Advanced Solubility Enhancement Techniques in Oral Drug Delivery Systems

Poor aqueous solubility remains a major challenge in oral drug development. According to the Biopharmaceutics Classification System (BCS), nearly 40% of approved drugs and up to 90% of candidates in the discovery pipeline fall into BCS Class II or IV — where solubility becomes a limiting factor for bioavailability.

This article explores modern techniques used to overcome solubility barriers and enhance the performance of oral formulations.

1. Solid Dispersion Systems

Solid dispersions involve dispersing poorly soluble drugs in hydrophilic carriers. These systems improve wettability, reduce crystallinity, and enhance the dissolution rate.

Common carriers include:

• Polyvinylpyrrolidone (PVP)
• Hydroxypropyl methylcellulose (HPMC)
• Polyethylene glycol (PEG)

Methods: Hot-melt extrusion and spray drying are the most common manufacturing techniques.

2. Nanocrystal Technology

By reducing particle size to the nanometre range, the surface area increases significantly, enhancing dissolution. Stabilisation of nanocrystals is typically achieved using surfactants or polymers.

Advantages:

• High drug loading
• Minimal use of excipients
• Enhanced stability over amorphous systems

3. Lipid-Based Drug Delivery Systems (LBDDS)

These include self-emulsifying drug delivery systems (SEDDS), self-microemulsifying (SMEDDS), and lipid suspensions. They enhance solubility of lipophilic drugs and promote lymphatic absorption.

Key components:

• Oils (e.g. medium-chain triglycerides)
• Surfactants (e.g. polysorbates)
• Co-solvents (e.g. ethanol, propylene glycol)

4. Cyclodextrin Complexation

Cyclodextrins form inclusion complexes with lipophilic molecules, improving water solubility and stability. Modified cyclodextrins like hydroxypropyl-β-cyclodextrin are often used for oral delivery.

5. Amorphous Solid Dispersions (ASDs)

By locking drugs in an amorphous, higher-energy state, ASDs bypass the solubility limitations of crystalline forms. However, their physical stability must be carefully managed to avoid recrystallisation.

6. Co-crystals and Salt Formation

Co-crystals combine the API with a co-former to enhance solubility, without altering pharmacological activity. Salt formation, when applicable, remains one of the most traditional and effective methods for ionisable compounds.

Conclusion

Solubility enhancement is no longer a supplementary step — it is a critical component of modern drug formulation strategy. Selecting the appropriate technology depends on the physicochemical properties of the API, regulatory acceptance, and scalability.