**5. Solid form impact on physicochemical and biopharmaceutical properties**

As described above, the crystallization process determines different habit crystals associated with particular lattice energy, resulting in measurable differences in physical properties. Therefore, different crystalline forms of a drug can be used in pharmaceutical science to improve their physicochemical and biopharmaceutical properties such as melting point, hygroscopicity, solubility, dissolution rate, stability (physical and chemical) mechanical and optical properties. The wettability of an API, for example, has an impact on its solubilization and dissolution processes. The absorption rate of many poorly soluble drugs is determined by their dissolution rate. Hence, drug molecules with poor solubility may lead to slow dissolution in biological fluids, resulting in an erratic bioavailability and consequent sub-optimal efficacy when delivered via the oral route [28, 30, 46].

The crystal morphology of solid drugs influences their dissolving rate due to critical factors such as surface area, size, and even the polymorphic form of the material, which may have a potential impact on the rate and extent of drug absorption.

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

The size of drug particles and their ability to be wetted by gastrointestinal fluids determine the drug surface area accessible for dissolution. The particle size is dependent on the crystallization conditions or on milling procedures. Therefore, controlled crystallization methods must be used to produce powders with high purity and predetermined particle size distribution for API administration.

The effect of crystal form on the dissolution and bioavailability of the API has been demonstrated. The kinetic transformation and growth conditions in crystallization have a direct effect to generate a particular architecture, which can be a stable polymorph or a metastable form. The polymorph selection process requires a high level of manipulation and control to obtain specific crystal structures grown in selected solvents.

In general, different polymorphs show solubility differences typically smaller than 10 times due to relative differences in free energy. Some examples include the evaluation of solubility, in aqueous and buffer solutions, of several forms of furosemide [47], norfloxacin [48–50], albendazole [51], and oxytetracycline hydrochloride [52]. These studies demonstrate that the molecular arrangement of each polymorphic form and its degree of ionization has a considerable impact on drug solubility (**Table 1**).

Additionally, the effect of polymorphs on bioavailability has a direct impact on pharmacokinetic parameters. A typical example is chloramphenicol palmitate, which exists in 4 solid forms: A, B, C and amorphous structure. Form A is the most stable, however, only the metastable form B and the amorphous solid have biological activity. Aguiar [53] reported that the blood serum level of form B is substantially higher than form A, by nearly an order of magnitude, after oral administration of suspensions at the same dose. It was concluded that form B has high free energy, then is more soluble and thus has a higher rate of absorption and bioavailability.

In some situations, occasionally metastable crystalline or amorphous forms are utilized for drugs orally administered if a faster dissolution rate or higher concentration is desired, in order to achieve rapid absorption and therapeutic effectiveness.


#### **Table 1.**

*Influence of crystal form on drug solubility.*

Although metastable polymorphs can improve solubility, dissolution, and bioavailability, they can also be transformed into a more thermodynamically stable form during manufacture and storage, which results in unacceptable bioavailability and limits their potential performance. As an example, the polymorphic transformation of chlorpropamide caused by the mechanical energy of tableting compression was described. The heat generated by the compaction process would accelerate the transformation process of the metastable form C into the stable form A, in consequence, its dissolution rate decreases after compression [54, 55].

Furthermore, physical form stability in the gastrointestinal environment should also be considered. During gastrointestinal transit, the transformation in the most stable form is a relevant factor to consider. If the conversion occurs in the course of oral administration, a less soluble form will precipitate reducing oral absorption. For example, Kobayashi [56] demonstrated some differences in the oral pharmacokinetics and bioavailability between carbamazepine polymorphs (anhydrous forms I and III) and the dihydrate form. The plasma concentration-time profiles of polymorphs and dihydrate form differ in correlation with their dissolution profiles, which were in the order form III \form I\dihydrate; furthermore, form III was transformed in situ to dihydrate form faster than form I. By comparing the in vivo performance of carbamazepine at high doses, the form I provide better pharmacokinetic parameters than the other two forms. The inconsistency between the order of initial dissolution rates and pharmacokinetics values suggested a probable rapid transformation of form III to the dihydrate form in the gastrointestinal fluids, resulting in a slowing of dissolution due to the production of the dihydrate form.

A substantial solubility difference between amorphous and crystalline API is observed. The high-energy amorphous solids significantly enhance the solubility of poorly soluble drugs as compared to crystalline forms, resulting in a faster dissolution rate and subsequent oral absorption, which are linked to their metastable nature. In the dry state, the amorphous solid is typically more reactive than the crystalline form due to its higher thermodynamic activity. Furthermore, if exposed to humid conditions, amorphous solids become more hygroscopic, and the absorbed moisture works as a plasticizer, resulting in a substantial increase in molecular mobility. As a result, the chemical stability of an amorphous material is significantly lower than that of the crystalline phase when exposed to moisture. On the other hand, these metastable phases are susceptible to phase transformation during storage, which limits their application in pharmaceutical dosage forms. Although physical and chemical stability of amorphous phases is a major concern, if these high-energy forms can be stabilized to prevent crystallization over their intended storage life using excipients of conventional solid dosage formulation, these solids can be a useful tool for increasing API dissolution in biological fluids given bioavailability enhancement. For example, Yang [57] compared the bioavailability of amorphous and crystalline itraconazole nanoparticles administered via pulmonary. It was observed that amorphous nanoparticulate itraconazole had a rapid dissolution that produced a significantly higher systemic bioavailability than crystalline nanoparticles due to its supersaturation 4.7-times larger, which increased the drug permeation and will be thus beneficial for both local and systemic therapy.

Crystal engineering of co-crystals is another alternative formulation for improving drug attributes including solubility, dissolution, bioavailability, and physical stability of poorly soluble API. The modification of the physicochemical properties of the API and bulk material while maintaining the intrinsic activity of the drug molecule is enabled by co-crystallization during dosage form design [28, 58]. Several examples

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

of API co-crystals with pharmaceutically approved coformers can be found in the literature. Screening for obtaining the optimal solid form is critical in co-crystal development, given the risks and high development industrial costs, because not every co-crystal may significantly enhance the solubility and dissolution rate of the API. A typical example is the carbamazepine-nicotinamide co-crystal that spontaneously converts to carbamazepine dehydrate during dissolution, which has a lower solubility, and the theoretical solubility/dissolution improvement of the co-crystal cannot be obtained [59]. Similarly, co-crystals of efavirenz were developed using several coformers [60]. When compared to pure efavirenz, efavirenz-DL-alanine and efavirenz-oxalic acid co-crystals had higher solubility and enhanced dissolution profiles, while efavirenz-maleic acid and efavirenz-nicotinamide co-crystals had decreased dissolution.

The salt formation has been used to improve the bioavailability since the solubilities of salts are typically higher. Changing the counterions in a salt varies its solubility and dissolution rate, affecting bioavailability, pharmacokinetic profile, and potential toxicity. Also, the salt will impact the chemical stability. Different microenvironmental pH and different molecular patterns in a specific lattice are factors that contribute to the difference between salt and its unionized form or between different salts. Recently, multi-drug salts of norfloxacin have been obtained with diclofenac, diflunisal, and mefenamic acid, as well as norfloxacin salt hydrate with indomethacin. Among them, norfloxacin salts with diflunisal and indomethacin showed higher solubility and permeability and hence increased bioavailability [61].

### **6. Conclusion**

Understanding the characteristics of APIs in the solid state is critical in the field of pharmaceutical sciences since it is the basis for controlling the pharmaceutical performance of final formulations. In order to obtain solid pharmaceutical materials with improved properties, the crystal engineering strategy is used. Different crystallization processes are the experimental key to the solid form screening aiming to select the suitable physical form of a drug. As discussed above, the change in crystal form may not only affect the stability and mechanical attributes of the solid but, more importantly, may compromise the drug absorption through a change in solubility. In practice, is desirable that the drug's physical form does not change during its manufacture and storage life to prevent a significant impact on its quality and bioavailability. Therefore, the characterization of the API solid phases such as polymorphs, solvates, hydrates, salts, co-crystals, and amorphous forms is critical in the early stages of the solid form development as well as a tool for evaluating the influences of manufacturing processes and storage on phase transitions as important factors for product quality assurance.

#### **Conflict of interest**

The authors declare no conflict of interest.
