Parenterals bpk

Parenterals

Formulation development

Pragati Kumar BAsst ProffNimra College of PharmacyVijayawada

Introduction and importance of the studybull Parenteral products are products that are administered to

the body by injection bull Because this route of administration bypasses the normal

body defense mechanisms it is essential that these products are prepared with a high degree of care and skills than utilized in preparing conventional oral or topical products

bull The finished product must be sterile non-pyrogenic and free from extraneous insoluble materials These products must satisfy a number of requirements for parenteral products

Sterile formulations must meet a number of special criteria such as

bull Sterilitybull Particulate materialbull Pyrogen freebull Stabilitybull pHbull Osmotic pressure

During the formulation of parenteral products the following factors are critical

bull The vehicle in which the drug is dissolved or dispersed

bull Volume (dose) of the injectionbull Adjustment of isotonicitybull Adjustment of pHbull Stabilisersbull Preservativesbull Adjustment of specific gravity (for spinal anaesthesia)bull Concentration units

Difference between parenterals and other products

bull Limits to the level of pyrogens present and of particulate matter

bull The injection route dictates the volume of formulation Hence the solubility of the drug in the selected vehicle is critical in the formulation

Vehicle bull The preferred vehicle is water as it is well tolerated

by the body easy to administer and a large solvent capacity

bull Water for injection must be sterile and free from pyrogens

bull Cellulose glass rubber cores cloth or cotton fibres may constitute the contaminants list

bull Suitable filtration media for removal of particulate material are sintered glass filters or membrane filters with a pore size of 045-12 microns

Ph and Buffersbull As parenteral products are administered directly to tissues

and systemic circulation formulations prepared should not vary significantly from physiological pH which is about 74

bull The acceptable pH range is 3-105 for iv preparations and 4-9 for other routes

bull Buffers are included in injections to maintain the pH of the packaged product

bull The buffers used in the injection must allow the body fluids to change the product pH after injection

bull Acetate citrate and phosphate buffers are commonly used in parenteral products

Osmotic pressurebull The osmotic pressure of the blood is approx

300 milli OsmolesL and ideally any sterile solution would be formulated to have the same osmolarity

bull For eg 09 wv NaCl iv solution has an osmolarity of 308 milli OsmolesL

bull 5 wv Dextrose iv solution has an osmolarity of 280 milli OsmolesL

bull NaCl Mannitol or glucose can be used to adjust osmolarity

Antimicrobial agentsbull Aqueous preparations which are prepared

using aseptic preparations and which cannot be terminally sterilized may contain a suitable antimicrobial preservative in an appropriate concentration

bull Antimicrobial agents are added to multiple dose vials to inhibit the growth of microbial organisms which may occur accidentally and contaminate the product during use

bull Antimicrobial agents must be effective in the parenteral formulation

Antimicrobial preservativesSNO ANTIMICROBIAL AGENT CONCENTRATION (wv)

1 Benzalkonium chloride 0012 Benzyl alcohol 1- 23 Chlorobutol 025 ndash 054 Phenol 055 Chlorocresol 01 ndash 036 Phenyl mercuric salts 00027 Methyl hydroxy benzoate 01- 02

Atioxidants

bull Aqueous solutions are more susceptible to oxidation

bull Bisulphites and metabisulphites are commonly used antioxidants in aqueous injections

bull Injection formulations may in addition also contain chelating agents such as EDTA or citric acid to remove trace elements which catalyse oxidative degradation

Sterilization bull Sterility Absence of life or absolute

freedom from biological contaminationbull Sterilization inactivation or elimination of all

viable organism and their sporesbull Disinfectant substance used on non- living

objects to render them non- infectious kills vegetative bacteria fungi virus but not spores Eg Formaldehyde

bull Bactericide ( Germicide) substance that kills vegetative bacteria and spores

Advantages and disadvantages

Moist Heat

bull Spore are killed by moist heatbull Culture media amp other liquids

required to retain their content of water

bull Not applicable to waterproof materials such as oils and greases or dry materials

Pasteurization

bull Moist heat at temperature below 1000 Cbull Heat labile fluids may be disinfected not

sterilized by heating at 560 C for 30 minbull Sufficient to kill mesophilic bacteria but

not sporesbull For serum or other body fluids containing

proteins temp to rise above 59o Cbull UHT 140o C less than 1 sec

bull Cold Pasteurizationbull High pressure pasteurization

Washer Disinfectorsbull Washing machines using hot

water steam and detergents may be used

bull Washing action at 710 C for 3 min or 800 C for 1 minute sufficient to kill vegetative organism

bull Recommended for instruments contaminated with HBV and HIV

bull Accordingly it is set at 93o C for 10 min

Boiling at 100o C

bull Heating in boiling water at 100o C for 5 minutes sufficient to kill all vegetative bacteria HBV and some bacterial spore

bull Used only in case of emergencies to sterilize medical and surgical equipment

bull Heat labile articles and hollow or porous items where water will not penetrate lumen cannot be disinfected this way

Steaming at 100o C

bull To prevent glass from cracking which happens when it is heated directly

bull Also in case of heat labile culture media

bull Pure steam in equilibrium with boiling water at normal atmospheric pressure

bull Exposure to this temperature for 5 minutes will kill microorganism

Free Steaming

bull Koch and Arnold steamers are used

bull Useful for selective heat labile media like DCA XLD TCBS and Slenite F broth

bull These media do not support the growth of heat resistant bacteria

bull Tyndallization- 20 min for 3 succesive days

Steam sterilization

bull Irreversibly coagulates and denatures microbial enzymes and proteins

bull Important parameters for effectiveness

1 Exposure time2 Temperature of process3 Level of moisture4 Pressure

1) Advantagesbull 1048708 Non-toxicbull 1048708 Cycle easy to control and monitorbull 1048708 Inexpensivebull 1048708 Rapidly microbiocidalbull 1048708 Least affected by organicinorganic soilsbull 1048708 Rapid cycle timebull 1048708 Penetrates medical packing device lumens2) Disadvantagesbull 1048708 Deleterious for heat labile instrumentsbull 1048708 Potential for burns

Autoclaves

bull Invented by Charles Chamberland in 1879

bull Precursor was the Steam digester invented by Denis Papin in 1679

bull At correct temp lethal to all bacteria viruses fungi amp protozoa

bull Example of usage of autoclaves arebull Hospitals amp OPD- Porous load

autoclavesbull Mortuary- Bench top autoclavesbull Microbiology Lab Media preparators

or fluid cycle steam sterilizersbull Pharmaceutical- Fluid Cycle Sterilizer

Types of autoclavesbull Simple laboratory autoclavebull Transportable bench top autoclavesbull Large simple autoclavebull Downward displacement autoclavebull Multipurpose laboratory autoclavebull Pre vacuumbull High security autoclavebull Porous load sterilizerbull Low temperature steambull Steam flash pressure pulsing steam sterilization

autoclaves

bull Sterilization Hold Timebull Heat Penetration Timebull Condensation of steam 3 effects1 Wets microorganisms2 Liberates latent heat3 Significant contraction of steam

bull Time and temperature with pressure required for sterilization by steam under pressure in autoclave

bull 121-124o c at 11 bar for 15 minbull 134-138o c at 22 bar for 3 min1 bar=1 atm pressure=147

pounds per square inch

bull Steam which is present must be 1 Saturated 2 Dry3 Pure Steam supply1 Superheated steam ( Dry gas)2 Wet steam

bull Removal of air1 Simple transportable (pressure-cooker)

autoclaves2 Downward displacement autoclaves3 Porous load autoclavesbull Items to be put in autoclave1 Unwrapped non porous items2 Porous loads3 Discard loads4 Fluids in sealed containers5 Nutrient media

Simple laboratory autoclave

1 Considered unsatisfactory2 Not monitor temperature of load

and therefore cannot prevent spoiling nutritive value

3 No safety interlock

Transportable bench top autoclaves

bull Sophisticated version of air displacement autoclave

bull Possess automatic cycle control with indicator for cycle failure and thermal safety

bull Disadvantages of this are1 Not fitted with vacuum assisted air

removal2 No assisted drying3 Cannot be used for porous loads

packaged items or discard loads4 Cant handle liquid loads

Large simple autoclave

bull Larger version of simple pressure cooker

bull No means of assisted air removalbull Size too large to permit removal of

airbull Unsuitable for wrapped articles and

make safe loads

Downward displacement laboratory autoclaves

bull Provision for removal of air from chamber balanced pressure steam trap

bull Other devices assist the drying of the loadbull No vacuum assistance for air removalbull Air removal was found to be inadequatebull Only value is sterilization of unwrapped

non-porous metallic itemsbull Cooling may take many hours to be below

80o C

Multipurpose laboratory autoclaves

bull Different types of load require different cycles required for these different loads

Special featurebull Presence of efficient means of assisted air

removal and drying assisted cooling and a temperature sensitive probe reading directly from the load

Multipurpose laboratory autoclaves ( Contd)

bull Aqueous media1 Accelerated cooling required to avoid damage

to nutrient properties of culture medium2 Cooling to below 80o C before autoclave is

opened minimize risk of breakage and explosions

3 Volume of DIN bottle which is used should be not over 80

4 Duration of heating up period should be controlled automatically with a thermocouple placed in one of the largest bottle or simulators which reproduces thermal characteristic of bottle

Multipurpose laboratory autoclaves ( Contd)

bull 121o c for 15 min Cooling of load should be assisted so that media are cooled to under 80o c in 30 min

bull Methods of coolingbull Cooling time duration set by a

thermocouple placed in simulator bull Air blastingbull Glasswares are satisfactorily

processed as part of a fluid cycle

1 High security autoclave

2 Porous load sterilizer

3 Low temperature steam

Gas sterilization

bull For delicate heat labile equipmentsbull Monitoring their efficacy by biological test