Nucleation inhibition

Kellogg RM, Kaptein B, Vries TR (2007) Dutch Resolution of Racemates and the Roles of Solid Solution Formation and Nucleation Inhibition. 269 159-197 Kessler H, see Weide T (2007) 272 1-50... 

Other explanations of the DR effect can be offered, as has been suggested by Collet.24 It is also not unlikely that various effects, likely complementary, are involved. For instance, nucleation inhibition and crystal growth inhibition can play an important role during many DR experiments... 

Even more interesting is the addition of the (.S )-cnantiomcr of 2-amino-1-butanol, which itself forms a salt with (R)-mandelic acid. This salt has almost inhnite solubility. With this additive, the resolution of alaninol with (W)-mandelic acid results in the crystallization of an almost diastereoiso-merically pure salt, without incorporation of 2-amino-l-butanol. On use of this method enantiopure (R)-alaninol can be obtained after an additional recrystallization, without the need to separate the alaninol from the 2-amino-l-butanol. We call this procedure reverse Dutch Resolution, to indicate that the family mix remains in solution. Most likely in this case stereoselective nucleation inhibition plays a role by suppressing the nucleation of the (.S )-alaninol-(A )-mandclic acid diastereoisomer. 

Nucleation inhibition studies show that the crystallization of both diastereoisomeric salts is inhibited, whereas the dissolution temperatures remain more or less identical. This results in a larger operating window in which to perform a resolution and in a higher efficiency. In addition to nucleation inhibition, the crystal growth also seems to be inhibited by the additive. 

Accounts of nucleation inhibition in the pharmaceutical literature are sometimes confusing because the dependence of the nucleation event (nucleation rate, metastability zone width, or induction time) on supersaturation is not considered. In search of additives that inhibit nucleation, induction times are often measured as a function of additive concentration, while the dependence of the nucleation event on supersaturation is neglected. Results from such studies possibly lead to the erroneous conclusion that the additive inhibited nucleation when indeed the additive decreased the supersaturation and frequently led to an undersaturated state. Hence, the system is under thermodynamic control instead of kinetic control. 

Jenne (1992) suggests that in the presence of a few mg/L of inhibiting DOC, which is common in many groundwaters, SI, values may have to exceed +0.3 or more for calcite nucleation and precipitation. (See also Appelo and Postma 1993.) Jacobson et al. (1971) reported no carbonate precipitation in a stream in which SI values averaged 0.74 diurnally and were as high as 1.5 (see below). The.se experiences, presumably reflect both nucleation-inhibition effects and the relatively slow rate of calcite precipitation compared to the re.sidence times of streams. 

Burst nucleation inhibition of additional nucleation during growth complete... 

Non-thermoplastic API must plasticize Excellent nucleation inhibition Difficult to mill API must plasticize Potential for H-bonding Hygroscopic Residual pa-oxides EasHy milled... 

Hydroxypropyl methycellulose Methocel E5 170-180 1. Non-thermoplastic 2. API must plasticize 3. Excellent nucleation inhibition 4. DUHcult to mill... 

These observations led to the conclusion that the reaction system had to be modified to achieve controlled nucleation and crystal growth while minimizing the concentration of nucleation-inhibiting compound (identity unknown but... 

Kellogg RM, Kaptein B, Vries TR. Dutch resolution of racemates and the roles of sohd solution formation and nucleation inhibition. Top. Curr. Chem. 2007 269 159-197. 

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