Parentral emulsion and suspension sunil kokate

1. Presented by : Sunil B. Kokate . M. Pharm 3 rd sem Dept. of P’ceutics , Govt. college of Pharmacy, Aurangabad. Parentral Suspension and Emulsion 26/08/2013 1

2. Content: A) Introduction to Parentral suspension . a) Formulation consideration. b) Formulation development. c) Evaluation of suspension. B) Introduction to Parentral emulsion. a) Formulation development. b) Stability of emulsion. c) Evaluation of emulsion. C) Packaging . D) References . 26/08/2013 2

3. Parentral Suspension:- Introduction: Parentral suspensions are dispersed, heterogeneous systems containing insoluble drug particles which, when are to be resuspended in either aqueous or oil vehicles before administering to a patient. They administered by either subcutaneous (S.C.) or intramuscular (I.M.) route. For example procaine Penicillin G . 26/08/2013 3

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7. Formulation Considerations: Factors affecting release of drug from suspension: Solubility of drug in biological fluids at the injection site. Lipid solubility and oil-water partition coefficient of the drug. pKa of the drug. Dissolution rate of solid from its dosage from. Particle size of the of drug in suspension. Compatibility with other ingredient. 26/08/2013 7

8. Formulation Considerations: Preformulation data needed for the formulation development: Particle size and particle size distribution. Dissolution. pKa. Solvates and polymorphs. Solubility. pH stability. 26/08/2013 8

9. Formulation development: Suspension ingredients: Parentral suspension contain both active ingredient(s) and excipients . Excipients used in the parentral preparations must be…. Physically and chemically compatible with active ingredient. Nonpyrogenic , nontoxic, nonhaemolytic and nonirritating. Must not interfere with the therapeutic effect of the active ingredient. Must maintain stability during sterilization and during the shelf life Effective at low concentration. 26/08/2013 9

10. Typical excipients used in parentral suspensions: Flocculating/suspending agents: Wetting agent Solvents Preservatives Antioxidants. Chelating agents . Buffering agents. Tonicity agents. 1) Flocculating/suspending agents: a) Surfactants: e.g. Lecithin, Polysorbate 20, Polysorbate 40, Polysorbate 80,Pluronic F-68. 26/08/2013 10

11. b) Hydrophilic colloids: e.g. Sodium CMC, Acacia, Gelatin, MC, PVP. c) Electrolytes : e .g. Potassium/sodium chloride, Potassium/sodium citrate, Potassium/sodium acetate. 2) Wetting agent : They reduce the contact angle between the surface of the particle and the wetting liquid. Useful when hydrophobic powders are suspended in aqueous systems. e.g. Nonaqueous solvents (glycerin, alcohol, and propylene glycol). Non ionic surfactant. ( polysorbate 80, Polysorbate 20,Polysorbate 40 ). 26/08/2013 11

12. 3) Solvents: May be aqueous or non aqueous. Water for injection is preferred aq. solvent system . Non aqueous solvent may be.. Water miscible ( Ethanol, Glycerin, Propylene glycol, N-( β hydroxyethyl )- lactamide . Water immiscible includes fixed oils like Sesame oil, Peanut oil, Castor oil, almond oil, sunflower oil, iodinated poppy seed oil. 26/08/2013 12

13. 4) Preservatives: Benzyl alcohol (0.9% to 1.5%), Methylparaben (0.18% to 0.2%), Propylparaben (0.02%), Benzalkonium chloride (0.01 % to 0.02%), and Thimersal (0.001 % to 0.01 %). 5) Antioxidants: water soluble: Ascorbic acid- 0.02-0.1%, Sodium bisulfite - 0.1-0.15%, Sodium metabisulfite - 0.1-0.15 %, Sodium formaldehyde sulfoxylate - 0.1-0.15%, Thiourea - 0.005% b) Oil soluble: Ascorbic acid esters-0.01-0.15, BHT-0.005-0.02%, Tochopherol - 0.05-0.075%. 26/08/2013 13

14. 6) Chelating agents: EDTA 7) Buffering agents: Citric acid, Sodium citrate. 8) Tonicity agents : Dextrose, Sod. Chloride. 26/08/2013 14

15. Manufacturing Considerations: Two basic method used to prepare Parentral suspension are- Aseptically combining sterile powder and vehicle In situ crystal formation by combining sterile solutions. Previously sterilized & milled active ingredienr (s) Vehicle & Excipients Sterilizing filter (i.e. 0.22 micron) Sterile receiving vessel Mixed/ milled Final suspension Aseptically disperse active ingredient(s) Aseptic filling Aseptically combining sterile powder and vehicle 26/08/2013 15

16. Active ingredient(s) in solution (organic solvent Vehicle and necessary Excipients Sterilizing filter (i.e. 0.22 micron) Counter solvent Sterilizing filter (i.e. 0.22 micron) Sterilizing filter (i.e. 0.22 micron) Mill/ Mix Remove organic solvent 2. In situ crystal formation by combining sterile solutions. 26/08/2013 16

17. Stability and Evaluation: Physical: Syringeability . Injectability Resuspendibility . Sedimentation Volume. Freeze‐Thaw cycles. Crystal Growth. Particle Size Measurement. Zeta Potential determination. Shipping Characteristic. Product‐Package Interaction. 26/08/2013 17

18. B) Biological: a) Sterility test. b) Pyrogen test . 26/08/2013 18

19. Official example of parentral suspension: (1) Sterile ampicillin suspension USP’95 dispense as powder which is to be reconstituted at time of administration. (3) Tetanus toxoid adsorbed USP’95, IP’96 – aq. Suspension. (4) Betamethasone acetate suspension USP’96 aq. Suspension. (5) Insulin Zinc suspension USP’95, IP’96 aq. Suspension. (6) Procaine penicillin suspension IP’96 26/08/2013 19

20. Parentral Emulsion: Introduction: Parentral emulsion is O/W or W/O emulsion with mean droplet diameter 200-500 nm. Mainly employed as Total parentral nutrition's. These are milky white in appearance. W/O emulsion (S.C.). O/W Sustained release depot preparation (I.M.). O/W nutrient emulsion (I.V.) 26/08/2013 20

21. Emulsion Ingredients: A) Oils : The oils most commonly used are Long Chain Triglycerides (LCTs) from vegetable sources (soybean or sunflower oil. ) B) Emulsifiers: Natural and synthetic emulsifier are Natural emulsifier- eg . lecithins . Synthetic emulsifier- eg . Spans and Tweens . C) Aqueous phase: a) Water for injection is aqueous phase for parentral emulsion. b) Various substances have been added to the aqueous phase to adjust osmolarity , pH. 26/08/2013 21

22. D) Tonicity modifier :- Glycerol, sorbitol , xylitol are added in aqueous phase. E) Antioxidants :- α- tocopherol , ascorbic acid may be added in aq. Phase to prevent peroxidation of unsaturated fatty acids. F) Preservatives :- p- hydroxy benzoic acid (methyl and butyl derivatives) can be dissolved in the aqueous phase. 26/08/2013 22

23. 26/08/2013 23 Emulsion Manufacture: A) Formulation Preparation:

24. B) Homogenization and particle size reduction: Can be done by Ultrasonic homogenizers, C ) Filtration: Membrane filter is used for final filtration to remove larger particles. D) Sterilization: For large-volume (l00 to 1000 ml.) injectable fat emulsions, sterilization is achieved by autoclaving. 26/08/2013 24

25. Stability of parentral emulsions: 1) Stability of the formulation: Influenced by processing conditions, autoclaving, storage conditions, excessive shaking, or the addition of electrolytes or drugs. 2) Physical stability: Indicated by Particle size changes. Flocculation. Creaming, coalescence. Extreme temperature fluctuation such as freezing can result in an increased oil droplet size, leading to aggregation, coalescence, and ultimate separation. 26/08/2013 25

26. 3) Chemical Stability : Indicated by Oxidation. Hydrolysis. Change in pH. Rancidity of oil. 4) Microbiological Stability: For bacterial and fungal growth. Precaution should be taken to prevent microbial contamination during processing and maintain sterility. 26/08/2013 26

27. Evaluation of Emulsions: Physical examination: Visual observation of creaming, coalescence, and oil separation. Chemical analysis: Determination and characterization of drug substance, oil, phosphatide , and excipients present, including free fatty acids and oxidative degradation products. pH determination. Particle size surface charges. Sterility test. Pyrogen test. 26/08/2013 27

28. Packaging for parenteral Suspension and Emulsion: Container components for parenteral products must be considered an integral part of the product because they can dramatically affect product stability, potency, toxicity, and safety. Injectable suspension and emulsions provided in volumes of 100 to 1000 ml are packaged in USP type I & II Glass bottles. Siliconized Bottles with hydrophobic inner surface can be used. Rubber closures are most commonly used. Closures must not be permeable to oxygen or become softened by contact with the oil phase of emulsion. 26/08/2013 28

29. Ampoules Small volume parenterals (SVPs): Ampoules Glass vials sealed with rubber stoppers Plastic ampoules (blow-fill-seal) Pre-filled syringes Needle-free injection Glass vials Plastic ampoules 26/08/2013 29

30. Glass bottles Large volume parenterals (LVPs): Glass bottles sealed with rubber stoppers. Plastic bags. Plastic bags. 26/08/2013 30

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32. References: Lieberman H.A.,, Leon L. The Theory and Practice of Industrial Pharmacy. Third edition, Varghese puglising house, Bombay, pp- 639-680. Francoise N., Gilberte M. Pharmaceutical emulsion and suspension. Marcel Dekker,inc , New York, pp- 229-270 Remington, The Science and Practice of Pharmacy 21 th edition, Volume I, Lippincott Williams & Wilkinss , pp- 802-836. L.C. Collins-Gold, R.T. Lyons and L.C. Bartholow Parenteral emulsions for drug delivery Advanced Drug Delivery Reviews, 5 189-208, 1990. Rajesh M. Patel; Parenteral suspension: An overview , International Journal of Current Pharmaceutical Research Vol 2, Issue 3, 2010 . 26/08/2013 32

33. Thanks For listening . . . .! 26/08/2013 33