Department of Pharmaceutics, C. L. Baid Metha College of Pharmacy
Limited water solubility poses a major challenge to the oral bioavailability of many active pharmaceutical ingredients (APIs), particularly those categorized as BCS Class II and IV drugs. Traditional approaches to enhance solubility, such as micronization, solid dispersion, and salt formation, have limitations, especially for compounds that cannot be ionized. Pharmaceutical co-crystals offer a promising alternative by modifying the crystal lattice through non-covalent interactions between the API and a pharmaceutically acceptable co-former, without altering the drug's pharmacological properties. This approach can enhance the solubility, dissolution rate, bioavailability, stability, mechanical strength, and manufacturability of drugs. Co-formers are generally selected from the GRAS list to ensure safety, and co-crystals can be produced using various methods, including grinding, solvent evaporation, hot-melt extrusion, anti-solvent addition, and spray drying. Research has demonstrated the successful use of co-crystals in improving physicochemical properties and enabling controlled release or taste masking. Several co-crystal-based formulations have been commercialized, underscoring their clinical and market importance. With advancements in co-former screening and regulatory acceptance, co-crystals are expected to play a vital role in overcoming formulation challenges in modern drug development.
The aqueous solubility of an active pharmaceutical ingredient (API) is a critical factor in determining its potential for successful clinical application. Improved solubility can have a major effect on the pharmacokinetics of oral medications by enhancing gastrointestinal absorption and enabling lower dosage requirements. [1] Particle size reduction (micronization), solid dispersion methods, surfactant incorporation, self-emulsifying drug delivery systems, use of various polymorphic forms, and complexation with cyclodextrins are some of the strategies that have been investigated to improve the solubility of APIs. [2]. More than half of BCS Class II drugs are made as salts to improve solubility, and salt production is one of the basic methods for altering the physical characteristics of APIs. To employ the Salt Formation Method, the API must have a suitable (simple or acidic) ionizable site. Co-crystals provide an alternate method, though, where any API may co-crystallize regardless of whether it has acidic, basic, or ionizable groups. Therefore, cocrystal formation is considered a novel and useful crystal engineering technique in the field of solubility enhancement. [3] The cocrystal approach to increasing solubility is currently gaining a lot of attention. A crystalline compound is one way to describe a cocrystal. consists of two or more neutral molecules that are solid at room temperature and combine to form a crystal lattice in a particular stoichiometric ratio using non-covalent bonds. [4] The co-crystal approach differs from the other techniques because it preserves the drug's pharmacological characteristics, making it an environmentally friendly means of improving its bioavailability and a number of physicochemical characteristics, such as solubility, permeability, bioavailability, stability, and melting point. [5]
Co crystals
A drug cocrystal is a solid made up of two different neutral molecules — one is the active drug (API) and the other is a conformer mixed in stoichiometric ratio. These components exist together in solid form at room temperature. [6] A variety of intermolecular forces, including hydrogen bonding, Van der Waals forces, π–π stacking, ion-dipole and dipole-dipole interactions, halogen bonding, and occasionally even metal-ligand coordination, are necessary for cocrystallization. A coformer, which is frequently chosen from the U.S. Food and Drug Administration's Generally Recognized as Safe (GRAS) list to ensure its suitability for human consumption, is typically combined with an active pharmaceutical ingredient (API) to create pharmaceutical cocrystals. [7]
IMPORTANCE OF CO-CRYSTALS
Increase Solubility and Rate of Dissolution
By changing their crystal lattice without changing the API's chemical structure, co-crystals greatly increase the aqueous solubility of poorly soluble medications. [8]
Increased Bioavailability
Co-crystals improve the drug's solubility and rate of dissolution, which improves absorption and increases bioavailability. [8]
Adjust and Enhance Physical Characteristics
They enhance stability and manufacturing by enabling control over mechanical strength, hygroscopicity, compressibility, and melting point. [9]
Improve Physical and Chemical Stability
Co-crystals can extend shelf life by lowering moisture sensitivity and degradation. [9]
Relevant to Ionizable and Non-Ionizable APIs
Co-crystals can be formed with neutral molecules, which makes them appropriate for a greater variety of APIs than salts, which need ionizable functional groups. [9]
ADVANTAGES
Stable Solid Form:
One benefit of co-crystals is that they can exist in a stable crystalline state without the need for extra formulation additives or excipients. [10]
Role of conformer:
The type of coformer used in the co-crystal design determines the degree and kind of improvement in the API's properties. [11]
Advantage Over Salts:
Co-crystals have a clear advantage over traditional salt forms, especially for non-ionizable APIs, which can still improve drug properties without ionization. [12]
Environmentally Friendly Process:
Numerous co-crystal synthesis methods are regarded as green chemistry strategies since they frequently produce large quantities of product, reduce or do away with the need for solvents, and generate little waste or byproducts. [13]
Cost effectiveness:
Pharmaceutical companies can greatly benefit from shorter development timelines since they can result in lower overall costs. [13]
Enhance api properties:
Enhancing the drug's physicochemical properties (such as solubility, stability, and dissolution) while maintaining its pharmacological activity is one of the main advantages of co-crystal formation. [13]
DISADVANTAGES:
Dissociation of Phases and Instability
Under conditions of dissolution or humidity, some co-crystals may dissociate into separate components, thereby losing their stability. [14]
Mechanical Sensitivity
Co-crystals may change into different solid forms (such as amorphous or distinct phases) as a result of operations like compression or milling. [15]
Interference of Excipients
Excipients or other additives may displace the co-former during formulation, changing the crystal form and possibly impacting the effectiveness of the drug. [15]
Difficult and Expensive Description
Advanced techniques like PXRD or single-crystal XRD are frequently needed for accurate confirmation of co-crystal formation; the use of DSC may be restricted by overlapping melting points. [15]
Time-Consuming Co-former Screening
Finding a suitable co-former is unpredictable and necessitates computational simulations or time-consuming screening. [15]
PREPARATION OF CO CRYSTALS
With the advancement in drug development, various methods are being used for the preparation of multicomponent solid forms such as cocrystals, cosolvates, coamorphous, polymorphs, hydrates/salts, and eutectics. The key factors include solvent selection, API, and coformers. The several types of techniques that are most frequently employed include:
Fig 1: methods of preparation
Figure 2: techniques used for co crystal preparation [16]
Grinding
In recent years, grinding techniques have become more popular for co-crystal formation because they are superior to other approaches (melt or solution). There are two categories of grinding methods: wet grinding and dry grinding.
One solvent-free cocrystallization technique is dry grinding. Using a mortar and pestle, a ball mill, or a vibrator mill, the solid ingredients that will form the cocrystal are combined in the proper stoichiometric quantities, then compressed and crushed.
The typical grinding time is between 30 and 60 minutes. Many cocrystals can be made with this technique, and any failure is typically the result of using the wrong parameters. The specific surface area of interaction between the materials for the formation of intermolecular bonds increases when the particle size is decreased. Copared to cocrystallization through dissolution, this approach offers better selectivity. It is simple and allows for the targeted cocrystal to form quickly. It has also been used to investigate hydrogen bond preferences. Dry grinding, however, can have drawbacks like partial conversion, unsuccessful cocrystal formation, or crystalline defects that could cause some amorphous material to form. Similarly, partial transformation into the desired cocrystal can produce a mixture of unreacted starting materials and the cocrystal. This result is undesirable since a pure cocrystal frequently requires additional purification procedures. [17]
Grinding that is aided by the addition of a very small amount of solvent to the mixture both before and during the grinding process is known as liquid-assisted grinding, or LAG. The solvent plays a catalytic role, which speeds up and encourages the co-crystal's development. Several co-crystals have been created with LAG. This approach speeds up cocrystallization if time and the grinding process are not managed correctly, producing low-quality co-crystals. simultaneously benefit from a shorter preparation time for cocrystals. [18]
Slurry Crystallization
The process of slurry crystallization involves mixing an API with an appropriate coformer and adding various solvents to create a suspension. The mixture is allowed to react, the solvent is extracted (decanted), and the residual solid is dried for approximately five minutes under a nitrogen stream. Powder X-Ray Diffraction (PXRD) is then used to analyze the dried material. When the drug and coformer are both stable in the selected solvent, this method works well for cocrystal formation. [19]
Anti-solvent addition
Figure 3: Anti Solvent Addition [20]
This is one technique for creating co-crystals of superior quality. The coformers are dissolved in various solvents throughout this procedure, including organic solvents, and the API is distributed in a dispersion homogenizer to mix the coformer solution. The coformer on the medication is then precipitated by adding this solution to distilled water or another appropriate solution. This method's disadvantage is that a large amount of solvent is needed for the preparation. One popular method for creating high-quality cocrystals is the anti-solvent method, also known as vapor diffusion. This method involves adding a solvent with limited solubility for the drug and coformer to a solution that contains the desired ingredients. The cocrystal crystallizes as a result of this addition's promotion of supersaturation. The anti-solvent usually does not dissolve the resulting cocrystals easily, but it is miscible with the original solvent. Following crystallization, the suspension is filtered, and X-ray powder diffraction (XRPD) is used to gather and characterize the solid product. [21]
Hot melt extrusion method
Figure 4: Hot melt extrusion method [22]
With this technique, coformers and the active pharmaceutical ingredient (API) are added to a temperature-controlled system and heated until they melt, creating cocrystals as a new solid phase. Because the drug and coformer must be molten in order to interact, this method is inappropriate for compounds that are sensitive to heat. Without a solvent, the molten state guarantees improved surface contact between the constituents. [23]
Sonocrystallization
Figure 5: Sonocrystallization [24]
This technique was created to create nanocrystals, or co-crystals of extremely small size. This process involves dissolving the drug and coformer in a single solvent and maintaining the mixture at a steady temperature for sonication. In order to keep the sonicator's temperature steady and avoid fragmentation, coldwater is supplied. For drying, the solution is left overnight. Cocrystals are created when the solvent continues to evaporate. This process produces pure co-crystals, and an X-ray diffraction study can be used to evaluate the co-crystals' purity. [25]
Spray drying
Figure 6: Spray Drying [26]
One popular technique for creating cocrystals is spray drying. It is a quick, one-step, continuous process that turns liquids like slurries, suspensions, or solutions into solid powders. The drug and coformer are first dissolved in a common volatile solvent in order to create cocrystals. After that, the solvent is rapidly evaporated and solid cocrystal particles are left behind when this solution is sprayed into a stream of hot air. Because it provides a special setting for quick cocrystal formation and works well for large-scale manufacturing, spray drying is widely used. The four primary steps of the spray drying process are: (1) interaction between the hot air and the sprayed liquid; (2) solvent evaporation from the sprayed droplets; (3) solid particle formation via atomization at the spray nozzle; and (4) collection of the finished dried product. [27]
Solvent evaporation method
Figure 7: solvent evaporation [28]
One of the most popular processes for creating cocrystals is evaporative cocrystallization, particularly when single crystals are required for in-depth analysis. This technique involves dissolving a predetermined quantity of the drug and coformer in the same solvent. The premise behind this method is that a stable cocrystal is more likely to form if the drug and coformer can establish strong hydrogen bonds with one another. The solution becomes concentrated as the solvent gradually evaporates, aiding in the formation of the cocrystals. It's critical to gather crystals before the solution dries out entirely in order to obtain pure and clean crystals. Since slow evaporation promotes the formation of fewer, larger, and higher-quality crystals, it is preferable. To identify whether the obtained solid is a cocrystal, a salt, a hydrate, or another polymorphic form of the drug or coformer, it is crucial to ascertain the crystal structure. Three different kinds of solutions should ideally be used for evaporative cocrystallization in order to accomplish this correctly: one with extra coformer, one with extra drug, and one with equal amounts of drug and coformer (1:1 ratio). This guarantees the proper formation of the desired cocrystal and aids in understanding how the components interact. [29]
Crystallization by Reaction
Figure 8: Crystallization By Reaction [30]
A quick technique for creating cocrystals on both small and large scales at regulated temperatures is reaction crystallization. Cocrystal nucleation and formation in this process are dependent on the drug and coformer's solubility behavior. Methanol is used to dissolve the less soluble drug until it reaches saturation, after which it is filtered. The coformer is added to the solution in a tiny quantity, just below its solubility limit. This cautious balancing helps prevent the use of excessive amounts of the coformer or the drug, which could cause the resulting solid to be mistakenly identified as a real cocrystal. The resulting cocrystals are extremely pure since the constituents are used near the limits of their solubility. High-Performance Liquid Chromatography (HPLC) is used to track concentrations and verify that the solid product is, in fact, a cocrystal throughout the process. [31]
Cooling co crystallization
Figure 9: Cooling Co Crystallization [32]
By adjusting the solution's temperature to produce supersaturation, the drug is recrystallized using this technique. First, a specified solvent at 40.0 ± 0.5°C is used to fully dissolve a measured amount of the drug. After that, the mixture is gradually cooled in a water bath at a rate of 0.25°C per minute until it reaches 10.0 ± 0.5°C while being constantly stirred. Once the crystals have cooled, they are separated using vacuum filtration, cleaned with distilled water, and allowed to dry for a full day at room temperature. To stop the crystals from absorbing moisture, they are finally kept in a desiccator. [33]
Table no 1: Various research in pharmaceutical co-crystals
|
Sr. No |
Researcher/Year |
Title of Research |
Conclusion |
|
1. |
Imanto et al. 2024 [34] |
Preparation and solid-state characterisation of Ketoprofen succinic acid Saccharin cocrystal with improved solubility. |
PXRD, DSC, FTIR, and dissolution studies all confirmed that ketoprofen cocrystals made with succinic acid and saccharin had better solubility, with the 1:1:1 molar ratio (Formula 1) showing superior dissolution and changed physicochemical properties. |
|
2. |
Jadhav et al. 2023 [35] |
Formulation Of Tablet Of Ivermectin Co-Crystal For Enhancement Of Solubility And Other Physical Properties |
Ivermectin–fumaric acid cocrystals with improved solubility and dissolution were successfully formed by solvent-assisted grinding, indicating its potential to improve the properties of BCS class II drugs. |
|
3. |
Dr Dipti Srivastava et al. 2022 [36]
|
Glibenclamide–malonic acid cocrystal with an enhanced solubility and bioavailability. |
These findings show that GLB's solubility and dissolution behavior were successfully altered by the cocrystallization process, leading to better pharmacokinetic characteristics. |
|
4. |
Khushbu R Chaudhari et al. 2021 [37] |
Improved pharmaceutical properties of ritonavir through co-crystallization approach with liquid-assisted grinding method |
Improvement of Ritonavir's Solubility and Bioavailability through Cocrystallization Using the Liquid-Assisted Grinding Method |
|
5. |
de Almeida et al. 2020 [38] |
Cocrystals of ciprofloxacin with nicotinic and isonicotinic acids: mechanochemical synthesis, characterization, thermal and solubility study. |
Cocrystals of ciprofloxacin containing nicotinic and isonicotinic acid were effectively created using thermal and mechanochemical techniques. These new cocrystals improved the thermal stability and solubility of CIP, potentially leading to better pharmaceutical applications. |
|
6. |
Gajda et al. 2019 [39] |
Continuous, One-step Synthesis of Pharmaceutical Cocrystals via Hot Melt Extrusion from Neat to Matrix-Assisted Processing. |
Hot-melt extrusion (HME) continuous cocrystallization provides a scalable, solvent-free substitute for traditional techniques. This method is further improved by polymer-assisted grinding, which makes it possible to customize properties by using different amorphous or semi-crystalline polymers. |
|
7. |
Srivastava Dipti et al. 2018 [40] |
Tailoring the Dissolution Rate of Candesartan through Cocrystal Formation |
Several analytical methods verified the enhanced drug release and improved solubility of a candesartan benzoic acid cocrystal that was created by solution crystallization. |
|
8. |
Panzade et al. 2017 [41] |
Pharmaceutical Cocrystal of Piroxicam: Design, Formulation and Evaluation |
Orodispersible tablets containing piroxicam cocrystals and sodium acetate showed improved dissolution rate and faster disintegration. |
|
9. |
Rajbhar et al. 2016 [42] |
Formulation and Evaluation of Clarithromycin Co Crystals Tablets Dosage Forms to Enhance the Bioavailability |
Compared to commercially available tablets, clarithromycin–urea cocrystal tablets demonstrated better solubility, 80.23% drug release in 30 minutes, and superior in-vitro performance, suggesting increased bioavailability via the cocrystal approach. |
|
10. |
Sanaa et al. 2015 [43] |
Aerosil as a novel co-crystal co-former for improving the dissolution rate of hydrochlorothiazide |
Aerosil 200's potential as an efficient coformer was demonstrated when hydrochlorothiazide was ground with liquid assistance using Aerosil 200 and acetone, resulting in a new cocrystal with noticeably faster dissolution. |
Table no 2: Marketed products of co crystal formulation: [44-49]
|
Pharmaceutical co crystal |
Components |
Use |
|
Depakote® |
Valproic acid… [valproate sodium |
Epilepsy |
|
Lexapro® |
[Escitalopram oxalate] …Oxalic acid |
Depression |
|
Suglat® |
Ipragliflozin… L-proline |
Diabetes |
|
Entresto® |
[Valsartan sodium] … [sacubitril sodium] |
Heart failure |
|
Cafcit® |
Caffeine… [citric acid] |
Infantile apnoea |
|
Steglatro® |
Ertugliflozin… L-pyroglutamic acid |
Diabetes |
Novell ingredients in formulation of co crystallization
|
Name Of The Research |
Coformer |
Method |
Result |
|
Design, Formulation and evaluation of Amiodarone HCl co-crystal tablet [50] |
UREA |
Dry grinding |
the result shows that solubility of drug was increase in co crystal form |
|
Formulation and Solid-State Characterization of Nicotinamide-based Co-crystals of Fenofibrate [51] |
nicotinamide |
Anti-solvent |
Enhanced dissolution rate and increased solubility |
|
Cocrystal Formulation: A Novel Approach to Enhance Solubility and Dissolution of Etodolac [52] |
Glutaric acid |
cooling crystallization |
Significant improvement in dissolution rate and solubility |
|
Formulation and evaluation of buccal films of piroxicam co-crystals [53] |
Sucralose |
Solvent evaporation |
Shows six folds more solubility than parent drug |
|
Development of Paracetamol-Caffeine co-crystals to improve compressional, formulation and in-vivo performance [54] |
caffiene |
Liquid assisted grinding and solvent evaporation |
Dissolution profile of co crystal shows 2.84-fold dissolution rate |
|
Preparation and formulation of progesterone para-aminobenzoic acid co-crystals with improved dissolution and stability [55] |
para-aminobenzoic acid (PABA) |
Liquid assisted grinding |
Progesterone-PABA co-crystal showed a significant increase in the dissolution |
APPLICATIONS
Bioavailability: [56]
Pharmaceutical co-crystal formation has become a successful method for improving drug performance through the modification of characteristics like pharmacokinetic behavior, bioavailability, and solubility. This method is particularly useful for medications that fall under BCS Classes II and IV, where oral absorption is restricted by poor aqueous solubility. The absorption profile of these poorly soluble medications has been demonstrated to be considerably enhanced by cocrystallization. For instance, compared to the drug in its pure form, the bioavailability of indomethacin was greatly increased when it was prepared as a co-crystal with saccharin. Likewise, co-crystals were created with 2-[4-(4-chloro-2-fluorophenoxy) phenyl] and glutaric acid.In comparison to the unaltered active pharmaceutical ingredient, pyrimidine-4-carboxamide showed enhanced oral bioavailability.
Tabletability [57]
Co-crystallization has been demonstrated to improve flowability and mechanical strength, two crucial characteristics needed for tablet formulation. For example, the co-crystal that was created between carbamazepine and saccharin had a higher density than carbamazepine alone. Furthermore, when paracetamol was co-crystallized with substances like theophylline, oxalic acid, naphthalene, and phenazine, its compressibility was enhanced.
Solubility [57]
A major obstacle to successful medication therapy is still limited water solubility. A compound's crystal structure is changed by co-crystallization, which frequently results in a solubility that is different from that of the constituent parts. Excessively high solubility can be problematic, even though improved solubility is typically beneficial for raising bioavailability. This is due to the possibility that a supersaturated solution will form, raising the possibility of the original drug substance precipitating and compromising therapeutic efficacy.
Controlled Release [58]
Cocrystallization can be used to purposefully slow down the rate at which some medications dissolve, even though it is frequently used to increase solubility. V. Chen et al., for instance, showed that the formation of a cocrystal of the water-soluble antiviral drug ribavirin resulted in a slower rate of dissolution. By reducing the amount of peak-to-trough variability, this decrease assisted in reaching more stable plasma concentrations.
Taste Masking [59]
Orally disintegrating tablets (ODTs), sometimes referred to as quick-dissolving tablets, provide a convenient dosage form that does not require chewing or water, which makes them perfect for patients who are young, elderly, or constantly on the go. Using coformers made of sugar has been shown to be a successful method for increasing dissolution rates. Sucralose, for instance, has been utilized as a coformer in hydrochlorothiazide co-crystals, improving dissolution and masking taste. And theophylline in bitter taste and frequently needs sweeteners like sodium saccharin or vanilla. Through liquid-assisted grinding, a 1:1 co-crystal of theophylline and saccharin was created, which demonstrated enhanced sweetness and dissolution capabilities. Likewise, trimethyl glycine (TMG)-formulated paracetamol co-crystals showed improved mechanical strength, compressibility, dissolution speed, and taste.
CONCLUSION
Pharmaceutical co-crystals have become a potent tactic in contemporary drug development, providing a flexible platform to improve the physicochemical characteristics of active pharmaceutical ingredients (APIs) without compromising their pharmacological activity. Co-crystal research and development has expanded, however, because of their designation as "new solid forms" by regulatory bodies such as the FDA and EMA. Co-crystals, in summary, are a promising new area in the science of pharmaceutical formulation. In the future of drug delivery systems, co-crystals are expected to be crucial due to ongoing developments in crystal engineering and regulatory frameworks. They are an important weapon in the formulation scientist's toolbox because they provide customized performance while maintaining the therapeutic identity of APIs.
REFERENCE
Anandha Krishnan B.*, Selvi G., Mohammed Fazan O., Co-Crystallization as a Strategy for Solubility Enhancement: Design, Development, and Pharmaceutical Applications, Int. J. Sci. R. Tech., 2025, 2 (8), 347-360. https://doi.org/10.5281/zenodo.16915126
10.5281/zenodo.16915126
