Crystal form Polymorphism

An API is closely controlled in terms of crystal form, polymorph identity, particle size, impurity profile and content, solvent, and water levels. All of these quality parameters are defined in creating a drug product that has the desired pharmacological properties (e.g., tablet dissolution rate to give needed blood levels) and desired physical properties (e.g., stability and compatibility with drug delivery systems). 

The investigation of different rotational isomers of the same compound in different crystal forms (polymorphs) is another efficient tool in elucidating intermolecular interactions. The phenomenon is called conformational polymorphism. The energy differences between... 

As polymorphism has become an increasingly important factor in the commercial aspects of many solid materials, the number of patents relating to the discovery and use of particular polymorphic forms has increased. This is particularly important for pharmaceuticals, pigments and dyes, and explosive materials, which are discussed in Chapters 7-9. Some examples of the role of polymorphism in patent litigation are described in detail in Chapter 10. The patent literature is readily searchable using terms such as crystal form , polymorph etc., and since polymorphic behaviour often forms the basis of a patent (as opposed to many journal publications, where it may be peripheral to the main point of the paper) instances of polymorphism are relatively straightforward to locate. 

Polymorphism refers to the arrangement of a drug in various crystal forms (polymorphs). Polymorphs have the same chemical structure but different physical properties, such as solubility, density, hardness, and compression characteristics. Some polymorphic crystals may have much lower aqueous solubility than the amorphous forms, causing a product to be incompletely absorbed. Chloramphenicol, for example, has several crystal forms, and when given orally as a suspension, the drug concentration in the body depended on the percentage of p-polymorph in the suspension. The p-form is more soluble and better absorbed (Fig. 7). In general, the crystal form that has the lowest... 

Polymorph assessment, on the other hand, is part of the system of quality control. It is necessary to make sure that the scale-up from laboratory preparation to industrial production does not introduce variations in crystal form. Polymorph assessment also guarantees that the product conforms to the guidelines of the appropriate regulatory agencies and does not infringe the intellectual property protection that may cover other crystal forms. 

The investigation of different rotational isomers of the same compound in different crystal forms polymorphs) is also an efficient tool in elucidating intermolecular interactions. The phenomenon is called conformational polymorphism. The energy differences between the polymorphs of organic crystals are similar to the free energy differences of rotational isomers of many free molecules, viz., a few kilocalories per mole. When the molecules adopt different conformations in the different polymorphs, the change in rotational isomerism is attributed to the influence of the crystal field since the difference in the intermolecular forces is the single variable in the polymorphic systems. 

The X-ray powder diffraction pattern for lovastatin is shown in Figure 9. This spectrum was obtained on a Phillips APD 3720 X-ray diffractometer using CuKa irradiation. No crystal forms (polymorphs) other than that represented by the X-ray pattern in Figure 9 have been observed. 

Certain thermoplastics, e.g., PET, can be frozen in the amorphous state below the Tg by quench-cooling of the melt. The occurrence of different crystal forms (polymorphism of polyamides (PA), as an example) and melting gaps caused by tempering can be read from the DSC curve. If recrystallisation is studied, crystal growth rate and supercooling can be measured. 

What was concluded from these observations was as follows. (1) The intrinsic reactivity of a molecule is less important in the crystal state than environmental and crystallographic features. (2) Within the crystal, the separation distance and relative orientation of the functional groups are critical in determining whether or not reaction will occur and, if so, the symmetry of the photoproduct. (3) Because of this direct link between reactivity and crystal form, polymorphism (ubiquitous among organic crystals) may lead to reactivity or stability. Increased selectivity to certain desired reaction products may therefore result when the reaction is carried out in the solid state rather than in solution or melt. 

The isolation, identification and characterization of different crystal forms (polymorphs, solvates, salts and co-crystals) of the same molecule or of aggregates of the same molecule with other molecules represents one of the most active areas of modem solid state chenfistry. The investigation of crystal forms impacts on fundamental science as well as on utilitarian objectives because different crystal forms may display a range of different physico-chemical properties, which may affect application and utilization of the solid materials. 

Zhu B, He Y, Asakawa N, Yoshie N, Nishida H, Inoue Y. A new crystal form, polymorphism, and multimorphology in biodegradable poly(3-hydroxypropionate). Macromol Rapid Commun 2005 26 581-5. 

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