Study on the influence of rubber plug on the residual moisture of freeze-dried products

Moisture is one of the key quality attributes of freeze-dried products Freeze drying is a key process step Its main function is to use sublimation to reduce the water content of the product, so as to achieve long-term stable preservation However, even if the residual moisture (RM) of the drug is controlled below the standard by freeze-drying, it will often encounter the problem of gradual increase of moisture in the stable period If we exclude the factors that the packing material is not tightly sealed, the water transferred into the drug can only come from the rubber plug, then how the rubber plug affects the residual water of the drug is discussed in this paper in combination with the relevant research in P Hesley's book freeze drying The results show that there are also bound water and free water in the plug First of all, like freeze-dried products, the water in the plug also contains free water and bound water In the literature of Wang et al., the free water and the combined water in the rubber plug are distinguished Figure 1 shows that the water distribution of the rubber plug does not change after drying for one week The remaining 0.35% of the water is combined with the plug material and cannot be removed even at 100 ℃ The author concludes that the binding water which can not be removed at 100 ℃ has no harm to the drug Only free water will spread from the cork to the product Fig 1 how to measure the distribution of water in the rubber plug after autoclave at 121 ℃ for 30min and drying at 100 ℃ for different times? In the drying room, the content of water at different temperatures was measured by Karl Fischer method, the composition of free water was determined at 100 ℃, and the content of free water and combined water was measured by heating to 300 ℃ The author suggests that similar method can be used for other plugs Because the relative time of this method is relatively short (one week), it can replace rm of long-term observation of products (evaluate the amount of free water in the rubber plug) Table 1 summarizes the evaluation results of free water binding water for a rubber plug Table 1 Analysis of water content of rubber stopper drying time water content (%) ± SA content of free water% no 0.52 ± 0.02 0.21 16 h 0.34 ± 0.02 0.03 0.31 ± 0.02 a week- Note: the drying time refers to the time free water measurement and rubber plug screening in the high temperature drying room at 100 ℃ after 16 minutes of high-pressure sterilization and 30 minutes of vacuum drying Assuming that the product is easily hygroscopic (the current situation is that the hygroscopicity of different products varies greatly), the free water in the rubber plug can be transferred to the product According to the water limit standard of the product, the limit value of free water in the rubber plug can be calculated The commonly used specifications and weights of rubber plug are 2.5G and 0.6g respectively, assuming that the weight of the product varies from 0.05 to 0.4g, and the increase limit of the final water content in the stable period of the product is 0.5%, then the allowable free water content limit in the rubber plug can be seen in the following table: Table 2 assumes that the maximum value of the water content in the plug is 0.5% when the large increase of rm of the product is 0.5% Plug mass / g product mass / g limit value of free water /% 2.5 0.4 0.13 2.5
0.2
0.07
2.5
0.1
0.03
2.5
0.05
0.02
0.6
0.4
0.56
0.6
0.2
0.28
0.6
0.1
0.14
0.6
0.05
0.07
So the significance of combined water measurement is to provide a fast method to screen the rubber plug (including material and pre-treatment methods, which will be mentioned later), which can be preliminarily screened without long stability test What does free water have to do with? The content of free water in the plug is related to the material, quality and pre-treatment of the plug The water content of rubber plug depends on the composition of rubber plug De grazio and Flynn demonstrated that the selection of polymers, vulcanization additives and fillers affect the adsorption and desorption of water However, the rm of 215 mg sucrose increased from 1.95% to 2.56% even when the plug mixture was stored at room temperature for 3 months, and the rm of other plug mixtures increased by as much as 1.7% Pikal and Shah showed that the water desorption from the plug and the water adsorbed by the product, in the equilibrium state, depends on the quality and water content of the plug as well as the water content and adsorption behavior of the dry product Conclusion: there is a relationship, but its law needs to be further studied Relationship with pretreatment process (cleaning, sterilization, drying, storage): if the rubber plug is small enough technically and the material is also used, the water content of the rubber plug depends on its pretreatment process: the water absorbed by the steam sterilization plug (for example, 1.1% of its mass), which can be extracted by 8 hours of vacuum drying or dried to 0.1% by 8 hours of circulating hot air (110 ℃) Figure 2 shows the steam sterilization plug After 8 hours of vacuum drying, the water released into lactose is slightly less than that of untreated rubber plug The RM increased 2.4 times when the rubber plug was dried for 1 hour and stored at 25 ℃ for 6 months It is also shown in the figure that it will not actually change after reaching the equilibrium state, and the time to reach the equilibrium state mainly depends on the temperature For a given product, the time required to reach half of the maximum value is 4 days at 40 ℃ and 10 months at 5 ℃ Conclusion: cleaning and steam sterilization can increase the free water, vacuum drying can reduce the free water and increase the water content during long-term preservation Other literatures have mentioned that freeze-drying process has no effect on free water of rubber plug Fig 2 function relationship between water content and time of 100mg lactose at + 25 ℃ (sv1 steam sterilization plug); u, untreated; SV8, steam sterilization plug, and vacuum drying for less than 8h This paper provides the idea of the influence of rubber plug on the residual water content of freeze-dried products in the stable period, and recommends a method that can quickly screen rubber plug, hoping to help you In addition, there are many knowledge points in the book freeze drying, which we will present to you in the form of reading notes Please keep your attention.