Glycine Crystallization during Spray Drying: The pH Effect on Salt and Polymorphic Forms

Abstract

Spray drying of aqueous solutions of glycine revealed a strong pH effect on the salt and polymorphic forms of the resulting powders. Adjusting pH by aqueous HCl or NaOH between 1.7 and 10.0 caused the glycine solutions to crystallize as two polymorphs (α and γ) of the neutral glycine (+H3NCH2CO2−) and as three salts (diglycine HCl, +H3NCH2CO2− · +H3NCH2CO2H · C1−; glycine HCl, +H3NCH2CO2H · C1−; and sodium glycinate, H2NCH2CO2− · Na+). Although α‐glycine crystallized from solutions without pH adjustment (pH 6.2), changing the pH to 4.0 and 8.0 caused γ‐glycine to crystallize as the preferred polymorph. This phenomenon is attributed to the pH effect on the dimeric growth unit of α‐glycine. The formation of α‐glycine by spray drying solutions of neutral glycine contrasts the outcome of freeze drying, which yields β‐glycine. Because γ‐glycine is thermodynamically more stable than α‐glycine, the crystallization of γ‐glycine by pH adjustment provides a way to improve the physical stability of glycine‐containing formulations. Spray drying at low pH yielded various mixtures of neutral glycine and its HCl salts: pH 3.0, γ‐glycine and diglycine HCl; pH 2.0, diglycine HCl; and pH 1.7 (the natural pH of glycine HCl), diglycine HCl (major component) and glycine HCl (minor component). Spray drying glycine HCl solutions (pH 1.7) yielded the same diglycine HCl/glycine HCl mixture as did spray drying neutral glycine solutions acidified to pH 1.7. Obtaining diglycine HCl by spray drying glycine HCl solutions indicates a 50% loss of HCl during processing. The extent of HCl loss could be altered by changing the inlet temperature of the spray drier. Spray drying glycine solutions at pH 9.0 and 10.0 gave predominantly γ‐glycine and an additional crystalline product, possibly sodium glycinate. The glycine powders spray dried at different pH had different particle morphologies and sizes, which may influence their suitability for pharmaceutical formulations. © 2002 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91:2367–2375, 2002