1. Define Parenterals
Parenterals is one of the route of Drug Administration, In which the drug does not pass through the GIT (Gastro intestinal track) and is delivered through IV injections is called parenterals.
2. Define Parenterals Meaning
In Parenterals method of drug administration, The drug is given in the form of sterile injection to the specific tissues like muscles-called as Intramuscular parenteral, Drug through Veins are called Intravenous and so on.
Above are the two define parenterals definition to understand the parenteral method.
The parenteral method is named on the site of tissues at which the sterile parenteral injection are given
FORMULATION OF PARENTERAL PREPARATION
In the preparation of parenteral products active drug, vehicle or solvent and other substances i.e. Adjuvants are used.
1. Active drug
The active drug should have sufficient aqueous solubility.
It act as medium during the formulation of parenteral solutions, suspensions and emulsion: It may be aqueous or non-aqueous.
a. Aqueous vehicle
Water of special grade is selected during formulation of parenteral because it is safe and also well tolerated by body. Different type of aqueous vehicle used are:
Water for injection
Water for injection free from CO2
Water for injection free from dissolved air
Bacteriostatic water for injection
Water for injection Parenteral preparation
Water for injection is water that-is intended for use in the manufacture of parenteral. Water for injection is free from volatile and non-volatile impurities and as well as from pyrogens.
The USP allows Water for injection to be produced by one of two means; either distillation or reverse osmosis. It should be used within 24 hours.
Water for injection free from CO2
It is sterile water for injection which is free from carbon dioxide. It is prepared by boiling water for injection for 10 minutes.
Water for injection free from dissolved air
It is water for injection which is free from dissolved air. It is prepared by boiling distilled water for 10 minutes and should be used immediately.
Bacteriostatic water for injection
Bacteriostatic Water for Injection, USP is a sterile, non-pyrogenic preparation containing 0.9% (9 mg/ml) of benzyl alcohol as a bacteriostatic preservative. It is supplied in a multiple-dose container. The pH is 5.7 (4.5 to 7.0). The bacteriostatic preservative must be chemically compatible with medicament.
Additives used in parenteral dosage form
Antimicrobial Benzyl alcohol, Benzethonium chloride, Propyl paraben, Phenol, Methyl paraben.
Anti-oxidants Ascorbic acid, Sodium bisulphite,thiourea
Buffers Acetates, phosphates, citrates.
Chelating agents Disodium edentate, Disodium calcium edentate,
Stabilisers Glycerin, Niacinamide, Sodium capeylate
Solubilizing agents Ethyl alcohol, Glycerin.
Tonicity adjusting agents Dextrose, Sorbitol, Lactose.
1. Washing of container and closures of parenterals
Containers and closures may be contaminated by various particles such as glass, rubber, fiber, or metal, as well as by bacteria, alkaline oxides or calcium oxides which need to be removed before the containers ate filled.
Effective washing is essential. Detergents are used for washing. Steam is also used to remove debris effectively and final rinse is done with water for injection. The containers and closures should be sterilized after cleaning.
2. Preparation and compounding
The product should be prepared and compounded under aseptic process. The specific parts of the final product are usually exposed to various sterilization practises. HEPA filters are mostly preferred at compounding area.
3. Filtration and sterilization
The prepared solution must be filtered and then sterilized. Filters having nominal pore size 0.22 um or less are used for filtration. They are used to remove bacteria and moulds but not viruses & Mycoplasmas. The product is then subjected to a sterilization Process such as heat or irradiation.
The filling of liquid preparation is done by vacuum filling, pressure filling, Gravity filling. In vacuum filling process, Vacuum is produced which draws liquid through delivery tube from reservoir into the bottle. Pressure filling is semiautomatic process. It is generally attached with an overflow tube connected to receiver which stop excess filling of containers. The gravity filling Process is slow and used for filling free high level so that the product is moved by gravity through the feed mechanisms into the containers.
4.1 Ampoule filling technologies
Ampoules are filled using modern and sophisticated machines. The sanitised ampoule tray directly kept in hopper of the unit. The wheel delivers ampoules one by one. On moving eccentric ampoule rack. During the slowdown of stand sequentially pre-gassing, post gassing, pre heating, filling and final sealing is achieved. Accordingly filled wrapped ampoules then collected on collection tray automatically.
Automatic liquid filling machine are machines are available to fill many bottles simultaneously and automatic control using programmable logic controllers to ensure precision. Specialized machines are also available that draws a precise amount of powder or granules which is delivered to ampoules through a compressed air jets, mechanical or vibrating fillers or using a vacuum, The system also includes washing, sealing and labelling sections.
4.2 Vial filling technologies
The sterilized dry vial are fed below filling unit. The filling unit comprises of Filling Head, Needles & Nozzles which are used for liquid filling. After achievement of filling operation, starwheel delivers 6 vials organized on conveyor for rubber stoppering process.
Star wheel, Bowl, Vibrator unit are present. Then vial further move on sealing station. Vial during its rotation movement picks up aluminium seal. Now sealed vials are transferred on to the flat conveyor belt. Fully sealed vials are placid on out-feed tray.
The filling and sealing unit should be done under laminar flow work station. The ampoules after filling are sealed by either pull seal or tip seal method. In tip sealing, heat is consistently applied to the neck on all sides to allow melting and formation of a knot. Tip seals are common in liquid filled ampoules. Pull seal are used for containers filled with powder. The neck is heated for some time till glass gets softens. An automated device is then used to pull and twist the top.
Sterilization is process of removal of microorganism. Different methods of sterilization are:
a. Moist heat sterilization: It is the most common and efficient sterilization agent. Autoclaves are used for this purpose. Autoclaves use steam heated to 121-134 °C under pressure. Oils are not sterilized by this method.
b. Dry heat sterilization: This is done either by flaming, incineration or a hot air oven. Burning is used for metallic devices like scalpels, scissors, needles, etc. Incineration is used especially for inoculating loops used in microbe cultures. The hot air oven is appropriate for dry material like some metal devices, powders, glassware, etc.
c. Filtration through bacteria proof filters: This is the quickest way to sterilize solutions without heating. Normally filters with a hole width of 0.2 um are used for the removal of bacteria. Membrane filters are more commonly used filters over sintered or Seitz or candle filters.
d. Radiation sterilization: This method used radiation (UV, X-rays, gamma rays) for sterilization. X-rays and gamma rays have far more penetrating power as compared to UV rays. Gamma radiation is usually used for sterilization of throwaway medical equipment, such as needles, cannulas, syringes and IV sets, and food items.
e. Chemical method of sterilisation: In this method, gases are used for sterilisation. The commonly used gases for sterilization are a combination of ethylene oxide and carbon-dioxide, Carbon dioxide is added to minimize the chances of an explosion.
Ozone gas is also used which oxidize most organic matter. Other examples of chemicals used for sterilization are Hydrogen peroxide, Nitrogen dioxide, Glutaraldehyde and formaldehyde solutions, Phthalaldehyde, and Peracetic acid.
f. Packing and Labelling: Injection’s are packed either in single dose and multi-dose containers. The packing should provide accurate information regarding the product to be used. Those parentrals preparation which are in solution or dispersion form, the concentration of active ingredients should be mentioned in term of mass or biological activity per volume. In case of concentrated solution, label should indicate both composition and dilution to be carried out before use.
There are several different parenteral formulations are available;
1. Injectable solution
It is most common type of dosage form. It is prepared by dissolving the drug and excipients in a vehicle. The resulting solution is filtered through 0.22 um membranes filter and adjust the pH, Preservatives can be used for small volume parenterals with multiple dose.
2. Injectable suspension
These are the formulation in which active ingredient is suspended in aqueous vehicle containing antimicrobial preservative, suspending agent, a surfactant and buffer. Suspension are formulated to provide prolonged drug action.
Suspension are never injected by IV route. They are administered by Intramuscular, subcutaneous, intradermal routes.
Suspension should have good syringe ability and inject ability to be properly administered. The drug particle should be easily re-suspended with mild shaking.
3. Injectable Emulsion
Emulsion consist of aqueous phase, oily phase and emulsifying agent. They are either oil in water (o/w) or water in oil (w/o) type. Some drug shows more stability, efficacy or safety in the emulsion form. The anti-inflammatory activity of dexamethasone palpitate parenteral emulsion is 5-6 times of dexamethasone solution parenterals.
4. Dry powder parenteral
Many drugs are formulated in powders to be reconstituted prior to administration due to their instability in water. e.g. Penicillin’s, barbiturates, benzocaine. Sterile water. For injection is supplied with dry powders to make solutions / suspensions for injections.
Different methods of preparing a sterile drug powder are:
1. Sterile recrystallization: In this method, drug is dissolved in a solvent and the resulting solution is sterilized through 0.22 um membrane filter. A sterile anti-solvent is then added to crystalize the drug particles, which is filtered and dried aseptically.
2. Lyophilisation: It is a process of separating a solid substance from solution by freezing the solvent and evaporating the ice under vacuum. Drug solution is disinfected into sterile plates which are aseptically loaded into a Freeze dryer.
CONTAINERS AND CLOSURES
The container for parenteral product should maintain the integrity of the product as a sterile, pyrogen-free, high Purity preparation till it is used. The container should also be attractive and strong enough. It allow easy withdrawal of the contents. It should not interact with the product.
a. MATERIAL USED FOR CONTAINER
Glass is used for containers of parenteral products. Soda lime glass and borosilicate glass are mostly preferred. The thin film of silicone are applied to coat the inside surface of the vials and ampoules to prevent interaction of the product with the glass surface. This process is called siliconization.
b. MATERIAL USED FOR CLOSURE
Rubber is the material of choice for closures for multi-dose vials, intravenous fluids bottles, Plugs for disposable syringes and bulbs for ophthalmic pipettes, Rubber closures allow ease in introduction of a needle into a multi-dose vial.
A variety of natural polymer and synthetic rubber polymers are used. In addition a vulcanizing agent usually sulphur, an accelerator e.g. accelerator, usually zinc oxide, fillers such as carbon black or limestone, Anti-oxidants and lubricants etc. may also be present in rubber closures.
These substances may cause leaching or chemical interaction. Therefore, Lacquer or plastic coating is applied to the surface of the rubber closures to reduce leaching and also permeation.
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