Complementary Gel and Microemulsion Strategies for Pharmaceutical Solid Form Control
Lead Research Organisation:
Durham University
Department Name: Chemistry
Abstract
The issue of the solid form of drug substances is of key importance to the UK pharmaceutical industry. Different crystal forms have different bioavailability and solubility characteristics, and the crystal shape (needle, plate, block etc.) significantly affects processing and tabletting behaviour. Moreover discovery and patenting of all polymorphic forms is a necessary part of current drug discovery research. There have been a number of high profile cases where failure to identify the most stable crystal form of a drug has led to severe formulation problems in manufacture. This is often because the stable form has a high nucleation energy barrier so is very slow to nucleate and only appears late in the production process, resulting in huge encumbant cost. Drug solid form is a major issue for the UK economy and tremendous investments focus on calculating crystal structure and on empirical polymorph screening by a wide variety of crystallisation techniques. This project will use the complementary techniques of crystallisation from microemulsions and crystallization within tailored low molecular weight organogels to provide a general solid form discovery method as well as a means of influencing crystal shape and surface characteristics that will greatly enhance both the robustness and scope of present polymorph screening techniques in the pharmaceutical industry. By use of the 3D-nanoconfinement in microemulsions to initially limit the crystal nucleus size, the novel microemulsion method allows systematic identification and preparation of the most thermodynamically stable polymorphic form. Crystallisation in individually tailored (i.e. chemically complementary to a particular drug substance), low molecular weight gels, will allow isolation and identification of kinetic polymorphic forms and offers the advantage of heteronucleation sites that can catalyse the growth of forms that are very slow to begin crystallising. Between them, therefore, the two crystallisation strategies offer a step change in the systematic approach to pharmaceutical polymorph screening and identification strategies and hence solid form discovery and selection.
Planned Impact
The primary beneficiary of this research is the UK Economy and public health within the pharmaceutical sector.
This project will develop an integrated strategy in which we take a new chemical entity (usually a drug but also potentially an agrochemical), and subject it to crystallisation in microemulsions and specifically designed gels to provide a comprehensive description of its solid state behaviour including identifying the most stable polymorph, provision of high quality seed crystals and identification of most, if not all, of the metastable alternatives and solvates.
The ability to exert thermodynamic control in crystallisation by using microemulsions is of huge value for the pharmaceutical industry as it will provide the first generic method for finding the most stable polymorph for any given drug. Currently pharmaceutical companies have to rely on high throughput screening of different crystallisation conditions in the hope of identifying suitable stable polymorphs, but with no guarantee of success. This project will provide a rigorous, generic and reliable method for finding the thermodynamically stable polymorph, and so will provide assurance that no post-marketing transformations will occur. Furthermore it is likely to so at a reduced cost and typically within a shorter time frame than high throughput screening, once we have optimised our methodology through this proposal. UK pharmaceutical companies will take the global lead using this new approach.
The gel technique will allow both the formation of high quality crystals for easy characterisation and the discovery of alternative metastable polymorphs, some of which may represent suitable candidates for development depending on properties such as solubility, morphology, electrostatic surface characteristics, bulk density, stability and hydroscopicity. Even if the thermodynamic form (under ambient conditions) is the most suitable development candidate, regulatory concerns require the characterisation of all other polymorphs and full knowledge of all solid forms is required for IP protection. Moreover samples of all polymorphs are required to establish long term stability of the development form in the presence of nanoscopic amounts of alternative polymorph seeds. Thus the microemulsion and gel methods are highly mutually complementary and together represent a hugely commercially useful package.
Additional beneficiaries will be academic and industrial scientists in the pharma, agrochem and food industries who will be able to adapt our methods to their own particular problems in solid state materials, resulting in better formulated products. The economy will also benefit from better and faster protection of solid form intellectual property. The researchers actually involved in the project will benefit from the training provided and the fundamental aspects of the project are of huge interest within the academic community, as detailed in the case for support.
This project will develop an integrated strategy in which we take a new chemical entity (usually a drug but also potentially an agrochemical), and subject it to crystallisation in microemulsions and specifically designed gels to provide a comprehensive description of its solid state behaviour including identifying the most stable polymorph, provision of high quality seed crystals and identification of most, if not all, of the metastable alternatives and solvates.
The ability to exert thermodynamic control in crystallisation by using microemulsions is of huge value for the pharmaceutical industry as it will provide the first generic method for finding the most stable polymorph for any given drug. Currently pharmaceutical companies have to rely on high throughput screening of different crystallisation conditions in the hope of identifying suitable stable polymorphs, but with no guarantee of success. This project will provide a rigorous, generic and reliable method for finding the thermodynamically stable polymorph, and so will provide assurance that no post-marketing transformations will occur. Furthermore it is likely to so at a reduced cost and typically within a shorter time frame than high throughput screening, once we have optimised our methodology through this proposal. UK pharmaceutical companies will take the global lead using this new approach.
The gel technique will allow both the formation of high quality crystals for easy characterisation and the discovery of alternative metastable polymorphs, some of which may represent suitable candidates for development depending on properties such as solubility, morphology, electrostatic surface characteristics, bulk density, stability and hydroscopicity. Even if the thermodynamic form (under ambient conditions) is the most suitable development candidate, regulatory concerns require the characterisation of all other polymorphs and full knowledge of all solid forms is required for IP protection. Moreover samples of all polymorphs are required to establish long term stability of the development form in the presence of nanoscopic amounts of alternative polymorph seeds. Thus the microemulsion and gel methods are highly mutually complementary and together represent a hugely commercially useful package.
Additional beneficiaries will be academic and industrial scientists in the pharma, agrochem and food industries who will be able to adapt our methods to their own particular problems in solid state materials, resulting in better formulated products. The economy will also benefit from better and faster protection of solid form intellectual property. The researchers actually involved in the project will benefit from the training provided and the fundamental aspects of the project are of huge interest within the academic community, as detailed in the case for support.
Publications
Jones C
(2017)
Scrolling of Supramolecular Lamellae in the Hierarchical Self-Assembly of Fibrous Gels
in Chem
Kennedy SR
(2016)
Trimeric cyclamers: solution aggregation and high Z' crystals based on guest structure and basicity.
in Chemical communications (Cambridge, England)
Ruiz-Palomero C
(2016)
Pharmaceutical crystallization with nanocellulose organogels.
in Chemical communications (Cambridge, England)
Kaufmann L
(2016)
Cavity-containing supramolecular gels as a crystallization tool for hydrophobic pharmaceuticals.
in Chemical communications (Cambridge, England)
Hooper AE
(2016)
Gelation by supramolecular dimerization of mono(urea)s.
in Chemical communications (Cambridge, England)
Cayuela A
(2015)
Fluorescent carbon dot-molecular salt hydrogels.
in Chemical science
Foster JA
(2017)
Pharmaceutical polymorph control in a drug-mimetic supramolecular gel.
in Chemical science
Kumar DK
(2014)
Supramolecular gel phase crystallization: orthogonal self-assembly under non-equilibrium conditions.
in Chemical Society reviews
Jayabhavan S
(2021)
Crystal Habit Modification of Metronidazole by Supramolecular Gels with Complementary Functionality
in Crystal Growth & Design
Kennedy S
(2018)
Tailored supramolecular gel and microemulsion crystallization strategies - is isoniazid really monomorphic?
in CrystEngComm
Description | This award is likely to have impact in the control of the solid crystalline form of pharmaceuticals in the longer term. New gel and microemulsion systems have been developed that allow control of pharmaceutical crystallization processes. |
Exploitation Route | Integration into industrial processes by collaborators. |
Sectors | Chemicals Pharmaceuticals and Medical Biotechnology |
Description | As a result of a paper published in Jan 2017 arising from this project TCI Chemicals now market two of the gel-forming compounds produced in this project. These are sold to customers interested in using gels to crystallize small molecule organic compounds such as pharmaceuticals. |
First Year Of Impact | 2019 |
Sector | Chemicals,Pharmaceuticals and Medical Biotechnology |
Impact Types | Economic |
Description | AstraZeneca CASE Studentship |
Amount | £34,000 (GBP) |
Organisation | AstraZeneca |
Sector | Private |
Country | United Kingdom |
Start | 09/2016 |
End | 09/2019 |
Description | Responsive Mode |
Amount | £647,452 (GBP) |
Funding ID | EP/R013373/1 |
Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
Sector | Public |
Country | United Kingdom |
Start | 03/2018 |
End | 02/2021 |
Description | Scrolling, Braiding and Branching in Fibrous Soft Materials |
Amount | £408,980 (GBP) |
Funding ID | EP/S035877/1 |
Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
Sector | Public |
Country | United Kingdom |
Start | 03/2020 |
End | 02/2023 |
Description | Collaboration with AstraZeneca |
Organisation | AstraZeneca |
Department | Pharmaceutical Technology & Development |
Country | United Kingdom |
Sector | Private |
PI Contribution | Collaboration on the use of gel phase crystallization for AZ drugs |
Collaborator Contribution | Analysis of solid form, advice, ideas, instrument time, project meetings. |
Impact | Joint pharmaceutics and chemistry |
Start Year | 2018 |