CELLETS® are pellets or spheres made of microcrystalline cellulose. The size ranges from 100 µm to 1400 µm. Being neutral starter cores, they can be used as carrier system for low-dosed APIs and allow diverse functional coating. See pellet technologies for a detailed description.

CS_sphericity_image_4

Electron microscopy yield perfect imaging data of the MCC pellets’ surfaces. Magnification: 250x, working distance 8.0 mm, voltage: 10 keV.

Available size classes are (click for more information):

  • CELLETS® 100
  • CELLETS® 200
  • CELLETS® 350
  • CELLETS® 500
  • CELLETS® 700
  • CELLETS® 1000

Any size class of CELLETS® have same striking advantages:

  • low friability and extreme hardness
  • insolubility in water
  • high spherictity
  • smooth surface
  • good monodispersity

See case studies to see these starter pellets in action!

Delayed release oral pharmaceutical compositions
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Delayed release oral pharmaceutical compositions: scientific background, patent insights, and future potential

Introduction to delayed release oral pharmaceutical compositions

Delayed release oral pharmaceutical compositions enable drug delivery at a defined time after oral administration. Unlike immediate release dosage forms, these systems control when the active pharmaceutical ingredient becomes available for absorption. As a result, they protect acid-sensitive drugs and allow targeted delivery to specific gastrointestinal regions. Moreover, delayed release forms can reduce gastric irritation and peak-related side effects. Therefore, they often improve patient tolerance and adherence. From a consumer compliance perspective, these formulations support simplified dosing schedules and more predictable therapeutic effects. Consequently, they play a key role in chronic therapies that demand long-term adherence and consistent drug exposure.

Summary of US12521351B1: delayed release oral pharmaceutical compositions

The patent US12521351B1 describes delayed release oral pharmaceutical compositions designed primarily for treating inflammatory bowel disease. Specifically, the invention focuses on multiparticulate systems containing mesalamine and hyaluronan within an oral capsule. These particles use an inert core that serves as a substrate for successive functional layers. First, a mesalamine-containing drug layer is applied. Next, a hyaluronan layer follows, which contributes both therapeutic and release-modifying functions. Finally, an outer coating controls the onset of drug release in the gastrointestinal tract.

Importantly, the patent emphasizes controlled release timing rather than simple gastro-resistance. The coating system delays drug exposure until the dosage form reaches intestinal regions associated with inflammation. As a result, the formulation minimizes drug loss in the stomach and improves local efficacy. Furthermore, the multiparticulate design allows uniform drug distribution throughout the intestine, which reduces variability in drug exposure.

In addition, the patent outlines manufacturing methods such as fluid-bed coating and encapsulation. These processes ensure reproducible layer thickness and particle size distribution. Consequently, the formulations achieve consistent dissolution behavior across batches. The patent also defines preferred ranges for core size, drug load, and coating thickness. Therefore, it provides a framework for scalable industrial production.

Overall, US12521351B1 demonstrates how delayed release oral pharmaceutical compositions can combine therapeutic targeting with patient-friendly oral delivery. By integrating functional excipients and structured layering, the invention advances existing mesalamine therapies toward improved clinical performance.

Technical considerations and formulation context

Delayed release oral drug forms differ fundamentally from uncontrolled release systems. While immediate release products dissolve rapidly after ingestion, delayed release formulations intentionally suppress early dissolution. Consequently, they reduce exposure in the stomach and shift drug availability to later intestinal segments. This distinction becomes critical for drugs that cause gastric irritation or degrade in acidic environments.

Dissolution profiles represent a central design parameter. Ideally, delayed release systems show minimal drug release under acidic conditions. Then, they exhibit a rapid and reproducible release once intestinal pH thresholds are reached. Therefore, formulators must carefully balance coating composition, thickness, and particle size. In addition, variability in gastrointestinal transit times must be considered during development.

However, delayed release formulations face several obstacles. Uniform coating of multiparticulates remains technically demanding. Moreover, small variations in process parameters can significantly affect release kinetics. Stability during storage also presents challenges, especially for moisture-sensitive coatings. As a result, robust process control and extensive dissolution testing are essential.

Within this patent context, CELLETS® 500 play a supportive yet important role. These microcrystalline cellulose starter cores provide a smooth, inert, and size-defined substrate. Consequently, they enable uniform drug layering and coating application. Their narrow particle size distribution improves batch reproducibility and dissolution consistency. Therefore, CELLETS® 500 contribute directly to the functional reliability of delayed release oral pharmaceutical compositions.

Delayed release oral pharmaceutical compositions

Conclusion and outlook

Delayed release oral pharmaceutical compositions continue to shape modern oral drug delivery. They align pharmacokinetics with disease physiology and patient needs. The US12521351B1 patent illustrates how structured multiparticulate systems can enhance intestinal targeting and therapeutic consistency. Looking ahead, advances in coating polymers, starter core technologies, and process analytics will further refine these formulations. Consequently, delayed release oral pharmaceutical compositions will remain central to improving efficacy, safety, and long-term patient compliance in oral therapies.

Patent Summary

  • Name of Patent: Delayed release oral pharmaceutical composition
  • Patent Number: US12521351B1
  • Year of Patent: 2026
  • Patent Holders: Tsung-Chung Wu, Yu-Chih Chen
  • Affiliation: Aihol Corp
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Chewable formulations with MCC starter cores
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Chewable formulations with MCC starter cores

Chewable formulations with MCC starter cores: Patient-centric design and pharmaceutical relevance

Chewable formulations with MCC starter cores are an advanced oral dosage form that combines patient-friendly administration with robust pharmaceutical performance. Thereby, patient refers includes humans and non-human mammalian animals, such as dogs, cats, mice, rats, guinea pigs, rabbits, ferrets, cows, horses, sheep, goats, and pigs. At the outset, these formulations address a key challenge in drug therapy, namely patient compliance, by offering a dosage form that patients can chew without water. Consequently, they are particularly suitable for pediatric, geriatric, and veterinary applications. Moreover, chewable dosage forms allow formulators to improve taste, mouthfeel, and ease of use, which directly supports adherence to therapy. At the same time, MCC starter cores provide excellent mechanical stability, uniformity, and processing reliability. Therefore, they enable consistent drug loading, predictable disintegration, and scalable manufacturing. As a result, this combination creates significant opportunities for modern, patient-centric drug delivery.

Chewable formulations with MCC starter cores according to WO2022049149A1

The patent WO2022049149A1 describes chewable pharmaceutical compositions designed to disintegrate rapidly while maintaining acceptable texture and stability. In particular, the invention focuses on soft chewable dosage forms that contain at least one active pharmaceutical ingredient together with carbonate or bicarbonate compounds that act as efficient disintegrants. As a result, the dosage form breaks down quickly when exposed to aqueous or gastric media. This rapid disintegration directly supports fast and reproducible dissolution of the API. Furthermore, the patent emphasizes that surface structure, porosity, and wettability of the chewable matrix strongly influence drug release. Therefore, careful control of formulation and processing parameters becomes essential. The disclosed chewable products typically achieve disintegration within pharmacopeial limits and release a high proportion of the API within short dissolution times. In addition, the patent highlights the importance of balancing lipophilic excipients, since excessive hydrophobicity can delay disintegration. Consequently, the invention aims to deliver chewable dosage forms that combine good palatability with reliable pharmaceutical performance. Overall, the patent demonstrates how optimized excipient systems can overcome common limitations of chewable drugs while improving patient acceptance.

Chewable formulations with MCC starter cores

Chewable formulations with MCC starter cores

Advances, dissolution considerations, and API challenges in chewable dosage forms

Chewable formulations with MCC starter cores illustrate clear advances in chewable drug technology. First, the use of spherical MCC cores supports multiparticulate designs that improve content uniformity and process robustness. Moreover, these cores enable precise API layering, which enhances dose accuracy and reproducibility. When considering dissolution profiles, formulators must carefully manage core porosity, disintegrant efficiency, and wettability. Therefore, rapid liquid penetration and controlled matrix breakdown remain critical success factors. At the same time, APIs in chewable formulations face both obstacles and opportunities. On one hand, taste masking, stability, and dissolution control present technical challenges. On the other hand, chewable formats open new possibilities for poorly compliant patient groups and combination therapies. Consequently, successful products require a well-balanced formulation strategy that aligns API properties with excipient functionality.

Role of CELLETS® in the context of this patent

Although WO2022049149A1 does not explicitly name commercial products, its technical concept strongly aligns with MCC starter cores such as CELLETS® 100 (100-200 µm) and CELLETS® 200 (200-355 µm). These microcrystalline cellulose spheres offer high sphericity, low friability, and narrow particle size distribution. Therefore, they provide an ideal substrate for API layering in chewable multiparticulate systems. CELLETS® 100 and CELLETS® 200 support uniform coating, predictable dissolution behavior, and efficient processing in fluidized bed systems. In addition, their inert and tasteless nature helps minimize interactions with APIs and flavoring agents. As a result, they play a crucial functional role in achieving stable, reproducible, and patient-acceptable chewable formulations.

Conclusion and outlook for chewable formulations with MCC starter cores

Chewable formulations with MCC starter cores represent a strategic convergence of patient-centric design and pharmaceutical engineering. In conclusion, the integration of MCC starter cores enhances manufacturing reliability, dose uniformity, and dissolution performance while supporting improved patient compliance. Moreover, patents such as WO2022049149A1 demonstrate how modern excipient systems can overcome traditional limitations of chewable dosage forms. Looking ahead, further innovation will likely focus on advanced taste-masking technologies, tailored dissolution profiles, and broader API compatibility. Therefore, chewable formulations with MCC starter cores are well positioned to play an increasingly important role in future oral drug delivery.

Patent Summary

  • Name of Patent: Chewable formulations
  • Patent Number: WO2022049149A1
  • Year of Patent: 2021
  • Patent Holders: Clément Maxime Chevreau, Pascal Grenier, Claudia Reitz
  • Affiliation: Elanco Tiergesundheit AG
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Soft tabletting of pellets - Cellets small
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Soft tabletting of pellets into Multiple Unit Pellet Systems (MUPS)

Introduction to soft tabletting of pellets and MCC pellet functionality

Soft tabletting of pellets is a specialized pharmaceutical compaction approach that enables the compression of coated pellet subunits into tablets while preserving pellet integrity and drug release performance. In this context, Multiple Unit Pellet Systems, or MUPS, combine the biopharmaceutical advantages of multiparticulates with the handling and patient benefits of tablets. MCC-based pellets play a central role in this technology because they deform plastically, cushion mechanical stress, and maintain coating functionality during compression. As a result, MCC pellets support robust tabletting, rapid tablet disintegration, and reliable dissolution behavior. Moreover, MUPS tablets reduce dose dumping risk, improve gastrointestinal distribution, and enhance patient compliance compared to conventional single-unit tablets. Consequently, soft tabletting of pellets has become a preferred strategy for modified-release, delayed-release, and combination products where performance consistency matters.

Soft tabletting of pellets - Cellets

Summary of the publication on soft tabletting of pellets

The referenced publication investigates soft tabletting of pellets using MCC 102 and UICEL-A/102 as key pellet-forming and cushioning materials. The research focuses on producing MUPS tablets that achieve sufficient mechanical strength while preserving the original dissolution profile of coated pellets. Therefore, the work examines how pellet composition, morphology, and compaction behavior interact during tabletting.

The study uses sodium diclofenac as a model drug and applies a sustained-release polymer coating to the pellets. Both homogeneous pellets, produced by extrusion–spheronization, and inhomogeneous pellets, produced by dry powder layering on inert cores, were evaluated. As a result, the work provides insight into how pellet structure affects deformation and coating integrity during compression.

MCC 102 pellets demonstrated strong plastic deformation, which enabled softer compaction and better preservation of pellet structure. In contrast, UICEL-A/102 pellets showed higher porosity and swelling capacity. Consequently, UICEL-A/102-based MUPS disintegrated faster and released the drug more rapidly. However, this same swelling behavior limited their suitability for sustained-release applications.

When used in MUPS tablets, MCC 102 pellets achieved crushing strengths between 70 and 100 N while still disintegrating rapidly. Therefore, these tablets closely matched the dissolution behavior of uncompressed pellets. UICEL-A/102 pellets also formed mechanically stable tablets, but their higher swelling led to faster disintegration and altered release kinetics.

The study further highlights the importance of pellet production method. Inhomogeneous pellets layered onto inert starter cores responded differently to compression than homogeneous pellets. Notably, MCC-based starter cores supported softer tabletting and reduced coating damage. In contrast, sugar-based cores increased compaction stress and slowed tablet disintegration. Thus, the choice of core material directly influenced MUPS performance.

Overall, the publication demonstrates that successful soft tabletting of pellets requires careful alignment of pellet material, structure, and compaction parameters. Otherwise, coating damage or delayed disintegration may compromise therapeutic performance.

Role of Cellets, key insights, and material-related effects

In this publication, Cellets function as MCC-based inert starter cores for dry powder layering. Therefore, they provide a plastically deformable substrate that absorbs compression forces during tabletting. As a result, pellets layered onto Cellets show improved coating integrity and more predictable dissolution behavior compared to sugar-based cores.

The most important take-home message is that pellet material properties govern MUPS performance more than tablet hardness alone. Specifically, MCC 102 offers a balanced profile for sustained-release MUPS, whereas UICEL-A/102 favors immediate-release systems. Consequently, formulation goals should guide cellulose selection early in development.

Obstacles for MCC pellets include managing excessive densification during compression and controlling disintegration time. However, opportunities exist in tailoring MCC pellet porosity, size distribution, and deformation behavior. Advanced Cellets grades may further optimize cushioning and release stability.

Pellet sphericity improves flowability and die filling, which enhances tablet uniformity. At the same time, low friability limits coating damage and fines generation. Hardness requires precise adjustment, because excessive hardness delays disintegration, while insufficient hardness weakens tablets. Therefore, balancing these parameters remains critical for reliable soft tabletting of pellets.

Conclusion and outlook

Soft tabletting of pellets enables advanced MUPS dosage forms that combine multiparticulate performance with tablet convenience. This publication clearly shows that MCC pellets, especially Cellets, support soft compaction and stable drug release when formulation parameters align with material behavior. Although challenges remain, ongoing improvements in pellet engineering and MCC excipient design will expand MUPS applications. In the future, predictive formulation strategies and optimized MCC pellets will further strengthen soft tabletting of pellets as a core pharmaceutical technology.

References

[1] Dissertation, Balzano, Vincenzo; doi: 10.5451/unibas-004872301.

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Particle Size Distributions of Inert Spheres
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Particle Size Distributions of Inert Spheres: Introduction and Summary

Introduction to Particle Size Distributions of Inert Spheres and Their Role in Pelletized Pharmaceutical Products

In pharmaceutical formulation science, Particle Size Distributions of Inert Spheres represent a fundamental quality attribute for multiparticulate dosage forms. Inert spheres, such as microcrystalline cellulose pellets, act as neutral carriers for active pharmaceutical ingredients. They enable precise drug layering, predictable dissolution, and uniform content distribution in capsules or tablets. A narrow and well-characterized PSD improves processability and coating uniformity. It also supports reproducible drug delivery performance in multiparticulate systems. Inert spheres such as CELLETS® offer tight PSD and high sphericity. Therefore, they provide robust cores for dosage forms ranging from low-dose products to extended-release multiparticulates.

A Publication Worth Reading: computerized image analysis

The publication by Heinicke and Schwartz [1] evaluates computerized image analysis for measuring PSD in pharmaceutical spheres and pellets. The study covers particle size ranges from approximately 425 to 1400 micrometers. Traditional sizing methods, such as sieve analysis, provide limited resolution and statistical detail. In contrast, image analysis demonstrated high repeatability and sensitivity. It quantified size differences that traditional methods could not detect. The authors compared two inert sphere lots before drug layering in a fluid-bed rotor granulator. Differences in starting PSD appeared clearly in the resulting granulated products. This result highlights the importance of core PSD for downstream performance. Furthermore, image analysis detected coating thickness increments as small as four micrometers.

The authors also investigated sampling strategies and sample sizes necessary for reliable measurements, recognizing that an appropriate representativeness of sample draws is critical for statistically meaningful PSD outcomes. Importantly, image analysis captured not only size distribution but also provided visual and morphological data for each particle, thereby enriching the dataset beyond mere dimensional statistics. The technique’s effectiveness was tested in both laboratory and commercial scale contexts, including measuring polymer-coated nonpareils during continuous fluid-bed processing. The similarity between in-situ samples (collected via process sampling ports) and whole batch samples suggested that fluid-bed processes in these systems provide sufficiently homogeneous conditions for representative PSD capture by image analysis.

Beyond the direct findings, the work situates PSD measurement via image analysis within a broader pharmaceutical quality landscape. Historically, PSD has been a critical parameter because it influences particle flow, coating behavior, drug layering uniformity, content uniformity, and ultimately drug release characteristics. The continuous development of in-line and at-line image analysis methods positions this approach as part of process analytical technology (PAT), enabling more dynamic control and monitoring of multiparticulate manufacturing.

Advances in Image Analysis for Determining Particle Size Distributions of Inert Spheres

Image analysis has evolved rapidly as a high-resolution method for determining PSD in pharmaceutical spheres. It directly measures individual particle dimensions and morphologies with high precision. Unlike sieve analysis or laser diffraction, image analysis provides particle-by-particle size and shape data. Therefore, it improves PSD accuracy, reproducibility, and visualization during development and quality control. Dynamic image analysis platforms process thousands of particles within minutes. As a result, they generate robust PSD and shape statistics correlated with functional performance criteria.

Important facts include the distinction between number-based and volume-based PSD measures. Metrics such as D10, D50, and D90 describe the spread and balance of the size distribution. In addition, image analysis extracts shape parameters such as sphericity and aspect ratio. These parameters strongly influence flow properties and coating behavior. Moreover,  image analysis enables rapid in-process feedback for monitoring and control. This capability supports coating thickness control and ensures batch-to-batch consistency.

Persisting Obstacles

Despite these advances, obstacles persist. Adequate sample preparation is essential to avoid overlapping particles and bias, especially when using static imaging methods. Agglomeration, depth-of-field effects, and segmentation challenges in image processing can introduce measurement uncertainty if not properly managed. Opportunities exist to integrate enhanced machine vision, artificial intelligence (AI), and real-time imaging to improve discrimination of individual particles in complex mixtures or in high-throughput manufacturing environments. In-line imaging systems with real-time analytics can transform PSD from a static quality attribute to a dynamic process performance indicator.

CELLETS® exemplify the concept of narrow PSD and high surface homogeneity in inert spheres. These microcrystalline cellulose pellets exhibit tight particle size distributions within specified fractions (e.g., 100–200 µm, 150–300 µm, up to 1000-1400 µm) with high sphericity, low friability, and consistent surface characteristics that enhance coating uniformity and enable predictable performance in multiparticulate dosage forms. The narrow PSD and uniform surface enable reproducible drug layering, optimized flow properties, and controlled release profiles, making them ideal cores in fluid bed and Wurster coating operations.

Particle Size Distributions of Inert Spheres

Conclusion and Outlook

The study by Heinicke and Schwartz underscores the value of image analysis for PSD determination. They compared traditional sizing methods with image analysis for inert spheres and coated pharmaceutical pellets. The detection of fine particle diameter differences and detailed morphology supports formulation design, process control, and quality assurance. Future image analysis developments, including AI and in-line PAT integration, will further enhance PSD measurement capabilities. These advances will enable real-time adjustments and closed-loop control in pellet manufacturing. As multiparticulate drug delivery advances, precise characterization of Particle Size Distributions of Inert Spheres remains essential. This precision supports consistent therapeutic outcomes, regulatory compliance, and manufacturing efficiency. Ongoing innovations in imaging hardware, software, and data analytics will strengthen real-time quality control and predictive modeling.

References

[1] G. Heinicke, J. B. Schwartz, Pharmaceutical Development and Technology 2005 (9) 4, 359-367, doi:10.1081/PDT-200032996

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CELLETS pharmaceutical starter cores

Pharmaceutical Starter Cores For Scalable Solutions in Pharma

CELLETS® Pharmaceutical Starter Cores for Pellets & Functional Coatings

CELLETS® are high-purity pharmaceutical starter cores. They combine spherical geometry with narrow particle size distribution and defined density. They provide reproducible carriers for functional coatings and enable controlled layer formation in fluid bed and drum coating processes. Thanks to their uniform geometry, CELLETS® ensure stable fluidization, consistent rolling, and homogeneous wetting during coating. This guarantees uniform layer thicknesses and precise control of active ingredient release.

In controlled-release applications—such as sustained-release, delayed-release, or gastro-resistant systems—CELLETS® support reproducible release profiles. They minimize variability in active ingredient application and polymer layer thickness, creating robust, scalable formulations. CELLETS® enable efficient transfer from formulation development to production scale, improving process reliability and batch-to-batch consistency.

Standardized Starter Cores for GMP-Compliant Processes

CELLETS® are manufactured under controlled conditions with reproducible physical properties. Their narrow particle size, defined density, and high sphericity support consistent process control. This facilitates equipment and process qualification. Regulatory documentation (e.g., DMF information) and GMP compatibility allow CELLETS® to be used across the entire product lifecycle. Using standardized starter cores reduces regulatory risks and supports process validation and batch consistency.

CELLETS pharmaceutical starter cores

Seamless Transfer from Development to Production

CELLETS® enable a smooth scale-up from lab to pilot and commercial production without altering material properties. This simplifies understanding and control of critical process parameters (CPPs). Formulations developed on CELLETS® can scale reproducibly, shortening development timelines and minimizing process adjustments.

Controlled Release & Enteric Coating Precision

CELLETS® provide a neutral, robust core for controlled or delayed drug release. Their uniform surface allows homogeneous application of functional polymer layers, such as sustained-release or enteric coatings. They reduce variability in layer thickness and drug distribution, ensuring reproducible release profiles. CELLETS® support the development of stable controlled-release and enteric coating systems in both R&D and commercial production.

Are You Already Using MCC Starter Spheres?

Take your chance and request sampling units today.

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Different Pelletization Techniques Functionality and Key Insights
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Different pelletization techniques: Introduction and Summary of the Thesis by Azza A. K. Mahmoud

Introduction to Different Pelletization Techniques and Their Functionality in Drug Formulations

Different pelletization techniques form a core part of pharmaceutical manufacturing for solid dosage forms that deliver active pharmaceutical ingredients (APIs) with enhanced performance. Pelletization, a process that generates small, uniform spherical particles, improves flow properties, enables controlled or delayed release, and reduces local irritation in the gastrointestinal tract compared with conventional tablets and capsules. These techniques include direct pelletization, layering pelletization, extrusion-spheronization, spray drying, and other advanced methods, each offering specific functional benefits. Direct pelletization allows quick single-step formation with minimal equipment and lower cost. Layering pelletization deposits drug onto inert cores to improve drug loading and modify release profiles. More complex methods like extrusion-spheronization yield highly uniform pellets but require more processing time. Across all approaches, the choice of technique affects drug dissolution, stability, and manufacturability, and each technique opens opportunities to tailor drug release, enhance bioavailability, and optimize patient compliance through multiparticulate delivery systems.

Summary of the Thesis

The PhD thesis [1] “Application of High-Shear Granulator in Different Pelletization Techniques” by Azza Asim Khalid Mahmoud explores high-shear granulator applications. Furthermore, it demonstrates how these granulators improve different pelletization techniques to produce optimized drug delivery pellets. Consequently, different pelletization techniques become essential for solid dosage forms, enhancing flow properties and ensuring uniform size distribution. Moreover, the study highlights how these techniques enable precise control over drug release while equipment choice reduces cost and streamlines production. In addition, both direct pelletization and layering pelletization are analyzed within a high-shear granulator framework. Therefore, Quality by Design (QbD) principles guide the definition of process parameters that impact pellet quality. Through risk assessments, design of experiments (DoE), and optimization strategies, critical parameters are identified. These include impeller speed, chopper speed, binder volume, and granulating liquid, which strongly affect pellet size, yield, hardness, and dissolution. Overall, the research confirms that mastering different pelletization techniques enhances pharmaceutical pellet formulation efficiency and performance.

Direct pelletization with high-shear granulation

The thesis demonstrates that direct pelletization with high-shear granulation can produce pellets with desirable physical attributes and consistent drug distribution through careful experimental design. By applying a full factorial design and central composite design, the author constructs an optimal design space. The study also incorporates active pharmaceutical ingredients—amlodipine besylate and hydrochlorothiazide—showing how optimized pellets retain good content uniformity and dissolution performance when loaded. On the layering pelletization front, MCC cores serve as a base for drug deposition, with micro-computed tomography and thermal analysis confirming structural features that contribute to improved drug release. The research highlights how the high-shear granulator facilitates physical transformations such as partial amorphization of loaded drugs, which can enhance dissolution rates.

The thesis underscores the advantages of integrating QbD concepts into pelletization, improving reproducibility and understanding of how process variables interact. Overall, the study provides a comprehensive view of how different pelletization techniques benefit from high-shear granulation to produce robust pellet formulations with desirable critical quality attributes.

Use of CELLETS® in the Study

Within the thesis, CELLETS®—spherical microcrystalline cellulose cores—play a key role in the layering pelletization process. These inert cores are typically defined in uniform sizes of approximately 100 µm to 1400 µm. They provide a stable and consistent substrate onto which drug combinations (hydrochlorothiazide and amlodipine besylate) are deposited under high-shear conditions. The application of CELLETS® enhances layering efficiency, facilitates uniform drug distribution, and contributes to improved pellet morphology and mechanical integrity. Their use is integral to investigating how high-shear granulation affects drug layering and the resulting pharmacotechnical properties of the pellets.

Conclusion and Outlook

This thesis confirms that different pelletization techniques, particularly direct and layering methods, gain substantial functional advantages when implemented with high-shear granulation and QbD strategies. The research shows that such integration leads to pellets with optimized size, mechanical strength, and drug release characteristics. Moreover, the use of CELLETS® strengthens drug layering approaches and helps maintain uniformity in multiparticulate systems. Future research may expand on scaling these methods for commercial production, exploring additional API combinations. They are employing real-time monitoring technologies to further enhance control over pellet quality. By advancing the understanding of how process parameters affect critical quality attributes, this work positions high-shear granulation. This technology is a versatile tool for modern drug formulation technologies.

References

[1] SZTE Repository of Dissertations

Different Pelletization Techniques Functionality and Key Insights

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Enzyme-cleavable methadone prodrugs Innovations in formulation
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Patent on enzyme-cleavable methadone prodrugs and methods of use thereof

Enzyme‑cleavable methadone prodrugs: Functionality, Opportunities, and Summary of US20250361205A1

Introduction to Enzyme‑cleavable methadone prodrugs

Enzyme‑cleavable methadone prodrugs represent a novel class of pharmacological agents designed to provide controlled release of methadone only after specific enzymatic activation. These prodrugs attach an enzyme‑cleavable promoiety to the methadone molecule, rendering it inactive until a target enzyme cleaves the linkage in vivo. This mechanism reduces misuse potential and provides more predictable pharmacokinetics compared to conventional methadone formulations. By depending upon specific enzymatic activity, this prodrug design can improve safety and minimize risks associated with inappropriate administration or overdose, while maintaining therapeutic efficacy for opioid dependence or chronic pain management.

Beyond safety, enzyme‑cleavable methadone prodrugs offer opportunities in advanced drug formulation. They enable precise control over the timing and extent of methadone release based on the activity of endogenous enzymes. As a result, formulators can tailor release rates and reduce systemic peaks that commonly contribute to adverse effects or abuse. These prodrugs also permit formulation with excipients or technologies that further modulate release profiles, including multiparticulate systems or coatings. In addition, controlled enzyme activation provides a strategy to optimize oral delivery, enhance patient compliance, and potentially reduce the burden of supervised dosing programs in opioid maintenance therapy.

Summary of this patent

The patent application US20250361205A1 discloses enzyme‑cleavable methadone prodrugs and corresponding methods of use, focusing on prodrugs that deliver methadone through enzymatically‑controlled release. These prodrugs contain a promoiety linked to methadone that requires cleavage by specific enzymes, such as digestive proteases, before the active opioid is liberated. By requiring enzymatic cleavage followed by intramolecular cyclization to release active methadone, the design significantly lowers the susceptibility to accidental or intentional misuse, including inappropriate routes of administration or chemical tampering.

The disclosed prodrug moieties can include amino acid residues or peptides of up to about 100 amino acids linked via an amide bond to the methadone nitrogen. By selecting promoieties that are substrates for particular enzymes, formulators can adjust release kinetics based on the target enzyme’s activity and distribution. For example, gastrointestinal enzymes like trypsin are contemplated as triggers for prodrug activation. The application also describes including enzyme inhibitors in the pharmaceutical composition to attenuate the rate of enzymatic cleavage when desired. This addition can further control release profiles and reduce unintended rapid activation.

The patent describes general chemical structures of enzyme‑cleavable methadone prodrugs, outlining variations in functional groups and linkers that influence both stability and enzymatic susceptibility. These structures include several formulae (e.g., MD‑(I), MD‑(II), MD‑(III)), each representing different classes of promoieties attached to the methadone core. Notably, upon enzymatic cleavage of the promoiety, a stable cyclic urea or other cyclic group forms, which is pharmaceutically acceptable and of low toxicity. The description also covers pharmaceutically acceptable salts, solvates, and crystalline forms of the prodrugs, enhancing formulation versatility.

A key advantage emphasized in this disclosure is the reduction of excessive plasma methadone levels when the prodrug is administered improperly. Because the prodrug cannot be converted to methadone without specific enzymatic action and cyclization, the risk of overdose is reduced. Furthermore, the document details that trypsin inhibitors or other enzyme modulators may be co‑formulated to regulate the enzymatic activation rate. In addition to the chemical and pharmacokinetic considerations, the application mentions pharmaceutical compositions that include typical excipients, such as fillers, binders, and disintegrants, that support conventional formulation processes for oral delivery.

Use of CELLETS® in This Context

Although CELLETS® (highly spherical microcrystalline cellulose pellets used as starter cores in multiparticulate drug delivery systems) are not explicitly referenced in US20250361205A1, the broader formulation context suggests potential relevance. CELLETS® provide uniform and inert starter cores that support controlled layering of active pharmaceutical ingredients. In multiparticulate systems, CELLETS® improve coating uniformity, flow properties, and controlled release profiles in oral dosage forms. These characteristics make them useful for advanced prodrug formulations where release kinetics and consistency are critical, particularly when precise layering of enzyme‑cleavable prodrug moieties is required. Unlike conventional inert cores, CELLETS® enable predictable performance and facilitate scalable manufacturing for complex oral formulations.

In this patent, some particle sizes of CELLETS® are explicitely named:

Type Particle size distribution
(≥ 85 %)		 learn more
CELLETS® 100 100-200 µm
(150/80)		 more information
CELLETS® 200 200-355 µm
(80/50)		 more information
CELLETS® 350 350-500 µm
(50/35)		 more information
CELLETS® 500 500-710 µm
(35/25)		 more information
CELLETS® 700 700-1000 µm
(25/18)		 more information
CELLETS® 1000 1000-1400 µm
(18/13)		 more information

Conclusion and Outlook

In summary, enzyme‑cleavable methadone prodrugs offer a promising advancement in opioid therapy and formulation science, combining controlled enzymatic activation with enhanced safety. The patent US20250361205A1 details chemical constructs and methods that reduce misuse potential and allow sophisticated control of drug release. Given ongoing needs for safer opioid medications, these prodrugs could transform maintenance therapy and pain management by minimizing overdose risks and improving patient compliance. Looking forward, integrating technologies such as multiparticulate delivery systems and optimized excipients (e.g., CELLETS®) will further refine dosing precision and therapeutic outcomes. Future research and clinical evaluation will determine how these designs perform in real‑world settings, including their impact on pharmacokinetics, abuse deterrence, and commercial viability.

Patent Summary

  • Name of Patent: Enzyme-cleavable methadone prodrugs and methods of use thereof
  • Patent Number: US20250361205A1
  • Year of Patent: 2025
  • Patent Holders: Lynn Kirkpatrick
  • Affiliation: Ensysce Biosciences Inc.

Enzyme-cleavable methadone prodrugs Innovations in formulation

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cellulose-derived spherical activated carbon

Cellulose-Derived Spherical Activated Carbon

Cellulose-derived spherical activated carbon is a sustainable carbon material made from renewable cellulose sources. It forms uniform spheres with high surface area and excellent porosity after activation. Because of its spherical shape, this carbon flows smoothly, packs efficiently, and resists dust formation. These traits make it ideal for pharmaceutical and biomedical uses. In drug formulation, amorphized amlodipine besylate and hydrochlorothiazide offer exciting potential. Their amorphous states increase solubility, speed up dissolution, and enhance bioavailability. This improvement allows more consistent dosing and better combination therapies. Furthermore, a high-shear granulator helps mix and layer ingredients under controlled energy and moisture. It ensures uniform distribution of amorphous drugs and consistent granule quality, which improves final product performance.

Summary of the Publication

The publication by K. Shin et al [1] introduces an eco-friendly method to create cellulose-derived spherical activated carbon from microcrystalline cellulose. The researchers first carbonized cellulose spheres and then activated them with steam. This process produced strong, uniform carbon spheres with hierarchical pores and high adsorption capacity. The spherical design improved handling and flow compared to traditional irregular carbon particles. Moreover, the material demonstrated high performance in removing uremic toxins in simulated biomedical tests. It showed quick adsorption, strong selectivity, and good stability under different pH and ionic strengths.

Because the raw cellulose originates from renewable sources, this process aligns with circular-economy goals. It also reduces production costs while improving quality and uniformity. The study compared these spherical carbons with conventional activated carbons and found similar or superior adsorption properties. However, the new materials also offered better mechanical strength and shape stability. In addition, the pore size and surface characteristics could be tuned by adjusting activation conditions or cellulose template sizes. This tunability is vital for targeting specific biomedical and environmental applications. Therefore, the study links sustainable material design with real-world medical use.

Use of CELLETS® in the Study

The authors used CELLETS® microcrystalline cellulose spheres as templates to shape the final spherical activated carbon. These CELLETS® provided precise size control and reliable structure during carbonization. As a result, the produced carbon spheres maintained uniform shape, size, and mechanical stability. The templating method allowed predictable performance and made the process suitable for scaling up. In practical terms, this ensured consistent flow, packing, and adsorption performance—essential features in pharmaceutical and medical applications.

Conclusion and Outlook

Cellulose-derived spherical activated carbon offers a major step toward green, high-performance adsorbents. It combines renewable sourcing, excellent flow behavior, and strong adsorption capacity. The integration of CELLETS® templates made production reproducible and efficient. Future work should focus on in-vivo safety, selective adsorption of specific toxins, and process optimization under GMP standards. Furthermore, pairing this carbon material with amorphous APIs like amlodipine besylate and hydrochlorothiazide could lead to multifunctional systems for improved drug delivery and detoxification. As industries move toward sustainability and advanced pharmaceutical technologies, cellulose-derived spherical activated carbon will likely play a central role in next-generation biomedical materials.

References

[1] K. Shin et al., Materials & Design 259 (2025) 114892. doi: 10.1016/j.matdes.2025.114892.

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Characterization of Layered Pellets containing amorphized amlodipine besylate and hydrochlorothiazide

Characterization of Layered Pellets and the Role of Amorphized Amlodipine Besylate / Hydrochlorothiazide

Characterization of layered pellets forms the basis of advanced pharmaceutical pellet design. These pellets consist of inert cores coated with active drug layers. Their detailed analysis ensures uniformity, strength, and consistent drug release. Layered systems offer precise dosing, extended or modified release, and taste masking. When the solid-state properties of the drug are modified through amorphization, the pellets can show faster dissolution and better bioavailability. In this study, researchers examined how a high-shear granulator can produce pellets that combine amorphized amlodipine besylate and hydrochlorothiazide, focusing on structure, performance, and stability.

Amlodipine besylate normally appears in a crystalline form with high solubility and a melting point near 200 °C. In contrast, hydrochlorothiazide is poorly soluble and melts near 270 °C. Turning them into an amorphous or co-amorphous form breaks down the crystal lattice, improving solubility and dissolution rate. In co-amorphous systems, the two drugs interact through hydrogen bonding, which stabilizes the amorphous state and prevents recrystallization. This interaction increases the dissolution of both drugs and enhances their bioavailability. The study found that partially amorphized drug mixtures in layered pellets improved release rates while maintaining physical stability.

A high-shear granulator creates these layered systems efficiently. Its strong mechanical forces and controlled heat allow uniform coating and induce amorphization at the same time. Because it works without solvents, this process is clean, fast, and suitable for sensitive compounds.

Summary of the Publication

In the study The Development and Characterization of Layered Pellets Containing a Combination of Amorphized Amlodipine Besylate and Hydrochlorothiazide Using a High-Shear Granulator, Mahmoud et al. [1] developed layered pellets by coating microcrystalline cellulose cores (CELLETS®) with drug mixtures in different molar ratios (2:1, 1:1, 1:2). The high-shear granulator (ProCepT 4M8) operated at 1,500 rpm and 60 °C for three hours. The goal was to achieve partial amorphization and study its impact on dissolution and stability. After preparation, the pellets were stored at –20 °C before testing.

Differential scanning calorimetry showed that amlodipine lost its sharp melting peak, confirming full amorphization. Hydrochlorothiazide retained a broad, weaker peak, meaning it was only partly amorphous. X-ray diffraction supported this: the 2:1 mixture had the lowest crystallinity (26.8 %), while the 1:2 mixture showed the highest (53.6 %). Micro-CT imaging revealed that the drug formed an even layer around the CELLETS® cores. Although some pores appeared, they were inherent to the cores rather than defects from coating.

Texture analysis indicated a small increase in hardness—from 19.8 N for plain CELLETS® to around 21 N for layered pellets—showing the coating slightly strengthened the structure. Dissolution testing showed moderate improvement for amlodipine and a strong improvement for hydrochlorothiazide, with release rates increasing up to 2.6 times. The faster release resulted from reduced crystallinity, improved wettability, and closer contact between drug and medium. FTIR spectra revealed broadening and merging of N–H peaks, confirming new hydrogen bonding and lattice disruption. Stability testing over one month showed that 2:1 and 1:1 ratios stayed mostly amorphous, while the 1:2 mixture recrystallized heavily.

Use of CELLETS® in This Study

The authors used CELLETS®, spherical microcrystalline cellulose cores about 1 mm in size, as the foundation for layering. Their smooth and strong surfaces ensured even coating under high shear. Micro-CT confirmed complete drug coverage and consistent thickness. Moreover, the CELLETS® provided the mechanical strength needed to prevent pellet fracture during processing. Their stable core structure helped maintain uniform shape and resistance to deformation.

Conclusion and Outlook

The study proves that solvent-free high-shear granulation can produce layered pellets with amorphized drug mixtures. The characterization of layered pellets showed lower crystallinity, faster release, and stable structure. Using CELLETS® as cores provided excellent mechanical support. The co-amorphous state of amlodipine and hydrochlorothiazide improved dissolution, especially for the poorly soluble hydrochlorothiazide.

Looking ahead, future research should test long-term stability under stress and evaluate in vivo bioavailability. Scaling the high-shear process could make it viable for industrial use. Furthermore, exploring multi-layer systems or combining more drugs could expand the possibilities of characterization of layered pellets in modern pharmaceutical development.

References

[1] Mahmoud et al., Pharmaceuticals 2025, 18(10), 1496; doi:10.3390/ph18101496

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