Acid-catalyzed inversion of sucrose in the amorphous state at very low levels of residual water

• Published in: Pharmaceutical research Vol. 17; no. 3; pp. 366 - 370
• Main Authors: SHALAEV, E. Y, QUN LU, SHALAEVA, M, ZOGRAFI, G
• Format: Journal Article
• Language: English
• Published: New York, NY Springer 01-03-2000; Springer Nature B.V
• Subjects: Acids; Biological and medical sciences; Cellulose; Citric Acid - chemistry; Drug Storage - methods; Electrons; Freeze Drying; General pharmacology; Glucose - chemistry; Hydrogen-Ion Concentration; Kinetics; Medical sciences; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Sucrose; Sucrose - chemistry; Temperature; Water - chemistry; Degradation; Freeze drying; Pharmaceutical technology; Sucrose; Water content; Acid catalysis; Amorphous state; Citric acid
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1023/A:1007517526245

Factors affecting the solid-state acid-catalyzed inversion of amorphous sucrose to glucose and fructose in the presence of colyophilized citric acid, with less than 0.1% w/w residual water, have been studied.
Samples of citric acid and sucrose were lyophilized at a weight ratio of 1:10 citric acid:sucrose from solutions with initial pH values of 1.87, 2.03, and 2.43, as well as at a weight ratio of 1:5, at an initial pH of 1.87. Glass transition temperatures, Tg, were measured by DSC and the presence of any possible residual water was monitored by Karl Fischer Titrimetry. The inversion of sucrose was measured by polarimetric analysis after reconstitution of solid samples stored at 50 degrees C under P2O5.
Samples of 1:10 citric acid:sucrose at an initial pH of 1.87, 2.03, and 2.43 exhibited the same Tg. The initial rate of reactivity was affected at a 1:10 ratio by the solution pH before lyophilization in the order: 1.87 > 2.03 > 2.43 and by citric acid concentration at pH 1.87 in the order 1:5 > 1:10.
Sucrose, colyophilized with an acid such as citric acid, undergoes significant acid-catalyzed inversion at 50 degrees C despite the very low levels of residual water, i.e., <0.1% w/w. At the same ratio of citric acid to sucrose (1:10), and hence the same Tg, the rate of reaction correlates with the initial solution pH indicating that the degree of ionization of citric acid in solution is most likely retained in the solid state. That protonation of sucrose by citric acid is important is shown by the direct relationship between maximum extent of reaction and citric acid composition. It is concluded that colyophilization of acidic substances with sucrose, even in the absence of residual water, can produce reducing sugars capable of further reaction with other formulation ingredients susceptible to reaction with reducing sugars.