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The level of tastemasking required will depend on the API properties and the dosage form design.
Coating is one of the approaches used to mask the taste of bitter drugs. Coating for tastemasking purposes is a well-established technology used throughout various dosage forms, observes Felix Hofmann, technical sales manager, Evonik. “It ensures a reliable outcome of the manufacturing process, and has obvious advantages, such as short processing times, easy application, and straightforward upscaling on standard equipment,” he says. “Safe tastemasking properties can be achieved by covering the entire surface of the dosage form by a polymer film so that direct contact of the bitter substance with the taste receptors on the tongue is prevented.”
“From the patient’s view, coating not only masks bad taste and odors, but also makes the tablet easier to swallow and aids in recognition and differentiation between tablets, thus reducing the potential risk of medication errors,” Dr. Ali Rajabi-Siahboomi, vice-president and chief scientific officer, Colorcon, highlights. He notes that the coating also increases the mechanical strength of tablets and, therefore, reduces friability, breakages, or dusting associated with uncoated tablets.
“The selection of a tastemasking method is often dictated by the API’s physicochemical properties and taste profile,” explains Rajabi-Siahboomi. Hofmann adds that other characteristics such as drug load, shelf-life, the desired dosage form, and field of application also play a crucial role in selecting the appropriate tastemasking technology.
“There are various options available for consideration, such as the use of flavors and sweeteners, the application of barrier membrane coatings on drug particles, and the use of ion exchange resins-all of which can be applied individually or in combination to overcome the undesirable taste of an API,” says Rajabi-Siahboomi. “While these options exist, coating of tablets and multiparticulates, remains the simplest and preferred method for tastemasking of bitter APIs for many reasons, including ease of manufacturing, accurate dose administration, good product stability, convenience, good patient acceptability, and it delivers improved patience experience.”
Hofmann concurs that for single- and multiple-unit dosage forms, coating is generally considered the preferred tastemasking approach because of its specific benefits. “Overall, if the dosage form has a smooth surface that allows proper coating, we would certainly go for it,” he says. He also points out that film coatings for tastemasking purposes can even be applied for liquid dosage forms. “Usually, they are prepared as dry syrups that are going to be reconstituted before administration,” he explains. “Of course, in such set up, the shelf life of the ready-to-use dosage form is limited by potential diffusion of the active ingredient through the film as compared to solid drug products.”
A crucial consideration for formulators, according to Rajabi-Siahboomi, is to determine the level of tastemasking required, which depends on the API properties and the dosage form design. “In some cases, the API is only slightly bitter and may be masked with flavors and sweeteners. In other cases, the API has a very bitter taste requiring additional tastemasking techniques,” he says. “In general, for tablets that are swallowed whole by the patient, an immediate-release film coating is sufficient to mask an unpleasant taste of API, but it may not mask the unpleasant odor of the drug. With bitter APIs, however, even a small amount of exposure is sufficient to give the patient a poor experience. In these cases, formulators should consider using a barrier membrane film coating as their first choice to taste-mask the drug particles or granules,” he explains.
Various barrier membrane coating options are available. Rajabi-Siahboomi cites the example of the active substance, raltegravir, which has an intensely bitter taste and hence, tastemasking was seen as an essential part of the development program. “Several tastemasking options were evaluated by coating the raltegravir granules prior to processing into the final dosage form,” he says. “The chosen option was to use a coating comprised of an aqueous ethylcellulose dispersion in combination with a hypromellose-based film-coating system. Insoluble in water, ethylcellulose acts as the tastemasking agent by delaying the release of the drug in the mouth, while hypromellose is used as a pore-former in the coating, which allows immediate release of the drug once in the stomach.”
Rajabi-Siahboomi highlights that the dosage strength will also dictate whether a specific tastemasking formulation strategy is suitable. “Low-dose APIs are easier to mask, while high-dose APIs may be challenging because more material (with a greater surface area) needs to be coated,” he says, noting that this is especially true for formulations with fast-dissolving bases, which may leave the patient with coated drug particles in the mouth for a longer time.
As a production technique, coating typically has gentle processing conditions, with rather low temperature and energy intake, observes Hofmann. Nonetheless, he points out that careful adjustment of the process humidity and temperature must be considered for moisture- and/or temperature-sensitive drugs. “Solvent-based coatings can be applied for moisture-sensitive active if the parameter control strategy for aqueous processing fails,” he says. “Formulation adaptations might be required for free acidic or basic drug substances to circumvent ionic interactions depending on the coating polymer choice.”
For particle coating, Hofmann notes that particle size, morphology, flowability, and solubility of the active ingredient can have an impact on the overall processability. “Pre-treatment strategies such as granulation might be necessary for acceptable process performance and overall process time,” he explains. “In this respect, coating of tablets is generally less complex as the surface is well-defined and the drug substance is generally diluted with tableting excipients. Moreover, tastemasking of tablets can be considered less challenging compared with multiparticulate systems due to their shorter residence time in the mouth cavity.”
Different types of polymers are used in coating applications for tastemasking purposes. “Polymers can be clustered in natural and synthetic origin,” says Hofmann. “Among the natural-based polymers, cellulosics such as hydroxypropyl methylcellulose (HPMC) are often used for tastemasking applications. Typical characteristics of these polymers are the highly viscous spraying suspensions they produce, resulting in high spraying pressures, high product bed temperatures during spraying processes, and limited tastemasking capabilities due to their solubility in the saliva. Because of these limitations, poly (meth)acrylate-based coatings have become more popular recently.” Hofmann highlights that the (meth)acrylic copolymers can be applied as a low-viscous spraying suspension with low atomizing air pressures and low product temperatures. “The resulting films will stay intact at high pH values in the saliva resulting in superior tastemasking properties even if particles may stay in the mouth for a while,” he says. “The coating dissolves rapidly in the acidic conditions of the stomach and, therefore, has no impact on bioavailability of the drug.”
According to Andrea Vescovi, head of Global Technical Marketing Pharma Solutions, BASF, using pH-dependent polymers that are insoluble in the neutral pH of the mouth, but soluble in a pH range between 1 to 5 in the stomach where the coating immediately releases the API, is an efficient way of tastemasking. “In this case, the pH at which the respective polymer dissolves is an important factor because it determines the release of the API,” he explains. “Additionally, when coating a tablet with polymers that dissolve at a lower pH range, the residence time in the stomach needs to be regarded to allow the film to dissolve and subsequently release the API.” Rajabi-Siahboomi, however, cautions that there are some concerns around the potential failure of the system to release the drug if the pH of the stomach is elevated due to a patient taking other medications (such as proton pump inhibitors), or the presence of food in the stomach, affecting its bioavailability.
Even so, Vescovi believes that this effect can be minimized by using innovative polymers with wider pH-dependent solubility range (pH 1–5). He adds that besides addressing tastemasking challenges, polymers also offer the opportunity to provide additional functionality such as different release profiles or moisture protection.
The quality-by-design (QbD) considerations for tablet coating is well established, notes Rajabi-Siahboomi. “The working design space identified for immediate release coating formulations also apply for tastemasking,” he says, but adds that film-coating formulations and processing of particles and granules for tastemasking are more complex. “Having said this, as the particle size of drug particles or granules increases, and their distribution becomes narrower, the level of complexity and difficulty to coat them decreases significantly.”
As for coating formulations, it is important to consider choice and level of polymers, in addition to processing aids used for the coating process, observes Rajabi-Siahboomi. “These should provide suitable viscosity dispersion, correct ratios of components to provide functionality, and ease of processing without too much agglomeration of the particles.” He points out that the coating process should be designed to avoid granulation and agglomeration of drug particles and ensure individual particle coating with the barrier membrane system. “Critical parameters affecting optimum and consistent coating are: choice of bottom or top spray technology, spray gun set-up, and processing conditions such as spray rate, atomizing air, fluidizing air, and volume of air, among others,” he says.
According to Hofmann, the critical quality attributes (CQAs) and critical process parameters (CPPs) should be identified and incorporated into the development process at an early stage. “For functional coatings for tastemasking purposes, dissolution both in neutral and acidic pH is the most important CQA, as it reveals tastemasking efficiency through the lag time and bioavailability through the release,” he underlines.
Fully synthetic polymers consistently have low batch-to-batch variability and can be produced with tight specifications, Hofmann notes. “They are, therefore, less critical than naturally based polymers where batch-to-batch differences in molecular weight and substitution degree have to be considered as CQAs of the tastemasking polymer.” He adds that further to specific polymer properties, polymer amount, type, and individual quality have to be evaluated for optimum risk assessment. “Moreover, the amount and type of film-coating excipients have to be added to the CQAs of the coating formulation,” he says. “Among the CQAs of the substrate material, particle size distribution, specific surface area, and bulk density are key for multiparticulates; whereas for tablets, friability and weight variation are important.”
Hofmann adds that the setup of spraying process parameters will also have crucial influence on film quality and, therefore, the final product tastemasking performance. “Product bed temperature, spray rate, atomizing air pressure, inlet air temperature/humidity, and drying air capacity are among the CPPs. Their impact on film quality should, therefore, be evaluated carefully to create a robust and reliable design space for the individual coating process.
Vol. 42, No. 9
Pages: 26, 30, 32
When referring to this article, please cite it as A. Siew, “Coating for Tastemasking,” Pharmaceutical Technology 42 (9) 2018.