Multiple Unit Pellet System (MUPS): Design, Manufacturing, Evaluation, and Recent Advances in Oral Drug Delivery

Oral drug delivery remains the most widely accepted and preferred route of administration due to its convenience, cost-effectiveness, and high patient compliance. Conventional solid dosage forms, such as tablets and capsules, dominate the pharmaceutical market; however, these single-unit systems often suffer from limitations including variable gastric emptying, dose dumping, and inconsistent drug absorption profiles (Sántha K, 2020).

To overcome these challenges, multiparticulate drug delivery systems have gained considerable attention in recent years. These systems comprise multiple small, discrete units such as pellets, granules, microspheres, or minitablets, which collectively deliver the required drug dose. Among these, Multiple Unit Pellet Systems (MUPS) have emerged as a highly promising approach, combining the advantages of both multiparticulate systems and conventional tablets (Saad M. Majeed, 2020).

MUPS are typically composed of hundreds of coated pellets compressed into a single tablet or encapsulated within a capsule shell. Upon administration, the dosage form rapidly disintegrates into individual pellets that disperse uniformly throughout the gastrointestinal tract. This uniform distribution leads to predictable drug release, reduced local irritation, and improved bioavailability compared to single-unit dosage forms (Vivekanand Kisan Chatap, 2020).

Figure 1. Structure of a typical MUPS pellet.

A key advantage of MUPS lies in their ability to provide controlled and sustained drug release while minimizing fluctuations in plasma drug concentration. The multiparticulate nature of MUPS reduces the risk of dose dumping and ensures consistent therapeutic outcomes. Additionally, these systems allow for the incorporation of pellets with different release characteristics, enabling the development of combination therapies and customized drug release profiles within a single dosage form (Harshada Rajendra Bafna, 2025).

Recent research has focused on enhancing the performance of MUPS through advancements in pelletization techniques, coating technologies, and the use of functional polymers. For instance, extrusion–spheronization and fluidized bed coating have been extensively employed to produce pellets with controlled size, shape, and surface properties. Furthermore, the integration of novel polymers, including mucoadhesive and thiolated polymers, has opened new avenues for improving drug retention and targeted delivery within the gastrointestinal tract (Praveen Kumar S. Verma, 2025).

Despite their numerous advantages, the formulation and manufacturing of MUPS present several challenges. The compression of coated pellets into tablets may compromise pellet integrity, leading to altered drug release profiles. Additionally, factors such as pellet size distribution, coating thickness, and excipient selection play critical roles in determining the final product performance. Therefore, careful optimization of formulation and process parameters is essential for the successful development of MUPS (Saad M. Majeed, 2020).

In light of these considerations, MUPS have gained significant importance in modern pharmaceutical research and industrial applications. This review aims to provide a comprehensive overview of the design, formulation, manufacturing techniques, evaluation parameters, and recent advancements in MUPS, with a particular emphasis on their role in improving therapeutic efficacy and patient compliance.

2. MATERIALS USED IN MULTIPLE UNIT PELLET SYSTEMS (MUPS):

The successful development of Multiple Unit Pellet Systems (MUPS) depends on the rational selection of excipients, which directly influence pellet formation, mechanical integrity, drug release behavior, and stability. Each component plays a distinct functional role in achieving the desired physicochemical and biopharmaceutical performance (Daryl R. Thio, 2022).

2.1 ACTIVE PHARMACEUTICAL INGREDIENT (API):

The selection of the API is governed by its physicochemical properties such as solubility, stability, particle size, and dose. Drugs requiring controlled or modified release are particularly suitable for MUPS. The multiparticulate nature enhances dissolution and absorption by increasing the effective surface area and minimizing variability in gastrointestinal transit (Kumar S. Soppimath, 2020).

2.2 PELLET CORE MATERIALS:

Pellet cores or starter seeds act as substrates for drug loading. Commonly used cores include:

• Sugar spheres (non-pareil seeds)
• Microcrystalline cellulose (MCC) pellets
• Isomalt-based cores

Microcrystalline cellulose is widely used due to its excellent plasticity and binding properties, enabling the formation of spherical pellets with narrow size distribution during extrusion–spheronization (Daryl R. Thio, 2022).

2.3 BINDERS:

Binders provide cohesiveness during pellet formation and improve mechanical strength. Common binders include:

• Polyvinylpyrrolidone (PVP)
• Hydroxypropyl methylcellulose (HPMC)
• Hydroxypropyl cellulose (HPC)

These polymers facilitate the formation of a uniform wet mass and enhance pellet integrity (Khalid Usman Khan, 2021).

2.4 RELEASE-MODIFYING POLYMERS:

Polymers are critical in controlling drug release kinetics. Based on functionality, they are classified as:

• Hydrophilic polymers: HPMC, polyethylene oxide
• Hydrophobic polymers: Ethyl cellulose
• pH-dependent polymers: Eudragit® L and S

Recent studies emphasize the use of advanced functional polymers such as mucoadhesive and thiolated polymers, which enhance gastrointestinal retention and improve bioavailability (Bernkop-Schnürch, 2020).

2.5 FILLERS AND DILUENTS:

Fillers improve bulk properties and processing efficiency:

• Lactose
• Mannitol
• Dicalcium phosphate.

2.6 DISINTEGRANTS:

In MUPS tablets, disintegrants ensure rapid breakup into individual pellets:

• Crospovidone
• Sodium starch glycolate
• Croscarmellose sodium (Gilles Thoorens, 2021).

2.7 PLASTICIZERS:

Plasticizers improve film flexibility and prevent cracking during coating:

• Triethyl citrate
• Polyethylene glycol
• Dibutyl phthalate (Felton, 2020).

2.8 LUBRICANTS AND GLIDANTS:

These enhance flow and prevent sticking during processing:

• Magnesium stearate
• Talc
• Colloidal silicon dioxide (Sagar Patel, 2020).

3. PELLETIZATION TECHNIQUES:

Pelletization is a key process in MUPS development, transforming powders into spherical, free-flowing pellets with uniform size distribution. The choice of technique significantly influences pellet morphology, mechanical strength, and drug release characteristics.

3.1 EXTRUSION–SPHERONIZATION:

Extrusion–spheronization is the most widely used pelletization technique due to its ability to produce highly spherical pellets with narrow size distribution.

Process Steps:

• Dry mixing of drug and excipients
• Wet massing using granulating liquid
• Extrusion to form cylindrical extrudates

• Spheronization using a rotating friction plate

Drying:

This technique provides excellent control over pellet size, shape, and density, making it suitable for controlled-release formulations (Sagar Muley, 2016)

Recent literature highlights extrusion–spheronization as a cost-effective and scalable method for industrial production of pellets, offering improved flow properties and reduced friability (Nandlal B. Savaliya, 2025).

3.2 LAYERING TECHNIQUES:

a) Solution/Suspension Layering:

• Drug solution or suspension is sprayed onto inert cores in a fluidized bed processor.
• Suitable for low-dose drugs
• Provides uniform coating

b) Powder Layering:

• Drug powder is layered onto cores using a binder solution.
• Allows high drug loading
• Requires precise process control

3.3 SPRAY DRYING:

• Spray drying involves atomization of a drug solution into a hot drying chamber, producing spherical particles.
• Rapid process
• Suitable for thermally stable drugs

3.4 MELT PELLETIZATION:

• In this method, a meltable binder is used to agglomerate powders into pellets.
• Solvent-free technique
• Suitable for moisture-sensitive drugs

3.5 CRYOPELLETIZATION:

• Pellets are formed by dropping liquid formulations into cryogenic liquids (e.g., liquid nitrogen).
• Produces highly spherical pellets
• Useful for heat-sensitive drugs

3.6 FACTORS AFFECTING PELLETIZATION:

Pellet quality is influenced by:

• Moisture content
• Type of excipients
• Extrusion speed
• Spheronization time and speed

These parameters significantly affect pellet size, sphericity, and mechanical strength (Sagar Muley, 2016).

4. EVALUATION OF MUPS:

Evaluation of MUPS involves characterization of both pellets and compressed tablets to ensure consistent quality, performance, and stability (Dilip M R, 2020).

4.1 PRE-COMPRESSION PARAMETERS:

• Bulk density and tapped density
• Angle of repose
• Hausner ratio and Carr’s index

These parameters assess flow properties essential for uniform die filling.

4.2 PELLET CHARACTERIZATION:

a) Particle Size Distribution:

Determined using sieve analysis to ensure uniformity.

b) Shape and Sphericity:

Analyzed using microscopy or image analysis. High sphericity ensures uniform coating and flow properties.

c) Surface Morphology

Studied using Scanning Electron Microscopy (SEM) to evaluate coating integrity.

d) Density and Porosity:

Influence drug release and mechanical strength.

e) Friability:

Measures resistance to abrasion and mechanical stress.

These characterization parameters are essential for ensuring pellet quality and performance (Dilip M R, 2020).

4.3 POST-COMPRESSION EVALUATION OF MUPS TABLETS:

• Hardness
• Friability
• Weight variation
• Disintegration time

A key concern is pellet coat damage during compression, which can alter drug release profiles (Daryl R. Thio, 2022).

4.4 DRUG CONTENT UNIFORMITY:

Ensures uniform distribution of drug across pellets and tablets.

4.5 IN-VITRO DRUG RELEASE STUDIES:

Dissolution studies are performed using USP apparatus to evaluate release kinetics.

• Immediate release
• Sustained release
• Controlled release

4.6 STABILITY STUDIES:

Conducted as per ICH guidelines:

• Accelerated conditions (40°C/75% RH)
• Long-term stability studies

5. DRUG RELEASE MECHANISMS IN MUPS:

Drug release from Multiple Unit Pellet Systems (MUPS) is governed by the physicochemical properties of the drug, the composition of the polymer coating, and the structural characteristics of individual pellets. Unlike single-unit systems, each pellet acts as an independent drug delivery unit, ensuring predictable and reproducible release profiles across the gastrointestinal tract (Saad M. Majeed, 2020).

Figure 2. Drug release mechanism of MUPS

5.1 DIFFUSION-CONTROLLED RELEASE:

Diffusion is one of the most common mechanisms in MUPS, where the drug diffuses through a polymeric membrane into the surrounding medium. In coated pellets, water penetrates the polymer layer, dissolves the drug, and facilitates its diffusion outward.

Hydrophilic polymers swell upon hydration, forming a gel layer that controls drug diffusion, while hydrophobic polymers (e.g., ethyl cellulose) create a barrier that slows drug release. This mechanism is particularly useful for sustained-release formulations (Daniel Zakowiecki, 2020).

5.2 DISSOLUTION-CONTROLLED RELEASE:

In dissolution-controlled systems, the release rate depends on the solubility of the drug and/or the polymer coating.

Drug-controlled dissolution: The drug dissolves gradually from the pellet core.

Polymer-controlled dissolution: The coating dissolves over time, releasing the drug.

This mechanism is commonly employed for drugs with moderate to high solubility and is influenced by factors such as pH, temperature, and agitation (Giridharan Sivalingan, 2020).

5.3 EROSION-CONTROLLED RELEASE:

In erosion-controlled systems, drug release occurs due to the gradual degradation or erosion of the polymer matrix. Hydrophilic polymers such as HPMC swell and erode in the gastrointestinal fluids, allowing controlled drug release.

This mechanism is advantageous for designing sustained-release and gastroretentive MUPS formulations, where prolonged drug release is desired (Giridharan Sivalingan, 2020).

5.4 OSMOTICALLY CONTROLLED RELEASE:

Osmotic systems utilize osmotic pressure as the driving force for drug release. Water enters the pellet through a semi-permeable membrane, generating pressure that pushes the drug solution out through pores or channels.

Although less commonly used in MUPS compared to matrix systems, osmotic mechanisms offer precise control over drug release independent of gastrointestinal conditions.

5.5 PH-DEPENDENT RELEASE:

PH-sensitive polymers such as Eudragit® L and S enable site-specific drug release in different regions of the gastrointestinal tract.

Drug release in the stomach (acidic pH) is minimized

Drug release in the intestine (alkaline pH) is enhanced

This mechanism is widely used for enteric-coated pellets and colon-targeted drug delivery systems (Daniel Zakowiecki, 2020).

5.6 MULTI-MECHANISTIC RELEASE SYSTEMS:

In many advanced MUPS formulations, drug release is governed by a combination of mechanisms, including diffusion, erosion, and dissolution.

Such hybrid systems allow:

• Fine-tuning of release profiles
• Reduced dose dumping
• Improved therapeutic outcomes

Recent studies demonstrate the use of multilayer-coated pellets combining effervescent, drug, and polymer layers to achieve controlled and gastroretentive drug release (Praveen Kumar S. Verma, 2025).

Figure 3. Release process of MUPS Tablet in GIT

6. APPLICATIONS OF MULTIPLE UNIT PELLET SYSTEMS (MUPS):

MUPS have gained widespread application in pharmaceutical development due to their flexibility, improved bioavailability, and ability to provide controlled drug delivery.

6.1 CONTROLLED AND SUSTAINED DRUG DELIVERY:

MUPS are extensively used for sustained and controlled drug release formulations. Each pellet functions as an independent release unit, ensuring consistent plasma drug levels and reducing dosing frequency.

This approach minimizes fluctuations in drug concentration and enhances therapeutic efficacy (Giridharan Sivalingan, 2020).

Figure 4. Application of MUPS