Fluoroquinolone salts with carboxylic acids

Reddy, Jhansi; Ganesh, Saraswatula Viswanadha; Nagalapalli, Ravikumar; Dandela, Rambabu; Solomon, K. Anand; Kumar, Kaushlendra; Goud, N. Rajesh; Nangia, Ashwini

doi:10.1002/jps.22537

Cited by 63 publications

(64 citation statements)

References 28 publications

(27 reference statements)

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“…5 Taking the above into consideration, alternative forms of C, which do not contain the chloride counterion and Preparation of C salts with organic acids such as citric, tartaric and malonic acid has previously been presented. 6 Recently, we reported on the ability of another amphoteric molecule, salbutamol, to form a salt with succinic acid or a cocrystal of salbutamol adipate salt with adipic acid. 7 All of the above examples of counterions include organic acids with more than one carboxylic group, potentially presenting the possibility of the formation of salts with multiple stoichiometries.…”

Section: Introductionmentioning

confidence: 99%

Formation and Physicochemical Properties of Crystalline and Amorphous Salts with Different Stoichiometries Formed between Ciprofloxacin and Succinic Acid

Paluch¹,

McCabe²,

Müller‐Bunz

et al. 2013

Mol. Pharmaceutics

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Multi-ionisable compounds, such as dicarboxylic acids, offer the possibility of forming salts of drugs with multiple stoichiometries. Attempts to crystallise ciprofloxacin, a poorly water soluble, amphoteric molecule with succinic acid (S) resulted in isolation of ciprofloxacin hemisuccinate (1:1) trihydrate (CHS-I) and ciprofloxacin succinate (2:1) tetrahydrate (CS-I). Anhydrous ciprofloxacin hemisuccinate (CHS-II) and anhydrous ciprofloxacin succinate (CS-II) were also obtained. It was also possible to obtain stoichiometrically equivalent amorphous salt forms, CHS-III and CS-III, by spray drying and milling, respectively, of the drug and acid. Anhydrous CHS and CS had melting points at ~215 and ~228 °C, while the glass transition temperatures of CHS-III and CS-III were ~101 and ~79 °C, respectively. Dynamic solubility studies revealed the metastable nature of CS-I in aqueous media, resulting in a transformation of CS-I to a mix of CHS-I and ciprofloxacin 1:3.7 hydrate, consistent with the phase diagram. CS-III was observed to dissolve non-congruently leading to high and sustainable drug solution concentrations in water at 25 and 37 ºC, with the ciprofloxacin concentration of 58.8±1.18 mg/ml after 1 hour of the experiment at 37 ºC. This work shows that crystalline salts with multiple stoichiometries and amorphous salts have diverse pharmaceutically-relevant properties, including molecular, solid state and solubility characteristics.

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Section: Introductionmentioning

confidence: 99%

Formation and Physicochemical Properties of Crystalline and Amorphous Salts with Different Stoichiometries Formed between Ciprofloxacin and Succinic Acid

Paluch¹,

McCabe²,

Müller‐Bunz

et al. 2013

Mol. Pharmaceutics

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“…It has been previously reported that IDR studies on fluoroquinolone salts at neutral pH (pH 6.8) may result in complex non-linear dependencies due to the rapid conversion of salts into the parent drugs on an upper layer of the sample tablet during the experiment. 8,10 The experimental IDR values for the CIP and NFX fumarates are listed in Table S3. † The IDR of the salts in the pH 1.2 buffer followed the same trend as the solubility of the compounds.…”

Section: Solubility Of the Solid Forms At Different Ph Valuesmentioning

confidence: 99%

“…5 Salt formation changes the state of CIP molecules in their crystal form from zwitterionic to cationic, effectively reducing the lattice energy and improving aqueous solubility. 6 Therefore, a number of efforts have been made to extend the range of fluoroquinolone solid forms and to modify the poor solubility performance of CIP and NFX through salt preparation with different organic acids, including aliphatic [7][8][9][10][11][12] and aromatic carboxylic acids, [13][14][15][16] derivatives of sulfonic acids, and artificial sugars. [17][18][19][20] Recently, a new drug-drug multicomponent solid consisting of two antibacterial agents, namely norfloxacin and sulfathiazole, has been obtained.…”

Section: Introductionmentioning

confidence: 99%

Diversity of crystal structures and physicochemical properties of ciprofloxacin and norfloxacin salts with fumaric acid

et al. 2018

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adThe crystallization of norfloxacin and ciprofloxacin -antibacterial fluoroquinolone compounds -with fumaric acid resulted in the isolation of six distinct solid forms of the drugs with different stoichiometries and hydration levels. Each salt can be selectively obtained by mechanochemical treatment in the presence of water/organic mixtures of a particular composition. The new phases were analysed using TG, DSC and PXRD, and their structural parameters were determined using single crystal X-ray diffraction. Despite having the same counterion, the ciprofloxacin and norfloxacin fumarates crystallise to form distinct crystal structures, which consequently determine the differences in the relative stability and the corresponding physicochemical properties of the solid forms. The influence of water activity (a w ) on the solid form stability and transformation pathways of anhydrous and hydrated fumarates was elucidated. The solubility and phase stability of the salts were also investigated in pharmaceutically relevant buffer solutions with pH 6.8 and pH 1.2. The largest solubility improvement relative to the parent drug (≈33 times) in the pH 6.8 medium was observed in the case of ciprofloxacin hemifumarate sesquihydrate. In turn, the norfloxacin fumarates showed a moderate 3-fold enhancement in solubility.

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“…Novel CIP salts have also been produced using malonic, tartaric and oxalic acid, 10 mesylic, gluconic and glycolic acid, 11 and saccharin. 12 All of these salts showed an improvement in solubility compared to the pure drug.…”

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confidence: 99%

Amorphous Polymeric Drug Salts as Ionic Solid Dispersion Forms of Ciprofloxacin

et al. 2017

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Ciprofloxacin (CIP) is a poorly soluble drug that also displays poor permeability. Attempts to improve the solubility of this drug to date have largely focused on the formation of crystalline salts and metal complexes. The aim of this study was to prepare amorphous solid dispersions (ASDs) by ball milling CIP with various polymers. Following examination of their solid state characteristics and physical stability, the solubility advantage of these ASDs was studied, and their permeability was investigated via parallel artificial membrane permeability assay (PAMPA). Finally, the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of the ASDs were compared to those of CIP. It was discovered that acidic polymers, such as Eudragit L100, Eudragit L100C==, Carbopol and HPMCAS, were necessary for the amorphization of CIP. In each case, the positively charged secondary amine of CIP was found to interact with carboxylate groups in the polymers, forming amorphous polymeric drug salts. Although the ASDs began to crystallize within days under accelerated stability conditions, they remained fully XCray amorphous following exposure to 90% RH at 25 oC, and demonstrated higher than predicted glass transition temperatures. The solubility of CIP in water and simulated intestinal fluid was also increased by all of the ASDs studied. Unlike a number of other solubility enhancing formulations, the ASDs did not decrease the permeability of the drug.Similarly, no decrease in antibiotic efficacy was observed, and significant improvements in the MIC and MBC of CIP were obtained with ASDs containing HPMCASC") and HPMCASCMG. Therefore, ASDs may be a viable alternative for formulating CIP with improved solubility, bioavailability and antimicrobial activity.

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Fluoroquinolone salts with carboxylic acids

Cited by 63 publications

References 28 publications

Formation and Physicochemical Properties of Crystalline and Amorphous Salts with Different Stoichiometries Formed between Ciprofloxacin and Succinic Acid

Formation and Physicochemical Properties of Crystalline and Amorphous Salts with Different Stoichiometries Formed between Ciprofloxacin and Succinic Acid

Diversity of crystal structures and physicochemical properties of ciprofloxacin and norfloxacin salts with fumaric acid

Amorphous Polymeric Drug Salts as Ionic Solid Dispersion Forms of Ciprofloxacin

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