The standards and tests provided in this section characterize high-density and low-density polyethylene containers that are interchangeably suitable for packaging dry oral dosage forms not meant for constitution into solution.
Where stability studies have been performed to establish the expiration date of a particular dry oral dosage form not meant for constitution into solution in a container meeting the requirements set forth herein for either high- or low-density polyethylene containers, then any other polyethylene container meeting the same sections of these requirements may be similarly used to package such dosage form, provided that the appropriate stability programs are expanded to include the alternative container, in order to assure that the identity, strength, quality, and purity of the dosage form are maintained throughout the expiration period.
Both high- and low-density polyethylene are long-chain polymers synthesized under controlled conditions of heat and pressure, with the aid of catalysts from not less than 85.0% ethylene and not less than 95.0% total olefins. The other olefin ingredients most frequently used are butene, hexene, and propylene. The ingredients used to manufacture the polyethylene, and those used in the fabrication of the containers, conform to the requirements in the applicable sections of the Code of Federal Regulations, Title 21.
High-density polyethylene and low-density polyethylene both have an IR absorption spectrum that is distinctive for polyethylene, and each possesses characteristic thermal properties. High-density polyethylene has a density between 0.941 and 0.965 g per cm3. Low-density polyethylene has a density between 0.850 and 0.940 g per cm3. The permeation properties of molded polyethylene containers may be altered when re-ground polymer is incorporated, depending upon the proportion of re-ground material in the final product. Other properties that may affect the suitability of polyethylene used in containers for packaging drugs are: oxygen and moisture permeability, modulus of elasticity, melt index, environmental stress crack resistance, and degree of crystallinity after molding. The requirements in this section are to be met when dry oral dosage forms, not meant for constitution into solution, are intended to be packaged in a container defined by this section.
Multiple Internal Reflectance
Use an IR spectrophotometer capable of correcting for the blank spectrum and equipped with a multiple internal reflectance accessory and a KRS-5 internal reflection plate.4
A KRS-5 crystal 2 mm thick having an angle of incidence of 45
provides a sufficient number of reflections.
PREPARATION OF SPECIMEN
Cut 2 flat sections representative of the average wall thickness of the container, and trim them as necessary to obtain segments that are convenient for mounting in the multiple internal reflectance accessory. Taking care to avoid scratching the surfaces, wipe the specimens with dry paper or, if necessary, clean them with a soft cloth dampened with methanol, and permit them to dry. Securely mount the specimens on both sides of the KRS-5 internal reflection plate, ensuring adequate surface contact. Prior to mounting the specimens on the plate, they may be compressed to thin uniform films by exposing them to temperatures of about 177
under high pressures (15,000 psi or more).
Place the mounted specimen sections within the multiple internal reflectance accessory, and place the assembly in the specimen beam of the IR spectrophotometer. Adjust the specimen position and mirrors within the accessory to permit maximum light transmission of the unattenuated reference beam. (For a double-beam instrument, upon completing the adjustments in the accessory, attenuate the reference beam to permit full-scale deflection during the scanning of the specimen.) Determine the IR spectrum from 3500 to 600 cm1
: the corrected spectrum of the specimen exhibits major absorption bands only at the same wavelengths as the spectrum of USP High-density Polyethylene RS
or USP Low-density Polyethylene RS
, similarly determined.
Cut a section weighing about 12 mg, and place it in the test-specimen pan. Determine the thermogram under nitrogen at temperatures between 40
at a heating rate between 2
per minute followed by cooling at a rate between 2
per minute to 40
, using equipment capable of performing the determinations described under Thermal Analysis 891
The thermogram of the specimen is similar to the thermogram of USP High-Density Polyethylene RS
, similarly determined, and the temperatures of the endotherms and exotherms in the thermogram of the specimen do not differ from those of the standard by more than 6.0
The thermogram of the specimen is similar to the thermogram of USP Low-Density Polyethylene RS
, similarly determined, and the temperatures of the endotherms and exotherms in the thermogram of the specimen do not differ from those of the standard by more than 8.0
Polyethylene containers intended to provide protection from light meet the requirements under Light Transmission.
Water Vapor Permeation
Fit the containers with impervious seals obtained by heat-sealing the bottles with an aluminum foil-polyethylene laminate or other suitable seal.5
Test the containers as described under ContainersPermeation 671
: the high-density polyethylene containers so tested meet the requirements if the moisture permeability exceeds 10 mg per day per L in not more than 1 of the 10 test containers and exceeds 25 mg per day per L in none of them. The low-density polyethylene containers so tested meet the requirements if the moisture permeability exceeds 20 mg per day per L in not more than 1 of the 10 test containers and exceeds 30 mg per day per L in none of them.
Heavy Metals and Nonvolatile Residue
Prepare extracts of specimens for these tests as directed for Preparation of Sample
in the Procedure
under Physicochemical TestsPlastics
, except that for each 20.0 mL of Extracting Medium
the portion shall be 60 cm2
, regardless of thickness.
Containers meet the requirements for Heavy Metals under Physicochemical TestsPlastics.
Proceed as directed for Nonvolatile Residue
under Physicochemical TestsPlastics
, except that the blank shall be the same solvent used in each of the tests set forth below. The difference between the amounts obtained from the specimen and the blank does not exceed 12.0 mg when water maintained at a temperature of 70
is used as the extracting medium; does not exceed 75.0 mg when alcohol maintained at a temperature of 70
is used as the extracting medium; and does not exceed 100.0 mg for high-density polyethylene and does not exceed 350.0 mg for low-density polyethylene when hexanes maintained at a temperature of 50
are used as the extracting medium. Containers meet these requirements for Nonvolatile Residue
for all of the above extracting media. [NOTE
Hexanes and alcohol are flammable. When evaporating these solvents, use a current of air with the water bath; when drying the residue, use an explosion-proof oven.]