M. Pharm Quality Assurance-2-T (2009-2010) Title:- Evaluation of Packaging Materials Exp.No.:Roll No:Date:Page No.

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AIM: To Evaluate Packaging Materials (Glass, Rubber Closures, and Plastics) A) Glass: References: USP-NF 2007, Page No.1176; Pharmaceutical Packaging Technology, Edited by D. A .Dean, Page No.148,149. Requirements: Apparatus: Ampoules, Glass bottles, conical flask, Beakers, Measuring cylinder, Burette Equipments: Autoclave Reagents: High purity water, Methyl red indicator, Acetone, 0.02N H2SO4 Theory: The exact structure of glass is not clearly known. It can be formed by mixing together various inorganic substances which on heating give a homogeneous molten mass. On cooling this does not arrange itself into crystal pattern but becomes a supercooled liquid in which ultimately the state of flow has ceased to exist. When most liquids cool, the transition from a liquid to a solid state occurs abruptly at a specific temperature with the simultaneous evolution of heat. This freezing process depends on the formulation of crystal nuclei. However, certain liquids increase in viscosity with cooling and this hinders the formation of nuclei. Since, in the case of glass, nuclei are not formed, it remains in a super-cooled state until a solid state is reached. The properties may be varied according to the raw materials used. Sand, which is the main ingredient and consists mostly of silicon dioxide, requires very high melting temperatures (1700C+). If certain fluxing agents such as soda ash (sodium carbonate) are added, the melting temperature reduces to around 800C but the resulting substance, widely known as water glass (Na2SiO3), is soluble in water. If a stabiliser such as limestone (CaCO3) is added, conventional (insoluble) glass is obtained. Normal alkali glass is basically fifteen parts sand, five parts soda ash and four parts limestonethe mixture being heated to about 1500C. At this temperature the three ingredients gradually react. To help melting, cullet or broken glass (of the same type) is added to the basic raw materials. Early glasses had a green tinge due to the presence of iron. Today virtually colourless glass is produced by using decolourisers such as selenium or cobalt oxide. For each 10% of cullet added, energy (heat) can be reduced by approximately 2.5%. Compared to plastics, glass additives cover fewer purposes, i.e. colourants, opacifiers, decolourisers, modifiers, and stabilisers. Certain additional technical ingredients may be employed, e.g. alumina to improve durability. Coloured glass may be obtained by solution (glass acts as a solvent for certain oxides) or by colloidal dispersion: The following are examples. Amber: May vary from light yellowish to deep reddish brown. Obtained by the addition of carbon and sulphur or iron and manganese dioxide. Yellow: Compounds of cadmium and sulphur. Blue: Various shades of blue, cobalt oxide or occasionally copper (cupric) oxide. Green: A range of greens can be achieved by varying additions of iron oxide, manganese dioxide and chromium dioxide. _______________________________________________________________________ School of Pharmacy and Technology Management.

M. Pharm Quality Assurance-2-T (2009-2010) Title:- Evaluation of Packaging Materials Exp.No.:Roll No:Date:Page No.:-

Actinic green is the name usually given for glass of a bright emerald green which absorbs the ultraviolet wavelength of light. Opal: Involves fluorides or phosphates. Colourless white flint soda glass has the following composition range: silica (SiO2) 5975%, calcium oxide (CaO) 512%, sodium oxide (Na2O) 1217%, alumina (Al2O3) 0.53.0%, and possibly small quantities of ferric oxide, titanium dioxide, potassium and magnesium oxide. Type I glass: Neutral or borosilicate type glass has the following composition range: silica (SiO2) 6672% alumina (Al2O3) 410%, sodium oxide (Na2O) or potassium oxide (K2O) 710%, boric oxide (B2O3) 911%, calcium oxide (CaO) 15%, barium oxide (BaO) 03.0%, and possibly small quantities of magnesium oxide, ferric oxide and titanium dioxide. These types of glass require a higher working temperature, have a narrower working range and hence are more difficult to process (17001750C). Borosilicate glasses with high boric oxide contents (over 12%) show reduced chemical resistance, and are more prone to atmospheric weathering. Type I surface treated glass is also available with certain smaller tubular containers. Type II glass: This is a soda glass which has had the surface treated, usually by a process of sulphating or sulphuring. In the former a pellet of ammonium sulphate is dropped into each bottle before it passes passes through a heated tunnel known as the lehr. This then sublimes and coats the inside of the glass. Sulphuring usually involves sulphur dioxide being injected into the container while it is within the lehr. Evidence suggests that the ammonium sulphate process confers better resistance than sulphuring. In all these treatments the excess surface alkalinity is neutralised by forming a coating of sodium sulphate which is soluble in water. All treated containers must therefore be washed prior to use in order to remove the soluble coating which shows a bloom. Type III glass: These containers are usually of sodalime-silica glass with only moderate hydrolytic resistance. They are generally suitable for non-aqueous preparations for parenteral use, for powders for parenteral use (except for freeze-dried preparations) and for preparations not for parenteral use. Tests performed on different glasses: The tests on glass are designed to meet certain objective standards required for the containers that are used for storage and packaging even for short periods of time. A container intended to provide protection from light or offered as a light -resistant container meets the requirements for light transmission , where such protection or resistance is by virtue of the specific properties of the material of which the container is composed, including any coating applied thereto. Containers composed of glass meet the requirements for Chemical resistance. The test on Chemical resistance is designed to determine the resistance of water attack of new 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. The water attack test is mainly used for treated soda lime glass. Glass is also tested for the level of arsenic content. The powdered _______________________________________________________________________ School of Pharmacy and Technology Management.

M. Pharm Quality Assurance-2-T (2009-2010) Title:- Evaluation of Packaging Materials Exp.No.:Roll No:Date:Page No.:-

glass test is mainly used for highly resistant soda lime glass, soda lime glass and general purpose soda lime glass. Type 1 General Description Highly resistant,Borosilicate glass Treated sodalime glass Sodalime glass General purpose sodalime glass Type of test Powdered glass test Water attack test Powdered glass test Powdered glass test Limits Size All

ml of 0.02N H2SO4 1.0 ml

3 NP

100ml or less Over 100ml All All

0.7 0.2 8.5 15

Procedure : Powdered glass test: 1) Rinse thoroughly the container with purified water.Dry them. 2) Crush the containers into small fragments of about 25mm in size. 3) Divide them into 3 portions each of 100 gm of crushed glass. 4) Place one of the portion in the mortar pestle.Crush it. 5) Arrange the sieves with 20 on top and 50 on bottom with 40 in centre. 6) Keep crushed glass on sieve 20.Repeat same procedure for remaining two portions. 7) Remove the glass from 20,40 sieves,crush again.shake for 5 minutes. 8) Transfer portion retained on sieve 50 to glass dish which should weigh in excess of 10gm. 9) Pass magnet through it to remove iron particle.Transfer it to 250ml conical flask. 10) Wash with 30ml portions of acetone 6 times.dry for 20 min. at 140C. 11) Take 10gm of specimen to 250ml conical flask which is previously digested with high purity water in bath at 90C for atleast 24 hour or at 121C for 1 hour. 12) Add 50ml high purity water to this flask and to one similarly prepared to provide a blank. 13) Cap all flasks with borosilicate beaker in inverted position. 14) Place containers in the autoclave and close it.adjust temperature to 121C. 15) Hold this temperature for 30 min.Reduce temperature of autoclave. 16) Cool the flask in running water.Decant the water from flask into a suitably cleaned vessel. 17) Wash the residual powdered glass with four 15ml portions of high purity water. 18) Add decanted washings to the main portion. 19) Add 5 drops of methyl red solution and titrate immediately with 0.02N H2SO4 20) Perform blank using 50ml high purity water.

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M. Pharm Quality Assurance-2-T (2009-2010) Title:- Evaluation of Packaging Materials Exp.No.:Roll No:Date:Page No.:-

Water Attack Test: 1) Rinse thoroughly 3 or more containers selected at random twice with high purity water. 2) Fill each container to 90% of its overflow capacity with high purity water. 3) Cap all the containers with borosilicate beaker. 4) Place containers in autoclave and close it.adjust temperature to 121C. 5) Hold this temperature for 60 minutes. Reduce temperature of autoclave. 6) Remove contents of all the containers previously cleaned with high purity water. 7) Take 100ml of sample and add 5 drops of methyl red solution and titrate immediately with 0.02N H2SO4 while warm. 8) Perform blank using 100ml of high purity water.

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M. Pharm Quality Assurance-2-T (2009-2010) Title:- Evaluation of Packaging Materials Exp.No.:Roll No:Date:Page No.:-

B) Rubber Closures: Reference: Indian pharmacopoeia 2007, pg no. 371-372. Requirements: 1. 2. Apparatus: Glass beaker, aluminium foil, syringe and needle. Equipment: Autoclave and vacuum desiccators.

Reagents: Water for injection, 0.1% w/v solution of methylene blue

Theory: A closure for a container for an aqueous parenteral preparation or for a sterile powder is a packaging component which is in direct contact with the drug. A rubber closure is made of material obtained by vulcanisation (cross-linking) of elastomers with appropriate additives. The elastomers are produced from natural or synthetic substances by polymerisation, polyaddition or polycondensation. The nature of the principal components and of the various additives such as vulcanisers, accelerators, stabilising agents, pigments, etc. depends on the properties required for the finished closure. Rubber closures are used in a number of formulations and consequently different closures possess different properties. The closures chosen for use with a particular preparation should be such that the components of the preparation in contact with the closure are not adsorbed onto the surface of the closure to an extent sufficient to affect the product adversely. The closure should not yield to the product substances in quantities sufficient to affect its stability or to present a risk of toxicity. The closures should be compatible with the preparation for which they are used throughout the shelf-life of the product. It is impracticable to devise a set of standards which, if complied with, will ensure the compatibility of any closure with the preparation for which it is to be used. A compatibility test has, therefore, to be carried out before a rubber mix is approved. The user of the closures must obtain an assurance from the supplier that the composition of the closure does not vary from supply to supply and that it is identical to that of the closure used during compatibility testing. When the user is informed of changes in the composition,

compatibility testing must be repeated, totally or partly depending on the nature of the changes. The following test procedures apply to rubber closures which comprise wads (flat rubber discs), plugs (with or without skirt or flange) and caps (rubber covers held in position on the outsides of the _______________________________________________________________________ School of Pharmacy and Technology Management.

M. Pharm Quality Assurance-2-T (2009-2010) Title:- Evaluation of Packaging Materials Exp.No.:Roll No:Date:Page No.:-

containers by the tension of the rubber) so as to form with their appropriate seals an effective barrier against micro-organisms after sterilisation. Identification of the type of rubber used for closures is not covered in the following tests. The tests given distinguish elastomer and non-elastomer closures but do not differentiate the various types of rubber.

Description: Rubber closures are elastic and either translucent or opaque; the colour depends on the additives used. They are homogeneous and practically free from flash and adventitious materials such as fibres, foreign particles and adhering rubber pieces.

Preparation of samples: Wash the closures by agitation in a 0.2 per cent w/v solution of an anionic surface-active agent for 5 minutes at room temperature. Rinse five times with water, place a number of the washed closures corresponding to a surface area of about 100 cm 2, in a suitable container of borosilicate glass or inert material, add 200 ml of water per 100 cm2, surface area of the closures and weigh. Cover the mouth of the container with aluminium foil or a borosilicate glass beaker and heat in an autoclave so that a temperature of 119 to 123 is reached within 20 to 30 minutes and maintain at that temperature for 30 minutes. Cool to room temperature over about 30 minutes and make up to the original weight with Water for injection. Shake and immediately separate the solution from the closures by decantation (Solution A). Prepare a blank in the same manner using 200 ml of water for injection. Dry the treated closures at 64 to 66 at a pressure not exceeding 0.7 kPa for 24 hours.

Evaluation tests:

Fragmentation test: This test is applicable to closures intended to be pierced by a hypodermic needle. For closures that are intended to be used for aqueous preparations, place a volume of water corresponding to the nominal volume minus 4 ml in each of 12 clean vials, close the vials with the prepared closures secure with a cap and allow to stand for 16 hours. For closures that are intended to be used for dry _______________________________________________________________________ School of Pharmacy and Technology Management.

M. Pharm Quality Assurance-2-T (2009-2010) Title:- Evaluation of Packaging Materials Exp.No.:Roll No:Date:Page No.:preparations, close 12 clean vials with the prepared closures. Using a lubricated, long-bevel (bevel angle of 10 to 14) hypodermic needle with an external diameter of 0.8 mm (21 SWG) fitted to a clean syringe, inject 1 ml of water into the vial and remove 1 ml of air; carry out this operation 4 times for each closure, piercing each time at a different site. Use a new needle for each closure and check that the needle is not blunted during the test. Pass the liquid in the vials through a filter with a nominal pore size of 0.5 m. Count the number of fragments visible to the naked eye. The total number of fragments is not more than 10 except in the case of butyl rubber closures where the total number of fragments is not more than 15.

Self-Sealability: This test is applicable to closures intended to be used with multidose containers. Fill 10 suitable vials with water to the nominal volume, close the vials with the prepared closures and secure with a cap. For each closure, use a new hypodermic needle with an external diameter of 0.8 mm (21 SWG) and pierce the closure 10 times, piercing each time at a different site. Immerse the vials upright in a 0.1 percent w/v solution of methylene blue and reduce the external pressure by 27kPa for 10 minutes. Restore the atmospheric pressure and leave the vials immersed for 30 minutes. Rinse the outside of the vials. None of the vials contains any trace of coloured solution.

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M. Pharm Quality Assurance-2-T (2009-2010) Title:- Evaluation of Packaging Materials Exp.No.:Roll No:Date:Page No.:-

C) Plastics: Reference: Indian Pharmacopoeia 1996 Theory: A plastic container for pharmaceutical use is a plastic article which contains or is intended to contain a pharmaceutical product and is, or may be, in direct contact with it. The closure is a part of the container. Plastic containers and closures for pharmaceutical use are made of materials in which may be included certain additives; these materials do not include in their composition any substance that can be extracted by the contents in such quantities as to alter the efficacy or the stability of the product or to present a risk of toxicity. The most commonly used polymers are polyethylene (with and without additives), polypropylene, poly(vinyl chloride), poly(ethylene terephthalate) and poly(ethylene-vinyl acetate). The nature and amount of the additives are determined by the type of the polymer, the process used to convert the polymer into the container and the intended purpose of the container. Additives may consist of antioxidants, stabilisers, plasticisers, lubricants, colouring matter and impact modifiers. Antistatic agents and mould-release agents may be used only for containers for preparations for oral use or for external use for which they are authorised. Acceptable additives are indicated in the type specification for each material described in the Pharmacopoeia. Other additives may be used provided they are approved in each case by the competent authority responsible for the licensing for sale of the preparation. For selection of a suitable plastic container, it is necessary to know the full manufacturing formula of the plastic, including all materials added during formation of the container so that the potential hazards can be assessed. The plastic container chosen for any particular preparation should be such that: the ingredients of the preparation in contact with the plastic material are not significantly adsorbed on its surface and do not significantly migrate into or through the plastic, the plastic material does not release substances in quantities sufficient to affect the stability of the preparation or to present a risk of toxicity. Using material or materials selected to satisfy these criteria, a number of identical type samples of the container are made by a well-defined procedure and submitted to practical testing in conditions that reproduce those of the intended use, including, where appropriate, sterilisation. In order to confirm the compatibility of the container and the contents and to ensure that there are no changes detrimental to the quality of the preparation, various tests are carried out such as verification of the absence of changes in physical characteristics, assessment of any loss or gain through permeation, detection of pH changes, assessment of changes caused by light, chemical tests and, where appropriate, biological tests. The method of manufacture is such as to ensure reproducibility for subsequent bulk manufacture and the conditions of manufacture are chosen so as to preclude the possibility of contamination with other plastic materials or their ingredients. The manufacturer of the product must ensure that containers made in production are similar in every respect to the type samples. For the results of the testing on type samples to remain valid, it is important that: there is no change in the composition of the material as _______________________________________________________________________ School of Pharmacy and Technology Management.

M. Pharm Quality Assurance-2-T (2009-2010) Title:- Evaluation of Packaging Materials Exp.No.:Roll No:Date:Page No.:-

defined for the type samples, there is no change in the manufacturing process as defined for the type samples, especially as regards the temperatures to which the plastic material is exposed during conversion or subsequent procedures such as sterilisation, scrap material is not used. Recycling of excess material of well-defined nature and proportions may be permitted after appropriate validation. Subject to satisfactory testing for compatibility of each different combination of container and contents, the materials described in the Pharmacopoeia are recognised as being suitable for the specific purposes indicated, as defined above. Evaluation Tests: 1) Leakage Test(Non injectable and Injectable): Fill ten container with water and fit the closure. Keep them inverted at room temperature for 24 hours and observe any signs of leakage from any container. 2) Water vapooure permeability test (Injectable preparations): Fill 5 containers with nominal volune of water and seal them properly. Weigh each container and allow to stand for 14 days at RH of 605% at 20-25C. Reweigh the containers and observe the loss of weight in each container which should not be more than 0.2%

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M. Pharm Quality Assurance-2-T (2009-2010) Title:- Evaluation of Packaging Materials Exp.No.:Roll No:Date:Page No.:-

Observations: A) For Glass: For Powdered glass test: Volume of 0.02N H2SO4 consumed(x): 4 Volume of 0.02N H2SO4 consumed(Blank) (y): 5 y-x= 1 For Water attack test: Volume of 0.02N H2SO4 consumed(x): 2 Volume of 0.02N H2SO4 consumed(Blank)(y): 2.2 y-x=0.2 Sr.No. Type Of Test Observation (ml of 0.02N H2SO4) 1ml 0.2ml Limits (ml of 0.02N H2SO4) NMT 1ml NMT 0.7ml Results

1 2

Powdered glass test Water attack test

Pass Pass

B) For Rubber Closure: Evaluation test Fragmentation test Observation Greater fragments than 25 Limits Total number of Inference Fail

fragments is not more than 10 except in the case of butyl rubber closures where the total number of fragments is not more than 15.

Self-Sealibility test

One bottles

coloured

None

of

the

vials

Fail

contains any trace of coloured solution.

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M. Pharm Quality Assurance-2-T (2009-2010) Title:- Evaluation of Packaging Materials Exp.No.:Roll No:Date:Page No.:-

C) For Plastics: Sr.No. 1 Test Leakage Test Observation No leakage Limit No leakage from any single container NMT 0.2% wt loss Results Pass

Water vapooure permeability test

Wt. loss 0.1%

Pass

Results: A) Volume of 0.02N H2SO4 consumed by glass in powdered glass and water attack test were within the limits, so glass containers passes the test B) Fragments and self sealability for rubber closures were not within the limits, so they dont pass the test. C) Leakage and weight loss for plastic containers were within the limits, so they pass the test.

Conclusions: From above observations and results it can be concluded that glass and plastic containers are of good quality while rubber closures does not have good quality.

DATE:

GRADE:

SIGN:-

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