An ideal topical formulation can be produced using a simple, flexible process. Most topical formulations developed today,
however, are complex and, therefore, require tightly controlled processing parameters. Following are five critical process
parameters (CPPs) and additional strategies to optimize the manufacturing process for topical dosage forms.
Understand critical process parameters
Temperature. Processing at the right temperature is critical for successful manufacturing. Too much heating during processing can result
in chemical degradation. Insufficient heat can lead to batch failures, and excess cooling can result in the precipitation
of solubilized ingredients. An example of the need for good temperature control is the emulsification step of a traditional
oil-in-water emulsion. If the temperature of the water phase is much cooler than that of the oil phase, the melted constituents
of the oil phase may solidify upon introduction into the aqueous phase and never properly form the emulsion, possibly even
resulting in solid matter in the batch.
Heating and cooling rates. Heating too slowly can result in poor yields from evaporative loss. Heating too rapidly may burn areas of the batch in contact
with the heating surface, which raises the potential for burnt material in the batch. Rapid cooling can result in precipitation/crystallization
or increased viscosity. The successful consistency of ointments, for example, depends on proper rates of heating and cooling.
Mixing methods and speeds. It is essential to determine the required amount of shear and the optimal mixing methods and speeds. Emulsification typically
requires high shear or homogenization to obtain the optimal droplet size and dispersion, while the mixing of a gel may require
low shear in order to preserve certain physical characteristics, such as viscosity. Proper mixing speeds must be obtained
for each phase at every batch scale. Optimal hydration depends on the amount of shear imparted to initially disperse the polymer
into the medium. If the process involves only very low shear mixing, a polymer may never be completely dispersed and hydrated,
which may result in an out-of-specification viscosity. Equipment, such as a recirculation loop, may also be used to correct
uniformity without changing mixing speed or time, as shown in Figure 1.
Figure 1: Diagram of mixer with recirculation loop. When top, middle, and bottom active uniformity samples differed by more
than 15%, DPT added a recirculation loop during mixing. The loop produced a far more uniform product without increasing the
speed or time of mixing. (FIGURE COURTESY OF THE AUTHOR)
Mixing times. Optimizing mixing time requires identifying the minimum time required for ingredients to dissolve and the maximum mixing
time before product failure (e.g., when viscosity begins to drop). For polymeric gels, particularly acrylic acid-based types,
over-mixing, especially high shear, can break down the polymer's structure. In an emulsion, over-mixing may cause the product
to separate prematurely, resulting in a drastic decline in viscosity.
Flow rates. Optimizing flow rate involves determining the amount of shear or throughput needed. For example, a water-in-oil emulsion may
require a slower addition speed than a traditional, oil-in-water emulsion, and the flow rate must be modified appropriately.
Care must be taken for any product using a pump. Overshearing can occur if the formulation is pumped too quickly. If pumping
is too slow, the formulation will experience extra time in an in-line homogenizer, thus also exposing the formulation to additional
Two processes that require experimentation to optimize flow rates are the use of a powder eduction system and an in-line homogenizer.
Theoretical calculations can determine the number of times a sample will pass through either, but actually performing the
experiments is necessary to achieve optimal results.
Raw material dispersers and in-line homogenizers require proper flow rates for optimal usage. If the product is not flowing
through a disperser at the proper rate, there will not be enough suction for properly incorporating the powders. Suction can
be tested by measuring the vacuum being pulled at the inlet of the disperser with a vacuum/pressure gauge. Monitoring the
flow rate when using an in-line homogenizer is necessary in order to calculate the theoretical number of times the product
passes through it.