Physical Stability of Freeze-Dried Isomalt Diastereomer Mixtures

Abstract

Isomalt was shown to be a suitable excipient for freeze-drying. Preferably a mixture of the diastereomers should be used, as the mixture containing only one of the isomers showed physical instability. A mixture containing a 1:1 ratio of the two diastereomers showed the best physical stability in the amorphous form.

Isomalt and its diastereomer mixtures as stabilizing excipients with freeze-dried lactate dehydrogenase

“…After freezedrying, the samples containing a 1:3 ratio of GPM and GPS had the lowest Tg of 40.3ºC, and the Tgs of other isomalt grades were 49.3, 51.5 and 58.9ºC for samples containing 1:1, 2:1 and 1:0 GPM:GPS ratios, respectively. As might be expected, and also observed in a previous study with amorphous isomalt (Koskinen, et al 2016), the samples' residual moisture contents had an effect on their Tgs: as the Tg of isomalt samples grew higher, their moisture contents decreased. After freezedrying, residual moisture contents of 3.6, 3.1, 2.6 and 2.2% were recorded for the 1:3, 1:1, 2:1 and 1:0 GPM:GPS ratios, respectively.…”

“…A high concentration of sucrose or isomalt used in this current study increases the viscosity of the solutions, which can also stabilize LDH during the freezing stage by restricting diffusion of the solute molecules and minimizing the rate of chemical reactions (Hagen, et al 1995). During freeze-drying, sucrose and isomalt are transformed from crystalline excipients to amorphous (Carstensen and Van Scoik 1990;Koskinen, et al 2016), which enables them to stabilize LDH during the drying stage of lyophilization by forming a glassy matrix, in which the protein is stabilized by reduction of conformational changes and by conformational relaxation (Hagen, et al 1995). The formation of a viscous glassy matrix is considered to be one of the most important stabilization mechanisms of sugars and polyols in general (Hagen, et al 1995;Kadoya, et al 2010).…”

“…Secondary drying was carried out by heating the chamber 0.1°C/min to 35ºC, while retaining the pressure at 150 mTorr. Maintaining the pressure in the same level during primary and secondary drying was found to work with isomalt samples in a previous study (Koskinen, et al 2016). After the freeze-drying cycle was complete, the chamber temperature was lowered from 35ºC to 25°C and the chamber was filled with N2 gas to bring the pressure inside the chamber back to atmospheric pressure.…”

“…The vials intended for storage stability studies were transferred into a desiccator containing a saturated salt solution of lithium chloride, thus producing a relative humidity of approximately 16%. In our previous study even this low relative humidity condition was observed to cause stress to the physical stability of freeze-dried isomalt samples stored in the desiccator without stoppers (Koskinen, et al 2016), and was thus chosen to this current study. The vials were opened inside the desiccator and were stored without stoppers at ambient temperature of approximately 22°C.…”

“…Some polyols, such as mannitol and sorbitol, tend to crystallise during freeze-drying and/or storage (Al-Hussein and Gieseler 2012;Costantino, et al 1998;Kadoya, et al 2010), which reduces their ability to stabilize proteins. Previously, we have characterized the solid state changes of isomalt and its diastereomer mixtures during freeze-drying and storage in the absence of proteins (Koskinen, et al 2016). It was found that crystalline isomalt could be transformed into the amorphous form with freeze-drying, and that during storage at up to 16% RH amorphous isomalt had good physical stability.…”