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PARENTERALSPrepeared by: Saran TahirRoll No.66-E-14Subject: PharmaceuticsPresented to: Madam Bushra Nasir

Introduction Theadministrationofdrugsthroughthepatientbyinjectionunderthroughoneormorelayeroftheskinormucousmembrane.ThetermparenteralderivesfromthegreekwordPara(outside)Enteron(Intestine)Itdenotesthatrouteofadministrationotherthanoralroute.

Advantages ItprovidesrapidonsetofactionItprovidesimmediatetherapeuticactionItcanbeadministeredaccuratedose.Itcanbegiventopatientswhocannottakeoral medication.Itminimizethefirstpasseffect.Itprovidesmorebioavailability.

Disadvantages ItshouldbeadministredasepticallyItproducespainatthesiteofinjectionTheadministredofdrugthroughwrongroutemay provefataleffectSelfadministrationisnotpossibleIfpyrogenicpreparationsleadtoveryharmfuleffect.

Routes of administration IntraMuscular(IM) (Solutions , oils , emulsions , suspension)Intradermal(ID) Intravenous(IV)(Aqueous sol. Liposome , emulsions , )Subcutaneous/Hypodermic(SC) (vaccine , Insulin , Scopolamine)Intraarticular (NSAids , Morphine , Antibiotics)Intrathecal (Analgesics , Neuroleptics) Intracardiac ( cardiotonic , calcium salt as Channel blockers)Intraplueral (Narcotics , Chemotherapeutic agent)

Types of ParenteralsPowderforinjection.egCefuroximeforinjectionColloidalsolution.eg.IrondextranInjectableemulsion.egPropofolUSPInjectablesuspension.egMethylprednisoloneacetateOilyinjection(solution).egDimercaprolinjection.Infusionfluid

Preformulation factors Itisstudyaboutphysical&chemicalpropertiesofdrugsubstance priorformulationiscalledaspreformulation.pHSolubiltypkaDissociationconstantCompatabiltystudiesFTIR/DSCOxidation&reductionparticlesize

Formulation of parenterals Solutes Addedsubstance Antimicrobialagent Buffers Antioxidants Tonicityagent cryoprotectant Suspendingagent Emulsifyingagent Vehicle AqueousWFI NonaqueousEg.arachisoil

Formulation Of parenteral ProductIn the preparation of parenteral product the following substances are added to make a stable preparation.The active drugVehicles(Aqueous&Non-aqueous)(Aqueous vehicle)Water for injection free from CO2(Non-Aqueous vehicle)Ethyl-alcohol,Propylene glycol,Almond oil

Adjuvants1: Solubilizing Agents (Pureens & Polisorbates)2:Stabilizers & Antioxidants (Thio-urea,Ascorbic Acid,Tocopherol)3:Buffering Acids (Citric Acid , Sodium-citrate)4:Anti-bacterial Agents (EDTA-Ethylene-diamine tetraacetic-acid)5:Suspending-Emulsifiying & Wetting agents (MC & CMC)6:Toxicity factors (Sodium-chloride , Dextrose)

Production Facilities of ParenteralsThe production area where the parenteral preparation are Manufactured can be divided into five sections.Clean Up AreaPreparation areaAseptic AreaQuarantine AreaFinishing & Packaging Area

Clean-up-AreaIt is not Aseptic areaAll the Parenteral Product must be free from foreign particles & micro-organism.Clean up area should be kept clean so that contaminents may not be carried out into Aseptic Area

Preparation AreaIN this area the ingredients of the parenterals preparation are mixed & preparation is made for filling operationIt is not essentially aseptic area but strict precautions are required to prevent any contamination from outside

Aseptic Area The parenteral preparation are filtered , filled into final containers & sealed should be in aseptic areaThe entry of personnel into aseptic area should be limited & through an air lock Coiling, wall of that area should sealed & paintedThe air in the aseptic area should be free from fibres ,dust & micro-organismsThe high efficiency particulate air filters (HEPA) is used for air UV lamps are fitted in order to maintain sterility

Quarantine AreaAfter filling sealing of sterilization the parenteral product are Held up in Quarantine area.Randomly samples were kept for evaluation tests are transfer into finishing or packaging area

Finishing & Packaging areaParenteral products properly labelled & packed .Provide protection against physical damage Packed in cardboard or plastic containers Ampules should be packed in portioned boxes

Containers & Closures1 : Glass2 :Plastics Ampoules (single dose) Vials (Multiple Dose) Cartridges Automatic Injector3 : Rubber closure with aluminium caps Small volume parentrals : less than 100ml Large volume Parentrals : more than 100ml

Evaluation Of Parenteral PreparationThe finished Parenteral product are subjected to the following tests , in order to maintain quality control .1 : Sterility test 2 : Clarity test3 : Leakage test4 : Pyrogen test & LAL test 5 : Assay test

Sterility testIt is a procedure carried out to detect and conform absence of any viable form of microbes in or on pharmacopeia preparation or product Method of sterility test Membrane Filtration MethodDirect inoculation Method

Membrane Filtration MethodMembrane filtration appropriate for ( Advantage)Filtration Aqueous PreparationsAlcoholic preparationsOily preparations Preparation miscible with or soluble in aqueous or oily (Solvents with no anti-microbial effect)All steps of this procedure are performed aseptically in a class of laminar flow Hood.

Direct inoculation MethodSuitable for samples with small volumes Volume of the product is not more than 10% of the volume of medium .Suitable method for aqueous solution oily , liquids , ointments and creams Direct inoculation of the culture medium suitable quantity of preparation to be examined is transferred directly into the appropriate culture medium & incubate for not less than 14 days

Observation & Results

Clarity Test Particulate matter is defined as unwanted mobile insoluble matter other than gas present in the product.If the particle size of foreign matter is larger than the size of foreign matter is larger than the size of R.B.Cs it can block the blood vessel .The permit limits of particulate matter as per I.P as follows .

Particle size in Micrometer Maximum No. of particles 10 5025 0550 Nil

Methods for Particulate Matter contaminationVisual MethodFiltration MethodCoulter counter MethodLight blockage Method

Leakage test

Pyrogen testPyro = (Greek=Fire) + Gen (Greek = Beginning)Fever producing metabolic by products of microbial growth & death Bacterial pyrogen are called Endotoxins Gram-negative bacteria produce more potent endotoxins than Gram + ve bacteria & fungi Endotoxins are heat stable lipopolysaccharides (LPS) present in bacterial cell walls , present in cell free bacterial filtrates .

Rabbit pyrogen testRabbits shows a physiological response to pyrogens similar to humansNot valid for products that could mask the test by having a physiological effect on rabbit.

USP Rabbit pyrogen testMethodGroups of three healthy , mature rabbits are chosen.Accurate thermometers are inserted into the rectum of the rabbits to record their body temperature (control temperature)Test solutions are warmed to 37 degree C prior to injection and then injectedRabbit temperature are recorded at 30 min intervals between 1-3 hours

Rabbit pyrogen TestResults :- Temperature decreases are considered as zero rise If no rabbits are individual temperature rise of 0.5 degree C or more its control temperature the products meets the requirement for the absence of pyrogensIf any rabbit shows an individual temp rise of 0.5 or more , continue the test using five other rabbits if not more than three of the eight rabbits show individual rise in temperature of 0.5 or more and the sum of the eight individual maximum temperature rise does not exceed 3.3 degree C the material under examination meets the requirements for the absence of pyrogens .

LAL (Limulus Amebocyte Lysate)TestLimulus amebocyte tet or bacterial endotoxin test for the validation of depyrogenation process .Reagent LAL reagent (limulus-Polyphemus)Reaction: In the presence of endotoxins a firm gel is formed within 60 minutes when incubated at 37 degree .

Chrachterstics of LAL TESTTest tube scale Only pyrogens of gram negative bacteria is detectedSemi quantitative testSenstivity in terms of endo-toxins unitIn-vitro testDosent measure fever producing potential of endotoxinSenstivity varies with different microbial sources of LAL