Polymorphism and Crystallisation 2010: An Interview with Martin Wijaya Hermanto

Poster Awards Session Finalist: Martin Wijaya Hermanto

IQPC: Hi, Martin. Tell us a bit about the Institute of Chemical and Engineering Sciences and the work that you do there.

Martin Wijaya Hermanto: We are one of Singapore’s family of research institutes under the Agency for Science, Technology and Research (A*STAR). In ICES, our research and development focused on chemistry and chemical engineering, and we have seven skill groups:

1. Applied catalysis, which is directed at developing novel catalysts and processes relevant to the petrochemical, fine chemical and pharmaceutical industries

2. Chemical Synthesis Laboratory, which is to advance in chemical sciences, particularly chemical synthesis and chemical biology.

3. Crystallisation and Particle Science, which I am in. The major focus for its research is to apply the understanding of crystallization and formulation science to pharmaceutical and fine chemical active ingredient manufacture and formulation. We also aim to apply the latest PAT (Process Analytical Technology) for the monitoring and control of both crystallisation and solid handling processes, and develop novel formulation such as nanocomposite particles, microemulsions and co-crystals.

4. Industrial Biotechnology, which focuses on utilisation of renewable resources to produce fuels and chemicals using microorganisms or enzymes as catalysts.

5. New Synthesis Techniques and Applications, which actively researches areas pertaining to the efficient synthesis of organic molecules for the pharmaceutical, fine and specialty chemical industries.

6. Process Science and Modelling, which cover a wide spectrum of disciplines, from analytical and physical chemistry, to core chemical engineering areas such as reaction engineering, process control, process supervision and optimisation.

7. Experimental Power Grid Centre, which is a new research programme under ICES. EPGC aims to be a world class centre for technologies in intelligent grids, micro grids and Distributed Energy Resources.

Where do you see the future focus to lie–or where the focus should lie, in your opinion–within the field of Polymorphism and Crystallisation?

In my opinion, we should investigate more into co-crystal. Basically, co-crystal is a crystal which has two or more distinct molecular components within the crystal lattice. Compared to free drugs or salts, co-crystals exhibit different physico-chemical parameters such as solubility, dissolution rate, chemical stability, melting point, and so on. Therefore, through proper screening and selection, co-crystal can result in solids with superior properties as compared to the free drug or salts. In addition, including co-crystal in drug development increases the options in best solid form selection for drug discovery and development.

Currently, the research in co-crystal is still relatively new. Many of the current research focus on the methods of co-crystals formation and co-crystals characterisation. However, the implementation of PAT to monitoring and control of co-crystallization is still rare and it gives a good opportunity for research in the future.

In your poster abstract, you describe Focused Beam Reflectance Measurement (FBRM) as a method to achieve consistency in the size distribution of the product crystals. What are the challenges of achieving consistency in the size distribution of the product crystals?

In short, the main challenge lies on primary nucleation due to its stochastic nature. As we know, primary nucleation is significantly affected by the presence of impurities in the system. Since it is impossible to control the amount of impurities, we are likely to have batch-to-batch variation in crystals size distribution.

One way of tackling this problem is to perform external seeding at the start of the crystallization. By doing this, we provide more surface area for crystal growth instead of nucleation. This has been shown to improve the consistency in the product quality. However, this method requires preparing consistent external seed every batch, which can be tedious and the seed may not be readily available.

Another way of obtaining consistent CSD is by implementing concentration control, in which a supersaturation profile is followed during the batch. This approach utilizes ATR-FTIR to infer solute concentration. The drawback is that it requires tedious calibration of ATR-FTIR in order to predict the solute concentration. In addition, it has been shown that this method does not produce consistent CSD without external seeding.

Could you tell us a little more about the work you are doing on FBRM?

I will only explain the main concept here. Fundamentally, the proposed method is based on internal seed generation and conditioning. It consists of 3 stages. First, the seed is generated through primary heterogeneous nucleation by adding antisolvent. The amount of nucleation is limited by stopping antisolvent addition when the coarse counts given by FBRM reach a predetermined setpoint. Then, in the second stage, solvent is added to condition the seed generated. The extent of solvent addition is determined by the setpoint of coarse-to-fine ratio. When the setpoint is reached, the seed crystals are ready to be grown. Hence, antisolvent is added at the final stage until the crystals yield is reached or until a predetermined amount of antisolvent is added. By using this approach, we can achieve consistency in the product CSD.

And how will the implementation of FBRM benefit the pharmaceutical industry?

I believe product consistency or reproducibility is the first and most fundamental goal that we need to achieve in any pharmaceutical industry. Of course, we don’t want a drug that has variation in dissolution rate between tablets of the same drug. Since CSD inconsistency in crystallization product may cause adverse variation in downstream processing and eventually may affect the properties of the final product, it is imperative to minimize the variation in the CSD of crystallization product. And this can be achieved through the proposed method.

Another plus point of this method is that it is simple to implement and easy to adopt industrially. It does not require any tedious calibration such as concentration control and does not need any preparation of external seed.

To attend this year’s Polymorphism & Crystallisation event between 16^th-17th March at the Hilton London Olympia Hotel, London, UK, visit www.polyandcrys.com, e-mail enquire@iqpc.co.uk, or call +44 (0)20 7368 9300.