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IPAPI-Improving the Properties of Active Pharmaceutical Ingredients – IPAPI

Submission summary

IPAPI, Improving the Properties of Active Pharmaceutical Ingredients Partners : 1=LPMG, EMSE ; 2=LAPEP, Univ. Lyon 1 ; 3= ETH, Zurich ; 4=Univ. Sheffield. In order to produce Active Pharmaceutical Ingredients (API) with specified properties, the advanced control of industrial crystallizers has been curbed for a long time by the lack of in-line sensors allowing to monitor the development of crystallization processes (supersaturation measurements) and the properties of the dispersed solid (crystal shape and size distribution …) The situation has now evolved thanks to the so-called 'PAT' (Process Analytical Technologies), which explains in particular the increasing requirements of regulatory agencies such as the FDA for improving industrial production practices. Recent works have reported on the monitoring of supersaturation during crystallization operations using in situ infrared spectroscopy (ATR FTIR). New techniques (In situ image acquisition, FBRM) also allow monitoring the evolution of sizes, but these techniques do not really provide quantitative evaluation of the 'real' CSD (Crystal Size Distribution). As far as the control of crystallization processes is concerned, a second major problem lies in the complexity of the elementary phenomena involved. To cope with the lack of reproducibility resulting from such phenomena (Nucleation, growth …) new control strategies still have to be developed. Actually, designing such strategies requires: 1. to develop crystallization models, in particular through the resolution of Population Balance Equations (PBE), 2. to estimate the involved kinetic parameters from relevant experimental data, 3. to design feedback control algorithms allowing one to deal with undesirable batch to batch variations 4. to be in a position of applying the control strategies through the use of in-line sensors. The four partners involved in this project can account for a significant expertise in the field of industrial crystallization, and were among the very few groups to report early on the use of PATs in the field of crystallization (Partners 1,2 and 4). The partners have also a worldwide experience in the application of PBEs, including their theoretical study and their experimental validation. In particular, Partner 4 has a track record of nearly 20 years for work on PBEs in process engineering. Through a close collaboration Partners 1 and 2 aim at investigating the application of the state observation theory to PBEs (Infinite dimensional systems), from both theoretical and practical viewpoints. This part of the project is intended to cope with the lack of CSD sensors though the design of new state observers. Partner 4 will focus his activity on the continuation of recent works on 'Product Engineering' and will benefit from the expertise of Partners 1 and 3 for the experimental validation of the proposed control approaches. Partners 1-2 and 3 have reported experimental results concerning the in-line use of vibrational spectroscopy (ATR FTIR, Raman) and of FBRM probes (Focused Beam Reflectance Measurement) for the modeling, identification and monitoring of organic crystallization processes. They now propose to develop a two-dimensional model for crystallization systems: population balance describing two characteristic sizes of the particles in order to describe the evolution of crystal shapes, and population balances describing one characteristic size and the concentration of impurity of the particles. Partner 1 therefore aims at studying the problem of the chemical purity of crystals, which to the best of our knowledge was never envisaged in the open literature. The contribution of Partner 1 will be to design phenomenological PBE models relating the purity of crystals to the cooling operating conditions. The experimental part of the work will be based upon ATR FTIR supersaturation measurements, on the one hand, and on off-line CSD measurements using image analysis and Coulter Counter, on the other hand. The experimental results will be used to estimate the kinetic parameters of the crystallization process, in collaboration with Partner 2. The parameters will then be used to 'feed' the PBEs mentioned above. Due to their hyperbolic and non linear features, solving these equations in the bidimensional case is not an easy task,. This is why specific numerical techniques will be sought by both Partners 2 and 4.

Project coordination

Gilles FEVOTTE (Université)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.


Help of the ANR 340,000 euros
Beginning and duration of the scientific project: - 36 Months

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