Impurities polymorphs

In a recent study of twenty disperse and solvent dyes, data for water solubility, octanol/ water partition coefficient, entropy of fusion and melting point were subjected to regression analysis. Complicating factors such as impurities, polymorphism, tautomerism, polarisation and hydrogen bonding precluded the development of reliable predictions of solubility and partition coefficient. Anthraquinone dyes exhibited much lower entropy of fusion than many of the azo dyes [64,65]. 

QbD on stability studies are science and risk-based approach to understanding API physical and chemistry properties. The API s KSAs are typically moisture, solvent content, impurities, polymorph, particle size, stoichiometry, and other attributes specific to the individual API. Risk-based criticality analysis of these KSAs can address their potential influence on the API stability, therefore, help to define the API stability control strategy. " °... 

Calcium Pyrophosphates. As is typical of the pyrophosphate salts of multiple-charged or heavy-metal ions, the calcium pyrophosphates are extremely insoluble ia water. Calcium pyrophosphate exists ia three polymorphic modifications, each of which is metastable at room temperature. These are formed progressively upon thermal dehydration of calcium hydrogen phosphate dihydrate as shown below. Conversion temperatures indicated are those obtained from thermal analyses (22,23). The presence of impurities and actual processing conditions can change these values considerably, as is tme of commercial manufacture. 

The primary phases all contain impurities. In fact these impurities stabilize the stmctures formed at high temperatures so that decomposition or transformations do not occur during cooling, as occurs with the pure compounds. For example, pure C S exists in at least six polymorphic forms each having a sharply defined temperature range of stability, whereas alite exists in three stabilized forms at room temperature depending on the impurities. Some properties of the more common phases in Portland clinkers are given in Table 2. 

The determination of precise physical properties for elemental boron is bedevilled by the twin difficulties of complex polymorphism and contamination by irremovable impurities. Boron is an extremely hard refractory solid of high mp, low density and very low electrical conductivity. Crystalline forms are dark red in transmitted light and powdered forms are black. The most stable ()3-rhombohedral) modification has mp 2092°C (exceeded only by C among the non-metals), bp 4000°C, d 2.35 gcm (a-rhombohedral form 2.45gcm ), A77sublimation 570kJ per mol of B, electrical conductivity at room temperature 1.5 x 10 ohm cm- . 

Process validation should be extended to those steps determined to be critical to the quality and purity of the enantiopure drug. Establishing impurity profiles is an important aspect of process validation. One should consider chemical purity, enantiomeric excess by quantitative assays for impurity profiles, physical characteristics such as particle size, polymorphic forms, moisture and solvent content, and homogeneity. In principle, the SMB process validation should provide conclusive evidence that the levels of contaminants (chemical impurities, enantioenrichment of unwanted enantiomer) is reduced as processing proceeds during the purification process. 

There are other soUd states which sometimes confuse the measurement and definition of solubiUty. The dmg may crystaUize as a hydrate, i.e. under inclusion of water molecules. If the hydrate form is more stable than the pure form it may be difficult to measure the intrinsic solubility of the drug at all. Often drugs tend to precipitate in an amorphous form, often under the inclusion of impurities. As with metastable polymorphs, such amorphous precipitates may lead to erroneously high solubility measurements. CommerciaUy, drugs are often crystallized in salt form, e.g. as the hydrochloride salt, a cation with a chloride anion. In these co-crystallized salts, a much lower solubility than the intrinsic solubility will typi-... 

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. 

Zeolite structures sometimes remain unsolved for a long time, because of either their complexity, the minute size of the crystallites or the presence of defects or impurities. One extreme example of stacking disorder is provided by zeolite beta [1,2], Different stacking sequences give rise to two polymorphs (A and B) in zeolite beta that always coexist in very small domains in the same crystal. Not only do the small domains make the peaks in the powder X-ray diffraction pattern broad and thereby exacerbate the reflection overlap problem, but the presence of stacking faults also gives rise to other features in the diffraction pattern that further complicate structure solution. 

These non-existent allotropes, which are impurity-stabilized phases, are fee Sc, fee Y-Ce, the bcc Ho, Er, Tm and Lu and fee phases of Nd, Sm, Gd and Dy, some of which have been described as formed at room temperature during mechanical milling. A number of fee high-pressure polymorphs, for instance, are actually compounds, with a structure related to the NaCl-type, formed by reaction with O, N and/or H during mechanical milling (see also Alonso et al. 1992). 

Anion conduction, particularly oxide and fluoride ion conduction, is found in materials with the fluorite structure. Examples are Cap2 and Zr02 which, when doped with aliovalent impurities. Fig. 2.2, schemes 2 and 4, are F and 0 ion conductors, respectively, at high temperature. The 3 polymorph of 61303 has a fluorite-related structure with a large number of oxide vacancies. It has the highest oxide ion conductivity found to date at high temperatures, > 660 °C. 

Impurities generally fall into three main categories process impurities, degradation impurities, and contaminant impurities. Additionally, enantiomers and polymorphs may be considered impurities under some circumstances. 

Crystals are ordered atoms (or molecules) in a crystal lattice. This internal structure is accessible by x-ray diffraction and is available for most cortunon solids. Unless a crystal displays polymorphism, the crystals internal structure will not vary with the conditions of its growth. This, however, is not the case for the external crystal habit. Crystal habit can vary with the conditions of growth, solvent used and the presence of impurities. 

Ideally all subsequent batches will be prepared by the route and process used for tox and/or Phase 1 batches, so that on-scale impurities and impurity profiles will meet the guidelines above. Of course it is difficult to predict the final optimized process for a dmg candidate. The best approach to control impurities is to determine the optimal starting materials, reagents, process, and final form (salt, polymorph) early ( freeze the final step... 

The oxidation of an API in an oral liquid formulation can be difficult to control due to the trace amounts of impurities, which may be present from the API or excipient vendor, and oxidation and photolysis have relatively low activation energies (2-12 Kcal/mol) compared to solvolysis, dehydration, and polymorphic transformations (10-56 Kcal/mol) (Table 11) (10). 

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