The role of inter-molecular bonding for the structure and dynamics of organic amorphous systems

At present, 40% of all leading compounds that emerge from drug discovery are not developed further due to their poor solubility. Currently, drug molecules are almost exclusively made into a medicine using a crystalline drug which has an inherent solubility disadvantage due to the lattice energy associated with its crystalline state that needs to be overcome before dissolution occurs. The amorphous state, where the molecules are completely disordered and hence the cohesive energy is smaller, is a potential alternative state for drug-molecule formulations. Given that the amorphous state is higher in energy, such drug formulations are currently perceived to be high risk, as it is not possible, using the existing technology and understanding, to predict their stability against recrystallisation reliably. In addition, there is still no comprehensive understanding of the physics of the amorphous state in general and the factors governing devitrification (the crystallisation process from the amorphous phase) even though this area of research has been the focus of very intense activities over the past decades.

Unforeseen stability issues due to recrystallisation could lead to enormous costs for pharmaceutical companies if such formulations fail during the later stage clinical trials or, even more catastrophically, once the product is on the market. However, the improvement of solubility in the amorphous state would be sufficient to permit greater than 50% of poorly soluble leading compounds to be selected as candidates for the drug-development pipeline. This would permit an extensive range of hitherto untested chemistries to move through to the clinic to address unmet therapeutic needs for patient benefit. Here, we aim to develop a better understanding of structural changes occurring in organic amorphous formulations of drugs, with the ultimate goal of improving their efficacy and stability.

This proposal is developed around the ability to quantify directly terahertz and/or picosecond-nanosecond inter-molecular dynamics that govern the crystallisation in organic amorphous systems. The majority of experimental evidence will be gathered by means of terahertz time-domain spectroscopy (THz-TDS) and low-frequency Raman spectroscopy but will be complemented by theoretical and simulational studies, and other experimental techniques as necessary. There are two ultimate goals of the proposed work: 1) To develop an analytical method that can be used to quantify the likelihood of structural changes, ultimately culminating in crystallisation, occurring in amorphous materials over extended periods. Furthermore, to allow a systematic optimisation of amorphous drug formulations and their storage conditions with respect to their stability against structural changes. 2) To provide high-quality experimental data to stimulate and support the development of theory aimed at better understanding the fundamental physics of non-equilibrium organic solids.

If successful, the terahertz or Raman methods could be implemented for drug-development activities almost immediately, as such turn-key equipment is now commercially available and, once we are able to develop the detailed understanding as outlined in this proposal, they can be operated and the data interpreted by technicians, much like any other analytical technique today. The lab-based measurements proposed here could further remove the requirement for costly and time-consuming measurements at central facilities, such as neutron sources, for similar analysis, and thus free up this critical resource for other research activities.

The main beneficiaries from this research proposal will be:

- Patients who will benefit if the technology allows for the availability of pharmacologically highly active molecules as oral solid-dosage forms that can be conveniently administered and which would have otherwise dropped out of the drug-development pipeline due to their insufficient aqueous solubility (so-called BCS class II molecules)

- Companies specialising in the development of analytical terahertz or low-frequency Raman instrumentation, such as TeraView Ltd. or Renishaw Plc. in the U.K. and, internationally, Advantest in Japan or Ondax in the U.S.A., by opening up new markets to which to sell and develop terahertz or low-frequency Raman spectrometers.

- Companies specialising in the development of temperature-control solutions for spectroscopy, such as Oxford Instruments in the U.K. or Janis in the U.S., through the opportunity to develop integrated temperature-controlled sample environments that can be sold as accessories for existing or new terahertz and Raman spectrometers.

- Innovator and generics companies in the pharmaceutical industry, through the provision of a tool to ensure the quality of their amorphous formulations. This will open up business opportunities in terms of increasing the number of molecules that can be developed into a marketable product (originator companies) as well as reducing the time to market for developing bioequivalent formulations once patent protection expires for the originator product (generics companies). Overall, this would support the development of new therapies by unlocking new drug-delivery technologies whilst also being able to investigate how these formulations could be processed using scalable manufacturing methods such as spray-drying and ball-milling.

- Contract research organisations will benefit by offering the stability characterisation by terahertz spectroscopy as a commercial service for companies who do not want to make the initial investment into the technology or training required.

- Regulators, such as the U.S. Food and Drug Administration and the European Medicines Agency, will benefit from the availability of a quantitative technique to measure amorphous drug stability as a potential new reference technique for the assessment of such drug products for the purpose of registration and quality testing.

- The neutron-scattering community will benefit if we are able to demonstrate the possibility of measuring the molecular mobility in hydrogen-bonded molecules using THz-TDS in a similar way to what is currently achieved by measuring the mean-squared displacement by neutron scattering. This would free up capacity at the neutron sources and allow for a larger number of users to be able to complete their experiments in other fields at these facilities.