Formulation of small & large volume parenteral

formulation and evaluation of small volume and large volume parenteral

1. Formulation oF SVP & LVP Presented by – sagar s. bhor Guided by – Dr. shital butani

2. contents INTRODUCTION TO SVP & LVP ADVANTAGES DISADVANTAGES FORMULATION OF SVP & LVP PROCESSING OF PARENTRALS EVALUATION OF PARENTRALS REFERENCE

3. INTRODUCTION Parentrals preparation refers to injectable route of administration It is derived from Greek word para (outside ) & enteron (intestine) i.e other than oral route . Administered the drug into layers of skin

4. Primary Parentral Routes - Routes Volume administered Sub-cutaneous 2 ML Intramuscular 3 ML Intradermal 0.5ML Intravenous 1-100 ML

5. Advantages Of Parentral

6. Disadvantages –

7. Small volume parentral - According to USP “ an injection that is packaged in containers labelled as containing 100 ml or less contents “ Generally contains drug formulation .

8. Large Volume Parentral Lvp mainly contains contents more than 100 ml LVP CONTAINS FOLLOWING Hyperalimentation Solution  large amount of nutrients to maintain a patient who is unable to take food Cardioplegia Solution In heart surgery to help prevent ischemic injury to the myocardium during the time the blood flow supply to the heart is clamped off & during reperfusion., Solution are slightly alkaline & hypertonic in order to compensate for metabolic acidosis & to minimize reperfusion injury resulting from tissue edema. Peritoneal Dialysis Solution Infused in abdominal cavity To remove the toxic substances from the body  Irrigating Solutions Not given parentrally . Are intended to irrigate, flush, & aid in cleansing body cavities & wounds.

9. Formulation -

10. Vehicle – For dissolution of solute and other formulation additives. Types of vehicles -

11. Sterile Water for injection – Sterile Non-pyrogenic pH 5.5 Bacteriostatic water for injection – 0.9% benzyl alcohol added as preservative Applied in multiple –dose container pH 5.7

12. Antioxidant Prevent oxidation process Used alone or in combination with chelating agent Eg. Ascorbic acid , tocopherol ,Butylated hydroxy anisole (BHA) Butylated hydroxy toluene (BHT) Antimicrobial agents – prevent microbial growth in preparation added only in SVP and not in LVP 4 classes of Antimicrobial agents used 1.quaternary ammonium compounds 2. alcohols 3.esters 4.mercurial acids Eg. Thiomersal , benzyl alcohol, phenyl mercuric nitrate & acetate

13. Tonicity Adjustment Agent – Minimises following - A) Tissue damage & irritation B) Haemolysis of blood cells C) Prevent electrolyte imbalance upon administration Eg.Dextrose , Nacl , Tonicity is important for Suubcutaneous (SC) , Intradermal (ID) , Intramuscular route (IM) Buffers acetic acid , glutamic acid ,citric acid , phosphoric acid surfactant improve solubility eg. Sorbital monooleate etc. tweens 20(16.7 HLB) & 80 (HLB 15)

14. Packaging Packaging is an art and science which involves preparing articles for transport , storage purpose Ideal requirements of good package 1) They should hold the product without loss of contents (leakage ,spoilage ) 2) should protect from environmental condition like temp. light , moisture 3) should not permeate gases 4) Matter of packaging material should not interact with formulation

15. Container & closure system –

16. Glass containers – Generally employed with Solid rubber stoppers are used for container closure system . Washed ,cleaned glass container should be held at minimum of 70 C to suppress microbial growth. Pyrogens removed by subjecting to 210C for 3-4 hrs or 650 C for 60 sec.

17. Types Of Glass -

18. Plastic container - Thermoplastic polymers soften upon heating & solidify upon cooling . Commonly used for parentrals . Thermosets – Chemically reactive Harden irreversibly by cross linking Epoxy , melamine resins , cross linked polyesters

19. Commonly used polymers in sterile products - Polyethylene (PE) Polyvinyl chloride (PVC) Polypropylene (PP) Ethyl vinyl acetate (EVA) Polyamide(nylon)

20. Tests for plastic containers 1. Leakage test 2. transparency test 3. water vapour permeability test Leakage test - fill 10 conatiners with water & keep them in inverted position with intended closure system for 24 hrs . Check for leakage after that period Transparency test – fill 5 containers with nominal capacity with diluted suspension as described in IP 1966 . And cloudiness of each container Is checked as compared with container filled with water Water vapour permeability test – Fill five container with nominal volume and heat seal the bottle with aluminium foil . Weigh accurately each container and keep them at 14 days at RH of 60+/- 5% and temp in 20-25 C and reweight and loss in weight should not more than 0.2 %

21. Large volume flexible containers - Advantages – Durable & light weight Bag collapses as it empties Material – Polyvinylchloride Ethylvinyl acetate films

22. Blow fill seal technology (BFS) Technology originally developed in Europe Aseptic packaging of pharmaceutical products Machine fills volume from 0.1 ml to 1000 ml

23. BFS Process outline Polymer granules are fed to a machine hopper Within extruder, polymer is subjected to high temperatures (160'c) and pressure (up to 350bar) and become molten. It is extruded through a die and pin set to form open-ended tube of moltenpolymer known as PARISON, Parison - supported by sterile air that is fed into center of parison through 3 sterilizing grade air filter,

24. The nozzle assembly lowers into the parison until the nozzles form a seal with the neck of the mould. Container formation is completed by applying a vacuum on the mould-side of the container and blowing sterile filtered air into the interior of the container. The patented electronic fill system delivers a precise dosage of product into the container. The nozzles then retract into their original position. Following completion of the filling process, the top of the container remains semi-molten. Separate seal moulds close to form the top and hermetically seal the container. The moulds open and the container is then conveyed out of the machine. Mold set in two halves moves over to the parison and closes around it part moved to filling position and containers are sealed by second mold set, which forms the neck and closure of BFS containers.

25. Evaluation- Sterility Freedom from pyrogens Freedom from particulate matter Isotonicity

26. Sterility testing - Sterility means complete absence of viable microorganisms. Test must be carried out in aseptic environment. (grade A laminar flow ) Exterior surface is cleaned with suitable antimicrobial agent . METHOD 1 – Membrane filtration Method 2 – Direct inoculation technique

27. Membrane filtration Fluid thioglycolate media (FTG) – Anaerobic bacteria Soyabean casein digest media (SCD)- Fungi & aerobic bacteria

28. Direct inoculation

29. Pyrogen testing Rabbit test LAL test Rabbit test – body temp of rabbits are measured upon injection of the formulation Temp recorded at 30 min interval between 1-3 hrs If any rabbit shows rise in temp more than 0.5 C then continue the test with 5 other rabbits If not more than 3 rabbits out of 8 shows rise in temp by 0.5 C or more OR sum of temp rise not more than 3.3 C then test passes . LAL test (Limulus Amebocyte Lysate)- Lysate derived from haemolymph cell of horseshoe crab limulus polyphemus Precipitation or gelation occurs upon addition of endotoxin containing sample .

30. Container Closure Integrity Test / leaker test - Contents may leak outside & spoil the package The sealed container are dipped in colored solution of 0.5 – 1 % of methylene blue & vacuum is applied . The solution inside leaked container shows blue colour Particulate matter evaluation – The parentral preparation should have particulate matter in range of 30-40 micrometer USP states that all container should check visually inspected for visible particle against dark background

31. In lvp permitted limits of particulate matter is maximum of 50 particles of 10 micrometer & 5 particles of 25 micrometer & no particle above 50 micrometer Coulter counter method & filtration method are used for monitoring particulate matter

32. reference USP MONOGRAPH STERILE WATER FOR INJECTION TEXTBOOK OF REMINGTON Theory & practice of industrial pharmacy Leon Lachman , H. Liberman https://www.allfordrugs.com/large-volume-parenterals/ PHOTOS FROM GOOGLE.COM

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