KEYWORDS: Orally dispersive tablets, ODT, granulation, direct compression, taste-masking, disintegration time, stability, storage

INTRODUCTION

ODT formulations are referred to as quick disintegrating tablets, mouth dissolving tablets, fast disintegrating tablets, rapid dissolving tablets, rapid melts among others.¹ United States Pharmacopoeia (USP) monographed these dosages as fast “Orally Disintegrating Tablet” or ODT that disintegrates within 30 seconds or less. European Pharmacopoeia also published a similar monograph on “Orodispersible Tablet” “for solid oral dosage that disperse inside the mouth readily and within 180 seconds or less. The FDA’s Guidance for Industry: Orally Disintegrating Tablet, was issued in 2008.²

Orally disintegrating tablets (ODTs) have drawn attraction in the recent past in certain patient population and expect that market will continue to grow in the future. A survey conducted in 2017 predicts that ODT market will grow from 11 billion to over 27 billion.³ This upward trend is due, in part, to demands, in pediatric, geriatric population, and also in those who suffer from ailments like dysphagia.⁴ A typical ODT solid dosage form is aimed at improving the disintegrating and dissolution rate of drug in a short time, leading to faster absorption and onset as opposed to conventional swallowed pills. The rapid disintegration time, requiring 30 sec or less, results from enabling excipients possessing high porosity and low density with high compressibility at low compaction force.⁵ The ingredients used in an ODT should meet certain criteria like hydrophilic in nature and quickly dissolves and possesses good mouthfeel and taste-masking effect. Finding all these criteria in an ODT excipient might be challenging, especially when addressing poor solubility, taste masking of bitter drugs, higher drug loading among others.⁶

Figure 1 illustrates the disintegration of an ODT tablet prepared by blending and direct compression of an API with an ODT excipient. The resulting tablet is subjected to disintegration and dissolution to achieve the desired dosages.

Other processing methods are also used to prepare ODT dosages and those include spray drying, extrusion, lyophilization, molding, among other patented technologies.⁵ These technologies, however, require expensive equipment as compared with the standard direct compression manufacturing process and with some requiring special packaging.

ODT offers several advantages including the patient compliance, faster dissolution in saliva, rapid onset, to avoid hepatic metabolism, greater stability, accurate dosing, easy manufacturing, small packaging size, and easy transportation.^7,8 A SeDeM-ODT expert system tool is also used to predict the powder blending to produce conventional tablets by direct compression.⁹ This predictive tool provides information about the powder or mixture of different excipients, which could help in optimization of ingredients in direct compression (DC) to avoid granulation in the initial formulation.¹⁰

ODT EXCIPIENTS

There are several co-processed excipients commercially available for orally dispersive tablets. Table 1 lists several ODT excipients commercially available by different manufacturers.¹¹

Many of them contain mannitol with disintegrants to yield rapid disintegration within the desired time to meet an ODT requirement. Mannitol is used as non-cariogenic excipient as sweetener and good mouth feel and crospovidone with smaller particles provides creamy palatability.⁶

This article sheds light on the composition and utilities of a few selected ODT excipients.

LUDIFLASH^®

Ludiflash, a co-processed excipient is comprised of 90% mannitol, 5% crospovidone and polyvinyl acetate 30% dispersion with 5% povidone. It is highly compressible and at compression force as low as 4.8 kN with 98% Ludiflash and 2% sodium stearyl fumarate, it yields placebo tablets (each weighing 300 mg and 10 mm diameter in size) with hardness of 44 N and < 0.2% friability. These placebo tablets showed the disintegration time of < 20 seconds in water and as well as in mouth saliva of healthy volunteers.¹²

On loading with drugs, Ludiflash maintains the ODT properties, meaning the disintegration time is still within 30 seconds. For example, cetirizine dihydrochloride ODT prepared by direct compression of granulated API with 6.5% PVP K30 and magnesium stearate as lubricant, showed the disintegration of 25 seconds in water for the tablet with hardness of 34 N, each weighing 200 mg with 8 mm flat surface and with < 0.4% friability.

PEARLITOL^® FLASH

A co-processed ODT excipient is comprised of 80% mannitol and 20% starch with <3% moisture content. It is widely used for different active ingredients.13 Kollmer et al. (2013) investigated benzocaine in ODT formulations comprised of different orally dispersive excipients. Oral palatability, good mouth feel, disintegration time, and stability of drug was investigated in the mannitol based, a less hygroscopic filler in combination with a disintegrant and a lubricant. Since many ODT excipients are ready to use, benzocaine was directly compressed in tablets.¹³

PROSOLV^® ODT G2

A highly functional ODT excipient is comprised of mannitol, fructose, MCC, and crospovidone as disintegrant. Ondansetran containing 5 mg and 10 mg in ODT dosages prepared by compression with hardness of 50 N containing 0.7 mg and 1.4 mg sodium stearyl fumarate (Pruv), respectively, showed the disintegration time < 30 seconds, which is comparable to the reference drug. If required, the additional disintegrant could be added to meet the criteria for a quick dissolving tablet to 30 sec or less, especially, those requiring higher drug loading.¹⁴

F-MELT^®

F- Melt is commercially available in Type C and Type M. Type C and Type M are comprised of dibasic calcium phosphate anhydrous (Fujicalin^®) and magnesium aluminometasilicate (Neusilin^®), respectively. Both are commonly used depending on the compatibility and performance with active ingredients. Type C leads to faster disintegration needs, whereas, Type M offers better flowability and improves tablet quality. In acetaminophen ODT formulations comprised of 10%, 20% and 40% drug, the disintegration times of tablets, with each 8 mm in diameter and hardness of 30 N, were within 20 seconds.¹⁵

PHARMABURST^® 500

Comprised of mannitol, crospovidone, croscarmellose sodium, starch and colloidal silica, it has been used in several marketed ODT drugs. It is designed to improve patient compliance, rapid disintegration, and to yield robust tablets with higher drug loading coupled with good mouth feel with disintegration time of < 30 seconds. For example, with 25% and 50% loading of a highly crystalline drug, the hardness varied within 50 N – 100 N but the disintegration (Dt) was within the monograph range of 30 seconds or less.¹⁶

STARLAC^® ODT

A lactose based co-processed excipient contains 15% corn starch as functional binder and disintegrant, and 85% lactose monohydrate as filler, diluent and binder. With its exceptional flowability and binding properties, it can be compressed with a lubricant at lower compression force to yield desired hardness and disintegration time. For example, when compressed to tablet hardnesses of 40 N to 120 N, the disintegration time remains within 30 seconds. On compression with 30% highly crystalline vitamin C. it achieved the fastest disintegration and a complete dissolution within 10 min.¹⁷

GRANFILLER- D™

Comprised of mannitol, MCC, carmellose and crospovidone, it is highly compressible at low compression force due to its higher porosity. When compressed with higher drug loadings as high as 50% of acetaminophen or ibuprofen or 70% ethenzamide, each tablet containing 250 mg of drug, the disintegration time was within 30 sec regardless of tablets hardness which varied between 30 N and 60 N. It also yielded an excellent content uniformity throughout the tableting.¹⁸

Kollmer et al., (2013) evaluated a range of selected ODT excipients including Pearlitol Flash, Ludiflash, Prosolv and F- Melt in tablets comprised of 6% benzocaine and 1.5% magnesium stearate and compressed at 20kN with hardness of 100N. The friability test passed for each tablet, and disintegration times were 68 sec for Pearlitol, 150 sec each for Ludiflash and F-Melt and was 600 sec for Prosolv ODT.¹⁹ On stability at 25ºC/60% RH and under the accelerated conditions (40ºC/75%RH), Perlitol Flash, Ludiflash, and F-Melt ODT tablets were shiny, and showed no degradation of drug as N-formylbenzocaine but Prosolv ODT showed a significant degradation over 6 months, especially at the accelerated conditions, suggesting the fructose in ODT was susceptible to humidity and higher temperature. The critical relative humidity (CRH) of fructose was 64% when stored at 40ºC.

Tayel et al. (2017) evaluated sumatriptan succinate in an ODT formulation comprised of Pharmaburst, Ludiflash, Pearlitol, Prosol ODT, StarLac as sublingual ODTs.²⁰ Other mucoadhesive polymers like HPMC K4M, Carbopol, chitosan, and Polyox were used with aims at improving the residence time in the sublingual area. Pharmaburst showed the disintegration time of <30 seconds with over 83% release in 5 min, the relative bioavailability as compared with marketed Imitrex^® tablet was over 132%, and HPMC was able to prolong the disintegration time to 184 sec and was considered the optimal best optimal for sublingual formulation. This data can be taken to suggest that Pharmaburst can be used for increasing the residence time while maintaining the lower disintegration time. With the understanding that Ludiflash and Prosolv ODT all contain mannitol and crospovidone as compared to Pharmaburst, their rate of hydration was different due to lack of sorbitol, suggesting a rapid hydration for Pharmaburst, caused by equatorial position of hydroxyl groups. In vitro disintegration times of Pharmaburst, Pearlitol Flash and StarLac excipients showed the following order: Pharmaburst < Perlitol Flash < StarLac, meaning the wetting was significantly much greater in Pharmaburst due to higher water absorption uptake of crospovidone.²¹ In a comparative study with carvedilol in Pharmaburst and Ludiflash, the latter did not yield the desired disintegration time of drug in Soluplus^® amorphous dispersion when compressed with ODT excipients, which could be attributed to particle size differences of two crospovidone grades (Kollidon^® CL vs Polyplasdone^® XL) used in the tablets.²²

FDA APPROVED ODT DRUGS

ODT products have been marketed for different indications ranging from migraine to anti-emetic agents, antihistamine and to most serious chronic diseases such as depression and schizophrenia. Table 2 list the ODT drugs approved by FDA.⁶

Click image to enlarge

Although these drugs have tendencies to quickly disintegrate in mouth with saliva, their good creamy mouth feel and physical attributes vary considerably from one to other as some require special packaging in blisters and others as lyophilized powder.²³

STORAGE OF ODT DOSAGES

Storage of the ODTs is important to meet the critical quality attributes of drug products. Moisture protection is required to protect the excipients and API to prolong the shelf life and to maintain the integrity of tablets and/or to avoid unpleasant mouth feel. Excipient manufacturers typically provide guidance for stability and packaging of ODTs. Since the ODTs are not coated, the protection from humidity, atmosphere and heat makes it highly inevitable. For example, mannitol based Ludiflash ODT requires storage at ambient condition at 25ºC or less with dense packaging material to control the humidity and moisture permeation. In a study, stability data showed that disintegration of Ludiflash placebo ODT dosage remains unchanged (< 30 seconds) even on exposure to higher humidity at ambient temperature.⁶ In another study with Ludiflash, containing 2 mg loperamide in an ODT, when stored in closed polyethylene bottle for 12 month under relevant ICH climate conditions, the disintegration time remained constant (< 30 seconds), and was found to be independent of the storage conditions.

CONCLUSION & FUTURE PERSPECTIVES

As more new chemical entities (NCEs) being discovered, the industry is weighing all options for evaluating those molecules in different dosages to improve solubility and oral bioavailability. With requirement for taste-masking of bitter drugs with commercially available ODT excipients, it poses additional challenges for improving taste-masking and performance of molecules for the intended usages. A recent market trend suggests that half of the patient population prefers ODTs over other dosages like regular pills or liquids. Faster absorption in the mucous civility makes ODTs better choice for children and geriatric patients. ODTs offer clinical advantages with reference to safety and improved efficacy for broad range of therapeutic indications. For those advantages, coupled with regulatory and patient compliances, the excipient manufacturers have developed their ODT platforms to serve the industry by expanding the products to formulate the drugs for life cycle management and extend the patent protection.

As more repurpose drugs and new molecules become part of the life cycle management, the regulatory requirements for ODTs could play an important role in drug development with respect to appropriate tablet size and weight, ingredients/components, drug solubility, taste-masking for an intended use to satisfy the patient compliance. For instance, a tablet weight of 300 mg – 500 mg is generally recommended but higher weight ODT dosages can also be justified based on the product performance such as ingredient solubility and stability, and packaging conditions.

Ascendia, with its expertise in cGMP manufacturing of oral and injectable drug products, can help clients interested in solid oral dosage forms (SODFs), and ODTs as well. With its four enabling platform technologies including LipidSol^®, EmulSol^®, NanoSol^® and AmorSol^®, Ascendia can handle the challenging molecules across all modalities in oral tablets and liquids and injectables.

REFERENCES

1. (i) M. Chinwala, Recent formulation advances and therapeutics usefulness of orally disintegrating tablets (ODTs), Pharmacy-MDPI, 2020, 8, 186; (ii) E. A. Yapar, Orally disintegrating tablets: An Overview, J. Applied Pham. Sci., 2014, 4, 118-125.
2. FDA Guidance for Industry Orally Disintegrating Tablets – Center for Drug Evaluation and Research (CDER), December 2008.
3. Persistence market research “Global market study on orally disintegrating tablets.” 2017.
4. S. V. Sastry, J. R. Nyshadham and J. A. Fıx, Recent technological advances in oral drug delivery. A review. Pharm Sci Technol Today, 2000, 3, 138–145.
5. S. Bandari, R. Kumar, R. Mittapalli, and R. Madhusudan, Orodispersible tablet: An overview. Asian Journal of Pharmaceutics, 2008, 2- 10.
6. S. Ali and K. Kolter, A recent advancement in orally disintegrating formulations, Am. Pharm. Rev. 2014, 1-6.
7. H. Seager, Drug-delivery products and Zydis Fast dissolving dosage form. J Pharm Pharmacol, 1998, 50, 375-382.
8. P. Pandey and M. Dahiya, Oral Disintegrating Tablets: A Review, Intern. J. Pharma Res. & Rev., 2016, 5, 50-62.
9. J. E. Aguilar-Díaz, E. García-Montoya, J. M. Suñe-Negre, P. Pérez-Lozano, M. Miñarro, J. R. Ticó, Predicting orally disintegrating tablets formulations of ibuprophen tablets: An application of the new SeDeM-ODT expert system, Eur. J. Pharm. Biopharma, 2012, 80, 2012, 638-648.
10. S. S. Fatima, F. Zafar, H. Ali, F. Raees, G. R. Naqvi, S. Alam, R. Yasmin, A. Tariq, R. Saeed, and S. Khan, Development and characterization of orally disintegrating flurbiprofen tablets using SeDeM-ODT tool, PLOS One, https://doi.org/10.1371/journal.pone.0309894.
11. C. D. Quijano, Orally disintegrating tablet, Tablets & Capsules, 2018 July.
12. Ludiflash® – BASF Technical Brochure, 2016.
13. Perlitol® Flash – Co-processed mannitol starch, Roquette Technical Brochure
14. Prosolv® ODT G2 – JRS Technical Information
15. F-Melt®- Fuji Technical Brochure
16. Pharmaburst® 500- SPI Pharma- Technical Bulletin
17. StarLac®- Meggle Technical Bulletin
18. Granfiller®-D- Daicel- Technical Bulletin
19. M. Köllmer, C. Popescu, P. Manda, L. Zhou and R. A. Gemeinhart, Stability of benzocaine formulated in commercial oral disintegrating tablet platforms, AAPS PharmSciTech, 2013, 14, 1333–1340.
20. S. A. Tayel, M. A. El-Nabarawi, M. M. Amin, and M. H. H. AbouGhaly, Comparative study between different ready to made orally disintegrating platform for the formulation of sumatriptan succinate sublingual tablets, AAAPS PharmSCITech., 2017. 18, 410-423.
21. C. Caramella, F. Ferrari, M. C. Boneferoni, and M. Ronch, Disintegrants in solid dosage forms, Drug Dev Ind. Pharm., 1990, 16, 2561-2577.
22. R. N Shamma and M. Basha, Soluplus®: a novel polymeric solubilizer for optimization of carvedilol solid dispersions: formulation design and effect of method of preparation. Powder Tech., 2013, 237, 406-414.
23. W. R. Pfister and T. K. Ghosh, Orally disintegrating tablets products, technologies, and development issues. Pharm Tech, 2005, 29, 136

Dr. Shaukat Ali joins Ascendia Pharmaceutical Solutions as Senior Director of Scientific Affairs and Technical Marketing after having worked in the pharma industry for many years. His areas of expertise include lipid chemistry, liposomes, lipid nanoparticles, surfactant-based drug delivery systems, SEDDS/SMEDDS, oral and parenteral, topical and transdermal drug delivery, immediate- and controlled-release formulations. He earned his PhD in Organic Chemistry from the City University of New York and carried out his post-doctoral research in Physical Biochemistry at the University of Minnesota and Cornell University. He has published extensively in scientific journals and is inventor/co-inventor of several US and European patents.

Dr. Jim Huang is the Founder and CEO of Ascendia Pharmaceutical Solutions. He earned his PhD in Pharmaceutics from the University of the Sciences in Philadelphia (formerly Philadelphia College of Pharmacy and Sciences) under Joseph B. Schwartz. He has more than 20 years of pharmaceutical experience in preclinical and clinical formulation development, manufacturing, and commercialization of oral and parenteral dosage forms. His research interests are centered on solubility/bioavailability improvement and controlled delivery of poorly water-soluble drugs through nano-based technologies.