Enhancing Solubility and Bioavailability with Nanotechnology

Drug solubility directly impacts bioavailability and absorption levels, and thus efficacy and safety.Improving the solubility properties of drug substances is therefore important for achieving optimal drug performance. Many different formulation strategies can be used to enhance solubility and bioavailability and provide consistent absorption rates that support optimal drug levels. One of the most affective approaches is use of nanoscale delivery systems for which the size, surface properties, and other attributes can be carefully controlled to support not only enhanced bioavailability, but targeted delivery and controlled release of APIs, as well as both diagnostic and therapeutic functionality (1).

Limited solubility a growing problem

Review of recent FDA approvals of small-molecule drugs indicates an increase in the percentage of novel drug products leveraging innovative mechanisms of action (2,3). Many of these molecules, according to Christian Jones, chief commercial officer at Nanoform, represent increasing structural diversity, complexity, and lipophilicity, with many insoluble in aqueous media.

In fact, with more than 90% of new drug candidates under investigation classified as poorly soluble, achieving optimal bioavailability remains a significant challenge in pharmaceutical development, adds Harsh Shah, a senior scientist with BASF Pharma Solutions. In oral formulations, poorly soluble APIs can result in high pill burdens due to the need for patients to take multiple or larger doses to achieve the desired therapeutic effect. Similarly, in parenteral formulations, poor solubility can lead to increased particle sizes, causing pain and discomfort at the injection site. Both contribute to reduced medication compliance.

Enabling technologies are therefore needed to improve dissolution and solubility in intestinal fluids, Jones says. Due to the diversity of API structures and physicochemical properties, however, no ‘one-size-fits-all’ solutions are available. “Nanoscale technologies are one area of investigation with the potential to bring previously undruggable drug candidates to the market and to reduce preclinical and clinical attrition,” Jones observes.

Nanotechnology offers unique approach

Nano drug delivery systems have, in fact, emerged at the forefront of advanced solubility enhancement technologies for improving drug dissolution, absorption, and overall therapeutic performance, according to Shah. Not only does nanosizing increase dissolution rates, reduce aggregation, and improve bioavailability, it achieves these enhanced properties without the need to form salts or other types of complexes, adds Nitin Swarnakar, North American application labs manager with BASF Pharma Solutions. Nanoscale systems are also often more stable and can be designed to enable controlled API release, and they can increase the performance of other approaches to solubility enhancement, such as amorphous solid dispersions (ASDs).

Drug products are considered to involve the application of nanotechnology, according to FDA, if one external dimension or an internal or surface structure is in the nanoscale range (approximately 1–100 nm) or a material or end product is engineered to exhibit properties or phenomena, including physical or chemical properties or biological effects, that are attributable to its dimension(s), even if those dimensions fall outside the nanoscale range up to 1 μm (1000 nm) (4).

Nanoform differentiates between two broad applications of nanoscale technologies: API particle-size reduction (e.g., nanomilling [5] and nanoforming [6]) and solubilization of APIs in excipient nanostructures (nanoemulsions, lipid nanosystems, polymeric nanoparticles, inorganic nanocarriers, etc.) (7). API particle size reduction improves dissolution rates and, at the lower end of the nano range, apparent solubility, ultimately boosting the fraction of the dose absorbed from of the intestinal tract, Jones explains. Within the second application, various mechanisms are at work. “Nanocarriers can keep the API in the amorphous state and improve solubility. Lipid systems might enhance solubilization into bile salt micelles or even enhance lymphatic absorption, whereas polymeric or magnetic nanoparticles might target specific tissues,” he says.

Many nanoscale delivery options

Lipid-based delivery systems, including liposomes and solid lipid nanoparticles (LNPs, particularly for messenger RNA delivery), nanocrystals, nanoemulsions, iron-polymer complexes, and micelles represent the most widely investigated nano-based drug-delivery systems (8). Others include inorganic, polymeric, hybrid, and biologic (exosomes, virus-like particles) nanoparticles.

Of particular interest are self-nanoemulsifying drug delivery systems (SNEDDS), notes Swarnakar. SNEDDS formulations typically consist of a mixture of lipids, surfactants, and cosolvents that can self-emulsify upon gentle agitation, forming stable nanoemulsions with high surface areas, improved drug dissolution properties, and enhanced permeability across biological membranes, resulting in improved drug absorption and bioavailability.

“Polymeric nanoparticles, micelles, and lipid-based nanoparticles have shown tremendous potential in improving the delivery and efficacy of drugs, particularly in the field of cancer therapy,” Swarnakar observes. Careful formulation is essential in designing these systems, though, as abrupt precipitation of the API or carrier in plasma upon administration by the parenteral route can lead to serious side effects. “Appropriate selection of functional lipids, polymers, and surfactants is crucial to ensuring the success of these drug-delivery systems,” he contends.

Nanoscale delivery optimal for the most challenging APIs

Nanotechnology is often applied to drug substances that present high solubility challenges. “Nanoscale delivery systems have emerged as a key strategy for enhancing the bioavailability of BCS [Biopharmaceutics Classification System] Class II and IV drugs, which suffer from poor aqueous solubility and incomplete gastrointestinal absorption,” notes Swarnakar.

Compounds with high lipophilicity or hydrophobicity (indicated by high logP values) usually benefit from lipid solubilization and nanoemulsifying drug-delivery systems, comments Jones. “‘Simple’ solubilization technologies can be insufficient for BCS class 4 compounds exhibiting both poor permeability and solubility (such as proteolysis targeting chimera molecules) and compounds for which solubility can be enhanced through alternative absorption mechanisms such as paracellular transport and lymphatic absorption,” he observes.

Drug substances that experience rapid and extensive metabolization can also benefit from nanoscale delivery approaches. “Avoiding first-pass gut-wall and liver metabolization by using cleverly designed nanoformulations could yield better therapies for these types of molecules,” Jones explains. He adds that for both BCS Class IV and heavily metabolized APIs, administration routes other than oral that are enabled by nanotechnology can and should also be considered.

LNPs, meanwhile, have been clearly shown to protect biologic payloads (particularly mRNA) from enzymatic degradation and enhance systemic delivery (9). Many types of nanoscale carriers have also been used in cancer treatments to enable targeted drug delivery while minimizing systemic toxicity, according to Swarnakar.

Solutions for several indications

Nanoscale delivery technologies are more frequently applied to certain therapeutic areas where they address critical challenges in drug solubility, stability, targeted delivery, and bioavailability, according to Shah. Based on the approved indications for marketed drugs, application of nanoscale technology has been significant in the oncology space, followed by infectious diseases, pain management therapy, and others (8,10).

For instance, many kinase inhibitors used in cancer therapy exhibit poor solubility (11). “These compounds need enabling technologies, even more so if patient-centric treatment regimens are to be developed,” Jones remarks.

Another driver of interest in nanoscale delivery solutions noted by Jones is the shift from daily oral medications to subcutaneous long acting injectable (LAI) formulations, such as in the case of treatments for psychiatric diseases and viral infections (12,13). “In a subcutaneous matrix, an API’s release rate is governed by particle dissolution. Considering the poor solubility of most of these APIs, nanoparticle-based LAI formulations are becoming more common because they allow for tunability of the API release window/profile,” he explains.

It is important, adds Shah, to highlight the crucial role that surfactants and functional lipids play in the successful development of formulations utilizing nanoscale delivery technologies. “These excipients not only aid in solubilizing the drug, but also improve the safety and bioavailability of the therapeutic agent. By carefully selecting and optimizing these components, therefore, researchers can enhance the performance and efficacy of nanodrugs,” he states.

Complementary technology

Due to the nature of most nanoscale solutions, they are ideal for use in combination with other delivery technologies. Combination or hybrid approaches, according to Jones, can often provide synergistic or symbiotic effects on apparent solubility, absorption, and in certain cases, even permeability.

SNEDDs are a prime example. Another is the use of nanoparticles with bound/adsorbed cyclodextrins. Amorphous solid dispersions, traditionally not categorized as a nanotech approach, can also fall into this category, Jones observes, because upon dissolution in the gastrointestinal tract, the API from a solid dispersion can form drug-rich nanoscale domains before being dissolved into bile salt micelles. Use of permeation enhancers, such as in nanocarriers with bile salts for enhanced intestinal absorption of BCS Class IV drugs, and the attachment of ligands to nanoparticles, such as mRNA-LNP vaccines with PEGylated lipids for improved stability and cellular uptake, are other hybrid approaches of note, says Swarnakar. BASF has also integrated SNEDDs and ASD technologies to improve the physical stability, solubilization, and absorption of the model drug ritonavir.

“By combining nanoscale solutions with other delivery technologies, it is possible to significantly enhance solubility, stability, absorption, and targeted delivery, making these approaches powerful tools in modern drug development,” Swarnakar states.

Jones concludes that, “Drawing hard boundaries around enabling technologies is usually needless.”

Challenges across the development cycle

Although nanoscale delivery technologies clearly enhance solubility and bioavailability for many types of drug substances and formulated drug products, developing them is not easy. Several challenges across raw material sourcing, manufacturing, formulation, quality control, and regulatory approval must be overcome in the process, according to Shah.

One of the primary obstacles in developing nanoscale delivery solutions for poorly soluble APIs is ensuring the quality and purity of the excipients used in these formulations. For instance, liposomal drug-delivery systems and solid LNPs rely on excipients of natural origin, making excipient purity a critical factor. “Variability in starting materials can lead to inconsistencies in batch manufacturing, ultimately affecting drug efficacy and safety. Endotoxins, meanwhile, pose a significant challenge in manufacturing processes due to their presence in bacterial sources,” Swarnakar observes. Thorough testing and control of elemental impurities, microbial content, and endotoxin burden is therefore essential for all parenteral excipients.

Ensuring formulation and process robustness can also be difficult but is crucial for minimizing batch-to-batch variability. “Maintaining critical quality attributes (CQAs) such as particle-size distribution, surface charge, and stability throughout the product’s shelf life requires a comprehensive understanding of formulation science and process parameters,” Shah says. He adds that degradation pathways must be well-characterized to ensure long-term stability and therapeutic performance.

Another important issue noted by Jones is the need for economical production scaling, as without a robust production process, no nanotechnology can reach clinical and market maturity.“Joint efforts of experienced engineering and formulation teams and well-grounded science are needed to overcome the challenges of efficient scale-up,” he contends. To that end, Nanoform developed a proprietary nanoforming technology that has been shown to be effective at producing several tons of API nanoparticles per year.

Even choosing appropriate packaging can present hurdles. “Ensuring the compatibility of a formulation with container materials to prevent leaching of components is particularly important if solubilizers are used in the formulation,” Swarnakar explains. BASF is working on research projects to target chemistries that help reduce compatibility issues. For instance, he notes that recent studies show that the company’s biosurfactants ensure the physical stability of proteins by covering their interactions with interfaces (air-water) and vial surfaces (e.g., glass or polydimethylsiloxane), as well as with themselves.

The regulatory aspects of nanoformulations can also present challenges. While regulatory approval of orally administered “simple” nanoformulations (e.g., nanomilled or nanoformed APIs) is straightforward, Jones notes that for nanocarriers that might linger in the body (e.g., inorganic nanosystems), early consultation with regulatory bodies is highly recommended to avoid caveats at later stages of development.

Despite these challenges, Shah emphasizes that advances in formulation technologies, process optimization approaches, and regulatory standardization are making nanoscale drug delivery more viable. Strategic collaborations between industry, academia, and regulatory agencies are also playing a crucial role in accelerating the development and approval of nanomedicines for poorly soluble APIs.

References

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About the author

Cynthia A. Challener, PhD, is a contributing editor for Pharmaceutical Technology®.

Article details

Pharmaceutical Technology®
Vol. 49, No. 3
April 2025
Pages:16–19

Citation

When referring to this article, please cite it as Challener, C.A. Enhancing Solubility and Bioavailability with Nanotechnology. Pharmaceutical Technology 2025 49 (3).