Intro to USP <1062>: What it is and why you should use it

A variety of factors like powder flow, material characteristics, compression pressure, turret speed, etc can affect tablet quality and production run time. Any resulting tablet defects can exacerbate production costs or even result in no product at all! Therefore, it’s 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's 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 several 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’. Having a data-driven process at the outset of your tableting journey, much like what USP Chapter <1062> provides, 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 analyzing, 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 like 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 type of 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
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. That’s 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 US standard, it should be considered a set of guidelines for creating a tablet that will accommodate US FDA standards for marketing tablets in phase 1 trials and beyond. It doesn’t 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 US regulations.

Understanding the rotary tablet press

While USP <1062> compactability 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 quickly, with the speed determining how effectively a powder can be compacted into a tablet. Speeds could be as fast as 100RPM, as it’s on our 32-station NP-400. The 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.

Each revolution of the turret takes one station through four 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 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. 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 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 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.
   
   
3. Decompression
   The powder has just been compressed, and a newly minted tablet is about to be born. 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 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 hasn’t been compressed properly, the ejection force 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’s often used to compare various pharmaceutical materials.

Solid fraction
Solid fraction quantifies how much of the tablet is solid. It’s 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’s extremely porous; ‘flowability’ is the technical term. Like air or other gases, molecules can freely move about. As the powder moves through the compression cycle, particularly in Stage 2 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 pycnometer. 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’s 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 (known as tensile strength)? This is a question of compactability.

What is compactability?

Compactability represents the relationship between tensile strength and solid fraction. It’s important to know the compactability of the material to understand the powder tabletting performance with respect to tablet porosity.

What’s the difference between compressibility and compactability?
Compression is determined in part by a powder’s flowability. It determines how easily (or with how much difficulty) 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 (ie, 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’s 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 the die (which also depends on the machine’s RPM). Simply put, compaction increases the density of the material by removing air using mechanical equipment. While 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 (ie, compactability), 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 (ie, have a smaller eraser head). So, compactability is a measure of a material’s ability to be compacted.

What is tabletability?

There’s one last crucial aspect of USP <1062> that remains to be covered: tabletability. It’s just as complex as the other aspects of this USP Chapter we’ve reviewed today and it deserves its own space. Check out this article for more information on tabletability. Whether you’re a scientist or an operator, having a ‘solid’ understanding of tabletability will help you manufacture better tablets and turn your craft from an art into a science.