Insights from Dielectric Spectroscopy on the physical states reached by milling of an Active Pharmaceutical Ingredient

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Milling as a tool to play with physical state of a pharmaceutical molecule: input from Dielectric Relaxation Spectroscopy

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Disorders in Pharmaceutical Polymers

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Analyse des relaxations diélectriques dans les polyméthacrylates de n-alkyle par spesctroscopies dynamique et thermo-stimulée

TOULOUSE3-BU Sciences (315552104) / SudocSudocFranceF

Disorders in Pharmaceutical Polymers

This chapter discusses the performance and applications of pharmaceutical polymers in relation to their structure and degree of disorder. It first gives an overview of the main characteristics of polymers in terms of their architecture, physical states, and mobility. The chapter highlights the different origins and types of disorders that can be found in polymers, namely structural disorders and dynamic disorders. Pharmaceutical polymers are widely used in solid dosage forms such as drug/excipient amorphous solid dispersions, which are mixtures of polymers and low molecular weight (MW) drugs. The chapter particularly focuses on the influence of drug incorporation on the polymer mobility and the issues of the limits of polymer-drug miscibility and solubility. Finally, it discusses the relationship between the disorder and the physical properties and behavior of pharmaceutical polymers when used in solid dosage forms through a few illustrative examples involving the most widely used polymers

Vitrification à l'état solide du glucose et maîtrise de la mutarotation

Ce mémoire est consacré à la vitrification à l état solide du glucose par broyage mécanique et à la maîtrise de sa mutarotation. L ensemble de ces résultats a été obtenu par DRX, DSC, ATG et Raman. Nos résultats montrent que les anomères a et ß du glucose cristallin s amorphisent sous broyage à haute énergie. Cette voie d amorphisation conduit à des états amorphes anomériquement purs extrêmement originaux qui ne peuvent être obtenus par les procédés classiques d amorphisation (trempe du liquide ). Nous avons exploité cette opportunité unique pour : 1. Montrer que l amorphisation par broyage mécanique s opère directement à l état solide au travers de mécanismes qui diffèrent fondamentalement de ceux impliqués lors de la trempe thermique classique du liquide. 2. Former de véritables alliages moléculaires amorphes homogènes a-glucose / ß-glucose en toute proportion par co-broyage. La possibilité de contrôler la concentration anomérique a permis d étudier, pour la première fois, le diagramme de phases d un mélange binaire anomérique. 3. Etudier de manière originale les cinétiques de mutarotation directement à l état solide. Cette étude a révélé l existence d un couplage inattendu entre le mécanisme de mutarotation (processus local) et les relaxations structurales lentes au voisinage de Tg (processus coopératif). De plus, l évolution microstructurale du glucose sous broyage montre que l amorphisation résulte de deux mécanismes : une amorphisation en surface des cristallites induite par les chocs violents lors du broyage et une amorphisation spontanée des cristallites lorsque leur taille devient inférieure à une taille critiqueThis thesis deals with the solid state vitrification of glucose by mechanical milling and the control of its mutarotation. All the results have been obtained by XRD, DSC, TGA and Raman experiments. Our results show that crystalline a and ß glucose can be amorphized upon high energy ball milling. This route to the glassy state leads to remarkable anomerically pure amorphous states which cannot be obtained by the usual amorphisation processes (thermal quench ). We use this unique opportunity: 1. To show that the amorphisation upon milling occurs directly in the solid state through mechanisms which are fundamentally different from those implied in the quench of the liquid. 2. To form amorphous molecular alloys a-glucose / ß-glucose by co-milling on the whole concentration range. Furthermore, the control of the anomeric concentration gives the possibility to study, for the first time, the phase diagram of an anomeric binary mixture. 3. To study, from original way, the kinetics of mutarotation directly in the solid state. This study revealed the existence of an unexpected coupling between the mechanism of mutarotation (local process), and, the slow structural relaxation around Tg (cooperative process). Moreover, the microstructural evolution of glucose upon milling shows that amorphisation results from two mechanisms: an amorphisation on the crystallite surface area induced by violent shocks during milling and a spontaneous amorphisation of crystallites when their size becomes smaller than a critical size.LILLE1-Bib. Electronique (590099901) / SudocSudocFranceF

Nouvelles méthodes de détermination des diagrammes de solubilité polymère / principe actif

La dispersion moléculaire d un principe actif (PA) dans un polymère est généralement utilisée pour accroitre à la fois la solubilité et la stabilité physique de sa forme amorphe. Cependant, ce type de formulation demande une parfaite connaissance de la solubilité du PA dans le polymère. Cependant, les méthodes actuelles pour déterminer les courbes de solubilité sont longues et fastidieuses à mettre en oeuvre. Dans cette thèse, nous présentons une méthode originale pour déterminer efficacement la solubilité des PA dans les polymères. L originalité de cette méthode réside dans le fait que les états d équilibre saturés sont ici atteints par démixtion d une solution solide amorphe sursaturée en PA et non par la méthode classique de dissolution du PA cristallin au sein du polymère amorphe. Les états d équilibre saturés sont donc beaucoup plus rapides à atteindre en raison de la mobilité moléculaire accrue résultant de la forte plastification du polymère imposée par les conditions de sursaturation. Nous avons aussi testé la possibilité de prédire les courbes de solubilité par des méthodes numériques ab-initio (par dynamique moléculaire et méthodes quantiques). Les méthodes expérimentales et numériques ont été validées en étudiant des systèmes polymère/PA dont les courbes de solubilité ont déjà été déterminées par des méthodes classiques. Les systèmes étudiés sont : PVPK12/indométacine, PVPK30/griséofulvine et b-cyclodextrine méthylée/griséofulvine. Les techniques d investigations utilisées sont esentiellement l analyse enthalpique différentielle à balayage (DSC) et la diffraction des rayons X sur poudre (DRX).The molecular dispersion of a drug into a polymer is generally used to increase both its solubility and the physical stability of its amorphous form. However, this formulation route requires a perfect knowledge of the solubility of the drug in the polymer. This property is in particular important for selecting appropriate polymers for formulations since it defines the maximal drug loading which prevents recrystallization. However, up to now, the determination of the solubility curve of drug/polymer systems is a long and tedious task. In this thesis we present an original method to determine faster the solubility of drugs into polymers. The originality of the method lies in the fact that the equilibrium saturated state is here reached by demixing of a supersaturated amorphous solid solution and not by the usual dissolution of a crystalline drug into an amorphous polymer. The equilibrium saturated states are thus much faster to reach due to the extra molecular mobility resulting from the strong plasticizing effect associated with the supersaturation conditions. We also test the ability of ab-initio numerical techniques (using molecular dynamics and quantum methods) to predict solubility curves. Both experimental and numerical techniques are validated using drug/polymer systems whose solubility curves have already been determined by conventional methods. The investigated systems are: PVPK12/indomethacin, PVPK30/griseofulvin and methylated b-cyclodextrine/griseofulvin. The investigation techniques are mainly Differential Scanning Calorimetry (DSC) and Powder X-Ray Diffraction (PXRD).LILLE1-Bib. Electronique (590099901) / SudocSudocFranceF

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

International audienceThe 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

Investigation of complex molecular dynamics in multi-component systems

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