Published May 08, 2026

The Challenge: Solubility and Bioavailability in Drug Development

Poor aqueous solubility is one of the leading causes of failure in oral drug development. Approximately 40% of marketed drugs and up to 70–90% of drug candidates in development exhibit poor aqueous solubility, placing many compounds in Biopharmaceutics Classification System (BCS)  Class II or IV categories where dissolution rate or solubility limits oral bioavailability.

The core challenge is thermodynamic: crystalline drug molecules are held together by lattice energy, and the energy required to solvate these molecules in gastrointestinal fluids may exceed what the physiological environment can provide. Without intervention, a poorly soluble API may never reach therapeutic concentrations in systemic circulation.

Overcoming solubility-related bioavailability barriers requires a formulation strategy grounded in physical chemistry, material science, and biopharmaceutical principles. The optimal approach must be tailored to the API's physicochemical profile, target product profile (TPP), clinical stage, and scalability requirements.

A successful formulation is not defined by solubility alone—it must balance bioavailability, physical stability, and manufacturability to ensure a seamless transition from early development to clinical and commercial stages.

The M3 Philosophy: Molecule · Material · Medicine

Molecule

We begin with a deep scientific understanding of your compound:

• Target Product Profile (TPP) alignment

• Early drug metabolism and pharmacokinetics (DMPK) and pharmacodynamics assessment

• Safety margin integration

• Biopharmaceutical properties

• Physiochemical properties

Material

We analyze the physical and chemical foundation of the formulation:

• Crystal/salt form and solid-state properties

• Crystallinity and polymorphism

• Excipient compatibility and functionality

• Mechanical and compaction behavior

• Surface/wetting properties

Medicine

We design for the final patient experience and industrial scale drug product:

• Label-driven formulation development strategy

• Critical Quality Attributes/Critical Process Parameters (CQA/CPP) impact analysis

• Risk-based Quality by Design (QbD) strategy

• Regulatory-compliant scalability

Why Solubility Enhancement Is Challenging

In pharmaceutical development, solubility enhancement technologies are rooted in three principles:

• Thermodynamic stability — The equilibrium state of drug molecules determines solubility supersaturation tendency and long-term physical stability.

• Kinetic accessibility — High-energy physical forms can be generated through controlled processing but require stabilization strategies.

• Biopharmaceutical context — Physiological factors such as pH, enzymes, bile salts, transit time, and permeability influence how formulation choices perform in vivo.

Technical Approaches to Bioavailability Enhancement

A range of enabling technologies is available to improve exposure for poorly soluble APIs. The optimal choice is not universal; it depends on compound properties, dose, and the intended development path.

Amorphous Solid Dispersions (ASD)

ASD disperses drug molecules in a polymer matrix at the molecular level, creating a high-energy amorphous state that eliminates the lattice energy barrier to dissolution. ASD is widely used to enhance solubility and oral bioavailability of poorly water-soluble drugs.

Spray Drying

Spray drying atomizes a drug-polymer solution into a heated chamber for rapid solvent evaporation, producing amorphous dispersion particles with controlled morphology. It is particularly useful for heat-sensitive compounds and early-stage formulation development.

Hot Melt Extrusion (HME)

HME processes drug-polymer mixtures above the glass transition temperature using mechanical shear. It is a solvent-free, continuous process with regulatory precedent, but requires careful assessment of API thermal stability.

Lipid-Based Formulations

Lipid-based systems, including self-microemulsifying drug delivery systems (SMEDDS), self-emulsifying drug delivery systems (SEDDS), and other self-emulsifying formulations, present drugs in a pre-dissolved state. They can be particularly effective for highly lipophilic compounds and may enhance absorption through intestinal solubilization and lymphatic transport pathways.

Particle Size Reduction

Nano-milling and micronization increase surface area to improve dissolution kinetics. These approaches are often effective for  Developability Classification System (DCS) IIa compounds with good permeability but dissolution rate control.

Salt and Co-Crystal Formation

Ionizable APIs may benefit from salt formation, while non-ionizable compounds may benefit from co-crystal strategies. These approaches modify solid-state properties while maintaining a crystalline structure, which can offer better physical stability than amorphous approaches.

Advanced and Emerging Techniques

• KinetiSol® — A solvent-free, high-energy mechanical dispersion process for ASD production.

• Electrospinning — A nanofiber-based ASD approach with high surface area and rapid dissolution potential.

• Mesoporous silica drug delivery — Geometric confinement can inhibit crystallization for compounds with poor polymer miscibility.

• Co-amorphous systems — Drug plus co-former systems that enhance dissolution without a polymer carrier.

• Co-precipitation — ASD particles form by mixing the solvent and anti-solvent streams

When to Choose Each Technology

The following decision layer helps development teams identify a practical starting point for formulation screening. In practice, early-stage teams often screen more than one technology in parallel to reduce risk and avoid platform bias.

Quick Decision Summary

Technology Comparison: Selecting the Right Approach

The table below summarizes practical attributes of common solubility enhancement approaches. It is intended as a guide for early decision-making and should be paired with compound-specific feasibility studies.

Implementation Workflow

A systematic workflow ensures efficient use of limited API and supports data-driven formulation decisions throughout development.

• Characterization — Physicochemical profiling of the API: solubility, logP, pKa, Tm, Tg, thermal stability, and solid-state properties.

• Screening — Evaluate multiple formulation approaches in parallel using film casting and lab-scale spray dryer or extruder

• Selection — Select the optimal formulation with in vitro and in vivo testing results

• Scale-up — To pilot scale equipment to support GMP manufacturing.

• Verification — Confirm scaled product matches lab performance through dissolution testing, solid-state characterization, and stability studies.

Key Considerations for Formulation Development

Physicochemical Properties

The API profile drives formulation strategy. Key parameters include aqueous solubility, pH-solubility profile, logP/logD, pKa, Tm/Tg, TGA/DSC thermal behavior, glass transition potential, polymorphism, and crystal form options.

Dose Requirements and Therapeutic Window

Target dose strongly influences technology selection. High-dose compounds may require solid oral dosage strategies such as ASD tablets, while lower-dose compounds can sometimes be effectively delivered through lipid-based systems.

Regulatory Expectations

Regulatory agencies expect science-based formulation justification, robust solid-state characterization, stability data, impurity control, and appropriate documentation for enabling formulations.

Stage-Appropriate Strategies

Early-stage programs benefit from rapid, material-sparing feasibility screening. Later-stage programs require deeper characterization, long-term stability data, scalable processes, and regulatory-grade technical reports.

Partner Evaluation Criteria

When selecting a CRO or CDMO partner for bioavailability enhancement, evaluate whether the partner can provide breadth, not just a single preferred technology.

• Technology breadth — ASD, lipid-based systems, particle size reduction, solid-state approaches, and advanced characterization.

• Scale-up capability — Smooth transfer from feasibility screening to GMP clinical manufacturing.

• Analytical support — In-house XRPD, ssNMR, MicroED, PLM, DVS, dissolution, and stability programs.

• Regulatory track record — Ability to support IND/NDA-enabling documentation and technical reports.

• Material-sparing workflows — Feasibility screening with limited API quantities.

Bioavailability Enhancement Capabilities at Crystal Pharmatech

Crystal Pharmatech offers a comprehensive suite of bioavailability enhancement technologies, including ASD (spray drying and HME), lipid-based formulations (SMEDDS), and advanced characterization. The First-Time-Right strategy ensures that the optimal technology is selected based on the compound profile—not platform availability.

Our approach includes:

• Comprehensive developability assessment with physicochemical profiling and in silico physiologically based pharmacokinetic (PBPK) modeling (GastroPlus).

• Material-sparing feasibility screening across multiple technologies in parallel.

• GMP clinical manufacturing with spray drying, HME, and lipid-fill capabilities.

• Advanced solid-state characterization: XRPD, ssNMR, MicroED, PLM, and DVS.

• Stability programs and technical documentation supporting IND/NDA filings worldwide.

• For teams at candidate selection or early preclinical stage, Crystal Pharmatech can support rapid feasibility screening using as little as 1-2g of API, with actionable data generated in weeks rather than months.

Conclusion

Improving bioavailability of poorly soluble drugs requires a strategic approach that considers the full spectrum of enabling technologies. No single approach works for every compound. The best choice depends on the API's physicochemical properties, target product profile, dose, clinical stage, and scalability requirements.

By combining scientific understanding, parallel feasibility screening, and stage-appropriate development, drug development teams can overcome solubility barriers earlier and reduce downstream risk.

Crystal Pharmatech helps sponsors identify the right formulation path early, generate decision-ready data, and advance poorly soluble molecules toward clinical development with confidence.

Frequently Asked Questions

What is amorphous solid dispersion in simple terms?

Amorphous solid dispersion is a formulation technique where drug molecules are dispersed at the molecular level within a polymer carrier. This eliminates the crystal structure and can  increase the apparent solubility and maintain higher drug concentrations in the body.

Why are so many drugs poorly soluble?

Modern drug discovery often favors larger and more lipophilic molecules that bind strongly to biological targets but dissolve poorly in water-based gastrointestinal fluids.

What does BCS Class II mean?

BCS Class II drugs have low solubility but high permeability. Once dissolved, they can cross intestinal membranes, so dissolution is often the rate-limiting step for absorption.

How do you know if ASD will work for a specific drug?

A feasibility study evaluates polymer miscibility, drug loading, physical stability, and the ability to achieve and maintain supersaturation in biorelevant dissolution media.

When should I choose ASD over a lipid-based formulation?

ASD is often favored when a solid oral dosage form is preferred, the API has moderate lipophilicity, or the target dose is higher. Lipid-based systems may be preferred for highly lipophilic, lower-dose compounds, or when ASD does not work.

How much API is needed for feasibility studies?

Initial feasibility screening can often begin with approximately 1-2 g of API for film casting and 40-50 g for lab-scale spray drying , depending on the study design and the technologies being evaluated.

References

1. Lipinski, C.A., et al. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Advanced Drug Delivery Reviews, 2001.

2. Tambe, S., et al. Recent Advances in Amorphous Solid Dispersions. Pharmaceutics, 2022.

3. Bhujbal, S.V., et al. Pharmaceutical amorphous solid dispersion: A review of manufacturing strategies. International Journal of Pharmaceutics, 2021.

4. Porter, C.J.H., Trevaskis, N.L., and Charman, W.N. Lipids and lipid-based formulations: optimizing the oral delivery of lipophilic drugs. Nature Reviews Drug Discovery, 2007.

5. Hancock, B.C. and Zografi, G. Characteristics and significance of the amorphous state in pharmaceutical systems. Journal of Pharmaceutical Sciences, 1997.

6. Jermain, S.V., Brough, C., and Williams, R.O. Amorphous solid dispersions and nanocrystal technologies for poorly water-soluble drug delivery. International Journal of Pharmaceutics, 2018.

7. Amidon, G.L., et al. A theoretical basis for biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharmaceutical Research, 1995.