Formulating for Convenience and Compliance

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Today, FDA expects drug formulators to not only consider patients outcomes when developing new products, but to also focus on the overall patient experience. Four main factors address the patient experience, according to Sarath Chandar, chief science officer with SPI Pharma: convenience, compliance, safety, and efficacy. Orally disintegrating tablets (ODTs) and other fast-dissolving oral dosage forms address the first two factors-and to some extent efficacy as well- from the standpoint of sublingual delivery, which can lead to increased bioavailability for poorly soluble APIs.

Convenience is increased with ODTs and fast-dissolving products across all patient populations. “Pediatric patients benefit from this group of products because they dissolve faster than what they are able to spit-out and can also be mixed with foods for easy administration. These products can also be taken without water, so they are also amenable for adults on the go,” says Krizia Karry, global technical marketing manager at BASF Pharma Solutions.

The fact that ODTs do not need to be washed down with water provide additional benefits as well. ODTs are, for instance, attractive to those who do not want to swallow liquids or hard tablets because they are feeling nauseous, adds Ralph Gosden, head of product development at Catalent Swindon. They are also useful when there is a need for rapid drug release, such as to relieve a headache, according to Torkel Gren, science and technology officer for Recipharm. “Orally disintegrating products are an ideal platform for delivery of active ingredients for the treatment of pain, allergies, diarrhea, Parkinson’s disease, travel-related illness, and other indications where rapid dosing and absorption is required,” he observes.

In addition, ODTs can help patients who have an aversion to swallowing a tablet or capsule, and those who find it extremely difficult to take standard tablets because they may have dysphagia or other problems with swallowing (e.g., the elderly and infirm), Gosden notes. “Patients suffering from mental impairments can benefit as well,” he adds, “as they will sometimes deliberately avoid taking medications or pretend to have swallowed a standard tablet or capsule by hiding it in their mouth to spit out later-a practice referred to as ‘cheeking’. This tactic is nearly impossible with an ODT as it disintegrates quickly and completely.”

Other benefits of orally disintegrating products in some cases are higher bioavailability and the fact that faster drug uptake can be achieved, according to Gren. “Instantaneous disintegration allows the drug to be dissolved and absorbed more rapidly, and for drugs that can be absorbed via the mucous membranes within the oral cavity, it can help to avoid the harsh environment within the gastrointestinal tract and bypass first-pass metabolism by the liver.”

Films, granules, and tablets

Orally dissolving products include tablets, granules, and films. “For tablets, the most common manufacturing technology is direct compression into tablets or minitablets,” Karry asserts. The use of 3D printing is also being explored for the production of ODTs, Gosden notes. “Granules are mostly produced via fluid bed granulation/drying and twin-screw granulation to ensure adequate size control. On the other hand, films are cast and dried on moving Teflon membranes from solutions or suspensions of APIs and soluble polymers,” Karry comments. More advanced technologies are often protected by patents, which may restrict competition, according to Gren. “In addition,” he stresses, “a more complex technology should not be used if it does not result in significantly better product properties.”

Thin film strips are a delivery technology that can be used for both systemic and local delivery by oral, buccal, and sublingual routes, according to Gosden. “Although they dissolve rapidly in the mouth and are considered self-administrable, the application of thin-film strips is somewhat limited as the maximum dose that can be formulated for delivery via the digestive tract is only in the 20–50 mg range,” he says.

In addition, Chandar adds that FDA has not approved many thin-film products for pharmaceutical applications because the strips can stick together, resulting in the patient taking multiple doses at once. This challenge has been addressed by individually packaging the oral strips, according to Karry.

The distinguishing properties between orally dissolving products are the form factor and drug delivery methods (e.g., sublingual, buccal, oral, etc.). “The form is selected taking into consideration the target population and the API solubility. For example, a drug dissolved in a polymeric matrix in the form of a fast-dissolving film may avoid first-pass effects through buccal drug delivery and thus show higher bioavailability due to the design of the drug product,” Karry says.

Several distinguishing features

To be successful, orally disintegrating formulations must have certain features. The most important property is rapid-within 30 seconds or less-disintegration or dissolution in the oral cavity with or without water, according to Chandar. Because they are placed in the mouth, they also ideally should have a pleasant mouth feel that is creamy rather than chalky. An attractive taste is also ideal, which requires taste masking if the API is bitter, which many are.

Excipients: The most important component

Excipients are the most important part of orally disintegrating/fast-dissolving products, according to Karry, because they ensure good sensory properties and adequate technical performance. “When developing conventional tablets, the drug developer will focus on a limited number of characteristics that are easy to measure quantitatively, such as hardness, friability, disintegration, and in-vitro dissolution. When working with ODTs, several parameters that are difficult to measure are affected by the excipient,” Gren explains.

“Examples include creating a clean mouth feeling, or creaminess and overall good palatability, as opposed to grittiness and lingering bad flavors, all the while leading to tablets with high tensile strength, low friability, and fast disintegration,” Karry says. She also points out that the interplay between tensile strength and disintegration is particularly important, because the stronger the tablet, the lower its porosity and the slower it disintegrates. “In this case, having both an efficient binder and a super-disintegrant is necessary for good performance of the drug product,” she comments.

Compressed tablets require super-disintegrants, which either swell or wick up saliva, disrupting the tablet’s structure and encouraging dispersion, according to Gosden. Other important excipients include binders and fillers, according to Karry. Numerous other excipients can also be added to impart specific properties, such as lubricants, sweeteners, colors, and flavorings. “However,” Gosden notes, “some of the additional ingredients that may be required to manufacture the tablet can impede its disintegration. For example, if high levels of lubricant are necessary, the particle size must be carefully considered. If the particle size is too large, then the tablet may give a gritty and unpleasant mouthfeel as it disperses.”

Certain excipients also enhance the bioavailability of poorly soluble APIs (e.g., Biopharmaceuticals Classification System [BCS] II and IV) by helping to increase the dissolution rate, according to Chandar.

Selecting the right excipients

The type and amount of excipient needs to be carefully selected in order to get the right balance between a number of technical characteristics, including stability, flavor, and mouthfeel, Gren comments. It is particularly important to choose the right filler(s), he says, because the filler is often present in large quantities and has a significant impact on the taste and mouthfeel of the product. “A judicious use of quality-by-design and multivariate methods are helpful here,” notes Gren.

Some excipients found in orally dissolving products such as sweeteners and flavoring agents are not normally used in conventional tablets, according to Gren. “Here it is extremely important to work in close collaboration with the marketing professionals when selecting the type and amount of all excipients, but especially the flavoring agents. The taste of the product should be developed in order to suit the intended patient population,” he says. “In my experience, sugar alcohols, mannitol in particular, are extremely useful in orally disintegrating products; they provide sweetness and pleasant mouthfeel and also have relatively favorable technical properties,” Gren observes.

The most important excipients are those that ensure adequate technical and sensorial performance, notes Karry. She lists binders to give strength to the formulation, super-disintegrants to ensure fast hydration and disintegration, taste-masking polymers to decrease the interaction between the bitter or acidic drugs and tongue receptors, and flavors, which are used as needed based on the target population and to stimulate saliva secretion. Strawberry and apple flavors stimulate more saliva than cinnamon, for example.

“The absolute most important excipient for these products, in my opinion, are disintegrants,” Karry says. “As a patient, I can accept having a bad tasting medicine-there are many out there already-but what I cannot accept is having a bad taste in my mouth for minutes or hours. Disintegrants help to ensure this does not happen. They enable complete drug product disintegration in the mouth so that the small particles can be swallowed, and if designed right, they clean our mouth as well,” she explains.

Karry notes that studies have shown that both particle size and shape play an important role in mouthfeel. Hard irregular particles are perceived as larger than soft and smooth particles (1), while particles of 100 µm in size are perceived as creamy or fatty and thus activate salivary secretions and swallowing (2). “These studies demonstrate that a systematic science-based approach is needed when formulating orally disintegrating products,” Karry concludes.

For lyophilized ODTs, Gosden says the most critical excipients are those that form the porous structure, specifically gelatin and mannitol. “While the freeze-drying process is under way, it is important to ensure that all of the mannitol remains crystalline, or there will be a risk that the finished dosage form will collapse during storage,” he explains.

Chandar notes that for poorly soluble APIs, surfactants and plasticizers are used for bioavailability enhancement. He stresses, though, that no excipient should be used unless there is a demonstrated need and each ingredient in an ODT formulation should be justified.

It is also worth noting, according to Gosden, that some excipient suppliers have developed proprietary blends of excipients in ready-to-use form (i.e., co-processed excipients) for the creation of compressed ODTs.

Synergies with co-processing

Co-processed excipients based on microcrystalline cellulose (Prosolv ODT from JRS Pharma) and mannitol (Ludiflash from BASF and Pharmaburst from SPI Pharma) have been increasingly used in orally disintegrating/fast-dissolving products owing to their ease of use and overall particle characteristics, according to Karry. “In particular,” she observes, “those containing mannitol have the advantage that this alcohol sugar has a negative heat of solution and upon dissolving in the mouth imparts a cooling effect with a sweet taste. Mannitol is also amenable for ketogenic diets (important for epileptic patients) and diabetics (due to the low carbohydrate count).”

Co-processing, unlike simple blending or mixing, of different excipients, enables the enhancement of functional performance, according to Chandar. “Whether via spray drying, granulation, congealing, or other methods, co-processing-when done effectively-creates synergies between the excipients involved, leading to unique properties and functionality not achievable any other way,” he states.

As an example, Chandar points to SPI Pharma’s latest addition to the Pharmaburst line (500), in which the excipients are subjected to a three-step process that includes spray drying and granulation. “The result is a microplate structure of the combined excipients that exhibits a 30–40% improvement in compactability compared to simple, physical mixing. This higher compactability opens up a broader design space for formulating robust ODTs by providing a much higher API carrying capacity of up to 500–600 mg,” he remarks.

Other important advances

Catalent has developed Zydis Ultra, a next-generation ODT technology that provides better taste-masking properties in a lyophilized ODT combined with an increased drug loading capacity, according to Gosden. A coating is applied to the outside of micronized API particles (as small as 100 µm in diameter) using a dry-coating process.

“Gelatin forms the overall polymeric structure of the tablet, while mannitol increases robustness and makes the tablet look aesthetically elegant. Both ingredients dissolve readily in saliva, giving a quick-acting, melt-in-the-mouth experience for the patient,” Gosden says. In addition, he observes that unlike compressed ODTs, they are not reliant on the use of super-disintegrants to provide rapid dispersion. Instead, the rapid disintegration results from the way in which lyophilized ODTs are manufactured as well as the formulation of excipients.

BASF, meanwhile, has developed Kollidon CL-SF, a superfine disintegrant with unique properties for ODTs, according to Karry. “This super-fine version of crospovidone was specifically designed to provide formulators a disintegrant that generates upon hydration smooth particles that are less than 100 µm for a non-gritty, melt-in-your-mouth feeling,” she explains.

Separately, Karry notes that many companies in South America and Europe are moving to twin-screw granulation methods for manufacturing fast-disintegrating granules. “Twin screw allows for better control of granule size and is easily converted and integrated into continuous manufacturing processes,” she says.

Regardless of the technology, the advantageous properties of new and more advanced excipients should be balanced against the higher costs that are often associated with them, asserts Gren. “For example,” he comments, “a more expensive excipient may allow you to avoid complex process steps and hence reduce manufacturing costs. As a result, the overall costs must be considered.”

Compatibility and flexibility are important

As with any formulation, one of the biggest challenges to developing orally disintegrating/fast-dissolving products is ensuring API-excipient compatibility. “Even though the majority of the excipients are pharmacologically inert, sometimes physical and chemical interactions between the API and excipients can occur that affect the stability, safety, and efficacy of the drug,” Gosden explains.

For fixed-dose combinations involving two or more APIs, the question of whether the APIs are chemically compatible or prone to interact when combined must also be considered. Catalent addresses this issue when using its Zydis technology by using two or more homogenous formulations that are dosed sequentially under different conditions prior to freeze-drying. “This approach addresses issues of incompatible APIs/excipients and temperature-sensitive APIs,” says Gosden.

ODT formulators should also prioritize exploring the relationship between tensile strength, friability, and disintegration, according to Karry. “Tensile strength is lower for ODTs compared to regular tablets due to fact that you need higher porosity for solvent uptake and core hydration. Similarly, disintegration tests are decent in-vitro predictors of palatability as patients prefer dosage forms that do not linger in their mouth for too long,” she adds.

Given the wide range of APIs and the drive to develop more patient-centric formulations including orally disintegrating fast-dissolving products, it is also important for formulators to have access to broadly flexible platform technologies that can be used for multiple drugs, Chandar asserts. “An antiretroviral drug may require a very high dose, while a cardiovascular therapy may need minimal loading. A universal excipient platform that can be used for both types of formulations and generate robust tablets that don’t apart when the patient opens the package dramatically simplifies the process,” he comments.

Chandar goes on to note that excipient technologies that provide rapid dissolution and can also aid in enhancing bioavailability are particularly attractive given than nearly 75% of pipeline candidates fall in BCS Class II or IV. In addition, ODT excipient technologies if designed appropriately may even be able to facilitate the oral delivery of some smaller biologic drugs- notably peptides-by enabling sublingual dosage forms that dissolve under the tongue in just five seconds, avoiding first-pass metabolism in the liver.

References

1. L. Engelen, et. al. J. Texture Studies, online doi.org/10.1111/j.1745-4603.2005.00022.x. (Sept. 19, 2005),
2. J. R. Stokes, M. W. Boehm, and S. K. Baier, Current Opinion in Colloid Science, 18(4), 349–359 (August 2013).

Article Details

Pharmaceutical Technology
Vol. 44, No. 6
June 2020
Pages: 20–23, 60

Citation

When referring to this article, please cite it as C. Challener, “Formulating for Convenience and Compliance," Pharmaceutical Technology 44 (6) 2020.