U.S. PHARMACOPEIA

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POLYETHYLENE TEREPHTHALATE BOTTLES AND POLYETHYLENE TEREPHTHALATE G BOTTLES
The standards and tests provided in this section characterize polyethylene terephthalate (PET) and polyethylene terephthalate G (PETG) bottles that are interchangeably suitable for packaging liquid oral dosage forms.
Where stability studies have been performed to establish the expiration date of a particular liquid oral dosage form in a bottle meeting the requirements set forth herein for either PET or PETG bottles, any other PET or PETG bottle meeting these requirements may be similarly used to package such dosage form, provided that the appropriate stability programs are expanded to include the alternative bottle in order to assure that the identity, strength, quality, and purity of the dosage form are maintained throughout the expiration period.
The suitability of a specific PET or PETG bottle for use in the dispensing of a particular pharmaceutical liquid oral dosage form must be established by appropriate testing.
PET resins are long-chain crystalline polymers prepared by the condensation of ethylene glycol with dimethyl terephthalate or terephthalic acid. PET copolymer resins are prepared in a similar way, except that they may also contain a small amount of either isophthalic acid (not more than 3 mole percent) or 1,4-cyclohexanedimethanol (not more than 5 mole percent). Polymerization is conducted under controlled conditions of heat and vacuum, with the aid of catalysts and stabilizers.
PET copolymer resins have physical and spectral properties similar to PET and for practical purposes are treated as PET. The tests and specifications provided in this section to characterize PET resins and bottles apply also to PET copolymer resins and to bottles fabricated from them.
PET and PET copolymer resins generally exhibit a large degree of order in their molecular structure. As a result, they exhibit characteristic composition-dependent thermal behavior, including a glass transition temperature of about 76 and a melting temperature of about 250. These resins have a distinctive IR absorption spectrum that allows them to be distinguished from other plastic materials (e.g., polycarbonate, polystyrene, polyethylene, and PETG resins). PET and PET copolymer resins have a density between 1.3 and 1.4 g per cm3 and a minimum intrinsic viscosity of 0.7 dL per g, which corresponds to a number average molecular weight of about 23,000 daltons.
PETG resins are high molecular weight polymers prepared by the condensation of ethylene glycol with dimethyl terephthalate or terephthalic acid and 15 to 34 mole percent of 1,4-cyclohexanedimethanol. PETG resins are clear, amorphous polymers, having a glass transition temperature of about 81 and no crystalline melting point, as determined by differential scanning calorimetry. PETG resins have a distinctive IR absorption spectrum that allows them to be distinguished from other plastic materials, including PET. PETG resins have a density of approximately 1.27 g per cm3 and a minimum instrinsic viscosity of 0.65 dL per g, which corresponds to a number average molecular weight of about 16,000 daltons.
PET and PETG resins, and other ingredients used in the fabrication of these bottles, conform to the requirements in the applicable sections of the Code of Federal Regulations, Title 21, regarding use in contact with food and alcoholic beverages. PET and PETG resins do not contain any plasticizers, processing aids, or antioxidants. Colorants, if used in the manufacture of PET and PETG bottles, do not migrate into the contained liquid.
Multiple Internal Reflectance—
APPARATUS— 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.6 A KRS-5 crystal having a thickness of 2 mm and 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 bottle, 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.
PROCEDURE— 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 beams. (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 4000 to 400 cm1. The corrected spectrum of the specimen exhibits major absorption bands only at the same wavelengths as the spectrum of the USP Polyethylene Terephthalate RS, or the USP Polyethylene Terephthalate G RS, similarly determined.
Thermal Analysis— Cut a section weighing about 12 mg from the bottle, and place it in the test-specimen pan. Determine the thermogram under nitrogen, using the heating and cooling conditions as specified for the resin type and using equipment capable of performing the determinations as described under Thermal Analysis 891.
Polyethylene Terephthalate— Heat the specimen from room temperature to 280 at a heating rate of about 20 per minute. Hold the specimen at 280 for 1 minute. Quickly cool the specimen to room temperature, and reheat it to 280 at a heating rate of about 5 per minute. The thermogram of the specimen is similar to the thermogram of USP Polyethylene Terephthalate RS, similarly determined: the melting point (Tm) of the specimen does not differ from that of the Standard by more than 9.0, and the glass transition temperature (Tg) of the specimen does not differ from that of the Standard by more than 4.0.
Polyethylene Terephthalate G— Heat the specimen from room temperature to 120 at a heating rate of about 20 per minute. Hold the specimen at 120 for 1 minute. Quickly cool the specimen to room temperature, and reheat it to 120 at a heating rate of about 10 per minute. The thermogram of the specimen is similar to the thermogram of USP Polyethylene Terephthalate G RS, similarly determined: the glass transition temperature (Tg) of the specimen does not differ from that of the Standard by more than 6.0.
Light Transmission— PET and PETG bottles intended to provide protection from light meet the requirements under Light Transmission.
Water Vapor Permeation— [NOTE—Throughout the following procedure, determine the weights of bottles and closures, both as tare weights and weights of filled bottles, to the nearest 0.1 mg if the bottle volume is less than 200 mL; to the nearest mg if the bottle volume is 200 mL or more but less than 1000 mL; or to the nearest centigram (10 mg) if the bottle volume is 1000 mL or more.] Select 10 bottles of a uniform size and type, clean the sealing surfaces with a lint-free cloth, and close and open each bottle 30 times. Apply the closure firmly and uniformly each time the bottle is closed. Close screw-capped bottles with a torque that is within the range of tightness specified in the table provided under Containers—Permeation 671. Weigh each empty bottle and its closure. Fill ten bottles with water at 25 ± 2 until the meniscus is tangent to the top of the bottle opening. Record the weight of each bottle and its closure, and determine the average bottle volume, in L, taken by the following formula:
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where Woi is the total weight, in g, of bottle i and its closure, Wti is the tare weight, in g, of bottle i and its closure, and 9970 is the density of water at 25 times 10,000 (the number of bottles tested times the conversion factor for converting milliliters to liters).
Using a pipet, adjust the water level in the bottles to the fill point. Apply the closures using a torque that is within the range specified in the table provided under Containers—Permeation 671, and store the bottles at a temperature of 25 ± 2 and a relative humidity of 50 ± 2%. After 168 ± 1 hours (7 days), record the weight of the individual bottles. Return the bottles to storage for another 168 ± 1 hours. After the second 168 ± 1 hours, remove the bottles, record the weights of the individual bottles, and calculate the water vapor permeation rate, in mg per day per L, for each bottle taken by the formula:
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in which Wli is the weight, in mg, of bottle i at 14 days, Wfi is the weight, in mg, of bottle i at 7 days, 7 is the test time, in days, after the 7-day equilibration period, and Va is the average bottle volume, in L.
The bottles so tested meet the requirements and are tight containers if the water vapor permeation rate exceeds 100 mg per day per L in not more than 1 of the 10 test bottles and exceeds 200 mg per day per L in none of them.
Colorant Extraction— Select 3 test bottles. Cut a relatively flat portion from the side wall of one bottle, and trim it as necessary to fit the sample holder of the spectrophotometer. Obtain the visible spectrum of the side wall by scanning the portion of the visible spectrum from 350 to 700 nm. Determine, to the nearest 2 nm, the wavelength of maximum absorbance. Fill the remaining two test bottles, using 50% alcohol for PET bottles and 25% alcohol for PETG bottles. Fit the bottles with impervious seals, such as aluminum foil, and apply closures. Fill a glass bottle having the same capacity as that of the test bottles with the corresponding solvent, fit the bottle with an impervious seal, such as aluminum foil, and apply a closure. Incubate the test bottles and the glass bottle in a constant temperature room or in an oven at 49 for ten days. Remove the bottles, and allow them to equilibrate to room temperature. Concomitantly determine the absorbances of the test solutions in 5-cm cells at the wavelength of maximum absorbance (see Spectrophotometry and Light-Scattering 851), using the corresponding solvent from the glass bottle as the blank. The absorbance values so obtained are less than 0.01 for both test solutions.
Heavy Metals, Total Terephthaloyl Moieties, and Ethylene Glycol—
EXTRACTING MEDIA—
Purified Water— (see monograph).
50 Percent Alcohol— Dilute 125 mL of alcohol with water to 238 mL, and mix.
25 Percent Alcohol— Dilute 125 mL of 50 Percent Alcohol with water to 250 mL, and mix.
n-Heptane.
PROCEDURE— [NOTE—Use the 50 Percent Alcohol Extracting Medium with PET bottles. Use the 25 Percent Alcohol Extracting Medium with PETG bottles.] For each Extracting Medium, fill a sufficient number of test bottles to 90% of their nominal capacity to obtain not less than 30 mL of extract. Fill a corresponding number of glass bottles with Purified Water Extracting Medium, a corresponding number of glass bottles with 50 Percent Alcohol Extracting Medium or 25 Percent Alcohol Extracting Medium, and a corresponding number of glass bottles with n-Heptane Extracting Medium for use as Extracting Media blanks. Fit the bottles with impervious seals, such as aluminum foil, and apply closures. Incubate the test bottles and the glass bottles in a constant temperature room or in an oven at 49 for ten days. Remove the test bottles with the Extracting Media samples and the glass bottles with the Extracting Media blanks, and store them at room temperature. Do not transfer the Extracting Media samples to alternative storage vessels.
HEAVY METALS— Pipet 20 mL of the Purified Water extract of the test bottles, filtered if necessary, into one of two matched 50-mL color-comparison tubes, and retain the remaining Purified Water extract in the test bottles for use in the test for Ethylene Glycol. Adjust the extract with 1 N acetic acid or 6 N ammonium hydroxide to a pH between 3.0 and 4.0, using short-range pH paper as an external indicator. Dilute with water to about 35 mL, and mix.
Into the second color-comparison tube, pipet 2 mL of freshly prepared (on day of use) Standard Lead Solution (see Heavy Metals 231), and add 20 mL of Purified Water. Adjust with 1 N acetic acid or 6 N ammonium hydroxide to a pH between 3.0 and 4.0, using short-range pH paper as an external indicator. Dilute with water to about 35 mL, and mix.
To each tube add 1.2 mL of thioacetamide-glycerin base TS and 2 mL of pH 3.5 Acetate Buffer (see Heavy Metals 231), dilute with water to 50 mL, and mix: any color produced within 10 minutes in the tube containing the Purified Water extract of the test bottles does not exceed that in the tube containing the Standard Lead Solution, both tubes being viewed downward over a white surface (1 ppm in extract).
Total Terephthaloyl Moieties— Determine the absorbance of the 50 Percent Alcohol or 25 Percent Alcohol extract in a 1-cm cell at the wavelength of maximum absorbance at about 244 nm (see Spectrophotometry and Light-Scattering 851), using the corresponding Extracting Medium blank as the blank: the absorbance of the extract does not exceed 0.150, corresponding to not more than 1 ppm of total terephthaloyl moieties.
Determine the absorbance of the n-Heptane extract in a 1-cm cell at the wavelength of maximum absorbance at about 240 nm (see Spectrophotometry and Light-Scattering 851), using the n-Heptane Extracting Medium blank as the blank: the absorbance of the extract does not exceed 0.150, corresponding to not more than 1 ppm of total terephthaloyl moieties.
ETHYLENE GLYCOL—
Periodic Acid Solution— Dissolve 125 mg of periodic acid in 10 mL of water.
Dilute Sulfuric Acid— To 50 mL of water add slowly and with constant stirring 50 mL of sulfuric acid, and allow to cool to room temperature.
Sodium Bisulfite Solution— Dissolve 0.1 g of sodium bisulfite in 10 mL of water. Use this solution within seven days.
Disodium Chromotropate Solution— Dissolve 100 mg of disodium chromotropate in 100 mL of sulfuric acid. Protect this solution from light, and use within seven days.
Standard Solution— Dissolve an accurately weighed quantity of ethylene glycol in water, and dilute quantitatively, and stepwise if necessary, to obtain a solution having a known concentration of about 1 µg per mL.
Test Solution— Use the Purified Water extract.
Blank— Use the Purified Water Extracting Medium blank.
Procedure— Transfer 1.0 mL of Standard Solution to a 10-mL volumetric flask. Transfer 1.0 mL of Test Solution to a second 10-mL volumetric flask. Transfer 1.0 mL of Purified Water Extracting Medium blank to a third 10-mL volumetric flask. To each of the three flasks, add 100 µL of Periodic Acid Solution, swirl to mix, and allow to stand for 60 minutes. Add 1.0 mL of Sodium Bisulfite Solution to each flask, and mix. Add 100 µL of Disodium Chromotropate Solution to each flask, and mix. [NOTE—All solutions should be analyzed within one hour after addition of the Disodium Chromotropate Solution.] Cautiously add 6 mL of sulfuric acid to each flask, mix, and allow the solutions to cool to room temperature. [Caution—Dilution of sulfuric acid produces substantial heat and can cause the solution to boil. Perform this addition carefully. Sulfur dioxide gas will be evolved. Use of a fume hood is recommended. ] Dilute each solution with Dilute sulfuric acid to volume, and mix. Concomitantly determine the absorbances of the solutions from the Standard Solution and the Test Solution in 1-cm cells at the wavelength of maximum absorbance at about 575 nm (see Spectrophotometry and Light-Scattering 851), using the solution from the Purified Water Extracting Medium blank as the blank: the absorbance of the solution from the Test solution does not exceed that of the solution from the Standard solution, corresponding to not more than 1 ppm of ethylene glycol.