# Investigations of pharmaceutical compounds co-crystallization for application to chiral resolution assisted by supercritical CO2

Fatma Ercicek, Christelle Harscoat-Schiavo, Mathieu Marchivie, Samuel Marre, Pascale Subra-Paternault

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Fatma Ercicek, Christelle Harscoat-Schiavo, Mathieu Marchivie, Samuel Marre, Pascale Subra-Paternault. Investigations of pharmaceutical compounds co-crystallization for application to chiral resolution assisted by supercritical CO2. 27th International Workshop on Industrial Crystallization, Aug 2022, Espoo, Finland. hal-03718287

HAL Id: hal-03718287

https://hal.science/hal-03718287v1

Submitted on 21 Nov 2022

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Distributed under a Creative Commons CC BY 4.0 - Attribution - International License
Investigations of pharmaceutical compounds co-crystallization for
application to chiral resolution assisted by supercritical CO₂

F. Ercicek<sup>1,2*</sup>, C. Harscoat-Shiavo<sup>2</sup>, M. Marchivie<sup>1</sup>, S. Marre<sup>2</sup> and P. Subra-Paternault<sup>1</sup>

<sup>1</sup> CNRS, Univ. Bordeaux, CBMN, UMR 5248, F-33600 Pessac, France

² CNRS, Univ. Bordeaux, ICMCB, UMR 5026, F-33600 Pessac, France

*fatma.ercicek@u-bordeaux.fr

**Keywords:** co-crystallization, supercritical CO₂, chiral resolution, in-situ observations, microfluidics

Co-crystalline products are becoming increasingly important in the pharmaceutical industry, due to the chirality, low water solubility and low bioavailability of most active pharmaceutical ingredients (API). Solids with a single crystalline phase composed of two entities (API + coformer COF) linked *via* non-covalent interactions are called co-crystals. The modification of the API crystal lattice through the incorporation of the COF enhances the physicochemical properties of the initial drug without altering its therapeutic purposes. Thus, understanding crystallization processes can help to obtain products with desired properties. The formation of metastable conglomerates by co-crystallization can be a solution for optical resolution [1]. With the rising demand for green technologies, a co-crystal manufacturing strategy has been coupled with supercritical fluids. Supercritical CO₂ (scCO₂) is non-toxic, inexpensive, and manageable, which is frequently employed as an anti-solvent, like in the Gaseous Anti-Solvent (GAS) method. It enables reaching high supersaturation and directly obtaining dry products [2].

This work, first, highlights the manufacturing process (batch inox reactor) and the characterization of unknown co-crystals of chiral compounds produced by supercritical CO₂. The solubility of the selected chiral API and COF in the initial solvent system is reduced by the anti-solvent effect of CO₂, resulting in co-precipitation. The parameters influencing the purity of the co-crystals, such as the choice of solvents, temperature, and stoichiometric ratio were studied. The results demonstrate the obtaining of unidentified co-crystal structures, which were elucidated by XRD.

In parallel, a high-pressure microfluidic device has been
developed to investigate crystallization phenomena under
scCO2. Thanks to optical access being provided by such a
device, in-situ observations of time-related events are possible.
Visualization of racemic naproxen crystals is shown in Figure
1. From these data, knowledge on the growth kinetics under
scCO2 can be acquired. In-situ precipitation monitoring of
racemic and enantiopure co-crystals in a high-pressure optical
cell thanks to FTIR spectroscopy is in progress. Relevant
information on the behavior of racemic and enantiopure
compounds precipitation are being obtained thanks to in-situ
analysis. These first results could be an opening perspective for enantioseparation in
supercritical conditions.

<figure><img src="image_2.png" /><figcaption>Figure 1: On-chip precipitation
of RS-NPX by optical
microscope in a micro-pool</figcaption></figure>

[1] L. C. Harfouche, C. Brandel, Y. Cartigny, S. Petit, and G. Coquerel (2020): **Resolution by Preferential Crystallization of Proxyphylline by Using Its Salicylic Acid Monohydrate Co-Crystal**, *Chemical Engineering & Technology*, 43, 1093-1098.

[2] C. Neurohr, A.L. Revelli, P. Subra-Paternault (2013): *Naproxen–Nicotinamide Cocrystals Produced by CO₂ Antisolvent*, *J. Supercrit. Fluids*, 83, 78-85.