〈 660 〉 CONTAINERS—GLASS DESCRIPTION Glass containers for pharmaceutical use are intended to come into direct contact with pharmaceutical products. Glass used for pharmaceutical containers is either borosilicate (neutral) glass or soda-lime-silica glass. Borosilicate glass contains significant amounts of boric oxide, aluminum oxide, and alkali and/or alkaline earth oxides in the glass network. Borosilicate glass has a high hydrolytic resistance and a high thermal shock resistance due to the chemical composition of the glass itself; it is classified as Type I glass. Soda-lime-silica glass is a silica glass containing alkaline metal oxides, mainly sodium oxide, and alkaline earth oxides, mainly calcium oxide, in the glass network. Soda-lime-silica glass has a moderate hydrolytic resistance due to the chemical composition of the glass itself; it is classified as Type III glass. Suitable treatment of the inner surface of Type III soda-lime-silica glass containers will raise the hydrolytic resistance from a moderate to a high level, changing the classification of the glass to Type II. The following recommendations can be made as to the suitability of the glass type for containers for pharmaceutical products, based on the tests for hydrolytic resistance. Type I glass containers are suitable for most products for parenteral and nonparenteral uses. Type II glass containers are suitable for most acidic and neutral aqueous products for parenteral and nonparenteral uses. Type II glass containers may be used for alkaline parenteral products where stability data demonstrate their suitability. Type III glass containers usually are not used for parenteral products or for powders for parenteral use, except where suitable stability test data
〈1660〉〉. This chapter also
delamination.
in opaque enclosure (see transmission.
The Glass Grains Test
Container Type Test Reason
Distinguishes Type I borosilicate glass
I, II, III Glass Grains Test from Type II and III soda-lime-silica glass
The inner surface of glass containers is the contact surface for pharmaceutical preparations, and the quality of this surface is determined by the Surface Glass Test for hydrolytic resistance. The Surface Etching Test may be used to determine whether high hydrolytic resistance is due to chemical composition or to surface treatement. Alternatively, the comparison of data from the Glass Grains Test and the Surface Glass Test may be used in Table 2.
Table 2. Determination of Inner Surface Hydrolytic Resistance
Container Type Test Reason
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Container Type Test Reason
Determines hydrolytic resistance of inner
surface; distinguishes between Type I and Type II containers with high hydro- lytic resistance and Type III containers I, II, III Surface Glass Test with moderate hydrolytic resistance
Where it is necessary, determines
whether high hydrolytic resistance is due Surface Etching Test or comparison of to inner surface treatment or to the che- Glass Grains Test and Surface Glass Test mical composition of the glass contai- I, II data ners
Glass containers must comply with their respective specifications for identity and surface hydrolytic resistance to be classified as Type I, II, or III glass. Type I or Type II containers for aqueous parenteral products are tested for extractable arsenic.
Hydrolytic Resistance
APPARATUS Autoclave: For these tests, use an autoclave capable of maintaining a temperature of 121 ± 1°, equipped with a thermometer, or a calibrated thermocouple device, allowing a temperature measurement independent of the autoclave system; a suitable recorder; a pressure gauge; a vent cock; and a tray of sufficient capacity to accommodate the number of containers needed to carry out the test above the water level. Clean the autoclave and other apparatus thoroughly with Purified Water before use. Mortar and pestle: Use a hardened-steel mortar and pestle, made according to the specifications in Figure 1.
Figure 1. Mortar and pestle for pulverizing glass.
Other apparatus: Also required are a set of three square-mesh stainless steel sieves mounted on frames consisting of US Sieve Nos. 25, 40, and 50 (see Particle Size Distribution Estimation by Analytical Sieving 〈786〉〉, Table 1. Sizes of Standard Sieve Series in Range of Interest); a mechanical sieve-shaker or a sieving machine that may be used to sieve the grains; a tempered, magnetic steel hammer; a permanent magnet; weighing bottles; stoppers; metal foil (e.g., aluminum, stainless steel); a hot air oven, capable of maintaining 140 ± 5°; a balance, capable of weighing up to 500 g with an accuracy of 0.005 g; a desiccator; and an ultrasonic bath.
REAGENTS Carbon dioxide-free water: This is Purified Water that has been boiled vigorously for 5 min or more and allowed to cool while protected from absorption of carbon dioxide from the atmosphere, or Purified Water that has a resistivity of not less than 18 Mohm- cm.
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Methyl red solution: Dissolve 50 mg of methyl red in 1.86 mL of 0.1 M sodium hydroxide and 50 mL of ethanol (96%), and dilute with Purified Water to 100 mL. To test for sensitivity, add 100 mL of carbon dioxide-free water and 0.05 mL of 0.02 M hydrochloric acid to 0.1 mL of the methyl red solution. The resulting solution should be red. NMT 0.1 mL of 0.02 M sodium hydroxide is required to change the color to yellow. A color change from red to yellow corresponds to a change in pH from pH 4.4 (red) to pH 6.0 (yellow).
Glass Grains Test
The Glass Grains Test may be performed either on the canes used for the manufacture of tubing glass containers or on the containers.
SAMPLE PREPARATION Rinse the containers to be tested with Purified Water, and dry in the oven. Wrap at least three of the glass articles in clean paper, and crush to produce two samples of about 100 g each in pieces NMT 30 mm across. Place in the mortar 30–40 g of the pieces between 10 and 30 mm across taken from one of the samples, insert the pestle, and strike it heavily with the hammer once only. Alternatively, transfer samples into a ball mill-breaker, add the balls, and crush the glass. Transfer the contents of the mortar or ball mill to the coarsest sieve (No. 25) of the set. Repeat the operation until all fragments have been transferred to the sieve. Shake the set of sieves for a short time by hand, and remove the glass that remains on sieves No. 25 and No. 40. Submit these portions to further fracture, repeating the operation until about 10 g of glass remains on sieve No. 25. Reject this portion and the portion that passes through sieve No. 50. Reassemble the set of sieves, and shake for 5 min. Transfer to a weighing bottle the glass grains that passed through sieve No. 40 and are retained on sieve No. 50. Repeat the crushing and sieving procedure with the second glass sample until two samples of grains are obtained, each of which weighs more than 10 g. Spread each sample on a piece of clean glazed paper, and remove any iron particles by passing the magnet over them. Transfer each sample into a beaker for cleaning. Add 30 mL of acetone to the grains in each beaker, and scour the grains, using suitable means such as a rubber-tipped or plastic-coated glass rod. After scouring the grains, allow to settle, and decant as much acetone as possible. Add another 30 mL of acetone, swirl, decant, and add a new portion of acetone. Fill the bath of the ultrasonic vessel
cool in a desiccator.
Filling and heating: 50 mL of carbon dioxide-
1.
2. 3.
4. 5. 6. Cool down to 100° at a rate of 0.5°/min, venting to prevent formation of a vacuum, within 40–44 min. 7. Do not open the autoclave until it has cooled to 95°. 8. Remove the hot samples from the autoclave using appropriate safety precautions, and cool the samples cautiously down to room temperature within 30 min, avoiding thermal shock. Titration: To each of the three flasks add 0.05 mL of Methyl red solution. Titrate the blank solution immediately with 0.02 M hydrochloric acid, then titrate the test solutions until the color matches that obtained with the blank solution. Subtract the titration volume for the blank solution from that for the test solutions. Calculate the mean value of the results in mL of 0.02 M hydrochloric acid per g of the sample. Repeat the test if the highest and lowest observed values differ by more than the permissible range given in Table 3.
Table 3. Permissible Range for Values Obtained
Mean of the Values Obtained for the Consumption of Hydro-
chloric Acid Solution per g of Glass Grains (mL/g) Permissible Range of the Values Obtained
NMT 0.10 25% of the mean
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Mean of the Values Obtained for the Consumption of Hydro-
chloric Acid Solution per g of Glass Grains (mL/g) Permissible Range of the Values Obtained
0.10–0.20 20% of the mean
NLT 0.20 10% of the mean
[NOTE—Where necessary to obtain a sharp endpoint, decant the clear solution into a separate 250-mL flask. Rinse the grains by swirling with three 15-mL portions of carbon dioxide-free water, and add the washings to the main solution. Add 0.05 mL of the Methyl red solution. Titrate, and calculate as before. In this case also add 45 mL of carbon dioxide-free Purified Water and 0.05 mL of Methyl red solution to the blank solution.]
LIMITS The volume does not exceed the values indicated in Table 4.
Table 4. Test Limits for Glass Grains Test
Maximum Volume of 0.02 M HCl per g of Test Glass (mL)
Filling Volume (mL) Type I Types II and III
All 0.1 0.85
Surface Glass Test
shoulder. Vials and bottles: 100 mL, and remove any dirt
Cartridges and syringes: Luer cone or staked
Vials and Bottles. Ampuls: Place at ). Read the capacities,
Figure 2. Filling volumes of ampuls up to point A.
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TEST The determination is carried out on unused containers. The volumes of the test solution necessary for the final determination are shown in Table 5.
Table 5. Volume of Test Solution and Number of Titrations
Volume of Test Liquid for One Titration
Filling Volume (mL) (mL) Number of Titrations
NMT 3 25.0 1
3–30 50.0 2
30–100 100.0 2
NLT 100 100.0 3
METHOD Cleaning: Remove any debris or dust. Shortly before the test, rinse each container carefully at least twice with Purified Water, refilled, and allow to stand. Immediately before testing, empty the containers; rinse once with Purified Water, then with carbon dioxide-free water; and allow to drain. Complete the cleaning procedure from the first rinsing within 20–30 min. Closed ampules may be warmed in a water bath or in an air oven at about 40° for approximately 2 min before opening to avoid container pressure when opening. Do not rinse before testing. Filling and heating: The containers are filled with carbon dioxide-free water up to the filling volume. Containers in the form of
the Glass Grains Test cooling
Titration: Carry out
carbon for each 25
Table 6.
Type III
NMT 1 2.0 20.0
1–2 1.8 17.6
2–3 1.6 16.1
3–5 1.3 13.2
5–10 1.0 10.2
10–20 0.80 8.1
20–50 0.60 6.1
50–100 0.50 4.8
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Maximum Volume of 0.01 M HCl per 100 mL of Test Solution (mL)
Filling Volume (mL) Types I and II Type III
100–200 0.40 3.8
200–500 0.30 2.9
NLT–500 0.20 2.2
Surface Etching Test
The Surface Etching Test is used in addition to the Surface Glass Test when it is necessary to determine whether a container has been surface treated and/or to distinguish between Type I and Type II glass containers. Alternatively, the Glass Grains Test and Surface Glass Test may be used. The Surface Etching Test may be carried out either on unused samples or on samples used in the Surface Glass Test.
METHOD Vials and bottles: The volumes of test solution required are shown in Table 5. Rinse the containers twice with Purified Water, fill to the brimful point with a mixture of one volume of hydrofluoric acid and nine volumes of hydrochloric acid, and allow to stand for 10 min. Empty the containers, and rinse carefully five times with Purified Water. Immediately before the test, rinse once again with Purified Water. Submit these containers to the same autoclaving and determination procedure as described in the Surface Glass Test. If the results are considerably higher than those obtained from the original surfaces (by a factor of about 5–10), the samples have been surface treated. [CAUTION—Hydrofluoric acid is extremely aggressive. Even small quantities can cause life threatening injuries.] cartridges, and syringes [NOTE—Ampuls, cartridges, ]
. For Type I glass
Use as the Test Preparation smaller containers, 35
Surface Glass Test. The limit does not exceed 0.1 µg/g.
sphere
SAMPLE PREPARATION Break the glass container or cut it with a circular saw fitted with a wet abrasive wheel, such as a carborundum or a bonded diamond wheel. Select sections representative of the wall thickness, and trim them as suitable for mounting in a spectrophotometer. After cutting, wash and dry each specimen, taking care to avoid scratching the surfaces. If the specimen is too small to cover the opening in the specimen holder, mask the uncovered portion of the opening with opaque paper or tape, provided that the length of the specimen is greater than that of the slit. Before placing in the holder, wash, dry, and wipe the specimen with lens tissue. Mount the specimen with the aid of wax, or by other convenient means, taking care to avoid leaving fingerprints or other marks.
METHOD Place the specimen in the spectrophotometer with its cylindrical axis parallel to the slit and in such a way that the light beam is perpendicular to the surface of the section and the losses due to reflection are at a minimum. Measure the transmission of the specimen with reference to air in the spectral region of 290–450 nm, continuously or at intervals of 20 nm.
LIMITS
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The observed spectral transmission for colored glass containers for products for nonparenteral use does not exceed 10% at any wavelength in the range of 290–450 nm, irrespective of the type and capacity of the glass container. The observed spectral transmission in colored glass containers for parenteral products does not exceed the limits given in Table 7.
Table 7. Limits of Spectral Transmission for Colored Glass Containers for Parenteral Products
Maximum Percentage of Spectral Transmission at Any Wavelength between 290
nm and 450 nm
Nominal Volume (mL) Flame-Sealed Containers Containers with Closures
