Tableting: Minitablets and Microtip Tooling

Orally administered tablets are a popular pharmaceutical dosage form because they provide consistent dosing, ease of administration, low manufacturing costs, and long stability times. In recent years, minitablets have become an increasing portion of the tablet market. While the exact definition of “mini” can vary, I include in the category any round tablet with a diameter smaller than 4.76 millimeters or any shaped tablet with a width smaller than 4 millimeters.

Minitablet benefits 

Due to their smaller size, minitablets are easier to swallow than conventional tablets, which can be particularly helpful for pediatric and geriatric patients. Dysphagia, or difficulty swallowing, can reduce patient compliance, negatively impacting health outcomes and quality of life¹. 

Minitablets have a higher surface-area-to-volume ratio than conventional tablets, so they can achieve faster dissolution profiles. Also, minitablets can be beneficial for products containing high-potency drugs when used as multiple units within a capsule. They provide a more consistent dissolution profile than conventional tablets and allow the dissolution to be spread across a larger area of the digestive system¹. 

Placing multiple minitablets into empty capsules can minimize the effects of tablet defects and weight variations between tablets. For example, compare a single 350-milligram tablet to 35 minitablets—each 2.5 millimeters in diameter and 10 milligrams in weight—filled into a #1 capsule. If the 350-milligram tablet is defective, increasing 50 percent in weight, then the patient will receive a 50 percent higher dosage. If one of the minitablets is defective, also increasing 50 percent in weight to 15 milligrams, then the capsule’s overall weight is 355 milligrams, and the patient only receives a 1.4 percent higher dosage. Similarly, an individual surface defect on a minitablet, such as delamination resulting in faster dissolution, has less impact on the overall dissolution profile of a collection of minitablets in a capsule than the same defect would have on a conventional tablet. 

While the manufacturing process is similar to that of conventional tablets, minitablet production requires some special considerations with respect to formulation characteristics and tablet design. 

Formulation characteristics 

Flowability and compactibility are critical characteristics when evaluating a formulation’s feasibility for minitablet production. 

Flowability. 

Flowability is important because the formulation must flow into smaller die bores for minitablets than for conventional tablets, and the ratio between the fill depth and the die bore size is higher. Flowability is often measured indirectly using the Carr’s index. A lower Carr’s index value indicates better flowability, and you can expect good flow when the value is below 15². 

Good microtip tooling design can mitigate some flowability issues for minitablet production. Since vacuum pressure aids in filling the die bores, optimizing the clearance between the punch tip and the die bore can improve vacuum pressure and help ensure adequate filling.

Compactibility. 

Compactibility is also of concern because poorly compactible formulations require higher compression forces and increase the likelihood of bending or buckling the sensitive microtip tooling that is used to compress minitablets. A common means of evaluating a formulation’s compactibility is to conduct a Heckel plot. 

A common Heckel plot simplifies to ln(1/E) versus P to plot K, where E (porosity) is 1 − D. The slope of the linear regression is the Heckel constant. Larger values indicate better plastic deformation at low pressures than do lower values³. 

Tablet design 

Tablet shape

Minitablets are most often round because round tablets are easier to eject and film coat than other shapes. Also, round punch tips are stronger for any given tablet size than other shapes. Other minitablet shapes include capsule, modified capsule, rectangular, bean-shaped, and oval. 

While you can coat modified-capsule- and ovalshaped minitablets, capsule-shaped and rectangular minitablets tend to suffer from twinning during film coating, which is when the tablets’ flat sides stick together. In applications where the minitablets are inserted into implantable silicone tubes for targeted release, rectangular tablets can maximize volume, but their small corner radii increase the risk of dies cracking during compression. Bean-shaped tablets are generally impractical because of the increased tooling costs. 

Cup profile

Cup profile affects a tablet’s surface area, overall thickness, and sideband (or belly band) thickness. Many tablet presses are limited in how close the upper and lower punch tips can be during compression, so the tablet sideband must be a thickness that your machine can achieve while also providing the target tablet weight. Table 1 shows a range of cup profiles used for minitablets. 

Table 2 shows a comparison of cup profiles and tablet dimensions for 10-milligram, 2.5-millimeter-diameter minitablets. The Tableting Specification Manual provides minimum land-width values for conventional tablets, but for minitablets, you may need to reduce the land width to make it proportional to the tablet size². Two factors come into play. First, the edge volume of material lost from dedusting increases for a given land width as the tablet size gets smaller. Second, for tablets with deep cup profiles, tablet ejection becomes more difficult as the tablet becomes smaller because the cup angle—the angle between the cup and the land at their intersection— becomes steeper.

Table 3 shows how tablet size and land width affect friability and cup angle for minitablets with a deep, convex cup profile. While you might think that a larger land width would decrease friability due to increased tablet hardness at the land, as the table shows, the friability advantage provided by a deeper cup is lost when the land width isn’t proportional to the tablet size. 

In addition to the formulation characteristics and tablet design, several tablet press settings and options are important to consider when manufacturing minitablets. These considerations will help to ensure that the formulation adequately fills the die cavities, that the tablets eject properly from the die cavity without damage, and that the microtip tooling is protected from damage due to excessive compression force. 

Ensuring adequate fill 

A tablet press fills formulation into the die cavities using a combination of gravity, feeder paddles (for power feeders), and the vacuum pressure created by the retraction of the lower punch tip pulling the material into the die bore. When producing minitablets, minimizing the fill-cam depth helps control tablet weight, improve yields, and maintain content uniformity. It also allows the lower punch tip’s design to be maximized for strength, which I will discuss later. A fill cam depth of 6 millimeters is usually optimal for minitablet production, which is shallower than the depth used for standard tablets. 

With power feeders, a reduced-volume hopper design is best. Consider installing a feeder restrictor plug to block the feeder’s first opening. Because minitablets require less formulation than standard tablets, reducing the paddle speed is advisable. Reducing the hopper volume can also be beneficial because the total amount of material needed for a batch is often lower for minitablets than for standard tablets, and the formulations tend to be more expensive. Depending on your formulation’s characteristics, minimize the clearance between the feed pan and the die table during setup. Generally, heat-sensitive formulations need more clearance and formulations with high percentages of fines need less clearance. Verify the turret face runout since proper feed-pan clearance depends on a die table that doesn’t rise and fall excessively as it rotates. Have the tablet press serviced if needed. 

To avoid overfilling the feeder chamber, choose a feeder with a metering capability that uses a combination of sensors and a vibrator to convey the desired amount of formulation. The amount of clearance between the punch tip and the die bore wall can affect the vacuum pressure. Reduce this clearance by 0.005 to 0.008 millimeter (0.0002 to 0.0003 inch) to increase vacuum pressure, particularly for formulations with a bulk density below 0.5 gram per milliliter. 

Tablet ejection 

Perhaps the most common issue related to minitablet production is tablet damage during ejection. Small tablets have thinner side walls than large tablets, and as a result, are more sensitive to the takeoff plate’s height and location. Proper height and placement of the tablet stripper is necessary to maintain a smooth, stable path off the press. Often you will need to move the tablet stripper slightly forward and closer to the die plate for minitablets. Improper setting of the ejection height and incorrect overall lengths for the lower punches can introduce instability in the tablet stream at takeoff, resulting in chipped or broken tablets and potentially damaging the punch tips and takeoff plate. 

To assist in tablet ejection, several technologies are available, including: 

• Air-assisted takeoff using a low-pressure air stream, either coming from a dedicated line or using a single tablet reject line; 
• Deionizer misters, which eliminate static energy buildup on minitablets that can affect the ejection stream; 
• Plastic rather than stainless-steel stripper plates, which allow a lower height without risking catastrophic damage; 
• Teflon coating of the discharge chute, which reduces the coefficient of friction to decrease tablet damage; 
• Chute designs optimized for minitablets, which may include air assist and special reject and sampling gates; and 
• Tablet reject gates on the discharge chute, which can be especially helpful for multitip minitablet production.

Compression-force monitoring 

Tablet presses often use strain gauges to monitor the amount of compression force applied to the tooling. This monitoring allows for automatic tablet weight control, reject functions, and overload protection to safeguard the tooling from excessive loads. 

When compressing minitablets, the tablet press may apply only 0.5 to 2 kilonewtons of force. A strain gauge designed for a 100-kilonewton range may be accurate only to 1 kilonewton. The gauge’s accuracy depends partly on the signal-to-noise ratio, and signal amplification to detect low forces can increase noise levels. As a result, such a gauge may not be sensitive enough to control tablet weight effectively. This issue crops up most often with poorly compactible formulations. 

A high-sensitivity force-control system may help when using a tablet press dedicated solely to minitablets. The natural result of higher sensitivity is reduced range, so your tablet press force monitoring may be reduced to only 20 kilonewtons or so, depending on the kit. If your tablet press must run both minitablets and standard-sized tablets, consider using high-sensitivity strain gauges for precompression only and using software that can toggle weight control between main and precompression. When you compress tablets to a fixed thickness as set by the pressure-roll positions on the tablet press, a direct relationship exists between tablet weight and compression force, as shown in Figure 1. This relationship is described by the equation: 

This equation is helpful in determining the ideal settings for the weight control limit. To determine the C0 and C1 values for your formulation, first collect data by varying the depth of fill in 2 percent increments from 90 to 110 percent of the set point values and recording the average tablet weight and compression force for each fill depth for a group of 20 tablets, as shown in Table 4. 

After you collect the data, use a least squares power curve to determine the equation. Then simply plug in the desired high and low values for the tablet weight to determine the reject-force values. 

Lower punch pulldown 

Compared to standard tooling, microtip tooling has much thinner punch tips, which can be susceptible to bending or buckling under high compression loads. You can prevent this by using lower punches with a punch-tip support shoulder and matching dies with a counterbore to fit the shoulder, as shown in Figure 2. The lower punch pulldown determines how much tip support you can use. 

Some tablet presses are well suited to accommodating minitablet tooling because the tablet press doesn’t pull down the lower punch further than the fill cam. On other machines, lower punch pulldown is a fixed feature, and you must either install a shim or lengthen the lower punch tip to match the press’ pulldown requirements. Flight control is especially important for minitablet tooling. Be sure to perform proper maintenance and adjustment of lower punch retainers. 

Calculating force ratings for microtip tooling 

Traditional punch-tip force ratings, such as those based on formulas in the TSM, are often higher than what you can safely apply to microtip tooling because the formulas don’t consider bending or buckling as possible failure modes. A number of methods are available to calculate the force ratings for microtip tooling. They include the Euler-Bernoulli formula and Rankine-Gordon formula, which I will discuss here, as well as the secant formula and finite element analysis (FEA), which are beyond the scope of this article. 

Classic beam theory, as introduced by Leonhard Euler and Jacob Bernoulli, can be a helpful place to begin calculating microtip force ratings. 

The resulting number will be higher than needed in reality for tablet tooling for several reasons: the formula assumes a longer column ratio than microtip tooling requires; the load (axial) is applied directly over the punch tip’s center; no side loading occurs; and the formula doesn’t consider crushing strength. 

The Euler-Bernoulli formula is useful in two ways: 1) you can later use the result to calculate a more accurate result for the Rankine formula, and 2) by using the punch-tip length in the calculation, you can determine how much you can increase tool strength by reducing the punch-tip length. Shortening the punch tip by using a tip support shoulder can increase the rating. 

Empirical Rankine-Gordon formula

The Rankine- Gordon formula provides a good quick approximation of the amount you need to reduce the TSM force rating for microtip applications. 

For a precise answer, you must use the secant formula or FEA because they consider additional factors, such as side loading, eccentricity, and torque. Understanding these factors can help you to minimize tool damage. 

Side loading. 

In practice, a side load develops due to the relative sideways motion or sliding between the tablet press’ pressure roll and the punch head, which applies the load to the punch tip during compression. The side load’s magnitude is equal to the compression force times the coefficient of friction between the punch head and the pressure roll. The free body diagram in Figure 3 illustrates how side loading is distributed. 

To protect microtip tooling, ensure that the punch heads are well lubricated by manually applying grease. The coefficient of friction is 0.16 for a well-lubricated steel punch, so the side load will equal 0.16 times the applied compression force. 

The punch barrel takes up most of the side load, but about 4 percent of the compression force ends up being applied to the punch tip. You can protect upper punch tips a bit more from side loads by increasing upper punch penetration. 

Eccentricity 

In practice, the pressure roll doesn’t apply the compression load directly to the center of the punch head at first but rather to the edge of the head flat. The larger the head flat in comparison to the punch tip diameter, the more off-center (or eccentric) the load and the lower the resulting tip-force rating. As a result, smaller head flats may be helpful for microtip tooling. 

In addition, friction and inertia between the punch head and the pressure roll can cause the punch to deflect angularly in the turret guideway. The clearance between the guideway and the punch barrel determines the amount of angular deflection. Worn guideways increase eccentricity, which reduces the amount of force you can safely apply to microtip tooling. 

A close-fitting set of guideways, with no excessive wear, may be helpful when running microtip tooling on a tablet press. The upper and lower punch barrel diameters should match unless the lower turret’s guideways are smaller in diameter. In other words, a B lower punch barrel with a 0.745-inch diameter isn’t recommended for microtip tooling unless the specific press requires a lower barrel of that diameter. Most don’t. 

Torque 

For shaped minitablets and for multitip applications, the interaction between the punch head and the pressure roll can also apply a torque to the lower punch tips. To protect the lower punch tips from torque in this situation, consider using a rotating punch head to decrease the loads applied to the punch tips. However, rotating heads increase the cost and complexity of the tooling, so you should select them only when necessary for a particular application.

References 

1.  Ezgi Ilhan, Timucin Ugurlu, and Oya Kerimoglu. “Mini tablets: A short review-revision.” Peertechz J Med Chem Res. July 2017. 3(1):012-022. DOI: 10.17352/ ojc.000007. 

2. American Pharmacists Association. Tableting specification manual, seventh edition. Available at: https://ebusiness. pharmacist.com/PersonifyEbusiness/Shop-APhA/ Product-Details/productId/115810. 

3. Metropolitan Computing Corporation. Pharmaceutical process scale-up. Michael Levin, ed. Boca Raton, FL: CRC Press (Marcel-Dekker), pages 228-231.