Unlocking Bioavailability: Advances in Solubility Enhancement Strategies for Oral and Parenteral Drug Administration

Matt Finkelhor, Commercial Manager, Global Novel Polymers, Lubrizol

Poor aqueous solubility remains one of the most difficult challenges in pharmaceutical development, affecting up to 90% of new chemical entities (NCEs) and over 40% of those in reformulation. Low solubility impairs dissolution, absorption, and pharmacokinetics, resulting in poor bioavailability, increased formulation complexity, and a higher risk of failure to bring a promising drug to market.

This article reviews solubility-related challenges and the evolving toolkit of formulation strategies, including novel polymer-based excipients.

Introduction: Key Solubility and Bioavailability Challenges

The market for new therapeutics is expanding. This is driven by the unique health needs of a growing and aging population, as well as by rising demand for support across various life stages and conditions. As research advances the understanding of chronic and potentially life-threatening diseases, the race is on to develop efficient and safe therapeutics, including parenteral dosage forms for oncology. While early-stage drug development teams are increasingly pursuing these treatments, significant formulation challenges persist, particularly as drug candidates become more complex and poorly soluble.

The Biopharmaceuticals Classification System (BCS) categorises active pharmaceutical ingredients (APIs) into four groups according to their relative aqueous solubility and gastrointestinal-membrane permeability. BSC Class II APIs are highly permeable but poorly soluble, while Class IV APIs exhibit both low permeability and low solubility, making them difficult to disperse in water-based formulations.

Both classes of APIs are characterized by high molecular weight, high crystallinity, and an elevated melting point. These “brick-dust” APIs dissolve slowly and poorly, both during formulation and in the gastrointestinal tract. This creates challenges for formulation as well as low bioavailability of the finished drug. What’s more, these hydrophobic APIs may precipitate in the gastrointestinal tract before absorption, particularly when exposed to aqueous fluids, limiting effective systemic exposure even at high doses.

Solubility-Enhancement Strategies to Improve Bioavailability

Over the years, formulators have developed a range of technologies addressing solubility challenges in APIs to enable the development of drug products that deliver the desired therapeutic effect.

These include physical modifications, which can be used to increase the API’s surface-area-to-volume ratio. Nanomilling, for example, reduces particle size in a liquid vehicle via grinding, while micronization employs a similar approach, using jet milling to reduce particle size to the micron scale. Co-crystallization is another option, involving the incorporation of APIs and co-crystal formers (coformers) into a single crystal lattice. Amorphous solutions and dispersions (ASDs) are also used to increase dissolution rate by disrupting the API’s crystalline structure and maintaining it in a more soluble amorphous state.

Encapsulation techniques can also be used to enhance the solubility of brick-dust APIs for both oral and parenteral administration. Polymer encapsulation, for example, incorporates APIs into natural or synthetic polymer carriers. Meanwhile, micelles – colloidal structures with a hydrophilic shell and a hydrophobic core – sequester the poorly soluble API within their core, allowing them to be dispersed in aqueous environments. Other strategies include the use of liposomes and solid lipid nanoparticles.

Another increasingly accepted approach is supersaturation, in which a highly concentrated solution of the API is formulated to maximize its intraluminal concentration and exceed its thermodynamic equilibrium solubility. This achieves a transient concentration gradient high enough to drive more drug across the gut membrane, increasing its bioavailability. The key issue here is in balancing these factors, which may introduce additional obstacles for formulators. Supersaturation is inherently unstable and prone to precipitation or crystallization, requiring careful design to control its rate and maintain post-administrative supersaturation.

The common link between all these technologies is that they rely on excipients to interact with the API or to stabilize formulations to maintain solubility. Excipient choice should be decided during the early stages of drug development and after the target product profile (TPP) has been defined. The TPP specifies the desired characteristics of a drug, which can include safety or efficacy-related properties. This is crucial, because from a technical standpoint, a drug may require solubility improvements to meet the TPP. The optimal method for formulators will vary, depending on drug moiety and the dosage form required. However, many of the established technologies require complex manufacturing processes that are difficult to optimize efficiently and at scale.

Common Excipient Challenges for Formulators

Excipients are critical to the formulation of ASDs, influencing several essential parameters such as solubility enhancement, drug loading, stability, release kinetics, ease of manufacturing, and patient-centricity. Traditional polymers like hydroxypropyl methylcellulose (HMPC), its acetate succinate variant HPMC-AS, and povidone are widely used for stabilizing therapeutics as ASDs yet struggle to stabilize high drug concentrations above 40%. Consequently, there is an increasing need for innovative high-loading polymer excipients that improve solubility and drug-loading while being compatible with spray-drying and solvent-based production methods.

Another key issue for formulators is reducing tablet size. Large tablets are uncomfortable to swallow and can reduce compliance with a treatment regimen or prevent patients from taking their medication. As many as 40% of children have difficulty swallowing even normal-sized tablets. Meanwhile, for the growing elderly population, who can have swallowing problems due to age-related loss of muscle tone and strength, large tablets can present a choking hazard.

When it comes to developing excipients for injectable administration, formulators face unique safety and regulatory hurdles, which have limited innovation in this space for over 30 years. Many excipients available for parenteral use fall short when it comes to enhancing the solubility of poorly water-soluble or highly crystalline drugs, and some are linked to adverse reactions. For instance, polyethylene glycol (PEG), a commonly used solubilizer in injectable drugs, has been associated with side effects such as neuropathy and severe allergic responses.

Parenteral dosage forms are also a key delivery system for the oncology sector, with a 2022 review finding that 27.5% of parental NCEs were for oncology drugs. Drug developers seeking viable oncology therapies have to mitigate the challenges of potent APIs and potential side effects, while striving to achieve an acceptable bioavailability threshold with brick-dust APIs.

The Potential of Novel Excipients

As the number of poorly soluble APIs has grown, so has interest in novel excipients, even those that may not yet have precedence of use in the chosen administration route. This is particularly where innovators have explored the approved Inactive Ingredient Database (IID)-listed excipients and identified that a novel excipient offers superior benefits. In addition, novel excipients supported by safety data for the intended use can be the key to unlocking the benefits of the FDA 505(b)(2) expedited regulatory pathway for drug approval.

Polymer excipients are one of the main areas gaining traction with formulators. These include Lubrizol’s novel Apinovex™ polymer – a high molecular weight, linear polyacrylic acid excipients that significantly boost dissolution rates, up to tenfold compared to crystalline APIs. It also supports high drug-loading levels – up to 80% in spray-dried ASDs. In turn, this allows for smaller, more potent oral dosage forms, including smaller-sized tablets, which are more acceptable to patients.

For enhancing the solubility of brick-dust APIs for injectable, intravenous, and also oral administration, novel polymer micelle excipients offer an alternative route. They are also an attractive option for the development of oncology therapeutics, where drug regulators tend to tolerate a higher risk-to-benefit ratio. As a consequence, oncology formulators are more likely to be open to leveraging novel excipients, allowing for the creation of therapeutics that are better tolerated by patients.

Novel polymer micelle excipients include Lubrizol’s injectable-grade Apisolex™, an amphiphilic polymer excipient with a polyamino-acid base. It provides a biodegradable, biocompatible, and non-toxic alternative to conventional solubilizers like PEG and PVA and is compatible with simple formulation techniques. By increasing drug solubility up to 50,000-fold and achieving drug loadings of up to 40%, compared to 1% with traditional inclusion complexing agents, this enables higher API concentrations in smaller volumes. This can potentially lower the frequency or duration of dosing, which is a key consideration when designing oncology therapeutics in particular.

Conclusion

Solubility challenges continue to hinder drug development and this is likely to become a growing problem, given the increasing number of NCEs exhibiting poor aqueous solubility.

Traditional tools remain essential, but polymer excipients – such as those used in spray-dried ASDs or micellar injectable systems – offer powerful alternatives. Lubrizol’s Apinovex™ and Apisolex™ exemplify how modern polymer science can enable high-loading oral and parenteral formulations with improved scalability, manufacturability, and regulatory fit. The progression of Apisolex™ into a phase I human trial underscores real-world feasibility and accelerating innovation.

Novel excipient-based approaches have the potential to rescue poorly soluble APIs, support differentiated drug products and deliver meaningful value in pharmaceutical research and patient care.

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