Buclizine crystal forms: First Structural Determinations, counter-ion stoichiometry, hydration, and physicochemical properties of pharmaceutical relevance

Bitencourt, Monalisa; Viana, Olímpia Maria Martins Santos; Viana, André Luiz Machado; Freitas, Jennifer Tavares Jacon; Melo, Cristiane C. de

doi:10.1016/j.ijpharm.2020.119840

Cited by 8 publications

(8 citation statements)

References 24 publications

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“…The piperazine rings maintain an almost perfect chair conformation due to the near 60° N-C-C-N torsion angles and comparable distances between the C-C-C-C planes and nitrogen atoms. The same conformation was also observed in other piperazine-class antihistamine structures such as buclizine monohydrochloride monohydrate (CSD entry: HUQVAT), 8 and levocetirizine dihydrochloride (CSD entry: KIMDOD), 14 suggesting the rigid conformation of piperazine ring which is unaffected by different charge states.…”

supporting

confidence: 68%

“…The crystal structures of the piperazine-class antihistamines were mostly solved by single-crystal X-ray diffraction (SC-XRD) over the last several decades: cyclizine (1980), 5 quetiapine (2005), 6 cetirizine (2015), 7 buclizine (2020). 8 The disordered hydroxyzine model was derived by powder X-ray diffraction (PXRD) in 2019. 9 The conventional SC-XRD encounters difficulties in obtaining large crystals from powdery substances, 10 and solving PXRD structure can be challenging due to peak overlapping and broadening, 11 therefore certain challenging crystal structures of piperazine-class H1 antihistamines were left unattainable for decades.…”

mentioning

confidence: 99%

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Unraveling the Structure of Meclizine Dihydrochloride with MicroED

Lin,

Unge,

Gonen

2023

Preprint

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Meclizine (Antivert, Bonine) is a first-generation H1 antihistamine used in the treatment of motion sickness and vertigo. Despite its wide medical use for over 70 years, its crystal structure and the details of protein-drug interactions remained unknown. In this study, we used microcrystal electron diffraction (MicroED) to determine the three-dimensional (3D) crystal structure of meclizine dihydrochloride directly from a seemingly amorphous powder. Two racemic enantiomers (R/S) were found in the unit cell, which packed as repetitive double layers in the crystal lattice. The packing was made of multiple strong N-H...Cl- hydrogen bonding interactions and weak interactions like C-H...Cl- and pi-stacking. Molecular docking revealed the binding mechanism of meclizine to the histamine H1 receptor. A comparison of the docking complexes between histamine H1 receptor and meclizine or levocetirizine (a second-generation antihistamine) showed the conserved binding sites. This research illustrates the combined use of MicroED and molecular docking in unraveling protein-drug interactions for precision drug design and optimization.

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supporting

confidence: 68%

mentioning

confidence: 99%

Unraveling the Structure of Meclizine Dihydrochloride with MicroED

Lin,

Unge,

Gonen

2023

Preprint

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“…Methylene groups next to the nitrogen atom in the tertiary amine group of the free base resulted in bands at 2816 cm −1 which were absent from the salt spectra. The protonation of the tertiary amine group increased the C-H binding constant, displacing these bands to a higher frequency region, causing them to overlap with other bands in this spectral range (such as C-H stretch aromatic and aliphatic) [41] , [42] , [43] , [44] .…”

Section: Resultsmentioning

confidence: 99%

Combining enabling formulation strategies to generate supersaturated solutions of delamanid: In situ salt formation during amorphous solid dispersion fabrication for more robust release profiles

Duong

Nguyen

Taylor

2022

European Journal of Pharmaceutics and Biopharmaceutics

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“…The units of an RIB molecule and a Na cation were linked together with a 180° rotation in the b -axis direction, resulting in a one-dimensional structure. It has been reported that water molecules incorporated into the structure stabilize the crystal structure by tightening the packing and forming hydrogen bonds between molecules. ,− In accordance, the crystal structure of LOXNa-RIB-H 2 O was stabilized by an intermolecular hydrogen bond network via water molecules. Along the a axis (Figure c), the LOX carboxylate anions formed a hydrogen bond network that cross-linked the layer of Na cations and RIB molecules, resulting in a two-dimensional planar structure.…”

Section: Resultsmentioning

confidence: 99%

Salt Cocrystallization of Loxoprofen Sodium with Sugar: Reduction of the Propensity for Hydrate Formation by Forming a Continuous One-Dimensional Chain Structure of Sodium and Sugar

Fujito

Oshima

Higashi

et al. 2021

Crystal Growth & Design

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Compared to free base forms, salt forms are more frequently obtained as hydrates during solid form screening, although physically unstable hydrates are difficult to select for drug development. In this study, loxoprofen sodium dihydrate (LOXNa-2H2O), a widely used anti-inflammatory drug, was selected as a model drug to investigate the potential use of sugar as a coformer for cocrystallization with Na salts and the effect of salt cocrystallization with sugars on hydrate formation. In a screening study by liquid-assisted grinding with ethanol, two sugars, ribose (RIB) and fructose (FRU), formed new salt cocrystals with LOXNa. Differential scanning calorimetry, thermogravimetry, temperature-programmed powder X-ray diffraction, and water vapor sorption/desorption isotherm measurements revealed that the LOXNa·RIB and LOXNa·FRU salt cocrystals were a monohydrate and anhydrate, respectively. Single-crystal X-ray structural analysis of both salt cocrystals showed that direct ionic interaction did not occur between the Na cation and the carboxylate anion of LOX. Instead, sugars were coordinated around a Na cation, and a consecutive alternating structure of Na cations and sugars with a one-dimensional chain was formed along the b-axis. These characteristic chain structures prevented water molecules from approaching the Na cation and reduced the propensity for hydrate formation. FRU possesses one more hydroxyl group than the RIB molecule. The resulting strong hydrogen bonding network stabilized the LOXNa-FRU as an anhydrate without water molecules. Since sugars are safe and inexpensive excipients with various species, they can be useful coformers for salt cocrystals with various drug Na salts.

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Buclizine crystal forms: First Structural Determinations, counter-ion stoichiometry, hydration, and physicochemical properties of pharmaceutical relevance

Cited by 8 publications

References 24 publications

Unraveling the Structure of Meclizine Dihydrochloride with MicroED

Unraveling the Structure of Meclizine Dihydrochloride with MicroED

Combining enabling formulation strategies to generate supersaturated solutions of delamanid: In situ salt formation during amorphous solid dispersion fabrication for more robust release profiles

Salt Cocrystallization of Loxoprofen Sodium with Sugar: Reduction of the Propensity for Hydrate Formation by Forming a Continuous One-Dimensional Chain Structure of Sodium and Sugar

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