INTRODUCTION:

Discovery and design of Solid form entirely depends on the type of physical property challenges faced in its development and nature of the molecule of interest. Generally the preferred solid form is the more thermodynamically stable crystalline form of the compound.^1,2. However, the stable crystal form of the parent compound may exhibit inadequate solubility or dissolution rate resulting in poor oral absorption, particularly for water-insoluble compounds. When this is the case, alternative solid forms with adequate solubility and dissolution rate need to be investigated.

Components can be broadly classified into amorphous and crystalline forms. Crystalline for solids implies an ideal crystal in which the structural units, termed unit cells, are repeated indefinitely and regularly in three dimensions in space. The unit cell, containing at least one molecule, has a definite orientation and shape defined by the translational vectors, a, b, and c. The unit cell therefore has a definite volume that contains the atoms and molecules necessary for generating the crystal. Amorphous solids lack the long-range order present in crystals.³ Crystalline forms for APIs are strongly preferred because they tend to be more stable, reproducible and amenable to purification than other types of solids.

Molecular crystals can be classified into single-component and multi component crystals. Multi component crystals further constitutes salts, solvates, hydrates and co-crystals. The molecules in an organic pharmaceutical crystal may be chiral or achiral. Some pharmaceuticals are salts. Based on its internal structure, a pharmaceutical crystal may be a molecular adduct (hydrate or solvate), or may be one of a group of polymorphs.⁴

Polymorphism is referred as the ability of a molecule to crystallize in different crystal forms. In the case of elements, this phenomenon is called allotropism. More than half of the pharmaceutically important molecules exhibit polymorphic behavior. A solvent molecule may also occupy a lattice point and thereby form a hydrate or a solvate. Hydrates and solvates are often called pseudopolymorphs and can exhibit different polymorphic distribution. More recently, APIs have been synthesized as co-crystals either by using a co-former or another useful API ⁵.

The number of polymorphic co-crystals that are being added to the database is increasing, and the tendency of solvate/hydrate formation is significantly higher for co-crystals when compared to the crystalline solvates/hydrates of a single solid component⁶.

Co-crystals:

The term co-crystal is used to describe a crystal containing two or more components together.[Figure No. 1] Thus, co-crystals include molecular compounds, molecular complexes, solvates, inclusion compounds, channel compounds, clathrates and other types of multicomponent systems in a crystalline state.

A co- crystal may be defined as a crystalline material consisting of two or more molecular (and electrically neutral) species held together by non-covalent forces ⁷.

Figure No. 1: Co-crystal Stratagy

There has been much debate about the use of the term co- crystal. Desiraju challenges use of the term co- crystal and favours the term molecular complex to describe multi-component crystals having specific non-covalent interactions between the molecules⁸. In contrast Dunitz defends the use of co- crystal as encompassing molecular compounds, molecular complexes, solvates, inclusion compounds, channel compounds, clathrates and possibly other types of multi-component crystals⁹. Dunitz argues that the terms molecular complex, molecular compound and intermolecular complex should not be used exclusively to describe the crystalline state but have typically been used in a very broad sense and should also be used to describe the solid, liquid and even gaseous states in which the constituent molecules are considered to be more strongly associated than in a simple mixture.

There are several definitions proposed by various authors which include

1. Stahly,G. P. defined co-crystals as “a molecular complex that contains two or more different molecules in the same crystal lattice”¹⁰_.

2. Nangia, A. explained them as “multi-component solid-state assemblies of two or more compounds held together by any type or combination of intermolecular interactions”¹¹.

3. Childs, S. L. had given the definition of co-crystals as “crystalline material made up of two or more components, usually in a stoichiometric ratio, each component being an atom, ionic compound, or molecule”¹².

4. Aakero¨y, C. B. defined co-crystals as “compounds constructed from discrete neutral molecular species...all solids containing ions, including complex transition-metal ions, are excluded”¹³.

5. Co-crystals are also defined as “made from reactants that are solids at ambient conditions” “structurally homogeneous crystalline material that contains two or more neutral building blocks that are present in definite stoichiometric amounts”

6. Bond, A. described co-crystals as “synonym for multi-component molecular crystal”¹⁴.

7. While Jones, W. had given the definition as “a crystalline complex of two or more neutral molecular constituents bound together in the crystal lattice through non covalent interactions, often including hydrogen bonding”¹⁵.

8. Zaworotko, M. J. defined co-crystals as “which are formed between a molecular or ionic API and a co-crystal former that is a solid under ambient conditions”¹⁶.

Supramolecular synthons can occur in common functional groups such as carboxylic acids, amides which are particularly amenable to formation of supramolecular synthon. Noncovalant bonds between the molecules are responsible for the formation of co-crystals. Noncovalent bonds mainly include hydrogen bonds. The strong hydrogen bonds include (N-H---O), (O-H---O), (-N-H---N) and (O-H---N). The weak hydrogen bonds involve the (–C-H---O) and (C-H---O=C).[8]. Supramolecular interaction is not limited to hydrogen bonds but it may also include other intermolecular interactions like π-π stacking, halogen bonds or any other non-covalent interactions.

By the application of crystal engineering of co- crystals, historically referred to as molecular complexes the enhancement of drug solubility, dissolution and bioavailability is possible. During dosage form design, the attractive alternative to polymorphs, salts and solvates in the modification of an active pharmaceutical ingredient (API) will be Pharmaceutical co-crystallization. While maintaining the intrinsic activity of the drug molecule, the physicochemical properties of the API and the bulk material properties can be modified. The intellectual property implications of creating co-crystals are also highly relevant. Interest in co-crystals is being increased as potential applications of co-crystals in nonlinear optics (NLO)¹⁷, solvent free organic synthesis^{18, 19}, host-guest chemistry ^20-22, and photographic film formulation are increased.

Co-crystal Vs salt:

Salts and co-crystals though both can be described as multicomponent crystals ¹⁰ as there exists smooth transition between these two categories. But this does not mean that a salt is a co-crystal, but rather salts and co-crystals are both multicomponent crystals. Salts and co-crystals can be distinguished based on whether a proton transfer has occurred from an acid to a base ²³. Multicomponent crystals are composed of two or more components associated through intermolecular interactions where a component is an atom, ion, or molecule. There are numerous molecular complexes to which definitions of salts and co-crystals do not clearly apply.

When a solution containing an organic acid and an organic base deposits a crystalline solid containing both components, to know whether the product is salt or co-crystal presently the way is to determine to which species the proton is attached to. If the proton resides on the base, then proton transfer has occurred and the crystalline acid-base complex formed is a salt. If proton transfer has not occurred and the proton remains on the acid, then it is called co-crystal.

The inclination of an acid to give up a proton can be represented by its pKa, the negative logarithm of the dissociation constant. It is generally accepted that reaction of an acid with a base is expected to form a salt if the ΔpKa (pKa (base) - pKa(acid)) is greater than 2 or 3. ΔpKa criterion is often viewed as essential for the selection of appropriate counterions in a salt selection. Although in general a larger ΔpKa (greater than 3) will result in salt formation and as a smaller ΔpKa (less than 0) will almost exclusively result in co-crystal formation, that parameter is inappropriate for accurately predicting salt formation in the solid state when ΔpKa is between 0 and 3. The majority of crystalline acid-base complexes have a ΔpKa value of less than 1 or greater than 3. Very few will fall in between the range of 0 and 3. In the narrow transition region where salts and co-crystals overlap, the type of resulting complex appears to be random, suggesting that pKa is not a good predictive tool in this ΔpKa region. ²⁴ If the ΔpKa value is negative, then solid state will almost be un-ionized which supports the formation of co-crystals. But, pKa values describe equilibrium phenomena in solution and are not meant to be applied to the solid state. The situation sometimes corresponds to the use of vander Waals radii in characterizing crystal structures. In some situations, same acid-base pair forms salts and co-crystals in different cases. This can be attributed to the narrow ΔpKa transition state where the acid and base may be non-ionized in one crystal structure while in a different crystal structure the same acid and base may be ionized²⁵.

Co-crystal Vs Solvate:

Morissette et al.²⁴ claim that co- crystals (of drugs and drug candidates) are part of the broader family of multi-component crystal systems that includes salts, solvates, clathrates, inclusion crystals (complexes) and hydrates. The primary difference between solvates and co-crystals is the physical state of the individual components²⁴. If one component is liquid at room temperature then the crystals are designated solvates, whereas if both components are solids at room temperature then the crystals are designated as co-crystals. Solvates usually occur due to unexpected result of crystallization from solution ²⁶ and are shown to have the potential to increase drug dissolution rate, as seen in case of the solvated forms of Spironolactone.

Co-crystal Vs Solid dispersion:

Co-crystals are not classified as solid dispersions; nevertheless solid dispersions may occur when attempting to prepare co-crystals from solution. The generic term solid dispersions refers to the dispersion of one or more active ingredients in an inert carrier in a solid state, frequently prepared by the melting (fusion) method, solvent method, or fusion solvent-method ^27,28. The solid dispersion approach to reduce particle size and therefore increase the dissolution rate and absorption of drugs ²⁷. In the preparation of solid dispersions, drugs with a poor ability to form the glassy state, and which demonstrate notable propensity to crystallize, have generally been made amorphous by deliberately preventing crystallization. Under appropriate conditions of temperature and humidity, amorphous materials can crystallize when sufficient molecular mobility exists.

False co-crystals:

It should be emphasized that there can sometimes be bias concerning whether or not a compound is a co-crystal, a solvate or a salt. The distinction between a co-crystal and a salt can be especially problematic if X-ray crystallography is the only method of characterization and the difference between the two extremes is 1 Å in a hydrogen atom position. There are several questions on the number of co-crystals of the APIs whether or not they are salts or co-crystals. This category includes trimethoprim sulfametrole (CSD refcode: HEKRUK), even though it was reported under the title “1:1 Molecular complex of trimethoprim and sulfametrole” the authors described it as ionic complex.²⁹ JATMEW, 3-[2-(N′,N′-dimethylhydrazino)-4-thiazolylmethylthio]-N²-sulfamoylpropionamidine maleic acid (1:1) was reported as a neutral complex³⁰ but, the structural parameters C--O bond lengths, C--N--C bond angles suggest the formation of a maleate anion and a propionamidinium cation. The physical state of the components must also be taken into consideration. For instance, SAGQEW is the crystal structure of Mebendazole and propionic acid³¹. The latter exists as a liquid phase at ambient temperatures (M.p. −21°C). Therefore, SAGQEW should be classified as a solvate rather than a co-crystal.

These examples suggest that one should not completely rely on CSD for the identification of co-crystals For example, salts EBIBEW, PIKLEA, QAWNAD, VAPBAP, VENLUV, etc. are all retrieved as neutral compounds.. The database findings should be supported by inspection of the structural parameters of co-crystal components, and/or revision of the corresponding publications^32-36_.

Advantages of co-crystals:

1. Solubility Advantage of Pharmaceutical Co-crystals

Pharmaceutical co-crystals can improve solubility, dissolution, and bioavailability of poorly water soluble drugs. However, true co-crystal solubility is not readily measured for highly soluble co-crystals because they can transform to the most stable drug form in solution. David J. Good and Nair Rodriguez-Hornedo developed a method to estimate the co-crystal solubility in pure solvent and establish the influence of constituent drug and ligand (i.e., coformer) properties. Co-crystal solubility and solubility product were derived from transition concentration measurements where a solution is in equilibrium with solid drug and co-crystal. Transition concentrations and solubility’s are reported for carbamazepine co-crystals in water, ethanol, isopropanol, and ethyl acetate. The aqueous solubility for seven carbamazepine co-crystals was estimated to be 2-152 times greater than the solubility of the stable carbamazepine dihydrate form. Co-crystal solubility is shown to be directly proportional to the solubility of constituent reactants for carbamazepine, caffeine, and theophylline co-crystals³⁷.

The dissolution of co- crystals of Itraconazole, a triazole drug, with succinic acid, malic acid and tartaric acid, was compared to that of the pure crystalline and amorphous drug ³⁸. The co- crystals behaved in a similar manner to the amorphous form compared with the crystalline drug in achieving and sustaining from 4- to 20-fold higher concentrations on dissolution testing. The practical implications of this finding are important, as the ability to form and sustain a supersaturated solution can have a dramatic impact on drug absorption and bioavailability³⁹. Also co- crystal formed with glutaric acid increased its aqueous dissolution rate by 18 times over that of the homomeric crystalline form⁴⁰.

Designing of cocrysals:

Prediction of Co-crystal formation has been reported to include the following steps: (1) determination of possibility that two or more molecular components to undergo co-crystallization; (2) to identify the primary intermolecular interactions, e.g., hydrogen-bond motifs that exist within a particular structure of co-crystal; and (3) an overlook on the overall packing arrangement in the resulting co-crystal structure⁴¹.

co-crystals can be subjected to various type of studies which involve i) to select suitable co-crystal formers for particular API, ii) screening of pharmaceutical active ingredients with selected co-crystal formers for co-crystals iii) to develop reliable method to prepare pharmaceutical co-crystals and nano co-crystals, iv) to characterize the prepared pharmaceutical co-crystals, v) to scale up the pharmaceutical co-crystals, and vi) to screen for co-crystal polymorphism⁴².

Crystal engineering is being evolved in a manner that it is now synonymous with the archetype of supramolecular synthesis that is, it promotes self assemblage of already existing molecules to generate a wide range of new solid forms without the need to form covalent or break bonds⁴³.

Crystal engineering can be defined as ‘the understanding of noncovalent intermolecular interactions between the molecule in the context of crystal packing and the utilization of such intermolecular interactions in the design of new solid.” For designing the co-crystals, understanding of the supramolecular chemistry of the functional group in the given molecule is a prerequisite because it aids in the selection of suitable co-crystal former. Supramolecular synthon’ is defined as ‘structural units within supermolecules which can be formed and/or assembled by known conceivable synthetic operations involving. Crystal engineering and supramolecular chemistry can be applied to all crystal forms and with no exception to co-crystals. The ultimate goal of this approach, namely, the crystal engineering approach, was to effectively prioritize all possible guest molecules for crystal form screening of drugs, and to avoid the “tactless” high-throughput screening based on trial-and-error. In practice, the crystal engineering will be performed by careful analysis through the Cambridge Structural Database (CSD). Cambridge Structural Database contains over 450 000 crystal structures and user-friendly fragment and motif search protocols, it is possible to estimate the probability of various synthons in the global archive⁴⁴ [Figure No. 2, Table No. 1]

Figure No. 2: Possible homosynthons and heterosynthons in supramolecular chemistry and their occurrence

Table No. 1: Possible homosynthons and heterosynthons in the supramolecular chemistry

Sl. No.	Type of bond	Occurrence
1.	Acid-acid	33%
2.	Acid-pyridine	91%
3.	Acid-amide	47%
4.	Amide-amide	35%
5.	Amide-pyridine	4%
6.	Amide-pyridine-N-Oxide	78%

The robust supramolecular heterosynthons represent perhaps the most reliable and rational route to co-crystals. Furthermore, complementary supramolecular heterosynthons that seem to clearly favor formation of co-crystals are not limited to carboxylic acids. The alcoholamine^{45- 47} and alcohol-pyridine^48-50 supramolecular heterosynthons are also well established in crystal engineering.

The ability of pharmaceutical co-crystals being susceptible to get designed by crystal engineering distinguishes them from other API crystalline forms. First step in a crystal engineering experiment is analyzing the existing crystal structure which is executed through the CSD. This facilitates analyzing packing motifs in a statistical manner and thereby providing empirical information which concerns about common functional groups, the way they are engaged in molecular association, that is, the way they form supramolecular synthons⁵¹. At least 22 years ago Allen and Kennard noted the importance of the CSD in the context of design ⁵². They envisaged that “the systematic analysis of large numbers of related structures is a powerful research technique, capable of yielding results that could not be obtained by any other method.” ⁵³.

Other approach to co- crystal design has been based on consideration of pKa which also sometimes play a major factor for distinguish salts from co-crystals.

Phase diagrams can also be used to produce the co-crystals in an effective manner. The phase diagrams show the conditions where the co-crystal is supersaturated in solution, i.e., the favored solid phase for crystallization can be shown in the phase diagrams. By using these conditions, individual components crystallization can be prevented. The construction and use of ternary phase diagrams should be considered when scaling up co-crystals from solution because it gives the information about the relationship between equilibria of the solid phases and choice of solvent. Based on the presence of similar solubility of individual components, the phase region of the thermodynamically stable co-crystal will be altered and so it is important to determine and map the solubilities of the individual components⁵⁴. Many of the Carbamazepine co-crystals were successfully produced directly from water by increasing the concentration of the co-former based on the ternary solubility phase diagrams¹⁶. In a study by Zai Qun Yu, the phase diagram of caffeine-glutaric acid-acetonitrile in the temperature range of 10-35⁰C was charted using attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy to measure concentrations in situ. Solution-mediated phase transformation was exploited to locate the eutectic points. The operating region was then prescribed according to the stoichiometry of the co-crystal, and the boundary of stability zones at the initial and final temperatures of cooling crystallization. It was demonstrated that co-crystal purity could be compromised when crystallization occurs outside the safe operating region⁶⁹.

Methods of preparation of co–crystals:

Co-crystal is a heteromeric system and its formation occurs only if the non-covalent forces between two (or more) molecules are stronger than between the molecules in the corresponding homomeric crystals. So it is very difficult to prepare a single co-crystal of suitable quality for single X-ray diffraction analysis. The mechanism of formation of co-crystals is far from being understood and Design strategies for co-crystal formation are still being investigated ⁵⁵.

Crystallization is an efficient and effective method of purification and it is used widely in the pharmaceutical industry for isolation of single component crystals. So Synthesis of a co-crystal from solution can be considered as counterintuitive. If different molecules with complementary functional groups form hydrogen bonds which are energetically favorable than those between like molecules of either components, then co-crystals are likely to be thermodynamically (although not necessarily kinetically) favored. Co-crystals involving these supramolecular synthons are usually synthesized by slow evaporation from a solution that contains stoichiometric amounts of the components (co-formers); however, sublimation, growth from the melt, slurries, and grinding two solid co-crystal formers in a ball mill are also suitable methodologies. More often than not, the phase that is obtained is independent of the synthetic methodology. The recently reported technique of solvent-drop grinding, addition of a small amount of suitable solvent to the ground mixture to accelerate co-crystallization appears to be a particularly promising preparation method⁵⁶.

Solution co-crystallization:

In general, similar solubility of the compounds and polymorphic compounds favor the solution co-crystallization. If the two components do not have similar solubility, the least soluble component will be exclusively precipitated out. When crystal has structural flexibility i.e. when exists in several polymorphic forms, it shows that it is not locked into a single type of crystalline lattice or packing. The chance of bringing such a molecule into a different packing arrangement in coexistence with another molecule is more. But, similar solubility and polymorphism alone will not guarantee success⁵⁷.

In solution co-crystallization, at laboratory level, the two components will be dissolved in a solvent and left for evaporation of the solvent. Scale-up crystallization was performed in a crystallization vessel surrounded by a water-jacketed glass. Temperature will be maintained. A digital thermometer, reflux column and overhead stirrer with a Teflon blade and glass shaft will be attached to vessel ports. The drug and co-crystal former were added to a reaction vessel. The solids will be dissolved in suitable solvent mixture and the temperature will be increased first and decreased later at constant intervals to induce crystallization ⁵⁸.

Crystallization by cooling – this technique is effective as usually solubility decreases with temperature. The compound is heated in a solvent to dissolve it and then the system is allowed to cool, preferably slowly, thus forming crystals.

Mixed solvents – this involves two solvents, one of which the compound is readily soluble in (the ‘good’ solvent) and another in which it is mostly insoluble (the ‘poor’ solvent). The compounds are first dissolved in the ‘good’ solvent then the ‘poor’ solvent is added drop wise with a pipette causing the solute to crystallize out.

Layered solvents – this technique is based on the fact that solvents of substantially different densities mix remarkably slowly when they are not stirred. The compound is dissolved in the ‘good’ solvent and then a top layer of the ‘poor’ solvent is added slowly. The layered solvents are left for several days for the layers to mix, during which the slow diffusion across the solvent boundary results in crystals.

Antisolvent addition-This is one of the methods for precipitation or recrystalization of the co-crystal former and active pharmaceutical ingredient. Solvents include buffers (pH) and organic solvents. For example preparation of co-crystals of aceclofenac using chitosan, in which chitosan solution was prepared by soaking chitosan in glacial acetic acid. A weighed amount of the drug was dispersed in chitosan solution by using high dispersion homogenizer. This dispersion was added to distilled water or sodium citrate solution to precipitate chitosan on drug ⁵⁹.

Grinding:

The two compounds were taken in a neat mortar and pistle and ground well to let the two compounds interact at the molecular level. Solid state grinding offers a facile and low or no waste methodology for discovery or processing of new or existing compounds and is an inherently green approach to synthetic chemistry, so today solid state grinding represents a striking alternative to solution processes ⁶⁰. The product obtained from grinding is usually consistent with that obtained from solution. This may indicate that hydrogen-bond connectivity patterns are not idiosyncratic or determined by non-specific and unmanageable solvent effects or crystallization conditions. Nevertheless there are exceptions. Whilst many co-crystal materials can be prepared from both solution growth and solid-state grinding, some can only be obtained by solid-state grinding.

Slurry conversion:

Solvent was added to the solids and the resulting suspension was stirred at room temperature for some days. The resultant solid material was dried under a flow of nitrogen for 5 min. The remaining solids were then characterized using PXRD. Slurry conversion experiments were conducted in water and different organic solvents.

Sublimation:

If a compound is sufficiently volatile at accessible vacuum pressures it can be crystallized. This technique is often used in the purification of crude mixtures. Crystals may form from a fusion, or by sublimation; but crystallization almost always takes place from solution.

Melting:

Melts have generated an interest in co-crystal formation. By simply melting two co-crystal formers together and cooling, a co-crystal may be formed. If a co-crystal is not formed from a melt, a seed from a melt may be used in a crystallization solution in order to afford a co-crystal.

Seeding:

A seed crystal of the same or a similar material is added to a supersaturated solution in order to induce the growth of single crystals of a certain form as the solution evaporates.

Factors that influence crystal habit in co-crystal formation:

Due to the practical implications of hydrate formation upon processing, formulation, storage and packaging, to the pharmaceutical industry the stability of a solid drug material with respect to atmospheric moisture is important. The relative humidity stability of a series of caffeine/dicarboxylic acid co- crystals ⁵⁷ has been examined with respect to the pure crystalline anhydrous caffeine. No co-crystal hydrates were observed, and the co- crystals that were unstable with respect to relative humidity tended to dissociate to the crystalline starting materials. A humidity induced polymorphic transformation was also observed. The caffeine/oxalic acid co- crystal was stable at all measured relative humidities, displaying better stability than the anhydrous caffeine.

Characterization of co-crystals:

A comprehensive characterization includes thermal, crystallographic, spectroscopic temperature, moisture dependent analysis, stability and transition characteristics. In the solid state, the extent of proton transfer can be determined from single-crystal X-ray (or neutron) diffraction analysis by evaluating (1) proton location and/or (2) bond lengths of atoms involved, for example, C-O distances of carboxyl groups or phenolic alcohol groups as well as (3) bond angles.

The evaluation can be also carried out by spectroscopic analysis using techniques such as RAMAN and IR spectroscopy to observe O-H, N-H, and COOH signals and IR peak shifts due to hydrogen bonding,^{17,61- 64} and solid-state nuclear magnetic resonance (ssNMR) to observe carbon, nitrogen, and phosphorus chemical shifts^65-67.

Characterization at the molecular level establishes X-ray photoelectron spectroscopy (XPS) as a useful technique for determining the extent of proton transfer in molecular crystals. This was supported by studying theophylline-citric acid co-crystals alongside ssNMR and attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR). A complex has been formed by milling theophylline with either anhydrous or monohydrate citric acid and established as a 1:1 co-crystal by a combination of both conventional and novel analytical methods. The absence of peaks from the starting materials in the X-ray diffraction powder pattern indicates that the product was formed quantitatively, with elemental analysis and XPS revealing a 1:1 stoichiometry. Thermogravimetric analysis demonstrated the complex was anhydrous, with differential scanning calorimetry showing a melting temperature different from that of the starting materials. The small magnitude of ssNMR and ATR-FTIR shifts relative to anhydrous theophylline revealed that proton transfer, and hence salt formation, had not occurred. The combination of analytical techniques allows the complex to be assigned as a 1:1 co-crystal without the need for a single crystal structure³¹.

ssNMR has the unique advantages like analyzing small amounts of samples nondestructively and yielding data with higher information. This can be utilized in the analysis of pharmaceutical co-crystals. The co-crystals used to be produced initially by solvent drop grinding techniques which do not lend themselves to single crystal growth for X-ray diffraction studies. Frederick G. Vogt et al used ssNMR to study hydrogen bonding, intermolecular contacts, and spin diffusion to link individual molecules together in a crystal. On the basis of the results the authors suggested that ssNMR is an agreeable, suitable experimental approach for confirmation of co-crystal formation⁶⁸.

Case studies:

The early examples of pharmaceutical co-crystals in the scientific literature may be due to the result of serendipity than design. The earliest literature in the context of API's relates to a series of studies conducted by Higuchi in the 1950's. They formed and studied complexes between macromolecules and certain pharmaceuticals, for example complexes of polyvinylpyrrolidone with procaine hydrochloride, caffeine, cortisone, chloramphenicol, benzylpenicillin, sulfathiazole, phenobarbital, etc. were isolated. However, these are not be classified as pharmaceutical co-crystals. the first application of crystal engineering to the formation of pharmaceutical co-crystals perhaps might be a series of studies by Whitesides et al. concerning the use of substituted barbituric acid, including barbital and melamine derivatives to generate supramolecular ‘linear tape,’ ‘crinkled tape,’ and ‘rosette’ motifs sustained by robust three-point N-H^…O and N-H^…N hydrogen bonds. Ironically the focus of these studies was not so much the physical properties of the resulting co-crystals but rather the supramolecular functionality of barbitals and their complementarity with melamine⁷⁰. Some co-crystals reported in the literature were listed in Table No.2.

Pharmaceutical co-crystals of Carbamazepine (CBZ),

Carbamazepine (CBZ) [5H-dibenzazepine-5-carboxamide], is known to exist as four well characterized polymorphs^71-78, a dihydrate,⁷⁹ an acetone solvate,⁷² and two ammonium salts⁸⁰. From a supramolecular perspective, CBZ is a simple molecule with only one hydrogen bonding group, a primary amide. This amide moiety manifests itself in a predictable manner as all forms of CBZ exhibit supramolecular homosynthon. Therefore, CBZ has been used as an ideal candidate to demonstrate how APIs can be converted to pharmaceutical co-crystals, and how these co-crystals could offer optimized physicochemical properties over existing forms of an API. Two strategies have been adopted for co-crystal formation of CBZ. One crystal engineering strategy is to employ the peripheral hydrogen bonding capabilities that are not engaged in the pure form of CBZ. A second strategy for co-crystallization of CBZ involves breakage of the CBZ amide-amide dimer and formation of a supramolecular heterosynthon between CBZ and a co-crystal former.

The primary amide dimer, like the carboxylic acid dimer, is well-documented in the CSD. In CBZ, the peripheral H-bond donors and acceptors are unused, presumably due to steric constraints imposed by the azepine ring of CBZ. CBZ dimer does not engage its peripheral H-bonding capabilities and CBZ forms a number of co-crystals and solvates that retain the primary amide dimer. CBZ forms pharmaceutical co-crystals with benzoquinone, terephthalaldehyde by maintaining the amide dimer. CBZ dimers H-bond to the syn positions of the nicotinamide amide group through an exterior translation-related pattern. The anti-oriented H-bonding sites of the nicotinamide amide group form a catemer motif with adjacent nicotinamide molecules. In saccharin, the molecules serve as H-bond donors by forming N--H^…O hydrogen bonds with CBZ carbonyl groups. They also serve as H-bond acceptors: the S=O group of the saccharin bonds to the exterior N---H moiety of CBZ. Saccharin co-crystal shows improved physical stability, suspension stability, favorable dissolution properties.

A second strategy for co-crystal formation involving CBZ involves breakage of homosynthon and formation of a supramolecular heterosynthon. This would be expected to occur with a functional group that is complementary with the amides, that is, a moiety with both an H-bond donor and an H-bond acceptor. Carboxylic acids fit this criterion and 71 of the 153 structures in the CSD that contain both a carboxylic acid and a primary amide are sustained by supramolecular heterosynthon. Co-crystal formation between CBZ and carboxylic acids occurs.

Co-crystals of Sulfamethazine-Theophylline:

Jie Lu, Sohrab Rohani synthesized molecular complex of sulfamethazine (STH) with theophylline (TP) as the co-formers.. Neat cogrinding, solvent-drop cogrinding and slow evaporation were applied to synthesize the sulfamethazine–theophylline co-crystal (STH–TP). The co-crystalline phase was characterized by DSC, TGA, Raman, PXRD, and dynamic vapor sorption (DVS) techniques. The results from single crystal X-ray diffraction data revealed that, the STH–TP co-crystal, obtained in a 2:1 molar ratio of sulfamethazine and theophylline only by slow evaporation, possesses unique thermal, spectroscopic, and X-ray diffraction properties. Besides, in the STH– TP co-crystal, the sulfamethazine molecules form a dimer through the intermolecular hydrogen bonding (O---H-N), and two intermolecular hydrogen bonds (O---H-N and N---H-N) keep the theophylline attached the dimer⁸¹.

Co-crystals of Isoniazid:

Isoniazid has the potential to be a supramolecular reagent and so far has been put to very limited use in making co-crystals. Andreas Lemmerer et al co-crystallize isoniazid with the dicarboxylic acids malonic, succinic, glutaric, adipic and pimelic acid, and the monocarboxylic acids 4-hydroxybenzoic acid and 2,4-dihydroxybenzoic acid. literature has been surveyed through the Cambridge Structural Database and the authors have identiﬁed the possible homosynthons and heterosynthons that are likely to form in the co-crystallization of isonizaid with carboxylic acids. The dominant interaction is the COOH/N hydrogen bond, which is used in all seven co-crystals ⁸².

Table No. 2: Case Studies of Co-crystals

Sl. no.	API	CO-FORMER	PROPERTIES	Reference
1.	Carbamazepine (CBZ)	succinic acid, nicotinamide, benzoquinone, 1-hydroxy-2-naphthoic acid, adipic acid, camphoric acid, terephthalaldehyde, benzoic acid, ketoglutaric acid, 4 hydroxybenzoic acid, fumaric acid, saccharin, trimesic acid, 5-nitroisophthalic acid, salicylic acid, maleic acid, malonic acid, glutaric acid, oxalic acid, DL-tartaric acid, L-tartaric acid, glycolic acid	Physical stability, dissolution rate, oral bioavailability	16
2.	Caffeine	Glutaric acid Oxalic acid	Improved physical stability	30
3.	Itraconazole	1,4-dicarboxylic acids, L-malic acid	Improved dissolution rate	38
4.	Sildenafil	acetylsalicylic acid	Improved dissolution	88
5.	Melamine	cyanuric acid	Decreased dissolution	89
6.	Theophylline	oxalic acid, malonic acid, maleic acid, glutaric acid		90
7.	Piroxicam	Saccharin		91
8.	Aceclofenac	Chitosan	Enhanced dissolution and bioavailability	58
9.	5-nitrouracil	piperazine, N,N'-dimethylpiperazine, 3-aminopyridine and diazabicyclooctane		92
10.	Indomethacin	Saccharin	Physical stability and dissolution rate	93
11.	Salicylic acid	nicotinic acid, DL-phenylalanine, and 6-hydroxynicotinic acid (6HNA) benzamide		94 95
12.	Pyridines and Carboxylic Acids	maleic, fumaric, phthalic, isophthalic, or terephthalic acids		96
13.	Spironolactone	Saccharin	Improved solubility	97
14.	1,4-cyclohexanedione	4,4-bipyridine		98
15.	Benzamide	Benzoic Acid		99
16.	Gabapentin	3-hydroxybenzoic acid (3HBA) 1, 4-hydroxybenzoic acid (4HBA) 2, salicylic acid 3, 1-hydroxy-2-napthoic acid (1H2NA) 4, and RS-mandelic acid	Improved stability and altered solubility	100
17.	Acetazolamide	4-hydroxybenzoic acid (4HBA) and nicotinamide (NA)	ACZ-NA Improved Solubility, Improved Stability	101
18.	Sulfamethazine	Theophylline		102
19.	2-Chloro-4-Nitrobenzoic Acid	Nicotinamide		103
20.	Acetaminophen	2,4-Pyridinedicarboxylic Acid		104
21.	Tiotropium Fumarate	Fumaric acid		105
22.	Ornidazole	3,5-dinitrobenzoic acid		106
23.	Lamotrigine	Nicotinamide Methylparaben	Co-crystals show altered solubility, dissolution and pharmacokinetic behaviour	107
24.	Benzo[18] Crown-6	urea, thiourea, 1-methyl thiourea and nicotinamide		108
25.	Sulfadimidine	2-aminobenzoic acid		109
26.	ethyl-paraben	Nicotinamide		110
27.	Chlorzoxazone	2,4-dihydroxybenozoic acid 4-hydroxybenzoic acid		111
28.	Flurbiprofen	4,4′-bipyridine trans-1,2-bis(4-pyridyl)ethylene	Intrinsic dissolution rate	112
29.	Ibuprofen	4,4′-bipyridine	Solubility	112
30.	Norfloxacin	Isonicotinamide	Solubility	113
31.	Fluoxetine Hydrochloride	benzoic acid, succinic acid and fumaric acid	Altered solubility, solubility improved to two folds especially with succinic acid	114
32.	Isoniazid	Malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, 4-dihydroxybenzoic acid, 2,4-dihydroxybenzoic acid		115
33.	2-[4-(4-chloro-2-fluorophenoxy)phenyl]pyrimidine-4- Carboxamide	Glutaric Acid	Improved solubility and bioavailability	116
34.	Meloxicam	1-hydroxy-2-naphthoic acid glutaric acid, L-malic acid, salicylic acid, fumaric acid, succinic acid		71

Table No. 3: Some of the recent patents on co-crystals

Sl. No.	Patent No	Patent inventors	Title	Reference
1	US2010/0184792A1	Christian sowa, Heidi Emilia Saxell, Ralf Vogel	Co-crystals of pyrimethanil and dithianon	84
2	US007803786B2	Mc Mahon, Matthew Peterson, Michael Zaworotko, Tainse Shattock,cMagali Bourghol Hickey	Pharmaceutical co-crystal compositions and related methods of use	85
3	US7625910B2	George Joseph Sependa, Richard Storey	Co-crystal	86
4	WO2008/013823 A2	Chiarella, Renato, Andres	Co-crystals of (2R-Trans)-6-chloro-5-[[4-[(4-Fluorophenyl)Methyl]-2,5-Dimethyl-1-Piperazinyl]carbonyl]-n,N-Trimethyl-alpha-Oxo-1H-Indole-3 Acetamide	87

There are some issues associated with the co-crystal patents. These include

Regulatory approvals and intellectual property rights:

Pharmaceutical co-crystals have not yet been officially addressed as the perspective of generic regulatory approval. Co-crystals can be considered as the intermediate between salts (which are not ANDA-eligible in general) and hydrates (which are ANDA-eligible). Co-crystals are nonionic supramolecular complexes like co-crystals but co-crystals involve complexation with substances in resemblance to salts and which are of greater potential toxicity than water. Impact on the overall utility of co-crystal technology to the generic pharmaceutical industry decides whether a new co-crystal of a marketed API will be eligible for regulatory approval via the ANDA mechanism or not. This may also possibly bear on the future marketplace abundance of pharmaceutical products containing co-crystals ⁴¹.

Co-crystals also play a major role in lifecycle management. Lifecycle management may involve drug product improvements along with new solid forms. Co-crystals will also raise IP and regulatory questions. Much of these compounds are developed, which are later moved into development and are eventually marketed. Like any solid form, they have their own challenges and on a case by case basis many issues will need to be dealt. Early in the development process, chemical structures are patented and additional IP protection can be obtained by patenting different solid forms throughout development.

From a regulatory point of view for generic products, co-crystals may present an interesting option. Currently, when generic pharmaceutical companies use polymorphs and hydrates as alternatives to ethical drugs, they file Abbreviated New Drug Applications (ANDAs), which requires the submission of minimal bioavailability and clinical data and does not require proving safety or efficacy. New salts of an API, however, use a slightly different regulatory pathway, a so-called 505(b) (2) application, and require more testing and clinical data than an ANDA submission. The classification of co-crystals as a generic has not yet been addressed. Co-crystals contain nonionic interactions like hydrates, but they also contain substances with possible toxicity issues, similar to salts. The decision on how to regulate co-crystals for generic products may affect their use in the generic industry ¹⁶. Some of the recent patents on the co-crystals which are pharmaceutically relevant are listed in the Table no.3.

Utility:

A patent to be filed by European more tests/data is to be filed when compared to that required to U.S. filing. In US utility can be based on underlying API.

Anticipation and Novelty:

There is always the question that how far the co-crystals are successful in decreasing the problem of polymorphism in APIs. Though co-crystals offer more advantage in aspects of stability, improving bioavailability the aspects of polymorphism also needs to be considered.

Enablement:

While patenting the co-crystal can be claimed in the manner we prepared and characterized as there are many factors that influence the crystal formation⁸³.

CONCLUSION:

Consideration of established approaches such as the use of high-energy amorphous and metastable crystalline forms is still widespread. In particular substantial advancements in methods for isolating metastable crystalline have been achieved since the early days of chloramphenicol palmitate, whilst a greater understanding of the production and stabilization of amorphous forms is also leading to a renaissance in their use.

The formation of molecular complexes and co- crystals is becoming increasingly important as an alternative to salt formation, particularly for neutral compounds or those having weakly ionizable groups. It is clear that the crystal and particle engineering strategies have notable potential to strengthen the available methods for addressing problems of low aqueous solubility of drug substances. These methods are applicable not only to molecules of a specific physical and chemical nature, but to a wide range of crystalline materials, although a comprehensive knowledge of drugs at the molecular level is required to determine the appropriate approach to improving solubility and dissolution rate.

There is a clear need for greater understanding and control of crystalline forms in the context of pharmaceutical development, the concepts of supramolecular synthesis, and crystal engineering remain largely underexploited. This contribution highlights the need to think ‘‘supramolecularly’’ for structural analysis of API’s. In particular, applying the concepts of supramolecular synthesis and crystal engineering to the development of pharmaceutical co-crystals represents a paradigm that offers many opportunities related to drug development and delivery. It seems inevitable that pharmaceutical co-crystals will gain a broader foothold in drug formulation.

Despite lack of precedence in marketed products and concerns about the safety and toxicity of co- crystal forming agents, there is growing interest and activity in this area, which aims to increase the understanding of co-crystal formation and methods of preparation.

The emerging area of pharmaceutical research in co-crystals is still relatively unexplored and requires further study before co-crystals can be considered to be a reliable toolbox technology for the improvement of physico-chemical properties of drugs.

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Received on 04.03.2011 Modified on 10.04.2011

Research J. Pharm. and Tech. 4(6): June 2011; Page 891-902