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Rob Blanchard, R&D manager, I Holland.
Rob Blanchard, R&D manager, I Holland.
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Clare Taylor, marketing manager, I Holland.
Clare Taylor, marketing manager, I Holland.
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Laboratory of biophysics and surface analysis group.
Laboratory of biophysics and surface analysis group.
In January 2012, tablet tooling specialist I Holland and the University of Nottingham’s School of Pharmacy launched the two-year TSAR (Tabletting Science Anti-Stick Research) project to investigate and solve the most common tabletting issue of formulation ‘sticking’ to the tool face, which frequently results in long periods of downtime and substantial losses of product. I talked to I Holland’s Rob Blanchard, R&D manager, and Clare Taylor, marketing manager, about how TSAR will be used to help customers in the future to eliminate sticking and therefore protect productivity and profitability.
How many people are involved in the TSAR project and what are their roles?
Rob: There are six core people involved; four from I Holland and two from the University of Nottingham. From I Holland, there’s Chris Prideaux, the Managing Director, who is chairing the project, myself, the project lead, and Tim Sefton, an R&D engineer. All three of us have our own defined roles within the project, with Chris and I using Tim as a resource for carrying out compression trials and helping with the analysis of formulations and mechanical testing.
We also draw on other resources as and when needed, for example, the manufacturing team was instrumental in producing the samples that we’ve used for the project. Then there’s Dr. Abdennour Bouhroum, who is the associate from the University employed by I Holland as part of the project team. He is completing the analytical research for us. He’s planning and project managing the resources that are available to us at the University.
Also from the University, there’s Professor Clive Roberts, the academic lead, and Professor Morgan Alexander. They both have their own different skill sets and areas of expertise that are complimentary to the project.
Professor Roberts is Chair of the Pharmaceutical Nano Technology group and Director of the Nottingham Nano Technology Science Centre, both part of the Faculty of Science at the University. Clive has a fantastic reputation in the field of particle adhesion; he’s carried out many different studies looking into different kinds of adhesion. We’ve been working with Clive since 2009, so it’s not a new relationship.
Professor Alexander is Professor of Biomedical Services and Head of the Division of Biophysics at the Surface Analysis group, one area of his expertise and focus is on understanding surface interactions.
What are the factors that cause sticking and how is it currently dealt with?
Rob: TSAR is not the start of our anti-stick research as we began using advanced techniques such as atomic force microscopy to understand all the factors for sticking back in 2009.
There are several factors that we know have a major influence on sticking. I will start with the main ones. First to consider is Van der Waals forces or molecular attraction, which is when elements within the formulation are naturally attracted to elements within the tablet punch material. These forces are very low and can only be measured in nanonewtons but in bulk behaviour, when lots of these forces interact on the face of a tablet, they can cause sticking.
Another major influencer of sticking is capillary action, which can be linked to high moisture content. If moisture is present, there’s the potential for sticking in both direct compression or wet granulation. On the other hand, if the granules are very dry, you can get static electricity, also a major cause of sticking.
Those are the three main ones but there are others. You’ve also got the roughness or the morphology of the contact, or in other words, the punch tip face used to compress the powder. How that surface face interacts with the granule is critical.
Then you’ve got the deformation mechanics of the granule itself. Under compression, the granule is either elastic or plastic, which will have an influence again on sticking. So the characteristics of the granule itself under compression are also very important.
There’s also the environment that you are compressing in and that comes back to capillary action because if you have a very humid environment, then you’re going to get capillary action causing sticking.
Also linking back to Van der Waals forces, different chemistries on the punch tip face can influence sticking. For example, if Van der Waals forces are causing sticking where you’ve got chromium, the structure of the chemical coating can be changed so that the element is no longer present.
Understanding what factors cause sticking is what we did in 2009 to develop our PharmaCote range of coatings, way before TSAR started. The objective was that if we could understand what causes sticking, our R&D team could tailor the development of coatings for punch tip faces that prevent sticking. That’s what we’ve been doing since 2009 and as a result we’ve got a proven range of anti-stick solutions based on that research, but the one thing that could be improved across the industry is the ability of the tooling manufacturer to select the right coating solution straight away and that leads into what TSAR is really about.
Clare: At present, when a customer presents us with a sticking problem, we have to do a lot of testing in the field to select the right coating solution for their specific problem. This involves taking time out of their production schedule to run test punches on their tablet presses, then we have to analyse the results before getting back to them with a recommendation.
We released a case study regarding an anti-stick trial we did with Pfizer five years ago and that took a good few weeks worth of preparation and testing at both I Holland and their facility. TSAR will help us eliminate the need for that costly in-the-field testing process.
Rob: This type of testing is a successful way of identifying the right solution but it’s very costly, very slow and therefore doesn’t offer the most efficient customer service.
Are you able to offer an insight into the project’s findings so far?
Rob: What we’re developing with TSAR is a predictive tool, which will comprise data on a range of parameters such as surface chemistry, temperature, humidity and size of the granule, whether it’s elastic or plastic for example. We obviously won’t release the final parameters to be included in the model until the end of the project. The predictive tool will allow us to enter parameter information and straightaway provide an exact answer as to what the customer requires. It’s completely different to what anyone else is doing and will eliminate the need for the costly and slow in-the-field testing for the customer.
The project is based around two main elements. Firstly, we’re compressing the final formulation and creating tablets with various excipients and APIs using all of our anti-stick coatings (a couple of which are still in development) as well as our PharmaGrade range of raw materials. The results of this testing is then being put to one side and will be used to validate the predictive tool at the end of the project.
The second part consists of five sub-stages, starting with the initial research into our PharmaCote and PharmaGrade material solutions and their surface characteristics.
Secondly, we carried out a case study by testing the well-known formulation Ibuprofen. This proved that the analytical techniques used to predict the correct solution matched what actually happened in the tablet press, which validates the concept of our predictive tool. Having obtained the desired results from the Ibuprofen trial, we moved onto conducting compression trials with different formulations supplied by our international customer base. From these tests, we have built up a database of results that will also be used to validate the results of the predictive tool. We’ve just finished the compression trials and at the end of the project we will enter the details of all formulations compressed into the predictive tool and see whether it gives us the result we got in the tablet press.
As well as carrying out compression trials, we’re also doing a lot of analysis using very complex techniques such as atomic force microscopy (AFM) and time-of-flight- secondary ion mass spectrometry (ToF-SIMS). There’s a long list of different pieces of equipment and techniques that we are utilising and are key to helping us develop the predictive tool.
Next, we move on to adhesion mapping, which is where we use techniques like AFM and ToFSIMS to look at particles that are stuck to a punch tip and analyse exactly what they are chemically, thus working out what those interactions are.
Once we’ve completed the adhesion mapping stage, we’re onto the development of the predictive tool, which we’ve just started. The predictive tool is going to take some time to develop because of the utilisation of complex techniques. We’re using Principle Component Analysis to understand the key interactions that are causing the formulation to stick to the punch tip faces.
What will the results ultimately mean for I Holland customers?
Clare: The main advantage for the customer will be that by using the predictive tool we can recommend the right punch material or coating solution very quickly based on proven scientific knowledge of how the different elements within their formulation behave and interact to cause the sticking. The aim is that they will no longer have to buy a test set of tooling and take time out of their production schedule to ascertain which solution is right for their specific problem.
What we’re trying to get across to our customer base is yes, we’re known for producing excellent quality punches and dies, however we’re not just an engineering business turning out the core product. Our headline brand is ‘tabletting science’ and that’s what we offer to customers. All this research is essentially free added value that we provide to customers throughout our entire product and service portfolio.
Rob: The TSAR project is totally unique, we’re the first tablet tooling manufacturer to do anything like this. We began our anti-stick research and developing our anti-stick coatings back in 2004 and we really started to understand what caused sticking in 2009, now here we are in 2013 over half way through developing a predictive tool that will allow us to use that research and those products that we have developed already in a much more efficient way.
What does I Holland’s recent HSBC Global Connections competition funding win mean for the project?
Rob: We’ve won the regional final, which has given us a nice financial reward and some kudos that we’re a well-performing business. We’re now through to the national final in June.
We’re not normally a company that enters award competitions but with this one there was a financial benefit for our customers, allowing us to invest further in our R&D programme and thus our customer service offering.
I Holland Ltd, +44 115 972 6153, info@iholland.co.uk, www.iholland.co.uk.