Polymorphic system specification

Given the complementary nature of molecular recognition, it would appear that, when a compound crystallizes, the crystallization pathway, and hence the crystal structure obtained, should be quite specific to the molecule in question. However, the very existence of the phenomenon of polymorphism indicates that, under certain conditions, alternative crystallization pathways are feasible. In the special circumstance of concomitant polymorphism, or the simultaneous appearance of polymorphic forms in the same crystallization batch, these pathways even co-exist.1321 So, in general, the study of polymorphic systems has a bearing on a better... 

Some of the genetic aspects of clozapine-induced agranulocytosis have been evaluated (143). Polymorphisms of specific clozapine metabolizing enzyme systems were determined in 31 patients with agranulocytosis and in 77 without. Genotyping of a recently discovered G-463 A polymorphism of the myeloperoxidase gene and CYP2D6 showed no evidence of an association. 

The full specification of a polymorphic system is specified by the thermodynamic properties of the phases involved. A solid phase has a uniform structure and composition throughout, is separated by other phases by defined boundaries, and undergoes a phase transition when a particular solid phase becomes unstable under a given set of environmental conditions. The course of these phase changes is dictated by differences in free energy at the transition that are associated with structural or compositional changes. Classical thermodynamics provides a basis for understanding the nature of these transitions. 

Threlfall s analysis has direct applications in the isolation of the desired polymorphs on scale. For this, it is essential to know the solubility as a function of temperature and metastahle zone widths of the polymorphic system in order to reach those regimes in which the desired polymorph is exclusively crystallized. The analysis also has implications for polymorph screening, where the emphasis in experimental design is commonly focused on solvent diversity. This is born from the pervasive assumption that polymorphic outcome is primarily governed by specific interactions between solute and solvent. While solvent diversity is certainly an important consideration, Threlfall s analysis shows that other factors such as supersaturation, concentration, cooling rate, nucleation temperature, and collection temperature should also receive adequate attention in experimental design for polymorph screening. 

For the specific instance of polymorphic systems, the substance itself will ordinarily be the only component present. The situation complicates for solvates or hydrates since the lattice solvent will comprise a second component. Hydrate/solvate systems cannot be systems of one component, since the different phases will not have the same composition. The general rule is that the number of components present in an equilibrium situation are to be chosen as the smallest number of the species necessary to express the concentration of each phase participating in the equilibrium. 

That a given solid can exist in more than one crystalline form was first established by Mitscherlich for the specific instance of sodium phosphate [16]. The phenomenon has been shown to be widespread for both inorganic and organic systems, with various compilations of polymorphic systems having been published for compounds of pharmaceutical interest [17-19]. For the purpose of the present discussion, one must remember that the structural phase differences exist only in the solid state, and that the liquid and vapor phases of all polymorphs of a given component must necessarily be identical. 

An example of the use of polyacrylamide gels in an ief system in combination with immun obi otting is given in Reference 40 where this method is used to detect low quantities of group specific component (GC) subtypes. Another example of polyacrylamide in combination with ief is given in Reference 41 where the technique is used as a screening tool for inheritance of a certain polymorphic protein. 

Studies of polymorphs in recent years have pointed out the effects of polymorphism on solubility and, more specifically, on dissolution rates. The aspect of polymorphism that is of particular concern to the parenteral formulator is physical stability of the product [8]. Substances that form polymorphs must be evaluated so that the form used is stable in a particular solvent system. Physical stresses that occur during suspension manufacture may also give rise to changes in crystal form [9]. 

Hereditary deficiency of phosphoglycerate kinase (PGK) is associated with hereditary hemolytic anemia and often with central nervous system dysfunction and/or myopathy. The first case, reported by Kraus et al. (K24), is a heterozygous female, and the results are not so clear. The second family, reported by Valentine et al. (V3), is a large Chinese family, whose pedigree study indicates that PGK deficiency is compatible with X-linked inheritance. To date, 22 families have been reported (04, T25, Y3). Nine of these have manifested both symptoms five have shown only hemolysis seven have shown the central nervous system dysfunction and/or myopathy but without hemolysis and one case, PGK Munchen, is without clinical symptoms (F5). PGK II is an electrophoretic variant found in New Guinea populations (Y2). Red blood cell enzyme activity, specific activity, and the kinetic properties of this polymorphic variant are normal. 

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