16 2. Glass and heat. 2. Glass and heat. 2.1 Viscosity. Viscosity is the resistance against flowing.

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1 16 2. Glass and heat 2. Glass and heat 2.1 Viscosity Viscosity is the resistance against flowing. The higher the viscosity, the slower the substance flows. Knowing the viscosity of glass is particularly important in the melting and converting process because this determines the temperature and the time window available to work and form the glass. Each glass composition has a different viscosity at a certain temperature so changing the glass tubing type should ideally be followed by the adjustment of the temperature settings in the converting process. lg (viscosity [dpas]) 16 Tg 14 annealing working, hot forming 2 melting Temperature [ C] strain point upper annealing point softening point working point melting point Type I glass, CTE 4.9 Type I glass, CTE 3.3 Type III glass, CTE 9.1 Quartz Fig. 7 Temperature-viscosity diagram of different exemplary types of glass used in the pharmaceutical industry and quartz. An exemplary viscosity-temperature curve of quartz, two different glasses of Type I and one Type III glass, are shown in figure 7. Usually 1600 C is the temperature at which the raw materials of the glass are melted in the melting tank. The melt now has approximately the viscosity of honey. The hot forming of the glass melt into a tube is dictated by the working point (working temperature), which is around 1160 C for FIOLAX (Type I glass, CTE of K -1 ; for CTE see chapter 2.3), 1260 C for Boro-8330 TM / Duran (Type I glass, CTE of K -1 ), and is different for each glass.

2 2.2 Stress 17 This is also the minimum temperature needed in the converting process to form the tube into a container. During heating in the forming process, stress is introduced into the glass (see chapter 2.2), which has to be released later on. This is done in the annealing oven, where the container has to be heated above its annealing range (limited by the strain point and the (upper) annealing point). At this annealing temperature a relaxation of residual stress will occur within 15 minutes [8 p. 90]. This annealing temperature is also distinct for each glass, e.g., for FIOLAX 565 C, for DURAN 560 C. 2.2 Stress Stress is the force acting on a specific area resulting in a dislocation of atoms. Stress, defined as force per area, is generated as an internal reaction to a mechanical impact. If a mechanical impact acts upon the glass, the structure tries to rearrange in order to neutralize the impact. Atoms in the glass structure have their ideal distances being neither too close nor too far away from each other. If this distance is changed by an external force, e.g. a compressive or a tensile force, the atoms strive to regain their original distance again by counteracting the external force (Figure 8). No stress External tensile stress External compressive stress External force Internal force Fig. 8 Illustration of stress within the glass structure. Left: No stress in the glass. Middle: Tensile stress. Right: Compressive stress.

3 18 2. Glass and heat Stress is mainly induced physically or chemically. Physically induced stress is generated by hitting the glass or through local temperature differences within the glass. Chemically induced stress is caused by a chemical reaction such as chemical toughening (see chapter 5.7). As explained in the beginning for crystals, the transition from the solid to the liquid state occurs exactly at the melting temperature. Unlike crystals, glass has no fixed melting point. It gradually softens and stiffens as the temperature changes. Figure 9 shows a close-up of figure 7. The phase in which the transition from liquid to solid glass occurs is called the annealing zone. The limits of the annealing zone are determined by the upper annealing point and the strain point. The upper annealing point (commonly referred to as annealing point ) is the upper end of the annealing zone, where the glass begins to return to a liquid state. At this point, the glass is liquid enough for the atoms to move around and release any stresses. The strain point (also lower annealing point) is the lower end of the annealing zone, representing the temperature where the glass finds its final structure. Stress remaining in the glass at this point is unlikely to be changed or released as the atoms have found their final position within the network [9 pp ]. Volume large glass crystal small high melting point crystal strain point upper annealing point Tg low Temperature Fig. 9 Temperature-volume diagram of glass and a crystal, comparing the melting point of the crystal and the annealing range of the glass.

4 2.2 Stress 19 The temperature at the intersection of the extrapolated slopes in the volume-temperature diagram of the glass (Figure 9) is called the transition (or transformation as the German term) temperature Tg (Tg = glass temperature according to Tammann [1]). Every glass type has its own characteristic transition and annealing temperature. Typical values for the annealing point and Tg for glasses for pharmaceutical packaging are between 500 and 600 C (Table 2). heating and forming quick cooling down after forming Stress area Fig. 10 Illustration of the creation of stress in the glass during production of the container. Upper left: Heating of the glass tube where the atoms start oscillating. Upper right: After forming, the atoms are cooled down quickly and remain in the position they currently hold. Bottom: In the annealing oven all atoms are heated up uniformly, leading to a release of the stress. When forming the container, temperatures over 1000 C (at least temperatures as high as the working point, figure 7) have to be applied on the glass tube (Figure 10). The heated atoms (Figure 10 upper left, orange) start oscillating whereas the atoms (Figure 10 upper left, light blue), which were not heated remain in place. After the forming is done, the glass is cooled down quite quickly, thus causing a sudden removal of energy. The atoms do not have

5 20 2. Glass and heat time enough to rearrange and to return to their former structure but they get stuck in the position they occupy at that time. At the transition zone, which consists of atoms that have been heated and those that were not, compressive and tensile stress is created (Figure 10: light blue and yellow atoms strive to create distance; yellow and orange atoms strive to get closer). To release this stress, the containers are passed through an annealing lehr (oven). Hereby they are heated above the annealing point and kept there for a defined period of time so that the atoms have the chance to rearrange themselves. In a strictly controlled cooling process, the atoms have the chance to cool down and arrange in a proper way with minimum stress. Whether the stress has been released properly from the glass can be checked using a polarimeter (so-called polariscope). After forming, but not yet having being annealed, the glass changes at the stressed areas from an isotropic (ordered) to an anisotropic (more chaotic) state. The latter state in the glass causes a beam of light to be refracted twice, which means, the light is split into two vertically polarized partial rays, which pass through the layer of glass at varying speeds. The phase difference between these two partial rays after leaving the layer is a measure of the amount of stress in the glass. It can be visualized by placing the glass sample between two crossed polarizers. Fig. 11 Left: Unannealed vial. Right: Annealed vial.

6 2.3 Coefficient of thermal expansion (CTE) 21 An example for an unannealed and annealed glass container is given in figure 11. Glass without any stress appears completely bright whereas stressed areas in the glass appear dark. Stress which is not released properly can increase the risk for breakage. 2.3 Coefficient of thermal expansion (CTE) The coefficient of thermal expansion describes how much a material changes in volume when it is heated up or cooled down. Most of the materials, with few exceptions, expand with increasing temperature. This expansion can be measured as change in volume and as change in length and depends on the glass composition or the temperature range in which it is measured. It is described by the coefficient of mean linear thermal expansion (CTE or α) and is given as change per temperature unit. The more the material expands in length, the higher is its CTE. As it is a temperature-dependent factor, it is always given for a certain temperature range. A metal (e.g., aluminum) has a CTE of around K -1, it expands and shrinks significantly when it is heated and cooled down again. In contrast, quartz glass has a CTE of below K -1 as in the perfectly symmetrical structure the atoms are strongly bound and leave almost no space for expansion. Thus it becomes clear that the CTE depends on the chemical composition of the glass in such a way that it increases in accordance with the amount of network modifiers. For pharmaceutical applications the lower the CTE is, the more stable the glass is in any given type of temperature process, e.g., lyophilization. The CTE for glasses typically used for pharmaceutical applications range between K -1 and K -1 (Table 3).

7 22 2. Glass and heat Table 3 Comparison of the coefficient of mean linear thermal expansion (CTE) of different pharmaceutical glasses. Material CTE [10-6 K -1 ] Temperature range Quartz glass < C Type I glasses SCHOTT Boro-8330 TM C Gerresheimer Gx C Nipro W C SCHOTT FIOLAX C Gerresheimer Gx 51-D C Nipro NSV C Type III glasses SCHOTT AR-Glas C SCHOTT ILLAX C Nipro G C Aluminum C 2.4 Thermal conductivity Thermal conductivity is the ability of a material to conduct heat. The thermal (or heat) conductivity describes which amount of heat passes within 1 second through a substance of 1 m thickness at a temperature change of 1 K. The lower this value is, the slower the heat passes through the substance. This means that a temperature gradient develops throughout the glass wall, which can lead to local internal mechanical stress. Glass in general has a quite low thermal conductivity with values of around W/(m K), whereas copper has a value 340 times as high. For pharmaceutical applications this is of particular interest in temperature-related processes, like freeze drying, freezing and thawing, etc. There is a direct correlation between thermal conductivity, the wall thickness, and the temperature shock resistance of a glass.

8 2.5 Thermal shock resistance Thermal shock resistance Thermal shock resistance describes how stable a material is when subjected to a sudden change of temperature. The thicker the glass wall is, the longer the heat needs to pass through it. If a glass is heated to high temperatures (e.g., over 300 C in the depyrogenation oven) and then comes in contact with a cold material, the contact spot on the outside wall cools down immediately. But as glass has a very low thermal conductivity, the temperature cannot penetrate through the glass wall fast enough. This can lead to a high local internal stress inside the glass that might eventually result in a thermal shock crack. Using a thinner-walled container, the temperature gradient can be equalized faster, thus preventing the possibility of creating a thermal shock crack. 2 CTE Temperature difference [ C] wall thickness [mm] borosilicate glasses 3.3 (BORO-8330 ) borosilicate glasses 5.0 (FIOLAX ) borosilicate glasses 7.0 soda-lime glasses (AR-GLAS ) Fig. 12 Dependence of wall thickness, glass composition, and respective CTE on temperature shock resistance. For example a soda-lime glass container with a CTE of around K 1 and a wall thickness of 1.0 mm cannot endure an immediate temperature dif-

9 24 2. Glass and heat ference of greater than 80 C. Its temperature shock resistance is exceeded and it would most probably exhibit a thermal shock crack. On the other side, a borosilicate glass with a CTE of around K 1 and a wall thickness of 1 mm could endure 150 C immediate temperature difference without breaking (if there are no defects on its surface).the relation between CTE, wall thickness, and temperature difference is given in figure 12. The lower the CTE and the smaller the wall thickness, the higher the temperature shock resistance of the glass. 2.6 Lyophilization Lyophilization is a procedure by which water is removed from the drug solution to form a dry powder. Within the past decades, more and more drugs on the market are derived from biological origins. The FDA states that: Products are manufactured in the lyophilized form due to their instability when in solution. Many of the antibiotics, such as some of the semi-synthetic penicillins, cephalosporins, and also some of the salts of erythromycin, doxycycline and chloramphenicol are made by the lyophilization process. [11]. The basic principle shall be explained only briefly. The process starts with a freezing step, where a number of containers with loosely stoppered closures are placed on a tray in a lyophilization oven and frozen. In the next step, vacuum is applied and the temperature is increased slightly leading to sublimation (i.e., the ice crystals are being transferred into a gaseous state directly while skipping the liquid state) of the ice crystals, which are removed at the same time. After this first drying cycle, both the vacuum is intensified and the temperature is increased as well in order to remove even the last hidden ice crystals. What is left should be a dry powder as a well formed cake [12].

10 2.6 Lyophilization 25 Heating of the formulation is achieved by radiation and mostly by conduction through the glass container, which is in direct contact with the heating shelf (Figure 13). radiation vapor freezing nucleus (-30 C) sublimation zone product convection conduction Fig. 13 Drug product with frozen nucleus. The vial is heated by radiation, conduction, and convection. As the glass is between the frozen crystal and the heating shelf, the temperature gradient at the contact spots is critical. Thus, for this process, a glass with an adequate CTE (i.e., a Type I glass) is needed, which is why the Ph. Eur. recommends not to use soda-lime glass for freeze-drying processes. Due to its low thermal conductivity, the temperature is only transferred slowly through the glass wall, which is why the geometry of the glass container bottom (whether an ampoule or a vial) is critical. The bottom wall thickness is recommended to be around 60 ± 5% of the container side walls thickness to allow quicker heat transfer [13]. Other important geometrical considerations are the concavity or flatness of the bottom and the bottom/wall angle and radius.

11 26 3. Glass and radiation and gases For temperature applications, glass with a low CTE is recommended. Current Ph. Eur. recommends to only use Type I glass for lyophilization. 3. Glass and radiation and gases 3.1 Light transmission Glass is highly appreciated for one major property: its optical transparency in the visible range. When light meets the glass surface, part of it is reflected, another part is absorbed, and the remaining part is transmitted through the glass. The amounts reflected, absorbed, and transmitted depend on both the wavelength of the light and the chemical and physical structure of the glass. Borosilicate and soda-lime clear glasses are highly transmissible for visible light ( nm) but also for the near-infrared light (> 700 nm) up to 2500 nm. Certain long-wave infrared radiations (> 2500 nm) interact with whole atom groups within the glass and are thus absorbed. The short-wavelength, highly energetic UV light ( nm) is partly absorbed (< 300 nm) because it interacts with the electrons but is also partly transmitted (> 300 nm). In ultrapure synthetic quartz glass on the other side, the electrons are packed so tightly that UV light down to approx. 160 nm is transmitted without interaction with the glass. By adding different elements this interaction can be controlled in specific ways. Sulfide glasses absorb the whole range of visible light, which is why they appear completely black. Addition of iron, manganese, chromium, nickel, copper or cobalt each leads to different colors. If a greater transmission is required, the glass has to be kept as free of these metals as possible [9,14].