Real-Time Monitoring of Continuous Pharmaceutical Mixed Suspension Mixed Product Removal Crystallization Using Image Analysis

Abstract

In this work, we developed an in-line image analysis system for the monitoring of the continuous crystallization of an active pharmaceutical ingredient. Acetylsalicylic acid was crystallized in a mixed suspension mixed product removal crystallizer, which was equipped with overflow tubing as an outlet. A steep glass plate was placed under the outlet onto which the slurry dripped on its surface. The glass plate spread and guided the droplets toward the product collection filter. A high-speed process camera was mounted above the glass plate to capture images of the crystals. Several light sources were tested in various positions to find the appropriate experimental setup for the optimal image quality. Samples were taken during continuous operation for off-line particle size analysis in order to compare to the crystal size distributions calculated from the images. The results were in good agreement, and the trends of the process could be followed well using the images. As a next step, image analysis was operated throughout the entire continuous crystallization experiment, and a huge quantity of information was collected from the process. The crystal size distribution of the product was calculated every 30 s, which provided a thorough and detailed insight into the crystallization process.

Condensed Phase Membrane Introduction Mass Spectrometry: A Direct Alternative to Fully Exploit the Mass Spectrometry Potential in Environmental Sample Analysis

“…However, in most cases, the matrix complexity usually leads to side phenomena which make the use of specific techniques mandatory [55]. Moreover, conventional procedures require to perform several samplings at regular intervals followed by sample preparation and chromatographic separation steps [56,57]. Recently, ambient ionization mass spectrometry (AMS) has been successfully applied to monitor online and offline chemical reactions.…”

Process Analytical Technology for the Production of Parenteral Lipid Emulsions According to Good Manufacturing Practices

“…For both devices, the inline microscope showed that increasing the input power significantly reduced the induction time. Another inline image monitoring system known as dynamic image analysis (DIA) was developed for the continuous crystallization of acetylsalicylic acid [102]. This system was used for the first time in a continuous mixed suspension mixed product removal (MSMPR) crystallization process.…”

Development of Continuous Additive-Controlled MSMPR Crystallization by DoE-Based Batch Experiments

“…Continuous crystallization is a well-established research field with two basic operational implementations, which are the mixed suspension mixed product removal (MSMPR) crystallizers , and different tubular crystallizers (TC). − The assembling of more MSMPR units into a cascade crystallizer system or the connection of different types of continuous crystallizers − allows even more possibilities to control crystallization on its subprocess levels. The elevated performance of merging continuous and additive-controlled crystallization is demonstrated through the following examples from the literature.…”

“…25,26 In addition, these benefits fit well with the idea of additive-controlled crystallization to simplify downstream formulation by targeted morphology alteration to make solid API production more efficient and economical. Continuous crystallization is a well-established research field with two basic operational implementations, which are the mixed suspension mixed product removal (MSMPR) crystallizers 27,28 and different tubular crystallizers (TC). 29−34 The assembling of more MSMPR units into a cascade crystallizer system 35 or the connection of different types of continuous crystallizers 36−40 allows even more possibilities to control crystallization on its subprocess levels.…”