When Glass meets Pharma E-Book

Dr. Bettine Boltres

• Herausgeber: ECV Editio Cantor
• Kategorie: Fachliteratur
• Serie: ecvINSIGHTS!
• Sprache: Englisch

Seitenzahl: 105

Veröffentlichungsjahr: 2015

Beschreibung

Demands on a primary packaging material are not easy to meet these days. Increasingly, intense optical inspection, zero defect programs, and higher regulatory specifications require that drug packaging materials can no longer be taken for granted. Bringing us to the material "glass": What is glass anyway? How does it react with my drugs? Can I freeze it? Why is it breaking? Why is my drug being adsorbed to it? Why is this over 100-year-old borosilicate glass still the gold standard? If you have asked yourself these or other glass-related questions, this book is the right choice for you. It will guide you through the world of glass in a comprehensible and pharma-focused manner. Furthermore, this guide will keep you well-covered with the fundamentals on your first voyage into the world of glass. Die Anforderungen an Primaerpackmaterialien sind heutzutage nicht leicht zu erfuellen. Intensive optische Pruefungen, Null-Fehler-Programme und strengere Behoerdenanforderungen haben dazu gefuehrt, dass Hersteller ein erhoehtes Augenmerk auf Packmittel fuer Medikamente richten muessen. Nehmen wir zum Beispiel den Werkstoff Glas: Was ist Glas ueberhaupt? Wie reagiert es mit meinen Arzneimitteln? Kann ich es einfrieren? Warum geht es kaputt? Warum lagert sich mein Medikament auf der Glasoberflaeche an? Warum ist Borosilikat-Glas, das es schon seit über 100 Jahren gibt, immer noch der Goldstandard? Wenn Sie sich diese oder andere Fragen rund um Glas schon einmal gestellt haben, ist dieses Buch das richtige fuer Sie. Es wird Sie umfassend und aus dem pharmazeutischen Blickwinkel durch die Welt des Glases fuehren. Gleichzeitig wird dieses Handbuch Sie auf Ihrer ersten Reise in die Welt des Glases sicher geleiten und Ihnen alle Grundbegriffe erlaeutern.

Leseprobe

Contents

Preface

1. The nature of glass

1.1 Structure of glass

1.2 Chemical composition

1.3 Type I and Type III glass

1.4 Production of tubular and molded containers

2. Glass and heat

2.1 Viscosity

2.2 Stress

2.3 Coefficient of thermal expansion (CTE)

2.4 Thermal conductivity

2.5 Thermal shock resistance

2.6 Lyophilization

3. Glass and radiation and gases

3.1 Light transmission

3.2 Light protection

3.3 Gamma radiation

3.4 Permeability

4. Glass and liquids—chemical resistance

4.1 Reactions with acidic solutions

4.2 Reactions with basic solutions

4.3 Reactions with water

4.4 Testing methods for hydrolytic resistance

4.5 pH shift

4.6 Reactions with organic acids

4.7 Extractables and leachables

5. Glass surface reactions

5.1 Surface layer

5.2 Charge of the glass surface

5.3 Water contact angle

5.4 Weathering

5.5 Roughness

5.6 Sulfate surface treatment

5.7 Chemical toughening

5.8 Delamination

5.9 Protein adsorption

6. Glass strength

6.1 Ductile and brittle materials

6.2 Elasticity and plasticity

6.3 Stress and strain

6.4 Stiffness and modulus of elasticity

6.5 Hardness

6.6 Damage to glass

6.7 Crack growth

6.8 Breakage

References

Preface

Talking with pharmaceutical companies and giving technical seminars about glass for pharmaceutical packaging, I was faced by a huge curiosity for this material “glass”. Up to now, glass has always been taken for granted because it has been used for centuries. Therefore, it never really was in the spotlight of interest for pharmaceutical companies. However, with the increase in quality awareness, the development of new packaging materials, and the growing development of biopharmaceuticals, the possible interactions of the drug with the container have increasingly come into focus.

Several good books about glass chemistry, glass physics and its applications are available. On the other side, there are several good books on the market summarizing the various pharmaceutical packaging choices.

In order to close this gap, the book sets out to combine the world of inorganic glass chemistry with the world of organic drug molecules. Therefore, it focuses exclusively on pharmaceutical applications and endeavors to make the complicated chemical and physical fundamentals accessible to everyone, including non-scientists. This book was written especially for manufacturers, suppliers, and personnel working in regulatory affairs in the pharmaceutical industry but should also be of interest to all others who would like to dive into those parts of the glass world that are relevant for pharmaceutical applications. The topics covered in this book arose from the numerous fruitful discussions with staff of pharmaceutical companies over the past years.

Acknowledgements

Finally I would like to thank all colleagues and partners who contributed to this work, especially Volker Rupertus, Folker Steden, Michael Rössler, Daniel Haines and Florian Maurer.

Summer 2015 Dr. Bettine Boltres

1. The nature of glass

1.1 Structure of glass

Glass is one of the oldest materials in use. The art of working glass is known to be around 5000 years old. At that time, naturally occurring glass, e.g., obsidian, was already used for the production of hunting tools. Then the glass, due to its shiny appearance and because it can be stained so easily, was soon appreciated for valuable jewelry and decoration purposes. The oldest remaining glass recipe was found in the clay tablet library of the Assyrian king Assubanipal (700 BC) and reads approximately: ‘Take 60 parts sand, 180 parts ash from sea plants and 5 parts chalk—and you get glass.’ Up to modern times, this so-called soda-lime glass was used for packaging herbs, natural medicines, oils and other substances used for medicinal purposes. Around 200 BC, Syrian craftsmen invented the glassmaker pipe and melting ovens with which it was then possible to produce flat glass and hollow glass vessels. As widely spread as the use of glass is, it is hard to precisely describe it and find a definition that is internationally recognized and understood.

Fig. 1Left: Structure of crystalline quartz. Right: Structure of amorphous quartz.

From the extensive scientific literature only a few attempts to describe the nature of glass can be mentioned here. One of the pioneers of glass research, Gustav Tammann (1861–1938), writes: In the glassy state substances are solid but not crystallized [1]. The American Society for Testing Materials (ASTM) stated in its compendium C162 in 1945 that “glass [is] an inorganic product of fusion which has cooled to a rigid condition without crystallizing.” This definition is still used in its most current version. In 1986, it was integrated into its German counterpart, the DIN 1259. The difference between the crystalline and the glassy state can be described by using its atomic structure. In figure 1, the structures of a quartz crystal and a quartz glass are shown. Quartz, which is found in nature as pure sand (SiO2 or silica) is built of SiO4 tetrahedra. In a crystal these are connected to form a six-sided prism as a member of the trigonal crystal system. It resembles perfect symmetry. Amorphous quartz (quartz in the glassy state) displays a more random chaotic arrangement.

Fig. 2 Solidification behavior of a crystal and amorphous material glass are shown in a temperature-volume diagram.

The transition from the crystalline structure to the amorphous structure takes place when the quartz is melted and rapidly cooled down to ambient temperature. The melting is done by introducing heat into the system. This energy is used to break the bonds between the atoms, whereupon they are able to move around freely in the system. At this point the glass melt is liquid. While it is cooled down, energy is removed (Figure 2), the atomic rearrangement (frequency of movement) becomes slower and the atoms try to position themselves in the pattern of an organized crystal. Only their very high viscosity (in the melting tank the viscosity is 102 dPas, which compares to honey) slows them down so that they freeze in the chaotic spot they currently hold. Thus, the amorphous state is only created because the atoms in the melted glass do not have enough time to arrange themselves into a crystal but instead they freeze in their random liquid position.

When water is cooled down gradually, it reaches its melting point, i.e., the transition from the fluid to the solid state, at precisely 0°C, where it promptly solidifies into a crystal. Due to the rate of cooling and the viscosity of glass, there is no “precise point”, thus allowing for the creation of an amorphous structure.

Given that the Si-O bond is one of the strongest bonds and—because it contains extremely low concentration of compositional impurities—quartz has a very high melting temperature of around 2000°C [2 p. 121]. Accordingly, it has a very high working temperature combined with a narrow working window (which complicates the conversion into a pharmaceutical container) and a very high thermal and chemical resistance. Despite and also due to these properties, silica glass is not suitable for bulk production as it makes the production of pharmaceutical glass rather costly.

1.2 Chemical composition

Glasses that are used in everyday life represent a mixture of different ingredients. The main component building the backbone (network) of pharmaceutical glass is silica, also called network former. In order to make the glass more economically feasible for production, the melting temperature needs to be decreased. This is done by adding so-called network modifiers, which disrupt the silicon/oxygen backbone bonding, creating more space for movement of the atoms. Due to this, less energy is now needed to soften the glass in the converting process. Typical network modifiers are alkali and alkaline earth metals, such as sodium, potassium, and calcium.

Table 1 Common elements used for pharmaceutical glass containers.

Element in network

Raw material as found in nature

Network formers

Silicon (Si)

SiO2

sand

Boron (B)

Na2B4O7

borax

Network intermediates

Aluminum (Al)

Al2O3

alumina/bauxite

Network modifiers

Sodium (Na)

Na2CO3

soda

Potassium (K)

K2CO3

potash

Calcium (Ca)

CaCO3

CaMg(CO3)2

chalk, marble, limestone

dolomite

Magnesium (Mg)

MgCO3

CaMg(CO3)2

magnesia

dolomite

Barium (Ba)

BaSO4

barite

One of the disadvantages of adding network modifiers is the creation of more space in-between the atoms, which thus causes lessening of the chemical resistance because it allows for ion exchange with water. As the glass needs to have a high chemical resistance for pharmaceutical applications, this is not favorable.

To overcome this problem, significant amounts of boron and aluminum are added. Boron and aluminum atoms enter the network, thereby strengthening the same and improving the chemical stability again. Table 1 presents typical network formers and network modifiers used in pharmaceutical containers. Mainly the amount of network modifiers added to the glass dictates the chemical stability of the glass. The more network modifiers are added, the less stable the glass is against chemical attack [3].

The network of glass is formed by silicon (Si) and boron (B), whereas alkali and alkaline earth elements such as sodium (Na), potassium (K), calcium (Ca), magnesium (Mg), etc., modify the network structure.

1.3 Type I and Type III glass

The Assyrian recipe mentioned above describes a typical soda-lime glass. Over the centuries, this soda-lime glass was used as standard pack­aging material due to its manageable melting and forming process. At the end of the nineteenth century Otto Schott (1851–1935), a chemist and technologist from a dynasty of glassmakers, studied the dependence of the optical qualities of glass on its composition and developed the first borosilicate glass [2]. This type of glass has been used ever since as the standard packaging material for pharmaceutical applications. The main components—such as network formers and network modifiers—are basically the same for Type I and Type III glasses used in the pharmaceutical industry, only that Type III glasses possess higher amounts of network modifiers and less boron (Figure 3).

According to the current European Pharmacopeia (Ph. Eur.) and United States Pharmacopeia (USP), glass containers for pharmaceutical use are intended to come into direct contact with the pharmaceutical product and suitable glass types for this purpose are recommended. The glass types are referred to as Type I and Type III glass:

Type I glass, borosilicate glass, contains significant amounts of boric oxide, aluminum oxide, alkali, and/or alkaline earth oxides. Due to its composition, it is stated to have a high hydrolytic resistance and a high thermal shock resistance. It is thus recommended to be used for most parenteral or non-parenteral products.

Type III glass, soda-lime glass, on the other side, due to its composition has a moderate hydrolytic resistance and is usually not recommended for parenteral applications. Table 2 shows typical compositions of Type I and Type III glasses:

Fig. 3 Chemical structure of Left: Borosilicate glass. Right: Soda-lime glass.

Table 2 Typical composition of Type I and Type III glasses available on the pharmaceutical packaging market.

Borosilicate glass

Soda-lime glass

Type I

3.3 group

Type I

5.0 group

Type I

7.0 group

Type III

Element

Weight %

SiO2

80–82

72–75

70–74

70–75

B2O3

12–13

9–11

5–8

0–1

Al2O3

2

5–7

4–6.5

2–4

Na2O/ K2O

4

6–9

9–12

12–16

CaO/MgO

0

1–3

5–7

10–15

Working point

1260°C

1145–1170°C

1030–1100°C

1015–1045°C

Annealing ­temperature

560°C

560–575°C

550–580°C

525–540°C

CTE [10-6 K-1]; 20–300°C

3.3

4.9–5.5

6.3–7.0

7.8–9.5

It should be noted that Type II glass does not possess a different chemical composition but is a surface-treated Type III glass (see chapter 5.6).

Up to now, these are the predominantly used glasses in pharmaceutical packaging globally. However, it might well be that in future new glass compositions may challenge both current regulations and primary packaging engineers and this may change our current view on glass and its requirements.

Current USP and Ph. Eur. definition: Borosilicate glass is a Type I glass and mainly used for parenteral drugs. Soda-­lime glass is a Type III glass mainly used for non-parenteral drugs.

1.4 Production of tubular and molded containers

As the production of glass containers is a thoroughly described process [4,5,6], it is only summarized shortly for the sake of completeness.

Regardless of tubular or molded containers, the production always starts with the melting of the raw materials. The melting is done at approx. 1600°C in a furnace made of refractory bricks (Figure 4).

Tubing production

For the production of pharmaceutical glass tubing two different techniques can be employed:

Fig. 4 Melting furnace used to melt the different raw materials for glass production and the following Danner (upper picture) or Vello (lower picture) process.

Danner process. The process developed in 1912 by E. Danner is based on a rotating mandrel (cylinder), which is inclined downwards. The glass flows onto the turning mandrel, wraps around it and is pulled over its head onto the drawing lines. As air is blown through the mandrel, the dimensions of the tubing can be adjusted.

Vello process. The process developed in 1929 by L. Sanchez-Vello is based on the glass melt being drawn downwards from a hollow nozzle, which at the same time forms the diameter of the tubing. The internal diameter is determined by blowing air through the middle of the nozzle.