Metastable crystal phases

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

Polymer crystallization has been described in the framework of a phase field free energy pertaining to a crystal order parameter in which = 0 defines the melt and assumes finite values close to unity in the metastable crystal phase, but = 1 at the equilibrium limit (23-25). The crystal phase order parameter (xj/) may be defined as the ratio of the lamellar thickness (f) to the lamellar thickness of a perfect polymer crystal (P), i.e., xlr = l/P, and thus it represents the linear crystallinity, that is, the crystallinity in one dimension. The free energy density of a polymer blend containing one crystalline component may be expressed as... 

A light scattering method has recently been described for the determination of the solubility of drugs, and its application to solubility evaluations of metastable phases has also been demonstrated [27]. Using this technique to deduce solubility data for theophylline anhydrate (metastable with respect to the monohydrate phase in bulk water at room temperature), agreement with the most reliable literature data was excellent. The light scattering method appears to be most useful in the determination of solubility data for metastable crystal phases in dissolution media in which they spontaneously and rapidly convert into a more stable crystal phase. 

The variable properties of solids are coimected with the ability of molecules to exist in different states of order, ranging from closely packed molecular crystals with a minimum free energy to metastable crystal phases and, finally, to the glassy state with the highest free energy. This phenomenon is commonly referred to as polymorphism. Lattice defects in crystals and particularly solvate formation add another level of complexity. Whether a solid in any metastable state can be handled and analysed is a kinetic issue, which again is affected by many factors (e.g. chemical impurities, solvent residues, moisture, and interactions with drug excipients). 

CF] 112 (Cf2 89) I designates a material with a metastable crystal phase formed on cooling the isotropic melt slowly and having a lower melting point than the stable crystal phase. 

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 hydration equilibria and phase transformations associated with a cytotoxic drug, BBR3576, have been studied [72]. The initially hydrated form could be made to undergo a phase transition where it lost approximately half of its water content, but the hemidesolvated product could be easily rehydrated to regenerate the starting material. If however, the original sample was completely dehydrated, the substance first formed a metastable anhydrate phase that underwent an irreversible exothermic transition to a new anhydrate crystal form. The hydration of this latter anhydrate form yielded a new hydrate phase whose structure was different from that of the initial material. 

Supersaturation is the driving force for crystallization and is a prerequisite before a solid phase will appear in a saturated solution. Figure 1. shows the situation for a cooling crystallization. At point 1 the system is under saturated and the concentration of dissolved solute is below the solubility curve defined by Eq 3. As the system cools it becomes saturated at point 2 but remains as a metastable liquid phase until the metastable zone is crossed at point 3, where... 

The area of conditions called the metastable zone is situated between the solubility and supersolubility curves on the crystallization phase diagram (Fig. 3.1). The supersolubility curve is defined as the line that separates the conditions where spontaneous nucleation (or phase separation or precipitation) occurs, from those where the crystallization solution remains clear if left undisturbed (Ducruix and Giege, 1992 Ducruix and Giege, 1999). 

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. 

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. 

Thus far, two types of solvent-assisted solid-to-solid transformations of a kinetically formed metastable crystalline phase into a thermodynamically stable one in a process of crystal growth, relevant to the occurrence of Preferential Enrichment, have been observed One is a relatively fast polymorphic transition noted in the case of ( )-NNMe3,18 and the other is a slow one in the case of ( )-NPMe3.18,26... 

Preferential Enrichment is a secondary phenomenon caused by a polymorphic transition occurring during crystallization from a highly supersaturated solution. This unique dynamic enantiomeric resolution phenomenon has proved to be observable for a fairly ordered racemic mixed crystal showing a polymorphism a solvent-assisted solid-to-sohd type of polymorphic transition from the kinetically-formed metastable crystalline phase comprising homochiral R and S chains into the thermodynamically stable crystalline phase consisting of a heterochiral 2D sheet structure during crystallization is responsible for this phenomenon. That is, it is essential that homochiral R and S ID chain structures are stable in solution while a heterochiral 2D sheet structure is stable in the crystal. 

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