Counter-intuitive effect of non-crystallizing sugars on the crystallization of gemcitabine HCl in frozen solutions

Bhushan Munjal, Arvind K. Bansal

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


In this study, the effect of four non-crystallizing sugars, namely fructose, trehalose, sucrose and raffinose, was assessed on the crystallization of gemcitabine hydrochloride (GHCl) in frozen solutions. Aqueous solutions containing GHCl (50 mg/mL) and a sugar at varying concentrations (10-60 mg/mL) were frozen in situ in DSC and analyzed in the subsequent heating run. Crystallization propensity of GHCl was quantified in terms of reduced crystallization temperature (RCT) as a function of sugar type and concentration. Multivariate analysis option in JMP® software was employed for calculating correlation between the variables. All sugars inhibited GHCl crystallization in a concentration dependent manner. At equal concentration, fructose (with the lowest Tg′) exerted the strongest inhibitory effect, whereas raffinose (with the highest Tg′) exerted the weakest inhibitory effect. Additionally, RCT showed a poor correlation with Tg′ (r = 0.2327). Thus, the inhibitory effect of sugars could not be described by their anti-plasticization effect. This counter-intuitive behavior was explained by the inhibitory effect of sugars on ice crystallization, which increased the unfrozen water content (UWC) in the freeze concentrate, thereby lowering the supersaturation of GHCl. This was established by observing a good correlation (r = 0.9666) between RCT and ln(1/UWC). Additionally, reduced diffusion kinetics of GHCl in presence of sugar molecules was also postulated. This study highlights the importance of unfrozen water towards governing the crystallization behavior of solutes in multi-component frozen systems.

Original languageEnglish (US)
Pages (from-to)46-52
Number of pages7
JournalInternational journal of pharmaceutics
Issue number1
StatePublished - Feb 15 2015
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2014 Elsevier B.V. All rights reserved.


  • Bulking agent
  • Calorimetry (DSC)
  • Correlation
  • Lyophilization
  • Supersaturation
  • Unfrozen water


Dive into the research topics of 'Counter-intuitive effect of non-crystallizing sugars on the crystallization of gemcitabine HCl in frozen solutions'. Together they form a unique fingerprint.

Cite this