Slide 2: PARENTERAL FORMULATION FORMULATION OF PARENTERAL PRODUCTS : FORMULATION OF PARENTERAL PRODUCTS PRESENTED BY
ABIKESH PRASAD KUMAR MAHAPATRA
1ST SEMESTAR Slide 4: Sterile products are dosage forms of therapeutic agents that are free of viable microorganism
Principally these include
opthalmic Parenteral products : Parenteral products Derived from Greek words
Para – Beside Enteron – Intestine
So parenteral administration includes the administration of drugs by any route other than intestine.
Definition:- in pharmaceutical practice however parenteral products are considered to be the sterile drugs,solutions,suspension or emulsions that are administrated by hypodermic injection either in the form in which they are supplied or after the adition of suitable solvent or suspending agent.
These are unique among dosage forms of drugs because they are injected through skin or mucus membrane into the body compartments. Slide 6: The parenteral products by passes the 1st line of body defence , the skin and mucus membrane they must be free from
High level of purity
All component and process involved in the preparation of these products must be Selected and designed to eliminate as much as possible contamination of all types whether of physical, chemical or microbial origin. The steps to be given important : The steps to be given important The organizational divisions normally responsible for the preparation of sterile products in the pharmaceutical industry are
Packaging Product development : Product development Formulation goals: Adequate conc. of the drug at the site of action
IV route – absence of absorption
I.V. – adequate solubility, minimize probability of precipitation at site of injection
I.M. and S.C. – absorption from the site of injection Active drug : Active drug Thorough evaluation of properties of active drug/s is highly essential for safe and stable dosage form
Solubility and rate of absorption.
Aqueous solubility of the drug for dissolution
Physical state of the drug – crystalline /amorphous, particle size, formulation pH Chemical modification of the drug : Chemical modification of the drug Improvement of the properties of the drug may be achieved by the chemical modification of the parent drug
Preparation of ester, salt, or other modification may be employed to increase stability, alter solubility, enhance depot action, avoid formulation difficulties, decrease pain on injection
Prodrug – modified drug converts back into the active parent structure – in body system or after reconstitution
Antibiotic prodrugs – benzathine penicillin, procaine penicillin, metronidazole phosphate, chloramphenicol sodium succinate
Steroids- methyl prednisolone formulated as methyl prednisolone sodium succinate, hydrocortisone as hydrocortisone sodium succinate Slide 11: a drug is prepared for parenteral use by the mfg. depend on :-
The physical & chemical properties of the drug
If a drug is unstable in solution it may be prepared as
prepared as suspension of drug particle
Dry powder intended for reconstitution with the proper solvent at the time of administration.
If a drug is unstable in presence of waterthatsolvent may be replaced in part or totally by a solvent in which the drug is insoluble.
If a drug is insoluble in water prepared a s an :-
Solution of drug in an suitable non aqueous solvent
The onset & duration of a drug is increased by:-
Chemical form of the drug used
Physical state of injection (solution or suspension)
vehicle employed Added substances (excipients) : Added substances (excipients) Purpose:
Provide safe and efficacious parenteral product
Control product attributes
Aid in parenteral administration
Every attempt should be made to choose added substances that are accepted by regulatory agencies. Types of excipients : Types of excipients Antioxidants
Tonicity contributors Selection of excipients : Selection of excipients Addition of any additive should have a clear purpose /function/ justification
Meet the regulatory requirements all over the world since most pharmaceutical development is international in scope
Most formulators continue to depend on materials already being used in marketed products because extensive pharmacological and toxicological data is required to obtain approval for any new additive Antioxidants : Antioxidants Salts of sulphur dioxide, including bisulphite, metabisulphite, and sulphite are commonly used.
The antioxidants mainly function in 2 ways:-
By oxidised itself(acting as reducing agent).
By blocking an oxidative chain reaction .
Certain antioxidants act as synergistic which increases the effectiveness of other antioxidants particularly those blocking reactions.
Certain other group are there which form complex with catalyst and acclerate the reaction.
On oxidation sulphites may be converted to sulphates and other species
Sulphites can also react with drugs like epinephrine
Sulphites reported to cause allergic reactions in some asthmatics. Alternatives may be considered Preservatives : Preservatives Used in Multidose containers and Single dose products that are not terminally sterilized.
Used to inhibit the growth of microorganism.
the formulation scientist must be aware of Interactions between preservatives and other components .
Proteins can bind with thimersol reducing the efficacy
Benzalkonium chloride which is positively charged are incompatible with products containing anionic drugs and excipient.
Partitioning into a micellar phase or an oil phase in an emulsion can reduce the effective concentration of preservative
Preservative efficacy testing be done on proposed formulation to assure on effective preservative concentration.
Rubber closures and other containers used are incompatible with preservatives Buffers : Buffers Many drugs requires a certain pH range to maintain product stability.
Drug stability also depend on pH
Parenteral products formulated to possess sufficient buffer capacity to maintain proper pH
Factors influencing pH include:
Diffusion of gases through the closure
Effect of gases in the product
Weak base and salt of a weak base or weak acid and salt of a weak acid are normally used
Eg:-Acetates, citrates, phosphates
Amino acid are increasingly used for polypeptide injectable. Chelating agents : Chelating agents Form complexes and inactivate metals such as copper, iron and zinc that catalyze oxidative degradation of drug molecules
Sources of metal contamination:
Raw material impurities
Solvents such as water
Containers and Equipment
Most commonly used are Edetate disodium , citric acid and tartaric acid Inert gases : Inert gases The air within an injectable product is frequently replaced with an inert gas such as nitrogen to enhance the stability of the product by preventing chemical reaction between the oxygen in the air and the drug.
Butyl rubber stock is used with rubber stoppered products that are sensitive to oxygen because It provides better resistance to gas permeation than other rubber stocks. Tonicity adjustment agents : Tonicity adjustment agents IV solutions isotonic must be required.
Hypotonic causes haemolysis of RBC
Hypertonic causes crenation
Dextrose, Sod. Chloride, pot. Chloride are commonly used to adjust isotonicity ` : ` C. Vehicles : C. Vehicles Water for injection:-
Contains not more 1 mg per 100 ml water for injection.
Not require to sterile but must be pyrogen free.
Free from ions
Must be useeeeeed within preparation of 2 hours.
Sterile water for injection:-
Sterilized & sitabely packaged in a closed container not exceeding 1000 ml capacity.& not containing bacteriostatic agent.
Free from pyrogen & used inn the vials to prepare the desired injection.
Bacteriostatic water for Injection:-
A sterile water of injection containing one or more bacteriostatic agent.
Boiling of water makes it free from atmospheric gases & such water should be stored suitably so that reabsorption of oxygen should not be possible.
It is packaged in prefilled syringes or in vials containing not more than 30 ml of vials.
The water is employedb as a sterile vehicle in the preparation of small volume of injectable preparation.
Theoritically presence of bacteriostatic agent gives theflexibility of multiple dose vials. Slide 26: In addition to water some co-solvents are used to replace portion of water in certain formulation.
These co-solvents must be used either to increase the solubility of drug or to reduce its hydrolytic degradation.
commonly used water miscible solvents are ethyl alcohol,Glycerine,PPG,PEG and Dimethyl acetamide Nonaqueous vehicles : Nonaqueous vehicles WHY NON AQUEOUS VEHICLE?
Water precluded in a formulation due to limited water solubility of medicinal substance or susceptible to hydrolysis.
The solvent must be nonirrigating,Non-toxic and mustnt exert pharmacological activity of its own.
Physical & chemical properties of solvent must be considered.
Other consideration are :-
Viscosity-which allow ease of injection(syrengebility)
Fluidity-must be maintained over a wide range of tempreature
boiling point– high to permit heat of sterilization
Imiscibility-- with the body fluid
Purity and Standarddisation
No single solvent free o f limitation.
Mainly fixed vegetable oils are used
Restriction of Fixed oil:-
Must remain vclear when cooled to 10 celsius to ensure stability and clarity or injectable product upon storage under refrigereation.
Oils mustnt contain mineral oil such as paraffin as these materials are not absorbed by body tissue.
Must meet official requirement of saponification value & Iodine value. Slide 28: Vegetable oil:-
Toxicity is less but some persons show allergic reaction so the label state the specific oil present.
Most commonly used are corn oil, cottonseed oil,peanut oil,sesam oil.castor oil, and olive oil.
oleagenous injections are given I.m but not I.V because the oil globules will occlude the pulmonary circulation. D. Types of parenteral dosage forms : D. Types of parenteral dosage forms Solutions
Novel formulation Solutions : Solutions Most injectables are solution.
Solution of drugs suitable for parenteral administration are refered as injection.
According to USP injections are separated into
[Drug] Injection Eg:- Insulin
[Drug] for Injection Eg:-Cefamandole sodium
[Drug] injectable emulsion Eg:- Propofol
[Drug] injectble suspension Eg:-Methyl prednisolone acet
[Drug] for Injectable suspension Eg:-Imipenem
Dissolve the drug, excipients, adjust pH, sterile filter through 0.22micron membrane filter
Mix all ingredients
Filter all the resultant solution in 0.22 µm membrane filter
If possible autoclave the final product Slide 31: Sterile filtration with subsequent aseptic filling is common because of heat sensitivity of many drugs
LVPs and SVPs with no preservatives should be terminally sterilized
The formulator must be aware of the potential for binding when filtering protein solutions Dry powders : Dry powders Many drugs are too unstable either physically or chemically in an aqueous medium to allow formulation as a solution,suspension or emulsion.
Instead, the drug is formulated as a dry powder that is reconstituted by addition of water before administration.
The reconstitution product is usually an aqueous solution but occasion it may be aqueous suspension.
Freeze drying is the most common form of sterile water. Suspensions : Suspensions Solid content ranges from 0.5 to 5%. But may goes as high as to 30% in some antibiotic preparation.
Passage through 18-21 gauge needle
To achieve this:
Proper particle size distribution It is very important because of
predictable rate of dissolution
Uniform rate of sedementation
Various technique used for this purpose are
Fluid energy grinding
Dry milling Main problems associated : Main problems associated Solid granules forms cake
Surface active agent may reduce the interfacial tension between particle and vehicle
Eg:-Polysorbate 80,lecithin,emulphor EL-620
Hydrocolloid like sodium CMC increases the effect of surfectant
Stability sometime increase by increasing viscosity:-
By adding some amount of protective colloid
By adding compound such as sorbitol. Syringeability– Related to viscosity
Injectability – pressure required to inject,
Syringeability and injectability are related to viscosity and particle characteristics that is amount of solid. Emulsions : Emulsions The main problem is attainment and maintaince of uniform oil droplets of 1-5µ size as internal phase.
The important aspect is selection of emulgent.
The emulsion must be stable to autoclaving.
Elevated tempreature tend to produce coalscence of dispersed phase & excessive shaking cause accleration of rate of creaming.
Small amount of gelatin,dextran & microcrystalline cellulose added to stabilize the emulsion.
Preparation of parenteral emulsion is troublesome becoz of control of particle size control to prevent emboli in blood vessel by the limited choice of emulsifier and stabilizer of low toxicity & difficult to prevent the rancidity of oil phase. Novel Formulation : Novel Formulation Used to prepare sustained & control release formulation.
Carrier system like microsphere,liposomes,monoclonal antibodies & emulsions are used.
Drugs are incorporated into these system to increase the duration of action & to provide selective delivery of the drug to a specific site or organ.
Unwanted side effects & adverse reaction are reduced
Because of selective delivery. Protein formulations : Protein formulations The first biotech derived is human insulin approved by FDA.
Special problems with formulation and processing of proteins arise from the hierarchy of structural organization of proteins
In addition to primary structure, proteins have secondary structure , tertiary structure and in some cases quaternary structure and disruption of this higher order structure can lead to loss of biological active and leads to exposure of hydrophobic amino acid residue which cause problem in manufacturing process or in primary package.
Disruption of the higher order structure can lead to loss of biologically active or native conformation which may also cause physical and chemical instability
Suitable aspects of mfg. is important in protein preparation:-
Vigorous agitation causes foaming & air water interface which is excellent site for denaturaion & precipitation.
Loss of protein byadsorption tosurfaces when filter used in Mfg. process.
Maintaince of St. during process like temp.,pH.organic solvent Slide 39: Stabilization strategies include:-
Addition of additives such as other proteins (serum albumin), amino acids, and surfactants to minimize adsorption to surfaces
Modification of protein structure to enhance stability by genetic engineering methods
Chemical modification of protein such as formation of a conjugate with PEG REFERENCES : REFERENCES THANK YOU : THANK YOU THANK YOU