STUDY ON PHARMACEUTICAL DEVELOPMENT AND QUALITY CONTROL OF ANTIBIOTIC INJECTION ADMINSTRATION BY PERENTRAL ROUTE FOR PUBLIC HEALTH CARE

Prevesh Kumar 1* , Pawan singh 2 and Mr. Mohd. Semimum Akthar 3 . 1. Research Scholar, OPJS Institute of Pharmacy, OPJS University, Churu, Rajasthan. 2. Assistant Professor, Department of Pharmacy Academy, IFTM University, Moradabad. 3. Assistant Professor, Department of Pharmacy, SRMS , college of pharmacy, Bareilly. ...................................................................................................................... Manuscript Info Abstract ......................... ........................................................................ Manuscript History

For example, some antibiotic producing bacteria were isolated from a wound infection and others from a sewage, a chicken's throat, and a wet patch of wall in Paris. In 1962, one of the later discoveries was a synthetic drug, nalidixic acid, the first of the quinolones to be described, and although not therapeutically important by itself, modification of nalidixic acid led to the production of the highly effective fluroquinolones. Members of this class, such as ciprofloxacin, norfloxacin, enrofloxacin and ofloxacin have become very important in the treatment of the diseases in both humans and animals. [11] Classification of Antibiotics:-Antimicrobial drugs can be classified according to their chemical structure and mechanism of action. [12] [13] Parenterals:-Parenteral (Greek, parabeside and enteron -intestine) formulations are injected directly into body tissue through the primary protective systems of the human body, the skin, and mucous membranes. Parenteral preparations are sterile preparations intended for administration by injection, infusion or implantation into the human or animal body. [22] Certain pharmaceutical agents, particularly peptides, proteins, and many chemotherapeutic agents, can only be given parentrally, because they are inactivated in the gastrointestinal tract when given by mouth.
Parenteral preparations may require the use of excipients, for example to make the preparation isotonic with blood, to adjust the pH, to increase solubility, to prevent deterioration of the active substances or to provide adequate antimicrobial properties but not to adversely affect the intended medicinal action of the preparation or, at the concentrations used, to cause toxicity or undue local irritation. Parenteral preparations must be free from visible particulate matter and also from pyrogenic (endotoxin) contamination. Parenteral preparation must be compatible, if applicable, with IV diluents, delivery systems and other drug products co-administered. Most of the parenteral preparation are of immediate action, which is in the form of solution, suspension or emulsion. [23] Routes of administration:- [24] 1. Intra-cutaneous or Intra-dermal: These are made into the skin, between the inner layer, or dermis, and the outer layer, or epidermis. 2. Subcutaneous or Hypodermic: These are made under the skin, into the subcutaneous tissue. 3. Intramuscular: These are made into a muscle, the needle passing through the skin, subcutaneous tissue and the membrane enclosing the muscle, and opening into muscle tissue. 4. Intra-venous: These are made into vein and, therefore, are introduced directly into the blood stream. 5. Intra-arterial: These are given directly into the artery when an immediate effect in a peripheral area is required. 6. Intra-cardiac: These are given into the heart muscle or ventricle in an emergency only. 7. Intra-thecal: These are made into the subarachnoid space that surrounds the spinal cord. 8. Viii. Intra-cisternal :These are inserted in the mid-line between the atlas and axis (first and second cervical vertebrae respectively) and directed forward and upwards. 9. Peridural :These are given between the duramatter and the inner aspects of the vertebrae. 10. Intra-articular: These are made into the synovial fluid the liquid that lubricates the articulating ends of bones in a joint.

Epidermis
Dermis Sub Subcutaneous adipose tissue Muscle  Types of Parenteral preparations: It can be categorized as [27] i.
Small scale dispensing -Usually one unit at a time. ii.
Large scale manufacturing -In this hundreds of thousands may constitute one lot of product. Several categories of parenteral preparation may be distinguished : [28]  injections  infusions  concentrates for injections or infusions  powders for injections or infusions  implants Injections: Injections are sterile solutions, emulsions or suspensions. They are prepared by dissolving, emulsifying or suspending the active substance(s) and any added excipients in Water for injections, in a suitable, sterile nonaqueous liquid or in a mixture of these vehicles.

Infusions:
Infusions are sterile solutions, aqueous solutions or emulsions with water as a continuous phase; they are usually made isotonic with blood. They are principally intended for administration in large volume. Infusion do not contain any added antimicrobial preservative.

Concentrates for injections or infusions:
Concentrates for injections or infusions are sterile solutions intended for injection or infusion after dilution. They are diluted to a prescribed volume with a prescribed liquid before administration. After dilution, they comply with the requirements for injections or for infusions.

Powders for injections or infusions:
Powder for injections or infusions are solid, sterile substances distributed in their final containers and which, when shaken with the prescribed volume of a prescribed sterile liquid, rapidly from either clear and practically particle-free solutions or uniform suspensions. After dissolution or suspension, they comply with the requirements for injections or for infusions.
Implants: Implants are sterile solid preparations of a size and shape suitable for parenteral implantation and release the active substance(s) over an extended period of time. Each dose is provided in a sterile container.
Formulation of Parenterals: [29] 1 Active drug 2 Added substances -Antimicrobial agent -Buffer -Antioxidant -Tonicity agent -Chelating agent -Complexing and surface active agent -Solublizers 3.Vehicle -Aqueous -Non-aqueous Active drug:-It is active pharmaceutical ingredient. A thorough evaluation of properties of the active drug or drug is essential in developing a stable and safe parenteral dosage form.

Added substances:-
Antimicrobial agent:-Substance that kill or slow the growth of microbes. Antimicrobial agent serves to maintain the sterility of the product during its shelf life and use. They are required in preparations intended for multiple dosing from the same container because of the finite probability of accidental contamination during repeated use. They are also included, in some single dose products to provide additional assurance of product sterility. Most commonly used parenteral antimicrobial preservative includes phenylmercuric nitrate and thiomersol 0.01%, benzethonium chloride and benzalkonium chloride, phenol or cresol 0.5%, chlorobutanol 0.5%, methyl paraben, propyl paraben. [30] [31] 988 Buffer:-Buffers are added to a formulation to adjust the pH in order to optimize solubility and stability. For parenteral preparations, the pH of the product should be close to physiologic pH. The selection of buffer concentration (ionic strength) and buffer species are important. Citrate and acetate buffer, phosphate buffer. [32] Antioxidant:-Salts of sulfur dioxide, including bi sulfite, metabisulfite, and sulfite are the most common antioxidants used in aqueous parenterals. These antioxidants maintain product stability by being preferentially oxidized and gradually consumed over shelf life of the product. Irrespective of which salts is added to the solution, the antioxidant moiety depends on the final concentration of the compound and the final pH of the formulation. [33] Tonicity agent:-It is important that injectable solutions that are to be given intravenously are isotonic, or nearly so. Because of osmotic pressure changes and the resultant exchange of ionic species across red blood cell membranes, non isotonic solutions, particularly if given in quantities larger than 100 ml, can cause haemolysis or crenation of red blood cells. Tonicity can be measured by osmometer and fragility point. Electrolytes : sodium chloride; Nonelectrolytes : glucose, mannitol, glycerine; Isotonic : dextrose injection 5% and sodium chloride injection 0.9%. [34] Chelating agent:-Only a limited number of chelating agents are used in parenteral products. They serve to complex heavy metals and therefore can improve the efficacy of antioxidants or preservatives. disodium edta, citric acid, tartaric acid and some amino acids also can act as chelating agents. [35] Complexing and surface active agent:-Increase and maintain drug solubility. Examples include complexing agents and surface active agents. The most commonly used complexing agents are the cyclodextrins, including captisol. The most commonly used surface active agents are polyoxyethylenesorbitanmonolaurate (tween 20) and polyoxyethylenesorbitanmonooleate (tween 80). [36] Solublizers:-Solublizers are used to enhance and maintain the aqueous solubility of poorly water soluble drugs. [37] Vehicles:-Aqueous: It can be water and water miscible liquids. Water: Most liquid injections are quite dilute, the component present in the highest proportion is the vehicle. The vehicle of greatest importance for parenteral products is water. WFI is highly purified water used as a vehicle for injectable preparations which will be subsequently sterilized. USP requirements include not more than 10 parts per million of total solid. pH of 5 -7 WFI may be prepared by either distillation or reverse osmosis. Stored for less than 24 hr at RT or for longer times at specific temperature should meet USP pyrogen test. [38] Water miscible: A number of solvents that are miscible with water have been used as a portion of the vehicle in the formulation of parenteral. These solvents are used to solubilize certain drugs in an aqueous vehicle and to reduce hydrolysis.
The most important solvents in this group are ethyl alcohol, liquid polyethylene glycol, and propylene glycol.
Ethyl alcohol is used in the preparation of solutions of cardiac glycosides and the glycols in solutions of barbiturates, certain alkaloids, and certain antibiotics. Such preparations are given intramuscularly.
There are limitations with the amount of these co-solvents that can be administered, due to toxicity concerns, greater potential for haemolysis, and potential for drug precipitation at the site of injection. [39] Non-Aqueous : The most important group of non-aqueous vehicles is the fixed oils. The oils most commonly used are corn oil, cottonseed oil, peanut oil, and sesame oil. Fixed oils are used as vehicles for certain hormone (eg., progesterone, testosterone, deoxycorticosterone) and vitamin (eg., Vitamin K, Vitamin E) preparations. [40] 989 intra-arterial), distribution,metabolism, and excretionfor a drug have some effect on the selected route of administration and, accordingly, the type of formulation. 4. Drug solubility -If the drug is insufficiently soluble in water at the required dosage, then the formulation must contain a co-solvent or a solute that sufficiently increases and maintains the drug in solution. If relatively simple formulation additives do not result in a solution, then a dispersed system dosage form must be developed. 5. Drug stability -If the drug has significant degradation problems in solution, then a freeze-dried or other sterile solid dosage form must be developed. Stability is sometimes affected by drug concentration that, in turn, might affect size and type of packaging system used. 6. Compatibility of drug with potential formulation additives and packaging systems -It is wellknown that drugexcipient incompatibilities frequently exist. Initial preformulation screening studies are essential to ensure that formulation additives, although possibly solving one problem, will not create another. 7. The use of silicone to lubricate vial rubber closures, syringe rubber plungers to coat the inner surface of glass syringes, and cartridges potentially can induce protein aggregation. 8. Desired type of packaging -Selection of packaging (i.e. type, size, shape, color of rubber closure, label, and aluminum cap) is often based on marketing preferences and competition. [42] Main Steps Involved in the Formulation of a New Parenteral Drug Product: Physical properties of active drug substance -Structure, molecular weight -Solubility in water at room temperature -Effect of pH on solubility -Solubility in certain other solvents -Unusual solubility properties -Isoelectric point for a protein or peptide -Hygroscopicity -Potential for water or other solvent loss -Aggregation potential for protein or peptide Chemical properties of active drug substance -‗Validated' analytical method for potency and purity -10% degradation at room temperature in aqueous solution in the pH range of anticipated use -Time for 10% degradation at 5°C -pH stability profile -Sensitivity to oxygen 990 -Sensitivity to light -Major routes of degradation and degradation products Initial formulation approaches -Single dose vs multiple dose -Shelf life goals -High temperature storage -Temperature cycling -Light and/or oxygen exposure -Selection of primary container and closure [43] Materials:-Water for Injection:-It can be prepared by distillation or by membrane technologies (i.e., reverse osmosis or ultra filtration). The water must be pretreated by one or a combination of the following treatments: chemical softening, filtration, de ionization, carbon adsorption, or reverse osmosis purification. Distillation is a process of converting water from a liquid to its gaseous form (steam). Since steam is pure gaseous water, all other contaminants in the feed water are removed. [44] Glass:-Glass is employed as the container material of choice for most SVIs. It is composed, principally, of silicon dioxide, with varying amounts of other oxides, such as sodium, potassium, calcium, magnesium, aluminum, boron, and iron. [45] Types:-The USP provides a classification of glass: • Type I, a borosilicate glass; • Type II, a soda-lime treated glass; • Type III, a soda-lime glass; and • NP, a soda-lime glass not suitable for containers for parenteral.
Type I glass will be suitable for all products, although sulfur dioxide treatment is sometimes used for even greater resistance to glass leach-ables. Because cost must be considered, one of the other, less expensive types may be acceptable.
Type II glass may be suitable, for example, for a solution that is buffered, has a pH below 7, or is not reactive with the glass.
Type III glass is usually suitable for anhydrous liquids or dry substances.
Types II and III glass compounds are composed of relatively high proportions of sodium oxide (~14%) and calcium oxide (~8%). This makes the glass chemically less resistant. Both types melt at a lower temperature, are easier to mold into various shapes.
Type II glass has a lower concentration of the migratory oxides than Type III. In addition, Type II has been treated under controlled temperature and humidity conditions, with sulfur dioxide or other de alkalizers to neutralize the interior surface of the container.
The glass types are determined from the results of two USP tests: The Powdered Glass Test The Water Attack Test.
The Powdered Glass Test challenges the leaching potential of the interior structure of the glass, whereas the Water Attack Test challenges only the intact surface of the container.

991
Selecting the appropriate glass composition is a critical facet of determining the overall specifications for each parenteral formulation. Glass can be the source / cause of leach-ables / extractable, particulates (glass deamination or glass lamellae formation), adsorption of formulation components, especially proteins, and cracks / scratches.

Plastic:-
Plastic packaging has always been important for ophthalmic drug dosage forms and is gaining in popularity for injectable dosage forms. Plastic bottles for large volume injectable (LVIs) have been used for many years. Plastic vials for SVIs may be a wave of the future plastic packing offers such advantages of cost savings elimination of the problems caused by breakage of glass and increase convenience of use. [46] Rubber:-Rubber formulations are used as rubber closures, rubber plungers and other applications. The most common rubber polymers used in SVIs closures are natural and butyl rubber. Silicone and neoprene also are used but less frequently in sterile products. Butyl rubber has great advantages over natural rubber in that butyl rubber requires fewer additives, has low water vapor permeation properties and has good characteristics with respect to gaseous permeation reactivity with the active ingredient. [47] Labeling:-The package and in particular, the labeling for parenteral dosage forms are integral and critical parts of the product. The labeling must be legible and clearly identify the drug, its concentration, handling or storage conditions and any special precautions, the dose or concentration must be predominantly displayed when other concentrations of the same drug are marketed, proper labeling is difficult with the space limitation dictated by small containers used for many parenteral products. Smaller containers have become increasingly popular because of the unit dose concept. [48] Controlled environment required for parenteral preparation:-Clean Room Classified Areas: Due to the extremely high standards of cleanliness and purity that must be met by parenteral products, it has become standard practice to prescribe specifications for the environments (clean rooms) in which these products are manufactured. [49] The Critical and General area of clean room: The clean room divides into 1. Critical Area 2. General Area The critical area is the area around the point of the production where contamination can gain direct access to the process. This area often protected by localized laminar flow clean benches and workstations. The General area is the rest of the clean room where contamination will not gain direct entry into the product but should be kept clean because of the transfer of contamination into the critical area. It is necessary that the critical area be cleaned most often with the best cleaning ability without introducing contamination. [50][51][52]

Classification of Clean Rooms:-
The class is directly related to the number of particles per cubic foot of air equal to or greater than 0.5 micron. 1. Class 100,000: Particle count not to exceed a total of 100,000 particles per cubic foot of a size 0.5μ and larger or 700 particles per foot of size 5.0μ and larger. 2. Class 10,000: Particle count not to exceed a total or 10,000 particles per cubic foot of a size 0.5μ and larger or 65-70 particles per cubic foot of a size 5.0μ and larger. 3. Class 1,000: Particles count not to exceed a total of 1000 particles per cubic foot of a size 0.5μ and larger or 10 particles per cubic foot of a size 5.0μ and larger. 4. Class 100: Particles count not to exceed a total of 100 particles per cubic foot of a size 0.5μ and larger. [53][54] [55] Class 1: The particle count shall not exceed a total of 3000 particles/m 3 of a size 0.5μ. Class 2: The particle count shall not exceed a total of 3000 particles/m 3 of a size of 0.5μ or greater; 2000 particles/m 3 of size 0.5μ or greater; 30 particles of a size 10μ.
992 Class 3: The particle count shall not exceed a total of 1,000,000 particles of a size of 1μ or greater; 20,000 particles/m 3 of size 5μ or greater; 4000 particles/m 3 of a size 10μ or greater; 300 particles of a size of 25μ or greater. Class 4: The particle count shall not exceed a total of 200,000 particles of a size of 5μ or greater [54] [55] For the manufacture of sterile medicinal products normally 4 grades can be distinguished: Air flow velocities of 0.36 m/s to 0.56 m/s (70 fpm to 110 fpm) are recommended as standard design for laminar air flow clean room systems. Air is supplied at a much higher pressure than its surrounding area.

Liquids:-
There are three main methods for filling liquids into containers with high accuracy: • volumetric filling, time • pressure dosing, • net weight filling. [55] Sterilization:-The processes (thermal and chemical) are designed to destroy or eliminate micro-biologic contaminants present in a product.
Thermal methods:- • Most common, cost-effective and rapid means of sterilization • Lethal effectiveness of heat on microorganisms depends upon the degree of heat , the exposure period, and the moisture present.
• The range of sterilizing temperatures, the time required to produce a lethal effect is inversely proportional to the temperature employed.
• Sterilization by thermal methods may be effected at lower temperatures in the presence of moisture. [56] Thermal methods of sterilization may be divided into: Chemical methods:- [58] Chemical methods are used for sterilization. Although heating provides the most reliable way to rid objects of all transmissible agents, it is not always appropriate, because it will damage heat sensitive materials such as biological materials, fiber optics, electronics and many plastics. Low temperature gas sterilizers function by exposing the articles to be sterilized to high concentrations (typically 5 to 10% v/v) of very reactive gases (alkylating agents such as ethylene oxide, and oxidizing agents such as hydrogen dioxide and ozone) 1. Ethylene oxide: (EO or EtO) Commonly used to sterilize the the objects that are sensitive to temperature greater than 60°C. EO treatment is generally carried out between 30°C and 60°C with relative humidity above 30% and gas concentration between 200 and 800 mg/l and typically lasts for at least 3 hours.
2. Nitrogen dioxide: (NO2) Used against wide range of microorganisms, including common bacteria, viruses and spores. The mechanism for lethality is the degradation of DNA in the spore core through nitration of the phosphate backbone, which kills the exposed organism as it absorbs (NO2).
3. Ozone: Used in industrial setting to sterilize water and air. It has benefit of being able to oxidize most organic matter.
4. Hydrogen peroxide: It is a strong oxidant and these oxidizing properties allow it to destroy a wide range of pathogens and is used to sterilize heat or temperature sensitive articles.

994
Applications of sterilization:= 1. Accelerated electrons or gamma rays may be used to sterilize select products by a continuous process. 2. Vitamins, antibiotics and hormones in dry state have been successfully sterilized by radiation.
Evaluation Parameters:- [59] The basic quality control test which are performed on sterile parenteral product includes: volume of a sample in two tests containing a culture medium that is FTM, SCDM. This method is simply in theory but difficult in practice when the demand for repetition in opening container, sampling transferring, and mixing increases causes potential error in operator technique. d. Membrane Filtration Technique:It is official in USP 1970. This method basically involves filtration of sample through membrane filters of porosity 0.22 micron and diameter 47mm. The filtration is associated under vacuum, after filtration completion the membrane is cut into 2 halves and one halve is placed in two test tubes containing FTM, SCDM medium.


Interpretation: If no visible evidence of microbial growth in culture medium in test tube then it is interpreted that the sample representing lot is without intrinsic contamination. 1. Pyrogen Test: Pyrogens are product of metabolism in microorganism gm-ve bacteria produces most potent pyrogen. When these pyrogens are introduced into the body they produce a mark response of fever with body ache and vasoconstriction within an onset of one hour. Pyrogen test is done on rabbit ear vein.

Leaker Test:
The leaker test is intended to detect incompletely sealed ampoules so that they may be discarded.
Ampules are dipped in 1% methylene blue solution. It is performed in vacuum chamber. Vials & bottles not subjected to this test because of flexibility of rubber. 3. Particulate matter: Particulate matter is a primary concern in the parenteral products given by iv routes, all parenteral products should be free from insoluble particles. White screen for the detection of black particles and black screen for the detection of white particles to detect heavy particles. 4. Uniformity of mass: Weight variation requirements are applied to sterile solids with or without inactive substances that have been prepared from true solution and freeze-dried in the final containers. Content uniformity requirements are applied to all cases of sterile solids that contain inactive or active substances except for special products. 5. Bacterial Endotoxin test :The bacterial endotoxin test (BET) is a test to detect or quantify endotoxins from gram negative bacteria using Amoebocyte lysate from the horse shoe crab (Limulus polyphemus or Tachypleustridentatus) 996 about the formulation of injection. Its comparable clinical efficacy of their antibacterial and favorable route of administration and the pharmacokinetic and preformulation parameters for injection and microbiological studies of antibiotic injection. It is one area where major development changes are required to give more efficient effect injection and reduce side effect of it.