Spherical Cocrystal Technology - Role of Polymers in Enhancing Physicochemical and Mechanical Properties of Drugs

Spherical cocrystal technology is an emerging and innovative approach in pharmaceutical formulation aimed at improving the physicochemical and mechanical properties of drug substances. Many active pharmaceutical

ingredients (APIs) suffer from poor solubility, low flowability, and inadequate compressibility, which can limit their effectiveness and complicate manufacturing processes.^1-2 To overcome these challenges, cocrystallization is used, where an API is combined with a suitable coformer to form a stable crystalline structure without altering its pharmacological activity. In spherical cocrystal technology, these cocrystals are further modified into spherical agglomerates using techniques such as spherical crystallization. This transformation improves particle size distribution, surface morphology, and micromeritic properties. The spherical shape enhances powder flow and packing ability, making the material more suitable for direct compression into tablets.³

Polymers play a vital role in this technology by acting as crystallization modifiers and stabilizers. They help control nucleation and crystal growth, prevent aggregation, and improve wettability and dissolution behavior. As a result, spherical cocrystals not only enhance drug solubility and bioavailability but also simplify downstream processing.^4-5

Direct tableting of active pharmaceutical ingredients (APIs) is possible when powders have a good flow property and compression characteristics, which is a problem for major of the active ingredients that have poor compressibility and flow. However, on addition of excess amount of diluents or by wet or dry granulation satisfactory results can be obtained.^6-8 The addition of excess amount of directly compressible diluents is not favored, as they may increase the compressibility but may not increase the flow property of powder blend while wet granulation is a process that consumes time, energy, and required maintenance of lot of documentation.⁹ The spherical crystallization (SC) is a technique, which has shown promising results in the improvement of particle size, flowability and compression characteristics of active pharmaceutical agents. The SC by the spherical agglomeration (SA) method is defined as an agglomeration process that transforms crystals directly into a compacted spherical form during the crystallization stage and this process also ensures the tablet size reduction by omitting the use of large amounts of fillers.¹⁰ The direct compression method for tablet manufacturing is cost efficient and easy to validate. Various other techniques such as hydrotropy, sono crystallization, hot melt extrusion technique, steam aided granulation, floating granulation, dried nano suspensions, liquisolid technology, and cryo techniques are available for improvement of solubility, but SA technique not only increases the dissolution it also improves the powder characteristics of the active ingredient.

2 Spherical Crystallization Techniques

2.1 Spherical agglomeration method

In this process, drug is dissolved in a system of water, ethanol and chloroform behaving as poor solvent, good solvent, and bridging liquid, respectively.¹¹ As the drug solution is poured in the poor solvent simultaneous crystallization of the API takes place, a third liquid known as bridging liquid that has low miscibility with the poor solvent but having a good affinity with the drug is added in a controlled manner to the crystallization vessel.¹² Therefore, it forms a bridge between the particles and cause binding of the particles.¹³ In this process, it should be taken care of that the good solvent and poor solvent should have greater affinity than drug affinity of drug and the good solvent.^14-15 The process is shown in Figure 1.

 

 

Fig 1. Process of spherical agglomeration²

 

 

Fig 2. Crytsallo-co-agglomeration process for preparation of spherical crystals²

6. Applications in Advanced Drug Delivery Systems³¹

Polymers are used in many advanced formulations such as:

1. Spherical cocrystals – Improve solubility and flow
2. Hydrogels – Used for topical and wound healing
3. Nanoparticles – Enhance drug targeting
4. Transdermal patches – Controlled drug delivery

7. Advantages of Using Polymers

1. Improve drug solubility and stability
2. Enhance bioavailability
3. Provide controlled drug release
4. Improve manufacturing properties
5. Reduce production cost

8. Limitations of Polymers

1. Some polymers may interact with drugs
2. High concentration may affect drug release
3. Cost of some synthetic polymers is high
4. Moisture sensitivity in some cases

CONCLUSION

Polymers are essential components in pharmaceutical formulations. They play a key role in improving both physicochemical and mechanical properties of drugs. By enhancing solubility, stability, flowability, and compressibility, polymers help in developing effective and stable dosage forms. Their use in advanced technologies like spherical cocrystals further improves drug performance. Therefore, polymers are highly valuable in modern drug delivery systems and continue to be an important area of research in pharmaceutical science.

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