LASENTEC FBRM/PVM USERS CONFERENCE

Transcription

1 LASENTEC FBRM/PVM USERS CONFERENCE Barcelona, Spain 25 to 28th February 2001

2 Pseudo polymorph transition the use of the FBRM and PVM. Olivier MONNIER Wouldn't it be nice if they were one probe! I would like to do a short presentation about pseudo polymorph transition and the use of FBRM and PVM probes. My first title was Wouldn t it be nice if they were one probe! In other words, wouldn t it be nice if we could join FBRM and PVM together?

3 Overview Why tracking pseudo-polymorphism? PVM measurments FBRM measurments Conclusions I will show a setup of pseudo polymorph transition through FBRM and PVM measurements. At first, we have big crystals. As the transition begins they disappear, then we have lighter crystals coming out. Finally, the crystals go into this pseudo polymorph or solvate. I will speak about why we track pseudo polymorphism, then I will show the PVM and FBRM measurements we got.

4 Solvent selection Residual solvent Final Purity Shape of the crystals Physical properties of the powder Why tracking pseudo-polymorphism? Better understanding of the crystal/solvent interactions Thermodynamical stability of solvates Transformation during the drying step Alerting for pharmaceutical sciences for the use of certain solvent during formulation In the first step of any crystallization process definition you have to choose your solvent of crystallization. If you choose a solvent that could give you a pseudo polymorph during your crystallization process, then you will have problems getting out the non-solvated form. Your non-solvated form may be less stable in the solvent. We have some products that keep some solvent (out of specification) within the powder, even after drying. To understand the way your process is working you need to have a better understanding of crystal/solvent interactions. The reason why we were also interested in pseudo polymorphism was to increase the final purity of our drug substance. We show that this purity was increased using a two-step process, the first step consisting in a pseudo polymorph formation and the second step of the crystallization of the nonsolvated form. Also, we have seen through pseudo polymorph transition that we can have a lot of different crystal shapes. Pseudo polymorph tracking can help you obtain crystals with different shapes, which then give the final powder different physical properties. Choosing the right shape can let you improve flow-ability or electrostaticity of your final powder. In another example we show that 90% of the product was transformed in

5 PVM measurments These PVM measurements show crystals of the non-solvate form. You can see very large needle-shaped crystals. The transformation is quite fast. Sometimes you can see some of the non-solvate form and after that you obtain these types of crystals. Here I show just the transformation. It takes 24 hours to come to the point where this transformation occurs. Basically, we determined that we can track the transformation with PVM.

6 FBRM measurments We can also track the transformation with FBRM. Here I bring up the statistics related to the form I am interested in and I am waiting for the transformation to occur. You can see that when it does, the number of counts increases. This is true for all of the different particle size classes. FBRM allows us to very easily see the change in fine particles and transformation. FBRM allows us to see the beginning of the transition faster than PVM, but for us it was also important to see the needles remaining with the pear-shaped crystals. This we could only see with PVM

7 Conclusion That kind of information has to be known as soon as possible at the beginning of the chemical development of the drug substance. Both PVM and FBRM give us useful informations for a better understanding of the behaviour of our drug substances in solvent. For us, this kind of information has to be known as soon as possible at the beginning of the chemical development. As I said, it is important to choose your solvent and not change it later on. Both PVM and FBRM give us useful information for better understanding about the behavior of our drug substances in solvent.

8 Acknowledgement.. Corinne BOUILLE Lasentec team Rich Becker Jérôme ROCHE Corinne GAVORY Isabelle ZIRI Kim LE Bernard Cellard Renu Olivier MONNIER I would like to thank both my team and the Lasentec team that helped us with our crystallization.

9 Questions and Answers Q: In your FBRM data, immediately after the transformation from one pseudo polymorph to another takes place, the counts go up and then they come back down again. Do you know why this is happening? OM: I think it is an obscuration of the probe due to the high quantity of material. Q: Does that difference in square weight correspond to the length change that you saw? If you look at the square-weight mean do you see the change in the length of the precursor particles to the length of the fine needles? OM: It seems to correspond fairly well. The length of the needles is very high, so you don t see all 900 microns. RB: Yes, you can clearly see the transition to the fines.

10 Questions and Answers Q: Why does it take so long for that change in form to occur? OM: I don t know yet. It is part of the kinetics, but as soon as you arrive at the change, it goes faster. Maybe it is due to the small difference you have in terms of solubility between the non-solvate form and the solvate form. The solubility curves are very close together. The solubility of the solvate form is under the solubility of the non-solvate form. I think this is due to the solubility difference because as soon as you do the transformation, you need to dissolve your first form and then nucleate and grow the other one.