Salt Forms of Amides: Protonation and Polymorphism of Carbamazepine and Cytenamide

Abstract

In situ generation of HCl or HBr in alcohol leads to O-protonation of the amide group of carbamazepine. Six salt phases have been produced using this method and their crystal structures determined by single crystal diffraction. A new polymorph of carbamazepine hydrochloride is described as are two polymorphs of carbamazepine hydrobromide. All are protonated at the amide O atom to give RC(OH)NH 2 cations. Prolonged exposure to air results in addition of water to the solid salt forms. Such hydration of carbamazepine hydrobromide simply gives a monohydrated phase, but similar treatment of the equivalent hydrochloride results in partial loss of HCl and the transfer of the remaining proton from the amide group to water to give [carbamazepine][H 3 O] 0.5 [Cl] 0.5 •H 2 O. A similar hydronium chloride species is the only product isolated after reaction of the carbamazepine analogue cytenamide with HCl generated in methanol.

Structural study of salt forms of amides; paracetamol, benzamide and piperine

“…Although a simple hydrated iodide structure of PAR has previously been reported, [19] Previously, analysis of CBZ and DCBZ structures showed that protonation of the amide O atom led to characteristic lengthening of the C=O bond length and shortening of the C-NH2 and C-N(ring) bond lengths. [1,7] This effect was so diagnostic of neutral and cationic species that it could even be used to assign "intermediate" status to structures where the acidic proton was in dynamic equilibrium between CBZ(H) and an O atom of a second crystal component. [6,8] A similar analysis of bond length variation for the known PAR(H) species (Scheme 2) is shown in Figure 3.…”

“…All samples were prepared using general methods described elsewhere. [1,8] In each case approximately 0.2 g of API was dissolved with heating in the minimum amount (2 to 4 ml) of methanol. After cooling to room temperature, 2 equivalents of the selected acid were added with gentle stirring.…”

“…It has been shown that although organic amide functionalities are normally thought of as being non-basic, it is possible to protonate them using strong acids and even to isolate and characterise their salt forms in the solid state. [1][2][3] Such salt formation reactions are a staple of pharmaceutical form screening, where they are used to modify the physicochemical properties of basic Active Pharmaceutical Ingredients (APIs). [4] Whilst the acidic materials formed by protonating amides are unlikely to make commercially viable APIs, it has been suggested that access to such forms may confer substantial benefits during the manufacturing process.…”

“…[2] Since then several groups have crystallographically investigated series of multiple salt forms of particular amide APIs, notably the paracetamol work already mentioned above and structures of the model APIs carbamazepine (CBZ) and its congener dihydrocarbamazepine (DCBZ). [1,[6][7][8] The interest in looking at multiple related structures rather than single salt forms is of course the increased ability to compare and contrast both structures and the properties that arise from these structures. We are particularly interested in the CBZ and DCBZ studies that have shown systematic differences between the neutral and protonated forms in terms of both molecular structure and of typical hydrogen bonding motifs.…”

“…We are particularly interested in the CBZ and DCBZ studies that have shown systematic differences between the neutral and protonated forms in terms of both molecular structure and of typical hydrogen bonding motifs. [1,[6][7][8] Here we report an extension of these comparative structural studies by examining new salt forms of three pharmaceutically relevant amides, the simple building block and primary amide benzamide (BEN), the well known analgesic and secondary amide paracetamol (PAR) and the naturally occurring alkaloid and tertiary amide piperine (PIP), see Scheme 1. Scheme 1.…”