Variable stoichiometry cocrystals: occurrence and significance

Saikia, Basanta; Pathak, Debabrat; Sarma, Bipul

doi:10.1039/d1ce00451d

Cited by 32 publications

(22 citation statements)

References 133 publications

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“…269 Disparities in the hydrogen bond donor and acceptor ratio, awkward shape, larger molecular structure, competition between hydrogen bonding groups, and packing frustration are the main reasons for multiple stoichiometry and/or incorporation of guest/solvent/water molecules to complete the hydrogenbonding pairing for maximum packing efficiency and adjustment of crystal symmetry. 270 The existence of variable stoichiometry cocrystals offer additional solid forms of a drug for property management and intellectual property space. Dicarboxylic acids are common coformers for multiple stoichiometry cocrystals or salts.…”

Section: Ternary and Higher-order Cocrystalsmentioning

confidence: 99%

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

2022

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

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Section: Ternary and Higher-order Cocrystalsmentioning

confidence: 99%

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

2022

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“…The synthesis of cocrystal and/or salt relies on the intermolecular interactions, explicitly the directional hydrogen bonds between solute···solute and solute···solvent. − Thus, the rational multicomponent crystal design with desirable properties is centered on the expected supramolecular interactions. − Stability, solubility, and membrane permeation are a few fundamental prerequisites in the development of a drug to achieve maximum efficacy . Molecular salt formulation is a proven technology to modify drug pharmacokinetic properties, and over 50% of drug compounds in the market are administered in salt formulations treasured today. − The only limitation is that it only works for drug candidates with an ionizable functional group.…”

Section: Introductionmentioning

confidence: 99%

Isomeric Coformer Responsive Conformational Adjustment to Recuperate Stability, Solubility, and In Vitro Permeation Behavior of Drug Molecular Salts

Zeleke

Sarma

2022

Crystal Growth & Design

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The N–H or O–H systems are highly electron-deprived, and hence they easily interact with lone pairs usually on other N or O atoms in an extra bonding interaction. Such steering interactions stimulate the drug conformation to reposition that mounts well with all interactions and the packing in the lattice. Conformationally flexible histamine H2-receptor inhibitor drug famotidine (FAM) that shows low bioavailability and rapid degradation in an acidic environment was picked from the shelves. Six molecular salts of FAM with coformers of isomeric aminobenzoic acids (ABAs) and isomeric hydroxybenzoic acids (HBAs) from the GRAS list were synthesized via mechanochemical grinding. The obtained multicomponent solids show enhanced phase stability when compared to the parent drug in different pH media. The FAM molecular salts with ortho-HBA, ortho-ABA, and para-ABA show comparable solubility at pH 1.2, whereas the rest exhibited superior solubility and membrane permeation behavior in simulated physiological pH environments. This improvement of the drug properties is attributed to (i) the formation of directional hydrogen bond heterosynthons between the drug and coformers and the (ii) solute···solvent interactions. The change in the functional group(s), i.e., OH to −NH2, and the isomeric position variation aided in altering drug conformation leading to unique crystal packing in the solid states and corroborating with improved properties.

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“…Nevertheless, the formation of cocrystals by solid-state grinding followed by solution growth techniques is common, , while many are selectively prepared only by solid-state grinding or solution growth . To understand the mechanism of formation and/or the kinetics of cocrystallization, it is imperative to understand the various factors that can affect the (i) stability and (ii) phase transformations of the product cocrystals. , Reports are available demonstrating the role of solution chemistry, mechanochemical methods, and conformer stoichiometric ratio , in the cocrystallization of different stoichiometric cocrystals. Sarma et al reported the role of π-stacking interactions and hydrogen bond synthons in the alteration of cocrystal stoichiometries .…”

Section: Introductionmentioning

confidence: 99%

Deciphering the Role of Environmental Variables in the Nucleation of Stoichiometric Cocrystals

Bora

Pathak

Kalita

et al. 2023

Crystal Growth & Design

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The subsistence of dissimilar stoichiometry in cocrystals offers more solid forms with varied therapeutic advantages. Crystallization is a delicate process, and even an insignificant deviation in the process can impact the overall product performance. The significance of seasonal environmental variables in designing such different stoichiometric cocrystals is assessed by nucleating at least six different cocrystals from phenazine and protocatechuic acid. The cocrystals were isolated under continuously changing seasonal environmental variables in a time window of two comprehensive calendar years. The results are concurrent with the imitated in vitro laboratory crystallization conditions and are demonstrated. Competitive slurry and mechanochemical grinding experiments are employed to probe the phase relationships between these cocrystal phases.

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Variable stoichiometry cocrystals: occurrence and significance

Abstract: The occurrence of variable stoichiometry cocrystals offers the prospect to acquire more solid forms of the same system. The control of stoichiometry is extremely important concerning the purity and intellectual...

Cited by 32 publications

References 133 publications

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

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

Isomeric Coformer Responsive Conformational Adjustment to Recuperate Stability, Solubility, and In Vitro Permeation Behavior of Drug Molecular Salts

Deciphering the Role of Environmental Variables in the Nucleation of Stoichiometric Cocrystals

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