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Development of thermal methods for characterizing complex molecular nanosystems for vectorization – P. Espeau

Solid state of the pharmaceutical raw material :

Study of the polymorphism of pharmaceutical raw materials (active ingredients, excipients) using thermal analysis (DSC, ATG) and X-ray diffraction. Thanks to these analyses and a thermodynamic treatment, the stability hierarchy of these polymorphs is established as a function of temperature and pressure.

“Polymorphic and Pressure-induced phase transformations of Malonamide System.” Espeau. Thermochimica Acta, 2014, 589, 19-24.
“Kinetics of the solid-solid transformations for the Piracetam Trimorphic system: incidence on the construction of the p-T equilibrium phase diagram”. Corvis, A. Spasojević-de Biré, C. Alzina, N. Guiblin, P. Espeau. J. Chem. Thermodyn. 2016, 97, 167–172.

As part of F. Rosa’s thesis, a method was developed for using the results of thermal analyses as a function of heating rate, thus making it possible to obtain the melting characteristics of melt-degrading compounds.

“Crystal Structure Determination and Thermal Behavior upon Melting of p-Synephrine”. F. Rosa, P. Negrier, Y. Corvis, P. Espeau. Thermochim. Acta, 2016, 632, 18-22.
“Characterization of the heat behavior of Amiodarone hydrochloride”. Mhoumadi, M. Elkashab, S. Prillieux, J.-B. Dumas, F. Collas, N. Louvain, B. Fraisse, P. Espeau. Thermochim. Acta, 2022, 708, article 179121.

Thermal analysis at very high scanning speeds.

Because of this technique, it is now possible not only to determine the melting temperatures of active substances that degrade on melting, but also to freeze the glassy state of these same substances. Another advantage is the ability to stabilize polymorphs previously inaccessible by crystallization.

“Vitreous State Characterization of Pharmaceutical Compounds Degrading upon Melting by using Fast Scanning Calorimetry.” Y. Corvis, A. Wurms, C. Schick, Espeau. J. Phys. Chem. B, 2015, 119, 6848-6851.
“New Menthol Polymorphs Identified by Fast Scanning Calorimetry.” Y. Corvis, A. Wurms, C. Schick, Espeau. CrysEngComm., 2015, 17, 5357-5359.
“New melting data of the two polymorphs of prednisolone”. Corvis, P. Négrier, J. Soulestin, P. Espeau. J. Phys. Chem. B, 2016, 120, 10839-10843.

Thermodynamic characterization of enantiomer-based systems.

Many active ingredient molecules are chiral. While physico-chemical and thermodynamic characterizations of enantiomers are often reported, the same cannot be said for racemic mixtures.

“Racemate and Conglomerate of Anhydrous Sibutramine Hydrochloride: A Rare Case of Relative Stability”. Rosa, P. Négrier, P. Espeau. CrystEngComm, 2016, 18, 6903-6907.
“Adrenaline system: another rare case of conglomerate with partial solid solutions.” Ianno’, P. Négrier, P. Espeau. J. Therm. Anal. Calorim. 2019, 138, 997-1002.
“;Scalemic mixtures preparation for optimized composition of ibuprofen solid dosage forms”. Y Corvis, N. Guiblin, P. Négrier, I. Marenco, O. Dembele, P. Espeau. Eur. J. Pharm. , 2021, 169, 91-96.
“p-Synephrine Enantiomers: Binary Phase Diagram, Crystal Structure and Kinetic Stability of Metastable Conglomerate Monitored by Nonlinear Optic”. Ianno’, S. Clevers, P. Négrier, V. Dupray, G. Coquerel, P. Espeau. CrysEngComm., 2020, 22, 6071-80.

Studies of solid-state interactions between active ingredients and/or excipients.

This study is approached by establishing the binary phase diagram. Any interactions in the solid state can then be highlighted by means of differential thermal analyses involving the constituents in different proportions.

“Revised phase diagrams based on racemic ibuprofen with thymol and L-menthol”. Maruchenko, P. Espeau. J. Therm. Anal. Calorim. 2021, 145, 3087-3091.

 Studies in multiphase systems (micro- and nano-emulsions).

This project involves the physico-chemical characterization, by thermal analysis, of single and multiple self-emulsifying emulsions. These emulsions can be used to improve the contrast of ultrasound images, as well as to vectorize active ingredients.

“Co-encapsulation of fisetin and cisplatin into liposomes for glioma therapy: from formulation to cell evaluation”. Renault-Mahieux, V. Vieillard, J. Seguin, P. Espeau, D. T. Le, R. Lai-Kuen, N. Mignet, M. Paul, K. Andrieux. Pharmaceutics, 2021, 13, 970.
“Thermal Analysis Tools for Physico-chemical Characterization and Optimization of Perfluorocarbon Based Emulsions Formulated for Ultrasound Imaging”. Corvis, F. Rosa , M.-T. Tran, N. Mignet, G. Renault, S. Crauste-Manciet, P. Espeau. Colloids & Interfaces, 2022, 6, 21.

Design of new pharmaceutical forms using 3D printing.

The aim of this project is to use 3D printing technology to develop a technique for manufacturing patient-tailored drug doses. A doctoral thesis defended in February 2021 enabled us to choose, among the various 3D printing techniques currently available, the extrusion method as being the most suitable for the research work we are proposing. This method offers several advantages :

• Multifunctional drug delivery systems ;
• Adjustable, customized dosages ;
• Production of small batches of individually selected doses.

This approach is part of a collaborative project with pediatric hospitals in the Paris region and the Delpharm company. The aim is to adapt dosage regimens according to patients’ body weight, with a particular focus on the pediatric population. A CIFRE thesis funded by Delpharm began in January 2023 on this project.

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