Characterisation of the physico-chemical and solid-state behaviour of drugs in HFA-134 and 227

Most drugs have a considerably low solubility in the environmentally friendly hydrofluoroalkane propellants (HFAs) currently used in pressurized metered dose inhalers (pMDIs). As a consequence, instability can occur from crystal growth and Ostwald ripening of the system altering the therapeutic performance of the pMDI. Understanding and being able to predict the behaviour of such drugs in the propellant will help in selecting the correct co-solvents and/or surfactants to increase the stability of such formulations. When anhydrous beclomethasone dipropionate (BDP) is suspended in tricholoromonofluoromethane (CFC-11) rapid crystal growth occurs, leading to the formation of a clathrate. Since chlorofluorocarbon (CFCs) propellants have been replaced by HFAs, many questions arose concerning the ability of BDP to form clathrates in the HFA and any stability issues that arise from such reformulation. Clathrates are crystalline compounds consisting of a lattice of one type of molecule that hosts a second type of “guest” molecule within its structure. Since the solid state chemistry can significantly alter the physical interactions within a suspension formulation, it is crucial to determine the most stable crystalline form in the presence of the propellant. Successful formation of BDP CFC-11 clathrates were observed in this work as well as positive outcomes in terms of reduction in the surface energy and the force of adhesion within a model pMDI formulation (even after processing i.e. size reduction). Following this, HFA-134a and 227-ae were selected to determine any potential clathrate formation and to monitor their stability within a pMDI formulation. The focus of this project was to determine the stability of BDP and budesonide in HFA propellants, as well as the appropriateness of each formulation for pMDI use. This project considered the potential use of complementary surface and solid-state analytical tools to provide fundamental understanding of clathrate formation and their physicochemical characteristics. A special interest in understanding the fundamentals behind the process of Ostwald ripening, a process that affects drug particle size and their related stability and hence ultimately dose consistency was also considered. Atomic force microscopy (AFM) was used in order to determine its applicability in studying Ostwald ripening and surface activity of the different APIs in model propellant. Furthermore, the effects of a range of parameters that included storage time, co-solvents and surfactants on Ostwald ripening were taken into account. The work presented in this thesis has demonstrated that the formation of a propellant clathrate is favourable for APIs that to improve formulation stability through a reduction in particle surface energy. However, isolation and full characterisation of such HFA clathrates remains challenging due to their decreased stability when removed from the high pressure media of the pMDI device. This thesis shows that a combination of co-solvent and surfactant provides an effective reduction in instabilities due to Ostwald ripening of the pMDI formulation and a better control of particle size of the APIs within the formulation. This work provides a platform for future formulation development for pMDIs

Characterisation of the physico-chemical and solid-state behaviour of drugs in HFA-134 and 227

Most drugs have a considerably low solubility in the environmentally friendly hydrofluoroalkane propellants (HFAs) currently used in pressurized metered dose inhalers (pMDIs). As a consequence, instability can occur from crystal growth and Ostwald ripening of the system altering the therapeutic performance of the pMDI. Understanding and being able to predict the behaviour of such drugs in the propellant will help in selecting the correct co-solvents and/or surfactants to increase the stability of such formulations. When anhydrous beclomethasone dipropionate (BDP) is suspended in tricholoromonofluoromethane (CFC-11) rapid crystal growth occurs, leading to the formation of a clathrate. Since chlorofluorocarbon (CFCs) propellants have been replaced by HFAs, many questions arose concerning the ability of BDP to form clathrates in the HFA and any stability issues that arise from such reformulation. Clathrates are crystalline compounds consisting of a lattice of one type of molecule that hosts a second type of “guest” molecule within its structure. Since the solid state chemistry can significantly alter the physical interactions within a suspension formulation, it is crucial to determine the most stable crystalline form in the presence of the propellant. Successful formation of BDP CFC-11 clathrates were observed in this work as well as positive outcomes in terms of reduction in the surface energy and the force of adhesion within a model pMDI formulation (even after processing i.e. size reduction). Following this, HFA-134a and 227-ae were selected to determine any potential clathrate formation and to monitor their stability within a pMDI formulation. The focus of this project was to determine the stability of BDP and budesonide in HFA propellants, as well as the appropriateness of each formulation for pMDI use. This project considered the potential use of complementary surface and solid-state analytical tools to provide fundamental understanding of clathrate formation and their physicochemical characteristics. A special interest in understanding the fundamentals behind the process of Ostwald ripening, a process that affects drug particle size and their related stability and hence ultimately dose consistency was also considered. Atomic force microscopy (AFM) was used in order to determine its applicability in studying Ostwald ripening and surface activity of the different APIs in model propellant. Furthermore, the effects of a range of parameters that included storage time, co-solvents and surfactants on Ostwald ripening were taken into account. The work presented in this thesis has demonstrated that the formation of a propellant clathrate is favourable for APIs that to improve formulation stability through a reduction in particle surface energy. However, isolation and full characterisation of such HFA clathrates remains challenging due to their decreased stability when removed from the high pressure media of the pMDI device. This thesis shows that a combination of co-solvent and surfactant provides an effective reduction in instabilities due to Ostwald ripening of the pMDI formulation and a better control of particle size of the APIs within the formulation. This work provides a platform for future formulation development for pMDIs

Suivi de cibles radar dans l'espace temps-fréquence par filtrage particulaire appliqué à la fonction d'inter-ambiguïté

National audienceLaide à la conduite est une application émergente du radar. Parmi les questions technologiques qui y sont associées, la détection et le suivi des obstacles potentiels (les voitures, les piétons, les objets statiques . . . ) sont dun intérêt majeur. Dans ce contexte, nous proposons uneméthode originale de suivi, basée sur le filtrage particulaire où lobservation du modèle détat est constituée par la fonction dinter-ambiguïté dusignal rétrodiffusé. Les simulations réalisées pour différentes formes dondes montrent lamélioration apportée par rapport à lapproche classique, dans laquelle une étape de détection précède le suivi

ANSER, Layachi .- Sociologie de Démocratie et de la rébellion en Algérie

Présenter une œuvre sociologique comporte toujours le risque d’édulcorer, voire de travestir son apport à la connaissance sociale objective, par le fait même de lui superposer un nouveau discours dont les conditions de production prétendent à masquer son historicité propre, qui se détache et prétend se libérer de cette inhérence à l’œuvre initiale. Aussi existe-t-il une certaine prétention à vouloir relire un discours qui s’est approprié un objet de connaissance en vue de révéler son sens cac..

Characterisation of the physico-chemical and solid-state behaviour of drugs in HFA-134 and 227

Most drugs have a considerably low solubility in the environmentally friendly hydrofluoroalkane propellants (HFAs) currently used in pressurized metered dose inhalers (pMDIs). As a consequence, instability can occur from crystal growth and Ostwald ripening of the system altering the therapeutic performance of the pMDI. Understanding and being able to predict the behaviour of such drugs in the propellant will help in selecting the correct co-solvents and/or surfactants to increase the stability of such formulations. When anhydrous beclomethasone dipropionate (BDP) is suspended in tricholoromonofluoromethane (CFC-11) rapid crystal growth occurs, leading to the formation of a clathrate. Since chlorofluorocarbon (CFCs) propellants have been replaced by HFAs, many questions arose concerning the ability of BDP to form clathrates in the HFA and any stability issues that arise from such reformulation. Clathrates are crystalline compounds consisting of a lattice of one type of molecule that hosts a second type of “guest” molecule within its structure. Since the solid state chemistry can significantly alter the physical interactions within a suspension formulation, it is crucial to determine the most stable crystalline form in the presence of the propellant. Successful formation of BDP CFC-11 clathrates were observed in this work as well as positive outcomes in terms of reduction in the surface energy and the force of adhesion within a model pMDI formulation (even after processing i.e. size reduction). Following this, HFA-134a and 227-ae were selected to determine any potential clathrate formation and to monitor their stability within a pMDI formulation. The focus of this project was to determine the stability of BDP and budesonide in HFA propellants, as well as the appropriateness of each formulation for pMDI use. This project considered the potential use of complementary surface and solid-state analytical tools to provide fundamental understanding of clathrate formation and their physicochemical characteristics. A special interest in understanding the fundamentals behind the process of Ostwald ripening, a process that affects drug particle size and their related stability and hence ultimately dose consistency was also considered. Atomic force microscopy (AFM) was used in order to determine its applicability in studying Ostwald ripening and surface activity of the different APIs in model propellant. Furthermore, the effects of a range of parameters that included storage time, co-solvents and surfactants on Ostwald ripening were taken into account. The work presented in this thesis has demonstrated that the formation of a propellant clathrate is favourable for APIs that to improve formulation stability through a reduction in particle surface energy. However, isolation and full characterisation of such HFA clathrates remains challenging due to their decreased stability when removed from the high pressure media of the pMDI device. This thesis shows that a combination of co-solvent and surfactant provides an effective reduction in instabilities due to Ostwald ripening of the pMDI formulation and a better control of particle size of the APIs within the formulation. This work provides a platform for future formulation development for pMDIs.EThOS - Electronic Theses Online ServiceGBUnited Kingdo