Solution mediated transformation

As indicated above, evaluation of the thermodynamics of a polymorphic or solva-tomorphic system provides valuable insight into the nature of the system, but is all too often overlooked in many studies. However, Sacchetti [6] used aqueous/organic slurries of the anhydrate and hydrate forms of GW2016 to determine the relative stability of crystal forms interrelated by solution-mediated transformation. It was reported that the use of slurries enabled experiments to be completed in a day that enabled an understanding of the relative stability of the forms as a function of relative humidity. 

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... 

Secondary processing does not always lead to phase transformations, as was shown during studies of the polymorphs of ranitidine hydrochloride [92]. No solid-solid transformation could be detected during either the grinding or compression of metastable Form I, stable Form II, or of a 1 1 mixture of these forms. The dissolution rates of both forms were found to be equivalent, and the solution-mediated transformation of Form I to Form II was observed to be slow. 

There is a lot of evidence that the crystallization of zeolites from aluminosilicate gels is a solution-mediated transformation process in which the amorphous phase is a precursor for silicate, aluminate and/or aluminosilicate species needed for the growth of the crystalline phase (1-9). Generally, it is well known that the kinetics of most gel-zeolite and zeolite-zeolite transformations can be expressed mathematically by the simple kinetic equation (1,2, 10-12),... 

Our earlier studies of zeolite-zeolite (10,26) and gel-zeolite (11, 12) transformations have shown that, under the assumption that the crystallization of zeolite is a solution-mediated transformation process (1-9) and that the crystal growth is size-independent (5,6, 12-16), the crystallization (transformation) kinetics can generally be expressed as ... 

Fig. 20 Raman peak position with respect to time showing the solution-mediated transformation of anhydrous CBZflll) to cocrystal CBZ NCT at 23 C according to the following pathway CBZ(III) CBZ(D) CBZ NCT. (Reproduced from Ref. l)...

Fig. 16 Simulation of the supersaturation-time profiles as a function of the relative rates of dissolution and crystallization during a solution-mediated transformation. Generated from a kinetic model developed by Cardew and Davey, assuming that both dissolution and growth rates are linearly dependent on their respective driving forces. (Adapted from Ref ll)...

Ferrari ES, Davey ly, Cross WI, Gillon AL, and Towler CS. Crystallization in Polymorphic Systems The Solution-Mediated Transformation of /i to a Glycine. Cryst Growth Des 2003 3 53-60. 

The differences between polymorphs and hydrates are significant. The basis for all these differences is that polymorphs are different crystal structures of the same molecules(s) while hydrates are crystals of the drug molecule with different numbers of water molecules. As discussed above, the hydration state (and therefore the structure) of a crystalline hydrate is a function of the water vapor pressure (water activity) above the solid. Polymorphs, however, are typically only affected by changes in water vapor pressure if water sorption allows molecular motion, which in turn allows a reorganization into a different polymorph (i.e., a solution mediated transformation). This distinction is particularly important in defining the relative free energy of hydrates. A simple (only one molecule) anhydrous crystalline form is a one component system, and the free energy is, practically, specified by temperature and pressure. A crystalline hydrate is a two-component system and is specified... 

These examples are all solution-mediated transformations, which depend upon the solution phase to provide the mobility necessary to rearrange in the most stable form. Solid-state transformations are also possible when temperature and pressure changes can move the system across a phase boundary. These conditions often favor the metastable phase, however, unless there is a temperature reduction. Solid-state relaxation is more likely to be a slow (kinetically controlled) process, which is also possible during storage. 

Only a few generalities can be advanced regarding the kinetics of phase transformation. Constant temperature solution mediated transformations typically proceed much faster than do those in the solid state. The rate of a solution mediated transformation is proportional to the solubility of the species involved, and this is particularly true of the relaxation transformations previously mentioned. Some transformations that proceed rapidly and are apparently occurring in the solid state may be taking place in the absorbed water layer or in the amorphous fractions. Hydrate transformations can be thought of as reactions that are not necessarily occurring in the solid state, since the water may be in the vapor phase. These may even be considered as solution mediated, which would explain the relative rapidity with which many hydration/ dehydration reactions occur. 

The process of solution mediated transformation can be considered the result of two separate events, (a) dissolution of the initial phase, and (b) nucleation/growth of the final, stable phase. If crystals do not grow as expected from a saturated solution, the interior of the vessel can be scratched with a glass rod to induce crystallization by distributing nuclei throughout the solution. Alternatively, crystallization may be promoted by adding nuclei, such as seed crystals of the same material. For example, Suzuki showed that the a-form of inosine could be obtained by crystallization from water, whereas isolation of the 3-form required that seeds of the 3-form be used [13]. 

Isolation of intermediate, metastable polymorphs can generally be achieved by inhibiting their transformation to stable forms through the mediation of additives. A recent report on tiie isolation of a metastable form (Form IV) of tolbutamide (Figure 1, 3) is a case in point [17]. This species crystallized exclusively from an aqueous solution containing dimethylated p-cyclodextrin (DMB), whereas tiie stable form (I) crystallized in the absence of DMB. The proposed mechanism involves inhibition of the solution-mediated transformation of Form IV to Form I by complexation of tolbutamide with DMB. While not yet established as a general method, it is likely that this approach will be applied to the isolation of metastable polymorphs of other organic substrates. 

In most work on zeolite synthesis, crystallization is assumed to occur via solution-mediated transformations. In some cases the participation of the solid amorphous phase in the formation of nuclei has been clearly established [160]. 

One of the issues relating to the stability of the amorphous state, particularly in vivo, is its solution-mediated transformation characteristic. Solution-mediated transformation of amorphous to crystalline state is the conversion of metastable solids such as amorphous solids to the crystalline state when the solids are exposed to a solvent, in this case water. The transformation to the thermodynamically stable crystalUne state occurs at a higher rate in the presence of solvents than in the dry state because of higher molecular mobility in the presence of solvents. 

Characterization of solution-mediated transformations in the amorphous state can give an insight into amorphous crystallization (Zhang et al. 2(X)9). The importance of the phase transition kinetics, molecular interpretations, and process implications has been emphasized in numerous studies (Cardew and Davey 1985 Davey et al. 1986, 1997a, 1997b Rodriguez-Homedo et al. 1992 Blagden et al. 1998). 

The presence of the solvent does not change the thermodynamics and stability relationship, unless a solvate/hydrate is formed with the solvent. However, owing to the much higher mobility in the solution state than in the solid, transformation to the stable phase is much faster. This process is analogous to the effect of catalysts for chemical reactions (Zhang et al. 2009). The schematic representation of concentrations in the solution, as well as the solid compositions as a function of time, is shown in Fig. 15.3 for a typical solution-mediated transformation process (Zhang et al. 2009). 

As depicted in Fig. 15.3, three consecutive steps are involved in a solution-mediated transformation (Cardew and Davey 1985 Zhang et al. 2002 Rodriguez-Hornedo et al. 1992) (1) initial dissolution of the metastable phase into the solution to reach and exceed the solubility of the stable phase, (2) nucleation of the stable... 

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