A Q&A with Karl Kolter, PhD, Head of Pharmaceutical Excipients R&D, BASF
Q. Excipients add important functionality to a formulation. With respect to solubility improvement specifically, how can excipients
be used to improve solubility and therefore bioavailability? Can you provide examples in terms of the functionality and the
type of excipients that may be used?
A. Solubility and speed of dissolution can be influenced by various excipients. Here, I would distinguish between excipients
that act directly on the active and those, such as disintegrants, that simply ensure quick disintegration of the dosage forms.
The first class is represented by wetting agents, solubilizers, protective colloids, adsorbents and so forth. All of these
can contribute to improved dissolution, the strongest effect coming from solubilizers. Solubilizers are typically surfactants
of a relatively low molecular weight, such as Polysorbate 80, Kolliphor® EL (formerly Cremophor® EL) and many other ethoxylated
materials. With the launch of Soluplus® in 2009, the first polymeric solubilizer appeared on the market offering new opportunities,
particularly for tablets.
Karl Kolter, PhD
Q. What are the key properties of an excipient to determine whether it will be an effective solubilizing agent? What type of
pharmacodynamic and pharmacokinetic data is used to evaluate solubility and bioavailability, and what is the influence of
the excipient on these levels?
A. The main prerequisites for a solubilizer/bioavailability enhancer are that it is capable of overcoming the crystal lattice
energy of a drug and that it can be delivered into the aqueous fluids of the GI-tract. Taking into account that the ideal
excipient has to act as a bridge between the high lipophilicity of the poorly soluble active and the high hydrophilicity of
aqueous fluids, it should be amphiphilic.
At the end of the day, in-vitro dissolution studies must be accompanied by in-vivo studies in animals or humans to reveal whether improved dissolution really leads to enhanced bioavailability. To give you
an example of what excipients can generate: a Soluplus® -itraconazole formulation resulted in 25-fold higher bioavailability
than itraconazole alone and outperformed the marketed drug by a factor of 2.3. This shows the potential associated with unique
Q. What type of predictive tools can be used to evaluate the optimal levels or type of excipient(s) to be used in a formulation
with respect to bioavailability enhancement?
A. There are screening methods available which can be used to find the best solubilizer for a particular active such as the solubilizing
power in aqueous solution and the solid solution capacity. These tests, which are described in detail in the BASF booklet
"Hot-Melt Extrusion Compendium" determine how much drug can be dissolved either in the aqueous or solid phase, which is mainly
the polymer. From the results of these tests, a preliminary formulation can be derived which of course needs to be further
optimized not only regarding performance but also processing.
Q. What role can excipients play with respect to certain technologies such as hot-melt extrusion, as an approach in resolving
solubility challenges? Do they facilitate the formation of the solid dispersion? Can the excipient also facilitate processing
in a hot-melt extrusion process? Can you offer specific examples of either application?
A. For the preparation of solid dispersions or solid solutions, two technologies have become popular so far: hot-melt extrusion
and spray drying with organic solvents. These are completely different from a processing point of view and also have different
For hot-melt extrusion, a low glass-transition temperature and low melt viscosity enable processing at lower temperatures
to be carried out, thus avoiding drug degradation. Soluplus® for instance was developed especially for hot-melt extrusion
and fulfills this target profile ideally. There is no other material that runs so smoothly on an extruder and that is able
to take up so much poorly soluble active.
Q. Poor solubility is an obvious barrier to advancing potentially efficacious drug candidates. Looking into the future of solubilization,
what key technologies are currently being employed and which are being evaluated for further development? What role will excipients
play in those efforts?
A. Hot-melt extrusion is currently in the stage of becoming a mature technology in pharma; however, this process can still be
modified further to obtain even better results. Furthermore, new solubilizers with unique properties need to be developed
so that all kinds of poorly soluble actives can be addressed. The area of nanoformulations, for example, has not been fully
However, one of the biggest hurdles facing industry is the regulatory issue of using a new excipient. There is some reluctance
to use a new excipient for the first time. A Novel Excipients Consortium of pharmaceutical companies and excipient suppliers
has just been created with the specific aim of paving the road for new excipients. To use the words of Martin Luther King,
"I have a dream" that one day excipients will have their own approval process. This achievement would remove the risks from
pharmaceutical companies and their drug approvals, speed up drug development, innovate formulations, and ultimately improve