Polymorphs nucleation

Because of the interplay between thermodynamic, kinetic, and molecular recognition factors (Fig. 1) in determining nucleation of a new phase, it is essential to consider the effects of these factors when using solvents to selectively nucleate polymorphs. Threlfall has thoroughly considered thermodynamic and kinetic factors and the conditions in which the solvent may or cannot affect polymorphic outcomes. The analysis is briefly summarized here. These concepts are also discussed extensively elsewhere. ... 

Tempering. The state, or physical stmcture, of the fat base in which sugar, cocoa, and milk soHds are suspended is critical to the overall quaHty and stabiHty of chocolate. Production of a stable fat base is compHcated because the cocoa butter in soHdified chocolate exists in several polymorphic forms. Tempering is the process of inducing satisfactory crystal nucleation of the Hquid fat in chocolate. 

Spherical vaterite crystals were obtained with 4-mercaptobenzoic acid protected gold nanoparticles as the nucleation template by the carbonate diffusion method [51]. The crystallization of calcium carbonate in the absence of the 4-MBA capped gold nanoparticles resulted in calcite crystals. This indicates that the polymorphs of CaCOj were controlled by the acid-terminated gold nanoparticles. This result indicates that the rigid carboxylic acid structures can play a role in initiating the nucleation of vaterite as in the case of the G4.5 PAMAM dendrimer described above. 

It seems also meaningful to recall that, for both PVL and iPP, the metastable chiral modification is not obtained from solution. This fact is hard to rationalize if polymorphic discrimination occurs on the basis of the secondary nucleation site which should exist also in the presence of the solution it rather points to diffusion and to transport problems in the melt, or thermodynamic control in solution. 

The importance of temperature-controlled scanning calorimetry for measurements of heat capacity and of scanning transitiometry for simultaneous caloric and pVT analysis has been demonstrated for polymorphic systems [9]. This approach was used to study an enantiotropic system characterized by multiphase (and hindered) transitions, the role of heat capacity as a means to understand homogeneous nucleation, and the creation of (p, T) phase diagrams. The methodology was shown to possess distinct advantages over the more commonly used combination of characterization techniques. 

Crystallization conditions can often be manipulated to favor the nucleation of alternate crystal forms. A metastable polymorph of metformin hydrochloride has been isolated using capillary crystallization techniques, and subsequently studied using thermal microscopy [24]. Calculations based on classical nucleation theory indicated that a metastable form could be obtained using high degrees of... 

An enantiotropically related pair of polymorphs was obtained for p-aminoben-zoic acid, with the system being characterized by a transition temperature of 25 °C [31]. The a-form was obtained as fibrous needles, while the /M orm was obtained in the form of prisms. The solubilities of the two forms are almost the same, indicating the existence of comparable values for AG, which in turn explained the slow transformation of the a-form into the [>-form. Nucleation of the a-form was found to be favored, which is reasonable considering that the structural motif of the a-form consists of carboxylic acid dimmers that would be expected to be stable association species in solution. 

A rate enhancement effect due to secondary nucleation has been identified in the solution-mediated transformation of the 7-phase of (i)-glutamic acid to its / -phase [82]. In this study, the kinetics of the polymorphic transition were studied using optical microscopy combined with Fourier transform infrared, Raman, and ultraviolet absorption spectroscopies. The crystallization process of n-hexatriacontane was investigated using micro-IR methodology, where it was confirmed that single... 

US patent 6,759,521, Polarization switching to control crystal form [113]. This patent describes a method to select and prepare polymorphs of materials by switching the polarization state of light and employing non-photochemical laser-induced nucleation. 

Wada, N., Yamashita, K. and Umegaki, T. (1995) Effects of divalent cations upon nucleation, growth and transformation of calcium carbonate polymorphs under conditions of double diffusion. Journal of Crystal Growth, 148, 297-304. 

In electrolytic systems the crystallization solvent type will affect the degree of solute ionization. This is an important factor in the rate of nucleation and can be successfully utilized for polymorphic control [11]. 

The rate of nucleation is dependent on the degree of supersaturation as described in section 2.4.1, and because this will always be larger for Form 1 it may be incorrectly assumed that Form I will always precipitate first. The true situation is somewhat more complicated because the critical size, activation energy and nucleation rate also depend on the solid state that is being formed [6]. It is quite feasible and a regular occurrence, that a less stable polymorph will have a higher rate of nucleation than a more stable form, as illustrated in figure 6. 

Whenever the solubility curve is crossed for the less stable Form II there is a risk that it will nucleate and contaminate the product. This situation is very probable when the solubility curves of the two polymorphs lie close together, as shown in Figure 21 of the Cimetidine case study. The addition of seed crystals of Form I, close to its solubility curve, and minimization of the supersaturation during the growth process is a good method of control in this instance. Solvent selection to extend the width of the Form II metastable zone would also be desired, as discussed in section 2.4.4. 

As discussed in section 2.4.4 the coordinating ability of a solvent will often affect the rate of nucleation and crystal growth differently between two polymorphs. This can be used as an effective means of process control and information on solvent effects can often be obtained from polymorph screening experiments. There are no theoretical methods available at the present time which accurately predict the effect of solvents on nucleation rates in the industrial environment. 

Where competing polymorphs may occur it is better to have systems where there is a large difference in the relative solubility of the two forms at the point of nucleation. This enables seeding of the crystallizer with the desired form at a temperature between the two solubility curves. A typical seed loading is 1 to 2 % by weight of the product. 

Where a metastable polymorph is required the crystallizer should ideally operate below the supersaturation curve for the more stable form, thus preventing any primary nucleation of the more stable form. 

FBRM provides a real time chord length distribution within the crystallizer. The technique is excellent for determining the onset of nucleation and in following general growth rate and rate transitions associated with polymorphic transformation, reaching equilibrium and attrition effects. 

It is clear that kinetic effects must be utilized in the design of a process to make the commercially available Form A, because it is never the most thermodynamically stable form. Information from the literature and patents in reference [14] indicates that Form A can be successfully isolated from Acetonitrile, Acetone, Methyl isobutyl ketone, Toluene, the C2 to C4 alkenols, Ethanol, Methanol and Propan-2-ol. In these solvents it is likely that solvation is favourable to the nucleation rate of Form A or detrimental to crystal growth of the other forms, or both. For a new development compound there should be similar solvent interaction data available from polymorph screening experiments. 

Davey, R.J., Blagden, N., Righini, S., Alison, H., Quayle, M.J., Fuller, S., 2001, Crystal Polymorphism as a Probe for melecular Self-Assembly during Nucleation from Solutions The Case of 2,6-Dihydroxybenzoic Acid, Crystal Growth and Design, Vol. l,No. 2, 59-65. 

At a high degree of supersaturation, the nucleation rate is so high that the precipitate formed consists mostly of extremely small crystallites. Incipiently formed crystallites might be of a different polymorphous form than the final crystals. If the nucleus is smaller than a one-unit cell, the growing crystallite produced initially is most likely to be amorphous substances with a large unit cell tend to precipitate initially as an amorphous phase ("gels"). 

Effect of Molecular Structure on Polymorphic Nucleation of BPT Derivatives... 

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