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DR.B.G.PRAJAPATI SKPCPER STERILE FORMULATIONS 10/5/2018 1 Dr.B.G.Prajapati
DR.B.G.PRAJAPATI
SKPCPER
STERILE FORMULATIONS
10/5/2018
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Dr.B.G.Prajapati
PARENTERAL INTRODUCTION
para: outside enteron: intestine (i.e. beside the intestine) Defined as sterile drug,solution or suspension that is
packaged in a manner for suitable administration byhypodermic injection either in the form prepared or afteraddition of a suitable solvent or suspending agent.
Parenteral products are injected through the skin ormucous membranes into the internal bodycompartments.
These are the preparations which are given other thanoral routes.
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CONTENTS
Definition
Introduction
Advantages
Disadvantages
Routes of administration
Formulation of product
Packaging
Sterilization
Special product of parenterals
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DEFINITION
Sterile products are dosage forms of therapeutic agents thatare free of viable microorganism.These includes parenteral, ophthalmic and irrigatingpreparation.Sterile products are more frequently solutions orsuspensions, but may even be solid pellets for tissueimplantation.
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Sterile Dosage form Categories
Pharmaceutical products. Biological products.Diagnostic agents. Allergenic extracts.Radiopharmaceutical products. Dental products.Genetically engineered or biotechnology products.Liposome and lipid products.
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ADVANTAGES
Quick onset of action.
Suitable for the drugs which are not administeredby oral route.
Useful for unconscious or vomiting patients.
Useful for patients who cannot take drugs orally.
Useful for emergency situations.
Suitable for nutritive like glucose and electrolyte.
Suitable for drug with low bioavailability.
Can be used for Modified/Controlled/Novel DrugDelivery System.
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DISADVANTAGES
Pain on injection.
Difficult to reverse an administered drug’s effects.
Sensitivity or allergic reaction at the site of injection.
Requires strict control of sterility & non pyrogenicitythan other formulation.
Only trained person is required Require specializedequipment, devices, and techniques to prepare andadminister drugs.
More expensive and costly to produce.
In overdose difficult to retrieve.
Route specific
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ROUTES OF ADMINISTRATION
ROUTES OF ADMINISTRATION
Three primary routes of parenteral administration are commonly employed
Subcutaneous
Intramuscular
Intravenous
Other routes: Intra–arterial, Intraarticular,Intraspinal, Intracerebral, Intracardial ,Intrapleural,Intraocular. Intrapritoneal.
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ROUTES OF ADMINISTRATION
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including the joints (intra-articular),
joint fluid area (intrasynovial),
spinal column (intraspinai),
spinal fluid (intrathecal),
arteries (infra-arterial),
the heart (intracardiac; in an emergency),
into a vein (intravenous, IV; most common),
into a muscle (intramuscular, IM),
into the skin (in-tradermal, ID, intracutaneous),
under the skin (subcutaneous, SC, sub-Q, SQ,hypodermic, hypo)
Intravenous Route
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Intravenous injection of drugs had its scientific origin in 1656in the experiments of Sir Christopher Wren, architect of St.
Paul's a Cathedral and amateur physiologist. Using a " bladderand quill for a syringe and needle, he injected wine, ale, opium,and other substances into the veins of dogs and studied theireffects.
Intravenous medication was first given to humans by JohannDaniel Major of Kiel in 1662 but was abandoned for a periodbecause of thrombosis and embolism in the patients so treated.
The invention of the hypodermic syringe toward the middle ofthe 19th century created new interest in intravenous techniques,and toward the turn of the 20th century, intravenousadministration of solutions of sodium chloride and glucosebecame popular.
Today intravenous administration of drugs is a routineoccurrence in the hospital, although recognized dangers are stillassociated with the practice.
Advantages
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Intravenous drugs provide rapid action compared-withother routes of administration, and because drugabsorption is not a factor.In emergencies, intravenousadministration of a drug may be lifesaving because of theplacement of the drug directly into the circulation andthe prompt action that ensues.
Optimum blood levels may be achieved with accuracyand immediacy not possible by other routes.
Drugs that are too irritating for intramuscular orsubcutaneous administration (e.g., chemotherapyagents) can be given by this route.
Both small and large volumes of drug solutions maybe administered intravenously
Disadvantages
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once a drug is administered intravenously, it cannot beretrieved. In the case of an adverse reaction to the drug,for instance, the drug cannot be easily removed from thecirculation, as it could, for example, by induction ofvomiting after oral administration of the same drug.
the intravenous dose may differ greatly from the oraldose. Thus, great care must be taken to preventoverdosing or underdosing. Example:The beta-blockerdrug class, such as metoprolol, there are vast differencesbetween intravenous (three bolus injections of 5 mg eachat about 2-rninute intervals) and oral dosing (100mg/day).
Possible Complications
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Thrombosis formation can results from many factors:extremes in solution pH, particulate material, irritantproperties of the drug, needle or catheter trauma, andselection of too small a vein for the volume of solutioninjected.
Phlebitis, or inflammation of the vein, can be caused bythe same factors that cause thrombosis.
Air emboli occur when air is introduced into the vein.The human body is not harmed by small amounts of air,but a good practice is to purge all air bubbles from theformulation and administration sets before use.
Particulate material is generally small pieces of glassthat chip from the formulation vial or rubber that comesfrom the rubber closure on injection vials.
Intramuscular Route
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Provide effects that are less rapid but generallylonger lasting than those obtained from IV.
Aqueous or oleaginous solutions or suspensions ofdrug substances may be administeredintramuscularly.
Depending on the type of preparation, absorptionrates vary widely. Solution>Suspension>Emulsion…
Given deep into the skeletal muscles.
The point of injection should be as far as possiblefrom major nerves and blood vessels.
Intramuscular Route
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Injuries may include paralysis resulting from neuraldamage, abscess, cyst, embolism, hematoma,sloughing of the skin, and scarring.
The volume of medication that may be convenientlyadministered by the intramuscular route is limited,generally to a maximum of 5 mL in the gluteal regionand 2 mL in the deltoid of the arm.
Subcutaneous Route/hypodermic
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Used for injection of small amounts of medication.
Injected at the loose interstitial tissue of the outerupper arm, the anterior thigh, or the lower abdomen.
The site of injection is usually rotated wheninjections are frequently given, as with dailyinsulin injections.
The maximum amount of medication that canbe comfortably injected subcutaneously is about 1.3mL, and amounts greater than 2 mL will mostlikely cause painful pressure.
SC
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Most typically, subcutaneous insulin needles are25 to 30 gauge with length of five-sixteenthsto five-eighths of an inch.
Irritating drugs and those in thick suspension mayproduce induration, sloughing, or abscess andmay be painful. Such preparations are not suitablefor subcutaneous injection.
Intradermal Route
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A number of substances may be effectively injectedinto the corium( dremis ), the more vascularlayer of the skin just beneath the epidermis.
These substances include various agents fordiagnostic determinations, desensitization,or immunization. The usual site for intradermalinjection is the anterior forearm.
A short (three-eighths of an inch) and narrow(23- to 26-gauge) needle is usually employed.
Usually only 'about 0.1 mL may be administeredin this manner.
IDEAL REQUIREMENTS
Sterility (must)
Pyrogen free (must)
Free from particulate matter (must)
Clarity (must)
Stability (must)
Isotonicity Solvents or vehicles used must meet specialpurity and other standards.
Restrictions on buffers, stabilizers, antimicrobialpreservative. Do not use coloring agents.
Must be prepared under aseptic conditions.
Specific and high quality packaging.
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FORMULATION OF STERILE DOSAGE FORM
Sterile dosage forms can be formulated as solutions,suspension, emulsion, liposomes, microspheres,nano systems and powders to be reconstituted assolution.
Solvent system suitable for sterile products arelimited to those that produce little or no tissueirritation, water is the most common.
All components must be pure.
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STERILE FORMULATIONS
Sterile dosage forms and delivery systems includeinjectables (ie, solutions, suspensions, emulsions,and dry powders for reconstitution), intramammaryinfusions, intravaginal delivery systems, andimplants.
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SOLUTIONS
A solution for injection is a mixture of 2 or morecomponents that form a single phase that ishomogeneous down to the molecular level.
“Water for injection” is the most widely used solvent forparenteral formulations.
However, a nonaqueous solvent or a mixedaqueous/nonaqueous solvent system may be necessary tostabilize drugs that are readily hydrolyzed by water or toimprove solubility.
A range of excipients may be included in parenteralsolutions, including antioxidants, antimicrobial agents,buffers, chelating agents, inert gases, and substances foradjusting tonicity. Antioxidants maintain productstability by being preferentially oxidized over the shelflife of the product
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SOLUTIONS
Antimicrobial preservatives inhibit the growth of anymicrobes that are accidentally introduced while doses arebeing withdrawn from multiple-dose bottles and act asadjuncts in aseptic processing of products.
Buffers are necessary to maintain both solubility of theactive ingredient and stability of the product.
Chelating agents are added to complex and therebyinactivate metals, including copper, iron, and zinc, whichgenerally catalyze oxidative degradation of drugs.
Inert gases are used to displace the air in solutions andenhance product integrity of oxygen-sensitive drugs.Isotonicity of the formulation is achieved by including atonicity-adjusting agent.
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SOLUTIONS
Failing to adjust the tonicity of the solution can result inthe hemolysis or crenation of erythrocytes whenhypotonic or hypertonic solutions, respectively, are givenIV in quantities >100 mL.
Injectable formulations must be sterile and free ofpyrogens. Pyrogenic substances are primarily lipidpolysaccharides derived from microorganisms, withthose produced by gram-negative bacilli generally beingmost potent.
Injectable solutions are very commonly used, andaqueous solutions given IM result in immediate drugabsorption, provided precipitation at the injection sitedoes not occur.
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SUSPENSION
A suspension for injection consists of insoluble solidparticles dispersed in a liquid medium, with the solidparticles accounting for 0.5-30% of the suspension. Thevehicle may be aqueous, oil, or both.
Caking of injectable suspensions is minimized throughthe production of flocculated systems, comprisingclusters of particles (flocs) held together in a loose openstructure.
Excipients in injectable suspensions includeantimicrobial preservatives, surfactants, dispersing orsuspending agents, and buffers.
Surfactants wet the suspended powders and provideacceptable syringeability while suspending agents modifythe viscosity of the formulation.
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SUSPENSION
The ease of injection and the availability of the drug in depottherapy are affected by the viscosity of the suspension and theparticle size of the suspended drug.
These systems afford enhanced stability to active ingredientsthat are prone to hydrolysis in aqueous solutions.
Compared with that of injectable solutions, the rate of drugabsorption of injectable suspensions is prolonged becauseadditional time is required for disintegration and dissolutionof the suspended drug particles.
The slower release of drug from an oily suspension comparedwith that of an aqueous suspension is attributed to theadditional time taken by drug particles suspended in an oildepot to reach the oil/water boundary and become wettedbefore dissolving in tissue fluids.
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EMULSION
An emulsion for injection is a heterogeneous dispersionof one immiscible liquid in another; it relies on anemulsifying agent for stability.
Parenteral emulsions are rare because it is seldomnecessary to achieve an emulsion for drugadministration.
Untoward physiologic effects following IV administrationmay occur, including emboli in blood vessels if thedroplets are >1 µm in diameter.
Formulation options for injectable emulsions are alsoseverely restricted because suitable stabilizers andemulsifiers are very limited. Examples of parenteralemulsions include oil-in-water sustained-release depotpreparations, which are given IM, and water-in-oilemulsions of allergenic extracts, which are given SC.
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EMULSION
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Intravenous fat emulsions (e.g., In-tralipid, 10, 20,30%, Clintec; Liposyn II, 10, 20%, Abbott; LiposynIII, 10,20,30%, Abbott) have gained acceptance foruse as a source of calories and essential fatty acidsfor patients requiring parenteral nutrition forextended periods, usually more than 5 days.
The product contains up to 30% soybean oilemulsified with egg yolk phospholipids in a vehicle ofglycerin in water for injection. The emulsion isadministered via a peripheral vein or by central ve-nous infusion.
DRY POWDER
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A dry powder for parenteral administration isreconstituted as a solution or as a suspensionimmediately prior to injection.
The principal advantage of this dosage form is that itovercomes the problem of instability in solution.
Intravaginal delivery systems
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Intravaginal delivery systems include controlledinternal drug release (CIDR) devices, progesterone-releasing intravaginal devices (PRID), and vaginalsponges. These systems are used for estrussynchronization in sheep, goats, and cattle.
Silicone is used in the manufacture of the T-shapedCIDR device and the coil-shaped PRID, whereasintravaginal sponges are made from polyurethane.
The active ingredients in these systems are syntheticor natural hormones such as progesterone,methylacetoxy progesterone, fluorogestone acetate,or estradiol benzoate.
Intravaginal delivery systems
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An applicator consisting of a speculum and aseparate plunger is used to insert sponges into thevaginal cavities of sheep and goats, and PRID intothe vaginal cavities of cattle.
A different type of applicator is used for insertingCIDR devices into the vaginal cavities of sheep,goats, and cattle.
Retention in the vagina depends on either the entiredevice (sponges and PRID), or the wings (CIDRdevice), expanding. With all 3 devices, gentlepressure exerted on the vaginal wall is responsiblefor retention of the device, which is >95%.
IMPLANTS
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The majority of implants used in medicine arecompressed tablets or dispersed matrix systems in whichthe drug is uniformly dispersed within a nondegradablepolymer.
Drug release from dispersed matrix systems involvesdissolution of the drug into the polymer, followed bydiffusion of the drug through the polymer, andpartitioning from the surface of the polymer into thesurrounding aqueous environment.
Implants are available to increase weight gain and feedconversion efficiency in food-producing animals. Theseimplants are typically prepared in a manner similar totablets.
IMPLANTS
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One controlled-release implant consists of a cylindricalcore of silicone, surrounded by an outer layer ofestradiol-loaded silicone.
A range of implants is available to enhance reproductiveperformance in breeding animals.
These include ear implants containing norgestometdispersed in polyethylene methacrylate or silicone, abiocompatible tablet implant containing deslorelin (aGnRH agonist) for use in mares that does not requireremoval, and a sustained-release pellet of melatonin,which is implanted in the ear of ewes to enhancebreeding performance.
Testosterone pellets are available for implanting in theears of wethers at doses of 70-100 mg every 3 mo for theprevention of ulcerative posthitis.
Formulation of sterile dosage forms/ Product Development
API/Drug
Vehicles: Water, Water Miscible vehicles, Non aqueous
vehicles
Excipient/Cosolvent/Cosolubilizers
Antimicrobial/Preservatives:
Benzyl alcohol, Bezethonium chloride, Butyl Paraben,
Chlorobutanol, Metacresol, Methylparaben, Phenol,
Phenylmercuric citrate, Propyl paraben, Thimersol
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COMPOSITION
Solubilizers, Wetting agents or emulsifiers:
Dimethylacetamide, Dioctyl sodium sulfosuccinate, Egg yolkphospholipid, Ethyl alcohol, Ethyl lactate, Glycerin, Lecithin,PEG40, castor oil, PEG 300, Polysorbate 20,40, 80Povidone , propylene glycol
Buffers:
Acetic acid, adipic acid, Benzoic acid and sodium benzoateCitric acid, ;lactic acid, maleic acid, potassium phosphate,sodium actate , sodium citrate and tartrate , tartaric acid
Bulking agents or tonicity modifiers:
Glycerin, lactose, mannitol , dextrose, NaCl , sodium sulfate,sorbitol
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COMPOSITION
Suspending Agents
Helatin , methyl cellulose, pectin, PEG 4000, Na CMC, Sorbitolsolution
Chelating Agents
EDTA disodium, Edetate calcium disodium, EDTA tetrasodium
Local Anaesthetics
Procaine HCl , Benzyl alcohol
Stabilizers
Creatinine , glycine , naicinamide , sodium acetyltryptophanate ,sodium caprylate , sodium saccharine
Antioxidants
Ascorbic acid Sodium bisulfate Sodium metabisulfate , thiourea ,BHT, Tocopherol
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VEHICLE
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AQUEOUS VEHICLES
NON AQUEOUS VEHICLES
WATER-MISCIBLE VEHICLES
AQUEOUS VEHICLES
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WATER
Used for washing, rinsing, and as a vehicle
The quality aspects of a water system are affected bythe quality of the raw or potable water, anyprocessing it receives, and the distribution system.
If microorganism can exist in water means that theproduction of sterile water poses special problems ofpreparation, storage, and distribution.
The microbial and chemical quality of water is ofgreat importance in parenteral products.
AQUEOUS VEHICLES
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Most raw or potable water used in pharmaceutical processescontains a wide variety of contaminating electrolytes, organicsubstances, gross particulate matter, dissolved gases, such ascarbon dioxide, and microorganisms.
Bacteria indigenous to fresh raw water include Pseudomonassp., Alcaligenes sp., Flavobacter sp., Chromobacter sp., andSerratia sp. Bacteria that are introduced by soil erosion, rain,and decaying plant matter include Bacillus subtilis, B.megaterium, Klebsiella aerogenes, and Enterobacter cloacae.
Bacteria that are introduced by sewage contamination includeProteus sp., Escherichia coli and other Enterobacteria,Streptococcus faecalis, and Clostridium sp. Stored waterbacteria contamination include mainly gram-negative bacteriaand other microorganisms, such as Micrococcus sp.,Cytophaga sp., yeast, fungi, and Actinomycetes.
Classification of Water
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Drinking Water
Essentially, it should be free from known pathogens andfrom fecal contamination, such as E. coli, but it maycontain other microorganisms.
Frequently contains significant levels of microorganismsand a variety of chemical impurities.
Chemical and microbiological testing of drinking waterusually includes pH, free chlorine, chloride, sulfate,ammonia, calcium and magnesium, carbon dioxide,heavy metals, oxidizable substances, total solids, andbacteriological purity for total microbial count and E.coli.
Classification of Water
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Purified Water
Produced by passing the drinking water throughanion and cation exchange resin beds or reverseosmosis.
Ion-exchange treatment will remove dissolved ionicimpurities but it does nothing to improve themicrobiological quality of the water.
Ion-exchange beds that are not frequentlyregenerated with strong acid and alkali willcontribute significantly to bacteriologicalcontamination, leading often to pyrogenic problems.
Classification of Water
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Reverse osmosis treatment will remove a largeportion of the dissolved minerals, particulates,bacteria, viruses, and pyrogens.
Chemical and microbiological testing of purifiedwater includes determination of pH, chloride,sulfate, ammonia, calcium, carbon dioxide gas, heavymetals, oxidizable substances, total solids, andbacteriological purity for total microbial count and E.coli.
Water for injection
Bacteriostatic Water for Injection
Sterile Water for Injection
AQUEOUS VEHICLES
A. Aqueous vehicle :1.Water For Injection(WFI) USP :
Water for injection is intended not only to conform to ahigh degree of chemical purity but also to be free frompyrogenic substances.
USP requirement include not more than 10 parts permillion of total solids.
WFI may prepared by either distillation or reverseosmosis.
Distillation is the most widely used and acceptedmethod of producing sterile pyrogen-free water.
pH of 5.0 to 7.010/5/2018
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AQUEOUS VEHICLES (WFI)
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The bacterial contaminants of distilled water areusually gram-negative bacteria.
The heating and storing of water for injection at80°C will prevent bacterial growth and theproduction of pyrogenic substances that accompanysuch growth.
Chemical and microbiological testing of water forinjection include pH, chloride, sulfates, ammonia,calcium, carbon dioxide, heavy metals, oxidizablesubstances, total solids, and pyrogen.
Stored in chemically resistant tank.
AQUEOUS VEHICLES
2. Bacteriostatic Water for Injection (BWFI) :
This type of water used for making parenteralsolutions prepared under aseptic conditions and notterminally sterilized. Need to meet USP sterility test.It can contain an added bacteriostatic agent when incontainers of 30ml or less
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AQUEOUS VEHICLES
3. Sterile Water for Injection USP
SWFI containing one or more suitable bacteriostaticagents. Multiple-dose containers not exceeding 30ml. They are permitted to contain higher levels ofthan WFI because of the possible leaching of glasscontainer. Sterile Water for Irrigation. Washwounds, surgical incisions, or body tissue
4. Sodium Chloride Injection, USP
5. Bacteriostatic Sodium Chloride Injection, USP
6. Ringer's Injection, USP,Ringer's Injection, USP
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NON AQUEOUS VEHICLES
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Used when limited water solubility of amedicinal substance or its susceptibility tohydrolysis.
Fixed vegetable oils, glycerin, polyethyleneglycols, propylene glycol, alcohol, and a num-ber of less often used agents, including ethyloleate, isopropyl myristate, and dimethylacetamide.
NON AQUEOUS VEHICLES
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Properties of a non aqueous vehicles The selected vehicle must be nonirritating, nontoxic in the
amounts administered, and not sensitizing It must not exert a pharmacological activity of its own It should not adversely affect the activity of the medicinal agent It should be physicallyl and chemically stable at various pH levels Its viscosity must be such as to allow ease of injection (suitable for
use in syringes,syringeability) Its fluidity must be maintained over a fairly wide temperature range Its boiling point should be sufficiently high to permit heat ster-
ilization It should be miscible with body fluids It should have low vapor pressure to avoid problems during heat
sterilization It should have constant purity or ease of purification and
standardization
NON AQUEOUS VEHICLES
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Nonaqueous vehicles may be used provided they are safe in theamounts administered and do not interfere with the therapeuticefficacy of the preparation or with its response to prescribedassays and tests.
USP specifies restrictions on the fixed vegetable oils inparenteral products.
They must remain clear when cooled to 10°C (50°F) to ensure the stability and clarity of the injectable product during refrigeration.
The oils must not contain mineral oil or paraffin, as these materials are not absorbed by body tissues.
The fluidity of a vegetable oil generally depends on the proportion of unsaturated fatty acids, such as oleic acid, to saturated acids, such as stearic acid.
Oils to be employed in injections must meet officially stated requirements of iodine number and saponification number.
NON AQUEOUS VEHICLES
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Examples of fixed oils used in injections
Corn oil, cottonseed oil, peanut oil, and sesame oil.Castor oil and olive oil have been used on occasion .
Although the toxicity of vegetable oils is generallyconsidered to be relatively low, some patients exhibitallergic reactions to specific oils.
Thus, when vegetable oils are employed in parenteralproducts, the label must state the specific oil.
WATER-MISCIBLE VEHICLES
Primarily used to effect solubility of drugs and/orreduce hydrolysis.
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PRESERVATIVES & BUFFERS
Preservatives
Required to prevent microorganism growth Limitedconcentration of agents - Phenylmercuric nitrate andThiomersol 0.01% Benzethonium chloride andbenzalkonium chloride, Phenol or cresol 0.5% -Chlorobutanol 0.5%
Buffers
Added to maintain pH Results in stability Effectiverange, concentration, chemical effect
e.g Citrate and Acetate buffer, and Phosphate buffer
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TONICITY ADJUSTERS
Electrolytes:Nacl
Non elecrolytes: Glucose,Mannitol,Glycerine
Ex. Of isotonic:Dextrose injection 5%&Nacl injection 0.9%
Not important in IM& SC
Important in ID,intraspinal
Toncity can be measurement by:
osmometer,Fragility point
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OTHER ADDITIVES
Surfactant:Polysorbate ethers
Suspending agent:Methyl cellulose,CMC,PVP
Emulsifiers:Lecithin
Chelating agents:Disodium EDTA
Compexing agent:2-OH propyl b-cyclodextrane
Protein stabilisers:Amino acids,pvp
Antioxidants:Ascorbic acid,Cysteine
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PACKAGING
The microbial flora of parenteral packagingcomponents is affected by its composition,transportation exposure, and storage conditions.Packaging components and closure systems used forparenteral filling have to be sterile and pyrogen free.
Glass containers and rubber stoppers, particularlythose transported in cardboard boxes, often containmold spores of Penicillium sp. and Aspergillus sp., andbacteria, such as Bacillus sp. andMicrococcus sp.
Aluminum, Teflon, metal foils, and other polymericmaterials, all of which usually have a smoothimpervious surface free from crevices or interstices, areusually free from microbial contamination.
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Packaging Design
Commercially available packaging designs forparenteral products are
glass single-dose ampuls sealed by fusion,
glass single- or multiple-dose vials with elastomericclosure and
aluminum overseal; glass or polymeric bottles ofmore than 50 ml for large volume intravenousadministration, and
cartridges of various designs and components thatinvolve one or more of the above materials, plus theattached needle.
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Packaging Material Reqirment
Parenteral containersintended to provideprotection from light mustmeet the requirements forthe USP lighttransmission test (Table).The light-resistant ambercolor of parenteralcontainers results from aninteraction between ironand sulfur for greenishamber or iron andtitanium for brownishamber.
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PACKAGING
Packaging materials:Glass ,Plastic,Rubber
Sealing Ampoules Ampoules are unique in that the primary and secondary seal are the same.
Ampoules are sealed by melting a portion of glass in a flame.
Pull seal – Slow, Reliable, powder or other types with wide opening Roll or Tip seal
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CONTAINERS AND CLOSURES
GLASS CONTAINER
Glass is still the container of choice for small volumeparenterals because of its chemical resistivity as well asresistant to water, acids, bases, and salts to varyingdegrees. .
It is composed of silicon dioxide, with varying amounts ofother oxides such as sodium, potassium, calcium,magnesium, aluminium, boron and iron.
The basic structural network of glass is formed by siliconoxide tetrahedron.
However, glass can be chemically active under certainconditions, for example, the formation of flakes inneutral saline solutions.
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CONTAINERS AND CLOSURES
Boric oxide will enter into this structure, but most ofthe other oxides do bot.
The latter are only loosely bound and relatively freeto migrate.
These migratory oxides may leached into a solutionin contact with the glass.
The oxides thus dissolved may hydrolysed to raisepH of the solution and catalyse or enter intoreaction.
Such occurrences can be minimize by properselection of glass composition.
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TYPES OF GLASS
Type I : A borosilicate glass
Type II: a soda lime treated glass, silicone coated
Type III: a soda lime glass NP: General Purpose sodalime glass, not for parenteral.
Type I glass is composed of silicon dioxide (81%) andboric oxide (13%) with low level of non-networkforming oxides.
While Type II and type III glass compounds arecomposed of relatively high proportion of sodiumoxide (14%) and calcium oxide (8%).
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Typical Composition of Glass
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Type I and II Glass
As Type I glass is made from a chemically highresistant borosilicate glass. It has low leachability, lowthermal coefficient of expansion, and is generallysuitable for all parenteral drug products
Type II glass is made from dealkalized soda-lime glass,containing approximately 10% each of sodium oxideand calcium oxide. The presence of these two oxidesmakes this type of glass chemically less resistant thanType I.
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Type II and III Glass
However, its chemical resistance can be improved bydealkalization using sulfur dioxide.
This improved glass inner surface will break down, ifit is repeatedly exposed to heat sterilization, thermaldepyrogenation, or alkaline detergent treatments.
Thus, it is suitable for a one time use, for a drugsolution that has been buffered to a pH below 7, or aproduct that is not reactive with this type of glass,like most antibiotic sterile solids.
Type III glass is also made from a soda-lime glassthat contains relatively higher levels of sodium andcalcium oxides than Type II. It is generally used fordry drug products.
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Treatment to Glass
Parenteral containers made of glass may be treatedin order to reduce alkalinity or improve the innersurface.
This is usually accomplished by sulfur dioxide hotgas treatment, glass annealing at highertemperature, or hydrofluoric acid washing.
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Polymeric Container
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PLASTIC COTAINERS
Principle ingredient of plastic containers are thermoplasticpolymers like polyethylene, polypropylene, PVC,polycarbonate, polyamide, polystyrene, teflon. Plasticmaterials used in the medical field have less otheradditives.
In certain cases, some amount of plasticizer, fillers,antistatic agents, antioxidents and other ingredients maybe added.
Most of the plastic containers melt at elevatedtemperatures except polyethylene and polystyrene.Plastic materials used mainly because they are lightweight, no breakable and with low additives have lowtoxicity and low reactivity with products.
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PLASTIC COTAINERS
Reactivity can be occur with sorption of the polymer insome cases. Additive leached and may react with theproducts.
Most polymers are adversely affected by elevatedtemperatures required for thermal sterilization andhave a relatively high permeability for water vapor.
Significant permeation of gases like oxygen may occurwith some plastic containers.
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RUBBER CLOSURES
Rubber closures are used to seal the openings ofcartridges, vials and bottles and permeate andwithdrawal of needle without loss of integrity of thesealed containers.
Rubber closures are compounded of severalingredients like natural rubber or synthetic polymersusually sulfur and 2 mercaptobenzothiazole.
Closure should be completely nonrective with theproducts.
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SEALING
Sealing of Bottles, Cartridges and Vials Primary sealconsisting of a tight rubber or plastic closure andsecondary seal that holds the primary seal in place.Secondary seals are usually aluminum caps that arecrimped on to a thread less container.
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Parenteral containersintended to provideprotection from light mustmeet the requirements forthe USP lighttransmission test (Table).The light-resistant ambercolor of parenteralcontainers results from aninteraction between ironand sulfur for greenishamber or iron andtitanium for brownishamber.
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STERILIZATION
STERILIZATION
Steam sterilization
Dry heat sterilization
Sterilization by filtration
Gas sterilization
Sterilization by ionizing radiation
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SPECIAL TYPES OF PARENTERALS
Suspension
Emulsion
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SUSPENSION
Parenteral suspension is a dispersed,multiphased,heterogeneous system of insoluble solid particlesintended principally for intramuscular andsubcutaneous injection.
Because a delicate balance of variables is required inorder to formulate a suitable product, a suspension isone of the most difficult parenteral forms to prepare.
Such a product must not cake during shipping andstorage and should be easy to suspend and injectthrough an 18 to 21 gause needle throughout its shelflife.
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SUSPENSION
To achieve these goals it is necessary to control thecrystallization, particle size reduction,andsterilization of the drug substance.
Suspension give prolong drug relese.particle size ofdrug shoud be small and uniform.
Suspension require following additives wettingagent,suspending agent,buffering agent,preservative, antioxidant,ionicity agents
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Example of ingredients used in aqueous parenteral suspensions
Suspending agent
Gelatin, mannitol,povidone
Surfactants
Lecithin,polysorbate 80.
Solubilizing agents
Propylene glycol
PH adjustment
Citric acid, sodium citrate.
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Methods for Parenteral Suspension
Two basic method are used to prepare parenteralsuspension;
1 .sterile vehicle and powder are combinedaseptically.
2.sterile solutions combined and crystalformed in situ.
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Problems in Parenteral Suspension
Problems encountered in suspension formulation are:
Settling and caking.
Polymorphic transformation.
Crystal growth.
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EMULSIONS
An emulsion is a heterogenous dispersion of one immiscibleliquid in another.
This inherently unstable system is made possible through theuse of an emulsifying agent, which prevent coalescence of thedispersed droplet.
Parenteral emulsion are rare because it is necessary(anddifficult) to achieve stable droplet of less than 1 micron meterto in prevent emboli in blood vessels and it is not usuallynecessary to achieve an emulsion for drug administration.
Formulation options are severely restricted through a verylimited selection of stabilizers and emulsifiers primarily dueto the dual constraints of autoclave sterilization andparenteral injection.
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EMULSIONS
Parenteral emulsions are used for several purposes, including :
Water-in-oil emulsions of allergenic extracts
Oil-in-water sustained-release depot preparations
Oil in-water nutrient emulsion.
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EMULSIONS
Problems encountered in emulsion formulation:
1.creaming and cracking
2.Rancidity in oil phase
3.Partitioning of preservative between oil and water phase
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TESTING
The physicochemical tests includes
pH,
Turbidity,
Residue on drying,
Iodine number and
Heavy metal content.
The biological tests on saline, polyethylene glycol400 and cottonseed oil extracts includes acute andchronic toxicity on mice and rabbits.
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