ERT 430 PHARMACEUTICAL PROCESS ENGINEERING PARENTERAL FORMULATION

Transcription

1 ERT 430 PHARMACEUTICAL PROCESS ENGINEERING PARENTERAL FORMULATION

2 OUTLINE Introduction Parenteral Product Requirement Parenteral Product Formulation: Solution Emulsion Suspension Evaluation of Parenteral Product

3 Introduction Parenteral refers to injectable route of administration. It is derived from Greek words Para (Outside) and enteron (Intestine). So it is a route of administration other than the oral route. This route of administration bypasses the alimentary canal

4 Necessities of Parenteral preparations: Sterility (must) Pyrogen (must) Free from particulate matter (must) Clarity (must) Stability (must) Isotonicity (should) Solvents or vehicles used must meet special purity and other standards. Restrictions on buffers, stabilizers, antimicrobial preservative. Do not use coloring agents. Must be prepared under aseptic conditions. Specific and high quality packaging.

5 PARENTERAL PRODUCTS REQUIREMENT All products must be sterile. All products must be free from pyrogenic (endotoxin) contamination. Injectable solutions must be free from visible particulate matter. This includes reconstituted sterile powders. Products should be isotonic, although strictness of isotonicity depends on the route of administration.

6 PARENTERAL PRODUCTS Solutions Emulsions Suspension (If the drug is insoluble, or poorly soluble in a suitable solvent)

7 SOLUTION Most of injectable product are solutions Preparation: Dissolving drug and any excipients Adjusting ph Sterile filter (for heat sensitive) through 0.22μm membrane filter to achieve sterility & remove particulate matter. Most solutions have a viscosity and surface tension similar to water, athoughstreptomycin sulfateinjection and ascorbic acid injection are quite viscous.

8 SOLUTION Formulation Choice of solvent: water is the most widely used (eg: water for injection, prepared by RO or distillation) Other formulation additives Buffers Isotonicitymodifiers (to avoid pain & irritation): eg: dextrose, sodium chloride Density modifier (rarely necessary except when formulating spinal anaesthetics: to precisely control the area to be anaesthetized.) Reducing agents & antioxidants: eg: sodium metabisulphite, butylated hydroxyanisole

9 EMULSION Emulsion is a dispersion of one immiscible liquid in another. Using emulsifying agent: prevents coalescence of the dispersed droplets 2 types Oil-in-water (o/w): Oil droplets are dispersed throughout the aqueous phase (usually given intramascularly) Water-in-oil (w/o): water is dispersed throughout the oil (usually given subcutaneously)

10 EMULSION An increasing popular class of IV emulsions is lipid emulsions. Fat is transported in the bloodstream as small droplets called chylomicra. Chylomicraare 0.5 to 1.0 μm spheres consisting of a central core of triglycerides and an outer layer of phospholipids. This emulsion yield triglycerides that provides essential fatty acids and calories during total parenteralnutrition of patients who are unable to absorb nutrients through GI tract. Glycerol is commonly added to make product isotonic. IV lipid emulsions are usually administered in combination with dextrose and amino acids.

11 EMULSION 2. FORMULATION: severely restricted through a very limited selection of stabilizers and emulsifiers.

12 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 a) Natural emulsifier- eg. lecithins. b) Synthetic emulsifier- eg. Spans and Tweens. C) Aqueous phase: a) Water for injection is aqueous phase for parenteral emulsion. b) Various substances have been added to the aqueous phase to adjust osmolarity, ph. 26/08/

13 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 peroxidationof unsaturated fatty acids. F) Preservatives :- p-hydroxybenzoic acid (methyl and butyl derivatives) can be dissolved in the aqueous phase. 26/08/

14 Emulsion Manufacture: A) Formulation Preparation: 1) The emulsifier, and any preservatives are usually dissolved or dispersed in the aqueous phase. 2) The phospholipids, antioxidants, and any lipophilic drugs to be incorporated are usually dissolved or dispersed in the oil phase. 3) Both phases are then heated to o C with agitation. 4) The coarse emulsion is then formed by vigorous stirring or mixing. 5) Final ph of formulation is adjusted. 26/08/

15 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.) injectablefat emulsions, sterilization is achieved by autoclaving. 26/08/

16 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 a) Particle size changes. b) Flocculation. c) Creaming, coalescence. d) Extreme temperature fluctuation such as freezing can result in an increased oil droplet size, leading to aggregation, coalescence, and ultimate separation. 16

17 Physical instability

18 3) Chemical Stability: Indicated by a) Oxidation. b) Hydrolysis. c) ChangeinpH. 4) Microbiological Stability: For bacterial and fungal growth. Precaution should be taken to prevent microbial contamination during processing and maintain sterility. 26/08/

19 SUSPENSION Parentralsuspensions are dispersed, heterogeneous systems containing insoluble drug particles which, are to be resuspendedin 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. One of the most difficult to formulate: requires a delicate balance of variables to formulate a product that is easily resuspended and can be ejected through an 18- to 21 gauge needle through its shelf life (To achieve these properties, it is necessary to select and carefully maintain the particle size and rheological properties, as well as the manufacturing steps that control the wettability and surface tension)

20 3) Particle size should be small & uniform. 4) Resuspension of particles occur easily. 5) Dispersed particles do not settle rapidly after shaking 6) Cake formation not occur during its shelf life. 7) Maintain its stability and elegance during its shelf life 2) Syringeability & injectability of a suspension are closely related to viscosity & particle characteristics. 8) Isotonic & non irritating 1) Sterility during its storage & use. Ideal characteristics of suspension 9) Contain 0.5% to 5.0% solids & particle size less than 5 micrometer. 26/08/

21 Advantages of parenteral suspension 1) Better for drugs that are insoluble in convention solvents. 2) Increased resistance to hydrolysis & oxidation as drug is present in the solid from. 3) Formulation of controlled released drug is possible 4) Elimination of hepatic first pass effect. 26/08/

22 5) Difficulty in formulation: selecting the ingredients, like suspending agent, viscosity inducing agent, wetting agent, stabilizers and preservative. 1) Stabilization of suspensions for the period between manufacture & use present a number of problems. e.g. solids gradually settle & may cake, causing difficulty in redispersion prior to use. Disadvantages of parenteral suspension 4) Difficulty in manufacturing: Special facilities required to maintain aseptic condition for manufacturing processes such as : crystallization, particle size reduction, wetting, sterilization 2) Maintenance of physical stability is very difficult in this dosage form. 3) Non uniformity of dose at the time of administration. 26/08/

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

24 Typical excipients used in parenteral suspensions: 1) Flocculating/suspending agents(to prevent caking) 2) Wetting agent 3) Solvents 4) Preservatives 5) Antioxidants. 6) Chelating agents. 7) Buffering agents. 8) Tonicity agents. 1) Flocculating/suspending agents: a) Surfactants: e.g. Lecithin, Polysorbate 20, Polysorbate 40, Polysorbate 80,Pluronic F /08/

25 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. Nonaqueoussolvents (glycerin, alcohol, and propylene glycol). Non ionic surfactant. (polysorbate 80, Polysorbate 20,Polysorbate 40). 26/08/

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

27 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%to0.01%). 5) Antioxidants: a) water soluble: Ascorbic acid %, Sodium bisulfite %, Sodium metabisulfite %, Sodium formaldehyde sulfoxylate %, Thiourea % b) Oil soluble: Ascorbic acid esters , BHT %, Tochopherol %. 26/08/

28 SUSPENSION 2 basic methods of preparation: i) Sterile vehicle and powder are combine aseptically Eg: procaine penicillin, an aqueous vehicle containing the soluble components (such as lecithin, sodium citrate, providone& polyoxythylenesorbitanmonooleate) is filtered through a 0.22 μm membrane filter, heat sterilized, and transferred into presterilized mixing-filling tank. The sterile antibiotic powder, which has previously been produced by freeze drying, sterile crystalizationor spray-drying, is aseptically added to the sterile solution while mixing. After all tests have been completed on the bulk formulation, it is aseptically filled.

29 SUSPENSION Previously sterilized & milled active ingredient(s) Vehicle & Excipients Sterile receiving vessel Sterilizing filter (i.e micron) Aseptically disperse active ingredient(s) Mixed/ milled Aseptic filling Final suspension 26/08/ Aseptically combining sterile powder and vehicle

30 SUSPENSION 2 basic methods of preparation: ii) Sterile solutions are combined and the crystals formed in situ. Eg: testosterone suspension. The vehicle is prepared and sterile-filtered. The testosterone is dissolved separately in acetone and sterile-filtered. The testosterone-acetone solution is aseptically added to the sterile vehicle, causing the testosterone to crystallize. The resulting suspension is then diluted with sterile vehicle, mixed, the crystals allowed to settle, and the supernatant solution is siphoned off. This procedure is repeated several times until all the acetone has been removed. The suspension is then brought to volume and filled in the normal manner.

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

32 EVALUATION OF PARENTERAL PREPARATIONS The finished parenteralproducts are subjected to the following tests, in order to maintain quality control: A) sterility test B)clarity test C)leakage test D)pyrogentest E)assay

33 A) sterility test It is a procedure carried out to detect and conform absence of any viable form of microbes in or on pharmacopeia preparation or product. 1) Method of sterility testing i) METHOD 1 Membrane filtration method ii) METHOD 2 Direct inoculation method

34 Membrane filtration method (METHOD 1): Membrane filtration, appropriate for: Filterable aqueous preparations Alcoholic preparations Oily preparations Preparations miscible with or soluble in aqueous or oily (solvents with no antimicrobial effect) All steps of this procedure are performed aseptically in a Class 100 Laminar Flow Hood

35 Membrane filter 0.45μ porosity Filter the test solution After filtration remove the filter Cut the filter in to two halves First halves (For Bacteria) Second halves (For Fungi) Transfer in 100 ml culture media (Fluid Thioglycollate medium) Transfer in 100 ml culture media (Soyabeans-Casein Digest medium) Incubate at C for not less then 7 days Incubate at C for not less then 7 days Observe the growth in the media Observe the growth in the media

36 Direct inoculation method (METHOD 2): Suitable for samples with small volumes volume of the product is not more than 10% of thevolumeofthemedium suitable method for aqueous solutions, oily liquids, ointments and creams Direct inoculation of the culture medium suitable quantity of the preparation to be examined is transferred directly into the appropriate culture medium &incubatefornotlessthan14days.

37 Observation and results Culture media is examined during and after at the end of incubation. The following observations are possible: 1) No evidence of growth Pass the test for sterility. 2) There is evidence of growth Re-testing is performed same no. of sample, volume& media as in original test No evidence of growth Pass the test for sterility. 3) There is evidence of growth isolate& identify the organism. Re-testing is performed with twice no. of sample if: No evidence of growth Pass the test for sterility.

38 B)clarity test Particulate matter is defined as unwanted mobile insoluble matter other than gas bubble present in the product. If the particle size of foreign matter is larger than R.B.V (red blood cell), it can block the blood vessel. ThepermitlimitsofparticulatematterasperI.P.arefollows:

39 Methods for monitoring particulate matter contamination: 1) Visual method 2) Coulter counter method 3) Filtration method 4) Light blockage method

40 C)leakage test The sealed ampoules are subjected to small cracks which occur due to rapid temperature changes or due to mechanical shocks. Filled & sealed ampoules Dipped in 1% Methylene blue solution Under negative pressure in vacuum chamber Vacuum released colored solution enter into the ampoule Defective sealing Vials & bottles are not suitable for this test because the sealing material used is not rigid

41 D)pyrogentest Pyrogen = Pyro (Greek = Fire) + gen (Greek = beginning). Fever producing, metabolic by-products of microbial growth and death. Bacterial pyrogens are called Endotoxins. Gram negative bacteria produce more potent endotoxins than gram + bacteria and fungi. Endotoxins are heat stable lipopolysaccharides (LPS) present in bacterial cell walls, not present in cell-free bacterial filtrates

42 Method Dissolve the subs being examined in, or dilute it with a pyrogen free saline solution Warm the liquid being examined to approx o C temp before injection Thevolumeofinjectionis NLT0.5ml/kg&NMT10ml/kgofbody weight Withhold water during test Clinical thermometer is inserted into the rectum of rabbit to record body temp 2normalreadingofrectaltempareshouldbetakenpriorto the testinjectionatanintervalofhalfanhr&itsmeaniscalculatedinitial temp Thesolutionundertestisinjectedthroughanearvein Recordthetempofeachrabbitinanintervalof30minfor3hrs The difference between initial temp & maximum temp is recorded- taken as response

43 Interpretation of results

44 Limulus amebocytelysate[lal] test Limulus amebocyte lysate [LAL] test another method for the determination of pyrogenic endotoxins Inthis methodthetestsolutioniscombinedwith a cell lysate from the ameabocyte [blood celels] ofhorseshoecrab Any endo toxin that might be present will be coagulated with protien fraction of the ameabocytes and results in the formation of a gel This consider to be simple,rapid and of greater sensitivity that the rabbit test

45 E)assay Assay is performed according to method given In the monograph of that parental preperation in the pharmacopoeia Assay is done to check the quantity of Assay is done to check the quantity of medicament present in the parenteral preperation

46 Thank You..