Cocrystals by Design: A Rational Coformer Selection Approach for Tackling the API Problems

Active pharmaceutical ingredients (API) with unfavorable physicochemical properties and stability present a significant challenge during their processing into final dosage forms. Cocrystallization of such APIs with suitable coformers is an efficient approach to mitigate the solubility and stability concerns. A considerable number of cocrystal-based products are currently being marketed and show an upward trend. However, to improve the API properties by cocrystallization, coformer selection plays a paramount role. Selection of suitable coformers not only improves the drug’s physicochemical properties but also improves the therapeutic effectiveness and reduces side effects. Numerous coformers have been used till date to prepare pharmaceutically acceptable cocrystals. The carboxylic acid-based coformers, such as fumaric acid, oxalic acid, succinic acid, and citric acid, are the most commonly used coformers in the currently marketed cocrystal-based products. Carboxylic acid-based coformers are capable of forming the hydrogen bond and contain smaller carbon chain with the APIs. This review summarizes the role of coformers in improving the physicochemical and pharmaceutical properties of APIs, and deeply explains the utility of afore-mentioned coformers in API cocrystal formation. The review concludes with a brief discussion on the patentability and regulatory issues related to pharmaceutical cocrystals.


Introduction
In pharmaceutical research and development portfolios, about 40% of commercialized APIs exhibit low water solubility. As stated by the biopharmaceutical classification system (BCS), drugs having low solubility and high permeability fall under class II [1]. One of the most critical challenges of BCS II drugs is to improve the solubility and dissolution rate [2]. In addition to poor aqueous solubility, most APIs exhibit undesirable physicochemical properties, flowability, compactability, etc., which hampers the solid dosage form development. The purity and performance of a drug product is severely impacted due to instabilities caused by polymorphic changes and degradation due to heat, light, and humidity during processing/storage [3,4]. Among the said problems, the poor aqueous solubility of active pharmaceutical ingredients (APIs) can be enhanced by micronization, amorphization, salt formation, cocrystallization, etc. [1]. Micronization, amorphization, and salt formation can micronization, amorphization, salt formation, cocrystallization, etc. [1]. Micronizat amorphization, and salt formation can improve the aqueous solubility of drugs, but stability and processability are compromised in some cases [5,6]. The cocrystals proach has the potential to provide a safe way to improve solubility in addition to creasing/retaining the stability [7,8].
Cocrystals can be considered superior to amorphous API forms or solid dispersi because they possess the solubility advantages of high-energy solids and have a crys line structure with good thermodynamic stability [9,10]. Cocrystals are defined by European Medicines Agency (EMA) as "homogenous (single phase) crystalline st tures made up of two or more components in a definite stoichiometric ratio where arrangement in the crystal lattice is not based on ionic bonds (as with salts) and components of a cocrystal may nevertheless be neutral as well as ionized" [11]. United States Food and Drug Administration (USFDA) defines cocrystals as "Crystal materials composed of two or more different molecules, typically API and cocry formers (coformers), in the same crystal lattice in a defined stoichiometric ratio." Coc tals are different from salts, polymorphs, solvates and hydrates [12]. The hydrog bonding interactions of API with the coformer alter its physicochemical properties lead to enhanced pharmaceutical attributes [13]. Various methods [14] have been lized till the present by researchers to prepare pharmaceutically acceptable cocrys and have been illustrated in Figure 1. Commercialized drug products provide some evidence of the efficacious appl tion of cocrystallization in the pharmaceutical industry. Depakote ® , Entresto ® , Sug Steglatro ® , Lexapro ® , ESIX-10 ® , Beta-chlor ® , Cafcit ® , Zafatek ® , and Lam dine/zidovudine Teva ® , etc., are some commercially available pharmaceutical prod that contain cocrystal-based APIs [15,16].
The coformer selection plays an important role in deciding the final cocrystal tributes. The coformers have the ability to modulate the API stability and solub when prepared as a cocrystal by inducing changes in its crystal structure [1]. There h Commercialized drug products provide some evidence of the efficacious application of cocrystallization in the pharmaceutical industry. Depakote ® , Entresto ® , Suglat ® , Steglatro ® , Lexapro ® , ESIX-10 ® , Beta-chlor ® , Cafcit ® , Zafatek ® , and Lamivudine/zidovudine Teva ® , etc., are some commercially available pharmaceutical products that contain cocrystal-based APIs [15,16].
The coformer selection plays an important role in deciding the final cocrystal attributes. The coformers have the ability to modulate the API stability and solubility when prepared as a cocrystal by inducing changes in its crystal structure [1]. There have been a few studies that have reported deterioration of API properties after cocrystallization [3]. A variety of (GRAS) coformers generally regarded as safe are used to prepare pharmaceutically acceptable cocrystals [1,[17][18][19]. The nature of the coformer used (acidic/basic/neutral) is known to influence the stability of the final cocrystal [1]. There have been a few instances wherein the cocrystallization technique was applied to improve the hygroscopic stability of moisture-sensitive drugs [20]. Other common instabilities such as hydrolysis, isomerization, photodegradation, etc., can also be effectively overcome by means of cocrystal preparation [21,22]. A large number of coformers with different functionalities have been used till present to prepare pharmaceutical cocrystals. The utility of chemicals as coformers depends upon the hydrogen-bonding ability of the molecules with the API. The good hydrogen-bonding strength and molecular geometry between the coformer and the API plays a vital role in the development of cocrystals [23]. According to the Etter rule, the hydrogen bond is formed if good hydrogen-bond donors and acceptors participate in the hydrogen bonding [24].
Currently available literature on coformer selection is predominantly focused on the mere cocrystal formation using different coformers. However, there is very little emphasis on selecting a coformer specifically to improve a particular aspect of an API [13,[25][26][27]. In this review article, the authors discuss the coformer selection, their properties and impacts on enhancing a particular physicochemical property of an API. Authors have provided statistical analyses on most commonly used coformers. The properties, applications and recent reports on the usage of commonly used aliphatic carboxylic acid-based coformers, such as succinic acid, fumaric acid, oxalic acid, and citric acid, is discussed in detail. The marketed formulations based on these four coformers are discussed and their applicability in improving the API properties of all four coformers is compared. The patentability and regulatory factors governing the development of cocrystals is briefly discussed towards the end of the article.

Selection of Coformer
As mentioned earlier, coformers have a major role in the cocrystal development. The factors such as the type of functional group, pKa, their physical form, and their molecular size are to be considered during cocrystal formation using a particular coformer [28]. The coformer selection is primarily done by the experimental method and knowledge-based method. The experimental method is based on trial and error. Herein, an API is cocrystallized with empirically selected coformers and the formation of cocrystals is later confirmed by employing analytical techniques such as powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), etc. This method of cocrystal screening is thus very tedious and requires a huge amount of resources. Alternatively, various knowledge-based approaches can be put to use. Suitable coformers are being selected based on the hydrogen-bonding, pKa-based models, supramolecular synthon compatibility using the Cambridge Structure Database (CSD), lattice energy calculation, Hansen solubility parameter, thermal analysis, saturation temperature measurements, virtual cocrystal screening (using molecular electrostatic potential surfaces-MEPS), etc. [29,30]. The Hansen solubility parameter (HSP) compares the aqueous solubility of the coformer and the API, and the compounds with similar HSP have a higher probability of forming cocrystals [31]. The knowledge-based methods thus predict the formation of cocrystals even before experimentation, based on the structural features of API and coformer. Another method for selecting coformers is based on the supramolecular synthons. Supramolecular synthons are the structural units within the supermolecules that can be generated due to intermolecular interactions. Supramolecular synthons are of two types: supramolecular homosynthons with identical self-complementary functionalities and supramolecular heterosynthons with different but complementary functionalities. The heterosynthons are typically more durable. In general, amide homodimers and carboxylic acid heterosynthons are preferred [32,33]. Figure 2 shows some of the common supramolecular synthons occurring in the cocrystals.
The most preferred approaches for the selection of coformer and the generation of cocrystals are Cambridge Structural Database (CSD)-based screening, hydrogen-bond rules, and pKa rules, which are briefly discussed below.

Cambridge Structural Database (CSD)
It is possible to carry out supramolecular retrosynthetic analysis, which entails locating intermolecular units for the desired cocrystal structure, using the CSD [34]. The CSD contains crystallographic information regarding the hydrogen bonds formed between the drug and the coformer. Currently, the CSD repository contains over 1.2 million crystal structures [35,36]. Every entry in the CSD contains information on chemical structure and crystallographic data (such as space groups, lattice, symmetry, and crystal systems), crystal packing, molecular dimensions, molecular geometry, stereochemistry, structure representation, and conformational analysis [37]. Based on the understanding of geometries and preferred orientations of current intermolecular interactions, coformers can be chosen for cocrystallization with the APIs [34,38].

Hydrogen-Bond Rules
The hydrogen-bond rule is another approach for the selection of coformer. The hydrogen bond (X-H) is an attractive interaction between a hydrogen atom and an electronegative atom (X). Hydrogen bonding can occur within a molecule or between two different molecules [39]. The hydrogen bond rule provides valuable information about the favored hydrogen-bond selectivity, connectivity patterns, and stereo-electronic properties of hydrogen bonds for a specific functional group or combination of functional groups, in which hydrogen bonds are formed. There are generally three rules of hydrogen bond formation. The first rule was proposed by Donohue: all available acidic hydrogen in the molecular crystal structure of that compound will be used in hydrogen bonding. The second rule states that if hydrogen-bond donors are present, all good acceptors will be engaged in hydrogen bonding. According to the third rule, hydrogen bonds will form especially between the finest hydrogen-bond acceptor and the finest hydrogen-bond donor [40].

pKa Rule
The pKa difference between the acid-base pair can be estimated to predict whether the pair forms salt or cocrystal [41]. The acid dissociation constant (pKa) affects how well certain medications are absorbed orally. The BCS Class II drugs are further classified into Iia (acidic drugs), Iib (basic drugs), and Iic (neutral drugs) based on their pH-dependent solubility (and dissolution rate). Weakly acidic drugs with pKa ≤ 5 (flurbiprofen, ketoprofen, etc.) exhibit higher aqueous solubility at alkaline pH of the intestine and are classified as class Iia drugs. The weakly basic drugs with pKa ≥ 6 (carbamazepine, rifampicin, etc.), in contrast, exhibit higher aqueous solubility at acidic pH of the stomach and are classified as class Iib drugs. Drugs which do not exhibit pH-dependent solubility are classified into the class Iic category (neutral drugs such as danazol, fenofibrate, etc.) [18,42,43]. The formation of cocrystals and salt can be predicted by a study of the transfer of protons and is determined by the ∆pKa = [pKa (base) − pKa (acid)]. A pKa value difference of greater than 2 or 3 between the API and coformer symbolizes the transfer of proton between acid and base. The smaller pKa value difference (less than 0) indicates cocrystal formation whereas a large difference in the pKa values (≥ 2 or 3) indicates salt formation [13].

Coformer Impact on Pharmaceutical Attributes
Coformers, along with drugs, have an ability to alter the pharmaceutical attributes of a cocrystal system. Thus, when designing a cocrystal, it is crucial to consider the physicochemical properties of coformers as well. The applicability of coformers to improve the stability, mechanical properties, solubility, and permeability of APIs is discussed in the current section. Figures 3 and 4 depict the different aspects of API and coformers that need to be considered during cocrystal preparation. dependent solubility (and dissolution rate). Weakly acidic drugs with pKa ≤ 5 (flurbiprofen, ketoprofen, etc.) exhibit higher aqueous solubility at alkaline pH of the intestine and are classified as class Iia drugs. The weakly basic drugs with pKa ≥ 6 (carbamazepine, rifampicin, etc.), in contrast, exhibit higher aqueous solubility at acidic pH of the stomach and are classified as class Iib drugs. Drugs which do not exhibit pH-dependent solubility are classified into the class Iic category (neutral drugs such as danazol, fenofibrate, etc.) [18,42,43]. The formation of cocrystals and salt can be predicted by a study of the transfer of protons and is determined by the ∆pKa = [pKa (base)-pKa (acid)]. A pKa value difference of greater than 2 or 3 between the API and coformer symbolizes the transfer of proton between acid and base. The smaller pKa value difference (less than 0) indicates cocrystal formation whereas a large difference in the pKa values (≥ 2 or 3) indicates salt formation [13].

Coformer Impact on Pharmaceutical Attributes
Coformers, along with drugs, have an ability to alter the pharmaceutical attributes of a cocrystal system. Thus, when designing a cocrystal, it is crucial to consider the physicochemical properties of coformers as well. The applicability of coformers to improve the stability, mechanical properties, solubility, and permeability of APIs is discussed in the current section. Figures 3 and 4 depict the different aspects of API and coformers that need to be considered during cocrystal preparation.

Role of Coformers in Solubility, Dissolution, and Bioavailability
Oral delivery of drugs is the most favored and patient-compliant method of drug administration in spite of other available routes such as parenteral, pulmonary, transdermal, etc. The oral route offers a painless method of drug administration with high acceptance that makes it the most convenient route. Most of the APIs can be formulated as an oral solid dosage at comparatively low cost, which in totality makes them an attractive avenue for patients and pharmaceutical companies alike. The cocrystal formation effectively improves the solubility of poorly water-soluble APIs, and the coformer selected has a major role to play in deciding the solubility of the cocrystal prepared. The physicochemical properties of coformers, such as solubility, ionization, etc., are to be considered while designing cocrystals of poorly water-soluble APIs. A few examples related to the mentioned coformer properties are discussed below.
Putra et al. [21] reported cocrystals of epalrestat with betaine in which they depicted a two-fold increase in solubility. The reason was attributed to the formation of a layered structure between drug and coformer, as depicted in Figure 5. As compared to epalrestat, betaine has higher water solubility with a higher tendency to go into solution, resulting in the formation of cocrystal with higher solubility. On contact with water, the rate of epalrestat dissolution is accelerated due to rapid dissolution of betaine, which was supported by the cocrystal having a 3.5-fold higher intrinsic dissolution rate compared to the parent drug (shown in Figure 6).

Role of Coformers in Solubility, Dissolution, and Bioavailability
Oral delivery of drugs is the most favored and patient-compliant method of drug administration in spite of other available routes such as parenteral, pulmonary, transdermal, etc. The oral route offers a painless method of drug administration with high acceptance that makes it the most convenient route. Most of the APIs can be formulated as an oral solid dosage at comparatively low cost, which in totality makes them an attractive avenue for patients and pharmaceutical companies alike. The cocrystal formation effectively improves the solubility of poorly water-soluble APIs, and the coformer selected has a major role to play in deciding the solubility of the cocrystal prepared. The physicochemical properties of coformers, such as solubility, ionization, etc., are to be considered while designing cocrystals of poorly water-soluble APIs. A few examples related to the mentioned coformer properties are discussed below.
Putra et al. [21] reported cocrystals of epalrestat with betaine in which they depicted a two-fold increase in solubility. The reason was attributed to the formation of a layered structure between drug and coformer, as depicted in Figure 5. As compared to epalrestat, betaine has higher water solubility with a higher tendency to go into solution, resulting in the formation of cocrystal with higher solubility. On contact with water, the rate of epalrestat dissolution is accelerated due to rapid dissolution of betaine, which was supported by the cocrystal having a 3.5-fold higher intrinsic dissolution rate compared to the parent drug (shown in Figure 6).   Selection of a coformer of intermediate solubility directly influences cocrystal solubility, as it will lead to a prolonged parachute effect. This hypothesis is effectively highlighted by furosemide and 2-picolinamide sesquihydrate cocrystal, as reported by Banik et al. [44]. Sustained super-saturation levels of dissolved drug were maintained over the period of 24 h. This was attributed to the fact that the coformer 2-picolinamide has intermediate solubility, which led to gradual leaching of the drug. Such a phenomenon was described by a new term, the 'synthon-extended-spring-parachute effect', and is depicted in Figure 7. Further, the cocrystal with higher polarity will have higher solubility and consequently higher dissolution compared to neutral ones. Surov et al. [45] reported non-ionic cocrystal of diclofenac with theophylline where only a 1.6-fold increase in solubility was observed, whereas Nugrahani et al. [46] reported zwitterionic cocrystal of the same drug with l-proline showing a 7.69-fold increase in solubility.
The solubility and dissolution improvement of API are correlated with coformer solubility. In some cases, this correlation is not followed, which could be due to the interplay of other factors. One of the most plausible reasons attributed to such behavior is the existence of a stronger interaction between drug and coformer, leading to the formation of differently behaving cocrystal. There have been numerous examples of such cases in the literature. One such case was reported by Aitipamula et al. [47], who found that although nicotinamide had higher solubility than theophylline, cocrystal of Figure 6. Intrinsic dissolution rate experiment results of epalrestat and its cocrystal. Reprinted (adapted) with permission from [21]. Copyright (2018) American Chemical Society.
Selection of a coformer of intermediate solubility directly influences cocrystal solubility, as it will lead to a prolonged parachute effect. This hypothesis is effectively highlighted by furosemide and 2-picolinamide sesquihydrate cocrystal, as reported by Banik et al. [44]. Sustained super-saturation levels of dissolved drug were maintained over the period of 24 h. This was attributed to the fact that the coformer 2-picolinamide has intermediate solubility, which led to gradual leaching of the drug. Such a phenomenon was described by a new term, the 'synthon-extended-spring-parachute effect', and is depicted in Figure 7. Further, the cocrystal with higher polarity will have higher solubility and consequently higher dissolution compared to neutral ones. Surov et al. [45] reported non-ionic cocrystal of diclofenac with theophylline where only a 1.6-fold increase in solubility was observed, whereas Nugrahani et al. [46] reported zwitterionic cocrystal of the same drug with l-proline showing a 7.69-fold increase in solubility. flufenamic acid with theophylline showed higher solubility and dissolution compared to one with nicotinamide due to the existence of a stronger intermolecular interaction between the drug and nicotinamide. The effect of cocrystal selection on solubility and dissolution rate is summarized in Table 1.   The solubility and dissolution improvement of API are correlated with coformer solubility. In some cases, this correlation is not followed, which could be due to the interplay of other factors. One of the most plausible reasons attributed to such behavior is the existence of a stronger interaction between drug and coformer, leading to the formation of differently behaving cocrystal. There have been numerous examples of such cases in the literature. One such case was reported by Aitipamula et al. [47], who found that although nicotinamide had higher solubility than theophylline, cocrystal of flufenamic acid with theophylline showed higher solubility and dissolution compared to one with nicotinamide due to the existence of a stronger intermolecular interaction between the drug and nicotinamide. The effect of cocrystal selection on solubility and dissolution rate is summarized in Table 1.

Role of Coformers in Improving the Mechanical Properties of Drug Molecule
The APIs must have optimal mechanical properties to ensure easy processing of unit operations like mixing, granulation, tableting, etc. The properties relating to plasticity, elastic recovery, tensile strength, presence of slip planes, attachment energy, etc., are significantly influenced by the crystal packing of molecules in API [3,57,58]. Introduction of a coformer in the API crystal structure can either enhance, deteriorate or retain the mechanical properties [3,4]. Therefore, the mechanical properties can be tuned by the proper selection of coformer. There are several reports where the incorporation of coformer leads to improved mechanical properties of APIs [59]. Sun et al. [59] improved the tabletability of caffeine by co-crystallizing with methyl gallate. The synthesis of cocrystal leads to improvements in the compaction properties due to the presence of slip planes in the structure of cocrystal. The planes are held by the weak van der Waals forces and can be easily overcome by applying pressure. The planes slide over each other, which improves the tabletability of the cocrystal form. Similarly, Karki et al. [58] and Ahmed et al. [60] improved the tabletability of paracetamol by preparing its cocrystals. Further, the bending flexibility of probenecid was transformed from a single-component system to the multiple-component system by choosing a coformer having symmetrical hydrogen bond donor/acceptor groups [61]. The bending flexibility of probenecid was also retained by introducing a molecular spacer coformer, as reported by Nath et al. [62]. This indicates that, based on design strategy, the mechanical properties of drug molecules can be altered. Other examples of coformers that influence the mechanical properties of drugs are provided in Table 2.

Role of Coformers in Stabilizing the Drug Molecule
The stability of a drug during processing and storage is the most important concern of the pharmaceutical industry. Any changes in the polymorphic form of an API leads to changes in its physicochemical properties and can deteriorate the quality and safety of the final product. APIs face physical stability issues, such as pseudopolymorphism, polymorphic transition, hygroscopicity, and chemical stability issues such as hydrolysis, photolysis, thermal degradation, chemical transformation, dimerization, etc. These instabilities are mainly related to the crystal structure of API molecules. Cocrystals are ideal to avoid these instabilities [70]. The depiction of utility of cocrystals in improving the stability of APIs is shown in Figure 8. A few research works aimed at improving the stability of API are reported below.
Andrew et al. [71] employed cocrystallization to inhibit the hydration of anhydrous caffeine. Cocrystals of caffeine were synthesized with acid coformers, such as oxalic acid, glutaric acid, maleic acid, and malonic acid. It was reported that the stability of the cocrystal towards hydration followed the order of strength of acid groups in coformers, where the oxalic acid cocrystal was stable while the glutaric acid, which has the weakest acid groups, showed the least stability. It was hypothesized that the driving force for stabilization of cocrystals was achieved by employing the hydrogen bond donor such as the carboxylic acid group for the basic imidazole nitrogen. This effectively prevents water incorporation into the lattice of a cocrystal. Similar studies were conducted with etoricoxib as well, where stability enhancement was seen due to the strong hydrogen bonding between the coformer and API [72]. Gao et al. [22] improved the chemical stability of adefovir dipivoxil by cocrystallizing with acidic and basic coformers, saccharin and nicotinamide, respectively. The results showed that the acidic coformer enhanced the stability while the basic coformer did not stabilize it to such an extent. The study authors hypothesized three reasons for this: (1) the acidic coformer provided a micro-acidic environment to the structure, inhibiting the hydrolysis, whereas the basic coformer enhanced the degradation; (2) the acidic coformer introduced into the crystal lattice inhibits the dimerization, which later may lead to degradation; (3) the strong hydrogen bond of an acidic coformer prevents the moisture attack on the functional groups of drugs which are prone to hydrolysis. the stability while the basic coformer did not stabilize it to such an extent. The study authors hypothesized three reasons for this: (1) the acidic coformer provided a micro-acidic environment to the structure, inhibiting the hydrolysis, whereas the basic coformer enhanced the degradation; (2) the acidic coformer introduced into the crystal lattice inhibits the dimerization, which later may lead to degradation; (3) the strong hydrogen bond of an acidic coformer prevents the moisture attack on the functional groups of drugs which are prone to hydrolysis. Instabilities due to the isomerization of API can also make them unstable. This mechanism of instability was controlled by a coformer in the cocrystal of epalrestat [21]. The reaction cavity in the cocrystal was decreased compared to the drug, leading to hindered molecular motion, and thus inhibited the isomerization. This leads to improved photostability of the cocrystal compared to the drug molecule. Similarly, stability improvement of various APIs was achieved by cocrystal formation with a coformer, as summarized in Table 3. Table 3. Examples of studies reporting on coformers' effect on stabilization of drug molecules in cocrystals. Instabilities due to the isomerization of API can also make them unstable. This mechanism of instability was controlled by a coformer in the cocrystal of epalrestat [21]. The reaction cavity in the cocrystal was decreased compared to the drug, leading to hindered molecular motion, and thus inhibited the isomerization. This leads to improved photostability of the cocrystal compared to the drug molecule. Similarly, stability improvement of various APIs was achieved by cocrystal formation with a coformer, as summarized in Table 3.

Role of Coformers in Enhancing the Permeability of Cocrystals
Oral administration of compounds is the preferred route for the administration of medicines owing to its well-established benefits. The majority of cocrystal synthesis is done with an objective to improve oral bioavailability of drugs posing problems of either low solubility or low permeability or both. Abundant literature is available to demonstrate solubility improvement by the cocrystallization technique. On the other hand, the problem of poor permeability still remains underexplored. Permeability depends on complex factors, such as transporters, gastric transit time, intestinal epithelial metabolism and many other in vivo factors. As summarized in Table 4, the available literature indicates most of the experiments for permeability evaluation have been conducted through Franz-diffusion cells employing an artificial membrane.
There are multiple reasons for permeability enhancement in cocrystals. An increase in the concentration gradient due to high supersaturation levels of drug in solution leads to the increased flux rate (rate of drug permeation) [54]. The heterosynthon interactions in cocrystals can also improve the permeability by increasing thermodynamic activity. This feature can be attributed to the reduced packing efficiency of heterosynthons compared to the homosynthons, and as result, the packing efficiency and density of crystals reduces. Another reason could be the use of relatively lipophilic coformers that enhance the partition coefficient of drugs after cocrystallization and improve the rate of permeation across the cell membrane [78]. In rare cases, the coformer used may inhibit various drug transporter proteins, such as P-glycoprotein (P-gp). P-gp are efflux proteins present in the apical region of the small intestine and involved in the out-transportation of absorbed drug molecules. Drugs such as caffeine, stearic acid, etc., can inhibit the P-gp transporters and increase the permeation of drugs [69,79].
Dai et al. [78] employed Franz-type diffusion cells to study the permeability of 5fluorouracil, its cocrystals and corresponding physical mixtures through a silicon membrane. The studied cocrystals were 5-fluorouracil (5-FU) with 3-hydroxybenzoic acid (1), 4-aminobenzoic acid (2), and cinnamic acid (3). Cumulative amounts of cocrystal permeated per unit area (Q n ) and steady penetration rate (J s ) were higher than those of the drug ( Figure 9A). 5-FU physical mixtures with 3-hydroxybenzoic acid (1PM) and cinnamic acid (3PM) showed similar Q n while the physical mixture with 4-aminobenzoic acid (2PM) showed lesser cumulative diffusion compared to 5-FU ( Figure 9B). The permeability of the 5-FU cocrystals was improved due to the replacement of the homosynthons formed between drug-drug by new drug-coformer heterosynthons. The weaker interaction between drug and coformer leads to rapid dissociation, which results in higher concentration of 5-FU cocrystals. Due to the higher concentration of 5-FU cocrystals, the flux rate increases, which leads to improved permeability. lism and many other in vivo factors. As summarized in Table 4, the available literatur indicates most of the experiments for permeability evaluation have been conducte through Franz-diffusion cells employing an artificial membrane.
There are multiple reasons for permeability enhancement in cocrystals. An increas in the concentration gradient due to high supersaturation levels of drug in solution lead to the increased flux rate (rate of drug permeation) [54]. The heterosynthon interaction in cocrystals can also improve the permeability by increasing thermodynamic activity This feature can be attributed to the reduced packing efficiency of heterosynthons com pared to the homosynthons, and as result, the packing efficiency and density of crysta reduces. Another reason could be the use of relatively lipophilic coformers that enhanc the partition coefficient of drugs after cocrystallization and improve the rate of permea tion across the cell membrane [78]. In rare cases, the coformer used may inhibit variou drug transporter proteins, such as P-glycoprotein (P-gp). P-gp are efflux proteins presen in the apical region of the small intestine and involved in the out-transportation of ab sorbed drug molecules. Drugs such as caffeine, stearic acid, etc., can inhibit the P-g transporters and increase the permeation of drugs [69,79].
Dai et al. [78] employed Franz-type diffusion cells to study the permeability of 5 fluorouracil, its cocrystals and corresponding physical mixtures through a silicon mem brane. The studied cocrystals were 5-fluorouracil (5-FU) with 3-hydroxybenzoic acid (1 4-aminobenzoic acid (2), and cinnamic acid (3). Cumulative amounts of cocrystal perme ated per unit area (Qn) and steady penetration rate (Js) were higher than those of th drug ( Figure 9A). 5-FU physical mixtures with 3-hydroxybenzoic acid (1PM) and cin namic acid (3PM) showed similar Qn while the physical mixture with 4-aminobenzoic a id (2PM) showed lesser cumulative diffusion compared to 5-FU ( Figure 9B). The perme ability of the 5-FU cocrystals was improved due to the replacement of the homosynthon formed between drug-drug by new drug-coformer heterosynthons. The weaker interac tion between drug and coformer leads to rapid dissociation, which results in higher con centration of 5-FU cocrystals. Due to the higher concentration of 5-FU cocrystals, the flu rate increases, which leads to improved permeability. Amaral et al. [79] reported cocrystal of dapsone with caffeine in which the permea bility of drug, cocrystal and the corresponding physical mixture was evaluated in caluhuman bronchial epithelial cells. The greater permeability in apical to basolateral direc tion was attributed to the complete dissociation of cocrystal and the absence of any cry tal lattice interaction in the solution. Amaral et al. [79] reported cocrystal of dapsone with caffeine in which the permeability of drug, cocrystal and the corresponding physical mixture was evaluated in calu-3 human bronchial epithelial cells. The greater permeability in apical to basolateral direction was attributed to the complete dissociation of cocrystal and the absence of any crystal lattice interaction in the solution.
The discussed works do not consider factors such as transporter, gastric blood flow, metabolism inhibition, and beyond. Hence, there is a need to explore the role of coformer in improving permeability under the influence of the above-mentioned factors. In Table 4, instances of coformers enhancing the permeation of drugs are given. For better evaluation of permeability of cocrystals, there can be experimentation using the in vitro models that better correlate with an in vivo intestinal environment. In vitro methods consisting of artificial lipid membranes, such as parallel artificial membrane permeability assays (PAMPA) instead of cell-based such as Mardin-Darby canine kidney cells (MDCK), caco-2 cells, or tissue-based assays like intestinal membrane vesicles, would serve as better indicators of permeability improvement [80]. Figure 10 depicts the mechanism of permeability enhancement by cocrystals. The discussed works do not consider factors such as transporter, gastric blood flow, metabolism inhibition, and beyond. Hence, there is a need to explore the role of coformer in improving permeability under the influence of the above-mentioned factors. In Table 4, instances of coformers enhancing the permeation of drugs are given. For better evaluation of permeability of cocrystals, there can be experimentation using the in vitro models that better correlate with an in vivo intestinal environment. In vitro methods consisting of artificial lipid membranes, such as parallel artificial membrane permeability assays (PAMPA) instead of cell-based such as Mardin-Darby canine kidney cells (MDCK), caco-2 cells, or tissue-based assays like intestinal membrane vesicles, would serve as better indicators of permeability improvement [80]. Figure 10 depicts the mechanism of permeability enhancement by cocrystals.

Coformers Reported in the Literature
The discussion in the earlier sections of this review explains the significance of coformer properties in deciding the final characteristics of a cocrystal. In this section, the authors present a list of coformers reported in the literature with different APIs in Table 5. The fully exhaustive list is provided in Table S1 of the Supplementary Materials. The following table can be used as a reference for further cocrystallization experiments.

Coformers Used in High Demand
In the last two decades, the demand for coformers has upscaled, as depicted in Figure 11. Urea, nicotinamide, benzoic acid, etc., are in high demand compared to other coformers. The utility of carboxylic acid-based coformers such as succinic acid, citric acid, fumaric acid, and oxalic acid has also increased marginally. The carboxylic acid-based coformers are discussed in detail in the upcoming section of the review article.

Commercially Available Drug Products Based on Cocrystals
The ultimate aim of developing any technology/process is to make it reach the target population. Cocrystals play a vital role in improving the pharmaceutical properties of APIs. Commercialized cocrystal-based drug products are evidence of the efficacious application of cocrystallization in the pharmaceutical companies. Depakote ® , Entresto ® , Suglat ® , Steglatro ® , Lexapro ® , ESIX-10 ® , Beta-chlor ® , Cafcit ® , Zafatek ® , and Lamivudine/zidovudine Teva ® , etc., are some commercially available pharmaceutical products that contain cocrystal-based APIs. The purpose of this section is to make the readers aware of the current scenario of the cocrystal technology.

Depakote ®
Depakote ® (other names Epilim, divalproex sodium, and Depakene) is used as an anti-epileptic agent that increases the level of gamma-aminobutyric acid. A depakote delayed-release tablet was approved by FDA in 1983, while ER was granted approval in 2002. Depakote contains valproic acid as an API and valproate sodium as a coformer. Valproic acid is in liquid form at room temperature, and sodium salt is highly hygroscopic. The cocrystal form of these two is less hygroscopic than the API itself [15,16,[103][104][105][106].

Entresto ®
Entresto ® contains sacubitril and valsartan as an API in the fixed-dose combination. The Entresto is used in the treatment of symptomatic heart failure and to reduce the risk of cardiovascular death. It is available in the form of a film-coated tablet containing sacubitril and valsartan: 24/26 mg and was approved by FDA in 2015. Entresto ® is a type of drug-drug cocrystal industrialized and marketed by Novartis, Basel, Switzerland.

Commercially Available Drug Products Based on Cocrystals
The ultimate aim of developing any technology/process is to make it reach the target population. Cocrystals play a vital role in improving the pharmaceutical properties of APIs. Commercialized cocrystal-based drug products are evidence of the efficacious application of cocrystallization in the pharmaceutical companies. Depakote ® , Entresto ® , Suglat ® , Steglatro ® , Lexapro ® , ESIX-10 ® , Beta-chlor ® , Cafcit ® , Zafatek ® , and Lamivudine/zidovudine Teva ® , etc., are some commercially available pharmaceutical products that contain cocrystal-based APIs. The purpose of this section is to make the readers aware of the current scenario of the cocrystal technology.

Depakote ®
Depakote ® (other names Epilim, divalproex sodium, and Depakene) is used as an anti-epileptic agent that increases the level of gamma-aminobutyric acid. A depakote delayed-release tablet was approved by FDA in 1983, while ER was granted approval in 2002. Depakote contains valproic acid as an API and valproate sodium as a coformer. Valproic acid is in liquid form at room temperature, and sodium salt is highly hygroscopic. The cocrystal form of these two is less hygroscopic than the API itself [15,16,[103][104][105][106].

Entresto ®
Entresto ® contains sacubitril and valsartan as an API in the fixed-dose combination. The Entresto is used in the treatment of symptomatic heart failure and to reduce the risk of cardiovascular death. It is available in the form of a film-coated tablet containing sacubitril and valsartan: 24/26 mg and was approved by FDA in 2015. Entresto ® is a type of drugdrug cocrystal industrialized and marketed by Novartis, Basel, Switzerland. Valsartan is a neprilysin inhibitor and block angiotensin II receptor. Entresto ® is the best example of a drug-drug cocrystal for the improvement of the pharmacokinetics properties of API due to cocrystallization. Valsartan shows a bioavailability enhancement of 50% in Entresto ® compared to valsartan alone [15,16,107].

Suglat ®
Suglat ® is effective against selective SGLT2 (Sodium-Glucose Co-Transporter 2) inhibitor used in the treatment of diabetes and is available in the form of a tablet. Astellas, Tokyo, Japan and Kotobuki Pharmaceutical Co., Ltd., Nishina, Shizuoka, Japan ("Kotobuki") discovered Suglat through research collaboration. Suglat ® was launched by Astellus Pharma Inc. Tokyo, Japan and Kotobuki Pharmaceutical, Nishina, Shizuoka, Japan on 17 April 2014 in Tokyo. It is available in Suglat ® tablets 25 mg and 50 mg. It is a good example of a cocrystal-based product that contains ipragliflozin as an API and L-proline as a coformer. Ipragliflozin absorbs moisture and is converted to a hydrate form under storage conditions. The cocrystallization of ipragliflozin' with L-proline imparts stability against hydrate formation [15,16,105,108].

Steglatro ®
Steglatro ® is indicated for treatment of insufficiently controlled type 2 diabetes mellitus in adults. It acts by inhibiting SGLT2. Steglatro ® contains ertugliflozin as an API and Lpyroglutamic acid as a coformer. The daily recommended starting dose is 5 mg. If more prominent glycemic control is required, the dose of ertugliflozin can be raised in individuals who tolerate 5 mg once daily to 15 mg once daily. It was approved by US FDA in 2017 and is marketed by Pfizer, New York, United States. Cocrystallization here serves the purpose of stability enhancement of the API, because ertugliflozin exists as an unstable amorphous material. In this, ertugliflozin and L-pyroglutamic acid are used in a 1:1 ratio to enhance the stability and physicochemical properties of ertugliflozin [15,105,109,110].

Lexapro ® & ESIX-10 ®
Lexapro ® contains escitalopram oxalate, which is a selective serotonin reuptake inhibitor (SSRI) used to manage and treat major depressive and generalized anxiety disorders. Escitalopram is a pure S-enantiomer of racemic citalopram, which is also an antidepressant medication. It was approved by US FDA in 2002 and is marketed by Allergan, Dublin, Ireland. A similar example of escitalopram oxalate cocrystals is ESIX-10. It is available in the market in tablet form (10 mg). It was approved in 2009 for the treatment of anxiety and depression [15,16,111,112].

Beta-Chlor ®
The existence of chloral betaine as a cocrystal was discovered only recently, in 2016, though it was first chemically synthesized. Another example is chloral betaine (Betachlor ® ), which was afterward recognized as a cocrystal in 2016. Chloral hydrate was the first sedative that was chemically synthesized in 1832. This cocrystal was made up of betaine and chloral hydrate. The cocrystals improve the thermal stability of chloral betaine compared to the pure drug substance. The melting point of chloral hydrate is 60 • C, whereas the melting point of the prepared cocrystal of chloral betaine was reported to be 120 • C [15,105].

Cafcit ®
Cafcit ® is another cocrystal that contains citrated caffeine or caffeine citrate. It is used to treat breathing problems in premature babies. Cafcit ® shows better dissolution behavior and exhibits lower hygroscopicity than caffeine. According to X-ray diffraction studies, the cocrystal is held together by O-H···N hydrogen bonds between citric acid's carboxylic acid

Zafatek ®
Zafatek ® is a cocrystal-based tablet used as an anti-diabetes agent. It contains trelagliptin and succinic acid as API and coformer, respectively. Trelagliptin is an oral dipeptidyl peptidase IV inhibitor and was approved for use in Japan in March 2015. It is marketed by the Takeda pharmaceutical company, Tokyo, Japan [16,114].

Lamivudine/Zidovudine Teva ®
Lamivudine-zidovudine cocrystal is the best example of a drug-drug cocrystal. It is indicated in antiretroviral combination therapy for the treatment of human immunodeficiency virus (HIV) infection. Lamivudine/zidovudine Teva is a generic product marketed by Teva pharmaceuticals. Zidovudine and lamivudine both have a number of hydrogen bond donor and acceptor groups. The cytosine fragment of lamivudine and the thymine fragment of zidovudine seem to be capable of forming synthons with substances that have complementary hydrogen-bonding groups [16,[115][116][117].

Odomzo ®
Odomzo ® contains sonidegib as an active ingredient for the treatment of basal cell carcinoma. Odomzo ® was approved by U.S. FDA in July 2015 and by EMA in August 2015. This is an example of cocrystals in which phosphoric acid is used as a coformer. The daily recommended dose is 200 mg of sonidegib, administered orally, and separated from the meal. Odomzo ® is available in capsule form and is manufactured by Sun Pharmaceutical Industries Ltd., Mumbai, India [118][119][120].

Mayzent ®
Mayzent ® is used to treat multiple sclerosis. Mayzent ® contains siponimod as an API and fumaric acid as a coformer in a stoichiometric ratio of 2:1. Mayzent ® cocrystal is thermodynamically stable and is manufactured by Novartis, Basel, Switzerland. Mayzent ® was approved by U.S. FDA in 2019 and available in tablet form [121][122][123].

Seglentis ®
Seglentis ® is a drug-drug cocrystal comprising celecoxib and tramadol. Seglentis ® was approved by U.S. FDA in 2021 and is manufactured by Kowa pharmaceuticals, Alabama, United States. It is used in the treatment of acute pain, and the daily recommended dose of Seglentis ® is 100 mg (56 mg celecoxib and 44 mg tramadol hydrochloride) [122,124].

Dimenhydrinate
Dimenhydrinate is the cocrystal of diphenhydramine (drug) and 8-chlorotheophylline (coformer). It was approved by U.S. FDA in 1982 and is manufactured by Watson Laboratories Inc, New Jersey, United States. Dimenhydrinate is available in tablet form (50 mg) for the treatment of motion sickness, including nausea and vomiting [17,125,126].

Ibrutinib
Ibrutinib, an anticancer medication used to treat chronic lymphocytic leukemia, was combined with fumaric acid to create a cocrystal that has better stability while exhibiting similar solubility to the original API. This cocrystal is still waiting for FDA clearance [15,127]. TAK-020 with Gentisic acid (coformer) is used in the treatment of rheumatoid arthritis. Currently TAK-020 is available in oral solution form. Takeda Pharmaceuticals, Tokyo, Japan is currently working on the TAK-020-gentisic acid cocrystals to form the tablet. TAK-020 is in phase 1 clinical trial. If Takeda Pharmaceuticals get positive outcomes from the clinical trials, it would be the first solid dosage form of the TAK-020. Kouya Kimoto also reported that cocrystals of TAK-020 with gentisic acid showed an enhanced dissolution rate [128,129,133,134]. All the above-mentioned cocrystal-based products are enlisted in Table 6.

Most Popular Coformers Utilized in Cocrystal-Based Marketed Formulations
On the basis of the available literature, aliphatic carboxylic acid-based coformers are the most commonly used in the marketed cocrystal preparations. These coformers exhibit favorable hydrogen-bonding interactions with the APIs, resulting in the formation of cocrystals. Though other coformers are reported to be used extensively in cocrystal research, the carboxylic acid-based coformers have surpassed all other coformers in terms of usage in marketed formulations. The reason for the usage of these coformers is not exactly known but they do possess a good number of hydrogen-bond donors and acceptors, which is an essential feature of cocrystal formation. Currently, the usage of coformers in marketed formulations is in the following order: fumaric acid, oxalic acid > succinic acid > citric acid. Additionally, a literature search was carried out in common search engines such as ScienceDirect, Web of Science and PubMed with the "name of coformer" followed by the word "cocrystals" as key words. The results are shown in Figure 12. From this search we can assess the current scenario of the scientific publications based on the mentioned coformers.

Fumaric Acid (FA)
The first instance of natural fumaric acid isolation was carried out from the plant fumaria officinalis. The other names of fumaric acid are trans-1,2-ethylenedicarboxylic acid or (E)-2-butenedioic acid; the term "fumarates" is also used synonymously. Chemically, fumaric acid can be synthesized from maleic anhydride. Fumaric acid is a colorless crystalline solid. The molecular formula of fumaric acid is C 4 H 4 O 4 . Fumaric acid is degraded by both aerobic and anaerobic microorganisms [136][137][138][139]. The chemical structure of fumaric acid is shown in Figure 13. The properties of fumaric acid along with other carboxylic acid-based coformers are tabulated in Table 7.

Fumaric Acid (FA)
The first instance of natural fumaric acid isolation was carried out from the plant fumaria officinalis. The other names of fumaric acid are trans-1,2-ethylenedicarboxylic acid or (E)-2-butenedioic acid; the term "fumarates" is also used synonymously. Chemically, fumaric acid can be synthesized from maleic anhydride. Fumaric acid is a colorless crystalline solid. The molecular formula of fumaric acid is C4H4O4. Fumaric acid is degraded by both aerobic and anaerobic microorganisms [136][137][138][139]. The chemical structure of fumaric acid is shown in Figure 13. The properties of fumaric acid along with other carboxylic acid-based coformers are tabulated in Table 7.

Fumaric Acid (FA)
The first instance of natural fumaric acid isolation was carried out from the plant fumaria officinalis. The other names of fumaric acid are trans-1,2-ethylenedicarboxylic acid or (E)-2-butenedioic acid; the term "fumarates" is also used synonymously. Chemically, fumaric acid can be synthesized from maleic anhydride. Fumaric acid is a colorless crystalline solid. The molecular formula of fumaric acid is C4H4O4. Fumaric acid is degraded by both aerobic and anaerobic microorganisms [136][137][138][139]. The chemical structure of fumaric acid is shown in Figure 13. The properties of fumaric acid along with other carboxylic acid-based coformers are tabulated in Table 7.     Esters of fumaric acid such as mono and dimethyl fumarate have good pharmaceutical application in the treatment of multiple sclerosis and psoriasis. In 1994, DMF was initially made available on the market as Fumaderm ® [145].

Fumaric Acid as a Coformer
Yang et al. [7] reported that fumaric acid can be a choice of coformer to form cocrystals. Dezhi et al. reported that fumaric acid has good water solubility compared to berberine chloride (BBC). BBC possess good pharmacological activities, but poor stability limits its applications. BBC-fumaric acid cocrystals improve the stability and dissolution rate compared to BBC alone. Similarly, cocrystals of promethazine hydrochloride with the fumaric acid as coformer in the ratio 2:1 possess good solubility and stability [146]. A few research works have demonstrated the use of fumaric acid as a coformer in improving the dissolution rate (approximately 6.1 × 10 −3 mmol cm −2 min −1 ) of fluoxetine hydrochloride [147,148]. It is also reported that fumaric acid can effectively improve the therapeutic efficacy of the APIs by improving their physicochemical properties. Enoxacin is an anti-bacterial of the fluoroquinolone class having poor aqueous solubility. The cocrystal of enoxacin with fumaric acid enhanced the solubility and permeability of the drug and thereby improved its anti-bacterial activity as well [149][150][151]. The cocrystals of 6-nitroquinoline were grown using fumaric acid as a coformer in a 1:1 ratio by using the slow solvent evaporation method. The hydrogen bonds C-H···O and O-H···N in 6-nitroquinoline fumaric acid cocrystals stabilized the structure of the API [152]. Chaitanya et al. [153] reported that the use of fumaric acid as a coformer enhances the solubility, dissolution rate, and permeability of nicorandil. They also reported that nicorandil fumaric acid cocrystals have a good hardness property at lower compaction pressure. It is also reported that single crystals of L-histidinium can be synthesized by using fumaric acid as a coformer [154]. Similarly, another report shows that fumaric acid is capable of forming single crystals with L-phenylalanine. The obtained single cocrystal of L-phenylalanine has good thermal stability [155]. The hydrogen-bonding interaction of API with fumaric acid in cocrystals is depicted in Figure 14.
According to the reported literature, fumaric acid used as a coformer in the formation of cocrystals plays a vital role. Fumaric acid showed the higher impact on the solubility and dissolution rate. Sildenafil-fumaric acid cocrystals obtained by the slow solvent evaporation method showed a great improvement in the solubility of nearly 5-fold compared to sildenafil alone. Not only did sildenafil cocrystals show improved solubility, but other cocrystals with fumaric acid also showed an increment in the solubility [156]. In the case of ketoconazole-fumaric acid cocrystals taken in the molar ratio 1:1, 1:2, and 1:3 made by using the slow solvent evaporation method, all three-molar ratio cocrystals showed improvement in the solubility, dissolution rate, and stability of the ketoconazole. The dissolution rate of ketoconazole-fumaric acid cocrystals was enhanced 1.65-fold compared to ketoconazole alone [157]. Cocrystals of promethazine hydrochloride with fumaric acid were prepared by mechanochemistry and slow solvent evaporation in the same molar ratio of 2:1. Both the promethazine hydrochloride-fumaric acid cocrystals have improved solubility and stability [146]. Below are the some reported cocrystals with fumaric acid as coformer showing improvement in solubility, dissolution rate, permeability, and stability. The utility of fumaric acid as coformer and its impact on the properties of prepared cocrystals is summarized in Table 8. According to the reported literature, fumaric acid used as a coformer in the formation of cocrystals plays a vital role. Fumaric acid showed the higher impact on the solubility and dissolution rate. Sildenafil-fumaric acid cocrystals obtained by the slow solvent evaporation method showed a great improvement in the solubility of nearly 5fold compared to sildenafil alone. Not only did sildenafil cocrystals show improved solubility, but other cocrystals with fumaric acid also showed an increment in the solubility [156]. In the case of ketoconazole-fumaric acid cocrystals taken in the molar ratio 1:1, 1:2, and 1:3 made by using the slow solvent evaporation method, all three-molar ratio cocrystals showed improvement in the solubility, dissolution rate, and stability of the ketoconazole. The dissolution rate of ketoconazole-fumaric acid cocrystals was enhanced 1.65-fold compared to ketoconazole alone [157]. Cocrystals of promethazine hydrochloride with fumaric acid were prepared by mechanochemistry and slow solvent evaporation in the same molar ratio of 2:1. Both the promethazine hydrochloride-fumaric acid cocrystals have improved solubility and stability [146]. Below are the some reported cocrystals with fumaric acid as coformer showing improvement in solubility, dissolution rate, permeability, and stability. The utility of fumaric acid as coformer and its impact on the properties of prepared cocrystals is summarized in Table 8. Table 8. Impact of fumaric acid as coformer on drugs.

Cocrystal
Method of Preparation Impact on Solubility

Impact on Dissolution Rate
Impact on Bioavailability  Table 8. Impact of fumaric acid as coformer on drugs.

Impact on Stability References
Berberine-Fumaric acid

Oxalic Acid (OA)
Oxalic acid can be naturally obtained from bacteria, plants, fungi, and animals or can be chemically synthesized. Oxalic acid is odorless alpha, omega-dicarboxylic acid. The IUPAC name is ethanedioic acid and the formula is C 2 H 2 O 4 [91,140,141]. The chemical structure of oxalic acid is shown in Figure 15. Refer to Table 7 for the other physical and chemical properties of the oxalic acid.

Oxalic Acid (OA)
Oxalic acid can be naturally obtained from bacteria, plants, fungi, and animals or can be chemically synthesized. Oxalic acid is odorless alpha, omega-dicarboxylic acid. The IUPAC name is ethanedioic acid and the formula is C2H2O4 [91,140,141]. The chemical structure of oxalic acid is shown in Figure 15. Refer to Table 7 for the other physical and chemical properties of the oxalic acid.

Oxalic Acid as a Coformer
From the earlier discussion, it is clear that a coformer plays a vital role in the formulation of cocrystal-based products. Oxalic acid is a coformer which has a good water solubility. Hrinova et al. [91] used oxalic acid as a coformer in the preparation of rivaroxaban cocrystals. Rivaroxaban belongs to BCS class II, having low solubility and high permeability. Oxalic acid is a highly water-soluble coformer that interacted with the rivaroxaban, forming the hydrogen bond. Rivaroxaban oxalic acid cocrystal not only increased the solubility but also showed significant improvement in the dissolution rate. Chen et al. [166] reported enhancement in solubility and bioavailability of apixaban cocrystal with oxalic acid as coformer. The prepared cocrystal performed better than the marketed product Eliquis ® . Another report by Kusuma et al. [167] described improvement in stability of temozolomide which is an anti-cancer drug, marketed under the brand name Temodar ® or Temodal ® . Temozolomide often changes in physical appearance from white to light tan/pink during storage. This discoloration is indicative of the degradation of temozolomide. Upon cocrystallization with oxalic acid, temozolomide showed better storage stability. Similarly, escitalopram oxalate-oxalic acid cocrystals are

Oxalic Acid as a Coformer
From the earlier discussion, it is clear that a coformer plays a vital role in the formulation of cocrystal-based products. Oxalic acid is a coformer which has a good water solubility. Hrinova et al. [91] used oxalic acid as a coformer in the preparation of rivaroxaban cocrystals. Rivaroxaban belongs to BCS class II, having low solubility and high permeability. Oxalic acid is a highly water-soluble coformer that interacted with the rivaroxaban, forming the hydrogen bond. Rivaroxaban oxalic acid cocrystal not only increased the solubility but also showed significant improvement in the dissolution rate. Chen et al. [166] reported enhancement in solubility and bioavailability of apixaban cocrystal with oxalic acid as coformer. The prepared cocrystal performed better than the marketed product Eliquis ® . Another report by Kusuma et al. [167] described improvement in stability of temozolomide which is an anti-cancer drug, marketed under the brand name Temodar ® or Temodal ® .
Temozolomide often changes in physical appearance from white to light tan/pink during storage. This discoloration is indicative of the degradation of temozolomide. Upon cocrystallization with oxalic acid, temozolomide showed better storage stability. Similarly, escitalopram oxalate-oxalic acid cocrystals are marketed under the trade name Lexapro ® in which oxalic acid is used as a coformer. The escitalopram oxalate has the stability issue, which is improved by oxalic acid after successful generation of escitalopram oxalate cocrystals [15,105]. Another report by Karki et al. [58] demonstrated that paracetamol (acetyl-para-aminophenol)-oxalic acid cocrystals are capable of improving the poor compressibility during tablet production. Chen et al. [168] reported that oxalic acid used as coformer in the preparation of xanthotoxin cocrystals enhanced its solubility, dissolution rate, and stability. The hydrogen-bonding interaction between the different APIs and oxalic acid is shown in Figure 16. Oxalic acid is also used as a coformer to enhance the solubility, dissolution rate, permeability, stability, and bioavailability of the drugs. According to some reported literature, there was no impact on the permeability of the drug, but there was a higher impact on the solubility on the drugs. The solubility of the drug increased up to 12-fold depending on the molar ratio, method of preparation, and other factors. Xanthotoxinoxalic acid cocrystals showed a nearly 1.6-fold solubility improvement, while rebamipide-oxalic acid cocrystals showed a 7.29-fold solubility increment. Both cocrystals were made by liquid-assisted grinding, but there was a difference in the molar ratio of drug and oxalic acid. Rebamipide-oxalic acid cocrystals also showed an improvement in bioavailability [169]. It is also reported that apixaban-oxalic acid cocrystals taken in a molar ratio of 4:3 increased solubility approximately 2-fold and bioavailability 2.7-fold [166]. Table 9 summarizes the applications of oxalic acid as coformer in improving the physicochemical properties of APIs. Table 9. Impact of oxalic acid as a coformer on drugs.

Method of Prepa-Impact on
Impact on Impact on Bioa-Impact on Oxalic acid is also used as a coformer to enhance the solubility, dissolution rate, permeability, stability, and bioavailability of the drugs. According to some reported literature, there was no impact on the permeability of the drug, but there was a higher impact on the solubility on the drugs. The solubility of the drug increased up to 12-fold depending on the molar ratio, method of preparation, and other factors. Xanthotoxin-oxalic acid cocrystals showed a nearly 1.6-fold solubility improvement, while rebamipide-oxalic acid cocrystals showed a 7.29-fold solubility increment. Both cocrystals were made by liquidassisted grinding, but there was a difference in the molar ratio of drug and oxalic acid. Rebamipide-oxalic acid cocrystals also showed an improvement in bioavailability [169]. It is also reported that apixaban-oxalic acid cocrystals taken in a molar ratio of 4:3 increased solubility approximately 2-fold and bioavailability 2.7-fold [166]. Table 9 summarizes the applications of oxalic acid as coformer in improving the physicochemical properties of APIs. Table 9. Impact of oxalic acid as a coformer on drugs.

Impact on Solubility
Impact on Dissolution rate

Succinic Acid (SA)
Georgius Agricola, a German chemist, discovered succinic acid (also known as butanedioic) with the molecular formula C4H6O4 [173]. SA is a dicarboxylic acid that exists as white, glittering crystals [174]. The chemical structure of succinic acid is shown in Figure 17. Other physical and chemical properties of succinic acid are given in Table 7. The global demand for succinic acid is increasing and is approximately 30,000 tons per annum [175]. Market demand for SA is increasing tremendously, from USD 131.7 million in 2018 to USD 182.8 million in 2023 at a 6.8% CAGR (compound annual growth The global demand for succinic acid is increasing and is approximately 30,000 tons per annum [175]. Market demand for SA is increasing tremendously, from USD 131.7 million in 2018 to USD 182.8 million in 2023 at a 6.8% CAGR (compound annual growth rate) [176].
Succinic acid has a good aqueous solubility that triggers the solubility and dissolution rate of APIs that belong to BCS class II. Succinic acid is commonly used as a coformer for the preparation of cocrystals [142]. Coformers are the backbone of cocrystal formation and of their solubility enhancement. Succinic acid is soluble in water (71 mg/mL) and is used as a coformer to improve the solubility of BCS class-II drugs. By introducing a more soluble coformer into the crystal lattice, which results in a lower solvation barrier, significant attempts have been undertaken in recent decades to increase the solubility, permeability, or bioavailability of poorly water-soluble medicines. The ultimate aim of using the coformer is to improve the solubility and dissolution rate of a poorly aqueous soluble drug by introducing the coformers into the BCS class-II drugs [18,92,142].

Succinic Acid as a Coformer
Alhalaweh et al. [177] reported that urea-succinic acid cocrystals improve the solubility and thermodynamic stability of urea. In this work, urea as an API (e.g., to treat eczema & psoriasis) and succinic acid as a coformer was used to form the cocrystals. An acid-amide heterosynthon stabilized the 1:1 U-SA cocrystal, whereas amide-amide homosynthons and acid-amide heterosynthons stabilized the 2:1 cocrystals. The hydrogen bond interaction takes place between different APIs and succinic acid (coformer) to form the cocrystals, as shown in Figure 18. solubility, permeability, or bioavailability of poorly water-soluble medicines. The ultimate aim of using the coformer is to improve the solubility and dissolution rate of a poorly aqueous soluble drug by introducing the coformers into the BCS class-II drugs [18,92,142].

Succinic Acid as a Coformer
Alhalaweh et. al. [177] reported that urea-succinic acid cocrystals improve the solubility and thermodynamic stability of urea. In this work, urea as an API (e.g., to treat eczema & psoriasis) and succinic acid as a coformer was used to form the cocrystals. An acid-amide heterosynthon stabilized the 1:1 U-SA cocrystal, whereas amide-amide homosynthons and acid-amide heterosynthons stabilized the 2:1 cocrystals. The hydrogen bond interaction takes place between different APIs and succinic acid (coformer) to form the cocrystals, as shown in Figure 18. In the case of itraconazole-succinic acid cocrystals, the dissolution rate and stability were increased compared to pure itraconazole. Two formulations were made by a liquid anti-solvent method (F1) and a gas anti-solvent method (F2). F1 achieved 50% drug release in 2 h while F2 achieved 92% drug release in 2 h. Carbamazepine-succinic acid cocrystals showed enhanced solubility, dissolution rate, stability and bioavailability com- In the case of itraconazole-succinic acid cocrystals, the dissolution rate and stability were increased compared to pure itraconazole. Two formulations were made by a liquid anti-solvent method (F1) and a gas anti-solvent method (F2). F1 achieved 50% drug release in 2 h while F2 achieved 92% drug release in 2 h. Carbamazepine-succinic acid cocrystals showed enhanced solubility, dissolution rate, stability and bioavailability compared to pure carbamazepine. Furthermore, fluoxetine-succinic acid cocrystals were made by using the slow solvent evaporation method in which fluoxetine-succinic acid was taken in the molar ratio 2:1. In this case, only the solubility of fluoxetine increased, approximately 2-fold. Table 10 below summarizes the role of succinic acid in enhancing the solubility, dissolution rate, bioavailability and stability of drugs. Isoniazid-Succinic acid (2:1) Slow solvent evaporation ---Improved ------ [180] Imidazopyridazine-Succinic acid (1:1) Neat grinding method Improved Improved ------ [181] Brexpiprazole-Succinic acid (1:1) Solvent-drop grinding method

Other Applications
Succinates (most commonly calcium succinate, potassium succinate, and sodium succinate) are extremely helpful in the treatment of long-term illnesses and injuries. These are typically employed medically as sedatives, antispasmodics, antirheumatics, and contraceptives. Succinic acid is also employed as an antioxidant and a potassium ion inhibitor. Succinic acid is also a useful product for athletes. As a result, the dicarboxylate could be considered as an "elixir of youth" [96].

Citric Acid
Citric acid is a colorless, odorless white crystalline powder; its chemical name is 2-hydroxypropane-1,2,3-tricarboxylic acid. The molecular formula of citric acid anhydrate is C 6 H 8 O 7 . The other physical and chemical properties of the citric acid are mentioned in the Table 7. Lemon, orange, pineapple, strawberry, red currant, cranberry, and other fruits mostly contain citric acid. In 2021, the volume of the global citric acid market was 2.7 million tons. By 2027, the market is anticipated to grow to 3.2 million tons [187,188]. The chemical structure of citric acid is shown in Figure 19.

Citric Acid as a Coformer
There are various studies showing the successful applicability of citric acid as a coformer in increasing the solubility of poorly aqueous soluble drugs by many times. Yan et al. [143] reported that the solubility of metformin HCl was increased by using citric acid as a coformer. A similar example of berberine chloride was studied by Lu et al. [6] who reported that berberine chloride shows stability issues during wet granulation for tablet production. Cocrystals of berberine chloride with citric acid as a coformer were more stable compared to berberine chloride alone. A study by Hsu et al. [189] reported that the stability of theophylline improved after preparation of its cocrystal with citric acid. Deng et al. [190] reported that dapagliflozin possess the stability problem at high temperature and also has hygroscopicity issues. Cocrystals of dapagliflozin made by the use of citric acid (coformer) improved the stability of dapagliflozin. Furthermore, Wang et al. [56] described in their research that pyrazinamide (an anti-tuberculosis drug) belongs to BCS class II and has a solubility problem. Cocrystals of pyrazinamide with citric acid enhanced both the solubility and dissolution rate compared to pyrazinamide alone. Additionally, norfloxacin-citric acid cocrystals showed improved solubility compared to norfloxacin alone [191]. Another report by Revika et al. [192] described that ethyl pmethoxycinnamate used as anti-inflammatory agent showed a 44.19% increase in solubility in its cocrystal form compared to ethyl p-methoxycinnamate alone. Fahad et al. [193] reported that cocrystals of simvastatin in which citric acid was used as a coformer showed greater solubility, dissolution rate, and bioavailability. The hydrogen-bonding interaction between the different APIs and citric acid is shown in Figure 20.

Citric Acid as a Coformer
There are various studies showing the successful applicability of citric acid as a coformer in increasing the solubility of poorly aqueous soluble drugs by many times. Yan et al. [143] reported that the solubility of metformin HCl was increased by using citric acid as a coformer. A similar example of berberine chloride was studied by Lu et al. [6] who reported that berberine chloride shows stability issues during wet granulation for tablet production. Cocrystals of berberine chloride with citric acid as a coformer were more stable compared to berberine chloride alone. A study by Hsu et al. [189] reported that the stability of theophylline improved after preparation of its cocrystal with citric acid. Deng et al. [190] reported that dapagliflozin possess the stability problem at high temperature and also has hygroscopicity issues. Cocrystals of dapagliflozin made by the use of citric acid (coformer) improved the stability of dapagliflozin. Furthermore, Wang et al. [56] described in their research that pyrazinamide (an anti-tuberculosis drug) belongs to BCS class II and has a solubility problem. Cocrystals of pyrazinamide with citric acid enhanced both the solubility and dissolution rate compared to pyrazinamide alone. Additionally, norfloxacin-citric acid cocrystals showed improved solubility compared to norfloxacin alone [191]. Another report by Revika et al. [192] described that ethyl p-methoxycinnamate used as anti-inflammatory agent showed a 44.19% increase in solubility in its cocrystal form compared to ethyl pmethoxycinnamate alone. Fahad et al. [193] reported that cocrystals of simvastatin in which citric acid was used as a coformer showed greater solubility, dissolution rate, and bioavailability. The hydrogen-bonding interaction between the different APIs and citric acid is shown in Figure 20.
Metformin hydrochloride-citric acid cocrystals obtained by solution crystallization, neat grinding, and liquid-assisted grinding in the ratio of 1:1 increased its solubility by 1-4fold. The bioavailability enhancement of metformin cocrystals was seen as well. Furthermore, rebamipide-citric acid cocrystals exhibited 12.58-fold improvement in solubility compared to rebamipide alone. The intrinsic dissolution rate of the cocrystal was~13.2 times higher than the API alone [169]. It is essential to consider the molar ratio of API:coformer taken during the cocrystallization experiments [194]. For example, simvastatin-citric acid required a molar ratio of 1:1 to form cocrystals having improved the solubility profile. Conversely, nefiracetam-citric acid cocrystals required an API:coformer ratio of 2:1 to show improvement in the solubility. Various other examples have been summarized in Table 11. Metformin hydrochloride-citric acid cocrystals obtained by solution crystallization, neat grinding, and liquid-assisted grinding in the ratio of 1:1 increased its solubility by 1-4-fold. The bioavailability enhancement of metformin cocrystals was seen as well. Furthermore, rebamipide-citric acid cocrystals exhibited 12.58-fold improvement in solubility compared to rebamipide alone. The intrinsic dissolution rate of the cocrystal was ~13.2 times higher than the API alone [169]. It is essential to consider the molar ratio of API:coformer taken during the cocrystallization experiments [194]. For example, simvastatin-citric acid required a molar ratio of 1:1 to form cocrystals having improved the solubility profile. Conversely, nefiracetam-citric acid cocrystals required an API:coformer ratio of 2:1 to show improvement in the solubility. Various other examples have been summarized in Table 11.   Table 11. Impact of citric acid as a coformer on drugs. Berberine chloride-Citric acid (1:1)

Comparison of Coformers
On the basis of scientific papers and the literature trend, four coformers are selected: fumaric acid, oxalic acid, succinic acid, and citric acid. All the coformers used in the cocrystals showed the improvement in the solubility, dissolution rate, bioavailability, and stability, while only fumaric acid also showed the permeability enhancement. Table 12 summarizes the role of fumaric acid, oxalic acid, succinic acid, and citric acid in improving the physicochemical properties of drug. The number of commercialized products comprised of fumaric acid or oxalic acid as a coformer are higher compared to the other two coformers. The scientific literature and approved commercialized products indicate the successful application of fumaric and oxalic acid as coformers in generating cocrystals of problematic APIs. However, there is a need for studies exploring the applicability of any particular coformer in improving the physicochemical properties of a particular class of APIs. The cocrystal formation is principally governed by the intermolecular hydrogen-bonding interactions and the changes these interactions bring about in the crystal structure. Hence, further research is required to support the claim of fumaric and oxalic acid as the best-suited coformer for API cocrystallization. Based on currently available marketed cocrystal-based formulations, it can be said that the carboxylic acid-based compounds (fumaric acid and oxalic acid in particular) can be best suited for cocrystallization to improve pharmaceutical properties. However, the authors feel that industrial input is essential to prove the potential of any coformer. Figure 21 shows the major steps involved in the development of cocrystal-based formulations. After the successful development of a cocrystal-based product, the next stage is to obtain the necessary approvals from the concerned regulatory bodies for commercialization of the developed product. Hence, this section briefly explains the current regulatory scenario with respect to product patenting and filing. id and oxalic acid in particular) can be best suited for cocrystallization to improve pharmaceutical properties. However, the authors feel that industrial input is essential to prove the potential of any coformer. Figure 21 shows the major steps involved in the development of cocrystal-based formulations. After the successful development of a cocrystal-based product, the next stage is to obtain the necessary approvals from the concerned regulatory bodies for commercialization of the developed product. Hence, this section briefly explains the current regulatory scenario with respect to product patenting and filing. It is necessary to improve the regulatory procedure for the filing and granting of patent as well as for the regulatory approval to commercialize the product. There are generally three conditions for the granting of patent, such as novelty, non-obviousness and utility. There are two ways to file the patent application in patent office: either by national phase application or an international phase application (PCT route). The guidelines for the pharmaceutical cocrystals were first published by the USFDA in 2013. As per the guideline, pharmaceutical cocrystals are considered to be a drug product intermediate that requires additional regulation. In the latest guidelines from USFDA in 2018, cocrystals were included as a drug substance and defined as "crystalline materials composed of two or more different molecules, one of which is the API, in a defined stoichiometric ratio within the same crystal lattice that are associated by nonionic and noncovalent bonds". The USFDA also stated that a coformer is the component that interacts nonionically with the API in the crystal lattice, that is not a solvent (including water), and is typically nonvolatile. For the regulatory approval of pharmaceutical cocrystals, there are two possibilities: the new drug application (NDA) pathway (505(b)(2)), and the abbreviated new drug application (ANDA) pathway (505(j)). The condition for an NDA application is that the cocrystals not have an active pharmaceutical ingredient that is already a reference listed drug (RLD) [199]. On the other hand, the applicant can file an ANDA application for the cocrystals which contains the previously approved drug (RLD). Mayzent is the best example for the newly approved cocrystals through the NDA route because its active pharmaceutical ingredient was not mentioned in the RLD [12,122,129,200]. It is necessary to improve the regulatory procedure for the filing and granting of patent as well as for the regulatory approval to commercialize the product. There are generally three conditions for the granting of patent, such as novelty, non-obviousness and utility. There are two ways to file the patent application in patent office: either by national phase application or an international phase application (PCT route). The guidelines for the pharmaceutical cocrystals were first published by the USFDA in 2013. As per the guideline, pharmaceutical cocrystals are considered to be a drug product intermediate that requires additional regulation. In the latest guidelines from USFDA in 2018, cocrystals were included as a drug substance and defined as "crystalline materials composed of two or more different molecules, one of which is the API, in a defined stoichiometric ratio within the same crystal lattice that are associated by nonionic and noncovalent bonds". The USFDA also stated that a coformer is the component that interacts non-ionically with the API in the crystal lattice, that is not a solvent (including water), and is typically nonvolatile. For the regulatory approval of pharmaceutical cocrystals, there are two possibilities: the new drug application (NDA) pathway (505(b)(2)), and the abbreviated new drug application (ANDA) pathway (505(j)). The condition for an NDA application is that the cocrystals not have an active pharmaceutical ingredient that is already a reference listed drug (RLD) [122]. On the other hand, the applicant can file an ANDA application for the cocrystals which contains the previously approved drug (RLD). Mayzent is the best example for the newly approved cocrystals through the NDA route because its active pharmaceutical ingredient was not mentioned in the RLD [12,122,129,199].

Conclusions
In the current scenario, poor solubility, poor dissolution rate, poor permeability, low bioavailability, and instability are the major reasons for the failure of an active pharmaceutical ingredient (API). The researchers are focusing on mitigating these APIs issues. Cocrystallization is a proven approach to enhance the physicochemical properties of APIs and thus overcome the problems associated with APIs. Coformers play a paramount role in cocrystallization, as the final properties of cocrystal are dependent on the coformer characteristics and its interaction with the API. Research works have been presented wherein the cocrystallization experiments have resulted in improvement of the earlier-mentioned API properties. However, there is not enough evidence to prove the usage of any particular coformer to solve all API issues. A coformer must be selected based on the nature of the interaction with the API and the positive changes it brings about in the crystal structure after association. On the basis of commercialization potential, the aliphatic carboxylic acid-based coformers have gained prominence. Almost six commercialized cocrystal-based products are based on fumaric acid (two products), oxalic acid (two products), succinic acid (one product), and citric acid (one product). A few research works have been presented in this article, which shows the nature of the association of these coformers with the API and their utility in cocrystallization experiments. The ongoing research on these coformers indicates that their utility is still under exploration, which is a positive indication for cocrystallizationbased research. Moreover, a small but important section related to the patentability and regulations concerning cocrystals is presented. Herein, the possible routes for filing a patent or product are discussed. Finally, the authors urge the readers/researchers to consider the carboxylic acid-based coformers for cocrystallization experiments so as to obtain concrete information on their utility as ultimate coformers.

Conflicts of Interest:
The authors declare no conflict of interest.