Suspensions are an important class of pharmaceutical dosage forms. The advantages of suspension dosage forms include effective dispensing/ administration of insoluble or poorly soluble drugs; masking of unpleasant or bitter taste of drugs and certain ingredients; easy swallowing for young or elderly patients; offering resistance to degradation of drugs due to hydrolysis, oxidation, or microbial activity; and efficient intramuscular depot therapy.
During suspension formulation, the main aim of the formulation scientist is to control the process of separation and, in so doing, optimize the stability of the formulation. This is because, on storage, the internal (drug) phase will separate. A pharmaceutical suspension would be considered stable if, after agitation (shaking), the drug particles are homogeneously dispersed for a sufficient time to ensure that an accurate dose is removed for administration to the patient.
The manufacture of pharmaceutical suspensions involves several steps. The first step is to obtain particles of the proper size typically in the micrometer range.
Pharmaceutical suspensions are usually prepared either by direct incorporation/ dispersion method or by precipitation method. Suspensions can also be formulated using controlled flocculation method.
This method involves
1. Dissolution of the soluble components in the appropriate volume of diluent (vehicle).
2. Dispersion of the solid therapeutic agent into the vehicle with the aid of mixing, prior to correction for volume.
When the dispersion method is used for suspension preparation, the vehicle must be formulated so that the solid phase is easily wetted and dispersed. Wetting agents and suspending agents may be used to achieve that.
The mixing rate employed during the dispersion of the solid therapeutic agent is an important determinant in the manufacture of the formulation. If the suspension is flocculated, high-speed mixing may be employed as the flow properties of the system are pseudoplastic (shear thinning). However, if the formulation has been poorly designed and has poor flocculation properties, high-speed mixing will result in an increase in the viscosity of the product (termed dilatant flow).
The preparation of suspensions by precipitation method is as follows:
1. The drug is dissolved in the vehicle (or a portion of the available volume), prior to precipitation following the addition of a counterion; the salt formed is insoluble (such systems are frequently deflocculated and are therefore mixed at low shear rates).
2. The excipients are then dissolved in the vehicle, or dissolved in a portion of the vehicle, which is then added to the suspension of drug.
3. At this stage, the formulation may be exposed to high shearing rates to ensure homogeneity.
4. The volume of the formulation is then corrected by adding the required mass of diluent.
One potential problem with this method of suspension formulation is the production of ionic byproducts from the precipitation interaction. If the concentration of these is too high, then there is need to wash the precipitated therapeutic agent with an aqueous solvent.
Flocculation imparts structure to suspensions with virtually no increase in viscosity. The preparation of suspensions by controlled flocculation is as follows:
1. The wetting agent is dissolved in approximately half the final volume of the aqueous vehicle.
2. The drug is micronized and is uniformly spread over the surface of the vehicle at the desired concentration.
3. The drug is allowed to be wetted undisturbed and the wet slurry thus formed is passed through a fine wire sieve or a colloid mill to remove poorly wetted powder.
4. The slurry concentrate of the drug is agitated and the flocculating agent is added till flocculation endpoint is reached. To determine the endpoint, small samples are transferred to a graduated cylinder, an equal amount of vehicle is added and the cylinder is gently shaken and allowed to stand undisturbed. The sample with the highest ratio of sediment to total suspension volume, exhibiting a clear supernate and good drainage characteristic, is considered to be at the appropriate endpoint.
5. The remaining formulation adjuvants (preservatives, colorant, flavor, buffer etc.) are added and the slurry is brought to final volume with liquid vehicle.