Glass containers for pharmaceutical use are intended to come into direct contact with pharmaceutical preparations. Glass used for pharmaceutical containers is either a borosilicate (neutral) glass or a soda-lime glass. Borosilicate glass contains a significant amount of boric oxide, aluminum oxide, and alkali and/or alkaline earth oxides. Borosilicate glass has a high hydrolytic resistance due to the chemical composition of the glass itself; it is classified as Type I glass. Soda-lime glass is a silica glass containing alkali metal oxides. Soda-lime glass has a moderate hydrolytic resistance due to the chemical composition of the glass itself; it is classified as Type III glass. The inner surface of glass containers may be treated, for example, to improve hydrolytic resistance. The treatment of Type III soda-lime glass containers will raise their hydrolytic resistance from a moderate to a high level, changing the classification of the glass to Type II.
The outer surface of glass containers may be treated to reduce friction or for protection against abrasion or breakage. The treatment of the outer surface does not come into contact with the inner surface of the container. Glass may be colored to provide protection from light or may have a coating applied to the outer surface. Such containers will meet the requirements for Light Transmission under ContainersPerformance Testing 671. A clear and colorless or a translucent container that is made light-resistant by means of an opaque enclosure (see Light-Resistant Container in Preservation, Packaging, Storage, and Labeling under the General Notices) is exempt from the requirements for Light Transmission.
The quality of glass containers is defined by measuring their resistance to chemical attack. In addition, Type I containers for aqueous parenteral preparations are tested for arsenic release, and colored glass containers are tested for light transmission.
The following tests are designed to determine the resistance to water attack of new (not previously used) glass containers. The degree of attack is determined by the amount of alkali released from the glass under the influence of the attacking medium under the conditions specified. This quantity of alkali is extremely small in the case of the more resistant glasses, thus calling for particular attention to all details of the tests and the use of apparatus of high quality and precision. The tests should be conducted in an area relatively free from fumes and excessive dust.
Glass Types Glass containers suitable for packaging Pharmacopeial preparations may be classified as in Table 1 on the basis of the tests set forth in this section. Containers of Type I borosilicate glass are generally used for preparations that are intended for parenteral administration. Containers of Type I glass, or of Type II glass (i.e., soda-lime glass that is suitably dealkalized) are usually used for packaging acidic and neutral parenteral preparations. Type I glass containers, or Type II glass containers (where stability data demonstrate their suitability), are used for alkaline parenteral preparations. Type III soda-lime glass containers usually are not used for parenteral preparations, except where suitable stability test data indicate that Type III glass is satisfactory for the parenteral preparations that are packaged therein.
Table 1. Glass Types
Autoclave For these tests, use an autoclave capable of maintaining a temperature of 121 ± 2.0, 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.
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 Glass1
Other Equipment Also required are 20.3-cm (8-inch) sieves made of stainless steel, including the Nos. 20, 40, and 50 sieves, along with the pan and cover (see Sizes of Standard Sieve Series in Range of Interest under Particle Size Distribution Estimation by Analytical Sieving 786); 250-mL conical flasks made of resistant glass aged as specified; a 900-g (2-lb) hammer; a permanent magnet; a desiccator; and an adequate volumetric apparatus.
High-Purity Water The water used in these tests has a conductivity at 25, as measured in an in-line cell just prior to dispensing, of not greater than 0.15 µS 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 0.45 µm.2 Do not use copper tubing. Flush the discharge lines before water is dispensed into test vessels. When the low conductivity specification can no longer be met, replace the deionizer cartridge.
Carbon DioxideFree Water This is Purified Water that has been boiled vigorously for 5 minutes 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.
Methyl Red Solution (Powdered Glass Test and Water Attack at 121) 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 5 drops of indicator, does not require more than 0.020 mL of 0.020 N sodium hydroxide to effect the color change of the indicator, which should occur at a pH of 5.6.
Methyl Red Solution (Surface Glass Test) Dissolve 50 mg of methyl red solution in 1.86 mL of 0.1 M sodium hydroxide and 50 mL of ethanol (96%) and dilute to 100 mL with Purified Water. 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 solution should be red). Not more than 0.1 mL of 0.02 M sodium hydroxide is required to change the color to yellow. Color change: pH 4.4 (red) to pH 6.0 (yellow).
Powdered Glass Test
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 25 mm in size, divide about 100 g of the coarsely crushed glass into three approximately equal portions, and place one of the portions in the special mortar. With the pestle in place, crush the glass further by striking 3 or 4 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 5 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 10 g, to a closed container, and store in a desiccator until used for the test.
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 seconds, 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 minutes at 140, transfer the grains to a weighing bottle, and cool in a desiccator. Use the test specimen within 48 hours after drying.
Procedure Transfer 10.00 g of the prepared specimen, accurately weighed, to a 250-mL conical flask that has been digested (aged) previously with High-Purity Water in a bath at 90 for at least 24 hours or at 121 for 1 hour. 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 minutes. Close the vent cock, and adjust the temperature to 121, taking 19 to 23 minutes to reach the desired temperature. Hold the temperature at 121 ± 2.0 for 30 minutes, counting from the time this temperature is reached. Reduce the heat so that the autoclave cools and comes to atmospheric pressure in 38 to 46 minutes, 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 5 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 10 g of the prepared specimen of glass, corrected for a blank. The volume does not exceed that indicated in Table 2 for the type of glass concerned.
Surface Glass Test
Determination of the Filling Volume The filling volume is the volume to be filled with Purified Water in the container for the purpose of the test. For vials and bottles the filling volume is 90% of the brimful capacity. For ampules it is the volume up to the height of the shoulder.
Vials and Bottle Select, at random, 6 containers from the sample lot, or 3 if their capacity exceeds 100 mL, and remove any dirt or debris. Weigh the empty containers with an accuracy of 0.1 g. Place the containers on a horizontal surface, and fill them with Purified Water to about the rim edge, avoiding overflow and introduction of air bubbles. Adjust the liquid levels to the brimful line. Weigh the filled containers to obtain the mass of the water, expressed to 2 decimal places, for containers having a nominal volume less or equal to 30 mL, and expressed to 1 decimal place for containers having a nominal volume greater than 30 mL. Calculate the mean value of the brimful capacity in mL, and multiply it by 0.9. This volume, expressed to 1 decimal place, is the filling volume for the particular container lot.
Ampules Place at least 6 dry ampules on a flat, horizontal surface, and fill them with Purified Water from a buret until the water reaches point A, where the body of the ampule decreases to the shoulder of the ampule (see Figure 2). Read the capacities, expressed to 2 decimal places, and calculate the mean value. This volume, expressed to 1 decimal place, is the filling volume for the particular ampule lot. The filling volume may also be determined by weighing.
Test The determination is carried out on unused containers. The volumes of the test liquid necessary for the final determination are indicated in Table 3.
Table 3. Volume of Test Liquid and Number of Titrations
Cleaning Remove any debris or dust. 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 with Purified Water, then with Carbon Dioxide-Free Water and allow to drain. Complete the cleaning procedure from the first rinsing in not less than 20 minutes and not more than 25 minutes. Heat closed ampules in a water bath or in an air-oven at about 50 for approximately 2 minutes before 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 cartridges or prefilled syringes are closed in a suitable manner with material that does not interfere with the test. Each container, including ampules, shall be loosely capped with an inert material such as a dish of neutral glass or aluminum foil previously rinsed with Purified Water. Place the containers on the tray of the autoclave.
Place the tray in the autoclave containing a quantity of water such that the tray remains clear of the water. Close the autoclave, and carry out the following operations:
The extraction solutions are analyzed by titration according to the method described below.
Method Carry out the titration within 1 hour of removal of the containers from the autoclave.
Combine the liquids obtained from the containers, and mix. Introduce the prescribed volume indicated in Table 3 into a conical flask. Place the same volume of Carbon Dioxide-Free Water into a second similar flask as a blank. Add 0.05 mL of Methyl Red Solution to each flask for each 25 mL of liquid. Titrate the blank with 0.01 M hydrochloric acid. Titrate the test liquid with the same acid until the color of the resulting 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 mL of 0.01 M hydrochloric acid per 100 mL. Express titration values of less than 1.0 mL to 2 decimal places and titration values of more than or equal to 1.0 mL to 1 decimal place.
Limits 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.
Table 4. Test Limits for Surface Glass Test
Water Attack at 121
Option The Water Attack at 121 test can be used to qualify Type II glass.
Rinse thoroughly 3 or more containers, selected at random, twice 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 minutes instead of 30 minutes, and ending with to prevent the formation of a vacuum. Empty the contents from 1 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 5 drops of Methyl Red Solution, and titrate, while warm, with 0.020 N sulfuric acid. Complete the titration within 60 minutes 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 5.
Arsenic 211 Use as 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, prepared as directed for Procedure under Water Attack at 121 or Surface Glass Test: the limit is 0.1 µg per g.
1 A suitable mortar and pestle is available (catalog No. H-17280) from Humbolt Manufacturing Co., 7300 West Agatite Avenue, Norridge, IL, 60706, www.humboldtmfg.com
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