Pressurized metered dose inhalers (pMDIs) are widely utilized to manage diseases of the lungs, such as asthma and chronic obstructive pulmonary disease. They can be formulated such that the drug and/or nonvolatile excipients are dissolved or dispersed in the formulation, rendering a solution or suspension formulation, respectively. While the formulation process for solution pMDIs is well defined, the formulation process of pMDIs with any type of suspended entity can be lengthy and empirical. The use of suspended drug or the addition of a second drug or excipient in a suspension pMDI formulation may non-linearly impact the product performance of the drug of interest in the formulation; this requires iterative testing of a series of pMDIs in order to identify a formulation with the most potential for success. One of the primary attributes used to characterize the product performance and quality control of inhaled medications is the residual aerodynamic particle size distribution (APSD) of the aerosolized drug. Along with clinical factors, formulation and device parameters have a significant impact on APSD. In this study, a computational model was developed using the principles of statistics and physical chemistry to predict the residual APSD generated by suspension pMDIs based on formulation, device, and raw drug or excipient substance considerations. The formulations modeled and experimentally evaluated consist of a suspended drug or excipient with/without a dissolved drug or excipient in a cosolvent-propellant system. The in silico model enables modeling a process that is difficult to delineate experimentally and contributes to understanding the link between pMDI formulation and device to product performance. The ability to identify and understand the variables that affect atomization and/or aerosol disposition , such as initial droplet size, suspended micronized drug or excipient size, and drug or excipient concentration, facilitates defining the design space for suspension pMDIs during development and improves recognizing the sensitive of the APSD is on each hardware and formulation variable. This model can later be applied to limit batch-to-batch variation in the manufacturing process and selecting plausible suspension pMDI formulations with quality design as the end goal.

Este trabalho apresenta uma nova abordagem experimental para determinar a reatividade de sistemas subcríticos. O método a ser apresentado utiliza o modelo da cinética subcrítica desenvolvido por Gandini e Salvatores e baseia-se apenas em grandezas medidas, tais como a taxa de contagem no detector, e nos parâmetros que surgem do ajuste dos mínimos quadrados APSD (Auto Power Spectral Density) e CPSD (Cross Power Spectral Density), não sendo necessário lidar com as quantidades de maior complexidade como a eficiência de detector. A única hipótese feita neste método foi que a fração efetiva de nêutrons atrasados e o tempo de geração de nêutrons prontos fossem independentes do nível de subcriticalidade do sistema. O método proposto foi aplicado nas medidas de reatividade de várias configurações subcríticas do reator IPEN/MB-01. Foram realizadas medidas da APSD e CPSD em diversos graus de subcriticalidade (até em torno de -7000 pcm). Nos dados das densidades espectrais foram feitos ajustes por meio do método de mínimos quadrados para obter a constante de decaimento pronto (α) e outras grandezas. Com a finalide de melhorar as estatísticas de contagem de nêutrons, fonte externa de nêutrons de Am-Be foi instalada próximo ao núcleo, além da fonte de partida. O método experimental proposto mostra claramente que, a teoria da cinética pontual clássica não descreve a reatividade medida. Em vez disso, a reatividade inferida a partir do modelo da cinética pontual clássica é próxima, em seus valores absolutos, ao índice de subcriticalidade (ζ) para um determinado arranjo das fontes do experimeno. A concordância dos resultados obtidos por MCNP5 e GPT-TORT, ambos utilizando os dados nucleares da biblioteca ENDF/B-VII.0, com os resultados experimentais correspondentes são de boa qualidade. / This work presents a new experimental approach to determine the reactivity levels of subcritical systems. The method employs the subcritical kinetic model developed by Gandini and Salvatores and it is based only on measured quantities such as counting rates of the detectors employed in the experiments and the parameters arising from the least squares fitting of the APSD (Auto Power Spectral Density) and CPSD (Cross Power Spectral Density). Detector efficiencies, quantity required in other procedures such as Neutron Source Multiplication (NSM) method, are not needed in the proposed method. The only hypothesis made in the method was the independence of the effective delayed neutron fraction and the prompt neutron generation time to the subcriticality level of the system. The proposed method was applied to measure the reactivity of several subcritical configurations of the IPEN/MB-01 reactor. Measurements of APSD and CPSD were performed in several degrees of subcriticality (up to around -7000 pcm). The spectral densities data were least squares fitted to get the prompt decay mode (α) and other quantities. Beside the startup source of the facility, an external neutron source of Am-Be was installed near the core in order to improve neutron counting statistics. The final experimental results are of good quality. The proposed experimental method shows clearly that the classical point kinetic theory cannot describe the measured reactivity. Instead, the reactivity inferred from this model follows closely the subcriticality index (ζ) for the source arrangements in the experiment. The agreement of the MCNP5 and GPT-TORT results, both with ENDF/B-VII.0 as the basic nuclear data library, when compared to the corresponding experimental ones was also good.

Este trabalho apresenta uma nova abordagem experimental para determinar a reatividade de sistemas subcríticos. O método a ser apresentado utiliza o modelo da cinética subcrítica desenvolvido por Gandini e Salvatores e baseia-se apenas em grandezas medidas, tais como a taxa de contagem no detector, e nos parâmetros que surgem do ajuste dos mínimos quadrados APSD (Auto Power Spectral Density) e CPSD (Cross Power Spectral Density), não sendo necessário lidar com as quantidades de maior complexidade como a eficiência de detector. A única hipótese feita neste método foi que a fração efetiva de nêutrons atrasados e o tempo de geração de nêutrons prontos fossem independentes do nível de subcriticalidade do sistema. O método proposto foi aplicado nas medidas de reatividade de várias configurações subcríticas do reator IPEN/MB-01. Foram realizadas medidas da APSD e CPSD em diversos graus de subcriticalidade (até em torno de -7000 pcm). Nos dados das densidades espectrais foram feitos ajustes por meio do método de mínimos quadrados para obter a constante de decaimento pronto (α) e outras grandezas. Com a finalide de melhorar as estatísticas de contagem de nêutrons, fonte externa de nêutrons de Am-Be foi instalada próximo ao núcleo, além da fonte de partida. O método experimental proposto mostra claramente que, a teoria da cinética pontual clássica não descreve a reatividade medida. Em vez disso, a reatividade inferida a partir do modelo da cinética pontual clássica é próxima, em seus valores absolutos, ao índice de subcriticalidade (ζ) para um determinado arranjo das fontes do experimeno. A concordância dos resultados obtidos por MCNP5 e GPT-TORT, ambos utilizando os dados nucleares da biblioteca ENDF/B-VII.0, com os resultados experimentais correspondentes são de boa qualidade. / This work presents a new experimental approach to determine the reactivity levels of subcritical systems. The method employs the subcritical kinetic model developed by Gandini and Salvatores and it is based only on measured quantities such as counting rates of the detectors employed in the experiments and the parameters arising from the least squares fitting of the APSD (Auto Power Spectral Density) and CPSD (Cross Power Spectral Density). Detector efficiencies, quantity required in other procedures such as Neutron Source Multiplication (NSM) method, are not needed in the proposed method. The only hypothesis made in the method was the independence of the effective delayed neutron fraction and the prompt neutron generation time to the subcriticality level of the system. The proposed method was applied to measure the reactivity of several subcritical configurations of the IPEN/MB-01 reactor. Measurements of APSD and CPSD were performed in several degrees of subcriticality (up to around -7000 pcm). The spectral densities data were least squares fitted to get the prompt decay mode (α) and other quantities. Beside the startup source of the facility, an external neutron source of Am-Be was installed near the core in order to improve neutron counting statistics. The final experimental results are of good quality. The proposed experimental method shows clearly that the classical point kinetic theory cannot describe the measured reactivity. Instead, the reactivity inferred from this model follows closely the subcriticality index (ζ) for the source arrangements in the experiment. The agreement of the MCNP5 and GPT-TORT results, both with ENDF/B-VII.0 as the basic nuclear data library, when compared to the corresponding experimental ones was also good.