Carolina Diaz Quijano Omya International
Orally disintegrating tablets (ODTs are not just another fancy dosage form; they address a very important component of treatment success: compliance. This is especially true for pediatric and geriatric patients. Children and the elderly are not easily persuaded to take medicines and can have difficulty swallowing tablets or capsules whole, making therapeutic compliance a significant challenge.
The world’s aging population has increased the demand for geriatric drug products, and this trend is expected to continue. Also, evidence shows that children are not just small-sized adults when it comes to medication. For example, a child’s metabolism differs significantly from that of an adult, so pediatric medicines may require not only different dosages but also different API release profiles than adult medicines. In fact, since 2007 the European Medicines Agency has required pharmaceutical companies to submit a pediatric investigation plan to the agency’s pediatrics committee at the end of the first phase of testing a new drug in adults1.
The need to develop age-appropriate formulations targeting pediatric and elderly patients is clear. ODTs can help improve compliance for these two populations because ODT tablets are usually smaller than traditional tablets and capsules, they disintegrate rapidly in the patient’s mouth, and they have a pleasant mouthfeel and flavor.
In the combined regions of the US, the European Union, and Japan, the ODT market has doubled in the last four years. A 2017 study by Persistence Market Research predicted that the global ODT market will grow at a significant pace in coming years, with annual revenue anticipated to rise from an estimated $11.4 billion in 2017 to about $27 billion in 20252. Table 1 lists some examples of the more than 450 over-the-counter (OTC) and prescription ODT products currently available on the market
ODT Formulation Technologies
In addition to fast disintegration, an ODT platform must also be stable, have a good level of inertness, have good flowability and compactability, and must contribute to the pleasant mouthfeel of the final formulation. Formulators produce ODTs using several different technologies, including direct compression (DC), lyophilization (freeze drying), molding, mass extrusion, and spray drying3. Each of these technologies has disadvantages such as relatively slow disintegration, poor mouthfeel or taste masking, high manufacturing costs, special packaging requirements due to hygroscopicity, or low chemical and/or mechanical stability. However, DC ODT platforms have a clear advantage over other technologies in terms of cost-effectiveness and ease of manufacturing. The key performance attributes expected in a DC ODT platform and the associated formulation challenges are shown in Figure 1, and Table 2 lists some currently marketed DC ODT platforms.
Comparing DC ODT Platforms
The study presented here compared the key performance attributes of several DC ODT platforms with those of the Omyapharm ODT platform, which is composed of dispersible granules containing Omyapharm 500-OG and croscarmellose sodium. Omyapharm 500-OG is a novel co-processed multifunctional mineral excipient. This structured mineral, comprised of calcium carbonate and tribasic calcium phosphate, has an external lamellar structure that encloses a core of interconnected pores. Both features give the material’s particles several desirable properties, including high compactability, the ability to be used in dry granulation without requiring a binder, and dilution potential.
To compare these ODT platforms, both placebo tablets and caffeine-containing tablets were manufactured. The placebo tablets consisted of 99 percent ODT platform ingredient and 1 percent lubricant (magnesium stearate), while the caffeine tablets consisted of 10 percent caffeine, 89 percent ODT platform ingredient, and 1 percent lubricant. It is worth mentioning that tablets consisting of 0.3 percent lubricant were initially tested, but most of the ODT platforms (with the exception of the Omyapharm platform) showed very poor compactability at that lubricant concentration, so 1 percent lubricant was selected to allow the manufacturing of tablets from all of the available excipients.
Flow and Compactability
Compactability is the most important functional consideration when producing a tablet5. To characterize the compactability of the different ODT platforms, the study tested the flowability of each platform as well as tablet hardness and friability versus compression force. The flow properties of each ODT platform are described in Table 3. Each of the platforms showed good or at least fair flow properties. Figure 2 shows the tablet hardness achieved at different compression forces for each platform. The tableting machine settings were defined to reach, whenever possible, tablet hardness values between 30 and 140 newtons (N). The study used a Fette 1200i rotary tablet press operating at a speed of 10,000 tablets per hour.
The results show that, for the placebo tablets, ODT platform 3 did not achieve hardness above 60N, regardless of the compression force used. To reach a tablet hardness above 40N, ODT platform 2 required significantly higher compression force than platforms 1, 4, or 5. Platforms 4 and 5 showed a linear correlation between compression force and hardness in the studied range (R2=0.9862 and R2=0.9686, respectively). Moreover, ODT platform 5 was able to reach hardness above 130N at compression forces lower than 14 kilonewtons (kN). In the placebo tablets, platform 1 reached hardness above 110N at lower compression forces than any of the other ODT platforms tested. For the tablets containing 10 percent caffeine, all of the ODT platforms were able to achieve hardness above 80N but at different compression forces. In general, platforms 2 and 3 required a higher compression force than platforms 1, 4, and 5 to achieve equal hardness. All platforms showed a linear correlation between compression force and hardness, but platform 1 had the highest linear correlation coefficient (R2=0.9912). In addition, in the range of hardness studied, platform 1 required lower compression forces than most of the other studied platforms to achieve caffeine tablets of equal hardness. Friability was measured according to the European Pharmacopoeia and compared among the different platforms, as shown in Figure 3. For the placebo tablets, ODT platform 5 showed the lowest friability, but friability was relatively low (1 percent or less) for all platforms—at least for tablets with hardness above 40N.
For the caffeine-containing tablets, the friability was also below 1 percent in most cases. ODT platform 1 achieved friability lower than 1 percent on placebo tablets with hardness higher than 45N and caffeine-containing tablets with hardness higher than 50N.
Disintegration Time
An ODT should disintegrate in less than 30 seconds, according to the US Pharmacopeia (USP), and less than 180 seconds, according to the European Pharmacopoeia. This study compared the disintegration time of the ODT platforms according to the European Pharmacopoeia for tablets with equal hardness (80N), as shown in Figure 4. The disintegration times varied significantly between ODT platforms.
ODT platforms 2, 3, and 4 showed disintegration times ranging from 19 to 34 seconds, with longer disintegration times for the caffeine tablets than for the placebo tablets. Note that, while the placebo tablet for ODT platform 3 had a disintegration time of 10 seconds, this test was run with 60N tablets because platform 3 could not achieve the 80N hardness value.
While ODT platform 5 showed better compactability than other ODT platforms, disintegration time was significantly higher, at around 230 seconds for the placebo and 220 seconds for the caffeine tablets. ODTs manufactured with platform 1 had significantly lower disintegration times than the other platforms, at 4 seconds for the placebo and 5 seconds for the caffeine-containing samples.
To study the effect of tablet hardness on disintegration time, the disintegration time was also measured at increasing ODT hardness values, as shown in Figures 5 and 6. For both placebo and caffeine-containing ODTs, the disintegration time increased most significantly for platform 5 as the hardness increased. Of the remaining ODT platforms, platform 4 showed the highest gradient, followed by platform 2, platform 3, and, finally, platform 1, which had a slope close to zero, indicating that the disintegration time was only slightly affected by increasing tablet hardness. In fact, the 114N placebo ODTs and 134N caffeine ODTs manufactured with platform 1 disintegrated in 6 seconds and 7 seconds, respectively.
To determine whether the disintegration time affected the API release, the caffeine release profile of the ODTs was compared according to USP Apparatus 2 for 80N ODTs in a Sotax AT7 Smart tester (n=3). Caffeine was completely released from all ODT platforms, as shown in Figure 7, but the release profiles varied. ODT platforms 1 and 3 had the fastest caffeine release, at less than 3 minutes. Platforms 2 and 5 completed caffeine release shortly before or after 5 minutes, respectively, while platform 4 completed caffeine release only after more than 10 minutes.
Stability and Organoleptic Perception
This study primarily focused on compactability and disintegration time as key performance attributes. Organoleptic perception is a highly subjective attribute and also depends on several factors unrelated to the ODT platform, such as the amount of API needed in the formulation and the target population. On the other hand, stability is an attribute that can clearly be measured. Stability trials were run as part of this comparison but are not covered in this article.
Conclusions
A successful DC ODT platform should simultaneously address several key performance attributes such as poor compactability, slow disintegration, lack of stability, and inferior organoleptic properties. Each of the DC ODT platforms in this study demonstrated advantages and disadvantages, but platform 1 (the Omyapharm ODT platform) combined good compactability with the fastest disintegration time of the platforms studied, overcoming several challenges to ODT formulation.
References
1. Regulation (EC) No. 1901/2006 of the European Parliament and of the Council, Official Journal of the European Union, 2006, https://ec.europa.eu/health//sites/ health/files/files/eudralex/vol-1/reg_2006_1901/ reg_2006_1901_en.pdf.
2. Persistence Market Research, “Global Market Study on Orally Disintegrating Tablets”, 2017, https://www.aboutpharma.com/blog/2017/08/28/orally-disintegratingtablets-market-to-reach-us-27-bn-by-2025-persistencemarket-research/, (Accessed January 26, 2018).
3. P. A. Hannan, J. A. Khan, A. Khan, and S. Safiullah, “Oral Dispersible System: A New Approach in Drug Delivery System,” Indian Journal of Pharmaceutical Sciences, Vol. 78, No. 1, 2016.
4. F. B. Abay and T. Ugurlu, “Orally Disintegrating Tablets: A Short Review,” Journal of Pharmaceutics & Drug Development, Vol. 3, No. 3, 2015.
5. Michael Levin, Pharmaceutical Process Scale-Up, CRC Press, 2001.
Carolina Diaz Quijano is head of technical services for consumer goods at Omya International (+41 62 789 2274, www.omya.com). She previously worked as a research collaborator in protein engineering at the University of Zurich and in diagnostics and genetic profiles at Stab Vida, Caparica, Portugal. She holds a PhD in life sciences from ETH Zurich and a licentiate degree in biotechnology and molecular biology from the University of Buenos Aires in Argentina.