Formulating for success with ODTs

An ageing global population, consumer demand for greater convenience and the need to improve patient compliance are driving the development of new platforms for orally disintegrating dosage forms

The convenience and consumer appeal of medications that can be taken “on the go” has led to a rise in the popularity of oral disintegrating tablets (ODTs).

This dosage form has expanded from over-the-counter preparations, such as nutraceuticals and vitamins, into the realm of prescription (Rx) drugs. From a consumer point of view, the availability of a tablet that disintegrates rapidly in saliva and can therefore be taken without water makes ODTs an easy and convenient solution for today’s pressured lifestyle. A pleasant taste and smooth mouthfeel are also crucial to consumer acceptance.

The format is also popular with hospitals and other healthcare providers because it increases patient compliance, particularly among psychiatric, paediatric and geriatric patient populations and those with dysphagia who are unable to swallow conventional solid dosage forms. Offering products that benefit both patients and healthcare providers gives a clear competitive advantage to pharmaceutical manufacturers.

ODTs can also offer improved lifecycle management and an opportunity to create strong brands through innovation and differentiation in a crowded market.

The benefits of ODTs go much further than mere convenience and palatability. In particular, ODTs are suitable for drugs with medium or high potency active pharmaceutical ingredients (APIs); low potency drugs with a high proportion of API do not result in a good ODT.

Furthermore, for some drugs, the orodispersible formulation may result in greater bioavailability through buccal and pregastric absorption, thereby reducing first-pass gastric and liver metabolism.

Market growth will also be driven by the introduction of new manufacturing processes. Spritam (levetiracetem), the first orally dispersible tablet produced by 3D printing, has been approved by the US FDA; this technology opens the way to personalised drug delivery, tailoring treatments to suit individual patients.

Furthermore, the increased popularity of ODTs on the market has been the main driver behind the creation of ready-to-use platforms by the excipients industry. The challenge for manufacturers is to create a tablet that will satisfy the requirement for fast disintegration but, at the same time, have the mechanical properties that enable it to be produced efficiently.

Preferred properties

The need for prompt disintegration is met by formulating the ODT with mannitol, one of the only water-soluble excipients that delays water adsorption. During this delay, saliva is able to enter the porous structure, and disintegrants or superdisintegrants act immediately.

Furthermore, mannitol is non-hygroscopic and protects the stability of the active ingredients. The consumer requirement for palatability and a pleasant mouthfeel also works in favour of mannitol, which has a mild, natural sweet taste and cooling effect in the mouth.

Other diluents may have a less acceptable mouthfeel; they are also known to contain reactive groups and impurities that can reduce the shelf-life of ODT formulations.

There are a variety of methods that can be used to manufacture ODTs, including freeze-drying, spray-drying, direct compression, moulding sublimation and mass extrusion. However, direct compression is the method that is most cost-effective and easy to do using standard equipment, producing a tablet that combines the targeted rapid disintegration and meets pharmaceutical friability requirements.

The main challenge in ODT formulation is to find the excipients that offer the right balance between disintegration time, friability, API stability and mouthfeel.

To meet these requirements, a number of companies have developed ready-to-use ODT platforms by coprocessing the filler, usually mannitol, with a superdisintegrant. Although these excipients offer fast disintegration, they also contain traces of the reagents used in their synthesis that can lead to drug degradation. Furthermore, at the levels of inclusion needed for rapid oral disintegration, their taste and texture can make them unpleasant to consumers.

A new excipient

Roquette is the world’s leading producer of mannitol for pharmaceutical applications and has developed PEARLITOL Flash, a patented compound that offers the compactability, friability and disintegration properties required to manufacture optimal ODTs.

The Japanese Pharmacopeia (JPE) has recently published the monograph, “D-Mannitol and Corn Starch Granules,” describing PEARLITOL Flash.1 The listing of PEARLITOL Flash in JPE is significant: it means it is now recognised by the Ministry of Health, Labor and Welfare (MHLW) as an acceptable ingredient in medicine for the Japanese market in tablet formulation.

Pharmaceutical companies prefer to use excipients that are compliant with the main regional pharmacopeias whenever possible because it can speed up formulation registration. The superior wettability of PEARLITOL Flash compared with other platforms results in rapid self-disintegration without the need to add a superdisintegrant.

Mannitol used in conventional ODT formulations requires a porous tablet structure to achieve the required disintegration times whereas the disintegration time of PEARLITOL Flash is independent of the tablet’s porosity.

The excipient has a simple composition based on mannitol and maize starch for direct compression, achieves good flow properties and requires only a low level of lubricant (0.4% magnesium stearate). It melts in the mouth in seconds and has a smooth, creamy mouthfeel with a sweet taste.

The use of native starch, which is neutral and requires no reagent, offers taste and stability advantages compared with the use of a superdisintegrant.

A 2013 paper examined whether four commercially available ODT platforms, including PEARLITOL Flash, induce the degradation of APIs under standard and accelerated conditions.2 Benzocaine was selected as the model API because of its known degradation through ester and primary amino groups.

The ODTs were formulated with 6% benzocaine, 1.5% magnesium stearate and 92.5% of the respective ODT platform and were investigated under ICH conditions at 25 °C and 60% relative humidity (RH) and 40 °C and 75% RH for up to 6 months.

No degradation was observed in the tablets exposed to subtropical conditions (25 °C and 60% RH) but, under accelerated degradation conditions, benzocaine decomposition was identified in the tablets made using an ODT platform containing microcrystalline cellulose, colloidal silicon dioxide, fructose and crospovidone, in addition to mannitol.

The researchers felt that the silicified MCC and crospovidone in the platform could be potential sources of organic acid and aldehyde impurities, which caused the degradation.

Although degradation of the API was detected in only one of the four ODT platforms, the physical appearance of the tablets varied greatly, especially under accelerated conditions. Mannitol is not hygroscopic and does not absorb water even under accelerated conditions, and the shape changes in the tablets were attributed to the propensity of the disintegrants to absorb water — as observed with crospovidone.

Tablets made with three of the platforms maintained a shiny and relatively smooth surface for the 6-month period under subtropical conditions (25 °C/60% RH). However, after storage under accelerated stability conditions (40 °C/75% RH) the tablets made using PEARLITOL Flash were the only ones to maintain a satisfactory aesthetic appearance, the research found.

It is clear that the ODT platform plays a significant role in the success of the formulation. Making the wrong choice can compromise the stability of the API and reduce the shelf-life of the medicine.

References

  1. Japanese Pharmacopeia, “D-Mannitol and Corn Starch Granules,” 704–706 (30 March 2018): http://jpdb.nihs.go.jp/jp17e.
  2. M. Köllmer, et al., “Stability of Benzocaine Formulated in Commercial Oral Disintegrating Tablet Platforms,” AAPS PharmSciTech 14(4), 1333–1334 (2013).

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