Solution-mediated phase transformation

It has been found that both the anhydrous Form III and dihydrate phases of carbamazepine exhibit fluorescence in the solid state [78]. The fluorescence intensity associated with the dihydrate phase was determined to be significantly more intense than that associated with the anhydrate phase, and this difference was exploited to develop a method for study of the kinetics of the aqueous solution-mediated phase transformation between these forms. Studies were conducted at temperatures over the range of 18 40 °C, and it was found that the phase transformation was adequately characterized by first-order reaction kinetics. The temperature dependence in the calculated rate constants was used to calculate activation energy of 11.2 kCal/ mol (47.4 cal/g) for the anhydrate-to-dihydrate phase conversion. 

G.G.Z. Zhang, R.F. Henry, T.B. Borchardt, X. Lou, Efficient co-crystal screening using solution-mediated phase transformation, J. Pharm. Sci. 96 (2007) 990-995. 

Murphy, D. Rodriguez-Cintron, F. Langevin, B. Kelly, R.C. Rodriguez-Hornedo, N. Solution-mediated phase transformation of anhydrous to dihydrate carbamazepine and the effect of lattice disorder. Int. J. Pharm. 2002, 246, 121-134. 

Mukuta T, Lee AY, Kawakami T, and Myerson AS. Influence of Impurities on the Solution-Mediated Phase Transformation of an Active Pharmaceutical Ingredient. Cryst Growth Des 2005 5 1429-1436. 

Murphy D, Rodriguez-Cintron F, Langevin B, Kelly RC, and Rodriguez Homedo N. Solution-Mediated Phase Transformation of Anhydrous to Dihydrate Car-bamazepine and the Effect of Lattice Disorder. Int JPharm 2002 246 121-134. 

Due to the differences in melting point and other characteristics of polymorphs, solubility differences are often observed. Usually the most stable form of the compound has the lowest solubility in any solvent. It has already been noted that solids can undergo phase changes by way of the solution phase (Davey et al. 1986). When the solvent is in contact with the metastable phase, it dissolves, and the stable phase nucleates and grows from solution. So it is always worth slurrying a compound and assessing the solid phase to determine whether a solution mediated phase transformation to the stable phase has taken place. 

Fig. 15.3 Concentration in the solution and the solid compositions as a function of time during the solution-mediated phase transformation. (Reproduced with permission from Zhang et al. 2009)...

Greco K, Bogner R (2012) Solution-mediated phase transformation significance during dissolution and implications for bioavaUabitity. J Pharm Sci 101(9) 2996-3018 Guo Y, Shalaev E, Smith S (2013) Physical stability of pharmaceutical formulations solid-state characterization of amorphous dispersions. Trends Anal Chem 49 137-144 Hancock BC (2002) Disordered drag delivery destiny, dynamics and the Deborah number. J Pharm Pharmacol 54(6) 737-746... 

If a multitude of solid-state forms is possible, the most unstable form will nucleate first. This can either be an unstable crystalline form or even an amorphous solid or oil. As unstable solid-state forms are prone to a (solution-mediated) phase transformation, the unstable form might have transformed into a more stable one before sampling. 

Equilibrium solubility measurements are not always technically feasible, however. For example, solution-mediated phase transformations may occur. 

Solution-mediated phase transformations to other forms, labUe solvates, slow transformation kinetics due to poor solubility or when near T, Solution-mediated phase transformations, non-ambient temperature control throughout measurement Thermal lag with fast heating, solution-mediated phase transformations with slow heating Compression-induced phase transformations... 

Reproducibility, not accessible for all polymorph pairs - only relates to forms involved in transition Larger sample size, solution-mediated phase transformations... 

D. Aging Ostwald ripening and solution-mediated phase transformation... 

B. Nucleation, crystal growth, and solution-mediated phase transformation of crystal hydrates... 

B. Nucleation, Crystal Growth, and Solution-Mediated Phase Transformation of Crystal Hydrates... 

An interesting kinetic study deals with the solution-mediated phase transformation of COT and COD into the thermodynamically stable COM [50]. The experimental conditions were adjusted so that either COT or mixtures of COD and COM crystallized initially as confirmed by X-ray diffraction powder patterns. The systems were then aged in contact with the mother liquid, and the transformation of COT or COD into COM was followed by monitoring the total crystal volume as a function of time (by Coulter counter) and determining (by thermo-gravimetric analysis) the relative proportion of the crystal hydrates at fixed time intervals. In addition, supersaturation profiles (i.e., activity products) were determined by solution calcium analysis. In all cases the transformation was completed within approximately 80-100 h. 

FIG. 6 Kinetic analysis of solution-mediated phase transformation of in situ precipitated calcium oxalate trihydrate (COT) into calcium oxalate monohydrate (COM), (a) Solution analysis Variation of ion activity product vs. time, (b) Solid phase analysis Total crystal volume (curve 1) and volume fractions of COT (curve 2) and COM (curve 3) vs. time. 

In another set of experiments [68] the kinetics of solution-mediated phase transformation of preprepared, well-defined model COD crystals was investigated in the presence of micellar concentrations of an anionic (SDS) and a cationic (DDACl) surfactant. Figure 9 shows that both surfactants almost completely inhibited phase transformation (SDS was slightly more effective than DDACl [68], which is not shown in Fig. 9). 

We have thus demonstrated that (1) anionic surfactants can control the composition of crystallizing calcium oxalates (Fig. 8), whereas (2) both anionic and cationic surfactants inhibit the solution-mediated phase transformation of COD into the thermodynamically stable COM (Fig. 9). Both results can be readily explained if one considers the respective adsorption isotherms and adsorption densities of surfactants at COM and COD crystal/solution interfaces (see Fig. 10 and Table 2) [68,69]. 

FIG. 9 Schematic presentation of the kinetics of solution-mediated phase transformation of preprepared, well-defined COD crystals into COM. tp, (horizontal axis) is the aging time. Curves (1) suspension of COD crystals without surfactant (for control) and (2) in the presence of micellar concentrations of SDS or DDACl. Samples were filtered at different time intervals, and the composition of the solid phase was analyzed by thermogravime-tiic analysis. (Adapted from Ref. 68.)... 

Gong, Y., CoUiman, B. M., Mehrens, S. M., Lu, E., Miller, J. M., Blackburn, A., et al. 2008. Stable-form screening Overcoming trace impurities that inhibit solution-mediated phase transformation to the stable polymorph of sulfamerazine. J. Pharm. Sci. 97 2130. 

Mukuta, T., Lee, A. Y., Kawakami, T., and Myerson, A. S. 2005. Influence of impurities on the solution-mediated phase transformation of an active pharmaceutical ingredient. Cryst. Growth Des. 5 1429. 

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