What are crystal polymorphs

At first glance this definition seems straightforward. What are some of the complications For flexible molecules McCrone would include conformational polymorphs, wherein the molecule can adopt different conformations in the different crystal structures (Corradini 1973 Panagiotopoulis et al. 1974 Bernstein and Hagler 1978 Bernstein 1987). But this is a matter of degree dynamic isomerism or tautomerism... 

Most of the drugs on the market are obtained as a defined crystalline structure and formulated as solid dosage forms. It is well known that a molecule can crystallize to give different crystalline structures displaying what is called polymorphism. The crystal structures may be anhydrous or may contain a stoichiometric number of solvent molecules leading to the formation of solvates (hydrates in case of water molecules). Pseudopolymorphism is the term used to describe this phenomenon. 

The U U pair is polymorphic. What are called cis U U wobble pairs have been observed in two RNA dodecamer structures (46,47). The U U pairs, each held together with two hydrogen bonds are formed (Fig. 6a) and although an ordered solvent is not observed in both crystal structures, this pair has what appears to be an attractive site to bring in a water molecule in both major and minor groove sides. This would be similar to the G T mismatch discussed above. The nonameric... 

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. 

It is essential to understand how and when the polymorphs of drug substance in oral liquid dosage forms and suspensions can be controlled. One approach to study this phenomenon is to seed the formulation with a small amount of a known polymorphic crystal (other than what is used for the product), which is a common practice to rapidly determine what effect this may have on long-term storage. From these types of studies, the appropriate excipients can be used to preserve the specific polymorphic form desired. However, even when the drug in its crystalline form is studied extensively, there are cases when a previously unknown polymorph may be formed in solution and lead to precipitation (14). 

McCrone (1965) notes that polymorphs, existing only in the solid, can convert at least in one direction without going through the melt. On the other hand Curtin and Engelman (1972) observed that the equilibrium in melt or in solution between the two configurational isomers may be shifted by crystallization or by chemical reaction to form a derivative of one of the isomers. In solution, the two isomers will have different solubilities, in the same way that different polymorphs can have different solubilities (Sections 3.2 and 7.3.1). The solubility curves may cross, and with a change in temperature the solution can become saturated with one form. This is apparently what happens in the case of l-I, as the C form is obtained from the room temperature crystallization, while at lower temperatures, a mixture of A and B is obtained. Dynamic isomers exist in both the melt and the solid state. Each isomer can exist in polymorphic forms, which is true for forms B and C. Details on the experimental techniques and observations are given in Chapter 4. 

Many other difficult questions arise when a situation described as a disappearing polymorph is encountered. Among them are Why did the new polymorph appear at all (often after years of no hint of its existence) Why does a previously robust process no longer yield the crystal form that had been obtained prior to the appearance of the new one What crystallization parameters must be modified to obtain either the old or the new form exclusively and robustly ... 

---