By Agnes Shanley, Editor in Chief *
|Photo of capsules courtesy of Capsuline.com.
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 .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  using the Froude number (Fr), defined by the following equation:Fr = Ω2R/gwhereΩis the rotation rate,Ris the vesselradius 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 . 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 .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.It is important to add enough, but not too much lubricant, particularly with dosator machines. Overlubricating can lead to dissolution failure. Lubricant requirements are particularly important when changing machine types — e.g., from a dosator to a tamping-disk machine type.Overmixing should also be avoided, since it decreases the formulation’s plug density, leading to weight variation. Early development studies should focus on the influence of mixing time and the amount of magnesium stearate in the formulation on the plug density, ejection and flow of the powder blend.Granulations can be even more challenging to scale up than direct-blend capsule formulations. Not only must process parameters be optimized, but the composition of the formulation, including components such as binder solution, must also be defined. The most important properties to consider are particle size distribution, especially the percent of fines present in the material as well as bulk density, moisture content and the porosity of the granules.Preventing dissolution failure
Dissolution failure typically results from:
- overlubrication during blending or capsule filling;
- change in the filling mechanism;
- changes in plug strength;
- changes in API particle size.
Excess magnesium stearate lubricant often results in the formation of a hydrophobic coating around the drug particles, preventing wetting and delaying dissolution. Using an intensifier bar to introduce shearing action in a V-blender generally results in a longer dissolution time . The rate by which mixing is slowed depends on the amount of magnesium stearate in the blend. Thus, introducing an intensifier bar in the V-blender during scaleup can have a significant impact on the capsule’s dissolution profile.Changes in the capsule machine filling mechanism can also result in dissolution failure. For example, moving from a dosator to a tamping machine increases the shear on magnesium stearate particles, leading to slower dissolution of the larger batch. This problem can be resolved by reducing the concentration of magnesium stearate in the formulation.Differences in plug strength can also change a formulation’s dissolution profile — for example, if the hardness of the plug formed during scaleup differs from that of the plug formed during lab-scale development. Where magnesium stearate formulations are involved, plug strength depends on tamping pressure, powder or granule properties, and mixing. Tamping pressure can be adjusted to obtain similar plug strengths.Changes in the particle size distribution, especially the percentage of fines or differences in bulk density between development and scaled-up batch, can also lead to differences in plug strength.Changes in the API’s particle size can also affect dissolution during scaleup. This is particularly true for high-dose drugs that are insoluble or only partly soluble in water. These changes aren’t typically considered a scaleup issue, but they are extremely important. At the very earliest formulation development stages, it is essential to evaluate the influence of API particle size on dissolution rate to avoid undesirable particle size lots for the scaled up batches.In short, successful capsule manufacturing process scaleup requires a clear understanding of the process, equipment and formulation involved. A systematic approach to scaleup not only saves money, but also time wasted in trial-and-error experimentation.*The generic best practices summarized in this article were graciously provided by Dr. Renuka Nair, a former research investigator with Sanofi-Aventis.References
- Nair, R.; Vemuri, M.; Agrawala, P.; and Kim, S. Investigation of Various Factors Affecting Encapsulation on the In-Cap Automatic Capsule-Filling Machine. AAPS PharmSciTech. 2004; 5(4): article 57.
- Muzzio, F., and Alexander, A. Scale up of blending operations. Pharm. Tech., S34-S44 (2005).
- Samyn, J., and Jung, W. In vitro dissolution from several experimental capsule formulations. J. Pharm. Sci., 59 (2): 169-175 (1970).