Crystalline Sponge Technology - A Breakthrough in Molecular Structure Analysis



Merck KGaA, Darmstadt, Germany is a leading science and technology company, operating in Healthcare, Life Science and Performance Materials. The company has approximately 57,000 employees around the world and generated sales of € 16.2 billion in 2019. MilliporeSigma, the company’s Life Science business in the U.S., and Versum Materials are affiliates of Merck KGaA, Darmstadt, Germany.

The company recently announced a partnership with Rigaku, a leading analytical equipment instrumentation provider, to make molecular structure analysis faster, more direct and applicable to samples on sub-microgram scale using metal-organic frameworks (MOFs). The innovation project is managed out of their Innovation Center. Additional information can be found here.

Material Insights spoke with the project’s technical lead Clemens Kühn, and commercial lead Wolfgang Hierse, on their pioneering work in commercializing the crystalline sponge technology.


Insights: When did MOFs first come on your radar and what was it about them that peaked your interest and led to an innovation project focused on crystalline sponge technology?


We knew MOFs with their large void volumes were used as effective gas storage materials for quite a long time. But when Prof. Fujita published his work describing use of a single crystal of a MOF to elucidate the structure of captured molecules, we initially thought, this could be a game changer in structure analytics. He called his approach the “crystalline sponge method”. By reducing the amount of substance necessary for structure elucidation by three orders of magnitude, the crystalline sponge technology will open completely new application fields everywhere molecule structures are needed, especially in pharmaceutical R&D and agrochemistry.


Insights: Why does this solution matter to Merck KGaA, Darmstadt, Germany and to its customers?


With our pharmaceutical and performance materials businesses, we have two large groups of potential customers – our own colleagues – a perfect group of alpha-testers who will help ensure, we are developing exactly what the market needs in relation to this breakthrough technology. On the other hand, with our Life-Science sector and our various brands like Millipore Sigma, we have prospective customers in chemical and pharmaceutical labs all over the world. So we are creating and validating business opportunities as well as solving problems of our internal project teams.


Take for example the field of metabolite identification. Metabolites are formed in the body by chemical transformation of molecules. The metabolites of drugs can contribute to their desired therapeutic effect but may also have adverse or even dangerous side-effects. A well-known example is acetaminophen (Paracetamol ®). As we know today, high doses may lead to certain metabolites giving rise to liver toxicity. In effect, acetaminophen is by far the prime cause of acute liver failure in the western world.


Given such risks, it’s not surprising that a large part of the development effort for new drugs is spent on toxicological assessment of metabolites. For this assessment however, the structures of the molecules are required. And right now, the techniques available to scientists require a large amount of the metabolites – at least a few hundred milligrams. These quantities are typically not available, especially for human metabolites. Human metabolites can only be obtained in sub-microgram amounts. Thus, elucidation of their structure requires synthesis of larger amounts. This is time consuming and expensive and is usually being done late in the drug development process when starting clinical trials – after a significant investment has been made in the respective drug candidate. Crystalline sponges can help pharmaceutical companies, assess and manage metabolite-related risks, earlier and more efficiently and help them avoid costly problems later on, like having to stop a late stage project, limiting applicability or even having to withdraw from the market.


Insights: Can you tell us more about the Innovation Center and why it’s uniquely positioned to commercialize this opportunity?


While we do have two potential customer markets in-house and the Life-Science sector with its vast portfolio of lab consumables, this project would not easily fit into the R&D focus of either business. This is exactly where our Innovation Center comes in. Here, cutting-edge projects and technologies are developed to create viable new businesses that go beyond the current scope of our company The Innovation Center combines the agility of a startup company and the more complex processes of an established corporate group, allowing innovative ideas like ours to flourish in a pioneering startup atmosphere. At the same time, the Innovation Center is collaborating closely with the business sectors. In our case we extensively collected market assessment and feedback from our pharmaceutical division and performance materials. And for market access, we rely on the valuable support of our Life-Science sector. You cannot get this amount of cross-sector support from within a single business unit.


Insights: How has your philosophy to open innovation and global collaboration played a role in developing the Crystalline Sponge Technology?


At the beginning of our activities, it was not clear if the technology would work at all. Many scientists around the globe, including our own, have tried to reproduce the published paper and failed. It was our personal interaction with the Japanese inventor and his scientists that kept our curiosity alive and convinced us to keep trying. We invited members of the team from Japan to our lab and even hired a member of their lab to learn and develop the method’s protocols in order to enable other scientists to apply the technology. We soon realized, that we needed partners; Merck KGaA, Darmstadt, Germany did not have the required crystallographic hardware nor good sales channels to the respective scientists. We also needed to find “beta testers” for our product development to address the specific needs of this complex market. We found exactly what we needed through international collaboration and signed a joint development agreement with Rigaku, a key player in scientific analytical instrumentation.


Insights: Can you share any of the lessons learned through your development process?


One lesson that we learned very quickly is that you need to remain agile. Be prepared to pivot your product idea, your business model and your customer definition based on the insights you collect on the technology, as well as from market insights. If your market insights suggest a higher value capture using a different business model or a different kind of product: Do not hesitate.


Insights: Beyond the MOF structure itself, what’s the vision for using MOFs as part of an integrated solution?


While the MOF crystals themselves are key to our application, execution of the entire process including sample purification and preparation requires significant, specialized know-how and skillful handling of the tiny MOF crystals. Our vision is to create a fully integrated solution including customer enablement, in order to facilitate adoption of this new technology. The MOF crystals themselves will obviously be a major part in that concept.


Insights: The Crystalline Sponge Technology offers a multitude of opportunities. Which industries and markets will benefit mostly from it in the next 5-10-30 years?


It is an emerging technology, which renders long term projections really difficult. In the next few years we do see high demand in the fields of pharma and agrochemicals. Here we can help by elucidating structures of impurities, degradants or metabolites earlier on and enable better management of the risks associated with such compounds in these regulated markets.


But other fields of chemistry will follow like discovery programs for nature-derived compounds, as we see in cosmetics and food or novel pharmaceuticals. Such screening programs could be enabled on a much larger scale with our technology.

This has the potential to change a number of different areas of research and maybe even entire industries. In 30 years, this technology may be a commodity with broad enough applicability to enable completely new applications that cannot be foreseen today. We’ll be able to move research into areas that just haven’t been possible so far.

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