Parentral Preparations

PARENTRALS The term parentral derived from para meaning beside and enteron meaning intestine. So any route that bypasses the gastro intestinal tract should come under the parentrals but in pharmaceutical point of view parentrals are referred to injectabels only. That is any sterile solution suspension or emulsion that is administered by puncturing the protective barrier of body i.e. skin and other outer layer using an injection or hypodermic needle .they may be also termed as sterile products. now a days needle free injection are also prepared which gives more patient continence over the conventional used needles.

The earliest documented record of parentrals drug administration using hypodermic needles dates back to the mid 19th century when Alexander Wood reported the injection of morphine in the treatment of neuralgia. There comes the term injection. An injection is an infusion method of putting liquid into the body, usually with a hollow needle and a syringe which is pierced through the skin to a sufficient depth for the material to be forced into the body. An injection follows a parentrals route.

ADVANTAGES OF PARENTRAL • Direct route of achieving drug effect in the body • Bypasses pre systemic or first pass metabolism • Considered to be highest bioavailability among all available dosage forms (nearly 100%) • Drugs sensitive to gastric fluid can be given • Drugs which are unabsorbed orally can be easily given through this route

DIS ADVANTAGES • Production difficulties i.e. sterile condition is require to be maintained through out the processing cycle • Administration requires a special skilled personnel • Puncture of skin is always essential so pain is always associated during administration

CLASSIFICATION OF PARENTRALS- the classification of parentrals are done on the basis of the volume injected

Small volume parental –when volume is less than 50 ml Large volume parental-volume is more than 100ml injection is called as large volume parental which are mainly employed for supplying nutrient to the body when a patient is unable to take in the oral route or improper gig condition. They essentially need to be isotonic as may cause haemolysis due to large volume.

CHARACTERS OF PARENTRAL 1. Sterility 2. free of pyrogen 3. stability 4. freedom from particulate matter 5. isotonicity

ROUTE OF ASMINISTRATION

There are various routes of administration for parentrals generally categorized as per their site of injection. The various routes for administration are described in the table with some properties of this route. ROUTES

specification

VOLUME INJESTED(m

TYPES OF MEDICATION ADMINISTERED

l) Subcutaneous Intramuscular Intravenous Intra arterial Intra cardial

introduced under the skin within a muscle

Given into a vein Give in to an artery Given in cardiac

0.5-2

Insulin vaccine

0.5-2 1-1000 2-20

Nearly all classes of drugs Nearly all classes of drugs Antibiotics, radio opaque media,

0.2-1

anti neoplastics Cardio tonic drugs, calcium

6-30

LA, narcotics , steroids,α2

2-20

agonists Morphine, NSAIDS, steroids,

2-30

antibiotics LA, narcotics

muscle Intra epidural

the spinal cord and the Dura

Intra articular

In the joint

Intra plural

In to lungs wall or

Intra peritoneal

cavity injection of a

Chemotherapeutic agent chemotherapy

substance into the peritoneum (body Intra thecal

cavity) Inside the spinal cord

1-4

LA, analgesics Neurolytic agents

Intrasynovial

In to the synovial fluid

Intra cisternal

In to a reservoir or receptacle of some natural fluid of the body

INTRA MUSCULAR ROUTE:It is second to IV in the quickness of onset of action. the injection is given in to any striated muscle at the site of gluteus muscle (buttocks), deltoid muscle(upper arm), vastus lateralis(lateral thigh muscles).the volume injected are 0.5-2 ml but can extended up to 5ml. normal onset of action is 15-30 minutes. Major problem is vein damage and infusion in to vein so aspiration before injection is advisable .the formulation given in intramuscular generally form a depot from there drug is slowly absorbed. The absorption depend of particle size, type of vehicle used, volume injected and isotonicity . INTRAVENOUS ROUTEIntravenous administration is injected directly in to vein to achieve fastest action. This route provides maximum availability of drugs and highest assurance that drug is given into the site of action. These are some advantage associated with disadvantage that drug effect is very difficult to terminate in case of toxicity. In this case duration of action is dependent of initial dose and biological half life and kinetics of drug. It is the only method of administration of large volume parentrals also called as IV drips.

SUBCUTANEOUS ROUTE It is the route in which the drug is introduced under the skin near the fat layer. Here the maximum volume can be administrated is 2ml. as in case of intramuscular injection this route has also there is a probability of puncture of veins so aspiration is needed here also. Drugs given through this route give a

slower onset of action then intravenous or intramuscular. Increased volume is injected called as hypo dermoclysis but irritation, pain and tissue damage always accompanies. Administration of hyaluronidase may help by increasing absorption and decreasing tissue damage. Arm, leg and abdomen are the body portions suitable for SC administration.

PREFORMULATOON OF PARENTRALS Preformulation study is done for all most all drug for choosing suitability of dosage form s. here a brief idea given about the parameter to be studied so that to ensure suitability of a drug for parentral administration. For preformulation study for parentral preparation we need to study the analytical property, physicochemical property and stability profile of a drug. The list of parameters to be studied given below. Preformulation parameter Analytical property

Character to be studied Molecular structure, absorption spectra, assay of drug ,

Psychochemical properties

impurities molecular weight, melting point, color odor ,solubility, particle size and shape, hygroscopicity, ionization constant, optical activity solvate formation

Stability and excipient

polymorphism etc Thermal stability, photo stability, effect of oxygen,

compatibility

resistance to sterilization, resistance to ph change. and finally excipient compatibility study

The detailed study of preformulation parameter are discussed somewhere else in this book.

FORMULATION ADDITIVES The parentrals dosage form is very special among all the dosage forms available due to the special features i.e. it’s starting from its route of administration t o its characters such as sterility, free of pyrogenicity, isotonicity and free of any foreign or antigenic particles. So to formulate a safe and effective medication the formulation should contain excipient to maintain stability, product characters, ensure sterility and should aid to injectibility and syringibility. The commonly added excipient in parental are antimicrobial agent, antioxidants, buffers, tonicity contributors, solubilizing agent and bulking agents. In the design of parentral dosage form the selection of these excipient should fulfill all the criteria and should have approvals from regulatory body.

ANTI-OXIDANTS An antioxidant is a molecule capable of slowing or preventing the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons from a substance to an oxidizing agent. Oxidation reactions can produce free radicals, which start chain reactions that damage cells. Antioxidants terminate these chain reactions by removing free radical intermediates, and inhibit other oxidation reactions by being oxidized themselves. As a result, antioxidants are often reducing agents such as thiols or polyphenols. Some of examples are ascorbic acid and tocopherols ,as well as synthetic antioxidants cystine, sulfates and propyl gallate , tertiary butylhydroquinone , butyrate hydroxyanisole butylated hydroxytoluene etc. but the sulfates such as sodium bisulfite ,sodium metabisulfates and sulfur dioxides are primly used in parental. Best suited sulfates are shown to show

allergic reactions in some asthmatics so to avoid antioxidant deoxygination of vial using an inert gas is proffered. ANTIMICROBIAL AGENT An antimicrobial is a substance that kills or inhibits the growth of microbes such as bacteria, fungi, protozoals or viruses. Antimicrobial drugs either kill microbes (microbicidal) or prevent the growth of microbes (microbistatic).Any preservative system is necessary for multiple dose vials for parentral use.before use of preservative the factors to be considered are efficacy of preservative, incompatibility with the active ingradient and vehicle as well as regulatory aproval.there is a number of ways bu which the effectiveness may be decreased for eg protein bind to thio merosal decreasing preservative efficacy and partitoning of preservative into micellar oil phase or carrier may reduce the effective concentration of perservative. The Preservation Effectiveness Test should be done previously which demonstrates the effectiveness of a substance when used as a preservative or additive-- to stop the growth of such pathogenic organisms as E. coli, Aspergillus niger, Candida albican, Pseudomonas aeruginosa, and Staphylococcus aureus. The preservatives used in parentral are meta cresol, para hydroxy benzoate esters, benzalkonium chloride, chlorobutanol.phenol etc BUFFERING AGENTS A buffering agent adjusts the pH of a solution. The function of a buffering agent is to drive an acidic or basic solution to a certain pH state and prevent a change in this pH. Buffering agents and buffer solutions are similar except for a few differences: 1. Solutions maintain pH of a system, preventing large changes in it, whereas agents modify the pH of what they are placed into

2. Agents are the active components of buffer solutions. The prime aim of adding a buffering agent is maintain pH as change in pH may lead to product instability, again solubility of drug is dependent on pH. Buffer to be maintained to have maximum stability and solubility. The factor which may aid to change of pH of product are leaching from container, closure, dissolved gases and chemical changes in any of component Here buffer capacity of a system need to be studied before selection of a buffering agent .some buffering agents used In parentral are acetate, citrate, phosphate etc CHELATING AGENTS Chelation is the binding or complexation of a bi- or multidentate ligand. Chelating agents form multiple bonds with a single metal ion. Presence of metal ion such as copper, Zinc, iron catalyze the oxidative degradation. Sources of metal contamination are raw material impurities,solvent, rubber stopper container and equipment employed in product manufacture. The chelating agents used are Dicarboxymethylglutamic acid , Ethylenediaminedisuccinic acid (EDDS) ,Ethylenediaminetetraacetic acid (EDTA), Oxalic acid ,Phosphoric acid , citrica acid, tartaric acid etc

TONICITY ADJUSTING AGENTS It is the important criteria of parentrals that the dossage form to be injected must be isotonic or nearly isotonic. Because as they are direct contact with blood the difference in tonicity will lead to exchange of ionic in erythrocytes. This may cause hemolysis if the volume given more than 100ml. the agents added to aid tonicity are dextrose, sodium chloride etc. . following table contain the additives used and their concentration used in parentral

Additive class antioxidants

Antimicrobial

Use Prevetion of oxidation

To maintain sterility till formulation is used

buffers

Buffering agents

Tonicity modifiers Chelating agents

To maintain pH

To achive buffering capacity

Comcentration(%) 0.01-0.05

Tocopherol

0.05-0.5

Sodoum meta bisulfate

0.1-1.0

Monothio glycerol

0.1-1.0

Benzalkonium chloride

0.01

Benzyl alcohol

1-2

Chlorbutonol

0.25-0.5

Metacresol

0.1-0.3

Butyl hydroxyl benzoate

0.015

Acetates

1-2

Citrates

1-5

phosphate Lactose

0.8-2.0 1-8

Mannitol

1-10

Sorbitol

1-10

glycine To maintain isotonicity with blood Dextrose To chelate any metallic ions present

Surfactants and

example Ascorbic acid

To improve solubility and

1-2 4-5

Sodium chloride EDTA salts

0.5-0.9 0.01-0.05

Glucose

2-5

Lactose

2-5

Maltose Poly oxyethylene

2-5 0.1-0.5

solubilizing agent

stabilize if a dispersion

Spans

0.05-0.25

Ethyl alcohol

1-50

Glycerin

1-50

lecithin

0.5-2.0

PRODUCTION OF PARENTRALS Production of parentral requires special production criteria i.e. asceptic processing. as it is a very specialized method for drug supplying to the body Again the production of parentrals involves both the batch and continuous processes i.e. cleaning sterilization of container and closure, filtration, and filling are the continuous processes where as weighing of raw material batch, fabrication, terminal sterilization are the batch processes involved in the manufacturing of parentrals. . In this section of this book we will be dealing with some practical considerations during synthesis of parentral. The following chart gives an over all view of the parentrals processing.

PREPAREATION OF FASCILITY

1. ENVIRONMENTRAL AND DESIGN 2. PRODUCTION AREA 3. PERSONEL

COLLECTIION OF RAW MATERIALS

EQUIPMENT

INGRADIENT

CONTAINER AND CLOSURE

CLEANING

COMPOUNDING OF PRODUCT

STERILIZATION

FILTRATION

CLEANING

STERILIZATION

FILLING

SEALING

PACKING

STORAGE

PREPARATION OF FASCILITY ENVIRONMENTRAL REQUIREMENT AND DESIGN OF PRODUCTION AREA

The environment refers to both the physical as well as biological environment .physical environment refers to the air born particles and the physical condition of air i.e. the temperature and moisture. Biological environment deals with the environmental water the purity and finally the microbial content of environmental air and water. The location of parentrals i.e. in an asceptic method of manufacturing the location should be selected on the basis of available facilities and cleanliness of the area. For selection of a particular location the site master plan should first studied to evaluate the suitability of site. The site chosen for plant establishment should provide adequate supply of raw materials, transportation market proximity, energy availability, water quality, air conditions and waste disposal facilities Design of production area should have all the quality to carry out production process smoothly. Design parameters for a facility and selection of Appropriate manufacturing technologies for the product require that The formulation process and packaging components be chosen and evaluated in advance. The layout should be designed such a way that the in flow of water, air handling units, and waste disposal easier. The different operational area should be arranged according to the order of performing the processes so that unidirectional flow of product line will be maintained. The lay out for batch and continuous production is given below.

For batch production

For continuous production

PRODUCTION AREA The production are of parentral require absolute control of microorganism

and particulate mater

control. The production area must have sufficient rooms and space to carry out the systematic processes of production cycle. Each are should fulfill the GMP criteria and should have all the facilities required for maintenance of required conditions i.e. sterility, air conditioning, humidity control etc. the whole area like wall, floor, ceiling, should smooth, non- shedding and should easy to clean. And the internal conditioning should such that there should minimum area for particle collection. Finishing

should provide with vinyl polymer or ceramic epoxy sheets. In the production area certain essential conditions to be maintained for specific processes i.e. for preparation and filling sterile condition is essential, for filling lyophilized product humidity control is essential . general air controls is essential in warehousing area as well as general laboratories. For each process cleaning, drying and other operations like air filtration, sterilization cycle, and air control also maintenance of the facilities written procedures called standard operating procedures are followed. For visual inspection the partitions in the production area should made up of transparent glass. the air control, sterility maintenance and cleaning system in production area are the important factors discussed below.

AIR CONTROL-

Mainly done by laminar air flow

Laminar air flow systems contain three basic elements - a blower, a high efficiency air filter, and a plenum. The flow is called laminar because the turbulent air upstream is changed by the filter into a straight-line flow off the downstream face of the filter. Many blowers, many filters, and very large plenums, but all have the same basics. The necessity of laminar air flow is to remove most of the particulate matter, as a matter of fact 99.99% of everything air-borne down to 0.3 microns should be screened out to have an environment whose air supply is free of bacteria, fungi, pollen, and practically all air-borne dirt How The HEPA filters are tested by the DOP-dioctylphthalate-method when manufactured. DOP, a liquid plasticizer is heated to the point of vaporization and reconstituted into 0.3 micron particles to form a mono disperse aerosol. These single size particles re diluted wit air until a concentration of 100 micrograms per liter is reached, and the aerosol-air mixture is passed through the

filter. in case of in place filter test the DOP is polydispersed, ranging from 0.32 microns to 1 micron, averaging approximately 0.45 microns generated the DOP is generated by air using a special Laskin nozzle. efficiency of filter is indicated by percent penetration.

In the following table the different zones in sterile processing of parentrals or air classification CLA SS (ISO

NUMBER

MICROBIOLOGIC

OF

AL LIMIT(CFU/FT3)

PARTICLES(IN

(USFDA)

ZONES MAINTAINED

1FT

)

SQUARE)SIZE LIMIT <0.5ΜM

3 4 5

1 10 100

-

<1

Critical zone, Aseptic preparation and filling(grade-A) Background room conditions for activities requiring Grade

6 7

1000 10000

<2 <3

A(grade-B) Sterile processing, Preparation of

8

100000

<25

Solution to be filtered(grade-c) Supporting zone, Handling of components after washing(grade-d) , blowing (pre-forming) operations of plastic containers

Note –various grades of Operations for Aseptic Preparations indicated by grade A, B, C, and D

PERSONEL

The personnel in the pharmaceutical industry are very important for carrying out manual procedures but they are the largest source of contamination so they can be stated as performer as well as transmitter of contamination. The main source of contamination is skin flakes, scales, fragments of human hair, droplets of air from breathing and coughing, cosmetic, fabric etc. Another important personal are the cleaning job personals as it is critical one and effect whole process conditions. So selection of personal for cleaning should meet the physical (to carry out, personnel safety, health conditions) and mental condition (attitude of person and understand the importance). So the train programs held to carry out cleaning process efficiently. The training programs generally held are class room training or orientation training, technical training, on the job training etc

CLEANING PROCEDURES

Cleaning is of prime importance because it affects the whole production system. Improper cleaning may facilitate microbial contamination, contamination of product, which may induce toxicity as well as decrease therapeutic activity of drug formulation .specially in case of parental change of pH or isotonicity, incorporation of metallic ions from detergent and other visible floating or non-solubilized particle may cause the rejection of whole batch. In this concern for cleaning we will discuss the machines cleaning and cleaning of container and closures is described.

CLEANING OF EQUIPMENT Equipment cleaning plays a vital role as the raw material come direct contact with machinery so it is a critical parameter in case of parentrals. Good house keeping principles are the first step to maintain cleanliness of equipment. cleaning as soon as the production processes is finished should be practice

zed as dirty equipment provide growth of micro organisms. It is nice to use good, non abrasive scrubbing with detergent and water .cloth or brush used for cleaning must not leave any fibers or shedded particles. Sufficient amount of water should be used to ensure that there is no detergent subsisted on the equipment .final cleaning should be 180 ºF pyrogen free water for injection. The end point of cleaning is determined by analysis of rinsing water. After cleaning drying of equipment should be done profoundly with shed free material and laminar flow area and covered with a shed free material. The cleaning of equipment may be clean in place (CIP) and steam in place (SIP) In clean in place system various sprayers with tank are attached to cover different component of machinery. Cleaning agent selected on the basis of rapid solubilization in soiled area and quick removal from machinery. The system is generally used for small volume parentrals. The number of cycles, spray force, spray pattern, the spray nozzle and their position is important which varies as per type of product to be cleaned. In steam in place system steam pressure is applied for both drying of residual moisture and simultenousl sterilization. Difficulty in establishing SIP as the portions should withstand the pressure applied. Variables in this case are steam temperature, steam penetration and length of exposure. Note –both the system requires special complex arrangement so the system requires proper validation and the effectiveness should be checked before installation set up.

CLEANING OF PACKAGING COMPONENT The cleaning procedures for different material of packaging is different i.e. rubber glass or plastic. When to clean rubber primary goal is to remove particulate matter, dirt and surface contaminations .the problems are abrasion during washing and passage of drainage liquid through the cleaned rubber components. Huber companies over flow rinse cycle capable of preventing only the

second one but have abrasion problem. Capsult washer gently agitates by flow of air which move dirt to surface and flow of water from bottom remove those eradiating both the problems. The cleaning evaluation is done by analyzing both inlet and outlet water for particulates, pH and clarity. In case of glass avoidance of chipping and leaching problem is very important. To remove various contaminants separate processes are under taken like sulfur to remove alkali, acid treatment to remove alkali, clay contact to remove Na+ , O2- and fluoride contact to improve surface durability but replacing oxygen and –OH groups . during shipment and transport the glass containers prone to contain surface glass chips, debris, particulate from card board packs etc. so finally they are rinsed with hot filtered pyrogen free water both inside and outside and dried under filtered air. Plastic containers are also washed same as glass but exposure to higher temperature to heat sensitive low density plastic is avoided.

STERILIZATION OF CONTAINERS Sterilization of container is necessary before final product filled in to the container. For sterilization of rubber components moist heat sterilization is preferred as it penetrates rapidly (slow penetrator like dry heat may dry and crack rubber).Ethylene oxide may also used but it is difficult to release from the surface of rubber. For glass containers dry heat sterilization is the preferred one. as glass mainly used as a primary packaging component coming direct contact with formulation so it need to be pyrogen free and dry heat is the, method which destroys pyrogen. For plastic containers both steam sterilization and ethylene oxide sterilization is used steam for high density plastic and ethylene oxide for low density plastic. As surface removal of the gas is difficult the containers kept in forced draft hot air oven (50-60º C) or

laminar air flow for a period till lower limit of less than one ppm is maintained. Plastic may also be sterilized by ionizing radiation. NOTE- Siliconization is generally done for rubbers and glass. In case of rubber it facilitates insertion of closure in to containers via high speed automatic sealing machines. This removes requirement of wet closure and most suitable for powder fill-in case of glass it helps to drain the product especially suspension and dry powders from wall of container .generally silicone oil or aqueous emulsion of silicone is used .for glass after application of silicone emulsion by spraying in to vials it is dried at 250C for 5hrs that sticks the silicone on the surface and kills pyrogen as well.

Parentral formulations

There are various dosage form can be filled in to vial or container for parentrals administration. This is one on the advantage of parentrals that if the drug is not suitable For parentral administration in one dosage form it can be given in another suitable so flexibility of dosage form is there. The parentrals dosage form can be given as solutions, suspensions, emulsions or powders that may be lyophilized or spray dried or simple powder for reconstitution. The various formulation those can be filled in to a parntral dosage form are summeerized with their manufacturing considerations below.

solutions

most of parentrals are prepared as solution. The preferred one is aqueous solution is water is the most common solvent used .the formulation may also contain some co solvents like glycerin and alcohol can be added. Solution are prepared by dissolving active ingredient , excipient in solvent then maintaining ph and tonicity by using suitable agents. The viscosity and surface tension of most of the product are similar to water but may slightly vary. The sterilization can be done by filtrations sterilization of the solution and also autoclaving the final product after filling and sealing (limited to heat stable substances) but preferred as it gives better assurance over sterility. Multiple vial solutions should contain antimicrobial agents.

Suspensions

It is a biphasic liquid dosage form and the active ingredient have to suspend in the vehicle. In case of suspension intended for parntral infusion the viscosity of product as well as particle size are the prime factors to be considered. The formulation stability variable such as particle size and particle size distribution , zeta potential, manufacturing variables are to be carefully monitored. The foremost requirement of parentrals suspension is syringibility and injectibility. syringibility deals with withdrawing formulation from container to syringe , clogging, foaming tendencies and accuracy of dose measurement while injectibility deals with the considerations during injection ie force required to inject, evenness of flow, aspiration qualities and freedom from clogging.

Before filling the syringibility and injectibility is evaluated by plotting a graph between time required at a particular force and injection pressure applied.

The parentrals suspension can be prepared by two methods ie combining sterile vehicle and powder aseptically and combination of sterile vehicle crystallizing particles in situ. In former method first sterile vehicle system and powder are dispersed followed by milling aseptically to produce the require particle size. In second method the active ingredient first solubilized in a suitable solvent (generally organic) followed by addition of counter solvent that re-crystallize the active drug. Then organic solvent then removed aseptically followed by milling after addition of necessary ingradients .the final suspension is prepared by volume make up by the solvent.

Emulsions As in case of suspension it is also a biphasic dosage form of oil phase and aqueous phase where both the phases are liquid and immiscible and the system is a thermodynamically instable one. The emulsion must be physically and chemically stable, pyrogen free, sterilizable, non antigenic, particle in the range 1-2 µm , and stable to external temperature variations.

Aqueous phase is water and oils used are soybean oil, safflower oil, sea same oil, linseed oil, coconut oil, olive oil etc. as purity of oil is very important for parentrals various treatment such as silicic acid treatment , winterization are done . emulsification agents used are purified lecithin , spans and tweens. Lecithin is natural derivative and easily available but it shown toxicity in many cases. However purified lecithin is less toxic is nature and it is the first choice for parentals. Other ingrsadient such as pH controlling buffers, anti oxidants, and tonicity contributors are generally contained in aqueous phase. The neutrals agents such as glycerin and propylene glycol are used as ionic agent like NaCl, KCl and reducing sugars are less useful as they react with lecithin to make the emulsion in stable .

The increased use of emulsion is because of they contain drug in the inner most phase by which solubility and stability problems can be minimized. Again as the drug does not come directly in contact with the external environment or body fluid so partitioning of drug from internal phase to external phase contribute to sustained release of drug. Injectible emulsion widely used for a patient requiring long term parentrals nutrition. Patients with deficiency of fatty acid, low weight premature babies given parentrals fat emulsion containing 10-20% of oil. Again patients who cannot absorb through git are caloriezed by using parentral fat emulsion.

The emulsion is prepared by mixing the two sterile phases of oil and water , in which water phase homogenized after mixing with emulsifying agent and other agents contributing to pH and tonicity .the system then dispersed , homogenized and ph maintained before filling.

Dry powders The dry powder as parentral gives many flexibility in manufacturing, handling as well as usage of parentrals. Dry powders filled in to vials for parentral injection are widely used for water sensitive drug or drugs unstable in presence of moisture. The dry powders produced may lyophilize, spray dried or simple powders for re constitution.

Lyophilization or spray drying is a drying process mainly applied for pharmaceutical and biological products which are thermo labile. It is a process of stabilization by removal of water or moisture. Again freeze drying results in high specific surface of powders allowing rapid dehydration of powders. This process renders sterile filling of powder minimizing chances of contamination. In Lyophilization process a frozen mass is subjected to vacuum. The freezing temperature should be below the eutectic point of mixture as freeze drying occur below the triple point of water .when vacuum is applied the sublimation of water occur. This drying is known as primary drying. The temperature increases then the frozen mass but pressure decreases during primary drying phase. The resultant is a cake like mass. To remove solvent still remained slight heat is applied and the process is secondary drying in which temperature increases and vacuum decreases. In secondary drying removal of water takes place by diffusion and desorption . After freeze drying the product is stoppered in that chamber only as sealing outside may increase the risk of contamination or variation of moisture content.

Note Eutectic point is the point at which intimate mixing of ice and solute occurs such that they appear as single phase. This point is present only if solute crystallizes when solvent is frozen.

Powder for re construction is the process of sterile filling of dry powder or powder dispersion in to a sterile vial. The requirement of powder for reconstitution is cleanliness, sterility, minimized moisture content, uniformity, good powder properties, fast dissolving and elegant appearance. When we consider about properties of freeze dried products, they are generally amorphous, or mixture of crystalline and amorphous substances. As solid state stability generally affected by crystallinity so lyophillization may produce in stability . again it is an expensive process requiring careful monitoration of temperature, heat gain or heat loss ,saturation moisture level of the chamber as well drying rate.

Sterilization methods

Sterility or free of micro organism is an important criteria for parentrals. The methode employed for sterilization should fulfill all the required criteria. In parentral products there are two sterilization points ie sterilization of raw materials and sterilization of finished product. During practice both step are performed to have assurance of sterility. The method of sterilization employed is dry heat, moist heat, filtration, gaseous sterilization and radiation sterilization. Dry heat, gaseous and radiation sterilization is generally preferred for machineries, equipments, container and closures. Filtration sterilization is used to sterilize vehicles, raw materials and finished products which are heat sensitive. The dry heat and

moist heat sterilization methods can be utilized for terminal sterilization but moist heat is the preferred one.

Before selecting a sterilizing method validation of sterilization methods are important to measure their effectiveness. The tests employed are using biological indicator which are spores of certain microorganisms and testing of a product sample which first under taken the particular sterilization cycle. Bubble point test is done for mechanical sterilization such as filtration.

Dry heat sterilization

Dry heat sterilization is mainly used to to sterilize the glass ware and equipment parts. The character which increases the importance is that it is the only methode available to make the machine and equipments pyrogen free.it has high penetration power and the cycle of sterilization includes high operating temperature and for long periods. The main mechanism by which dry heat sterilization kills microbe is oxidation and coagulation of proteins of cell wall. The cycle of sterilization is 260°C for 45 mins or 180°C for 120 mins which destroys pyrogen effectively.

STEAM STERILIZATION It is more effective then dry heat as increased penetration power and more heat content. The medication in which packaging is not sensitive to pressure can be sterilized by this method. It involves temperature as well as steam pressure for sterilization. Due to pressure and extra latent heat content of steam the coagulation of proteins can be brought out at lower temperature.it is widely used for terminal

sterilization as a sterilization method as it is a quicker as well as inexpensive pressure. The instrument ie autoclaves are desined as per various requirement.in lab scale small equipments the steam generally included from bottom. But in industrial scale the steam is passed from top of chamber and it displaces air at the bottom as it is heavier then air. The normal cycle include 20 min 15lb pressure for 121°C or 3 min 27 lb pressure at 132°C.

FILTRATION Filtration is an important method of sterilization for products which cannot be terminally sterilized by heat or for heat sensitive products both liquids and gases can be sterilized by this process. For this purpose membrane filters are widely used as filter media.the filters may be made up of plastic or sintered material . hydrophilic membrane filter are more preffered over hydrophobic as requirement of extra pressure in case of hydrophobic material during filtration. Hydrophobic filters amy be coated with hydrophilic material or made hydrophilic by using surfactant.eg hydrophilic – cellulose acetate.polycarbonate , polysulfone, poly vinyl difluoride, nulon etc or hydrophobic- poly tetra fluoro ethylene. The pore or holes of filter consist of various size ranges. 0.2µm pored size is generally preferred for sterilization though smaller pore size also available they significantly reduce the flow rate. during large scale manufacturing prefilter is used to avoid clogging of filters. The filter media choosed such that it should have no effect on the product to be filtered for example during filtration of proteins the binding of protein to the filter media should avoided. (Note- Additionally ozone can be used as a disinfecting agent for water. Ozone (O3) is an unstable tri-atomic form of oxygen. It is a very strongly oxidizing gas that is injected into water to remove organics that may contribute color, odor or taste. Most importantly, ozone sanitizes the water, rapidly

destroying any microbiological contamination. Dissolved ozone reverts back to harmless oxygen in a matter of minutes, depending on the temperature and pH of the water, so it must be generated and measured right next to the process. Ozone leaves virtually no harmful breakdown products. However, it is an undesirable addition to point of use pharmaceutical water. In order to eliminate the ozone, a UV light source is employed to effectively destroy it after the disinfection process is complete. The UV light also has the added benefit of providing further disinfection. )

FILLING OF PARENTRALS Filling of parentral has the importance because as it require accuracy of fill volume, avoidance of contamination during filing ie dust pyrogen etc, and also the integrity of product.during filling the maching should maintain the parentral quality is sterility pyrogen free and free of foreign particles.during filling for proper volume used by the user to give a particular dose so parentrals generally filled slightely more in volume so that the user can take out the required volume from the container. in this concern we will be dealing with various equipment that can be used for filling of parentrals which satisfy the ideal requirements.the following table gives an overall idea about the type of machine used for filling and their filling mechanisms.

TABLE

Piston type filler consist of a syringe or piston attached with a vernier volume adjustment which allows filler to adjust the travel the length of piston or volume of formulation to be filled. rotary displacement pump fills on the principle of positive e displacement pump driven up by maotar.both filling and drawing the filling solution from bulk can ve done by mortar gears and fill volume controlled by number of counts . time or pressure filler is same as that rotary mechanical pump but here a desired volume is delivered through the delivery tube pinched stop to stop the fluid flow. The flow or fill volume can be controlled by both time and pressure.of flow of formulation. For filling of suspension or powder vacuum pressure displacement or auger fill is used to have uniformity of content.in vacuum displacement a gas is used to quantitize the powder filled in to and the guns are under vacuum to draw powder and adjusted to volume of certain weight equivalent .auger feed is based on volume displacement bu screw feed . the length of auger travel is predetermined which controls the volume to be forced in to container.

After filling the vial or ampule is to be sealed. Before sealing the oxygen in the container should removed which is essential for oxygen sensitive products because it may bring instability.the removal of oygen is done by passing on inert gas like nitrogen or argon at an pressure of 2-3 psig before stopper insertion . for this purpose though argon is more costlier but it is preffered due to its havier nature that fascilitates easi filling in to container.

DESIGN OF FILLING EQUIPMENT To fill the liquids a certain orifice tube is designed which goes into the ampule or bottle and pass a mesasured amount of liquid through the orifice.design of tube depend up on the mouth of ampule it is to be entered, viscosity and density of liquid to be entered and flow pressure desired. The tube should be freely pass through the mouth of the ampule to allow escape of air during filling.as excessive

pressure may cause splashing of liquid and cause foaming so flow pressure shoud be optimum. A drop of liquid generally hang at the tip of delivery tube after delivery which may wet the neck of container. So a retraction device is designed to avoid hanging and retract of the drop. In case of emulsion and suspension as the viscositye is high and suspended globules or particles a preciously designed equipment is essential. Additional required agitation in hoper to maintain uniformity,increase temperature to decrease viscosity, enlarge delivery tube, high pressure to fill are some conditionals used for proper filling.when equipment for filling of solids are to be designed flow rate, homoginity, particle size, irregularity of flow must be considered. Generally for large mouthed containers used with slow filling rate weight feeders are used for filling.

SEALING Sealing of ampules are done by applying heat and melting the mouth. Two basic processes applied while sealing a.Tip sealing b.

Pull sealing

tip sealing- it involves melting at the tip of the ampule to form a bead of glass and close the opening pull sealing-it is done by heating the ampule at neck with simultenous rotation of ampule below the tip and pulling away the tip to form a small twisted capillary prior to melt is closed. Generally high temperature flames are used for sealing. Excessive heating at the neck causes expansion of the gases which lead to fragile bubbles at the point of seal. Pull sealing is a slow but reliable process than tip sealing.

Wetting at the neck of vial leads to fracture at the neck or increases bubble formation which may leads to crack. If droplets of product are stick to the sealing surface or neck and getting heat black spots of carbon oxides will be formed .

Sealing of cartridge vials or bottle requires no heat and they are sealed by close rubber as a primary packing component and aluminum foil to keep the rubber cap in its position.. The aluminum wrap may have a hole at the centre to facilitate withdrawing of product during use.

BLOW FILL SEAL TECHHIQUE It is a novel technique in which all processes of parentral starting from moulding of ampule to filling, sealing and packing is done in a series or an innovative production system in which forming the container and filling the parentral preparation as well sealing takes place at the same time. In the process in process quality maintenance plays an important role . The Blow-Fill-Seal system is an innovative production system to produce products where forming the container and filling the solution takes place at the same time and sealing is accomplished immediately under aseptic conditions. A direct-blow forming machine incorporating sophisticated forming technology and high-performance filling machine with time pressure method are combined that forms the container and fills the solution at the same time.Steps involved in the technique are as follows.

The process begins from Extrusion of plastic granule in the form of hot hollow pipe of molten plastic called parison. Following step is Blow moulding of the container from plastic granule. The parison is closed between the mould, and the container gets formed either by blowing compressed air or by vacuum or by using vacuum as well as blowing. Container assumes shape of the cavity in mould. Container thus produced is open from the top and in its top part, plastic is still hot and in molten state until the subsequent steps of filling and container sealing. Subsequent step is Filling of the formed container from the top which is still open (and still in hotmolten state!). Filling nozzles enter from the top of container and filling is done. Filling nozzles are specially designed and constructed to facilitate automatic cleaning and automatic sterilization. Additional functions of filling nozzles are to blow the bottles and also to provide exhaust path for air in the container. Filling process can be carried out under a shower of sterile filtered air to avoid contamination. The blower on the sterile air shower can have variable speed which can be made to change automatically so as to maintain constant air speed under various situations. The air shower is validated at certain air pressure, and an automatic device can maintain the same pressure by automatically modulating the speed of the blower. Next step is Sealing the top of the container which is still open and in hot molten state. The top gets pressed between head moulds and as a consequence, top part of the container gets formed, sealed and at the same time gets cooled. The result is a hermetically sealed container. The final steps are for De-flashing to remove the flash or scrap, trimming the containers and delivering the containers outside the machine. The whole process of Extrusion-Blowing-Filling-and Sealing and removing scrap takes between 12 to 18 seconds depending upon the type and size of the container. The advantage of Blow-Fill-Seal process is derived mainly from the fact that container is

formed, quickly filled and sealed under protected environment automatically without human intervention. SYFPAC® is an acronym for: "System for Filling Parenterals Aseptically into Containers of plastic materials". This system has been specifically studied to address the packaging needs of Parenteral fluids and injectables. The SYFPAC® system works on principal of Blow Fill and Seal, and has been conceived by creative application of fantasy, engineering design and thorough knowledge of advanced materials and techniques. The SYFPAC® is designed to perform reliably and precisely throughout its long working life. The simple and robust construction does not need much of maintenance.

QUALITY CONTROL TESTS FOR PARENTRALS Parentrals are the foremost dosage form among all in which the quality to be monitored very closely. So with in process quality control there is a need to evaluate the final product. The parentrals are mainly evaluated for their sterility, free of pyrogenicity ,packaging integrity and for any visual particles or particulate matter. Above test are very important as failure to those may lead to rejection of whole batch.

STERILITY TEST Sterility is the character of parentrals which indicate that it is free of any microorganisms. So to test if any viable microorganisms present or not two methods generally employed those are direct inoculation and membrane filtration. The sampling technique depends on volume liquid per container, method of sterilization, number of units in a batch etc. If the volume of container is less than 10 ml, 1ml sample is taken for test other wise 10% of total volume is taken for test incase of svps and entire container or

500ml for lvps. Similarly 10 units are taken as sample if sterilized by steam but for other method 20 units taken for sterility test. Detailed description of sampling technique is outside the scope of this book. Again when we consider about the medium used for inoculation is important as certain micro organisms connot grow in certain media.the culture media suggested by USP is fluid thioglycolate media for both aerobic and anaerobic environments. But this cannot used for Bacillus subtilis . other preffered medias are soybean-casein digest or Trypticase soy broth media . after inoculation the time and temperature depend up on the culture media and methode of inoculation. At final the test is confirmed by positive or negative control tests. positive control test ensures no defect in test procedure where as negative control test is to ensure whether the sterilization method for the culture media is effective or not. PYROGEN TESTING Pyrogens are mainly bacterial lip polysaccharides obtained from gram negative bacteria. They may lead to increased body temperatures and hypersensitivity reaction chills , fever and other complications.the main tests employed for detection of pyrogen is rabbit test and LAL test. For rabbit test dose should not exceed 10ml per kg of body weight but varies as per individual monograph. The sensitivity of thermocouple should be 0.1°C and capable of a reading a value reached with in five minutes. Rabbits develop tolerance on repeated use so a rabbit showing temperature increase of 0.6°C cannot used for 2 weeks. The group of rabbits taken should not vary temperature more than 1°C and not exceed 39.8°C. Inject the volume after worming to 37°C. Rectum insertion of thermocouple should nor less then 7.5cm. Record the temperature for 1-3 hours at an interval of 30 minute. The limit to pass is rise of temperature should not more than 0.5°C or selected as non pyrogenic if not more than 3 out of 8 rabbits show rise of 0.5°C.

LAL test is base on the property of limulus amoebacyte lysate that it precipitates in presence of pyrogen . Amoebocyte lysate of horse shoe crab Lumulus polyphemus is taken for test . it is highly unstable so generally stored as freeze dried product and it is stable till one month after reconstitution. The sensitivity of LAL is increased by divalent metal ion such as Ca, Mn, Mg etc. the presence of pyrogen is indicated by silod clot or turbid solution. The mechanism by which it produces clot is described below.

ENDOTOXIN + Ca

ACTIVE CLOTTING ENZYME

+ LAL PRO ENZYME

+ COAGULOGEN (C----N)

BREAKING OF COAGULOGEN (C-\---N)

SOLIBLE PEPTIDE + INSOLUBLE COAGULIN (appear as precipitate)

PARTICULATE MATTER TEST

The various methods used to study the particulate matter is direct visual method, light automated method, coulter current method and light obscuration technique. In all method if any visible particulates found it leads to rejection of that pack or may whole batch.

PACKAGIG INTEGRITY TEST Pack integrity test is done for detection of characters of primary as well as secondary component and seal integrity. The tests used are dye test, tracer test, weight change, microbial challenge test, water hammer test, helium mass spectroscopy etc

During large scale manufacturing prefilter is used to avoid clogging of filters. The filter media choosed such that it should have no effect on the product to be filtered for example during filtration of proteins the binding of protein to the filter media should avoided.

NEWER TRENDS IN PARENTRAL FORMULATION There are various developments are carried out for easy, site specific and effective therapy through parentral route. The various approaches to modify drug release rate,chareacters and site are varies from changing particle size and using a carrier for site specific delivery. This portion of this book gives a review of number of technological advances have since been made in the area of parenteral drug delivery leading to the development of sophisticated systems that allow drug targeting and the sustained or controlled release of parenteral medicines. The various delivery systems are Liposomes, Niosomes, Nanoparticles , Microparticles, Cyclodextrins, Polymer drug conjugates, Implant system, Needle free injections etc. . Liposomes are formed by the self-assembly of phospholipid molecules in

an aqueous environment.( 70 and 200nm).they are used for passive tumour targeting, as vaccine adjuvents, targeting of regional lymph node, and for sustained release.

Non-ionic surfactant vesicles (niosomes) expected to accumulate within tumours in a similar manner to that liposomes.(200and800nm) they are used for passive tumor targeting, vaccine adjuvants and sustained release. Solid nanoparticles and microparticles differ from liposomes and niosomes in that they are prepared from polymers and do not have an aqueous core but a solid polymer matrix. Microparticles and nanoparticles are usually prepared by the controlled precipitation of polymers solubilised in one of the phases of an emulsion. Precipitation of the polymer out of the solvent takes place on solvent

evaporation, leaving particles of the polymer suspended in the residual solvent.their use also same as

nanosmoes . Cyclodextrins are water-soluble cyclic carbohydrate compounds with a hydrophobic cavity due to the specific orientation of the glucosidic substituents Lipophilic drug solubilisation for parenteral use. So they are mainly used for delivery of lipophilic drugs for parentral use.implant system is used to form localized depot formulation for sustained release of drugs to the cancer cell.

Polymeric prodrugs (polymer drug conjugates) Drug delivery with polymeric prodrugs, first envisioned 25 years ago, involves the use of an active substance and possibly a targeting moiety, both linked via spacers to a water-soluble polymeric backbone. And used for passive tumor targeting

References 1. Pharmaceutical dosage forms: parentral medication: 2nd edition volume1 & 2 Edited by Kenneth E. avis. Herbert A Liberman & leon Lachaman . 2. Morden Pharmaceutics. Gilbert Banker . 4th edition

Marcel Dekker

3. http://en.wikipedia.org/wiki/Antioxidant 4. http://en.wikipedia.org/wiki/Antimicrobial 5. http://www.balancedforhealth.com/cellfoodantimicrobial.htm 6. http://en.wikipedia.org/wiki/Buffering_agent 7. Pharmaceutical Journal Vol 263 No 7060 p309-318 August 28, 1999 Special FeatureScience in pharmacy Parenteral drug delivery: 1By Ijeoma F. Uchegbu, BPharm, PhD 8. Quality control of parentral.