More from INFORMEX 2012: SAFC’s Chris Frampton Discusses Cocrystallization

Last week, more than 5,000 exhibitors and attendees descended upon the Morial Convention Center in New Orleans, Louisiana for global chemical and Pharma tradeshow, Informex 2012. SAFC was one of these companies; as an exhibitor and sponsor of the Informex Networking Lounge, SAFC fully maximized its participation at Informex this year which included a feature presentation in the newly introduced Elsevier Tech Talks series.


On Thursday, 2/16 at 2:30pm, Chris Frampton, CSO of SAFC Pharmorphix in Cambridge, UK, presented the “Structure & Property Optimization of Cocrystal Phases” in Booth 950. His presentation looked at what cocrystals are, why pharmaceutical companies are increasingly looking to cocrystals to solve their formulation problems and what other applications they have. Here, Chris takes some time to tell us about cocrystals and how they are impacting the industry.


SAFC Live: Hi Chris. Could you start by telling us what a cocrystal is?


Chris: It is a crystalline material that is composed of two or more different molecules in the same crystal lattice. They are formed on a molecular level, rather than a macroscopic level. While you could argue that an intimate mixture between an API and an excipient might be a cocrystal, actually it is not – the API and the excipient are both crystals in their own right and small particles of each have been mixed together. In a cocrystal, the two different molecules actually form a single crystalline lattice together.


SAFC Live: What are they used for?


Chris: They can be used to alter the physical properties of pharmaceutical materials, in particular the dissolution rate, but they also have potential in any application where it would be useful to modify the crystal structure of a material to deliver a functional property; for example, agrochemicals, personal care products, optoelectronics and even solid state electronics. If we can modify the crystal structure in some way, then we can finely tune the properties of that crystalline material to give the properties that are required.


As an example, the agrochemical pyrimethanil is a very simple molecule, with a melting point of 96°C. If we make a 1:1 cocrystal of it with benzoic acid, we can raise that melting point by 32°, but as a cocrystal with stearic acid, we can lower it to just 50°C. Melting point is just one property that can be altered – there are many other properties of materials that might be changed, such as the dissolution rate, which is particularly important for pharmaceuticals. To get the required pharmacokinetic profile, typically you want to get more than 80% of the material into solution in the first 30 minutes, and this is one of the first areas cocrystallization has been targeting.


SAFC Live: What other properties can cocrystals modify?


Chris: Another important one is processability. For example, many drugs are sodium salts which can have very bad problems with hygroscopicity. This makes them hard to process, as they often form channel hydrates that pick up and lose water very easily. At Pharmorphix, we are using oxygen-rich materials like glycerol to stabilise these phases as a cocrystal. The oxygen atoms of the glycerol interact with the sodium atoms, making a cocrystal, and block the attack of water. Other potential applications include enhancing bioavailability, and even engineering new solid state forms for functional crystalline materials.


SAFC Live: How do you go about finding a suitable cocrystal?


Chris: We like to start with the crystal structure of the API itself, and look at how the molecules interact within that structure. We then choose a coformer molecule that mimics those interactions within the crystal structure. Of course, it all depends on the solubility of the API and the coformer – if one is much more soluble than the other, then it’s very difficult to get the two materials to “dance”. But if their solubilities are approximately the same in a particular solvent, we’ve found that’s where we have the best chance of preparing cocrystals. And then, once we’ve produced them and have a seed crystal, scale-up is not a problem – or at least not as much of a problem as people might think.


SAFC Live: Are there any potential problems?


Chris: One problem that cocrystals themselves can suffer from is polymorphism, so you really need to screen for different crystal forms very thoroughly as you would for a regular drug substance. When we were working on pyrimethanil, we observed many polymorphic forms. So you do need to be very careful about that.


SAFC Live: So are cocrystals becoming more widely used now their benefits are becoming clearer?

They are, yes. Over the past three or four years, momentum has been gradually building, the number of patents has been increasing, and the FDA have just released a set of draft guidelines on the topic. One of the big challenges for the pharma industry at the moment is producing materials that have the required pharmacokinetic profile. It is difficult enough getting a drug to market as it is and a lot of materials out there are about as soluble as brick dust. Finding a path through crystal engineering to make these drugs work is increasingly important, particularly in terms of solubility issue. It all started off with polymorphism, where the API can exist in several different crystal forms, each with their own set of physicochemical properties and solubilities. If there is an ionisable group within the API, then typically a salt can be made, which can give the required solubility and dissolution rate. Cocrystals are, essentially, an extension of salt formation. For a salt to form, there has to be a difference in pKa between the two partners – one must be more acidic than the other. With cocrystallisation, there is no requirement for this difference in pKa – there may or may not be one, but the important factor is the way the crystal lattice is modified to give the properties you need.

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