Discovery of new cocrystals beyond serendipity: lessons learned from successes and failures

CrystEngComm, Год журнала: 2024, Номер 26(11), С. 1505 - 1526

Опубликована: Янв. 1, 2024

A holistic understanding of reaction kinetics, the presence catalysts, and annealing conditions can advance accelerate screening elusive cocrystals, expediting development novel drug cocrystals for future clinical use.

Язык: Английский

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Virtual Coformer Screening by Crystal Structure Predictions: Crucial Role of Crystallinity in Pharmaceutical Cocrystallization

The Journal of Physical Chemistry Letters, Год журнала: 2020, Номер 11(20), С. 8832 - 8838

Опубликована: Сен. 24, 2020

One of the most popular strategies optimization drug properties in pharmaceutical industry appears to be a solid form changing into cocrystalline form. A number virtual screening approaches have been previously developed allow selection promising cocrystal formers (coformers) for an experimental follow-up. significant drawback those methods is related lack accounting crystallinity contribution formation. To address this issue, we propose study two coformer based on modern cloud-computing crystal structure prediction (CSP) technology at dispersion-corrected density functional theory (DFT-D) level. The CSP-based were first time validated challenging cases indomethacin and paracetamol cocrystallization, which provided poor predictions. calculations demonstrated dramatic improvement performance relative other methods. It that formation cocrystals dominant one and, therefore, should not ignored calculations. Our results encourage broad utilization proposed as only method directly accounts contribution.

Язык: Английский

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In-silico methods of cocrystal screening: A review on tools for rational design of pharmaceutical cocrystals

Journal of Drug Delivery Science and Technology, Год журнала: 2021, Номер 63, С. 102527 - 102527

Опубликована: Апрель 19, 2021

Язык: Английский

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Emerging Landscape of Computational Modeling in Pharmaceutical Development

Journal of Chemical Information and Modeling, Год журнала: 2022, Номер 62(5), С. 1160 - 1171

Опубликована: Фев. 28, 2022

Computational chemistry applications have become an integral part of the drug discovery workflow over past 35 years. However, computational modeling in support development has remained a relatively uncharted territory for significant both academic and industrial communities. This review considers workflows three key components preclinical clinical development, namely, process chemistry, analytical research as well product formulation development. An overview each step respective is presented. Additionally, context solid form design, special consideration given to modern physics-based virtual screening methods. covers rational approaches polymorph, coformer, counterion, solvent selection design.

Язык: Английский

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Virtual Screening, Structural Analysis, and Formation Thermodynamics of Carbamazepine Cocrystals

Pharmaceutics, Год журнала: 2023, Номер 15(3), С. 836 - 836

Опубликована: Март 3, 2023

In this study, the existing set of carbamazepine (CBZ) cocrystals was extended through successful combination drug with positional isomers acetamidobenzoic acid. The structural and energetic features CBZ 3- 4-acetamidobenzoic acids were elucidated via single-crystal X-ray diffraction followed by QTAIMC analysis. ability three fundamentally different virtual screening methods to predict correct cocrystallization outcome for assessed based on new experimental results obtained in study data available literature. It found that hydrogen bond propensity model performed worst distinguishing positive negative experiments 87 coformers, attaining an accuracy value lower than random guessing. method utilizes molecular electrostatic potential maps machine learning approach named CCGNet exhibited comparable terms prediction metrics, albeit latter resulted superior specificity overall while requiring no time-consuming DFT computations. addition, formation thermodynamic parameters newly evaluated using temperature dependences Gibbs energy. reactions between selected coformers be enthalpy-driven, entropy being statistically from zero. observed difference dissolution behavior aqueous media thought caused variations their stability.

Язык: Английский

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Cocrystal Synthesis through Crystal Structure Prediction

Molecular Pharmaceutics, Год журнала: 2023, Номер 20(7), С. 3380 - 3392

Опубликована: Июнь 6, 2023

Crystal structure prediction (CSP) is an invaluable tool in the pharmaceutical industry because it allows to predict all possible crystalline solid forms of small-molecule active ingredients. We have used a CSP-based cocrystal method rank ten potential coformers by energy cocrystallization reaction with antiviral drug candidate, MK-8876, and triol process intermediate, 2-ethynylglyclerol. For was performed retrospectively successfully predicted maleic acid as most likely be observed. The known form two different cocrystals 1,4-diazabicyclo[2.2.2]octane (DABCO), but larger landscape desired. screening triol-DABCO one, while triol-l-proline two. Computational finite-temperature corrections enabled determination relative crystallization propensities stoichiometries polymorphs free-energy landscape. obtained during subsequent targeted experiments found exhibit improved melting point deliquescence behavior over triol-free acid, which could considered alternative synthesis islatravir.

Язык: Английский

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Virtual coformer screening by a combined machine learning and physics-based approach

CrystEngComm, Год журнала: 2021, Номер 23(35), С. 6039 - 6044

Опубликована: Янв. 1, 2021

Cocrystals as a solid form technology for improving physicochemical properties have gained increasing popularity in the pharmaceutical, nutraceutical, and agrochemical industries.

Язык: Английский

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A combined experimental and theoretical study of miconazole salts and cocrystals: crystal structures, DFT computations, formation thermodynamics and solubility improvement

Physical Chemistry Chemical Physics, Год журнала: 2021, Номер 23(21), С. 12456 - 12470

Опубликована: Янв. 1, 2021

Experimental and theoretical screening of multi-component crystal forms miconazole (MCL), an antifungal drug, with ten aliphatic dicarboxylic acids was performed.

Язык: Английский

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Extending the Range of Nitrofurantoin Solid Forms: Effect of Molecular and Crystal Structure on Formation Thermodynamics and Physicochemical Properties

Crystal Growth & Design, Год журнала: 2022, Номер 22(4), С. 2569 - 2586

Опубликована: Март 11, 2022

In this work, four novel pharmaceutical cocrystals of nitrofurantoin, an antibacterial drug, with isonicotinamide, picolinamide, 2-hydroxybenzamide, and 2-aminobenzamide have been obtained thoroughly characterized by various analytical techniques. The crystal structures the solid forms elucidated single-crystal X-ray diffraction, energy distribution intermolecular interactions has further quantified on basis QTAIMC analysis. Eight distinct supramolecular heterosynthons hydrogen bonding identified in studied crystals, their relative stability ranked terms total interaction energies. thermodynamics cocrystallization reactions systematically investigated using two independent experimental techniques, namely solution calorimetry phase solubility diagram, which allowed us to assess both enthalpic entropic contributions cocrystal formation driving force. pH-solubility behavior at different pH values eutectic concentrations components. Although all reported here were found be more soluble than parent advantage thermodynamic did not translate into enhanced dissolution performance due a rapid solution-mediated transformation aqueous media. addition, effect other pharmaceutically relevant properties including photostability membrane permeability, considered analyzed.

Язык: Английский

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Rational Design of the Carbamazepine Ternary Cocrystals

Crystal Growth & Design, Год журнала: 2024, Номер 24(11), С. 4862 - 4873

Опубликована: Май 28, 2024

The first ternary cocrystals of carbamazepine (CBZ) were successfully identified through a large-scale screening. A design strategy involved the use an aliphatic dicarboxylic acid to link CBZ and third component into hydrogen-bonded trimeric unit. Out 10 acids tested, only malonic produced positive response in attempt obtain with benzamide picolinamide. crystal structures novel obtained by vapor diffusion crystallization determined single-crystal X-ray diffraction. Structural analysis revealed that are isostructural exhibit packing trimers ladder-like chains. relationship between binary was confirmed comparing structures. cocrystal solubility method applied estimate thermodynamic parameters formation. negative values Gibbs free energy, enthalpy, entropy indicate reaction formation is thermodynamically favored process driven enthalpy. Despite nature, physicochemical properties cocrystals, including melting point solubility, strongly influenced variable coformer.

Язык: Английский

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