Modification of Physicochemical Properties of Active Pharmaceutical Ingredient by Pharmaceutical Co-Crystals

Abstract

The oral drug delivery is widely used and accepted routes of administration, but it fails to provide the therapeutic effectiveness of drugs due to low solubility, poor compression and oral bioavailability. Crystal engineering is the branch where the modification of API is of great importance. Co-crystallization of API using a co-former is a hopeful and emerging approach to improve the performance of pharmaceuticals, such as micromeritic properties, solubility, dissolution profile, pharmacokinetics and stability. Pharmaceutical co-crystals are multicomponent systems in which one component is an active pharmaceutical ingredient and the others are pharmaceutically acceptable ingredients that are of GRAS category. In multidrug co-crystals one drug acts as API and other drug acts as coformer. This chapter illustrates the guidance for more efficient design and manufacture of pharmaceutical co-crystals with the desired physicochemical properties and applications.

1. Introduction

A drug compound is classified using the biopharmaceutical categorization system according to its permeability and solubility in water [1]. When making decisions on the discovery and early development of new drugs, the Biopharmaceutical Classification System is a helpful resource. By categorizing drug compounds into four classes backed by their solubility associated with dose and intestinal permeability in combination with the dissolution properties of the dosage form, it enables the prediction of in vivo pharmacokinetics of oral immediate-release (IR) medicinal products [2]. The US Food and Drug Administration (FDA) guidelines for the Biopharmaceutical Classification System (BCS) were made available to increase the effectiveness of the drug product development process [3]. The Biopharmaceutical Classification Technique is a system for categorizing medicines according to their permeability and solubility. The US Food and Drug Administration has supplied it as a forecasting tool for intestinal drug absorption.

Oral administration is the most suitable and commonly employed route of drug delivery thanks to its simple administration, patient acceptability, cost efficiency, least sterility maintenance, and flexibility in the design of a dosage form. However, the main disadvantage with the formulating of oral drug delivery system lies with their poor oral bioavailability. The oral bioavailability of drug substances lies on several parameters including water solubility, drug permeability across biological membrane, dissolution rate, pre-systemic metabolism [4].

It is a factor that the poor water solubility and dissolution profile of drugs in GI fluid often causes the poor bioavailability. The oral bioavailability of drugs may be improved by increasing the aqueous solubility and dissolution profile of the drug substance in the GI fluids. As far as considering the BCS Class II drugs, the rate-limiting step is the drug release from the formulation in GI fluid and not the absorption from biological membrane; therefore, increase in the solubility may increase the bioavailability of BCS Class II drugs [5, 6, 7, 8].

Only 1% of medication compounds entered the market in the pharmaceutical sector, and this is always due to inadequate biopharmaceutical qualities rather than toxicity or a lack of therapeutic efficacy [9, 10, 11, 12]. Solubility is one of these biopharmaceutical qualities that is a big problem, because of their weak solubility, medications are always useless during production that can be sold. Increasing the solubility of medication ingredients is currently one of the pharmaceutical company’s biggest concerns. Particle size reduction is one of the techniques that have been utilized to increase the water solubility of pharmaceuticals [5, 6]. Creating salt [7], emulsification [8, 9], co-solvent solubilizations [10], and employing polymers to transport medications that are not highly water soluble [11] are some examples. Even though it has been demonstrated that these techniques increase oral bioavailability, their effectiveness depends on the particular physicochemical characteristics of the medications under investigation [13, 14]. Pharmaceutical co-crystal formulation has been increasing interest over the past few years as a potential means of enhancing the bioavailability of medications with poor water solubility. Co-crystal and pharmaceutical co-crystal are two terms that must first be understood. There are several ways to define co-crystals [15]. Co-crystals are defined as structurally homogeneous/heterogeneous crystalline solids that include drug and coformer in specific stoichiometric proportions. The discrete neutral molecular reactants that make up co-crystals are solids at room temperature. According to this definition of co-crystals, a pharmaceutical co-crystal is a mixture in which one of the co-crystals’ elements serves as an active medicinal ingredient and the other elements serve as coformers. An active drug hydrate is not a co-crystal, as is evident from the statement, but a solid-state drug hydrate is co-crystalline with a coformer to produce a co-crystal. [16]. The pharmaceutical sector currently places a lot of attention on co-crystal methods. Pharmaceutical co-crystals can successfully enhance the drug substance’s solubility, dissolving profile, bioavailability and physical stability, in addition to other crucial features such as flowability, chemical stability, compressibility and hygroscopicity [17].

Because of the ability to tailor the physicochemical properties of the solid while preserving the chemical integrity of the medicine, co-crystals have sparked a great deal of interest in pharmaceutical research and development. Co-crystals are a subset of a larger category of multicomponent crystals, which are made up of two or more molecules that form a uniform crystalline lattice in a stoichiometric ratio that is clearly specified (often referred to as the drug and coformer). The drug and coformer are solid at higher temperatures than other types of multicomponent crystals like salt and solvates, and the intermolecular relationships in co-crystals are non-ionic in nature. Through co-crystallization, the variety of solid forms that can be produced from a medicine significantly expands; the physicochemical properties of co-crystals can change based on the properties of constituent molecules. Solubility, dissolution, moisture uptake, chemical stability, mechanical characteristics, and bioavailability are just a few of the pharmaceutically significant features that can change by co-crystallization. The most frequently praised property in literature is solubility [18]. The solubility restrictions of poorly soluble medicinal chemicals may be overcome through co-crystals (Figures 1 and 2).

Figure 1.

Formations of co-crystals [18].

Figure 2.

Crystalline forms exist in different forms: Amorphous form, polymorph of pure API, solvates/hydrate forms, salt form and pharmaceutical co-crystals [19].

1.1 Crystal engineering and supramolecular chemistry in co-crystals formation

Crystal engineering can be used to create pharmaceutical co-crystals with the goal of enhancing an API’s solid-state characteristics without changing its fundamental structure. A model for the quick development of medicinal co-crystals was created through crystal engineering. It can be described as an application of supramolecular chemistry concepts to solid states, with a focus on the notion that crystalline solids are real-world examples of self-assembly [20, 21] Co-crystals are created through intermolecular interactions such as hydrogen bonds, stacking interactions, and van der Waals contact forces. By changing the intermolecular interactions that regulate the breaking and formation of non-covalent bonds, such as hydrogen bonding, van der Waals force, stacking, electrostatic interactions, and halogen bonding, crystal engineering involves changing the crystal packing of a solid material [22, 23]. In the study of co-crystals, the term supramolecular synthon is widely employed. It is referred to as structural units inside supramolecular that can be created by known hypothetical synthetic procedures involving intermolecular interactions. This guarantees generality, which subsequently results in the predictability of one-, two- and three-dimensional patterns produced by intermolecular interactions. Supramolecular chemistry is nothing more than non-covalent molecular bonding that is recognized as a lock and key principle in biological processes through the concept of complementarity and selectivity. Carboxylic acids, amides, carbohydrates, alcohols and amino acids are good examples of pharmaceutically approved crystallizers that can be combined with APIs. Figure 3 depicts the most prevalent supramolecular synthon used in pharmaceutical co-crystals.

Figure 3.

Typical hydrogen bond utilized in crystal engineering [24].

The carboxylic acid functional group, which is present in many medications, has been extensively researched in the field of pharmaceutical co-crystals. The synthesis of carboxylic acid homosynthon through the C∙O⋯H∙O hydrogen bond is highly frequent when the hydrogen bond donor and acceptor are self-complementary [25]. A second popularly researched homosynthon is the amide homodimer, which forms co-crystals via the CO⋯H∙N hydrogen bond.

A part from homosynthons, some favourable heterosynthons are carboxylic acid-pyridine, carboxylic-amide and alcohol-ether. Recently, studies of hydrogen bonds competition have attracted increasing interest from a number of researchers [26, 27]. Heterosynthons are stronger than homosynthons; for example, the acid-amide heterosynthons favoured over both carboxylic acid and amide homodimer [28]. Through analysis of the Cambridge Structural Database (CSD) [29], it is discovered that the competitive hydroxyl-hydroxyl homosynthon is substantially favoured over the hydroxyl-pyridine and hydroxyl-cyano heterosynthons. One of the most popular heterosynthons, carboxylic acid-pyridine heterosynthons, contains an O∙H⋯N hydrogen bond, which is generated when the carboxylic acid reacts with a suitable N-containing heterocycle [30, 31]. In contrast to carboxylic acid homodimer, carboxylic acid-pyridine heterosynthons were preferred, according to the CSD study [32]. These empirical findings about the hierarchy of supramolecular synthons are very helpful for designing co-crystals. Reality, however, does not always support this. The structure of the indomethacin and saccharin (IND-SAC) co-crystals revealed that, contrary to the more advantageous indomethacin carboxylic acid saccharin imide heterosynthons predicted by empirical rules, the indomethacin carboxylic acid dimer interacts with the saccharin imide dimer synthon through a weak N∙H⋯O bond in Figure 4 [33].

Figure 4.

Indomethacin: Saccharine co-crystal structure [33].

1.2 Physicochemical properties of co-crystals

For the creation of APIs, co-crystals’ physicochemical characteristics are crucial. Adjusting the physicochemical parameters of pharmaceutical co-crystals during drug development improves the stability and efficacy of the dosage form [34]. Numerous studies have been conducted on physicochemical characteristics such as solubility, dissolution, crystallinity, melting point, bioavailability, and stability. The following list summarizes some important physicochemical characteristics of pharmaceutical co-crystals [35].

1.2.1 Melting point

The temperature at which the solid and liquid phases are in balance determines the melting point, which is a fundamental physical characteristic. The value is calculated using the ratio of the change in fusion enthalpy over the change in fusion entropy because melting point is a thermodynamic process where the free energy of transition is equal to zero [35]. Over a conventional melting point apparatus or the Kofler method, DSC is the preferred approach for getting precise melting point data because it allows for the determination of additional thermal data, such as the enthalpy of fusion [35]. It is a common practice to determine a compound’s melting point in order to characterize or identify its purity. However, in the field of pharmaceutical sciences, the melting point also has significant value because of its relationships with water solubility and vapour pressure [21]. Although it was necessary to make assumptions about the entropy of fusion, the melting point has actually been directly connected to the log of solubility [36]. In order to tune an API’s aqueous solubility towards a specific purpose, it would be highly helpful to know the melting point of that API before it was synthesized.

1.2.2 Stability

Stability has the great importance during the development of new chemical entity. For the evaluation parameters of pharmaceutical co-crystals, stability also plays an important role. A newly produced co-stability crystal is often tested under four conditions: relative humidity (RH) stress, temperature stress, chemical stability and solution stability. Because the amount of water in the co-crystals might cause quality degradation, the relative humidity stress is used to determine the ideal storage conditions for the product. During investigations involving the sorption and desorption of water, it was discovered that co-crystals performed better [37]. Thermal stress and chemical stability are relatively less studied areas about co-crystals properties. Very few reports were discovered, and the few research conducted demonstrated that thermal stress investigations can be a useful tool for learning more about physicochemical stability [38]. When creating these materials, it is critical to evaluate the co-crystals’ chemical stability. According to Schultheiss and Newman, solubility stability is the capacity of the co-crystals’ constituents to remain in solution and not rapidly crystallize. Solution stability is a crucial factor in the creation of new drugs. To understand how co-crystals behave in release media, stability tests are conducted in addition to solubility or dissolution experiments [39].

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 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 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).

Figure 5.

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

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. 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 single-component 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 co-crystals as the temperature decreases, co-crystals will form [53].

1.4.2 Grinding methods

There are two distinct methods for producing co-crystals through grinding [51, 54, 55]. The first technique, known as neat grinding or dry grinding, entails mixing the drug and coformer components together and then physically pounding them into powder using a mortar and pestle, a ball mill or a vibratory mill (mechanically). The second method for creating co-crystals through grinding involves adding small amounts of a suitable solvent. This method is known as liquid-assisted grinding, also known as solvent drop, or wet co-grinding. By adding small amounts of a suitable solvent, the kinetics of co-crystal formation by grinding can be significantly increased [56].

1.4.3 Hot melt extrusion

Extrusion is a helpful technique for producing co-crystals because it involves improved surface contacts and highly effective mixing without the need for solvent. The compound’s thermodynamic stability is the main factor that determines whether this method should be used. Four co-crystal formation models were used to study this method. Utilizing the solvent drop extrusion technique, the process was optimized and made more adaptable. The benefit of using the solvent drop extrusion technique is the ability to run the process at a lower temperature. The synthesis of carbamazepine-nicotinamide co-crystals with polymer as former was done using the hot melt extrusion method. Co-former, API and continuous co-crystallization were poured into the twin extruder. The temperature of the barrel also rises as a result of the mixture being added continuously [57].

1.4.4 Sonocrystallization method

Organic co-crystals of finite size have been prepared using a sonochemical technique that has been developed. The creation of nanocrystals was the primary motivation behind this technique. The preparation of caffeine-maleic acid co-crystals began with the application of the ultrasound technique. The comparison of the sonochemical method and the solvent drop grinding method for producing caffeine, theophylline, and L-tartaric acid as API and co-formers has begun. The methods produced consistent results, demonstrating the importance of the sonocrystallization method [58].

1.4.5 Supercritical fluid atomization technique

In the supercritical atomization process, CO2, a highly pressurized supercritical fluid, is used to combine the drug and coformers. By atomizing this solution with an atomizer, co-crystals are created. Co-crystals are prepared from solution using the supercritical antisolvent (SAS) method, which utilizes the antisolvent effect of supercritical fluid [59].

1.4.6 Spray drying technique

Co-crystals are made by spray drying, which involves evaporating the solvent from a solution or suspension of the drug and the coformer. This technology is the most popular because it uses a quick, continuous, and one-step process. As a result, the spray drying process will present a distinctive setting for the creation and expansion of co-crystals [60, 61].

1.5 Characterization and evaluation of co-crystals

Co-crystal characterization is an important constituent part within co-crystal research. The basic physicochemical properties of co-crystals can usually be characterized using scanning electron microscopy, Fourier transform infrared spectroscopy, differential scanning calorimetry, powder X-ray diffraction, Raman spectroscopy, solid-state nuclear magnetic resonance spectroscopy and terahertz spectroscopy.

1.5.1 Scanning calorimetry (DSC)

In this characterization method, two specimens—one serving as a sample and the other as a reference—are each subjected to the same temperature as well as a controlled-rate environment of heating or cooling. Plotting the amount of energy required to achieve a temperature difference between the two specimens that is zero leads to illuminating conclusions. Two different types of DSC are employed frequently. First up is the power compensation DSC, which keeps the two samples in various identical furnaces. By adjusting the power input, the temperature of both is brought to the same level. As a result, the energy is translated into enthalpy or heat capacity. Another type of DSC involves keeping both sample holders in the same furnace and connecting them via a low-resistance heat flow path. The remainder of the interpretation is unchanged. The most widely used technique for the thermal analysis of co-crystals is differential scanning calorimetry. Differential scanning calorimetry is an ideal technique for obtaining complete melting point data and additional thermal records, such as enthalpy of melting, can also be concurrently obtained. Addition to the characterization technique, DSC has presently been used as a selection tool for rapid co-crystal screening [62, 63].

1.5.2 XRD

Phase identification is used in this analytical technique to provide information on unit cell dimension. The crystalline sample and monochromatic X-ray are constructively diffracted to produce this. The cathode ray tube used to create the monochromatic ray filters and collimates the radiation to create monochromatic radiation, which is then directed at the sample. In the sample preparation scenario, the sample is finely ground to create a homogeneous sample and to analyse the average bulk composition. D-spacing analysis is performed on the sample. A set of d-spacing is produced as the sample is positioned in a random orientation. The sample is therefore examined because each mineral has a unique set of d-spacing. The sample must adhere to Bragg’s law, which links the electromagnetic radiation’s wavelength to the diffraction angle 2 (nλ = 2d sin θ), in order for any of this to occur. Co-crystals’ solid-state structure can be determined at the atomic level using a characterization method called XRD. The issue is that it is not always possible to produce a single pharmaceutical co-crystal that is suitable for SXRD testing. PXRD is therefore used more often to confirm the formation of co-crystals [64].

1.5.3 Vibrational spectroscopy (IR and Raman)

For determining organic structure, electromagnetic radiation with frequencies between 4000 and 400 cm⁻¹ has been one of the most powerful tools. This electromagnetic radiation is known as infrared (IR) radiation and IR spectroscopy for its use in organic chemistry. The interatomic bonds absorb the bombarded radiation. A particular chemical bond will therefore absorb various radiations at various frequencies in various environments. Thus, inferring some conclusions about the structure from their absorption data, which is provided as a spectrum, is helpful [64].

1.5.4 Scanning electron microscopy (SEM)

SEM is a kind of electron microscope that uses a raster scan model to scan an object with a high-energy electron beam to image it. The sample’s surface morphology can be learned from the signals produced by the interaction of the electrons with the atoms that make up the sample. Finding the co-crystals photomicrograph and particle size is helpful [65].

1.5.5 Saturation solubility study

In accordance with the procedure described by Higuchi and Connors, saturation solubility studies were carried out in triplicate in distilled water. To reach equilibrium, excess co-crystals were added to distilled water in a screw cap tube and shaken for 24 hours at room temperature in a rotary flask shaker. An appropriate aliquot was taken out, filtered through filter paper and then analysed with a spectrophotometer. Statistics were used to validate the data from saturation solubility studies [66, 67].

1.5.6 Micromeritic properties

1.5.6.1 Bulk density (D_b)

It is the proportion of the powder’s total mass to its bulk volume. The weight of the powder was measured by pouring it into a measuring cylinder, and the volume was recorded. It is calculated using a formula and expressed in gm/ml.

$$D_b=M/V_0.$$E1

where M is the mass of powder, and V₀ is the Bulk volume of the powder.

1.5.6.2 Tapped density (D_t)

It is the proportion of the powder’s total mass to its tapped volume. By tapping the powder to a fixed volume, the tapped volume was calculated. It is calculated using a formula and expressed in gm/ml,

$$D_b=M/V_t.$$E2

1.5.6.3 Angle of repose

The angle of repose depicts a solid’s ability to flow. It is a quality that has to do with how difficult it is for particles to move around one another. The surface of the powder or granule pile can only be angled away from the horizontal plane at this maximum angle.

$$tan\theta =h/r.$$E3

$$\theta =ta{n}^{-1}h/r.$$E4

where $\theta$= angle of repose, h = height of heap, r = radius of base of heap circle.

Method: The fix funnel method was used to calculate the angle of repose. A funnel was positioned 2–4 cm above the platform. The sample powder was gradually pushed through the funnel until the tip of the cone of sample powder that was created barely touched the stem. The height of the sample powder cone and the radius of the powder heap’s circular base were then measured in order to estimate the angle of repose.

1.5.6.4 Compressibility index and Hausner’s ratio

Compressibility index and the closely related Hausner’s ratio have recently emerged as the most straightforward, quick and well-liked techniques for forecasting powder flow characteristics. Because all of these factors can affect the compressibility value, the compressibility index has been projected as an indirect evaluation of size and shape, surface area, bulk density, moisture content and cohesiveness of materials. By measuring the bulk density and the tapped density of crystals, the compressibility index and Hausner’s ratio are estimated [68].

$$\begin{array}{l}CompressibilityIndex=Tappeddensity–Bulkdensity/Tappeddensity\\ \times 100.Hausne{r}^{’}sratio=Tappeddensity/Bulkdensity.\end{array}$$

1.5.7 Tabletability

The crystal packing, tabletability and compaction, which are crucial factors during preformulation research, can be impacted by the co-crystallization of the drug and coformer. Co-crystals of paracetamol with trimethylglycine and oxalic acid were found to have better compaction behaviour than pure drug [38]. The formation of co-crystals with 4-aminobenzamide and isoniazid improved resveratrol’s tabletability. Comparing co-crystals to conformers or pure drugs, tabletability of co-crystals was higher [24]. Co-crystallization allowed for the modification of the mechanical properties of APIs, and it demonstrated higher tabletability for vanillin isomer co-crystals than for isomers and conformer [29].

1.5.8 Dissolution studies

The dissolution study is a crucial tool for figuring out the drug’s bioavailability. The dissolution test is used to determine whether an API is soluble. Dissolution studies are used to calculate the rate of drug release over time in the dissolution medium and forecast how well the formulation will work in vivo. The dissolution apparatus can be used to conduct dissolution studies for co-crystals. The appropriate dissolution medium is described in the drug protocol of the referred pharmacopoeia, and it can be used to conduct the dissolution studies for the co-crystals. The drug samples can be gathered in the right amount at the right time and can be examined using the right tools, like HPLC or UV [69, 70].

1.5.9 Stability

Stability study is extremely important during the development of new dosage formulation. During the development of pharmaceutical co-crystals, several stability studies should be performed such as relative humidity stress, chemical stability, thermal stability, solution stability and photostability study. In relative humidity stress, automated water sorption/desorption studies are performed to determine the effect of water on the formulation. Several researchers studied the behaviour of co-crystals under relative humidity stress conditions [71, 72, 73].

1.6 Case study of multicomponent co-crystals and drug-drug co-crystals

Fael H et al. have prepared co-crystal of norfloxacin-based solvent-mediated transformation experiment in toluene, using resorcinol as a coformer. Norfloxacin has a solubility of 0.32 ± 0.02 mg/mL, whereas the co-crystal has a solubility of 2.64 ± 0.39 mg/mL, approximately 10-fold higher [74]. Machado Cruz et al. develop a new co-crystal of the poorly water-soluble antifungal agent itraconazole. The co-crystal is stable in aqueous solution, and comparison with previously described itraconazole co-crystals revealed a relationship between the coformer’s solubility and the intrinsic and powder dissolution rates. Analyses of the physical co-crystal and common excipient mixtures’ dissolution behaviour were also conducted [75].

Nugrahani et al. prepared the mono- and tetrahydrate of the salt co-crystal diclofenac sodium-l-proline. Single-crystal X-ray analysis was used to characterize the hydrates, which were found to have higher solubilities and dissolution rates than the sodium salt of diclofenac acid and the anhydrous diclofenac acid-l-proline co-crystal. The salt co-crystal dissociated into a physical mixture of diclofenac acid and L-proline as a result of the release of water during drying. It is interesting that this process can be reversed. Diclofenac sodium-L-proline tetrahydrate was restored when the dried sample was maintained at 72% relative humidity and 25°C [76].

Kale et al. studied co-crystallization on the tabletability of rivaroxaban and found an improved tabletability for rivaroxaban-malonic acid. The crystal packing, specifically the presence or absence of slip planes, slip plan topology, the degree of intermolecular interactions and d-spacing, could be used to explain the tabletability of alonic acid and rivaroxaban combined with malonic acid. Slip planes with zigzag and flat-layered topologies are both present in rivaroxaban. This study’s findings on the relationships between crystal structure and mechanical properties shed light on the deformation of crystals with multiple slip-plane systems [77].

Jiaxin PI et al. prepared baicalein (BE) is one of the main active flavonoids representing the variety of pharmacological effects including anticancer, anti-inflammatory and cardiovascular protective activities, but it is very low solubility, dissolution rate and poor oral absorption limit the therapeutic applications. In this study, a nano-co-crystal approach was successfully used to increase the bioavailability and dissolution rate of BE. High-pressure homogenization was used to create baicalein-nicotinamide (BE-NCT) nano-co-crystals, which were then tested both in vitro and in vivo. BE-NCT has formed the new solid phase as co-crystals, as shown by physical characterization results from scanning electron microscopy, dynamic light scattering, powder X-ray diffraction and differential scanning calorimetry [78]. Latif et al. synthesized paracetamol co-crystals to improve compaction or tabletability of paracetamol. The author created a co-crystal of paracetamol using caffeine as a conformer using techniques such as dry grinding, liquid-assisted grinding, solvent evaporation and anti-solvent addition. He then observed that the paracetamol’s mechanical properties and compaction power have increased [79]. Iyan et al. developed simvastatin-nicotinamide co-crystals by solvent evaporation to improve the solubility of simvastatin by co-crystallization using nicotinamide as co-crystal agent or co-former and evaluated for solubility. When compared to raw simvastatin, saturated solubility of the co-crystal increased threefold, according to the observation [80]. Shubhangi et al. synthesized co-crystals of poorly water-soluble drug darunavir. It is a BCS Class II medication with a poor solubility. Succinic acid was used as a conformer during the cooling crystallization process that produced co crystals. By dissolving an excess amount of co-crystals in water for 24 hours on a rotary shaker and measuring the saturation solubility with a spectrophotometer, the author was able to determine the aqueous solubility of darunavir. This technique resulted in 1.92-fold increases in saturation solubility [81]. Prabhakar et al. also prepared co-crystal of piroxicam and studied for solubility. Author used various conformers such as adipic acid, benzoic acid, cinnamic acid, citric acid, glutaric acid, phydroxybenzoic acid, hippuric acid, malonic acid, resorcinol, 6 saccharine sodium, 1-hydroxy-2-napthoic acid, sodium acetate, urea, catechol, ferulic acid, aerosil-200, nicotinamide, para amino benzoic acid, anthranilic acid and succinic acid for synthesis of co-crystals and performed saturated aqueous solubility of co-crystal and found significant increase in solubility of drug after formulating as co-crystals [82]. Zheng et al. synthesized co-crystals of resveratrol with conformers 4 aminobenzamide and isoniazid and studied its enhanced solubility and tabletability. Author observed that tabletability of RES is poor and because of this even at high pressure that is 0.6 MPa and lamination of tablets, while tablets are prepared with co-crystals of resveratrol-4-aminobenzamide, and tensile strength more than 3 MPa is attained at 250 MPa compaction pressure. Author concluded that co-crystal formation improved tabletability of drug. Co-crystals of paracetamol with trimethylglycine and oxalic acid were found to have better compaction behaviour than the drug alone. The formation of co-crystals with 4-aminobenzamide and isoniazid improved resveratrol’s tabletability. The tabletability of co-crystals was higher than that of coformers or pure drugs. Co-crystallization allowed for the alteration of the mechanical properties of APIs, and co-crystals of the vanillin isomers with the same coformer demonstrated greater tabletability than the isomers and conformer [65]. Muddukrishna et al. studied synthesis of paclitaxel and naringen co-crystal to improve solubility by solvent-assisted grinding method. The drug paclitaxel (PTX), which belongs to class IV, has a low solubility in water. Shake flask method was used to study the solubility of paclitaxel and naringen co-crystal for 72 hours at room temperature. HPLC analysis of the samples revealed 2.4-fold increases in the saturation solubility [83]. Pinky et al. formulated co-crystal tablet dosage form of clarithromycin to enhance the bioavailability. As clarithromycin is BCS Class II drug author prepared co-crystals by using urea as conformer by solvent evaporation method, and developed tablet formulation and evaluated for solubility, dissolution and bioavailability studies. Author concluded that the formulated tablets of clarithromycin co-crystals showed improved solubility and in vitro drug release profile as compared to Marketed Tablet, and thereby increase oral bioavailability and therapeutic effect [84]. Mounika et al. prepared co-crystals of fexofenadine. According to the BCS classification, fexofenadine belongs to the class II of drugs because of its high permeability and low solubility, which acts as rate-limiting factors in achieving the desired bioavailability. Therefore, by evaporating solvent, the author created co-crystals of fexofenadine using tartaric acid as a co-former, and they found that 7 of them had a higher drug release than the formulation [85]. Carmen Almansa et al. identified co-crystal of tramadol hydrochloride-celecoxib, a brand-new active pharmaceutical ingredient (API)-API co-crystal with favourable physicochemical and dissolution properties that result from the intrinsic 1:1 molecular ratio of rac-tramadol HCl and celecoxib. A medical need that is frequently met by combination therapy is the adequate treatment of pain. In comparison with individual APIs or their combination, API-API co-crystals represent a new strategy that has the potential to enhance physicochemical properties, bioavailability, stability or formulation capacity. This could result in improved pharmacokinetic profiles and clinical benefits. The single-crystal X-ray diffraction structure of ctc revealed a supramolecular 3D network in which the two active enantiomers of tramadol and celecoxib are connected by hydrogen bonds and chloride ions. Ctc also displayed a clearly defined differential scanning calorimetry profile. The saturation effect for highly insoluble celecoxib occurred at a higher concentration in ctc than in celecoxib alone, according to oversaturation studies. Celecoxib and tramadol were released from ctc more quickly and more slowly than they were from the individual APIs, respectively, according to comparative intrinsic dissolution rate studies, which suggested that ctc would have better pharmacokinetic behaviour. These data support the clinical development of ctc for the treatment of pain along with those from preclinical studies [86]. Shivarani Eesam et al. prepared drug-drug co-crystal of carvedilol with hydrochlorothiazide: A significant challenge in the discovery and development of new drugs is increasing the hydrophilicity of poorly water-soluble drugs. One method for improving the hydrophilicity of such drugs is co-crystallization. Carvedilol (CAR), a non-selective beta/alpha1 blocker with poor aqueous solubility and high permeability, is categorized as BCS class II and is used to treat mild-to-moderate congestive heart failure and hypertension. The goal of this work is to increase the solubility of CAR by creating co-crystals using the diuretic hydrochlorothiazide (HCT) as a coformer. Slurry conversion was used to create CAR-HCT (2: 0.5) co-crystals, which were then analysed using DSC, PXRD, FTIR Raman and SEM. The co-crystals were the subject of solubility, stability and dissolution (in vitro) studies [87]. Kang Zheng et al. presented study reports on the MNZ-PYR co-crystal, a new co-crystal of the antimicrobial drug metronidazole (MNZ) that uses pyrogallol (PYR) as a co-crystal former. Utilizing single-crystal X-ray diffraction, infrared spectroscopy, thermal analysis and density functional theory calculations, the crystal structure of the MNZ-PYR co-crystal is investigated. Due to the high-energy conformer of PYR in the co-crystal’s crystal lattice, the MNZ-PYR co-crystal exhibits a higher dissolution rate than MNZ. The colour of the MNZ-PYR co-crystal changes from white (raw MNZ and PYR) to yellow as it forms, and this theoretical interpretation is based on calculations using time-dependent density functional theory. UV-vis spectroscopy is used to characterize this colour change. The findings point to the potential use of the co-crystal strategy for API colour tuning, providing opportunities for formulation development [88]. Braham Dutt et al. create aspirin (AN) and benzoic acid (BZ) co-crystal by using the solvent evaporation technique. CSD (Cambridge Structure Database) software and ΔpKa value method were used for the choice of the drug and coformer and for prediction of CC formation. Differential scanning calorimetry, Fourier transformation infrared spectroscopy and X-ray diffraction methods were used for the analysis of CCs. A total of 24 Wistar rats divided into four groups participated in in vivo anti-inflammatory studies [89]. Bwalya A. Witika et al. prepared co-crystal of zidovudine (AZT) and lamivudine (3TC) that are antiviral agents used orally to manage HIV/AIDS infection. The development and production of 3TC and AZT nanocrystals were carried out using a pseudo one-solvent bottom-up methodology. Rapid injections of AZT in methanol and 3TC in de-ionized water were combined with sonication at 4°C in a vessel that had been pre-cooled. A Zetasizer was used to characterize the resulting suspensions. The Zeta potential, polydispersity index and particle size were clarified. Powder X-ray diffraction, Raman spectroscopy, Fourier transform infrared spectroscopy, differential scanning calorimetry and scanning electron microscopy were all used for further characterization. The stability of the nano co-crystals and the production of nano co-crystals with particular and desirable critical quality attributes (CQA), such as particle size (PS) < 1000 nm, polydispersity index (PDI) < 0.500 and Zeta potential (ZP) < −30 mV, were evaluated for various surfactants. In the nanometer range, co-crystals were produced by all surfactants. When sodium dodecyl sulphate was used in the process, only ZP was within specification, whereas the PDI and PS are concentration-dependent for all nano co-crystals produced [90]. Dnyaneshwar P. Kale et al. presented purpose of this work is to comprehend the crystallographic underpinnings of the mechanical behaviour of rivaroxaban-malonic acid co-crystal (RIV-MAL Co) in comparison with its parent constituents, rivaroxaban (RIV) and malonic acid (MAL). By performing “out of die” bulk compaction and nanoindentation, the mechanical behaviour was assessed at both the bulk and particle levels. MAL < RIV < RIV-MAL Co was the order of tabletability for the three solids. Despite having a reasonably strong bonding strength, MAL demonstrated “lower” tabletability due to its lower plasticity (BS). This behaviour was influenced by the absence of a slip plane and “intermediate” BS. The different surface topologies of the slip planes were primarily blamed for RIV’s “intermediate” tabletability. While the corrugated topology of secondary slip planes (1, 0, 2) may adversely affect the plasticity, the presence of a primary slip plane (0, 1, 1) with flat-layered topology may favour the plastic deformation of RIV. Additionally, RIV crystal’s tabletability was aided by its higher elastic recovery. RIV-MAL Co′s significantly “higher” tabletability compared to the other two molecular solids was caused by its greater plasticity and BS. The higher degree of intermolecular interactions, the larger separation between adjacent crystallographic layers and flat-layered topology slip across the (0, 0, 1) plane all helped RIV-MAL Co. exhibit better mechanical behaviour. It is interesting to note that the relationship between a particle level deformation parameter and a bulk-level deformation parameter, H/E (i.e. the ratio of mechanical hardness H to elastic modulus E), was found to be inverse (i.e. tensile strength at zero porosity). The co-crystal crystallographic properties of materials were highlighted in this study as having a positive impact on tabletability [91]. Ilma Nugrahani et al. prepared zwitterionic co-crystal of L-proline and diclofenac acid. This multicomponent crystal’s solubility, though, was still inferior to that of diclofenac sodium salt. In order to determine whether a multicomponent crystal of diclofenac sodium hydrate could be produced using the same coformer, L-proline, which was anticipated to enhance the pharmaceutics performance, screening, solid phase characterization, structure elucidation, stability and in vitro pharmaceutical performance tests were among the methods used. In order to determine the molar ratio of the multicomponent crystal formation, a phase diagram screen was first performed. The single crystals were then created by slowly evaporating the material under two different conditions, yielding two different forms: one was shaped like a rod, and the other was like a flat square. The formation of the new phases was confirmed by the characterization using infrared spectroscopy, thermal analysis and diffractometry. The new salt co-crystals were finally solved structurally as stable diclofenac-sodium-proline-water (1:1:1:4) and unstable diclofenac-sodium-proline-water (1:1:1:1), known as NDPT (natrium diclofenac proline tetrahydrate) and NDPM, respectively (natrium, diclofenac, proline monohydrate). These multicomponent crystals had better solubility and dissolution rates than diclofenac sodium by itself. According to the experimental findings, this salt co-crystal can be developed further [92]. Xavier Bull et al. identified and prepared 13 co-crystals of nefiracetam, a poor water-soluble nootropic compound. The co-crystallization agents citric acid, oxalic acid and zinc chloride were used to produce three of them. The stability, solubility and rate of dissolution of the latter have all undergone thorough structural and physical characterization, and they have been compared to the original Active Pharmaceutical Ingredient (API) [93]. Prafulla P. Apshingekar et al. prepared co-crystal by ultrasound, which is known to affect crystallization; consequently, using a slurry co-crystallization method, the impact of high-power ultrasound on the ternary phase diagram has been thoroughly investigated. To comprehend how the accelerated circumstances during ultrasound-assisted co-crystallization will impact various areas of the ternary phase diagram, a thorough investigation was conducted. The ternary phase diagram was significantly affected by the use of ultrasound, especially in the regions where the co-crystals of caffeine and maleic acid were 2:1 and 1:1 (which narrowed). Additionally, the solution region was expanded in the presence of ultrasound, while the stability regions for pure caffeine and maleic acid in water were contracted. Maleic acid and caffeine solubility as well as the stability of co-crystal forms in water were found to be related to the observed effect of ultrasound on the phase diagram [94]. Dwi Setyawan et al. analysed the physicochemical characteristics and in vitro dissolution profile of co-crystals of quercetin and malonic acid made by solvent-drop grinding. Using the solvent-drop grinding method and 20% (w/v) ethanol addition, quercetin (Q) and malonic acid (MA) were co-crystallized in the molar ratios of 1:1 (CC1) and 1:2 (CC2) in a shaker mill that was run for 30 minutes. Differential scanning calorimetry (DSC), powder X-ray diffractometry (PXRD), scanning electron microscopy (SEM) and Fourier transform infrared (FT-IR) spectroscopy were used to identify the co-crystal phase. The paddle method was used to perform in vitro dissolution at 100 revolutions per minute in a medium of citrate buffer (pH 5.0 ± 0.05) containing 2.0% (w/v) sodium lauryl sulphate at 37 ± 0.5°C [95]. Agnes Nuniek Winantari et al. prepare and characterize co-crystals of acyclovir through co-crystallization of acyclovir-succinic acid (AS) for the purpose of enhancing the drug’s physical properties. Using the solvent evaporation method, AS co-crystals were created. By using the polarization microscope, scanning electron microscopy (SEM), differential scanning calorimetry, powder X-ray diffraction (PXRD) and Fourier transform infrared spectroscopy, the co-crystals were characterized [96]. Jose Lopez-Cedrun et al. prepared co-crystal of tramadol–celecoxib (CTC), containing equimolar quantities of the active pharmaceutical ingredients (APIs) tramadol and celecoxib (100 mg CTC = 44 mg rac–tramadol hydrochloride and 56 mg celecoxib), which is a novel API-API co-crystal for the treatment of pain. In order to effectively treat acute pain following oral surgery, we sought to determine the CTC dosage. Nine Spanish hospitals participated in a phase II dose-finding, double-blind, randomized, placebo- and active-controlled study (EudraCT number: 2011-002778-21) on male and female patients under the age of ≥18 who were experiencing moderate-to-severe pain after having two or more impacted third molars that required bone removal extracted. A computer-generated list was used to randomly assign eligible patients to receive one of six single-dose treatments (CTC 50, 100, 150, 200 mg; tramadol 100 mg; and placebo). The sum of pain intensity difference (SPID) over 8 hours as measured in the per-protocol population was the main efficacy endpoint [97]. Muhammad Inam et al. designed two new co-crystals, nicotinamide and ticagrelor, have been prepared with improved solubility. An innovative co-crystallization technique has been developed to increase ticagrelor’s solubility because it has a low solubility and a high rate of dissolution. This technique uses a structurally homogenous crystalline material, an active pharmaceutical ingredient (API) and co-former indefinite stoichiometric amount. A 1:1 co-crystal of ticagrelor (TICA) and nicotinamide (NCA) was created and characterized using FTIR, DSC and XRD. TICA-NCA hydrate’s single-crystal structure was also examined. When compared to the solubility of a free drug, the solubility of co-crystals was investigated in pH 2 acidic medium, which was a significant improvement. Co-crystal had a higher in vitro dissolution rate than the commercial product [98]. Heinrich Buschmann et al. invented co-crystals of duloxetine and co-crystal formers selected from active agents preferably with analgesic activity, processes for preparation of the same and their uses as medicaments or in pharmaceutical formulations, more particularly for the treatment of pain [99]. Carlos Ramon Plata Salaman et al. invented a co-crystal of celecoxib and venlafaxine, methods for making it and its use as medications or in pharmaceutical formulations, more particularly for the treatment of pain, including chronic pain, or of depression in patients who suffer from chronic pain and/or chronic inflammation, or in patients with a chronic musculoskeletal inflammatory illness, with the inflammatory illness preferably being chosen from osteoarthritis or rheumatoid arthritis [100]. Prabhakar Panzade et al. prepared, formulated and evaluated the co-crystal of piroxicam by testing various coformers. Piroxicam co-crystals were created using the dry grinding method. The crystalline phase’s melting point and solubility were established. DSC, IR and XRPD were used to characterize the potential co-crystal. Evaluations were also conducted on solubility and dissolution rate, two additional pharmaceutical properties. Piroxicam co-crystal orodispersible tablets were created, improved upon and tested using a 3² factorial design [101]. Mirela Nicolo et al. prepared co-crystal of betulinic acid and ascorbic acid. It has been shown that betulinic acid (BA) is a very effective anticancer agent against a variety of tumour cell lines, including those from the breast, colon, lung and brain. Betulinic acid has a strong cytotoxic effect but has a low water solubility, which is reflected in its low bioavailability. Co-crystallization emerged as a promising strategy among the many tactics used to enhance its physicochemical and pharmacokinetic profile in order to address these drawbacks. Thus, the goal of our research was to create BA and ascorbic acid co-crystals (BA+VitC) in isopropyl alcohol using a hydrothermal process. SEM, DSC, XRPD and FT-IR spectroscopy were used to characterize the newly formed co-crystals, showing that BA+VitC co-crystals were formed, and their antioxidant activity showed an additive antioxidant effect. BA+VitC co-crystals were tested on a variety of cell lines, including HeLa (cervical cancer), MCF7 and MDA-MB-231 (human breast cancer), B164A5 and B16F0 (murine melanoma), and immortalized human keratinocytes (HaCat). Results of BA on the examined tumour cell lines after co-crystallization with vitamin C showed a superior cytotoxic effect while maintaining a good selectivity index, most likely as a result of an improved BA water solubility and consequently an optimized bioavailability [102]. Abdolati Ali Mohamed Alwati et al. developed a new method for co-crystal preparation, which adhered to green chemistry principles, and provided advantages over conventional methods. It was decided that the best technology to achieve these goals was a brand-new, solvent-free, high-power ultrasound (US) technique for creating co-crystals from binary systems. Ibuprofen nicotinamide (IBU-NIC), carbamazepine-nicotinamide (CBZNIC) and carbamazepine-saccharin (CBZ-SAC) co-crystals were investigated for the use of this technology for solid-state co-crystal preparation [103].

1.7 Applications of co-crystals

1.7.1 Permeability enhancement

Drug absorption and distribution of drugs mainly depend upon the permeability of drugs across the biological membrane. The permeability of the drug is generally expected to depend upon hydrophobic interactions on the crystal surface that may interact with nonpolar cell membranes during diffusion, hydrophobic (π⋯π/H⋯π) and hydrophilic (N/O⋯H) interactions may play an improving role in the permeability. Co-crystals improve the penetration of drugs inside the biological membrane by changing their crystalline structure [104]. Hydrochlorothiazide is a diuretic and BCS class IV drug with low solubility and low permeability, exhibiting poor oral absorption solubility and permeability [68].

Another example, 5-fluorouracil (5FU) a BCS class III drug with good solubility and poor permeability was subjected to co-crystallization with the use of coformers such as 3-hydroxybenzoic acid, 4-aminobenzoic acid and cinnamic acid. 5FU has dense packing in the crystal lattice, which may cause its poor permeability. The 5FU have disrupted and loose molecular packing during the co-crystallization process. When 5FU is co-crystallized with carboxylic acid, the hydrogen bonding sites of two components would adjust to achieve a balance, whereas new drug-coformer heterosynthons and packing generated. This modification may change 5FU’s activity and subsequently improve its permeability when across a membrane [105].

1.7.2 Stability enhancement

Stability study is very important in case of development of new dosage formulation. Stability studies of pharmaceutical co-crystals have several studies such as relative humidity stress, chemical stability, thermal stability, solution stability and photostability study. Lithium drugs have a narrow therapeutic window and are hygroscopic. Lithium co-crystals exhibit modulated pharmacokinetics compared to lithium. The co-crystals of lithium chloride (LIC) and glucose (GLU) were prepared by slow evaporation method and the physical stability of LIC-GLU was compared to lithium chloride at 50% RH and 25°C and through dynamic vapour sorption analysis. LIC-GLU co-crystals improve the physical stability of the solid form of a drug substance with respect to humidity without impacting its pharmacokinetic performance [106]. In adefovir dipivoxil-saccharin co-crystals showed thermodynamic stability at temperatures 40°C and 60°C. The change in the appearance of the samples was also visually examined. The adefovir dipivoxil started to clump together and form a cake-like structure at the first sampling time point at 60°C, whereas adefovir dipivoxil-saccharin co-crystals remained in a powder state [106]. The theophylline-oxalic acid and theophylline-caffeine co-crystals were subjected to relative humidity to check their stability in relation to crystalline theophylline anhydrate. None of the co-crystals in this study converted into a hydrated co-crystal upon storage at high relative humidity (up to 98%). Co-crystals avoid hydrate formation and improvement in the physical stability of the product [107]. Polymorphic changes can also be prevented by using the co-crystallization technique. 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 [108].

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 co-crystal structure is the second way for enhancing solubility in co-crystals. Because hydrophobic BCS Class II drugs are frequently solubility-limited by reduced solvent-solute 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 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 0.1 N 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]. Meloxicam-aspirin 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, 119, 120, 121, 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].

1.7.7 Mechanical properties enhancement (Tablatability)

Because of its numerous technical and economic advantages, tablets are the most commonly used pharmaceutical dosage form. Among these advantages are low manufacturing costs, high production throughput, ease of consumption, storage and handling. Several deficiencies caused by poor flowability and mechanical properties, on the other hand, have always been a challenge in the path to successful tablet production [124]. Some of these techniques include adding silicon dioxide to improve tablet mechanical strength and magnesium stearate to improve flowability. Co-crystallization has also been studied as a technique for improving the chemical and physical properties of powders, such as mechanical strength and flow properties [125]. Co-crystallization with theophylline, oxalic acid, naphthalene and phenazine conformers, for example, improved the compression properties of paracetamol form I [126].

1.7.8 Taste masking

Oral disintegrating tablets require fast disintegrating tablets with rapid dissolution. This strategy allows the use of tablets without the need for chewing or water intake, broadening the range of drug users to include geriatric, paediatric and travelling patients who do not have access to water. To improve the patient experience, readily disintegrating tablets require the use of taste masking agents. So far, the main approach has been to use sugar excipients. Co-crystallization could be a good strategy to improve dissolution rate using sugar-based coformers such as sucralose as coformer for preparing co-crystals with hydrochlorothiazide. The formed co-crystals provide the benefits of increased dissolution rate and taste masking of the product [127]. Another example, theophylline with the bitter taste was masked by formulating co-crystals with artificial sweeteners such as sodium glutamate, sodium saccharin and d-sorbitol. In 1:1 stoichiometric ratio via liquid-assisted grinding, the prepared co-crystal showed enhanced dissolution and sweet taste, which was detected by automated sweetness tasting machine [128].

1.7.9 Generation/extension of intellectual property

Intellectual property (IP) is vital for pharmaceutical companies. The intellectual property (IP) protection of new ideas, inventions, processes or products grants exclusivity over the manufacturing process and products. Patents, copyright and trademarks, for example, are legal mechanisms that allow individuals or organizations/companies to gain recognition or financial benefit from their work or investment in a creation. A total of 138 patents are granted to recognize an invention that meets the criteria of global novelty, non-obviousness and industrial application. Pharmaceutical companies must deal with drug or drug product patent life cycle management to keep their pharmaceuticals on the market for as long as possible. Screening of novel solid dosage forms of marketed drugs, such as polymorphs, salts and co-crystals, provides the opportunity to grant new IP and extend the patent life cycle of those drugs. Pharmaceutical co-crystals have regulatory and intellectual property advantages that provide them with unique possibilities, benefits and challenges. From a regulatory standpoint, drugs containing a novel co-crystal are considered similar to a new polymorph of the API. This guidance takes novel co-crystals to be considered as a new drug substance, which promotes their independent patentability as novel solid forms [129].

1.7.10 Melting point

Melting point is the physical property of solids, which is used to determine the purity of the product [130]. The high melting point of the new materials demonstrates their thermodynamical stability; that is, the thermal stability of an API can be increased by selecting a coformer with a higher melting point. When working with thermolabile drugs, co-crystals with low melting points can also be useful. The melting point of pharmaceutical co-crystals can be managed by judicious selection of the coformers. Melting point contributes to a major consideration during the formulation of co-crystals. Co-crystals with high melting points are usually needed but they have poor aqueous solubility, whereas low melting point co-crystals have problems with processing, drying and stability, so further study within this area is required [130].

1.7.11 pH-independent solubility

In pharmaceutical co-crystal design and screening in most cases the API is uncharged. There are very few reports on the co-crystallization of charged APIs. Co-crystals constitute an important class of pharmaceutical solids for their ability to modulate solubility and pH dependence of water-insoluble drugs [131]. Co-crystals with acidic coformers, indomethacin−saccharin (IND − SAC) carbamazepine−saccharin (CBZ − SAC), not only enhance aqueous solubility but also impart a pH sensitivity than the drugs. IND − SAC exhibited solubilities 13 to 65 times higher than IND at pH values of 1 to 3, whereas CBZ − SAC exhibited a 2 to 10 times higher solubility than CBZ dihydrate in acidic pH values of 1 to 3 [132]. Gabapentin is shown to form co-crystal with 3-hydroxy benzoic acid and salts with salicylic acid, 1-hydroxy-2-napthoic acid and RS-mandelic acid. There is partial proton transfer from 4-hydroxy benzoic acid to gabapentin. Multicomponent crystals gabapentin-3-hydroxybenzoic acid (1:1), gabapentin-4-hydroxybenzoic acid (1:1), gabapentin-salicylic acid (1:1), gabapentin-1-hydroxy-2-napthoic acid (1:1) and gabapentin-RS-mandelic acid (1:1) are thermodynamically more stable and equal or less soluble than gabapentin hydrate and carboxylic acid coformers in pure water. Gabapentin-3-hydroxy benzoic acid co-crystal is stable at pH 4.0 and 5.7. This indicates that gabapentin3HBA co-crystal is less soluble at pH 4.0 and 5.7, while co-crystal is more soluble at pH 2.6 [133].

1.7.12 Hygroscopicity reduction

The ability of a solid substance that absorbs moisture from its surroundings is known as hygroscopic material. Hygroscopicity is a term that refers to materials that easily absorb water in a non-structured way. Thus, the adsorbed water is reversible and not structured inside a crystal lattice. The categorization of hygroscopic and non-hygroscopic materials in pharmaceuticals are regarded as hygroscopic if they absorb more than 5% of their mass in RH between 40 and 90% at 25°C. Non-hygroscopic materials are those that absorb less than 1% moisture under the same conditions. If the critical RH of a hygroscopic material is lower than that of the surrounding atmosphere, it may deliquesce (where adsorbed water starts to solvate molecules of the solid) [134]. Co-crystals of levofloxacin (LVFX) and N-acetyl-meta-aminophenol (AMAP) using a grinding and heating approach crystallized from a eutectic melting of the 2 drugs after water desorption from an LVFX hydrate. Levofloxacin monohydrate contains one ½ H2O, while co-crystal formation coformer metacetamol contains OH group at meta position, which binds with LVFX through hydrogen bonds leaving no binding site for H2O to make compound hygroscopic. This co-crystal exhibited dramatic improvements in physicochemical properties of LVFX, including hygroscopicity, physical stability and photostability, while retaining its good dissolution characteristics and chemical stability under various temperature and humidity conditions [133]. Co-crystal of metoclopramide HCl (MCPHCl), with oxalic acid (OXA), is acting as the coformer. The crystal structure of metoclopramide HCl-oxalic acid (MCPHCl–OXA) co-crystal was determined by single-crystal X-ray crystallography. The salt co-crystal has higher stability than its parent drug against high humidity and dissociation in an aqueous environment. These properties are attributed to the utilization of all hydrogen bond donors and acceptors of MCP, suggesting the OXA acts as a substitute for a water molecule in the structure, which makes it less hygroscopic. In addition, the salt co-crystal is promising for extended-release drug formulation by exhibiting a lower dissolution rate compared to the parent drug. These findings demonstrate the utility of salt [134]. The amide groups of individual nicotinamide molecules are all involved in intermolecular hydrogen bonding in co-crystals of ibuprofen-nicotinamide and flurbiprofen-nicotinamide, leaving the pyridine nitrogen free to interact with the environmental water vapour molecules, contributing to its hygroscopic nature. However, in co-crystal form with IBU or FLU, all of nicotinamide’s pyridine nitrogen forms hydrogen bonds with the profens’ carboxylic hydrogens and is thus unavailable for bonding with water, resulting in a decrease in moisture sorption at relatively low RHs [135, 136, 137, 138, 139, 140].

2. Conclusion

Co-crystals enable a wide range of APIs to be used in pharmaceutical therapy. Some of the most appealing properties of co-crystallized APIs are increased solubility and chemical and physical stability. Because of their patentability, they are also appealing from an economic and legal standpoint. Several difficulties arise when attempting to create co-crystals. The prediction of the crystal structure of larger molecules is time consuming and difficult. The predicted structure will not always match the experimental result. Even though methods such as liquid-assisted grinding are very efficient in the lab, they are economically unfavourable in large-scale synthesis. Overall, because of improved drug delivery performance, stability and an important intellectual property status, co-crystals are expected to play an important role in future drug development.