Solvent-mediated transformation

Examples of solvent-mediated transformation monitoring include the conversion of anhydrous citric acid to the monohydrate form in water [235,236], CBZ with water [237] and ethanol-water mixtures [238,239], and cocrystallization studies of CBZ, caffeine, and theophylline with water [240]. Raman spectroscopy was used to monitor the crystallization rate and solute and solvent concentrations as griseofulvin was removed from an acetone solution using supercritical CO2 as an antisolvent [241]. Progesterone s crystallization profile was monitored as antisolvent was added [242]. 

The solvent-mediated transformation of o -L-glutamic acid to the S-form was quantitatively monitored over time at a series of temperatures [248]. The calibration model was built using dry physical mixtures of the forms, but still successfully predicted composition in suspension samples. Cornel et al. monitored the solute concentration and the solvent-mediated solid-state transformation of L-glutamic acid simultaneously [249]. However, the authors note that multivariate analysis was required to achieve this. Additionally, they caution that it was necessary to experimentally evaluate the effect of solid composition, suspension density, solute concentration, particle size and distribution, particle shape, and temperature on the Raman spectra during calibration in order to have confidence in the quantitative results. This can be a substantial experi-... 

J.H. ter Horst, P.W. Cains, Cocrystal polymorphs from a solvent-mediated transformation, Cryst. Growth Des. 8 (2008) 2537-2542. 

At room temperature and atmospheric pressure, the relative thermal stability of the four modifications has been determined by solvent-mediated transformations and thermal analysis to be > y > Q -hemihydrate > p (Foltz et al. 99Aa,b Foltz 1994). Of the anhydrate materials is indeed the most dense as expected from this ordering (see Section 2.3), but in contradiction to the expected correlation between density and relative stability p is more dense than y (Nielsen et al. 1998). 

Maruyama, S., Ooshima, H. and Kato, J. (1999). Crystal structures and solvent-mediated transformation of taltireline polymorphs. Chem. Eng. J., 75, 193-200. [252]... 

Okamoto, M. Hamano, M. Ooshima, H. Utilization of solvent-mediated transformation for exclusive production of metastable polymorph crystals of AEl-923. J. Chem. Eng. Jap 2004, 57, 95-101. 

Figure 15. Solvent-mediated transformation of carbamazepine polymorphs in ethyl acetate at 25 °C and initial c/Sf , hi = 2.0. Reprinted from Kelly, 2003 with permission. (See color insert after Index.)...

The greatest concern with this approach is lack of nucleation of the most stable form. If the starting API does not contain seeds of the stable form, a successful screen will produce nucleation of the stable form within the duration of the slurry experiments in at least one of the solvents. Lack of adequate solubility, or inhibition of nucleation due to solvent-solute interactions, may preclude transformation to the stable polymorph (Gu et al., 2001). Moreover, impurities or additives, even in trace amounts, can dramatically affect the rate of solvent-mediated polymorphic transformation (Gu et al., 2002 Okamata et al., 2004 Mukuta et ah, 2005). Thus, it is important to have starting API with the highest possible purity. Recrystallization prior to starting this or any type of polymorph screen can be used in an attempt to purify the API. While this could reduce an impurity that might stifle solvent-mediated transformation to the most stable polymorph, it should be noted that recrystallization from solution does not... 

Okamoto M, Hamano M, and Ooshima H. Active Utilization of Solvent-Mediated Transformation for Exclusive Production of Metastable Polymorph Crystals of AEl-92 >. ] Chem Eng Jap 2004 37 95-101. 

Among the different modes of polymorphic modification, solvent-mediated transformation is of particular relevance to crystal form control... 

If left in solution, crystals of a polymorph can convert into other polymorphs (a solvent-mediated transformation). The products of these transformations might be unpredictable and irreproducible. Through kinetic factors in the crystallization, the so-called slurry experiments might mislead in attempts to estimate the relative stability of polymorphs from observations of their interconversion in the presence of solvents. In slurry experiments not the most stable polymorph is formed, but the polymorph growing best under these particular conditions. Preferential crystallization of a polymorph does not directly depend on its relative stability. 

Theoretical and experimental studies of the role of solvent on polymorphic crystallization and phase transformations abound in the literature of the last few years and some pertinent examples are described here. For solvent-mediated transformations, the driving force is the difference in solubility between different polymorphs. An important earlier paper on the kinetics of such phase transformations [51 ] described a model featuring two kinetic processes in sohd to solid phase changes via a solution phase, namely dissolution of the metastable phase and growth of the stable one. 

Shan, G. Igarashi. K. Noda. H. Ooshima, H. Control of solvent-mediated transformation of crystal polymorphs using a newly developed batch crystallizer (WWDJ-erystallizer). Chem. Eng. J. 2002, 85 (2-3). 169-176. 

Figure 6.44. Six frames from a sequence of time-lapse cinemicrographs showing the solvent-mediated transformation of anhydrous Na2S04 to Na2S04 -H20 at ambient temperature...

Figure 6.45. Solvent-mediated transformation of vaterite to calcite...

This concept of a size-dependent phase stability in polymorphic materials is addressed here by confronting this model and testing it against the well-characterised H-bonded compound L-glutamic acid (l-GA) which is a material with two mono-tropically related polymorphic modifications the metastable a-form that transforms into the stable p-form through a solvent-mediated transformation [66]. 

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