Drug–drug salts of mefenamic acid\tolfenamic acid and piperazine to improve physicochemical properties for potential veterinary use

Wang, Xinyi; Xu, Shijie; Jia, Lina; Yang, Yujia; Liu, Yu; Gong, Junbo; Wu, Songgu

doi:10.1039/c9ce00781d

Cited by 10 publications

(8 citation statements)

References 40 publications

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“…In addition to improving the solubility, a typical physicochemical property, crystal engineering may provide other benefits by employing different cocrystal/salt formers, such as a pleasant taste, hepatoprotective effects, and multiple curative efficacies. − It has been demonstrated that phenolic acids have some positive pharmacology activities. − Especially, the antifungal and anti-inflammatory activity of these phenolic acids may bring an enhanced therapeutic effect and reduce the risk of hepatotoxicity at the same time. In recent years, the applicability of phenolic acids as potential cocrystal/salt formers has been widely reported.…”

Section: Introductionmentioning

confidence: 99%

Ketoconazole: Solving the Poor Solubility via Cocrystal Formation with Phenolic Acids

Chen

Deng

et al. 2020

Crystal Growth & Design

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Ketoconazole (KTZ) is an imidazole derivative that is used to treat a wide variety of fungal infections and other human diseases. As a class II compound in the biopharmaceutics classification system, KTZ has low aqueous solubility. To improve this disadvantage, five phenolic acids were employed to form cocrystals with KTZ. The antifungal and anti-inflammatory activity of the phenolic acids may bring an enhanced therapeutic effect and reduce the risk of hepatotoxicity at the same time. The structural information on these five crystalline samples and KTZ were fully disclosed by single-crystal X-ray diffraction. In addition to a previously reported carboxylic acid••• imidazole N interaction, hydroxyl•••imidazole N hydrogen bonding also appears in the KTZ cocrystals as a main supramolecular heterosynthon. The short strong hydrogen bonds were observed in two cocrystal structures, which contain slightly longer carboxylic O−H length. 15 N solid-state NMR also provided valuable clues for the confirmation of the molecular/ionization states. The dissolution tests revealed that all the newly obtained cocrystals exhibit significantly improved solubility compared to KTZ.

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Section: Introductionmentioning

confidence: 99%

Ketoconazole: Solving the Poor Solubility via Cocrystal Formation with Phenolic Acids

Chen

Deng

et al. 2020

Crystal Growth & Design

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“…Conformational analysis was carried out to indicate which conformations of a molecule with flexible groups were adopted within the crystal. − The overlay of TM on the benzene ring is shown in Figure a. Two arms of TM can rotate around C-N near the benzene ring; interactions on the thioureido can be monitored by the dihedral angle of C 8 –C 9 –N 3 –C 10 .…”

Section: Resultsmentioning

confidence: 99%

Enhancing Stability and Formulation Capability of Fungicides by Cocrystallization through a Novel Multistep Slurry Conversion Process

Jin

Gong

et al. 2020

Crystal Growth & Design

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Solid agrochemicals with poor thermal stability pose a huge challenge to their production and application. Herein, two low-melting-point fungicides, pyraclostrobin (ZJ) and flusilazole (FZ), were designed to form cocrystals with the high melting point fungicide of thiophanate-methyl (TM), respectively. An infrequent multistep slurry conversion crystallization process was discovered and studied, which accelerated the formation of cocrystals, and the mechanism was revealed. Oiling-out of FZ and ZJ was the key process to multistep slurry conversion crystallization. The heterogeneous system possessed the advantage of high energy, which accelerated the synthesis of cocrystals. Furthermore, the variations of physicochemical properties containing thermal stability, tap density, formulation ability, and storage stability of both the parent fungicides and cocrystals were analyzed and compared. Packing coefficient and crystal structure analysis revealed the structure–property relationships of cocrystals. The single-crystal structure showed the strong N-H···N hydrogen bonds between the FZ and TM, and N-H···O and N-H···S interactions in the ZJ-TM cocrystal. Strong hydrogen bonds stabilize the structures of cocrystals, which enables ZJ-TM and FZ-TM to be made into a greener water suspension concentrate, instead of an emulsifiable concentrate with pollution.

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“…Pharmaceutical cocrystallization provides great convenience for optimizing the physicochemical properties of solid drugs, including their stability, dissolution rate, permeability and mechanical properties, without changing their molecular structures and pharmacological activity. [14][15][16][17][18][19][20] Moreover, both salts and cocrystals tremendously expand the solid-state scope of drugs, which present non-negligible intellectual property value. 21 Different solid forms always demonstrate different physicochemical properties, which further affect the production process and efficacy of drugs.…”

Section: Introductionmentioning

confidence: 99%

Salts of rucaparib with dicarboxylic acids: synthesis, crystal structures and solubility

Xiong

Dai

et al. 2022

CrystEngComm

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Drug–drug salts of mefenamic acid\tolfenamic acid and piperazine to improve physicochemical properties for potential veterinary use

Abstract: Drug–drug salts of mefenamic acid\tolfenamic acid and piperazine were designed to improve the solubility and hygroscopicity, which could possibly extend the drug–drug salt form into veterinary use.

Cited by 10 publications

References 40 publications

Ketoconazole: Solving the Poor Solubility via Cocrystal Formation with Phenolic Acids

Ketoconazole: Solving the Poor Solubility via Cocrystal Formation with Phenolic Acids

Enhancing Stability and Formulation Capability of Fungicides by Cocrystallization through a Novel Multistep Slurry Conversion Process

Salts of rucaparib with dicarboxylic acids: synthesis, crystal structures and solubility

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