Crystallization, metastable

Since zeolites are metastable crystallization products tliey are subject to Ostwald s mle which states tliat metastable phases are initially foniied and gradually transfonii into tlie tlieniiodynaniically most stable product. The least stable zeolitic phase (tliat witli tlie lowest framework density) is tlierefore foniied first and consumed with furtlier syntliesis time at tlie expense of a more stable phase due to a continuous crystallization/redissolution equilibrium. 

The problem is certainly more complex at conditions of low temperature and pressure where thermal energy is low and slight fluctuations in configurational energy can probably provide metastable crystallization as experienced often in the laboratory. However, we will retain the general principle that authigenic minerals will more closely represent equilibrium phases than will detrital minerals inherited from other geological cycles. 

Fig. 17. DSC-trace of 2,3-dimethylbutane. The PC-glass transition occurs at 76 K. This is followed by the formation of a metastable crystal form (III), which transforms at about 110 K to the fully ordered crystal (II), which then changes to the plastic crystal (I) at 136 K and to the melt at 145 K (see also Table 7). Drawn after data of Ref. 1041...

To confirm the occurrence of the polymorphic transition predicted in the section 4 and to elucidate the mechanism, it is primarily necessary to clarify the enantiomeric assembly mode in the first-formed metastable crystal prior to the polymorphic transition and compare it with the stable crystal structure after the polymorphic transition with respect to a compound showing Preferential Enrichment. Since it is very possible that the stable molecular assembly structure in solution would be retained in the crystalline phase first-formed by crystallization from the same solvent,20 at first, we have investigated the enantiomeric association mode in solutions of the racemates showing Preferential Enrichment. Consequently, in our case, the variable temperature H NMR technique proved to be inapplicable to deciding which molecular association mode is more stable in solution, homochiral or heterochiral.21 Instead, the combined use of the solubility and supersolubility measurements under various conditions and the number-averaged molecular weight measurement by vapor pressure osmometry turned out to become a potent tool for this objective. 

Finally, it should be stressed that when the original supersaturated solution for crystallization was strictly racemic (0.0% ee), the probability for either the R or the S enantiomer to be enriched in solution after crystallization was 50% 9a this is because initial capricious formation of the very first nonracemic metastable crystal nucleus should doom which enantiomer is enriched in solution later. 

The melting range of spironolactone is between 198 and 207°C, accompanied by decomposition. Occasionally materials may show preliminary melting at about 135°C, followed by re-solidification [8], and this behavior indicates the existence of another, metastable, crystal form. 

Utilizing an amorphous form of an API is not, however, universally desirable. Amorphous compounds are often metastable. As a result, there is a real risk that they will transform to crystalline materials in the final dosage form. Novobiocin again provides a case in point. The amorphous form, in aqueous suspension, will transform on standing into the inactive crystalline form.10 Similarly, the highly soluble metastable crystals of riboflavin revert to less soluble forms if they are washed with water above 10°C.9... 

Thus obtained results show that the polyamorphic transitions occur not only at compression (Si02, H20, etc.) but at extension as well (C) in the systems having stable or metastable crystal analogs with a different density and a different coordination number z. At the minimal z=2 (chain structures) the transitions may occurs only at compression, at the maximal z=12 (close-packed structures) - only at extension, at the intermediate z (2structure-sensitive properties change and new metastable phases can appear. Amorphization under radiation (crystal lattice extension) can be associated with a softening of phonon frequencies. The transitions in the molecular glasses consisted from the molecules with unsaturated bonds are accompanied by creation of atomic or polymeric amorphous systems. 

The Hg-0 distances within the chains is 2.03 A while the closest interchain distance is 2.82 A. If a Hg+ salt solution is treated with warm, aqueous NaOH for several hours, metastable crystals of HgO form that have the hexagonal cinnabar (HgS) sfructure. Again the basic building blocks are O-Hg-O chains but now they wrap in a helical fashion and are cross-linked to other chains by Hg-O bonds to form a highly distorted octahedron of oxygens about each mercury with the motif of 2 short linear Hg bonds being maintained. 

It is essential to determine the range of crystalline forms that are accessible to a potential drug substance and to determine which of the various forms will be the one used in products used in pivotal trials. To answer this question, investigators must conduct whatever studies might be required to evaluate the full range of possible polymorphs and solvatomorphs. The situation can be further complicated by the phenomenon of disappearing polymorphs, where metastable crystal forms become impossible to produce once more stable forms are uncovered. " ... 

By virtue of having a higher apparent solubility, a metastable crystal will have an increased dissolution rate over the more stable form. The change in mass, M, as a function of time, t, for a solute is directly proportional to its apparent solubility, app, and is given by... 

Each polymorph contains the same chemical contents of the respective unit cells. If the chemical contents differ, for example by the presence of different amounts of solvent, they are called pseudopolymorphs. Polymorphs may differ with respect to physical properties such as melting points, or solubilities, as also may pseudopolymorphs. Their existence often presents a serious problem in the pharmaceutical industries since physical properties of crystals are often used as criteria for quality control and thereby the effectivity of a given preparation. Polymorphs and pseudopolymorphs are usually obtained when crystals are grown under different conditions. For example, metastable crystals of the 7T-donor acceptor complex between biphenylene and pyromellitic dianhydride were obtained when crystals were grown by sublimation at high temperatures, whereas a different polymorph, stable at room temperature, was grown by the same method at a lower temperature. ... 

The Avrami model (19,20) states that in a given system under isothermal conditions at a temperature lower than V. the degree of crystallinity or fractional crystallization (70 as a liinction of time (t) (Fig. 11) is described by Equation 5. Although the theory behind this model was developed for perfect crystalline bodies like most polymers, the Avrami model has been used to describe TAG crystallization in simple and complex models (5,9,13,21,22). Thus, the classical Avrami sigmoidal behavior from an F and crystallization time plot is also observed in TAG crystallization in vegetable oils. This crystallization behavior consists of an induction period for crystallization, followed by an increase of the F value associated with the acceleration in the rate of volume or mass production of crystals, and finally a metastable crystallization plateau is reached (Fig. 11). 

Brittain HG. A Method for the Determination of Solubility of Metastable Crystal Phases Based on Total Light Scattering. Langmuir 1996 12 601—604. 

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