A meeting in Leuven

Although their labs at TU Delft are not far apart, the collaboration spark ignited in an auditorium of the KU Leuven in Belgium. Eral: ‘There I heard Ghatkesar talk about the remarkable technology he has at his disposal: the femtopipette, which enables the production of the smallest imaginable droplets.’ To give an impression, 10¹² - 10¹⁵ of these droplets fit into a litre. The laws of physics turn out differently in such small volumes. Can this difference be exploited to make the crystallisation process more efficient? Ghatkesar was immediately excited, and the brainstorming about a joint cohesion project had begun. Soon, the researchers realised that a number of fundamental question needed to be answered before it could be shown that their idea would be attractive for the production of crystals, for example for medicines. ‘In science, you seldom follow a straight path towards your final goal,’ says Eral. He therefore advices cohesion project candidates to be both realistic and flexible in their plans and ambitions.

Wrong crystal form

Eral illustrates the challenge faced by the pharmaceutical industry: although the medicinal crystals are grown in a fluid with the utmost care, multiple crystal forms can still occur. A drug in the wrong crystal form could turn out to be insoluble, which has far-reaching consequences for administering it. Not only does it imply that the medication must be injected intravenously, which is much less comfortable for the patient, it also increases the cost of the treatment. In the late 90s, the antiretroviral drug Ritonavir infamously needed to be recalled on a huge scale because there was too much variation in the crystal form. Eral’s expertise is in using laser light to enhance the crystallisation in the fluid or even direct it. ‘Until now we worked with large volumes of liquid (‘bulk’) to optimise the crystallisation process. In the cohesion project we do so inside the droplets produced by the femtopipette. Because of the small dimensions of the droplet, the crystallisation process is slightly different here. Combined with the use of laser light we think we can produce crystals in a much more controlled and reproducible fashion.

Cohesion researchers introduce crystals in the world of origami
Of course, the small volume of the droplets also represents a disadvantage: ‘To get the same amount of medicine, we may have to produce and irradiate 100.000 droplets. We still have a long way to go but we are convinced that these are challenges we can handle.’ Finally, Eral and Ghatkesar have also added an innovation to their plans. ‘The droplets and therefore the crystals still need to be processed into a pill-like form. How do you do that without losing or damaging the crystals?’ Again, the collaboration between the disciplines led to a solution. ‘The Department of Precision & Microsystems Engineering has a lot of experience in using the principles of origami, the Japanese art of paper folding, for engineering purposes. We intend to deposit the droplets onto the surface of an edible sheet, and fold this layer into a pill according to the principles of origami. This is the most efficient and careful way to squeeze as much surface and therefore as many medicinal crystals as possible into a small volume.’    

Dr. Murali Ghatkesar (Dept. of Precision and Microsystems Engineering) graduated summa cum laude from the University of Basel in Switzerland. After that he worked among others at CalTech and the University of Virginia in the US. As assistant professor ‘Micro and Nano Engineering’ at the TU Delft he develops micro and nanotechnology based tools to help solve intriguing problems in chemistry/biology  and unravel some of the mysteries of nature at small scale.