**1. Introduction**

Oral drug delivery is the most used route in the pharmaceutical industry. Over 80 percent of drugs are formulated in solid state, not only because of the advantages referred to noninvasive administration and medication adherence but also for reasons of stability from manipulation and storage of unprocessed material to the drug development process [1–3]. Generally, solid drugs are more chemically stable in the solid state than in solution, where degradation occurs more easily [4]. However, despite the oral delivery potential in comparison with other routes, the oral absorption mechanism of drugs is more complex and requires adequate solubility and stability values in the different portions of the gastrointestinal tract, as well as appropriate dissolution profiles [3]. Furthermore, the numerous structural possibilities of a particular active pharmaceutical ingredient (API) in the solid state, as well as several pharmaceutical production parameters, can have a considerable impact on its chemical, physical, and biopharmaceutical properties [1, 5].

In this context, the aim of solid screening is to select the optimal form with the best characteristics for development. This chapter will go through some of the most important aspects of the API study in solid state.

### **2. Solid forms of pharmaceutical crystals**

A drug can exist in different solid forms, including crystalline and amorphous materials, which are classified into single-component systems and multicomponent systems. In addition, each crystal form may crystallize in many different forms, a property known as polymorphism. Polymorphism can be defined as the ability of a molecule to crystallize in multiple crystal structures with identical chemist composition but different molecular packing, and in some cases, also different conformation [6, 7]. Its study is critical in pharmacy because more than 80% of drugs exhibit this phenomenon in which different polymorphs of the same API may have different properties, affecting the viability, safety, shelf life, solubility, dissolution, stability, toxicity, and bioavailability of oral formulations [8].

Single-component systems include anhydrous or non-solvated drugs. These drugs may have multiple polymorph forms, each of which is identified by a different number (roman or arabic). Ritonavir is a historic case involving problems of dissolution and bioavailability in commercialized drugs associated with a polymorphic transformation of form I to form II, which is more stable but less soluble [9]. Other drugs with polymorphic anhydrous forms include sulfathiazole [10], carbamazepine [11], paracetamol [12], fluconazole [13], among others.

On the other hand, the multicomponent crystal systems comprise drug molecules that have different intermolecular interactions with other molecules (guest molecule or coformer) or ion, resulting in the formation of a new solid form without alterations in the covalent chemistry [7, 14, 15]. This group is formed by solvates, hydrates, co-crystals, salts, and a combination of these (like salt hydrates, salt solvates, co-crystal solvates, co-crystal salt, and co-crystal salt solvates) [14, 16–20]. In addition, each multi-component system may have polymorphs [21]. The multicomponent systems can modify different properties of the API without changing its molecular structure, resulting in improved solubility, dissolution, and bioavailability, among others benefits [15].

Solvates are systems in which the drug molecule and the solvent molecule are trapped in the crystalline lattice interacting via hydrogen bonds (mainly). When the solvent molecule is water the system is called hydrate. Crystal hydrates can exist in stoichiometric relations (monohydrate, dihydrate, etc.) or non-stoichiometric relations [22]. The role of the solvate or water molecule can be as a guest or as a stabilizer of the crystal structure [23]. Some examples of solvents used for forming solvates are dimethyl sulfoxide, ethanol, dimethylformamide, ethyl acetate, acetone, and others [24].

Co-crystals are formed by a neutral drug molecule and a co-crystal former in stoichiometry relation [15, 25]. Both molecules reside in the same crystal lattice and are bonding through non-covalent interactions. In particular, hydrogen bonds are especially important in co-crystals but dipolar, π-stacking, van der Waals and halogen-hydrogen interactions may also stabilize the crystalline structure [6, 14, 15]. *Pharmaceutical Crystals: Development, Optimization, Characterization and Biopharmaceutical… DOI: http://dx.doi.org/10.5772/intechopen.105386*

The selection of co-crystal formers is based on the functional groups of the API, so molecular recognition is favored by using complementary functional groups. Examples of co-crystal formers are acids, amides, carbohydrates, alcohols, and amino acids [26].

Salts are formed by strong ionic interaction of drug molecules with other molecules or atoms ionized, which act like an oppositely charged counterion. Therefore, the ionizable groups of the API limited its formation [23]. In addition, other interactions can act cooperatively to stabilize the crystal form like hydrogen bonding or coordination interactions [14]. The "pKa rule" is an accepted method used in the salt formation that uses the difference between pKa values of API and coformer to predict their behavior. The salt formation is possible if ΔpKa (ΔpKa = pKabase - pKaacid) is less than 3 [15].

In order to guarantee the API solid form present in the bulk material and its pharmaceutical formulations it is critical to evaluate and characterize each solid form, this topic will be detailed in Section 4.

#### **3. Mechanism of synthesis**

As mentioned in the previous section, there exist numerous types of pharmaceutical solid forms in the crystalline state (polymorph, solvate/hydrate, co-crystal, salt). Crystals are solids with a regular array of atoms and molecules built from a translational repetition of the basic structure denominated by unit cell. Thereby, a complete description of the concept of crystallization is fundamental.

Crystallization is a phenomenon that occurs as a result of two different processes. The first is called nucleation, which is the beginning of a phase transition from a supersaturated state that gives rise to the appearance of a small nucleus in a second phase. The second one is the crystal growth process, which involves the evolution layer by layer to determine the crystal packing of the unit cell [27]. The strength of the intermolecular interactions within the unit cell is what determines which layers dominate the crystal growth process [28]. Therefore, the crystals of an API can differ in size relative to the growth of particular faces and the number and type of faces present, ergo they can have different crystal habits, which characterizes the crystal shape (acicular, prismatic, pyramidal, tabular, columnar or lamellar type).

Crystallization is a process of transformation from a solution or melt to the crystalline state. The generation of crystal nuclei is controlled by the crystallization conditions (e.g., solvent, temperature, and supersaturations). Moreover, a solvent or additive in the process of growth may cause competition for a site at an incoming point associated with the layer-by-layer growth process that would be capable of disrupting the magnitude of the intermolecular interactions generating inhibition or interference in the growth directions which is manifest as a change in the overall morphology of the crystal. In industrial crystallization, seeding the supersaturated solution with crystalline material is a common strategy for ensuring batch-to-batch reproducibility and optimizing process robustness by controlling the whole crystallization process by minimizing spontaneous nucleation. In particular, the addition of desired form seeds is the technique most used to control polymorphism [27].

The crystallization process was described using a variety of methodologies (summarized in **Figure 1**), each with its own characteristic, including crystallization from a single solvent, evaporation from a binary mixture of solvents, antisolvent addition, temperature gradient, vapor diffusion, slurrying, and liquid assisted grinding [4, 6, 15].

**Figure 1.** *Methodologies for manufacturing solid pharmaceutical materials.*

The crystallization from a solution could proceed in different ways, including slow cooling of a hot saturated solution, slow warming, or by heating the solution to boiling and then quenching cool using an ice bath. On the other hand, if crystallization from a solution is not possible, there are a number of processes that do not require the use of a solvent such as sublimation, thermal treatment, crystallization from the melt, neat grinding, capillary crystallization, laser-induced crystallization and sono-crystallization [27, 29].

The techniques applied for the preparation can use thermodynamic or kinetic conditions, depending on whether the thermodynamic equilibrium is maintained or the situation moves away from equilibrium, respectively, to obtain the crystallization of different crystal forms. The synthesis mechanisms that obtain thermodynamic conditions include slow evaporation, and slow cooling, among others. While kinetic conditions refer to high supersaturation degree, quench cooling, and rapid solvent evaporation, among others [30]. Under stress situations, crystallization kinetics will control the crystal shape, rather than thermodynamics conditions, and the production of more unstable solid forms will be favored kinetically [6].

Additionally, the initial phases of crystallization, determined by the time between supersaturation and the development of nuclei, are critical in regulating the characteristics of the final solid phase, such as purity, crystal structure, and particle size [27]. In general, the most thermodynamically stable crystalline form is preferable. Crystallization performed in close proximity to equilibrium are likely to generate forms of relatively stable or ground-state polymorphs. Though the production of amorphous or metastable forms with increased solubility and dissolution rates may be favored by bioavailability requirements [6]. For example, techniques that produce an abrupt change in the system, such as sublimation or crystallization from the melt, result in a metastable solid form. Thermal desolvation of crystalline solvates can generate amorphous materials, with the solvent contributing to stabilizing the lattice. While techniques such as quench cooling can also be used to obtain amorphous forms. However, these high-energy forms tend to be transformed into a stable form through a solid-solid physical transition, a phase transformation with solvent mediation, or both.

*Pharmaceutical Crystals: Development, Optimization, Characterization and Biopharmaceutical… DOI: http://dx.doi.org/10.5772/intechopen.105386*
