Optimising Pharmacokinetics via Novel Formulation Strategies in Poorly Soluble Drugs

Pharmacokinetics — the study of how drugs are absorbed, distributed, metabolised, and excreted — forms the foundation of rational drug design. However, poor aqueous solubility remains a major barrier to optimal pharmacokinetic performance, especially for Biopharmaceutics Classification System (BCS) Class II and IV compounds. These molecules typically exhibit high permeability but low solubility, limiting their oral bioavailability.

This article explores cutting-edge formulation techniques used to overcome these challenges and optimise pharmacokinetic profiles.

1. Lipid-Based Formulations

Lipid-based drug delivery systems (LBDDS) like self-emulsifying drug delivery systems (SEDDS) and SMEDDS enhance solubility and facilitate lymphatic transport, bypassing first-pass metabolism.

• Benefits: Increase oral absorption of lipophilic drugs.
• Mechanism: Promote formation of microemulsions in the gut, enhancing dissolution and permeation.

2. Amorphous Solid Dispersions (ASDs)

Converting crystalline drugs to their amorphous form significantly improves dissolution rates due to higher free energy states.

• Stabilisation methods: Use of polymeric carriers (e.g. HPMC, Soluplus®) to inhibit recrystallisation.
• Effect: Rapid supersaturation in the GI tract, increasing Cmax and reducing Tmax.

3. Nanotechnology-Based Approaches

Nanoparticles increase surface area and improve dissolution velocity.

• Nanocrystals: Pure drug particles reduced to nanometre scale, stabilised by surfactants.
• Polymeric nanoparticles: Encapsulation using biodegradable carriers (e.g. PLGA) for controlled release and targeted delivery.

4. Supersaturating Drug Delivery Systems (SDDS)

These systems induce a temporary supersaturated state upon contact with GI fluids, increasing absorption before precipitation occurs.

• Examples: Supersaturating SMEDDS (S-SMEDDS), which combine solubilisation and precipitation inhibition.
• Application: Especially useful for weakly basic drugs subject to pH-dependent solubility.

5. Cyclodextrin Complexation

Cyclodextrins form inclusion complexes with lipophilic drugs, improving aqueous solubility and stability.

• Advanced use: β-cyclodextrin derivatives like hydroxypropyl-β-cyclodextrin offer improved safety and solubilisation.
• Pharmacokinetic benefit: Increased AUC and reduced inter-patient variability.

6. Prodrug Design and Salt Formation

Chemical modification of the parent molecule can significantly improve solubility and absorption.

• Prodrugs: Temporarily inactive derivatives converted in vivo to the active form (e.g. valacyclovir → acyclovir).
• Salts: Counter-ions enhance solubility and stability (e.g. mesylate, hydrochloride, phosphate salts).

Conclusion

Poor solubility need not be a limitation. By strategically applying advanced formulation technologies, it is possible to optimise the pharmacokinetic profiles of challenging APIs, unlocking their full therapeutic potential. The future of drug development lies not just in molecule discovery — but in how we deliver it.