Succeeding with Encapsulation Scaleup

What works in the lab won’t work in the plant: Success demands close control of parameters that depend on batch size.

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By Agnes Shanley, Editor in Chief *

Although research and development of new drug delivery systems continues at a rapid pace, capsules remain one of the most widely used commercial dosage forms. At the laboratory level, capsules can be much easier to manufacture than tablets, which may explain why so many Phase I or IIa drug development projects involve capsules.

During the early stages of drug development, when batches are usually on the order of 5,000 to 7,000 capsules, formulation is generally simple. The amount of active pharmaceutical ingredient (API) dictates the process and equipment chosen. Filling is usually done manually, although automated systems can also be used, such as Autodose America, Inc.’s (Iselin, N.J.) Autodose system, which dispenses weighed quantities of API or blended powder directly into the capsule. Dottore Bonapace e Co.’s (Milan) In-Cap, an automatic tamping-type machine, is ideal for early formulation development [1].

Later on during development, when batch sizes increase by a factor of 100 or more, parameters such as blend uniformity, weight variation, dissolution, and even API particle size and morphology, must be closely controlled. This article will summarize best practices to ensure scaleup success.

Blend uniformity

Even though dry ingredients are mixed well before encapsulation occurs, blending has a major impact on content and weight uniformity. Uniform and efficient mixing, in turn, depends on blender type, rotation rates, and filling levels in the blender. If any one of these factors is changed, or if the blender geometry changes, variation will result.

The approach used to optimize blending will depend on whether powders are cohesive or free-flowing.

Free-flowing materials are typically granular materials whose particles’ diameters exceed 100 µm. Since these particles are only mildly attracted to each other, free-flowing powders typically require only low shear in tumbling blenders, and number of revolutions is more critical than rotation speed.

During scaleup in large tumbling blenders, rotation rate must be optimized [2] using the Froude number (Fr), defined by the following equation:Fr = Ω2R/g

whereis the rotation rate,Ris the vessel
radius andgis acceleration due to gravity.Cohesive powders are highly attracted to each other and tend to agglomerate, reducing material flow in the blender. An intensifier placed in the blender can help increase shear during mixing to break up agglomerates [2]. Screening can also be effective.

The role of API morphology

API morphology is also critical, so it is extremely important to control both particle size and shape during scaleup. The same API can lead to dramatically different results if its particles are of different shapes and sizes; in the same blender, for example, a blend including an API with short, rod-shaped particles may be more uniform than an otherwise identical blend of the same API with longer, rod-shaped particles.

It is also important to realize that agglomeration won’t generally occur to the same extent in lab- and commercial-scale installations. Generally, it is more of an issue in small-scale operations. As blender scale increases, gravitational and convective forces take over from cohesive forces between particles, so mixing typically improves [2].

Weight uniformity depends on equipment scale

Weight uniformity can also vary depending on the scale of the equipment being used. Capsules encapsulated on a low-speed, lab-scale machine may show little variation in weight. However, when the same formulation is encapsulated on high-speed presses, variation may increase. This is due to the simple fact that lower-speed machines allow more time for plug formation. On a full-scale machine, where there is limited time for filling, powders that don’t inherently flow well may not fill the capsules uniformly.

Weight variation is often seen during scaleup of high-dosage capsule formulations. In such cases, the active ingredient accounts for most of the fill weight, so scaleup depends on the API’s physical properties such as particle size distribution and bulk density.

Although its chemical composition may be unchanged, API produced during early development stages may have very different physical properties — a different particle size, morphology, and density — from API produced later on, as impurities are reduced and yields increase.

For example, a change in API morphology from spherulites to needle-shaped particles can reduce flow of the powder blend. A reduction in the bulk density of API may not only increase the weight variation but also decrease the amount of powder blend that can be filled into a capsule shell. Therefore, it is critical to evaluate the effect of API physical qualities on formulation flow during development. If necessary, specifications should be set for API and even excipient particle size and bulk density.

Mixing time and lubrication

Mixing time and the impact of lubricants should also be considered. It is important to remember that mixing time is usually reduced during scaleup, since larger-volume mixers are much more efficient than lab-scale equipment.

However, lubricants such as magnesium stearate will be required to prevent product from sticking to the tamping pins and dosing disk, or to facilitate ejection from the dosator tube. Lubrication is important during scaleup, since longer run times can lead to powder buildup, which, in time, results in weight variation.
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