Decisive Brunt of Physical and Chemical Exploration on Pharmaceutical Sterile Containers

 

Om Bagade *, Mangal Sable, Madhuri Dhamale, Reshma Tathe

PES’s Modern College of Pharmacy (For Ladies), Moshi, Pune-412105

*Corresponding Author E-mail: ombagadescop@gmail.com

 

ABSTRACT:

Introduction: Packaging of pharmaceutical formulation is one of the key important point consider during the manufacturing of such sterile product. Plastic container should not interact with physicochemical properties of formulation thus its evaluation parameters are crucial. While selecting appropriate container for formulation   dimension, size, solubility, elemental analysis must be check. Unless it will be difficult task to opt for evaluation of an appropriate container. Objective: The main objective of the present study was to investigate the physicochemical parameters and to ascertain the quality attributes within the best packaging materials for sterile plastic containers.  Results: Depending upon the different findings the result was furnished as mentioned. Average dimension of infusion bottle containing total height of bottle (body with cap), total height of body (body without cap), total height of cap was determined as 196.66mm (S.D. ± 0.58), 195mm (S.D. ±1 ), 30mm (S.D. ± 1) respectively. Average dimension of ophthalmic bottle containing total height of bottle (body with cap), total height of body (body without cap), total height of cap was determined 73mm (S.D. ±1 ), 67mm (S.D. ±1 ), 23.33mm (S.D. ±0.577 ) respectively. Average overflow volume for infusion and ophthalmic bottle was found to be 549.33ml (S.D. ± 1.53) and 16ml (S.D. ±1) respectively. Elemental analysis   for Halogen, Nitrogen, Sulphur was absent in both the containers. Insolubility was observed in solvents like toluene, ethyl acetate, carbon tetrachloride, 1,4-dioxane etc. Conclusion: Thus, Pharmaceutical packaging should look into concerned issues like child safety, correct dosage, patient traceability, tampering and diversion of pharmaceutical products.

 

KEYWORDS: Packaging, Height, Thickness, Dimensions, Solubility.

 

 


INTRODUCTION:

Package engineering and Packaging Science, is a broad topic ranging from design conceptualization to product placement. Package design and development are often thought of as an integral part of the new product development process. Quality control of a packaging component starts at the design stage.

 

Packaging is a critical tool in the pharmaceutical industry for product delivery and regulatory compliance, many pharmaceutical companies will do all their packaging within a contamination free environment or Clean room. The terms active packaging, intelligent packaging, and smart packaging refer to packaging systems used with foods, pharmaceuticals, and several other types of products. Packaging of materials is an integral part of any pharmaceutical industry. Packaging affects the quality stability and identification of drug product. Packaging provide an adequate degree of protection, minimize the loss of constituents and should not interact physically or chemically with the contents in a way that will alter their quality to an extent beyond the limits given in the individual monograph, or present a risk of toxicity [1-5].

 

Pharmaceutical packaging is the means of providing protection, presentation, identification, information and convenience to encourage compliance with a course of therapy [6]. The commonly used packaging materials are Container, Closure, Carton or Outer and Box. The containers may be made of glass, plastic, metal or paper. The material for closure may include Cork, Glass, Plastic, Metal or rubber. There are various tests for determination of quality, integrity and compatibility of packaging materials. The specification and requirement of quality testing depends on type of pharmaceutical materials used. The requirement of packaging material testing is set according to specification of regulatory agencies like WHO GMP, USFDA and ICH guidelines [7].

 

PLASTIC TESTING - PHYSICAL PROPERTIES:

Coefficient of Friction:

A material’s coefficient of friction is the ratio of the force acting between the material surfaces to the pulling force. Measurements are usually made material surface against itself, with a lower friction coefficient indicating a lower resistance [3].

Friction has two components; dynamic and static:

·        Dynamic friction (or kinetic friction) is the force needed to maintain motion between two surfaces.

·        Static friction is the force needed to create movement between two surfaces.

 

The coefficient of friction is a critical property of all materials which run on high speed manufacturing lines; particularly those in the printing and packaging industry. Coefficient of friction is routinely specified for plastic flow wrapping films.

 

Slip coefficient = 1/coefficient of friction:

A high coefficient of static friction is often desirable for sacks which need to resist sliding when stacked.

 

Density:

The density of plastic films is determined by placing test specimens in water and adding isopropanol (or other liquid if sample density > 1 kg/m3) until the plastic sample achieves a neutral buoyancy in the solution. The density of plastic films is tested to British standard and International standard ISO 1183.

 

The density of plastic and other non-absorbent materials such as glass in finished form can be determined by weighing a sample in air, and in a test liquid, using a balance and   pan straddle.

 

 

Flex Resistance:

The flex resistance or flex durability of a plastic film is a measure of its toughness, specifically its resistance to pin holing when subjected to flexing abuse [3]. A cylinder of the film is repeatedly flexed under specified conditions using a Gelbo flex tester and the sample inspected for pinholes after a set number of full or partial flex cycles.

Alternatively, in the case of barrier films, the oxygen or water vapor transmission rates can be tested after flexing. A breakdown in the metallization, oxide coating or foil layer will often compromise the barrier performance of a plastic film laminate long before a pinhole through the structure is seen [1].

 

Free Shrinkage:

Free shrinkage tests are used to evaluate the unrestrained linear heat shrinkage of thin plastic films for packaging applications e.g. shrink wrap and shrink sleeve materials.

Heat shrinkage is determined by comparing the dimensions of pre cut samples before and after heating in an oil bath, typically set at 90°C for polyvinyl chloride (PVC) or 115°C for low density polyethylene (LDPE).

 

Film Thickness [1]

1.    Spot Thickness:

The thickness of a sample of plastics film or sheeting can be measured by mechanical scanning using a digital deadweight micrometer. This method is used to look at the thickness uniformity across a film sample.

 

2.    Gravimetric Thickness and Yield:

The gravimetric thickness is calculated from measurements of mass, area and density of a sample. It can provide a more accurate determination of the average thickness of a plastic film and is used in particular for measuring the thickness of embossed sheeting.

 

Plastic film yield is the area per unit mass of a film roll. The film yield determines the number of packs that can be produced from a roll weight.

 

Lamination Bond Strength:

The lamination bond strength of flexible laminates is determined in accordance with ASTM F904 - essentially the same test procedure as that described in ASTM F88 used to determine seal strength. After initiating de-lamination between the relevant film plies, the average force required to peel the two "legs" of the test piece is recorded. A static loading methodology is also used when the issue relates to long term creep failure. Although usually determined at ambient laboratory conditions, Smithers Pira is able to determine such tensile properties at sub-ambient or elevated temperatures using a "hot box" attachment to the tensile test apparatus [1].

 

Puncture Resistance:

Puncture resistance is a measure of the maximum force or energy required to penetrate a material. This type of biaxial stress is seen by packaging films when packing hard protuberances such as pelleted dry foods and frozen vegetables.

 

Seal Strength:

Seal strength is related to the pack opening force and a measure of the consistency of the packaging process. The maximum seal force, average peel force and total energy absorbed in peeling the seal can be recorded.

 

The strength of seals in flexible barrier materials is also routinely measured as part of the validation exercise on medical device packaging. Seal strength tests are typically performed on pouches and lidded trays as a measure of heat seal quality. Dynamic seal strength testing is made in accordance with ASTM F88. The resistance to log term creep separation of the seal is assessed using a static loading.

 

Tear Resistance:

There are two types of plastic tear strength test:

·        Elmendorf Tear (high speed pendulum  test)

·        Trouser Tear (low speed using standard tensile test apparatus)

 

1.      Elmendorf Tear:

The test piece is clamped and a cut introduced such that when the pendulum is released, a tear is propagated from the cut at high speed. The tear resistance is measured as the average force in mN propagating the tear to the edge of the test piece.

 

2.      Trouser Tear:

A straight cut is introduced into a rectangular sample, parallel to the long edge. The sample is then mounted in the jaws of a tensile test apparatus, one "leg" clamped in the lower jaw and one "leg" clamped in the upper jaw. The average force required to tear the sample is measured.

 

Tensile Properties:

Tensile testing is used to characterize and compare the performance of plastic materials separately in machine and cross (transverse) material directions. The tensile properties of plastics are measured on either of two Tinius Olsen universal tensile test machines, including a hot box facility allowing tests to be made over a wide range of temperatures from -50°C to +150°C [1].

 

Packaging is the art, science and technology of enclosing or protecting products for distribution, storage, sale, and use. Packaging also refers to the process of design, evaluation, and production of packages [8].

 

Packaging means a collection of different packaging materials which encase the pharmaceutical product from the time of manufacturing to the end of the user. Encasing of drugs is important for life-saving drugs, medical devices, medical treatments, and new products like medical nutritionals [9].

 

Advanced packaging methods shows a couple of sorts of packaging materials taken after by bleeding edge packaging methods. Packaging materials are picked in light of the particular support sorts. Oxygen-sensitive sustenances require packaging with limit properties that can neutralize squander as a result of oxidation. Plastics have been used for a long time, yet down to earth and green traditions recommend managing without plastics for various materials that are biodegradable and all around arranged [10].

 

The Code of federal regulation, Title 21, Drug current good manufacturing practice in manufacture, Processing, Packaging or Holding requires that containers, closure and component parts that they are not reactive, additive or absorptive to an extend that significantly affect the identity, strength, quality or purity of the drug and furnish adequate protection against its deterioration or contamination. Factors responsible for plastic properties such as Chemical structure, Molecular weight, Crystallinity and orientation, Cross-linking, Addition of other agents [11].

 

Drug plastic consideration:

In selecting a plastic container consideration must be given to:

·        Composition of material.

·        Its mechanical and chemical properties.

·        Its ease of fabrication and printability.

·        Requirement of rigidity and flexibility.

·        Acceptance of plastic ingredients by FDC.

 

Depending on the type of plastic the total constituents may include the following: Basic polymer, residual monomer, plasticizers, accelerators, modifiers, stabilizers, fillers, colorants, antistatic agent, slip or anti-slip additives, U.V absorbers, lubricants, antioxidants [12].

 

Validation of sterility:

Pharmaceutical preparation required to be sterile must undergoes test to confirm the absence of the microorganisms. The USP contain monographs and standards for biologic indicators of sterilization. They may be use to monitor a sterilization cycle and/or periodically to revalidate the process.

 

 

 

Packaging, Labeling and Storage of Injection:

Injection are placed either in single dose container (quantity of sterile drug intended for parenteral administration as a single dose; cannot be resealed with assurance of sterility has been maintained) or multiple dose container (withdrawal of successive portion of contents without changing strength, quality or purity of remaining portion). Some of injectable products are package in prefilled syringes, with or without special administration devices. To keep unwanted particles out of parenteral products, a number of precaution must be taken during manufacture, storage and use of products. After the containers are filled and hermetically sealed, they are visually or automatically inspected for particulate matter. Having passed inspection, the product may be labeled [13].

 

MATERIAL AND METHOD [1]:

MATERIALS:

Toluene, Ethyl acetate, 1,4-Dioxane, Carbon tetrachloride, Ferrous sulphate, Lead acetate, Dil. Nitric acid, Acetic acid, Silver nitrate. All chemical used were of   analytical grade.

 

METHODS:

PHYSICAL EVALUATION OF PLASTIC CONTAINER:

A.     Infusion And

B.     Ophthalmic Plastic Bottles:

Experimental Work:

By visual inspection various parameter like colour, finishing, shape of container were checked.

 

1. Color of container: 

Determine visually by naked eyes.

 

2. Finishing:

To check the inner & outer surface of container visually.

 

3. Shape:

To identify shape of container through visual observation.

 

4. Dimension: 1cm =10mm (unit)

Various dimensions with respect to infusion as well as ophthalmic bottle were checked by using Vernier caliper (in mm).wherever, Vernier caliper is not suitable, for them dimensions were measured by using ruler scale (in mm).

 

Reading of dimensions of bottle (body with cap), dimensions of body (body without cap), dimensions of cap, height of ophthalmic container with cap and without cap, dimensions of neck where checked.

 

 

 

5. Overflow volume:

Fill containers up to their overflow volume with water and then transfer to measuring cylinder and measure the volume.

 

6. Number of threads:

For number of thread determination, while burning of bottle part whether complete or incomplete thread were determined.

 

CHEMICAL EVALUATION OF PLASTIC CONTAINER:

A.     Infusion and

B.     Ophthalmic Plastic Bottles:

 

1.      Elemental analysis:

For this elemental analysis test sodium fusion extract was prepared.

 

Procedure for preparing sodium fusion extract:

Take a small piece of sodium in sodium infusion tube and heat gently till sodium melts. Then add 0.03-0.04gm of sample to molten sodium and heat sodium fusion tube strongly to become red hot. Plunged into a beaker containing 10-15 ml of distilled water then heat content to boiling and filter. Use filtrate for further test.

 

  I.      Test for Nitrogen:

To 3 ml of filtrate, add 0.3gm of ferrous sulphate and boil the solution. Observe for prussian blue colour.

 

 II.     Test for Sulphur:

To 1-3ml of filtrate, add acetic acid and few drops of lead acetate. Observe for black or brown precipitate

 

Test for Halogen:

III.    To 2-3ml of filtrate, dilute nitric acid was added, boiled, cooled and add few drops of silver nitrate. Observe for any white precipitate.

 

2.      Heating test:

In this test, place a small piece (2 x 2mm) of given sample on stainless steel spatula and heat the spatula in flame.

 

3.      Solubility Test:

In this test, take solvent Toluene, Ethyl acetate, 1,4-Dioxane, Carbon tetrachloride in individual four test tubes and add a piece of given sample in each test tube. Check for solubility.

 

RESULT AND DISCUSSION:

A.     Infusion Bottle:

Advantages of plastic container over other container are like low in cost, light in weight, durable, pleasant to touch, leak proof, unbreakable, odorless and inert to most chemicals, able to retain their shape throughout their use.

Transfer of gases, liquid, vapors through plastic packaging material have an adverse effect on shelf life of drug. They should not allow any loss of product during leakage, spoilage or permeation [2].

 

Physical Evaluation:

1.      Colour of container      -Colourless

2.      Finishing                       -Plain inner surface

3.      Shape                            -Elongated cylindrical body

4.      Dimension of bottle-  

 

Size of container must be selected according to size of preparation.

 

Different attributes of the dimensions of the bottle was studied which is mention in the following table:

 

Table No. 1 –Dimension of infusion bottle (body with cap)

Sample no-

Total height

(mm)

Outer diameter

(mm)

Inner diameter

(mm)

1

196.66±0.58

85.33±0.58

84±1

 

5.    Dimension of body:

Different attributes of the dimensions of body was studied which is mention in following table:

 

Table No.2- Dimension of   infusion bottle body (body without cap)

Sample no-

Total height of the body

(mm)

Outer diameter of the body

(mm)

Inner diameter of the body

(mm)

Diameter of base

(mm)

1

195±1

85.33±0.58

24.67±0.58

69.67±0.58

 

6. Dimensions of cap:

Different attributes of dimension of cap was studied which is mention in following table:

 

Table No.3-   Dimension of infusion bottle cap

Sample no-

Total height

(mm)

Outer diameter

(mm)

Inner diameter

(mm)

Thickness of cap

(mm)

1

30±1

23.33±1.52

22.67±0.58

2.33±0.58

 

7. Height of infusion bottle:

Different attributes of the dimensions of the height of ophthalmic bottle was studied which is mention in the following table:

 

Table No .4- Height of infusion bottle

  Sr. no-

With cap (mm)

Without cap (mm)

1

71±1

7.33±0.58

 

8. Dimension of neck:

Different attributes of the dimensions of the neck was studied which is mention in the following table.

 

Table No.5- Dimension of infusion bottle neck

Sample no-

Outer diameter of neck

(mm)

Inner diameter of neck

(mm)

1

26.33±1.15

23±1

 

 

9. Overflow volume:

Table No.6- Overflow volume of infusion bottle

Sample no:

Overflow volume(ml)

1

549.33±1.53

 

10. Number of threads:

Complete –one

Incomplete –not observed                                  

 

Chemical Evaluation:

Chemical incompatible substances can alter appearance of drug product and plastic container. Here we performed elemental analysis for   Nitrogen, Sulphur, Halogen, so as there was no seen any such elemental contamination in infusion bottles.

 

1.      Elemental Analysis:

Observation for test conducted on sodium fusion extract of infusion plastic container:

 

Table No.7- Elemental analysis of infusion bottle

Sample no.

Test

observation

Inference

1

Test for Nitrogen

Prussian blue colour is not observed.

Nitrogen is absent

2

Test for Sulphur

No black or brown precipitate observed.

Sulphur is absent

3

Test for Halogen

No white precipitate was observed.

Halogen is absent

 

2.      Heating Test:

By this heating test, we come to know that whether container material is inflammable or not. Its ignition speed (large or small). On ignition there should be no any specific evolution of gases, by this control harmful impact on environment.

 

Table No.8- Heating test for infusion bottle

Sr. No.

Test

Observation

1

Inflammation

observed

2

Ease of ignition

Slow

3

Self extinguishing

observed

4

Evolution of gases

No specific gas was evolved

5

Colour of flame

Yellow

6

Formation of droplets

Not observed

7

Sooty flame

Not observed

 

3.       Solubility :

Many of solvent used in formulation may leach out of container and lead to contamination chances, so that its necessary to view solubility of solvent on infusion containers.

 

Result of solubility found as per following:

Table No.9- Solubility effect of different solvent on infusion bottle

Sr. No.

Solvent used

Observation

1

Toluene

Insoluble

2

Ethyl acetate

Insoluble

3

1,4-Dioxane

Insoluble

4

Carbon Tetrachloride

Insoluble

 

 

B.   Ophthalmic Plastic Container:

Currently almost all commercially available ophthalmic product are packaged in plastic container. Having advantages like ease of use, less spillage, little breakage. They must be maintain product sterility until the time of use and must be prevent contamination of content.

 

Physical examination: 

Table No.1 – Physical examination parameter of ophthalmic plastic container

Sr. no

Test

Observation

1.

Color of container

White opaque

2.

Finishing

Inner plain surface, smooth

3.

Shape

Elongated cylindrical body

 

Dimensions:                        

Size of container must be selected according to size of preparation.

 

a)  Dimensions of bottle: 

Different attributes of the dimensions of the bottle was studied which is mention in the following table:

 

Table No.2 –Dimensions of ophthalmic plastic bottle (body with cap)

Sr. no

Total height

(mm)

Outer diameter

(mm)

Inner diameter

(mm)

1.

73±1

40.33±0.55

36.33±1.15

 

b) Dimensions of body:

Different attributes of the dimensions of the body was studied which is mention in the following table:

 

Table No.3 –Dimensions of ophthalmic body (body without cap)

 Sr. no.

Total  height

(mm)

Outer diameter

(mm)

Inner diameter

(mm)

1.

67±1

40.33±0.57

3.33±0.57

 

c) Dimensions of base:

Different attributes of the dimensions of the base was studied and found to be 40 mm.

 

d) Dimensions of cap:

Different attributes of the dimensions of the cap was studied which is mention in the following table:

 

Table No.4 –Dimensions of ophthalmic bottle cap

Sr. no

Total height

(mm)

Outer diameter

(mm)

Inner diameter

(mm)

Thickness

(mm)

1.

23.33±0.57

23.33±0.57

22±1

3.33±0.57

 
e) Height of Ophthalmic bottle:

Different attributes of the dimensions of the height of ophthalmic bottle was studied which is mention in the following table:

 

Table No.5 –Height of ophthalmic bottle

Sr.  no.

With cap (mm)

Without cap (mm)

1.

72.33±0.57

7.66±0.57

f) Diameter of neck:

Different attributes of the dimensions of the neck was studied which is mention in the following table:

 

Table No.6 –Diameter of ophthalmic bottle neck

Sr. no.

Inner diameter (mm)

Outer diameter (mm)

1

15.66±0.57

18.66±0.57

 

Number of threads:

Complete –one

Incomplete –not observed                                  

 

Overflow volume:

 

Table No.7 –overflow volume of ophthalmic bottle

Sample no.

Overflow volume (in ml)

1.

16±1

 

B) Chemical Evaluation:

Chemical incompatible substances can alter appearance of drug product and plastic container. Here we performed elemental analysis for Nitrogen, Sulphur, Halogens, so as there was no any such elemental contamination in ophthalmic   plastic   container.

 

1. Elemental Analysis:       

Observation for test conducted on sodium fusion extract of ophthalmic plastic container:

 

Table No.8 –Elemental analysis of ophthalmic plastic bottle

Sample no.

Test

Observation

Inference

1

Test for Nitrogen

Prussian blue colour is not observed.

Nitrogen is absent

2

Test for Sulphur

No black or brown precipitate observed.

Sulphur is absent

3

Test for Halogen

No white precipitate was observed.

Halogen is absent

 

2. Heating Test:

Significance of this is to see any harmful or unwanted impact on near site.

 

Table No.9 –Heating test of ophthalmic plastic bottle

Sr. no

Test

Observation

1.

Inflammation

Inflammation Observed

2.

Ignition of ease

Slow

3.

Self extinguishing

Observed

4.

Evolution of gas

No specific gas

5.

Color  of flame

Yellow

6.

Formation of droplet

Not observed

7.

Sooty flame

Not observed

 

3. Solubility:

Many of solvent present in formulation may leach out of container, so that solubility for mostly used solvent was checked.

 

 

Result of solubility was found as per following:

 

Table No.10 –Solubility effect of different solvent on ophthalmic plastic bottle

Sr. no

Solvent used

Observation

1.

Toluene

Insoluble

2.

Ethyl acetate

Insoluble

3.

1,4-Dioxane

Insoluble

4.

Carbon Tetrachloride

Insoluble

 

CONCLUSION:

Pharmaceutical packaging technology is structured to meet the needs of the global market, and assesses a wide range of current knowledge, catering for the requirements of the pharmaceutical industry as well as for pharmaceutical companies in emerging nations who are still seeking a basic grounding in the subject. Packaging should provide protection, identification, information, convenience and compliance for a product during storage, carriage, display and until such time the product is consumed. Pharmaceutical packaging should look into concerned issues like child safety, correct dosage, patient traceability, tampering and diversion of pharmaceutical products. The introduction of robotics has given a new dimension to packaging. Considerable steps have to be taken to ensure packaging traceability. Some manufacturers have affixed the use of barcodes to pharmaceutical products.

 

REFERENCES:

1.       Donald C. Liebe, G.S.Banker, Packaging of Pharmaceutical Dosage Form, Modern Pharmaceutics by Marcel Dekker, pp. 681-725,

2.       C.P.Croce, Leon Lachman, Packaging material Science, The theory & Practice of Industrial Pharmacy, 2009,3 rd ed, pp.711-732.

3.       Paul Beringer et al, Plastic Packaging, Remington: The Science and Practice of Pharmacy, Volume I, 2005, 21st ed, pp.1048.

4.       USP 24, NF 19, 2000, pp. 10.

5.       Aulton ME. Aulton’s Pharmaceutics: The Design and Manufacture of Medicines. Edited by Churchill Livingstone Elsevier limited. 2007, 3rd ed, pp. 636-639.

6.       Cooper and Gunn’s. Tutorial pharmacy. 6th edition, Edited by Carter SJ. Delhi: CBS publisher and distributors; 2005, pp. 133-141.

7.       http://www.fda.gov.

8.       Kushe SSRaveendran PT. Product Packaging and Competitive, Advantage, Asian J. Management. 2016; 7(1): 01-04.

9.       Manukondakeerthi, Lakshmiprasanna. J, Santhosh AM, Rama Rao N A Review on Packaging for Different Formulations, , Asian J. Res. Pharm. Sci. 2014; 4(3): 140-150

10.     Swarnakala, Natarajah Srikumaran, Survey on Food Packaging methods, Processes, and Systems, Research J. Pharm. and Tech. 2017; 10(9): 2880-2882.

11.     Gilbert S. Bankar, Christopher T. Rhodes, Modern Pharmaceutics, Marcel Dekker, 2005, 4th  edition, 591.  

12.     Jain UK, Goupale DC, Nayak S, Pharmaceutical Packaging Technology, PharmaMed Press, 2015; 2nd ed: pp.79. 

13.     Allen LV, Jr. Popovich NG, Ansel HC, Ansel’s Pharmaceuticals Dosage forms and Drug Delivery Systems, Lippincott Williams and Wilkins, 2009; 8th ed: pp. 463-475.

 

 

 

 

Received on 05.12.2017       Accepted on 21.05.2018     

© Asian Pharma Press All Right Reserved

Asian J. Pharm. Ana. 2018; 8(3): 140-146.

DOI: 10.5958/2231-5675.2018.00026.1