Anandha Krishnan B.*
Selvi G.
Mohammed Fazan O.
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
10.5281/zenodo.16915126