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The definition of a cocrystal has been debated in the crystallography field. The simplest definition of a cocrystal is a crystalline structure made up of two or more components in a definite stoichiometric ratio, where each component is defined as either an atom, ion, or molecule. However, this definition encompasses many types of compounds, including hydrates, solvates and clathrates, which represent the basic principle of host-guest chemistry. Cocrystallization is an area of study with hundreds of new scientific articles published every year.

History
Cocrystals represent only about 0.5% of the crystal structures archived in the Cambridge Structural Database (CSD) as of 2009. 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.

The first known cocrystal, quinhydrone, was studied by Friedrich Wöhler in 1844. Quinhydrone is composed of the two organic components quinone and hydroquinone (or quinol). While studying quinone, Wöhler created quinhydrone after mixing solutions of quinone and hydroquinone. He found that this new 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.

Many cocrystals discovered in the late 1800s and early 1900s were reported in Organische Molekulverbindungen, published by Paul Pfeiffer in 1922. 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.

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.

Definition
There exists a disagreement on the meaning of the term "cocrystal." 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. This definition is sometimes extended to specify that the components be solid in their pure forms at ambient conditions. However, it has been argued that this separation based on ambient phase is arbitrary. A more inclusive definition is that cocrystals “consist of two or more components that form a unique crystalline structure having unique properties.” 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. It should be noted that 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.

Properties
Cocrystal structures exhibit long-range order and the components interact via non-covalent interactions such as hydrogen bonding, ionic interactions, van der Waals interactions and Π-interactions. The intermolecular interactions and resulting crystal structures can generate physical and chemical properties that differ from the properties of the individual components. 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.

Phase diagrams determined from the "contact method" of thermal microscopy proved valuable in the discovery of new cocrystals. 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.

Synthesis and Characterization
There are a multitude of 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.

A common way to synthesize cocrystals is through slow evaporation of a solution that contains stoichiometric amounts of the cocrystal components, or cocrystal formers. This has been shown to work when different molecules of complimentary functional groups afford hydrogen bonds that are more favorable than each of the individual molecular components. In this case, the cocrystal is likely to be thermodynamically favored.

A multitude of 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.

Melts have generated an interest in cocrystal formation. By simply melting two cocrystal formers together and cooling, a cocrystal may be formed. If a cocrystal is not formed from a melt, a seed from a melt may be used in a crystallization solution in order to afford a cocrystal. Another phase change in order to form cocrystals is that of sublimation. Sublimation may more often than not form hydrates.

Grinding has attracted interest into the formation of cocrystals. Both neat and liquid-assisted grinding are techniques employed in order to produce these materials. In neat (dry) grinding, cocrystal formers are ground together manually using a mortar and pestle, using a ball mill, or using a vibratory mill. 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. and nucleation through seeding. and nucleation through seeding.

Using intermediate phases to synthesize these solid-state compound are also employed. Through 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, 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 are needed in addition to the thermodynamic requirements in order to form these compounds.

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.

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 new compound is formed and if it could possibly be a cocrystal or not owing to each compound having its own distinct powder diffractogram. 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.

Other common spectroscopic methods may be used. FT-IR and Raman spectroscopy are the commonly employed vibrational spectroscopic methods used in order to characterize these materials. These can be compared to individual cocrystal formers in order to match peaks to find a cocrystal. Solid state NMR has also generated recent interest in order to characterize cocrystals. The advantage of using solid state NMR spectroscopy is that it has the ability to differentiate chiral and racemic cocrystals of similar structure.

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
Cocrystal engineering involves utilizing science to combine and optimize the properties of separate compounds for specific applications such as improving 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, or API’s. Changing the structure and composition of the API will have great influence on the properties and particularly, the bioavailability of the drug. 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.

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. 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 API’s.

It should be clear that the objective of pharmaceutical cocrystals is to create a cocrystal or cocrystal analogs that have properties that differ vastly from that expected of the pure API’s without making and/or breaking covalent bonds. Among the earliest pharmaceutical cocrystals reported are of sulfonamides. The area of pharmaceutical cocrystals has thus increased on the basis of interactions between API’s and cocrystal formers. Most commonly, API’s 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 imporant 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. 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.

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. 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. 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.

A screening procedure has been developed and can be done in order to help determine the possibility of 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 ability of the two components to cocrystallize is evaluated. Finally, phase diagram screening and powder X-ray diffraction (PXRD) are further investigated to find optimum conditions for cocrystallization between the components. This procedure is still done to find new pharmaceutical cocrystals of 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.

Another great 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. 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.