Welcome to Vidyasirimedhi Institute of Science and Technology. Website from Thailand


Professor Dr. Adrian Flood

Department of Chemical and Biomolecular Engineering
Energy Science and Engineering
Tel. 66 33 01 4253
Email adrian.flood@vistec.ac.th


Industrial and Pharmaceutical Crystallization


Research Overview

Design of novel processes for the separation and purification of active pharmaceutical ingredients and other specialty industrial chemicals. The research includes projects relating to separation of the enantiomers of pairs of chiral molecules (optical resolution) by; temperature induced deracemization; Viedma ripening; diastereomeric salt formation; preferential crystallization, and the use of chiral solvents to break symmetry. Projects also include preparation and phase transformations in systems of cocrystals, kinetics and thermodynamics of the phase transition of polymorphs, and studies to improve the fundamental understanding of crystal growth and nucleation.

Separation of Enantiomers

The majority of Active Pharmaceutical Ingredients (APIs) are chiral molecules – one of a pair of stereoisomers that have identical physical and chemical properties in achiral environments, but different effects and activities inside the human body, which is a chiral environment. One of the pair of enantiomers has the desired pharmaceutical effect within the body while the other may have a different effect unrelated to that of its pair, may have no effect, or in some cases may be toxic to the body. A famous case is that of the drug thalidomide – the R-enantiomer of this molecule was used to treat morning sickness in pregnant women; the S-enantiomer causes birth defects. Around 10,000 babies died due to contamination of the S-enantiomer in drug formulations (or conversion within the body) and countless other babies were born with severe birth defects. Because of this all new APIs registered as pharmaceutical products may only be registered as the pure enantiomer.
Most APIs are created through chemical synthesis however unless special – and difficult – asymmetric syntheses are used then the product will be a racemic (or equimolar) mixture of the two enantiomers. This leads to the necessity to separate the two enantiomers. Crystallization methods are the most economic and convenient to achieve the separation since the molecules have identical physical and chemical properties, however crystallization can in many cases have complete selectivity in the solid phase.

Schematic of the mechanism of deracemization due to temperature cycles and solution phase racemization. Cryst. Growth Des. 13(8), 9630-9636 (2013).
Our group at VISTEC is creating and improving many processes for the industrial separation of enantiomers. These methods include a novel process developed by our group, namely Temperature Cycle Induced Deracemization. For conglomerate forming and racemization species this process can convert 100% of a racemic suspension of enantiomers into a suspension containing only the target enantiomer at a purity greater than 99%, thus doubling the yield of conventional processes, where the 50% of material which is the undesired enantiomer must be discarded.

Another process being investigated by our group is the use of diastereomeric salts to achieve separation of enantiomers. This is the most popular method for resolution of chiral molecules since it can be easily used for species that crystallize into a racemate – a crystal that contains both enantiomers in equal amounts. The method uses a chiral resolving agent to form a salt (or a cocrystal) with the enantiomers requiring separation. However there needs to be case-by-case optimization of the process, including selection of the resolving agent, in order to achieve an economic process with suitable product purity. Our group is optimizing the process for some common APIs and investigating routes for further understanding of the selection of resolving agents.
Preferential crystallization is an effective method to separate enantiomers if the racemic solution crystallizes into a conglomerate – a mixture of R-crystals and S-crystals. This process is similar to traditional industrial crystallizations, although the very high amount of impurity (the 50% of the solute in the form of the undesired enantiomer is an impurity) and the fact that the two enantiomers have identical properties, makes it especially challenging. We are involved in modeling and optimization of the process of preferential crystallization.

A novel process for enantioseparation is the use of chiral solvents to create differences in the properties of the two enantiomers in solution – thus leading to traditional separations being available for the separation of the enantiomers. This method is new and so far has proven to be very challenging. However the potential uses and benefits for this new technique are immense, and so we hope to achieve novel processes using the technique.

Fundamental Studies on Nucleation and Growth

Our group also undertakes research to resolve fundamental issues in the mechanisms of crystal nucleation and growth. Such studies are important for a complete understanding of how the phase change occurs, and the thermodynamics and kinetics of the process. Our most significant results are an understanding of how the crystal growth history impacts on current crystal growth rates, which has led to a more complete understanding of the reasons for crystal growth rate dispersion.

Chemical Engineering & Technology (2016), 39(2), 199-207. Atomic Force Microscopy of the surface of crystals under increasing levels of driving force. Degraded surfaces lead to lower future growth rates.


Polymorphism is where a species occurs in two or more distinct crystal structures. The phenomenon is very common, however is very important in the pharmaceutical industry because different polymorphs have different properties, and different bioavailability in particular. Our group is active in developing and parameterizing models for the thermodynamics and kinetics of polymorphic phase transformations of pharmaceutical molecules.


Powder X-Ray Diffraction of the α- and γ- polymorphs of the amino acid DL-methionine and photomicrographs of the crystals. Unstable α- DL-methionine converts to the stable γ- DL-methionine within 5 days. (Wantha and Flood).



Cocrystals occur when two distinct species occur within a crystal structure, excluding forms such as hydrates, solvates, and salts. Cocrystals are an emerging field in the pharmaceutical industry because two APIs with complementary effects may be loaded into the same formulation in a very reproducible way. In addition, cocrystals enable the creation of new patents for existing drugs. The creation of new cocrystal species is a well-developed research field, however the industrial processing of these species is not. Our group is actively improving models and processes for the conversion of pure species crystals into cocrystals, based on a more complete understanding of the thermodynamics and kinetics of the transformations.

Selected Publications

  1. Pantaraks, P., Matsuoka, M., Flood, A. E. Cryst. Growth Des. 7(12), 2635-2642 (2007).
  2. Flood, A. E., CrystEngComm 12(2), 313-323 (2010).
  3. Maosoongnern, S., Diaz Borbon, V., Flood, A. E., Ulrich, J. Ind. Eng. Chem. Res. 51(46), 15251-15257 (2012).
  4. Flood, A. E., Wantha, L. J. Cryst. Growth 373, 7-12 (2013).
  5. Srimahaprom, W., Flood, A. E. J. Cryst. Growth 362, 88-92 (2013).
  6. Suwannasang, K., Flood, A. E., Rougeot, C., Coquerel, G. Cryst. Growth Des. 13(8), 3498-3504 (2013).
  7. Galbraith, S. C.; Schneider, P. A.; Flood, A. E. Water Res. 56 122-132 (2014).
  8. Srisanga, S., Flood, A. E.; Galbraith, S. C., Rugmai, S., Soontaranon, S., Ulrich, J. Cryst. Growth Des. 15(5), 2330-2336 (2015).
  9. Galbraith, S. C., Flood, A. E., Rugmai, S., Chirawatkul, P., Chem. Eng. Tech. 39(2), 199-207 (2016).

Research Group Members:

Dr. Adrian Flood (Professor)
Dr. Kittisak Suwannasang(Postdoctoral Research Fellow)
Mr. Brian Pornsakulsak
Mr. Kritsada Intaraboonrod
Mr. Ratchanon Uchin
Ms. Tanaree Patirupanon
Mr. Thanawit Suwannikom

International Research Collaborator:

Prof. Gerard Coquerel University of Rouen
Prof. Joop ter Horst University of Strathclyde
Prof. Joachim Ulrich Martin-Luther University Halle-Wittenberg
Prof. Andreas Seidel-Morgenstern Max Planck Inst. for Dynamics of Complex Technical Systems