Blending/Mixing of Liquids in Compounding Dosage Forms
Loyd V. Allen, Jr., PhD, RPh
International Journal of Pharmaceutical Compounding
Mixing is a unit operation; it is the process of thoroughly combining different materials to produce a homogeneous product. Mixing and blending are very demanding, as the final preparation depends upon how well and completely the process is accomplished. Blending is a process of combining materials and is a relatively gentle process compared to "mixing." Mixing of liquids that are miscible or at least soluble in each other occurs frequently in everyday life. An example would be adding milk or cream to tea or coffee. However, mixing in a more viscous liquid, such as honey, requires more mixing power per unit volume to achieve the same homogeneity in the same amount of time.
In pharmacy, examples of mixing "liquids in liquids" involve intravenous admixture programs, sterile compounding of liquids, and non sterile compounding of liquids.
Fluids are generally classified as Newtonian or non-Newtonian, depending on the relationship between their shear rates and the applied stress. Newtonian fluids are generally easier to mix than non-Newtonian. Shear forces are generated by interactions between moving fluids and the surfaces over which they flow during mixing.
The nature of the liquid(s) to be blended determines the equipment used for mixing; single-phase blending tends to involve low-shear, high-flow mixers to cause liquid engulfment, while multi-phase mixing generally requires the use of high-shear, low-flow mixers to create droplets of one liquid in another. Liquid-liquid mixers operate in laminar, turbulent, or transitional flow regimes. Turbulent or transitional mixing is frequently conducted with turbines or impellers; laminar mixing is conducted with helical ribbon or anchor mixers.
Mixing immiscible liquids often necessitates different equipment than is used for single-phase blending. For example, mixing oil in water/vinegar necessitates the use of a whisk or fork rather than a spoon or paddle mixer.
Mixing mechanisms for fluids involve four different categories:
1. Bulk transport
2. Turbulent flow
3. Laminar flow
4. Molecular diffusion
Generally, more than one of these processes occur in most mixing situations.
- Bulk transport involves the movement of a relatively large portion of material being mixed from one location to another location. For it to be effective, it must result in a rearrangement or permutation of the various portions of the materials to be mixed. This is usually accomplished with the use of paddles, blades, or other devices with the mixer to move adjacent volumes of the fluid in different directions, resulting in shuffling the system in three dimensions.
(Examples include: mixing liquids using paddle-type mixers; the addition of a drug to a large-volume parenteral in a plastic container mixed by kneading.)
- Turbulent mixing is a direct result of turbulent fluid flow, which is characterized by a random fluctuation of the fluid velocity at any given point within the system. Generally, turbulence involves a fluid having different instantaneous velocities at different locations at the same instant in time.
(Examples include: syringe-to-syringe mixtures; syringe additions to LVP glass containers and bags; use of a magnetic stirrer or Lightnin'-type mixer.)
- Laminar mixing is frequently encountered when highly viscous fluids are being processed and can also occur if stirring is relatively gentle and may exist adjacent to stationary surfaces in vessels in which the flow is predominantly turbulent. When two dissimilar fluids are mixed using laminar flow, the shear generated stretches the interface between them, a "mixer" folds them back upon themselves, and the process continues, resulting in mixing.
(An example is a magnetic stirrer.)
- Molecular diffusion is the primary mechanism responsible for mixing at the molecular level; it can result from thermal motion of the molecules. Also, the concentration gradient at the original boundary is a decreasing function of time and approaches zero as mixing approaches completion. Diffusion mixing, which is a relatively slow process, is a mechanism where two different fluids come together. It can occur when adding one liquid to another and letting it set for a time.
(Examples include: adding water to propylene glycol or glycerin and letting it set; adding syringe contents to bags, in the outer areas of paddle mixing, etc.)
Other Mixing Methods/Considerations
Time is important in any mixing process, and the time required must be determined to bring about acceptable uniformity, completeness, or "goodness of mixing."
Y-site mixing, T-junctions, three-way intersections, and other designs can be used to enhance the interfacial area between the two fluids. Twisting channels can also assist the two fluids to mix, including multilayered devices where the fluids will corkscrew, loop, or flow around obstructions and wavy devices where the channel will constrict and flare out. Also, channels with features on the walls like notches or grooves have been used.
Selection of appropriate equipment for mixing involves consideration of the physical properties of the materials to be mixed (i.e., density, viscosity, miscibility). Also, a "mixer" is not just a generic production tool but a critical and decisive piece of equipment that helps determine the quality of the final preparation. Mixers generally involve an "impeller" and are of two types; axial and radial, depending upon the angle that the impeller/agitator blade makes with the plane of impeller rotation.
Axial flow impeller: The impeller blade makes an angle of less than 90° with the plane of impeller rotation, resulting in the flow occurring along the axis of the impeller (parallel to the impeller shaft).
(Examples include: a marine propeller; a pitched-blade turbine)
Radial flow impeller: the impeller blade is parallel to the axis of the impeller, resulting in a discharging flow along the impeller radius in distinct patterns.
(Examples include: a flat-blade turbine; a paddle)
In a compounding pharmacy, mixing is often achieved using magnetic stirrers, simple hand-shaking, stirring rods and beakers, and Lightnin'-type mixers. Magnetic stir bars are radial-flow mixers that induce solid body rotation in the fluid being mixed. This is acceptable on a small scale, as the vessels are small and mixing generally occurs rapidly. A variety of stir bar configurations are available but because of the small size and low-fluid viscosity of the fluid, it is possible to use one configuration for nearly all mixing tasks. One peculiarity of magnetic stir bar mixing is that the stir bar rests on the bottom of the vessel instead of being located up near the center. The impellers in Lightnin'-type mixers can be placed almost anywhere within the system to obtain optimum mixing in the shortest time.
The quality of mixtures is ultimately judged on the basis of some measure of the random distribution of their components (i.e., uniformity throughout the batch) and can be referred to as the "goodness of mixing." It should be evident that the uniformity of the finished preparation is dependent upon each mixing step involved in the procedure.