There's No Such Thing As A "Perfect Blend" – Uniformity Factors In Pharmaceutical Mixed Powders
By Mike Tousey, Techceuticals, LLC and Matt Hicks,
Introduction
The "perfect blend" for mixed powders is best defined as a blend with 100% uniformity, but that is impossible. It can be relatively easy to achieve the close to the perfect blend in a one-time mixing and blending process, however, ensuring as close to 100% uniformity as possible batch-after-batch is one of the most difficult issues those in bulk-solids processing operations face. Although demonstrating a perfect blend across batches is a huge undertaking, it is key to showing an effective, repeatable bulk-solids manufacturing process. There are many factors that influence how powders mix—ingredient characteristics, blend hold times, and the equipment used for mixing and blending, all affect blend uniformity. [1]
Ingredient Characteristics
One of the reasons it can be so difficult to achieve blend uniformity has to do with the variations in raw ingredients. No two powders are ever alike, even when made by the same manufacturer, using the same processing equipment. Factoring in these slight differences, the general characteristics of the ingredients can help determine the best processes and equipment for the product's flow capabilities, as well as the batch hold times for any given powder blend. A common characteristic to factor in is a product’s density—specifically the bulk density and tapped density.
Bulk density of a product is determined by the density of the powders and the space between particles (i.e. air) in the powder bed. How a product is prepared, handled and stored influences its bulk density or bulking properties.
Tapped density is the increased bulk density noticed after mechanically tapping a container holding the powder sample. The difference between the bulk and tapped densities reveals clues as to how the powder will flow. This is beneficial because the better a product flows, the easier it is to achieve uniformity and compressibility later in the manufacturing operations. The closer the two measurements are, the more free-flowing the product will be. On the other hand, the further apart the measurements, the more likely the product will have poor flow characteristics. [2] In addition to these factors, tapped density can be used to predict how long a mix will stay uniform.
Blend Hold Times
The blend hold time is how long a mix of powder will stay together after being blended. Almost all bulk-solid powders have a window of time before they start to "unblend" by segregating and compacting inside the bulk container. Powders with high tapped density, or fluffy products, will have shorter blend hold times. As the powder mass sits, it begins to deaerate. During deaeration, air escapes upward, taking small, lighter particles along the way while the dense particles compact and move down. This results in the product becoming segregated. Lower tapped density products tend to settle less in this manner and have longer blend hold times. Establishing blend hold times for each product will help identify peak performance for compression operations. [1]
Equipment Used for Mixing and Blending
In order to obtain a uniform blend, the mixing and blending equipment must match the ingredients. It’s important to note that a blender used in one process many not provide the results needed for a different process. In each case, the product’s characteristics drive the selection of blender, as well as the proper sizing for the equipment to make the desired batch.
For instance, low shear mixers randomly mix powders that are free flowing. Common low shear mixers that are used to mix powders include the twin-shell blender or v-blender (based upon the "v" shape), the double-cone blender, and bin blenders or "tumblers" that actually mix the product inside the bulk container. Twin-shell blenders can be used for products that are not free-flowing if they have an intensifier bar that forces the products to move. However, be mindful that the overuse of an intensifier bar can cause dry and friable particles to break down. Additionally, a liquids bar can be used to introduce a liquid ingredient to the mix.
Ribbon and paddle blenders are low to medium shear mixing equipment, often used to mix powders slowly and gently. These types of blenders are not always effective equipment for mixing small quantities into large quantities or at mixing lubricants into the blend needed for later compression activities. Random-flow blenders also tend to mix faster than the gentle and slow action of ribbon and paddle blenders. This equipment is best suited for powder ingredients with close density and morphology.
For ingredients with unequal density and morphology that are hard to mix and not brittle or fragile, a high-shear mixer is recommended. High-shear mixing, as the name suggests, is an intense process used to treat ingredients in different forms that would not ordinarily mix, including solids, liquids and even gasses. The high shear mechanical force is often used to increase a blend's bulk density, which increases flow, blend hold time and compressibility.
After selecting the type of mixing equipment (again, based on ingredients) you have to properly size for your process. In order to fit the blender, determine the weight of the product along with its density—most people usually know the product's weight, but not the density. A simple way to calculate product density is to get the weight of a quart or liter of product. For example, 16 quarts or 15 liters is equal to one cubic foot (cf) at a density of 35 pounds per cubic foot (lbs/cf).
Conclusion
Obtaining the perfect blend for your powder formulation is a combination of many factors including ingredient characteristics, equipment used in the process, handling, and time (among other factors). Most blended powders compact and deaerate over time, leading to segregation and "unblending." Understanding the product's hold time before it begins to unblend will help consistently achieve the peak performance in your process. Additionally, the equipment used for mixing and blending should be sized for volume and appropriate for your product's characteristics, in order to reliably produce powders with enough density for good flow and compressibility.
References
[1] Tech-Talk by Techceuticals, "Mixer and Blender Selection for Powders," by Mike Tousey, prepared for Federal Equipment Company 2017.
[2] The International Pharmacopoeia, “S.3.6 Bulk Density and Tapped Density of Powders,” World Health Organization, March 2012.
Mike Tousey
CEO & Technical Director, Techceuticals, LLC
Phone: 216-658-8038
For nearly 40 years, Mike Tousey has been providing manufacturing training, equipment and process support, and formulations advice to bulk solids and solid-dose manufacturers.
Matt Hicks
COO & Counsel, Federal Equipment Company
Phone: 216-271-3500
Matt Hicks has been involved in all aspects of pharmaceutical business for nearly 20 years including drug distribution, drug and chemical manufacturing, equipment supply and as a service provider.