Application and Comparison of Cocrystallization Techniques on Trospium Chloride Cocrystals

Abstract

To identify as many solid forms of active pharmaceutical ingredient (API) as possible and to monitor their cocrystallization potential, synthetic methods are needed. According to API properties (solubility, melting point, stability), suitable screening methods have to be considered. In this study, the performance of most of the commonly available cocrystallization techniques such as neat grinding, liquid-assisted grinding, slurrying, co-melting, and slow evaporation was compared. We applied them to four pharmaceutical cocrystals of trospium chloride (TCl, a muscarinic antagonist urinary antispasmodic) with adipic (AD), glutaric (GA), oxalic (OX), and salicylic acids (SA), which were identified as hits from previous slow evaporation experiments. Their structures were determined by single-crystal X-ray diffraction (TCl-SA and TCl-OX cocrystals) or from powder X-ray diffraction data (TCl-AD and TCl-GA cocrystals). Other methods to characterize the cocrystal phases were applied ( 1 H NMR, DSC, IR, and Raman spectroscopy). Comparison of cocrystallization methods and of the prepared cocrystals was discussed.

Systematic solvate screening of trospium chloride: discovering hydrates of a long-established pharmaceutical

“…That makes 16 structures containing TCl in total. The cocrystal with salicylic acid forms most readily from all described cocrystals of TCl, even with simple mixing and heating of both components 12 . The diagram is used for a clear analysis of similarity in crystal packing of structures of one compound.…”

“…The cocrystal with salicylic acid forms most readily from all the described cocrystals of TCl, even with simple mixing and heating of both components. 12 For all of the four main branches in the tree diagram, theoretical crystal shape and packing were calculated in Mercury (Bravais, Friedel, Donnay and Harker (BFDH) theoretical crystal morphologies, Fig. 3 and 4).…”

“…The precipitation of a new solid form also presents a risk which could endanger a robust production of an API 1 and might appear even if minor changes in the technology are installed, an appearing polymorph of ritonavir representing a very challenging scenario. 11,12 An ethanol solvate has been reported as well. 6,7 The possibility of the preparation of various polymorphs can be also investigated/controlled via desolvation of the solvate as was reported in the case of furosemide 8 , sulfamerazine 9 or spironolactone 10 polymorphs.…”

“…Recently, the structural characterization of new cocrystals, as well as the polymorphs of TCl, has been reported. 11,12 An ethanol solvate has been reported as well. 11 The motivation of this study was to further investigate its propensity to include small molecules within the crystal structure, thus forming solvates, as trospium chloride seems to be a very accommodating molecule providing a whole range of different phases.…”

Hydrogen Bond Hierarchy: Persistent Phenol···Chloride Hydrogen Bonds in the Presence of Carboxylic Acid Moieties

“…This low variability 423 demonstrates that substituent effects are only small with the majority of the stabilization energy 424 (2−3 kJ mol −1 ) due the weak resonance assistance from the aromatic ring. 42 This is clearly 425 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 methyl propanoic acid (−70.6 kJ mol -1 ) and benzoic acid (−73.2 kJ mol -1 ). An additional minor 427 meta-effect from the carboxyl group present in HPA is also observed with an interaction of −75.7 428 kJ mol −1 .…”