Parenteral formulations and Quality control tests
In previous article on parenterals (Parenteral I) we have seen some of the basic concepts. In this article, additives used in parenteral preparations, types of formulations and quality control tests are given shortly.
In previous GPAT exams, questions on the antioxidant examples, organism used for LAL test, pyrogen test, osmolarity, isotonicity were asked.
FORMULATION OF PARENTERALS
Parenteral formulations include water, co-solvents and several additives.
In previous article on basics of parenterals, we have seen first two components i.e. solvents (aqueous and non-aqueous).
In this point, we are going to see some of the important additives/excipients used in the parenteral formulations.
Additives/ Excipients
¶Local anesthetics: Benzyl alcohol & Procaine HCl
¶Antioxidants: These prevent oxidation of active ingredient(s) by either reducing or blocking action.
i) Reducing agents: Ascorbic acid, sodium bisulfite, sodium metabisulfite, thiourea.
ii) Blocking agents: Ascorbic acid ester, BHT, BHA, tocopherol.
iii)Synergist: citric acid, tartaric acid, phosphoric acid, ascorbic acid.
iv) Chelating agent: EDTA salt
Sodium bisulfite is not used in the intraspinal injections.
¶Chelating agents: EDTAate disodium, Edetate calcium disodium, Edetate tetrasodium.
¶Buffers:
Acetate buffers: pH range 4 to 6
Phosphate buffers: pH range 6 to 8
Glutamate buffers: pH range 2 to 5 & 8.5 to 10.5
Citrate buffers: pH range 2 to 6
¶Antimicrobial agents:
Benzyl alcohol, benzethonium chloride, methyl paraben, propyl paraben, phenyl mercuric nitrate, phenol, chlorobutanol, thiomersal.
¶Solubilizers:
Dimethyl acetamide, ethyl alcohol, ethyl lactate, glycerin.
¶Emulsifiers:
Lecithin, PEG, PEG 300, polysorbates (20,40,80), povidone.
¶Bulking substances:
Glycerin, sorbitol, lactose, mannitol, dextrose, sodium chloride, sodium sulfate.
¶Stabilizers:
Creatinine, niacinamide, glycine, sodium saccharine.
¶Tonicity modifiers:
Above mentioned bulking substances are used as tonicity modifiers.
Isotonicity of parenterals:
Parenteral preparations must be isotonic with body fluids. Preparations for intravenous and intraspinal administration must be isotonic in order to avoid lysis (breakdown) of cells and to maintain the integrity of RBCs and nerves.
For rapid absorption of drug from muscles, intramuscular injections are formulated slightly hypertonic. Due to hypertonicity local tissues undergo irritation and blood flow towards such site increases which leads to rapid absorption of drugs.
Methods to determine tonicity:
1. Freezing point depression
2. Hemolytic method using RBCs.
PARENTERAL SUSPENSIONS
¶Solid content: 0.5 to 5% but may go upto 30% in case of antibiotic preparations.
¶Stabilizing agent: Polysorbate 80 and lecithin. These reduce interfacial tension among solid & vehicle.
¶Viscosity enhancers: Sorbitol and protective colloid.
¶Stability of flocculated parenterals: Monosodium citrate increases the surface charge on particles causing formation of loose floccules (easily redispersible) avoiding compact cake formation.
¶Small and uniform particle size can be achieved by fluid energy grinding, micropulverization, ultrasonic isonation of shock cooled saturated solution.
PARENTERAL EMULSIONS
¶Parenteral emulsions must possess uniform globule size of internal phase in the range of 1 to 5 micron.
¶Commonly used emulsifiers are lecithin and oxyethylene oxypropylene polymer.
¶Emulsions must stand sterilization (autoclave) process. Heat caused formation of larger droplets and creaming of internal phase.
OSMOLARITY OF PARENTERAL PREPARATIONS
Solutions that have same osmotic pressure as that of RBCs are considered isotonic.
Osmolarity measures the potential of solution to move water across semi-permeable membrane from solution of low osmolarity (hypotonic) to the solution of high osmolarity (hypertonic).
Units of osmolarity: osmols/ milliosmoles/ mosmol.
Osmolarity of plasma: 360 mosmol/liter.
Glucose 5% infusion: 280 mosmol/liter.
Sodium chloride 0.9%: 308 mosmol/liter.
Large volume intravenous solutions have osmolarity between 260-340 mosmol/liter.
Osmolarity of hypotonic solution is adjusted by addition of NaCl, glucose or mannitol to make it isotonic.
QUALITY CONTROL TESTS FOR PARENTERALS
A) Leaker test:
* It is intended to detect incompletely sealed ampoules so that these can be discarded.
* Leakers can be detected by applying negative pressure on ampoules using vacuum chamber, ampoules are submerged in colored solution of 0.5 to 1% methylene blue.
* If there is incompletely sealed ampoule, dye will get mixed in solution.
B) Pyrogen test: It shows the presence/absence of pyrogens in the parenterals. In vivo (biological test using rabbits) and in vitro (LAL test) are utilized for pyrogen testing.
I) In vivo test:
In this test sterile preparation which is to be examined is administered to rabbits (ear vein) and fever response is measured within 3 hours.
Preparation 10 ml per kg is administered intravenously within a period of not more than 10 minutes.
Rabbits show similar physiological response to pyrogens as humans.
II) In vitro test:
It is 5-10 times more sensitive than rabbit test.
In LAL test, the reagent used is lysate of the Amebocytes of Limulus polyphemus (the horseshoe crab). To the reagent, the formulation is added and mixed properly and incubated at 37°±1°C for 60 ± 2 minutes.
If the endotoxins are present then a firm gel is formed within 60 minutes. This gel maintains its integrity even of it is inverted through 180°. Such gel formation is considered as positive result (presence of pyrogens).
If the endotoxins are present then a firm gel is formed within 60 minutes. This gel maintains its integrity even of it is inverted through 180°. Such gel formation is considered as positive result (presence of pyrogens).
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