{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T20:21:40Z","timestamp":1787948500645,"version":"build-2784847793"},"update-to":[{"DOI":"10.12688\/f1000research.165282.1","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T00:00:00Z","timestamp":1765497600000}}],"reference-count":27,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T00:00:00Z","timestamp":1765497600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["f1000research.com"],"crossmark-restriction":false},"short-container-title":["F1000Res"],"abstract":"<ns3:p>Background Extrusion-spheronization is the most commonly used technology to produce pellets using microcrystalline cellulose as a pelletizing agent. However, it has the major drawbacks of lack of disintegration and prolonged drug release. This study aimed to develop rapidly disintegrating microcrystalline cellulose-based pellets. Methods Several pellet formulations were prepared via extrusion spheronization using a combination of microcrystalline cellulose, mannitol, polyethylene glycol 400(PEG 400), polyplasdone (PPXL), and croscarmellose sodium (CCS). Subsequently, they were evaluated for their physical characteristics. Results Process optimization indicated that 500 RPM is the ideal extrusion speed. Furthermore, the best spheronization speed was to start with a speed of 3000 RPM speed to cut off the extrudate at a shorter length and then lower the speed to 1000 RPM to reduce fine production and allow for spherical pellet formation. Increasing the polyethylene glycol content to 20% and maintaining the percentages of croscarmellose sodium (15%), 15%), and polyplasdone xl (5%), respectively, demonstrated a significant improvement in disintegration time (DT). Conclusions MCC-based pellets with fast-disintegrating characteristics were obtained by extrusion and spheronization. Incorporating the soluble filler mannitol, hydrophilic polymer PEG 400 with super-disintegrant CCS, and PPXL 400 resulted in a more porous matrix that facilitated water entry and rapid swelling of the pellets to explode and disintegrate quickly (2 min).<\/ns3:p>","DOI":"10.12688\/f1000research.165282.2","type":"journal-article","created":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T05:34:08Z","timestamp":1765517648000},"page":"711","update-policy":"https:\/\/doi.org\/10.12688\/f1000research.crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Fast disintegrating pellets: Formulation and evaluation"],"prefix":"10.12688","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-2974-7700","authenticated-orcid":false,"given":"Suhad","family":"Anabousi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9700-8532","authenticated-orcid":false,"given":"Hani","family":"Naseef","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1994-7910","authenticated-orcid":false,"given":"Moammal","family":"Qurt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7771-5608","authenticated-orcid":false,"given":"Abdallah","family":"AbuKhalil","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdullah","family":"Rabba","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"2560","published-online":{"date-parts":[[2025,12,12]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","DOI":"10.1155\/2020\/8583540","article-title":"Solid Dispersion Pellets: An Efficient Pharmaceutical Approach to Enrich the Solubility and Dissolution Rate of Deferasirox.","volume":"2020","author":"A Farmoudeh","year":"2020","journal-title":"Biomed. 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Research on extrusion-spheronization usually highlights that challenge. In contrast to earlier research that concentrated on individual excipients, our work employs a systematic four-stage experimental design to evaluate the synergistic effect of individual excipients. This has been emphasized in greater detail in the Introduction and Discussion sections. \n<b>2. Experimental Design<\/b> \n<i>\u201cThe number of formulations is large; rationale should be clearer. Drug selection should be justified.\u201d<\/i> \n<b>Response: <\/b>The large number of formulations (X, P, C, CP series) was intentional to evaluate progressive changes in excipient type, concentration, and interactions. Each series represented a distinct optimization stage, as described in Sections 3.1\u20133.5. Pseudoephedrine HCl (freely soluble) and orphenadrine citrate (sparingly soluble) were selected to represent two different solubility classes, demonstrating the broad applicability of the developed platform for immediate-release pellets. \n<b>3. Methodology<\/b> \n<i>\u201cBinder volume not numerically specified; replicates unclear; disintegration method adapted; statistics missing; no pure MCC control.\u201d<\/i> \n<b>Response: <\/b>The binder volume was adjusted empirically, approximately 1:1 (water : MCC), to obtain optimal wet mass plasticity, as noted in Section 3.2. All experiments\u2014including friability, moisture content, and disintegration\u2014were performed in triplicate, and mean values were reported. The modified disintegration method employed a 300 &micro;m mesh based on the USP disintegration principle and is consistent with previous multiparticulate studies (e.g., Chamsai et al., 2013). A pure MCC formulation was indeed evaluated during preliminary trials and\u2014as expected\u2014did not disintegrate within two hours, serving as our internal reference benchmark. We acknowledge that including standard deviations and statistical analysis (e.g., ANOVA) would strengthen the study and plan to incorporate this in future work. \n<b>4. Results and Data Interpretation<\/b> \n<i>\u201cResults lack statistical indicators; consider reducing repetitive tables.\u201d<\/i> \n<b>Response: <\/b>The experimental trends were consistent across replicates, with minimal batch-to-batch variation (&lt;5%). While full statistical analysis was not included in the published version, we agree that presenting mean &plusmn; SD and significance testing would enhance interpretation and will be considered in future studies. All data were kept in the main manuscript for transparency; however, we appreciate the suggestion to move repetitive data to supplementary materials in future work. \n<b>5. Discussion<\/b> \n<i>\u201cMechanisms are discussed qualitatively; additional evidence (SEM, porosity) would help.\u201d<\/i> \n<b>Response: <\/b>We appreciate this insightful comment. The mechanistic explanation\u2014enhanced porosity through mannitol and PEG 400, combined with the swelling effect of CCS and PPXL\u2014is supported by microscopic observations and disintegration behavior.  \n<b>6. Conclusion<\/b> \n<i>\u201cInclude future applications and perspectives.\u201d<\/i> \n<b>Response: <\/b>We agree and have highlighted the potential of these pellets for pediatric use, orally disintegrating multiparticulates, and immediate-release platforms suitable for drugs with varying solubilities. Future work will address scale-up feasibility, long-term stability, and coating strategies for taste masking. \n<b>7. Literature and Terminology<\/b> \n<i>\u201cSome references are old; \u201cplacebo\u201d vs \u201ccontrol\u201d terminology.\u201d<\/i> \n<b>Response: <\/b>While some foundational references are more than five years old, they remain seminal in extrusion\u2013spheronization and MCC pellet research. We also incorporated multiple recent studies (2019\u20132024) to ensure updated context. Regarding terminology, &quot;placebo formulation&quot; in our manuscript refers to CP12, the control formula without active ingredient. Both terms are appropriate in pharmaceutical formulation contexts. \n<b>8. Comparative Dissolution<\/b> \n<i>\u201cConsider comparing dissolution with marketed product.\u201d<\/i> \n<b>Response: <\/b>We appreciate this suggestion. Unfortunately, no comparable fast-disintegrating pellet product exists commercially. Nevertheless, achieving &gt;90% drug release within 20 minutes demonstrates significant enhancement relative to conventional MCC pellets, which typically exhibit delayed or incomplete release, as documented in literature.","URL":"https:\/\/f1000research.com\/articles\/14-711\/v2#referee-comment-14929","order":1,"name":"referee-comment-14929","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.5256\/f1000research.181895.r422849, Ramadan Al-Shdefat, Jadara University, Irbid, Irbid Governorate, 07 Nov 2025, version 1, indexed","URL":"https:\/\/f1000research.com\/articles\/14-711\/v1#referee-response-422849","order":2,"name":"referee-response-422849","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Hani Naseef<\/b>; \n<i>Posted: 10 Nov 2025<\/i>; Dear Ramadan Al-Shdefat We sincerely thank the reviewer for the thoughtful and constructive feedback on our manuscript. Below we provide detailed clarifications addressing the key points raised.  \n<b>1. Literature update<\/b> \n<i>\u201cSeveral cited references are older than five years; please include more recent ones.\u201d<\/i> \n<b>Response: <\/b>We agree that some references predate 2020. However, many of these are seminal works that remain highly relevant to MCC-based extrusion\u2013spheronization studies. Additionally, several recent publications (2019\u20132024) were included to ensure that the study reflects up-to-date developments in pellet formulation and disintegration enhancement. \n<b>2. Units and symbols<\/b> \n<i>\u201cEnsure consistent units and symbols throughout the text and tables.\u201d<\/i> \n<b>Response: <\/b>All units and symbols were standardized (%, \u03bcm, rpm, min, w\/w, etc.) and verified during the proofreading stage for consistency across tables and figures. \n<b>3. Emphasis on novelty and significance<\/b> \n<i>\u201cThe novelty claim could be strengthened<\/i>.\u201d \n<b>Response: <\/b>The novelty of this work lies in the synergistic combination of PEG 400, mannitol, and dual superdisintegrants (CCS + PPXL) within an MCC-based matrix\u2014an approach not previously reported. This formulation successfully overcomes MCC\u2019s inherent disintegration limitation and demonstrates a reproducible fast-release performance across two model drugs of different solubilities. \n<b>4. Control formulation terminology<\/b> \n<i>\u201cThe placebo formulation should be explicitly named the \u201ccontrol formula.\u201d<\/i> \n<b>Response: <\/b>Thank you for this suggestion. The placebo formulation corresponds to the control composition (CP12) without the active ingredient. The term \u201cplacebo\u201d was used to remain consistent with standard pharmaceutical formulation terminology, but \u201ccontrol formula\u201d is an equally valid expression. \n<b>5. Comparative dissolution data<\/b> \n<i>\u201cInclude comparative dissolution against a marketed product.\u201d<\/i> \n<b>Response: <\/b>We appreciate this suggestion. However, no directly comparable marketed fast-disintegrating pellet formulation was available at the time of study. Despite this, the &gt;90% release within 20 minutes achieved by our optimized formulation represents a significant advancement compared to conventional MCC-based pellets reported in the literature, which typically display slower disintegration and incomplete release. \n<b>6. Justification for excipient concentrations<\/b> \n<i>\u201cClarify the rationale for selected excipient levels.\u201d<\/i> \n<b>Response: <\/b>The chosen concentrations of PEG 400, mannitol, CCS, and PPXL were based on preliminary screening trials assessing pellet sphericity, friability, and disintegration time. The final levels reflected the best balance between mechanical integrity and rapid disintegration, as described in the Materials and Methods section. \n<b>8. Drug loading clarification<\/b> \n<i>\u201cSpecify whether drug loading was via dry mixing or wet granulation.\u201d<\/i> \n<b>Response: <\/b>The drug loading step was performed during wet massing before extrusion (wet granulation). As presented in Tables 6\u20138, drug incorporation had no significant effect on pellet sphericity, friability, or size distribution. \n<b>9. Discussion and conclusion focus<\/b> \n<i>\u201cRefine the discussion and conclusion to highlight practical implications.\u201d<\/i> \n<b>Response: <\/b>We agree that practical implications are essential. The revised sections highlight that the developed pellets can serve as orally disintegrating multiparticulate systems suitable for pediatric and geriatric use, with potential for scale-up and modified-release applications. \n<b>10. Publication date and literature timeline<\/b> \n<i>\u201cThe study could include newer references.\u201d<\/i> \n<b>Response: <\/b>The experimental work was largely completed in 2022, and the cited literature reflects the research landscape at that time. Nevertheless, newer relevant studies (up to 2024) were added during manuscript finalization to ensure comprehensive coverage. \n<b>Final statement<\/b> We are grateful for the reviewer\u2019s balanced and thoughtful comments. These insights confirm the technical strength of our work and provide valuable direction for future studies involving statistical validation, scale-up feasibility, and long-term stability assessments.","URL":"https:\/\/f1000research.com\/articles\/14-711\/v2#referee-comment-14930","order":3,"name":"referee-comment-14930","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"The author(s) declared that no grants were involved in supporting this work","order":4,"name":"grant-information","label":"Grant Information"},{"value":"This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.","order":0,"name":"copyright-info","label":"Copyright"}]}}