THE ACTIVE PHARMACEUTICAL INGREDIENT/DRUG

Active pharmaceutical ingredient/drug is the essential component of a medicated sterile product. Such product may be available as “ready-to-use” or as “to be reconstituted” with appropriate sterile solvent. A thorough evaluation of the physical and chemical properties of the active drug is essential in developing a stable and safe sterile dosage form. One of the most important properties to be evaluated is the solubility and the rate of solution. The factors that influence solubility include the particle size, salt, ester or other chemical forms, solution pH, polymorphism, purity and the hydrate formation.

Added substances in sterile preparations

To provide efficacious, safe and elegant sterile dosage forms, added substances are frequently, incorporated into the formula to maintain pharmaceutical stability, control product attributes, ensure sterility, or aid in administration. These substances are antioxidants, antimicrobial agents, buffers, bulking materials, chelating agents, solubilizing agents, tonicity modifiers and inert gases.

A) Antioxidants

Antioxidants are added to protect active pharmaceutical ingredient or the drug susceptible to oxidation, particularly under the accelerated conditions of thermal sterilization. An antioxidant may function by following ways: 1) by being preferentially oxidized and gradually used up, 2) by blocking one of the oxidative chain reactions, in which they are not usually consumed and 3) by making complex with catalysts that otherwise would accelerate oxidation reaction. Metals such as copper, iron and zinc catalyze oxidation.

Metals can be inactivated by complexation with chelating agents. In addition, certain compounds have been found to act as synergists which increase the effectiveness of an antioxidant, particularly those blocking oxidative reactions. To enhance the effectiveness of antioxidants, combinations of substances are added. Sometimes, chelating agents are also added to increase the efficiency of antioxidant which inactivate the metals in the preparations. The examples of antioxidants are given below.

Agents Concentration (%)

Antioxidants

Ascorbic acid 0.02-0.1

Sodium bisulfite 0.1-0.15

Sodium metabisulfite 0.1-0.15

Oxidation blocking agents

Ascorbic acid esters 0.01-0.015

Butyl hydroxyl toluene 0.005-0.02

Tochopherols 0.05-0.075

Synergists

Ascorbic acid 0.01-0.05

Citric acid 0.005-0.01

Chelating agents

Ethylendiamine tetra acetic acid salts 0.01-0.075

For the product in which oxygen enters into a degradation reaction, the antioxidant effect can be achieved by displacing oxygen (air) from contact with the product. This is accomplished by saturating the liquid with either nitrogen or carbon dioxide and sealing the final container after displacing the air above the product with the gas.

B) Antimicrobial agents (preservatives)

Preservatives are required for all multiple-dose products. They are also added in unitdose solutions which are not terminally sterilized. Antimicrobial preservatives serve dual role in preparation. In multi-dose preparations, the preservative is required as a

bacteriostatic to inhibit any microbes accidentally introduced while doses are being withdrawn. Preservatives also serve as an adjunct in aseptic processing of the products where they may be product exposure during transfer and filling operation, as in the aseptic filling of the solution or suspensions. Should a minor contamination occur in the manufacturing process, the preservative should render the product sterile.

The most commonly used antimicrobial agents along with the recommended concentrations are given below. While selecting the antimicrobial agent, consideration must be given to the stability and the efficacy of the preservative with the active ingredients and other added substances.

Agents Concentration (%)

Benzalkonium chloride 0.01

Thiomerosil 0.015

Methyl parabens 0.2

Propyl paraben 0.25

Chlorobutanol 0.25-0.5

Phenol 0.25-0.5

Benzyl alcohol 1-2%

C) Buffers

Buffers are added to maintain a required pH for many products. Change of pH may cause significant alterations in the rate of degradation reactions. Changes in pH may occur during storage as a result of the dissolving of glass constituents in the product, release of constituents from rubber closures or plastic components in contact with the product, dissolving of gases and vapors from the air space in the container and diffusion through the rubber or plastic component or reactions within the product. Buffer must have the capacity to maintain the pH of the product against these influences. However, the buffer capacity of a formulation must be overcome by the biological fluids, thus the concentration and ratios of buffer ingredients must be carefully selected.

The buffer systems for sterile products consist of either a weak acid or the salt of weak acid and either weak base or salt of weak base. Buffer systems commonly used for sterile products are acetates (1-2%), citrate (1-5%) and phosphates (0.8-2%). Amino acids are receiving increased used as buffer, especially for product containing polypeptidic drugs.

D) Chelating agents

The chelating agents are added to complex and thereby, inactivated metals such as copper, iron and zinc which generally catalyze oxidative degradation of drug molecules.

The sources of metallic contamination include raw materials, impurities, solvents such as water, rubber stoppers and containers and equipments employed in the manufacturing process.

The most widely used chelating agents are ethylenediamine tetra acetic acid (EDTA) derivatives and salts. However, in Japan these chelating agents are not allowed. Citric acid and tartaric acid is also used as chelating agents.

E) Solubilizing agents

Solubilizing agents are required to increase the solubility of certain drugs. The

solubilizing agents usually used are alcohol (1-50%), glycerin (1-50%), polyethylene glycol (1-50%), propylene glycol (1-50%) and lecithin (0.5-2.0%). Surfactants are also used as solubilizing agents. When utilizing solubilizing agents, their effect on the safety and stability of the drug must be considered.

F) Surfactants

A surfactant is a surface active agent that is used to disperse water insoluble drug as a colloidal dispersions. Surfactants are utilized for wetting of dry solid (powder), to prevent crystal growth in a suspension and to enhance syringability. (Syringability refers to the handling characteristics of a suspension while drawing it into and manipulating in syringe). The surfactants are also used in emulsions and for solubilizing steroids and fat soluble vitamins. Among the surfactants, the most commonly used are polyoxyethylene

sorbitane mono oleate (0/1-0.5%) and sorbitane mono oleate (0.05-0.25%).

G) Tonicity modifiers

Tonicity adjustment agents are necessary for the ophthalmic preparations and sterile solutions to be given intravenously. Due to 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 hemolysis or crenation of red blood cells due to hypotonic or hypertonic solution, respectively. Non-isotonic ophthalmic preparations cause eye irritation which results in the production of excessive tears and thus drug is washed away leading to lesser drug-eye contact. Dextrose and sodium chloride or potassium chloride are commonly used to achieve isotonicity in sterile formulations.

H) Inert gases

The integrity of the oxygen-sensitive products can further be enhanced by displacing the air in the solution with nitrogen or carbon dioxide. This technique may be made more effective by first purging the product with nitrogen or boiling water to reduce the dissolved oxygen. The container is also purged with nitrogen or carbon dioxide prior to filling and may also be tapped off with the gas before sealing. Glass-seal ampoules proved most impervious barrier for gas transmission. A butyl rubber stock is utilized with rubber-stopper products which are sensitive to oxygen because it provides better resistance to gas permeation than other rubber stocks.