Attributes related to lyophilization of glass containers

As an important member of pharmaceutical packaging materials, glass packaging has withstood the test of time, meeting the vast majority of requirements from the early stages of drug development (such as physical and chemical properties, pharmaceutical compatibility, etc.), through production scale-up (process adaptability, etc.), to clinical trials and market launch (safety, etc.). Despite its long history, however, there is still a lack of understanding about glass packaging materials among pharmaceutical professionals or packaging professionals to some extent. Therefore, we will share knowledge with you based on industry literature and reviews, hoping it will be helpful to everyone.

I. The lyophilization process of pharmaceuticals

In the production process of pharmaceuticals, if it involves lyophilized powder injections, the lyophilization process will be involved. Before discussing the correlation between the attributes of glass packaging and the lyophilization process, we first need to understand what lyophilization process and products are, as shown in Figure 1. As you can see, the process can be simplified into three steps: after the liquid medicine is lyophilized, the rubber stopper is in a semi-inserted state (to provide a channel for moisture to evaporate outward). In Stage I, unbound free water molecules are removed, and then the temperature is further increased to remove bound water molecules (bound through hydrogen bonds, etc.) in Stage II. After that, inert gas is reintroduced to complete the stoppering process.

Figure 1: Lyophilized Products and Related Process

II. Glass attributes related to lyophilization

After understanding the lyophilization process mentioned earlier, let's delve into the glass attributes related to lyophilization. There are five aspects as follows:

(1) Coefficient of Thermal Expansion (CTE).

From a materials science perspective, it characterizes the volume change of a material when heated or cooled, and its value is related to the glass composition and the measurement range. The smaller this value, the more stable the material is during temperature changes. Strictly speaking, CTE can be further divided into linear expansion, areal expansion, and volumetric expansion, and the essence of these is the increase in the gaps between the atoms material. Pharmaceutical glass packaging is mostly made of borosilicate glass, with a CTE of approximately 3-10**10^-6K^-1.

Figure 2: Coefficient of Expansion and Its Principle

(2) Thermal conductivity

This is an indicator of a material's thermal conduction performance. Different media have different mechanisms for heat conduction. For example, metals rely on electrons, nonmetals rely on lattice structure vibrations, and gases rely on molecular thermal motion. For glass materials, their thermal conductivity is low. If glass packaging containers are involved in temperature changes in pharmaceutical manufacturing, such as cleaning empty bottles to remove pyrogens or product lyophilization, this property becomes important. Generally, glass materials are similar, so the only significant difference lies in the impact of the product's geometric design on heat conduction.

(3) Residual Stress

Residual stress refers to the self-balancing internal stress that remains in an object after the elimination of external forces or uneven temperature fields. For example, if a spring is subjected to a compressive or tensile force, ideally, after the force is removed, it has a driving force to return to its original state. However, if the recovery process is particularly slow after the external force is removed, this force will persist for some time, known as residual stress. For glass, during the processing and refining stages, such as melting and shaping, when the heat source is removed, the movement of atoms is not as smooth as it is at high temperatures. This force trying to return to the original state is residual stress. The residual stress in glass can be revealed using polarized light. Glass is an isotropic material with the same refractive index in all directions. If there is stress in the glass, the isotropic nature is disrupted, causing changes in the refractive index. The refractive indices in the two principal stress directions are no longer the same, leading to birefringence.

                                                                                                             Figure 3: Stress Detection Process

(4) Thermal shock resistance

This indicator is actually a combined result of the expansion coefficient, packaging container design, and stress. It measures the ability of the packaging container to withstand temperature changes, such as transitioning from high temperature to room temperature or from room temperature to high temperature. Due to different glass materials having varying expansion coefficients, and glass being a poor conductor of heat, theoretically, the smaller the expansion coefficient, the stronger its ability to withstand thermal shock under the same thickness conditions. This is why borosilicate glass has a stronger resistance to thermal shock than soda-lime glass.

Figure 4: Thermal expansion caused by temperature gradient

(5) Crack resistance

Crack resistance refers more to the ability to withstand cracking due to mechanical forces. Its strength is related to the design of the container, the type of material, and whether there are defects on the surface. Sometimes, the cracking of glass bottles is caused by mechanical forces, such as expansion during freeze-drying.

Figure 5: Cracking caused by expansion during the freeze-drying process

III. Parameters related to cracking during freeze-drying

The characteristics of lyophilized preparations are that the glass packaging material undergoes thermal shock, while the internal formulation undergoes a process of cooling and expansion. Therefore, the cracking during the lyophilization process may primarily be due to the following reasons:

◇ The process and design of glass packaging materials: Sometimes, the entire bottom of the bottle may fall off, which may be related to insufficient annealing of the bottle and the fragile edge of the bottom molding.

◇ Formulation-related: Sometimes certain special ingredients in the formulation may tend to cause excessive expansion.

◇ Filling volume: Sometimes the container is overfilled, leaving insufficient space for freezing expansion during the lyophilization process.

◇ Local defects in glass packaging during the manufacturing process: Defects become the starting point for cracking.小结

Ⅳ. Conclusion
◇ The lyophilization performance of glass packaging is related to many attributes.

◇ Cracking during the lyophilization process is related to the material, design of the glass packaging, and the formulation of the product.