*1.7.3 Solubility*

Lowering the crystal lattice energy and increasing solvation are two mechanisms that increase the solubility of the API in a co-crystal. API solubility can be increased using either technique to varying degrees. Co-crystal solubility in non-polar solvents can be improved through a number of mechanisms, one of which is lowering the crystal lattice energy. Hydrogen bonding, van der Waals forces and electrostatic forces all affect the crystal lattice energy [109]. The solvation of the API in the cocrystal structure is the second way for enhancing solubility in co-crystals. Because hydrophobic BCS Class II drugs are frequently solubility-limited by reduced solventsolute interactions, this is the primary method of increasing solubility in water. The incorporation of a polar, water-soluble molecule into the crystal structure can help to solvate the hydrophobic API more easily. Coformer solubility is related to co-crystal

#### *Modification of Physicochemical Properties of Active Pharmaceutical Ingredient… DOI: http://dx.doi.org/10.5772/intechopen.110129*

solubility. This is due to improved solvation with a conformer with a higher solubility [110]. For example, the drug-drug co-crystal of carvedilol-hydrochlorothiazide was prepared by solvent evaporation method and their solubility was significantly improved 7.3 times in 0.1N HCl than the pure carvedilol and *in vitro* dissolution rate of co-crystals was enhanced by 2.7 times than pure carvedilol, which may lead to enhanced bioavailability [29].

#### *1.7.4 Bioavailability*

The bioavailability of an API is the fraction of the dose that reaches the system circulation in its unchanged form, as well as the rate at which the API enters the systemic circulation. The low oral bioavailability of APIs is a major challenge in the development of new formulations. The pharmaceutical co-crystal approach enhanced the aqueous solubility and oral bioavailability of the product [111]. Meloxicamaspirin co-crystals showed better oral bioavailability as compared to pure drug and showed 12 times faster onset of action than a pure drug in rats [112]. Co-crystals of aceclofenac-nicotinamide and aceclofenac-gallic acid prepared with solvent evaporation method both co-crystals exhibited excellent dissolution rate and bioavailability increased with 1.77 and 1.37 time as compared to the pure drug [113, 114].

#### *1.7.5 Controlled release*

Co-crystallization is used to modify the product's physicochemical properties, such as solubility and dissolution rate. The dissolution rate of the API in water or a buffer solution can be increased or decreased over time, depending on the coformer that co-crystallized with the API [115]. Zonisamide-caffeine co-crystals were prepared by solvent evaporation method. It was found that the co-crystals showed lower solubility and dissolution rates and offer potential benefits in the development of sustained release of drug for the treatment of obesity [116]. Co-crystals also bear the potential to reduce the dissolution rate of the original APIs. Chen et al. used the co-crystallization approach to sustain the dissolution behaviour of ribavirin, a water-soluble antiviral drug. The most useful hydrogen bonding group of ribavirin is the amide functionality, which is known to form robust hydrogen bonding interactions with carboxylic acids and amide compounds. The ribavirin-gallic acid forms co-crystals with reduced release rate [117].

#### *1.7.6 Multidrug co-crystals*

Combining multiple active pharmaceutical ingredients (APIs) into one unit dose is a new approach for patient compliance. It becomes a popular trend in drug formulation industries, the need to target multiple receptors for the effective treatment of complex disorders such as HIV/AIDS, cancer, and diabetes. Multiple APIs have been combined in a single delivery system using salts, mesoporous complexes, co-amorphous systems and co-crystals [113]. Multidrug co-crystals (MDCs) have an advantage over co-amorphous systems in terms of enhanced stability and reduced payload compared to mesoporous and cyclodextrin complexes [118]. As dissociable solid crystalline supramolecular complexes, multidrug co-crystals contain two or more therapeutically beneficial components in a stoichiometric ratio within the same crystal lattice, where the components may predominantly interact *via* non-ionic interactions and rarely *via* hybrid interactions (a combination of ionic and non-ionic interactions

involving partial proton transfer and hydrogen bonding) with or without the presence of solvate molecules. MDC has potential advantages over pure drug components such as increased solubility, dissolution, bioavailability, improved stability of unstable APIs *via* intermolecular interactions, increased mechanical strength and flowability [118–122]. Techniques generally used for formulation multidrug co-crystals are solvent evaporation, neat and liquid-assisted grinding, slurry reaction, melting and cooling crystallization. MDC formulations are evolving day by day exploring different combinations of APIs. But still more efforts are required for medically relevant APIs, which could be beneficial to the patients and pharmaceutical industry. Much more steps in terms of MDCs still have to be taken for improved and evolved formulation [123].
