Polymorphism and Phase Transitions

Loisel, C., Keller, G., Lecq, G., Bouigaux, C., and Ollivon, M. (1998). Phase transitions and polymorphism of cocoa butter. Journal of Amer. Oil Chem. Soc. 75,425-439. 

Loisel, C., G. Keller, G. Lecq, C. Bourgaux, and Ollivtui M. Phase transition and polymorphism of eocoa butter. American Oil Chemists Society, 75 425—439, 1998. 

Olivon, M.R. et al. Phase transitions and polymorphism of cocoa butter. JAOCS, 75, 4, 1998. 

Handa, Y. P, Zhang, Z., Wong, B. Effect of compressed CO2 on phase transitions and polymorphism in syndiotactic polystyrene. Macromolecules, 30, 8499-8504 (1997). 

Fig. 2.12. If solids undergo a shock-induced polymorphic transformation, the volume change at the transformation causes significant changes in the wave profile produced by shock loading. In the figure, is the applied pressure, Pj is the pressure of the phase transition, and HEL is the Hugoniot elastic limit.

The sample temperature is increased in a linear fashion, while the property in question is evaluated on a continuous basis. These methods are used to characterize compound purity, polymorphism, solvation, degradation, and excipient compatibility [41], Thermal analysis methods are normally used to monitor endothermic processes (melting, boiling, sublimation, vaporization, desolvation, solid-solid phase transitions, and chemical degradation) as well as exothermic processes (crystallization and oxidative decomposition). Thermal methods can be extremely useful in preformulation studies, since the carefully planned studies can be used to indicate the existence of possible drug-excipient interactions in a prototype formulation [7]. 

Pressure-induced amorphization of solids has received considerable attention recently in physical and material sciences, although the first reports of the phenomenon appeared in 1963 in the geophysical literature (actually amorphization on reducing the pressure [18]). During isothermal or near isothermal compression, some solids, instead of undergoing an equilibrium transition to a more stable high-pressure polymorph, become amorphous. This is known as pressure-induced amorphization. In some systems the transition is sharp and mimics a first-order phase transition, and a discontinuous drop in the volume of the substance is observed. Occasionally it is strictly not an amorphous phase that is formed, but rather a highly disordered denser nano-crystalline solid. Here we are concerned with the situation where a true amorphous solid is formed. 

Typical applications of x-ray powder diffraction methodology include the evaluation of polymorphism and solvatomorphism, the study of phase transitions, and evaluation of degrees of crystallinity. More recently, advances have been made in the use of powder diffraction as a means to obtain solved crystal structures. A very useful complement to ordinary powder x-ray diffraction is variable temperature x-ray diffraction. In this method, the sample is contained on a stage that can be heated to any desired temperature. The method is extremely useful for the study of thermally induced phenomena, and can be a vital complement to thermal methods of analysis. 

DSC, in contrast, is sensitive both to phase transitions within polymorphs and to polymorphic transformations, and the equipment needed is... 

A remarkable property of lipid bilayers is their structural phase transitions (thermotropic polymorphism). For example, fully hydrated pure diacyl-phosphatidyl cholines exibit one fluid phase. La and three crystalline phases Pp/, Lp/. and Lc (12). Because of the high degree of disorder caused by defects, the Pp/ and Lp/ phases usually are called gel phases. The Pp/ phase is sometimes called a ripple phase, because the surface of the bilayer is rippled (13) and presents a wave-like appearance in electron micrographs (Fig. 2). Depending on the nature of the lipid and the presence of additional components (cholesterol etc.), the Pp/ phase may be present or absent in the phase diagram, and a tilted gel Lp/ could be replaced by the Lp phase, which has similar physical properties but no tilt of the hydrocarbon chains. 

Thermomechanical methods are very useful for the determination of phase transformations such as polymorphic solid-solid transitions or glass transitions. Fig. 4 shows some theoretical curves for glass transition and polymorphic transition in extension or in penetration mode. Recently TMA has been proposed for the measurement of the internal stress of tablets of ethylcellulose of different molecular weight and for measurement of swelling of polysaccharide hydro-gels and of polymeric films. 

Handa, T., Ichihashi, C., and Nakagaki, M. Polymorphic phase transition and monomolecular spreading of synthetic phospholipids. Progress Colloid Polym. ScL, 71, 26,1985. 

S. Folch, A. Gruger, A. R6gis, R. Baddour-Hadjean Ph. Colomban (1999). Synth. Met., 101, 795-796. Polymorphism and disorder in oligo- and polyanilines. A. El Khalki, Ph. Colomban B. Heimion (2002). Macromol., 35, 5203-5211. Nature of protons, phase transitions, and dynamic disorder in poly- and oligoaniline bases and salts an inelastic neutron scattering study. 

An interest in the crystals of amino acids and small peptides has reemerged with attention to the dynamic properties of these systems, the subtle kinetic factors determining their crystallization and polymorphism, phase transitions and anisotropic structural response to variation of temperature, pressure and an environment. The systems can serve as a unique interface between biology, chemistry, material science and nanotechnology of immediate and future importance. 

In a DSC scan, the difference of energy input (heat flow) into a sample and into a reference material is plotted as a function of temperature. In a plot of heat flow vs. temperature, endothermic minima correspond to desolvation of solvates or phase transitions of polymorphs, and exothermic maxima correspond to crystallization or decomposition. Integration over the area of a transition feature yields the associated transition enthalpy. 

We have so far reviewed the thermodynamic concept of phase transitions and introduced a classification system for hydrates. It remains to explore where in the dosage form development process such transitions are most likely to occur and what we can say about them in light of the preceding discussion. The following discussion will be divided into situations where processing induces transitions, and transitions taking place in the final product. When appropriate, polymorphic systems are also illustrated for contrast and completeness. 

Variable-temperature vibrational spectroscopy can be a powerful tool for the study of phase transitions and/or desolvation processes. The technique has been combined with factor analysis to deduce the three phase transitions and four conformational changes associated with pentaerythritol tetrastearate [129]. In this particular work, each thermal event was substantiated by analogous DSC studies. The dihydrates prepared from the two polymorphs of carbamazepine were also studied using variable-temperature techniques [130]. 

The DSC analysis is amenable to a wide variety of applications. Properties of pure compounds, such as melting point, boiling point, sublimation temperature, glass-transition temperature, decomposition temperature and energetics, are readily obtainable. In situ production of polymorphs and determination of the phase transitions and their kinetics makes DSC analysis a valuable tool to investigate polymorphs. Studies of physical interactions between drug substance and excipients can be performed quickly and with a minimal amount of material. These and other applications are discussed in a series of publications by Giron [66-69]. 

Lipid phase transitions and lipid polymorphism as visualized by freeze-fracturing... 

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