Parenteral Added Substances

The details and quantities of substances added in the parenteral pharmaceutical products.

Introduction:

Added substance or additives are generally employed in a parenteral preparation to enhance its chemical or physical stability, i.e., shelf life or esthetic appearance. To provide efficacious and safe parenteral dosage forms, added substances must frequently be incorporated into the formula to maintain pharmaceutical stability, control product attributes, ensure sterility or aid in parenteral administration.

Criteria for added substance:

must be prevented from adversely affecting the product
must be nontoxic in the quantity administered to the patient
should not interfere with the therapeutic efficacy nor with the assay of the active therapeutic compound
must also be present and active when needed throughout the useful life of the product

Types of parenteral additives:

Antimicrobials
Antioxidants
Buffers
Bulking agents
Chelating agents
Protectants
Solubilizing agents
Surfactants
Tonicity adjusting agents
Antifungal agents
Hydrolysis inhibitors
Antifoaming agents

Antimicrobial agents:

A suitable preservative system is required in all multiple-dose parenteral products to inhibit the growth of micro-organisms accidentally introduced during withdrawal of individual doses. Preservatives may be added to single-dose parenteral products that are not terminally sterilized as a sterility assurance measure, i.e., to prevent growth of any micro-organisms that could be introduced of there were any inadvertent breach of asepsis during filling operations.

S. No.	Additives	Concentration range (%)
1.	Benzalkonium chloride	0.01
2.	Benzethonium chloride	0.01
3.	Benzyl alcohol	0.5-10.0
4.	Butylparaben	0.015
5.	Chlorobutanol	0.25-0.5
6.	Metacresol	0.1-0.25
7.	Methy paraben	0.01-0.18
8.	Phenol	0.065-0.5
9.	Phenylmercuric nitrate	0.001
10.	Propylparaben	0.005-0.035
11.	Thimerosal	0.001-0.02

2. Antioxidants:

Many drugs in solution are subject to oxidative degradation. Such reactions are mediated either by free radicals or by molecular oxygen and often involve the addition of oxygen or the removal of hydrogen. Oxidative decomposition is catalyzed by metal, hydrogen, and hydroxyl ions. Drugs possessing a favorable oxidation potential will be especially vulnerable to oxidation. For example, a great number of drugs are formulated in the reduced form (e.g., epinephrine, morphine, ascorbic acid, menadione, etc.) and are easily oxidized. By increasing the oxidation potential of the drug, oxidation can be minimized.

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 preferentially oxidized and gradually consumed over the shelf life of the product.

S. No.	Additives	Concentration range (%)
	*Reducing agents*
1.	Ascorbic acid	0.02-0.1
2.	Sodium bisulfite	0.1-0.15
3.	Sodium metabisulfite	0.1-0.15
4.	Sodium formaldehyde sulfoxide	0.1-0.15
5.	Thiourea	0.005
	*Blocking agents*
6.	Ascorbic acid esters	0.01-0.015
7.	Butyl hydroxytoluene (BHT)	0.005-0.02
8.	Tocopherols	0.05-0.075
	*Synergist agents*
9.	Ascorbic acid	0.01-0.05
10.	Citric acid	0.005-0.01
11.	Citraconic acid	0.03-0.45
12.	Phosphoric acid	0.005-0.01
13.	Tartaric acid	0.01-0.02
	*Chelating agents*
14.	Ethylenediaminetetraacetic acid salts	0.01-0.075

3. Buffers:

Many drugs require a certain pH range to maintain product stability. Drug solubility strongly depends on the pH of the solution. Change in pH may occur during storage by the following ways:-

by the dissolving of glass constitutes in the product
by the releasing of constituents from rubber closures or plastic components in contact with the product
by dissolving of gases and vapors from the airspace in the container
reactions within the product

Buffer systems for parenterals consist of either a weak base and the salt of a weak base or a weak base or a weak acid and the salt of weak acid.

S. No.	Additives	Concentration range (%)
1.	Acetic acid	0.22
2.	Adipic acid	1.0
3.	Benzoic acid and sodium benzoate	5.0
4.	Citric acid	0.5
5.	Lactic acid	0.1
6.	Maleic acid	1.6
7.	Potassium phosphate	0.1
8.	Sodium phosphate mono basic	1.7
9.	Sodium phosphate dibasic	0.71
10.	Sodium acetate	0.8
11.	Sodium bicarbonate	0.115
12.	Sodium carbonate	0.06
13.	Sodium citrate	4.0
14.	Sodium tartrate	1.2
15.	Tartaric acid	0.65

4. Chelating agents:

Chelating agents are added to complex and, thereby, inactivate metals, such as copper, iron, and zinc that generally catalyze oxidative degradation of drug molecules. Source of metal contamination include raw material impurities; solvents, such as water, rubber stoppers, and containers; and equipment employed in the manufacturing process.

S. No.	Additives	Concentration range (%)
1.	Edetate disodium	0.00368-0.05
2.	Edetate calcium disodium	0.04
3.	Edetate tetrasodium	0.01

5. Inert gases:

Another means of enhancing the product integrity of oxygen sensitive medicaments is by displacing the air the solution with nitrogen or argon. This technique may be made more effective by first purging with nitrogen or boiling the water to reduce dissolved oxygen. The container is also purged with nitrogen or argon before filling and may also be topped off with gas before sealing.

6. Solubilizing, Wetting agents:

Solubilizing agents are used to increased drug solubility by using non aqueous solvents.

S. No.	Additives	Concentration range (%)
1.	Dimethylacetamide	0.01
2.	Ethyl alcohol	0.61-49.0
3.	Ethyl lactate	0.1
4.	Glycerin	14.6-25.0
5.	Lecithin	0.5-2.3
6.	PEG-40 castor oil	7.0-11.5
7.	Polyethylene glycol 300	0.01-50.0
8.	Polysorbate 20	0.01
9.	Polysorbate 40	0.05
10.	Polysorbate 80	0.04-4.0
11.	Povidone	0.2-1.0
12.	Propylene glycol	0.2-50.0
13.	Sorbitan monopalminate	0.05

7. Surfactants:

Surfactants are used:

to dispose a water-insoluble drug as a colloidal dispersion
for wetting powder
to prevent crystal growth in a suspension
to provide acceptable syringability
for Solubilizing steroids and fat-soluble vitamins

S. No.	Additives	Concentration range (%)
1.	Polyethylene	0.1-0.5
2.	Sorbitan monooleate	0.05-0.25

8. Bulking substance or Tonicity adjustment agents:

Isotonicity is important for parenteral preparations because the possibility that the product may penetrate red blood cells and cause hemolysis is greatly reduced if the solution is isotonic with blood i.e., the cells maintain their “tone”.

Solution that less osmotic pressure than the blood plasma called hypotonic and solution that more osmotic pressure than the blood plasma called hypertonic. When introduce hypotonic solution, cell may swell and offers burst because of diffusion of water into the cell i.e., hemolysis, if introduce hypertonic solution. The cell may lose water and shrink. In isotonic solution (e.g. 0.9% sodium chloride) the cells maintain their “tone” and the solution is isotonic with human erythrocytes.

S. No.	Additives	Concentration range (%)
1.	Gelatin	1.6-2.25
2.	Lactose	0.14-5.0
3.	Mannitol	0.4-2.5
4.	Dextrose	3.75-5.0
5.	Sodium chloride	varies
6.	Sodium sulfate	1.1
7.	Sorbitol	2.0

9. Protectants:

Protectants are used

to protect against loss of activity caused by some stress
to prevent loss of active ingredients by adsorption to process equipment or to primary packaging materials. These protectants are used primarily in protein formulation.

S. No.	Additives	Concentration range (%)
1.	Sucrose	2-5
2.	Glucose	2-5
3.	Lactose	2-5
4.	Maltose	2-5
5.	Trehalose	2-5
6.	Human serum albumin	0.1-1.0

10. Other added substance:

S. No.	Additives	Concentration range (%)
	*Suspending agents*
1.	Gelatin	2.0
2.	Methylcellulose	0.03-1.05
3.	Pectin	0.2
4.	Polyethylene glycol 4000	1.7-3.0
5.	Sodium carboxymethyl cellulose	0.05-0.75
6.	Sorbitol solution	50.0
	*Stabilizers*
7.	Creatinine	0.5-0.8
8.	Glycine	1.5-2.25
9.	Niacinamide	1.25-2.5
10.	Sodium caprylate	0.4
11.	Sodium saccharin	0.03

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Parenteral Added Substances