Light--responsive hydrogel valves with enhanced response characteristics compatible with microfluidics have been obtained by optimization of molecular design of spiropyran photoswitches and gel composition. Self--protonating gel formulations were exploited, wherein acrylic acid was copolymerized in the hydrogel network as an internal proton do--nor, to achieve a swollen state of the hydrogel in water at neutral pH. Light--responsive properties were endowed upon the hydrogels by copolymerization of spiropyran chromophores, using electron withdrawing and donating groups to tune the gel--swelling rate. Faster macroscopic swelling of the hydrogels was obtained by changing an ester to an ether at the 6' position (factor of 4) or shifting the ether group to the 8' position of the spiropyran (factor of 2.5) producing a 10 fold increase in total. The effect was also visible in the swelling behavior of the corresponding hydrogel valves, where the ob--served macroscopic changes were reversible and reproducible and in agreement with the molecular kinetics. Gel--valves integrated within microfluidic channels have been fabricated and allow reversible and repeatable operation, with opening of the valve effected in 1 minute, while closing takes around 5.5 minutes.
A key challenge during the transition from laboratory/small batch to continuous manufacturing is the development of a process strategy that can easily be adopted for a larger batch/continuous process. Industrial practice is to develop the isolation strategy for a new drug/process in batch using the design of experiment (DoE) approach to determine the best isolation conditions and then transfer the isolation parameters selected to a large batch equipment/continuous isolation process. This stage requires a series of extra investigations to evaluate the effect of different equipment geometry or even the adaptation of the parameters selected to a different isolation mechanism (e.g., from dead end to cross flow filtration) with a consequent increase of R&D cost and time along with an increase in material consumption. The CFD25 is an isolation device used in the first instance to develop an isolation strategy in batch (optimization mode) using a screening DoE approach and to then verify the transferability of the strategy to a semicontinuous process (production mode). A d-optimal screening DoE was used to determine the effect of varying the input slurry. Properties such as solid loading, particle size distribution, and crystallization solvent were investigated to determine their impact on the filtration and washing performance and the characteristics of the dry isolated product. A series of crystallization (ethanol, isopropanol, and 3-methylbutan-1-ol) and wash solvents (n-heptane, isopropyl acetate and n-dodcane) were used for the process. To mimic a real isolation process, paracetamol-related impurities, acetanilide and metacetamol, were dissolved in the mother liquor. The selected batch isolation strategy was used for the semicontinuous isolation run. Throughput and filtration parameters, such as cake resistance and flow rate, cake residual liquid content and composition, cake purity, particle−particle aggregation, and extent and strength of agglomerates, were measured to evaluate the consistency of the isolated product produced during a continuous experiment and compared with the isolated product properties obtained during the batch process development. Overall, the CFD25 is a versatile tool which allows both new chemical entity process development in batch and the production of the active pharmaceutical ingredient in semicontinuous mode using the same process parameters without changing equipment. The isolated product properties gained during the semicontinuous run are overall comparable between samples. The residual solvent content and composition differs between some samples due to filter plate blockage. In general, the mean properties obtained during semicontinuous running are comparable with the product properties simulated using the DoE.
We have compared the rate of thermal reversion of Spirooxazine (SO) from its merocyanine (MC) form within ionic liquids and molecular solvents. E t (30) and Kamlet-Taft parameter studies indicate ILs are comparable to polar protic and aprotic solvents. The observed reversion kinetics within the ionic liquids were slower than that of molecular solvents with similar polarity, 15 indicating a greater degree of interactions between the ionic liquid ions and the zwitterionic MC isomer, which led to increased lifetimes for the MC-ion complexes. Pre-metathesis cleaning of precursor salts was found to be necessary in order to obtain spectroscopic grade ILs for physiochemical analysis using solvatochromic probe dyes.
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