Steffen Denzinger, head of portfolio development for pharmaceutical raw materials and chemicals solutions at Merck Millipore, looks at how to improve the bioavailability of drugs by enhancing solubility.

Bioavailability is one of the major topics of conversation in the pharmaceutical industry. This is due to the fact that, of the drugs in the clinical pipeline at this point in time, 90% are BCS class II or IV, meaning that most newly developed drug substances are poorly water-soluble and often poorly permeable through membranes as well. This high percentage shows that the issue is not just related to certain classes of active ingredients but to all new molecular entities, whether they are small or large.

There is a strong need to overcome the problems resulting from these issues and to improve bioavailability by modifying the active pharmaceutical ingredient itself or using the formulation to enhance bioavailability.

Given the wide variety of chemical structures of actives and the numerous administration routes, there cannot be a single strategy for bioavailability enhancement of an API that shows low solubility and/or permeability. There are some strategies that can be applied on a rather broad base like micronisation, but even these are limited because they can only be applied to small molecules.

"Of the drugs in the clinical pipeline at this point in time, 90% are BCS class II or IV."

Such particle engineering technologies may lead to other challenges in the formulation of the final dosage form; for instance, the issue of content uniformity in solid application forms of micronised water susceptible drugs where wet granulation cannot be applied.

So, how can pharmaceutical companies deal with this challenging issue? Because most major work today is indication-driven rather than structure-driven, one possible solution is a toolbox that offers a variety of technologies to enable the enhancement of bioavailability.

Depending on the molecular structure of the active and the intended administration route, the most suitable technology or combination of technologies could be chosen from such a toolbox. An example of a situation in which a combination of technologies are needed is a IV delafloxacin formulation currently in clinical phase III, where the weakly basic counter ion meglumine and a cyclodextrin have to be used to achieve the required solubility for a liquid dosage form of this antibiotic.

This toolbox should span multiple solutions for all types of actives, ranging from small to large molecules and for all available dosage forms. Some of these technologies, especially the ones that are related to a physical modification of the active like micronisation, nanomilling and co-spraying, will most probably have to be taken from in-house resources or from CMOs.

Home truths

For other technologies dealing with formulation and chemical modification of especially large molecules, this toolbox can be built in-house using specialist providers of single technologies as partners. This may be challenging in an environment that is usually low on resources, especially when a combination of technologies need to be used.

"Merck Millipore has launched a programme that offers a wide variety of solutions that bolster the bioavailability of drugs."

However, there is the possibility to work with one major partner from the supplier side if there is a partner available that can offer a broad variety of technologies. This can be achieved either by using a contract research organisation, which has the disadvantage that such an organisation is completely dependent on products already in the market, or a supplier partner that can offer a huge set of technologies and is able to adapt products if necessary, due to its own manufacturing of excipients. Such suppliers can be of tremendous help to the pharmaceutical industry.

Therefore, Merck Millipore has launched a programme to address this issue by offering a wide variety of solutions that bolster the bioavailability of drugs by enhancing solubility, better controlling release profiles and more acurately targeting the active to the site of action. This portfolio is constantly enlarged to be able to cope with the numerous problems that can arise during pharmaceutical development. The aim is to support the formulation scientist in providing solutions to problems they are having rather than searching for a problem to solve.