1. PARENTRAL PRODUCTS

2. o Parenteral products are dosage forms, which are delivered to the patient by a route other than the alimentary canal. o The parenteral route of administration is often used for drugs, which cannot be given orally  This may be due to patient intolerance, to the instability of the drug, or to poor absorption of the drug if given by the oral route. o In practice, parenteral products are often regarded as dosage forms, which are implanted, injected or infused directly into vessels, tissue spaces or body compartments. o From the site of administration, the drug is transported to the site of action. Introduction

3. Route of Administration 1. Intracutaneous or intradermal injections:  These are made into the skin, between the inner layer (dermis) and the outer layer (epidermis).  The volume that can be injected intradermal is necessarily small, usually 0.1- 0.2 ml.  The route is use mainly for diagnostic purposes in investigations of immunity and allergy. 2. Subcutaneous or Hypodermic injections  These are made under the skin, into the subcutaneous tissue.  The volume injected is 2 ml or less.  This is the most popular route for administration of a great variety of drugs.  Drugs given by this route will have a slower onset of action than by I.M. or I.V. routes.

4. 3. The Intramuscular route  The I.M. route of administration is second only to the I.V. route in ­rapidity of onset of systemic action.  The principal sites of injection are the gluteal (buttocks), deltoid (upper arm), and vastus lateralis (lateral thigh) muscles.  The volume is rarely greater than 2 ml and should not exceed 4 ml at one site.  Aqueous or oily suspensions and oily solutions cannot be given subcutaneously, because they cause pain and irritation, or intravenously, because blockage of small blood vessels might occur; muscle tolerates them relatively well and,  therefore, the I.M. route is used for their administration. I.M. injections, except is small volumes, are very painful unless administered slowly.

5. 4. Intravenous injections:  These are made into a vein and, therefore, are introduced directly into the blood stream.  The volume injected varies from 1ml or less, to 500ml or even more.  Small­ volume injections are given by this route when a very rapid effect is required, as in the administration of certain anesthetics (e.g. thiopentone).  The I.V. infusion of large volumes of fluid (100-1,000ml) has become increasingly popular. 5. Intra- arterial injections  These are used for an immediate effect in a peripheral area;  for example, to improve circulation to the extremities when arterial flow is restricted by arterial spasm, early gangrene or to direct the drug to the target organ e.g. (liver spleen, lung) to minimize the side effect of the drug in the other body tissues (anticancer drugs) etc. Tolazoline hydrochloride, a peripheral vasodilator, is sometimes administered by this route.

6. 7. Intraspinal injections These are aqueous solutions, which are injected in volumes less than 20ml into particular areas of the spinal column. They are categorized as intrathecal, subarachnoid, intracisternal opidural and peridural injections. The specific gravity of these injections may be adjusted to localize the site of action of the drug. 8. Intra- articular injections These are administered as an aqueous solution or suspension into the synovial fluid in a joint cavity. They are often used for the local administration of anti-inflammatory agents. 6. Intracardiac injections These are given into the heart muscle or ventricle in emergency only; for example, as a stimulant following cardiac arrest. Adrenaline or isoprenaline sulphate may be used for this purpose.

7. Additives Substances in Parenteral products In order to provide efficacious, safe and elegant parenteral dosage forms, added substances must frequently be incorporated into the formula to (1)maintain pharmaceutical stability, (2) control product attributes, (3) ensure sterility, or (4) aid in parenteral administration. 1. Antibacterial Agents: o In all multiple-dose parenteral products. o Most unit-dose solutions which are not terminally sterilized.  Antimicrobial preservatives can serve a dual role in parenteral formulations: (l) The preservative is required as a bacteriostatic to inhibit any microbes accidentally introduced while doses are being withdrawn. (2) Adjuncts in aseptic processing of products, as in the aseptic filling of a solution or suspension. (3) Adjuncts in intermittent heat sterilizations.

8. 2. Chelating Agents Chelating agents are added to complex and thereby inactivate metals such as copper, iron and zinc which generally catalyze oxidative degradation of drug molecules. Sources of a metal contamination include: (1) raw material impurities, (2) solvents such as water, (3) rubber stoppers, (4) containers, and equipment employed in the manufacturing process e.g. ethylenediamine tetraacetic acid derivatives and salts, Citric and tartaric acids.  The effectiveness of antibacterial agents can be tested by challenging the product with selected organisms to evaluate the bactericidal activity.  Throughout and near the end of the expiration date to ensure that adequate levels of preservative are still available.

9. 3. Antioxidants  Salts of sulfur dioxide, including bisulfite, metabisulfite, and sulfite are the most common antioxidants used in aqueous parenterals.  These antioxidants maintain product stability by being oxidized and gradually consumed over the shelf life of the product.  Irrespective of which salt is added to the solution, the antioxidant moiety depends on the final pH of the formulation. 4. Tonicity Adjustment Agents  It is important that injectable solutions to be given intravenously are isotonic or nearly so. Dextrose and sodium chloride or potassium chloride are commonly used to achieve isotonicity in a parenteral formula.

10. 5. Buffers:  Many drugs require a certain pH range to maintain product stability.  Drug solubility may be strongly dependent on the pH of the solution.  Parenteral products should be formulated to Posses sufficient buffer capacity to maintain proper product pH.  Factors which influence pH include: (l) product degradation, (2) container and stopper effect, (3) diffusion of gases through the closure, and (4) the effect of gases in the product or in the headspace.

11.  Buffer systems for parenteral consist of either a weak base and its salt or a weak acid and its salt.  Buffer systems commonly used are acetates, citrates, and phosphates. The pH of a buffer could be computed through Henderson- Haselbalch equation, e.g. an acetate buffer system consisting of 0.1 M acetic acid and 0.05 M sodium acetate would result in a pH of 4.5. pH = pk a + log [Salt] / [Acid] pH = 4.76 + log 0.05 / 0.1 = 4.5

12. 6. Inert Gases  Another means of enhancing the product integrity of oxygen­ sensitive medicaments is by displacing the air in the solution with nitrogen or carbon dioxide. o This technique may be made more effective by first boiling the water to reduce dissolved oxygen. o The container is also purged with nitrogen or carbon dioxide prior to filling and may also be topped off with the gas before sealing. 7. Solubilizing Agent and Surfactants  Surfactants are used quite extensively in parenteral suspension for wetting powders and to provide acceptable syringeability.  Surfactants are also used in emulsions and for solubilizing steroids and fat- soluble vitamins.

13. VEHICLES (SOLVENTS)  Although there are many parenteral dosage forms:-  suspensions and emulsions,  aqueous solutions (the vast majority)  reconstituted with an aqueous diluent.  Water is always the preferred solvent, but it is not always possible why?  Due to limited aqueous solubility or the harmful effect of water on the stability of certain drugs. Advantage of aqueous solutions parenteral dosage forms:- 1.Provide the most uniform dose and 2.The easiest to deliver drug. 3.Solutions manufactured in clear containers  can also be visually inspected for particulate contamination, chemical precipitates, and color instability.

14. Moreover, water for injection (WFI) is used as the vehicle because aqueous preparations are tolerated well by the body and are the safest and easiest to administer. When an oily vehicle may be necessary? (a)If the medicament insoluble or only slightly soluble in water, (b)When a depot effect is desired, and (c)When an oily medium is more suitable for a diagnostic procedure. But the main problems to use oily vehicle are: (a)Too viscous in cold (warming needed), (b)Pain on injection, (c)The syringe and needle difficult to clean, and (d)Accidental intravenous injection lead to thrombosis. "For intramuscular use only"

15. 1- Aqueous Vehicles: Water for Injections (WFI): the most widely used. It must be: (1) clear, colourless and odourless, (2) having a pH 5-7 (3) Purity specifications, limits for cl -, ca ++, SO 4 --, NH 3, CO 2, heavy metal contents and oxidizable substances and total dissolved solid (10 ppm).  Microorganisms, dissolved organic and inorganic substances, and foreign particles are the most common contaminants found in water.  The purification methods: (to improve the quality of water):- (1)Inorganic compounds (distillation, reverse osmosis, deionization), (2)Membrane and depth filters (particulate contaminants), (3)Charcoal beds (organic materials). (4)Filtration, chilling or heating, (to reduce the microbial growth and prevent pyrogen formation.

16. 1- Distillation: It is a well-established process, and if the still is properly constructed and operated, water of the highest quality can be obtained. 1.The vapor generated by the still must be free of entrained water droplets possibly containing pyrogens and other contaminants from the feed water. 2.Still designs frequently include devices to "scrub" the vapor to prevent water droplets from being carried over in the distillate. 3.Stills are designed to operate at a given rate (gallons per hour); operations at a more rapid rate will result in carry-over of distill and water droplets from the evaporator. 4.All parts of the still contacted by the vapor or distillate  high quality material, such as tin-coated metal to prevent metal contamination. 5.The yield of pure water is approximately 70% of the total quantity of water used. WFI can be prepared either by distillation or reverse osmosis.

17.  Distillation is an expensive process because of the low yield, the energy requirement and the resultant scaling problems.

18. 2- Reverse osmosis  Osmosis:  The flow of water between two aqueous solutions of varying dissolved solids concentrations, separated by a semipermeable membrane.  The flow of water from the solution with the lower concentration into the solution with the higher concentration.  Flow continues until the concentrations reach equilibrium.  The pressure applied by the second solution is called its osmotic pressure. o In reverse osmosis, the direction of flow of the feed water passing through a semipermeable membrane can be reversed by applying pressure exceeding the osmotic pressure of the feed water.

19. Schematic of reverse osmosis compared to osmosis. The semipermeable membrane, particulates and most dissolved solids are excluded, resulting in pure water passing through the membrane.

20.  The semipermeable membranes used for reverse osmosis include:- A. The cellulose acetate membrane (1) Particulates, microorganisms, and dissolved organic compounds with molecular weights over 200 are rejected because of their molecular size. Thus, pyrogens are eliminated from the permeate. (2) Dissolved electrolytes are rejected because of the repulsion of the ions from the surface of the membrane, higher valence ions being repelled a greater distance from the membrane. (3) Rejection of small valence ions such as the chloride ions is not complete, and a small percentage of these ions pass through the membrane. These can be trouble some to eliminate.

21.  So, pretreatment of the feed water and the use of a sufficient number of membrane passes; the chloride ion can be reduced to limits acceptable for purified water and WFI. B. The polyamide membrane material  Fine, hollow fiber with diameters in the range of 80 to l00 µ.  The fibers are bundled, looped, and secured within a housing.  The feed water under pressure passes through the fiber's walls, and the permeate is carried out through the open ends of the loop, while the rejected water flows from the housing. ­

22. The USP also lists: (1) Sterile Water for Injection (2) Bacteriostatic Water for Injection, which unlike WFI must be sterile. Higher levels of solids are allowed in these vehicles because of the possible leaching of glass constituents into the product during high-temperature sterilization and sub- sequent storage. Bacteriostatic Water for injection must not be placed in containers larger than 30 ml. This is to prevent the administration of large quantities of bacteriostatic agents (such as phenol) which could become toxic if large volumes of solution were administered.

23. 2. Non-aqueous and Mixed Vehicles:  A non-aqueous solvent or a mixed aqueous/non-aqueous solvent system may be necessary :- (1) to stabilize drugs (e.g. barbiturates), which are readily hydrolyzed by water, (2) to improve solubility (e.g. digitoxin).  Non-aqueous solvent must be carefully tested to ensure that they exhibit no pharmacological action, non-toxic and non-irritating and are compatible and stable with all ingredients of formulation.  The major class of non-aqueous solvents is the fixed oils.  The commonly used oils are corn oil, cottonseed oil, peanut oil, and sesame oil.  Because fixed oils  quite irritating and sensitivity reactions in some patients.  Sesame oil is the preferred oil for most injection because it is the most stable (except to light).

24. The following should be considered: 1.Fixed oils must never be administered intravenously and are in fact restricted to I.M. use. 2.The main use of oils is the steroid  produce a sustained release effect. Sesame oil  slow release of fluphenazine esters given intramuscularly. 3.Excessive unsaturation of oil can produce tissue irritation. 4.The use of injections in oil has diminished somewhat in precedence to aqueous suspensions, which generally have less irritating and sensitizing properties. 5.Benzyl benzoate may be used to enhance steroid solubility in oils if desired.