Blanc SIMI 8 - Blanc - SIMI 8 - Chimie du solide, colloïdes, physicochimie

Microstructure of stressed pharmaceutical solids – MI-PHA-SOL

Microstructure of Pharmaceutical Solids

Characterization of the microstructure of partially disordered pharmaceutical solids: impact of mechanical stress, pressure and downstream operations. Applications of the PDF resolution method for powder X-Ray Diffraction and integration in the automated software FullProf.

Defined axes for the microstructural characterization of molecular solids

The ANR MI-PHA-SOL project, as accepted, started on September 1st 2012 and will end on February 4th 2016 (total duration : 42 months). The main objective of this project consist in characterizing the microstructures of some pharmaceutical solids, via 5 axes : 1) the preparation, synthesis and production of model samples for the analyses performed in the following axes; 2) the structural and microstructural analysis (based on powder diffraction diagrams determined on classical or synchrotron diffractometers) of these samples; 3) In parallel, the development of a software dedicated to PDF analyses integrated in FullProf Suite Software; 4) some structural studies under pressure of the samples obtained in axis 1 and 5) the sharing and exploitation of the results obtained in the different axes. <br />The application of the work program aims at determining on some model molecules the solid phases microstructures (more and less well crystallized), in a continuum between the amorphous state and the perfect crystal.

Preparation of the samples: High Energy Milling, Vibro-Milling and Spray Drying.
X-Ray analyses: usual laboratory diffractometers, and synchrotron radiation (CRISTAL line Soleil synchrotron in september 2013, ID11 line of ESRF in October 2014 and ID15B line of l'ESRF in november 2014).
Implementation of the PDF module in FullProf suite: the module is currently being inetegrated in FullProf Suite.
Building of the analysis cell under moderate pressure (silica capillar).

Isolation of new racemic Modafinil polymorph under HEM or spray-drying. The structural resolution of this « common » form allows identifying crystallographic directions impacted by the mechanical stress. Surprisingly, these directions were not in accordance with gliding planes of molecular chains (as expected previously). A publication on this compound is currently planned.
A second multi-partners publication (IMR Rouen and ESRF Grenoble) concerning Agomelatine Form V crystal structure (isolated by HEM and spray-drying) is also planned.
Diffraction tests with synchrotron radiation consisted in following the micro structural evolution under milling of 2 organic molecules: Trehalose and Hydrochlorothiazide (HCT). These analyses confirmed a fast decrease (for both compounds) of the diffracting domains size before reaching a “plateau” value, illustrating the limits of detection of diffraction.
Thermal analyses performed on these compounds confirmed a growing evolution of the amorphization upon milling and evidenced an increase of the specific surface area leading to a bimodal recrystallization of the compounds upon heating, for moderate milling times.
Spray-drying tests on both compounds (Trehalose and HCT) did not lead to isolate amorphous states stable enough among time (presence of water for Trehalose which could lead to a recrystallization towards the dihydrate, fast recrystallization for HCT).
Integration of the PDF module in FullProf Suite: the current state of the project is available at:
The body of the moderate pressure cell which will serve for diffracttion and In Situ Raman spectroscopy experiments was built.

PDF analysis on the last synchrotron data recorded (November 2014) concerning the evolution upon heating of amorphous Trehalose and HCT (Monitoring of the recrystallization by PDF).
Using of the PDF module in FullProf Suite in routine mode for the structural study of molecular compounds.
X-Ray and In Situ Raman analyses performed under moderate pressure with the cell which has been built previously.

1. Oral communication (accepted) during CGOM 11 congress (Kyoto, June 2014): IMR Rouen + Institut Néel Grenoble
2. Poster during Hercules formation (Higher European Research Course for Users of Large Experimental Systems) : UMET + Institut Néel
3. Chapter of book : «Use of the Pair Distribution Function analysis in the context of Pharmaceutical Materials« in “Disordered pharmaceuticals«(Wiley), to be published : Institut Néel
4. 7th IDMRCS, «7th International Discussion Meeting on Relaxations in Complex Systems”, Barcelona, Spain (21-26 july 2013)
5. IWPCPS 15: International Workshop on Physical Characterization of Pharmaceutical Solids Philadelphia, Pennsylvania, U.S.A. (24-27 june 2013)

2 multi-partners publications currently on project (Agomelatine and Modafinil)

This project aims at improving the knowledge on stressed organic solids including Active Pharmaceutical Ingredients (APIs). Indeed, precipitations and drying processes as well as the various mechanical, thermal or other physical treatments commonly used during the manufacture of APIs and excipients can lead to significant modifications of the thermodynamic and physico-chemical properties of materials which may have eventually a dramatic impact on: structural purity, solubility and bioavailability. The insufficient understanding of the modifications occurring at molecular level during processes such as milling, compaction, desolvation, drying, granulation or freeze-drying has prevented a satisfying description of their consequences. From a fundamental point of view, the situation is very complex when the phase transformation takes place in a system undergoing dynamical strains. In this project, emphasis will be put on the effect of three specific perturbations: Milling, Desolvation and Pressure; all representatives of common stresses. We propose a comprehensive research strategy which combines, in a continuous round trip, the production of compounds stressed in a controlled way and a detailed characterization of the effects of various stresses (nature and intensity) on the (local) structures, molecular mobility, thermodynamics, surface and reactivity. This will be carried out on a selection of few molecular systems, considered as model API and excipients, known to have interesting behaviors under thermo-physical treatment. In order to fulfil this goal a key point will be to develop and apply to these systems the Pair Distribution Function Analysis (PDF) method to obtain unprecedented information about their structural evolution when submitted to stress. Confrontation to low frequency Raman spectroscopy will also permit to gain insight in the potentiality of the latter techniques to provide nano-structural information. This will be particularly useful to investigate in situ transformations under pressure of model systems by PDF /diffraction analysis and Raman spectroscopy, in a wide range of applied pressure (<0.1 to 10GPa). The PDF method based on the analysis of the total scattering of x-rays by matter has the potential to become one of the most useful tools in this context (multi-scale approach of the structure description, independent from the crystalline state of the material). The structural coherence length as well as the local atomic arrangement can be obtained, on scales ranging from the nearest neighbour distances to tens of nanometers. One of the main tasks of the project will be to include the PDF in the FullProf Software Suite, which already contains the rigid body approach and provides efficient algorithms for full profile structure refinement and simulated annealing techniques for structure solution. Properties of amorphous materials fundamentally depend on the nature of structural relaxations existing both above and below their glass transition temperature (Tg). The latter will thus be carefully investigated by combining broad band dielectric spectroscopy and calorimetry. Possible bias introduced by surface effects will be also investigated. Molecular dynamics simulations will be performed with the ambition of describing the mechanisms at the origin of the various structural effects of applied stress. A coherent picture of the link between the changes of reactivity of stressed materials with their structure/dynamics properties should emerge from these comprehensive complementary studies.

Project coordinator

Monsieur COQUEREL Gérard (Institute for Material Research) –

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.


IMR 4114 Institute for Material Research
ILL Institut Max von Laue - Paul Langevin

Help of the ANR 606,999 euros
Beginning and duration of the scientific project: August 2012 - 42 Months

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