Glass Containers for Pharmaceutical Use

Types of Glass

- Type I: Borosilicate glass (neutral)

- Type II: Soda-lime-silica glass (treated for high hydrolytic resistance)
- Type III: Soda-lime-silica glass (moderate hydrolytic resistance)

Properties

- Type I: High hydrolytic resistance, high thermal shock resistance

- Type II: High hydrolytic resistance
- Type III: Moderate hydrolytic resistance

Suitability for Pharmaceutical Products

- Type I: Suitable for most parenteral and nonparenteral products

- Type II: Suitable for most acidic and neutral aqueous products, and alkaline
parenteral products with stability data
- Type III: Not suitable for parenteral products or powders for parenteral use,
except with stability data

Tests

- Glass Grains Test: Determines glass type

- Surface Glass Test: Determines hydrolytic resistance of inner surface
- Surface Etching Test: Determines if high hydrolytic resistance is due to surface
treatment or chemical composition
- Spectral Transmission Test: Determines light transmission properties of colored
glass containers
- Extractable Arsenic Test: Determines amount of arsenic extractable from Type I or
Type II containers for aqueous parenteral products
- Hydrolytic Resistance Test: Determines resistance of glass to water attack
- Thermal Shock Resistance Test: Determines resistance of glass to thermal shock
- Chemical Durability Test: Determines resistance of glass to chemical attack

Specifications

- Glass containers must comply with identity and surface hydrolytic resistance
specifications to be classified as Type I, II, or III glass
- Type I or Type II containers for aqueous parenteral products must be tested for
extractable arsenic
- Glass containers must meet specifications for hydrolytic resistance, thermal
shock resistance, and chemical durability

Reference Materials

- National Institute of Standards and Technology (NIST) provides reference

materials for borosilicate glass (SRM 623) and soda-lime-silica glass (SRM 622)

Test Selection

- Table 1: Determination of Glass Types

- Glass Grains Test: Distinguishes Type I borosilicate glass from Type II and
III soda-lime-silica glass
- Table 2: Determination of Inner Surface Hydrolytic Resistance
- Surface Glass Test: Determines hydrolytic resistance of inner surface;
distinguishes between Type I and Type II containers with high hydrolytic resistance
and Type III containers with moderate hydrolytic resistance
 - Surface Etching Test or comparison of Glass Grains Test and Surface Glass
Test data: Determines whether high hydrolytic resistance is due to inner surface
treatment or chemical composition

Packaging and Storage Requirements

- Light-Resistant Packaging: Required for light-sensitive products

- Opaque Packaging: Required for products sensitive to light
- Special Packaging: Required for products with specific packaging needs

Hydrolytic Resistance Apparatus

1. Autoclave
- Temperature control: 121 ± 1°C
- Equipment:
- Thermometer or calibrated thermocouple device
- Recorder
- Pressure gauge
- Vent cock
- Tray (sufficient capacity to hold containers above water level)
- Cleaning: Clean the autoclave and other apparatus thoroughly with Purified
Water before use
2. Mortar and Pestle
- Material: Hardened steel
- Specifications: Figure 1
4. Sieves
- US Sieve Nos. 25, 40, and 50
- Square-mesh stainless steel
5. Sieve Shaker
- Mechanical sieve-shaker or sieving machine
6. Hammer
- Tempered, magnetic steel
7. Magnet
- Permanent magnet
8. Weighing Bottles
- For weighing samples
9. Stoppers
- For weighing bottles
10. Metal Foil
- Aluminum or stainless steel
11. Hot Air Oven
- Temperature control: 140 ± 5°C
12. Balance
- Accuracy: 0.005 g
- Capacity: 500 g
13. Desiccator
- For drying samples
14. Ultrasonic Bath
- For cleaning and degassing samples

Reagents

1. Carbon Dioxide-Free Water

- Preparation:
- Boil Purified Water vigorously for 5 minutes or more
 - Allow to cool while protected from carbon dioxide absorption
- Alternative:
- Use Purified Water with a resistivity of at least 18 Mohm-cm

2. Methyl Red Solution

- Preparation:
- Dissolve 50 mg of methyl red in:
- 1.86 mL of 0.1 M sodium hydroxide
- 50 mL of ethanol (96%)
- Dilute with Purified Water to 100 mL
- Sensitivity Test:
- Mix:
- 100 mL of carbon dioxide-free water
- 0.05 mL of 0.02 M hydrochloric acid
- 0.1 mL of methyl red solution
- Result: Solution should be red
- Add NMT 0.1 mL of 0.02 M sodium hydroxide to change color to yellow
- Color change indicates pH change from 4.4 (red) to 6.0 (yellow)
.........
Glass Grains Test

Sample Preparation

1. Rinse containers with Purified Water and dry in oven.

2. Crush containers into pieces ≤ 30 mm across.
3. Take 30-40 g of pieces (10-30 mm) and crush in mortar or ball mill.
4. Transfer to coarsest sieve (No. 25) and repeat until all fragments are
transferred.
5. Shake sieves, remove glass from sieves No. 25 and No. 40, and re-crush.
6. Repeat until ≈ 10 g remains on sieve No. 25.
7. Reject this portion and the portion that passes through sieve No. 50.
8. Reassemble sieves, shake for 5 min, and transfer grains to weighing bottle.

Cleaning and Drying

1. Remove iron particles with magnet.

2. Add 30 mL acetone, scour grains, and decant.
3. Repeat acetone washing and ultrasonic cleaning until clear.
4. Dry grains on warm plate and in drying oven at 140°C for 20 min.
5. Transfer dried grains to weighing bottles, stopper, and cool in desiccator.

Procedure

1. Perform test on canes or containers.

2. Use at least three glass articles.
3. Crush and sieve until two samples of grains are obtained, each weighing more
than 10 g.
4. Clean and dry grains as described above.
5. Transfer grains to beakers for cleaning.
6. Add acetone, scour, and decant.
7. Repeat ultrasonic cleaning and acetone washing until clear.
8. Dry grains and transfer to weighing bottles.

Equipment

1. Mortar and pestle

2. Ball mill-breaker
3. Sieves (No. 25, No. 40, No. 50)
4. Hammer
5. Magnet
6. Glazed paper
7. Beakers
8. Acetone
9. Ultrasonic vessel
10. Drying oven
11. Desiccator
12. Weighing bottles

Sample Requirements

1. Minimum of three glass articles

2. Pieces ≤ 30 mm across
3. 30-40 g of pieces (10-30 mm)
4. Two samples of grains, each weighing more than 10 g

Test Conditions

1. Temperature: 140°C
2. Time: 20 min
3. Acetone volume: 30 mL
4. Ultrasonic cleaning time: 1 min
5. Cooling: Desiccator

Method

Filling and Heating

1. Weigh 10.00 g of cleaned and dried grains into two separate conical flasks (test
solutions) and one conical flask (blank).
2. Pipet 50 mL of carbon dioxide-free Purified Water into each of the conical
flasks (test solutions and blank).
3. Distribute the grains evenly over the flat bases of the flasks by shaking
gently.
4. Close the flasks with neutral glass dishes or aluminum foil rinsed with Purified
Water or with inverted beakers so that the inner surfaces of the beakers fit snugly
down onto the top rims of the flasks.
5. Place all three flasks in the autoclave containing water at ambient temperature,
ensuring they are held above the level of the water in the vessel.
6. Insert the end of a calibrated thermometric device in a filled container through
a hole of approximately the diameter of the thermocouple and connect it to an
external measuring device. If the container is too small to insert a thermocouple,
apply a thermocouple in a suitable, similar container. Alternatively, use the
internal thermometer of the autoclave.
7. Close the autoclave door or lid securely but leave the vent-cock open.
8. Start automatic recording of the temperature versus time, and heat the autoclave
at a regular rate such that:
- Steam issues vigorously from the vent-cock after 20–30 min.
- Maintain a vigorous evolution of steam for a further 10 min.
- For autoclaves using a steam generator, it is not necessary to maintain the
temperature for 10 min at 100°.
9. Close the vent-cock, and raise the temperature from 100° to 121° at a rate of
1°/min within 20–22 min.
10. Maintain the temperature at 121 ± 1° for 30 ± 1 min from the time when the
holding temperature is reached.
11. Cool down to 100° at a rate of 0.5°/min, venting to prevent formation of a
vacuum, within 40–44 min.
12. Do not open the autoclave until it has cooled to 95°.

Titration

1. Add 0.05 mL of Methyl red solution to each of the three flasks.

2. Titrate the blank solution immediately with 0.02 M hydrochloric acid.
3. Titrate the test solutions until the color matches that obtained with the blank
solution.
4. Subtract the titration volume for the blank solution from that for the test
solutions.
5. Calculate the mean value of the results in mL of 0.02 M hydrochloric acid per g
of the sample.
6. Repeat the test if the highest and lowest observed values differ by more than
the permissible range.

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.

Surface Glass Test: Determination of Filling Volume

Objective: To determine the filling volume of containers (vials, bottles,

cartridges, syringes, and ampuls) for the Surface Glass Test.

Method:

Vials and Bottles:

1. Select six dry vials or bottles from the sample lot, or three if their capacity
exceeds 100 mL.
2. Remove any dirt or debris.
3. Weigh the empty containers with an accuracy of 0.1 g.
4. Place the containers on a horizontal surface.
5. Fill them with Purified Water to about the rim edge, avoiding overflow and the
introduction of air bubbles.
6. Adjust the liquid levels to the brimful line.
7. Weigh the filled containers to obtain the mass of the water expressed to:
- Two decimal places for containers having a nominal volume less than or equal
to 30 mL.
- One decimal place for containers having a nominal volume greater than 30 mL.
8. Calculate the mean value of the brimful capacity in mL.
9. Multiply it by 0.9 to get the filling volume for the particular container lot,
expressed to one decimal place.

Cartridges and Syringes:

1. Select six dry syringes or cartridges.

2. Seal the small opening (mouth of cartridges; Luer cone or staked needle of
syringes) using an inert material.
3. Follow steps 2-9 for Vials and Bottles.

Ampuls:

1. Place at least six dry ampuls on a flat, horizontal surface.

2. Fill them with Purified Water from a buret until the water reaches point A,
where the body of the ampul starts to decrease to the shoulder of the ampul (see
Figure 2).
3. Read the capacities to two decimal places.
4. Calculate the mean value.
5. This volume, expressed to one decimal place, is the filling volume for the
particular ampul lot.

Alternative method: Weighing instead of volume measurement.

Result: Filling volume (mL) for the particular container lot.

Surface Glass Test

Cleaning and Preparing Containers

1. Rinse each container carefully at least twice with Purified Water.

2. Refill and let stand.
3. Empty containers and rinse once with Purified Water and once with carbon
dioxide-free water.
4. Allow to drain.
5. Complete cleaning procedure from the first rinsing within 20–30 min.
6. 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.
7. Do not rinse before testing.

Filling and Heating

1. Fill containers with carbon dioxide-free water up to the filling volume.

2. Containers in the form of cartridges or prefillable syringes are closed in a
suitable manner with material that does not interfere with the test.
3. Each container, including ampuls, shall be loosely capped with an inert material
such as a dish of neutral glass or aluminum foil previously rinsed with Purified
Water.
4. Place the containers on the tray of the autoclave.
5. Place the tray in an autoclave containing a quantity of water such that the tray
remains clear of the water.
6. Close the autoclave, and carry out autoclaving procedure steps 1–8 as described
in the Glass Grains Test, except that the temperature is maintained at 121 ± 1° for
60 ± 1 min.
7. If a water bath is used for cooling samples, take care that the water does not
make contact with the loose foil caps to avoid contamination of the extraction
solution.

Titration

1. Carry out the titration within 1 h of the removal of the containers from the
autoclave.
2. Combine the liquids obtained from the containers, and mix.
3. Introduce the prescribed volume (see Table 5) into a conical flask.
4. Transfer the same volume of carbon dioxide-free water, to be used as a blank,
into a second similar flask.
5. Add to each flask 0.05 mL of Methyl red solution for each 25 mL of liquid.
6. Titrate the blank with 0.01 M hydrochloric acid.
7. Titrate the test solution with the same acid until the color of the resulting
solution is the same as that obtained for the blank.
8. Subtract the value found for the blank titration from that found for the test
solution, and express the results in mL of 0.01 M hydrochloric acid per 100 mL of
test solution.
9. Express titration values of less than 1.0 mL to two decimal places; express
titration values of greater than or equal to 1.0 mL to one decimal place.

Surface Etching Test

Objective: Determine if a container has been surface treated and distinguish

between Type I and Type II glass containers.

Method:

Vials and Bottles:

1. Rinse containers twice with Purified Water.

2. Fill to brimful point with a mixture of one volume of hydrofluoric acid (HF) and
nine volumes of hydrochloric acid (HCl) (1:9 HF:HCl).
3. Let stand for 10 min.
4. Empty and rinse carefully five times with Purified Water.
5. Immediately before the test, rinse once again with Purified Water.
6. Submit these containers to the same autoclaving and determination procedure as
described in the Surface Glass Test (Table 5).

Ampuls, Cartridges, and Syringes:

1. Apply the test method as described in Vials and Bottles.

2. If the ampuls, cartridges, and syringes are not surface treated, the values
obtained are slightly lower than those obtained in the previous tests.

Distinction between Type I and Type II Glass Containers:

1. Compare the results obtained from the Surface Etching Test to those obtained
from the Surface Glass Test.
2. For Type I glass containers, the values obtained are close to those found in the
Surface Glass Test.
3. For Type II glass containers, the values obtained greatly exceed those found in
the Surface Glass Test; and they are similar to, but not greater than, those
obtained for Type III glass containers of the same filling volume.

CAUTION: Hydrofluoric acid (HF) is extremely aggressive and can cause life-
threatening injuries. Even small quantities can cause severe burns and permanent
damage. Handle with extreme caution and wear appropriate protective equipment.