Investigations concerning the residence time distribution of twin-screw-extrusion processes as indicator for inherent mixing

Over recent years Twin-Screw-Extrusion (TSE) has been established as a platform technology for pharmaceutical manufacturing. Compared to other continuous operation, one of the major benefits of this method is the combination of several unit operations within one apparatus. Several of these are linked to the Residence Time Distribution (RTD), which is typically expressed by the residence time density function. One relevant aspect for pharmaceutical processes is the mixing capacity, which is represented by the width of this distribution. In the frame of this study the influence of the mass flow, the temperature and the screw-barrel clearance were investigated for a constant barrel load (specific feed load, SFL). While the total mass flow as well as the external screw diameter affected the mixing performance, the barrel temperature had no influence for the investigated range. The determined results were additionally evaluated with respect to a fit to the Twin-Dispersion-Model (TDM). This model is based on the superimposition of two mixing functions. The correlations between varied process parameters and the obtained characteristic model parameters proved this general physical view on extrusion

Development and Validation of an In‐Line API Quantification Method Using AQbD Principles Based on UV‐Vis Spectroscopy to Monitor and Optimise Continuous Hot Melt Extrusion Process

open access journalA key principle of developing a new medicine is that quality should be built in, with a thorough understanding of the product and the manufacturing process supported by appropriate process controls. Quality by design principles that have been established for the development of drug products/substances can equally be applied to the development of analytical procedures. This paper presents the development and validation of a quantitative method to predict the concentration of piroxicam in Kollidon® VA 64 during hot melt extrusion using analytical quality by design principles. An analytical target profile was established for the piroxicam content and a novel in‐line analytical procedure was developed using predictive models based on UV‐Vis absorbance spectra collected during hot melt extrusion. Risks that impact the ability of the analytical procedure to measure piroxicam consistently were assessed using failure mode and effect analysis. The critical analytical attributes measured were colour (L* lightness, b* yellow to blue colour parameters—in‐process critical quality attributes) that are linked to the ability to measure the API content and transmittance. The method validation was based on the accuracy profile strategy and ICH Q2(R1) validation criteria. The accuracy profile obtained with two validation sets showed that the 95% β‐expectation tolerance limits for all piroxicam concentration levels analysed were within the combined trueness and precision acceptance limits set at ±5%. The method robustness was tested by evaluating the effects of screw speed (150–250 rpm) and feed rate (5–9 g/min) on piroxicam content around 15% w/w. In‐line UV‐Vis spectroscopy was shown to be a robust and practical PAT tool for monitoring the piroxicam content, a critical quality attribute in a pharmaceutical HME process

Проект установки получения синтез-газа

ВКР 91 страницу, 6 рисунков, 40 таблиц, 24 литературных источника. Ключевые слова: синтез-газ, конверсия, применение синтез-газа, сырье, природный газ, технологическая схема, производство, метан, метанол. Объект разработки: производство синтез-газа методом паровой каталитической конверсии природного газа. Цель работы: изучение всех физико - химических свойств процесса и их влияния на протекание реакции, а также конструирование основного аппарата установки получения синтез - газа. В результате исследования выполнен расчет материального и теплового балансов, также конструктивный и механический расчеты, на основании которых был выполнен чертеж основного аппарата. ВКР выполнена на кафедре ТОВПМ ст. группы 2Д2А Якимовой В.А., под руководством к.х.н. Мананковой А.А.The final qualifying work contains 91 page, 6 figures, 40 tables and 24 literature sources. Content words are conversion, synthesis gas. The object of the development is the production of synthesis gas by catalytic steam reforming of natural gas. The mission is the study of physical - chemical properties of the process and their influence on the reaction, as well as the construction of the main unit installation producing synthesis - gas. The study was carried out payment of material and heat balances, the constructive and mechanical calculations, drawing on the basis of which the main unit was made. The final qualifying work carried out at the Department of TOVPM student group 2D2A Vera Yakimova, under the leadership of Candidate of Chemical Sciences Ann Manankova

Inline determination of residence time distribution in hot-melt-extrusion

In the framework of Quality-by-Design (QbD), the inline determination of process parameters or quality attributes of a product using sufficient process analytical technology (PAT) is a center piece for the establishment of continuous processes as a standard pharmaceutical technology. In this context, Twin-Screw-Extrusion (TSE) processes, such as Hot-Melt-Extrusion (HME), are one key aspect of current research. The main benefit of this process technology is the combination of different unit operations. Several of these sub-processes are linked to the Residence Time Distribution (RTD) of the material within the apparatus. In this study a UV/Vis spectrophotometer from ColVisTec was tested regarding the suitability for the inline determination of the RTD of an HME process. Two different measuring positions within a co-rotating Twin-Screw-Extruder were compared to an offline HPLC–UV as reference method. The obtained results were overall in good agreement and therefore the inline UV/Vis spectrophotometer is suitable for the determination of the RTD in TSE. An influence of the measuring position on repeatability was found and has to be taken into consideration for the implementation of PATs. An effect of the required amount of marker on process rheology is not likely due to the low Limit-of-Quantification (LoQ)

Distinguishing between pre- and post-treatment in the speech of patients with chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) causes lung inflammation and airflow blockage leading to a variety of respiratory symptoms; it is also a leading cause of death and affects millions of individuals around the world. Patients often require treatment and hospitalisation, while no cure is currently available. As COPD predominantly affects the respiratory system, speech and non-linguistic vocalisations present a major avenue for measuring the effect of treatment. In this work, we present results on a new COPD dataset of 20 patients, showing that, by employing personalisation through speaker-level feature normalisation, we can distinguish between pre- and post-treatment speech with an unweighted average recall (UAR) of up to 82% in (nested) leave-one-speaker-out cross-validation. We further identify the most important features and link them to pathological voice properties, thus enabling an auditory interpretation of treatment effects. Monitoring tools based on such approaches may help objectivise the clinical status of COPD patients and facilitate personalised treatment plans

UV-VIS spectra as potential process analytical technology (PAT) for measuring the density of compressed materials: Evaluation of the cielab color space

In this study, a novel approach was developed for determining the density of compacts using ultraviolet–visible spectrophotometry. The assumption within this context was that a change in density affects the corresponding color information of the compact. From the obtained spectra of the visible range, the color information of the compact was calculated which turned out to be directly proportional to the density of the compact. In comparison, the obtained spectra were analyzed using partial least square regression. The results of this study showed that both methods could be used predicting the density of a compact from the corresponding visible spectrum at identical accuracy. In contrast to the partial least square regression, the correlation of the color information as a direct output parameter of the spectrophotometer with the density required no excessive data pre-processing. Subsequently, the easier and faster data processing of the color information over the partial least square regression, conceives using this novel approach as potential process analytical technology tool for implementation into a compression process e.g., tableting or roller compaction

Distinguishing between pre- and post-treatment in the speech of patients with chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) causes lung inflammation and airflow blockage leading to a variety of respiratory symptoms; it is also a leading cause of death and affects millions of individuals around the world. Patients often require treatment and hospitalisation, while no cure is currently available. As COPD predominantly affects the respiratory system, speech and non-linguistic vocalisations present a major avenue for measuring the effect of treatment. In this work, we present results on a new COPD dataset of 20 patients, showing that, by employing personalisation through speaker-level feature normalisation, we can distinguish between pre- and post-treatment speech with an unweighted average recall (UAR) of up to 82\,\% in (nested) leave-one-speaker-out cross-validation. We further identify the most important features and link them to pathological voice properties, thus enabling an auditory interpretation of treatment effects. Monitoring tools based on such approaches may help objectivise the clinical status of COPD patients and facilitate personalised treatment plans.Comment: Accepted in INTERSPEECH 202

B-RAF and N-RAS Mutations Are Preserved during Short Time In Vitro Propagation and Differentially Impact Prognosis

In melanoma, the RAS/RAF/MEK/ERK signalling pathway is an area of great interest, because it regulates tumor cell proliferation and survival. A varying mutation rate has been reported for B-RAF and N-RAS, which has been largely attributed to the differential source of tumor DNA analyzed, e.g., fixed tumor tissues or in vitro propagated melanoma cells. Notably, this variation also interfered with interpreting the impact of these mutations on the clinical course of the disease. Consequently, we investigated the mutational profile of B-RAF and N-RAS in biopsies and corresponding cell lines from metastatic tumor lesions of 109 melanoma patients (AJCC stage III/IV), and its respective impact on survival. 97 tissue biopsies and 105 biopsy-derived cell lines were screened for B-RAF and N-RAS mutations by PCR single strand conformation polymorphism and DNA sequencing. Mutations were correlated with patient survival data obtained within a median follow-up time of 31 months. B-RAF mutations were detected in 55% tissues and 51% cell lines, N-RAS mutations in 23% tissues and 25% cell lines, respectively. There was strong concordance between the mutational status of tissues and corresponding cell lines, showing a differing status for B-RAF in only 5% and N-RAS in only 6%, respectively. Patients with tumors carrying mutated B-RAF showed an impaired median survival (8.0 versus 11.8 months, p = 0.055, tissues; 7.1 versus 9.3 months, p = 0.068, cell lines), whereas patients with N-RAS-mutated tumors presented with a favorable prognosis (median survival 12.5 versus 7.9 months, p = 0.084, tissues; 15.4 versus 6.8 months, p = 0.0008, cell lines), each in comparison with wildtype gene status. Multivariate analysis qualified N-RAS (p = 0.006) but not B-RAF mutation status as an independent prognostic factor of overall survival. Our findings demonstrate that B-RAF and N-RAS mutations are well preserved during short term in vitro propagation and, most importantly, differentially impact the outcome of melanoma patients