Preparing ingredients for tablet making is far more critical than most give it credit. The main objective in milling is to reduce particle size to within a specific range while minimizing the generation of fines (dusty particles). Particle size distribution (PSD) is essential to flow, compression, ejection, friability, disintegration, dissolution, machine downtime, changeovers, yields, product quality attributes, and, most importantly, tablet weights. Despite the central and essential role of milling on the manufacturing floor, it is often overlooked in discussions of critical operations. It’s not the most thrilling of unit operations, but it is far more important than most give it credit. When I worked in manufacturing, we put people in the milling department when they weren’t good at anything else, dismissing them along the lines of, “Here, take this product into that small closet and mill it.” Looking back, that was a huge mistake. What went on in that room could have been all wrong!
Most standard operating procedures (SOPs) are vague, and results were undefined and mostly overlooked. How does an operator know if they have successfully milled a batch of product? They don’t; the results aren’t typically even evident until we try to make the tablet. The only real metric for the quality of the milling itself is the sieve analysis. However, when it comes to making a good tablet, proper milling can truly make all the difference in the world. Properly reducing the particle size of all ingredients is a truly critical task that requires skill and careful attention to detail.
Selecting the right mill for the job and using the mill correctly can make the difference between a successful tablet production run and a difficult one. There are many key characteristics that impact tablet quality, such as moisture content, morphology, polarity, bulk density, and tapped density, but the most critical is PSD. Determining the ideal PSD and achieving it through proper milling a true indicator of quality. Even identical mills running side by side –– same make and model with the same screen and running at the same rpm –– can produce entirely different results. The devil is in the details.
There is a direct relationship between PSD and performance when it comes to making tablets. As a general rule, we want the PSD to fall between 850 µ (20 mesh) to 75 µ (200 mesh). There is one caveat here: we can allow a small percentage of particles smaller than 200 mesh or 75 µ, but we cannot allow any particles larger than 20 mesh or 850 µ for oral solid dosage tablets. We refer to particles smaller than 200 mesh (75µ) as fines.
Fines do not flow predictably, which directly impacts tablet weight control. Fines do not compress as well as larger particle, which impact tablet hardness and friability. Fines are the particles that cause black spots, and are the main reason for cross-contamination. Fines are the enemy. They are the defining factor for the longevity of a production run. While it is typically thought that batch size is the primary predictor of how often a tablet press must be is stopped for cleaning, this is a common error. The frequency at which a tablet press needs to be cleaned is primarily dependent on how dust-free –– or fines-free –– the batch is. Many companies have procedures in place to allow for minor cleaning or partial cleaning. This “in-process cleaning” aims to eliminate the effects of the fines.
In general, most batches have too many fines. Prolonging a tablet press run to get to the end of the batch is typically when problems occur. Tablet defects, such as black spots, are just the tip of the iceberg; continuing to run when punch lubrication is absorbed by fines creates tight punches, generating heat and ultimately damage to the tablet press’s cams, pressure rolls, and turret. The effects of these fine particles reduce profits across the board. We truly need to push back on the ingredients suppliers and API manufacturers to stress that there is such a thing as a “tablet-grade ingredient.” Everyone talks about direct compression, but few know what “tablet-grade” –– in the sense of achieving sufficiently high quality to prevent issues in tableting operations –– really means.
Across the board, active pharmaceutical ingredients (APIs) and excipients (non-active ingredients used to enhance one or more tablet attributes) are both likely to be contain excessive fines. When it comes to preparing ingredients for manufacturing, there are three main processing methods: direct blending, dry granulating, and Wet granulating. One of the main goals of dry or wet granulating is to eliminate fines.
Direct blending (a.k.a. direct compression) ingredients means that the ingredients are “tablet-grade,” which is defined as having fewer than 20% fines. However, if ingredient preparations require granulating processes, then ingredients with a higher percentage of fines are acceptable, because they will be granulated. This term granulated means that particles are joined by a wet or dry process to form controlled agglomerates called granules. If granulation processes are successful, a “tablet-grade” particle profile is achieved. This is where many granulated products fail. The manufacturer must specify PSDs based on their process. However, most buyers of ingredients are unaware of this need and often use the ingredients supplier’s specifications as their own. This is a common and often fatal mistake.
Even if ingredients of the right particle size are in hand, using the mill type selection correctly is a critical key for success. When ingredients are received, they must be screened or sieved to eliminate lumps or clumps of agglomerated particles. This screening step equalizes each bag or drum of ingredients. Most ingredients consolidate during travel. When ingredients are shipped on a truck, a drum or bag of product in the front or middle of the truckload gets a much different ride than product in the back of the truckload. Each one of these drums now bears unique characteristics and will not perform identically to the others. The best way to assure that all ingredients are equalized with some uniformity is to screen them through a 20 mesh (75 µ) screen. Some ingredients, like magnesium stearate and dyes, are screened “at use;” these are ingredients that re-agglomerate if screened ahead of time. Also, they are often screened through a much finer screen, like a 30 mesh (600 µ) or 40 mesh (425 µ) screen.
There are many different types of mills used to prepare ingredients for tablet making. The most common are screeners and sieves, oscillating granulators, conical mills, and hammer mills. Product toughness and resistance determine the best mill for a given application. The size-reduction method using these milling technologies is categorized by the amount of energy ––or shear force –– imparted on the ingredients (sorting the technologies from low shear to high shear: screeners and sieves, oscillators, conical, and hammer mills). Keep in mind, many ingredients are tough and abrasive, requiring an aggressive mechanical action, such as a high shear mill. The more shear force a machine can impart, the greater the tendency to produce fines. The bottom line here is that it is unlikely that one mill type will be effective for all applications. The goal of milling is straightforward: reduce or eliminate all particles larger than 20 mesh (850 µ) without producing particles smaller than 200 mesh (75 µ).
Low Shear sieving, aka low energy screening, is excellent at reducing agglomerates and eliminating over- and under-sized particles.
The Oscillator is considered a low-shear mill. It can handle a wide range of products wet or dry, from very light fluffy products to very tough and hard-to-mill products. The most common mistake with this technology is to make too big of a change in particle size. For most operations, several passes with ever decreasing mesh size is necessary.
The Conical Mill is a medium-shear mill with great output. A 360° discharge reduces dwell and evacuation time and minimizes fines production. It is capable of working with wet or dry applications. Its weak spot is that it is not great at milling tough products.
The Hammer Mill (high shear) maximizes output and, can handle tougher products. The main issue in high-shear milling is the production of too many fines. It is not okay to reduce quality for higher output, and that is a common error with this technology. There is a right way to mill using a hammer mill. While it is tempting to grind big particles and agglomerates down to size in one pass, the result is too many fines, which impacts many tablet attributes, along with many other performance issues.
Ingredient characteristics are as variable as the number of ingredients themselves. The goal in milling is simple: we want to reduce particle size so that we maintain an equal distribution from 20 through 200 mesh with minimal production of fines. Investigating the specific percentages of each particle size range can aid in determining the best performance.
Remember, fines (dust) are the enemy. In reality, a small percentage of fine particles in tablet making can be beneficial: the fines fill in interstitial spaces, adding elegance to the appearance of the tablet.
Dust collection and containment is a very important element during milling and during tablet compression. Dust means the potential for cross-contamination. Controlling infeed and discharge involves an attentive and methodical technician with an ear tuned into the machine. I’ve never read a procedure that mandates listening to the machine, but every great technician will tell you that maintaining consistency has a sound that confirms optimized results.
If products are sticky, they may extrude if feed rates aren’t controlled. Other products are dry and fine and often very friable. Gentle feed rates and controlled temperatures at the screen surface helps to optimize conditions. There are many occasions when pre-chilling a sticky product or heating a friable product can greatly enhance the results.
It’s true that a milling technician doesn’t really know when they have been successful, because they aren’t making the tablet. But I can tell you that when a rookie operator decides it doesn’t matter how quickly or slowly they feed a mill, this is when we see and hear potential problems. Making better tablets and eliminating defects has a direct relationship to successful milling.
The bottom line is that many companies use one mill for all products. This is an indicator that they aren’t optimized for tablet performance. Better particle size control has everything to do with press speed. A faster press means improved ROI.
A recent troubleshooting visit to solve capping on a tablet press resulted in an investigation of the milling department. The facility had five hammer mills of the same make and model. However, upon close inspection, it was discovered the cutting blade condition varied greatly from machine to machine. This is a very difficult problem to assess, because there is no industry standard for blade condition. A dull blade tends to pulverize particles, while a sharp one cuts particles. The milling results using the dull blades showed significant higher levels of capping, hardness variation, friability, and delamination as a result of having too many fines. A similar investigation revealed the use of different screen thicknesses. Particles do not travel straight through the screen holes, they travel on a trajectory. The slower the operation of the mill, the larger the particle size, and the slower the speed of the mill, the finer the product size. The takeaway here is you that must know what screen is being used and the thickness of that screen. It is important to create, know, and record screen thickness and to create your own in-house standard for blade sharpness. Even new blades aren’t always the same, and it matters.
Successful milling of ingredients is a very important step in the process, and variables will influence the results. Controlling these variables will define why one batch performs differently on a tablet press than another.
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