Why Most Modern Drug Candidates Fail at Solubility 

Drug discovery capabilities continue to advance rapidly. Medicinal chemists are designing molecules with unprecedented potency and selectivity, enabling therapies that were not possible even a decade ago. Yet despite these scientific gains, many promising drug candidates still struggle to reach patients. One of the most common reasons is poor solubility. 

For today’s formulation scientists, solubility challenges are no longer isolated edge cases. They are a defining feature of modern pharmaceutical development. As discussed during one of our recent educational webinars on pharmaceutical extrusion technologies, poor solubility remains one of the most persistent barriers to bioavailability, manufacturability, and clinical success. 

In pharmaceutical manufacturing, understanding why this problem has become so widespread, and how formulation teams can address it earlier and more systematically, is essential. 

Poor Solubility Is Now the Norm, Not the Exception 

Modern drug candidates are often larger, more complex, and more lipophilic than their predecessors. These properties are frequently necessary to achieve target specificity and metabolic stability, but they come at a cost. Increased lipophilicity and molecular complexity typically reduce aqueous solubility. 

Peer-reviewed research consistently shows that a majority of new chemical entities exhibit low water solubility, and a significant portion of marketed oral drugs still fall into this category. From a formulation perspective, this creates immediate risk. If a drug cannot dissolve efficiently in gastrointestinal fluids, absorption becomes limited or highly variable, regardless of how potent the molecule may be. 

As a result, formulation teams are often asked to solve solubility problems late in development, when timelines are tight and options are constrained. 

Why Traditional Solubility Strategies Often Fall Short 

Conventional approaches to improving solubility include salt formation, particle size reduction, and the use of solubilizing excipients. While these methods remain valuable tools, they are not universally applicable. 

Salt formation may not be feasible for molecules without suitable ionizable groups. Particle size reduction can improve dissolution rates but may introduce stability, handling, or downstream processing challenges. Solvent-based techniques can be effective but bring added complexity related to solvent selection, removal, environmental considerations, and scale-up. 

As pipelines continue to shift toward poorly soluble compounds, these incremental fixes are increasingly insufficient on their own. 

Amorphous Solid Dispersions Offer Promise and Complexity 

One of the most effective strategies for addressing poor solubility is the use of amorphous solid dispersions (ASDs). By disrupting the crystalline structure of an active pharmaceutical ingredient and dispersing it within a carrier, dissolution rates and apparent solubility can be significantly improved. 

The science behind this approach is well established. Crystalline APIs are thermodynamically stable but dissolve slowly, while amorphous forms possess higher free energy and dissolve more readily. However, this benefit comes with a tradeoff. Amorphous systems are inherently unstable and prone to recrystallization over time if not carefully designed. 

Recent peer-reviewed studies demonstrate that high levels of amorphization can be achieved, but long-term stability depends on formulation composition, residual crystallinity, and processing conditions. In practice, creating an amorphous system is only part of the challenge. Maintaining its performance throughout shelf life is equally important. 

Why Process Design Matters for Solubility 

A key insight emphasized during our webinar is that solubility enhancement is not only a formulation challenge. It is also a process challenge. 

Manufacturing technologies influence molecular dispersion, thermal exposure, mechanical stress, and ultimately stability. Continuous processing approaches, including hot-melt extrusion (HME) and other extrusion-based techniques techniques, give formulators precise control over temperature, residence time, and mechanical energy input. These parameters directly affect whether an API becomes fully amorphous or retains crystalline regions that can act as seeds for recrystallization. 

In extrusion-based processes, factors such as screw design, specific mechanical energy, and feeding strategy play a critical role. Insufficient energy may lead to incomplete dispersion, while excessive energy can risk degradation. The value of extrusion lies in its ability to balance these variables in a controlled, reproducible way. 

Why Solvent-Free, Continuous Manufacturing Is Gaining Momentum 

As development timelines shorten and molecules become more challenging, solvent-free and continuous manufacturing approaches are receiving increased attention. These methods reduce process steps, eliminate solvent-related risks, and improve reproducibility from development through scale-up. 

Extrusion technologies, including HME, align well with current regulatory expectations around process understanding and control. When applied thoughtfully, they allow formulation scientists to integrate solubility enhancement and manufacturability into a single, scalable process rather than treating them as separate problems. 

Designing for Solubility from the Outset 

The most important lesson from both scientific research and real-world experience is that solubility should not be treated as a downstream rescue operation. It must be addressed early and holistically. 

Successful formulation strategies increasingly share common characteristics: 

• Early identification of solubility risk 

• Integration of formulation and process development 

• Thoughtful use of enabling technologies such as amorphous dispersions 

• Careful consideration of processing approaches, including extrusion and HME 

• Focus on long-term stability, not just initial dissolution performance 

Most modern drug candidates do not fail because they lack efficacy. They fail because they cannot be delivered effectively. Designing for solubility from the outset, using a combination of formulation science and process technologies, gives promising molecules a far better chance to succeed on their path from discovery to patient. 

Resources 

Watch Webinar

 

• https://pubmed.ncbi.nlm.nih.gov/39598492/ 

• Learning Series and Implementation Tips: https://www.thermofisher.com/us/en/home/global/forms/industrial/mc-pharma-module-courses.html 
• Pharmaceutical Extrusion Systems: https://www.thermofisher.com/us/en/home/industrial/manufacturing-processing/extrusion-compounding-equipment/instruments/pharma.html
• Extrusion-based technologies: https://www.thermofisher.com/us/en/home/industrial/manufacturing-processing/extrusion-compounding-equipment.html

Frequently Asked Questions

1. Why do so many modern drug candidates have poor solubility?
Many modern drug molecules are larger, more complex, and more lipophilic to improve target specificity and stability. These properties often reduce water solubility, making poor solubility a common challenge rather than an exception.

2. How does poor solubility affect drug bioavailability?
If a drug does not dissolve efficiently in gastrointestinal fluids, absorption becomes limited or variable. This can prevent adequate drug levels in the body, regardless of the compound’s potency.

3. Why are traditional solubility enhancement methods sometimes insufficient?
Approaches such as salt formation, particle size reduction, and solubilizing excipients are not suitable for all molecules and can introduce stability, processing, or scalability challenges, especially for highly complex compounds.

4. What are amorphous solid dispersions and why are they used?
Amorphous solid dispersions improve dissolution by converting a crystalline drug into a higher-energy amorphous form within a carrier. This can significantly enhance apparent solubility, though stability must be carefully managed.

5. Why is manufacturing process design important for solubility?
Processing conditions influence molecular dispersion, stability, and the risk of recrystallization. Controlled, continuous processes allow formulation and manufacturability considerations to be addressed together, improving long-term performance.