Cosolvating crystallization

Since use of increasing amounts of cosolvents as antifreeze could perturb the conformation and thus the activity of lysozyme, a number of experiments were carried out to try to determine conditions for investigating lysozyme reactions and lysozyme-substrate intermediates in cooled mixed solvents as a preliminary to similar investigation by X-ray diffraction on crystals. Work began with an estimate of the solubility of... 

Concluding this brief survey of the effects of cosolvents and temperatures on noncovalent binding forces between proteins, we may assume that while the dielectric constant may play a role in the cryoprotection of protein crystals, changes in interaction forces may confer protection or in some cases be responsible for crystal destruction. However, we must bear in mind that hydrogen bonds and salt links involved in the regions of contact between proteins will be strengthened and/or stabilized at low temperatures within certain limits of pan values, which should aid in the cryoprotection of protein crystals. 

E. Effects of Cosolvent and Temperature on Donnan and Electrostatic Parameters of Protein Crystals... 

When the salt concentration is high enough (> 0.1 M) some of the salt will precipitate in proportion as the cosolvent concentration is increased and the temperature of the mixture decreased. While in such conditions the precipitating effect of the cosolvent toward proteins will increase (Edsall, 1947 Singer, 1962) and a new equilibrium of ions between the crystals (/ ") and the bulk solvent medium (/" ) will be established, modifying both the Donnan and electrostatic terms. In the presence of salt (say sodium chloride), the distribution of the hydrogen ions is correlated with that of the chloride ions by the Donnan relationship ... 

In recent years, it has been shown (Douzou and Maurel, 1976) that some proteins can behave as polyanions or polycations, and the stability of their solid state might be endangered at lower salt concentration due to repulsive forces between protein molecules. Much more important is the problem of enzyme activity in crystals suspended in cooled mixed solvents as a consequence of cosolvent- and temperature-induced changes in salt concentration and therefore in electrostatic potentials. 

When the protocol is applied to allylcarbamates 170, the deprotonation in the presence of (—)-sparteine does not occur with kinetic preference. Indeed, a dynamic resolntion by crystallization takes place. The epimeric allylfithinm componnds 171 and 172 are eqni-librating, whereby one of them crystallizes predominantly. Under optimized conditions, when n-butyllithium is used for the deprotonation and cyclohexane serves as a cosolvent, the preference of the diastereomer 172 leads to snbstimtion products in 90-94% gg393-395 enantioselective homoaldol reaction has been developed based on this protocol Transmetalation of the organolithium into the titaninm compound occnrring nnder inversion of the configuration (172 173) and subseqnent addition to aldehydes leads to... 

Crystallization is often used as a method of product isolation. Crystallization of the reaction product may be induced if, to the reaction medium, in which it is well soluble, a cosolvent is added in which the product is insoluble. Because for the latter purification method the solubility should be high at high temperatures but much lower at low temperatures, the temperature coefficient of the solubility becomes an important criterion for the employment of a solvent. A further guide is the fact that substances tend to dissolve in solvents with similar polarities, so that a solvent and cosolvent for the recrystallization of a given product can be selected according to the polarities. 

Similarly to the solubility of active drugs, the solubility of surfactants that were used in CFC systems has significantly changed. Surfactant solubility in HFA 134a ranges from 0.005% to 0.02% w/v, much lower than the concentration required to stabilize suspensions (0.1-2.0% w/v) (24,42). The surfactants can be solubilized with the addition of cosolvents such as ethanol. However, it is most likely that cosolvents will be incompatible with suspension formulations because drug solubility will also be promoted and crystal growth will occur. 

Deviations from log-linear behavior can still occur even if none of the above explanations is valid for your system [71-74], Deviations are typically at low and/or high concentrations of cosolvent. Typically, negative deviations are observed at low cosolvent concentrations and positive deviations are observed at high cosolvent concentrations. In Rubino and Yalkowsky s [72] review of this topic, deviations could not be consistently attributed to physical properties of the cosolvent-water mixtures or alterations in the solute crystal. They concluded that changes in the structure of the solvent play a role in deviation from expected log-linear solubilities. 

Differences in solubility between different crystal forms alter the driving force for dissolution, controlled by the difference between the solution concentration and the saturation concentration (Cs - C). Hamlin et al. (1965) have shown that dissolution rate correlates well with solubility for a large number of pharmaceutical compounds varying in solubility from 0.01 to 10 mg/mD t 37 Nicklasson and Brodin (1984) have shown that using cosolvent mixtures fordrugs with poor aqueous solubility produces a good correlation between dissolution rate and solubility. 

Practical advantage of the method is that it does not require dry solvents. The resolving agent can be prepared by simple solution of DBTA monohydrate and half an equivalent amount of calcium oxide in hot 95 % ethyl alcohol. Crystallization of the diastereoisomeric coordination complex can be achieved by cooling and addition of cosolvents (e.g. acetone, toluene, ethyl acetate, etc.) or change ethyl alcohol to an ester type solvent. The enantiomers can be liberated from the crystalline complex by simple acidic workup procedure. [23]... 

Nonideal Behavior. The discussion of phase behavior up to this point represents the ideal case. A number of factors cause deviation from ideality. The phases present may include liquid crystals, gels, or solid precipitates in addition to the oil, brine, and microemulsion phases (39, 40). The high viscosities of these phases are detrimental to oil recovery. To control the formation of these phases, the practice has been to add low-molecular-weight alcohols to the micellar solution these alcohols act as cosolvents or in some cases as cosurfactants. 

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