Methanesulfonic acid salt forms of carbamazepine and 10,11-dihydrocarbamazepine

Abstract

New methanesulfonic acid salt forms of the anticonvulsant and analgesic active pharmaceutical ingredient carbamazepine and its closely related structural analogue 10,11-dihydrocarbamazepine have been prepared and characterized by single-crystal X-ray diffraction at 120 and 100 K, respectively {namely [(5H-dibenzo[b,f]azepin-5-yl)(hydroxy)methylidene]azanium methanesulfonate, C15H13N2O(+)·CH3SO3(-), and [(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)(hydroxy)methylidene]azanium methanesulfonate, C15H15N2O(+)·CH3SO3(-)}. In light of the structural information obtained, the crystal structure of the carbamazepine trifluoroacetic acid monosolvate [dibenzo[b,f]azepine-5-carboxamide-trifluoroacetic acid (1/1), C15H12N2O·CF3COOH] was redetermined at 100 and 270 K, and from this data it was concluded that the protonation state for this solvate species is best described as in an `intermediate state' with the acidic proton located almost at the mid-point between the acid and base.

Exploring short strong hydrogen bonds engineered in organic acid molecular crystals for temperature dependent proton migration behaviour using single crystal synchrotron X-ray diffraction (SCSXRD)

“…2 is therefore a salt at this temperature 46 whilst the refined H-atom positions at 100 K for 3 indicate a centralised position (the d O-H 1.23(7) Å and d H⋯O 1.26(7) Å distances are not significantly different given the esds) meaning it is an intermediate between a salt and co-crystal. 47 Generally, where the interaction has a charge assisted component (O + -H⋯O − ), as in 2 and 3, the donor-acceptor distances are shorter. This can be explained where the charges on the donor-acceptor atoms significantly increase the strength of the interaction 33 by reinforcing its electrostatic character; 48,49 leading to the shorter donor-acceptor distances.…”

Observation of neutral, ionic and intermediate states in lamotrigine-acid complexes- inference from crystallographic bond geometries

“…Since no complexes exhibit negative ΔpKa values, pure cocrystal formation is almost unlikely and has not been observed. [26].…”

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

“…[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. As with CBZ and DCBZ, it is clear that protonated and neutral PAR species show different geometries with the C=O bond lengthening by approximately 0.05 to 0.06 Å and C-N shortening by 0.03 to 0.04 Å upon protonation.…”

“…[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.…”