Discover the physical limits

Jo Smewing, applications manager, Stable Micro Systems, explores new methods to measure pivotal physical characteristics of controlled release (CR) tablets

The pharmaceutical industry has fully embraced the benefits offered by controlled delivery drugs

Jo Smewing, applications manager, Stable Micro Systems, explores new methods to measure pivotal physical characteristics of controlled release (CR) tablets.

The pharmaceutical industry has fully embraced the benefits offered by controlled delivery drugs that enable manufacturers to determine the rate, site or time of targeted release. The systems" competitive advantage lies in improving patient compliance and convenience as well as prolonging product lifecycle.

Controlled-release (CR) dosage forms can be divided into two types: delayed-release (DR) and extended-release (ER). The choice is dictated by whether the dose is required at a time differing from that of administration, or whether a high concentration of active ingredient needs to be released gradually, over a prolonged period, to reduce the administration frequency.

Although a variety of administration methods exists, oral delivery accounts for 90% of all prescribed medication. The drug dispensed in the form of a tablet, capsule, pellet or elixir is degraded by stomach acid and enzymes, passed through liver metabolism and then absorbed.

CR drugs have become increasingly popular in the context of chronic ailments, including heart disease and cancer, as well as conditions such as Alzheimer's disease or obesity. To maintain functionality, the mechanical properties responsible for the manipulation of biological barriers or the regulation of diffusion rate have to undergo stringent quality control during manufacture. To achieve the desired results, it is advisable to test the properties of the individual ingredients first, followed by the finished product. Using texture analysis allows manufacturers to safeguard predefined quality standards in the physical characteristics of individual ingredients and final products.

As the most prominent dosage form, tablets come in a range of formats, including fast-dissolving, self-repairing and extended-release. "Compact" tablet formulation is determined by the compressibility and compactability of each component. Thus, to evaluate the performance characteristics of bulk and individual solid-dosage forms, it is necessary first to test powder compressibility and the effect of tooling geometry on tablets.

To measure the compression properties of powders, a Powder Compaction Rig, attached to a TA.HDplus texture analyser, can be used as a compaction simulator on "F" tooling sets, where two vertical probes with indentations to accommodate the powder compress the sample into a tablet shape. The force required to compress a sample is measured, indicating the compaction properties of the powder.

As tablets come in all shapes and sizes, a comparison between different types is possible only if their tensile strengths are known. Tensile strength is a good indicator of a tablet's ability to withstand the rigours of manufacturing processes, transportation and usage. There are various ways to measure this.

As tablets usually fracture along the diameter, diametrical compression is a commonly used method, whereby the sample is compressed from both sides: this determines the force required for a tablet to fail. The TA.XTplus and TA.HDplus texture analysers are widely used to perform these diametrical crushing tests. Another way to measure mechanical strength and fracture characteristics is the three-point bend test. The tablet is mounted on two lower supports and a central upper support is lowered onto the tablet until it fractures. The product's brittleness is then calculated.

For added efficacy, bi-layer dosage forms are often used to provide both immediate-release dose for fast-acting relief and a controlled-release dose to maintain the therapeutic effect. The Bilayer Tablet Shear Rig (Figure 1) was specifically developed to assess the physical characteristics of high-load active pharmaceutical ingredients (APIs), which often require bespoke formulations to overcome barriers such as low melting points or poor compressibility. To assess the force required to separate the layers of a bilayer tablet, a sample, placed in the central cavity of a guillotine-like blade, is compressed until the two components are sheared apart. This test helps to optimise the formulation to achieve perfect adhesion between the two tablet components.

Film tablet coatings are popular owing to their multiple roles: from aesthetics and masking taste and odour to eased ingestion and prolonged product shelf life. Problematically, aqueous film coatings tend to act as local stress concentrators, promoting cracking, edge splitting and peeling. To assess these risks accurately, Stable Micro Systems developed the Tablet Coating Adhesion Fixture, which calculates the force required to separate a tablet from its coating (Figure 2).

The coating is removed from around the circumference of the tablet using a scalpel, leaving it present only on the upper and lower surfaces. Lower and upper fixture cavities are covered with double-sided foam tape, and the prepared tablet is then positioned in the lower cavity. As the test starts, the upper fixture descends onto the tablet at a specific force for a defined time. Once the sample has been fully compressed into both cavities, ensuring full coating contact with the adhesive, the upper fixture is withdrawn, either removing the upper coating or leaving the lower one in the stationary fixture. The maximum force required to separate the tablet from its coating is known as the "tablet coating adhesion force".

tensile properties

Traditionally, tensile or pneumatic grips were used to assess the tensile properties of polymeric films, but the reproducibility of results is compromised as the pressure is unevenly distributed across the sample's surface area. By comparison, the Film Support Rig can hold small sections of film in a drum configuration, which means the pressure is evenly distributed around the circumference of the sample. A puncture test using a spherical probe determines the film's burst strength as well as resilience, stiffness and relaxation.

Similarly, some of the most popular dosage forms are hard two-piece capsules. Accurate testing of their hardness and flexibility is invaluable in early formulation screening. It determines their ability to withstand manufacturing and storage conditions.

The Capsule Tensile Rig provides a new method of calculating the force required to split open one half of a hard gel capsule. In soft gel capsule applications, the TA.XTplus texture analyser can also be used to measure seal strength and burst point. The test requires a cylinder probe exceeding the size of the capsule being tested, then depending on the force applied, the probe either punctures or compresses the capsule along the seal line.

granules and pellets

Pharmaceutical powders often undergo particle modification, such as granulation, before compaction. This inevitably changes their deformation and densification properties. The same is also true for pellets, whose round shape facilitates the easy application of polymer coatings, making them ideally suited to controlled drug delivery. A cylinder probe can measure the fracture strength of a single particle, which indicates its dissolution and drug release rates.

However, where the granules or pellets are irregular in form, single particle testing compromises the accuracy and consistency of results as parameters may vary significantly among samples. For this reason, testing of a larger fixed sample area is preferable as it creates an averaging effect. By using a cylinder probe of similar diameter to the testing area, the Granule Compaction Rig measures the hardness and compressibility of various samples (Figure 3).

With an increasingly aging population come associated health issues, such as the decline in swallowing ability. Soluble or granulated medication allows easy and convenient drug administration to people of all ages. To evaluate new dosage forms like these, it is crucial to quantify their release properties. In a simple test to calculate tablet disintegration and dissolution times, a sample is attached to a flat-ended cylinder probe that is lowered into a volume of simulated saliva or water. The TA.XTplus texture analyser is then used to measure the change of distance during the disintegration of the submerged tablet. The results of this test are illustrated above, providing a comparison of disintegration rates of different tablets.

Another critical parameter in both CR and ER formulations is dimensional change associated with matrix hydration and subsequent swelling. Once hydrated, tablets form gelatinous layers that dissolve one after another. In CR systems where an active agent is released through sequential swellings of its surface layers, measuring gel thickness is paramount.

To simulate gel dynamics, a sample is affixed to a petri dish and placed in a dissolution vessel filled with a medium to allow thorough ingression of the liquid. Swelling can be quantified by either calculating the change in force required to compress the sample as it swells, or measuring the difference in distance travelled under constant force.

Microcapsules and alginate beads are commonly used for slow drug release in water-soluble applications where the drug's performance depends on capsular membrane properties. Using a cylinder probe, the texture analyser quantifies the resilience of a bead's surface by measuring the force required to compress the sample. The same probe can also be used to measure the bead's burst characteristics by adjusting the impact distance from 25% to 90% of pressure applied. The probe can perform a relaxation test by adjusting the resilience test option to continue applying the force until a set time.

Despite their complex structure and sophisticated release mechanisms, CR dosage forms are increasingly prevalent among otc products. Having an optimal physical structure maximises efficacy and minimises adverse reactions. Facilitating repeatable and reliable testing of various mechanical properties of CR dose forms, texture analysis enables manufacturers to evaluate and evolve their products. Extensive tests help to identify optimal CR formulations that promote stability and long-term performance of a product.