Particle Control: ‘Flows like Water’—and Other Lies We Tell Ourselves

Perhaps the problem goes back to prehistoric peoples struggling to get their daily grain out of a narrow-mouthed clay pot? Or maybe it began in the Industrial Revolution with the mechanizing of food production and huge industrial grain silos? Certainly it has been an issue since long before we had modern pharmaceutical processing: “How do I get my particles to flow where, when, and how I would like, and in the exact quantity I would like?” is a tale as old as time. We stand on the shoulders of giants, but some industries require a bit more progress. 

The pharmaceutical industry brought a modern interest to truly perfecting powder flow. Each step in the process brings unique challenges—from formulation, to blending, to agglomeration, to particle size reduction. And downstream, a seemingly simple process gone awry can shut down a plant. Poor flow in pharma can mean inconsistent tablet sizes, inconsistent dosages due to powder segregation, and a general difficulty in getting material from one spot to another. We often say that particles in a good formulation and a robust process flow like water. But we still wonder why this doesn’t always happen easily. 

To avoid these issues, start with the proper formulation. Certain choices will be forced upon a formulator, like the quantity of drug and key functional excipients to achieve desired release or stability profiles. Some choices remain, in terms of which grades and particle sizes to select. Most excipients have been honed to behave as best as possible by their manufacturers and thus the “bad actor” is often the API itself. Innovative pharma companies must take what their drug substance colleagues can provide regarding bulk density and particle size, and pair it with the desired clinical dosage. Generic and CDMO organizations can find themselves in similar predicaments for entirely different business reasons. Some formulation decisions must still be made, though. 

The formulation choices we do have often revolve around flowability and its trade-offs with our other CQAs. Glidants can effectively improve the flow of some formulations, but with the wrong unit operations or a bad excipient/API pairing, their impacts can be deleterious. Other products may necessitate a granulation step, which can have its own implications on the formulation regarding choice of binders, lubricants, and disintegrant locations inside the tablet. Beyond this, once material types have been chosen, it is best to avoid disparities in particle size to avoid potentially encouraging segregation. 

Formulation development is the easiest time to make the most impactful changes to improve product flow. It can be tempting to skip this important step, but making sound decisions before the clinic can pay dividends when it comes to rapidly scaling up or launching a product. Obviously, precise and sufficient blending is a prerequisite for any cGMP drug product facility. Less obvious is the need to balance the degree of mixing with potential negative impacts of mixing, like particle attrition and over-lubrication. It is a balance. Glidants, for example, can require quite intensive shear forces to sufficiently disperse in a blend. However, lubricants can be quite shear sensitive and over-lubrication can defeat the purpose of improving flow by making tablet compression an impossible task. Batch processes can work around this, with multiple blending steps, but the adoption of continuous manufacturing has necessitated a closer look at how we blend. Some industry members have even returned to something that looks a lot like batch processing, while still harnessing the advantages of CM. The Xelum semi-continuous system is a fine example. 

Once a robust blending process is designed, we must transfer the powder out of the blender. Planning ahead with appropriate blender container designs (flat vs. angled walls), and discharge mechanisms helps to ensure complete discharge of your blend. Pneumatic transfer is the most intensive and complete transfer method, but sometimes causes unwanted particle attrition and segregation, whereas gravimetric flow requires a certain threshold of product density and flow to work out. Even if a blend does flow out of a blender, there is still a risk for powder segregation during a long drop and this can result in unit dose uniformity failure. At this point, granulation may be a necessary option to consider. 

Particle agglomeration, or granulation, can be performed as a dry or wet process. Agglomeration in general can improve flow by reducing the potential surface area for flow restricting interactions between particles. Additionally, flow is often improved through an increase of bulk density coming from agglomeration. Wet granulation, in particular, can be useful for improving the flow of extremely high drug load formulations. It can also be used to limit the risk of fines segregation in low dose formulations. Both extremes require the use of a binder, which must be applied under the proper conditions, usually in the wetting solution itself. In fluid bed granulation (one type of wet agglomeration), a seemingly simple problem is improper droplet formation from the binder solution. The binder solution is sprayed onto the fluidized bed of powder in fluid bed granulation. A controlled droplet size is crucial to the formation of good and uniform granules, and thus uniform downstream flow. Sometimes a spray gun might clog due to dried binder in the tip or powder adhering to the nozzle surface. Other times, a nearly indiscernible shift in droplet size might come from a small dent or chip in the spray nozzle tip. These might not seem like big issues, but they can ruin an agglomeration process. Good equipment maintenance and appropriate granulation technology choices are key to mitigating these issues. Spraying parallel to the incoming fluidizing air, rather than against the flow of fluidizing air, as is traditional, is one modern way to ensure that repeatable and robust agglomerates are formed. 

While fluid bed granulation does not require any subsequent particle size reduction, just about every other agglomeration technology in the pharma industry requires a post-granulation milling step. Particle size reduction techniques can also break up loose oversized agglomerates formed in materials during storage and shipment. Regardless of the reason for reducing particle size, some pitfalls lurk. They can be tied directly to particle flow. Mills common in pharma typically operate in a continuous fashion, forcing material through a screen of some desired size. This screen can quite easily become clogged or blinded with material, stopping flow and the process in its tracks. Some ways to avoid this are to ensure particles are metered into a mill slowly or considering a larger screen pore size. If this fails, one might also look back to a previous granulation step. Well-made agglomerates should be designed to break into subagglomerates, rather than falling back into their original fine micronized state. Stronger granules can lead to easier milling. 

Flow is a tricky attribute to control for any tablet or capsule manufacturer. Its issues may manifest in unexpected and seemingly minor ways. Formulation is always the foundation upon which the process is built. Blending, particle growth, and particle size reduction can be impacted by powder flow, but can also be used to control the flow of a product towards its final dosage formation via tablet compression, capsule filling, and others. Like any process consideration, idealized flowability must be balanced with operational efficiency and overall product quality. Every API is different and every formulation has new concerns, but the industry has developed a strong understanding of its key unit operations. Equipment vendors can provide perspective— beyond even their own equipment—but other customers might have solved a similar problem. Excipient providers can also be a key resource on the formulation side. Trust the experts at your disposal, and maybe your product too can “flow like water”.