Comparison of Amorphous Solid Dispersions of Spironolactone Prepared by Spray Drying and Electrospinning: The Influence of the Preparation Method on the Dissolution Properties.

This research aimed to compare two solvent-based methods for the preparation of amorphous solid dispersions (ASDs) made up of poorly soluble spironolactone and poly(vinylpyrrolidone-co-vinyl acetate). The same apparatus was used to produce, in continuous mode, drug-loaded electrospun (ES) and spray-dried (SD) materials from dichloromethane and ethanol-containing solutions. The main differences between the two preparation methods were the concentration of the solution and application of high voltage. During electrospinning, a solution with a higher concentration and high voltage was used to form a fibrous product. In contrast, a dilute solution and no electrostatic force were applied during spray drying. Both ASD products showed an amorphous structure according to differential scanning calorimetry and X-ray powder diffraction results. However, the dissolution of the SD sample was not complete, while the ES sample exhibited close to 100% dissolution. The polarized microscopy images and Raman microscopy mapping of the samples highlighted that the SD particles contained crystalline traces, which can initiate precipitation during dissolution. Investigation of the dissolution media with a borescope made the precipitated particles visible while Raman spectroscopy measurements confirmed the appearance of the crystalline active pharmaceutical ingredient. To explain the micro-morphological differences, the shape and size of the prepared samples, the evaporation rate of residual solvents, and the influence of the electrostatic field during the preparation of ASDs had to be considered. This study demonstrated that the investigated factors have a great influence on the dissolution of the ASDs. Consequently, it is worth focusing on the selection of the appropriate ASD preparation method to avoid the deterioration of dissolution properties due to the presence of crystalline traces.

In-line particle size measurement based on image analysis in a fully continuous granule manufacturing line for rapid process understanding and development.

The present paper serves as a demonstration how an in-line PAT tool can be used for rapid and efficient process development in a fully continuous powder to granule line consisting of an interconnected twin-screw wet granulator, vibrational fluid bed dryer, and a regranulating mill. A new method was investigated for the periodic in-line particle size measurement of high mass flow materials to obtain real-time particle size data of the regranulated product. The system utilises a vibratory feeder with periodically altered feeding intensity in order to temporarily reduce the mass flow of the material passing in front of the camera. This results in the drastic reduction of particle overlapping in the images, making image analysis a viable tool for the in-line particle size measurement of high mass-flow materials. To evaluate the performance of the imaging system, the effect of several milling settings and the liquid-to-solid ratio was investigated on the product's particle size in the span of a few hours. The particle sizes measured with the in-line system were in accordance with the expected trends as well as with the results of the off-line reference particle size measurements. Based on the results, the in-line imaging system can serve as a PAT tool to obtain valuable real-time information for rapid process development or quality assurance.

Fully automatic segmentation of right and left ventricle on short-axis cardiac MRI images.

Cardiac magnetic resonance imaging (CMR) is a widely used non-invasive imaging modality for evaluating cardiovascular diseases. CMR is the gold standard method for left and right ventricular functional assessment due to its ability to characterize myocardial structure and function and low intra- and inter-observer variability. However the post-processing segmentation during the functional evaluation is time-consuming and challenging. A fully automated segmentation method can assist the experts; therefore, they can do more efficient work. In this paper, a regression-based fully automated method is presented for the right- and left ventricle segmentation. For training and evaluation, our dataset contained MRI short-axis scans of 5570 patients, who underwent CMR examinations at Heart and Vascular Center, Semmelweis University Budapest. Our approach is novel and after training the state-of-the-art algorithm on our dataset, our algorithm proved to be superior on both of the ventricles. The evaluation metrics were the Dice index, Hausdorff distance and volume related parameters. We have achieved average Dice index for the left endocardium: 0.927, left epicardium: 0.940 and right endocardium: 0.873 on our dataset. We have also compared the performance of the algorithm to the human-level segmentation on both ventricles and it is similar to experienced readers for the left, and comparable for the right ventricle. We also evaluated the proposed algorithm on the ACDC dataset, which is publicly available, with and without transfer learning. The results on ACDC were also satisfying and similar to human observers. Our method is lightweight, fast to train and does not require more than 2 GB GPU memory for execution and training.

Digital UV/VIS imaging: A rapid PAT tool for crushing strength, drug content and particle size distribution determination in tablets.

The Process Analytical Technology (PAT) and the Quality-by-Design (QbD) approaches can efficiently facilitate the shift to the desired continuous manufacturing and real time release testing (RTRT). By this, it is vital to develop new, in-line analytical methods which fulfil the pharmaceutical requirements. The fast-developing digital imaging-based machine vision systems can provide revolutionary solutions not just in the automotive industry but in the pharmaceutical technology, as well. This study aimed to explore the capabilities of UV/VIS-based machine vision in tablet inspection as a PAT tool for the determination of compression force and crushing strength, drug content and drug distribution in tablets using meloxicam a yellow model drug. In the case of determining the compression force and crushing strength, the application of multivariate wavelet texture analysis (MWTA) based models provided relatively low prediction errors. To predict the drug content of meloxicam tablets CIELAB or RGB colorspace based algorithms were successfully developed and validated. UV/VIS imaging was also used to map the particle size distribution and spatial distribution of meloxicam, the results were compared to chemical maps obtained by Raman microscopy. Digital imaging combined with multivariate data analysis might be a valuable, high throughput, in-line PAT tool for automated inspection of pharmaceutical tablets.

Videometric mass flow control: A new method for real-time measurement and feedback control of powder micro-feeding based on image analysis.

The present paper reports the first monitoring and control of ultra-low dose powder feeding using a camera image-based mass flow measurement system. Caffeine was fed via a single-screw microfeeder as a model active pharmaceutical ingredient (API). The mass, mass flow and sizes of the particles were successfully monitored in real-time by the developed videometric system consisting of a high-speed process camera coupled with an image analysis software. The system was also tested in feedback control mode to automatically reach the desired mass flow values by adjusting the feeder speed based on the mass flow measured by the image analysis system. Based on these features, the developed videometric system can serve as a multi-purpose PAT-tool and can provide valuable real-time information about the process which is indispensable for modern continuous pharmaceutical manufacturing.

Real-time feedback control of twin-screw wet granulation based on image analysis.

The present paper reports the first dynamic image analysis-based feedback control of continuous twin-screw wet granulation process. Granulation of the blend of lactose and starch was selected as a model process. The size and size distribution of the obtained particles were successfully monitored by a process camera coupled with an image analysis software developed by the authors. The validation of the developed system showed that the particle size analysis tool can determine the size of the granules with an error of less than 5 µm. The next step was to implement real-time feedback control of the process by controlling the liquid feeding rate of the pump through a PC, based on the real-time determined particle size results. After the establishment of the feedback control, the system could correct different real-life disturbances, creating a Process Analytically Controlled Technology (PACT), which guarantees the real-time monitoring and controlling of the quality of the granules. In the event of changes or bad tendencies in the particle size, the system can automatically compensate the effect of disturbances, ensuring proper product quality. This kind of quality assurance approach is especially important in the case of continuous pharmaceutical technologies.