Packaging Materials: Glass
INTRODUCTION
Glass has been used for over 6000 years, dating to ancient times. Through the years and with more knowledge of its technology, glass has become the most widely used drug packaging material. The origin of the first synthetic glass is unknown; however, Egyptians were known to mold figurines from sand and silicon dioxide.[1] The American Heritage dictionary defines glass as a large class of materials with highly variable mechanical and optical properties, which solidify from themolten state without crystallization, that are typically based on silicon dioxide, boric oxide, aluminum oxide, or phosphorous pentoxide, that are generally transparent or translucent, and that are regarded physically as supercooled liquids rather than fine liquids.[2]
American Society for Testing and Materials (ASTM) defines glass as an inorganic product of fusion that has cooled to a rigid condition without crystallizing.[3] ASTM further states that glass is typically hard and brittle and has a conchoidal fracture. Glass may be colorless or colored. It is transparent but may be made opaque or translucent.[3] Glass is non-crystalline, is amorphous in structure, and may be formed from both organic and inorganic materials.
Glass is manufactured at very high temperatures, and it has the properties of a viscous liquid. With the properties of a viscous liquid, hot glass can be formed into many commonly used forms with precision and accuracy. As a result of its non-crystalline nature, it affords a unique transparent property that is maintained because it does not crystallize upon cooling.
There are a variety of uses of glass, one use being a pharmaceutical packaging material. Glass is favored over other types of packaging material because its transparent property enables it to provide good visualization of contained material. Another good quality of glass is its excellent resistance to attack by most liquids, and, therefore, it resists interaction with contained products. It is also totally impermeable to gases, and it can be sterilized with any appropriate process.
Glass, when properly colored, also provides protection to a product from light.
GLASS COMPOSITION
There are two glass compositions generally used—soda lime and borosilicate. The soda-lime compositions are used for ordinary tableware, food, and beverage products,
and window glass, among many others. Borosilicate glass is not widely used, but it is more durable and heat resistant than soda-lime glass. This glass is used for laboratory and scientific glassware, and heatresistant cookware, among many others. Borosilicate glass affords properties that make it a preferred composition for certain pharmaceutical containers. Glass composition will be discussed in detail below.
GLASS MANUFACTURE AND COMPOSITION
Raw Materials Silicon dioxide (SiO2), also known as silica, is the principal constituent of glass. Glass is made by melting its ingredients at very high temperatures such as 1550_C.
Because the melting point of silica alone is so high, and therefore, commercially difficult to melt and form into containers, other oxides are added to silica to lower the melting point and make it easier to fabricate and use commercially.[4] These oxides include sodium oxide (Na2O); aluminum oxide (Al2O3); potassium oxide (K2O); boron oxide (B2O3); and calcium oxide (CaO). The addition of one or more of these oxides reduces the melt viscosity for fabrication purposes.
Other materials may be added to change color, facilitate melting, or for other reasons. Sodium and potassium oxides are obtained as the product of chemical processing of naturally occurring materials, and an abundant source is the brines of Searles Lake in California.
Sodium is primarily added to silica to lower the melting temperature and aid in the removal of gas bubbles in a reasonable time. Potassium oxide is used in smaller amounts. All of these additives change the properties of silica in such a way that the resulting glass is less resistant to attack by aqueous solutions. Other additives such as calcium oxide, magnesium oxide, and aluminum Encyclopedia of Pharmaceutical Technology DOI: 10.1081/E-EPT-120042834 2508 Copyright # 2007 by Informa Healthcare USA, Inc. All rights reserved.
oxide are also used in various amounts to affect the properties of the glass. Silica has a very low coefficient of thermal expansion, and the addition of an alkali such as sodium oxide increases the thermal expansion.
When fluxing action is needed during melting, and glass with high thermal expansion is undesirable, boric oxide is added forming borosilicate glasses, which have lower thermal expansion and improved resistance to attack by aqueous solutions because of lower sodium oxide contents.
Conditions necessary for glass formation may be deduced from either geometric or bond strength considerations.
Silica sand deposit is available in all parts of the world. Silica sand is mined by hydraulic dredging, and any impurities are eliminated through further processing. One impurity, iron oxide, may be present, and, if present, may affect the final color of the glass.
There are other oxides that are potential glass formers and may be used in glass formation: GeO2, P2O5,
As2O5, P2O3, As2
O3, Sb2
O3, V2O5, Sb2
O5, Nb2
O5,
and Ta2O5.[5] Pharmaceutical containers may require amber glass to provide protection for light-sensitive pharmaceutical products. Amber glass is available in both—soda lime and borosilicate. The amber glasses have negligible transmission in ultraviolet (UV) and near UV regions and, hence, provide the required protection.
In these cases, glass is interacted with iron oxide to provide amber color.
For pharmaceutical products that undergo sterilization by means of ionizing radiation, cerium oxide of about 1% or less is added to the glass formulation. This is because ionizing radiation type sterilization [dosages as high as 20–30kGy (2–3 Mrad)] affects ordinary glass by darkening the glass and, thus, inhibits the final inspection of the glass products.
The mechanism by which ionization radiation acts on glass is by dislodging the electrons in the glass structure (usually intermediate density and low cost glasses) to form color centers and creating changes to the multivalent ions in such a way that they absorb visible light. The result is a formation of neutral atoms such as sodium that can agglomerate into colloid-like configurations.
Cerium oxide, which is multivalent when added to the formulation, counteracts the darkening effect of radiation by capturing these free electrons and minimizing the deleterious effects without adding color to the glass.
All raw materials used to formulate glass composition should be characterized using certain specifications of particle size, distribution, overall purity, and specific impurity content. It is necessary to match the particle size of the raw materials as much as possible to allow trouble-free melting.
Also classified as a raw material is cullet. Cullet is a scrap glass of desired composition, which results from scrap generated during forming operations and kept strictly segregated by composition. Cullet is then recycled through the melting process. The use of cullet conserves raw materials and aids in the melting process.
A typical diagram illustrating the process in glass manufacturing is shown in Fig. 1.
FORMULATION—BATCH MIXING,
CHARGING, AND MELTING
In a typical factory, a batch formulation is developed that provides the desired glass composition when melted. The raw materials are stored in large capacity silos. Depending on the type of plant facility, the raw material may be proportioned and mixed by a computer programmed with the batch formulation. The computer functions to control the automatic material transport system, weighing equipment, withdrawing the correct amount the raw materials from the perspective silos, and discharging them into a large mixing vessel. After mixing for the desired time, the batch is discharged into cans of mixed batch. These cans are transported to the charging end of the melting furnace.
Complete records are maintained for the weighing, mixing, and transportation of batch materials to the furnace.
Usually, when the intimately mixed batch is charged into the hot furnace, a series of melting, dissolution, volatilization, and redox reactions occur between the materials in a certain order and at the appropriate temperature.[6] At the furnace, the batch contents are discharged through a screw feeder into the furnace, with temperatures capable of exceeding 1700_C. The batch floats on the surface of the glass already in the furnace and gradually melts into the desired glass composition.
The temperature of the furnace is necessary to facilitate melting and producing glass of the desired homogeneity in a commercially acceptable time. The glass is allowed to stay in the furnace until a satisfactory homogeneous product is formed, after which the temperature is lowered at the discharge end to achieve a glass viscosity that allows the desired forming operations to take place.
In most cases, the glass made cannot be characterized by a batch or lot designation but only by the date and time of withdrawal from the furnace. This is because the glass-melting process is a continuous process, even though the glass materials are charged in discrete amounts. The residence time in the furnace permits extensive mixing to occur and, therefore, erases all identity of the batch from individual cans.
Devitrification is the uncontrolled formation of crystals in glass during melting, forming, or secondary processing. The optical properties, mechanical strength, and sometimes the chemical durability of the glass can be adversely affected by devitrification.
Packaging Materials: Glass 2509
These unwanted crystals grow homogeneously within the glass or heterogeneously at the air-glass or refractingglass interface. Devitrification occurs mainly in glasses where the optimum temperatures for maximum nucleation rate and for maximum growth rate nearly coincide. If these glasses are held too long in this critical temperature range or are cooled too slowly through it, the glass starts to crystallize. For soda-lime glasses, the crystal phase, devitrite, forms between 850 and 900_C.
However, as the glass is already quite viscous, the critical temperature range is short, and devitrification is not much of a problem.[1–3]
QUALITY OF A GLASS PRODUCT
Following a successful product fabrication, there are some qualities to observe, one of which is total homogeneity of product. Most glass manufacturers try to ensure that composition of the glass is homogeneous throughout. However, gas bubbles that did not escape the body of glass while in the furnace may cause a non-homogeneous composition to exist.
Glass bubbles in manufacturing result from chemical reactions that take place during melting. Glass bubbles evolve owing to the following conditions: (i) because of gas formation from decomposition of the carbonates, sulfates, or both; (ii) from air trapped between the grains of the fine-grained batch materials; (iii) from water evolved from the hydrated batch materials; and (iv) from the change in oxidation state of some of the batch materials, such as red lead. However, with enough time in the furnace, the air bubbles escape the melt by rising slowly to the top. In some cases, the gas bubbles may be withdrawn with glass from the furnace.
These bubbles are called seeds or blisters. They are not desirable and may be a cause for rejection of the final glass product, depending on the size and extent. When the surface of a glass final product is broken by the bubble, it is considered a functional defect.
However, if the bubble is surrounded by glass, it is considered a cosmetic defect, and while generally it may not be hazardous, it may still be rejected.
Cord is another attribute in glass formation that is not desirable and should be prevented. Cords are formed when glass is not stirred properly at appropriate Glass sand
Inspection and product testing
Packing, warehousing, and shipping
Fig. 1 Glass manufacture. Temperatures used may vary depending on the type of glass. (From Ref.[1].)
2510 Packaging Materials: Glass places in the furnace. It is referred to as the act of improper homogenization. Typically, in this case, glass melting occurs at a very high temperature, and some constituents vaporize from the surface glass and form regions of viscous glass. When small amounts of this glass mix into the body of the melt, they appear as very narrow and long inhomogeneous regions, referred to as cord.
Batch segregation, melt segregation, volatilization, and temperature fluctuations, as well as refractory corrosion from tank-lining material, cause stria or cord formation as well. These can also be prevented by melt homogenization and vigorous fining action. The homogeneity leading to cord formation can be removed by diffusion and flow and by vigorous fining, along with convection current mixing process before the glass is cooled. Homogeneity can also be improved by mechanical and static mixers that continuously shear the glass.
The bubble and cord defects that occur during the melting process are the two most commonly encountered defects. Melting defects should be held to a minimum as much as possible.
Fining is the physical and chemical process of removing glass bubbles (seeds and blisters) from the molten glass melt. Typically, fining agents that react at higher temperatures than are needed for melting are used. Some examples of fining agents are sulfates and sodium-potassium nitrates in combination with arsenic or antimony trioxides. Arsenic trioxide is used for melting glasses at higher temperatures, e.g., 1450–1500_C, whereas antimony is used for lower melting glasses at 1300–1400_C. As glasses cool, oxygen bubbles are removed by the reaction with arsenic or antimony trioxide to form pentoxide.[1]
Gas may be evolved from a typical amber soda-lime glass batch, and fining agents are usually employed to resolve the problem.[7] A typical batch mixture for amber soda-lime container glass is shown in Table 1.
QUALITY CONTROL IN BATCHING
AND MELTING
Producing glass containers for parenteral products requires strict control of all process aspects, starting with raw materials and ending with the testing of glass as amaterial and as containersor parts ofmedicaldevices.
The objectives of a quality-control program should be to maintain glass produced within physical and chemical specifications and to prevent off-specification material from reaching the pharmaceutical manufacturer.
Normal practice is to make sure that the raw material meets desired specifications and maintains its integrity during loading and shipping. There are physical as well as chemical requirements associated with each raw material, and these requirements are met by controlling for desired behavior during batching and melting and by the desired properties of the final glass product. The chemical impurity content is usually dictated by the desired attributes of the glass container.
For example, raw materials of low iron content are used to provide a virtually colorless final product.
Raw materials of low sulfur content (in the case of borosilicates) are used to minimize gas bubble formation during melting. Substances that would be
Packaging Materials: Glass 2511 harmful if extracted from the glass during terminal sterilization and subsequent storage (e.g., lead or arsenic) should be absent.
Most raw material suppliers provide certificates of analysis for the material they provide, and the information is checked by further testing on receipt.
Records of performance of raw materials are maintained.
The vendor s production facilities are usually inspected to ensure that mixing of raw materials of different grades cannot occur during loading and shipping. Ideally, this is a desirable situation and should be the goal of quality-oriented raw material suppliers and the glass manufacturers.
Scrap glass, or cullet, is also considered a raw material. Proper handling of cullet to prevent mixing of compositions and contamination by foreign materials requires constant attention and is just as important as preventing contamination of a raw material received from outside the plant.
Special considerations should be applied to ensure that all glass batch formulations are prepared by qualified technologists. The formulation for each composition is given in a batch sheet, which specifies the glass type, melting tank, date issued, amounts of raw materials, total batch weight, and weight of glass expected from the batch. In some companies, batch sheets are under the strict control of the glasstechnology department, and each sheet denoting a change requires approval by several levels of department management. Changes are made primarily to manage the cullet supply, which can vary. Batch sheets usually provide a continuous time record of a given composition melted in a given furnace, and the batch sheets are supplied to the department responsible for actual weighing and mixing of the raw materials. In most companies, batching and mixing operations are usually under computer control, involving automated weighing, mixing, and conveying operations. Great care is to be exercised in entering the batch formulations into the computer, with continual checking for accuracy.
The next step is the testing of the glass produced.
The testing program may be based on the following: (i) glasses are melted in large furnaces in a continuous operation, and the chemical and physical properties of any glass are dependent on one another; (ii) continuous melting in large furnaces does not create abrupt compositional changes as might be experienced with discrete batch melting; and (iii) changes take place slowly in the furnace because of the size and volume of glass contained; therefore, periodic sampling and testing is a necessary production control.Measurement of selected physical properties serves to determine the values of all other relevant physical properties and also serves to define the chemical composition. Samples of glass can be obtained daily from every producing position and subjected to a variety of tests. Each test is performed sufficiently often to ensure product quality.
The following properties are determined:
_ Seal stress
_ Softening (viscosity) point
_ Annealing and strain points (St.P.)
_ Density
_ Light transmission
_ Chemical durability
_ Chemical analysis
For most manufacturers, seal stress is determined on a daily basis and is a primary indicator of any shift in glass composition. Typically, a sample of daily production is flame sealed or fused to a reference glass of the same composition having the desired target properties.
Any deviation in composition is reflected in the generation of stress in the seal area. The physical property inferred from this test is thermal expansion, which is highly sensitive to changes in alkali content that, in turn, influence the chemical durability. If the test results show sufficient deviation from internal specifications, corrective action is initiated by issuing a slightly modified batch sheet. The effects of the corrective action should be observed in the next day’s production.
The other tests mentioned may be performed in time intervals ranging from weekly to biweekly and monthly. The results of all these tests provide a framework describing glass quality on an ongoing basis.
Thus, if the daily seal stress, the weekly viscosity points, and biweekly chemical durability tests are satisfactory, the monthly chemical analysis will be right on target. It also follows that glass produced at any time, although not specifically tested for durability, will, in fact, be satisfactory if the other tests are satisfactory.
In addition, an interlocking database can be used to certify to the pharmaceutical manufacturer that glass produced at any time meets specified requirements.
Process of Forming Pharmaceutical Containers Pharmaceutical containers can be made by a blowmolding process and by a glass rod or tube-shaping process. Commonly, the large-volume parenterals of 100 ml or more are made by a blow-molding process, whereas small-volume parenterals of 100 ml or less are made by the tube-shaping process.
Although for the purpose of this section, discussion will be limited to pharmaceutical containers, molten glass can be formed in all kinds of shapes and sizes such as bottles, jars, etc. Molten glass is molded, drawn, rolled, or quenched, depending on the desired shape and use.
2512 Packaging Materials: Glass Blow-molding process The blow-molding process uses hot glass as it leaves the furnace. The glass must be at the correct temperature and viscosity for forming to be successful. This process describes a typical blow-molding process. At the exit end of the furnace, the glass flows through an orifice in the bottom of the furnace section called the feeder. A pair of cooled blades cut the glass stream into discrete chunks called gobs. The gobs contain the correct volume of glass to make one container. The gob is delivered into blank molds where it is settled
with compressed air and, ultimately, forced to conform to the interior shape of a cast-iron mold that represents the bottle. This preformed (cast-iron mold shape) stage is obtained with a counterblow of compressed air. The formed bottle is inverted and transferred into the blow mold where it is further finished by blowing. The mold is hinged so that it opens and allows the removal of the bottle. The bottle is sent through a controlled cooling process, known as annealing, which allows the bottle to cool down to room temperature in a stress-free condition. A press-and-blow machine, such as the Hartford-Empire (H.E.) machine, is an example of a blow machine used for making articles such as drinking glasses. A typical process of blow-and-blow machine is shown in Fig. 2.
Blow-molded containers can be made in clear glass or glass that has been colored for protection of the product from light. In comparison to the tubing process, which will be discussed later, the walls of blown containers are usually thicker than those of the tubing process, and, hence, blow process containers have greater impact strength. However, containers made from tubing process have more uniform distribution of glass in the walls. This may be critical, depending on its intended use, and may impact on optical-inspection equipment.
Blow process containers also have thicker bottoms, and this could affect heat transfer during lyophilization.
Tubing process
The Danner process is a common method used for glass tubing, which is a mechanical process. There is also the hand drawn process described below. Glass tubing can be made with a precisely controlled outside diameter (OD) and wall thickness. There is an upper size limit of about 40-mm OD, which is not a limitation on the tubing-forming process, but on the subsequent forming operations used to make containers. In the hand drawn process, about 15m of 140-mm OD, 2-mm wall thickness tubing can be made on one draw by a gaffer and two helpers. Gathers of glass up to 30–35 kg can be made with bubble in their center at the end of the blowpipe. This is rotated in place by the gaffer, and rotated and stretched out by one of the helpers walking away from it. The size and the diameter of the tubing is a function of the helper s walking speed and is further controlled by a second helper that cools the tubing by fanning at specified times. Up to 150mof the much smaller diameter thermometer tubing can be made in this manner from one gather.[1,8]
In the Danner process, a continuous stream of glass, of the proper temperature, flows slowly and controllably onto a rotating mandrel, which is an inclined cylinder made of refractory ceramic materials or of platinum alloy. Glass tubing is drawn off the end of the mandrel, which is tapered, while air blowing through the mandrel helps to maintain tubing dimensions.
This air is pressurized to keep the tubing from collapsing toward the end. The glass temperature controls the diameter and the wall thickness of the tubing, the inflating air pressure, and the rate of withdrawal of glass from the cylinder. A schematic representation of the Danner process is shown in Fig. 3.
When tubing has cooled sufficiently, it is cut into lengths convenient to handle and is used as feedstock for the container-forming process. Hairpin cords of inhomogeneity and volatilization from the surface are capable of occurring during the tubing process. The tubing process can be used to make ampuls, vials, syringe barrels, cartridges, and a variety of containers used in medication delivery. Another type of tubing process is the Vello process. In the Vello process, the molten glass passes down through an annulus between a horizontal ring and a vertical bell. The moving stream connects to a nearly horizontal runway, and, as in the Danner process, it is drawn off at a suitable rate for dimensional specification and stability. The Vello process forms tubing faster because the glass is cooled more quickly to the appropriate forming viscosity in a stationary forehearth of the desired dimension.
However, the Vello process is more difficult to operate and is most suitable for longer production runs having few size changes.[1]
In comparison to sized molded containers from the blow-molded process, tubing process containers are made lighter in weight and provide more precisely controlled dimensions than blow-molded containers. The walls and bottom thickness are more uniform, and, hence, are more suited for use in automatic inspection systems. Clear and light-resistant glass compositions can be used in the tubing process.
GLASS COMPOSITION, PROPERTIES,
AND CLASSIFICATION
As mentioned earlier, the focus in this entry is on sodalime silica glasses and borosilicate glasses.
Packaging Materials: Glass 2513
Packaging–
Particle
Soda Lime-Silica Glasses
These compositions are for glass for every day use. The batch materials for soda-lime glasses are easily available at reasonably moderate cost. These materials readily meet at moderate temperatures. These glasses have a relatively high thermal expansion coefficient and only moderate resistance to attack by a contained product.
The actual compositions of soda lime are usually more complex than the term soda lime suggests.
As mentioned earlier, these glasses may contain MgO, Al2O3, BaO, or K2O and various colorants, in addition to Na2O, CaO, and SiO2. Alumina increases the durability of soda-lime glasses, whereas MgO prevents devitrification. Soda-lime glasses account for 90% of all glass produced and are used for containers, flat glass, pressed and blown ware, and some types of lighting products.[1]
In soda-lime glasses, the amber color is developed by the interaction of iron oxide and a small amount of sulfur (a few tenths of a percent), in the presence Reheat Final blow Takeout Transfer from blank mold to blow mold Delivery Settle-blow Counter-blow
Fig. 2 The H.E. is blow-and-blow machine. The gob is delivered into a blank mold, settled with compressed air, and then preformed with a counterblow. The parison or preform is then inverted and transferred into the blow mold where it is finished by blowing. (From Ref.[8].)
2514 Packaging Materials: Glass of a reducing agent during melting. As such, soda-lime amber glasses are called reduced ambers. Typical compositions of soda lime and borosilicate glassesare presented in Table 2. Borosilicate Glasses Borosilicate glasses are developed to meet more stringent requirements than soda-lime glasses. Because of their composition, these glasses require higher melting temperatures and more costly batch materials. As a result, these glasses are more expensive than soda-lime glasses.
Borosilicate glasses are also known as heat-resistant glasses because they have a lower coefficient of thermal expansion than soda-lime glasses and, hence, are more
resistant to fracture from rapid temperature changes (thermal-shock resistance). Borosilicate glasses are used widely as laboratory apparatus, chemical process piping and drain lines, and for baking and cooking dishes in the home. Borosilicates have excellent resistance to chemical attack, and this augments their use as laboratory apparatus and in packaging of pharmaceuticals as containers. The fluxing action of the boron facilitates melting by weakening the network. This is owing to the presence of planar three coordinate boron, which weakens the silicate network at high temperature.
Borosilicates are divided into two groups based on the coefficient of thermal expansion.
In borosilicate glasses, the amber color is developed through interaction between iron oxide and titanium oxide or iron oxide and manganese oxide. Reducing agents are not used in borosilicate glasses for color development. Borosilicate ambers are called oxidized ambers.
PROPERTIES OF GLASS
Rheology, the melting, forming, annealing procedures, and limitations of use at high temperature is determined by the viscosity of the glass. Viscosity is measured between 1013 and 101 Pa _ s[1014 and 102 p].
Also, viscosity of glasses is compared qualitatively.
Fig. 3 The Danner process for manufacture of tubing.
The addition of modifiers to a glass can alter the viscosity at certain temperatures. At low temperature, the effects of a modifier on viscosity are controlled by its coordinatioumber. Modifiers with high coordination numbers tend to increase low temperature viscosity owing to packing restraints.[1]
ASTM provides definition for the procedures and selected reference points discussed in this entry. Some frequently used reference points are annealing points (APs) and St.P. Below are presented some of the ASTM:[3]
_ Annealing: a controlled cooling process for glass designed to reduce residual stress to a commercially acceptable level and to modify structure.
_ AP: that temperature corresponding either to a specific rate of elongation of a glass fiber when measured by Test Method C336 or to a specific rate of midpoint deflection of a glass beam when measured by Test Method C598. At the AP of glass,
internal stresses are substantially relieved in a matter of minutes.
_ Annealing Range: the range of glass temperature in which stress in glass can be relieved at a commercially practical rate. For purposes of comparing glasses, the annealing range is assumed to correspond with the temperature between the A.P. and the St.P.
_ St.P.: that temperature corresponding to a specific rate of elongation of a glass fiber when measured by Test Method C336 or a specific rate of midpoint deflection of a glass beam when measured by Test Method C598.
_ Softening Point (S.P.) : that temperature at which a glass fiber of uniform diameter elongates at a specific rate under its own weight when measured by Test Method C338. The viscosity at the S.P. depends on the density and surface tension. For example, for a glass of density 2.5 g/cm3 and surface tension 300 dynes/cm, the S.P. temperature corresponds to a viscosity of 106.6 Pa _ s.
Discussion At the St.P., internal stresses are substantially relieved in a matter of hours.[3]
The Margules Viscometer, a calibrated instrument that measures the force exerted by molten glass on a rotating spindle, can be used to measure viscosity.
Glass is usually melted and fined at viscosities between 5 and 50 Pa _ s (50–500 P). However, the forming and final viscosity requirements may differ. Hard glasses usually have a high S.P. whereas soft glasses have a lower S.P. The length of a glass (i.e., long or short) can be used to explain the differences between the St.P. and the S.P. of glass. A long glass usually has a large difference between the St.P. and the S.P., meaning that it solidifies slower than a short glass as the temperature decreases.[1]
The temperature required for glass to form into useable shapes is usually above 1000_C for borosilicates and less than 1000_C for soda lime. The annealing process is very effective in relieving the residual stresses contained in formed glass.[9] The temperature range for proper stress-relief annealing of borosilicate is 600–650_C and less for soda lime. These forming stresses are relieved within minutes at these temperatures, and a subsequent slow cooling to room temperature retains the stress-free state.
Thermal Expansion
The value of thermal expansion is important in determining how a glass container survives sudden changes in temperature, that is, thermal shock resistance. The thermal expansion of a glass determines the range of materials to which it can safely be sealed. The thermal expansion characteristic indicates how much change in dimension (e.g., length) the article undergoes upon a change in temperature. The change in dimension in turn determines the stress generated in the glass. The ability of a glass as a heat exchanger thermal barrier and its ease of melting and forming depend on its heat-transfer properties and emissivity. In most cases, glass expands when heated and contracts when cooled.
If the thermal cycle is slow enough, there is no hysteresis effect. The slope of linear expansion vs. Temperature is known as the thermal expansion coefficient, a, which is virtually constant between 0 and 300_C for most glasses. However, as the temperature of the glass rises to near the set point (St.P. ю 5_C), the thermal expansion increases more rapidly. Glasses used to the extreme limits are vulnerable to thermal shock, and tests should be made before adapting the final design for any use.
For soda-lime glasses, when expansion is high, the stress is high, and the probability of fracture is greatly increased. Borosilicate glasses have lower coefficients of expansion than soda-lime compositions and, hence, can withstand larger temperature changes without fracture. This is important in processes where relatively rapid temperature changes occur such as in dry-heat sterilization and lyophilization, among other processes.
Stresses caused by steady-state thermal gradients may or may not cause failure, depending on the degree of constraint imposed by some parts of the item upon others or by external mounting. Thermal stress resistance (face-to-face temperature differentials) that causes tensile stress is observed in some types of glasses. When glass is suddenly cooled, as by the removal from a hot oven, tensile stresses are introduced in the surfaces and 2516 Packaging Materials: Glass compensating compressional stresses in the interior. On the other hand, sudden heating leads to surface compression and internal tension. In both cases, stresses are temporary and disappear once temperature uniformity is reached. Also, because glass fractures only in tension, usually at the surface, the temporary stresses from sudden cooling are much more damaging than those from sudden heating, assuming all surfaces are heated and cooled at the same time. Thermal shock endurance is generally determined by empirical testing because the strength of glass is greater under momentary stress than under prolonged load. Resistance to breakage can be determined by heating the ware to some appropriate temperature, then plunging it into cold water. For example, a resistance of 150_C means that no breakage occurred on heating to 150_C and plunging the glass into water at 15_C. A much higher value of thermal shock can be recorded when other cooling media such as air or oil is used.[1]
The thermal shock that a container receives as its temperature is lowered depends on the temperature differential and the time required to reach the lowest temperature. Glass as a material can withstand very low temperatures, but sufficient time must be allowed to reach the low temperature to avoid breakage.
Although it might seem that thick glass walls withstand thermal shock better because of higher strength, the fact is that thin walls resist thermal shock better because temperature change is accommodated more rapidly, lessening the stress created by the temperature differential.
The thermal expansion coefficient depends on the glass composition. It is usually assumed that the lower the expansion the better, but this is not necessarily true. It is true, if soda-lime glass with an expansion of about 90 is compared to borosilicates with expansion coefficients of 33–55. However, there is little to choose from between borosilicates in this range of expansion values. Glasses with expansion coefficients in this range perform satisfactorily under most circumstances.
If the application requires cooling rates higher than that normally experienced, the lowest expansion glass is of course the choice.
GLASS CONTAINER CHARACTERISTICS:
COMPARISON OF BLOW-MOLDING
AND TUBING PROCESS
As described earlier, some containers are made from tubing and some by the blow-molding process. Containers made from tubing have a maximum capacity of about 50 ml and a 40-mm OD. Blow molding is more suitable for larger sizes and is used for containers greater than 100 ml in volume. This flexibility in size causes great variation in wall and bottom thickness and weight.
Tubing used for containers is produced with closely held dimensions, including wall thickness, wall uniformity, cross section, and straightness. Because these dimensional attributes are strictly controlled, smaller volume containers can be made to much better dimensional precision and accuracy. At the same time, containers made from tubing are likely to exhibit different glass defects than blow-molded containers, mainly because of the kind of defects associated with the manufacture of tubing. Gas bubble inclusions, for example in blow-molded bottles, have a spherical or ovoidal shape, whereas those made from tubing have ‘‘air line’’ gas bubbles that have been stretched out during the forming of the tubing.
Another distinction between the two types of containers is the interior surface composition. For glass to be readily formed, it must be heated to a sufficiently high temperature. Because of this, more volatile glass constituents tend to escape the surface and condense in cooler regions. This effect is minimal in blow molding, because every part of the forming process leads to lower temperatures, reducing the tendency to vaporize.
Containers from tubing, on the other hand, are formed by reheating tubing in specific regions of a tubing length. The result is that some parts of a vial, for example, experience very high temperatures, whereas other parts are barely above room temperature. A typical example of this is the forming of the vial bottom.
The glass temperatures required cause vaporization of sodium and boron oxides, together with some chlorides; these compounds condense on the interior vial sidewall, just above the bottom. These so-called forming deposits or ‘‘bloom’’ can be removed by revaporization during the annealing step, or if this process is incomplete, by washing later.
A special discussion of tubing containers for lyophilization is warranted because a proper design embodies a combination of container and product characteristics that should be taken into account. Blow-molded bottles for lyophilization, although subject to some manufacturing control, cannot be made as uniquely as tubing containers. The same design considerations apply but are under much less control.
The following considerations have been found to be important in the design and use of containers for lyophilization:
_ Product characteristics
_ Amount of fill
_ Thermal shock
_ Glass composition
_ Container wall thickness
_ Container contours
_ Container surface damage
Packaging Materials: Glass 2517
The great variability in products to be lyophilized implies that there will be behavior variations in these products as they freeze. Any glass container considered for use should be evaluated with the actual product, rather than trying to simulate product behavior with test solutions.
The result of product freezing and thawing is internal pressure generation. If the container is overfilled, excessive pressure can result with subsequent container breakage. Fills of less than 50% of the container volume are recommended, with an optimum of about 35%.
The contour of the container is important in resisting the forces encountered during product freezing and in ensuring adequate heat transfer through the bottom.
There should be as gradual a transition as practicable between the sidewall and the bottom, to reduce the stress concentration effect caused by this angle. A sharp, reentrant angle between the sidewall and bottom is the worst condition. In addition, a flat bottom with a little ‘‘push up’’ in the center is best for heat transfer. This condition is in concert with a gradual transition in the heel region; both conditions improve performance.
Everything mentioned above as factors for satisfactory performance can be negatively affected by damage to the surface of the container. The container must be
as free as possible of scratches, scuffs, impact damage, etc., if the design criteria are to be effective. Maintaining a damage-free glass surface is also a requirement of the filling line, where contact with sharp metal objects should be minimized. The factors discussed above demonstrate that other factors are of importance besides low glass thermal expansion, usually the first and sometimes the only criterion considered.
Chemical Property—Durability ASTM defines chemical durability as the lasting quality (both physical and chemical) of a glass surface. It is frequently evaluated, after prolonged weathering or storing, in terms of chemical and physical changes in
the glass surface, or in terms of changes in the contents of a vessel.[3]
One of the main reasons for using glass compared to other containers or packaging material is owing to its resistance to chemical corrosion. The chemical durability of a glass varies from highly soluble to highly durable, depending on its composition and the solvent used. Glass used in packaging parenteral products and in direct contact with parenteral liquids or solids must have good chemical durability. Analysis is usually based on measurements of weight loss, changes in surface quality of the glass or finished container, or analysis of solutions that were in contact with a glass.
A method of determining the durability of a glass is by subjecting grains of uniform size distribution to accelerated attack by high purity water at a temperature characteristic of terminal steam sterilization. In addition, glass compositions can be directly compared with respect to their resistance to attack by aqueous solutions because glass grain is prepared and sized uniformly.
These processes will establish the intrinsic durability of the glass. However, the presence of other factors, such as glass constituents that may condense on the surface during high temperature forming process or other volatile deposits, can reduce or improve the durability.
When glass is attacked by water under accelerated test conditions, the pH of the solution increases as a result of an ion exchange process between the alkali (primarily sodium) content of the glass and the hydrogen ions in solution. The higher the pH, the less durable the glass. At large increases in pH, there are high effects on the contained parenteral product and there is an accelerated attack on glass. The extent of pH change can then be determined by titration of attacking solution with diluted acid. Glasses are rated based on the volume of diluted acid required to neutralize the extracted alkali. Additionally, the extent of attack can be determined by the analysis of the solution for specific constituents, including sodium boron, aluminum, calcium, and silicon. The amount of acid required to neutralize the extract solution will correlate with the amount of specific glass constituents found in the solution by direct analysis. The most durable glass will require smaller volumes of acid and lower concentration of the constituents in solution. These observations apply generally to both glass grain tests and container tests, except that the acid volumes and constituent
concentration are much lower when testing containers because of a much lower glass surfaceto-solution volume ratio.
The reaction of acids with glass may be either a leaching process or a complete dissolution process.
Acids such as hydrofluoric acid attack silica glasses by dissolving the silica network. Other acids such as hydrochloric acid or nitric acid may react by dissolving certain glasses. However, the reaction mechanism is by selective extraction of alkali and the substitution of protons in a diffusion-controlled process.
The reaction of bases with most silicate glasses produces dissolution rates when tested in 5% NaOH solution at 95_C. The mechanism also involves a complete dissolution process as that described for acid.
Weaker alkaline solutions may both leach and dissolve and sometimes show greater dependence on glass composition.
And, in the case of strong alkali solutions, the rate of attack doubles for each 10K increase in temperature or each increase in pH unit. Usually higher alkali durability glasses are used for laboratory wares.
2518 Packaging Materials: Glass Also, as stated earlier, the attack of water is related to the leaching mechanism described for acid. Low alkali, high alumina, or borosilicate glasses generally have high water durability. Weathering of glass is the result of the action of water, carbon dioxide, and other constituents. Water initially is absorbed by the glass and then exchanged for alkalies that form alkali salt solutions and, if left in contact with glass, may cause additional damage. As a result, weathering resistance may not correlate with acid durability. Test methods to accelerate the weathering process are designed in chambers at 50_C and 98% relative humidity.
A comparison of the chemical durability of sodalime glasses and borosilicate glasses show that borosilicates are far more durable than soda limes, requiring from 10 to 20x less acid to neutralize solutions in glass-grain tests. This is owing to the significantly lower alkali content of the borosilicates. The same result applies when comparing containers made from borosilicates and soda lime. Thus, when productcontainer interactions must be limited, as in the case of parenterals, the compositions of choice are the borosilicates.
SPECIAL TREATMENTS
Special treatments include treatments to the container after it has been formed into its final shape. These processes can be performed before or after the annealing process. The processes discussed here are concerned with printing and ‘‘sulfur’’ treatment to improve the chemical durability of the interior container surface.
Printing Treatment The printing of pharmaceutical containers may involve either applying the printed information as a step in the manufacture of the container or applying of labels as the filled container is processed by the pharmaceutical manufacturer. The printing of information on the container while still in the hands of the glass manufacturer is significant. A number of issues are connected with this, one of which is the strict accountability by the glass producer for containers printed with information on drug type, lot number, etc. Stringent safeguards must be employed during printing to ensure the integrity of the container lots.
Material for printing on glass can include ceramic glazes, epoxy formulations cured by heat, and UVcuring formulations. The latter two are applied after annealing, as the temperatures applied would destroy these materials. Ceramic glazes are applied before the annealing step and have properties such that the annealing temperatures are sufficient to fire on the glaze.
Ceramic glazes provide the most durable type of printing. They are vitreous or glass-like iature, and form a strong bond with the glass substrate.
Ceramic glazes are chemically the most durable. They provide the greatest resistance to abrasion and the highest hardness. However, the glaze and the glass have to be carefully matched. A great disparity in the thermal expansions of the two materials causes problems. The glaze should have a greater expansion than the underlying glass so that as the container cools from the fining process, the glass container develops compressive stress at the glaze-glass interface, rather than tensile stress.
Glass is much stronger in compression than in tension.
The glaze develops fine cracks or a crazed appearance during cooling, but the underlying glass will not be significantly damaged.
Ceramic glazes are used in ampuls to introduce a controlled-break site. A band of paint is applied at the constriction of the ampule where controlled breakage is desired, so the contents can be withdrawn. The band is used to make Colorbreak ampuls, and its function is to act as a stress concentrator when bending stress is applied to the ampul to break off the stem for product withdrawal. Very consistent ampul break forces are achieved by the use of ceramic bands.
Interior Surface Treatments Sometimes forming deposits become fused onto the glass surface and are difficult to remove, in effect compromising the durability of the interior surface. These effects are overcome by chemical neutralization of these deposits through surface treatment processes.
At the same time, the intrinsic ability of a glass surface to withstand attack by aggressive products is also improved. Thus, there is a twofold benefit in treatment processes for containers made from tubing: to remove the residual forming deposits and to improve the basic durability of the glass surface. These benefits are derived concurrently during treatment.
Blow-molded containers, although not subject to the forming deposit problem, can also benefit from surface treatment.
If an aggressive product of pH 8 and above is to be packaged in a borosilicate container, surface treatment is required. Otherwise, the glass is attacked by the product, resulting in contamination by both soluble and insoluble reaction products. The latter are manifested by entities variously called as flakes, shimmers, etc.
These flakes are essentially silica that has been stripped off the surface by the attack on the glass. Their presence is direct evidence of excessive attack. Proper surface treatment enhances resistance to attack and results Packaging Materials: Glass 2519
in a glass container that can contain products of pH 8 and higher without being damaged.
The basis of all treatment processes is the removal of alkali from the glass surface, resulting in improved resistance to attack by aqueous solutions. Alkali or sodium removal accomplishes this by greatly hindering the ion exchange process responsible for glass attack.
Exchange of sodium ions in the glass for hydrogen ions in solution results in a pH rise in the solution; this can accelerate attack on the basic glass structure. If hydrogen
ions cannot readily leave the solution because there are very few labile sodium ions with which to exchange, there will be little pH rise and, hence, little attack.
A common means of removing surface sodium is by reaction with sulfur dioxide in the presence of oxygen or by reaction with sulfur trioxide. The reaction product is sodium sulfate.
Surface treatment of blow-molded containers consists of several stages. As the freshly formed bottle leaves the mold and before it enters the annealing lehr or oven, it is still high in temperature. The bottle is filled with one or several of the following gaseous mixtures: sulfur trioxide, sulfur dioxide and oxygen, or 1,1- difluoroethane. If only moderate treatment is desired, one step suffices. The reaction of these gases with surface sodium starts immediately because of the glass temperature and continues as the bottle enters the annealing process at its elevated temperatures. The
reaction product of sodium sulfate is clearly seen in the cool bottle as a whitish haze on the inside surface just prior to packing into cartons. It is easily removed by subsequent washing processes. Blow-molded bottles treated by both of these steps can achieve high durability.
These two methods, however, are restricted t large containers with relatively wide openings. Smaller containers made from tubing with much more restricted entry must be handled in a different way.
The effective treatment of containers made from tubing is a much more crucial issue because of the adverse effects of residual forming deposits and because the high pH products are usually packaged in small volume ampuls and vials made from tubing. The same basic treatment scheme is used, that of reacting the surface sodium with a sulfur compound at elevated temperatures. A 3% ammonium sulfate solution is injected into the container just prior to entering the annealing lehr; the volume injected is several tenths of a milliliter. The ammonium sulfate decomposes during the annealing process, with temperatures of 600–650_C being typical.
The solution is thought to decompose, resulting in the formation of sulfuric acid vapors or possibly sulfur trioxide, which react with the surface sodium and any residual forming deposits, giving the characteristic sodium sulfate haze.
Containers given an effective surface treatment show a pronounced improvement in chemical inertness.
Products packaged in such containers remain unaffected for long periods of time. The improvement of the inside surface, resulting from the surface treatment, is permanent and is not destroyed even by repeated autoclaving.
An additional reason for sulfur treating the interior surface of bottles is to improve the durability of sodalime glass bottles. Normally, the surface inertness of soda-lime glass does not approach that of borosilicate.
Sulfur treatment of a soda-lime surface can improve this situation to the point where products not normally considered for soda-lime containers can be packaged in them. The reason for choosing a treated soda-lime bottle for a mild product rather than a borosilicate bottle is based on economics, as soda-lime bottles are less expensive than borosilicate. It should be noted that this approach is used primarily for blow-molded bottles.
There is compendial recognition and control of this, using treated soda-lime bottles in this way. Suffice it to say for the present that these bottles are known as Type-II bottles, according to the United States Pharmacopeia (USP). The USP and other methods of test and classification of glass for pharmaceutical products are discussed later.
Putting aside the question of testing and classifying Type-II bottles for the moment, it is of interest to consider test methods that determine the effectiveness of interior surface treatment of borosilicate containers made from tubing. It was stated earlier that a measure of durability, or inertness, is the pH rise of a contained solution. There are several commonly used ways of determining this. These methods are based on the pH rise of a water solution in the container after it has been autoclaved at 121_C for 60 min. The pH rise can be evaluated by titrating the solution with dilute acid in the presence of an indicator to a neutral end point. Another way is to include an indicator in the original water fill, autoclave, and observe the color change indicative of pH change. An example of this method uses bromothymol blue indicator adjusted to an initial pH of 5.8–6. The color of the indicator after autoclaving is compared to a series of standards having a range of pH up to at least 7.5 and the pH rise estimated.
The autoclave cycle time and temperature used for these tests is that of the Water Attack Test as set forth in the USP described later in this entry.
A solution autoclaved in a well-treated container consumes very small amounts of dilute acid upon titration or shows very small pH rise by color change of the indicator. Actual values of acid required, or pH rise, depend on various factors, including container size, as they control the interior surface area-tosolution volume ratio.
2520 Packaging Materials: Glass
Packaging–
Particle
Classification of Glass and Glass Containers– Compendial Perspective The chemical specifications of glassware were first contained in USP XII in which specifications of glassware as containers for injections were provided. In subsequent revisions, changes appeared and definitions of four types of glassware are described in USP XIX.[10,11]
Glass containers for pharmaceutical use are glass articles in direct contact with pharmaceutical preparation. In addition to the USP, the European Pharmacopeia (EP) and other pharmacopeias have grouped glass containers suitable for packaging pharmacopeial preparations into the four different classifications specified in USP XIX up to USP 29.[12]
The classes are based on the degree of chemical or hydrolytic resistance of these glasses to water attack.
The degree of attack is determined by the amount of alkali released from the glass under the influence of the attacking medium under conditions specified.
The quantity of alkali used is extremely small in some cases. These test designs and glass classification are described from USP 29-NF 24 under section 661 Containers.[12] These tests are designed to be conducted in areas relatively free from fumes and excessive dust.
Glass Types The USP and EP have provided similar classifications that are summarized below. Type I glass
Type I glass containers comprise a borosilicate glass with about 80% SiO2 and 10% B2O3 and smaller amounts of Al2O3 and Na2O. It is inert and has the lowest coefficient of thermal expansion. It is least likely to crack when a sudden temperature differential occurs. It is commonly used to make ampuls and vials for parenteral use. It is used for solutions that can dissolve basic oxides to cause an increase in pH that could alter the efficacy or potency of the drug.[4]
USP describes Type I glass as: highly resistant borosilicate glass, and usually used for packaging acidic and neutral parenteral preparations. Also, where stability data demonstrates their suitability, Type I are used for alkaline parenteral preparations.[12]
EP describes Type I glass as: neutral glass with high hydrolytic resistance owing to the chemical composition of the glass itself. Type I is suitable for all preparations whether or not for parenteral use and for human blood and blood components.[13]
Type II glass
A dealkalized form of soda-lime glass with higher levels of Na2O and CaO. It is less resistant to leaching than Type I but more than Type III. However, to make Type II and other types more resistant to leaching, the surface can be treated with SO2 to convert surface oxides present to soluble salts that are then washed off.
This surface treatment is effective for containers used once and those repeatedly exposed to heat. Type II has a lower melting point than Type I and, therefore, is easier to fabricate. It has a higher coefficient of thermal expansion, and is used in solutions that can be buffered to maintain a pH below 7.[4] USP: Soda-lime glass that is suitably dealkalized and is used for packaging acidic and neutral parenteral preparations, and, also where stability data demonstrates their suitability, is used for alkaline parenteral preparations.[12]
EP: Soda-lime silica glass with high hydrolytic resistance resulting from suitable treatment of the surface. These containers are suitable for acidic and neutral aqueous preparations for parenteral use.[13]
Type III glass
A soda-lime glass containing same amount of sodium and oxide levels as in Type II but contains more leachable oxides of other elements. And because of its high reactivity, it is used to package anhydrous liquids and other dry products.[4]
USP: These are soda-lime glass containers that are usually not used for parenteral preparations, except where suitable sensitivity test data indicates that Type III is satisfactory for the parenteral preparations that are packaged therein.[12]
EP: These are soda-lime glasses with only moderate hydrolytic resistance. They are suitable for non-aqueous preparations for parenteral use, for powders for parenteral use, and for preparations not for parenteral use.[13]
Tests These glass containers for pharmaceutical use have to comply with relevant tests such as tests for hydrolytic resistance for EP,[13] and tests chemical resistance for USP.[12] The test procedure and methods are slightly different for each of the pharmacopeias. However, this entry will emphasize the test procedure provided in the
USP 29-NF 24.
For the four types of glasses, there are designated relevant test types and expected limits. These are provided in Table 3. USP has provided procedure and test requirements for three types of tests. These are the powdered glass test, the water attack test, and the Packaging Materials: Glass 2521 arsenic test. These tests, apparatus, and reagents for the tests are described below.[12]
Apparatus used for these tests Autoclave. An autoclave capable of maintaining a temperature of 121 _ 2.0_C, equipped with a thermometer, a pressure gauge, a vent cock, and a rack adequate to accommodate at least 12 test containers, above the water level is used.
Mortar and Pestle. A hardened-steel mortar and pestle, made according to the specifications in the accompanying illustration. Other Equipment. Sieves, about 20.3cm (
Reagents used for these tests High-Purity Water. The water used in these tests has conductivity at 25_C, as measured in an in-line cell just prior to dispensing, of not greater than 0.15 ms per cm (6.67 megohm-cm). There must also be an assurance that this water is not contaminated by copper or its products (e.g., copper pipes, stills, or receivers). The water may be prepared by passing distilled water through a deionizer cartridge packed with a mixed bed of nuclear-grade resin, then through a cellulose ester membrane having openings not exceeding
Methyl Red Solution. Dissolve 24 mg of methyl red sodium in purified water to make 100 ml. If necessary, neutralize the solution with 0.02 N-sodium hydroxide or acidify it with 0.02 N-sulfuric acid so that the titration of 100 ml of high-purity water, containing five drops of indicator, does not require more than 0.020 ml of 0.020 N-sodium hydroxide to affect the color change of the indicator, which should occur at a pH of 5.6.[12]
Powdered glass test for types I and II Rinse thoroughly with purified water six or more containers selected at random, and dry them with a current of clean, dry air. Crush the containers into fragments about 25mm in size, divide about
With the pestle in place, crush the glass further by striking three or four blows with the hammer. Nest the sieves, and empty the mortar into the No. 20 sieve.
Repeat the operation on each of the two remaining portions of glass, emptying the mortar each time into the No. 20 sieve. Shake the sieves for a short time, then remove the glass from the Nos. 20 and 40 sieves, and again crush and sieve as before. Repeat again this crushing and sieving operation. Empty the receiving pan, reassemble the nest of sieves, and shake by mechanical means for five minutes or by hand for an equivalent length of time. Transfer the portion retained on the No. 50 sieve, which should weigh in excess of
Spread the specimen on a piece of glazed paper, and pass a magnet through it to remove particles of iron that may be introduced during the crushing. Transfer the specimen to a 250 ml conical flask of resistant glass, and wash it with six 30 ml portions of acetone, swirling each time for about 30 sec and carefully decanting the acetone. After washing, the specimen should be free from agglomerations of glass powder, and the surface of the grains should be practically free from adhering fine particles. Dry the flask and contents for 20 min at 140_C, transfer the grains to a weighing bottle, and cool in a desiccator. Use the test specimen within 48 hr after drying.le
Procedure
Transfer
Add 50.0 ml of high-purity water to this flask and to one similarly prepared to provide a blank. Cap all flasks with borosilicate glass beakers that previously have been treated as described for the flasks and that are of such size that the bottoms of the beakers fit snugly down on the top rims of the containers. Place the containers in the autoclave, and close it securely, leaving the vent cock open. Heat until steam issues vigorously from the vent cock, and continue heating for 10 min. Close the vent cock, and adjust the temperature to 121_C, taking 19–23 min to reach the desired temperature. Hold the temperature at 121 _ 2.0_C for 30 min, counting from the time this temperature is reached. Reduce the heat so that the autoclave cools and comes to atmospheric pressure in 38–46 min, being vented as necessary to prevent the formation of a vacuum.
Cool the flask at once in running water, decant the water from the flask into a suitably cleansed vessel, and wash the residual powdered glass with four 15 ml portions of high-purity water, adding the decanted washings to the main portion. Add five drops of methyl red solution, and titrate immediately with 0.020 N-sulfuric acid. If the volume of titrating solution is expected to be less than 10 ml, use a microburet. Record the volume of 0.020 N-sulfuric acid used to neutralize the extract from
Water attack at 121_C for type II glasses Rinse thoroughly twice three or more containers, selected at random, with high-purity water.
Procedure. Fill each container to 90% of its overflow capacity with high-purity water, and proceed as directed for procedure under ‘‘powdered glass test,’’ beginning with ‘‘Cap all flasks,’’ except that the time of autoclaving shall be 60 min instead of 30 min, and ending with ‘‘to prevent the formation of a vacuum.’’
Empty the contents from one or more containers into a 100 ml graduated cylinder, combining, in the case of smaller containers, the contents of several containers to obtain a volume of 100 ml. Place the pooled specimen in a 250-ml conical flask of resistant glass, add five drops of methyl red solution, and titrate, while warm, with 0.020 N-sulfuric acid. Complete the titration within 60 min after opening the autoclave.
Record the volume of 0.020 N-sulfuric acid used, corrected for a blank obtained by titrating 100 ml of high-purity water at the same temperature and with the same amount of indicator. The volume does not exceed that indicated in Table 1 for the type of glass concerned.[12]
Remove any debris or dust from six or more containers. Shortly before the test, rinse each container carefully at least twice with purified water and allow to stand. Immediately before testing, empty the containers, rinse once and allow them to drain.
The containers are then filled with purified water up to the filling volume, for vials and bottles 90% of capacity and for ampoules up to the shoulder. Place the containers on the tray in the autoclave and heat the autoclave to 100_C while allowing the steam to issue from the vent cock for 10 min. The temperature is then raised from 100_C to 121_ C at a rate of 1_C per min, once at 121_C the temperature is then maintained for 60 min. After the 60 min timeframe, the temperature is lowered from 121_C to 100_ C at a rate of 0.5_C per min. Once the autoclave has cooled down to 95_C, the containers are removed and placed in a water bath at 80_C.
For the test, the contents of the autoclaved containers are combined into a conical flask. The same volume of purified water is placed into a second similar flask as a blank. Add to each flask 0.05 ml of methyl red solution for each 25 ml of liquid. Then titrate the blank with 0.01M hydrochloric acid and the test liquid until the color of the testing solution is the same as that obtained for the blank. Subtract the value found for the blank titration from that found for the test liquid, and express the results in milliliters of 0.01M hydrochloric acid per 100 ml. The results, or the average of the results if more than one titration is performed, are not greater than the values stated in Table 4.icle
Arsenic test
For the Test Preparation, 35 ml of the water from one Type I glass container or, in the case of smaller containers, 35 ml of the combined contents of several Type I glass containers is used and prepared as directed for Procedure under Water Attack at 121_C and the procedure described for arsenic test in USP 29-NF 24 general chapter <211> Arsenic is then followed.
The limit provided for this test is 0.1 ppm.[16] Light transmission test In addition to the above-mentioned tests, compendial limits are provided for light transmission for colored light protecting glass containers. These containers intended to provide protection from light or supplied as ‘‘light resistant’’ are expected to meet the requirements for ‘‘light transmission’’ in this section. Light transmission characteristics of typical clear and amber borosilicates are shown in Fig. 4.
In this test, a spectrophotometer of suitable sensitivity is used to cut a section of the glass container.
The transmittance of the section is measured, and the observed light transmission is not expected to exceed the limits provided in Table 5.
These methods of testing glass are basically similar to other compendial limits and other standards on glass such as those in International Organization for Standardization (ISO), German DIN (Deutsches Institut fu¨ r Normung), and the ASTM. The expected limit and test result expectations and procedures may vary for each standard of compendial method.
There are differences in testing glass as a container compared to glass as a material (glass-grain tests). The glass surface area-to-solution volume ratio is higher in grain tests, resulting in higher concentrations of glass constituents in solution after autoclaving. This facilitates solution analysis and differentiation between glasses.
The other major difference is the presence of forming deposits, in the case of containers made from tubing, which influences test results. Blow-molded container test results are not affected by deposits.
CONCLUSIONS
Glass as a packaging material has many advantages. Glass provides the following advantages:
_ Total impermeability to gaseous environmental contaminants.
_ Total impermeability to loss of essential volatile ingredients by diffusion through the container walls.
_ Excellent clarity and attractive sparkle.
_ Ease of cleaning and sterilizing with heat.
_ A variety of shapes and it can accept a wide variety of closure types.
_ Ease of filling, closing, unscrambling, labeling, and cartoning.
_ Good compressional strength to allow efficient storage, especially allowing cartons of glass to be stacked high in warehouse.
_ Ease of hot filling. Glass has disadvantages that include the following:
_ Breakage—when it breaks, it shatters into numerous sharp fragments.ticle
_ Weight—with a density of 22.5 g/ml, along with brittle character thick container walls, they become quite heavy.
_ Cost—in some cases, they are very expensive because of their weight and the type of fabrication involved.[4]
REFERENCES
1. Boyd, D.C.; Danielson, P.S.; Thompson, D.A. Glass. In Encyclopedia of Chemical Technology; Kroschwitz, J.I., Howe-Grant, M., Eds.; John Wiley, Inc.: New York,
1994; 12, 555–623.
2. Glass. In The American Heritage Dictionary, 2nd College Ed.; Houghton Mifflin Company: Boston, MA, 1991; 561.
3. ASTM Standard C162-88, Standard defnitions of terms relating to glass and glass product. Annual Book of ASTM Standards. 1999; 15 (02), 1–14.
4. Jenkins, W.A.; Osburn, K.R. Packaging drugs and pharmaceuticals, drug packaging materials.. In Cooperation with Institute of Packaging Professionals; Technomic Publishing Co.: Lancaster, PA, 1993; 99–102.
5. Goldschmidt, V.M. Investigation concerning structure and properties of glass. J. Soc. Glass Technol. 1927, 11, 337.
6. Woolley, F.E. Engine Red Materials Handbook; ASM International: Bilthoven, The Netherlands, 1991; Vol. 4, 386–393.
7. Spinosa, W.C.; Stephen, P.M.; Schorr, J.R. Review of Literature on Control Technology Which Abates Air Pollution and Conserves Energy in Glass Melting Furnaces; Nov 11, EPA-600/2-77-005,/2-76-269,/2-76032b Corning, Inc.: Battelle, Columbus, OH, 1977.
8. Giegerich, W.; Trier, W. Glass Machine Construction and Operation of Machines for the Forming of Hot Glass; Kreidl, N.J., Ed.; Springer-Verlag: Berlin, 1969.
9. Pincus, A.G.; Holmes, T.R. Annealing and Strengthening of Glass Industry; Magazines for Industry, Inc.: New York, 1977.
10. Containers for Injection, USP XII; United States Pharmacopeia: Rockville, MD, 1942; 567–576.
11. Containers, USP XIX; United States Pharmacopeia: Rockville, MD, 1975; 643–647.
12. Containers <661>, USP 29–NF 24; United States Pharmacopeia: Rockville, MD, 2006; 2655–2663.
13. Containers; In European Pharmacopoeia, Council of Europe: 67075 Strasbourgh Cedex France, 2006.
14. Powder Fineness <811>, USP 29-24 United State Pharmacopeia: Rockville, MD, 2006; 2754–2755.
15. Containers—Glass <660>, PF 32 (3); United States Pharmacopeia: Rockville, MD, 2006.
16. Arsenic <211> USP 29-24 United State Pharmacopeia: Rockville, MD, 2006; 2554–
