<div>Drug solubility is a persistent challenge in pharmaceutical product development. The objective of this research is to develop a formulation/processing strategy by means of a biodendrimeric solid dispersion (BDSD) platform, for increasing the solubility and dissolution rate of poorly water-soluble drugs. The BSDS platform combines a novel type of excipient, referred to as DLB, with a new application of the hot melt extrusion (HME) process.</div><div><br></div><div>Four model compounds – phenytoin (PHT), griseofulvin (GSF), ibuprofen (IBU), and loratadine (LOR) – were used to evaluate the solubilization effect of an octenylsuccinate-modified dendrimer-like biopolymer (OS-DLB). Shake-flask solubility measurements show that OS-DLB exerts significant solubilizing effect when present at less than 0.2% in water. The presence of hydrophobic C₈ chains on OS-DLB creates the type of favorable nonpolar microenvironment necessary for producing a parallel liquid phase equilibrium responsible for the increase in the total amount of drug dissolved in aqueous media. The higher the hydrophobicity of the drug, the higher the observed solubilization effect. Isothermal titration calorimetry studies show that drug solubilization by OS-DLB occurs by means of entropy-driven interactions. These studies also show that the intermolecular interaction between IBU and OS-DLB in solution exhibits very small energy change upon mixing but a stronger effect on entropy. In comparison, the intermolecular interaction between the less hydrophobic GSF and OS-DLB have significant effects on both enthalpy and entropy. Consequently, in terms of solubilization enhancement, it was found that the interaction between IBU and OS-DLB is entropy-driven (more favorable), while in the case of GSF, the interacting molecules are arranged to maximize enthalpic interaction.</div><div><br></div><div>Based on the solubility studies, a formulation/processing approach for enhancing the dissolution rate of the model drugs was developed. The biopolymer serving as both carrier and solubilizing agent, was coprocessed with poloxamer, functioning as a processing aid, using hot melt extrusion (HME) as an enabling technology. The result is a non-amorphous solid dispersion, exhibiting high and long-lasting supersaturation upon dissolution. A 3-factor, 3-level Box-Behnken design was implemented to define the optimal design space for the formulation/extrusion process. The results obtained from multivariate data analysis (partial least squares and principal components analysis) and response surface modeling suggest that drug release performance of IBU BDSDs is strongly influenced by the processing variables, while maximum release of GSF from the BDSDs can be attained through selective combination of functional excipients.<br></div>

Les filaments composites cœur/peau ont été développés dans le but de proposer des capteurs et de effecteurs textiles pour des applications « smart textiles ». Le filage des filaments a été effectué avec une technique de type extrudeuse à piston. Le travail a porté sur la modification d’une machine de filage par fusion, de la caractérisation de polymères, de la caractérisation des filaments développés et de l’optimisation des techniques d’obtention des filaments. La conception du procédé ainsi que son optimisation ont été effectués avec du PET. La modification de la machine a consisté à concevoir les filières, modifier le piston et à introduire un canal d’alimentation sous forme de tube en inox pour sécuriser le passage du filament métallique d’âme dans le four. Ainsi, 10 filières différentes et trois pistons ont été conçus en se fondant sur les règles industrielles puis leurs performances ont été optimisées. Les polymères ont été caractérisés par DSC, par rhéologie et par techniques analytiques. Ces résultats ont montré la forte influence de la température en particulier une forte réduction de la cristallinité du filament composite. L’optimisation des paramètres d’extrusion a pris en compte la vitesse du piston, la vitesse de bobinage, les modifications de la machine dont le nombre de trous des filières, la position du tube dans la filière, les dimensions internes du tube, le diamètre de sortie de la filière. Il a été montré que la conception de la filière a une influence significative sur la forme des filaments obtenus ainsi que sur la concentricité de l’âme. Les propriétés physiques, morphologiques, tribologiques et mécaniques des filaments ont été mesurés. Ainsi, les filaments ont des diamètres compris entre 350 et 500 µm et peuvent être de formes elliptique, triangulaire, rectangulaire ou circulaire et les meilleures propriétés mécaniques sont obtenues avec les filaments le plus réguliers tandis que les filaments irréguliers présentent un coefficient de frottement plus important. Les résultats concernant la rigidité en flexion se sont avérés peu fiables. A partir des paramètres optimisés, un filament composite de polymère ferroélectrique (PVDF 70%-TrFE 30%) avec une âme cuivre a été filé et a montré de parfaites caractéristiques de forme et de concentricité. Ce filament composite peut maintenant être utilisé pour développer des capteurs et des effecteurs, des transmetteurs de signaux, des boucliers électromagnétiques et de l’électronique intégrable dans les vêtements. / A coaxial composite fiber has been developed for the intended application in textile based sensors, actuators and eletric signal transmissions in wearable textile products. The work focuses on melt extrusion machine modification, characterization of polymers, characterization of developed filaments and optimization techniques for obtaining required results. Melt extrusion machine has been used having piston based mechanism. The process design and optimization was done using polyester polymer. The machine modification includes design of spinnert, piston end modification and introduction of separate feeding channel for core filament in the oven. A number of 10 spinnerets designs were developed according to industrial die design rules and optimized for their performance. The piston end designs developed were 3 in number. A stainless steel tube has been introduced into the oven for a separate secure passage of core filament. The polymer characterization was done by thermal, rheological and analytical techniques. The obtained results exhibited thermal attibutes of the polymer and showed reduction in degree of crystallanity in composite filament. The optimization of extrusion parameters including piston speed, winding speed ; and modifications in machine which includes design parameters of number of holes, tube position, tube internal diameter and spinneret exit diameter were done. It was observed that design parameters have significant effect on cross-sectional shape, eccentricity of core and morphology of filament. The characterization of composite filament has been carried out by physical, morphological, mechanical, tribology and bending techniques. The composite filaments developed were in range of 350-500 µm diameter. The filaments developed have elliptical, triangular, rectangular and circular shapes. The regular filaments showed higher tenacity and breaking strength than irregular shaped filaments. The frictional coefficient values were found higher for irregular shapes. Bending stiffness results obtained were not reliable for irregular cross-sectional shapes. The optimized parameters wers used to develop composite filament using ferroelectric polymer (PVDF-TrFE) having 70 :30 ratio copolymer. The developed filament was very regular in shape with good eccentricity of core. The developed Cu/PVDF-TrFE core/sheath filament can be used for development of sensors and actuators. The Cu/Polyester core/sheath filament can be used for electrical signal transmission lines in wearable electronic textiles and for development of electromagnetic shielding effectiveness fabrics.

Yes / Three dimensional printing (3DP) was used to engineer novel oral drug delivery devices, with specialised design configurations loaded with multiple actives, with applications in personalised medicine. A filament extruder was used to obtain drug-loaded - paracetamol (acetaminophen) or caffeine - filaments of polyvinyl alcohol with characteristics suitable for use in fused-deposition modelling 3D printing. A multi-nozzle 3D printer enabled fabrication of capsule-shaped solid devices, containing paracetamol and caffeine, with different internal structures. The design configurations included a multilayer device, with each layer containing drug, whose identity was different from the drug in the adjacent layers; and a two-compartment device comprising a caplet embedded within a larger caplet (DuoCaplet), with each compartment containing a different drug. Raman spectroscopy was used to collect 2-dimensional hyper spectral arrays across the entire surface of the devices. Processing of the arrays using direct classical least squares component matching to produce false colour representations of distribution of the drugs showed clearly the areas that contain paracetamol and caffeine, and that there is a definitive separation between the drug layers. Drug release tests in biorelevant media showed unique drug release profiles dependent on the macrostructure of the devices. In the case of the multilayer devices, release of both drugs was simultaneous and independent of drug solubility. With the DuoCaplet design it was possible to engineer either rapid drug release or delayed release by selecting the site of incorporation of the drug in the device, and the lag-time for release from the internal compartment was dependent on the characteristics of the external layer. The study confirms the potential of 3D printing to fabricate multiple-drug containing devices with specialized design configurations and unique drug release characteristics, which would not otherwise be possible using conventional manufacturing methods. / The full-text of this article will be released for public view at the end of the publisher embargo on 10 Oct 2016.

High shear melt granulation (HSMG) is an established technology for a production of densified granules. In this project, it was used as a novel solvent-free method for the preparation of cocrystals. Cocrystals produced by HSMG were compared to those prepared by Hot Melt Extrusion (HME) to investigate the influence of variable parameters and conditions on the process of cocrystal conversion. The potential for the active control of cocrystals polymorphism utilising the intrinsic properties of lipids was also investigated in this project. Different cocrystal pairs were prepared by both cocrystallisation methods using glycol derivative polymers. Thermal analysis, powder X-ray diffraction and Raman spectroscopy were used as analytical techniques to determine the cocrystal yield and purity. The results obtained from HSMG suggest that sufficient binder concentrations (above 12.5% w/w) in a molten state and continuous shearing force are necessary to achieve a complete cocrystals conversion. Further increase in binder concentration (15% w/w) was found to provide more regular shape and smooth surface to the prepared spherical granules. Cocrystals preparation by HME was achievable after introducing a mixing zone to the extruder configuration (Conf B and Conf C) providing densified extrudates containing pure cocrystals. In conclusion, HSMG was found as a versatile technique for the preparation of pure pharmaceutical cocrystals embedded in polymer matrix within a spherical shape granule of smooth surfaces, providing additional desirable characteristics. Intensive surface interaction, enhanced by sufficient mixing under optimal parameters, was found as a key influencing factor in cocrystallisation. Cocrystals polymorphism was actively controlled by employing the intrinsic properties of polymers and lipids.

This project utilised a novel solvent-free continuous cocrystallisation (SFCC) method to manufacture pharmaceutical co-crystals. The objectives were to optimize the process towards achieving high co-crystal yields and to understand the behaviour of co-crystals under different conditions. Particular attention was paid to the development of near infrared (NIR) spectroscopy as a process analytical technology (PAT). Twin screw, hot melt extrusion was the base technique of the SFCC process. Changing parameters such as temperature, screw speed and screw geometry was important for improving the co-crystal yield. The level of mixing and shear was directly influenced by the screw geometry, whilst the screw speed was an important parameter for controlling the residence time of the material during hot melt extrusion. Ibuprofen – nicotinamide 1:1 cocrystals and carbamazepine – nicotinamide 1:1 co-crystals were successfully manufactured using the SFCC method. Characterisation techniques were important for this project, and NIR spectroscopy proved to be a convenient, accurate analytical technique for identifying the formation of co-crystals along the extruder barrel. Separate thermal and model shear deformation studies were also carried out to determine the effect of temperature and shear on co-crystal formation for several different pharmaceutical co-crystal pairs. Finally, NIR spectroscopy was used to create two partial least squares regression models, for predicting the 1:1 co-crystal yield of ibuprofen – nicotinamide and carbamazepine – nicotinamide, when in a powder mixture with the respective pure API. It is believed that the prediction models created in this project can be used to facilitate future in-line PAT studies of pharmaceutical co-crystals during different manufacturing processes. / Engineering and Physical Sciences Research Council (EPSRC)

Yes / A study has been carried out to investigate controlled release performance of caplet shaped injection moulded (IM) amorphous solid dispersion (ASD) tablets based on the model drug AZD0837 and polyethylene oxide (PEO). The physical/chemical storage stability and release robustness of the IM tablets were characterized and compared to that of conventional extended release (ER) hydrophilic matrix tablets of the same raw materials and compositions manufactured via direct compression (DC). To gain an improved understanding of the release mechanisms, the dissolution of both the polymer and the drug were studied. Under conditions where the amount of dissolution media was limited, the controlled release ASD IM tablets demonstrated complete and synchronized release of both PEO and AZD0837 whereas the release of AZD0837 was found to be slower and incomplete from conventional direct compressed ER hydrophilic matrix tablets. Results clearly indicated that AZD0837 remained amorphous throughout the dissolution process and was maintained in a supersaturated state and hence kept stable with the aid of the polymeric carrier when released in a synchronized manner. In addition, it was found that the IM tablets were robust to variation in hydrodynamics of the environment and PEO molecular weight. / The research was funded by AstraZeneca, Sweden.

Applications of Hot Melt Extrusion (HME) in pharmaceuticals have become increasingly popular over the years but nonetheless a few obstacles still remain before wide scale implementation. In many instances these improvements are related to both processing and product performance. It is observed that HME process optimisation is majorly focused on the active pharmaceutical ingredient's (API) properties. Characterising polymeric properties for their suitability in HME should be equally studied since the impact of excipients on both product and process performance is just as vital. In this work, two well-established cellulose ester derivatives: Hydroxy Propyl Methyl Cellulose Acetate Succinate (HPMCAS) and Hydroxy Propyl Methyl Cellulose Phthalate (HPMCP) are studied for their HME suitability. Their thermal, thermodynamic, rheological, thermo-chemical and degradation kinetic properties were evaluated with model plasticisers and APIs. It was found the thermal properties of HPMCP are severely compromised whereas HPMCAS is more stable in the processing zone of 150 to 200 °C. Thermodynamic properties revealed that both polymers share an important solubility parameter range (20-30 MPa P1/2P) where the majority of plasticisers and BCS class II APIs lie. Thus, greater miscibility/solubility can be expected. Further, the processability of these two polymers investigated by rheometric measurements showed HPMCAS possesses better flow properties than HPMCP because HPMCP forms a weak network of chain interactions at a molecular level. However, adding plasticisers such as PEG and TEC the flow properties of HPMCP can be tailored. The study also showed that plasticisers have a major influence on thermo-chemical and kinetic properties of polymers. For instance, PEG reduced polymer degradation with reversal in kinetic parameters whereas blends of CA produced detrimental effects and increased polymer degradation with reduction in onset degradation temperatures. Further, both polymers are observed to be chemically reactive with the APIs containing free -OH, -SOR2RN- and -NH2 groups. Finally, these properties prove that suitability of HPMCP is highly debated for HME and demands great care in use while that of HPMCAS is relatively better than HPMCP in many instances.

La principale difficulté lors de l'administration orale d'un ingrédient pharmaceutique actif (API) est de garantir que la dose clinique de l’API sera dissoute dans le volume disponible de liquides gastro-intestinaux. Toutefois, environ 40% des API sur le marché et près de 90% des molécules en cours de développement sont peu solubles dans l’eau et présentent une faible absorption par voie orale, ce qui entraîne une faible biodisponibilité. Les dispersions solides amorphes (ASD) sont considérées comme l’une des stratégies plus efficaces pour résoudre des problèmes de solubilité des principes actifs peu solubles dans l’eau et, ainsi, améliorer leur biodisponibilité orale. En dépit de leur introduction il y a plus de 50 ans comme stratégie pour améliorer l’administration orale des API, la formation et la stabilité physique des ASD font toujours l'objet de recherches approfondies. En effet, plusieurs facteurs peuvent influer sur la stabilité physique des ASD pendant le stockage, parmi lesquels la température de transition vitreuse du mélange binaire API-polymère, la solubilité apparente de l'API dans le polymère, les interactions entre l'API et le polymère et le procédé de fabrication. Cette thèse consistait en deux parties qui avaient pour objectif le développement de nouvelles formulations sous forme d’ASD d'un antirétroviral, l'Efavirenz (EFV), dispersé dans un polymère amphiphile, le Soluplus, en utilisant deux procédés différents, le séchage par atomisation (SD) et l'extrusion à chaud (HME). EFV est l’API BCS de classe II de notre choix car c’est un API qui représente un défi pour les nouvelles formulations. En effet, il a besoin d’ASD plus fortement concentrées, pour lesquelles la stabilité chimique et physique pendant le stockage et la dissolution seront essentielles. Dans le but de développer de manière rationnelle les ASDs EFV- Soluplus à forte concentration, la première partie s'est concentrée sur la construction d'un diagramme de phases EFV-Soluplus en fonction de la composition et de la température. Le diagramme de phases a été construit à partir d'une étude thermique de recristallisation d'un ASD sursaturé (85 %m EFV), générée par séchage par atomisation. À notre connaissance, il s'agit de la première étude à présenter un diagramme de phase pour ce système binaire. Ce diagramme de phases est très utile et démontre que la solubilité de l'EFV dans les solutions varie de 20 %m (25 °C) à 30 %m (40 °C). Les ASD de EFV dans le Soluplus contenant plus de 30 %m d'EFV doivent être surveillées pendant le stockage dans des conditions typiques de température. Ce diagramme de phases peut être considéré comme un outil de pré-formulation pour les chercheurs qui étudient de nouvelles ASD d'EFV dans le Soluplus afin de prédire la stabilité (thermodynamique et cinétique). Les ASD préparées par différentes techniques peuvent afficher des différences dans leurs propriétés physicochimiques. La deuxième partie de cette thèse portait sur la fabrication d’ASD par des procédés HME et SD. Cette étude montre clairement que la formation d’ASD est une stratégie de formulation utile pour améliorer la solubilité dans l'eau et la vitesse de dissolution de l'EFV à partir de mélanges binaires EFV-Soluplus. Les procédés de fabrication (HME et SD) se sont révélés efficaces pour générer des ASD dans une large gamme de compositions en EFV. L'optimisation du ratio EFV-Soluplus peut être utilisée pour adapter la libération cinétique des ASD. Le choix d’une charge EFV élevée dépassant la solubilité thermodynamique de l’EFV dans le Soluplus est possible, mais il convient de prendre en compte sa stabilité cinétique dans le temps. / The main difficulty when an Active Pharmaceutical Ingredient (API) is orally administered is to guarantee that the clinical dose of the API will be dissolved in the available volume of gastrointestinal fluids. However, about 40% of APIs with market approval and nearly 90% of molecules in the discovery pipeline are poorly water-soluble and exhibits a poor oral absorption, which leads to a weak bioavailability. Amorphous solid dispersions (ASD) are considered as one of the most effective strategies to solve solubility limitations of poorly-water soluble compounds and hence, enhance their oral bioavailability. Despite their introduction as technical strategy to enhance oral APIs bioavailability more than 50 years ago, ASD formation and physical stability remains a subject of intense research. Indeed, several factors can influence the physical storage stability of ASD, among them, the glass transition temperature of the API-carrier binary mixture, the apparent solubility of the API in the carrier, interactions between API and carrier, and the manufacturing process. This thesis consisted of two parts that aim on developing new formulations of ASD of an antiretroviral API, Efavirenz (EFV), dispersed in an amphiphilic polymer, Soluplus, by using two different processes, Spray-drying (SD) and Hot-melt extrusion (HME). EFV is the class II BCS API of our choice because it is a challenging API for new formulations. It needs higher-dosed ASDs, for which chemical and physical stability during storage and dissolution will be critical. Aiming a rational development of high-loaded EFV-Soluplus ASDs, the first part focused on the construction of a temperature- composition EFV-Soluplus phase diagram. The phase-diagram was constructed from a thermal study of recrystallization of a supersaturated ASD (85 wt% in EFV), generated by spray drying. To our knowledge, this is the first study reporting a phase-diagram for this binary system. This phase-diagram is very useful and demonstrated that the EFV solubility in Soluplus ranges from 20 wt% (25 °C) to 30 wt% (40 °C). ASD of EFV in Soluplus containing more than 30 wt% of EFV should be monitored over storage under typical temperature conditions. This phase-diagram might be considered as a preformulation tool for researchers studying novel ASD of EFV in Soluplus, to predict (thermodynamic and kinetic) stability. ASD prepared by different techniques can display differences in their physicochemical properties. The second part of this thesis focused on the manufacturing of ASD by HME or SD processes. This study clearly shows that ASD is a useful formulation strategy to improve the aqueous solubility and the dissolution rate of EFV from EFV-Soluplus binary mixtures. HME and SD manufacturing processes demonstrated to be efficient to generate ASDs in a large range of compositions and loads of EFV. The optimization of EFV to Soluplus ratio can be used to tailor the release kinetics from ASD. The choice of a high EFV load exceeding the thermodynamic solid solubility in Soluplus is possible but it needs the consideration of its kinetic stability over time.

No / OBJECTIVES: To compare the properties of solid dispersions of felodipine for oral bioavailability enhancement using two different polymers, polyvinylpyrrolidone (PVP) and hydroxypropyl methylcellulose acetate succinate (HPMCAS), by hot-melt extrusion (HME) and spray drying. METHODS: Felodipine solid dispersions were prepared by HME and spray drying techniques. PVP and HPMCAS were used as polymer matrices at different drug : polymer ratios (1 : 1, 1 : 2 and 1 : 3). Detailed characterization was performed using differential scanning calorimetry, powder X-ray diffractometry, scanning electron microscopy and in-vitro dissolution testing. Dissolution profiles were evaluated in the presence of sodium dodecyl sulphate. Stability of different solid dispersions was studied under accelerated conditions (40 degrees C/75% RH) over 8 weeks. KEY FINDINGS: Spray-dried formulations were found to release felodipine faster than melt extruded formulations for both polymer matrices. Solid dispersions containing HMPCAS exhibited higher drug release rates and better wettability than those produced with a PVP matrix. No significant differences in stability were observed except with HPMCAS at a 1 : 1 ratio, where crystallization was detected in spray-dried formulations. CONCLUSIONS: Solid dispersions of felodipine produced by spray drying exhibited more rapid drug release than corresponding melt extruded formulations, although in some cases improved stability was observed for melt extruded formulations.

No / PURPOSE: To explore hot melt extrusion (HME) as a scalable, solvent-free, continuous technology to design cocrystals in agglomerated form. METHODS: Cocrystal agglomerates of ibuprofen and nicotinamide in 1:1 ratio were produced using HME at different barrel temperature profiles, screw speeds, and screw configurations. Product was characterized for crystallinity by XRPD and DSC, while the morphology was determined by SEM. Dissolution rate and tabletting properties were compared with ibuprofen. RESULTS: Process parameters significantly affected the extent of cocrystallization which improved with temperature, applied shear and residence time. Processing above eutectic point was required for cocrystallization to occur, and it improved with mixing intensity by changing screw configuration. Product was in the form of spherical agglomerates, which showed directly compressible nature with enhanced dissolution rate compared to ibuprofen. This marks an important advantage over the conventional techniques, as it negates the need for further size modification steps. CONCLUSIONS: A single-step, scalable, solvent-free, continuous cocrystallization and agglomeration technology was developed using HME, offering flexibility for tailoring the cocrystal purity. HME being an established technology readily addresses the regulatory demand of quality by design (QbD) and process analytical technology (PAT), offering high potential for pharmaceuticals.