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.
Solving pharmaceutical crystal structures from powder diffraction data is discussed in terms of the methodologies that have been applied and the complexity of the structures that have been solved. The principles underlying these methodologies are summarized and representative examples of polymorph, solvate, salt and cocrystal structure solutions are provided, together with examples of some particularly challenging structure determinations.
An X-ray amorphous mixture of carbamazepine and indomethacin transforms upon annealing to produce a novel 1:1 cocrystal, whose structure has been determined from laboratory powder X-ray diffraction (PXRD) data. Carbamazepine (CBZ; Fig 1) crystallises in five known 65 method, CBZ:IND is detectable by PXRD after ca. 48hrs storage at 25°C and the characteristic CBZ:IND peaks continue to grow in intensity and sharpen with time as crystallization proceeds.
The crystal structure of an indomethacin-nicotinamide (1:1) co-crystal produced by milling has been determined from laboratory powder X-ray diffraction (PXRD) data. The hydrogen-bonding motifs observed in the structure represent 65
The simulated annealing approach to structure solution from powder diffraction data, as implemented in the DASH program, is easily amenable to parallelization at the individual run level. Very large scale increases in speed of execution can therefore be achieved by distributing individual DASH runs over a network of computers. The GDASH program achieves this by packaging DASH in a form that enables it to run under the Univa UD Grid MP system, which harnesses networks of existing computing resources to perform calculations.
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