cipients, 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
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 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-er-
ror based manual techniques. In addition to being more cost ef-
fective and using minimal volumes of materials, the approach can
achieve results in 3-5 days, making it a much faster alternative to
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. CP
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,
5. Alhalaweh, A., Roy, L., Rodríguez-Hornedo, N., & Velaga, S. P. (2012). pH-de-pendent 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.
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.