With more sophisticated analytical technology, some product deficiencies are being traced back to the failure to establish adequate controls and specifications. The Gold Sheet also reported that the identification and control of solid-state properties of drug substance is one of the specific areas where FDA expectations are being clarified. The decision trees bridge the gap between the existing FDA guidelines written in 1987 and evolving analytical techniques and approaches. In this way, they help address key issues about the solid state chemistry of the drug substance early in the drug development process. Polymorphs exist when a drug substance exists in different crystalline forms without solvent of crystallization.
Hydrates are crystalline substances which contain water.
Amorphous forms exist when the solid substance has no crystalline structure. It is advisable to investigate a drug substance for the existence of these forms. If, for example, there is no interest in marketing or producing the amorphous form, the corresponding flow charts do not need to be considered. If the properties of the polymorphs, hydrates, desolvated solvates or amorphous forms differ, specifications should be set. The specifications should ensure that the proper form is produced consistently.