How Do We Detect and Characterize Multiple Crystal Forms

In spite of the efforts of a great number of research groups worldwide, and of a familiarity with the experimental factors that can lead to multiple crystal forms, our ability to predict or control the occurrence of polymorphism is still embryonic. In many cases the crystallization of a new crystal form or of an amorphous phase of a given substance turns out to be the result of serendipity [7] rather than a process under complete human control. 

The exploration of the crystal form space (polymorph screening) of a substance is the search of the polymorphs and solvates with a twofold purpose (i) identification of the relative thermodynamic stability of the various forms including the existence of enantiotropic crystalline forms (that interconvert as a function of the temperature) or of monotropic forms (that do not interconvert) and of amorphous and solvate forms and (ii) physical characterization of the crystal forms with as many analytical techniques as possible. The relationships between the various phases and commonly used industrial and research laboratory processes are illustrated schematically in Fig. 3.3.3. 

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. 

Exposure to solvent/vapor uptake, 4, Freeze drying 5, Heating 6, Melting 7, Precipitation 8, Quench cooling 9, Milling 10, Spray drying  

Kneading 12, Wet granulation. Analogous relationships apply to polymorphic modifications of solvate forms. Note that the figure represents general trends rather than every possible transformation the presence or absence of an arrow or number does not represent the exclusive existence or absence of a transformation. 

---