A Recipe for Success: Mastering Tableting Requires Understanding Ingredient Attributes

Ask yourself, are you surviving batch to batch, or are you performing? It’s one thing to develop a batch that meets expectations at a small scale. It’s another to have ingredients perform well throughout the entire batch. Ingredient performance is proven when all of the necessary attributes are met. Weight (dose), hardness, thickness, disintegration, dissolution, friability, stability, shelf life, and potency, all fall within an acceptable range of performance.

Frequent stops throughout a batch or campaign are indicators of poor ingredient performance. We call it survival when one or more performance factors fail, and you’re forced to salvage the batch. Do you need to stop to clean, lubricate, polish punches, make adjustments, or solve a problem with sticking, picking, hardness, friability, capping, delamination, black spots, or weight?

If the answer is yes, then you are surviving, not performing. If this happens once in a long while, that’s one thing. If it happens batch after batch, you are non-optimized and not at all alone. Many products aren’t robust. And most struggle to maintain good performance, which requires frequent stoppage. When a product changes throughout the day or from one day to the next, it’s a message that action needs to be taken. It’s what separates the best operations from the rest. The best operations know that the tablet press and tooling are properly set up, not just put together. When a press and tooling aren’t in top condition, determining the root cause of problems and maximizing ingredient performance are more challenging.

Some of the key metrics to watch closely are machine controls, tablet quality, dust build-up, blend leakage, spills, tooling lubrication, and analyzing the machine and tooling after the run is over. A batch isn’t a success if a tablet press or tooling is compromised during a run. If the cams, pressure rolls, punch heads, or punch tips are in any way compromised, the batch was not a success.

Success is running within realistic parameters for the entire batch, resulting in excellent productivity within acceptable AQLs, including minimal tooling and machine wear, batch after batch. A few incredibly orchestrated blends can run as fast as the press from the start of the batch to the end producing a high-quality tablet with little to no machine wear. But these are the exceptions, not the rule.

Keep in mind there is no such thing as a perfect blend. API’s aren’t perfect. Excipients aren’t perfect. We work within a range. When we work to one end of the range or the other, the results can be significantly different. Also, most blends are not robust and most frequently are met with problems stemming from each ingredient’s characteristics, and then the cumulative effect from each unit of operation’s process to complete the batch.

In other words, no matter how you mix or how long you mix, it’s highly unlikely that we will ever have a “perfect” blend. Even if we only had one single ingredient, there would still be particle size range variations, which means that the morphology of some particles, moisture content, and friability would likely be different than other particles, even though they were the “same”, the result is likely to be very different. We know that the particle size range and distribution are a key set of factors. We must have a range of particles to work well on a tablet press, too large or too small presents a range of potential quality attribute problems; weight (dose), hardness, thickness, disintegration, dissolution, and friability. Often a single ingredient doesn’t possess all the needed attributes to make a great tablet. This is why we have excipients; they are meant to help the API perform.

Formulating involves studying how each ingredient acts and reacts to another. This is easy to demonstrate in the kitchen with common ingredients like flour, salt, sugar, pepper, and starch. If you mixed them, would they make a tablet? Would it flow, compress, eject, disintegrate, and dissolve properly? If you look closely at how each ingredient reacts to the other, you will quickly learn that some combinations will work and some will not. The key factors that predict success are; flow, particle size distribution, morphology, polarity, moisture content, friability, bulk density, and tapped density.

In the tablet-making world, “granulating” is a method of agglomerated powder particles. If an API will not perform, then there are two choices. Add excipients to assist, which is called “direct blending” (aka direct compression) or granulating. Granulation is accomplished using wet or dry processing methods of agglomeration. In manufacturing, there may be several methods of powder agglomeration, some using liquid solutions (suspensions), these are called “Wet Granulators” and some machines use dry powder agglomeration methods called “Dry Granulators”.

It goes another step or two further. The methods of agglomeration are often defined by the amount of energy or shear forces used to produce a granule. A low energy or low shear granulator can agglomerate ingredients to form a granule with no or very little change in bulk or tapped density. This has an advantage when making a sublingual or ODT (orally disintegrating tablet). However, a high-energy or high-shear granulator can produce a very dense granule with increased bulk density and decreased tapped density.

The more energy or higher the shear forces, the greater the change to the density and robustness of the granule, which will result in a more robust tablet. Similar to kneading bread, the more force (energy or shear) the greater the change in density. A denser granule will typically have a slower release. Different methods are often combined to produce a tablet with an immediate therapeutic effect and a slower mechanism for longer release rates.

It is important to talk about what we are granulating. We do not always granulate just one ingredient and we do not always granulate all the ingredients together at once. More often, we granulate some ingredients using a dry method and other times we granulate using a wet method. We granulate for the compatibility and performance of the ingredients.

When formulating from the beginning, decisions are made based on the nature of the API and the equipment available to accomplish the final goal of making a tablet. If the requirement was to make a small batch and you only have blending capability, then you become very reliant on excipients to achieve the goal(s). An excipient must have a purpose. That purpose should be based on the nature of the API: flow, compression, ejection, disintegration, and dissolution. An excipient might be granulated with other ingredients or it may be added separately. Within the realm of granulating, there are a variety of excipients that can be put into solution to manipulate release rates. So, imagine that manipulating density and pH levels can enable you to control when, where, and how the API is released in your body.

Take the kitchen example of making a tablet from flour, salt, sugar, pepper, and starch. They are all tremendously different. Let’s say that the flour, salt, sugar, and pepper are each equal percentages. If we tried to blend them, they wouldn’t mix well, because they have different densities, shapes, and polarities. However, I could use the starch, by creating a suspension that, when sprayed and dried, the starch acts as a bonding agent to attach different particles to form a granule of the ingredients.

In essence, we are gluing particles together to form granules and using evaporation to remove the excess moisture from the suspension. Just think, the suspension can contain an API as well. These are control attributes that cannot be accomplished by just blending ingredients. The only way dry blending could work is if those ingredients had particles that were compatible in particle size distribution, shape, density, moisture content, and polarity. This means that each ingredient must meet specifications within a narrow range of physical characteristics to be able to blend them repeatedly with complete reproducibility.

Important Terms to Understand Ingredient Attributes

Flow: A blend is a mixture of powders or granules specifically designed for tablet making. The first objective is to achieve followability. The blend must flow with uniformity and without segregating. Blends are often initially developed on small scale or lab-scale tablet presses which may not be adequate for higher speed operations. It’s not uncommon to see a company purchase a higher-speed tablet press, but be unable to run any faster because of the limited flow characteristics of the blend.

Compressibility: Once the ingredients possess the ability to flow and provide accurate weight control it is time to compress the ingredients into a tablet. Whereby air is evacuated and the powders or granules are locked to one another by squeezing them together. Increasing or decreasing thickness results in an increase or decrease in hardness. However, there is a limit here, pressing too hard could cause the particle bonds to fracture and become weak resulting in poor tablet hardness. Not enough force means that the particles aren’t locking together and the result again is low hardness. Low and high hardness typically mean problems, and the tablet crumbles or splits caps or delaminates.

Particle size distribution: The best particle size range for most consumable tablets is within the range of 75um-850um. When particles are larger than 850um, they negatively influence weight control, compressibility, and hardness. When there are more than 10% of particles smaller than 75um, there will be problems with weight, hardness, friability, capping, delamination, and DVDs (dark visual defects) will increase significantly. Too many fines usually means the press will need frequent stops for cleaning and punch polishing. A high percentage of fines limits the effectiveness of the lubricant within the blend, which in turn affects press and tooling performance.

Fines: Fines are particles smaller than 75um (200 mesh). Particle size distribution under this threshold causes mechanical clearance issues with the tooling. When these small particles block punch and die clearances, they cause performance issues and tablet defects: wear, metal fatigue, abrasion, sticking, picking, shortened run time, decreased overall tooling life, and require much higher maintenance during changeovers.

Tablet integrity is largely based on morphology. The finer the particle the worse the morphology, the weaker the table, and the lower the compressibility. We know that the majority of defects can be directly traced to extremes within the particle size distribution. Large particles can influence weight, hardness, and friability, while fine particles influence weight, hardness, friability, capping, delamination, splitting, chipping, and black spots.

One of the side effects of a high percentage of fines is that they slow disintegration and dissolution because they fill the interstitial spaces for the solution to effectively break the tablet down. However, if that fine particle is an excipient that swells in the presence of moisture, now there is a possibility of controlling the disintegration and potentially enhancing the potential for improved dissolution.

Interstitial space: The spaces between particles or the spaces between granules, and within each granule. Even with each granule.

Author Details

Michael D Tousey, CEO & Founder- Solid Dose Technology LLC®

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