Containers and closure system of parenterals.

University Institute of Pharmaceutical Sciences is a flag bearer of excellence in Pharmaceutical education and research in the country. Here is another initiative to make study material available to everyone worldwide. Based on the new PCI guidelines and syllabus here we have a presentation dealing with the types of containers and closure systems which are up to par with all the parameters defined by pharmacopoeias for parenterals.
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1. Presented by: ALISHA SACHDEVA ANUSHKA VASHISHTH B.PHARM III YEAR UNIVERSITY INSTITUE OF PHARMACEUTICAL SCIENCES, PANJAB UNIVERSITY,CHANDIGARH Submitted to: Dr. Amita Sarwal

2. CONTENTS Containers Glass containers Plastic containers Closures Natural rubber Synthetic rubber Types of injection containers Single dose small volume Single dose large volume Multiple dose Single dose v. multi dose Quality control References

3. 1. No interaction between the contents and container. 2. Should withstand high temperatures especially during sterilisation. 3. Should protect the contents from harmful light radiations. 4. Must be suitable for repeated use and easy to clean. 5. Should be transparent and colourless.

4. Polyethylene HDP PVC PMMA Polystyrene PTFE Polypropylene Polyamide Polycarbonate Phenol- formaldehyde Urea- formaldehyde Melamine- formaldehyde

5. General classification for glass containers

6. Type I glass containers Are made of borosilicate glass. High hydrolytic resistance. Suitable for most preparation whether or not for parenteral use. Type II glass containers Made of soda lime silica glass. High hydrolytic resistance resulting from suitable treatment of the surface. Suitable for most acidic and neutral aqueous preparations whether or not for parenteral use. Type III glass containers Usually made of soda lime silica glass. Moderate hydrolytic resistance. Generally suitable for non-aqueous preparations for parenteral use.

7. LIME SODA GLASS: “Ordinary Glass” Contains 75% SiO 2 , 15% Na 2 O and 10% CaO with less than 1% of K 2 O, MgO and Al 2 O 3 . Aluminium oxide improves mechanical strength and chemical durability while magnesium oxide reduces temperature required in manufacturing. 1. Yields an appreciable quantity of alkali to water. 2. Flakes separates easily. 3. Surface loses brilliance on repeated use. 4. High expansion coefficient makes it liable to fracture with sudden temperature change. 1. Can be manufactured at a convenient temperature. 2. Easy to process. 3. Inexpensive. 4. Sufficiently resistant to water action.

8. BOROSILICATE GLASS The defects of lime soda glass can be largely overcome by decreasing the proportion of alkali and including boric oxide. This improves heat resistance and confers great chemical durability. It is used for chemical glassware and containers for alkali sensitive preparations. They are now largely replaced by neutral glasses in manufacture of parenteral containers as they are expensive and difficult to melt and mould. NEUTRAL GLASS It is composed of 72-75% SiO 2 , 7-10% B 2 O 3 , 4-6% Al 2 O 3 , 6-8% Na 2 O, 0.5-2% K 2 O and 2-4% BaO . This grade of glass lies between lime soda and borosilicate glass. They are softer and more easily manipulated than borosilicate but have more resistance to autoclaving and solutions of pH up to about 8. Large transfusion bottles are more convenient to be produced from neutral glass to make them cost effective.

9. NEUTRAL TUBING FOR AMPOULES Its composition differs because after filling, ampoules are sealed by fusion and therefore the glass must be easy to melt. Consequently, the amounts of alkaline and aluminium oxides are slightly increased and the content of boric oxide and silica slightly reduced. It is satisfactory for the storage of alkali sensitive injections despite these modifications. They have good thermal resistance because of their small capacities and thin walls. LEAD-FREE GLASS Since lead is a cumulative poison, these are desirable for pharmaceutical preparations, particularly for liquids. Classical example is of the sequestering agents like sodium calciumedetate (for lead poisoning) and trisodium edetate (for hypercalcemia) injections which would have taken up lead ions from the glass (if not lead free) that is unacceptable in the parenterals ’ formulation. Hence lead free glass is must in these cases.

10. SULPHURED CONTAINERS Surface treatment is the approach for obtaining cheaper containers, particularly for large volume injections. By a process known as “sulphuring” , lime soda glass can be given a neutral surface through which extraction of alkali ions is very small. The containers are exposed to moist SO 2 at above 500 o C when it neutralises the surface alkali to produce sodium sulphate layer which can be removed by washing to expose a tough silica rich surface. These are used for storing of blood, plasma and infusion fluids. It has been used for dry salt penicillin vials because very little alkali will be extracted during its short storage life.

11. SILICONE TREATED CONTAINERS They are polymers composed of long chains of alternating oxygen and silicon atoms with organic groups attached to the latter. They have good heat and oxidation resistance, chemical inertness and freedom from colour, odour and toxicity. In addition, organic groups provide water repellent property. The degree of polymerisation and cross- linking between the chains depends upon the organic groups. ADAVANTAGES DISADVANTAGES Not wetted by aqueous solution or suspensions, so not cling to sides. With suspensions, the quick drainage following shaking makes it easy to see the position of the needle in the vial, and the remaining volume. Foaming is reduced. Extraction is not entirely prevented. Film gradually comes away after frequent autoclaving. Very little protection against flaking. Unpleasant greasy appearance. Difficult for normal labels to adhere.

12. PLASTIC CONTAINERS

13. THERMOPLASTIC THERMOSETTING On heating, these soften to a viscous fluid which hardens again on cooling. Hardness depends on degree of cross linkage or intermolecular attraction. They include: Polyethylene HDP PVC PMMA Polystyrene PTFE Polypropylene Polyamide Polycarbonate When heated, these may become flexible but they do not become fluid. They are usually hard and brittle at room temperature because of high degree of cross-linking. They include: Phenol- formaldehyde Urea- formaldehyde Melamine- formaldehyde

14. POLYETHYLENE Flexible, very light but tough plastic. Impermeable to water vapour but relatively high permeability to gases. Lack of transparency and non- adherence of labels. Sterilisation is difficult because of melting point range of 110- 115 o C.(soften up at 90 o C) HIGH DENSITY POLYTHENE More rigid, handling and filling of containers is easier. Permeability to gases is low and resistance to oil is high. Can be sterilised by autoclaving because of higher melting point. Used for disposable syringes, packaging of infusion fluids, etc. POLYTETRAFLUOROETHYLENE (PTFE) Translucent or opaque material. Possess excellent heat resistance.

15. POLYVINYL CHLORIDE (PVC) Less flexible, heavier and more permeable to water vapour. Has high clarity, practically unaffected by sunlight and unplasticised material is non- toxic. Less permeable to gases than polythene. Surface can be painted readily and plasticised grades with good oil resistance are obtained. Generally used for manufacturing eye ointment tubes. POLYMETHYL METHACRYLATE (PMMA) Hard, strong but light, glass clear material that retains its clarity on exposure. Used for aseptic screens, etc. POLYPROPYLENE Similar to HDP but is lighter, much less opaque and has greater heat resistance. Better gloss and superior barrier properties. Used for disposable syringes, tubings , etc.

16. POLYSTYRENE Hard, rigid, light material that is cheap and easy to mould. Odourless and tasteless. Excellent dimensional stability that permits manufacture of components to fine limits of accuracy. It is least suitable for sterile products because of its moisture vapour permeability. POLYAMIDES Produces a stronger container that is very resilient. It is not transparent and water vapour permeability is relatively high but has good resistance to vegetable oils and many solvents. Used for manufacturing syringes, tubing, clot filters, etc. POLYCARBONATES Excellent dimensional stability and is transparent. High impact strength and very good heat resistance; low water absorption.

17. PHENOL-FORMALDEHYDE They are dark and discolour easily. Good heat and moisture resistance allows sterilisation by autoclaving. Chosen for outer cap of injection bottle. UREA-FORMALDEHYDE Generally used for closures. Less heat and moisture resistant. MELAMINE-FORMALDEHYDE This has the advantage of both of the previous types. It is popular as bench surface in sterile product units rather than as a material for production of parenteral container.

18. R ubber consists of long chain polymers of isoprene units linked together in the cis position. The chief disadvantages of raw rubber are: Poor elasticity. Poor strength. Hardens when cold and becomes soft and sticky when warm. Dissolves in many solvents. T o give better physical and chemical properties, we add: Vulcanising agent - sulphur which forms cross links between the long rubber molecules thus improving its strength and reducing its susceptibility to temperature changes. Accelerators - reduces the time and amount of sulphur required, e.g. thiazoles . Activators - increase the activity of accelerators, e.g. stearic acid. Fillers - they are of two types: Reinforcing fillers : improves physical property, e.g. carbon black which increases tensile strength. Extending fillers : added mainly as diluents to reduce cost and partly to facilitate manufacture, e.g. talc.

19. Softeners - facilitate the incorporation of fillers, make the compound easier and cheaper to manipulate, and influence the hardness of finished product, e.g. mineral oil. Anti-oxidants - prevents oxidation of rubber, e.g. aromatic amines and phenols. Pigments - originally mineral pigments such as oxides of iron and sulphides of cadmium and antimony were used but these are being displaced by coal tar dyes. Special ingredients - examples include: Paraffin wax : migrates to the surface and produces a protective barrier to oxygen attack and water absorption. Rosin : increases tackiness. Lubricants - assists the removal of closures from their moulds after preparation, e.g. zinc stearate, talc.

20. S ynthetic rubbers are superior to natural rubbers in one or more respects but inferior in others. In general they are: More resistant to high and less resistant to low temperatures. More resistant to the agents that accelerate ageing (light, oxidation and its catalyst, copper and manganese). More difficult to process. More expensive. T he method of compounding differs in two major respects: Because synthetic rubber are harder, more softening is required and thus, esters are used to facilitate this and improve the resilience of the final article. Because they are more inert, higher concentrations of accelerators and longer vulcanisation times are needed.

21. SINGLE DOSE INJECTIONS OF SMALL VOLUMES Each dose is in a separate container from which it is given to the patient with a syringe. Usual volumes are from 0.5-10mL. They may be packed in ampoules, cartridges or injection units.

22. SINGLE DOSE INJECTIONS OF LARGE VOLUME Infusion fluids usually given IV, are slowly dripped into the patient’s body and 3-4L may be given in 24 hours. Containers must be large and strong enough to withstand frequent cleaning, sterilisation, transport and handling. Bactericides are not permitted in large volume intravenous injections, therefore infusion fluids must always be regarded as single dose injections. These may be classified as: British standard transfusion bottle : It is often called a blood bottle because it is used for giving and taking blood. It is most popular for IV fluids. The graduated capacity is 540mL, volume being the sum of anticoagulants(120mL) and blood when the bottle is used for taking blood(added 500mL, normally). There are two scales moulded on the outside, one reading from the base when the bottle is upright and the other from neck when the bottle is inverted. Other containers : There are alternatives to blood bottles which includes the use of plastic containers. Another is the use of large container that can be fitted to the normal giving sets, discussed later.

23. MULTIPLE DOSE INJECTIONS With this it is more difficult to comply with the official requirement that an injection must be dispensed in a container sealed to exclude microorganisms. Hence there have been various improvements in its design.

24. SINGLE DOSE v. MULTI DOSE

25. GLASS Powder glass test Water attack test Others

26. POWDERED GLASS TEST Preparation of specimen:

27. Powdered glass test: Transfer 10g of prepared specimen in a 250ml conical flask digested previously with high purity water in a bath at 90 o C.

28. WATER ATTACK TEST

29. PLASTICS Leakage test Water vapour permeation test Others

30. LEAKAGE TEST

31. WATER VAPOUR PERMEATION TEST

32. FEATURES ENSURING QUALITY Biological toxicity : The test is performed in vitro by placing the extract in contact with mammalian cells to check its toxicity. In vivo procedures are performed in mice and rabbits for systemic and intracutaneous injections respectively. Protection : A container intended to provide protection from light must meet the requirement of the USP light transmission test. Compatibility : Container component should not interact with the dosage form and may not show leaching. Other changes such as pH shift, precipitation and discoloration should be evaluated.

33. REFERENCES Indian Pharmacopoeia; Volume I, 2014, The Indian Pharmacopoeia Commission, Ghaziabad, pp. 889-899 Carter, S.J.(ed.); Cooper and Gunn’s dispensing for pharmaceutical students, CBS publishers, 12 th edition, pp. 357-391 Jain, N; Anwar, M; Avis, KE (ed.); Sterile products, In, Lachman/ Lieberman’s ‘The theory and practice of industrial pharmacy’; 4 th edition; CBS Publishers; pp. 842-845