Yu Lian, Ng Kingman
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA.
J Pharm Sci. 2002 Nov;91(11):2367-75. doi: 10.1002/jps.10225.
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 (alpha and gamma) of the neutral glycine ((+)H(3)NCH(2)CO(2) (-)) and as three salts (diglycine HCl, (+)H(3)NCH(2)CO(2) (-). (+)H(3)NCH(2)CO(2)H. C1(-); glycine HCl, (+)H(3)NCH(2)CO(2)H. C1(-); and sodium glycinate, H(2)NCH(2)CO(2) (-). Na(+)). Although alpha-glycine crystallized from solutions without pH adjustment (pH 6.2), changing the pH to 4.0 and 8.0 caused gamma-glycine to crystallize as the preferred polymorph. This phenomenon is attributed to the pH effect on the dimeric growth unit of alpha-glycine. The formation of alpha-glycine by spray drying solutions of neutral glycine contrasts the outcome of freeze drying, which yields beta-glycine. Because gamma-glycine is thermodynamically more stable than alpha-glycine, the crystallization of gamma-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, gamma-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 gamma-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.
甘氨酸水溶液的喷雾干燥显示，所得粉末的盐和多晶型形式受pH值影响很大。用盐酸或氢氧化钠水溶液将pH值调节在1.7至10.0之间，会使甘氨酸溶液结晶为中性甘氨酸（(+)H(3)NCH(2)CO(2) (-)）的两种多晶型物（α和γ）以及三种盐（二甘氨酸盐酸盐，(+)H(3)NCH(2)CO(2) (-). (+)H(3)NCH(2)CO(2)H. C1(-)；甘氨酸盐酸盐，(+)H(3)NCH(2)CO(2)H. C1(-)；以及甘氨酸钠，H(2)NCH(2)CO(2) (-). Na(+)）。尽管α-甘氨酸在未调节pH值（pH 6.2）的溶液中结晶，但将pH值改为4.0和8.0会使γ-甘氨酸成为优先结晶的多晶型物。这种现象归因于pH值对α-甘氨酸二聚体生长单元的影响。通过喷雾干燥中性甘氨酸溶液形成α-甘氨酸与冷冻干燥的结果形成对比，冷冻干燥得到的是β-甘氨酸。由于γ-甘氨酸在热力学上比α-甘氨酸更稳定，通过调节pH值使γ-甘氨酸结晶为提高含甘氨酸制剂物理稳定性提供了一种方法。在低pH值下喷雾干燥得到中性甘氨酸及其盐酸盐的各种混合物：pH 3.0时，为γ-甘氨酸和二甘氨酸盐酸盐；pH 2.0时，为二甘氨酸盐酸盐；pH 1.7（甘氨酸盐酸盐的天然pH值）时，为二甘氨酸盐酸盐（主要成分）和甘氨酸盐酸盐（次要成分）。喷雾干燥甘氨酸盐酸盐溶液（pH 1.7）得到的二甘氨酸盐酸盐/甘氨酸盐酸盐混合物与将中性甘氨酸溶液酸化至pH 1.7后喷雾干燥得到的相同。通过喷雾干燥甘氨酸盐酸盐溶液获得二甘氨酸盐酸盐表明在加工过程中有50%的HCl损失。HCl损失的程度可通过改变喷雾干燥器的进口温度来改变。在pH 9.0和10.0下喷雾干燥甘氨酸溶液主要得到γ-甘氨酸和一种额外的结晶产物，可能是甘氨酸钠。在不同pH值下喷雾干燥的甘氨酸粉末具有不同的颗粒形态和尺寸，这可能会影响它们在药物制剂中的适用性。
