Characterization of starch amorphous solid dispersions manufactured via hot-melt extrusion by calorimetry and diffractometry

Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, 2020, Universidade de Lisboa, Faculdade de Farmácia.Uma tarefa desafiadora para a indústria farmacêutica tem sido a melhoria da solubilidade de fármacos pouco solúveis em água. A produção de dispersões sólidas amorfas constitui uma das estratégias mais promissoras para aumentar a solubilidade, velocidade de libertação e biodisponibilidade destes fármacos. Este estudo propõe a produção de dispersões sólidas amorfas com fármacos de classe II do Sistema de Classificação Biofarmacêutica, através da extrusão a quente, tecnologia que permite o aumento da solubilidade em água, usando um polímero natural e biodegradável, o amido. Os fármacos em estudo, Ibuprofeno e Carbamazepina, classificados como fármacos de classe II (baixa solubilidade e elevada permeabilidade), foram formulados com amido de milho e amido de milho glutinoso. O amido é constituído por dois biopolímeros, amilose, uma macromolécula linear, e amilopectina, uma macromolécula altamente ramificada. O Ibuprofeno e a água foram usados pelos seus efeitos plastificantes. Primeiro, a mistura das formulações foi feita num misturador de tambor. A calorimetria diferencial de varrimento foi usada para determinar a temperatura de transição vítrea dos amidos. Durante a extrusão, a água foi adicionada ao extrusor de duplo parafuso co-rotativo através de uma bomba. Depois, as amostras foram secadas em estufa a 40°C durante ±12h e a moagem foi feita em almofariz e num moinho de bolas. Apresenta-se uma visão geral dos métodos de caracterização, a Calorimetria diferencial de varrimento e a Difração de Raios-X, para uma melhor compreensão das dispersões sólidas à base de amido. Os dados apresentados sugerem que a maiores rotações e com mais água, os produtos extrudados tornaram-se mais amorfos. Visualmente, a maioria das amostras exibia uma cor branca opaca homogénea, característica de um material cristalino. Os resultados da difratometria das dispersões sólidas de Ibuprofeno e Carbamazepina indicam que permaneceram na sua forma cristalina. Os termogramas, que exibem um pico endotérmico, indicam de que o Ibuprofeno permaneceu cristalino. Este trabalho permitiu uma melhor compreensão do processo de extrusão a quente, dos métodos de caracterização do estado sólido e do comportamento de amido extrudado com fármacos. Comparando os dois tipos de amidos, o amido de milho revelou-se uma melhor escolha para a produção de dispersões sólidas amorfas.A challenging task for the pharmaceutical industry remains the effort to improve the solubility of poorly water-soluble drugs. The production of amorphous solid dispersions is one of the most promising strategies to enhance the drug release rate and bioavailability of these active pharmaceutical ingredients. The current study explored the production of amorphous solid dispersions with Biopharmaceutical Classification System class II drugs via hot-melt extrusion, an aqueoussolubility enhancement technology, using a natural and eco-friendly polymer such as starch. As model drugs, Ibuprofen and Carbamazepine, categorized as class II drugs (low solubility, high permeability) were formulated with two different starch types, Maize Corn Starch and Waxy Corn Starch. Starch is made of two biopolymers, amylose, a linear macromolecule, and the highly branched amylopectin. Ibuprofen and the addiction of water had plasticizing effects. Prior to extrusion, the physical mixtures were mixed in a tumble blender and Differential Scanning Calorimetry was used to assess the glass transition temperature of both starches. During the extrusion, water was fed into the co-rotating twin-screw with a pump. Then, the samples were dried in an oven at 40°C for ±12h, and grinding was performed through hand grinding and a ball mill. An overview of the solid-state characterization methods, Differential Scanning Calorimetry and X-Ray Powder Diffraction, is put together for a better comprehension of the extrudates’ solid-state. The data presented suggest that at a higher rotation and with more water, the extrudates became more amorphous. The visual evaluation shows most samples exhibited a white opaque homogeneous colour, characteristic of a crystalline material. The diffractograms showed that Ibuprofen and Carbamazepine were embedded in the starch matrix in their crystalline form. The thermograms of Ibuprofen solid dispersions exhibited a single sharp endothermic peak, indicating that the drug remained crystalline. This work allowed for a better insight into the hot-melt extrusion process, the characterization methods and further understanding of the thermodynamic behaviour of hotmelt extruded starches with incorporated drugs. Comparing both starches, Maize Corn Starch revealed itself a better choice to produce amorphous solid dispersions.Com o patrocínio do Department of Pharmaceutical Technology, University of Bonn, German

Synthesizing Structured CAD Models with Equality Saturation and Inverse Transformations

Recent program synthesis techniques help users customize CAD models(e.g., for 3D printing) by decompiling low-level triangle meshes to Constructive Solid Geometry (CSG) expressions. Without loops or functions, editing CSG can require many coordinated changes, and existing mesh decompilers use heuristics that can obfuscate high-level structure. This paper proposes a second decompilation stage to robustly "shrink" unstructured CSG expressions into more editable programs with map and fold operators. We present Szalinski, a tool that uses Equality Saturation with semantics-preserving CAD rewrites to efficiently search for smaller equivalent programs. Szalinski relies on inverse transformations, a novel way for solvers to speculatively add equivalences to an E-graph. We qualitatively evaluate Szalinski in case studies, show how it composes with an existing mesh decompiler, and demonstrate that Szalinski can shrink large models in seconds.Comment: 14 page

Advanced physical characterisation of milled pharmaceutical solids

Milling has been the key unit operation in controlling particle size of pharmaceutical powders at scale. The work carried out in this thesis is a comprehensive study of the stability of pharmaceutical solids post-milling and upon storage, from molecular level up to bulk handling scale. It is an attempt to fill key gaps in knowledge with regard to the anomalous behaviour and physical instability of milled powder through the development of advanced novel techniques. The physical instability of milled or amorphous pharmaceutical powders often manifest in changes in derived powder properties. Moisture induced dimensional changes of amorphous lactose compacts were monitored by in-situ environmental controlled optical profilometry. The complex volumetric behaviour involves glassy-rubbery phase transition followed by amorphous-crystalline transformation under the influence of water. These associated changes were not observed in physical aging of amorphous lactose compacts by measuring specific surface area. At the molecular level these physical changes are governed by relaxation processes. By operating within the linear viscoelastic region, low strain uni-axial indentation of small molecule organic glasses at a range of temperature generated master curves using WLF analysis. Viscoelastic behaviour of these materials were determined to be controlled by local β-relaxation around the glass transition rather than globally for polymers. At the bulk level, due to the non-equilibrium nature of milled and amorphous powders, their surface energies tends to be significantly higher than the equivalent crystalline forms. This can be detrimental as highly cohesive and poor flowing powders are difficult to process. The unconfined compression test was adapted to measure cohesion of small weak pharmaceutical powder compacts. More significantly, a positive relationship was confirmed between surface energetics and cohesion of modified D-mannitol. At the particle level, the mechanism(s) by which milling or micronisation creates low levels of amorphicity remains unclear. MOUDI fractionation of bulk micronised α-lactose monohydrate and characterisation of fine fractions has clearly demonstrated that micronisation as well as mechanical particle size reduction also generates low levels of highly amorphous ultrafine particles within bulk crystalline powder which will have a significant effect on powder physical stability post-milling and upon storage. In conclusion, using the novel techniques developed here, significant progress has been towards understanding the physical behaviour of milled and amorphous pharmaceutical solids

The evolutionary responses of cuticular hydrocarbon production and compensatory feeding behaviours when crickets have evolved in different nutritional environments

Condition dependent traits are reliant upon the acquisition and allocation of resources, with studies theorising that those individuals able to acquire more resources are then able to allocate more resources to these sensitive traits. These traits are often related to sexual reproduction, one of the most important aspect of an organism’s life cycle. One such trait is chemical signalling, where the production of these chemicals is known to be linked to adequate, over- or under-consumption. However, relatively little is known on compensatory feeding behaviours and dietary adaptation to offset the nutritional value of resources. This includes either consuming more or less depending on the overall quality of the food sourced. Furthermore, little research has been conducted into how populations respond to diet over multiple generations, analysing whether feeding behaviours has the potential to evolve in response to different dietary environments. Thus, little is also known about whether potentially evolved dietary responses have an effect on condition-dependent traits. Here, nutritional geometry was used to determine the effect of protein and carbohydrate ratios and overall nutrition on compensatory feeding behaviours and cuticular hydrocarbon (CHC) production in the decorated cricket (Gryllodes sigillatus), studying the effect of different ratios on multiple generations. A common garden experiment was employed for to determine whether responses were genetic rather than phenotypic in nature. Populations of crickets were raised on either low or high nutritional diets, which were also either protein or carbohydrate biased. A population was also kept on a standard balanced diet (SCD) for comparison. For study into possible genetic dietary responses, some populations raised on the altered diets were switched back to the standard diet (SCD). Individuals maximised consumption when faced with low nutritional value diets, while those raised on high nutritional value diets consumed less. Individuals switched back to SCD consumed an amount similar to their ancestral diet, however still maintained a noticeable difference in consumption, suggesting an evolution of genetics behind compensatory feeding behaviour as well as the typical phenotypic response. This adaptation to differing diets has a direct influence on CHC production, impacting the overall amount and blend of short and long chain CHCs across and within all diet treatments. CHC composition was sex-specific, however, diet altered the overall production. Switched diet individuals showed evolved feeding behaviour, consequently affecting CHC production in line with altered macronutrient and caloric intake. CHC compositions indicated that while individuals changed from a protein or carbohydrate-biased diet to a more balanced diet, there is the possibility of a genetic tendency to produce CHC blends similar to their ancestors. Theoretically, this has a consequential effect on male fitness, as females are attracted to specific male CHC blends

Development of Multivariate Powder X-ray Diffraction Techniques and Total Scattering Analyses to Enable Informatic Calibration of Solid Dispersion Potential

The objective of this work was to introduce a novel method for predicting solid dispersion potential enabled by the ability to differentiate phase-separated co-solidified products from amorphous molecular solid dispersions. The central hypothesis states that a combination of materials properties exists that defines the propensity of an active pharmaceutical ingredient to form a binary amorphous molecular solid dispersion with polyvinylpyrrolidone:vinyl acetate copolymer using a melt-quench procedure. Testing this hypothesis required execution of specific aims directed to address issues inherent to characterizing amorphous materials. The work herein is presented with respect to two separate subjects: (1) analytical development and (2) theoretical applications. In the first few chapters, advanced powder X-ray diffraction data processing techniques are explored and adapted to composite pharmaceutical systems. Specific emphasis will be placed ontotal scattering data manipulations and their benefits over traditional practices. The concluding part of this work is devoted to illustrating the use of materials informatics in modeling solid dispersion potential, ultimately afforded by implementing the materials characterization methodologies developed in the initial stages. Molecular descriptors, commonly employed in quantitative structure-property relationship assessment, were tested for correlation to dispersion potential across a library of small molecule organic compounds. The final model accurately predicted dispersion potential for all 12 calibration compounds and three test compounds

Interactive ray tracing of arbitrary implicits with SIMD interval arithmetic

Journal ArticleWe present a practical and efficient algorithm for interactively ray tracing arbitrary implicit surfaces. We use interval arithmetic (IA) both for robust root computation and guaranteed detection of topological features. In conjunction with ray tracing, this allows for rendering literally any programmable implicit function simply from its definition. Our method requires neither special hardware, nor preprocessing or storage of any data structure. Efficiency is achieved through SIMD optimization of both the interval arithmetic computation and coherent ray traversal algorithm, delivering interactive results even for complex implicit functions

Selected Analytical Techniques of Solid State, Structure Identification, and Dissolution Testing in Drug Life Cycle

The textbook provides an overview of the main techniques applied in pharmaceutical industry, with the focus on solid-state analysis. It discusses spectral methods, thermal analysis, and dissolution testing, explains the theoretical background for each method and shows practical examples from a real-life drug-design and quality control applications. The textbook is thus intended for both pharmacy students and early career professionals

Development of a Kinetic Model to Investigate the Effect of Compositional Variation and a Processing Condition on the Solid-State Degradation of Gabapentin

Gabapentin is used in the treatment of seizures and neuropathic pain. Gabapentin undergoes intra-molecular cyclization to form a γ-lactam. The product lactam is twenty times more toxic than gabapentin, causing seizures in animal models. The United States Pharmacopeia (USP) limits the content of lactam in gabapentin formulations to 0.4% w/w. A number of patents have been issued for solid dosage forms formulated to stabilize gabapentin. Despite these efforts, factors contributing to gabapentin’s poor stability in the solid-state have not been explored completely. It was hypothesized, that physicochemical properties of the excipients and compaction pressure will accelerate the solid-state degradation of gabapentin, increasing the kinetic rate constant for lactam formation. To test the hypotheses, binary mixtures and compacts of gabapentin with different excipients were prepared and stored under accelerated study conditions. The concentration of lactam and gabapentin was measured using a validated analytical method. A concentration dependent catalytic effect by the excipients was determined by mixing different concentrations of the excipient with gabapentin. The effect of excipient particle size was determined by mixing different size fractions of the excipient with gabapentin. Significant degradation of unprocessed gabapentin in the presence of excipients strongly suggested a catalytic role of the excipients on gabapentin’s degradation. The existing model was expanded to account for the observed catalytic effect of excipients. A relationship was developed between the rate constant for lactam formation and physical properties of the excipients (such as particle size, morphology, molecular weight, molecular cross sectional area and specific surface area). Along with the catalytic effect of the excipients, compaction pressure and powder properties of the excipients such as moisture content, particle size and yield pressure appeared to be other potential contributing factors affecting gabapentin’s degradation