title: Understanding the structure details when drying hydrate crystals of pharmaceuticals - interpretations from diffuse scattering and inter-modulation satellites of a partially dehydrated crystal.
abstract: Simplified models for the crystal lattice of the sesquihydrate form of the hemi-sulfate salt of (5S,6S,9R)-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1H-imidazol[4,5b]pyridin-1-yl)-1-piperidine carboxylate (BMS-927711, C28H29F2N6O3(+)) are used to calculate diffuse diffraction features in order to develop a mechanistic understanding of the dehydration process with respect to disruption of the lattice, since a Bragg model cannot be established. The model demonstrates that what we observe when the water leaves the crystal is partial transformation from the parent form to a child form (a new form, less hydrated and structurally related to the parent). Yet this `dried' structure is not a pure phase. It consists of semi-random layers of both child, parent and an interfacial layer which has a modulated structure that represents a transitory phase. Understanding the fact that a single `dried' crystal can have the disordered layer structure described as well as understanding mechanistic relationships between the phases involved can have implications in understanding the effect of common large scale bulk drying procedures. During the development of BMS-927711, difficulties did arise during characterization of the dried bulk when using only routine solid-state analysis. The material is now better understood from this diffraction study. The diffraction experiments also reveal intermodulation satellites, which upon interpretation yield even more structural information about the crystal transformation. The model suggests the mechanism of transformation is laminar in which layers of the crystal are driven to approach a stable B-centered supercell phase of lower water content.
authors.affiliation: Solid State Modelling and Simulation, Materials Science, Drug Product Science and Technology, Bristol-Myers Squibb, 1 Squibb Drive, New Brunswick, NJ 08903, USA.
authors.forename: E J
authors.initials: EJ
authors.lastname: Chan
authors.affiliation: Solid State Chemistry, Materials Science, Drug Product Science and Technology, Bristol-Myers Squibb, 1 Squibb Drive, New Brunswick, NJ 08903, USA.
authors.forename: Q
authors.initials: Q
authors.lastname: Gao
authors.affiliation: Solid State Chemistry, Materials Science, Drug Product Science and Technology, Bristol-Myers Squibb, 1 Squibb Drive, New Brunswick, NJ 08903, USA.
authors.forename: M
authors.initials: M
authors.lastname: Dabros
mesh_terms: D018360:Crystallography, X-Ray; D003890:Desiccation; D008390:Markov Chains; D008958:Models, Molecular; D008968:Molecular Conformation; D009010:Monte Carlo Method; D010880:Piperidines / Q000737:chemistry*; D011725:Pyridines / Q000737:chemistry*; D014867:Water / Q000737:chemistry
chemical_list: D010880:Piperidines; D011725:Pyridines; D014867:Water; C578443:rimegepant sulfate
keywords: active pharmaceutical ingredients; dehydration; diffuse scattering; disordered layer structure; inter-modulation satellites