Improvement of drug processability in a connected continuous crystallizer system using formulation additive.

Continuous crystallization in the presence of polymer additives is a promising method to omit some drug formulation steps by improving the technological and also pharmacological properties of crystalline active ingredients. Accordingly, this study focuses on developing an additive-assisted continuous crystallization process using polyvinylpyrrolidone in a connected ultrasonicated plug flow crystallizer and an overflow mixed suspension mixed product removal (MSMPR) crystallizer system. We aimed to improve the flowability characteristics of small, columnar primary plug flow crystallizer-produced acetylsalicylic acid crystals as a model drug by promoting their agglomeration in MSMPR crystallizer with polyvinylpyrrolidone. The impact of the cooling antisolvent crystallization process parameters (temperature, polymer amount, total flow rate) on product quality and quantity was investigated. Finally, a spatially segmented antisolvent dosing method was also evaluated. The developed technology enabled the manufacture of purified, constant quality products in a short startup period, even with an 85% yield. We found that a higher polymer amount (7.5-14%) could facilitate agglomeration resulting in "good" flowability without altering the favorable dissolution characteristics of the primary particles.

Improvement of Component Flux Estimating Model for Pervaporation Processes.

Separating non-ideal mixtures by pervaporation (hence PV) is a competitive alternative to most traditional methods, such as distillation, which are based on the vapour-liquid equilibrium (VLE). It must be said, in many cases, accurate VLE data are already well known in the literature. They make the method of PV modelling a lot more complicated, and most of the viable models are (semi)empirical and focus on component flux (Ji) estimation. The pervaporation model of Mizsey and Valentinyi, which is based on Rautenbach's works, is further improved in this work and tested rigorously by statistical means. Until now, this type of exponential modelling was only used for alcohol-water mixtures, but in this work, it was extended to an ethyl acetate-water binary mixture as well. Furthermore, a flowchart of modelling is presented for the first time in the case of an exponential pervaporation model. The results of laboratory-scale experiments were used as the basis of the study and least squares approximation was used to compare them to the different model's estimations. According to our results, Valentinyi's model (Model I) and the alternative model (Model III) appear to be the best methods for PV modelling, and there is no significant difference between the models, mainly in organophilic cases. In the case of the permeation component, Model I, which better follows the exponential function, is recommended. It is important to emphasize that our research confirms that the exponential type model seems to be universally feasible for most organic-water binary mixtures. Another novelty of the work is that after PDMS and PVA-based membranes, the accuracy of the semiempirical model for the description of water flux on a PEBA-based membrane was also proved, in the organophilic case.

Membrane Flash Index: Powerful and Perspicuous Help for Efficient Separation System Design.

There are different factors and indices to characterize the performance of a pervaporation membrane, but none of them gives information about their capabilities in the area of liquid separation compared to the most convenient alternative, which is distillation. Membrane flash index (MFLI) can be considered the first and only one that shows if the membrane is more efficient or not than distillation and quantifies this feature too. Therefore, the MFLI helps select the best separation alternative in the case of process design. In this study, the evaluation and capabilities of membrane flash index are comprehensively investigated in the cases of six aqueous mixtures: methyl alcohol-water, ethyl alcohol-water, isobutyl alcohol-water, tetrahydrofuran-water, N-butyl alcohol-water, and isopropanol-water. It must be concluded that the separation capacity of organophilic type membranes is remarkably lower than hydrophilic membranes in all cases of separation. The study of the MFLI is extended with the consideration of other binary interaction parameters like separation factor, permeation flux, selectivity, and pervaporation separation index (PSI) in order to find a descriptive relationship between them. For the same membrane material type, descriptive function can be determined between feed concentration and MFLI and PSI and separation factor, which can be used to calculate each other's value. On the basis of the indices and especially the MFLI, a significant help can be given to the process design engineer to select the right liquid separation alternative and, in the case of pervaporation, find the most appropriate membrane.

High-throughput screening of organic reactions in microdroplets using desorption electrospray ionization mass spectrometry (DESI-MS): hardware and software implementation.

This study describes an automated system used for high throughput screening of reaction conditions based on accelerated reactions occurring in small volumes of reagents. Reaction mixtures are prepared in array format using a fluid handling robot and spotted on a flat polytetrafluoroethylene plate at densities up to 6144 per plate. The reaction and analysis steps are performed simultaneously using desorption electrospray ionization (DESI) to release microdroplets containing the reaction mixture from the plate for reaction prior to arrival at a mass spectrometer. Analysis rates are up to 1 reaction mixture per second and data are recorded in real time using an ion trap mass spectrometer. Beacon compounds are used to triangulate position on the plate and this allows tandem mass spectrometry (MS/MS) to be performed on confirm products of interest. Custom software allows the user to control the system. It is also used to receive data from the DESI mass spectrometer to screen the spectra for compounds of interest, to perform MS/MS and to save data. This custom software also communicates with the software controlling the fluid handling robot (Biomek i7) as well as the Beckman software used to prepare reaction mixtures and also the software that controls the solvent used as the DESI spray. Data were recorded for N-alkylation, N-acylation and N-sulfonylation reactions in three 8 hour experiments on successive days to establish the ruggedness and repeatability of the system. Repeatability is high (94-97%) over this period with false negative 6% (depending on noise threshold chosen). Plates containing 384 reaction mixtures are analyzed in 7 min by moving the DESI sprayer in steps under the sprayer instead of continuously.

End-to-end continuous manufacturing of conventional compressed tablets: From flow synthesis to tableting through integrated crystallization and filtration.

An end-to-end continuous pharmaceutical manufacturing process was developed for the production of conventional direct compressed tablets on a proof-of-concept level for the first time. The output reaction mixture of the flow synthesis of acetylsalicylic acid was crystallized continuously in a mixed suspension mixed product removal crystallizer. The crystallizer was directly connected to a continuous filtration carousel device, thus the crystallization, filtration and drying of acetylsalicylic acid (ASA) was carried out in an integrated 2-step process. Steady state was reached during longer operations and the interaction of process parameters was evaluated in a series of experiments. The filtered crystals were ready for further processing in a following continuous blending and tableting experiment due to the good flowability of the material. The ASA collected during the crystallization-filtration experiments was fed into a continuous twin-screw blender along with microcrystalline cellulose as tableting excipient. After continuous blending Near-Infrared spectroscopy was applied to in-line analyze the drug content of the powder mixture. A belt conveyor carried the mixture towards an eccentric lab-scale tablet press, which continuously produced 500 mg ASA-loaded compressed tablets of 100 mg dose strength. Thus, starting from raw materials, the final drug product was obtained by continuous manufacturing steps with appropriate quality.

High-Throughput Experimentation and Continuous Flow Evaluation of Nucleophilic Aromatic Substitution Reactions.

Nucleophilic aromatic substitution (SNAr) reactions were optimized using high-throughput experimentation techniques for execution under flow conditions. A total of 3072 unique reactions were evaluated with an analysis time of ∼3.5 s per reaction using a system that combines a liquid handling robot for reaction mixture preparation with desorption electrospray ionization (DESI) mass spectrometry (MS) for analysis. The reactions were performed in bulk microtiter arrays with and without incubation. In-house developed software was used to process the data and generate heat maps of the results. This information was then used to select the most promising conditions for continuous synthesis under microfluidic reactor conditions. Our results show that this HTE approach provides robust guidance for narrowing the range of conditions needed for optimization of SNAr reactions.