*1.2.3 Solubility*

An important factor in determining pharmaceutical qualities of co-crystal is its solubility. Salt generation, solid dispersion and particle size reduction are a few *Modification of Physicochemical Properties of Active Pharmaceutical Ingredient… DOI: http://dx.doi.org/10.5772/intechopen.110129*

traditional techniques for improving weakly aqueous medication solubility [40]. With these strategies, there are limitations in practice. Using pharmaceutical co-crystals is a novel way to alter the physicochemical characteristics of medicinal molecules, such as their solubility and dissolution. Researcher interest in solubility is high [40].

#### *1.2.4 Intrinsic dissolution*

It assesses the intrinsic qualities of the drug as a function of the dissolution medium, such as pH, ionic strength, and counter ions, and is independent of formulation effects [40]. Intrinsic dissolution measures the rate of dissolution of a pure pharmacological component from a constant surface area. When the sample is squeezed into a disc or pellet for the intrinsic dissolution test, there should not be any shape changes and the disc needs to stay intact throughout the experiment. The majority of the APIs investigated for co-crystallization are categorized as class II pharmaceuticals under the Biopharmaceutics Classification System (BCS), which have high permeability and low solubility. Therefore, intrinsic dissolution rate is a reliable predictor of API *in vivo* performance. Even if the intrinsic dissolution rate is a crucial factor to research, it can get trickier with co-crystals. In order to collect and correctly interpret intrinsic dissolution data on co-crystals, a number of aspects must be taken into account, and additional experiments may be required [41].

#### *1.2.5 Bioavailability*

Bioavailability is a determination of rate and extent of drugs that reaches to the systemic circulation [42] . The bioavailability of newly formed moiety is determined with the help of animal experimentation. The ultimate goal for co-crystal investigation is to improve bioavailability of an APIs. Animal bioavailability is important for a newly prepared compound. The limited numbers of animal bioavailability studies are available on co-crystals [43].

#### **1.3 Pharmaceutical co-crystal design strategies**

A pharmaceutical co-crystals have rapidly emerged as a new class of Active Pharmaceutical Ingedients. In order to get co-crystals first step is to study the structure of target drug and find out the functional group present in drug molecule, which can interact between molecules when a suitable coformer is present. The next step is to pick a coformer. The primary requirement for a coformer is that it must be suitable and acceptable for use in pharmaceutical products, such as pharmaceutical excipients and substances that have been designated as generally recognized as safe (GRAS) for use as food additives. Co-crystal design must start with the choice of coformer. There is a wealth of useful empirical and theoretical guidance available during the synthesis of co-crystals, including the Cambridge Structural Database, hydrogen bonds and intermolecular interactions. A useful tool for examining intermolecular interactions in crystals is the Cambridge Structural Database. By referring to the structural property relationships present in classes of recognized crystal structures found in the Cambridge Structural Database, it can be used to study the outline of stable hydrogen bonds. Based on data from Cambridge Structural Database, a supramolecular library of coformers has been created [44, 45].

When determining the intermolecular interactions between an API and a coformer molecule in the majority of pharmaceutical co-crystal structures, hydrogen bonds are a key factor [42]. To facilitate the design of hydrogen bonded solids, the following

**Figure 5.**

*Steps for co-crystal design and screening [49].*

guidelines were put forth [46]. (1) All good proton donors and acceptors are used in hydrogen bonding; (2) if six-membered rings can form intermolecular hydrogen bonds, they will frequently do so with a preference for doing so; and (3) the best proton donors and acceptor are left over after intermolecular hydrogen bonds have formed, from intermolecular hydrogen bonds to one another. The next step is screening of co-crystals, which is an experimental process to determine if the selected coformer candidate is able to crystallize with targeted API molecule. Various screening methods of co-crystals are solution method [47], hot stage thermal microscopy [48] and computed crystal energy landscape method [48]. The aim of co-crystals characterization includes the chemical structural confirmation and crystallographic analysis of newly formed supramolecular synthon, its thermal features, solubility and stability. The final step is performance of newly formed co-crystals that include both *In vivo* and *In vitro* tests. *In vitro* test comprises the dissolution and intrinsic dissolution rate and *in vivo* test refers to animal oral bioavailability measurements, the measurement of rate and extent of drug that reaches to the systemic circulation [49] (**Figure 5**).

### *1.3.1 Selection of coformer*

Pharmaceutical co-crystals are formed by incorporating a certain stoichiometric ratio of given API with pharmaceutically acceptable coformer molecule in the crystal lattice. Greater diversity is possible with co-crystal solid forms because of numerous choices of pharmaceutically acceptable coformers, including pharmaceutical excipients, food additives as well as other generally regarded as safe (GRAS) APIs. Since different physicochemical natures of coformers result in different physicochemical properties and *in vivo* behaviours of the produced co-crystal coformer selection become a crucial step for pharmaceutical co-crystal design, an ineffective and time-consuming initial method for choosing a coformer involved trying to co-crystallize a specific API with different pharmaceutically acceptable ingredients. Later, after the Cambridge Structure Database (CSD) was built, the "supramolecular synthon approach" was used to successfully screen coformer for the development of co-crystals [50].

There were two types of supramolecular synthons, including homosynthon and heterosynthon. In general, supramolecular heterosynthon represented more robust hydrogen bond than homosynthon and was the most reliable and rational channel to form co-crystals. Although the "supramolecular synthon approach" with computer assistance significantly accelerated the design of co-crystals, the physicochemical characteristics and *in vivo* behaviours of the resulting co-crystals could still not be predicted from chosen coformers because the main objective of such an approach was to determine whether hydrogen bonds could exist between APIs and coformers.

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

When selecting coformers for pharmaceutical co-crystal design, little attention is currently paid to the physicochemical (i.e. stability and its degradation pathway) and biopharmaceutical (i.e. intestinal absorption mechanism and metabolic pathway) properties of coformers and APIs. However, some coformers, particularly GRAS APIs, may accelerate drug degradation and may also inhibit efflux/influx transporters and metabolic enzymes involved in drug absorption and metabolism. Aspirin, for instance, was regarded as a GRAS API and used as a coformer in pharmaceutical co-crystals.

#### **1.4 Co-crystal formation methods**

Till date a number of techniques are used for the formulation of co-crystals. The most general method is based on solution method and grinding method [51]. The solution method is of great significance for synthesis of co-crystals, which qualify for single X-ray diffraction testing can only be prepared through this method. Solution methods include evaporation of heterometric solution method, reaction crystallization method and cooling crystallization. Grinding method comprises solvent drop grinding and neat grinding. Apart from these methods, there are also lots of recently promising techniques, such as hot stage microscopy, ultrasound-assisted co-crystallization and co-crystallization using supercritical fluid [52].

## *1.4.1 Solution methods*

Based on these two approaches, solution crystallization can occur [52]. In order to reach the crystal stability region in solvents that are not congruently saturated, either (1) use solvents or solvent mixtures where the co-crystals are congruently saturated and the components have similar solubilities, or (2) use non-equivalent reactant concentrations. When the two co-crystal components are equally soluble in solvent and solution, strategy one is used. The 1:1 co-crystals will form through co-crystallization with equimolar components using the solvent evaporation method. When the components of co-crystals have non-equivalent solubility, strategy two is used. A singlecomponent crystal or a combination of individual component and co-crystals may form during co-crystallization as a result of the evaporation of an equimolar solution. For this circumstance, the reaction co-crystallization approach has been used. In RC experiments, the more soluble reactant is dissolved in a saturated or nearly saturated solution of the less soluble reactant, which causes the solution to supersaturate in terms of co-crystals. Another solution method called cooling crystallization is varying the temperature of the crystallization system, which has great potential for large scale of production of co-crystals. In a reactor, particularly a jacketed vessel, substantial amounts of solvent and reactants are first combined. The system is then heated to a higher temperature to ensure that all solutes are completely dissolved in the solvent and is then cooled. When the solution becomes supersaturated with respect to cocrystals as the temperature decreases, co-crystals will form [53].
