Solute Crystallization in Frozen Systems–Use of Synchrotron Radiation to Improve Sensitivity

Abstract

By using synchrotron radiation, solute crystallization was detected with substantially increased sensitivity, making the technique useful for freeze-drying cycles of practical and commercial importance. Since numerous peaks of the crystalline solute appeared, the technique has potential utility in complex, multi-component systems.

Phase Transitions in Frozen Systems and During Freeze–Drying: Quantification Using Synchrotron X-Ray Diffractometry

“…Pronounced pH shift, up to 3 units, were observed when the initial buffer concentrations were ≥50 mM (15,16). In our previous report, using synchrotron X-ray diffractometry (SXRD), we have demonstrated the effect of initial solute concentration (ranging from 1 to 100 mM) on the selective crystallization of DHPD (19). Gomez et al developed an elegant method to monitor pH changes at temperatures ≥ −20°C by using a low temperature electrode (15,16).…”

“…Pyne et al demonstrated a complex interplay between the amorphous and crystalline phases in the ternary system composed of mannitol, glycine and sodium phosphate (14). The crystallization of buffer salts (e.g., in the case of sodium phosphate buffer) from the freeze-concentrate is not desired due to the potential for significant pH shifts that can affect the stability of API (7,9,(15)(16)(17)(18)(19).…”

“…Unfortunately, this approach will not be suitable to monitor the pH at the temperature of our interest (approximately −50°C), and also during drying. To this end, SXRD can be utilized for quantification of crystalline phases that are responsible for causing such pH-shifts (19,24). Alternative methods are being developed to monitor shift in acidity induced by freeze-drying.…”

Impact of Heat Treatment on the Physical Properties of Noncrystalline Multisolute Systems Concentrated in Frozen Aqueous Solutions

“…25 For example, heat-induced crystallization of a component salt in some buffer systems (e.g., sodium phosphate) significantly shift pH of the freeze-concentrated solutions and dried solids, and thus alters the stability of colyophilized proteins. 26,27 Reported phase separation of freeze-dried trehalose and dextran upon exposure to the higher temperature and humidity 28 suggested chances for similar component miscibility changes during the heat treatment of frozen solutions.…”

Polymorphism and Solvatomorphism 2006

“…173 In another study, synchrotron X-ray diffractometry has been used to detect solute crystallization in frozen sodium phosphate buffer solutions. 174 In this work, it was established that the use of synchrotron diffraction yielded substantially increased sensitivity, and that the technique was particularly useful in complex, multi-component systems.…”