It is estimated that some 50% of new chemical entities entering drug development pipelines suffer from low aqueous solubility. For Dr Andreas Ohm, head of early development in global pharmaceutical development at Bayer HealthCare, the fact that drugs must be in a solution in order to reach their site of action in the patient makes solubility an absolutely essential element of the formulation development process.

"When you consider infusion formulations it becomes crystal clear that the drug must be dissolved in a restricted volume of vehicle that is suitable for parenteral administration [via a route that involves piercing the skin or mucous membrane] – and this is water-based," says Ohm.

"In the case of orally administered drugs, solubility and dissolution kinetics are important because drug particles have to be dissolved before the drug molecules can be absorbed by the patient. That is why it is so important to have tools and tricks in place to overcome poor aqueous solubility and dissolution speed."

Advanced techniques

Advances in chemistry such as high throughput screening – where researchers use a combination of robotics with complex liquid handling devices, fast analysis and data processing software to run chemical, genetic and pharmacological tests with multiple thousands of compounds – are now allowing scientists to increase the potency and selectivity of many drugs.

"Advances in chemistry such as high throughput screening are allowing scientists to increase the potency and selectivity of many drugs."

As a result of these advanced screening tools, however, more and more water-insoluble and lipophilic drug candidates are detected that would probably not have been found previously.

"In research, a lot of effort is made to identify potent new drug compounds that would be highly effective in the respective disease models," says Ohm. "When later selecting a drug candidate for clinical development, one must not only look at the pharmacological efficacy of the drug, but also at its efficacy in combination with its aqueous solubility.

"There are drugs in pipelines and in the market place that won’t be orally bioavailable when administered in conventional oral dosage forms – for example, tablets containing the drug in finely dispersed crystalline form."

Alongside this, multiple and complex technologies are becoming available to scientists to improve active pharmaceutical ingredient solubility and dissolution kinetics for oral dosage forms.

"There are various measures to enhance the apparent aqueous solubility and the dissolution speed of poorly soluble drugs," Ohm explains. "All of these technologies are derived from the basic understanding of the respective laws of nature.

"Well-known and established techniques include increasing the drug’s surface by milling, helping the drug particles to be moistened by water through hydrophilisation of their surface – for example, by polymer coating or surfactants – complexation to ‘pre-dissolve’ the drug in a more water-soluble form, or just selecting the right polymorphic form or salt of the chemical entity.

"But formulators are in greater need of even more complex and sophisticated technologies to dissolve the drug, as, in many cases, these established technologies are no longer sufficient."

Amorphous non-crystallised drug forms

One way of enhancing gastrointestinal solubilisation is through the use of amorphous non-crystalline drug forms.

"Amorphous forms of pure drugs are often unstable and can recrystallised easily."

"The key advantage of the amorphous state is not only the fact that the drug dissolves faster in water, but that it produces a super-saturated solution, which means it can achieve a solubility much higher than its thermodynamic solubility," says Ohm. "With a super-saturated solution, you can dissolve more of the drug within the gastrointestinal tract for a certain period of time, sufficiently long for absorption of the dissolved drug by the patient.

"What we are doing is dissolving the crystal lattice of the drug particles and dispersing single drug molecules in a solid water-soluble polymer matrix – you could say we ‘pre-dissolve’ it."

One of the key issues pharmaceutical companies need to be aware of when using such complex technology is the shelf life of amorphous drug formulations. Amorphous forms of pure drugs are often unstable and can recrystallised easily.

"An amorphous state may have the greatest advantage when it comes to solubility, but its propensity to revert back to other, less soluble crystalline solid-state forms on storage can provide a headache for pharmaceutical companies," he says.

"One major challenge in the development of amorphous drug formulations is how to stabilise the amorphous state. It may be a case of finding the right amount of polymer in relation to the drug, or choosing the right type of polymer. It may be a question of looking at residual water and uptake of moisture during storage, the use of aluminium foil and so on."

Future application

Although the science behind drug solubility is complex, scientists have made incremental advances and introduced further innovative approaches to overcome poor solubility. As well as amorphous systems, lipidic self-emulsifying systems and nanosized particle-based formulations are two further options for improving active pharmaceutical ingredient solubility and dissolution speed for oral dosage forms.

"Lipidic self-emulsifying systems and nanosized particle-based formulations are two options for improving API solubility."

"These three technologies are highly sophisticated techniques," says Ohm. "They will be applied more in the future to meet the increasingly poor solubility of new chemical entities."

Despite the continuing need for new solubility-enhancement techniques, Ohm does not expect to see any further major technological innovation in the immediate future.

"The probable trend is likely to be more of the same, or just small steps leading to bigger advances," he explains. Researchers are identifying wonderful new drugs, but most of them will only work when applying these kinds of solubility enhancing techniques." 