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Cocrystal
Cocrystal
Cocrystal
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In materials science (specifically crystallography), cocrystals are "solids that are crystalline, single-phase materials composed of two or more different molecular or ionic compounds generally in a stoichiometric ratio which are neither solvates nor simple salts."[1] A broader definition is that cocrystals "consist of two or more components that form a unique crystalline structure having unique properties." Several subclassifications of cocrystals exist.[2][3]

Cocrystals can encompass many types of compounds, including hydrates, solvates and clathrates, which represent the basic principle of host–guest chemistry. Hundreds of examples of cocrystallization are reported annually.

History

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The first reported cocrystal, quinhydrone, was studied by Friedrich Wöhler in 1844. Quinhydrone is a cocrystal of quinone and hydroquinone (known archaically as quinol). He found that this material was made up of a 1:1 molar combination of the components. Quinhydrone was analyzed by numerous groups over the next decade and several related cocrystals were made from halogenated quinones.[4]

Many cocrystals discovered in the late 1800s and early 1900s were reported in Organische Molekülverbindungen, published by Paul Pfeiffer in 1922.[4] This book separated the cocrystals into two categories; those made of inorganic:organic components, and those made only of organic components. The inorganic:organic cocrystals include organic molecules cocrystallized with alkali and alkaline earth salts, mineral acids, and halogens as in the case of the halogenated quinones. A majority of the organic:organic cocrystals contained aromatic compounds, with a significant fraction containing di- or trinitro aromatic compounds. The existence of several cocrystals containing eucalyptol, a compound which has no aromatic groups, was an important finding which taught scientists that pi stacking is not necessary for the formation of cocrystals.[4]

Cocrystals continued to be discovered throughout the 1900s. Some were discovered by chance and others by screening techniques. Knowledge of the intermolecular interactions and their effects on crystal packing allowed for the engineering of cocrystals with desired physical and chemical properties. In the last decade there has been an enhanced interest in cocrystal research, primarily due to applications in the pharmaceutical industry.[5]

Cocrystals represent about 0.5% of the crystal structures archived in the Cambridge Structural Database (CSD).[5] However, the study of cocrystals has a long history spanning more than 160 years. They have found use in a number of industries, including pharmaceutical, textile, paper, chemical processing, photographic, propellant, and electronic.[4]

Definition

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The meaning of the term cocrystal is subject of disagreement. One definition states that a cocrystal is a crystalline structure composed of at least two components, where the components may be atoms, ions or molecules.[4] This definition is sometimes extended to specify that the components be solid in their pure forms at ambient conditions.[6] However, it has been argued that this separation based on ambient phase is arbitrary.[7] A more inclusive definition is that cocrystals "consist of two or more components that form a unique crystalline structure having unique properties."[8] Due to variation in the use of the term, structures such as solvates and clathrates may or may not be considered cocrystals in a given situation. The difference between a crystalline salt and a cocrystal lies merely in the transfer of a proton. The transfer of protons from one component to another in a crystal is dependent on the environment. For this reason, crystalline salts and cocrystals may be thought of as two ends of a proton transfer spectrum, where the salt has completed the proton transfer at one end and an absence of proton transfer exists for cocrystals at the other end.[8]

Properties

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A schematic for the determination of melting point binary phase diagrams from thermal microscopy.

The components interact via non-covalent interactions such as hydrogen bonding, ionic interactions, van der Waals interactions and Π-interactions. These interactions lead to a cocrystal lattice energy that is generally more stable than the crystal structures of the individual components.[9] The intermolecular interactions and resulting crystal structures can generate physical and chemical properties that differ from the properties of the individual components.[10] Such properties include melting point, solubility, chemical stability, and mechanical properties. Some cocrystals have been observed to exist as polymorphs, which may display different physical properties depending on the form of the crystal.[10]

Phase diagrams determined from the "contact method" of thermal microscopy is valuable in the detection of cocrystals.[4] The construction of these phase diagrams is made possible due to the change in melting point upon cocrystallization. Two crystalline substances are deposited on either side of a microscope slide and are sequentially melted and resolidified. This process creates thin films of each substance with a contact zone in the middle. A melting point phase diagram may be constructed by slow heating of the slide under a microscope and observation of the melting points of the various portions of the slide. For a simple binary phase diagram, if one eutectic point is observed then the substances do not form a cocrystal. If two eutectic points are observed, then the composition between these two points corresponds to the cocrystal.

Production and characterization

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Production

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There are many synthetic strategies that are available to prepare cocrystals. However, it may be difficult to prepare single cocrystals for X-ray diffraction, as it has been known to take up to 6 months to prepare these materials.[8]

Cocrystals are typically generated through slow evaporation of solutions of the two components. This approach has been successful with molecules of complementary hydrogen bonding properties, in which case cocrystallization is likely to be thermodynamically favored.[11]

Many other methods exist in order to produce cocrystals. Crystallizing with a molar excess of one cocrystal former may produce a cocrystal by a decrease in solubility of that one component. Another method to synthesize cocrystals is to conduct the crystallization in a slurry. As with any crystallization, solvent considerations are important. Changing the solvent will change the intermolecular interactions and possibly lead to cocrystal formation. Also, by changing the solvent, phase considerations may be utilized. The role of a solvent in nucleation of cocrystals remains poorly understood but critical in order to obtain a cocrystal from solution.[11]

Cooling molten mixture of cocrystal formers often affords cocrystals. Seeding can be useful.[10] Another approach that exploits phase change is sublimation which often forms hydrates.[12]

Grinding, both heat and liquid-assisted, is employed to produce cocrystal, e.g., using a mortar and pestle, using a ball mill, ResonantAcoustic mixer, or using a vibratory mill.[13] In liquid-assisted grinding, or kneading, a small or substoichiometric amount of liquid (solvent) is added to the grinding mixture. This method was developed in order to increase the rate of cocrystal formation, but has advantages over neat grinding such as increased yield, ability to control polymorph production, better product crystallinity, and applies to a significantly larger scope of cocrystal formers.[14] and nucleation through seeding.[12]

Supercritical fluids (SCFs) serve as a medium for growing cocrystals. Crystal growth is achieved due to unique properties of SCFs by using different supercritical fluid properties: supercritical CO2 solvent power, anti-solvent effect and its atomization enhancement.[15][16]

Using intermediate phases to synthesize solid-state compounds is also employed. The use of a hydrate or an amorphous phase as an intermediate during synthesis in a solid-state route has proven successful in forming a cocrystal. Also, the use of a metastable polymorphic form of one cocrystal former can be employed. In this method, the metastable form acts as an unstable intermediate on the nucleation pathway to a cocrystal. As always, a clear connection between pairwise components of the cocrystal is needed in addition to the thermodynamic requirements in order to form these compounds.[10]

Importantly, the phase that is obtained is independent of the synthetic methodology used. It may seem facile to synthesize these materials, but on the contrary the synthesis is far from routine.[11]

Characterization

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Cocrystals may be characterized in a wide variety of ways. Powder X-Ray diffraction proves to be the most commonly used method in order to characterize cocrystals. It is easily seen that a unique compound is formed and if it could possibly be a cocrystal or not owing to each compound having its own distinct powder diffractogram.[6] Single-crystal X-ray diffraction may prove difficult on some cocrystals, especially those formed through grinding, as this method more often than not provides powders. However, these forms may be formed often through other methodologies in order to afford single crystals.[14]

Aside from common spectroscopic methods such as FT-IR and Raman spectroscopy, solid state NMR spectroscopy allows differentiation of chiral and racemic cocrystals of similar structure.[14]

Other physical methods of characterization may be employed. Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) are two commonly used methods in order to determine melting points, phase transitions, and enthalpic factors which can be compared to each individual cocrystal former.

Applications

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Cocrystal engineering is relevant to production of energetic materials, pharmaceuticals, and other compounds. Of these, the most widely studied and used application is in drug development and more specifically, the formation, design, and implementation of active pharmaceutical ingredients (API). Changing the structure and composition of the API can greatly influence the bioavailability of a drug.[11] The engineering of cocrystals takes advantage of the specific properties of each component to make the most favorable conditions for solubility that could ultimately enhance the bioavailability of the drug. The principal idea is to develop superior physico-chemical properties of the API while holding the properties of the drug molecule itself constant.[12] Cocrystal structures have also become a staple for drug discovery. Structure-based virtual screening methods, such as docking, makes use of cocrystal structures of known proteins or receptors to elucidate new ligand-receptor binding conformations.[17]

Pharmaceuticals

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Cocrystal engineering has become of such great importance in the field of pharmaceuticals that a particular subdivision of multicomponent cocrystals has been given the term pharmaceutical cocrystals to refer to a solid cocrystal former component and a molecular or ionic API (active pharmaceutical ingredient). However, other classifications also exist when one or more of the components are not in solid form under ambient conditions. For example, if one component is a liquid under ambient conditions, the cocrystal might actually be deemed a cocrystal solvate as discussed previously. The physical states of the individual components under ambient conditions is the only source of division among these classifications. The classification naming scheme of the cocrystals might seem to be of little importance to the cocrystal itself, but in the categorization lies significant information regarding the physical properties, such as solubility and melting point, and the stability of APIs.[11]

The objective for pharmaceutical cocrystals is to have properties that differ from that expected of the pure APIs without making and/or breaking covalent bonds.[18] Among the earliest pharmaceutical cocrystals reported are of sulfonamides.[12] The area of pharmaceutical cocrystals has thus increased on the basis of interactions between APIs and cocrystal formers. Most commonly, APIs have hydrogen-bonding capability at their exterior which makes them more susceptible to polymorphism, especially in the case of cocrystal solvates which can be known to have different polymorphic forms. Such a case is in the drug sulfathiazole, a common oral and topical antimicrobial, which has over a hundred different solvates. It is thus important in the field of pharmaceuticals to screen for every polymorphic form of a cocrystal before it is considered as a realistic improvement to the existing API. Pharmaceutical cocrystal formation can also be driven by multiple functional groups on the API, which introduces the possibility of binary, ternary, and higher ordered cocrystal forms.[19] Nevertheless, the cocrystal former is used to optimize the properties of the API but can also be used solely in the isolation and/or purification of the API, such as a separating enantiomers from each other, as well and removed preceding the production of the drug.[11]

It is with reasoning that the physical properties of pharmaceutical cocrystals could then ultimately change with varying amounts and concentrations of the individual components. One of the most important properties to change with varying the concentrations of the components is solubility.[18] It has been shown that if the stability of the components is less than the cocrystal formed between them, then the solubility of the cocrystal will be lower than the pure combination of the individual constituents. If the solubility of the cocrystal is lower, this means that there exists a driving force for the cocrystallization to occur.[6] Even more important for pharmaceutical applications is the ability to alter the stability to hydration and bioavailability of the API with cocrystal formation, which has huge implications on drug development. The cocrystal can increase or decrease such properties as melting point and stability to relative humidity compared to the pure API and therefore, must be studied on a case to case basis for their utilization in improving a pharmaceutical on the market.[12]

A screening procedure has been developed to help determine the formation of cocrystals from two components and the ability to improve the properties of the pure API. First, the solubilities of the individual compounds are determined. Secondly, the cocrystallization of the two components is evaluated. Finally, phase diagram screening and powder X-ray diffraction (PXRD) are further investigated to optimize conditions for cocrystallization of the components.[6] This procedure is still done to discover cocrystals of pharmaceutical interest including simple APIs, such as carbamazepine (CBZ), a common treatment for epilepsy, trigeminal neuralgia, and bipolar disorder. CBZ has only one primary functional group involved in hydrogen bonding, which simplifies the possibilities of cocrystal formation that can greatly improve its low dissolution bioavailability.[11]

Another example of an API being studied would be that of Piracetam, or (2-oxo-1-pyrrolidinyl)acetamide, which is used to stimulate the central nervous system and thus, enhance learning and memory. Four polymorphs of Piracetam exist that involve hydrogen bonding of the carbonyl and primary amide. It is these same hydrogen bonding functional groups that interact with and enhance the cocrystallization of Piracetam with gentisic acid, a non-steroidal anti-inflammatory drug (NSAID), and with p-hydroxybenzoic acid, an isomer of the aspirin precursor salicylic acid.[11] No matter what the API is that is being researched, it is quite evident of the wide applicability and possibility for constant improvement in the realm of drug development, thus making it clear that the driving force of cocrystallization continues to consist of attempting to improve on the physical properties in which the existing cocrystals are lacking.[6][11]

Regulation

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On August 16, 2016, the US food and drug administration (FDA) published a draft guidance Regulatory Classification of Pharmaceutical Co-Crystals. In this guide, the FDA suggests treating co-crystals as polymorphs, as long as proof is presented to rule out the existence of ionic bonds.

Energetic materials

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Two explosives HMX and CL-20 cocrystallized in a ratio 1:2 to form a hybrid explosive. This explosive had the same low sensitivity of HMX and nearly the same explosive power of CL-20. Physically mixing explosives creates a mixture that has the same sensitivity as the most sensitive component, which cocrystallisation overcomes.[20]

See also

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References

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Revisions and contributorsEdit on WikipediaRead on Wikipedia

Cocrystal

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from Grokipedia
A cocrystal is a crystalline, single-phase composed of two or more distinct molecular and/or ionic species in a well-defined stoichiometric ratio, present as solids at ambient conditions, and interacting through non-covalent forces such as hydrogen bonding, π-π stacking, or van der Waals interactions within the same crystal lattice. These structures differ from salts, which rely on ionic bonds between proton transfer species, and from solvates or hydrates, which incorporate molecules as lattice components. The history of cocrystals traces back to 1844, when German chemist first identified quinhydrone, a 1:1 complex of and p-benzoquinone, marking the earliest documented example during studies of derivatives. Early applications emerged in the 19th and early 20th centuries in fields like dyes and pigments, but systematic exploration in crystal engineering began in the mid-20th century, with the term "cocrystal" gaining prominence in organic by the through work on molecular complexes. Regulatory recognition advanced in the 21st century, particularly with the U.S. Food and Drug Administration's 2018 guidance classifying pharmaceutical cocrystals as distinct from new chemical entities when the active ingredient remains unchanged. In modern applications, cocrystals are most prominently used in the to address challenges with poorly water-soluble drugs, enhancing properties such as aqueous , dissolution kinetics, , and while preserving therapeutic efficacy. For instance, they enable the formation of multi-component systems with coformers like carboxylic acids or amides, selected based on supramolecular synthons—predictable hydrogen-bonding motifs—to tailor physical characteristics. Beyond pharmaceuticals, cocrystals find utility in agrochemicals for improved delivery, in nutraceuticals for better absorption, and in for designing novel optoelectronic or energetic materials with controlled release or properties. Preparation techniques vary widely, including solution-based , mechanochemical grinding (solvent-free milling), hot-melt , and methods, allowing scalability from lab to industrial production.

Background

Definition

A cocrystal is a crystalline single-phase material composed of two or more distinct neutral molecular species in a defined stoichiometric ratio, linked together by non-covalent interactions such as hydrogen bonds, π-π stacking, and van der Waals forces. These interactions enable the formation of a homogeneous lattice without involving covalent bonds or charge transfer, distinguishing cocrystals as a key concept in . Although primarily composed of neutral molecular species to distinguish from salts, some definitions encompass ionic species interacting via non-covalent forces. Key distinctions set cocrystals apart from other crystalline forms: unlike salts, which arise from proton transfer between an acid and base to form ionic bonds between charged , cocrystals retain the neutrality of all components. Polymorphs consist of a single molecular arranged in different packing motifs, while solvates and hydrates incorporate molecules (including ) into the lattice, often regarded as pseudopolymorphs; in contrast, cocrystals feature multiple neutral, non-solvent molecular entities, typically an active pharmaceutical ingredient () and a coformer. The stoichiometric ratio, such as 1:1 or 2:1 API:coformer, underscores the precise, multi-component assembly unique to cocrystals. A representative pharmaceutical example is the 2:1 - cocrystal, in which serves as the coformer to , stabilized by hydrogen-bonded synthons forming ring motifs. The term "cocrystal" was first used in by W. R. Lawton and E. F. Lopez to describe crystalline complexes of organic amines and , gaining prominence in pharmaceutical contexts through discussions of polymorphism.

History

The concept of cocrystals traces back to the mid-19th century, with the first documented example being quinhydrone, a 1:1 complex of and , synthesized by in 1844 and described as one of the most beautiful substances in . Early reports of multi-component crystals, often termed addition compounds or molecular complexes, appeared throughout the 19th and early 20th centuries, reflecting observations of crystalline materials formed by neutral molecules without . In the and , systematic studies advanced this area, including the reporting of over 300 cocrystals of aromatic compounds in 1922 and the synthesis of hundreds of multi-component crystals by August and Hilde Kofler using thermomicroscopy techniques during the mid-1920s to 1950s. Research gained momentum in the 1970s and 1980s through the emergence of , pioneered by Jean-Marie Lehn, whose work on intermolecular associations—recognized with the 1987 —provided a theoretical foundation for designing multi-component s via non-covalent interactions. This period marked a shift from empirical observations to rational control over crystal assembly, influencing subsequent applications in . The 1990s saw a surge in pharmaceutical interest, driven by crystal engineering principles that enabled property modulation without altering the active pharmaceutical ingredient's covalent structure, leading to a boom in cocrystal exploration for drug formulation. Key milestones included the U.S. Food and Drug Administration's 2011 draft guidance classifying pharmaceutical cocrystals as drug product intermediates rather than new chemical entities, finalized in 2018, which facilitated regulatory pathways for their development. In the 2000s, applications expanded to energetic materials, with early proof-of-concept studies demonstrating cocrystals like /TATB (2011) and CL-20/TNT (2011) that improved stability and performance over pure explosives. Influential researchers shaped this evolution: Joel Bernstein advanced the understanding of supramolecular synthons and polymorphism in cocrystals, authoring seminal works on structural design and authoring the definitive text on molecular crystal polymorphism. Gautam R. Desiraju pioneered supramolecular engineering approaches, emphasizing hydrogen-bonded synthons for predictable cocrystal formation and higher-order structures. In pharmaceutical applications, Örn Almarsson and Michael J. Zaworotko highlighted cocrystals' potential for solubility enhancement, establishing design strategies that bridged academia and industry. Post-2010 advancements integrated computational tools and sustainable practices, with models emerging for coformer prediction and cocrystal screening, achieving accuracies over 89% in some frameworks by 2024. Green synthesis methods, such as , reduced solvent use, while the adoption of sustainable coformers like (GRAS) substances from natural sources addressed environmental concerns in pharmaceutical production. By 2025, these developments enabled efficient, eco-friendly cocrystal design, exemplified by thermodynamic-mechanistic ML hybrids for solvent and coformer optimization.

Formation Principles

Supramolecular Interactions

Cocrystals form through non-covalent supramolecular interactions between the active pharmaceutical ingredient (API) and coformer molecules, which dictate the assembly and stability of the resulting crystal lattice. Hydrogen bonding is the predominant interaction, often involving robust heterosynthons such as the carboxylic acid–pyridine motif, where the acidic proton of the carboxylic group forms a strong O–H···N hydrogen bond with the pyridine nitrogen, enabling predictable molecular recognition without proton transfer. This heterosynthon is frequently observed in pharmaceutical cocrystals, as in the case of benzoic acid with nicotinamide, where it contributes to ordered chain-like arrangements. Other key interactions include halogen bonding, where an electrophilic halogen atom (e.g., iodine) interacts directionally with a nucleophilic acceptor like nitrogen or oxygen, as demonstrated in cocrystals of 1,3,5-triiodo-2,4,6-trifluorobenzene with pyridine derivatives, enhancing lattice cohesion through linear I···N bonds. π–π stacking interactions between aromatic rings provide additional stabilization, particularly in systems lacking strong hydrogen bond donors or acceptors, such as in cocrystals of anthracene derivatives, where parallel displaced stacking motifs contribute to the overall packing efficiency. Ionic interactions, occurring without full proton transfer, arise from partial charge separation in polar groups, as in ionic cocrystals of phenolic compounds with carboxylate-like moieties, where electrostatic attractions between oppositely charged regions support neutral multi-component assembly. Supramolecular synthons are the fundamental structural units—typically hydrogen-bonded dimers, chains, or rings—that recur reliably in crystal structures, allowing for the design of cocrystals based on modular recognition patterns. Introduced by Desiraju, these synthons emphasize the transferability of intermolecular interactions from molecular to supramolecular scales, with robustness derived from the specificity of donor-acceptor complementarity. Graph-set notation, developed by Etter, provides a systematic way to describe these motifs; for instance, the (donor-acceptor-donor-acceptor) chain in – cocrystals forms infinite C(4) rings or chains, offering a predictive tool for motif selection. The predictability of such synthons stems from their prevalence in the Cambridge Structural Database, where – units appear in over 90% of relevant structures, facilitating targeted coformer pairing. Coformer selection relies on structural complementarity, where functional groups on the and coformer align to form favorable synthons, influencing the overall —commonly 1:1 but varying to 2:1 or 1:2 based on and hydrogen-bonding capacity. plays a critical role in determining packing motifs; for example, linear coformers like isonicotinamide promote chain-like assemblies, while angular ones such as 4,4'-bipyridine favor layered structures through balanced donor-acceptor distributions. These factors ensure efficient space filling and minimize voids, as seen in cocrystals where mismatched geometries lead to less stable polymorphs. Thermodynamically, cocrystal formation is driven by the minimization of , where intermolecular interactions contribute more favorably than in single-component crystals due to enhanced packing efficiency. Computational lattice energy calculations, such as those using methods, reveal that cocrystals often exhibit energies 2–5 kcal/mol lower per than their pure components, attributing stability to the additive effects of multiple synthons. Compared to single-component crystals, this energy advantage arises from optimized intermolecular contacts, as quantified in studies showing average lattice energy gains of -2.75 kcal/mol for observed cocrystals versus hypothetical alternatives.

Crystal Engineering Concepts

Crystal engineering principles provide the foundation for rationally designing cocrystals by leveraging supramolecular synthesis to control solid-state structures. In 1989, Gautam R. Desiraju defined crystal engineering as "the understanding of intermolecular interactions in the context of crystal packing and the utilization of such understanding in the design of new crystalline solids," emphasizing the deliberate manipulation of non-covalent forces to achieve desired architectures. This approach extends to cocrystals through , where potential coformers are selected by deconstructing target structures into supramolecular synthons—recurring motifs of intermolecular interactions that serve as building blocks—and matching complementary functional groups on the active pharmaceutical ingredient () and coformer to predict viable assemblies. Prediction methods in crystal engineering for cocrystals rely on computational tools to anticipate formation and stability without exhaustive experimentation. Mining the Cambridge Structural Database (CSD) enables statistical analysis of known intermolecular geometries and frequencies, guiding coformer compatibility by identifying patterns in successful multi-component systems. simulations assess dynamic hydrogen bonding and effects to evaluate pathways and structural feasibility, while PIXEL calculations compute pixel-by-pixel intermolecular energies to estimate lattice energies, helping rank hypothetical cocrystal polymorphs by thermodynamic stability. The multi-component crystal landscape of cocrystals involves navigating complex phase spaces, including polymorphism, through targeted screening strategies. Hansen solubility parameters (HSPs) facilitate coformer matching by quantifying molecular miscibility in three-dimensional space—dispersive, polar, and hydrogen-bonding components—predicting higher success rates when and coformer HSP values align closely, as differences below 7 MPa^{1/2} often correlate with cocrystal formation. Polymorphism in cocrystals, manifesting as conformational, packing, or variants, is managed by considering multiple forms during design, with computational screening identifying low-energy polymorphs to ensure reproducibility and control over properties like dissolution. Advanced concepts in cocrystal engineering refine predictive accuracy and synthetic control. Hydrogen bond propensity (HBP) rules, building on statistical evaluations of donor-acceptor competitions, prioritize likely bonding motifs by calculating formation probabilities from CSD-derived geometries, aiding in avoiding competing intra- versus intermolecular interactions. Solvents direct outcomes by modulating supersaturation and selective solvation of coformers, with polar aprotic solvents favoring hydrogen-bond-driven nucleation while protic ones may stabilize solvates over pure cocrystals. In the 2020s, AI-driven designs, such as artificial neural networks trained on synthon and coformer datasets, have emerged to predict cocrystal formation probabilities with over 90% accuracy on diverse test sets, accelerating rational coformer screening beyond traditional heuristics.

Properties

Physical Properties

Cocrystals exhibit a range of physical properties that differ from those of their constituent active pharmaceutical ingredients (APIs) and coformers, primarily due to modified crystal lattice structures and intermolecular interactions. These properties, such as , , dissolution rate, mechanical behavior, thermal characteristics, and optical/spectroscopic features, can enhance processability and performance without altering the chemical identity of the API. Melting points in cocrystals often vary relative to the parent compounds, with denser packing frequently leading to higher values, though lower or intermediate points are also common. In an of 49 pharmaceutical cocrystals, 51% displayed melting points between those of the and coformer, while 39% were lower than both. For example, the propofol-isonicotinamide cocrystal raises the melting point by approximately 50°C from the 's 18°C, transforming the liquid into a solid form suitable for handling. Solubility and dissolution rates represent key physical attributes frequently improved in cocrystals through changes in and surface energetics. Enhancements of 4- to 20-fold over the parent have been observed, as in cocrystals, which showed 4-20× higher in 0.1 N HCl compared to the crystalline . The ketoconazole-p-aminobenzoic acid cocrystal similarly achieved a 10-fold increase. Dissolution can accelerate accordingly; the HCl-succinic acid cocrystal dissolved about 3 times faster than the in , attributed to altered particle wetting and lattice disruption. Mechanical properties like and tabletability are often superior in cocrystals, aiding pharmaceutical by reducing and improving powder flow. The chlorzoxazone-picolinic acid cocrystal exhibited a tensile strength of ~1.6 MPa at 250 MPa compression pressure, demonstrating enhanced over the parent . Cocrystallization of with methyl gallate yielded forms with markedly better tabletability than pure , despite similar plasticity. Particle morphology in such cocrystals can further influence these traits, promoting uniform compaction. Thermal properties of cocrystals are reflected in binary phase diagrams, which typically feature two eutectic points surrounding a region for the cocrystal, contrasting with single-eutectic 'V'-shaped diagrams for simple mixtures. If amorphous intermediates arise during formation, they may show distinct temperatures, impacting transient stability. Optical and spectroscopic traits in cocrystals arise from supramolecular interactions, often manifesting as shifts that confirm structural changes. (IR) spectra display alterations in vibrational modes, such as carbonyl stretches shifting to lower wavenumbers (e.g., ~1700 cm⁻¹) due to hydrogen bonding, distinguishing cocrystals from APIs. (UV) spectra may exhibit bathochromic or hypsochromic shifts from modified electronic conjugation. Anisotropic packing can induce , observable under polarized light, while examples like furosemide-4,4’-bipyridine cocrystals show color variations from pale yellow to orange due to differing π-stacking.

Chemical and Stability Properties

Cocrystals maintain the chemical inertness of the (API) by forming through non-covalent interactions, such as hydrogen bonding, without altering the covalent or inherent reactivity of the API. This preservation ensures that the pharmacological activity remains unchanged while the coformer modulates other properties. For instance, in pharmaceutical applications, cocrystallization avoids the formation of new covalent bonds, distinguishing it from salt formation or chemical derivatization. Stability enhancements in cocrystals often include reduced hygroscopicity compared to the parent , which minimizes moisture uptake and potential . The caffeine-oxalic cocrystal, for example, exhibits superior resistance, remaining stable at high relative levels up to 98% without formation. Photochemical stability can also be improved. Additionally, pH-dependent dissociation occurs in many cocrystals, where acidic or basic conditions can lead to reversion to the parent components; cocrystals, for instance, show stable regions above pH 5 but dissociate below pH 3 due to differences between the API and coformer. Degradation pathways in cocrystals under stress conditions, such as or , may involve dissociation or limited coformer-API interactions, but these are generally slower than in pure APIs, leading to improved shelf-life. Kinetic studies on gemfibrozil-isonicotinamide cocrystals reveal a higher for thermal degradation (approximately 150 kJ/mol) compared to the API alone, indicating enhanced resistance to heat-induced breakdown and projecting a shelf-life extension beyond 24 months under accelerated conditions. Under , cocrystals like with phenolic coformers show reduced oxidation rates, with less than 5% degradation after 30 days in air versus over 50% for the free API. However, in the presence of reactive excipients, water-mediated proton transfer can occur, as seen in -oxalic acid systems where dissociation forms caffeine hydrate and metal oxalates under humid stress. Environmental factors further influence cocrystal durability; resistance to is exemplified by the indomethacin-saccharin cocrystal, which absorbs less than 0.05% water at 98% relative over extended periods, outperforming the hygroscopic . Oxidation resistance is notable in carbamazepine-saccharin cocrystals, which maintain chemical integrity under oxidative conditions for up to two months at varying levels, supporting longer storage viability. These properties collectively contribute to cocrystals' role in enhancing longevity without compromising chemical identity.

Synthesis and Characterization

Synthesis Methods

Solution-based methods are among the most common techniques for synthesizing cocrystals, involving the dissolution of an active pharmaceutical ingredient (API) and coformer in a suitable solvent followed by controlled precipitation. Solvent evaporation entails dissolving the components in a solvent like ethanol or acetonitrile and slowly removing the solvent to induce nucleation and crystal growth, as demonstrated in the formation of ibuprofen–nicotinamide cocrystals. Cooling crystallization starts with a hot saturated solution that is gradually cooled to achieve supersaturation and cocrystal formation, offering scalability for industrial production, such as in the synthesis of carbamazepine–nicotinamide cocrystals with yields up to 90% at a 1 L scale. Slurry techniques suspend the solids in a minimal volume of solvent where phase transformation occurs under stirring, converting starting materials to cocrystals efficiently, as seen in theophylline–benzoic acid systems with high purity outcomes. Solvent selection is guided by solubility diagrams to ensure the coformer and API have appropriate solubilities, favoring solvents where the cocrystal has lower solubility than the individual components to promote formation. Mechanochemical approaches provide solvent-free alternatives, aligning with principles by minimizing environmental impact and enabling synthesis without volatile organic compounds. Neat grinding involves manual or mechanical mixing of solid powders to induce cocrystal formation through shear forces and , exemplified by the preparation of –malonic acid cocrystals. Liquid-assisted grinding (LAG) adds a small amount of liquid to enhance reactivity and crystallinity, as in the synthesis of – cocrystals, which improves yield compared to neat methods. Ball milling employs high-energy milling with rotating balls to facilitate intimate contact and phase transformation, suitable for scalable production of paracetamol cocrystals, offering advantages in energy efficiency and reduced waste. Other techniques expand the toolkit for cocrystal synthesis, particularly for challenging systems or large-scale applications. Melt heats the and coformer mixture above their eutectic point and cools it to form cocrystals, as in the hot melt of – systems, which is solvent-free and continuous for industrial . Ultrasound-assisted methods apply sonic waves to solutions or slurries to accelerate , enhancing the formation of – cocrystals by reducing processing time. techniques utilize under supercritical conditions to dissolve and precipitate components, producing ibuprofen–nicotinamide cocrystals with precise particle size control and no toxic solvents. Scale-up considerations often involve continuous flow reactors, such as oscillatory baffled crystallizers for cooling methods or twin-screw extruders for mechanochemical processes, enabling kilogram-scale production while maintaining yield and purity. Emerging methods as of 2025 include deep eutectic solvent-mediated for regulating polymorphism and , and high-throughput encapsulated nanodroplet screening for rapid exploration of co-crystallization space. Coformer screening is essential for identifying viable partners and is often conducted via high-throughput methods to accelerate discovery. Techniques like liquid-assisted grinding in 96-well plates allow rapid testing of multiple coformers with an , as used for screening dicarboxylic acids with . Yield optimization focuses on factors such as temperature, which influences in solution methods, and stoichiometry, where equimolar ratios typically maximize cocrystal purity in systems like –. These parameters, adjusted based on preliminary data, ensure efficient synthesis guided briefly by supramolecular synthons for coformer selection.

Characterization Techniques

Characterization of cocrystals is essential to verify their formation, determine , assess purity, and evaluate composition following synthesis, ensuring they are distinct from physical mixtures, solvates, or salts. Analytical techniques provide complementary information on lattice parameters, molecular interactions, thermal behavior, and morphological features. These methods are routinely employed in pharmaceutical development to confirm the stoichiometric ratio of the active pharmaceutical ingredient () and coformer, as well as to detect any impurities or phase transformations. Structural methods primarily rely on diffraction to elucidate the crystal lattice and . Single-crystal diffraction (SCXRD) is the gold standard for obtaining precise three-dimensional structures of cocrystals, revealing atomic positions, bond lengths, and supramolecular motifs such as hydrogen bonds when suitable single crystals are available, often grown via solvent evaporation. For instance, SCXRD has been used to determine the structure of acemetacin-based cocrystals, confirming unique packing arrangements not seen in the parent . Powder diffraction (PXRD) complements SCXRD for polycrystalline samples, providing diffraction patterns that differ from those of the individual components, thus confirming cocrystal formation and enabling phase identification or quantification in mixtures. PXRD patterns of isoniazid-syringic acid cocrystals, for example, show distinct peaks indicative of a new crystalline phase. Lattice parameters and volumes derived from these techniques allow comparison with predicted structures and assessment of polymorphism. Thermal analysis techniques probe the stability, composition, and phase transitions of cocrystals. Differential scanning calorimetry (DSC) detects endothermic or exothermic events, such as melting points or eutectic behaviors, that are unique to the cocrystal and differ from the API or coformer alone, serving as a rapid screen for formation. In the case of salicylic acid-caffeine cocrystals, DSC reveals a single melting peak at a temperature intermediate between the components, confirming a homogeneous phase. Thermogravimetric analysis (TGA) measures mass loss as a function of temperature, verifying solvent-free composition or detecting residual moisture/volatiles, which is crucial for purity assessment. TGA coupled with DSC has shown no weight loss up to decomposition in stable cocrystals like those of carbamazepine, indicating high purity. These methods are solvent-free and require minimal sample, making them efficient for quality control. Spectroscopic techniques confirm intermolecular interactions at the molecular level without destroying the sample. Fourier-transform (FTIR) and detect shifts in vibrational frequencies, particularly for hydrogen-bonded functional groups, distinguishing cocrystals from simple mixtures. For example, FTIR spectra of alkaloid-5-nitrobarbituric acid cocrystals exhibit broadened or shifted O-H and N-H bands due to new hydrogen bonds. provides similar insights but is advantageous for aqueous environments or non-destructive analysis, with color-coded mapping used to visualize phase purity in ibuprofen-nicotinamide cocrystals. (ssNMR) offers detailed information on the local molecular environment, including chemical shifts that reveal states and distinguish cocrystals from ionic salts. ssNMR analysis of HCl systems has identified distinct carbon environments in cocrystals versus salts. These techniques are particularly valuable for confirming non-covalent interactions predicted during design. Recent advances as of 2025 incorporate computational modeling alongside these methods for predicting and verifying cocrystal structures. Other supportive methods include scanning electron microscopy (SEM) for morphological characterization, which visualizes particle shape, size, and surface features to assess uniformity and detect agglomeration or impurities in cocrystal powders. SEM images of cocrystal formulations often reveal needle-like or plate-shaped habits distinct from the . Solubility testing protocols, such as shake-flask or intrinsic dissolution rate methods, quantify enhancements post-characterization, with cocrystals like forskolin-nicotinamide showing up to 2.74-fold increases in aqueous compared to the pure , linking structure to performance. These evaluations ensure the cocrystal meets pharmaceutical standards for .

Applications

Pharmaceutical Applications

Cocrystals have emerged as a key strategy in pharmaceutical development to address the limitations of active pharmaceutical ingredients (APIs), particularly those classified under Class II and IV, which exhibit poor aqueous and often suboptimal . By forming non-ionic crystalline complexes with suitable coformers, cocrystals can modulate the physicochemical properties of APIs without altering their pharmacological activity, leading to enhanced dissolution rates and improved oral absorption. This approach is especially valuable for weakly acidic or basic drugs, where traditional salt formation may be limited by pH-dependent issues. Solubility enhancement is one of the primary benefits of pharmaceutical cocrystals, often achieving several-fold increases in aqueous compared to the parent . For instance, cocrystals of the BCS Class II antifungal with or other coformers have demonstrated up to a 25.77-fold increase in in buffer (pH 6.8), alongside a 2.4-fold improvement in 0.1 N HCl, facilitating better gastrointestinal absorption. Similarly, , a BCS Class II , forms cocrystals with coformers like that boost its by over 90 times, directly correlating with enhanced pharmacokinetic profiles in preclinical models. These improvements stem from altered and hydrogen bonding interactions in the cocrystal structure, which lower the activation energy for dissolution while maintaining in solution. For BCS Class IV drugs like , a with low and permeability, cocrystallization has been shown to increase up to 11-fold, potentially expanding its therapeutic utility. Beyond solubility, cocrystals offer formulation advantages such as improved for and taste masking for oral . The enhanced mechanical properties arise from optimized intermolecular forces, enabling denser packing and reduced during compression, as observed in carbamazepine-saccharin cocrystals, which exhibit superior tablet hardness without excipients. Taste masking is particularly beneficial for pediatric or geriatric formulations; for example, cocrystals of bitter APIs like acetaminophen with GRAS coformers like tetramethylglycoluril reduce palatability issues while preserving . Several cocrystals have advanced to clinical and commercial stages, underscoring their practical impact. Depakote, approved by the FDA in the 1980s and reformulated as a 1:1 cocrystal of valproic acid and sodium valproate, improves stability and reduces gastrointestinal side effects compared to the free acid form, making it a cornerstone for and . Entresto (sacubitril-valsartan), approved in 2015 for , leverages a cocrystal structure to enhance and dual-action . More recently, Seglentis (celecoxib-tramadol ), approved in 2021 for acute pain, utilizes an API-API cocrystal to achieve synergistic analgesia with improved dissolution over individual components. Additionally, Conduit Pharmaceuticals announced patents in 2025 for cocrystals aimed at extending treatment beyond current approvals. Design strategies for pharmaceutical cocrystals prioritize (GRAS) coformers to ensure regulatory acceptability and minimal toxicity. Amino acids such as L-proline or serve as versatile coformers due to their zwitterionic nature and hydrogen-bonding capabilities, forming stable cocrystals with APIs like ibuprofen that enhance solubility by 2- to 5-fold while being biocompatible. Sugars like or , also GRAS-listed, are commonly employed; for example, carbamazepine- cocrystals improve dissolution rates by nearly 2-fold through altered and reduced agglomeration. These selections focus on supramolecular synthons that promote predictable assembly, ensuring scalability from lab to manufacturing.

Non-Pharmaceutical Applications

Cocrystals have found significant utility in energetic materials, where they enable the tuning of detonation performance while reducing sensitivity to external stimuli. For instance, the 1:1 cocrystal of hexogen (HMX) and hexanitrohexaazaisowurtzitane (CL-20) exhibits a higher detonation velocity of approximately 9,400 m/s compared to pure HMX (9,100 m/s), alongside improved density and reduced impact sensitivity due to intermolecular hydrogen bonding that stabilizes the structure. This desensitization effect is particularly valuable for high explosives, as the cocrystal maintains high energy output while mitigating risks during handling and storage. In agrochemicals, cocrystals facilitate controlled release and enhanced stability of active ingredients, promoting sustainable agricultural practices. Urea-based cocrystals, such as CaSO₄·4, provide slow release over 90 days, achieving less than 70% nutrient liberation compared to rapid dissipation in pure , which improves use efficiency by up to 145% and boosts yields by 91%. Similarly, cocrystals with coformers like 1,4-diazabicyclo[2.2.2]octane enable sustained weed control through modulated solubility, reducing environmental leaching while preserving . These formulations also enhance thermal stability, as seen in urea-phosphate cocrystals that slow and cut emissions. Nutraceuticals benefit from cocrystals that improve and properties without altering core functionality. The curcumin-resveratrol cocrystal, prepared via supercritical methods, demonstrates 1.5-fold higher for both components and enhanced activity, attributed to synergistic π-π interactions in the lattice. In applications, cocrystallization stabilizes natural pigments; for example, betacyanins from Basella rubra extract co-crystallized with achieve high entrapment efficiency (>90%), preserving color intensity and thermal stability during processing. extracts from , when co-crystallized with , maintain vibrancy in formulations for over 42 days, offering a natural alternative for stabilization. Beyond these areas, cocrystals advance through designs that optimize charge transport. p-Type and n-type cocrystals exhibit tunable band gaps and improved (up to 0.1 cm²/V·s), enabling efficient organic field-effect transistors via controlled intermolecular stacking. In pigments and dyes, cocrystals desensitize explosives while enhancing color fastness, as in non-toxic organic variants that match synthetic dyes in heat and acid resistance. Recent developments emphasize sustainable materials, with urea-adipic acid cocrystals reducing volatilization by over 40%, supporting eco-friendly nutrient delivery in .

Regulatory and Future Aspects

Regulatory Considerations

The U.S. (FDA) classifies pharmaceutical cocrystals as drug product intermediates rather than new drug substances when the (API) remains chemically unchanged and the interactions are non-ionic, distinguishing them from salts; salts involving and forming a require full (NDA) review. This 2018 FDA guidance, which finalized a 2016 draft, mandates data—including solid-state properties like X-ray powder diffraction and —to confirm the cocrystal's identity, strength, quality, and purity for both NDAs and abbreviated new drug applications (ANDAs). Similarly, the (EMA) views cocrystals as solid-state variants of APIs, akin to polymorphs or solvates, and considers them potential new active substances if they modify the API's therapeutic properties, necessitating marketing authorization applications with detailed solid-state . In September 2025, India's (CDSCO) classified pharmaceutical cocrystals as new drugs, requiring comprehensive validation and regulatory approval processes similar to new chemical entities. protections for cocrystals hinge on demonstrating novelty, utility, and non-obviousness, distinguishing them from obvious combinations of known APIs and coformers; for instance, the U.S. Patent and Trademark Office has granted for specific cocrystal compositions that exhibit unexpected improvements in or stability. Notable examples include U.S. US7927613B2 for co-crystal compositions of APIs like with enhanced . Safety assessments for cocrystals emphasize to the parent , often established via under FDA's ANDA guidelines, particularly for immediate-release products where rapid dissolution profiles support waivers of studies. Coformers must typically hold (GRAS) status to minimize risks, with common examples like or listed in FDA's GRAS inventory for pharmaceutical use. International harmonization through the International Council for Harmonisation (ICH) applies via guidelines like ICH Q6A, which require specifications for polymorphic forms—including cocrystals—to ensure consistent quality across global submissions. Beyond pharmaceuticals, cocrystals in energetic materials for explosives are subject to U.S. Bureau of Alcohol, Tobacco, Firearms and Explosives (ATF) regulations under 27 CFR Part 555, mandating federal licenses for manufacturing, storage, and distribution based on explosive class (e.g., high explosives requiring secure magazines and quantity limits). In agrochemicals, cocrystal formulations of undergo U.S. Environmental Protection Agency (EPA) review under the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA), evaluating efficacy, environmental impact, and residue tolerances; as of 2025, no cocrystal-specific approvals have been widely documented, but general pesticide registration processes apply to novel solid forms.

Challenges and Emerging Developments

One significant challenge in cocrystal development is the scalability of mechanochemical synthesis methods, such as ball milling, which often suffer from issues like material clumping and inconsistent energy input during large-scale operations, limiting their transition from laboratory to industrial production. Controlling polymorphism during mechanochemical processes remains difficult due to the rapid kinetics and lack of precise thermal regulation, potentially leading to unintended crystal forms with variable properties. High-throughput screening for suitable coformers is costly, as it requires extensive experimental trials involving numerous combinations, often exceeding traditional solubility enhancement efforts in time and resources. Solvent-based cocrystallization methods, while effective, pose environmental concerns through the use of volatile organic solvents, contributing to waste generation and regulatory scrutiny on sustainability. Intellectual property challenges arise from the overlap between cocrystal patents and existing polymorph protections, where new cocrystal forms may infringe on prior substance patents, complicating generic development and market entry. across multi-site manufacturing is hindered by variations in equipment and process parameters, making it challenging to ensure consistent cocrystal quality and purity on a global scale. Emerging developments include the integration of and for virtual cocrystal screening, with models like achieving prediction success rates exceeding 90% by analyzing molecular descriptors and interaction energies, as demonstrated in a 2022 study. Green coformers derived from renewable sources, such as from plant extracts, are gaining traction to enhance while maintaining efficacy in cocrystal formation. Continuous techniques, including hot melt extrusion and solid-state shear milling, are being refined to enable scalable, solvent-free production of cocrystals with real-time monitoring for . Looking ahead, cocrystals hold promise in through tailored formulations that address individual patient needs, potentially revolutionizing customization. Nanoscale cocrystals, produced via processes like spray , offer enhanced and targeted release profiles for advanced therapeutics. Interdisciplinary advancements link cocrystal to metal-organic frameworks (MOFs), exploring hybrid structures for multifunctional materials in and beyond.

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