According to recent literature,
−
differential scanning calorimetry (DSC) is being proposed as an alternative technique
for the determination of solubility curves with the advantage of requiring a small quantity of sample (in the order of milligrams),
besides being a fast method: solubility data can be accessed in a few hours. In this work, DSC was applied for estimating the
solubility of organic molecules in aqueous and nonaqueous solutions. The method was carried out using four organic substances,
referred to here as substances A, B, C, and D, A and B being solubilized in water, C in a mixture of methanol−water 20 wt %, and
D in acetone.
-Crystallization is an important industrial-scale process for the purification of enantiomers that depends on a phase diagram. In this work, the ternary phase diagram of R-and S-ketamine in ethanol was determined. The eutectic point indicated that crystallization of pure enantiomers from solutions containing more than 75% of the desired enantiomer is feasible. Solubility studies showed the feasibility of using temperature control to conduct the process. Batch crystallization of ketamine (S/R:80/20) solutions at 25°C provided the isolation of S-ketamine (purity of 100%) with a yield from 65 to 70% and a productivity of 6.5 g/(l h).
Fiber optic Raman spectroscopy is used for in situ monitoring of supersaturation during the hanging-drop crystallization of aprotinin. Schwartz and Berglund (1999) previously demonstrated this technique for lysozyme
crystallization and showed it combines two critical elements for protein crystallization studies: real-time monitoring/control of supersaturation and small amounts of sample. Experiments were carried out using 10 μL of protein solution.
A partial-least-squares (PLS) calibration based on Raman spectra of standard solutions allowed an accurate
measurement of aprotinin in a range of 2−100 mg/mL with a standard error of 0.54 mg/mL determined by a leave-one-out cross validation. A 10× microscope attached to a Raman fiber optic probe allowed the monitoring of the
hanging-drop liquid phase in a noninvasive and real-time mode. Aprotinin solubility determined by measuring the
protein concentration of drop solution at equilibrium decreased with increase in NaCl concentration. By continuously
collecting Raman spectra of the liquid phase in the drop, the protein concentration was monitored in real time
during the whole process. Control of supersaturation by manipulating the evaporation rate of the drop solution
allowed the optimization of the process, leading to an increase in the resulting crystal size.
In this study, the binary and the ternary phase diagrams of R-/S-ketamine were determined based on differential scanning calorimetry (DSC) measurements. The binary phase diagram presented a eutectic point in the 50:50 (R/S) composition which characterizes the product as a conglomerate forming system. On the other hand, the ternary phase diagram in the presence of ethanol showed a eutectic point in the 75:25 (R/S) composition, indicating the occurrence of a racemic compound. The observed facts indicate that the solvent and the temperature may affect the eutectic point, and thus different crystal forming systems can be obtained from the melt and from the solution. The calorimetric method was demonstrated to be an excellent short-cut method for the fast construction of phase diagrams, taking only some hours and consuming only a few milligrams [(5 to 20) mg] of samples.
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