Blending/Mixing of Solids in Liquids in Compounding Dosage Forms
Loyd V. Allen, Jr., PhD, RPh
International Journal of Pharmaceutical Compounding
A suspension is defined as a two-phase system consisting of a finely divided solid dispersed in a solid, liquid, or gas. Pharmaceutical suspensions, sterile and nonsterile, generally contain insoluble particles, a liquid medium, a suspending agent/surfactant/viscosity enhancer, and a preservative. They may also contain a flavoring/perfume agent and a sweetener, if for oral administration. The order in which the ingredients are mixed is important to the stability of the final preparation.
Pharmaceutical suspension mixing primarily involves the subdivision or de-aggregation of one or more of the phases present, with subsequent dispersal throughout the vehicle or the rest of the material to be mixed. Liquid-solid mixing is usually done to suspend coarse free-flowing solids, or to break up lumps of fine agglomerated solids. Two examples can be presented; one where the particles are lifted into suspension (and separated from one another) by bulk motion of the fluid; in the second, the mixer itself (or the high shear field near it) must destabilize the lumps and cause them to disintegrate.
Suspensions generally have increased viscosity to keep the suspended particles uniformly distributed. This is accomplished by introduction of a viscosity-increasing agent that also serves to enhance physical stability. A good thickening agent is one that has the required viscosity to keep the drug particles suspended separately from each other but would be sufficiently fluid to allow the preparation to be poured from the container. These agents can result in different types of rheological properties, including formation of Newtonian and non-Newtonian liquids. This increased viscosity sometimes requires extended mixing times and/or a specific order of mixing.
Regarding rheological characteristics:
- Shear-thinning (pseudoplastic) liquids get easier to mix after stress is applied.
- Shear-thickening (dilatant) liquids become thicker after stress is applied and more difficult to mix.
- Thixotropic liquids become easier to mix after stress is applied and they thin-out.
- Generally, mixing non-Newtonian fluid requires heavier duty mixers.
- Newtonian fluids tend to be more predictable with which to work.
Axial-flow impellers are preferred for solid suspensions, although radial-flow impellers can be used in a tank with baffles, which converts some of the rotational motion into vertical motion. When the solid is more dense than the liquid (and collects at the bottom of the container), the impeller is rotated so that the fluid is pushed downwards; when the solid is less dense than the liquid (the floats on top), the impeller is rotated so that the fluid is pushed upwards.
Very fine powders may agglomerate or form lumps during transportation and storage and are not easily mixed into liquids. Upon exposure to liquids, they tend to wet on the outside but remain dry on the inside of the particles. In some ways, de-agglomeration of solids is similar to the blending of immiscible liquids, except that coalescence is not usually a problem. Shear is often required to break the agglomerates up.
The mixing of finely divided solids with a liquid of low viscosity in the production of a suspension depends on the separation of aggregates into primary particles and the distribution of these particles throughout the fluid. These processes are often carried out in a single-mixing operation, provided that shear forces of sufficient intensity to disrupt aggregates can be generated. High-speed turbines, frequently fitted with stators to produce an increased shearing action, are often employed. When aggregation is not a problem, or when de-aggregation is to be carried out following a general mixing step, the equipment used in mixing of suspensions is essentially the same as that previously discussed for liquids of comparable viscosity.
To prepare a suspension, one must first obtain uniform, small particles of the drug and any insoluble excipient. Then, the active pharmaceutical ingredient insoluble material should be thoroughly wetted before mixing with the vehicle. Hydrophilic materials are best wetted with water-miscible liquids (e.g., glycerin), whereas hydrophobic substances can be wetted with nonpolar liquids or with the use of a surfactant. Generally, one should use the minimal amount of wetting agent required to produce the desired preparation. Next, the vehicle is added geometrically with thorough mixing of each portion to obtain a uniform preparation.
Mixing suspensions is somewhat more complicated than mixing solutions or powders since many variables are involved, including agglomeration of particles and the viscosity of the vehicle to promote physical stability. However, when properly done, suspensions provide a necessary and efficacious dosage form for some patients.
Editor's Note: The next issue will complete this mini-series on "Mixing" and will cover "Mixing Immiscible Liquids."