Most of the drugs marketed worldwide are oral dosage form and 40 per cent of the existing therapeutic moieties and 90 per cent of new therapeutic moiety coming from the drug discovery are not brought to the market due to poor solubility and dissolution, low permeability and first–pass metabolism. Active Pharmaceutical Ingredients (API) can exist in a variety of distinct solid forms, which include polymorphs, hydrates, salts, solvates, amorphous solids and co-crystals. The differences between solvates and co-crystals lie on physical state of the individual components.

In a crystalline drug substance if one component is liquid at room temperature is called solvates and if both the components are solids at room temperature are designated as co-crystals. The physicochemical properties exhibited by each forms can influence the bioavailability, stability and other performance characteristics of the drug.

The pharmaceutical co-crystals are defined as crystalline materials consisting of an API and one or more unique co-crystal formers which are solid at room temperature. Co-crystals can be developed by several types of interaction such as Vander Waals forces, hydrogen bonding and pi-stacking. The co-crystal depends on hydrogen–bonded assembly, which form link between neutral molecules of API with other components.

Chemist and pharmaceutical technologist prefer crystalline forms of the active compounds in dosage forms, due to the inherent stability. The importance of co-crystals are more felt when the drugs have poor aqueous solubility, show first pass metabolism, low permeability, slow dissolution in GIT and having intrinsic barrier to drug delivery. The chemists are now giving more attention to material properties for designing new API in drug discovery process.

The method of preparation of crystal utilizes suitable solution with proper degree of super saturation. The different procedures adopted for super saturation of solution include evaporation, cooling and incorporation of solubility lowering solvent or substance. Evaporation is the most common technique used for crystal formation.The factor which influences the formation of co-crystals includes type of co-former, API co-former ratio, solvents, temperature, pressure and crystallization techniques.

The co-crystals are prepared by solvent and solid based methods. Solvent based method first involves the conversion of slurry followed by solvent evaporation, cooling crystallization and precipitation. The preparation of co-crystal by the slurry crystallization is a simple process. The yield obtained is comparatively low, when compared to solvent drop grinding method. Few examples of co-crystals formed by utilizing slurring process include celecoxib, venlafaxine etc.

In the method of preparation of co-crystal using solvent, the two components used should have the same solubility; otherwise the component having least soluble behaviour may precipitate out exclusively. In solvent based method all materials are mixed serially with the common solvent and left for complete evaporation. During the evaporation process the molecules undergo intermolecular interactions forming co-crystal.

The co-crystallization of Fluoxetine hydrochloride and benzoic acid are prepared by this method. Solid based method of preparation of co-crystals involve grinding; solvent assisted grinding and sonication. The co-crystal preparation by grinding involves the mixing of materials followed by pressing and crushing in a mortar and pestle. The procedure of pressing and crushing will help in size reduction of particle size and co-crystallization is affected by addition of solvent during grinding process. Examples of co-crystal formed by solid state process are pterostilbebe, caffeine etc. The solvent drop grinding method, also called modification of solid grinding technique is adopted for preparing co-crystals. The co-crystal of pterostilbebe and carbamazepine are prepared by this method.

 Hot melt extrusion is another method for preparing co-crystal. The shear and the temperature involved in the process will help the components to fuse together at the interface forming the co-crystal. The co-crystal so formed is more stable than the one prepared by traditional solvent based approach. The co-crystals prepared by hot melt extrusion     process include sorbitol, mannitol etc. The co-crystals can also be prepared by addition of anti solvent. Example of co-crystal prepared by this procedure includes preparation of co-crystals of aceclofenac using chitosan polymer. The supercritical fluid can be utilized for preparing co-crystals. The co-crystal of carbamazepine and acetyl salicylic acid is prepared by using this process.

 The sonochemical method is another process for preparing co-crystal of very finite size. This method was primarily developed for preparing nano crystals. The co-crystal of fluoxetine hydrochloride and benzoic acid in acetonitrile by sonication are few examples under this method. The high throughput-co-crystallization can be used for preparing co-crystal and involves three steps, namely first the designing of experiments followed by execution of protocol and finally the analysis of data. The designs of experiment include hardware and software, which will help to analyse the data for the conclusions and store them. The data are retrieved when required. The most widely used methods for preparing co-crystals is by solution and grinding procedure.

The characterization of co-crystals can be done based on the chemical and physical properties. The physical properties include the determination of melting point by thermo gravimetric analysis and differential scanning calorimetry. The above tools can also be made use for determining the phase transition and enthalpy. The other physical properties include solubility, pH etc. The morphology of crystals is studied by microscopic method. The chemical structures of the co-crystals can be revealed by infrared spectroscopy, solid state NMR, single crystal x- ray crystallography and powder x- ray diffraction.

FDA has provided guidance relating to the classification of pharmaceutical co-crystals. The guidelines will help the applicant for providing necessary data, which support the appropriate classification of co-crystals. Generally speaking, if the API and its excipient(s) have a ?pKa (pKa (base) - pKa (acid)) > 1, in which a substantial proton transfer result in ionization and formation of salt. On the other hand, if the API and its excipient(s) have a ?pKa (pKa (base) - pKa (acid)) < 1, creating a low substantial proton transfer. If these criteria’s is met, the active ingredient-excipient complex should be classified as a co-crystal.

If one believes that the classification of the pharmaceutical solid as a salt or co-crystal is not predicted on the basis of relative pKa values, then spectroscopic tools using various orthogonal approaches should be used. Another criterion for classifying the pharmaceutical co-crystal is the complete dissociation of the API from its excepient should occur prior to reaching the site of action. “API- excipient” co-crystal that meets these conditions is a “pharmaceutical co-crystal” and has a regulatory classification of a drug product intermediate

The carbamazepine (CBZ) is an antiepileptic drug used for more than three decades. The oral administration of CBZ shows poor solubility with high dosage requirement for therapeutic effect and show limited bioavailability. The CBZ saccharin co-crystal was prepared and has shown good chemical stability and dissolution. The pharmacokinetic studies have shown higher C max and comparable T max than the parent compound. In another study involving the conversion of fluoxetine hydrochloride (used for its antidepressant activity) to its co-crystal of an amine hydrochloride salt via chloride mediated carboxylic acid supramolecular synthon.

The synthon are defined as structural units within superior molecules which can be formed and/or assembled by known or conceivable intermolecular interactions. In crystal structures when crystal pattern repeat regularly, the pattern of interactions can be called as supramolecular synthon. The co-crystallization could modify the physical properties of fluoxetine hydrochloride. The fluoxetine hydrochloride prepared with succinic acid co-crystal exhibited a two fold increase in aqueous solubility after five minutes.

Itraconazole an antifungal agent is extremely water insoluble. The oral bioavailability is less and co-administration of acidified HP-ß-cyclodextrin beverages with sporanox capsule will give maximal absorption of API. The co-administration can also cause diarrhoea. Stable pharmaceutical co-crystal of itraconazole was developed and found that the dissolution has increased. Sildenafil a drug used for a variety of treatment like pulmonary arterial hypertension, congestive heart failure, atherosclerosis, peripheral vascular disease, male erectile dysfunction and female sexual disorders. The co-crystal form of sildenafil show better solubility of API in acidic condition, when co-crystallized with acetyl salicylic acid.

The aripiprazole a psychotropic drugs used for treating schizophrenia in tablet form do not readily disperse for rapid absorption in GIT. Aripiprazole co-crystals consist of aripiprazole and fumeric acid is a thermodynamically stable drug having enhanced solubility and bioavailability. The tenofovir disoproxil fumarate (DF) is a nucleotide reverse transcriptase inhibitor used for the treatment of HIV-1 infection either alone or in combination with other antiretroviral agents. The solid form currently used in the marketed product is not stable. It was estimated that the bulk molar ratio of tenofovir disoproxil to fumaric acid in commercially available product is 1:1. The TDFA 2:1 co-crystal was found to be more stable and low hygroscopic effect than the crystalline form of tenofovir.