Poorly water soluble, or hydrophobic, new chemical entities (NCEs) have dominated drug discovery programmes for many years.

"Poorly water soluble, or hydrophobic, new chemical entities (NCEs) have dominated drug discovery programmes for many years."

Traditionally, the main impediment to the speed of drug development was the discovery of compounds with high biological activity and strong affinity for receptor sites, but, more recently pharmacokinetic factors such as absorption and permeability across the GI epithelium have become critical.

"The low hanging fruit has already been picked, the well-established drugs with low molecular weights are already out there," said John Comer, chief scientific officer at Sirius Analytical, a company that designs and manufactures automated instruments to measure the physicochemical parameters of drugs.

"Nowadays, scientists are discovering drugs by identifying novel targets and they’re designing molecules that are big and complicated. Consequently, drugs end up poorly water soluble and very difficult to work with," he added.

Essentially, this leads to one central issue: if a drug is poorly water soluble, it is unable to get into solution in the gut. If it’s not in solution, it can’t be absorbed by the body.

Improved understanding

According to Comer, scientists have historically tackled this issue by employing a ‘suck it and see’ approach. "Drug formulators have had sets of tools, with which they’ve tried various ways of improving formulations to make them more soluble, but I’m not sure how much strong theoretical background or deep understanding there has been in the past," he said.

Fortunately, the situation has improved in recent years, largely due to the introduction of the Biopharmaceutics Classification System (BCS) in 1995, which is used by the US Food and Drug Administration (FDA) to judge what sort of work needs to be done on a drug to make it suitable to be brought to market.

"If a drug is very soluble and very permeable, that’s brilliant, but most drugs are not," Comer explained. "If it’s very permeable but not very soluble, it’s in BCS class II and the challenge then becomes to make it more soluble so it can be absorbed by the body."

Scientists’ knowledge of class II drugs has expanded still further since the BCS was established. "They have discovered that there are two ways in which drugs fail in terms of solubility," Comer said.

"They can either be ‘dissolution rate limited’, which means the dose can be quite soluble, but it takes a long time to make a solution, or ‘solubility limited’, which means the maximum amount of the drug you can get into solution isn’t very high."

Solubility enhancement strategies

The solubility of dissolution rate limited drugs can be enhanced by grinding the particles up until they become nanoparticles on the basis that the greater the surface area, the quicker the drug will dissolve. Elan Drug Technologies has successfully employed this technique with its nanocrystal technology.

"The situation has improved in recent years, largely due to the introduction of the Biopharmaceutics Classification System (BCS)."

"Elan makes the drug particles very, very small because you want the drug to have as much contact with the water as possible. If you break it down, it has more chance to interact with the water molecules and dissolve," Dr Woei Ping Cheng, senior lecturer in pharmaceutics at the University of Hertfordshire, explained.

However, this strategy is not effective with solubility limited drugs. For Comer, drug companies facing this issue have three other options.

The use of a solvent, such as a lipid, is one common technique. "The idea is that the drug dissolves more easily in the lipid than in water, giving a higher concentration," Comer said.

"The lipid is broken down and in that process the drug is released. Hopefully the rate of release is then more or less equal to the rate at which it then gets absorbed."

Option two is to attempt to trap the molecule in a ‘molecular cage’. "A typical example of this is the use of cyclodextrins. If you get the chemistry right, a drug can sit in the hole in the middle of the cyclodextrin, which is a large structure made out of sugar molecules."

Similarly, polymeric self-assemblies have been widely studied for their potential as hydrophobic drug solubilising agents, as hydrophobic drugs can physically be encapsulated inside their lipophilic cores.

While these have widely been developed for intravenous administration, particularly for cancer therapy, there has been little reported on their use for oral delivery.

This is where Cheng comes in. Her latest paper talks about the work she has done on synthesising four nano self-assemblies formed by polyallylamine (PAA) with the aim of improving the water solubility and oral absorption of three hydrophobic drugs. Not only did all modified PAAs described in the paper increase the drugs’ water solubility, two of the modified PAAs were able to significantly improve the oral bioavailability of griseofulvin, a class II drug.

However, it is still early days for Cheng. "It can be a very long process to get approval for the excipient itself when using a novel delivery technology," she acknowledged. "Although we have collaborations with industry, we are still in the early stages."

Finally, scientists are increasingly beginning to take advantage of the tendency of molecules to exist in different physical forms. The amorphous form of a drug, for example, is often much more soluble than its crystalline form.

While the industry has traditionally been opposed to the use of amorphous forms because of their inherent instability, there are now several techniques, such as hot melt extrusion and spray-dried dispersions, which can stabilise the amorphous form much more reliably than in the past.

"Essentially, this leads to one central issue: if a drug is poorly water soluble, it is unable to get into solution in the gut."

Sirius Analytical has spent a significant amount of time working on improving scientists’ and drug companies’ understanding of this approach. The company offers an automated instrument, the SiriusT3, which measures ionisation (pKa), lipophilicity (LogP/D), solubility and dissolution and offers novel ways of studying important characteristics relating to the amorphous state.

"As a result of our methods, we can characterise different classes of molecules as to whether or not they are likely to form amorphous forms, how long the amorphous form will last for, what the solubility of the amorphous form is, and how we can make it last longer," Comer said.

"We can measure the solubility of the amorphous form in solution, which is very difficult to do with traditional techniques."

It is essential to remember that different formulation approaches are appropriate for different sorts of molecules, there is no silver bullet. Yet, it is clear that progress is being made in the field of solubility enhancement. For Comer, Sirius Analytical’s goal is simple: "We’re developing understanding."