Functionalized calcium carbonate microparticles in ethyl cellulose films: A vehicle for sustained amoxicillin release for medical applications

Petru Niga; Simone Sala; Jenny Rissler; Lina Nyström; Anna Fureby; Ulla Elofsson; Joachim Schoelkopf; Roger Roth; Patrick Gane

doi:10.1371/journal.pone.0320280

Peer Review History

Original SubmissionFebruary 17, 2025
7 Apr 2025 Decision Letter - Mahmood Ahmed, Editor Dear Dr. Niga, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. ============================== One or more of the reviewers has recommended that you cite specific previously published works. Members of the editorial team have determined that the works referenced are not directly related to the submitted manuscript. As such, please note that it is not necessary or expected to cite the works requested by the reviewer ============================== Please submit your revised manuscript by May 22 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. 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Is the manuscript presented in an intelligible fashion and written in standard English??> Reviewer #1: Yes Reviewer #2: Yes Reviewer #3: Yes ****** Reviewer #1: Dear Authors, The research work is quite interesting with well problem statement but authors have designed the experiment for verifying material properties of amoxicillin loaded FCC not in a good manner and not thorough study to clearly understand the characteristic of the loaded FCCs. It is very difficult to follow mentioned experimental results step by step. It is very regret to recommend for rejection due to the quality of presented experimental data especially in the part of material characterization. For example: 1. To study the releasement of amoxicillin from FCC, FCC fines and FCC granules were used as carrier but to study the releasement of the amoxicillin from the Ethyl cellulose film, Omyapharm FCC500-OG was used instead without notifying the solid support to convince the possibility. Only particle size ranges of FCC fines and FCC granules were provided but not BET specific area not bulk density. 2. The content of amoxicillin is not informed for releasement study from the loaded FCC granules (Figure 4) but from the loaded FCC fines, the releasement results is presented both from 15% and 30% amoxicillin loading. The releasement of neat FCC is not comparatively studied. 3. XRD diffraction pattern of precipitated amoxicillin is presented but its SEM micrograph is not shown, to verify different morphology. 4. In the material characterization results from loaded FCC, the finding are rarely compared to other similar finding and made discussion. Reviewer #2: The study presents an interesting approach utilizing functionalized calcium carbonate (FCC) microparticles embedded in ethyl cellulose (EC) films for sustained antimicrobial drug release. This research is particularly relevant for indwelling medical applications, addressing the need for prolonged drug release in such devices. 1. Please explain the novelty compared to published work in this field. Pure drug used or its salt used? 2. The introduction can be improve with recent work in this filed, like, https://doi.org/10.1007/s12668-024-01722-3, https://doi.org/10.2174/0115748855274979231228103038, https://doi.org/10.1007/978-981-99-1655-9_6, https://doi.org/10.1016/j.foodhyd.2020.106206, https://doi.org/10.1016/j.jdent.2024.105489, https://journals.lww.com/jpbs/toc/2012/04001 etc 4. No clarity on how formulation optimized? 5. How , XRD, To understand the underlying mechanisms influencing amoxicillin release, give this understanding? 6. How author is sure that during casting in organic solvent, microparticle not dissolve/break? 7. Why HPMC K4m and HPMC K4M and Eudragit RS 100 selected as film former? 8. The characterization of film like, Muco adhesion, tensile strength, swelling etc should be compiled. Reviewer #3: Comment 1: Keep the term fixed either extended or sustained release system. Comment 2: Can you check this line ‘an increased release rate from the particles compared to pure amoxicillin powder’ release rate will be extended? And also make it which on e is considered here a paprticle? Comment 3: sustained 3drug delivery acts to release the drug at a controlled rate’ There is a difference between sustained and controlled release Comment 4: significant efforts are directed at developing new indwelling urinary catheters (IUCs)’ discuss related works on this. See such articles Int J Biol Macromol, 162, 2020, 1849-1861. Polymers. 2022; 14 (4): 746; J. Drug. Deliv. Sci. Tech., 72, 2022, 103380 Comment 5: mention the molecular weight of EC and the subsection process is not proper. Comment 6: the amoxicillin must first be dissolved in a solvent with a low boiling point. ‘ Mention the solvent Comment 7: amoxicillin release in water was determined using a thermogravimetric analyzer’ This procedure is not proper. Please cite some related works if anyone has followed the method. Comment 8: If XRD procedure is needed in so details Comment 9: Calibration curve can be added Comment 10: Please check Figure 5 ****** what does this mean?). If published, this will include your full peer review and any attached files.). If published, this will include your full peer review and any attached files.). If published, this will include your full peer review and any attached files.). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? 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Revision 1
3 Jun 2025 Author Response Reviewer #1: Dear Authors, The research work is quite interesting with well problem statement but authors have designed the experiment for verifying material properties of amoxicillin loaded FCC not in a good manner and not thorough study to clearly understand the characteristic of the loaded FCCs. It is very difficult to follow mentioned experimental results step by step. It is very regret to recommend for rejection due to the quality of presented experimental data especially in the part of material characterization. For example: The authors thank the Reviewer for the opinion regarding the worth of the work and acknowledge the aspects of concern. We hereby undertake to respond to the comments as follows: 1. To study the releasement of amoxicillin from FCC, FCC fines and FCC granules were used as carrier but to study the releasement of the amoxicillin from the Ethyl cellulose film, Omyapharm FCC500-OG was used instead without notifying the solid support to convince the possibility. Only particle size ranges of FCC fines and FCC granules were provided but not BET specific area not bulk density. To clarify: the material family of functionalised calcium carbonate (FCC) retains consistent structural and chemical properties irrespective of sample name definition. We now have put more emphasis to this in the new manuscript text. The use of a fractionated sample of FCC, in respect to fines and granules, was designed to study the impact of individual dispersed particle size versus structuration of those individual particles to form granules. The granular material has been shown earlier to accelerate advantageously pharmaceutical tablet disintegration in aqueous medium, for example, as illustrated in these extra references, which have now been added to the manuscript: D. Preisig, et al., ‘Drug Loading into Porous Calcium Carbonate Microparticles by Solvent Evaporation,’ Eur. J. Pharm. Biopharm. 87, 548–558 (2014). T. Stirnimann, et al., ‘Compaction of Functionalized Calcium Carbonate: A Porous and Crystalline Microparticulate Material with a Lamellar Surface,’ Int. J. Pharm. 466(1–2), 266–275 (2014). T. Stirnimann, et al., ‘Functionalized Calcium Carbonate as a Novel Pharmaceutical Excipient for the Preparation of Orally Dispersible Tablets,’ Pharm. Res. 30(7), 1915–1925 (2013). The context of exemplifying structuration of FCC in respect to release kinetic of amoxicillin is, therefore, undertaken here to establish if such structuration provides any release mechanistic advantages, stressing once again throughout that the particle structure and chemical nature of the particles remain intrinsically constant. Omyapharm FCC500-OG illustrates the current commercially available product from which the experimental fractions were similarly derived. This text is now included in the manuscript. Nitrogen adsorption analysis in terms of BET specific surface measurement and bulk density are now also reported. 2. The content of amoxicillin is not informed for releasement study from the loaded FCC granules (Figure 4) but from the loaded FCC fines, the releasement results is presented both from 15% and 30% amoxicillin loading. The releasement of neat FCC is not comparatively studied. The loading fraction of amoxicillin was consistently 30 w/w% and 15 w/w% for all samples. Section 2.2. was unfortunately somewhat misleading in this respect as the term FCC particles was specifically used to refer generically to all sample forms. The text is now modified to confirm the loading across all FCC sample types. We understand the implication raised by the reviewer in that granulated material has an additional pore space, i.e. between the individual particles, into which the amoxicillin will also enter. This is now also expressed in the manuscript as follows: [2.2. Particle Loading To load amoxicillin into the porous FCC particles, the amoxicillin must first be dissolved in a solvent with a low boiling point and associated high vapour pressure. This solution is then mixed with the FCC particles as present in all structural forms used in the study, namely FCC fines, granules and commercial Omyapharm, and the solvent is allowed to evaporate. During evaporation, amoxicillin precipitates both within the pores and on the surface of the FCC particles. In this study, a 3 g/L solution of amoxicillin in an ethanol/acetone mixture was prepared. This solution was then added to a predefined amount of particles (for 30 w/w% and 15 w/w % loading – 7 g FCC and 8.5 g FCC, respectively, per 1 L solution) and the solvent was evaporated using a rotary evaporator (30 °C and 400-150 mbar). It is recognised that the distribution of amoxicillin in the case of the granulated structure will include loading between particles, and not only on the surface, and within the pores of the individual particles. Given the nature of the granule concept, material between the particles, to a first approximation, is likely to behave similarly to that associated with the exterior of the particles, though it should be recognised that access of liquid to the interior of a granule may be hindered to reduced permeability. Such effects reveal themselves during the release experiment study.] We appreciate the reviewer’s suggestion regarding the inclusion of a neat FCC control. However, as the release studies were based on UV-Vis spectroscopy at 272 nm—a wavelength specific to amoxicillin—neat FCC does not exhibit any absorbance at this wavelength. Therefore, it does not contribute to the measured signal, and its inclusion as a control would not affect the release data. This point is now clarified in the revised manuscript. 3. XRD diffraction pattern of precipitated amoxicillin is presented but its SEM micrograph is not shown, to verify different morphology. The morphology of amoxicillin depends on two main factors, the dynamic of precipitation and the surface onto which the precipitate forms. Amoxicillin in free solution under slow evaporation leads to microscopic single crystals, however under induced rapid precipitation, such as by the presence of a surface or nucleation centres, naturally tends to be amorphous. When considering monomolecular layers, such as those deposited on the surface of the FCC particle pores, microscopic imaging, by definition, unfortunately fails to reveal such molecular structure information. It is for this reason that resort is made to XRD diffraction, as reported in the manuscript, it being sensitive to molecular and intermolecular structure of relevance here. 4. In the material characterization results from loaded FCC, the finding are rarely compared to other similar finding and made discussion. We appreciate the Reviewer’s suggestion to broaden the contextual discussion of amoxicillin release from particulate systems beyond FCC, and we have now included comparative insights from other porous carrier systems. For example, Li et al. (2010) reported on organically modified MCM-41 mesoporous silica materials for amoxicillin delivery, where drug release was about 13% within 24 hours. Also, we reference studies such as Vafayi et al., who demonstrated a three-stage release profile from hollow silica nanospheres in simulated body fluid, and Bohns et al., who evaluated amoxicillin-loaded Eudragit S100 microparticles in dental applications. Their best formulation achieved a release of 16% amoxicillin within 96 hours. Additionally, Wang et al. who worked on the release of amoxicillin from Mg-HA porous particles. In this work 89% of the amoxicillin was released within 40hours. These examples have been incorporated into the revised manuscript to contextualize our results within the broader field of porous drug delivery systems. In contrast, our FCC-ethyl cellulose film composites demonstrate markedly extended release, supporting applications requiring long-term antimicrobial activity. Li et al., J. Colloid Interface Sci., 342 (2010), 607–613, https://doi.org/10.1016/j.jcis.2009.10.073. L. Vafayi et al., Bioinorganic Chemistry and Applications 2013 Vol. 2013 Issue 1 Pages 541030 https://doi.org/10.1155/2013/541030 Bohns et al., Restor Dent Endod 2020 Vol. 45 Issue 4 Pages 50. DOI: 10.5395/rde.2020.45.e50 Wang et al., Materials and Manufacturing Processes 2022 Vol. 37 Issue 13 Pages 1500-1505 DOI: 10.1080/10426914.2021.2016824 Reviewer #2: The study presents an interesting approach utilizing functionalized calcium carbonate (FCC) microparticles embedded in ethyl cellulose (EC) films for sustained antimicrobial drug release. This research is particularly relevant for indwelling medical applications, addressing the need for prolonged drug release in such devices. The authors are grateful to the reviewer for recognising the value of the main target application for this work. 1. Please explain the novelty compared to published work in this field. Pure drug used or its salt used? In many cases, pure drugs tend to express hydrophobicity due to their organic molecular constituents. The advantage of depositing a monomolecular layer is that the dynamic of this arrangement is constrained prior to exposure to water, and the rapid dissolution thereby prevents the macro-induced hydrophobicity. The citation regarding the delivery of nutraceuticals and flavourings (11) (Lundin Johnson et al.) illustrates this nicely. In the case of amoxicillin sodium salt dissolution is not normally impaired by any hydrophobic effects, and, as the Reviewer correctly suggests, loading on porous media is not a prerequisite to ensure dissolution. The target here is to retain a reservoir of the amoxicillin whilst at the same time supporting a continuous release of the active substance at a level above the minimum bacterial inhibition concentration to ensure a continuous antibacterial activity in applications prone to recurring infection. 2. The introduction can be improved with recent work in this filed, like, https://doi.org/10.1007/s12668-024-01722-3, https://doi.org/10.2174/0115748855274979231228103038, https://doi.org/10.1007/978-981-99-1655-9_6, https://doi.org/10.1016/j.foodhyd.2020.106206, https://doi.org/10.1016/j.jdent.2024.105489, https://journals.lww.com/jpbs/toc/2012/04001 etc We thank the Reviewer for the suggested literature. We have carefully reviewed the references provided and acknowledge their contribution to the broader field of drug delivery. However, these works focus on different types of materials or delivery systems that do not closely align with the specific objective of our study—namely, the integration of drug-loaded FCC particles into ethyl cellulose films for sustained release. To maintain a focused and concise introduction that accurately reflects the scope of our work, we have decided not to include these particular references. Nevertheless, we appreciate the Reviewer’s effort in highlighting them. 4. No clarity on how formulation optimized? The formulation per se has two interactive aspects, (i) the dissolution and rapid evaporation properties required when loading the porous medium particles, and (ii) the distribution of the material in and on the FCC particles and granulate structure. To meet the criteria for step (i), simple reduction of pressure using a rotovap sufficed. Meeting an optimum for (ii), the distribution of material, is much more complex, and indeed depends strongly on the dynamic of permeation and absorption of the amoxicillin solution into the porous medium, and the time progression for partial dissolution and precipitation/deposition within it. We agree with the Reviewer that further work would be needed to optimise the spatial distribution of the active within the porous medium. We now emphasise this limitation to the work in the text and suggest the need for further optimisation. 5. How, XRD, To understand the underlying mechanisms influencing amoxicillin release, give this understanding? The Reviewer identifies an important link here between the XRD structure-related properties of the active agent, in this case amoxicillin, and the subsequent desired release into aqueous medium. The Reviewer will recognise the difficulty we faced, and discussed in some depth, regarding the likely structural nature of the active as deposited within the porous FCC particles. We had hoped that the evidence of molecular arrangement provided by XRD would be more convincingly displayed. Given the ambiguity the XRD data raised, we chose to be somewhat reserved in providing a detailed mechanism for the release. We agree this leaves some open questions, and resort to the experience shown by the nutraceutical and flavourings exercise reported earlier by Lundin-Johnson et al., especially noting the similar rapid early stage dissolution occurring during release from FCC in the absence of ethyl cellulose. We reference this difficulty in the manuscript and rely on future work revealing more clearly the specific mechanistic stages involved. Suffice it to say at this point that the controlled dynamic required for the proposed application has been reached despite the lack of a complete molecular-based mechanistic description. We trust this applications-focused result is of sufficient worth to support publication. 6. How author is sure that during casting in organic solvent, microparticle not dissolve/break? Here we assume that the Reviewer is referring to the stability of the FCC structures. Given the inorganic structural nature of the FCC, we would not expect any microparticle dissolution or breakage. Furthermore, the work reported by D. Preisig, et al., ‘Drug Loading into Porous Calcium Carbonate Microparticles by Solvent Evaporation,’ Eur. J. Pharm. Biopharm. 87, 548–558 (2014). T. Stirnimann, et al., ‘Compaction of Functionalized Calcium Carbonate: A Porous and Crystalline Microparticulate Material with a Lamellar Surface,’ Int. J. Pharm. 466(1–2), 266–275 (2014). T. Stirnimann, et al., ‘Functionalized Calcium Carbonate as a Novel Pharmaceutical Excipient for the Preparation of Orally Dispersible Tablets,’ Pharm. Res. 30(7), 1915–1925 (2013). and now cited in the references, confirms the stability of the physical structures. The granulation is formed by the compression in close proximity of particle-particle adjacent surface platelets displaying van der Waals attraction, which, without inorganic breakdown, remains ubiquitous throughout any solvent processing. Only mechanical forces would be expected to disturb further the surface platelet structure. 7. Why HPMC K4m and HPMC K4M and Eudragit RS 100 selected as film former? Here we assume that the Reviewer is referring to use ethyl cellulose (EC) as the film-forming polymer. We would like to clarify that HPMC K4M and Eudragit RS 100 were not part of our formulation work. The selection of EC was based on its well-established use in sustained-release systems, as it is a non-biodegradable yet biocompatible cellulose derivative widely studied for pharmaceutical encapsulation applications. EC is a biodurable polymer, and its molecular structure can be tuned through controlled degrees of substitution—specifically, the number of etherified hydroxyl groups per glucose unit—to achieve tailored solubility and viscosity profiles in various solvents. Moreover, although EC is not rapidly biodegradable under typical physiological conditions, cellulose and its derivatives are considered environmentally friendly materials, as they are ultimately degradable in natural ecosystems through microbial enzymatic activity (e.g., cellulases). This point is now explained in the revised manuscript. We hope this clarifies the rationale for choosing EC as a film forming polymer. 8. The characterization of film like, Muco adhesion, tensile strength, swelling etc. should be compiled. Here the Reviewer takes the work forward into the application environment in respect to both mechanical properties and properties in-vivo. We can but agree wholeheartedly that strength, swelling properties and surface interaction of the ethyl cellulose construct with surrounding mucous membranes is of crucial importance. Simply said, we have not moved on to the important applications environment at this stage and such questions are left open. We now draw attention to this next analytical step in the manuscript. Reviewer #3: Comment 1: Keep the term fixed eith Attachments Attachment Submitted filename: Response to Reviewers 2025-05-27.docx https://doi.org/10.1371/journal.pone.0320280.r002
21 Aug 2025 Decision Letter - Mehnath Sivaraj, Editor Dear Dr. Niga, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. Please submit your revised manuscript by Sep 19 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at . Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at . Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at . Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.... We look forward to receiving your revised manuscript.<gwmw style="display:none;"></gwmw> Kind regards, Mehnath Sivaraj Academic Editor PLOS ONE Journal Requirements: 1. If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author Reviewer #1: (No Response) Reviewer #2: (No Response) Reviewer #3: All comments have been addressed Reviewer #4: (No Response) Reviewer #5: (No Response) Reviewer #6: (No Response) ******** 2. Is the manuscript technically sound, and do the data support the conclusions??> Reviewer #1: Partly Reviewer #2: Yes Reviewer #3: Yes Reviewer #4: Partly Reviewer #5: No Reviewer #6: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? -->?> Reviewer #1: Yes Reviewer #2: I Don't Know Reviewer #3: Yes Reviewer #4: No Reviewer #5: No Reviewer #6: Yes ****** 4. Have the authors made all data underlying the findings in their manuscript fully available??> The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.--> Reviewer #1: No Reviewer #2: Yes Reviewer #3: Yes Reviewer #4: No Reviewer #5: No Reviewer #6: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English??> Reviewer #1: No Reviewer #2: Yes Reviewer #3: Yes Reviewer #4: No Reviewer #5: No Reviewer #6: Yes ****** Reviewer #1: Dear Authors, Thank you for the revisions made according to the reviewer's comments. Some revision has been done well. However please fulfill these following comments; 1. In Fig 4. please give information on the amoxicillin loading for loaded FCC granules as shown in blue squares. 2. If possibly, please provide the UV spectra of FCC fines, FCC granules and, Omyapharm particles (used to prepared EC film, in a range that cover wavelength of 272 nm as Data Availability. 3. Please workout more on the authors' response to reviewer's comment 3 on the aspect of molecular structure of the precipitated amoxicillin and intermolecular structure. In addition, the image of shown in Fig 7 (C) does not help to make relationship between the sustained release of precipitated amoxicillin from FCC. Not only the molecular and intermolecular structure affects the releasement performance but also the physical characteristics of the precipitated of amoxicillin inside the FCC and on the surface. Reviewer #2: The author has successfully addressed all the comments and suggestions provided in the previous review. The revisions and editions made are satisfactory and have enhanced the overall quality of the manuscript. Reviewer #3: The paper can be accepted. The comments have been addressed. The author has responded point to point comments Reviewer #4: This study investigates FCC microparticles integrated in ethyl cellulose films for sustained amoxicillin delivery—an innovative and clinically relevant concept targeting catheter-related infections. The combined use of SEM, UV‑vis, synchrotron XRD, and TGA strengthens the material analysis. Nonetheless, the manuscript currently falls short in methodological completeness, clarity, and novelty justification Major Issues (Essential for Revision): 1. Material transitions and clarity o The manuscript frequently switches between FCC fines, granules, and Omyapharm (e.g., in Chapters 2 and 3). A comparative table listing surface area (BET), morphology, rationale, and selection criteria for each form would greatly improve clarity. 2. Film characterization for application o Films designed for indwelling use require mechanical (tensile strength), swelling, and mucoadhesion data. At minimum, quantitative swelling or tensile information should be included, or limitations acknowledged. 3. Drug release quantification o Relying on TGA for drug release estimation is unconventional. While UV vis release curves are present, detailed release kinetics (e.g., cumulative release, release rate ± SD, model fitting) must be shown. Clarify that TGA data are supplementary and residual only. 4. Novelty and comparative context o Similar systems (e.g., Mg HA, Eudragit, MCM 41) have been used for amoxicillin delivery. The manuscript should explicitly highlight what is novel—such as use of FCC in EC films—and compare performance metrics (release duration, loading capacity) to existing systems. 5. Terminology consistency o Use “sustained” exclusively throughout. Currently, the manuscript alternates between “sustained” and “extended.” Ensure consistent usage. Minor Suggestions: • Correct remaining typographical and formatting issues (e.g., “Formatted: Font: 16 pt”). • Expand figure legends (e.g., labeling apparatus components in Figure 2). • Define all solvents and abbreviations in the Methods section first mention. • Clarify that ethyl cellulose and FCC are biocompatible and sterile, as relevant to medical application. The study is innovative and scientifically sound, but essential methodological work and clarity improvements are necessary for full publication. I encourage the authors to address these points comprehensively. Reviewer #5: I recommend that the authors substantially revise the manuscript to include detailed methodologies, robust characterization data, well-annotated images, and thorough discussions. Doing so will significantly improve the clarity, reproducibility, and scientific impact of the work. Reviewer #6: I can recommend publishing, however some the authors need to answer the following question and accordingly revise the manuscript. 1) How did the authors determine crystal unit cell parameters from a bench-top XRAY machine. Did they index the powder pattern ? If so the results should be documented ? If they grew single crystal , then did the simulated pattern from single crystal match the experimental pattern ? Has the structure been uploaded to the CCDC database ?. These details are missing and important to understand how these results were obtained. 2) For the different dissolution experiments the authors have not described whether the tests were conducted under sink or non-sink conditions ? If under sink conditions, how will this correlate to drug release from catheders once implanted ? 3) Did the authors do a mass balance experiment and confirm that at the end of 5 month dissolution experiments the amoxicillin loaded in omyapharm had the remaining drug in the intact in the films or had the drug degraded by that time ? 4) There is a lack of statistical data in the dissolution release models? No error bars seen and std deviation mentioned in the experiments. ****** what does this mean?). If published, this will include your full peer review and any attached files.). If published, this will include your full peer review and any attached files.). If published, this will include your full peer review and any attached files.). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our For information about this choice, including consent withdrawal, please see our For information about this choice, including consent withdrawal, please see our For information about this choice, including consent withdrawal, please see our Privacy Policy..--> Reviewer #1: No Reviewer #2: No Reviewer #3: No Reviewer #4: No Reviewer #5: No Reviewer #6: No ******** [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at . PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at . PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at . PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.. Please note that Supporting Information files do not need this step.. Please note that Supporting Information files do not need this step.. Please note that Supporting Information files do not need this step. Attachments Attachment Submitted filename: Review Comments-2.docx Attachment Submitted filename: review letter- PONE-D-25-08617-R1 (1)_anon.pdf https://doi.org/10.1371/journal.pone.0320280.r003
Revision 2
24 Oct 2025 Author Response The response to reviewers is loaded as a separate file. Attachments Attachment Submitted filename: Response to Reviewers_FCC-EC Sustained Release.docx https://doi.org/10.1371/journal.pone.0320280.r004
26 Nov 2025 Decision Letter - Mehnath Sivaraj, Editor Dear Dr. Niga, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. Please submit your revised manuscript by Jan 10 2026 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. 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Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.... We look forward to receiving your revised manuscript. Kind regards, Mehnath Sivaraj Academic Editor PLOS ONE Journal Requirements: If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise. Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author Reviewer #1: All comments have been addressed Reviewer #4: (No Response) Reviewer #5: All comments have been addressed Reviewer #6: All comments have been addressed ******** 2. Is the manuscript technically sound, and do the data support the conclusions??> Reviewer #1: (No Response) Reviewer #4: Partly Reviewer #5: Yes Reviewer #6: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? -->?> Reviewer #1: (No Response) Reviewer #4: Yes Reviewer #5: No Reviewer #6: N/A ****** 4. Have the authors made all data underlying the findings in their manuscript fully available??> The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.--> Reviewer #1: (No Response) Reviewer #4: Yes Reviewer #5: Yes Reviewer #6: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English??> Reviewer #1: (No Response) Reviewer #4: Yes Reviewer #5: Yes Reviewer #6: Yes ****** Reviewer #1: Dear Author, The revisions are fully fulfilled to all points of previous comments and suggestions. Reviewer #4: Thank you for the thoughtful revision. The manuscript is much improved in clarity and positioning. I appreciate the addition of the FCC materials comparison (particle size/BET/bulk density with usage rationale), the clearer description of sink (particles) vs non-sink (films) conditions, the inclusion of UV-vis controls showing no FCC absorbance at 272 nm, and the expanded comparison to prior amoxicillin delivery systems. The sustained multi-month release under non-sink conditions is a useful proof-of-concept for indwelling applications. Recommendation: Minor Revision What has been satisfactorily addressed Materials clarity: Table summarizing fines, granules, and Omyapharm with BET/density and rationale greatly improves readability. Terminology: Consistent, correct use of “sustained release” with a brief definition. Context/novelty: Stronger discussion vs MCM-41, Mg-HA, Eudragit, hydrogels, hollow silica; the FCC-in-EC approach and months-long profile are now well framed. Analytical specificity: UV spectra for FCC materials confirm no absorbance at 272 nm, supporting the release measurements. Requests before acceptance (minor but important) Statistics & replication for release data. Please report the number of independent replicates for particle (Figs 3–4) and film (Figs 8–9) release experiments. Where feasible, provide mean ± SD and indicate n in figure captions. If the 5-month film curve was run on a single representative sample (as stated), keep it as proof-of-concept but clearly label it as such in the text and captions. Basic kinetic analysis. Add simple model fits (e.g., Higuchi and/or Korsmeyer–Peppas) to the film data—separating the initial burst and the longer sustained phase is fine. A small SI table with parameters (and R², n for Korsmeyer–Peppas) is sufficient. If you believe non-sink conditions make a specific model inapplicable, a brief rationale will suffice. End-point mass balance for films. Provide an assay at the end of the 5-month study confirming remaining drug in the films and commenting on degradation. TGA (as used for particles) is acceptable; HPLC/LC-MS would be ideal if available. This will strengthen the long-duration result. Compact methods summary. Include a short table (main text or SI) listing, for each experiment: matrix (particles/films), sink vs non-sink, total volume, temperature, agitation/flow, exposed surface area (your coiled film geometry is clear—just recap the calculated area). This will improve reproducibility. XRD reporting clarity. Please clarify whether the powder pattern was indexed and temper any structural claims that would require single-crystal data. A one-sentence note is enough; a CCDC deposition is not necessary here. Limitations statement (applications). Keep/strengthen the explicit note that tensile strength, swelling, and mucoadhesion of EC films were not examined in this proof-of-concept and are planned for future work toward indwelling use. Minor edits Remove any residual tracked-changes artifacts (e.g., “Formatted: …”). Keep explicit loading information in Fig. 4 caption. If you add statistics/kinetic fits/mass-balance data to SI, please reference them in the Data Availability statement and relevant figure captions. With the above clarifications and small additions, the manuscript will meet PLOS ONE’s rigor and transparency standards. Reviewer #5: (No Response) Reviewer #6: I support publication, but I would like the authors to clarify the following before acceptance. 1) We can speculate that the driving mechanism for nanocrystal formation could be related to a sorption effect of molecules in contact with a surface which could provide a nanoscale molecular orientation effect, a conformation that prevents the lowest energy intermolecular structure, namely preventing crystal formation. • Could the authors clarify "lowest energy intermolecular structure"? Amorphous amoxicillin suggests a high-energy metastable state, while the crystalline form represents a low-energy conformation. 2) Did the authors examine, or can they propose, whether amoxicillin underwent crystallization during the release studies? This consideration could potentially account for the observed release profile in relation to the differences in solubility between crystalline and amorphous forms of amoxicillin. 3) How does the solubility of amorphous amoxicillin compare to crystalline amoxicillin? How can changes in crystal form during formulation affect the product's performance and release? ****** what does this mean?). If published, this will include your full peer review and any attached files.). If published, this will include your full peer review and any attached files.). If published, this will include your full peer review and any attached files.). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our For information about this choice, including consent withdrawal, please see our For information about this choice, including consent withdrawal, please see our For information about this choice, including consent withdrawal, please see our Privacy Policy..--> Reviewer #1: No Reviewer #4: No Reviewer #5: No Reviewer #6: No ******** [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] To ensure your figures meet our technical requirements, please review our figure guidelines: https://journals.plos.org/plosone/s/figures You may also use PLOS’s free figure tool, NAAS, to help you prepare publication quality figures: https://journals.plos.org/plosone/s/figures#loc-tools-for-figure-preparation. NAAS will assess whether your figures meet our technical requirements by comparing each figure against our figure specifications. Attachments Attachment Submitted filename: Review comments-2 (2).docx https://doi.org/10.1371/journal.pone.0320280.r005
Revision 3
5 Dec 2025 Author Response The Response to Reviewers is attached as a separate document. Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0320280.r006
19 Jan 2026 Decision Letter - Mehnath Sivaraj, Editor Dear Dr. Niga, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. Please submit your revised manuscript by Mar 05 2026 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. A letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at . Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at . Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at . Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.... We look forward to receiving your revised manuscript. Kind regards, Mehnath Sivaraj Academic Editor PLOS One Journal Requirements: 1. If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise. 2. Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. [Note: HTML markup is below. Please do not edit.] Reviewer's Responses to Questions Comments to the Author Reviewer #4: All comments have been addressed Reviewer #6: All comments have been addressed ******** 2. Is the manuscript technically sound, and do the data support the conclusions??> Reviewer #4: Yes Reviewer #6: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? -->?> Reviewer #4: N/A Reviewer #6: Yes ****** 4. Have the authors made all data underlying the findings in their manuscript fully available??> The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.--> Reviewer #4: Yes Reviewer #6: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English??> Reviewer #4: Yes Reviewer #6: Yes ****** Reviewer #4: The authors have carefully and satisfactorily addressed the major points raised in the previous review. The revised manuscript is substantially clearer, particularly regarding the distinction and rationale for the different FCC materials, the positioning of TGA versus UV–vis measurements for drug release, and the discussion of novelty relative to existing amoxicillin delivery systems. Terminology is now consistent, and the scope of the work is appropriately framed as a proof-of-concept study focused on sustained release behavior. While mechanical and swelling properties of the films and statistical replication of long-term release experiments remain outside the scope of the present work, these limitations are now explicitly acknowledged and no longer overstated in the conclusions. The experimental data presented support the claims made within this defined scope. Only minor points remain, mainly editorial in nature (e.g., wording, figure labeling, and formatting). Detailed comments and suggestions are provided in the attached review letter. These points do not affect the scientific validity of the study. Overall, the manuscript is technically sound and suitable for publication after minor editorial adjustments. Reviewer #6: All comments have been addressed satisfactorily. No further questions. I can now recommend publishing. ****** what does this mean?). If published, this will include your full peer review and any attached files.). If published, this will include your full peer review and any attached files.). If published, this will include your full peer review and any attached files.). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our For information about this choice, including consent withdrawal, please see our For information about this choice, including consent withdrawal, please see our For information about this choice, including consent withdrawal, please see our Privacy Policy..--> Reviewer #4: Yes: Sepideh AsadiSepideh AsadiSepideh AsadiSepideh Asadi Reviewer #6: No ******** [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] To ensure your figures meet our technical requirements, please review our figure guidelines: https://journals.plos.org/plosone/s/figures You may also use PLOS’s free figure tool, NAAS, to help you prepare publication quality figures: https://journals.plos.org/plosone/s/figures#loc-tools-for-figure-preparation. NAAS will assess whether your figures meet our technical requirements by comparing each figure against our figure specifications. Attachments Attachment Submitted filename: review letter- revised version.pdf https://doi.org/10.1371/journal.pone.0320280.r007
Revision 4
10 Feb 2026 Author Response 6. Review Comments to the Author Reviewer #4: The authors have carefully and satisfactorily addressed the major points raised in the previous review. The revised manuscript is substantially clearer, particularly regarding the distinction and rationale for the different FCC materials, the positioning of TGA versus UV–vis measurements for drug release, and the discussion of novelty relative to existing amoxicillin delivery systems. Terminology is now consistent, and the scope of the work is appropriately framed as a proof-of-concept study focused on sustained release behavior. While mechanical and swelling properties of the films and statistical replication of long-term release experiments remain outside the scope of the present work, these limitations are now explicitly acknowledged and no longer overstated in the conclusions. The experimental data presented support the claims made within this defined scope. Only minor points remain, mainly editorial in nature (e.g., wording, figure labeling, and formatting). Detailed comments and suggestions are provided in the attached review letter. These points do not affect the scientific validity of the study. Overall, the manuscript is technically sound and suitable for publication after minor editorial adjustments. Remaining Issues and Minor Comments 1. Statistical and quantitative language Long-term release experiments are still based on single representative samples. While this limitation is acknowledged, language such as “average release rate” should be softened to avoid over-interpretation. Terms such as “apparent” or “estimated” release rate would be more appropriate in this context. 2. Figure clarity Figures 8 and 9 would benefit from clearer, more explicit labeling of “loaded” versus “physical mixture” directly on the plots to improve readability without requiring extensive reference to the captions or text. 3. Formatting and presentation A small number of formatting artifacts and spacing inconsistencies remain in the revised manuscript and should be corrected during final editing. 4. MIC and biological relevance The discussion linking sustained release behavior to MIC values is informative; however, it should remain cautiously framed as indicative only. Care should be taken to avoid implying predictive relevance for in vivo efficacy at this stage. These points do not affect the scientific validity of the study. Overall, the manuscript is technically sound and suitable for publication after minor editorial adjustments. Response to reviewer #4 We thank the reviewer for these constructive and helpful final comments, which have improved the clarity of the manuscript. Remaining Issues and Minor Comments 1. Statistical and quantitative language We agree and have revised the manuscript to replace “average release rate” with “estimated release rate” to reflect that the long-term release data are based on single representative samples. 2. Figure clarity We have retained the legend and added explicit curve labels directly within Figures 8 and 9 to clearly distinguish “loaded” and “physical mixture” samples. 3. Formatting and presentation We have carefully reviewed the manuscript and corrected remaining formatting artifacts and spacing inconsistencies during final editing. 4. MIC and biological relevance We agree and have revised the MIC discussion to ensure it is framed as indicative only and does not imply predictive in vivo efficacy. Reviewer #6: All comments have been addressed satisfactorily. No further questions. I can now recommend publishing. Response to Reviewer #6 We thank the reviewer for their careful evaluation and for confirming that all comments have been satisfactorily addressed. Attachments Attachment Submitted filename: Response_to_reviewers_auresp_4.docx https://doi.org/10.1371/journal.pone.0320280.r008
10 Mar 2026 Decision Letter - Mehnath Sivaraj, Editor Functionalized Calcium Carbonate Microparticles in Ethyl Cellulose Films: A Vehicle for Sustained Amoxicillin Release for Medical Applications PONE-D-25-08617R4 Dear Dr. Niga, We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. 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For more information, please contact onepress@plos.org. Kind regards, Mehnath Sivaraj Academic Editor PLOS One Additional Editor Comments (optional): Reviewers' comments: Reviewer's Responses to Questions Comments to the Author Reviewer #3: All comments have been addressed Reviewer #4: All comments have been addressed ******** 2. Is the manuscript technically sound, and do the data support the conclusions??> Reviewer #3: Yes Reviewer #4: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? -->?> Reviewer #3: Yes Reviewer #4: Yes ****** 4. Have the authors made all data underlying the findings in their manuscript fully available??> The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). 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If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.--> Reviewer #3: Yes Reviewer #4: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English??> Reviewer #3: Yes Reviewer #4: Yes ****** Reviewer #3: This paper has addressed all the comments. This paper can be accepted now. Please arrange the references according to guidelines. Reviewer #4: (No Response) ****** what does this mean?). If published, this will include your full peer review and any attached files.). If published, this will include your full peer review and any attached files.). If published, this will include your full peer review and any attached files.). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? 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Formally Accepted
Acceptance Letter - Mehnath Sivaraj, Editor PONE-D-25-08617R4 PLOS One Dear Dr. Niga, I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS One. Congratulations! Your manuscript is now being handed over to our production team. At this stage, our production department will prepare your paper for publication. This includes ensuring the following: * All references, tables, and figures are properly cited * All relevant supporting information is included in the manuscript submission, * There are no issues that prevent the paper from being properly typeset You will receive further instructions from the production team, including instructions on how to review your proof when it is ready. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few days to review your paper and let you know the next and final steps. Lastly, if your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. You will receive an invoice from PLOS for your publication fee after your manuscript has reached the completed accept phase. If you receive an email requesting payment before acceptance or for any other service, this may be a phishing scheme. Learn how to identify phishing emails and protect your accounts at https://explore.plos.org/phishing. If we can help with anything else, please email us at customercare@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Mehnath Sivaraj Academic Editor PLOS One https://doi.org/10.1371/journal.pone.0320280.r010

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