Mechanochemistry applied to reformulation and scale-up production of Ethionamide: Salt selection and solubility enhancement

Melo, Cristiane C. de; Silva, Cecília C. P. da; Pereira, Carla C.S.S.; Rosa, Paulo; Ellena, Javier

doi:10.1016/j.ejps.2015.10.007

Cited by 19 publications

(14 citation statements)

References 37 publications

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“…These are a salt of ETN with malonic acid (ETN·MAL), a cocrystal between ETN and glutaric acid (ETN·GLU) and a salt cocrystal of ETN with tartaric acid (ETN·TAR). Two crystal forms of ETN were reproduced from the literature, namely a salt of ETN with maleic acid (ETN·MLE) [ 27 ] and a cocrystal between ETN and fumaric acid (ETN·FUM) [ 26 ]. Table 2 summarizes the techniques used for preparing the new crystal forms and the outcome, in terms of stoichiometry and ionization state.…”

Section: Resultsmentioning

confidence: 99%

“…The structures of ETN·FUM and ETN·MLE are already discussed in [ 26 ] and [ 27 ]. For the sake of clarity, the asymmetric units and the HB networks are reported in Figures S10–S13 .…”

Section: Resultsmentioning

confidence: 99%

“…ETN crystallizes in space group Cc [ 22 ], without any polymorphic forms known to date. On the other hand, there are several examples in the literature of salts and cocrystals of ETN, namely ETN hydrochloride [ 23 ], hydrobromide [ 24 ], nitrate [ 25 ], oxalate [ 26 , 27 ], maleate [ 27 ] and saccharinate [ 27 ]; ETN·adipic acid [ 26 ], ETN·fumaric acid [ 26 ] and ETN·suberic acid [ 26 ]. Notably, in all salts reported in the literature, N5 of ETN appears to be protonated, while in all cocrystal structures of ETN with carboxylic acids, the COOH group is involved in hydrogen bond (HB) contacts with both N5 (COOH···N) and N10 (C=O···HN).…”

Section: Introductionmentioning

confidence: 99%

“…These three novel forms were compared with two previously reported crystal forms of ETN with dicarboxylic acids fumaric (FUM) and maleic (MLE) acid [ 26 , 27 ], to observe similarities and differences with respect to our novel forms in terms of spectroscopic and physicochemical properties. All five forms were analyzed by single-crystal X-ray diffraction (SCXRD), while all but ETN∙TAR, which could not be reproduced as a bulk powder (see Materials and Methods section), underwent solid-state NMR (SSNMR).…”

Section: Introductionmentioning

confidence: 99%

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Molecular Crystal Forms of Antitubercular Ethionamide with Dicarboxylic Acids: Solid-State Properties and a Combined Structural and Spectroscopic Study

et al. 2020

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We report on the preparation, characterization, and bioavailability properties of three new crystal forms of ethionamide, an antitubercular agent used in the treatment of drug-resistant tuberculosis. The new adducts were obtained by combining the active pharmaceutical ingredient with three dicarboxylic acids, namely glutaric, malonic and tartaric acid, in equimolar ratios. Crystal structures were obtained for all three adducts and were compared with two previously reported multicomponent systems of ethionamide with maleic and fumaric acid. The ethionamide-glutaric acid and the ethionamide-malonic acid adducts were thoroughly characterized by means of solid-state NMR (13C and 15N Cross-Polarization Magic Angle Spinning or CPMAS) to confirm the position of the carboxylic proton, and they were found to be a cocrystal and a salt, respectively; they were compared with two previously reported multicomponent systems of ethionamide with maleic and fumaric acid. Ethionamide-tartaric acid was found to be a rare example of kryptoracemic cocrystal. In vitro bioavailability enhancements up to a factor 3 compared to pure ethionamide were assessed for all obtained adducts.

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Section: Resultsmentioning

confidence: 99%

“…The structures of ETN·FUM and ETN·MLE are already discussed in [ 26 ] and [ 27 ]. For the sake of clarity, the asymmetric units and the HB networks are reported in Figures S10–S13 .…”

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Molecular Crystal Forms of Antitubercular Ethionamide with Dicarboxylic Acids: Solid-State Properties and a Combined Structural and Spectroscopic Study

et al. 2020

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“…Low solubility of active compounds represents one of the major challenges in formulation development and thus gains attention of many pharmaceutical scientists. Improving drug solubility may be done by several approaches including: size reduction (Loh et al, 2015), formation of inclusion complexes (Miletic et al, 2013), salt formation (Melo et al, 2016), formulation of self (micro/nano) emulsifying systems (Čerpnjak et al, 2015), solid dispersions (Wlodarski et al, 2015). The term solid dispersion in general refers to dispersion of a solid drug in a solid carrier.…”

Section: Solid Dispersions For Solubility and Bioavailability Enhancementioning

confidence: 99%

Hot-melt extrusion and prilling as contemporary and promising techniques in the solvent free production of solid oral dosage forms, based on solid dispersions

Aleksovski¹,

Vervaet²,

Dreu³

2016

Maced. Pharm. Bull.

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Hot melt extrusion and prilling are gaining importance as solvent free and continuous techniques in the production of solid oral dosage forms with added value, by incorporating active compound in a molten carrier which is further solidified to form solid dispersion. This article reviews these two techniques in terms of understanding process basics, equipment characteristics, required properties of processed materials and application of the processes for development of solid oral dosage forms. Studies revealed that both hot-melt extrusion and prilling are regarded as simple, robust and continuous methods for processing different types of materials and production of solid dosage forms based on solid matrices. However, understanding of their concepts and requirements together with careful material selection is crucial for stable material processing and obtaining stable products of high-quality. Hot-melt extrusion proved to be a suitable method for production of modified release dosage forms, taste masked dosage forms and dosage forms offering improved drug dissolution rate and solubility. Prilling till now has been successfully applied just in the production of multiple unit drug delivery systems for immediate and sustained drug delivery. Further studies on product development and process understanding are required for full implementation of prilling in the pharmaceutical field.

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Pharmaceutical salts of ethionamide with GRAS counter ion donors to enhance the solubility

Nechipadappu

Trivedi

2017

European Journal of Pharmaceutical Sciences

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Mechanochemistry applied to reformulation and scale-up production of Ethionamide: Salt selection and solubility enhancement

Cited by 19 publications

References 37 publications

Molecular Crystal Forms of Antitubercular Ethionamide with Dicarboxylic Acids: Solid-State Properties and a Combined Structural and Spectroscopic Study

Molecular Crystal Forms of Antitubercular Ethionamide with Dicarboxylic Acids: Solid-State Properties and a Combined Structural and Spectroscopic Study

Hot-melt extrusion and prilling as contemporary and promising techniques in the solvent free production of solid oral dosage forms, based on solid dispersions

Pharmaceutical salts of ethionamide with GRAS counter ion donors to enhance the solubility

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