Vacuum packaging impact on cold-sensitive drugs: example of 5-Fluorouracil

A. Cèbe1, G. Bouguéon1,2, M. Sangnier1, A.Khan1, J-M. Bernadou1, P.Dufourcq3, S. Crauste-Manciet1,2
1 Pharmaceutical Technology Department, Bordeaux University Hospital, France
2 ARNA Laboratory ChemBioPharm U1212 INSERM - UMR 5320 CNRS, Bordeaux University, France
3 Biology of Cardiovascular Diseases, Inserm U1034, Pessac, France


Objective
To ensure preservation improvement of anticipated cytotoxic preparations, vacuum packaging appears to be a potential solution. High vacuum may lead to freeze sterile injectable solutions and raises the problem of maintaining physical stability of cold sensitive drugs. Preliminary tests showed that a 20 ml water for injection sample placed in vacuum packaging pouch (polyamide-polyethylene, 250x 350mm, MULTIVAC®) began to crystalize suggesting that water-freezing temperature was reached. The purpose of this study was to qualify the packaging method by assessing physical stability of 5-Fluorouracil (5-FU) solution selected as a worst case model drug because of its well-known crystallization under cold storage.

Materials and methods
The semi-automatic vacuum pack machine C200 (MULTIVAC®) was used. Previous works defined optimal parameters (i.e. remaining pressure in storage bags and welding time) to apply according bags volume; e.g. 4mbar and 2.3s for 50ml sodium chloride bags (Freeflex Fresenius®).
Three 5-FU (Accord Healthcare) preparations of 50mg/mL in 50mL sodium chloride bags were prepared and packed according to parameters mentioned previously. An optical microscopy observation (Observer Z1, DIC x20, ZEISS) was performed on 5-FU preparations before and after vacuum packaging and compared to one negative and two positive (PC1 and PC2) controls. PC1 was obtained by submitting 5-FU preparations to a 4-5°C storage. PC2 was a 5-FU solution crystallized in commercialized vial under cold storage. Precipitates from PC1 and PC2 were collected using a vacuum filtration technique.

Results - Discussion
Isolated crystals or more dense clusters were observed with PC1 and PC2 precipitates. PC1 crystals have an acicular structure, and needles length was between 50 to 100µm. PC2 appears as more prismatic crystals with a 100 to 600µm length. No crystals or other microscopic formation were observed in all samples before and after vacuum packaging. Several variables may explain this lack of crystallization: diluent composition (i.e. sodium chloride solution) where freezing point is lower than pure water, or short sealing time.

Conclusion
In our study conditions, we can safely conclude that vacuum packaging will not affect the physical state of cold-sensitive drugs. This simple test could be suggested as process validation method for cold-sensitive drugs when vacuum conditions (pressure or time) are modified.

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