Yes / The creation of salts is a frequently used approach for the modification of physicochemical properties of an active pharmaceutical ingredient. Despite the frequency of application, there has been little research into the structural-property relationships of the final material and the nature of the counterion present. This work reports on five new salts of sulfathiazole and compares the energetics of the intermolecular interactions with variation in the crystal packing motifs.

No

De nos jours, l'émergence de produits pharmaceutiques dans l'environnement aquatique et terrestre a été une préoccupation majeure. Ils ont été détectés dans les stations d'épuration, les sédiments et les sols ainsi qu'à la surface et dans l'eau potable. Jusqu'à présent, il y a peu d'informations dans la littérature sur le devenir de ces composés lorsqu'ils sont exposés à la lumière solaire dans les différents compartiments environnementaux. Dans le cadre de ce travail, notre objectif est l’étude de comportement des antibiotiques de la famille des Sulfonamides : Sulfaméthoxazole (STZ), Sulfathiazole (STL), Sulfamethazine (STN) et Hydrochlorothiazide (HCD) dans des solutions aqueuses lorsqu'ils sont exposés à la lumière solaire. Nous nous sommes principalement intéressés à l’étude cinétique en évaluant le rendement quantique de dégradation ainsi que l'effet de divers paramètres tels que la concentration en oxygène, le pH et la présence d'ions inorganiques. Nous nous sommes également intéressés à l'élucidation des principaux sous-produits intermédiaires. De nombreuses informations sont disponibles sur la stabilité et le devenir des composés d'origine et beaucoup moins sur leurs produits de transformation. Ces derniers peuvent présenter un niveau de toxicité plus élevé que le substrat précurseur et doivent ainsi être identifiés et analysés. L'élucidation de la structure a été obtenue en utilisant les techniques HPLC / ESI / MS et HPLC / ESI / MS2 en modes négatif et positif et par l'étude complète des différentes voies de fragmentation. Les principaux processus photochimiques impliqués sont : i) la scission du pont par photohydrolyse, ii) l'hydroxylation sélective de la partie aromatique iii) le processus de désulfonation et iiii) dans le cas de HCD une réaction de déchloration. Un mécanisme photochimique a été proposé sur la base des études cinétiques et analytiques. / Nowaday the emergence of pharmaceuticals in the aquatic and terrestrial environment have been a major concern. They have been detected in sewage-treatment plants, sediments, and soils as well as at surface and drinking water. So far, there is limited information in the literature on the fate of these compounds once they are exposed to solar light in the various environmental compartments. In the present work we have been interested in studying the behavior of antibiotics from Sulfonamide family: Sulfamethoxazole (STZ), Sulfathiazole (STL), Sulfamethazine (STN) and Hydrochlorothiazide (HCD) in aqueous solutions upon exposure to simulated solar light. We mainly concentrate our effort on the kinetic studies by evaluating the degradation quantum yield as well as the effect of various parameters such as oxygen concentration, pH and the presence of inorganic ions. The main effect was observed by molecular oxygen parameter. We also make an important effort in the elucidation of the main intermediate and stable by-products. A lot of information is available on the stability and fate of parent compounds and not so many on their transformation products. These may present a toxicity level higher than the precursor substrate and should be identified and analysed. The chemical structure elucidation was obtained by using the HPLC/ESI/MS and HPLC/ESI/MS2 techniques in negative as well as positive modes and through the complete study of the various fragmentation pathways. The main involved photochemical processes were identified as i) the scission of the bridge through a photohydrolysis process, ii) selective hydroxylation of the aromatic moiety iii) Desulfonation process and iiii) in the case of HCD to dechloration reaction. A mechanism was then proposed in the light of the kinetics and analytical studies.

Ce travail de thèse de doctorat a eu pour objectif d’étudier la cristallisation d’un principe actif pharmaceutique, le sulfathiazole, par procédé Supercritique Anti-Solvant. Nous nous sommes plus particulièrement intéressés à l’influence des conditions opératoires sur les caractéristiques des cristaux générés en termes de taille, nature polymorphique et faciès. Lors d’une campagne expérimentale de cristallisation, nous avons fait varier la température (313 K et 328 K), la pression (10 et 20 MPa), le rapport molaire solvant/CO2 (2,5 à 15%) et la concentration massique de la solution organique (0,5 à 1,8%). La durée de l’étape de cristallisation a été aussi variée de 4, 5 et 8 h. Nous avons également étudié au préalable les équilibres de phases et mesuré les solubilités du principe actif dans la phase fluide afin de connaître l’état de sursaturation dans le milieu de cristallisation pour toutes les conditions étudiées. Les résultats ont montré que dans certaines conditions la forme polymorphique IV (la plus stable à pression ambiante) est obtenue pure alors que dans d’autres conditions elle est obtenue en mélange avec la forme instable I. Nous avons par ailleurs observé une variation des caractéristiques des cristaux en fonction de la durée de l’étape de cristallisation. Dans les conditions correspondant à de faibles sursaturations et à des phénomènes de transfert limités, la forme IV est initialement obtenue alors que la formation de la forme I est ensuite favorisée au cours du temps. Ces résultats démontrent clairement l’importance du contrôle de la durée de l’étape de cristallisation par le procédé SAS. / This Ph.D. work aimed to study the crystallization of an active pharmaceutical ingredient, sulfathiazole, by Supercritical Anti-Solvent process. We have particularly focused on the influence of the operating conditions on the characteristics of the formed crystals in terms of size, polymorphism concerns more than 80% of active pharmaceutical ingredients and the formation of an undesired polymorphic form can have dramatic consequences on the drug bioavailability or on its stability over time. During an experimental crystallization campaign, we varied the temperature (313 K and 328 K), the pressure (10 and 20 MPa), the solvent / CO2 molar ratio (2.5 to 15%) and the mass concentration of the organic solution (0.5 to 1.8%). The duration of the crystallization step was also varied to 4, 5 and 8 hours. We have also studied the phase equilibria before hand and measured the solubilities of the active principle in the fluid phase in order to evaluate the supersaturation level in the crystallization medium for all the studied conditions.The results showed that under certain conditions, the polymorphic form IV (the most stable at ambient pressure) is obtained pure whereas under other conditions, it is obtained in mixture with the unstable form I. We also observed a variation of the crystal characteristics depending on the duration of the crystallization step. For conditions corresponding to low supersaturations and limited transfer phenomena, form IV is initially obtained whereas the formation of form I is favored over time. These results clearly demonstrate the importance of controlling the duration of the SAS crystallization step.

Ce manuscrit présente une étude du procédé Supercritique Anti-Solvant (SAS) en combinant un travail expérimental et une étude de modélisation moléculaire. En comparaison aux méthodes traditionnelles de cristallisation en solution, le procédé SAS permet une baisse significative des quantités de solvants utilisées, un meilleur contrôle des caractéristiques des poudres générées ainsi qu’une plus grande sélectivité polymorphique. De nombreuses études expérimentales ou de modélisation numérique ont permis une meilleure compréhension de ce procédé, mais certains aspects, liés aux mécanismes de cristallisation sous pression, demeurent moins discutés. Par une investigation de ces mécanismes, l’objectif de ce travail a été de développer et de valider des méthodes permettant un meilleur contrôle du faciès des poudres générées et de la forme du polymorphe. De ces caractéristiques dépendent certaines propriétés des cristaux, telles que leur cinétique de dissolution ou encore leur stabilité physique et chimique, particulièrement importante pour le domaine pharmaceutique / This manuscript presents a study of the Supercritical Anti-Solvent (SAS) process by combining an experimental work and a molecular modeling study. Compared with conventional crystallization methods in liquid solutions, the SAS process allows a significant decrease in the amounts of solvents used, a better control of generated powder characteristics as well as a greater polymorphic selectivity. Many experimental studies or numerical modeling have allowed a better understanding of this process, but some aspects, related to crystallization mechanisms under pressure, remain less discussed. Through an investigation of these mechanisms, the objective of this work was to develop and validate methods allowing a better control of the crystal habit and of the polymorphic form of generated powders. Certain crystal properties depend on these characteristics, such as their dissolution kinetics or their physical and chemical stability, which are particularly important in the pharmaceutical field

Presented diploma thesis deals with drug encapsulation of Sulfathiazole (STA) in thermosensitive hydrogel composed of amphiphilic fibrous molecules of copolymer poly(D,L-lactide-co-glycolide)-block-poly(ethylene glycol)-block-poly(D,L-lactide-co-glycolide) (PLGA-PEG-PLGA). In the experimental part, the structure of the micelles which is dependent on the concentration of the default copolymer, was thoroughly described. The method of dynamic light scattering (DLS) was used to dimensionally characterize the micellar size in aqueous solution. At the same time, the Cryo-Transmission Electron Microscopy (Cryo-TEM) imaging technique confirmed the transition from spherical micelles to fibrous branched structures with a number of topological interactions. The change in viscoelastic properties of micellar hydrogel after addition of STA was studied by rheological analysis. The studied triblock copolymer appears to be a suitable tissue engineering material as a carrier in applications for targeted drug delivery and tissue regeneration.

The process of milling drugs to obtain samples with a desirable particle size range has been widely used in the pharmaceutical industry, especially for the production of drugs for inhalation. However by subjecting materials to milling techniques surfaces may become thermodynamically activated which may in turn lead to formation of amorphous material. Polymorphic conversions have also been noted after milling of certain materials. Salt and cocrystal formation is a good way of enhancing the properties of an API but little or no work has been published which investigates the stability of these entities when subjected to milling. Different milling techniques (ball and jet) and temperatures (ambient and cryogenic) were used to investigate the milling behaviour of polymorphs, salts and cocrystals. All materials were analysed by XRPD and DSC to investigate any physical changes, i.e. changes in melting point and by inverse gas chromatography (IGC) to investigate whether any changes in the surface energetics occurred as a result of milling. Another aim of this thesis was to see if it was possible to predict the milling behaviour of polymorphs by calculating the attachment energies of the different crystal facets using Materials Studio 4.0. These results were compared to the IGC data to see if the predicted surface changes had occurred. The data collected in this study showed that different milling techniques can have a different effect on the same material. For example ball milling at ambient temperature and jet micronisation of the SFZ tosylate salt caused a notable increase in the melting point of the material whereas ball milling at cryogenic temperatures did not cause this to happen. The IGC data collected for this form also showed a contrast between cryomilling and the other two techniques. The study also showed that the formation of salts and cocrystals does not necessarily offer any increased stability in terms of physical properties or surface energetics. Changes in melting point were observed for the SFZ tosylate salt and the IMC:Benzamide cocrystal. Changes in the specific surface energies were also observed indicating that the nature of the surfaces was also changing. The materials which appeared to be affected the least were the two stable polymorphs, gamma IMC and SFZ III. The computational approach used has many limitations. The software does not allow for conversion to the amorphous form or polymorphic conversions. Such conversions were seen to occur, particularly for the metastable polymorphs used, meaning that this computational approach may only be suitable for stable polymorphs.

The process of milling drugs to obtain samples with a desirable particle size range has been widely used in the pharmaceutical industry, especially for the production of drugs for inhalation. However by subjecting materials to milling techniques surfaces may become thermodynamically activated which may in turn lead to formation of amorphous material. Polymorphic conversions have also been noted after milling of certain materials. Salt and cocrystal formation is a good way of enhancing the properties of an API but little or no work has been published which investigates the stability of these entities when subjected to milling. Different milling techniques (ball and jet) and temperatures (ambient and cryogenic) were used to investigate the milling behaviour of polymorphs, salts and cocrystals. All materials were analysed by XRPD and DSC to investigate any physical changes, i.e. changes in melting point and by inverse gas chromatography (IGC) to investigate whether any changes in the surface energetics occurred as a result of milling. Another aim of this thesis was to see if it was possible to predict the milling behaviour of polymorphs by calculating the attachment energies of the different crystal facets using Materials Studio 4.0. These results were compared to the IGC data to see if the predicted surface changes had occurred. The data collected in this study showed that different milling techniques can have a different effect on the same material. For example ball milling at ambient temperature and jet micronisation of the SFZ tosylate salt caused a notable increase in the melting point of the material whereas ball milling at cryogenic temperatures did not cause this to happen. The IGC data collected for this form also showed a contrast between cryomilling and the other two techniques. The study also showed that the formation of salts and cocrystals does not necessarily offer any increased stability in terms of physical properties or surface energetics. Changes in melting point were observed for the SFZ tosylate salt and the IMC:Benzamide cocrystal. Changes in the specific surface energies were also observed indicating that the nature of the surfaces was also changing. The materials which appeared to be affected the least were the two stable polymorphs, gamma IMC and SFZ III. The computational approach used has many limitations. The software does not allow for conversion to the amorphous form or polymorphic conversions. Such conversions were seen to occur, particularly for the metastable polymorphs used, meaning that this computational approach may only be suitable for stable polymorphs.