Crystal structures of two molecules with small chemical structure difference

Droperidol and benperidol, neuroleptic pharmaceuticals, both are used as antipsychotics. The chemical structure of these two compounds differs only by one double bond in the middle of the molecule (see Scheme). It is known that both of these substances can form several polymorphs and solvates. Crystal structures of most of these phases are known [1, 2]. Despite the molecular structure similarities, there are no known droperidol polymorph or solvate isostructural to those of benperidol. Although there has been studies characterizing the crystal structures of chemically very similar compounds, general explanation to observed structural differences was not found (e.g. [3]). In this study we analyse the crystal structures of benperidol and droperidol by comparing the molecule conformation and packing in crystal structures of both of these compounds. Molecule conformation is compared and torsion angles which differ and therefore lead to different crystal structures are identified. Theoretical calculation of potential energy surfaces of these torsion angles are performed in Gaussian09. Intermolecular interactions and molecule packing in all crystal structures are compared by trying to understand the general differences between both molecules. Analysis of structures deposited in Cambridge Structural Database is performed to find conformations and intermolecular interactions characteristic for similar molecules by therefore trying to generalize structural formation possibilities for both pharmaceuticals and understand the reasons for crystallization of only observed structures. Theoretical calculations of benperidol and droperidol crystal structures where benperidol molecules are replaced by droperidol and vice versa are performed in CASTEP to compare the energy of experimentally observed crystal structure with that of theoretically possible structure isostructural to double-bond-different molecule.

The solvent effect on the crystal morphology of two tegafur polymorphs

Pharmaceutical compounds are mostly produced in defined crystalline forms that are usually crystallized from solutions. Polymorphs, different crystalline phases of the same pharmaceutical compound, usually have different, precisely known dissolution rates and bioavailability, but crystal size and shape can affect these properties. Therefore, the crystal shape is monitored during the drug manufacturing process and a lot of work in the area of crystal engineering has been devoted to crystal habit control [1]. The crystallization solvent can have a significant effect on the resulting crystal shape; therefore solvent effect on crystal habit needs comprehensive studies. The compound studied in this research – tegafur (5-fluoro-1-(tetrahydro-2-furyl)-uracil) – is an antitumor agent, known to exist in α, β, γ, δ and ε polymorphs [2, 3]. Single crystal X-ray diffraction (SC XRD) was used to index crystal faces of α and β tegafur crystals grown in different solvents and molecular dynamics (MD) simulation was used as a tool to estimate the crystal face growth rates in several solvents. SC XRD results indicated that {011} and {110} faces dominated in β tegafur crystals when crystallized from ethanol, methanol, butyl acetate, tetrahydrofuran, whereas α tegafur crystals had a dominant {001}, {010} and {011} faces when crystallized from these solvents. Crystals grown in acetone had a different dominant faces for both polymorphs. The interaction between the solvents and each tegafur face was different, but the order of binding energy on these surfaces remained the same and was {011} > {110} > {010} for β tegafur and {001} > {011} > {010} for α tegafur. The analysis of MD data revealed that the system's primary interactions are weak hydrogen bonds. The achieved predictions were in agreement with experimental results. This work has been supported by the European Social Fund within the project «Support for Doctoral Studies at University of Latvia».

Understanding complex phase transition mechanism by crystal structure analysis

Xylazine hydrochloride (2-(2,6-xylidino)-5,6-dihydro-4H-1,3-thiazine hydrochloride) is an adrenergic α-agonist used as a sedative, analgesic, and muscle relaxant in veterinary medicine. It has four polymorphous forms (A, Z, M and X), monohydrate (H), hemihydrate and solvates with dichloromethane and 2-propanol. It has been reported that the polymorph X is thermodynamically the least stable of these polymorphs, while the A is the most stable form at temperatures above 50 ⁰C. The X forms only in H dehydration process, and at elevated temperature X transforms to polymorph A [1]. The crystal structures of the polymorphs A and X as well as hydrate H have been reported. Crystal structure of A and X have been determined from the powder X-ray diffraction data (PXRD), whereas that of hydrate have been determined from single crystal X-ray diffraction data [2-3]. In this study structure of A have been determined from single crystal data and compared to that determined by PXRD data. Crystal structures of A, X and H have been compared and analysed. Molecule conformation in crystal structure of all three forms is the same and molecular packing is similar. However, that in monohydrate H and polymorph X is basically the same and the only difference is the inclusion of the water molecules next to the chlorine anions, whereas relative xylazine moiety orientation and arrangement of the chlorine anions is different in the structure of polymorph A. The structural similarity or differences between all three forms noted above were also approved by the 2D-fingerprint plots of the Hirshfeld surfaces. Analysis of all three form crystal structures allowed to better understand complex solid-state phase transition from xylazine hydrochloride polymorph X to polymorph A during and after the dehydration of it monohydrate H.