The definition of a cocrystal has been debated in the crystallography
Crystallography is the experimental science of the arrangement of atoms in solids. The word "crystallography" derives from the Greek words crystallon = cold drop / frozen drop, with its meaning extending to all solids with some degree of transparency, and grapho = write.Before the development of...

 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
Host-guest chemistry
In supramolecular chemistry, host-guest chemistry describes complexes that are composed of two or more molecules or ions that are held together in unique structural relationships by forces other than those of full covalent bonds. Host-guest chemistry encompasses the idea of molecular recognition...

. Cocrystallization is an area of study with hundreds of new scientific articles published every year.


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
A quinone is a class of organic compounds that are formally "derived from aromatic compounds [such as benzene or naphthalene] by conversion of an even number of –CH= groups into –C– groups with any necessary rearrangement of double bonds," resulting in "a fully conjugated cyclic dione structure."...

 and hydroquinone
Hydroquinone, also benzene-1,4-diol or quinol, is an aromatic organic compound that is a type of phenol, having the chemical formula C6H42. Its chemical structure, shown in the table at right, has two hydroxyl groups bonded to a benzene ring in a para position. It is a white granular solid...

. 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
Paul Pfeiffer (chemist)
Paul Pfeiffer was an influential German chemist. He received his Ph.D. under Alfred Werner, the "father of coordination chemistry," at the University of Zurich...

 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
Eucalyptol is a natural organic compound which is a colorless liquid. It is a cyclic ether and a monoterpenoid.Eucalyptol is also known by a variety of synonyms: 1,8-cineol, 1,8-cineole, limonene oxide, cajeputol, 1,8-epoxy-p-menthane, 1,8-oxido-p-menthane, eucalyptol, eucalyptole,...

, 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.


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
In chemistry, salts are ionic compounds that result from the neutralization reaction of an acid and a base. They are composed of cations and anions so that the product is electrically neutral...

 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.


Cocrystal structures exhibit long-range order and the components interact via non-covalent interactions such as hydrogen bonding, ionic
Ionic bond
An ionic bond is a type of chemical bond formed through an electrostatic attraction between two oppositely charged ions. Ionic bonds are formed between a cation, which is usually a metal, and an anion, which is usually a nonmetal. Pure ionic bonding cannot exist: all ionic compounds have some...

 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
Polymorphism (materials science)
Polymorphism in materials science is the ability of a solid material to exist in more than one form or crystal structure. Polymorphism can potentially be found in any crystalline material including polymers, minerals, and metals, and is related to allotropy, which refers to chemical elements...

, which may display different physical properties depending on the form of the crystal.

Phase diagrams determined from the "contact method" of thermal microscopy
Microscopy is the technical field of using microscopes to view samples and objects that cannot be seen with the unaided eye...

 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
Eutectic point
A eutectic system is a mixture of chemical compounds or elements that has a single chemical composition that solidifies at a lower temperature than any other composition. This composition is known as the eutectic composition and the temperature is known as the eutectic temperature...

 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
A slurry is, in general, a thick suspension of solids in a liquid.-Examples of slurries:Examples of slurries include:* Lahars* A mixture of water and cement to form concrete* A mixture of water, gelling agent, and oxidizers used as an explosive...

. 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
Ball mill
A ball mill is a type of grinder used to grind materials into extremely fine powder for use in mineral dressing processes, paints, pyrotechnics, and ceramics.-Description:...

, 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.

Pharmaceutical cocrystals can be formed also by use of supercritical fluids. Supercritical fluids act as a new media for the generation of cocrystals. Supercritical fluid technology offers a new platform that allows a single-step generation of particles that are difficult or even impossible to obtain by traditional techniques. The generation of pure and dried new cocrystals (crystalline molecular complexes comprising the API and one or more conformers in the crystal lattice) can be achieved due to unique properties of SCFs by using different supercritical fluid properties: supercritical CO2 solvent power, anti-solvent effect and its atomization enhancement.

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, 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
Raman spectroscopy
Raman spectroscopy is a spectroscopic technique used to study vibrational, rotational, and other low-frequency modes in a system.It relies on inelastic scattering, or Raman scattering, of monochromatic light, usually from a laser in the visible, near infrared, or near ultraviolet range...

 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
In chemistry, a racemic mixture, or racemate , is one that has equal amounts of left- and right-handed enantiomers of a chiral molecule. The first known racemic mixture was "racemic acid", which Louis Pasteur found to be a mixture of the two enantiomeric isomers of tartaric acid.- Nomenclature :A...

 cocrystals of similar structure.

Other physical methods of characterization may be employed. Thermogravimetric analysis
Thermogravimetric analysis
Thermogravimetric analysis or thermal gravimetric analysis is a type of testing performed on samples that determines changes in weight in relation to change in temperature. Such analysis relies on a high degree of precision in three measurements: weight, temperature, and temperature change...

 (TGA) and differential scanning calorimetry
Differential scanning calorimetry
Differential scanning calorimetry or DSC is a thermoanalytical technique in which the difference in the amount of heat required to increase the temperature of a sample and reference is measured as a function of temperature. Both the sample and reference are maintained at nearly the same temperature...

 (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.


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
In pharmacology, bioavailability is a subcategory of absorption and is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. By definition, when a medication is administered...

 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
Polymorphism (materials science)
Polymorphism in materials science is the ability of a solid material to exist in more than one form or crystal structure. Polymorphism can potentially be found in any crystalline material including polymers, minerals, and metals, and is related to allotropy, which refers to chemical elements...

, especially in the case of cocrystal solvates which can be known to have different polymorphic forms. Such a case is in the drug sulfathiazole
Sulfathiazole is an organosulfur compound that has been used as a short-acting sulfa drug. It once was a common oral and topical antimicrobial until less toxic alternatives were discovered. It is still occasionally used, sometimes in combination with sulfabenzamide and sulfacetamide, and in...

, a common oral and topical antimicrobial
An anti-microbial is a substance that kills or inhibits the growth of microorganisms such as bacteria, fungi, or protozoans. Antimicrobial drugs either kill microbes or prevent the growth of microbes...

,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
Solubility is the property of a solid, liquid, or gaseous chemical substance called solute to dissolve in a solid, liquid, or gaseous solvent to form a homogeneous solution of the solute in the solvent. The solubility of a substance fundamentally depends on the used solvent as well as on...

. 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
Carbamazepine is an anticonvulsant and mood-stabilizing drug used primarily in the treatment of epilepsy and bipolar disorder, as well as trigeminal neuralgia...

 (CBZ), a common treatment for epilepsy
Epilepsy is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain.About 50 million people worldwide have epilepsy, and nearly two out of every three new cases...

, trigeminal neuralgia
Trigeminal neuralgia
Trigeminal neuralgia , tic douloureux is a neuropathic disorder characterized by episodes of intense pain in the face, originating from the trigeminal nerve. It has been described as among the most painful conditions known...

, and bipolar disorder
Bipolar disorder
Bipolar disorder or bipolar affective disorder, historically known as manic–depressive disorder, is a psychiatric diagnosis that describes a category of mood disorders defined by the presence of one or more episodes of abnormally elevated energy levels, cognition, and mood with or without one or...

. 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
Piracetam is a nootropic drug. Piracetam's chemical name is 2-oxo-1-pyrrolidine acetamide; it shares the same 2-oxo-pyrrolidone base structure with 2-oxo-pyrrolidine carboxylic acid . Piracetam is a cyclic derivative of GABA. It is one of the group of racetams...

, or (2-oxo-1-pyrrolidinyl)acetamide, which is used to stimulate the central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...

 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
Non-steroidal anti-inflammatory drug
Nonsteroidal anti-inflammatory drugs, usually abbreviated to NSAIDs or NAIDs, but also referred to as nonsteroidal anti-inflammatory agents/analgesics or nonsteroidal Anti-inflammatory medicines , are drugs with analgesic and antipyretic effects and which have, in higher doses, anti-inflammatory...

(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.
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