Monday, November 1, 2010

Suspensions ingredients

a.Active ingredients
b.Excipients; The excipients used in the case of injectable suspensions, must have –
ü Non-pyrogenic
ü Non-toxic and
ü Non-irritating
Typical excipients used in parenteral suspensions are -
a. Preservatives
b. Antioxidants
c. Chelating agents
d. Flocculating agents
e. Buffering agents
f. Tonicity modifiers
g. Solvents systems
a. Preservatives:
Formulation containing active ingredient (s) devoid of any antimicrobial activity must require one or more preservatives. A growth promotion study should be conducted in order to determine the microbiological power of the preservative free formulation. One procedure is to inoculate the preservative free formulation with approximately 1000 organisms and incubate at 30-320c for 7days. At the end of the incubation period, the sample should be examined quantitatively and qualitatively.
No growth upon qualitative examination → sample should streaked onto Tryptic Soya Agar-plate and incubate at 3days at specified temp. → no growth/growth → the formulation is bacteriocidal / bacteriostatic in nature.
The most commonly used preservatives are either benzyl alcohol or a combination of propyl and methyl parabens. But benzyl alcohol can cause convulsions in neonates and should be avoided in certain drug products with neonatal indications.

b. Antioxidants / chelating agents:
Oxidation (which is catalyzed by metals, heat, light, H+ or OH-) can lead to unacceptable discoloration of the drug product without necessarily causing potency loss. Antioxidants are used to increase stability of the drug product by inhibiting oxidation of the active ingredient(s). Some substances containing the functional groups e.g. – aldehydes, ketones, amines, alcohols and unsaturated fats and oils suffers oxidative degradation (auto-oxidation).
The antioxidants act by either – (i) preferential oxidation of the antioxidant due to a lower oxidation potential or (ii) termination of the propagation step by the antioxidant in the free radical oxidation mechanism.
Chelating agents are used to sequester heavy metals in a preparation, thus preventing the catalysis of oxidation reactions.
For auto-oxidation manner, the exposure of active ingredients to oxygen during the manufacturing processes we must follow the underline processes –
Boiling the WFI USP during manufacturing to displace the solubilized oxygen
Purging the solvent system with filtered (0.22μm) nitrogen during the manufacturing process
Blanketing the bulk drug product with filtered (0.22μm) nitrogen during the filling operation
Displacing oxygen form the headspace of the filled container with filtered (0.22μm) nitrogen

c. Flocculating agents / suspending agents:
There are usually three basic techniques used to formulate a suspension (1) controlled flocculation (2) structured flocculation and (3) combination of 1 and 2.

Types of flocculating agents –
Electrolytes: alter the electrical barrier between particles and allow the flocs to form e.g. -
KCl / NaCl
K-citrate / Na-citrate
K-acetate / Na-acetate
Surfactants: function same as electrolytes e.g. -
Lecithin
Tween (polyoxyethylene sorbitan monooleate)-20, 40, 80
Pluronic F-68
Sorbitan Trioleate(Span-85)

Hydrophilic colloids: provide a mechanical barrier to the particles and also affect the repulsive forces e.g. -
Na-CMC
Acacia
Gelatin
Methylcellulose
PVP




d. Wetting agents:
These are the most important for the injectable suspensions since the hydrophobic powders are often suspended in aqueous solvent systems e.g. – glycerin, alcohols and propylene glycol are the commonly used wetting agents in pharmaceutical field.
YS = YS / 1 + Y1 cosӨ


Where,
YS = surface tension of solid
YS / 1 = solid / liquid interfacial tension
Y1 = surface tension of liquid
e. Buffering agents:
These agents are used to maintain a specific pH of the drug product. pH profiles obtained during pre-formulation studies determine the most suitable pH at which the drug product should be formulate. Examples-
Na/K- acetate → acetic acid
Na/K-citrate → citric acid
Na/K-phosphate → Phosphoric acid
f. Tonicity modifiers:
Parenteral suspensions must be isotonic in nature to reduce paion at the injection site but they are less crucial for i.v administration than the s.c or i.m administration. Example- NaCl.

g. Solvent system:
The solvent system for injectable preparations provides a medium for incorporation of both the ingredients and excipients necessary to provide a stable, safe, and efficacious dosage form.

The type of solvent co-solvents used in parenteral preparations are-
(i) Aqueous vehicle: safest and most widely used e.g. - WFI
(ii) Non-aqueous vehicle:
Water miscible: these are widely used as co-solvents with WFI to promote solubility and stability e.g. – ethanol, benzyl alcohol, glycerin, propylene glycol and N-lactamide.
Water immiscible: e.g. – fixed oil in nature ethyl oleates, isopropyl myristate and benzyl benzoate. Examples of some fixed oils are sesame oil, peanut oil, cottonseed oil and corn oil.

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