Physical Stability of Freeze-Dried Isomalt Diastereomer Mixtures.

PURPOSE: Isomalt is a sugar alcohol used as an excipient in commercially available solid oral dosage forms. The potential of isomalt as a novel freeze-drying excipient was studied in order to increase knowledge of the behavior of isomalt when it is freeze-dried. METHODS: Isomalt was freeze-dried in four different diastereomer compositions and its physical stability was investigated with differential scanning calorimetry, Fourier-transform infrared and Raman spectroscopy, X-ray powder diffraction, Karl-Fischer titration and thermogravimetric analysis in order to verify the solid state form of isomalt after freeze-drying and observe any changes occurring during storage in three different relative humidity conditions. RESULTS: Isomalt was successfully transformed into the amorphous form with freeze-drying and three diastereomer combinations remained stable as amorphous during storage; one of the diastereomer compositions showed signs of physical instability when stored in the highest relative humidity condition. The four different crystalline diastereomer mixtures showed specific identifiable solid state properties. CONCLUSIONS: 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.

Stability of rituximab in freeze-dried formulations containing trehalose or melibiose under different relative humidity atmospheres.

The objective of the study was to compare the effectiveness of trehalose with that of melibiose in protecting a monoclonal antibody (rituximab) from aggregation, fragmentation, and secondary structure alterations during processing and subsequent storage. Because reducing disaccharides such as melibiose participate in Maillard reaction with proteins, especially in the presence of water, the lyophilizates were stored under different relative humidity (RH 5%, 11%, and 23%) atmospheres. Freeze drying was shown to cause clear alterations in rituximab secondary structure, an increase in noncovalent protein aggregation, and in some cases fragmentation. However, these changes were less pronounced in the formulation containing melibiose. Storing the lyophilizates under low RH (5%) proved to be most harmful to the stability of rituximab, intensifying secondary structure alterations and increasing protein aggregate content. Again, these changes were less aggravated in the formulation containing melibiose. Surprisingly, the concentration of aggregates larger than 1 µm decreased in some cases during storage at RH 11% and 23%. There was no indication that storage even under the highest RH (23%) would have caused significant amounts of Maillard reaction end products to be formed during 3 months of storage.

The effect of relative humidity on the physical properties of two melibiose monohydrate batches with differing particle size distributions and surface properties.

Melibiose monohydrate has shown promise when employed as a pharmaceutical excipient, but its physical properties have not been adequately characterized. Therefore, two different melibiose monohydrate batches were analyzed as received or after storage under different relative humidity (RH) atmospheres. The particle size distributions and specific surface areas of the two batches were shown to differ considerably, which also had an effect on their water sorption tendencies and on the intermolecular structure of melibiose after storage. The relatively large primary particles that were more abundant in one of the batches were shown to possess a porous surface structure, and water evaporation from them occurred in two phases when heated. Furthermore, storing the batch with smaller mean particle size under dry conditions affected the crystal structure and molecular vibrations of the sample more than in the case of the batch with larger mean particle size. It was concluded that the physical properties of melibiose monohydrate after storage at different RH atmospheres is largely governed by the primary particle size and porosity.