Review on Pharmaceutical Co-Crystals and Design Strategies


A.V.S. Ksheera Bhavani1, A. Lakshmi Usha2, Kayala Ashritha2, E. Radha Rani2

1Department of Pharmaceutics, Sri Venkateswara College of Pharmacy, Etcherla, Srikakulam.

2Department of Pharmaceutics, Maharajah’s College of Pharmacy, Vizianagaram, A.P., India.

*Corresponding Author E-mail:



Poor aqueous solubility and low oral bioavailability of an active pharmaceutical ingredient are the major constraints during the development of new product. Various approaches have been used for enhancement of solubility of poorly aqueous soluble drugs, but success of these approaches depends on physical and chemical nature of the molecules being developed. Co-crystallization of drug substances offers a great opportunity for the development of new drug products with superior physicochemical such as melting point, tabletability, solubility, stability, bioavailability and permeability, while preserving the pharmacological properties of the active pharmaceutical ingredient. Co-crystals are multi component systems in which two components, an active pharmaceutical ingredient and a coformer are present in stoichiometric ratio and bonded together with non-covalent interactions in the crystal lattice. This review article presents a systematic overview of pharmaceutical co-crystals, differences between co-crystals with salts, solvates and hydrates are summarized along with the advantages of co-crystals with examples. The theoretical parameters underlying the selection of coformers and screening of co-crystals have been summarized and different methods of co-crystal formation and evaluation have been explained.


KEYWORDS: Co-Crystals, Co Crystallisation, Solubility, Stability, Bioavailability, Supramolecular Synthons.




Out of the 40% or more NCEs being generated, nearly 60% of them are poorly water soluble. These poorly water-soluble are slowly absorbed leading to inadequate and variable bioavailability and gastrointestinal mucosal toxicity. Therefore, enhancing the aqueous solubility of poorly water-soluble drugs is the major challenge for the pharmaceutical researchers1. Multiple competent crystalline solids are formed in a stoichiometric ratio between two compounds that are crystalline solids under ambient conditions2. The first known co-crystal Quinhydrone was studied by Friedrich Wohler in 1844.They can be divided into


·       An hydrates of co- crystal

·       Hydrates of co-crystal

·       An hydrates of co-crystals of salts

·       Hydrates of co-crystals of salts


Pharmaceutical Co-Crystal:

Pharmaceutical co-crystals can be defined as crystalline materials comprised of an API and one or more unique co-crystal formers, which are solids at room temperature. Co-crystals can be constructed through several types of interactions like hydrogen bonding and Vander Walls forces. The first known co-crystal Quinhydrone was studied by Friedrich Wohler in 18443.



·       More stable compared to amorphous form

·       Give increased solubility, thus increased bio availability

·       Technique can be used for purification


Co- Crystal Coformers5:

·       Most important for co-crystal formation

·       Its structure is dictate structure of co-crystal

·       Also dictate solubility

·       Differ from excipient



Ascorbic acid, gallic acid, citric acid, glutamic acid, urea, saccharine, glycine tyrosine, valine.



·       Co-crystal formation depends upon selection of solvent.

·       Solubility of drug and co-former is considered while selecting of a solvent.



Ethanol, methanol, acetonitrile, and other organic solvents


Method of co-crystal preparation7:

·       Solution Method

·       Evaporative Co-Crystallization

·       Cooling Crystallization

·       Grinding Method

·       Neat/Dry Grinding Method

·       Liquid Assisted Grinding Method

·       Anti solvent Method

·       Slurry Conversion Method

·       Supercritical Fluid Technology


Fig 1: Methods of preparation of co-crystals


Type of Solid Forms:


Fig 2: Types of Solid forms


Steps Invovled in Preparation8:

·       Selection of API

·       Selection of coformer

·       Empirical and theoretical guidance

·       Co crystal screening

·       Co crystal characterization

·       Co crystal performance



·       PXRD (Powder x rays diffraction study)

·       IR Spectroscopy

·       Scanning Electron Microscopy

·       Percentage yield

·       Determination of melting point

·       Solubility Analysis

·       Compatibility studies (IR spectroscopy)

·       In vitro drug release studies


Design and Strategies of Pharmaceutical Cocrystal:

Pharmaceutical cocrystal design and preparation is a multi stage process. In order to get a desirable co-crystal product of an API with limited aqueous solubility, the first step is to study the structure of the target API molecule and find out the functional group which can form intermolecular interaction with suitable conformers10. As explained before, these intermolecular interactions include Vander Waals contacts, π-π stacking interactions, and the most common interaction in co-crystal structure of the hydrogen bonding. The next step is to choose a co-crystal former. The primary request for a coformer is to be pharmaceutically acceptable, for example, pharmaceutical excipients and compounds classified as generally as safe (GRAS) for use as food additives11. Coformer selection is the crucial step for designing a co-crystal. During the design process, there are lots of worthwhile reference resources, including both empirical and theoretical resources, such as Cambridge Structural Database (CSD), hydrogen bond theories, and many empirical conclusions. CSD is valuable tool to study intermolecular interactions in crystals. It can be utilized to identify stable hydrogen bonding motifs, through referring to structural property relationships present in classes of known crystal structures contained in the CSD12. A supramolecular library of co-crystal formers has been developed based on the information of CSD, within this library a hierarchy of guest functional groups is classified according to a specific contribution to a crystal packing arrangement, which is dependent on the functionalities contained on the host molecule13.

Co Crystal Production:

Co-crystal production routes can be broadly categorized as solid state or solution based. Solid state methods can be differentiated as methods using very little or no solvent, whereas solution based methods represents production routes that involve a large excess solvent necessitating a subsequent isolation stage to separate the crystalline product from the mother liquor14.


Solid State Methods:

This method involves spontaneous formation of co-crystal via mixing of pure API and conformer under a controlled atmospheric environment. In this method no mechanical forces are applied during cocrystallisation. In some cases, grinding of pure components individually for mixing has been done15. Rodriguez Horned studied the effect of premilling of the starting materials on the cocrystallization rate of carbamazepine and nicotinamide. It was shown that the cocrystallisation rate in the case of premilled reactants was marked faster than that of unmilled reactants. Moreover, higher cocrystallisation rates have been reported for the same system at higher temperatures and relative humidity16. Ssarcevica reported the formation of isoniazid-benzoicacid cocrystals via spontaneous cocrystallisation.  They reported that the rate of reaction was considerably increased at higher premilling frequencies of the pure reactants17. Moreover Ibrahim studied the effect of particle size of starting material on spontaneous cocrystallization of urea and 2-Methoxybezamide. It has been shown that smaller particle size distributions lead to faster co-crystal formation18. A rapid increase in cocrystallisation rate was observed in the case of small particle size distribution of 20-45micrometers where no amorphous intermediate phase was detected19. The mechanism of cocrystallization in the presence of moisture at deliquescent conditions consist of three stages

1    Moisture uptake

2    Dissolution of reactants

3    Co-crystal nucleation and growth.


Fig 3: Stages involved in Cocrystallisation in the presence of moisture


Berry used hot stage microscopy for co-crystal screening. They used the Kofler method to successfully probe the binary phase behaviour of a given cocrystal system, revealing potential co-crystal phases in 5 API mixtures. In this work nicotinamide was chosen as a molecular scaffold former with a series of APIs, example flubiprofen, ibuprofen, ketoprofen and salicylic acid. In this method, one component is melted then allowed to solidify, before another compound is brought into contact with it and a proportion of the first component is solubilised20. Thus, after recrystallisation of all materials, a zone of mixing is created. This is comparable to the binary phase diagram of the 2 components. With this method they were able identify formation of nicotinamide: ibuprofen, nicotinamide: salicylicacid, nicotinamide: flubiprofen, and nicotinamide: fenbufen21.


Solid state grinding:

Solids undergo neat (dry) grinding and liquid assisted grinding. Neat grinding involves the combination of the target molecules and conformer in their dry solid forms with the application of pressure through manual (mortar and pestle) or (automated ball mill) means. Dry grinding is distinct from melt crystallization as the solid starting materials are not expected to melt during grinding22. The temperature achieved during grinding is often monitored to ensure the same, and will often be reported. Two sulphathiazole: carboxylicacid for 90mins in are mixer mill at a 25hz frequency with the temperature ot allowed to exceed 37°C. There is an efficiency associated with solid state grinding, relative to solution based methods, in that yield is not lost to the solvent due to solubility23.


Issues with dry grinding include failure to form a co-crystal, incomplete conversion into co-crystal, and crystallised effects with possible generation of some amorphous content. Incomplete conversion to the co-crystal, resulting in a mixture in a mixture of co-crystals and excess starting material in the product, is not desirable as it requires the use if addition purification steps to yield a pure co-crystal product24. Increasing the grinding time can sometimes resolve this, but product mixtures can be also be an indication of non stoichiometric co-crystals formation. Dry grinding is typically attempted with stoichiometric mixtures of target and conformer solids. This will also facilitate discovery of alternative co-crystals if that exists for a system25.


Liquid assisted grinding involves the addition of a solvent, typically in a very small amount, to the dry solids prior to the initiation of milling. The solvent has a catalytic role in assisting co-crystal formation and should persist for the duration of the grinding process. More efficient co-crystal formation is suggested for liquid assisted methods than with neat methods, because tendency for the formation of co-crystal increases as the solvent added to the grinding media is increased but, the liquid component is thought to accelerate reaction kinetics by wetting the solid surface26. Liquid assisted grinding has been reported in a number of different formats. Trask applied caffeine and maleic acid to make a caf: maco crystals for the first time using neat and liquid assisted grinding (LAG) methods. Their research suggested that a 1:1 or 2:1 caf; maco crystal could be a manufactured after 30 and 60 min of grinding depending on the solvent selection27. But in 2010, another methods (ultra sound assisted solution cocrystallisation) was presented to form a purer co-crystal of caf: maco, because the synthesized co-crystals by trask contained impurities and were accompanied by different amounts of caffeine. Benzoic acid co-crystals were formed by wetting an equimolar mixture of benzoic acid and the carboxylic acid conformer in a mortar with methanol and grinding it to dryness. A total of 50µl of nitromethane was added to an equimolar mixture of caffeine and tetra fluoro succinic acid with grinding for 30 mins at 30 hz to form a 1:1 cocrystal28.


Grinding Method:

Grinding methods have been widely used for the co-crystal formation over the past few years and found to be superior than other methods (solutions or melt). Grinding techniques are of two types neat or dry grinding and wet drying. In dry grinding, drug and conformer are mixed together in a stoichiometric ratio and ground them by using either mortar and pestle or ball mill. Wet grinding was performed in a similar manner that of neat grinding by addition of some drops of solvent in the mixture29.



Fig 4: Preparation of Co-Crystals using Grinding Method


Ultrasound Assisted Solution Cocrystallisation:

Sono chemical method has been developed for the preparation of co-crystals of very small size i.e for preparation of nano crystals. In this method, API and co-crystal former are dissolved together in a solvent and the solution is kept in a sonicator to form the solutions turbid30. Cold water is supplied during the sonication to maintain the constant temperature of sonicator and prevent fragmentation. The solution is kept overnight for fragmentation. The solution was dried. Pure co-crystals were obtained by this method and the purity of co-crystals can be assessed31.


Supercritical Fluid Atomisation Technique:

In super critical atomization technique, the drug and coformers are mixed each other by using high pressurized supercritical fluid. Co-crystals are prepared by atomizing this solution with the help of atomizer. In supercritical anti solvent method, the co-crystals are prepared from solution by the anti solvent effect of supercritical fluid32.


Fig 5: Diagrammatic representation of Supercritical Fluid Atomisation Technique


Spraying Drying Technique:

In spray drying process, co-crystals are prepared by spraying the solution or suspension of drug and coformer with hot air stream to evaporate the solvent. This is the most preferred technology because this is a fast, continuous and one step process. Thus, spray drying process will offer a unique environment for the preparation and scale up of co-crystals33.


Fig 6: Diagrammatic representation of


Hot Melt Extrusion Technique:

In hot melt extrusion technique, the co-crystals are prepared by heating the drug and conformers with intense mixing which improved the surface contacts without use of solvent. The limitations of this method include both conformer and API should be miscible in molten form and not used34.


Fig 7: Schematic representation of Holt Melt ExtrusionTechnique apparatus



Cocrystallization offers one of the most promising approaches to improve physicochemical properties of APIs. A wide range of options exist to prepare co-crystals ranging from routine lab scale synthesis methods to potentially large scale continuous production methods. This review offers standard descriptions and examples of established and emerging co-crystal preparation routes. Moreover, detailed insight is given on the proposed mechanisms of co-crystallization in different techniques. As co-crystals continue to gain interest and prove their value, the range of demonstrated co-crystal application areas continues to expand. All demonstrated application areas for pharmaceutical co-crystals are included in this review with the aim of highlighting the wide ranging potential of these materials. It is anticipated that co-crystals will become more and more routine in pharmaceutical development as their benefits continue to be demonstrated and routine common methods of manufacturing are proven.



·       Pharmaceutical cocrystals of Carbamazepine (Tegretol)

·       Pharmaceutical cocrystals off Luoxetine hydrochloride (Prozac)

·       Pharmaceutical cocrystals of Itraconazole (Sporanox)

·       Pharmaceutical cocrystals of Sildenafil (Viagra)

·       Cocrystals of Melamine and Cyanuric acid

·       Cocrystalsoftheophylline⁸

·       Cocrystals of Acyclofenac

·       Cocrystals of 5-Nitrouracil

·       Cocrystals of Indomethacin



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Received on 04.12.2020            Modified on 16.01.2021           

Accepted on 15.02.2021   ©Asian Pharma Press All Right Reserved

Asian Journal of Pharmacy and Technology. 2021; 11(2):175-180.

DOI: 10.52711/2231-5713.2021.00029