Abstract
The pharmaceutical salt ivabradine hydrochloride is indicated for the symptomatic treatment of chronic stable angina pectoris and chronic heart failure. It exhibits extensive polymorphism and co-crystallization, which could be a way to provide an alternative solid form. We conducted a co-crystal screen, from which two hits were identified: with (S)-mandelic and (R)-mandelic acid. Both structures were determined from single-crystal X-ray diffraction data as co-crystals. The co-crystals were further characterized by common solid-state techniques, such as X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), solid-state NMR, IR and Raman spectroscopy, and dynamic vapor sorption (DVS). The co-crystal with (S)-mandelic acid was selected for further development; its physical and chemical stability was compared with two different polymorphs of the hydrochloride salt. The co-crystal exhibited a similar stability with the polymorph used in the original drug product and was, therefore, selected for formulation into the drug product. During the pre-formulation experiments, the in situ formation of the co-crystal was achieved during the wet granulation process. The following formulation experiments showed no influence of in situ prepared co-crystal on the overall stability of the bulk, when compared with pre-prepared co-crystal formulation.
Highlights
Multicomponent solid forms of pharmaceutical substances (APIs) are widely screened from early drug development, as they provide a whole range of forms with different physicochemical properties
When single crystals were obtained, the structures were determined from Single Crystal X-ray Diffraction (SXRD) data as ivabradine hydrochloride (S)-mandelic acid 1:1 co-crystal (IClSM) and ivabradine hydrochloride (R)-mandelic acid 1:1 co-crystal (IClRM)
In order to overcome the polymorphism issues of ivabradine hydrochloride, we concentrated on the preparation of a stable co-crystalline solid form
Summary
Multicomponent solid forms of pharmaceutical substances (APIs) are widely screened from early drug development, as they provide a whole range of forms with different physicochemical properties. Co-crystals, solvates and salts are multicomponent solid forms and, sometimes, the boundary between. Determination of crystal structure enables to boundary between co-crystal/salt and co-crystal/solvate is indistinct. An example of a salt forming co-crystals is fluoxetine hydrochloride, forming several co-crystals with carboxylic acids [12]. The formation of mixed salt-co-crystals, in which the API forms a co-crystal with its own salt, has been reported [15]. In such systems, the API the API forms a co-crystal with its own salt, has been reported [15]. While it has not been proven that co-crystals a solution to polymorphism (as co-crystals exhibit polymorphism) [17,18], they certainly can offer are a solution to polymorphism (as co-crystals exhibit polymorphism) [17,18], they certainly an alternative solid form, especially in generic pharmaceutical development
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