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Intro to USP <1062> – What it is and Why You Should Use it

Compression pressure, tensile strength, and solid fraction diagram

There are a variety of factors like powder flow, material characteristics, compression pressure, turret speed, etc. that can affect the quality of the tablets and production run time. Any resulting tablet defects can exacerbate production costs, or even worse: result in no product at all! Therefore, it is necessary to characterize the tablet compression process to achieve robust tablets. First published in 2017, USP <1062> Tablet Characterization offers universal guidelines for standardized compression test procedures and use of terminology.

It is difficult to discuss tableting by only asking one question, such as “how hard does a tablet have to be to compact successfully?” Answering this question depends on a number of mathematical equations, most of which are dependent on the other. To understand hardness, one must understand their formulation’s flowability and strain rate, depth of fill in a tablet press’s dies in the compression zone, which itself partially determines tablet thickness, which is determined by tablet land and, ultimately, tablet design. The entire tableting process is a sequence of events, measurements, and scientific insights in which “one thing leads to another.” So, having a data-driven process at the outset of your tableting journey, much like what USP Chapter <1062> provides to help create a data-driven process, can signal if your development efforts are heading in the right direction.

USP says: “although the fundamental concepts described [in Chapter <1062>] are also applicable to other processes such as plug formation during encapsulation and roller compaction, the focus of [USP Chapter <1062>] is on tableting.”

Why is USP Chapter <1062> Important?

In short, USP Chapter <1062> explains the experimental methodologies used to standardize the tablet compression process. It gives R&D Formulation Scientists best practices for analysing, evaluating, and identifying formulations that can be compressed into a tablet. Used properly, USP <1062> paves the way for a tablet to be manufactured at scale. While it may not completely prevent issues such as tablet capping from happening further downstream in the scale-up process, it does reduce these risks.

Minimize Risks of Capping

The term capping in tablet manufacturing refers to a tablet failure, a break across the horizontal plane, that you find when performing a breaking force or friability test. Many factors can contribute to capping, including a formulation’s blend characteristics, the material’s deformation properties, and the mechanical configuration of the tablet press and tooling. Pharmaceutical manufacturers commonly discover capping during manufacturing.

Reduce SUPAC Challenges

However, it’s preferable to identify capping in the developmental stage, because changing the formulation after a drug product has moved to full-scale manufacturing can be challenging. Adjusting a formulation requires following Scale-Up and Post Approval Changes (SUPAC) guidelines, which can be time-consuming and may halt manufacturing. And that is precisely why developing a formulation in accordance with USP <1062> standards is important. Additionally, by isolating any potential issues to the formulation, it can make future troubleshooting processes more efficient since it rules out tooling as being a cause of any issues.

Ship Products to Market More Quickly in the World’s Largest Drug Market

While USP may sound like strictly a U.S. standard, it should be considered a set of guidelines for creating a tablet that will accommodate U.S. FDA standards for marketing tablets in Phase I trials and beyond. It does not guarantee FDA approval in any way, but creating tablets in accordance with USP <1062> standards does help to make sure that a formulation developed elsewhere in the world will have a better chance of meeting U.S. regulations.

Understanding the Rotary Tablet Press

While USP <1062> compactibility data can (and should!) be collected on a single-station R&D tablet press, the integrity of that data is truly put to the test during scale-up. The goal is to create the same effective tablet on a multi-station rotary tablet press as one did on the single-station. Since this adds more independent variables to the compaction data results, understanding how a rotary tablet press works gives a deeper understanding of why those variables are important.

In a rotary tablet press, the compression cycle moves at a pretty fast clip, and the speed determines how effectively a powder can be compacted into a tablet. That could be as fast as 100 RPM, as it is on our 32-station NP-400. This size and diameter of the turret determines the machine’s torque and tangential velocity, both of which ultimately determine the final RPMs of the turret.

Animation of a tablet press
By Jeff Dahl – Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=3606080

Each revolution of the turret takes one station through 4 stages of powder compression:

1. Particle rearrangement

Before powder enters the die cavity, the powder must be optimized for flowability. Powder sifts through the hopper, where it rests on a bed of powder, inside of a feeder. From there, a scraper blade pushes some of this powder from inside a fill cam and into to a die cavity. For this to work seamlessly, a powder must have the right flowability and consistency, or else there may be a challenge in getting uniform tablet weights when they are ejected at the end of the compression cycle.

Also, the feeder does more than just over-fill the dies. If the feeder paddles are running at the correct speed, they can help to unmix blended powders, break up granules, and/or compact highly moist powders to prepare them for the main compression event. The end of this stage results in reduced volume of pores (more on porosity later), which makes the powder more dense.

2. Compression

As the upper tablet compression punch enters into the die shortly after it’s been filled, it increases the amount of force being applied to the powder.

When an upper punch and a lower punch converge within a die, the material within the die is pushed or squeezed together. This is where compression happens. This forces the air between all of the particle’s molecules (and within the die itself) to ‘exhale’ from the die. At this point in the compression cycle, peak force has not yet been reached. After peak force is achieved, the tablet press may hold this shape for a very brief amount of time (known as dwell time, measured in milliseconds), before we release pressure. This is when decompression begins.

Photo credit: United States Pharmacopia, Copyright 2017
The four stages of the compression cycle, relative to the compression pressure in each respective phase. Photo credit: United States Pharmacopeia, Copyright 2017

3. Decompression

So the powder has just been compressed, and a newly minted tablet is about to be born. The process is complete, right? Nope! In a matter of milliseconds, the new tablet will expand slightly. This is a measure of the powder’s mechanic property known as elasticity or elastic recovery. Ideally, this should only be a matter of millimeters or nanometers, but if the formulation isn’t properly adjusted to USP <1062> standards, the tablet could experience one of of many defects mentioned above (capping, sticking, picking, and so on).

4. Ejection

In this phase, the tablet press ejects the new tablet into a collection unit. If the tablet has not been compressed properly, the ejection force of in this phase could cause the tablet to cap or laminate. This is the first test of a tablet’s friability, or its ability to withstand turning and tumbling while in transit to packaging.

What is Compressibility?

With a proper technical understanding of how a tablet is compressed, let’s turn to the scientific understanding of this process, known as compressibility. This explains the relationship between solid fraction and applied compression pressure. Compression pressure is essential to forming a tablet with a specified solid fraction. It is often used to compare various pharmaceutical materials.

Solid Fraction

Solid fraction quantifies how much of of the tablet is solid. It is is a ratio of the tablet density relative to the powder’s true density, (where the true density can be measured from a helium pycnometer). Once porosity has been calculated (see below), a tablet’s solid fraction is the inverse of that. Mathematically speaking, solid fraction (SF) = (1−porosity)

Tablet Porosity

When a powder is placed in a die, it is extremely porous; flowability” is the technical term. Like air or other gases, molecules are able to freely move about. As the powder moves through the compression cycle, particularly in Stage 2 (Compression) where the punch enters the die in the compression phase, the material is compressed and molecules are pushed closer and closer together. “True or absolute density-the density once all voids are removed-can be measured using a helium pyncometer. This is a useful value because it represents the tablet’s density if the compression event were to expel all the air between the particles, including from inter-particulate and intra-particulate voids,” says Natoli Scientific’s Director, Robert Sedlock.

Tablet porosity, written as a percentage (%), is a measure of how much air is in the tablet after it has been fully compressed. Porosity is a factor of a tablet’s dimensions (thickness and diameter), as well as its hardness. If the tablet porosity equals one (1) solid fraction, this provides valuable data that will influence the disintegration. If tablet porosity were zero (0), then it would mean that all air has been completely pushed out of the powder, after peak pressure has been applied. Please keep in mind that this is only theoretically possible.

Depending on the speed at which a tablet is compressed, the powder should be compressed into a hardened tablet. But how hard should (or could) it be? How easily does it crush (otherwise known as tensile strength)? This is a question of compactibility.

What is Compactibility?

Compactibility represents the relationship between tensile strength and solid fraction. It is important to know the compactibility of the material to understand the powder tableting performance with respect to tablet porosity.

What’s the Difference between Compactibility and Compressibility?

Compression is determined in part by a powder’s flowability. It determines how easily (or difficult) a powder can displace the air within it. Compression is an active process that reduces the bulk volume of a powder when applying stress.

Compression

When an upper punch and a lower punch begin to converge within a die, it expels the air both within the die itself, and within the powder. As the two punches meet, the material within the die is pushed or squeezed together. This is the definition of compression.

Consider for a moment squeezing a stress ball. When compressed with your fist, the air molecules within the foam are pushed beyond the ball’s surface area, and the stress ball momentarily reduces in size. When the two opposing force vectors can no longer be pushed together using only brute force (i.e., without using additional machinery or other force applications), that’s when you’ve reached peak compression force.

When the ball is released (or decompressed), the air enters back into the ball through the pores within the foam surface area, and the stress ball resumes its shape prior to compression. So, compressibility is a measure of a material’s ability to be pushed or squeezed. It depends on the material’s hardness, which we’ll discuss in a separate article.

Compaction

Compaction, on the other hand, is a mechanical action. Mathematically, it is the amount of compaction force relative to the applied area. Today’s tablet presses allow the operator to set parameters like how quickly or with how much force a punch enters into the die (this in turn also depends on the machine’s RPM, discussed above). Simply put, compaction increases the density of the material by removing air using mechanical equipment. Whereas compression describes the stress a material can endure, compaction describes the amount of force required to create compression. For a material to be measured in its ability to compact (i.e., compactibility), the material, by definition, must be able to hold its form. The granulates and particles are condensed together during compression, and the new form (in this case, a tablet) must be able to hold its shape.

As an exercise, pick up a pencil with a flat eraser. Press the eraser down onto a flat surface. The amount of compaction force you apply is the compaction pressure. In order to increase this, you’ll either have to increase the amount of pressure (until the pencil breaks) or decrease the area to which the pressure is being applied (i.e have a smaller eraser head). So, compactibility is a measure of a material’s ability to be compacted.

Up Next — What is Tabletability?

There’s one last crucial aspects of USP <1062> that remains to be covered: tabletability. It is just as complex as all of the other aspect of this USP Chapter that we’ve reviewed today, that it deserves its own space. In this article, we covred what is tabletability, how it’s measured, and why it’s important. Please refer back to this article as often as needed to familiarize yourself with USP <1062>. Whether you’re a scientist or an operator, having a “solid” understanding of tableatabilty will help you manufacture better tablets, and turn your craft from an art into a science.


Natoli Scientific, a division of Natoli Engineering Company Inc., can help you generate a USP <1062> profile for your materials or formulations. Our training courses and suite of R&D software and tablet presses can help you understand how to gather your USP <1062> data, analyze it properly to mine rich insights on your formulation’s scalability.

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Thank you very much for all of the help and patience with these sets of tooling, I know it has been difficult at some points with a lot of changes along the way. All of your work is much appreciated.

- a Pharmaceutical and Biopharmaceutical Company