Cocrystal

Source: Wikipedia, the free encyclopedia.

In

crystalline structure having unique properties." Several subclassifications of cocrystals exist.[2][3]

Cocrystals can encompass many types of compounds, including

clathrates, which represent the basic principle of host–guest chemistry
. Hundreds of examples of cocrystallization are reported annually.

History

The first reported cocrystal,

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 Molekulverbindungen, published by

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

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.

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

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

The components interact via non-covalent interactions such as

polymorphs, which may display different physical properties depending on the form of the crystal.[10]

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

Production

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.

hydrates.[12]

Grinding, both heat and liquid-assisted, is employed to produce cocrystal, e.g., 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.[13] 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.[14][15]

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

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.[13]

Aside from common spectroscopic methods such as

racemic cocrystals of similar structure.[13]

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 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.[16]

Pharmaceuticals

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.[17] Among the earliest pharmaceutical cocrystals reported are of sulfonamides.

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.[17] 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

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

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

Two explosives

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.[19]

See also

References

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  17. ^ a b Adivaraha, J. (2008). Understanding the Mechanisms, Thermodynamics and Kinetics of Cocrystallization to Control Phase Transformations (PDF) (dissertation). University of Michigan.
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  19. ^ "Explosives: A bigger bang". The Economist. Sep 15, 2012.
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