Traditionally, excipient selection has been performed using trial-and-error based methodologies, which are time-consuming and expensive. In this article, Dr Amjad Alhalaweh, PhD, formulation scientist, Recipharm, discusses a new method, high-throughput screening (HTS), which can help to tackle excipient selection challenges.
Take your pick
Many companies are facing solubility challenges of new chemical entities (NCEs) during development processes. The solubility of a compound is fundamental in reaching the necessary concentration for the required pharmacological response.
During the early stages of drug development, liquid formulations are created to help understand an NCE’s pharmacology, pharmacokinetics and toxicology. Also, failure to adequately dissolve can have a negative impact on bioavailability and result in suboptimal drug delivery. Strategies to improve drug solubility are therefore of crucial importance, and usually compounds must be paired with excipients that can adequately solubilise them to achieve the required therapeutic response.1,2
The process of selecting excipients has relied on trial-and-error based methodologies, which are well-known to be both time-consuming and expensive for sponsors. These challenges have readied the market for the introduction of a new high-throughput screen (HTS) method that can accelerate and rationalise the selection process.
The potential of a HTS approach
A range of techniques are available to enhance solubility. These strategies include either solid form manipulation using amorphous, salt or cocrystal form, or solvation methods using materials that can solubilise the drug compound, such as co-solvents, surfactants or cyclodextrins.3,4
Solvent modification and carrier systems are used most frequently as they offer the ability to only impact the solvent characteristics of a drug rather than its solid-state properties.5 However, one of the limitations of current selection methods is that they risk missing the best excipient for a compound due to the high costs of traditional experimental procedures which rely on manual handling.
As a better alternative, a HTS approach has been developed to overcome the cost and time challenges of traditional techniques. The objective from the outset was to develop a robust, automatic platform that would use minimal amounts of a compound to provide conclusive information about a drug’s solubility and stability in a variety of solvents and excipients. To develop the methodology, a screening list of excipients was used, including water-soluble organic solvents, non-ionic surfactants, water-insoluble lipids, organic liquids/semi solids, cyclodextrins and phospholipids.6
Rather than testing every excipient manually, as has been required with previous approaches, the HTS methodology enables multiple tests to be undertaken concurrently. It provides research scientists with insight into which excipients, or combination of excipients, are most appropriate for different drug delivery systems, such as those suitable for oral excipients and those best suited to injectables. This insight is critical in ensuring patient safety as an incorrect number of excipients could result in unwanted side effects, such as pain, haemolysis, or inflammation following administration.
Testing the methodology
Six commercial drugs with diverse chemical properties were tested for their solubility with 30 excipients. These experiments ran in parallel in 96 well-plates, with each formulation being dispensed by a Tecan automated dispenser. The plates were shaken for 48 hours to ensure equilibrium. The results were compared with the solubility measurements achieved using a manual shake flask method. As well as proving understanding of the solubility of the various drugs in the different excipients, the process also determined any degradation.
The results
The HTS platform has been shown to provide detailed insight on the solubilisation capacity of different compounds in a variety of excipients, while also providing information on the stability of a compound in the excipients tested. During the experimental stage, it was found that the solubility levels achieved using the HTS approach were not statistically different to those achieved using a manual approach. A t-test was used to verify this at a 95% confidence interval.
Conclusion
Low aqueous solubility is one of the most frustrating aspects of formulation development and there is a recognised need for more optimised techniques to inform the selection of appropriate excipients.
The HTS method offers a strategy to overcome the challenges associated with manual approaches. Not only has the technique proven to be more cost-effective while using less materials, it can turnaround results in as little as 3–5 days per set of compounds.
Adoption of a HTS approach will provide research scientists with an optimised pathway in understanding solubility behaviour, which will ultimately pave the way for more efficient formulation development processes.
References:
- Li, P., and Zhao, L., International Journal of Pharmaceutics, 2007;341(1):1–19.
- Dahan, A., et al., Advanced Drug Delivery Reviews, 2016;101:99–107.
- Alhalaweh, A., et al., Journal of Controlled Release, 2016;229:172–182.
- Miyako, Y., et al., International Journal of Pharmaceutics, 2010;393(1):48–5
- Alhalaweh, A., et al., Molecular Pharmaceutics, 2012;9(9):2605–2612
- Strickley, R.G., Pharmaceutical Research, 2004;21(2):201–230.