SOLVENTS AND ANTISOLVENTS

Supercritical fluids have the ability to dissolve nonpolar solids, and this is what makes them useful for various applications, especially cleaning, though the fact that solids can dissolve in gases remains counterintuitive to most scientists. A number of attempts have been 

For supercritical fluids, the solvent strength of a given fluid is primarily dependent upon its density and pressure. It is much easier to directly measure and control the pressure of a supercritical fluid in a given operation than to measure and control the fluid density. 

It is possible, however, to detomine a relationship exists between the fluid pressure and its density, thus allowing in(tirect measurement and control of the density. For an ideal gas, the rdationship is simply, PV/RT = 1, where Fis the molar volume (reciprocal of the molar density). From the molecular wdght of the gas (M) the mass density, p, can be calculated as M/V. The simple equation breaks down at the high densities characteristic of supercritical fluids, but, the work of Pitzer et al.l allows the ideal gas law to be extended by introducing a term called the compressibility factor, z. It is a 

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Once a set of potential solvents (and antisolvents) have been identified then the solubility behavior should be assessed in the laboratory, confirming the effect of temperature, the isolated solid form and the limits of purification. 

The main driving force of a salting-out precipitation process is the supersaturation generated by the different solubilities of the solute in the solvent and antisolvent. The one-shot mode generally means that the necessary amount of the antisolvent is added in one portion to the initial solution (either saturated or undersaturated) as it is schematically shown in Fig. 2. In our cases the aqueous solution was added to the antisolvent. As a result of the antisolvent addition the original solubility of the substance will change until the new equilibrium solubility, ceq has been reached. To characterize the supersaturation driving force in a precipitation system the so called initial supersaturation,. S, is used ... 

The production of polymeric HYAFF microspheres loaded with the pharmaceutical is currently performed by solvent emulsion precipitation [4], This process requires the preparation of an emulsion of two immiscible liquids. The polymer and the co-precipitated pharmaceutical can be inactivated or degraded due to the temperature that is required for solvents removing. Moreover, a complete separation of the residual solvents cannot be achieved and a relevant percentage of liquid is retained within the final product. Finally, liquid solvent and antisolvent cannot be recovered. 

A typical particle size distribution of sample as in Figure 2 is shown in Figure 3. Every run produced particles smaller than 1 pm, average diameter is around 0.4 pm. Compared to the liquid antisolvent process, the improvement achieved in term of particle size is remarkable in addition, the number of organic solvents used is now reduced to one and both solvent and antisolvent can be recovered. 

Various solvents and antisolvents were screened experimentally. Among them, dimethyl formamide (DMF) and IP AC appeared to offer the best combination based upon product solubility and the ability to retain the desired crystal form. 

Figure 8.3 the precipitator is partially filled with the solution of the active substance. CO2 is then pumped up to the desired pressure and introduced in the vessel, preferably from the bottom to achieve a better mixing of the solvent and antisolvent. After a holding time, the expanded solution is drained under isobaric conditions to wash and clean the precipitated particles. 

MiCoS shares similar pros and cons to solvent-casting methods. With parallel preparation, it is highly efficient and effective in evaluating polymer types, drug loadings and antisolvent/solvent ratio comprehensively. However, the residue solvent and antisolvent content, which are critical for amorphous stability, cannot be determined due to low amount of solid products. The kinetic solubility results can only be interpreted qualitatively rather than quantitatively, as the particle size of the miniaturized products are not tightly controlled. 

Miscibility of solvent with the antisolvent Solvent must be miscible with the antisolvent. This is an important factor as the rapid precipitation is primarily afforded by rapid mixing of solvent and antisolvent. If organic solvent is partially miscible, precipitation inefficiency may result owing to liquid-phase separation. In addition, the extraction of solvent out of the precipitates will not be efficient in subsequent washing and rinsing cycles. 

Efficient and rapid removal of solvent and antisolvent is a vital component of the successful MBPprocess. Once the precipitation has been completed (concurrently for continuous process and at the end of the solvent addition for the semi-batch process), the MBP is filtered from the suspension. This is generally performed by any of the standard filtration processes such as vacuum filtration ranging from Buchner funnel to Nutsche filter or centrifugal filter. Centrifugal filters are preferred for filtration of MBP suspension because of the particle size, the hydrogel nature of the polymer, and the effectiveness in solid/liquid separation... 

The variability in an isothermal antisolvent precipitation can best be described in a triangular solubility diagram (Figure 12.15). The tie line for a certain concentration of the active in the organic solvent and the tie line for a certain mixing ratio of the solvent and antisolvent are shown. The intersection of both lines defines the supersaturation at ideal mixing. By varying the solute concentration and the ratio of solvent and antisolvent, different supersaturation can be realized Table 12.1 exemplifies typical values. 

Values are given for different starting concentrations of the solute in the solvent and mixing ratios of solvent and antisolvent. 

Operating parameters such as the initial polymer concentration, initial oil concentration (in the case of nanocapsules), and flow rates of solvent and antisolvent have to be carefully selected in consideration of future applications of nanoparticles, since, as clearly evidenced, they significantly affect the final size and PSD of polymeric nanoparticles [65,66]. 

Adopting intensive mixers, as discussed before, it is possible to modulate the size of the nanoparticles varying the intensity of the turbulence, and thus the mixing efficiency, by varying the inlet flow rate of solvent and antisolvent. 

An experiment usually follows the same procedure. First of all the vessel is pressurized with CO2 to the desired value and a constant antisolvent flow is adjusted. After that, pure solvent (without solute) is injected into the chamber. The ratio of solvent and antisolvent flow is set to achieve a certain molar fraction within the precipitator. Thereafter, the injecticm of pure solvent is stopped and the liquid solution is injected. At the end of the soluticHi injecticHi and the resulting precipitation, the whole plant is washed with supercritical CO2 in order to remove the residual solvent from the precipitator. After this washing step, the plant is depressurized and particle samples can be taken out [1]. 

The enantioselective synthesis of MK-4305 93 was achieved with the help of classic resolution by using a chiral dibenzoyl-D-tartaric acid (DBT) for resolving the racemic amine intermediate 96. By tedious optimization of the resolution protocol changing the solvent and antisolvent systems, excellent enantioselectivity could be achieved by using 1.85 equivalents of the chiral DBT and a mixture of tetrahydrofuran and dichloromethane as the solvent system. 

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