POLYETHYLENE TEREPHTHALATE BOTTLES AND POLYETHYLENE TEREPHTHALATE G BOTTLES, chemical structure, molecular formula, Reference Standards

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 PETor PETGbottles,any other PETor PETGbottle 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 PETor PETGbottle for use in the dispensing of a particular pharmaceutical liquid oral dosage form must be established by appropriate testing.

PETresins are long-chain crystalline polymers prepared by the condensation of ethylene glycol with dimethyl terephthalate or terephthalic acid.PETcopolymer resins are prepared in a similar way,except that they may also contain a small amount of either isophthalic acid (not more than 3mole percent)or 1,4-cyclohexanedimethanol (not more than 5mole percent).Polymerization is conducted under controlled conditions of heat and vacuum,with the aid of catalysts and stabilizers.

PETcopolymer resins have physical and spectral properties similar to PETand for practical purposes are treated as PET.The tests and specifications provided in this section to characterize PETresins and bottles apply also to PETcopolymer resins and to bottles fabricated from them.

PETand PETcopolymer 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 IRabsorption spectrum that allows them to be distinguished from other plastic materials (e.g.,polycarbonate,polystyrene,polyethylene,and PETGresins).PETand PETcopolymer resins have a density between 1.3and 1.4g per cm3and a minimum intrinsic viscosity of 0.7dLper g,which corresponds to a number average molecular weight of about 23,000daltons.

PETGresins are high molecular weight polymers prepared by the condensation of ethylene glycol with dimethyl terephthalate or terephthalic acid and 15to 34mole percent of 1,4-cyclohexanedimethanol.PETGresins are clear,amorphous polymers,having a glass transition temperature of about 81

and no crystalline melting point,as determined by differential scanning calorimetry.PETGresins have a distinctive IRabsorption spectrum that allows them to be distinguished from other plastic materials,including PET.PETGresins have a density of approximately 1.27g per cm3and a minimum instrinsic viscosity of 0.65dLper g,which corresponds to a number average molecular weight of about 16,000daltons.

PETand PETGresins,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.PETand PETGresins do not contain any plasticizers,processing aids,or antioxidants.Colorants,if used in the manufacture of PETand PETGbottles,do not migrate into the contained liquid.

Multiple Internal Reflectance—

APPARATUS— Use an IRspectrophotometer capable of correcting for the blank spectrum and equipped with a multiple internal reflectance accessory and a KRS-5internal reflection plate.6A KRS-5crystal having a thickness of 2mm and an angle of incidence of 45

provides a sufficient number of reflections.

PREPARATIONOFSPECIMEN— Cut 2flat 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-5internal 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 IRspectrophotometer.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 IRspectrum from 4000to 400cm-1.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 12mg 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 á891ñ.

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 1minute.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 1minute.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— PETand PETGbottles 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 0.1mg if the bottle volume is less than 200mL;to the nearest mg if the bottle volume is 200mLor more but less than 1000mL;or to the nearest centigram (10mg)if the bottle volume is 1000mLor more.]Select 10bottles of a uniform size and type,clean the sealing surfaces with a lint-free cloth,and close and open each bottle 30times.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 á671ñ.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:

where Woiis the total weight,in g,of bottle iand its closure,Wtiis the tare weight,in g,of bottle iand its closure,and 9970is 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 á671ñ,and store the bottles at a temperature of 25±2

and a relative humidity of 50±2%.After 168±1hours (7days),record the weight of the individual bottles.Return the bottles to storage for another 168±1hours.After the second 168±1hours,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:

in which Wliis the weight,in mg,of bottle iat 14days,Wfiis the weight,in mg,of bottle iat 7days,7is the test time,in days,after the 7-day equilibration period,and Vais the average bottle volume,in L.

The bottles so tested meet the requirements and are tight containersif the water vapor permeation rate exceeds 100mg per day per Lin not more than 1of the 10test bottles and exceeds 200mg per day per Lin none of them.

Colorant Extraction— Select 3test 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 350to 700nm.Determine,to the nearest 2nm,the wavelength of maximum absorbance.Fill the remaining two test bottles,using 50%alcohol for PETbottles and 25%alcohol for PETGbottles.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 á851ñ),using the corresponding solvent from the glass bottle as the blank.The absorbance values so obtained are less than 0.01for both test solutions.

Heavy Metals,Total Terephthaloyl Moieties,and Ethylene Glycol—

EXTRACTINGMEDIA—

Purified Water— (see monograph).

50Percent Alcohol— Dilute 125mLof alcohol with water to 238mL,and mix.

25Percent Alcohol— Dilute 125mLof 50Percent Alcoholwith water to 250mL,and mix.

n-Heptane.

PROCEDURE— [NOTE—Use the 50Percent Alcohol Extracting Mediumwith PETbottles.Use the 25Percent Alcohol Extracting Mediumwith PETGbottles.]For each Extracting Medium,fill a sufficient number of test bottles to 90%of their nominal capacity to obtain not less than 30mLof extract.Fill a corresponding number of glass bottles with Purified Water Extracting Medium,a corresponding number of glass bottles with 50Percent Alcohol Extracting Mediumor 25Percent Alcohol Extracting Medium,and a corresponding number of glass bottles with n-Heptane Extracting Mediumfor use as Extracting Mediablanks.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 Mediasamples and the glass bottles with the Extracting Mediablanks,and store them at room temperature.Do not transfer the Extracting Mediasamples to alternative storage vessels.

HEAVYMETALS— Pipet 20mLof the Purified Waterextract of the test bottles,filtered if necessary,into one of two matched 50-mLcolor-comparison tubes,and retain the remaining Purified Waterextract in the test bottles for use in the test for Ethylene Glycol.Adjust the extract with 1Nacetic acid or 6Nammonium hydroxide to a pHbetween 3.0and 4.0,using short-range pHpaper as an external indicator.Dilute with water to about 35mL,and mix.

Into the second color-comparison tube,pipet 2mLof freshly prepared (on day of use)Standard Lead Solution(see Heavy Metals á231ñ),and add 20mLof Purified Water.Adjust with 1Nacetic acid or 6Nammonium hydroxide to a pHbetween 3.0and 4.0,using short-range pHpaper as an external indicator.Dilute with water to about 35mL,and mix.

To each tube add 1.2mLof thioacetamide-glycerin base TSand 2mLof pH3.5Acetate Buffer(see Heavy Metals á231ñ),dilute with water to 50mL,and mix:any color produced within 10minutes in the tube containing the Purified Waterextract 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 (1ppm in extract).

Total Terephthaloyl Moieties— Determine the absorbance of the 50Percent Alcoholor 25Percent Alcoholextract in a 1-cm cell at the wavelength of maximum absorbance at about 244nm (see Spectrophotometry and Light-Scattering á851ñ),using the corresponding Extracting Mediumblank as the blank:the absorbance of the extract does not exceed 0.150,corresponding to not more than 1ppm of total terephthaloyl moieties.

Determine the absorbance of the n-Heptaneextract in a 1-cm cell at the wavelength of maximum absorbance at about 240nm (seeSpectrophotometry and Light-Scattering á851ñ),using the n-Heptane Extracting Mediumblank as the blank:the absorbance of the extract does not exceed 0.150,corresponding to not more than 1ppm of total terephthaloyl moieties.

ETHYLENEGLYCOL—

Periodic Acid Solution— Dissolve 125mg of periodic acid in 10mLof water.

Dilute Sulfuric Acid— To 50mLof water add slowly and with constant stirring 50mLof sulfuric acid,and allow to cool to room temperature.

Sodium Bisulfite Solution— Dissolve 0.1g of sodium bisulfite in 10mLof water.Use this solution within seven days.

Disodium Chromotropate Solution— Dissolve 100mg of disodium chromotropate in 100mLof 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 1µg per mL.

Test Solution— Use the Purified Waterextract.

Blank— Use the Purified Water Extracting Mediumblank.

Procedure— Transfer 1.0mLof Standard Solutionto a 10-mLvolumetric flask.Transfer 1.0mLof Test Solutionto a second 10-mLvolumetric flask.Transfer 1.0mLof Purified Water Extracting Mediumblank to a third 10-mLvolumetric flask.To each of the three flasks,add 100µLof Periodic Acid Solution,swirl to mix,and allow to stand for 60minutes.Add 1.0mLof Sodium Bisulfite Solutionto each flask,and mix.Add 100µLof Disodium Chromotropate Solutionto each flask,and mix.[NOTE—All solutions should be analyzed within one hour after addition of the Disodium Chromotropate Solution.]Cautiously add 6mLof 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 acidto volume,and mix.Concomitantly determine the absorbances of the solutions from the Standard Solutionand the Test Solutionin 1-cm cells at the wavelength of maximum absorbance at about 575nm (seeSpectrophotometry and Light-Scattering á851ñ),using the solution from the Purified Water Extracting Mediumblank as the blank:the absorbance of the solution from the Test solutiondoes not exceed that of the solution from the Standard solution,corresponding to not more than 1ppm of ethylene glycol.