Solvent-antisolvent ratio

Fig. 11 The calibration model relating IR spectra to solution concentration. The multivariate model relates IR absorbances of a selected frequency range and temperature or solvent-antisolvent ratio to solution concentration.

In the direct design approach, a desired supersaturation profile that falls between the solubility curve and the metastable limit of the system is followed based on feedback control of the concentration measurement. This is in contrast to the traditional first-principles approach, where a desired temperature profile or antisolvent addition rate profile is followed over time such as shown in Fig. 14. For a cooling crystallization, the direct design approach follows a setpoint profile that is solution concentration vs. temperature (or solvent-antisolvent ratio) as opposed to temperature (or addition rate) vs. time. Because the desired crystallizer temperature is determined from an in-situ solution concentration measurement, the batch time is not fixed. 

There are different approaches to implementing the feedback concentration control for the direct design. Various schemes to implement the concentration control for direct design are described in the literature for cooling and antisolvent crystallizations. " The basic steps are as follows (i) the solution concentration is estimated from IR absorbances and temperature or solvent-antisolvent ratio using the calibration model that relates IR spectra to concentration and (ii) the temperature or antisolvent flow rate setpoint is calculated from the concentration, solubility curve, and the user-specified supersaturation setpoint. 

Concentration, Solvent/Antisolvent Ratio, Processing Conditions... 

Precipitation conditions (pH, temperature, shear, solvent to antisolvent ratio, and time)... 

Fig. 3.9 Design space considerations during microprecipitation process design (solvent to antisolvent ratio and mixing). Other relevant factors related to supersaturation include pH, temperature, time, and shear...

Copredpitation Batch mode vs. continuous mode Flow rate Droplet size distribution Mixer design (shear and energy, e.g., stir bar, vortex, propeller, homogenizer, rotor-stator) Solvent to antisolvent ratio Temperature Processing times (scale dependent)... 

The influence of methanol proportions in solvents, and temperature, on the solubility and the transformation behavior of 2-(3-cyano-4-isobutyloxyphenyl) -methylthiazole-5-carboxylic acid (BPT) was investigated. The transformation behavior was explained by the chemical potential difference between the stable and metastable forms. It was shown that a specific solute-solvent interaction contributes to the preferential nucleation and growth of the stable or metastable forms and influences the transformation behaviors, and the solubility of the solvated crystals is much more influenced by the solvent compositions than the true polymorphs. The solubility ratio of the solvated crystals depends on the solvent composition, whereas the solubility ratio of the true polymorphs is considered to be independent of the solvents. The crystallization behavior was also investigated. The transformation rate after crystallization appeared to depend on the initial concentration of BPT and the addition rate of the antisolvent. The cause of this phenomenon was presumed to be a slight inclusion of the stable form in the metastable form <2005PAC581>. 

Emulsion Drying. Supercritical CO2 extracts the water and organic solvent (a heavy alcohol or ketone) and the same recycle system as proposed for the antisolvent process is applicable. The dilference is that, much lower fluid/substrate ratios, of the order of magnitude of 10 -10 are required, with the resulting savings in the recycle loop. 

For salt formation by salt exchange, the salt of the drug substance is combined with a salt containing the desired counterion in specific molar ratios in a suitable solvent system. As described above, there must be adequate solubility of each reactant in the solvent system. If the desired salt of the drug substance is less soluble than the starting materials, it will precipitate out and can be isolated by filtration. If no precipitate is obtained, other isolation methods can be employed. A method that was described for iodide salts (19) involved precipitation of the unwanted counterion first. In this case silver salts were used for the counterions (silver sulfate, silver orf/tophosphate, silver lactate) and a silver iodide precipitate was isolated first by filtration. The desired salt of the drug substance was then precipitated from the filtrate by addition of an antisolvent. 

In this case study, the encapsulation of quercetin in Pluronic F127 from acetone solutions by SAS process is described. Pressure and temperature operating conditions, 10 MPa and 40°C, were chosen in order to operate in the single phase region of the solvent (acetone)-C02 system. Solution flow rate and antisolvent flow rate were 2 mL/min and 2 kg/h. Different solution concentrations and carrier/quercetin ratios were tested in order to optimize the particle production process. 

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. 

Ratio of solvent to antisolvent can be from 1 5 to 1 20 depending on the solubility profile of the drug... 

The ratio of API/polymer solution (solvent) to antisolvent is one of the most important factors for the success of the precipitation process. For continuous process, it is controlled by the feed rates of the APFpolymer solution and the antisolvent into the high-shear mixing chamber and is generally constant for the process. For semi-batch... 

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