Phase separation monitoring

Solvent Process. In the solvent process, or solvent cook, water formed from the reaction is removed from the reactor as an a2eotropic mixture with an added solvent, typically xylene. Usually between 3 to 10 wt % of the solvent, based on the total charge, is added at the beginning of the esterification step. The mixed vapor passes through a condenser. The condensed water and solvent have low solubiUty in each other and phase separation is allowed to occur in an automatic decanter. The water is removed, usually to a measuring vessel. The amount of water collected can be monitored as one of the indicators of the extent of the reaction. The solvent is continuously returned to the reactor to be recycled. Typical equipment for this process is shown in Figure 2. The reactor temperature is modulated by the amount and type of refluxing solvent. Typical conditions are ... 

Excessive mixing Limit agitator power input and provide proper of reactants or impeller design impurities which, Return process to pilot or development to rede-promotes process to eliminate or minimize this emulsification. problem Poor phase separa- tion resulting in L it shaft speed problems in subse- Monitor shaft speed quent processing, phase separation steps or in down- stream equipment. I" " de-emulsifiers CCPS G-29 Lees 1996... 

Stability of a drug substance and product is monitored throughout the development and clinical phases. This monitoring requires stability-indicating assay methodology, and this is a subject that is separate from performulation per se. In most instances, the major, feasible decomposition products are identified early [51], and as such it is known if the pathways are hydrolytic, oxidative, or photochemical. 

Phase Separation. An approximate estimation of phase separation may be obtained visually. In general, creaming, flocculation, and coalescence have occurred before phase separation is visible, thus sometimes making quantitative evaluations more difficult. Accelerating the separation by centrifugation followed by appropriate analysis of the specimens may be useful to quantitatively determine the phase separation. Details on mechanisms of creaming and phase separation as well as some advances in the monitoring techniques of emulsion stability have been reviewed by Robins [146]. 

Phase separation of the saturated solution from the excess solid solute is a critical process. If a filter is employed, it must be inert to the solvent, it must not release plasticizers, and its pore size must be small enough to retain the smallest particles of the solid solute. Furthermore, steps must be taken to monitor, minimize, and preferably avoid losses of the dissolved solute by adsorption onto the filter material [27-30] and/or onto the vessels, pipettes, and syringes. Typically, the first small volume of filtrate is discarded until the surfaces of the filter and/or vessels are saturated with the adsorbed solute, to ensure that the filtrate analyzed has not suffered significant adsorption losses. Adsorption can be a serious problem for hydrophobic solutes, for which filtration would not be recommended. 

If decantation or centrifugation is employed for phase separation of the saturated solution, any disturbance and carryover of the undissolved solid solute (whether precipitated or floating) must be monitored and avoided. 

Polymers dynamics of polymer chains microviscosity free volume orientation of chains in stretched samples miscibility phase separation diffusion of species through polymer networks end-to-end macrocyclization dynamics monitoring of polymerization degradation... 

The increase of pore size with increasing amount of solvent can also be monitored with dynamic DSC-measurements. An endothermic peak at T=7 °C, corresponding to the melting point of crystalline cyclohexane, is observed in the opaque samples after the phase separation resulting from the formation of dispersed cyclohexane droplets (Fig. 53). 

Figure 5.10 shows an advanced version of this technique [16]. The apparatus incorporates a continuous monitoring of the rate and permits instantaneous data analyses that are accomplished by the use of a Teflon phase separator and an online microcomputer. The device allows measurement of extraction rates with half-lives as short as 10 s. 

A typical extraction manifold is shown in Figure 13.2. The sample is introduced by aspiration or injection into an aqueous carrier that is segmented with an organic solvent and is then transported into a mixing coil where extraction takes place. Phase separation occurs in a membrane phase separator where the organic phase permeates through the Teflon membrane. A portion of one of the phases is led through a flow cell and an on-line detector is used to monitor the analyte content. The back-extraction mode in which the analyte is returned to a suitable aqueous phase is also sometimes used. The fundamentals of liquid liquid extraction for FIA [169,172] and applications of the technique [174 179] have been discussed. Preconcentration factors achieved in FIA (usually 2-5) are considerably smaller than in batch extraction, so FI extraction is used more commonly for the removal of matrix interferences. 

As an aside, we note that the FDEMS sensor input information can also be used to detect the onset of phase separation in toughened thermoset systems and to monitor cure in thin film coatings and adhesive bond lines. It is particularly important that the FDEMS sensor is also very sensitive to changes in the mechanical properties of the resin due to degradation. As such, it can be used for accelerated aging studies and as a dosimeter to monitoring the composite part during use to determine the knockdown in the required performance properties with time. 

Physical stability. As indicated earlier, conventional emulsions are inherently unstable from a physical standpoint. Poor physical stability is ultimately exhibited by phase separation, which can be visually monitored. Certain properties of the emulsion will start to change long before this separation is visually apparent. An increase in particle size is particularly indicative of physical instability, since this monitors the coalescence or Locculation that is part of the process involved in ultimate phase separation. Increases in viscosity (due to Locculation) and changes in zeta potential (arising from a decrease in droplet surface area) are both indicative of poor physical stability. The presence of drug and cosolvents can potentially hasten the phase separation. 

The bilayer morphology of thin asymmetric films of may be unstable. A regularly corrugated surface structure of the films was ascribed to spinodal transition into a laterally phase separated structure, where the surface morphology depended on the polymer incompatibility and the interfacial interactions [347, 348]. Recently, the phase separation and dewetting of thin films of a weakly incompatible blend of deuterated PS and poly(p-methylstyrene) have been monitored by SFM [349, 350]. Starting from a bilayer structure, after 454 h at T= 154 °C the film came to the final dewetting state where mesoscopic drops of... 

The use of precision density measurements for monitoring polymerization reactions can be done rapidly and automatically using commercially available instrumentation. The method is independent of the reactor size and design but suffers from sampling difficulties. The examples of this paper show the rapidity of data collection and three distinct sampling problems pump failure from either monomer attack or polymer scale formation, monomer phase separation in the density cell, and the lag time for rapid polymerizations. Techniques have or can be devised to avoid or reduce the influence of these problems. 

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