Vastanvi College Of Pharmacy, Kannad, Aurangabad, Maharashtra, India - 431103.
Co-crystallization is a promising strategy in pharmaceutical formulation for improving the solubility, stability, and bioavailability of poorly water-soluble drugs. This review explores the mechanisms, advantages, and practical methodologies of co-crystallization, highlighting recent advances in the field. Co-crystals, composed of active pharmaceutical ingredients (APIs) and conformers linked by non-covalent interactions, present a viable alternative to traditional approaches such as salt formation and amorphization. This article summarizes the Biopharmaceutical Classification System (BCS) relevance, applications, advantages, limitations, and evaluation methods of co-crystals, with a comprehensive literature survey and discussion on various formation techniques.
Solid oral dosage forms such as tablets and capsules are the most common means of drug delivery. However, many active pharmaceutical ingredients (APIs) cannot be formulated in their pure form due to instability or poor solubility. Co-crystallization has emerged as a powerful technique to overcome these challenges, enhancing the physicochemical properties of APIs without altering their pharmacological profile. Co-crystals are crystalline materials composed of an API and a neutral coformer, held together through non-covalent interactions such as hydrogen bonding. They differ from other solid forms like salts, polymorphs, and solvates in that they do not require ionizable groups. This approach is particularly useful for BCS Class II and IV drugs, which suffer from poor water solubility and limited bioavailability.
2. Need and Objective
Many newly developed drugs exhibit poor aqueous solubility, limiting their therapeutic potential. Co-crystallization addresses this by enhancing the solubility and dissolution rate without chemical modification. This makes it a valuable tool in drug development, especially for non-ionizable drugs. The primary objective of co-crystallization is to create multicomponent systems that improve drug properties such as solubility, stability, mechanical strength, and bioavailability. By employing pharmaceutical coformers, a wide range of APIs can be improved through crystal engineering techniques.
3. BCS Classification and Examples
According to the Biopharmaceutical Classification System (BCS), drugs are categorized into four classes based on their solubility and permeability. Co-crystallization offers a targeted strategy to enhance the solubility of drugs in Classes II and IV. Examples include co-crystals of ibuprofen with nicotinamide (BCS Class II), and furosemide with caffeine (BCS Class IV), which have demonstrated improved dissolution and bioavailability.
|
Class 1 |
High solubility/ high permeability |
B- blockers propanol |
|
Class 2 |
Low Solubility / High Permeability |
NSAIDS Ketoprofen , Antiepileptic , Carbazepine , Phenytoin, Nifedepine |
|
Class 3 |
High Solubility / Low permeability |
B blockers Atenolol , H2 antiagonist Ranitidine |
|
Class 4 |
Low solubility / Low permeability |
Diuretics Hydroclorthiazide , Frusemide , Taxol |
4. Applications of Co-crystallization
Co-crystals improve various drug properties including:
- Bioavailability: Enhanced solubility leads to increased absorption.
- Dissolution: Intrinsic dissolution rate is improved without altering the drug chemically.
- Stability: Both physical and chemical stability of the drug is maintained.
- Mechanical Properties: Better compressibility and flow make them suitable for tablet formulation.
- Sustained Release and Therapeutic Effect: Modified release profiles and improved therapeutic outcomes are achievable.
5. Advantages and Limitations
Pharmaceutical co-crystallization presents several advantages:
- Can be applied to APIs without ionizable functional groups.
- Uses a broad range of pharmaceutically acceptable coformers.
- Enhances solubility, stability, mechanical strength, and tabletability.
- Solvent-drop grinding and other green methods reduce solvent use.
- Allows purification and formulation flexibility without altering pharmacological activity.
However, co-crystallization also has certain limitations:
- Lack of a complete understanding of co-crystal formation and structure-property relationships.
- Stability concerns under varying temperature and humidity.
- Challenges in separation and identification due to small particle size in grinding methods.
- Possible phase transitions during storage or processing.
6. Methods of Co-crystallization
Various methods are employed in co-crystal formation:
- Grinding Method (Dry and Liquid-Assisted): Simple, cost-effective, and environmentally friendly.
- Slurry Method: Involves suspension of API and coformer in solvent and stirring.
- Antisolvent Addition: Addition of miscible solvent to induce co-crystal precipitation.
- Hot Melt Extrusion: Solvent-free, continuous process involving heat and mixing.
- Spray Drying: Dissolution followed by rapid evaporation to yield fine co-crystals.
- Supercritical Fluid Technique: Uses CO2 under pressure for crystallization.
- Sonocrystallization: Ultrasonication promotes nucleation and crystallization.
7. Characterization Techniques
Co-crystals are characterized using various techniques to assess their properties:
- Solubility Testing: Measures improvements over pure API.
- Stability Studies: Assesses humidity and thermal stability.
- Melting Point Determination: Indicates successful co-crystal formation.
- Tabletability: Evaluates compression and flow properties.
- Permeability: Log P-based assessment using in vitro models.
- Bioavailability: In vivo and in vitro studies compare drug release from co-crystals vs. pure drugs.
8. RESULTS
Co-crystallization significantly enhances the physicochemical performance of poorly water-soluble APIs. Experimental and literature evidence shows that solubility, dissolution rate, stability, and tabletability are all improved using suitable coformers and optimized methods.
9. CONCLUSION
Co-crystallization offers a robust and flexible approach for improving drug delivery, particularly for BCS Class II and IV drugs. It bypasses the need for ionizable groups, allows the use of diverse coformers, and integrates well with existing pharmaceutical processes. With increasing interest in crystal engineering, co-crystals are poised to become a standard in formulation development.
REFERENCES
Mohiuddin Shaikh, Shaikh Taufique Akil*, Shaikh Aawez, Alaisa Khan, Aadil Ahmad, Umair Ali Khan, MD Rashid, Review on Co-crystallization for Solubility Enhancement, Int. J. of Pharm. Sci., 2025, Vol 3, Issue 6, 5816-5823. https://doi.org/10.5281/zenodo.15771618
10.5281/zenodo.15771618
