Many medicines with limited aqueous solubility have been found in the recent few years. Of the newly identified medications, between 60 and 70 percent of the compounds belong to BCS Class II (low solubility/high permeability) and IV (low solubility/low permeability). Due to their poor water solubility, which lowers drug bioavailability, many active pharmaceutical ingredients (APIs) have not been created in formulations. medications administered orally have varying solubilities in gastrointestinal fluids at varying pHs because different regions of the gastrointestinal system have varied pHs. This can result in nonlinear and variable absorption, making it impossible to accurately assess the efficacy and safety of medications. Researchers have created a number of methods to increase a drug’s solubility, which raises the drug’s bioavailability. Some of the techniques utilized for the solubility increase are size reduction, solid dispersion, complexation, salt formation, nanoparticles, self-emulsifying drug delivery system (SEDDS), addition of co-solvents, nano-suspension and emulsion, and cocrystal formation.

Scholars have characterized cocrystals in a variety of ways in the literature. At the 2012 Indo-US Bilateral Meeting titled “The Evolving Role of Solid State Chemistry in Pharmaceutical Science,” which was held in Delhi, India and supported by the Indo-US Science and Technology Forum, 46 scientists suggested the concept of cocrystals that is currently accepted.  

Difference between cocrystals, salt, solvates and hydrates:In the proposed guidance, the USFDA defined salt, polymorphs, and cocrystals. Compounds that exist in several crystalline forms, such as solvates or hydrates (sometimes referred to as pseudopolymorphs) and amorphous forms, are referred to as polymorphs


A pharmaceutical cocrystal is a multicomponent system in which two components are present in a stoichiometric ratio. 

A comprehensive definition of cocrystal that was in line with the body of scientific literature was put out by the researchers. Cocrystals are crystalline single-phase materials that are neither simple salts nor solvates, but rather are made up of two or more distinct molecular and/or ionic componentss in a stoichiometric ratio.Pharmaceutical cocrystals are formed through the process of cocrystallization, where the API and coformer molecules undergo self-assembly and crystallization in specific stoichiometric ratios.


The coformer is a component, often a benign food or drug-grade additive (generally regarded as safe, GRAS). The API and coformer are bonded together within the crystal lattice through non-covalent interactions.

 Coformers are molecules that interact with an active pharmaceutical ingredient (API) to form a cocrystal. 

 Coformers are typically inert, pharmaceutically acceptable compounds that have the ability to participate in non-covalent interactions with the API, such as hydrogen bonding, π-π stacking, or van der Waals forces. These interactions play a crucial role in stabilizing the cocrystal structure and modifying its physicochemical properties.

 Coformers are selected based on their ability to form favorable interactions with the API, such as hydrogen bonding donors or acceptors, aromatic moieties for π-π stacking, or complementary functional groups.

 Coformers should be pharmaceutically acceptable, non-toxic, chemically inert, and compatible with the API and other excipients in the formulation.

 Coformers can be organic or inorganic molecules, small molecules or polymers, and can vary in size, shape, and functional groups.

 Common types of coformers include carboxylic acids, amides, alcohols, amines, and halogenated compounds, as well as water or organic solvents.

 Coformers play a crucial role in modifying the physicochemical properties of the cocrystal, such as solubility enhancement, polymorph control, stability improvement, and taste masking.

 The choice of coformer can influence the crystallization kinetics, crystal packing arrangement, and overall performance of the cocrystal in drug delivery applications.

 The selection and optimization of coformers often involve experimental screening studies, computational modeling, and crystal engineering techniques to identify suitable candidates and assess their potential for cocrystal formation.

 Various analytical techniques such as X-ray crystallography, powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), and spectroscopic methods are used to characterize cocrystals and elucidate their molecular interactions.

Selection of a coformer

The selection of a coformer is a crucial step in pharmaceutical cocrystal development, as it influences the formation, properties, and performance of the resulting cocrystal.


 The coformer should have complementary functional groups that can form specific non-covalent interactions (such as hydrogen bonding, π-π stacking, or van der Waals forces) with functional groups on the API molecule.

 The coformer should be selected to maximize the potential for strong and directional interactions with the API, facilitating the formation of stable cocrystals.

 The coformer should be pharmaceutically acceptable, non-toxic, chemically stable, and compatible with the API and other excipients used in the formulation. Consideration should be given to the physicochemical properties of the coformer, including solubility, melting point, hygroscopicity, and potential for polymorphism, to ensure suitability for cocrystal formation and formulation development.

 The coformer should have sufficient solubility in common solvents to enable cocrystal preparation using methods such as solvent evaporation, grinding, or crystallization from solution.

 The crystallization kinetics of the coformer and its compatibility with the desired cocrystal formation method. Some coformers may exhibit rapid nucleation or growth rates, leading to challenges in controlling cocrystal morphology and purity.

 Assess the thermodynamic stability of the cocrystal relative to its components (API and coformer) and other potential solid forms (e.g., salts, solvates) to ensure long-term stability and shelf-life of cocrystal-based formulations. Experimental and computational methods such as differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and molecular modeling can be used to evaluate the stability and energetics of cocrystal formation.

Methods for the Preparation

Several methods are available for the preparation of pharmaceutical cocrystals, each with its advantages and limitations. Here are some common methods used for cocrystal preparation:

Solvent Evaporation: In this method, the API and coformer are dissolved in a suitable solvent or solvent mixture, followed by evaporation of the solvent under reduced pressure or at elevated temperatures to induce cocrystal formation. Solvent evaporation is a simple and widely used method but may result in low cocrystal yields and require optimization of solvent selection and evaporation conditions.

Grinding or Mortar and Pestle Method: This method involves grinding the API and coformer together in a mortar and pestle or other grinding apparatus to induce mechanical stress and promote cocrystal formation. Grinding is a simple and efficient method that does not require solvents but may require prolonged grinding times and can be challenging for large-scale production.

Slurry Conversion: In slurry conversion, the API and coformer are suspended in a solvent or solvent mixture and agitated to form a slurry, followed by crystallization and isolation of the cocrystal product. Slurry conversion is a versatile method suitable for various APIs and coformers but may require optimization of solvent composition, temperature, and agitation parameters.

Liquid-Assisted Grinding (LAG): Liquid-assisted grinding involves grinding the API and coformer with a small amount of liquid, typically a solvent or solvent mixture, to facilitate cocrystal formation under mild mechanical stress.

LAG combines the advantages of grinding and solution-based methods, resulting in shorter reaction times and higher cocrystal yields compared to dry grinding alone.

Antisolvent Crystallization: In antisolvent crystallization, the API and coformer are dissolved separately in a solvent and antisolvent, respectively, and then mixed to induce cocrystal nucleation and growth. Antisolvent crystallization allows for precise control over cocrystal composition and morphology but may require careful selection of solvents and antisolvents to prevent unwanted precipitation.

Hydrothermal Synthesis: Hydrothermal synthesis involves heating the API and coformer in an aqueous solution under elevated temperatures and pressures to promote cocrystal formation through hydrothermal reactions. Hydrothermal synthesis offers advantages such as higher cocrystal purity and crystallinity but requires specialized equipment and expertise.

Spray Drying: Spray drying involves atomizing a solution or suspension of the API and coformer into droplets, which are then dried rapidly in a hot air stream to form cocrystal particles. Spray drying is a scalable and continuous process suitable for large-scale production but may require optimization of process parameters to prevent cocrystal degradation.

Co-Crystallization from Solution: Co-crystallization from solution involves dissolving the API and coformer in a common solvent or solvent mixture, followed by controlled cooling or evaporation to induce cocrystal nucleation and growth. Co-crystallization from solution allows for precise control over cocrystal composition and purity but may require optimization of solvent composition, temperature, and cooling rate


Cocrystals offer several advantages in drug development and formulation, including improved physicochemical properties, enhanced solubility, stability, bioavailability, and tailoring of drug delivery characteristics.

Enhanced Solubility: Cocrystallization offers an opportunity to improve the aqueous solubility of poorly soluble drugs. This is crucial because low solubility often leads to low bioavailability.

Improvement of Physicochemical Properties: Cocrystallization allows for the modification of various physicochemical properties of active pharmaceutical ingredients (APIs), such as solubility, stability, dissolution rate, and bioavailability.

Enhancement of Drug Performance: The purpose of cocrystallization is to enhance the performance of APIs by addressing their inherent limitations, such as poor solubility, low stability, or variable bioavailability.

Tailoring Drug Delivery Characteristics: Cocrystals can be designed to modulate drug release kinetics, control polymorphism, and target specific drug delivery routes or release profiles, leading to improved therapeutic outcomes.

Intellectual Property Protection: Cocrystallization offers a strategy for patent extension and exclusivity by creating new solid forms of existing APIs, thus providing a competitive advantage and protecting intellectual property rights.


Improved Solubility and Dissolution Rate: Cocrystals can significantly enhance the solubility and dissolution rate of poorly soluble APIs, potentially leading to improved bioavailability and therapeutic efficacy.

Stability Enhancement: Cocrystals may improve the chemical stability of APIs, reducing degradation and increasing shelf-life, which is crucial for the development of stable pharmaceutical formulations.

Versatility and Flexibility: Cocrystallization offers versatility and flexibility in drug design and formulation, allowing for the customization of drug properties according to specific therapeutic requirements and patient needs.

Reduced Formulation Development Time and Costs: Cocrystals can streamline the drug development process by providing a rapid and efficient means of optimizing drug properties, thus reducing formulation development time and costs.

Dose Optimization: Cocrystals enable precise control over drug doses by allowing for the adjustment of drug concentrations and dosing regimens to achieve optimal therapeutic outcomes while minimizing side effects.

Regulatory Compliance: Pharmaceutical cocrystals are recognized and regulated by regulatory agencies such as the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA), ensuring compliance with quality, safety, and efficacy standards.


Drug Development: Pharmaceutical cocrystals are investigated during preformulation studies to optimize drug properties and develop new formulations with desirable characteristics.

Formulation Design: Cocrystals are incorporated into dosage forms such as tablets, capsules, or oral solutions to improve drug performance and patient compliance.

Intellectual Property (IP): Cocrystals provide a platform for patent protection, lifecycle management, and commercialization strategies for pharmaceutical products.

Polymorph Control and Formulation Flexibility: Cocrystals offer a versatile approach to polymorph control, allowing for the selection of specific crystal forms with optimized properties for formulation development. By manipulating intermolecular interactions between the API and coformer, cocrystals can stabilize preferred polymorphs or prevent unwanted polymorphic transitions, ensuring consistent product quality and performance.

Combination Therapy and Multicomponent Formulations: Cocrystals enable the combination of multiple APIs or active ingredients within a single crystal lattice, facilitating the development of fixed-dose combinations and multicomponent formulations. 

Characterization of Cocrystals

It is essential to assess their identity, purity, crystallinity, physicochemical properties, and performance for pharmaceutical applications. Some common Experimental and computational methods such as differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and molecular modeling can be used to evaluate the stability and energetics of cocrystal formation.


Pharmaceutical cocrystals represent a versatile approach to drug design and formulation, offering opportunities for innovation and optimization of drug properties to meet patient needs and regulatory standards in pharmaceutical development.  Coformers play a pivotal role in pharmaceutical cocrystallization by providing the necessary structural and chemical elements to form stable cocrystals with APIs. Their selection and design are critical considerations in the development of cocrystal-based formulations with enhanced drug properties and therapeutic benefit. Overall, the selection of a coformer requires a comprehensive understanding of the API, cocrystal chemistry, and formulation requirements, as well as careful consideration of the coformer’s properties and compatibility with the desired cocrystal formation method. Collaboration between medicinal chemists, formulation scientists, and regulatory experts is often necessary to make informed decisions and optimize the selection of coformers for pharmaceutical cocrystal development.s. The solvent evaporation method offers simplicity, versatility, and scalability for cocrystal preparation, making it suitable for both laboratory-scale research and industrial manufacturing. However, careful selection of solvent(s), optimization of evaporation conditions, and control over crystallization parameters are essential for the successful formation of high-quality pharmaceutical cocrystals.

Ms. Ranjana

Ms. Ranjana

Assistant Professor, GIP, Geeta University, Panipat