An exploration of oral solid dosage (OSD) testing, for capsules and tablets, coated or uncoated.
Tablets and capsules are so common in modern life that it’s easy to take them for granted. The workhorse product for drug delivery and bedrock of the modern pharmaceutical industry, OSD forms account for over two-thirds of the drugs prescribed worldwide. The generic and over-the-counter markets are substantial, and the contract OSD manufacturing market alone is expected to reach a value in the region of £32 billion this yeari.
OSD products are easy for patients to use, sufficiently versatile to accommodate a wide range of drug types, and amenable to differentiation for branding and safety purposes; they also benefit from well-established manufacturing practice. They flow from modern tablet presses at rates of hundreds of thousands per hour before sitting happily on shelves for extended periods of time, ready for use.
But there’s a lot of testing required to deliver the required stream of safe and effective tablets and capsules. Tablets need to be physically stable on the shelf but breakdown reliably and predictably in vivo with innovative OSD forms calling for precision control of breakdown and release profiles. Let’s take a closer look at in vitro test requirements and how they are met.
Trends in OSD
It’s easy to think of tablets and capsules as mature technology but innovation continues at pace. The OSD community is necessarily expanding the range of drugs that can be delivered, to deal with drug candidates that achieve beneficial therapeutic effect but are increasingly either poorly soluble, poorly permeable or both. At the same time, our ability to control and target delivery is improving, allowing us to realise more desirable therapeutic regimes. Highly potent active pharmaceutical ingredients (HPAPIs) are increasingly commonplace as OSDs are leveraged to treat prevalent diseases such as cancer while multi-active OSDs – ‘polypills’ – are increasingly prized for better patient compliance; oral biologics are on the horizon.
A couple of recent OSD product developments are helpful in illustrating current trends and the associated implications for testing practice. For example, earlier in August the FDA approved AKEEGA™ (Janssen Pharmaceutical Company), a once-a-day dual action tablet for the treatment of prostate cancer in patients with specific gene alterationsii . This is a common feature of cancer medications which currently dominate the ‘personalised’ therapeutic landscape. AKEEGA has delivered improved outcomes for disease progression without negatively impacting the safety profile, relative to each individually approved drug. This is the best possible outcome for a dual active tablet but it’s easy to see that reaching it requires careful study, and potentially control, of the release of each drug substance to avoid negative interaction.
Etrasimod (Pfizer), a yet unapproved drug for the treatment of ulcerative colitis is a second interesting example of OSD developmentiii. It combines encouraging results in clinical trials with the promise of an oral rather than injectable treatment regime, a highly desirable switch. For this drug, controlled release has been shown to reduce side effects, highlighting the potentially crucial benefit of being able to effectively modify in vivo behaviouriv.
Testing Critical Quality Attributes (CQAs) for tablets and capsules
Strong and stable…
Tablets that are too soft may break or crumble when removed from the packaging while excessive hardness can lead to long disintegration times and poor dissolution in vivo. In either case dosing is compromised which is why hardness is typically designated a CQA. Friability is a complementary CQA that quantifies the tendency for a tablet to chip, crumble, or break. And just as with hardness there is a balance to be struck between stability and breakdown characteristics in vivo.
Hardness testing involves measuring breaking force (USP) or crushing strength (Ph. Eur.) and is detailed in USP Chapter <1217>. and Ph. Eur. Chapter 2.9.8. Tablets are pressed between two platens or jaws to measure the force at which the tablet breaks.
Friability testing methods for uncoated tablets are covered in Ph. Eur. Chapter 2.9.7 and USP Chapter <1216> and involve determining the weight loss induced by rotation in a drum (the Roche friability drum) at a set speed. For tougher tablets and capsules Ph. Eur. 2.9.41 describes techniques that apply more significant abrasive action to generate a quantifiable change in surface mass.
Together these compendial tests allow us to assess physical stability and where necessary modify it. Coating, for example, can substantially alter the physical characteristics of a tablet, helping to preserve it intact through the stomach. This is valuable for targeted delivery to the small intestine and/or the protection of biologics. The layered structure associated with more sophisticated OSD forms such as polypills and gastroretentive tablets intensifies the need to robustly understand and control physical stability.
… With a requirement for controlled dissolution.
Disintegration and dissolution behaviours define bioavailability and by extension clinical efficacy and are manipulated to achieve targeted drug release – immediate release, extended release, or sustained release – whatever is required to achieve clinical efficacy while minimising side effects.
Methods for disintegration testing are detailed in Ph. Eur. Chapter 2.9.1 and USP Chapter <701>. A tablet or capsule is submerged in a defined volume of simulated gastric fluid to determine the time required to break it down to the point of no discernible residue (as assessed by capture on a mesh); 30 minutes is typical for ordinary tablets; 60 minutes for enteric-coated tablets.
Compendial methods for dissolution testing have evolved for different OSD forms with a range of apparatuses now detailed in the relevant pharmacopeial chapters: Ph. Eur. Chapter 2.9.3 and USP Chapter <711>. Results are influenced by the composition and de-aeration state of the dissolution media, the precise physical dimensions of the test apparatus; and the extent to which dissolution is inhibited by high localised concentration: the application or otherwise of sink conditions.
In vitro dissolution tests have been rigorously and comprehensively defined in the respective pharmacopoeias and are essential for predicting in vivo bioavailability, assessing bioequivalence, optimising the therapeutic effectiveness during development and stability assessment, and ensuring uniformity between production lots.
It is arguably dissolution testing more than any other in vitro method that we rely on to develop innovative OSDs such as the examples outlined. We can modify dissolution testing to look at the effect of taking tablets pre- or post-food, to see how the drug will be released if it transits through the stomach, to track the profiles of individual drugs released from a multi-active product, and to track even HPAPIs through the use of increasingly sensitive apparatus. The core dissolution testing apparatus offers endless possibilities to explore these and other scenarios, explaining its position as the primary in vitro tool for tablets and capsules.
In conclusion
Testing methods for tablets and capsules are mature and well-established, as are many of the products. But we’re still pushing forward on both fronts. OSDs are easy-to-administer and highly accepted products and maximising their utility is helpful for manufacturers, healthcare providers and patients alike. The same core tests we’ve long relied on are providing vital information for progress but flexing to support continued innovation. In upcoming blogs we’ll be taking a closer look at these tests and how they’ve been adapted over the years to tackle a growing diversity of OSD formulations and designs. Subscribe today to be sure of catching every post!
Want to learn more? Then why not sign up to our webinar ‘A Introduction to Oral Solid Dosage Testing’, taking place January 2024. Sign up here.
i https://www.giiresearch.com/report/ires1201481-oral-solid-dosage-contract-manufacturing-market.html
ii https://www.prnewswire.com/news-releases/us-fda-approves-akeega-niraparib-and-abiraterone-acetate-the-first-and-only-dual-action-tablet-for-the-treatment-of-patients-with-brca-positive-metastatic-castration-resistant-prostate-cancer-301899028.html
iii https://www.fiercepharma.com/marketing/top-10-most-anticipated-drug-launches-2023
iv https://www.sec.gov/Archives/edgar/data/1080709/000156459020014775/arna-ex991_6.htm
