Tackling the Big Issue of Solubility

Published on: 
Pharmaceutical Technology, Pharmaceutical Technology, January 2022 Issue, Volume 46, Issue 1
Pages: 26–27

Poor solubility remains a big issue for drug development and, as such, is driving innovation in approaches and use of novel technologies to help overcome the associated challenges.

Increasingly, poorly soluble compounds are forming part of the development pipeline, driving greater innovation in ways to overcome the associated challenges these compounds give rise to. To learn more about solubility and bioavailability considerations in drug development and innovations in the field, Pharmaceutical Technology spoke with Kyle Smith, president and COO of Aprecia, and Jim Huang, PhD, founder and CEO of Ascendia Pharmaceuticals.

Still a big issue

PharmTech: Could you provide some insight into the issue of poor solubility/bioavailability and how it impacts bio/pharmaceutical formulation, both currently and into the near future?

Smith (Aprecia): Up to 40% of commercial products require solubility/bioavailability enhancement for sufficient exposure to achieve therapeutic action (1). For compounds in development, it is estimated that up to 90% require solubility/bioavailability enhancement (1). Development of products to achieve required solubility and absorption presents a critical challenge to clinical dosage formulation and process development, which can add significant time to early formulation development work. Furthermore, scientific rationale, quality-by-design, and quality risk assessments become more critical when trying to formulate poorly soluble compounds, as they are necessary to define the functionality, reproducibility, and assurance of consistent performance related to efficacy and safety to patient.

Huang (Ascendia): Poor solubility/bioavailability is still a big issue for drug discovery and development in a high percentage of small molecules and a portion of peptide and large molecules. Low solubility causes poor oral bioavailability and insufficient drug loading for parenteral dosage forms, which cause issues in generating enough drug plasma concentration that is required for drug toxicity and efficacy evaluation in preclinical and clinical studies.

Common approaches

PharmTech: What formulation approaches are employed to overcome solubility/bioavailability challenges?

Huang (Ascendia): Using our practice and experience at Ascendia Pharma as an example, typical approaches for solubility and bioavailability enhancement includes salt formation, micronation, solution, micelle, lipidic solution, complex formation; advanced technologies to address the challenge include nanoemulsion formulation, amorphous solid dispersion, and nanosuspension; new technologies, such as amorphous nanoparticles and lipid nanoparticles, have been proved useful for certain challenging compounds.

Smith (Aprecia): A number of approaches can be explored based on the API’s inherent physicochemical nature. Some current approaches include micronization of API, nanoparticles of API (obtained via ball mill, cyromills, jet mill, and Nanoform’s Controlled Expansion of Supercritical Solutions [CESS] technology), cocrystals, complexes, prodrugs, solubilization (lipids, oils, surfactants, absorption enhancers, etc.), and amorphous solid dispersions (e.g., hot melt extrusion, high pressure dispersions [DisperSol], spray-dried dispersions, drug layering on substrate). However, many of these approaches require a larger design space and/or minimal exposure to process stress to ensure optimal solubility/absorption is achieved.

Novel techniques

PharmTech: Could you highlight some novel techniques and how such techniques or disruptive technologies, such as three-dimensional printing (3DP), can provide formulation advantages when approaching poorly soluble compounds?


Smith (Aprecia): 3DP can offer many advantages, such as rapid formulation prototypes, fast-to-clinic and to-market via expedited timelines for clinical supplies and commercialization, a reduced development time, improved stability due to less aggressive processing conditions (e.g., less heat, water activity, pressure, particle deformation), and dose flexibility. Additionally, the technology is inherently suitable for process condition monitoring and advanced process control; there is the option for flexible controlled drug delivery if it is required, and it is a mature technology that has been proven for commercial product good manufacturing practice (GMP) manufacturing. Further to these benefits, the technology can provide unique branding and commercial imagery possibilities and a unique and pleasant patient experience that aids with compliance. It can be used to create easy-to-administer and swallow products that allow patients to overcome dysphagia, and is suitable for use when formulating drugs for most patient age groups.

Essentially, 3DP can expediate formulation development, potentially allowing clinical supplies with minimal excipients or solid oral dosage forms with substantially higher API content, which can be a limitation of conventional tablets or capsules related to swallowable size limitations. To take advantage of these benefits, Aprecia is partnering with technology companies, including Glatt and Nanoform, to develop novel dosage forms that help to overcome many of the challenges associated with conventional manufacturing.

Huang (Ascendia): Novel technologies such as 3DP may prove to be useful for orally disintegrating dosage forms for certain patient populations, who have difficulties with swallowing traditional oral solid dosage forms, as well as for drugs that need fast absorption and to bypass first pass [metabolism]. When evaluating a new technology, a tailored approach would be practical because every compound has unique properties, its own specific patient population, intellectual property strategy, dose amount, and manufacturing cost requirements, which may impact the selection of technology for use in dosage form development.

Novel excipients

PharmTech: Are there any limitations with the current availability of excipients that might hinder formulation of poorly soluble compounds? Might the new pilot program for novel excipients drive innovation?

Huang (Ascendia): New excipients that improve solubility and bioavailability are certainly very welcome for use in dosage form development. However, expensive long-term pharmacology and toxic effects of novel excipients have to be evaluated using animal models before FDA can approve them for use in humans, which could be a barrier to exploration of novel excipients for use in drug development.

Smith (Aprecia): A broad range of excipients used in approved products are available that provide broad functionality to support novel approaches for solubility and bioavailability enhancement. This approach can potentially provide intellectual property advantages. In general, and in the interest of time to market, complexity, and cost, the preference is to use materials already approved for pharmaceutical use within the maximum amounts established by the FDA. Novel pharmaceutical-grade excipients can be utilized when necessary but require additional testing to meet FDA regulatory requirements.

The future is here

PharmTech: What does the future hold for formulators in terms of poor solubility and bioavailability?

Smith (Aprecia): The future is here! Up to 90% of new compounds for formulation and process development require solubility/bioavailability enhancement. In addition, over half of new compounds are eligible for accelerated registration pathways. New technology platforms provide opportunities for efficient and effective formulation and process development to move compounds quickly through Phase Ia and Ib so ‘go/no-go’ decisions can be made quickly. With earlier decisions, resources for failing candidates can be quickly redeployed to other programs.

Enabling Phase Ia and Ib product development programs to be robust enough to move quickly into Phase II, Phase III, and commercial without reformulation or redesign of the manufacturing process is a key driver for technology innovation. In addition, continuous processing provides a further opportunity for eliminating the risks and costs associated with scale-up and technology transfer of conventional batch processes.

Huang (Ascendia): For most of the compounds in development, traditional technologies in combination with nano-based technology should be able to address solubility and bioavailability issues. New technologies and processes, such as amorphous nanoparticles, are worth exploring for certain types of compounds.


1. S. Kalepu and V. Nekkanti, Acta Pharm. Sin. B, 5 (5) 442–453 (2015).

About the Author

Felicity Thomas is the European editor for Pharmaceutical Technology Group.

Article Details

Pharmaceutical Technology
Vol. 46, No. 1
January 2022
Pages: 26–27


When referring to this article, please cite it as F. Thomas, “Tackling the Big Issue of Solubility,” Pharmaceutical Technology 46 (1) 2022.