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Industry experts discuss key considerations in the development of orally disintegrating tablets.
Orally disintegrating tablets (ODTs) are designed to dissolve in the mouth within seconds without the need for water. Because of this convenience and ease of administration, ODTs have gained recognition as one of the most user-friendly oral dosage forms. “For people with an aversion to, or fear of, swallowing tablets, ODTs present an acceptable method of drug delivery that not only aids compliance but also greatly reduces the risk of choking,” says Mathias Bayru, group product manager, Catalent Advanced Delivery Technologies. Moreover, because of the quick dissolution, one can be sure that the medicine has been taken, which is a clear advantage for children, the elderly, and patients with mental disorders, adds Philippe Lefevre, global technical application specialist at Roquette. Bayru concurs that ODTs reduce the risk of patients successfully disguising swallowing by hiding the medication in their mouth and removing it later--a practice known as “cheeking.”
ODTs are stable formulations with good shelf lives, according to Rosie McLaughlin, director of scientific affairs, Zydis, Catalent Pharma Solutions. “They do not require refrigerated storage, making the products easy to store and transport,” she says. For pharmaceutical companies, ODTs can be part of a lifecycle management strategy, Lefevre highlights. ODTs are innovative dosage forms that can also be used to create new brands and product differentiation.
“Today, the most promising development of ODTs is in the pediatric field,” says Lefevre. Orodispersible minitablets (ODMTs), which have a maximum diameter of 3 mm, are currently one of the most studied pediatric dosage forms, he notes. Studies have shown that ODMTs are well adapted and well accepted by children. “For newborns, ODMTs can be dispersed in water prior to use,” explains Lefevre, “whereas for children who are six months old and above, ODMTs can be taken in single or multiple units based on the child’s weight and age.”
Pharmaceutical Technology spoke to industry experts from Roquette and Catalent about the development of ODTs.
PharmTech: What drugs are suitable candidates for formulation into an ODT?
Lefevre (Roquette): An obvious answer is drugs that people want to take immediately wherever they are and drugs targeting patients for which ODTs or ODMTs are considered useful. Unfortunately, there are technical restrictions on the type of drugs that can be concretely formulated into ODTs. Due to the specificity of the oral tablet, some constraints on drug taste and drug dosage are inevitable. Bad taste is the first hurdle to ODT development because the quick disintegration in the mouth intensifies the disagreeable taste feeling by the patient, but there are various taste-masking strategies available to tackle this challenge, such as encapsulation or molecular inclusion in cyclodextrins.
The ideal candidate for ODTs would be a drug with low dosage and neutral taste, with no side effects. Highly potent APIs (i.e., those with a low dosage in the final form) are easier to formulate as ODTs. The API will have less effect on the physical properties of the tablets.
Bayru (Catalent): ODTs are most suited for drugs that require rapid onset of action, such as pain management, allergy relief, and treatments for diarrhea and constipation. Formulations targeted at specific population groups are also typical candidates for ODTs, such as those with pediatric or geriatric applications, as well as anti-psychotics where ODTs can help overcome swallowing issues, and indeed resistance to swallowing.
PharmTech: What are the ideal characteristics of ODTs?
Bayru (Catalent): Typically, the characteristics would be a tablet weight below 500 mg with physical and chemical stability. Other ideal characteristics include disintegration of the tablet in less than 30 seconds with no adverse taste or residual texture in the mouth and no throat burn.
Lefevre (Roquette): A short disintegration time in the mouth is an essential prerequisite for ODTs, but patients will also appreciate pleasant taste and texture--these two characteristics will play a key role in keeping a patient loyal to a particular brand.
There is an optimum speed of disintegration. Disintegrations that are too quick are often associated with total drying of the mouth, which may create discomfort to the patient, or a suffocating feel. The important thing to remember is that ODTs have to be formulated to avoid any need for drinking water. The best sensation for the patient is when the disintegration starts quickly and ideally lasts 30 seconds or a maximum of 45 seconds.
After disintegration, the optimal texture is one that gives the patient a feeling that the tablet has turned into syrup. Soluble excipients have to dissolve quickly after tablet disintegration and the insoluble ingredients have to be as small as possible to avoid a sandy feeling in the mouth. Finally, ODTs must have a sweet and pleasant taste.
PharmTech: What are the excipients used in ODTs?
Lefevre (Roquette): The main challenge in developing ODT formulations is achieving a short disintegration time upon contact with saliva. This specific property of ODTs requires specific excipients compared with other oral tablets.
The first, and perhaps inevitable, excipient in ODTs is mannitol. Mannitol has a unique behavior--although it is soluble, it presents a delay of dissolution when in contact with saliva. This property is essential because it maximizes the action of disintegrants and gives access to short disintegration time. In the first few seconds, mannitol does not interact with water, so all the water (from the saliva) is available for the action of the disintegrant, which can be a super-disintegrant or a starch. Mannitol then dissolves slowly and gives a pleasant taste as well as other properties such as sweetness, a cooling effect, and palatability.
The second excipient is the super-disintegrant. For standard to large tablets, crosspovidone is the first choice because its action requires the smallest amount of water. For small ODTs, all super-disintegrants can be used.
To simplify and accelerate the development of ODTs, formulators may benefit from compounds that combine mannitol and a super-disintegrant or compounds that combine mannitol and starch. The composition of these compounds, however, has been optimized to address ODT formulation challenges. For example, when using a super-disintegrant, short disintegration time requires high tablet porosity and consequently low tablet hardness. Pearlitol Flash, which is made of mannitol and starch, has been developed to solve this disintegration/hardness antagonism. This compound gives fast oral disintegration time independently of the hardness of the tablet, and ODT friability is no longer a concern. Formulators will also benefit from the neutral taste of starch in comparison to super-disintegrants. Pearlitol Flash is designed to facilitate optimization of the organoleptic properties of ODTs.
McLaughlin (Catalent): The two major categories of ODTs are loosely compressed ODTs and lyophilized ODTs. For loosely compressed tablets, there are three main functional ingredients that help achieve rapid disintegration--super-disintegrants; effervescent agents; and highly water-soluble materials, either alone or in combination. Examples of super-disintegrants include croscarmellose sodium, crospovidone, and sodium starch glycolate. On exposure to water (i.e., saliva), the super-disintegrants either swell or ‘wick up’ the liquid, thus disrupting the tablet and aiding dispersion. Effervescent agents include, for example, sodium bicarbonate in combination with an organic acid such as citric or tartaric acid. On contact with water, the materials will effervesce and disrupt the tablet, aiding disintegration. Soluble agents include, for example, mannitol or xylitol, and their solubility contributes to the overall disintegration of the tablet.
There are some commercially available blended excipients that are ‘ready to use’ for loosely compressed ODTs, for example, BASF’s Ludiflash (a mixture of mannitol, crospovidone, and polyvinyl acetate) and Fuji’s F-MELT (a combination of inorganic excipients and disintegrants in a carbohydrate complex). In addition to these functional excipients that aid disintegration, other excipients related to the direct compression process, such as binder, lubricant, or fillers may also be used, as well as flavors, sweeteners, and colors.
Lyophilized ODTs such as Catalent’s Zydis technology do not rely on super-disintegrants to achieve rapid dispersion. Instead, the rapid-disintegration properties are related to both the formulation excipients and the manufacturing process. In the case of Zydis technology, gelatin is used as the polymeric structure-former in combination with mannitol to provide increased robustness and an elegant appearance. Both gelatin and mannitol will readily dissolve in saliva, contributing to the rapid disintegration and ‘melt-in-the-mouth’ experience. The structure imparted to ODTs manufactured by lyophilization is also a key component in achieving rapid disintegration. During lyophilization, ice crystals are sublimed to leave behind a multitude of air pockets within the ODT’s structure when it is freeze-dried. This approach results in a highly porous structure that ‘wicks up’ saliva and assists disintegration of the tablet.
During the freeze-drying process, it is important to ensure that all of the mannitol is crystalline in the finished product, so as to prevent collapse during storage. Freezing conditions are also critical because too rapid freezing will lead to the build-up of small ice crystals, thus reducing porosity and disintegration.
From a processing perspective, the key parameter for loosely compressed ODTs is compression force. Too low a compression force may improve disintegration but lead to a very friable product that is not robust when handled. Conversely, a higher compression force will result in a more robust ODT but at the cost of disintegration. In this respect, the use of compressible excipients is also a key consideration.
PharmTech: Can you describe the different technologies used to produce ODTs and how they compare with each other?
Bayru (Catalent): The two most common forms of ODTs are produced by lyophilization, which Catalent uses for its Zydis formulations, and low compaction or loose compression (as discussed in the previous section). There are also molded forms of ODT and, more recently, printed ODTs have appeared.
There are variations in molding techniques, but the principle is that the drug/excipient blend is moistened with a solvent (usually water or ethanol) and then molded into a tablet (usually by low compression). There is then a heat- or air- treatment step to remove excess solvent and/or promote solid-state excipient phase-transformation, thus increasing tablet hardness. A new technology to the market alongside these three approaches is 3D printing, and there is one ODT currently on the market that uses this technique--Aprecia’s ZipDose technology.
Lefevre (Roquette): Today, the majority of ODTs are made by direct compression. Wet granulation is commonly used in Japan where there is a history of sophisticated ODTs made using that process. Processes using a melting step have been developed to produce new textures that reach short disintegration times. But this approach adds complexity to the manufacturing of ODTs and creates some concerns about long-time stability. Such heating processes generate amorphous or unstable crystalline forms of ingredients--drugs or excipients--that could potentially evolve over time.
Among all the processes used to make ODTs, freeze-drying is the most efficient with regard to the disintegration properties of the final product. ‘Lyocs’ have high porosity compared to tablets obtained by tableting, and this porosity enables the high speed of saliva adsorption and the quick collapse of the dosage form on the tongue. Nevertheless, the development of lyocs has been constrained by the high cost of production.
PharmTech: What advances have you seen in the development and manufacture of ODT formulations? What areas are still lacking?
Lefevre (Roquette): In the past years, directly compressible compounds specifically developed for that application have demonstrated real benefits in the formulation of ODTs. Mannitol/disintegrant (super-disintegrant or starch) compounds ease the formulation and manufacturing of ODTs with regards to tablet cohesion and disintegration. They also help to improve taste and texture. Nonetheless, drugs having a bad taste are still a problem when formulating an ODT. This issue is, in fact, the most common cause of failure in the development of an ODT. Any solution to this problem will be appreciated, whether it is based on the improvement of existing systems such as film- or lipid-coating, or new approaches involving the use of specific additives that modify taste perception.
During ODT formulation, disintegration times are measured using the standard disintegration tests recommended in pharmacopeias. Studies have demonstrated that there is no correlation between this in-vitro test (using 800 mL of water) and the effective in-vivo disintegration in the mouth with only a few mL of saliva. Specific in-vitro tests have been described and evaluated. Having a real predictive and validated in-vitro test will simplify and accelerate excipient selection in formulation development.
McLaughlin (Catalent): In the case of loosely compressed ODTs, excipients have been developed that are especially designed for this type of dose form, for example, highly compressible excipients and excipient-blends to aid disintegration, such as Ludiflash and F-MELT. There have been several advances in the application of lyophilized ODTs, for example:
Thin film strips have been positioned as alternatives to the more established ODT, but still have limited applicability due to a maximum dose load of between 20-50 mg of API.
Vol. 40, No. 8
When referring to this article, please cite as A. Siew, "A Case for Orally Disintegrating Tablets," Pharmaceutical Technology 40 (8) 2016.