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

Lead Research Organisation: University of Cambridge
Department Name: Chemical Engineering and Biotechnology

Abstract

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.

Planned Impact

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.

Publications

10 25 50

 
Description We have made significant progress in developing a better understanding of the role of the anharmonic nature in the intermolecular potential for the structure and dynamics of hydrogen bonding molecular glasses. Our progress has been both in terms of our experimental work as well as in terms of simulations. For the measurement side we have transferred our measurements to a commercial terahertz spectrometer. We have previously secured the IP for this measurement method and this has now been licensed to a commercial partner. In terms of the numerical simulations we have made significant process in using ab initio molecular dynamics as well as quasi-harmonic simulations to understand the intermolecular dynamics in organic solids. Update 03/2018: We have published a number of exciting papers on the progress we made in this project to date. The key paper is the PCCP publication from 2017 in which we have resolved the physical origin of why the THz method works. We were able to demonstrate that the potential energy surface picture that was originally proposed by Goldstein in the 1960s fully explains our results and those acquired with other technologies. We have since written up another manuscript together with the group in Copenhagen that shows how to use this concept in order to predict the stability of pharmaceutical drugs in the amorphous state. Our results show that we do not carry out dielectric spectroscopy in order to measure the properties of interest but that we can use any experimental technique that clearly resolves the potential energy surface. In parallel we have driven forward our work in collaboration with MedImmune to expand our findings to polymers, biomolecules and pharmaceutical formulations.
Exploitation Route The work we have carried out thus far is of general interest to the physical chemistry and chemical physics community. Update 03/2018: We have since seen strong interest and detailed discussions with the pharmaceutical industry: BMS, MedImmune, Merck and Bayer Healthcare
Sectors Chemicals,Healthcare,Pharmaceuticals and Medical Biotechnology

 
Description We have started a range of collaborations with industrial partners interested in this work. Update 03/2018: The collaborations we started last year are strengthening and expanding
First Year Of Impact 2017
Sector Pharmaceuticals and Medical Biotechnology
Impact Types Economic

 
Description Neutron scattering experiments 
Organisation Science and Technologies Facilities Council (STFC)
Department ISIS Neutron and Muon Source
Country United Kingdom 
Sector Public 
PI Contribution Neutron scattering experiments on samples relevant to this project
Collaborator Contribution Expertise, provision of facility and help with measurements
Impact Data analysis still ongoing.
Start Year 2017
 
Description XPDF experiments using the Diamond beam line 
Organisation Diamond Light Source
Country United Kingdom 
Sector Academic/University 
PI Contribution This collaboration wrote the proposal, made the samples and visited the Diamond facility to acquire the data.
Collaborator Contribution Provided the XPDF beam line and expertise at Diamond.
Impact Data analysis and interpretation is still ongoing.
Start Year 2017
 
Description Best User of ARCHER HPC Award, London 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact Recipient of the Best ARCHER User award, presentation and award ceremony, including media interview.
Year(s) Of Engagement Activity 2017
 
Description Invited Lecture THz-Neutron Meeting in Grenoble 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Was invited to give a lecture on the insight into terahertz dynamics of amorphous materials.
Year(s) Of Engagement Activity 2017
 
Description Invited Lecturer CP2K User Meeting 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact A workshop on using ab initio MD for the study of materials. Invited to lecture on how to perform vibrational analyses.
Year(s) Of Engagement Activity 2017
 
Description Invited Presentation MTSA THz-Nano Meeting in Okayama 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Invited to give a lecture into terahertz spectroscopy of solids, and insights into THz-dynamics of amorphous pharmaceuticals, at an international meeting in Japan.
Year(s) Of Engagement Activity 2017
 
Description Pharmaceutical Solid State Research Cluster (PSSRC) Graz 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Gave a presentation on insights gained into the amorphous dynamics of pharmaceutical ingredients.
Year(s) Of Engagement Activity 2017
 
Description Presentation at IRMMW-2017 in Cancun 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Presented results in two separate presentations at the IRMMW annual meeting.
Year(s) Of Engagement Activity 2017
 
Description Spectroscopy of amorphous materials day meeting (Cambridge) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Day meeting in Cambridge bringing together a diverse cross-section of the research community spanning THz spectroscopy, physics of amorphous solids and physical chemistry. Participants ranged from experienced researchers, postdocs and PhD students to industrial colleagues.
Year(s) Of Engagement Activity 2016