Many newly discovered compounds are limited by issues associated with poor water solubility, meaning that drugs do not adequately dissolve in physiological fluids. Poor solubility can lead to low bioavailability resulting in suboptimal drug delivery, and despite possessing superior pharmacological properties, these drug molecules risk withdrawal from development. 

Solubility is critical in achieving the required concentration of a compound for the desired pharmacological response. In the initial stages of drug design and development, simple liquid formulations are used to evaluate a compound’s pharmacology, pharmacokinetics and toxicology. During this process, compounds that suffer from low aqueous solubility need to be paired with excipients that can adequately solubilize them.^1,2 Until recently, the identification of an appropriate excipient has relied on a trial-and-error-based methodology. The time-consuming and expensive nature of this process has paved the way for the development of a new high-throughput screen (HTS) method that can optimize the selection of appropriate solubilization excipients.

Drug solubility enhancement techniques
Solubility issues complicate the formulation and development of new chemical entities (NCEs), but there is an array of techniques available to enhance the solubility and improve the bioavailability of these drugs. The strategies include either solid form manipulation using amorphous, salt or cocrystal form, or solvation methods using materials that can solubilize the drug compound such as co-solvents, surfactants or cyclodextrins.^3,4 Selection of the solubility method will depend on several factors, including a compound’s unique properties, the physical state of the formulation, the site of adsorption and the required dosage form characteristics. Generally, solvent modifications and carrier systems are the most widely used approaches in developing liquid formulations due to their ability to only impact the solvation characteristics of a compound rather than its solid-state properties and ease of preparation.⁵

Exploring a more efficient approach
While there are many solubilization techniques available to formulation scientists, the trial-and-error-based approach of selecting the right methodology for a compound is both time-consuming and requires a considerable amount of active pharmaceutical ingredient (API) to be used for each test. This makes it an incredibly costly and resource heavy option for drug developers. Furthermore, the risk of missing the best excipient for a compound is high due to the limited experiments and cost associated with performing manual handling.

To overcome the challenges, a HTS approach has been developed to offer a more cost and time efficient alternative to existing techniques. The aim was to develop a robust, automatic platform that would use minimal amounts of compound to provide conclusive information about a drug’s solubility and stability in a variety of solvents and excipients. To establish the methodology, a large number of experiments were performed to optimize the technique, using a broad screening list of excipients, including water-soluble organic solvents, non-ionic surfactants, water-insoluble lipids, organic liquids/semi solids, cyclodextrins, and phospholipids.⁶

Using the approach, different excipients are shown to be most appropriate for varying drug delivery systems. For example, there are marked differences between the list of excipients identified as oral excipients and those considered most suitable for injectables. There is also a need to understand the necessary concentration for each excipient and each drug delivery system. This should be done in line with the Generally Recognized as Safe (GRAS) list of recommended concentrations.

Selection of an appropriate excipient, or combination of excipients, is critical to the drug formulation process. An incorrect number of excipients could result in pain, haemolysis, or inflammation on administration to a patient. Clearer insight into a compound’s solubility in a wide-range of excipients will assist formulation scientists in ensuring that unwanted side effects are minimized, bringing a more stringent approach to patient safety during drug development.

Testing the high-throughput screen methodology
The HTS approach shortens the time necessary to identify which excipients can adequately solubilize a compound, as well as which excipients a compound can remain stable in. Instead of testing every excipient manually, as has been required with previous approaches, this methodology involves multiple tests being undertaken concurrently.

To develop the method, six commercially available drugs were used with diverse chemical properties. These were tested with 30 excipients, dispensed in 96 well-plates via an automated TECAN-robotic system. During this experimental phase, the plates were shaken for 48-hours to achieve equilibrium.

The results of the testing process were compared with the solubility measurements achieved using a manual shake flask method (using 15mg of powder and 2mL of excipient). The samples were again shaken for 48-hours, centrifuged and analyzed by high-performance liquid chromatography (HPLC). All experiments were performed in triplicate. This process determined the solubility of the compounds in the excipient, while also detecting any degradation of the compound.

The results
The understanding of a compound’s unique physical properties and their impact on different characteristics not only enhances the selection of the most appropriate formulation strategy, but also ensures the most appropriate excipient for the drug delivery system. The solubilization extent for each molecule by each excipient is demonstrated in Figure 1.
The findings have highlighted that pH dependent solubility is a useful approach for ionizable compounds, especially if it can be combined with another solubilizing excipient. The contribution of solid-state barrier to solubilizing a compound appears to be more pronounced at a cut-off level of the solid-state properties. This has already been determined to some extent by previous research programs⁷ and is currently being investigated using a larger set of compounds. Before this cut-off, the solubilization of the compound was more compound specific which creates the need to also test on a larger set of excipients.

The testing phase demonstrated that solubility using the HTS method is not statistically different to the results achieved using a manual approach, this was verified at a 95% confidence interval using a t-test. The platform provides detailed insight on the solubilization capacity of different compounds in varying excipients, while also providing formulation scientists with information on the stability of a compound in each excipient tested, as well as in water, and acidic and basic buffers.

Establishing the HTS method has provided an approach that overcomes many of the challenges associated with trial-and-error based manual techniques. In addition to being more cost effective and using minimal volumes of materials, the approach can achieve results in 3-5 days, making it a much faster alternative to traditional techniques.

Final thought
Therapeutic effectiveness of a drug depends upon the solubility of drug molecules, with low aqueous solubility being regarded as one of the most challenging aspects in the formulation of NCEs. An understanding of the solubility behavior of a compound is a vital aspect of pre-formulation testing, and these problems can be readily addressed with the identification of an appropriate solubility technique. Selection of the right solubility excipient will come down to several factors relating to a drug’s unique characteristics. By adopting a HTS methodology, formulation scientists can not only identify the ideal excipient for a compound, but can do so in a more efficient and cost-effective way, while minimizing the amount of API required to achieve accurate results. By optimizing formulation design, the HTS method can bring improved timelines while ensuring patient safety, and enhancing the pathway for the development of new drugs. 

References

1. Li, P., & Zhao, L. (2007). Developing early formulations: practice and perspective. International Journal of Pharmaceutics, 341(1), 1-19.
2. Dahan, A., Beig, A., Lindley, D., & Miller, J. M. (2016). The solubility–permeability interplay and oral drug formulation design: Two heads are better than one. Advanced drug delivery reviews, 101, 99-107.
3. Alhalaweh, A., Bergström, C. A., & Taylor, L. S. (2016). Compromised in vitro dissolution and membrane transport of multidrug amorphous formulations. Journal of Controlled Release, 229, 172-182.
4. Miyako, Y., Khalef, N., Matsuzaki, K., & Pinal, R. (2010). Solubility enhancement of hydrophobic compounds by cosolvents: role of solute hydrophobicity on the solubilization effect. International journal of pharmaceutics, 393(1), 48-54.
5. Alhalaweh, A., Roy, L., Rodríguez-Hornedo, N., & Velaga, S. P. (2012). pH-dependent solubility of indomethacin–saccharin and carbamazepine–saccharin cocrystals in aqueous media. Molecular pharmaceutics, 9(9), 2605-2612
6. Strickley, R. G. (2004). Solubilizing excipients in oral and injectable formulations. Pharmaceutical research, 21(2), 201-230
7. Persson, L. C., Porter, C. J., Charman, W. N., & Bergström, C. A. (2013). Computational prediction of drug solubility in lipid based formulation excipients. Pharmaceutical research, 30(12), 3225-3237.

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Dr. Amjad Alhalaweh, Ph.D., is a research scientist at Recipharm’s development facility in Uppsala, Sweden. He is responsible for developing solutions for complex formulation challenges for both newly discovered compounds and existing drugs, along with finding new, cost-effective approaches for formulation design. He has specific expertise in the development of liquid formulations through understanding of the solubilization mechanism of different excipients, crystallization of a compound, solid-state characterization and solid form selection. He also delivers lectures at Uppsala University on the formulation of poorly soluble compounds. An active member of several professional bodies including the Controlled Release Society, the American Association of Pharmaceutical Science and the Swedish Association of Pharmaceutical Science, Amjad is also a registered pharmacist with the Syrian Pharmaceutical Association. Dr. Alhalaweh can be reached at amjad.alhalaweh@recipharm.com.