Pharmaceutical cocrystals and salts of enrofloxacin: Structure and properties

Yang, Shuang-Yun; Zhao, Fei-Ke; Pang, Hong Chen; Chen, Liang-Zhu; Shi, Ren-Bin; Fang, Binghu

doi:10.1016/j.molstruc.2022.133335

Cited by 13 publications

(9 citation statements)

References 34 publications

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“…In the spectra of MBF-FA-H 2 FA salt cocrystal and MBF-MA salt, the absorption peaks for the CO stretching vibration of carboxylic acids were seen to be displaced from 1725 to 1716 cm –1 and 1718 cm –1 , respectively, which may be the result from intramolecular or intermolecular interactions (hydrogen bonding). Significantly dissimilar to marbofloxacin is the broad infrared absorption band at ∼2500 cm –1 supporting the protonation of the N atom (NH + ) on the piperazine ring. − These changes were confirmed by crystal structure analysis.…”

Section: Resultsmentioning

confidence: 86%

Salt Cocrystal and Salt of Marbofloxacin with Butenedioic Acid: Impact of cis–trans Isomerism of Coformer on the Conformation and Properties of Marbofloxacin

Li,

Zhang,

et al. 2024

Crystal Growth & Design

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Based on the study of the effect of positional isomerism of coformer functional groups on the cocrystallization and physicochemical properties of the active pharmaceutical ingredients, the impact of cis−trans isomeric butenedioic acid as coformers on the conformation, crystal structure, and its physicochemical properties of marbofloxacin was further explored. In this work, fumaric acid (FA) and maleic acid (MA) with different configurations were chosen as coformers to synthesize the pharmaceutical salt cocrystal (MBF-FA-H 2 FA) and salt (MBF-MA) of marbofloxacin (MBF), and their structures were fully characterized. Significant differences between the conformations of marbofloxacin in the salt cocrystal and in salt were found. In the salt cocrystal, the N atom of the piperazine group from marbofloxacin is coplanar with the pyridone ring, and the whole is straight like fumaric acid, whereas the marbofloxacin piperazine group in the salt is bent like the maleic acid configuration. Furthermore, the conformational variability of marbofloxacin in the salt cocrystal and the salt resulted in different crystal structures and opposite physicochemical properties. Notably, both multicomponent crystals have a surface hydrophilic intercalation structure. However, the salt cocrystal and salt exhibited different solubility and permeability. Specifically, the MBF-MA salt showed improved solubility and permeability, while the MBF-FA-H 2 FA salt cocrystal showed a decreased solubility and permeation rate compared to MBF. In addition, in vitro bacterial inhibitory activity assays indicated that the MBF-MA salt has stronger inhibitory activity against Gram-negative and Gram-positive bacterial strains than the MBF-FA-H 2 FA salt cocrystal and pure MBF.

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Section: Resultsmentioning

confidence: 86%

Salt Cocrystal and Salt of Marbofloxacin with Butenedioic Acid: Impact of cis–trans Isomerism of Coformer on the Conformation and Properties of Marbofloxacin

Li,

Zhang,

et al. 2024

Crystal Growth & Design

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“…The DSC analysis of ENR (Figure 3a) exhibits a strong endotherm at 226 °C, corresponding to its melting point (onset 223.85 °C), and the measured melting enthalpy is about 100.82 J/g, which is consistent with previous studies. 47 Its weight loss appeared at 290 °C. The DSC analysis of ENR-3,5-DHBA (Figure 3b) exhibits a strong endotherm at 263 °C, corresponding to its melting point (onset 261.41 °C).…”

Section: Resultsmentioning

confidence: 99%

“…The melting points ( T onset ) and melting enthalpy (Δ H m ) obtained by the DSC profiles are listed in Table . The DSC analysis of ENR (Figure a) exhibits a strong endotherm at 226 °C, corresponding to its melting point (onset 223.85 °C), and the measured melting enthalpy is about 100.82 J/g, which is consistent with previous studies . Its weight loss appeared at 290 °C.…”

Section: Resultsmentioning

confidence: 99%

Enhancing the Bioavailability of a Novel Enrofloxacin Salt by Inhibiting Precipitation via a Crystallization Inhibitor

Mao,

Wang,

Liu

et al. 2024

Crystal Growth & Design

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Highly soluble cocrystals can improve the bioavailability of poorly soluble drugs by inducing supersaturation when absorption is limited by drug dissolution. Enrofloxacin (ENR) is a concentration-dependent fluoroquinolone antibacterial with poor solubility. In this study, two new ENR salts, 3,5-dihydroxybenzoic acid (ENR-3,5-DHBA) and 2,6-dihydroxybenzoic acid (ENR-2,6-DHBA•1/2H 2 O), were prepared, and their physicochemical properties were evaluated for suitability in formulation development.Results showed that the solubility of the two new salts enhanced. Although ENR-3,5-DHBA had a much higher solubility than ENR, it underwent rapid precipitation during dissolution, forming the poorly soluble ENR•6H 2 O in aqueous form. This negated the potential high-solubility advantage of the new salt, which might have enhanced its dissolution rate and in vivo bioavailability. To solve this problem, we systematically evaluated suitable crystallization inhibitors that could maintain the supersaturation generated by cocrystal/salt dissolution for a prolonged period. At 37 °C, the solubility and mean AUC 0−24h of ENR-3,5-DHBA increased by about 4.7 and 1.5 times, respectively (compared with ENR), when ENR-3,5-DHBA was dosed with 2.0 mg/mL methacrylic acidethyl acrylate copolymer (ME) solution instead of an active pharmaceutical ingredient. This study demonstrates that using a highly soluble salt and an appropriate crystallization inhibitor is a potentially effective formulation strategy for improving the oral bioavailability of poorly soluble drugs.

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“…20–23 The preparation of salts demands that APIs have ionizable functional groups and the acid–base differences between the drug substance and guest molecules meet the Δp K a rule of 3. 24–26 However, the design of salts with a suitable selection of counterions and synthon compatibility, which would render expected properties of a new solid form, is still a challenging area of research.…”

Section: Introductionmentioning

confidence: 99%

“…[20][21][22][23] The preparation of salts demands that APIs have ionizable functional groups and the acid-base differences between the drug substance and guest molecules meet the DpK a rule of 3. [24][25][26] However, the design of salts with a suitable selection of counterions and synthon compatibility, which would render expected properties of a new solid form, is still a challenging area of research. Cephalexin (CPX), ((6R,7R)-7-[(R)-2-amino-2phenylacetamido]-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid), is the rst generation of b-lactam cephalosporin antibiotics, which exhibits excellent activities in killing Gram-positive and some Gram-negative bacteria through inhibition of cell wall synthesis.…”

Section: Introductionmentioning

confidence: 99%

Novel pharmaceutical salts of cephalexin with organic counterions: structural analysis and properties

et al. 2022

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Pharmaceutical cocrystals and salts of enrofloxacin: Structure and properties

Cited by 13 publications

References 34 publications

Salt Cocrystal and Salt of Marbofloxacin with Butenedioic Acid: Impact of cis–trans Isomerism of Coformer on the Conformation and Properties of Marbofloxacin

Salt Cocrystal and Salt of Marbofloxacin with Butenedioic Acid: Impact of cis–trans Isomerism of Coformer on the Conformation and Properties of Marbofloxacin

Enhancing the Bioavailability of a Novel Enrofloxacin Salt by Inhibiting Precipitation via a Crystallization Inhibitor

Novel pharmaceutical salts of cephalexin with organic counterions: structural analysis and properties

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