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.

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.

Parmi les procédés de fabrication continue, l’extrusion par fusion à chaud est une technique dont l’intérêt dans le domaine pharmaceutique est grandissant. Ce procédé permet la formation des dispersions solides des substances actives au sein des matrices polymériques ou lipidiques. En fonction de l’excipient et de la substance active, cela peut être largement utilisé pour la conception des systèmes: (i) pour une libération immédiate, (ii) pour une libération modifiée et (iii) pour le masquage de goût. Les systèmes à libération modifiée sont des dispositifs intéressants qui permettent d’améliorer la biodisponibilité de la substance active, son efficacité ainsi que l’observance des patients. En fonction de la nature de l’excipient, différents systèmes avec des mécanismes de libération variés peuvent être produit, notamment des matrices inerte, érodable ou gonflante. Le poly éthylène oxide est un polymère semi- cristallin et hydrophile qui peut être utilisé pour la libération contrôlée. Son point de fusion compris entre 63 et 67 °C le rend adapté pour l’extrusion. Surtout, ses capacités de gonflement permettent d’administrer la substance active de façon contrôlée en fonction du poids moléculaire du poly éthylène oxide. Les objectifs de ce travail sont (i) d’étudier l’impact des paramètres critiques du procédé (température d’extrusion et vitesse des vis d’extrudeuse) sur le profil de libération de la substance active, (ii) de déterminer l’impact des paramètres de formulations (poids moléculaire du poly éthylène oxide, charge et type de la substance active) sur le profil de libération de la substance active et (iii) d’évaluer des formes galéniques solides conçues par le procédé d’extrusion à celui de la compression directe. Il a été montré que la variation de la température d’extrusion et de la vitesse des vis altérait l’apparence de l’extrudat et ainsi la distribution de la substance active au sein de l’extrudat. Il s’est avéré dans notre étude que la libération de la substance active n’était pas particulièrement affectée par ces changements de température et vitesse de vis de l’extrudeuse. De plus, cette étude a permis de fixer les paramètres pour les projets suivants: température 100 °C ; vitesse des vis 30 rpm ; longueur de la forme galénique 1 cm. Des extrudats de poly ethylène oxide contenant 10 % de théophylline et du poly éthylène oxide de 100 à 7000 kDa ont été utilisés dans ce travail. Il a été observé que lorsque le poids moléculaire du poly ethylène oxide augmente de 100 à 600 kDa, la libération en substance active diminue de façon importante alors qu’une augmentation jusqu’à 7000 kDa ne diminue que légèrement la libération. Des études du gonflement ont montré que ce phénomène corrélait aux variations de volume de la partie opaque de l’extrudat (gel non transparent et cœur solide). / Among continuous manufacturing processes, hot melt extrusion is a technique with growing interest in the pharmaceutical field. This process enables the formation of solid dispersions of many drugs within a polymeric or lipidic carrier. Hot melt extrusion can be widely used for different issues using the appropriate carrier and drug. Here are the mostly used concepts in pharmaceutical solid dosage forms: (i) immediate release, (ii) modified release and (iii) taste masking. Modified release systems have been taken into account to be very interesting devices for the improvement of drug- bioavailability, drug- efficacy as well as the patient compliance. Various systems with different release mechanisms can be manufactured, depending on the nature of the carrier (inert, erodible, and swelling matrices). Poly ethylene oxide is a semi crystalline and hydrophilic polymer which can be used to control drug delivery. The poly ethylene oxide melting point ranging from 63 to 67 °C makes it suitable for hot melt extrusion. Importantly, the swelling capacities of the hydrophilic poly ethylene oxide matrices are able to deliver drug in a time controlled manner, in respect of the poly ethylene oxide molecular weights. The purposes of this work were (i) to study the impact of critical process parameters (extrusion temperature and screw speed) on the drug release behavior, (ii) to determine the impact of formulation parameters (poly ethylene oxide molecular weight, nature of drug and drug loading) on drug release kinetics, and (iii) to evaluate solid dosage forms prepared by hot melt extrusion versus direct compression. Interestingly, the variation of the extrusion temperature and the screw speed leads to the altering of the extrudate appearance and thus the distribution of drug into the extrudate. However, this changing has not influenced the drug release remarkably. Thus, this study was useful to set the parameters for the following projects (temperature 100 °C; screw speed 30 rpm; dosage form size 1 cm). Poly ethylene oxide hot melt extrudates containing 10 % theophylline and based on 100 - 7,000 kDa poly ethylene oxide are used for this thesis. Importantly, the drug release decreased substantially with the increase of the poly ethylene oxide molecular weight from 100 to 600 kDa. However, further increasing of the molecular weights leads to only a slight decrease in the release rate. Swelling studies have shown that this phenomenon correlated with the change in volume of the opaque part of the extrudates (non-transparent gel and solid core).

Hot-melt extruded solid dispersion technique is increasingly employed to improve the solubility of poorly water-soluble drugs. The technique relies on the enhanced solubility of the amorphous form of the drug compared to its crystalline counterpart. These systems however are thermodynamically unstable. This means that the drug crystallises with time. Therefore, efforts to measure the stability of these systems over the life span of the product are crucial. This study focused on investigating the use of Hansen Solubility Parameters to quantify polymer-drug interaction and to predict the stability of solid dispersions. This was achieved through a systematic review of hot-melt extruded solid dispersion literature. The study also investigated the use of a combined mechanical and rheological model to characterise the physicochemical and release behaviour of three solid dispersion immediately after preparation and after storage for one month at 40oC or three months at room temperature. Results revealed that the total solubility parameter |ΔбT| was able to predict the stability of the systems for more than 4 months using a cut-off point of 3 MPa-1 with a negative predictive value of 0.9. This was followed by ΔбD with a cut-off point of 1.5 MPa- 1. Moreover, Dynamic Mechanical Analyser and shear rheometry data were shown to be more sensitive than Differential Scanning Calorimetry, Powder X-Ray Diffraction, Scanning Electron Microscope and Fourier Transform Infrared in detecting crystallisation and the interaction between the drug and the polymer. The Dynamic Mechanical Analyser data were consistent with the dissolution behaviour of the samples when comparing the freshly prepared samples with those after storage. The results highlight the need for a unified characterisation approach and the necessity of verifying the homogeneity of mixing during the extrusion process.

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.

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No. of bitstreams: 1 Tese - Luís Antônio Dantas Silva - 2017.pdf: 3852477 bytes, checksum: 3d70f0bfde2edb9fbe3baf236d1c369c (MD5) Previous issue date: 2017-04-07 / Fundação de Amparo à Pesquisa do Estado de Goiás - FAPEG / Introduction: Self-emulsifying drug delivery systems (SMEDDS) have been successfully used as carriers for poorly water-soluble drugs, because they can effectively solubilize them, as well as stimulate their intestinal lymphatic transport, reduce first-pass metabolism, and inhibit efflux proteins present in intestinal cells. All these effects together contribute to the improvement in the oral bioavailability of the incorporated drugs. The preparation of solid self-emulsifying systems is associated with additional advantages, such as increased stability, ease of transport, storage, and administration. Hot-melt extrusion is a technique that has attracted great interest in the pharmaceutical industry in recent years for enabling continuous production of solid dosage forms, with high productivity and low cost. In addition, it can be performed without the use of solvents. Despite this, there are no reports in the literature about the use of this technique in the production of solid self-emulsifying systems. Objectives: The objective of the present work was to perform preformulation studies and to develop solid self-microemulsifying systems containing carvedilol by hot-melt extrusion, aiming at improving the dissolution of this drug. Methods: Initially, carvedilol solubility and compatibility in different lipid excipients were determined, respectively, by the equilibrium solubility method and thermoanalytical, spectroscopic and isothermal stress techniques. An analytical method was developed and validated to carvedilol quantitation by high performance liquid chromatography. Next, the selected excipients were used in the construction of a ternary phase diagram, in order to determine the best ratio for SMEDDS production. Finally, the selected liquid formulation was mixed with a polymeric system consisting of an enteric polymer (hydroxypropylmethylcellulose acetate succinate) and other excipients. The resulting mixture was extruded in a twin screw hot-melt extruder. Box-Behnken factorial design was used to evaluate the effects of formulation (carvedilol concentration) and process variables (temperature and recirculation time) on the release of the drug (in 0.1 M HCl and phosphate buffer pH 6.8) and redispersion of the microemulsion from the solid system. The extrudates’ morphology was evaluated by light microscopy and scanning electron microscopy and the physical state of the drug in the preparation was investigated by differential scanning calorimetry and X-ray powder diffraction. Results: Preformulation studies showed that carvedilol is incompatible with the lauric acid, oleic acid, Gelucire® 44/14, Capmul® MCM, canola oil, castor oil, polyethoxylated castor oil, corn oil, soybean oil, sunflower oil and safflower oil. On the other hand, carvedilol was stable in mixtures with sesame oil, Plurol® Isostearique, Transcutol HP®, stearic acid, palmitic acid, Compritol® 888 ATO, Emulium® 22 and with the mixture of capric/caprilic triglycerides (CCT). The CCT showed to be the best solvent for carvedilol (3.93 ± 0.20 mg mL-1), among the compatible lipid excipients. Thus, the mixture of CCT, Plurol® and Transcutol HP® was selected for preparation of the self-emulsifying systems containing carvedilol. The phase diagram showed that the ratio of 50/37.5/12.5 (oil/surfactant/cosurfactant) resulted in the best parameters of self-emulsification (time, clarity and stability) average size (140.04 ± 7.22 nm) and size distribution (0.219 ± 0.011). These values were not significantly altered by the inclusion of carvedilol in the mixture (139.06 ± 7.28 nm and 0.221 ± 0.015). This self-microemulsifying concentrate with polymeric carriers were then extruded and the resulting product was a compact matrix. Factorial design showed that the drug concentration, temperature and recirculation time significantly influenced the drug release in different media, as well as the reconstitution efficiency of the microemulsion. Carvedilol release in acid medium was in the range of 12 to 25% and it was significantly affected by the temperature and recirculation time. The polymeric matrix was able to prevent redispersion of the system in acid. In turn, drug released was significantly affected by drug concentration in pH 6.8, ranging from 43 to 85%. Drug release in this medium was primarily affected by the concentration of the drug in the formulation. The reconstitution efficiency was significantly affected by the circulation time and process temperature, ranging from 55 to 100% in pH 6.8. Average size (145 to 164 nm) and PdI (0.209 to 0.262) were not significantly affected by the studied variables Conclusion: Self-microemulsifying extrudates were prepared from the lipid concentrate selected from the preformulation studies. The solid systems allowed a site-specific microemulsion redispersion, thus presenting potential for lymphatic absorption of carvedilol. The experimental results presented here are the first report about the production of solid self-microemulsifying systems containing carvedilol by hot-melt extrusion. / Introdução: Sistemas automicroemulsionáveis de liberação de fármacos (SMEDDS) têm sido empregados, com sucesso, como carreadores de fármacos pouco solúveis em água, pois conseguem solubilizá-los eficientemente, assim como podem estimular seu transporte linfático intestinal, reduzindo o metabolismo de primeira passagem e inibindo as proteínas de efluxo presentes nas células intestinais. Todos esses efeitos em conjunto contribuem para a melhora na biodisponibilidade oral dos fármacos incorporados. O preparo de sistemas automicroemulsionáveis sólidos está associado a vantagens adicionais, tais como o aumento da estabilidade, facilidade de transporte e armazenamento e maior conveniência de administração. A termoextrusão é uma técnica que tem atraído grande interesse na indústria farmacêutica nos últimos anos por possibilitar a produção contínua, com alta produtividade e baixo custo de formas sólidas, sendo ainda executada sem uso de solventes. Apesar disto, não existem relatos na literatura sobre o emprego dessa técnica na produção de sistemas automicroemulsionáveis sólidos. Objetivos: O presente trabalho teve como objetivo realizar estudo de pré-formulação e, em seguida, desenvolver termoextrusados automicroemulsionáveis contendo carvedilol, visando a melhora na dissolução deste fármaco. Métodos: Inicialmente, a solubilidade e compatibilidade do carvedilol em diferentes adjuvantes lipídicos foram determinadas, respectivamente, pelo método de solubilidade no equilíbrio e pelo emprego de técnicas termoanalíticas, espectroscópicas e de estresse isotérmico. A quantificação do carvedilol nestes estudos foi realizada por cromatografia a líquido de alta eficiência e, para tanto, o método analítico foi desenvolvido e validado. Em seguida, os adjuvantes selecionados foram utilizados na construção de um diagrama de fases ternário, no intuito de determinar a melhor proporção dos mesmos para o preparo de SMEDDS. Por fim, a formulação líquida selecionada foi misturada a um sistema polimérico constituído por polímero entérico (acetosuccinato de hidroxipropilmetilcelulose) e outros adjuvantes, sendo a mistura resultante processada por termoextrusão em extrusor de parafuso duplo. Planejamento fatorial do tipo Box-Behnken foi empregado para avaliar os efeitos de variáveis de formulação (concentração de carvedilol) e de processo (temperatura e tempo de recirculação) sobre a liberação do fármaco (em meio HCl 0,1 M e em tampão fosfato pH 6,8) e sobre a reconstituição da microemulsão a partir do sistema sólido. A morfologia dos termoextrusados foi avaliada por microscopia óptica e por microscopia eletrônica de varredura e o estado físico do fármaco na preparação foi investigado por calorimetria exploratória diferencial e difração de raios-X de pó. Resultados: Os estudos de pré-formulação mostraram que o carvedilol é incompatível com os adjuvantes ácido láurico, ácido oleico, Gelucire® 44/14, Capmul® MCM, óleo de canola, óleo de rícino, óleo de rícino polietoxilado, óleo de milho, óleo de soja, óleo de girassol e óleo de cártamo. Por outro lado, o carvedilol se mostrou estável nas misturas com o óleo de gergelim, Plurol® Isostearique, Transcutol HP®, ácido esteárico, ácido palmítico, Compritol® 888 ATO, Emulium® 22 e com a mistura de triglicerídeos dos ácidos cáprico e caprílico (TAC). O TAC mostrou ainda ser o melhor solvente para o carvedilol (3,93 ± 0,20 mg/mL), dentre os materiais oleosos compatíveis. Dessa forma, a mistura de TAC, Plurol® e Transcutol HP® foi selecionada para o preparo de sistemas automicroemulsionáveis. O diagrama de fases mostrou que a proporção 50/37,5/12,5 (óleo/tensoativo/cotensoativo) resultou nos melhores parâmetros de autoemulsificação (tempo, limpidez e estabilidade), tamanho médio (140,04 ± 7,22 nm) e distribuição de tamanho (0,219 ± 0,011). Esses valores não foram significativamente alterados pela inclusão do carvedilol na mistura (139,06 ± 7,28 nm e 0,221 ± 0,015). O concentrado automicroemulsionável, adicionado aos polímeros, contendo carvedilol foi então termoextrusado e o produto resultante apresentou matriz compacta. A concentração do fármaco, a temperatura de processamento e o tempo de recirculação influenciaram significativamente o perfil de liberação do fármaco nos diferentes meios, bem como a eficiência de reconstituição da microemulsão. A liberação do carvedilol em meio ácido esteve na faixa entre 12 e 25%, sendo significativamente afetada pela temperatura e tempo de recirculação. Em meio ácido, a matriz polimérica foi capaz de evitar a reconstituição da microemulsão. Por sua vez, em meio pH 6,8, a liberação do carvedilol foi maior e variou entre 43 e 85%, sendo afetada pela concentração do fármaco na formulação. Nesse meio, a eficiência de reconstituição foi significativamente afetada pelo tempo de recirculação e pela temperatura, apresentando eficiência de reconstituição na faixa entre 55 e 100%. O tamanho médio (145 a 164 nm) e PdI (0,209 a 0,262) das microemulsões não tiveram seus valores afetados significativamente pelas variáveis estudadas. Conclusão: Termoextrusados automicroemulsionáveis foram preparados a partir do concentrado lipídico composto por adjuvantes selecionados nos estudos de pré-formulação. Os sistemas sólidos conferiram reconstituição sítio-específica da microemulsão, apresentando assim potencial para proporcionar absorção linfática do carvedilol. Os achados experimentais aqui apresentados são o primeiro relato da obtenção de sistemas automicroemulsionáveis sólidos contendo carvedilol pela técnica de termoextrusão.

<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>

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.

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.