Development of Mini-Tablet and Multi-Unit Pellet Systems

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Pharmaceutical Technology, Pharmaceutical Technology, April 2024, Volume 48, Issue 4
Pages: 18–22

Advanced oral dosage forms allow for modulation of controlled- and sustained-release profiles.

Multi-unit pellet systems (MUPS) and intelligently encapsulated mini-tablet systems (EMTS) have unique combinations of advantages compared to conventional oral formulations. The drug release from MUPS and EMTS can be modified by combining pellets or mini tablets with different polymer coatings to achieve the desired profile, allowing modulation of controlled and sustained release. Reduced dose dumping allows for more consistent drug release, lowers risk of gastrointestinal irritations, improves bioavailability, and causes less variation in drug absorption between individuals, which results in improved efficacy with reduced side effects. These strategies also work well with fixed-dose combination (FDC) formulations, allowing controlled release of multiple drug substances, even those that are incompatible with one another, at different rates. MUPS and EMTS even have potential to enable oral formulation of biologics and the formulation of personalized medicines with tailored dosing.

Granules, pellets, and mini tablets (diameter less than three millimeters) are subunits of oral solid dosage forms. They are mixed with excipients and then enclosed within hard gelatin capsules or compressed into tablets. MUPS comprise pellets consolidated into tablets, while EMTS comprise mini tablets encased in capsules. Orodispersible matrices can be used to address swallowing issues. Modification of release profiles is accomplished by coating the individual pellets or mini tablets with functional polymers or other materials. Coatings can also prevent different interactions between incompatible drug substances and provide taste-masking. Dosages are easily adjusted by changing the number of subunits contained in each tablet or capsule.

Targeting numerous indications

Therapies on the market formulated as MUPS or EMTS include drugs for problems of the gastrointestinal tract—including gastroesophageal reflux disease, gastric acid-related disorders, and peptic ulcers, high blood pressure, diabetes, and diseases that benefit from targeted delivery strategies, such as ulcerative colitis and gastric, intestinal, duodenal and colon cancers, according to Rao Voleti, senior principal scientist for drug products and pharma services at Thermo Fisher Scientific.

Most of the MUPS/EMTS that treat diseases and conditions related to excessive stomach acid production are based on proton pump inhibitors (PPIs), adds Joao Marcos Assis, global technical marketing manager at BASF Pharma Solutions. He also notes that certain psychiatric conditions, such as depression and anxiety disorders, can be treated with controlled-release MUPS formulations of antidepressant and anxiolytic medications, which provide more stable blood levels of the drug substances for improved symptom management.

Pain management medications and treatments for hormonal disorders and some respiratory conditions (such as asthma, chronic and obstructive pulmonary disease) can also benefit from the sustained-release properties of MUPS/EMTS, according to Assis.

Finally, MUPS and EMTS, observes Voleti, are extremely effective dosage forms for patients with swallowing difficulties (dysphagia) across a variety of therapeutic areas, including cardiovascular, neurological, metabolic disorders, oncology, and more.

Suited for challenging APIs

A growing percentage of APIs in the development pipeline suffer from poor bioavailability, as well as other issues such as instability, narrow therapeutic ranges, and/or the need for specific release patterns. MUPS and EMTS formulations can help facilitate the delivery of these challenging APIs.

Instability, such as in the case of PPIs when exposed to acidic pH levels, can be overcome because of the protective coatings provided to the pellet or mini-tablet subunits within the formulation. “This approach helps enhance the overall shelf life of the formulation, ensuring the drugs remain stable and effective over time,” says Voleti. Similarly, he adds that multiple APIs can be combined in a single drug product even if they have the potential to interact chemically with one another, because the protective coatings prevent such interactions.

For APIs with narrow therapeutic indices, the ability to modulate release profiles ensures that the concentration of a drug substance is maintained within the desired therapeutic range (above the minimum effective concentration and below the toxic concentration) for a longer duration, ensuring a more effective treatment outcome, Assis comments. That translates to increased efficacy and enhanced safety, which can be difficult to achieve otherwise. MUPS/EMTS also allow for reduction of the high dosing frequencies often required for medications with narrow therapeutic windows, which can contribute to improved patient compliance, Assis adds.

Other drug types for which formulation as MUPS/EMTS leverage sustained release profiles include highly potent therapies and drugs with a short durations of action, according to Assis. The former require precise dosing and careful control of drug concentration, which can be achieved using a drug reservoir system like those found in MUPS/EMTS formulations. For the latter, Assis comments, a drug reservoir system may prolong the therapeutic effect by releasing the drug substance gradually.

Ideal for combination products

In addition to making it possible to incorporate multiple APIs that have the potential to interact with one another, MUPS/EMTS formulations can also accommodate APIs with different solubility profiles, allowing for the formulation of drugs that may have varying bioavailability profiles, Voleti says. MUPS and EMTS are also useful when different release rates are required to meet specific pharmacokinetic profiles. In fact, Voleti notes that combining drugs with variable absorption rates in a single formulation can help achieve a predictable pharmacokinetic profile. Reducing the number of different drugs patients must take can also help boost medication compliance.

Development is not a simple task

Given that MUPS/EMTS contain subunits that must be manufactured and then further processed into the final drug product, their development and production is more complex than those for basic tablets and capsules. Indeed, Voleti points to several technologies that may be used for the development of MUPS/EMTS, including extrusion-spheronization, hot-melt extrusion, spray drying plus compression, mini-tablet compression, drug layering, multi-layer coating, taste-masking, multi-population encapsulation, and others. “The development and commercialization of MUPS and EMTS formulations face several significant challenges for which strategic approaches are required,” he states.

Particular issues that must be addressed, according to Voleti, include ensuring the shelf life and stability of MUPS formulations; maintaining drug-excipient compatibility; preventing moisture ingress, oxidative degradation, and component interactions; achieving particle and functional coating uniformity; navigating and avoiding intellectual property infringement; and adhering to regulatory requirements.

Assis also emphasizes the fact that producing uniform pellets of consistent size, shape, and drug content can be challenging, and coating pellets to provide the desired controlled or delayed-release profiles—as well as doing so in a consistent manner can be complex. “Ensuring an even and consistent coating thickness and uniform coating distribution across all pellets is crucial for consistent drug release and [to] reduce batch-to-batch variability,” he says. That requires determination of optimal coating process parameters, which can be a lengthy effort.

Maintaining the integrity of the coating in subsequent processing steps, such as tableting and encapsulation, is also crucial, because coating damage or breakage can alter the release characteristics. “Since most MUPS comprise pellets with functional coatings, maintaining film elasticity and flexibility is crucial for retaining the intended functionality, and therefore overcoming challenges related to blending and tableting coated pellets is essential to prevent film breakage and segregation issues,” Assis contends.

All of these challenges can be magnified when scaling from the lab to commercial production, Assis adds.

Finally, Voleti points out that there is one key limitation of MUPS and EMTS formulations. “Large doses cannot be accommodated in these forms and may require multiple units for administration, which can impact patient acceptability and compliance,” he explains.

Many factors to consider

Beyond the challenges to MUPS/ENTS development outlined above, the need to consider several different factors when designing these formulations adds further complexity. The dose; desired release profile(s), including duration of action, lag times in release, and others; physicochemical properties of the APIs involved; the desired shape and size of the particles, which can impact properties processability, uniformity, and release; the manufacturing and filling processes; and the selection of optimum/appropriate coating technologies are examples highlighted by both Voleti and Assis.

The choice of pellets or mini-tablets must also be considered, Assis notes. Mini-tablets are produced using tablet presses with specific punches, which avoids the need for large investments in equipment. Their production involves few processes; they generally require less coating material than pellets; and they have a greater capacity to incorporate active ingredients, according to Assis.


However, due to the size of the punches, the drug and excipient mixture must have high compressibility to mitigate high compression forces, as well as excellent flow to avoid weight and dosage variations, Assis observes. The larger size of mini-tablets also means it can be difficult to incorporate them into tablets, and thus hard gelatin capsules are typically preferred.

Other factors noted by Assis as important to consider during development of MUPS/EMTS formulations include the attributes and proportions of other tablet ingredients and whether taste-masking will be needed. Cushioning excipients in particular, he says, can impact tablet compression, while differences in the particle sizes of these excipients and coated pellets can lead to segregation risks and dose uniformity concerns. “Selecting appropriate diluents (major components of cushioning excipients) and other additives is relevant for successful formulation development of MUPS, especially those containing functional coated pellets,” Assis concludes.

Improving functionality with excipients

Excipients, in fact, play a crucial role in determining the performance of MUPS/EMTS formulations. In addition to coating materials and cushioning agents, they can include diluents and fillers, binders, surfactants, solubilizers, and stabilizers. “By incorporating these excipients into the formulation, developers can enhance functionality and performance, ensuring optimal drug delivery and stability,” Voleti contends.

It is important to keep in mind, emphasizes Assis, that MUPS and mini tablets require highly compressible and flowable excipients to maintain the film integrity of pellets, reducing compression force and table weight variability.

Diluents and fillers, such as microcrystalline cellulose (MCC), sugar, starch, mannitol, and lactose, are frequently employed to increase the bulk volume of the formulation, while binders such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and polyvinyl pyrrolidone are commonly used to improve the cohesion and compressibility of the formulation, according to Voleti.

MCC, observes Assis, is a versatile diluent known for its compressibility, lubrication properties, and low moisture content that is widely used in MUPS, primarily because it presents excellent compressibility properties due to its high plasticity, allowing for easy formation of tablets with high hardness and low friability. “MCC also offers good binding capabilities, yet can help in the disintegration of tablets, ensuring rapid drug release and absorption,” he notes.

Crospovidone (cross-linked polyvinylpyrrolidone) is another excipient highlighted by Assis that has both disintegrant and binding properties, both of which are dependent on particle size. “Smaller crospovidone particles with high surface areas provide high compressibility, improving tablet hardness. Thus, super-fine crospovidone (Type B) is recommended for orodispersible tablets (ODTs),” he says.

Mannitol, meanwhile, is the diluent of choice for ODTs, according to Assis. This sugar alcohol offers high stability, fair compressibility, low hygroscopicity, and pleasant taste. It can act as a bulking agent and contribute to rapid tablet disintegration. Due to its poor binding ability, though, it generally must be used with other functional excipients such as binders and disintegrants.

Of binder options, Assis comments that hydroxypropyl cellulose can be used in tableting as a dry and wet binder at low concentrations (2 to 6 weight/weight %), but at higher concentrations can impact tablet disintegration. Copovidone can be used up to 10 weight/weight % and offers excellent dry binding properties, high plasticity, and low hygroscopicity, according to Assis. “Finer versions with high surface areas and high binding capacities are ideal for MUPS because much less material (1 to 5%) is required,” he comments.

An important trend regarding excipients using MUPS/EMTS formulations is increasing application of coprocessed excipients, which combine two or more excipients without changing their chemical composition but with improvement of physical properties. In addition to improved performance characteristics, coprocessed excipients often provide better processability along with time and cost savings.

“Coprocessed excipients are ideal for MUPS/EMTS formulations because they often exhibit better flow characteristics compared to individual excipients, leading to improved uniformity, reduced risk of segregation during compressing, and enhanced compressibility, allowing for easier tablet formation and better tablet hardness, which results in improved mechanical strength at low compression forces for reduced risk of pellet breakage and tool damage,” explains Assis.

Common coatings include ethyl cellulose, acrylic polymers, hydrophilic polymers, and lipid-based materials, with different grades employed to achieve different modified drug release characteristics, taste-masking, and protective properties, Voleti observes.

Examples of acrylic polymers noted by Assis include methacrylic acid-ethyl acrylate co-polymer (1:1) for film coating to create of enteric pellets, min-tablets, tablets, capsules, granules, and crystals and diethylaminoethyl-methacrylate and methyl methacrylate copolymer for taste-masking. He also highlights polyvinyl acetate plus povidone (polyvinylpyrrolidone) 30, which is available as an aqueous dispersion, for sustained-release formulations. In many coating formulations, Assis also emphasizes the importance of using appropriate plasticizers at the right concentrations for a given polymeric material to maintain flexibility during processing and thus prevent coating damage.

Finally, Voleti cautions that some excipients are to be avoided. They include those with known toxicity and safety concerns, those that are incompatible with the specific API of interest or the chosen manufacturing process, and those known to cause sensitivities for individuals in the target patient population.

In silico solutions accelerate development

Computer algorithms designed to aid formulators in the identification of optimum excipient combinations and concentrations, as well as formats for specific drug substances, are helping to reduce the number of physical experiments that must be conducted, saving time, money, and resources. “By leveraging in silico solutions, researchers and developers can streamline the formulation development process, making it more efficient and effective in creating optimal MUPS and/or EMTS formulations as well as reducing development time and conserving valuable API,” Voleti says.

Tools for accelerating the development of optimal MUPS/EMTS formulations include both computational modeling techniques enabled by artificial intelligence (AI) and machine learning (ML) that help in the design and optimization process, Voleti comments. More specifically, the behavior of excipients, processing parameters, and formulation variables can be predicted computationally, enabling the formulation design to be fine-tuned for optimal performance.

In addition, in silico techniques can be used to simulate drug-release kinetics from MUPS/EMTS, taking into account factors such as composition, environmental conditions, and predicted release profiles, according to Voleti. He points to tools such as GastroPlus (Simulations Plus), which considers the absorption, distribution, metabolism, and excretion characteristics of APIs and formulations, and the AI/ML predictive platform Quadrant 2 (Thermo Fisher Scientific) as valuable for predicting and overcoming solubility and bioavailability challenges.

Accelerated stability and assessment programs, meanwhile, provide the capability to predict stability and degradation pathways and select suitable formulation components and packaging configurations to enhance stability, Voleti observes. Compaction simulation modeling is also used to predict compression/compaction characteristics, ensuring scalability and process reproducibility, which helps to optimize the manufacturing process and shorten tech-transfer times, Voleti adds.

Comprehensive development strategy essential

Given the complexity of MUPS/EMTS formulations and the numerous challenges to realizing effective and optimal products, a strategic approach to their development is essential. Assis recommends a multi-pronged approach that leverages comprehensive pre-formulation characterization, quality-by-design and design-of-experiment (DoE) principles, robust manufacturing processes, coating optimization, and the use of advanced analytical techniques.

“Thorough pre-formulation characterization of the API and excipients is needed to understand their physicochemical properties, compatibility, and potential interactions, while a DoE approach enables systematic evaluation of formulation and process parameters and their impact on pellet/mini-tablet properties and performance in an efficient and targeted manner. That information can be used to implement appropriate process controls and quality assurance measures to minimize batch-to-batch variability and ensure reproducibility,” Assis explains.

Coating optimization is equally important, according to Assis, because it ensures a robust process that results in uniform coating distribution and proper adhesion, which are essential to achieving consistent drug release profiles. Finally, he notes that use of analytical techniques such as near-infrared reflectance and Raman spectroscopy and scanning electron microscopy provides valuable insights into formulation performance and aids in troubleshooting and optimization.

A comprehensive development strategy for MUPS/EMTS formulations should also encompass, says Voleti, the adoption of appropriate scale-up principles to ensure consistent performance and maintain product quality when scaling to commercial production; performance of stability studies to evaluate the chemical, physical, and microbial stability of the formulations; investigation of the intellectual-property landscape to identify potential infringement issues; a robust regulatory strategy that considers regional requirements, intended markets, and product classifications; and implementation of a patient-centric design strategy that includes a thorough literature review and evaluation of formulation excipients, coating materials, polymers, and formulation approaches.

Patient compliance implications

Indeed, patient centricity has become an increasingly important aspect of drug development, as regulatory authorities seek to decrease medication nonadherence through introduction of drug products that consider patient concerns about ease of use, convenience, dosing frequency, and other factors.

MUPS and EMTS are by design patient-centric, says Voleti, as they offer flexibility in developing tailored release profiles to meet specific patient requirements when they are developed as modified-release dosage forms. “These formulations are adaptable to various patient groups, including pediatric, geriatric, and general populations. The flexibility of dosing, taste-masking, and improved palatability attributes all contribute to enhancing patient adherence to their medication regimen[s],” he explains.

Other advantages that MUPS/EMTS formulations offer include increased ease of swallowing and the ability to provide combination therapies through fixed-dose combinations that leverage synergistic effects and minimize the pill burden associated with long-term treatments. They can also be used for oral formulations with special applications, such as gastro-retentive and mucoadhesive therapies, and are readily adapted for alternative routes of administration such as rectal or vaginal, according to Voleti.

About the author

Cynthia A. Challener, PhD, is a contributing editor to Pharmaceutical Technology®.

Article details

Pharmaceutical Technology®
Vol. 48, No. 4
April 2024
Pages: 18–22


When referring to this article, please cite it as Challener, C.A. Development of Mini-Tablet and Multi-Unit Pellet Systems. Pharmaceutical Technology 2024 48 (4).