Abstract
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.
Highlights
The obtainment of novel crystal forms is a well-consolidated strategy in the quest for solid molecular materials with enhanced physicochemical properties with respect to those of the pure components
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 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
Summary
The obtainment of novel crystal forms is a well-consolidated strategy in the quest for solid molecular materials with enhanced physicochemical properties with respect to those of the pure components. Some of us managed to selectively obtain both a salt and a cocrystal for the ETN−salicylic acid system, which display remarkable in vitro bioavailability properties [16] This further proves ETN to be a very feasible molecule to undergo the crystal engineering approach. All three new crystal forms are characterized by significantly higher dissolution rates than pure ETN 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. Despite many attemETpNts·,FEUTMN:·TCAryRstcaoluslwdenroetobbetarienperdodthurcoeudgihn spluowre efovrampotroautinodneartgroofoumrthteemr apnearalytuserse.of a methanol solutioEnTNco·FnUtaMin:inCgry3s0tamlsgw(e0r.1e8ombtmainoel)dotfhEroTuNghansldow21emvagp(o0r.a1t8iomnmatorlo)oomf FtUemMp.erature of a methanol soluEtiToNn ·cMonLtEai:nAinngo3r0anmgge(m0.1ic8romcmryoslt)aollfinEeTpNoawndde2r1wmags o(0b.t1a8inmemd obly) omfaFnUuMal.ly dry grinding 30 mg (0.18 mETmNo·Ml) LoEf :EATnNoraanndge21mmicrgoc(r0y.1s8talmlinmeopl)owofdeMr LwEasfoorbt3a0inmedinb.y Cmraynsutaallsly, sduriytagbrliendfoinrgS3C0XmRgD, w(0er.1e8ombtmainole)dotfhEroTuNghansdlow21emvagp(o0r.1a8tiomnmatorl)ooomf MteLmEpfeorra3tu0rme oinf.aCnraycsettaolsn,essuoitlaubtiloenfocronStCaXinRinDg, 1w5emreg (0.09 mmol) of ETN and 10.5 mg (0.09 mmol) of MLE
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