-Crystal(Elsevier B.V., 2017) Nechipadappu, S.K.; Tekuri, V.; Trivedi, D.R.Two novel pharmaceutical co-crystals of anti-inflammatory drug flufenamic acid (FFA) with 2-chloro-4-nitrobenzoic acid (CNB) and ethenzamide (ETZ) have been synthesized by solvent evaporation method as well as by solvent drop-assisted grinding method. The synthesized co-crystals were characterized thoroughly by various spectroscopic methods and crystal structures were determined by single-crystal x-ray diffraction technique. In FFA-CNB co-crystal, robust supramolecular acid-acid homosynthon was observed. FFA-ETZ co-crystal is formed via robust supramolecular acid-amide heterosynthon. In FTIR spectra, a significant shift in the carbonyl stretching frequency was observed for the co-crystals due to the presence of intermolecular hydrogen bond. 1H nuclear magnetic resonance study suggests the presence of hydrogen bond in the solution state of FFA-ETZ co-crystal; however, it was absent for FFA-CNB co-crystal. Solubility study in Millipore water revealed that the solubility of FFA is increased by 2-fold when it is in the form of FFA-CNB co-crystal and no increment in the solubility of FFA was observed in FFA-ETZ co-crystal. About 5-fold increment in the solubility of FFA was observed in both the co-crystals in 0.1 N HCl (pH 1) solution. The synthesized co-crystals were found to be non-hygroscopic at ?75% relative humidity and stable for a period of 6 months at ambient temperature (?25°C). © 2017 American Pharmacists Association®Item Structural and physicochemical characterization of pyridine derivative salts of anti-inflammatory drugs(Elsevier B.V., 2017) Nechipadappu, S.K.; Trivedi, D.R.Salts of common anti-inflammatory drugs mefenamic acid (MFA), tolfenamic acid (TFA) and naproxen (NPX) with various pyridine derivatives (4-amino pyridine (4AP), 4-dimethylaminopyridine (DMAP) and 2-amino pyridine (2AP)) were synthesized by crystal engineering approach based on the pKa values of API's and the salt former. All the salts were characterized systematically by various spectroscopic methods including FT-IR and 1H NMR and the crystal structure was determined by single-crystal X-ray diffraction techniques (SCXRD). DMAP salt of NPX and 2AP salts of MFA and TFA were not obtained in the salt screening experiments. All the molecular salts exhibited 1:1 molecular stoichiometry in the asymmetric unit and except NPX-2AP salt, all the molecular salts included a water molecule in the crystal lattice. Physicochemical and structural properties between drug-drug molecular salts of MFA-4AP, TFA-4AP and NPX-4AP have been evaluated and it was found that these molecular salts were found to be stable for a time period of six months at ambient condition and further hydration of molecular salts were not observed even at accelerated humid conditions (?75% RH). It was found that 4AP salts of MFA and TFA and DMAP salts of MFA and TFA are isostructural. © 2017 Elsevier B.V.Item Synthesis of cocrystals/salts of flucytosine: Structure and stability(Royal Society of Chemistry, 2018) Nechipadappu, S.K.; Ramachandran, J.; Naveen, N.; Lokanath, N.K.; Trivedi, D.R.5-Fluorocytosine or flucytosine (FLC) is a well-known drug for anti-fungal treatment and is one of the essential medicines needed in a health system. The main disadvantage of FLC drugs is their instability due to hydration under storage conditions. In the present work, cocrystal/salt screening experiments resulted in three molecular salts of FLC with dihydroxybenzoic acid derivatives, 2,3-dihydroxybenzoic acid (2,3HBA), 3,5-dihydroxybenzoic acid (3,5HBA), and 2,6-dihydroxybenzoic acid (2,6HBA), and two cocrystals with gallic acid (GAA) and glutaric acid (GLA). Since FLC drugs are highly susceptible to hydration, the present work concentrated on the stability of the synthesized molecular salts/cocrystals under different relative humidity (RH) conditions. All the newly formed crystalline adducts were characterized structurally, and the crystal structures were determined using single-crystal X-ray diffraction techniques (SCXRD). The FLC-2,6HBA salt was found to be a monohydrate, whereas the FLC-3,5HBA salt was crystallized as a hemipentahydrate. FLC-2,3HBA and FLC-GLA were crystallized in 2:1 equimolar ratios of FLC and the coformer. The FLC-GAA cocrystal crystallized in a 1:1 equimolar ratio. Two point heterosynthons between FLC and the coformer were observed in all the crystalline structures except FLC-GLA, where the structure was formed through a single point heterosynthon. Stability studies under different relative humidity conditions showed the non-hygroscopicity of the synthesized molecular salts/cocrystals. It was found that the FLC-2,3HBA salt, and the FLC-GAA and FLC-GLA cocrystals did not experience any hydration under the accelerated humidity conditions (both 70-75% RH and 90-95% RH) at ambient temperature (?30 °C). However, FLC-2,6HBA and FLC-3,5HBA were found to be hygroscopic under 70-75% RH conditions. Furthermore, all the synthesized salts/cocrystals except FLC-3,5HBA were found to be stable for 2 months under ambient conditions (?30 °C, 60-65% RH). Therefore, the FLC-2,3HBA salt, and the FLC-GAA and FLC-GLA cocrystals are better candidates for the preparation of new drug products of FLC. © 2018 The Royal Society of Chemistry and the Centre National de la Recherche Scientifique.Item Salt/Cocrystal of Anti-Fibrinolytic Hemostatic Drug Tranexamic acid: Structural, DFT, and Stability Study of Salt/Cocrystal with GRAS Molecules(American Chemical Society service@acs.org, 2019) Nechipadappu, S.K.; Reddy, I.R.; Tarafder, K.; Trivedi, D.R.Tranexamic acid (TXA) is an important and essential medicine needed in a health system and is approved by the US FDA for the treatment of excessive blood loss from trauma, postpartum bleeding, surgery, tooth removal, nosebleeds, and heavy menstruation. One of the notable disadvantages of the TXA drug is that has low absorption (â35-40%) in the gastrointestinal tract, possibly due to its amphoteric nature. In the present work, nine molecular salts and two cocrystals of the TXA molecule have been synthesized by a simple water-mediated solvent evaporation method. The coformers/counterions used were salicylic acid (SAL), 3-hydroxybenzoic acid (3HBA), 2,4-dihydroxybenzoic acid (2,4HBA), 2,5-dihydroxybenzoic acid (2,5HBA), 2,6-dihydroxybenzoic acid (2,6HBA), gallic acid (GAA), oxalic acid (TXA), tartaric acid (TTA), fumaric acid (FUM), succinic acid (SUA), and crotonic acid (CRA). The synthesized salts/cocrystals were characterized by various spectroscopic, thermal, and XRD techniques. The crystal structures of all of the molecular adducts were determined by SC-XRD techniques. In the synthesized salts, charge-assisted acid···amine heterosynthons and O-H···O hydrogen bonds between the acid group of TXA and the coformer are favored, and the salts TXA-FUM and TXA-SUA were found to be isostructural on the basis of the isostructural parameters Ï€ and Î? . In the cocrystal, molecules interacted through the acid group of the coformer with the carboxyl group of the TXA molecule. Further, these salts/cocrystals were found to be stable for a period of 6 months under ambient conditions (â25-30 °C, â60-65% RH). Furthermore, density functional theory (DFT) calculations were carried out to better understand the geometric structure of the molecules presented in our study. The interaction energies of the molecular salts and cocrystals were calculated, and they supported the reported structure of the crystalline adducts. The cocrystal formation in the case of TXA-GAA and TXA-CRA has been confirmed by a DFT calculation study, as the salt formation in these cases resulted in a higher interaction energy in comparison to the cocrystal. Consequently, these molecular salts offer promise for the development of new drug products of TXA, and a few salts, namely TXA-SAL and TXA-2,5HBA, offer the possibility of development of combination drugs. © 2018 American Chemical Society.