Application of Lactose Co-Processed Excipients as an Alternative for Bridging Pharmaceutical Unit Operations: Manufacturing an Omeprazole Tablet Prototype via Direct Compression

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Having perused the article titled "Application of Lactose Co-Processed Excipients as a Viable Alternative for Bridging Pharmaceutical Unit Operations: Fabrication of an Omeprazole Tablet via Direct Compression," I was left with some queries regarding its conformity to the stated theme of the journal and the overall caliber of its presentation.

Judging by both the title and the content, the subject matter of this article appears to be more appropriate for a publication dedicated to pharmaceutical manufacturing techniques rather than for a specialist journal focused on strategies for drug development, controlled release, and targeted delivery. The emphasis on the development of a specific omeprazole tablet prototype through direct compression using lactose-based excipients seems more akin to a technical description than a scholarly investigation.

The article in question is marred by several formal shortcomings. The layout of the text leaves much to be desired: the choice of font, alignment, and margin settings is unrefined. Figures 2 and 3 present issues with the display of information: the scale in Figure 2 is not clearly visible, and Figure 3 makes use of only half the available space. Table 5 is burdened with an excessive number of decimal places, rendering the data difficult to decipher. Moreover, the article appears to be overburdened with technical specifics; it would be advisable to relocate some of this information to an appendix, thereby enhancing readability and imbuing the text with a more structured approach.

The primary shortcoming of this paper is the absence of a clearly articulated scientific objective and rationale for the research conducted. The depiction of the process for producing a novel omeprazole pill does not constitute a comprehensive scientific investigation in and of itself. The findings appear to be more akin to a description of a patented technique rather than a scholarly publication.

Consequently, I deem that the present form of the paper fails to adhere to the standards of the journal and necessitates substantial revision. I propose that the manuscript be accepted for publication solely after a substantial overhaul, encompassing a profound re-evaluation of its structure, a stronger emphasis on the scholarly significance of the research, the eradication of these superficial flaws, and the reduction of excess technical details.

Author Response

Please see the attachment

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

The concept of current research focusing on the development of omeprazole tablets by direct compression approach is interesting. However, the quality of the manuscript is very low. The entire manuscript has to be revised for better representation of methodologies and for better presentation of data. The manuscript also needs to be cross checked for English. The current version of the manuscript cannot be accepted for publication. Authors are suggested to address the below comments and have an expert from the field to review the article before submission:

1. Line 21: Please update “upmost” as “utmost”
2. Line 28: Blends are not produced using single punch machine. Please correct the statement accordingly.
3. Line 32 & 33: what do authors mean by “displayed stability”. Was the formulation stable for 12M at long-term conditions?
4. Within the introduction can authors please provide some background information why wet granulation approach was employed for omeprazole historical formulations? What are the limitations of direct compression approach? What are the doses available for omeprazole in the market? What is the BCS class and other physicochemical properties of omeprazole drug? List the composition of Brand omeprazole product and how did authors conclude that it was developed by wet granulation approach? Provide any reference to support the statement.
5. Please update “microscope” as “microscopy” or “surface morphology” for section 2.2.1.2.
6. Please provide methodology for tablet characterization (hardness, friability, disintegration, thickness) following tablet manufacturing process. Authors are suggested to follow the process flow for better presentation.
7. Please provide detailed methodology for friability and disintegration rather than referring to the USP chapters. Additionally please provide the media used for disintegration studies.
8. Authors are suggested to provide a detailed list of formulations and their compositions in tabular form for better understanding and for differentiating the formulations.
9. Authors are suggested to provide a detailed procedure for blend preparation such as screens used to sieve the material and volume of container used for turbula mixing and batch size.
10. Please provide detailed procedure for tablet coating along with coating material and preparation of coating dispersion.
11. Please provide detailed methodology for scalup parameters calculation. How big the batch was scaled.
12. Authors are suggested to move Table 2 near the methodology for preparation of blends.
13. Figure 2: Please provide detailed information for each figure in the legends.
14. Table 4: Please provide the full form for the abbreviations as a foot note.
15. What do authors conclude with higher FF value of 18.51 for F2 formulations.
16. Why Prilosec assay was not provided in Table 8?
17. Table 8: Can authors please provide methodology for %drug dissolved at 45 min. Is this dissolution? If so please provide detailed methodology.
18. Please provide detailed procedure for stability studies with information for packaging material, sampling points, and characterizations performed.

Comments on the Quality of English Language

The English could be improved to more clearly express the research.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

The authors used the formulations with a high concentration (85 wt.%) of diluents-fillers: or physical mixture (25:75) of MCC and lactose (DuraLac® H); or co-processed MCC-lactose (25:75; Microcelac® 100); or lactose (Tablettose® 70); or lactose (Tablettose® 100). As a model drug was used omeprazole and formulations were used to show the advantage of Microcelac® 100 over others in the direct compression manufacturing of tablets. Microcelac® formulation was used for the scale-up and enteric (delayed-release) coating. Single-unit tablets prepared by direct compression were compared with Prilosec® (the multi-unit particulate system where every pellet/granule is coated with a delayed-release coating) to make a statement about the benefits of direct compression other than wet granulation.

 

Dear authors,

Despite the loud names among co-authors, in short, the concept and discussion are bad, the method and experiments (taken separately) are good (but their specific implementation is not always good), and the conclusions are irrelevant. Let me justify these.

Critical comments.

Conceptual flaw. First of all, I want to draw the attention of authors to the fact that wet granulation is not a traditional way to produce omeprazole tablets such as Prilosec®. There is a reason for the multi-unit particulate omeprazole system. Thus, using single-unit tablets instead of multi-unit tablets cannot be justified. And in this case, the comparison of directly compressed single-unit tablets with multi-unit (coated pellets) tablets is not acceptable.

Experimental design flaw. Lack of justification for excipients and their amount. At a constant concentration of lubricant and lubrication time, a single tableting force and speed for formulations was applied to conclude the preferred filler-diluent. No comparison of fillers-diluents (before the formulation) in terms of their fundamental mechanical properties, Py, and strain-rate sensitivity. No comparison for formulations in terms of Compactibility, Compressibility, Tabletability (USP<1062> standards), Strain Rate Profile, Formulation Lubrication Profiles, Force Profiles, Ejection Force, and Tablet take off Force.

So, the authors claim the process improvement (which is questionable based on the above-mentioned comments), but ignore the biopharmaceutical side of the story.

 

Some specific comments:

L 50-51: “One of these is having to consider the drug’s physical limitations and the physical properties of raw materials.” – to clarify

L 78: Here and elsewhere, please check the proper usage: compression vs. compaction and compressibility vs. compactibility.

L 80-91: The authors ignored the sub-coating which is responsible for the control of impurities content too: 10.1208/s12249-021-02038-2

L 99: QTPP – please formalise and justify

Methods: In certain places, please improve/standardise the equipment referencing style. For example: “(Sympatec)”, “Micromeritics Instrument Corporation, USA”, “Rotary Tablet Press, Model Fette 102i, by Fette Compacting GmbH”

L134-138: Particle size distribution: D10%, D50%, and D90%

L 139: Typo “Microscope”

Line 151-156: BET – please add more setting data incl. equilibration temperature and moisture content of your samples.

L 169: “Blends for the studied formulations were prepared in layers …” – please clarify

L 169-173: please provide the volume of blender, degree of filling, weight of the sample.

L 184-185: “Sodium 184 Stearyl fumarate” - ? capital letters

L 189-213: to add dissolution conditions (paddle/basket; rpm) and sample treatment history. Did you use the new sample for the “intestinal-phase” dissolution or the sample after the “stomach-phase”?

L 234-236: “Tablettose® 100 is produced from a smaller starting particle size than the material in Tablettose® 70, resulting in a higher dilution potential due to an increased compatibility” – please explain the “higher dilution potential”

Table 2: Please put the ingredients in the column.

Fig. 1: Q3 or q3? Please add SDs.

Table 3: D10%, D50%, and D90%

L 270-272: “This could indicate that the API particles adhered to the 270 microstructures of the material more effectively, which reduces the risk of segregation 271 during tableting.” – please consider the apparent volume of particles. The composition is weight by weight while PSD is measured based on volume.

L 278-279: oxford comma

Fig 2: Please visually separate F1-F4

L 297: “hydrostatic like” – please paraphrase

L 297: “spherical particles” – spheroids

L 304: “2 and 3 based on the cohesion” – please compare them using ANOVA and reconsider

Please put more efforts on connecting powder rheology and process explanations.

Statistical evaluation – Do we really need all this analysis? It is not compensating for the experimental flaw.

Fig 6: F4 – please explain 2 first points.

L 407: “The larger number of fines observed in both the PSD results and the microscope images of F4 could be responsible for a higher variation in weight during the process.” – too bold statement – please justify.

L 410: “highest tabletability potential among the diluents” – please justify.

L 424: “overall manufacturability” – please justify.

L 429-431: “enhances the material's suitability” and “compactability” – please justify.

L 435-436: “This is due to the slower dissolution rate of lactose monohydrate compared to the anhydrous one” – speculation. What about porosity, hardness, …?

L 442-443“Moreover, the core matrix encompasses the 442 compressed coated granules as well, which slows down disintegration” – please explain

Table 6: Please convert hardness to tensile strength to compare your tablets and Prilosec® with different size/weight/shape.

Table 8: the name of the second column – Av. content (dose %)? Please describe the sampling protocol and sampling points in the method section. Please explain the assay below 100%. Did you normalise the dissolution per assay?

L 465-466: “adherence to the nominal content” - ? “adherence”

L 471: “earlier physical evaluation” – please specify

L 475-479: Why?

L 487: “… Microcelac® dissolved slowly” – speculation

L 492-493: F1 justification is weak

Table 9: to combine with Table 6

Fig 8: Released in 45 minutes

Fig 9: to add details regarding test organisation

Table 10: Please add SDs; to explain the value for “Omeprazole related compounds F and G” in 6 months.

L 531: “n enhanced functionality” – what about biopharmaceutical aspects?

Conclusions: please reconsider in the context of the above-mentioned comments.

References: please improve the style.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The authors have thoroughly revised the manuscript, enhancing its overall quality. However, a few areas still require attention:

1. Figure 3: Consider the error bars. Currently, they appear to represent a percentage of the value. It might be beneficial to use standard deviation (SD) instead.

2. Figure 6: There are no error bars at all. If the experiment is repeated, does the distinctive pattern observed for F4 in the graph remain consistent?

3. Table 7: Columns 2 and 3 contain too many significant digits. It would be clearer to round these values to integers.

Overall, I recommend accepting the manuscript with minor revisions.

Author Response

Thanks a lot for your time and feedback on our manuscript.

1. Figure 3: Thank you for your observation. The error bar displayed is indeed the standard deviation.
2. Figure 6: Thank you for your observation. We have added the error bars to the figure.
3. Table 7: Thank you for your comment. We have presented the values with a single significant digit in the table.

Reviewer 2 Report

Comments and Suggestions for Authors

All the comments are well addressed with supporting literature and proper justification. The revised version can be accepted for publication. 

Author Response

Thanks a lot for your time and feedback on our manuscript.

Reviewer 3 Report

Comments and Suggestions for Authors

Dear Authors, 
I see your efforts toward improving the manuscript, and the current version is much better. I still don't like the concept, but I will not argue after already provided cosmetic changes. From my point of view, data visualisation (graphs) would be more concentrated and ordered. While I'm not completely satisfied with your responses to my comments, I guess this manuscript is good enough for this journal.
KR

Author Response

Thanks for your time and feedback on our manuscript.