Crystallization of Organic Compounds, 2nd Edition

Chapter 10Reactive Crystallization

10.1 INTRODUCTION

When supersaturation of a crystallizing compound is created by its formation between two chemical species via chemical reaction, ionization, or hydrogen bonding, the operation is termed reactive crystallization. These operations are also known as precipitation. The term reactive crystallization is generally applied only when the product is crystalline. The products of the more general term precipitation may be amorphous or crystalline.

The reaction may be between two complex organic compounds or may be neutralization by an acid or a base to form a salt of a complex compound or may be formation of co‐crystals between the compound and co‐crystal former via hydrogen bonding. These reactions can be very fast compared to both the mass transfer rates of the crystals and the growth rate of the crystals, possibly leading to high local supersaturations and, therefore, extensive nucleation.

Although crystallization by anti‐solvent addition shares many characteristics with that caused by chemical reaction, the processes often differ in the rate of creation of supersaturation (e.g. a rapid reaction leading to a compound of very low solubility). Reactive crystallization is also subject to other kinetic considerations which are sometimes less predictable than the known solubility effects caused by addition of an anti‐solvent.

In some cases, the fine crystals or precipitates resulting from high supersaturation (often in the range from 0.1 ...