Pharmaceutical Crystals: Development, Optimization, Characterization and Biopharmaceutical Aspects

Abstract

In the solid state, the active pharmaceutical ingredients tend to exhibit crystalline order. In this regard, the interest in the crystalline solid state has expanded to include single-component compounds as well as multicomponent systems such as salts, hydrates, solvates, and co-crystals. The study of crystalline behavior is recognized as an essential component of preformulation research in pharmaceutical sciences and industries. The crystalline form can impact the drug properties such as solubility, dissolution rate, stability, hygroscopicity, and toxicity profile. Therefore, each solid form must be appropriately identified and characterized because it will affect the drug formulation, including the pharmacokinetic, pharmacodynamic, and safety properties of the formulation. In this context, this chapter will cover topics such as synthesis approaches (including nucleation and crystallization procedures), crystal polymorphism, solid state characterization techniques and the impact of crystals on physicochemical and biopharmaceutical properties.

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, 2, 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, 17, 18, 19, 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]. 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 = pKa_base - pKa_acid) 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]. 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].

Figure 1.

Methodologies for manufacturing solid pharmaceutical materials.

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.

4. Solid state characterization techniques

As previously mentioned, changes in the properties of solids can occur during pharmaceutical drug manufacturing and storage. Normally, drugs are manufactured in a stable crystalline form because the risk of solid state transformations during storage is minimized. However, when developing a solid crystalline form, a rigorous control must be made to determine if the crystalline form is maintained or if there were changes during its production [31].

Currently, there are a variety of techniques to characterize a crystal. Characterization techniques are valuable tools that make it possible to determine the structure, chemical composition, and different properties of a pharmaceutical sample. However, simply one technique will not be able to offer complete information for a solid substance. It is vital to utilize them in a complementary manner in order to acquire acceptable outcomes (Figure 2). The most important techniques used in the pharmaceutical field for crystal characterization are those described below.

Figure 2.

A) Powder X-ray diffraction patterns and B) Fourier-transform infrared spectra of a) furosemide form I, b) furosemide form II, c) oxytetracycline hydrochloride form I, d) oxytetracycline hydrochloride form II, and e) oxytetracycline hydrochloride form III.

4.1 Thermal analysis techniques

Thermal analytical methods, which offer information on the thermal behavior of materials, are widely utilized in the physical characterization of pharmaceutical solids. When a sample is exposed to a temperature increase, the observed changes in characteristics can be measured [32, 33]. The thermal methods most commonly applied in the analysis of pharmaceutical solids are differential scanning calorimetry and thermogravimetric analysis.

4.1.1 Differential scanning calorimetry (DSC)

This technique provides information about the physical and energetic properties of a substance subjected to temperature variations. To obtain a DSC thermogram, the difference in heat flux of a sample as a function of temperature or time is measured. Typically, this study is performed by comparing the thermogram of a sample of interest, such as a crystal, to that of a reference sample. The deviation in the thermogram below the reference corresponds to an endothermic transition, while the deviation above the reference relates to an exothermic transition [34]. The curve obtained can be used to determine enthalpies of crystal fusion, phase transition temperatures, purity, degree of crystallinity, type of interaction between molecules, and thermal stability [34, 35].

Numerous studies reported the most popular application of DSC in the field of pharmaceuticals. Their application in the characterization of polymorphic drugs such as albendazole and clarithromycin can be seen in Figure 3A. The representative DSC curve for albendazole form I exhibits a fusion endotherm, whereas the profile for form II shows a preceding endo-exothermic event that indicates its polymorphic transformation to form I, followed by an endotherm attributed to form I melting, and lastly an exotherm of decomposition. Similarly, the profile for clarithromycin form 0 exhibits an exotherm corresponding to a solid phase transition, followed by an endotherm assigned to the form II melting event due to its coincidence with the melting endotherm evidenced in the clarithromycin form II DSC curve.

Figure 3.

A) Differential scanning calorimetry curves of a) albendazole form I, b) albendazole form II, c) clarithromycin form II, d) clarithromycin form 0 and B) thermogravimetric curves of a) oxytetracycline hydrochloride form I, b) oxytetracycline hydrochloride form II, c) clarithromycin form 0, d) clarithromycin form II.

4.1.2 Thermal gravimetric analysis (TGA)

TGA measures the mass change of a sample as a function of temperature or heating time. It is a simple technique that requires a smaller sample size [36]. A thermogravimetric curve shows the mass change due to physical and chemical phenomena such as absorption, melting, sublimation, vaporization, oxidation, reduction, and decomposition events [32].

It is a useful tool to quantify different processes such as crystalline melting, sublimation, or decomposition of a sample, and to elucidate the degree of purity of the API [37]. On the other hand, it is possible to elucidate on the curves, whether the crystals under study contain water or a solvent [36]. Moreover, it allows the detection of solvent loss in a crystal. For instance, information on dehydration/desolvation events for clarithromycin and oxytetracycline hydrochloride polymorphs was obtained (Figure 3B), as demonstrated by a mass loss at low temperatures in the TGA profiles. When the TGA profiles of Clarithromycin form 0 and form II are compared, it is clear that form 0 is a solvate, as demonstrated by the weight loss caused by the ethanol evaporation process. On the other hand, TGA profiles of oxytetracycline hydrochloride form I showed a larger mass loss until 100°C than those of form II, indicating variations in solid dehydration. These TGA curves also revealed that form II had higher thermal stability.

4.2 X-ray diffraction

The technique most commonly utilized for identifying and characterizing crystalline materials is X-ray diffraction. Differentiating between crystalline and amorphous forms, identifying distinct solid forms of crystals, defining the crystalline structure of the API, and analyzing the differences between different crystal forms are some of its applications. As a result, it is commonly used in the pharmaceutical field [36]. For example, X-ray diffraction experiments have provided an unequivocal identification of furosemide and oxytetracycline hydrochloride polymorphs (Figure 2A), which exhibited clear differences in terms of reflection positions and relative intensity.

Single crystal X-ray diffraction is employed to determine the molecular structure of pharmaceutical materials that exist as single crystals [7, 38, 39]. A three-dimensional picture of the molecule and geometrical properties data in the solid state can be produced by studying a perfectly crystalline sample [40]. Powder X-ray diffraction is applied when the crystalline material is found as a fine-grained powder, rather than a single crystal [7, 38, 39, 41].

4.3 Vibrational spectroscopic techniques

Vibrational spectroscopic techniques are widely used in the pharmaceutical field to identify crystalline solids due are fast, non-destructive, and can characterize solid samples with minimal or no preparation. The most commonly used methods for analyzing crystalline samples are Fourier-transform infrared (FT-IR) and Raman spectroscopy [7, 31].

These techniques are extensively utilized in the study of pharmaceutical solids to characterize amorphous and crystalline phases, identify the structure and composition of different pharmaceutical solid forms, determine the compatibility of mixtures, and establish molecular interactions [42].

For instance, FT-IR spectroscopy has been used in several studies to identify the individual polymorphic forms of a drug confirming that they are structurally distinct. Differences in characteristic FT-IR bands assigned to sulphonamide NH and secondary amine NH stretches were identified between furosemide polymorphs (Figure 2B). In the same way, significant differences between oxytetracycline hydrochloride polymorphs were observed in the bands attributed to the OH and amide NH stretching vibrations (Figure 2B).

4.4 Solid state nuclear magnetic resonance (ssNMR)

ssNMR is a non-destructive and multinuclear technique that exploits the magnetic properties of certain nuclei, for example, ¹H, ¹³C, ¹⁵N, ¹⁷O, and ¹⁹F. Although it is a non-routinary expensive methodology that has extensive experimental times and robust expertise users are required, it is widely used in pharmaceutical applications [32].

This technique is used to analyze crystalline and amorphous pharmaceutical samples qualitatively and quantitatively, as well as to characterize both APIs and formulations. Structural or dynamic information is obtained from mono and bidimensional experiments based on different nuclear interactions. Their pharmaceutical applications included identification, characterization, and quantitation of different solid forms of an API in bulk samples; determination of conformational and crystalline packing behavior, intra- and intermolecular interactions, internuclear distances; study of amorphous phase properties, stability of API forms, the effects of drug processing, molecular motions, chemical and physical interactions between API-excipient and excipient-excipient, solid state chemical reactivity; and identification of contaminants or degradation products, among others [7, 43, 44].

4.5 Microscopy

Microscopy is considered a tool of great interest in the pharmaceutical field, which is mainly used to examine shape and size and to identify the solid state form in the sample. Different types of microscopes are currently used for the characterization of pharmaceutical crystals [32, 45]. The most relevant are described below.

4.5.1 Scanning electron microscopy (SEM)

SEM is a very useful and versatile tool in the pharmaceutical field. It provides quantitative as well as qualitative information such as morphology, size, size distribution, crystal shape, and consistency of powders or compressed dosage forms by analyzing the images obtained by microscopy. In addition, it allows studying the effects of any interaction with its environment [7, 45].

Microscopic analysis of pharmaceutical crystals using SEM microphotographs reveals significant morphological differences between solids produced using distinct crystallization techniques, allowing each polymorphic form of the drug to be identified. In Figure 4, for example, significant differences in particle size and shape can be observed. Albendazole form I appear as small and irregular particles with a predisposition to aggregate while in contrast albendazole form II exhibits self-agglomerate lamellar particles with a smooth surface. Furosemide form I presented hexagonal and tubular compact crystals with a defined surface while furosemide form II shows fine and elongated prism particles. On the other hand, a compact structure with small particles adhered to the surface is observed for norfloxacin form B_I, while the norfloxacin form C crystals are typical hexagonal-like faceted, compact, and with well-defined smooth structures. Finally, oxytetracycline hydrochloride form I have particles with a smooth surface and well-defined edges, form II crystals show compact particles with an irregular surface, form III presents rod-shaped crystals with a smooth surface with defined edges, while the form IV appeared as thin agglomerated needles.

Figure 4.

SEM images of the morphology of a) abendazole form I, b) albendazole form II, c) furosemide form I, d) furosemide form II, e) norfloxacin form B_I, f) norfloxacin form C, g) oxytetracycline hydrochloride form I, h) oxytetracycline hydrochloride form III, i) oxytetracycline hydrochloride form II, and j) oxytetracycline hydrochloride form IV.

4.5.2 Optical microscopy and polarized light microscopy

An optical microscope is used to observe crystals directly providing information on particle size and shape. In addition, the nucleation events can be visualized by monitoring within situ cameras [32].

The utilization of polarized light, on the other hand, optimizes the utility of optical microscopes. Using polarized light microscopy, the interior structure of crystals can be analyzed and determined if the sample is amorphous or crystalline. Due to birefringence, several colors can be seen in a crystalline particle when viewed through crossed polarizers [7, 32, 45].

For example, significant differences in particle size and shape of sulphathiazole precipitated from a variety of solvents and techniques between them and compared additionally with commercial sulphathiazole can be observed by an optical microscope. In addition, these different sulphathiazole crystal forms exhibit different birefringence under a polarized light microscope. Figure 5 shows images of commercial sulphathiazole (Figure 5a and b) and samples obtained by the crystallization of commercial sulphathiazole from methanol heating the solution below the boiling point to the total solution (Figure 5c and d), from aqueous solution heating below the boiling point to total solution and immediately cooled at freezer temperature (Figure 5e and f), and from the saturated aqueous solution obtained below 80°C that was exposed to a temperature ramp of 90 to 25°C for one hour and then kept at 25°C for 24 hours (Figure 5g and h), 1hour (Figure 5i and j) and 30 minutes (Figure 5k and l).

Figure 5.

a), c), e), g), i) and k) images obtained using an optical microscope. b), d), f), h), j) and l) images obtained using a polarized light microscope.

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.

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, 49, 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).

Solution	Furosemide (ug/mL)a	Norfloxacin (mg/mL)a	Albendazole (ug/mL)b	Oxytetracycline hydrochloride (mg/mL)b
Aqueous	Form I: 35.6; Form II: 27.4	Form A: 0.32; Form BI: 0.30; Form C: 0.29	Form I: 1.2; Form II: 2.8	Form I: 91; Form II: 6.8; Form III: 6.7
Simulated gastric fluid	Form I: 4.4; Form II: 6.1		Form I: 183; Form II: 320	Form I: 93; Form II: FS; Form III: FS
Simulated intestinal fluid			Form I: 3.3; Form II: 7.1	Form I: 76; Form II: 1.20; Form III: 0.91
Buffer pH 6.0		Form A: 0.39; Form BI:1.40; Form C: 2.61
Buffer pH 8.0		Form A: 0.18; Form BI: 0.60; Form C: 1.38

Table 1.

Influence of crystal form on drug solubility.

^a

Solubility at 25.0 ± 0.1°C.

^b

Solubility at 37.0 ± 0.1°C, FS: freely soluble.

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. 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 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.