Crystal Engineering of Pharmaceutical Cocrystals in the Discovery and Development of Improved Drugs

Chemical Reviews, Год журнала: 2022, Номер 122(13), С. 11514 - 11603

Опубликована: Июнь 1, 2022

The subject of crystal engineering started in the 1970s with study topochemical reactions solid state. A broad chemical definition was published 1989, and supramolecular synthon concept proposed 1995 followed by heterosynthons their potential applications for design pharmaceutical cocrystals 2004. This review traces development synthons as robust recurring hydrogen bond patterns construction architectures, notably, beginning early 2000s to present time. ability a cocrystal between an active ingredient (API) pharmaceutically acceptable coformer systematically tune physicochemical properties drug (i.e., solubility, permeability, hydration, color, compaction, tableting, bioavailability) without changing its molecular structure is hallmark platform, bridge discovery development. With via prototype case studies improve solubility place (2000–2015), period 2015 time has witnessed launch several salt–cocrystal drugs improved efficacy high bioavailability. on design, synthesis, afford products substances will interest researchers engineering, chemistry, medicinal process development, materials sciences. scale-up salts using continuous manufacturing technologies provides high-value pharmaceuticals economic environmental benefits.

Язык: Английский

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Pillararene-Based Variable Stoichiometry Co-Crystallization: A Versatile Approach to Diversified Solid-State Superstructures

Journal of the American Chemical Society, Год журнала: 2022, Номер 145(1), С. 667 - 675

Опубликована: Дек. 27, 2022

Variable stoichiometry co-crystals are important in solid-state supramolecular chemistry as they allow studies of structure–property relationships while permitting the synthesis new scaffolds using identical synthons. In this work, we extend concept variable into realm pillararene and show that permits rational construction a diverse set structures solid state. Specifically, report series based on pillar[n]arenes tetracyanobenzene (TCNB) combination in-cavity complexation by (n = 5,6) outside binding with TCNB allows several types different self-assembled superstructures to be isolated. The study display physicochemical properties, including colors luminescence features. Among these pillar[n]arene-based co-crystals, discovered unique crystallographic architectures wherein two sets individual host–guest complexes co-exist These mixed co-crystal systems for vapochromic-based detection n-bromoalkanes. This work highlights strategy state tuning their intrinsic characteristics, luminescent substrate-responsive

Язык: Английский

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Opportunities and Challenges in Mechanochemical Cocrystallization toward Scaled-Up Pharmaceutical Manufacturing

Organic Process Research & Development, Год журнала: 2023, Номер 27(3), С. 409 - 422

Опубликована: Фев. 13, 2023

Recently, pharmaceutical cocrystals have gained immense interest because of their potential to tune mechanical, pharmacokinetic, and physicochemical properties active ingredients (APIs) while keeping therapeutic action intact. In this review, cocrystallization is raised as a viable strategy toward commercialized manufacturing, where attention has been paid solid-state cocrystal preparation methods opportunities challenges in overall product process development. A comparative study the form mechanical energy demonstrated with aid SELECT criteria qualitatively evaluate synthetic route selection scalable mechanochemical methods. Remedies alternatives for that arise synthesis are presented highlighting commercial perspectives sustainable, eco-friendly, less toxic

Язык: Английский

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Structural Landscape of α-Acetamidocinnamic Acid Cocrystals with Bipyridine-Based Coformers: Influence of Crystal Packing on Their Thermal and Photophysical Properties

Crystal Growth & Design, Год журнала: 2024, Номер 24(4), С. 1746 - 1765

Опубликована: Фев. 9, 2024

Controlling the supramolecular synthon outcome in systems with different functionalities has been a key factor for design of materials, which also affected their physicochemical properties. In this contribution, we have analyzed structural landscape α-acetamidocinnamic acid (HACA) aiming to find its from competitivity between acidic and amidic groups. We prepared four multicomponent forms including one dihydrate (HACA·2H2O) three cocrystals bearing bipyridine coformers formulas (HACA)2(1,2-bpe) (1), (HACA)2(4,4′-azpy) (2), (HACA)2(4,4′-bipy)3 (3) (1,2-bpe = 1,2-bis(4-pyridyl)ethylene; 4,4′-azpy 4,4′-azopyridine; 4,4′-bipy 4,4′-bipyridine). First, applied virtual screening approach assess feasibility cocrystal formation. Then, synthesized cocrystals, via liquid-assisted grinding (LAG) (1 2) or solvothermal techniques, single crystals HACA, were obtained showing synthons crystal packings. Besides, Cambridge Structural Database (CSD) search presenting bipyridine-type molecules amide was performed, observed occurrences as well possibility modification by tuning H-donor/H-acceptor propensity groups shown. Finally, measured thermal photophysical properties, correlated features.

Язык: Английский

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Molecular Salts of Drug Famotidine with Isomeric Dihydroxybenzoic Acids

Crystal Growth & Design, Год журнала: 2024, Номер 24(3), С. 963 - 976

Опубликована: Янв. 10, 2024

The space to find new stable solid-state formulations with value-added properties for the labile drug famotidine (FAM) exploiting its conformational flexibility and ionizable nature has been reconnoitered by isolating at least six molecular salts isomeric dihydroxybenzoic acids (DHBA). These solid forms were synthesized via a mechanochemical grinding method followed slow evaporation of solvents characterized. They exhibit better physical stability under aqueous various physiological pH conditions, which is attributed change in state. Such modification eventually leads strong hydrogen bonding synthons coformers. Except anhydrous salt 2,6-DHBA, all others display enhanced physiochemical viz. solubility, membrane permeation, flux, essentially bioavailability. improvement endorsed formation stronger ionic guanidinium···carboxylate interactions between active pharmaceutical ngredients (API) coformers as well solute···solvent interactions. difference position OH groups lattice water molecule(s) guided different auxiliary bonds, resulting unique packing emphasized.

Язык: Английский

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Mechanosynthesis of Stable Salt Hydrates of Allopurinol with Enhanced Dissolution, Diffusion, and Pharmacokinetics

ACS Omega, Год журнала: 2023, Номер 8(37), С. 34120 - 34133

Опубликована: Сен. 7, 2023

Allopurinol (ALO) is a medication that treats gout and kidney stones by lowering uric acid synthesis in the blood. The biopharmaceutics classification system (BCS) IV drug exhibits poor aqueous solubility, permeability, bioavailability. To overcome bottlenecks of ALO, salts with maleic (MLE) oxalic (OXA) were synthesized using solvent-assisted grinding method. novel multicomponent solids characterized PXRD, DSC, TGA, FT-IR, SEM images. crystal structures these variable stoichiometry obtained Rietveld refinement from high-resolution PXRD data. proton dicarboxylic transferred to most basic pyrimidine "N" ALO. N-H···N hydrogen-bonded ALO homodimer replaced N

Язык: Английский

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The pH-Dependent Microspecies Dissociations in the Trade-Off of Solubility and Permeability of Vitamin B2 Eutectic Solids

Molecular Pharmaceutics, Год журнала: 2025, Номер 22(4), С. 2246 - 2258

Опубликована: Март 5, 2025

The microspecies-specific physicochemical properties of eutectic solids sparingly water-soluble micronutrient, Vitamin B2 (Riboflavin), with a few representative BCS drugs, viz., Theophylline, Theobromine, Mesalamine, and Barbituric acid are established. interplay solubility drug permeation behavior is experimentally determined for the solids, corroborated concomitant relative concentrations pH-dependent microspecies Riboflavin drugs. Partner candidates selected from different quadrants classification to apprehend influence their on overall efficacy solids. coexistence inseparable ionic, neutral, and/or zwitterionic spotted, pH-reliant isomer-specific inflection pharmacokinetic in such multicomponent solid formulations demonstrated.

Язык: Английский

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A new hydrate and multicomponent complexes of syringic acid with bipyridyl coformers: Stoichiometry and synthon assessment

Journal of Molecular Structure, Год журнала: 2025, Номер unknown, С. 142869 - 142869

Опубликована: Июнь 1, 2025

Язык: Английский

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Intermolecular interactions and solubility behavior of multicomponent crystal forms of 2,4-D: design, structure analysis, and solid-state characterization

CrystEngComm, Год журнала: 2021, Номер 23(43), С. 7615 - 7627

Опубликована: Янв. 1, 2021

Five new multicomponent solid forms of 2,4-D were successfully synthesized. The equilibrium solubility measurement confirmed the improvements in water crystals.

Язык: Английский

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Modulation of Rotational Dynamics in Halogen-Bonded Cocrystalline Solids

Journal of the American Chemical Society, Год журнала: 2023, Номер 145(34), С. 19005 - 19017

Опубликована: Авг. 16, 2023

Dynamic processes are responsible for the functionality of a range materials, biomolecules, and catalysts. We report detailed systematic study modulation methyl rotational dynamics via direct indirect influence noncovalent halogen bonds. For this purpose, novel series cocrystalline architectures featuring bonds (XB) to tetramethylpyrazine (TMP) is designed prepared using gas-phase, solution, solid-state mechanochemical methods. Single-crystal X-ray diffraction reveals capacity molecular bromine as well weak chloro-XB donors act robust directional structure-directing elements. Methyl barriers (Ea) measured variable-temperature deuterium NMR from 3.75 ± 0.04 kJ mol–1 in 1,3,5-trichloro-2,4,6-trifluorobenzene·TMP 7.08 0.15 1,4-dichlorotetrafluorobenzene·TMP. Ea data larger TMP cocrystals chloro-, bromo-, iodo-XB shown be governed by combination steric electronic factors. The average number carbon–carbon close contacts group found key metric capable rationalizing observed trends within each Cl, Br, I series. Differences between accounted considering strength σ-hole on XB donor. One possible route modulating therefore designer variable stoichiometry, maintaining core chemical features interest given donor acceptor while simultaneously modifying carbon affecting dynamics. These principles may provide design opportunities modulate more complex geared or cascade involving functional groups.

Язык: Английский

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