Polymorphic form, changes

Transitions from one polymorphic form to another may be accompanied by changes in specific volume, which may lead to destmction of the crystal and containers in which the substance is stored. 

Although vitreous silica is nominally a homogeneous isotropic amorphous material, and should normally remain so during its service life, it is in fact in a metastable condition. The tendency to revert to crystalline forms with attendant deterioration in mechanical durability places severe limitations on the range of applications. Figure 18.2 illustrates the polymorphic forms of silica, and the dimensional changes accompanying each transition. 

This technique provides an easy and convenient method to evaluate the association of small molecules to various polymorphic forms of nucleic acid structures from the measurement of absorbance changes in the absorption maximum of the hgand, where the nucleic acid has no absorbance. Information about overall DNA/RNA base preference and nature of binding can also... 

Pharmacists should also take a dim view of changes in the particle size, size distribution, or particulate nature of semisolid suspensions. They are the consequence of crystal growth, changes in crystalline habit, or the reversion of the crystalline materials to a more stable polymorphic form. Any crystalline alteration can lead to a pronounced reduction in the drug-delivery capabilities and therapeutic utility of a formulation. Thus, products exhibiting such changes are seriously physically unstable and unusable. 

Various drugs are known to exist in different polymorphic forms (e.g., cortisone and prednisolone). The rate of conversion from a metastable into the stable form is an important criteria to be considered with respect to the shelf life of a pharmaceutical product. Polymorphic changes have also been observed during the manufacture of steroid suspensions. When steroid powders are subjected to dry heat sterilization, subsequent rehydration of anhydrous steroid in the presence of an aqueous vehicle results in the formation of large, needle-like crystals. A similar effect may be... 

Selection of the most suitable chemical form of the active principle for a tablet, while not strictly within our terms of reference here, must be considered. For example, some chloramphenicol esters produce little clinical response [13], There is also a significant difference in the bioavailability of anhydrous and hydrated forms of ampicillin [14], Furthermore, different polymorphic forms, and even crystal habits, may have a pronounced influence on the bioavailability of some drugs due to the different dissolution rates they exhibit. Such changes can also give rise to manufacturing problems. Polymorphism is, of course, not restricted to active ingredients, as shown, for example, in an evaluation of the tableting characteristics of five forms or sorbitol [15]. 

At a certain temperature of transition Tt, the two forms will be in equilibrium, AG will be zero, and m = m2. But at other temperatures the two forms will not be in equilibrium, and if ax > a2 then because AG = Z rin (a2/fli), AG will be negative and polymorph 1 will change spontaneously to polymorph 2 and will therefore be considered the less stable form and vice versa. Studies of the two polymorphic forms of methylprednisolone show that significant differences occur in the apparent solubilities of polymorphic forms and that these may be temperature-related. 

It is well known that many compounds are able to change their physical form whilst suspended in solution. For example, a compound of interest may change from one polymorphic form to another, while different crystalline aggregations of the same compound can have different solubility profiles. Impurities can mask the true solubility, and aggregation in solution can also change the thermodynamic equilibrium. Finally, errors which have been published in the literature data may in fact magnify from publication to publication. 

When a solid system undergoing a thermal change in phase exhibits a reversible transition point at some temperature below the melting points of either of the polymorphic forms of the solid, the system is described as exhibiting enantiotropic polymorphism, or enantiotropy. On the other hand, when a solid system undergoing thermal change is characterized by the existence of only one stable form over the entire temperature range, then the system is said to display monotropic polymorphism, or monotropy. 

It is recommended that concentration measurements for this type of modeling work are based on analytical standards of mole or mass fraction, to avoid the conversion error caused by density effects. The excess solid phase should always be characterized by a suitable analytical technique, before and after the equilibrium solubility measurements, to confirm that the polymorphic form is unchanged. It should be noted that the crystal shape (habit) does not always change significantly between different polymorphic forms, and visual assessments can be misleading. 

Crystal interactions may lead to a number of readily observable consequences. The molecular geometries may be different in different polymorphic forms of a given compound or, as in the case above, in symmetry-independent sites in a given crystal a change of molecular substituents remote from the torsionally flexible bonds may change the molecular conformation, as a result of modification... 

Raman spectroscopy s sensitivity to the local molecular enviromnent means that it can be correlated to other material properties besides concentration, such as polymorph form, particle size, or polymer crystallinity. This is a powerful advantage, but it can complicate the development and interpretation of calibration models. For example, if a model is built to predict composition, it can appear to fail if the sample particle size distribution does not match what was used in the calibration set. Some models that appear to fail in the field may actually reflect a change in some aspect of the sample that was not sufficiently varied or represented in the calibration set. It is important to identify any differences between laboratory and plant conditions and perform a series of experiments to test the impact of those factors on the spectra and thus the field robustness of any models. This applies not only to physical parameters like flow rate, turbulence, particulates, temperature, crystal size and shape, and pressure, but also to the presence and concentration of minor constituents and expected contaminants. The significance of some of these parameters may be related to the volume of material probed, so factors that are significant in a microspectroscopy mode may not be when using a WAl probe or transmission mode. Regardless, the large calibration data sets required to address these variables can be burdensome. 

Lastly, studies on the different polymorphic forms of the synapsins, that organize the mobilization of neurotransmitter vesicles thereby regulating neurotransmitter release, could account for some of the subtle changes in neurotransmission that occur in schizophrenia. However, to date linkage analysis studies have failed to reveal any positive associations between the various polymorphisms of the synapsin gene and schizophrenia. 

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