Crystallization: General Principles and Significance on Product Development

Authored by: Boris Shekunov

Encyclopedia of Pharmaceutical Science and Technology

Print publication date:  July  2013
Online publication date:  July  2013

Print ISBN: 9781841848198
eBook ISBN: 9781351124874
Adobe ISBN:

10.1081/E-EPT4-v1-56

 Download Chapter

 

Abstract

The importance of crystallization is reflected by the principal role it plays on the interface between drug discovery, process development for active pharmaceutical ingredients (APIs), and biopharmaceutical development which encompasses formulation and manufacturing of drug products. The most commonly encountered isolation process in pharmaceutical industry is solution crystallization of small molecules (typical molecular weight 200–1000 Da). Crystallization of peptides and proteins is also employed on industrial scale. The term “precipitation” is usually reserved for amorphous substances and separation of biologically derived macromolecules. Table 1 illustrates how different aspects of API crystallization may impact drug development. First, crystallization is the most effective and economical process of purification and separation during synthesis of API and intermediates: it defines the impurity profile which should meet regulatory control limits. This includes regular impurities as well as chiral impurities originated from the synthesis. Second, it determines the solid-state properties such as crystallinity, polymorphism, particle size distribution (PSD), and crystal shape (13), all of which have profound impact on downstream processing and properties of the drug product—potency, purity, stability, and efficacy (18). In commercial scale operations, crystallization often defines the product yield, utilization efficiency of equipment, cycle time, energy requirements, as well as material consumption. In general, uncontrolled crystallization (or recrystallization) of API should be avoided during processing steps such as milling, granulation, drying, and compaction. Solid form conversions during such unit operations are common and may require significant analytical and engineering efforts to characterize and monitor. Recrystallization phenomena in drug products can also undermine physicochemical stability of different drug delivery systems, and therefore have to be well understood and controlled (1).

 Cite
Search for more...
Back to top

Use of cookies on this website

We are using cookies to provide statistics that help us give you the best experience of our site. You can find out more in our Privacy Policy. By continuing to use the site you are agreeing to our use of cookies.