Papers by Jean-François WILLART
International Journal of Pharmaceutics
Le Centre pour la Communication Scientifique Directe - HAL - Université Paris Descartes, Dec 11, 2012
On the basis of dissolution enthalpy measurements, the aims of this study were i) to investigate ... more On the basis of dissolution enthalpy measurements, the aims of this study were i) to investigate the feasibility of classifying the dissolvability of various dairy powders, and ii) to establish whether a change in rehydration behaviour that occurs with ageing could be predicted. No clear correlations could be established between the exothermic or endothermic nature of the calorimetric response and the rehydration ability of the powders studied. Dissolution enthalpy cannot thus be considered an absolute parameter that could be used to classify one dairy powder among others, as ultrasound measurement can do. On the contrary, it is experimentally shown that dissolution enthalpy is very sensitive both to the composition and the physical state of the powder. Consequently, dissolution enthalpy value can be considered as a marker representative of the manufacturing process and storage conditions. Evidence is made that following dissolution enthalpy over time could be a way to detect changes in powders due to ageing
Acta Crystallographica Section C Structural Chemistry, 2021
The crystal structure of the stable form of vitamin B2 or riboflavin (C17H20N4O6) was solved usin... more The crystal structure of the stable form of vitamin B2 or riboflavin (C17H20N4O6) was solved using high-resolution powder X-ray diffraction (PXRD). The high-resolution PXRD pattern of riboflavin was recorded at room temperature at the European Synchrotron Radiation Facility (Grenoble, France). The starting structural model was generated using a Monte Carlo simulated annealing method. The final structure was obtained through Rietveld refinement. The positions of the H atoms belonging to hydroxy groups were estimated from computational energy minimizations. The symmetry is orthorhombic with the space group P212121 and the following lattice parameters: a = 20.01308, b = 15.07337 and c = 5.31565 Å.
Pour un large domaine de concentrations, les cristaux mixtes a base de cyanoadamantane et de chlo... more Pour un large domaine de concentrations, les cristaux mixtes a base de cyanoadamantane et de chloroadamantane presentent une transition de phase (ordre desordre) du premier ordre. De plus, par trempe rapide de la phase desordonnee, on obtient un verre d'orientation, analogue sur reseau d'un verre conventionnel. Les dynamiques moleculaires extraordinairement lentes de ce cristal ont permis une investigation en temps reel (diffraction x conventionnelle et synchrotron) de tout le domaine de non equilibre associe a la transition. Pour la premiere fois dans un systeme non diffusif la limite intrinseque entre metastabilite et instabilite (pseudo spinodale) a pu etre localisee et son approche caracterisee. Un lien a ete etabli entre cette limite et la transition vitreuse ou se produit une rupture d'ergodicite. La deuxieme partie du memoire consiste en une simulation numerique (methode de Monte Carlo) d'un modele (gaz sur reseau bidimensionnel) prenant en compte certains car...
International Journal of Pharmaceutics, 2020
In this paper, we present a kinetic investigation of the polymorphic transformation → of sorbit... more In this paper, we present a kinetic investigation of the polymorphic transformation → of sorbitol under milling in the objective to identify the microscopic mechanisms that govern this type of solidstate transformation. The milling was performed with a high energy planetary mill and the milled material was analysed by DSC, PXRD and Raman spectrometry. The transformation kinetics was found to be sigmoidal with a noticeable incubation time. Moreover, this incubation time was shown to shorten rapidly when seeding the initial form with the final form . The origin of the incubation period and its evolution upon seeding are puzzling as polymorphic transformations induced by milling are not expected to occur through a nucleation and growth process. To explain these puzzling kinetic features, we propose a two-step transformation mechanism involving local amorphisations due to the mechanical impacts, immediately followed by rapid recrystallizations of the amorphized fractions. The key point of the mechanism is that recrystallizations are oriented towards the forms or depending on the crystalline form of neighbouring crystallites. This mechanism has been validated by numerical simulations which were able to reproduce all the experimental kinetic features of the polymorphic transformation (kinetic law and effects of seeding) upon milling.
Acta Crystallographica Section A Foundations and Advances, 2019
European Journal of Pharmaceutics and Biopharmaceutics, 2020
A new method for determining solubility lines of drugs in polymers, based on low-frequency Raman ... more A new method for determining solubility lines of drugs in polymers, based on low-frequency Raman spectroscopy measurements, is described and the results obtained by this method are compared with those obtained using a more classical method based on differential scanning calorimetry investigations. This method was applied to the paracetamol / PVP system using molecular and crystalline dispersions (MCD) rather than usual physical mixtures to reach faster the equilibrium saturated states and make the determination of the solubility line more rapid.
Journal of Applied Polymer Science, 2019
Poly (lactic-co-glycolic acid) (PLGA)-based microparticles can be successfully used to control th... more Poly (lactic-co-glycolic acid) (PLGA)-based microparticles can be successfully used to control the release rate of a drug and optimize the therapeutic efficacy of a medical treatment. However, the underlying drug release mechanisms can be complex and are often not fully understood. This renders system optimization cumbersome. In this study, differently sized caffeine-loaded PLGA microparticles were prepared and the swelling and drug release behaviors of single microparticles were monitored upon exposure to phosphate buffer pH 7.4. Ensembles of microparticles were characterized by X-ray diffraction, DSC, SEM, GPC and optical microscopy. The observed tri-phasic drug release patterns could be explained as follows: The initial burst release can be attributed to the dissolution of tiny drug crystals with direct surface access. The subsequent 2 nd drug release phase (with an about constant release rate) could be attributed to the release of drug crystals in regions, which undergo local swelling. The 3 rd release phase (again rapid, leading to complete drug exhaust) could be explained by substantial polymer swelling throughout the systems: Once a critical polymer molecular weight is reached, the PLGA chains are sufficiently hydrophilic, insufficiently entangled and the osmotic pressure created by water soluble degradation products attracts high amounts of water into the system.
Molecular Pharmaceutics, 2019
The influence of the amorphisation technique on the physico-chemical properties of amorphous lact... more The influence of the amorphisation technique on the physico-chemical properties of amorphous lactulose has been investigated. Four different amorphisation techniques have been used: quenching of the melt, milling, spray-drying and freeze-drying, and amorphous samples have been analysed by DSC, NMR, and powder X-ray diffraction. Special attention has been paid to the tautomeric composition and to the glass transition of amorphised materials. It has been found that the tautomeric composition of the starting physical state (crystal, liquid or solution) is preserved during the amorphisation process and has a strong repercussion on the glass transition of the material. The correlation between these two properties as well as the plasticizing effect of the different tautomers have been clarified by molecular dynamic simulations.
Journal of Drug Delivery Science and Technology, 2019
Different types of hot melt extrudates were prepared based on a variety of blends of ethylcellulo... more Different types of hot melt extrudates were prepared based on a variety of blends of ethylcellulose with a 2 nd polysaccharide, namely hydroxypropyl methylcellulose (HPMC), pectin, maize starch, inulin, maltodextrin, guar gum, and chitosan. In selected cases, the
Journal of Drug Delivery Science and Technology, 2016
Je tiens à remercier tout d'abord Pr. Juergen Siepmann, directeur du laboratoire de Pharmacotechn... more Je tiens à remercier tout d'abord Pr. Juergen Siepmann, directeur du laboratoire de Pharmacotechnie industrielle INSERM U1008, qui m'a proposé et financé ce sujet de thèse, et, tout au long de son élaboration, m'a prodigué avis critiques et réorientations précieuses. Enfin, il m'a offert de très nombreuses opportunités de participation aux congrès et de collaboration avec d'autres scientifiques autour de l'extrusion, ainsi que la possibilité de réviser des articles en vue de leur publication. Mon directeur de thèse, Dr. Youness Karrout qui m'a encadré et prodigué avis critiques constructifs mais aussi laissé travailler avec une grande autonomie. Il m'a permis de m'exercer aux présentations en anglais, a mis en oeuvre une démarche de collaboration avec Lille 1, et m'a attribué des stagiaires. Dr. Florence Siepmann m'a fourni une aide administrative efficace, et de nombreuses idées et astuces scientifiques. Mes deux rapporteurs, Pr. Thomas De Beer et Dr. Mohamed Skiba ainsi Pr. Aurélie Malzert-Fréon qui complète ce jury, ont accepté de prendre le temps nécessaire pour examiner ma thèse. Les membres de mon comité de suivi de thèse, Dr. Christophe Carnoy et Pr. Alain Hédoux, ont fait preuve à mon égard d'une grande disponibilité et d'une gentillesse non moins grande, et m'ont donné des conseils et des encouragements dont j'espère avoir su tirer profit. Je n'oublie pas les personnes qui ont initié cette aventure : mes professeures d'université à Châtenay-Malabry, Pr. Véronique Rosilio, Pr. Florence Agnely et Pr. Amélie Bochot pour m'avoir tant appris sur la galénique ainsi que les directeurs rencontrés chez Gattefossé, Dr. Yvonne Rosiaux et Dr. Vincent Jannin qui m'ont encouragée dans ce projet. iii D'autres personnes encore m'ont aidée dans mon travail : l'équipe de Lille 1, Dr. Florence Danède, Dr. François Willart, Laurent Paccou et Pr. Alain Hédoux pour leur collaboration sur les analyses physiques ainsi que l'équipe du GRB, Claudia Flores, Mickael Maton et Dr. Nicolas Blanchemain pour le prêt et l'aide apportée avec l'USP III. Anna Krupa et Mark Eddleston m'auront permis de m'investir dans de nouveaux projets pour quelques mois. Dr. Susanne Muschert et Dr. Mounira Hamoudi-Benyelles m'ont apporté leur aide au laboratoire. La continuité de mon travail a été facilitée par Alexandra Machado et Monique Bonnier pour les commandes, et Hugues Florin pour les réparations de machine quand cela dépassait mes compétences. Un merci plus spécifique à : Emilie et Carine qui m'ont transmis le relais pour le HME, mes deux camarades de promo, Julie et Esther, qui m'auront accompagnée pendant ces trois années, et tous les doctorants et stagiaires que j'aurai croisés plus ou moins longtemps… Lisa,
International Journal of Pharmaceutics, 2019
The polymorphism of Sulindac was investigated by Raman investigations, mainly in the lowwavenumbe... more The polymorphism of Sulindac was investigated by Raman investigations, mainly in the lowwavenumber region in order to analyze the influence of the amorphization method on recrystallization and crystalline form stability. By devitrification of the quenched liquid, it was found that the undercooled liquid crystallizes into Form I, and a polymorphic transformation by cooling Form I toward Form IV, was clearly revealed. The lowwavenumber spectra of polymorphic forms are direct fingerprints of crystals, indicating a degree of disorder of Form IV intermediate between those of the ordered Form II (commercial form) and the relatively disordered Form I. This study has shown the enantiotropic relationship between Forms I and IV and that both the temperature of crystallization and the physical stability of Form I prepared is dependent on the technique used for preparing amorphous sulindac.
Crystal Growth & Design, 2017
We have investigated the solid-state transformation of anhydrous β-D-mannitol upon milling using ... more We have investigated the solid-state transformation of anhydrous β-D-mannitol upon milling using synchrotron X-ray powder diffraction. The 1720 diffraction patterns, collected in real time during the operation of the mill (6h), have been analyzed by sequential Rietveld refinements. From this analysis we confirm that a polymorphic conversion has occurred from the form β toward the form α. Moreover, the quantification and the microstructural analysis of both polymorphs have allowed obtaining new results: (i) the kinetic of the transformation is characterized by a sigmoidal shape (ii) little microstructural evolution occurs during the solidstate transformation, (iii) no intermediate amorphous phase, preceding the transformation toward the metastable crystalline α phase, can be detected. A comparison in depth of the two crystal structures is given and two models are proposed in order to explain this direct conversion β → α.
Journal of Pharmaceutical Sciences, 2019
This paper shows how milling can be used to explore the phase diagram of pharmaceuticals. This pr... more This paper shows how milling can be used to explore the phase diagram of pharmaceuticals. This process has been applied to sulindac. A short milling has been found to trigger a polymorphic transformation between form II and form I upon heating which is not seen in the non-milled material. This possibility was clearly demonstrated to result from crystalline micro strains induced by the mechanical shocks. A long milling has been found to induce a total amorphization of the material. Moreover, the amorphous fraction produced during milling appears to have a complex recrystallization upon heating which depends on the milling time. The investigations have been mainly performed by differential scanning calorimetry and powder X-ray diffraction.
International Journal of Pharmaceutics, 2016
Dexamethasone-loaded, poly(lactic-co-glycolic acid) (PLGA) microparticles were prepared using an ... more Dexamethasone-loaded, poly(lactic-co-glycolic acid) (PLGA) microparticles were prepared using an oil-in-water solvent extraction/evaporation method. The drug loading was varied from 2.4 to 61.9 %, keeping the mean particle size in the range of 52-61 µm. In vitro drug release was characterized by up to 3 phases: (1) an (optional) initial burst release, (2) a phase with an about constant drug release rate, and (3) a final, again rapid, drug release phase. The importance and durations of these phases strongly depended on the initial drug loading. To better understand the underlying mass transport mechanisms, the microparticles were thoroughly characterized before and after exposure to the release medium. The initial burst release seems to be mainly due to the dissolution of drug particles with direct access to the microparticles' surface. The extent of the burst was negligible at low drug loadings, whereas it exceeded 60 % at high drug loadings. The second release phase seems to be controlled by limited drug solubility effects and drug diffusion through the polymeric systems. The third drug release phase is likely to be a consequence of substantial microparticle swelling, leading to a considerable increase in the systems' water content and, thus, fundamentally increased drug mobility.
Journal of Pharmaceutical Sciences, 2017
In this paper, solid-state amorphization induced by mechanical milling is shown to be a useful to... more In this paper, solid-state amorphization induced by mechanical milling is shown to be a useful tool to explore the polymorphism of drugs and their mechanism of devitrification. We show in particular how the recrystallization of amorphous chlorhexidine dihydrochloride obtained by milling reveals a complex polymorphism that involves several polymorphic forms. Two new crystalline forms are identified, one of them appearing as a highly disordered precursor state which however clearly differs from the amorphous one. Several interpretations are here proposed to describe the puzzling nature of this phase. In addition, the possibility to amorphize chlorhexidine dihydrochloride by milling allowed to determine the main physical characters of the amorphous state which cannot be obtained through the usual thermal quench of the liquid because of a strong chemical degradation occurring on melting.
Crystal Growth & Design, 2016
We have investigated the amorphization of β-trehalose by high energy milling using in situ and ex... more We have investigated the amorphization of β-trehalose by high energy milling using in situ and ex situ synchrotron powder diffraction and PDF analysis. From this analysis we show that amorphization takes place through a two-phase process involving an amorphous and a long-range ordered phase. The proportion and coherent domain size of the latter rapidly decrease with milling time until the whole sample appears amorphized. The PDF describing the local structure of the amorphous phase after two hours of milling is very close to that of a sample quenched from the liquid, and seems to continue to evolve for longer milling times. Their differences with the PDF expected for a rigid THL molecule confirm the existence of a conformational disorder of the torsion angles from the glycosidic linkage between the two cycles forming the molecule.
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Papers by Jean-François WILLART