The feasibility of hot melt extrusion (HME) was explored for development of amorphous solid dispersion systems. Controlled release formulations were developed using a cellulose based derivative, AffinisolTMHPMC 100cP and 4M grades. BCS class II drugs ibuprofen and posaconazole were selected due to their difference in glass transition temperature and lipophilicity. This study focused on investigation of the impact the material attributes and process parameters on the critical quality attributes in preparation of amorphous solid dispersions using hot melt extrusion. The critical quality attributes were sub divided into three main attributes of material, process and product. Rheology of ibuprofen-Affinisol 100cP from melt phase to extrudate phase was tracked. A partial factorial design was carried out to investigate the critical parameters affecting HME. For optimisation of 40%IBU-Affinisol 100cP blends, a feed rate of 0.6kg/hr, screw speed of 500rpm and screw configuration with two mixing elements were found to be optimum for single phase extrudates. ATR-FTIR spectroscopy was found to be an indirect technique of choice in predicting the maximum ibuprofen drug load within extrudates. Prediction was based on the prepared extrudates without charging them to stability conditions. An alternative strategy of incorporation of di-carboxylic acids to increase the dissolution of posaconazole-Affinisol 4M blends was investigated. Succinic acid and L- malic acid incorporation was found to increase the dissolution of posaconazole. Although, the extrudates crystallised out quicker than the naïve posaconazole-Affinisol 4M, but free posaconazole formed eutectic and co-crystal with succinic and L-malic acid within extrudates. This lead to an increase in dissolution of the extrudates compared to day 0.

<p>Hot-melt adhesives have been commercially available for a long time and they are used in a wide range of applications. The adhesive performance is governed by the adhesive material property as well as the application conditions for each type of substrate. In order to achieve a good bond between the adhesive and the designated substrate, both wetting ability and open time of the adhesive material have to be considered. Three commercial hot-melts were used in this study in order to examine the relationship between the material property and the adhesive performance. The thermal properties of the materials were obtained through Differential Scanning Calorimetry while Dynamic Analysis (DA) described their viscoelastic behaviour, and the hysteresis loop helped to characterize the flow regime from which the application conditions for the adhesive could be chosen. The adhesive performance was evaluated in term of the force required to break the bond between the adhesive and the substrate through a series of standardized pull-off tests. The effect of the time-temperature trade-off on the adhesive performance by varying the application temperature as well as prolonging the available bond-formation time was also examined. In most cases, the adhesive performance improved with extended open time. However, improved adhesive performance was also shown to be the response of shorter Maxwell characteristic time which was evaluated from the DA data. By providing the characteristic time as a linkage, a relationship between the adhesive performance and the material properties could be established. These results also offer a basis for the formulation of adhesives using structure-property parameters derived from DA.</p> / Master of Applied Science (MASc)

The feasibility of the injection moulding (IM) was explored for the development of novel drug delivery systems. Controlled release formulations were developed using a substituted cellulose derivative, hydroxypropyl methyl cellulose acetate succinate (HPMCAS) and a graft co-polymer (Soluplus®). BCS class II drugs ibuprofen and the felodipine were selected based on their physicochemical properties. In the present work, a homogenous dispersion of drugs in the polymer matrices was achieved using Hot Melt Extrusion (HME) and extruded pellets obtained were used for the development of the injection moulded systems. Four systems were developed using the IM consisting of ibuprofen-HPMCAS, ibuprofen-Soluplus®, felodipine-PEO-HPMCAS and felodipine-Soluplus®. The ibuprofen acts as a good plasticiser compared to felodipine therefore, felodipine containing IM systems required a plasticiser (PEO) when processed with HPMCAS. The analysis of extruded pellets and injection moulded systems using modulated DSC (MDSC) and Raman spectroscopy confirmed the formation of an amorphous molecular dispersion (i.e solid solution) in the case of all four systems. The phase separation behaviour and the amorphous stability of the systems was studied at various stress conditions. This revealed the “surface crystallisation” behaviour of the ibuprofen-HPMCAS systems. Temperature-composition phase diagram constructed based on the melting point depression and the Flory-Huggins lattice solution theory provided the explanation for the phase separation and crystallisation behaviour of ibuprofen-HPMCAS systems. The advanced characterisation techniques like DMA, 2D XRD and 3D laser microscopy provided the detailed understanding of crystal habits, phase seperation and surface crystallisation. The significant effect of the stress conditions on the rate of shrinkage was observed where, higher shrinkage tendency of a HPMCAS IM system was observed compared to Soluplus® IM systems. The extruded pellets provided the faster drug release compared to the moulded tablets suggests the effect of particle size as well as the densification during IM on the dissolution rate of the dosage form. The nature of the polymer and processing history were the contributing factors for the dissolution of the dosage forms. / The thesis is hardbound in two volumes. Volume II starts at Chapter 5, page 135.

Yes / The present study demonstrates the application of decision tree algorithms to the co-crystallization process. Fifty four (54) batches of carbamazepine-salicylic acid co-crystals embedded in poly(ethylene oxide) were manufactured via hot melt extrusion and characterized by powder X-ray diffraction, differnetial scanning calorimetry, and near-infrared spectroscopy. This dataset was then applied in WEKA, which is an open-sourced machine learning software to study the effect of processing temperature, screw speed, screw configuration, and poly(ethylene oxide) concentration on the percentage of co-crystal conversion. The decision trees obtained provided statistically meaningful and easy-to-interpret rules, demonstrating the potential to use the method to make rational decisions during the development of co-crystallization processes. / Commonwealth Scholarship Commission in the UK (ZMCS-2018-783) and Engineering and Physical Sciences Research Council (EPSRC EP/J003360/1 and EP/L027011/1)

Yes / We present hot melt extrusion (HME) for the design of floating multiparticulates. Metoprolol succinate was selected as the model drug. Our foremost objective was to optimize the components Eudragit® RS PO, polyethylene oxide (PEO) and hydroxypropyl methylcellulose (HPMC) to balance both buoyancy and controlled release. Gas generated by sodium bicarbonate in acidic medium was trapped in the polymer matrix to enable floating. Eudragit® RS PO and PEO with sodium bicarbonate resulted in multiparticulates which exhibited rapid flotation within 3 minutes but inadequate total floating time (TFT) of 3 hours. Addition of HPMC to the matrix did not affect floating lag time (FLT), moreover TFT increased to more than 12 hours with controlled release of metoprolol succinate. Floating multiparticulates exhibited t50% of 5.24 hours and t90% of 10.12 hours. XRD and DSC analysis revealed crystalline state of drug while FTIR suggested nonexistence of chemical interaction between the drug and the other excipients. The assay, FLT, TFT and the drug release of the multiparticulates were unchanged when stored at 40 °C/75%RH for 3 months confirming stability. We present floating multiparticulates by HME which could be extrapolated to a range of other drugs. Our approach hence presents platform technology for floating multiparticulates.

Process Analytical Technology (PAT) is framed with the objective of the design and development of processes to ensure predefined quality of the product at the end of manufacturing. PAT implementation includes better understanding of process, reduction in production time with use of in-line, at-line and on-line measurements, yield improvement and energy and cost reductions. Hot Melt Extrusion process (HME) used in the present work is proving increasingly popular in industry for its continuous and green processing which is beneficial over traditional batch processing. The present work was focused on applications of Raman spectroscopy as off - line and in - line monitoring techniques as a PAT for production of pharmaceutical solid dispersions and co-crystals. Solid dispersions (SDs) of the anti-convulsant Carbamazepine (CBZ) with two pharmaceutical grade polymers have been produced using HME at a range of drug loadings and their amorphous nature confirmed using a variety of analytical techniques. Off-line and in-line Raman spectroscopy has been shown to be suitable techniques for proving preparation of these SDs. Through calibration curves generated from chemometric analysis in-line Raman spectroscopy was shown to be more accurate than off-line measurements proving the quantification ability of Raman spectroscopy as well as a PAT tool. Pure co-crystals of Ibuprofen-Nicotinamide and Carbamazepine-Nicotinamide have been produced using solvent evaporation and microwave radiation techniques. Raman spectroscopy proved its superiority over off-line analytical techniques such as DSC, FTIR and XRD for co-crystal purity determination adding to its key advantage in its ability to be used as an in-line, non-destructive technique.

Yes / A transflectance near infra red (NIR) spectroscopy approach has been used to simultaneously measure drug and plasticiser content of polymer melts with varying opacity during hot melt extrusion. A high temperature reflectance NIR probe was mounted in the extruder die directly opposed to a highly reflective surface. Carbamazepine (CBZ) was used as a model drug, with polyvinyl pyrollidone-vinyl acetate co-polymer (PVP-VA) as a matrix and polyethylene glycol (PEG) as a plasticiser. The opacity of the molten extrudate varied from transparent at low CBZ loading to opaque at high CBZ loading. Particulate amorphous API and voids formed around these particles were found to cause the opacity. The extrusion process was monitored in real time using transflectance NIR; calibration and validation runs were performed using a wide range of drug and plasticiser loadings. Once calibrated, the technique was used to simultaneously track drug and plasticiser content during applied step changes in feedstock material. Rheological and thermal characterisations were used to help understand the morphology of extruded material. The study has shown that it is possible to use a single NIR spectroscopy technique to monitor opaque and transparent melts during HME, and to simultaneously monitor two distinct components within a formulation.

S’intéressant aux interactions entre la formulation, le procédé et le produit, ce travail original axé sur la fonctionnalisation ignifuge de textiles utilisés dans les transports et le bâtiment porte sur le développement de poudres non feu. La ligne conductrice de cette étude étant de comprendre comment les propriétés ignifuges du textile technique peuvent être influencées par les choix de formulation ou de procédé de mélange. L'identification des besoins, c.-à-d. la réalisation d’un produit fini ignifuge, la conception de mélanges de granulométrie définie qui s’écoulent facilement et qui possèdent une sensibilité à l’inflammation faible, a permis de proposer et d’examiner diverses formulations. En matière de méthodologie ce projet combine l’approche sécurité à l’ingénierie produit. La sélection finale des mélanges sera fonction des résultats de cette analyse technique globale. Le travail expérimental a permis de sélectionner le polymère et l’agent ignifuge à la concentration de 40 % pour l’obtention en mélangeur interne de particules bifonctionnelles répondant aux spécifications fixées. Contrairement aux mélanges à retournement ou haute vitesse, les grains préparés par granulation Hot-Melt ont des liaisons mécaniques renforcées. Ce résultat semble s’expliquer par la bonne affinité, le bon rapport en termes de taille de particules entre les composants et une morphologie favorable à la formation de ce type de structures. Ce mode de fabrication a également permis de lever les deux principaux verrous à savoir préparer une poudre bifonctionnelle à haute teneur en agent ignifuge et réaliser un mélange qui ne se démélange pendant l’étape d’imprégnation du procédé DPreg / This original work deals with the functionalization of textile fire retardant used in transport and the building focused on the development of fire retardant powders while studying the interactions of three criteria: the formulation, process and product. The main line of this study is the understanding and quantification of the flame retardant properties of the textile, which can be influenced by the choice of formulation or mixing process. The identification of needs, i.e. the realization of a finished fire retardant, the design of defined particle size mixtures, which flow easily and possess low sensitivity to inflammation, allowed to propose and consider various formulations. This project methodology is a good example of the combination between two approaches: the product engineering and a safety approach. The final selection of mixtures will be based on the results of a comprehensive technical analysis. The experimental work allows us to select the polymer and the flame retardant at a concentration of 40% in order to obtain in an internal mixer of bifunctional particles meet the specifications set out in this study. Unlike conventional mixtures by inversion or high speed, the grains prepared by Hot-Melt granulation have enhanced mechanical linkages. This result seems to be due to the good affinity and good particle size ratio between the components and a good morphology to the formation of such structures. This manufacturing method also overcomes two obstacles; the preparation of a bifunctional powder with high content of flame retardant and the realization of a mixture which does not demix under the action of the electric field of the DPreg impregnation process

En raison de leur complexité croissante, la solubilité des nouvelles entités chimiques en milieu aqueux est de plus en plus faible. Ainsi, le développement de beaucoup de principes actifs échoue à cause d’une hydrosolubilité insuffisante. De nombreuses technologies existent pour améliorer la solubilité et/ou solubilisation de tels composés. Cette thèse est ciblée sur la formulation de dispersions solides amorphes par extrusion à chaud. En particulier, un principe actif d’intérêt industriel sera formulé en utilisant une extrudeuse bi-vis disponible sur la plateforme Gala®. Cette technologie autorise l’utilisation d’un grand nombre de matrices, ce qui peut nécessiter un grand nombre d’essais expérimentaux. Une attention particulière est donc portée à l’utilisation de méthodes prédictives de la miscibilité entre les composants qui peuvent ainsi permettre une première sélection des matrices. Sur la base de ces résultats, une étude sur le procédé de hot melt extrusion a ensuite été réalisée. / The aqueous solubility of new chemical entities is increasingly weak, due to their complex structure, and many API fail in development due to insufficient solubility. Many technologies exist to enhance the solubility and / or dissolution of such compounds in aqueous media. Among all of these methods, this thesis is focused on the formulation of amorphous solid dispersions by hot melt extrusion. A lot of matrix can be used to formulate with this technology, so few methods to estimate miscibility between API and matrices will also be presented in this thesis. Finally, a study about the hot melt extrusion process will also be presented.

Os sistemas multiparticulados são aqueles nos quais a dose do fármaco está dividida em pequenas unidades funcionais, tendo assim, uma série de vantagens sobre os sistemas monolíticos convencionais. Este trabalho teve por objetivo desenvolver formulações multiparticuladas de uso oral para fármacos anti-hipertensivos que serão utilizados na composição de associações. O material está dividido em seis capítulos, sendo inicialmente apresentada uma revisão da literatura a respeito da caracterização física destas pequenas unidades. Ensaios como análise granulométrica, morfologia, densidade, porosidade, avaliação de resistência mecânica e desintegração são os mais empregados para esta finalidade, possibilitando ao formulador conhecer os fatores de maior impacto relacionados às matérias primas e ao processo de fabricação no comportamento das formulações produzidas. Os demais capítulos seguem com o desenvolvimento dos sistemas multiparticulados, que foram embasados em diferentes delineamentos experimentais, seja pela utilização de planejamento fatorial fracionado ou projeto de mistura. Para o metoprolol, fármaco de alta solubilidade, foram produzidas formulações de liberação controlada, sendo a estratégia dividida em três etapas: (I) Produção de minicomprimidos revestidos, nos quais foram avaliadas diferentes combinações do polímero modulador de liberação; (II) otimização do perfil de liberação do fármaco, com avaliação de misturas das formulações produzidas na primeira etapa; (III) Processo de extrusão a quente, no qual diferentes proporções de fármaco e polímero hidrofóbico foram avaliadas. Para os fármacos hidroclorotiazida e olmesartana medoxomila, ambos de baixa solubilidade, a estratégia adotada foi a incorporação de uma dispersão dos fármacos e agentes solubilizantes em grânulos inertes obtidos por extrusão/revestimento. Adicionalmente, também foram produzidas formulações por extrusão a quente de diferentes proporções destes fármacos em polímero hidrofílico. De acordo com os resultados obtidos, foi possível obter formulações de minicomprimidos e grânulos com perfil de dissolução satisfatório, semelhantes aos apresentados pelos medicamentos adotados como referência. Em relação à extrusão a quente foi possível avaliar a influência do processo e polímeros empregados no perfil de dissolução dos grânulos produzidos. / Multiparticulate systems are dosage forms in which dose is divided into small functional units presenting some advantages over monolithic conventional systems. The objective of this work was developing multiparticulate formulations for oral use containing antihypertensive drugs to be used in association. The thesis is divided into six issues, been first presented a literature review about physical characterization of multiparticulate systems. Granulometric analysis, morphology, density, porosity, mechanical strength and disintegration are the most used physical characterization tests, enabling formulator knowing the major impact factors related to raw materials and manufacturing process in the performance of the produced formulations. The other issues present the development of the multiparticulate systems based on different statistical experimental design, as fractional factorial design or mixture project. For metoprolol, a highly soluble drug, controlled release formulations were obtained, and the strategy was divided into three steps: (I) coated minitablets production, where different combinations of the controlled release polymer were analyzed; (II) drug release profile optimization, evaluating formulations mixtures produced in the first step; (III) hot melt extrusion process, where different drug: hydrophobic polymer ratios were evaluated. For hydrochlorothiazide and olmesartan medoxomil, both low soluble drugs, the strategy was incorporating a dispersion containing the drugs and solubilizing agents in inert granules obtained by extrusion/coating processes. Additionally, formulations containing different ratios of these drugs and hydrophilic polymers were produced by hot melt extrusion. According to the results, it was possible to obtain minitablets and granules with good dissolution profile, similar to the reference products. Regarding to hot melt extrusion, it was possible to evaluate the influence of process and polymers used in the dissolution profile of the produced granules.