Cocrystal: A Review on the Design and Preparation of Pharmaceutical Cocrystals

 

Tanmay Jit¹*, Dibyendu Shil², Ramesh Kumari Dasgupta³, Sanglap Mallick¹,

Saptarshi Mukherjee⁴

¹Department of Pharmaceutics, Mata Gujri College of Pharmacy,

Mata Gujari University, Kishanganj, Bihar, 855107, India.

²Department of Pharmacognosy, Mata Gujri College of Pharmacy,

Mata Gujari University, Kishanganj, Bihar, 855107, India.

³Department of Pharmaceutical Chemistry, Mata Gujri College of Pharmacy,

Mata Gujari University, Kishanganj, Bihar, 855107, India.

⁴Department of Pharmaceutical Technology, University of North Bengal, Raja Ramohanpur,

Darjeeling-734013, India.

 

ABSTRACT:

The majority of the active pharmaceutical components have issues with poor solubility, bioavailability, chemical stability, and moisture absorption. Pharmaceutical crystals are a reliable way to change the aforementioned physicochemical properties of drugs without changing their pharmacological behaviour. However, the success of these approaches depends on the physical and chemical properties of the molecules being developed. The development of drug products with superior physicochemical characteristics, such as melting point, tablet ability, solubility, stability, bioavailability, and permeability, while preserving the pharmacological properties of the active pharmaceutical ingredient is greatly facilitated by co-crystallization of drug substances. All the components of a cocrystal, which is a stoichiometric homogeneous multicomponent system connected by non-covalent interactions, are solid under ambient conditions.

 

 

INTRODUCTION:

Most newly discovered chemical entities are lipophilic in nature and have poor biopharmaceutical qualities; among these properties, solubility continues to be a major challenge. One of the biggest challenges facing the pharmaceutical business is increasing a drug's solubility in water.

 

Various approaches are used for improving solubility of drugs like salt formation, various techniques include emulsification, co-solvency, polymer usage, marinization, solid dispersion, inclusion complex, etc.¹ By prolonging the life cycle of outdated Active pharmaceutical ingredients APIs, crystallisation may present the pharmaceutical sector with a chance to address the issue of intellectual property. The construction of pharmaceutical cocrystals to increase the bioavailability of drugs with limited water solubility has drawn more attention over the past ten years. Pharmaceutical Cocrystal can increase the flowability, chemical stability, compressibility, and hygroscopicity of APIs in addition to potentially improving their solubility, dissolving rate, bioavailability, and physical stability.^{2, 4}

 

According to the definition given in, a cocrystal is "a stoichiometric homogeneous multicomponent system connected by noncovalent interactions where all the components present are solid under ambient condition.⁵

 

According to this definition, a pharmaceutical Cocrystal is referred to as a conformer if it contains another component in addition to one that is an active pharmaceutical ingredient (API). The FDA-approved conformer is chosen from the list of products that are generally regarded as safe (GRAS).⁶

 

Difference between Crystals, Salt, Solvates and Hydrates:

In the draught advice, USFDA defined cocrystal, salt, and polymorphs. Compounds that exist in several crystalline forms, such as solvates or hydrates (sometimes referred to as pseudo polymorphs), as well as amorphous forms are referred to as polymorphs. Due to the varied crystal lattice arrangements in polymorphs, they exhibit different physicochemical characteristics. The full transfer of a proton from one chemical to another is what creates salts⁷.

 

By transferring protons from an acid to a base, salts and cocrystals can be distinguished from one another. Between pairs of acids and bases, there is a full proton transfer, but not during the creation of cocrystals. Noncovalent interactions between two components, such as hydrogen bonds, stacking and van der Waal forces, are what bind them together.^{8, 9} Cocrystals, on the other hand, are substances that are solid at normal temperature. Hydrates are solvating that have water acting as a solvent within their crystal lattice.¹⁰

 

Solvates and hydrates can change the physicochemical properties of APIs and are frequently generated during co-crystallization by solution or liquid assisted grinding. Due to the solvent's presence in the crystal lattice, solvates have a different level of stability than un-solvated forms. Because they lose their solvent or water at high temperatures and low humidity while being stored, solvates and hydrates are extremely unstable, and the physiochemical characteristics of hydrated and dehydrated forms will differ. We used liquid aided grinding to create several polymorphic cocrystals (Figure 1) and solvates of caffeine and anthranilic acid using various solvents.^{11, 12}

 

Figure 1: Schematic representation of (a) pure API; (b) polymorphs of API; (c) clathrates solvate/hydrate of API, (d) solvates/hydrates of API, (e) salt of API, (f) pharmaceutical cocrystals of API.

 

Pharmaceutical Cocrystal Design Strategies:

Pharmaceutical cocrystals have quickly become a new type of API solids with a lot of potential and benefits. The study of crystal engineering and design techniques that promote the development of cocrystals of APIs and crystal formers has received a lot of attention. As schematically shown in Figure 2, the design and manufacturing of pharmaceutical crystals involves a multi-stage procedure.^13,14

The first step in producing a desired cocrystal product from an API with restricted aqueous solubility is to investigate the structure of the target API molecule and identify the functional groups that can interact intermolecularly with the right co-formers. Van der Waals forces, p-p stacking, and the most prevalent hydrogen bonding are examples of intermolecular interactions.^15,16

 

Figure 2: A general guideline for Cocrystal design and screening.¹⁷

 

1. CO-FORMER SELECTION:

The selection of co-formers that are compatible with a given API represents one of the major challenges in pharmaceutical cocrystal creation. Researchers have employed a variety of knowledge-based techniques for the identification of appropriate co-formers and screening of cocrystals, including the supramolecular synthon, has been solubility parameter, Cambridge Structure Database (CSD), pKa-based models, hydrogen bonds, and Fabian's method, among others.¹⁸

 

1.1 Supramolecular Synthon Approach:

By using crystal engineering, a pharmaceutical cocrystal can be created with the goal of enhancing an API's solid-state characteristics without changing the API's fundamental structure. The fundamental knowledge of how non-covalent interactions produce synthons is equally important for crystal engineering. Synthons are "structural units within supermolecules which can be formed and/or assembled by known or conceivable intermolecular interactions, " according to Corey, who originated the term. A supramolecular synthon(Figure 3) is a pattern of interactions where crystal patterns repeat often. ^{19.20, 21}

 

 

Figure 3: The most common supramolecular Synthon²¹

1.2 Hansen Solubility Factor:

Hansen Solubility Parameters (HSPs) can predict the miscibility of a medication and a conformer, which can be used to forecast cocrystal formation and direct cocrystal screening. Before performing extensive cocrystal screening work, choosing candidate conformers can be guided by predicting the miscibility of cocrystal components using solubility criteria.²²

 

1.3 The Hydrogen Bond:

Hydrogen bonds play a significant part in driving intermolecular recognition between an API and a conformer molecule for the majority of pharmaceutical cocrystal structures. The following recommendations were made to make designing hydrogen bound solids easier: All good proton donors and acceptors are used in hydrogen bonding, and if intramolecular six-membered rings can form hydrogen bonds, they usually do so rather than intermolecular ones. (c) After the establishment of intramolecular hydrogen bonds, the best proton donors and acceptors that are still present create intermolecular hydrogen bonds with one another.^{23, 24, 25}

 

1.4 pKa:

For pKa 0, crystallisation is anticipated, and for pKa 3, salt formation. However, a pKa in the 0–3 range is less certain because salt or crystallisation could occur. However, a lot of issues are discovered while utilising this pKa evaluation method, and the criteria is not always relevant.²⁶

 

1.5 Fabian's Approach:

The molecular descriptors (single atom, bond and group counts, hydrogen bond donor and acceptor counts, size and shape, surface area, and molecular electrostatic) were calculated for each molecule²⁷. Different sets of trustworthy cocrystal forming structures were extracted from the CSD. The database listed pairs of chemicals that could form cocrystals based on computed molecular characteristics. The cocrystal formers' shape and polarity had the highest descriptive association.^{28, 29, 30}

 

Mechanisms by Which Cocrystals Enhance Solubility:

The strength of the crystal lattice and the solvation of cocrystal components are two separate elements that affect solubility. Lowering the lattice energy and/or increasing the solvent affinity are two ways to promote solubility.^31,32

 

In order to increase the solubility of the Cocrystal relative to medication, the conformer solubility must be roughly ten times higher than the API. Cocrystal solubility is also connected to conformer solubility.^{33, 34,}

 

1. Grinding Technique:

(a) Neat Grinding (Dry Grinding):

In this technique, stoichiometric amounts of crystal-forming chemicals are combined and ground using a mortar and pestle, a ball mill, or another mechanical device.³⁵

For this process to work, one or both of the reactants must have enough solid-state vapour pressure.

 

(b) Liquid Aided Grinding (Solvent Drop, Kneading, or Wet Cogrinding):

In this approach, crystallising agents are combined by adding the proper amount of solvent in small amounts. It is crucial to choose a solvent that can dissolve at least some of the original ingredients. This approach for finding novel crystals is economical, environmentally benign, and reliable because it uses very little solvent.³⁶

 

2. Methods of Solutions:

The following two tactics are used in solution cocrystallization in real life 15: To reach the cocrystal stability region in non-congruently saturating solvents, one can either use solvents or solvent mixtures where the cocrystal congruently saturates and the components have similar solubility, or use non-equivalent reactant concentrations, as shown by isothermal ternary phase diagrams (TPDs).^{37, 38}

 

3. Solution Co-Crystallization with Ultrasound Assistance:

For the creation of nanocrystals, or cocrystals of extremely small size, a sonochemical approach has been developed18. The API and cocrystal former are dissolved together in a solvent in this process, and the resulting solution is then maintained in a sonoreactor to make it turbid³⁹. To keep the sonicator's temperature consistent and avoid fragmentation, cold water is provided during sonication. The solution is allowed to dry overnight. By utilising this technique, pure cocrystals were produced, and an X-ray diffraction analysis can be used to determine the purity of the cocrystals.^{40, 41}

 

4. The Method of Supercritical Fluid Atomization:

In the supercritical atomization process, CO₂, a highly pressurised supercritical fluid, is used to combine the medication and coformers.⁴² By atomizing this solution with an atomizer, cocrystals are created. The cocrystals are created from solution using the supercritical antisolvent (SAS) method, which utilises the antisolvent properties of supercritical fluid.⁴³

 

5. The Spray-Drying Method:

Cocrystals are made via spray drying, which involves evaporating the solvent from a solution or suspension containing the medication and the coformer. This technology is the most popular since it uses a quick, continuous, and one-step approach. In order to prepare and scale up cocrystals, a special environment will be provided via the spray drying method.^{44, 45}

 

6. Miscellaneous Cocrystal Preparation:

a) Laser Radiation:

This technique involves irradiating powder mixtures of cocrystal formers with a high-power CO2 laser in order to cause their recrystallization into a cocrystal structure.

 

b) Co crystallization Induced by Electrochemistry:

Urbanus et al. showed the possibility of co crystallization and electrochemistry for in situ carboxylic acid product elimination. A cocrystal system made of cinnamic acid and 3-nitrobenzamide was used to establish proof-of-principle. This research demonstrated how electrochemistry can be utilised to locally change pH in order to produce neutral carboxylic acids and create a driving force for cocrystallization.⁴⁶

 

c) Spray Drying:

The continuous one-step process of spray drying converts liquids (solutions, suspensions, and slurries) into solid powders. Its continuous, highly controllable, and quick procedure makes it advantageous. Because of the quick solidification process, spray drying is frequently used to create amorphous solid dispersions, but it has also been utilised to create cocrystals⁴⁷.

 

d) Freeze-Drying

Technically known as lyophilization, freeze-drying has mostly been employed as a processing method to preserve a wide range of goods, including food and pharmaceuticals.In order for the frozen water in the material to transcend directly from the solid phase to the gas phase, the technique first freezes the substance and then lowers the atmospheric pressure.⁴⁸

 

e) Electrospray Technology

The process of electro spraying involves simultaneously creating and charging droplets with the help of an electric field. A capillary nozzle that is kept at a high potential discharges a solution containing the dissolved materials through an electric field, which causes the solution droplets to elongate and create a jet. Drying the solution jet produces particles, which are then collected on a charged powder collector.⁴⁹

 

Cocrystal Characterisation Techniques:

Structures and characteristics are evaluated as part of cocrystal characterisation. For characterising crystal structures and characteristics, a variety of analytical techniques are utilised. Powder X-ray diffraction (PXRD), single crystal X-ray diffraction (SXRD), infrared spectroscopy (IR), Raman spectroscopy (SSNMR), differential scanning calorimetry (DSC), scanning electron microscopy (SEM), and terahertz spectroscopy are frequently used to identify the fundamental physicochemical properties of cocrystals.⁵⁰

 

1. Melting Point:

The temperature at which the solid and liquid phases are in balance determines the melting point, which is a fundamental feature of matter. A crucial instrument for characterising and identifying the purity of compounds is the melting point. Due to its relationships with aqueous solubility and vapour pressure, it is also extremely valuable.⁵¹

 

2. Constancy:

When assessing a pharmaceutical cocrystal's qualities, stability is a crucial factor. Relative humidity stress, thermal stress, chemical stability, and solution stability are typically tested as part of a newly formed cocrystal's stability.⁵²

 

3. Liquidity:

To make a poorly soluble molecule more soluble is one of the key goals of cocrystal research. Salt creation, solid dispersion (emulsification), and particle size reduction (micronization) are examples of traditional techniques for enhancing the solubility of poorly water-soluble medicines. These methods do have some practical drawbacks, though.^{53, 54}

 

4. Intrinsic Disintegration:

The intrinsic qualities of the drug are measured as a function of the dissolution media, such as pH, ionic strength, and counterions, by intrinsic dissolution, which assesses the rate of dissolution of a pure drug component from a constant surface area and is independent of formulation effects^{55, 56}. The dissolving rate (in mg/cm2 min) is calculated from the solution concentration over time. The effectiveness of APIs in vivo can be determined by looking at their intrinsic dissolution rate. dia, such as pH, ionic strength, and counterions, by intrinsic dissolution, which assesses the rate of dissolution of a pure drug component from a constant surface area and is independent of formulation           effects^{57, 58,59}

 

The dissolving rate (in mg/cm2 min) is calculated from the solution concentration over time. The effectiveness of APIs in vivo can be determined by looking at their intrinsic dissolution rate.^{60, 61}

 

5. Bio Accessibility:

The rate and amount of the active medication that enters systemic circulation are measured by bioavailability. When creating novel compounds, animal bioavailability is a crucial factor to take into account. The ultimate goal of cocrystal research is to increase an API's bioavailability.^62,63

 

CONCLUSION:

One of the most promising methods for enhancing the physicochemical properties of APIs is co-crystallization. There are many ways to prepare cocrystals, from standard lab-scale synthesis techniques to perhaps large-scale continuous manufacturing techniques. Standard descriptions and illustrations of well-known and recently developed cocrystal production methods are included in this overview. Cocrystals continue to spark interest and demonstrate their worth, and as a result, more and more applications for them are being found in more and more fields. In order to demonstrate the broad application potential of these materials, this review includes all previously established application areas for pharmaceutical cocrystals. Cocrystals are expected to be used more frequently in pharmaceutical research as their advantages are continued to be confirmed and common manufacturing methods are validated.

 

CONFLICT OF INTEREST:

The authors declare that there is no conflict of interest.

 

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Received on 21.09.2023         Modified on 06.10.2023

Accepted on 16.10.2023   ©Asian Pharma Press All Right Reserved