Pharmaceutical development of effervescent tablets focuses on creating oral dosage forms that dissolve rapidly in water and deliver active ingredients in a convenient and patient-friendly manner. Effervescent tablets contain an acidic component, commonly citric acid, and an alkaline component such as sodium bicarbonate. When these substances come into contact with water, they generate carbon dioxide and form a solution that patients can drink easily. As a result, effervescent formulations often improve drug dissolution, accelerate absorption, and enhance patient compliance. In addition, they provide an attractive option for pediatric, geriatric, and dysphagic patients who struggle to swallow conventional tablets.
The use of pellet technology further advances the pharmaceutical development of effervescent tablets. Pellets can separate incompatible ingredients, improve content uniformity, and increase formulation stability. Moreover, pellet-based systems can mask unpleasant tastes and protect sensitive active ingredients from degradation. Consequently, they can improve both product quality and the patient experience. These advantages make pellets an increasingly valuable platform for modern effervescent formulations.
Pharmaceutical Development of Effervescent Tablets Containing Acetylsalicylic Acid, Paracetamol, and Ascorbic Acid
The publication [1] entitled Pharmaceutical Development of Composition of Effervescent Tablets with Acetylsalicylic Acid, Paracetamol, and Ascorbic Acid presents the development of a fixed-dose combination effervescent tablet containing 300 mg acetylsalicylic acid, 200 mg paracetamol, and 300 mg ascorbic acid. The authors aimed to create a high-quality formulation for the Ukrainian pharmaceutical market while ensuring therapeutic efficacy, patient acceptability, and manufacturing feasibility.
To achieve this goal, the researchers applied a Quality-by-Design (QbD) approach. First, they defined the Quality Target Product Profile and identified critical quality attributes. Next, they investigated the influence of different excipients on powder flow, compressibility, tablet strength, disintegration behavior, and sensory properties. Furthermore, they used statistical methods, including regression analysis and utility-function optimization, to determine the most suitable formulation.
Excipient Groups and their Effects on Technological Performance
The study evaluated several excipient groups and their effects on technological performance. The researchers measured bulk density, tapped density, Carr’s index, flowability, hardness, friability, mass uniformity, and dissolution characteristics. In addition, they assessed organoleptic properties because consumer acceptance plays an important role in effervescent products. Among other excipients. microcrystalline cellulose micropellets (CELLETS® 100), are often utilized to enhance tablet hardness, which is frequently a weak point in effervescent systems [2,3].
A major outcome of the study was the identification of an optimal ratio between anhydrous citric acid and sodium bicarbonate. The authors determined that a ratio of 1:1.312 provided efficient carbon dioxide generation and rapid tablet disintegration. Consequently, the formulation achieved fast dissolution while maintaining acceptable mechanical strength. The researchers also found that the interaction between sorbitol and the binder system significantly influenced tablet performance. Therefore, careful excipient selection proved essential for balancing stability, manufacturability, and patient experience.
Optimized Formulation
The optimized formulation contained acetylsalicylic acid, paracetamol, ascorbic acid, anhydrous citric acid, sodium bicarbonate, lactose, polyvinylpyrrolidone, crospovidone, sorbitol, sodium saccharin, lemon flavoring, and sodium stearyl fumarate. Subsequently, the team evaluated the final product against pharmacopoeial requirements and predefined quality criteria. The tablets met all quality specifications and demonstrated suitable technological characteristics.
The authors also conducted stability studies under long-term storage conditions. The results showed that the formulation remained stable for at least 24 months when stored in protective aluminum-polymer packaging. Therefore, moisture-resistant packaging emerged as a critical factor for preserving product quality. Overall, the study demonstrated that a systematic QbD strategy can successfully support the pharmaceutical development of effervescent tablets and generate a robust, patient-oriented product.
Active Pharmaceutical Ingredients
Acetylsalicylic Acid
Acetylsalicylic acid (ASA), commonly known as aspirin, is a non-steroidal anti-inflammatory drug (NSAID). It provides analgesic, antipyretic, anti-inflammatory, and antiplatelet effects. The compound is generally classified as a Biopharmaceutics Classification System (BCS) Class I drug because it exhibits high solubility and high permeability. Clinicians use ASA to treat pain, fever, inflammatory conditions, and cardiovascular disorders. In effervescent formulations, ASA dissolves rapidly and may reach therapeutic concentrations faster than conventional tablets. As a result, patients can experience quicker symptom relief.
Paracetamol
Paracetamol, also known as acetaminophen, is an analgesic and antipyretic agent. It is commonly classified as a BCS Class III drug due to its high solubility and relatively low permeability. Physicians frequently prescribe paracetamol for mild-to-moderate pain and fever. In this combination product, paracetamol complements the analgesic action of acetylsalicylic acid. Furthermore, its established safety profile supports its widespread use in over-the-counter therapies. The effervescent dosage form improves dissolution and simplifies administration for many patients.
Ascorbic Acid
Ascorbic acid, or vitamin C, is a water-soluble vitamin with strong antioxidant properties. It generally displays characteristics associated with high solubility and high permeability. Therefore, it is often considered to exhibit BCS Class I-like behavior. Clinicians use ascorbic acid to prevent or treat vitamin C deficiency and to support immune function. In addition, the antioxidant activity of vitamin C may complement the therapeutic effects of analgesic combinations. Effervescent formulations are particularly suitable for ascorbic acid because they provide rapid dissolution and pleasant sensory characteristics.
Conclusion and Outlook
The pharmaceutical development of effervescent tablets offers significant opportunities to improve oral drug delivery. The reviewed study demonstrates how a structured Quality-by-Design approach can optimize formulation performance, product stability, and patient acceptance. Moreover, the combination of acetylsalicylic acid, paracetamol, and ascorbic acid provides a multifunctional therapy for pain and fever management. The results also highlight the importance of excipient selection, effervescent component ratios, and protective packaging.
Looking ahead, pellet-based technologies could further strengthen the pharmaceutical development of effervescent tablets. For example, pellets can improve stability, separate incompatible ingredients, and enable modified-release profiles. In addition, they can support the development of personalized medicines and complex combination products. Consequently, pellet-containing effervescent tablets will likely play an increasingly important role in future pharmaceutical innovation.
[2] V. Nikam, et al., Design, development and physicochemical evaluation of effervescent tablets of antihistamine drug
Int. J. Drug Deliv.Technol., 13 (4) (2023), pp. 1520-1526, 10.25258/ijddt.13.4.61
[3] P. Kaur, et al., Formulation, development and evaluation of effervescent tablet of green tea (Camellia sinensis), Cent. Nerv. Syst. Agents Med. Chem., 25 (4) (2025), pp. 579-590, 10.2174/0118715249333134250116112001
https://cellets.com/wp-content/uploads/2026/06/Pharmaceutical-development-of-effervescent-tablets-small.png304608Bastian Arlthttps://cellets.com/wp-content/uploads/2016/10/Logo_Cellets_2016_website.pngBastian Arlt2026-10-23 17:06:482026-10-23 17:06:48Pharmaceutical development of effervescent tablets
Introduction to Multilayered Pharmaceutically Active Compound Technology
Multilayered pharmaceutically active compound-releasing microparticles in a liquid dosage form represent an innovative approach to oral drug delivery. This technology combines the benefits of coated pellets with the convenience of liquid administration. Effervescent tablets are solid dosage forms that release carbon dioxide when they dissolve in water. This reaction results from the interaction between an acid source, such as citric acid, and a carbonate or bicarbonate salt. Patients consume the resulting solution or suspension immediately after preparation. Consequently, effervescent tablets improve ease of administration and often enhance patient compliance.
Pellets play an increasingly important role in modern effervescent tablet formulations. Unlike conventional powder blends, pellets can carry individual functional coatings that protect active pharmaceutical ingredients (APIs) from degradation. In addition, pellets can separate incompatible ingredients within the same dosage form. They also improve taste masking and enable modified-release properties. As a result, formulators can develop more stable and effective products. Furthermore, pellet-containing effervescent tablets often reduce gastrointestinal irritation and improve dose uniformity. These advantages benefit both the final pharmaceutical product and the patient.
Multilayered pharmaceutically active compound-large
Summary of EP3117824A1
The European patent EP3117824A1 describes a drug delivery platform based on multilayered pharmaceutically active compound-releasing microparticles suspended in a liquid dosage form. The invention addresses a major challenge in pharmaceutical formulation. Many controlled-release and enteric-coated particles lose functionality when they remain in contact with water for extended periods. Therefore, maintaining stability during storage becomes difficult.
The patented technology uses microparticles that contain an API-loaded core surrounded by multiple functional coating layers. A controlled-release or enteric coating forms the intermediate layer. An additional outer protective layer surrounds this coating. The inventors designed this outer layer from a combination of hydrophilic and hydrophobic materials. Consequently, the layer protects the underlying release-controlling membrane from premature exposure to the liquid environment.
During storage, the protective coating minimizes drug leakage and preserves the integrity of the controlled-release system. As a result, the microparticles maintain their desired release characteristics for extended periods. Once the patient administers the formulation, the outer coating dissolves rapidly in the stomach. Subsequently, the underlying controlled-release coating resumes its intended function. This mechanism allows the formulation to deliver the API at a predefined location or rate within the gastrointestinal tract.
The invention offers particular advantages for drugs that require modified release, intestinal targeting, or protection from acidic gastric conditions. In addition, the technology supports the development of patient-friendly liquid formulations. This feature benefits pediatric, geriatric, and dysphagic patients who often struggle to swallow tablets or capsules. Overall, the patent combines the flexibility of pellet-based drug delivery with improved stability in aqueous dosage forms. Therefore, it represents an important advancement in oral pharmaceutical technology.
Impact of MCC spheres in this Patent
In EP3117824A1, CELLETS® or similar spherical starter cores serve as the fundamental substrate for producing the multilayered pharmaceutically active compound-releasing microparticles. These inert pellet cores, commonly composed of microcrystalline cellulose, provide a highly uniform and mechanically stable surface onto which drug-containing layers and subsequent functional coatings can be applied with high precision.
Their excellent sphericity promotes uniform coating thickness, which is critical for achieving reproducible controlled-release performance and minimizing variability between pellets. Furthermore, Cellets enable high drug loading while maintaining robust processing characteristics during fluid-bed coating operations.
Pellet size also plays an important role in the final product performance. Smaller pellets, typically in the range of 100–500 µm (such as CELLETS® 100, 200, 350), offer a larger surface area and can provide faster or more uniform drug release, whereas larger pellets, often between 500–1500 µm (such as CELLETS® 500, 700, 1000), facilitate the application of multiple coating layers and may support more sophisticated release profiles.
In addition, smaller pellets generally improve content uniformity and patient acceptability, especially in liquid and effervescent dosage forms, because they create a smoother mouthfeel and more homogeneous suspension. Therefore, selecting the appropriate Cellet size represents a key formulation parameter that influences coating efficiency, drug release kinetics, stability, and overall patient experience.
Acetylsalicylic Acid, Paracetamol, and Ascorbic Acid in Pellet-Based Effervescent Formulations
Although EP3117824A1 does not specifically focus on acetylsalicylic acid, paracetamol, or ascorbic acid, the technology applies well to these APIs. Acetylsalicylic acid, commonly known as aspirin, belongs to the nonsteroidal anti-inflammatory drug (NSAID) class. It treats pain, fever, inflammation, and cardiovascular disorders. Depending on the classification source and physiological conditions, aspirin generally falls within BCS Class I or Class III. Because aspirin can irritate the gastric mucosa, pellet-based controlled-release systems may improve gastrointestinal tolerability.
Paracetamol is an analgesic and antipyretic agent that treats pain and fever. It is generally classified as a BCS Class I compound due to its high solubility and permeability. Furthermore, pellet technology can improve taste masking and provide modified-release options. These properties make paracetamol formulations more suitable for pediatric and elderly patients.
Ascorbic acid, also known as vitamin C, functions as a water-soluble vitamin and antioxidant. Healthcare professionals use it to prevent and treat vitamin C deficiency. It exhibits high aqueous solubility and frequently appears in effervescent products. Moreover, pelletization can improve formulation stability by separating ascorbic acid from reactive ingredients. This approach may reduce degradation during storage and improve product quality.
Conclusion and Outlook
Multilayered pharmaceutically active compound technology offers a sophisticated solution for modern oral drug delivery. It combines coated pellet systems with liquid dosage forms while maintaining controlled-release functionality. Moreover, the technology supports improved stability, enhanced patient convenience, and flexible formulation design. When formulators incorporate pellets into effervescent tablets, they can protect sensitive APIs, reduce gastrointestinal side effects, and optimize therapeutic performance. As pharmaceutical research advances, multilayered pharmaceutically active compound systems will likely support more complex formulations and personalized treatment strategies. Consequently, this technology may become an increasingly important platform for next-generation oral medicines.
Patent Summary
Name of Patent: Multilayered pharmaceutically active compound-releasing microparticles in a liquid dosage form
https://cellets.com/wp-content/uploads/2026/06/Multilayered-pharmaceutically-active-compound-small.jpg533852Bastian Arlthttps://cellets.com/wp-content/uploads/2016/10/Logo_Cellets_2016_website.pngBastian Arlt2026-07-21 16:17:382026-07-21 16:17:38Multilayered pharmaceutically active compound-releasing microparticles in a liquid dosage form
MCC pellets under rheological investigation are ideal model spheres for studying powder behavior. In this study, we revisit the work of V. Mohylyuk and R. Dattani to analyze the effect of pellet size on powder properties. Understanding how pellet size influences flow and handling is essential for optimizing powder performance. Moreover, investigating size variations helps improve material processing and formulation strategies. By focusing on these aspects, researchers can better predict and control the behavior of MCC spheres in different applications.
Rheological behavior has a deep impact
The rheological behavior of powders greatly affects pharmaceutical formulations and processing steps. In particular, when studying MCC pellets under rheological investigation, powder rheology becomes a key area of focus. Typically, powders behave as solids under static conditions; however, they can fluidize under certain circumstances. Consequently, fluidization is widely used in pharmaceutical processes because it enables controlled and uniform coating or layering of starter beads with drugs and functional excipients. Moreover, while fluid behavior in liquids depends on inter- and intra-molecular interactions, network bonds, and temperature, powder fluidization primarily relies on micro-particular properties such as particle size, surface characteristics, and flowability. In addition, the exact gas speed and volume required for powder fluidization must be carefully adjusted for each system. Therefore, a thorough analysis of the powder is essential to achieve precise control and optimal performance.
In this study, CELLETS® are used for the investigation. These pellets consist of Microcrystalline Cellulose, featuring a smooth surface, high sphericity, and minimal friability. Due to these properties, CELLETS® are popular as starter beads in pharmaceutical formulations and are ideal model spheres for rheological studies. Four types—CELLETS® 90, CELLETS® 100, CELLETS® 200, and CELLETS® 350—were examined, with size distributions ranging from 90 µm to 500 µm. The D50 values for these types vary between 94 µm and 424 µm. The specific size distribution of each CELLETS® type is summarized in Table 1.
Table 1: Particle size distribution of selected MCC spheres.
Characterization Methods for MCC Pellets Under Rheological Investigation
First, we measured the particle size distribution of MCC pellets under rheological investigation using optical digital microscopy (Keyence VHX 600). This approach provides precise and reliable data on pellet dimensions, which is essential for understanding their flow and handling properties.
Next, we applied standard pharmacopoeia methods to determine bulk and tapped density, as well as flow rate using a gravitational funnel. In addition, we analyzed the dynamic angle of repose and dynamic cohesivity index with a rotating drum tester (GranuDrum). Furthermore, we used a powder rheometer (FT4 Powder Rheometer) to evaluate basic flowability energy, specific energy, aerated energy, permeability, and compressibility. Altogether, these measurements give a comprehensive understanding of MCC pellets under rheological investigation and offer detailed insights into their performance in pharmaceutical applications.
Results of the rheological investigations
Figure 1 presents the particle size distribution of MCC pellets under rheological investigation, as measured with an optical digital microscope.
With increasing particle size the apparent specific surface area (fig. 2) decreases obviously. Hence, a decrease in pellet size, allow an expectation in increase in mechanical interlocking.
With increasing particle size, the bulk and tapped density of CELLETS® increases; however, the densification kinetics remained approximately the same for all pellet sizes (Fig. 3). Moreover, a few periodic oscillations significantly influenced the density of the pellets, highlighting subtle variations in their behavior.
With increasing particle size the compressibility decreases (fig. 4). The applied force was identical for all pellets sizes. Worsening packing efficiency.
With increasing particle size the permeability increases while applying the same force for all pellet types. (fig. 5). increase in voids between particles.
The gravitational funnel method suggests an absence of correlation between the mass flow rate and pellet size or specific surface area (fig. 6).
Analyzing the dynamic angle of repose
We analyzed the dynamic angle of repose to evaluate the powder flow of MCC pellets under rheological investigation. All pellet sizes showed similar behavior: as the rotation speed increased, the angle of repose rose almost linearly. The measurements for all pellet types formed a funnel shape within the range of analytic errors (Fig. 7). These results clearly characterize the dynamic flow ability of the powders.
With increasing particle size the specific energy decreases (fig. 8). The level of interlocking and friction between powder particles decreased, the flowability increased.
With increasing particle size the basic flowability energy decreases (fig. 9). the flowability in a constrained environment increased.
The aerated energy rises as air velocity decreases (Fig. 10). This parameter helps determine the minimum fluidization velocity, as increasing air velocity alters interparticle interactions.
The aerated energy increased with increasing pellet size (fig. 11). dependent on particle mass and inter-particle interactions (friction).
with increasing pellet size, the cohesive index decreases (fig. 12). an indicator of the sum of inter-particle interaction forces.
Summary
Overall, researchers have now characterized MCC pellets under rheological investigation more comprehensively than ever before, providing new insights into their flow behavior and material properties. Powder rheology methods successfully revealed the bulk powder behavior, flow properties, and inter-particular interactions as a function of pellet size. CELLETS® served as robust model spheres made of Microcrystalline Cellulose, making them ideal for these detailed investigations. This study highlights the importance of pellet size in predicting and optimizing powder performance in pharmaceutical formulations.
References
[1] V. Mohylyuk and R. Dattani, “Assessment of the effect of microcrystalline cellulose (MCC) spheres size on the flow via powder rheology”, Conference: The FORGE: Hybrid Conference on Particle Characterisation (March 2022), doi:10.13140/RG.2.2.14935.75688
Research Advances in MCC Pellet Technology and Applications
Scientific literature on MCC pellets highlights the growing importance of CELLETS® in pharmaceutical and scientific research. These microcrystalline cellulose spheres play a key role in developing reliable multiparticulate drug delivery systems. Researchers have investigated improved rivaroxaban dissolution, efficient film coating kinetics, and their use in orally disintegrating films. In addition, studies focus on colon-targeted vitamin B₂ release and fluidized-bed coating performance. Moreover, academic theses explore uniform hot-melt coating techniques and detailed modeling of tablet disintegration. As a result, MCC pellets continue to prove their versatility across many dosage forms. Consequently, this expanding body of literature reinforces the value of CELLETS® in advancing modern drug delivery technologies.
Selected Scientific literature on MCC pellets
Please, find scientific literature on MCC pellets (CELLETS®), MCC spheres. This list is constantly updated and does not claim to be complete. If you are author, scientist or R&D specialist, please submit your present publication to us for improving the visibility.
Research article Optimising the in vitro and in vivo performance of oral cocrystal formulations via spray coating European Journal of Pharmaceutics and Biopharmaceutics, Volume 124, March 2018, Pages 13-27
Dolores R. Serrano, David Walsh, Peter O’Connell, Naila A. Mugheirbi, Zelalem Ayenew Worku, Francisco Bolas-Fernandez, Carolina Galiana, Maria Auxiliadora Dea-Ayuela, Anne Marie Healy
Conference abstract Multiple-unit orodispersible mini-tablets International Journal of Pharmaceutics, Volume 511, Issue 2, 25 September 2016, Page 1128
Anna Kira Adam, Christian Zimmer, Stefan Rauscher, Jörg Breitkreutz
Research article Asymmetric distribution in twin screw granulation European Journal of Pharmaceutics and Biopharmaceutics, Volume 106, September 2016, Pages 50-58
Tim Chan Seem, Neil A. Rowson, Ian Gabbott, Marcelde Matas, Gavin K. Reynolds, AndyIngram
Research article Physical properties of pharmaceutical pellets Chemical Engineering Science, Volume 86, 4 February 2013, Pages 50-60
Rok Šibanc, Teja Kitak, Biljana Govedarica, StankoSrčič Rok Dreu
Research article Understanding Fluidized-Bed Granulation Pharmaceutical Technology 35 (8), 2011, 63-67 A. Burggraeve, T. Van Den Kerkhof, M. Hellings, J.P. Remon, C. Vervaet, T. De Beer
Research article Labscale fluidized bed granulator instrumented with non-invasive process monitoring devices Chemical Engineering Journal, Volume 164, Issues 2–3, 1 November 2010, Pages 268-274
Jari T. T. Leskinen, Matti-Antero H. Okkonen, Maunu M. Toiviainen, Sami Poutiainen, Mari Tenhunen, Pekka Teppola, Reijo Lappalainen, Jarkko Ketolainen, Kristiina Järvinen
Research article New insights into segregation during tabletting International Journal of Pharmaceutics, Volume 397, Issues 1–2, 15 September 2010, Pages 19-26
S. Lakio, S. Siiriä, H. Räikkönen, S. Airaksinen, T. Närvänen, O. Antikainen, J.Yliruusi
Research article Granule size distribution of tablets Journal of Pharmaceutical Sciences, Volume 99, Issue 4, April 2010, Pages 2061-2069
Satu Virtanen, Osmo Antikainen, Heikki Räikkönen, Jouko Yliruusi
Research article In vivo evaluation of the vaginal distribution and retention of a multi-particulate pellet formulation European Journal of Pharmaceutics and Biopharmaceutics, Volume 73, Issue 2, October 2009, Pages 280-284
Nele Poelvoorde, Hans Verstraelen, Rita Verhelst, Bart Saerens, Ellen De Backer, Guido Lopes dos Santos Santiago, Chris Vervaet, Mario Vaneechoutte, Fabienne De Boeck, Luc Van Borteld, Marleen Temmerman, Jean-Paul Remon
List – Publications with MCC spheres, 2008 and earlier
Research article Attrition strength of different coated agglomerates Chemical Engineering Science, Volume 63, Issue 5, March 2008, Pages 1361-1369
B. van Laarhoven, S.C.A. Wiers, S.H. Schaafsma, G.M.H. Meesters
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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
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.
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.
https://cellets.com/wp-content/uploads/2025/12/Different-Pelletization-Techniques-Functionality-and-Key-Insights.jpg10171529Bastian Arlthttps://cellets.com/wp-content/uploads/2016/10/Logo_Cellets_2016_website.pngBastian Arlt2025-12-11 14:57:222025-12-11 15:02:32Different pelletization techniques: Introduction and Summary of the Thesis by Azza A. K. Mahmoud
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:
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
https://cellets.com/wp-content/uploads/2025/12/Enzyme-cleavable-methadone-prodrugs-Innovations-in-formulation.jpg10181531Bastian Arlthttps://cellets.com/wp-content/uploads/2016/10/Logo_Cellets_2016_website.pngBastian Arlt2025-12-11 14:13:432025-12-11 14:40:25Patent on enzyme-cleavable methadone prodrugs and methods of use thereof
Cellulose-derived spherical activated carbon offers a sustainable and efficient solution for adsorbing harmful compounds such as uremic toxins [1]. This carbon material is made from renewable cellulose, which is transformed into spherical particles and then activated to increase surface area and porosity. The spherical shape improves flow properties and reduces dust, making it ideal for pharmaceutical and biomedical applications. Moreover, it combines eco-friendly production with strong adsorption performance, providing a safer and more manageable alternative to traditional powdered carbon.
Uremic toxins are metabolic waste compounds that accumulate in the body when kidney function declines. These toxins interfere with biological processes and contribute to various health issues. Drugs and adsorbent therapies aim to remove them effectively, but such interventions must be selective to avoid removing essential molecules. Therefore, understanding both the functionality and potential toxicity of uremic toxins is crucial for designing safe and effective treatments. While adsorption therapies can improve toxin clearance, they also carry risks such as unintended drug adsorption or gut irritation, which must be minimized through precise material engineering.
Summary of the Publication
Shin et al. (2025) present a study on sustainable cellulose-derived spherical activated carbon designed for efficient uremic toxin removal. The research focuses on transforming cellulose into spherical carbon precursors and activating them to achieve high porosity and surface area. The resulting material combines uniform shape, hierarchical pore structure, and strong mechanical integrity. These properties make it ideal for biomedical use, particularly for toxin adsorption under gastrointestinal conditions. The authors report that the spheres maintain their shape across different pH levels and perform well even in dynamic or competitive adsorption environments.
Furthermore, the adsorption kinetics show that these spherical carbons quickly capture uremic toxin molecules such as indole derivatives. The authors compare the material with conventional activated carbon powders and find significant improvements in handling and biocompatibility. Importantly, the spheres demonstrate low cytotoxicity, which supports their suitability for oral or extracorporeal use. Because of their uniform size and reduced dusting, they minimize irritation risks and can be easily integrated into medical formulations or devices. In addition, the study discusses the environmental and economic benefits of using cellulose feedstocks, showing that this process supports circular material use and low-cost production.
A key part of the research involves CELLETS® 100 and CELLETS® 500. These cellulose microspheres act as templates during synthesis. CELLETS® 100, having a smaller diameter, produces finer activated carbon spheres, while CELLETS® 500 leads to larger ones. This variation allows the authors to tune pore structure, surface area, and mechanical properties. Consequently, CELLETS® 100-derived carbons show faster adsorption kinetics, whereas CELLETS® 500-derived carbons offer better durability. The study highlights that choosing the right CELLETS® grade directly influences the final adsorption performance and application potential of the spherical carbon.
Conclusion and Outlook
The development of cellulose-derived spherical activated carbon marks a major step toward safer and more sustainable toxin removal technologies. By merging green chemistry with advanced nanoengineering, these materials achieve both environmental and therapeutic goals. Their customizable size, stability, and porosity enable versatile use in pharmaceutical formulations and medical devices. Looking ahead, researchers must explore long-term biocompatibility, selective adsorption behavior, and performance in complex biological fluids. Moreover, scaling up production under pharmaceutical standards will determine clinical viability. With further optimization, cellulose-derived spherical activated carbon could revolutionize uremic toxin management and open new paths for eco-friendly therapeutic materials.
References
[1] Kyungmin Shin, Su-Bin Kim, Yong-Han Kim, Dae-Duk Kim, Seul-Yi Lee, Soo-Jin Park, Materials & Design,a available online 10 October 2025, 114892. doi:10.1016/j.matdes.2025.114892
Gamma‑hydroxybutyrate (GHB) is an endogenous neurotransmitter also used pharmaceutically—usually as sodium oxybate—for treating narcolepsy and related disorders. It exerts its therapeutic effects by modulating GABA_B receptors and promoting slow-wave sleep, alleviating cataplexy, and reducing excessive daytime sleepiness. Despite its efficacy, current twice-nightly dosing regimens present challenges: dose‑dumping in the presence of alcohol, variable pharmacokinetics depending on food intake, and patient inconvenience. To address these issues, modern formulations—and especially the innovative use of CELLETS® —pursue once-nightly controlled release.
API Benefits and Patient Advantages
Administering gamma‑hydroxybutyrate compositions in a modified‑release format brings multiple patient-centric benefits. A single nightly dose minimizes repeated nighttime awakenings and improves adherence. These formulations exhibit lower peak concentrations (C_max) with sustained therapeutic exposure (AUC)—achieving similar or better efficacy while reducing adverse events such as dizziness or nausea. This consistency is especially meaningful when dosing less than two hours after eating, which often is more convenient for patients; the controlled formulations are more forgiving of fed-state PK variability and less prone to alcohol-induced dose-dumping.
Use of CELLETS® in methods of administering gamma-hydroxybutyrate compositions
CELLETS® — spherical microcores used in multiparticulate drug delivery—are central to these modern GHB formulations. The patent US 20250186377 A1 introduces coated cellet-based microparticles that incorporate immediate-release (IR) and modified-release (MR) segments within a single unit dose. The MR portion involves CELLETS® (e.g. CELLETS® 90, CELLETS® 100 or CELLETS® 127, and other MCC beads) coated with polymers carrying free carboxyl groups combined with hydrophobic materials (e.g., high melting point waxes), engineered to delay GHB release until intestinal transit. CELLETS® enable precise layering, efficient coating, and reproducible drug release profiles while resisting pH- and alcohol-triggered dose dumping.
This multiparticulate approach achieves desired PK: IR CELLETS® ensure rapid onset while MR CELLETS® sustain plasma GHB levels up to 8 hours. In contrast to IR liquid sodium oxybate, the coated cellet formulation shows dose‑proportional C_max and AUC across doses of 4.5 g, 7.5 g, and 9 g, with most AEs clustering near C_max but at overall milder intensity. Remarkably, cellet-based formulations maintain comparable therapeutic exposure even with postprandial dosing, offering flexibility not seen in immediate-release forms.
Key Findings
The inventive cellet-based GHB composition delivers both immediate and controlled drug release in one unit, offering dose‑proportional pharmacokinetics and sustained therapeutic levels for 8 hours, under single-nightly dosing. It improves safety by reducing peak‑induced adverse events, lowers risk of alcohol‑related dose-dumping, and allows dosing within two hours after meals. Studies show comparable efficacy to twice-nightly IR sodium oxybate on sleep quality and daytime alertness, with better convenience and adherence.
Conclusion & Outlook
The patented cellet‑based modified-release formulation of GHB marks a significant advancement in administering gamma‑hydroxybutyrate compositions. By incorporating coated CELLETS® that combine IR and MR elements, this approach mitigates common limitations—meal dependency, alcohol interactions, multiple nightly doses—while preserving therapeutic efficacy. For patients with narcolepsy or cataplexy, this translates into improved sleep continuity, reduced daytime symptoms, and enhanced quality of life.
Looking ahead, further clinical evaluation could extend the CELLETS® platform to other formulations of gamma‑hydroxybutyrate salts or co‑therapies (e.g., with sodium valproate), further broadening the therapeutic utility. This modular, multiparticulate delivery system could set a new standard for nightly dosing regimens where controlled pharmacokinetics and patient preferences align.
Patent Holder(s): Not explicitly indicated in the publicly listed data, but associated inventors likely affiliated with pharmaceutical firms focusing on CNS therapeutics (e.g., Jazz Pharmaceuticals or Flamel Ireland).
https://cellets.com/wp-content/uploads/2025/07/US20250186377A1-cellet‑based-modified‑release-gamma‑hydroxybutyrate-formulation-ChatGPT-Image-11.-Juli-2025-13_12_09.jpg15361024Bastian Arlthttps://cellets.com/wp-content/uploads/2016/10/Logo_Cellets_2016_website.pngBastian Arlt2025-07-11 10:34:072025-07-11 13:42:48Patent on methods of administering gamma-hydroxybutyrate compositions with divalproex sodium
The present invention generally relates to enteric-coated particles containing lactoferrin. More specifically, the present invention provides an enteric-coated particle comprising (or consisting essentially of): a) a core comprising (or consisting essentially of) an inert core-forming material selected from cellulose polymer, sugar, sugar alcohol, starch and carnauba wax; b) a first coating layer substantially covering the core and comprising (or consisting essentially of) b-1) lactoferrin, b-2) a pharmaceutically acceptable binder and optionally b-3) one or more other suitable excipients, such as a plasticizer; and c) a second coating layer substantially covering the first coating layer and comprising (or consisting essentially of) c-1) an enteric coating material, and optionally c-2) one or more suitable excipients, such as a plasticizer and/or an anti-tacking agent. The present invention further provides pharmaceutical compositions and oral dosage forms comprising one or more particles according to the present invention. [1]
Enteric-coated particles with CELLETS® and other starter beads
This formulations is based on starter beads, exemplary such as sugar, wax or microcrystalline cellulose (MCC). For the latter material MCC, specifically such as CELLETS® 100, CELLETS® 200, CELLETS® 350, CELLETS® 500, CELLETS® 700, or CELLETS® 1000 are mentioned. Through coating and layering of CELLETS® with excipients and the active, a modified release is obtained wherein at most 10% of lactoferrin is released from the particle within 120 minutes.
Document information
Document Type and Number: (“enteric-coated particles containing lactoferrin”)
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