(A2PM) Advanced Physics of Pharmaceutical Materials

BCC1 Implementing fundamental physics tools and approaches to produce highly specialized knowledge

• Introduction to Pharmaceutical Materials Science – 6 ECTS
  The course provides an introduction to pharmaceutical materials science by presenting molecules, their interactions, and the nature of ordered and disordered associated materials and their transformations. It also introduces key experimental methods for structural and thermodynamic characterization.
• Drug product development and pharmaceutical technology I – 3 ECTS
  This course provides hands-on and theoretical training in drug formulation, manufacturing, and quality control of various pharmaceutical dosage forms.
• States of Matter and Materials Science Primers – 3 ECTS 
  Have a clear understanding of the different families of materials (metals and alloys, ceramics, polymers) based on their properties and microstructure.

BCC2 Producing and communicating highly specialized knowledge, including in a professional context

• Foreign language (French or English) – 3 ECTS
  Improve your communication skills in a foreign language
• PE or Graduate Programme Special Teaching – 3 ECTS
  Learn on current topic from the Materials for a Sustainable Future graduate programme
• Tutored trainings – 3 ECTS
  Discover new topics in physics based on the scientific literature, and develop your teaching and presentation skills in front of your peers.

BCC3 Solving complex problems by applying fundamental physics concepts

• Continuum mechanics – 3 ECTS
  Introduction to the principles of stress, strain, anisotropic and isotropic elasticity with applications covering a broad area relating to the mechanical behavior of materials.
• AI and advanced computational methods in physics – 3 ECTS
  Explore the intersection of AI, Machine Learning, and Physics in this class. Gain hands-on experience with cutting-edge techniques and applications tailored for the world of physics.
• Atomic scale modeling I – 3 ECTS
  Discover powerful simulation techniques like Molecular Dynamics and Monte Carlo to predict and design material properties at the atomic scale.

BCC1 : Implementing fundamental physics tools and approaches to produce highly specialized knowledge – 9 ECTS

• Satellites and remote sensing – 3 ECTS
  Master the principles and applications of remote sensing and satellite technology through comprehensive lectures and practical work with insights into environmental monitoring and cutting edge research.
• Radiative transfer and radiation-matter interactions – 3 ECTS
  Master the principles and applications of radiation-matter interaction in the context of atmospheric studies. Through a good balance between theoretical, numerical and practical elements.
• Large scale research infrastructures – 3 ECTS
  This course aims to introduce students to the principles, functioning, and applications of major large scale research infrastructures (LSRI) used in both fundamental and applied research.

BCC2 : Producing and communicating highly specialized knowledge, including in a professional context – 12 ECTS

• Tutored trainings – 3 ECTS
  Discover new topics in physics based on the scientific literature, and develop your teaching and presentation skills in front of your peers.
• Experimental project – 3 ECTS
  Develop students’ autonomy, scientific rigor, and technical skills through the realization of an experimental project in pairs. Apply theoretical knowledge acquired so far to solve a real-world problem.
• Internship – 6 ECTS
  A two-month-long experience in a professional working environment

BCC3 : Solving complex problems by applying fundamental physics concepts – 9 ECTS

• Condensed Matter II – Phonons – 3 ECTS
  This lecture explores the vibrational properties of crystalline solids, from lattice symmetries and phonon dispersion to thermodynamic behavior. It provides the fundamental tools to understand heat capacity, thermal transport, and the quantum nature of lattice vibrations in condensed matter systems.
• Fundamentals of molecular spectroscopy – 3 ECTS
  Gain a solid understanding of the quantum mechanical principles behind molecular spectroscopy, with emphasis on rotational and vibrational transitions and the role of symmetry in determining spectroscopic activity. 
• Microstructures and defects in materials – 3 ECTS
  Discover how grains, defects, and other microstructural elements and how they control the physical properties of materials.

BCC1 Implementing fundamental physics tools and approaches to produce highly specialized knowledge – 9 ECTS

• Thermal analysis of pharmaceuticals – 3 ECTS
  This course focuses on the thermal techniques to probe the different physical states of pharmaceutical materials and some of their transformations under typical constraints such as temperature changes and milling.
• Structural and dynamical characterization of pharmaceuticals – 3 ECTS
  This course focuses on complementary experimental and numerical techniques to probe the different physical states of pharmaceutical materials and their transformations
• Drug product development and pharmaceutical technology II – 3 ECTS
  This course equips students with advanced skills in formulating and manufacturing complex drug delivery systems, including poorly soluble and controlled release products.

BCC2 Producing and communicating highly specialized knowledge, including in a professional context – 6 ECTS

• Foreign language (French or English) – 3 ECTS
  Improve your communication skills in a foreign language
• PE or Graduate Programme Special Teaching – 3 ECTS
  Learn on current topic from the Materials for a Sustainable Future graduate programme

BCC3 Solving complex problems by applying fundamental physics concepts – 15 ECTS

• Advanced thermodynamics and phase transformations – 3 ECTS
  This course explores the principles governing crystalline and amorphous physical states and their transformations across diverse materials like metallic alloys, glasses, and polymers.
• Molecular mobility and amorphous state of matter – 3 ECTS
  This course presents the characteristics of molecular motions found in amorphous materials in the supercooled and glassy states, and the temperature dependence of these dynamics.
• Structural properties of matter : electron microscopy and diffraction – 3 ECTS
  Characterize the state of materials at the crystal to nanometer scale using advanced experimental methods such as the scanning and transmission electron microscope, and powder X-ray diffraction
• Atomic scale modeling II – 3 ECTS
  Discover quantum first principles methods to solve the problem of the electronic structure of molecular systems, from isolated molecules to solids   
• Advanced Spectroscopy of Molecular Systems: From Gas Phase to Condensed Matter (ASMS) – 3 ECTS
  This course aims to introduce fundamental principles in molecular physics characterization by optical (vibrational, rotational) and neutron spectroscopies, as well as dielectric techniques.

BCC2 : Producing and communicating highly specialized knowledge, including in a professional context

• Internship – 30  ECTS
  A five-month-long experience in a professional working environment

The aim of this work is to improve the understanding of the mechanisms underlying the polymorphic transformations of pharmaceutical materials during milling. Elucidating these mechanisms is essential for controlling the polymorphism of active pharmaceutical ingredients and thereby improving their performance

M. Guerain, A. Dupont, F. Danede, D. Barkhatova, J.-F. Willart, D. Barkhatova, New Kinetic Investigations to Better Understand the Mechanism of Polymorphic Transformations of Pharmaceutical Materials Induced by Milling, Pharmaceutics 17;11, 1404 (2025), [doi: 10.3390/pharmaceutics17111404]

Drug solubility and bioavailability are the most important formulation challenges in pharmaceutical development, probably because a major part of the active pharmaceutical ingredients (APIs) are synthesized in the crystalline state which is often a poorly water-soluble state. Mesoporous silica carriers have recently gained interest in the pharmaceutical domain because of their potential to significantly increase the solubility of poorly water-soluble drugs, by adsorbing the active molecule in an amorphous and relatively stable state. This work shows that co-milling of porous SBA-15 matrix with the drug makes it possible the drug loading without significant damage for the structure of the matrix, enhancing thereby the capacity of loading to almost 40 wt%. It is shown that the physical state of ibuprofen (IBP) confined to silica carriers was amorphous between temperatures Tg and Tm of the bulk form of IBP.

B. Malfait, N. Correia, A. Mussi, L. Paccou, Y. Guinet & A. Hédoux. Solid-state loading of organic molecular materials within mesoporous silica matrix: Application to ibuprofen (2019) Microporous and Mesoporous Materials 277 203-207 [doi: 10.1016/j.micromeso.2018.10.022]

Mixing polymeric excipients with drugs in amorphous solid dispersions (ASD) is known to enhance the bioavailability of drugs by inhibiting their recrystallisation. However, the mechanisms underlying stabilisation remain not fully understood. This study aims to improve our understanding of the role of dynamics, particularly the molecular movements that drive instabilities, through investigations of ASD made of Polyvinylpyrrolidone (PVP K12) and a model drug, Terfenadine. The analyses combine temperature modulated differential scanning calorimetry (MDSC) and dielectric relaxation spectroscopy. The results reveal that the produced ASDs are supersaturated with Terfenadine, regardless of the content, and that PVP slows down the dynamics of the blends, limiting the recrystallisation of the drug during heating. Although the ASDs appear homogeneous based on thermal analysis with a single glass transition consistently detected by MDSC, the investigation of the dynamics reveals a dissociation of the main relaxation into two components for PVP contents below 30 wt.%. This dynamic heterogeneity suggests a structural heterogeneity with the coexistence of two amorphous phases of different compositions, each characterised by its own dynamics. The complex evolution of these dynamics under recrystallisation is rationalised by the confrontation with the phase and state diagram of Terfenadine/PVP blends established by MDSC.

E. Dudognon, J.A. Bama, F. Affouard, Exploring the Relationship Between Stability and Dynamics in Polymer-Based Amorphous Solid Dispersions for Pharmaceutical Applications, Polymers 17;9, 1210 (2025), [doi: 10.3390/polym17091210]

Amorphous solid dispersions (ASD) are known to enhance the absorption of poorly water-soluble drugs. In this work we synthesise well-defined Polyvinylpyrrolidone (PVP) to establish the impact of dispersity and chain-end functionality on the physical properties of Curcumin (CUR)/PVP ASD. Thermodynamic characterisation of synthesised PVP emphasises a strong effect of the dispersity on the glass transition temperature (T_g), 50 °C higher for synthesised PVP than for commercial PVP K12 of same molar mass. This increase of T_g affects the thermodynamic properties of CUR/PVP ASD successfully formulated up to 70 wt% of CUR by milling or solvent evaporation. The evolution of both the T_g and CUR solubility values versus CUR content points out the development of fairly strong CUR-PVP interactions that strengthen the antiplasticising effect of PVP on the T_g of ASD. However, for ASD formulated with commercial PVP this effect is counterbalanced at low CUR content by a plasticising effect due to the shortest PVP chains. Moreover, the overlay of the phase and state diagrams highlights the strong impact of the polymer dispersity on the stability of CUR/PVP ASD. ASD formulated with low dispersity PVP are stable on larger temperature and concentration ranges than those formulated with PVP K12.

S. Samsoen, E. Dudognon, G. Le Fer, D. Fournier, P. Woisel, F. Affouard, Impact of the Polymer Dispersity on the Properties of Curcumin/Polyvinylpyrrolidone Amorphous Solid Dispersions, International Journal of Pharmaceutics 653, 123895 (2024), [doi: 10.1016/j.ijpharm.2024.123895]

The impact of low water concentration of strongly hydrogen-bonded water molecules on the dynamical properties of amorphous terfenadine (TFD) is investigated through complementary molecular dynamics (MD) simulations and dielectric relaxation spectroscopy (DRS) experiments. In this article, we especially highlight the important role played by some residual water molecules in the concentration of 1–2% (w/w) trapped in the TFD glassy matrix, which are particularly difficult to remove experimentally without a specific heating/drying process. From MD computations and analyses of the hydrogen bonding (HB) interactions, different categories of water molecules are revealed and particularly the presence of strongly HB water molecules. These latter localize themselves in small pockets in empty spaces existing in between the TFD molecules due to the poor packing of the glassy state and preferentially interact with the polar groups close to the flexible central part of the TFD molecules. We present a simple model which rationalizes at the molecular scale the effect of these strongly HB water molecules on dynamics and how they give rise to a supplementary relaxation process (namely process S) which is detected for the first time in the glassy state of TFD annealed at room temperature while this process is completely absent in a non-annealed glass. It also explains how this supplementary relaxation is coupled with the intramolecular motion (namely process γ) of the very flexible central part of the TFD molecule. The present findings help to understand more generally the microscopic origin of the secondary relaxations often detected by DRS in the glassy states of molecular compounds for which the exact nature is still debated.

J.A. Bama, E. Dudognon, F. Affouard, Impact of Low Concentration of Strongly Hydrogen-Bonded Water Molecules on the Dynamics of Amorphous Terfenadine: Insights from Molecular Dynamics Simulations and Dielectric Relaxation Spectroscopy, The Journal of Physical Chemistry B 125;40, p. 11292-11307 (2021), [doi: 10.1021/acs.jpcb.1c06087]

Morphological and structural properties of amorphous disaccharide lactulose (C₁₂H₂₂O₁₁), obtained by four different amorphization methods (milling, quenching of the melt form, spray-drying, and freeze-drying), are investigated by scanning electron microscopy, polarized neutron scattering, and molecular dynamics simulations. While major differences on the morphology of the different amorphous samples are revealed by scanning electron microscopy images, only subtle structural differences have been found by polarized neutron scattering. Microstructure of the milled sample appears slightly different from the other amorphized materials with the presence of remaining crystalline germs which are not detected by X-ray diffraction. Quantitative phase analysis shows that these remaining crystallites are present in a ratio between 1 and 4%, and their size remains between 20 and 30 nm despite a long milling time of about 8 h. The impact of the change in tautomeric concentrations on the physical properties of lactulose in the amorphous state has been investigated from molecular dynamics simulations. It is suggested that chemical differences between lactulose tautomers could be at the origin of small structural differences detected by polarized neutron scattering.

F. Ngono, G.J. Cuello, M. Jimenez-Ruiz, J.-F. Willart, M. Guerain, A.R. Wildes, A. Stunault, M. Hamoudi, F. Affouard, Morphological and structural properties of amorphous lactulose studied by scanning electron microscopy, polarised neutron scattering, and molecular dynamics simulations, Molecular Pharmaceutics 17, 10-20 (2020), [doi: 10.1021/acs.molpharmaceut.9b00767]