A Thermal-Analysis-Technique-Based Mechanistic Approach toward the Release of Omeprazole from Solid Dosage Forms
, Stefanos Kikionis 3, Marilena Vlachou 1,* and Natassa Pippa 1,*Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsHere the authors developed omeprazole sustained release formulations using various excipients and compared the dissolution profiles with those of the marketed product. They should address several issues for the article to be publishable.
- Line 126: Do the authors mean a regular sieve? This cannot be called “dry granulator”
- What is rational of the formulations in Table 1 ? I understand the use of NaAlginate or PVPk-30 but the change from Avicel 101 to 102 shouldn’t affect the dissolution.
- Table 1: The granule composition should be mentioned as a footnote at the end of the tablet as the current form is confusing.
- What is the rationale to use the
- Line 128: How the authors achieved content uniformity by blending omeprazole pellets with the excipient to form tablets? The size of those materials is completely non-uniform and pellets are expected to segregate.
- Fig. 2 doesn't show a uniform pellet distribution…
- Line 243-245: This line is very confusing. The pellets cannot be in the form of granules. Also this is the first time that authors mentioning that omeprazole was used in the form of powder. Up to this point it was clear that they only used pellets for all formulations
- Line 246-249: This is something they should definitely expect as the excipients are simple fillers with no specific functionality. Once the the Eudragit coating is dissolve the tablets with disintegrated relatively fast (depending on the hardness).
- Line: 249: please remove the word “probably”. All excipients are fillers and flow agents except NaAlginate which a polymer for controlled release.
- Paragraph 3.2: why the author investigated the thermal stability of omeprazole when none of the manufacturing steps includes any thermal processing of the API? The study looks irrelevant.
- Lines 277: please remove “which are tablets”
- Line 333: what the authors mean by “cooperativity” and how the thermal behaviour is linked to the compaction properties?
- Line 360: again how the thermotropic behaviour relates to the compressibility of Avicel grade?
- Line 378-379: This is an assumption as the authors do not provide Carr’s Index measurements.
- Line 379-385: this is partially right. In addition to the formation of stinger granules the particle size is completely different in comparison to the bulk excipients and hence the tablet hardness will not be the same. The authors provided data for each tablet hardness but those of F6 and F7 are completely different with 20N difference. The appropriate comparison would be to match their hardness and compare the release profile to prove their assumption.
- Line 386: how the melting peak relates to the dissolution rate?
- Line 396: wet granulation is not cost-effective process as it involves a drying step
- Line 397: please rephrase “time their application” Do you mean that are not time consuming?
- Line 402: F3 is not a prescription, it is a formulation.
- Line 413-414: I do not agree with this conclusion. Thermal behaviour can be related to compaction performance only if thermal processing is involved.
Comments on the Quality of English LanguageThe authors need to proof read some parts of the article and check for inappropriate use of specific words.
Author Response
Reviewer #1
Comment
- Line 126: Do the authors mean a regular sieve? This cannot be called “dry granulator”
Answer
According to the reviewer’s comment, we replaced it with the correct term, “regular sieve.”.
Comment
- What is rational of the formulations in Table 1 ? I understand the use of NaAlginate or PVPk-30 but the change from Avicel 101 to 102 shouldn’t affect the dissolution.
Answer
According to the reviewer’s comment, we added in the section “2.2.2. Formulation Production (Capsule Filling and Tablet Production)”: The rationale of the formulations of OME is to investigate how different excipients can affect the interactions between the API, its dissolution, and release from the prepared tablets.”
Comment
- Table 1: The granule composition should be mentioned as a footnote at the end of the tablet as the current form is confusing.
Answer
According to the reviewer’s comment, the granule composition is now mentioned as a footnote at the end of the table in order to avoid misunderstandings.
Comment
- Line 128: How the authors achieved content uniformity by blending omeprazole pellets with the excipient to form tablets? The size of those materials is completely non-uniform and pellets are expected to segregate.
Answer
We added some clarifications according to the reviewer’s comment: "In order to achieve content uniformity by blending omeprazole pellets with the excipient to form tablets, we used a regular sieve. Additionally, the pellets exhibited a high degree of uniformity, which is crucial for the next steps of the formulation process.”
Comment
- Fig. 2 doesn't show a uniform pellet distribution…
Answer
According to the reviewer’s comment, we added it in Section 3.1. “The size of the pellets is the same as visualized and measured in Figure 2. The pellet distribution was quite uniform, taking into account the size of the pellets and the formulation processes. In any case, we cannot claim that our pellets exhibited a high degree of uniformity.”
Comment
- Line 243-245: This line is very confusing. The pellets cannot be in the form of granules. Also this is the first time that authors mentioning that omeprazole was used in the form of powder. Up to this point it was clear that they only used pellets for all formulations
Answer
We rephrased the sentences: “Comparing formulations F6 and F7 that have the same excipients, but in F6 the excipients are mixed with the pellets in the form of granules, while in F7 in powder form, one could argue that the powder excipients favor a more direct drug release.”, as follows: “Comparing formulations F6 and F7 that have the same excipients, but in F6 the excipients are mixed with the pellets of OME in the form of granules, while in F7 the excipients are in powder form, one could argue that this powder form of the excipients favors a more direct and immediate drug release.”
Comment
- Line 246-249: This is something they should definitely expect as the excipients are simple fillers with no specific functionality. Once the Eudragit coating is dissolve the tablets with disintegrated relatively fast (depending on the hardness).
Answer
We added: “This phenomenology is definitely expected, as the excipients are simple fillers with no specific functionality. Once the Eudragit coating dissolves, the tablets disintegrate relatively quickly (depending on their hardness).”
Comment
- Line: 249: please remove the word “probably”. All excipients are fillers and flow agents except NaAlginate which a polymer for controlled release.
Answer
According to the reviewer’s comment, we deleted the word “probably”.
Comment
- Paragraph 3.2: why the author investigated the thermal stability of omeprazole when none of the manufacturing steps includes any thermal processing of the API? The study looks irrelevant.
Answer
In the paragraph 3.2., we added: “We studied the thermal behavior and stability of omeprazole when none of the manufacturing steps included any thermal processing of the API because it is well established in the literature that the tableting processes affect the thermotropic properties of the APIs due to the interactions between the formulation components and the process due to the tablets or granule formulations. Additionally, the investigation of the thermal behavior of pure omeprazole is very useful for comparison reasons.”
Comment
- Lines 277: please remove “which are tablets”
Answer
According to the reviewer’s comment, we deleted the words “which are tablets.”
Comment
- Line 333: what the authors mean by “cooperativity” and how the thermal behaviour is linked to the compaction properties?
Answer
According to the reviewer’s comment, we added: "The cooperativity is a thermal property that corresponds to how uniform the transition is and is equal to half the width at half the peak height of the transition. The thermal is linked to the compaction properties because this formulation process is strongly dependent on the interactions between the different components.”
Comment
- Line 360: again how the thermotropic behaviour relates to the compressibility of Avicel grade?
Answer
According to the reviewer’s comment, we added: "The cooperativity is a thermal property that corresponds to how uniform the transition is and is equal to half the width at half the peak height of the transition. The thermal is linked to the compaction properties because this formulation process is strongly dependent on the interactions between the different components.”
Comment
- Line 378-379: This is an assumption as the authors do not provide Carr’s Index measurements.
Answer
According to the reviewer’s comment, we rephrased as follows: “As mentioned in the literature, the granules showed better flowability, compressibility and compactability compared to direct compression formulation [51]. It is known that by the wet granulation method harder tablets are formed, compared to those prepared by the direct compression method, as tablet hardness is a function of compression load, granule or crystal hardness [51].”.
Comment
- Line 379-385: this is partially right. In addition to the formation of stinger granules the particle size is completely different in comparison to the bulk excipients and hence the tablet hardness will not be the same. The authors provided data for each tablet hardness but those of F6 and F7 are completely different with 20N difference. The appropriate comparison would be to match their hardness and compare the release profile to prove their assumption.
Answer
According to the reviewer’s comment, we added that: “Furthermore, in addition to the formation of stinger granules, the particle size is completely different in comparison to the bulk excipients, and hence the tablet hardness will not be the same. We provided data for each tablet's hardness, but those of F6 and F7 are completely different with a 20N difference. In our opinion, this phenomenology is strongly dependent on the hardness of these formulations and affects the release profile of the OME, too.”
Comment
- Line 386: how the melting peak relates to the dissolution rate?
Answer
We rephrased as follows: “Additionally, the second endothermic peak of F7 needs higher energy for the melting and could facilitate the OME release from the formulation F7 in comparison to F6 (Figure 5) because the dissolution rate and drug release are phenomena that are strongly dependent on the melting points of the excipients, as well as the interactions between excipients and APIs [53].”
We also added a new reference:
Park, J.H.; Kwon, D.Y.; Heo, J.Y.; Park, S.H.; Park, J.Y.; Lee, B.; Kim J.H.; Kim, M.S. Effect of Drug Carrier melting points on drug release of dexamethasone-loaded microspheres. Tissue Eng Regen Med 2017, 14(6):743-753.
Comment
- Line 396: wet granulation is not cost-effective process as it involves a drying step
- Line 397: please rephrase “time their application” Do you mean that are not time consuming?
Answer
According to the reviewer’s comment, we corrected as follows: “For the preparation of the tablets, two the excipients were used by different techniques, which are characterized by convenience, low cost (simple mixing, compression, and wet granulation) and time-consuming.”
Comment
- Line 402: F3 is not a prescription, it is a formulation.
Answer
According to reviewer’s comment, we changed to the correct term “formulation”.
Comment
- Line 413-414: I do not agree with this conclusion. Thermal behaviour can be related to compaction performance only if thermal processing is involved.
Answer
According to the reviewer’s comment, we rephrased as follows: “The use of thermal analysis techniques is of paramount importance for the study of the interactions between the formulation’s components and plays a key role in the mechanistic explanation of the release profile of the encapsulated APIs when different processes are involved.”
Reviewer 2 Report
Comments and Suggestions for AuthorsDear Author/s
The manuscript entitled "A thermal analysis techniques-based mechanistic approach on the release of omeprazole from solid dosage forms" is well written and provides a mechanistic explication in achieving modified drug release profile by designing a multi unit pellet's system. However, there are critical questions/ recommedations for the authors to address:
1. As the formulation of multi-unit pellet tablet's exhibit problem in drug content uniformity, I recommend authors to perform drug content uniformity test for the designed tablets.
2. What is the composition of omeprazole pellets? Authors has not mentioned which grade of Eudragit was used for coating?
3. What is the significance of the result of image analysis from F6 and F7 formulation?
4. The authors have not included DSC and TGA analysis for the pellets. I recommend adding DSC thermogram of Omeprazole pellets and interpreting the results accordingly.
5. Figure numbers are not correct in the manuscript.
Line 229 - in relation to figure 1- ???? There is no figure 1 in the manuscript.
Similarly line 310 and 312- Figure 6b-??? There is no figure 6b in the manuscript.
6. In the conclusion section, re-write the sentences ( line 395-397, line 398 and line 406.).
Comments on the Quality of English Language
Dear Author,
There are some grammar mistakes. Please have it proof ready by a professional editor.
Author Response
Reviewer #2
Comment
- As the formulation of multi-unit pellet tablet's exhibit problem in drug content uniformity, I recommend authors to perform drug content uniformity test for the designed tablets.
Answer
According to the reviewer’s comment, we added: “As it was observed from the dissolution studies, all formulations released the total amount of the encapsulated API. For this reason, the prepared formulations did not exhibit drug uniformity problems, too.”
Comment
- What is the composition of omeprazole pellets? Authors has not mentioned which grade of Eudragit was used for coating?
Answer
According to the reviewer’s comment, we added the composition of OME pellets and the grade of Eudragit used for coating in the Materials section, as follows: “ For the preparation of the tablets and capsules, omeprazole pellets (Cipla Ltd, India) according to the British Pharmacopeia formula, offered for free by Pharma Data SA (Greece), were used. The pellets consisted of 8.5% w/w omeprazole and various excipients (Batch No.YXX4086, CIPLA). Along with them, the following excipients were used: No 0 hard gelatin capsules (Syndesmos, Greece), alginic acid sodium salt of medium viscosity (Alfa Aesar GmbH & Co KG, Germany), Avicel® PH-101 (Alfa Aesar GmbH & Co KG, Germany), Avicel® PH-102 (Sigma-Aldrich, Germany), lactose monohydrate (Merck, Germany), magnesium stearate (Riedel-De Haen, Germany) and PVP K-30 (Sigma-Aldrich, Germany). All the excipients were pharmaceutical grade.”
Comment
- What is the significance of the result of image analysis from F6 and F7 formulation?
Answer
According to the reviewer’s comment, we added it in Section 3.1. “The size of the pellets is the same as visualized and measured in Figure 2. The pellet distribution was quite uniform, taking into account the size of the pellets and the formulation processes. In any case, we cannot claim that our pellets exhibited a high degree of uniformity.”
Comment
- The authors have not included DSC and TGA analysis for the pellets. I recommend adding DSC thermogram of Omeprazole pellets and interpreting the results accordingly.
Answer
According to the reviewer’s comment, we added that “The DSC and TGA analyses for the pellets are included in Figure 1 (for F1). The F1 are capsules of OME pellets, and the TGA and DSA are performed for the content of the capsules, which is the pellets.”
Comment
- Figure numbers are not correct in the manuscript. Line 229 - in relation to figure 1- ???? There is no figure 1 in the manuscript. Similarly line 310 and 312- Figure 6b-??? There is no figure 6b in the manuscript.
Answer
We corrected the numbering of the figures throughout the manuscript.
Comment
- In the conclusion section, re-write the sentences ( line 395-397, line 398 and line 406.).
Answer
According to the reviewer’s comment, we rephrased as follows: “As mentioned in the literature, the granules showed better flowability, compressibility and compactability compared to direct compression formulation [51]. It is known that by the wet granulation method harder tablets are formed, compared to those prepared by the direct compression method, as tablet hardness is a function of compression load, granule or crystal hardness [51].”.
Reviewer 3 Report
Comments and Suggestions for AuthorsThe topic of this manuscript is important and current, and results could be interesting for readers. The work is well planned and written with the support of current literature. However, some changes have to be entered into the revised version of the manuscript before it can be further processed:
1. If you use two different tableting techniques, different compositions, I believe that there are too many variables to draw conclusions without appropriately designing the experiment, e.g. using the design of experiment (DoE) approach.
2. Description of preparation of the formulation in chapter 2.2.2. is not very clear and confuses the reader. Especially since only in the results chapter are the names 'wet granulation' for the F6 formulation and 'direct compression' for the F7 formulation mentioned. Description in chapter 2.2.2. should be reworded.
3. There is no assessment of the influence of the composition on tabletability
4. In part of the discussion, I miss a comparison of the impact of the tableting method and the overall composition.
Author Response
Reviewer #3
Comment
- If you use two different tableting techniques, different compositions, I believe that there are too many variables to draw conclusions without appropriately designing the experiment, e.g. using the design of experiment (DoE) approach.
Answer
We would like to thank the reviewer for this comment. We used different tableting techniques and different compositions, but the aim of this study was to examine the release kinetics of the various dosage forms of omeprazole and provide explanations based on the interactions between the excipients and the active substance. The design-experiment approach will be useful in the case where we want to ameliorate the critical quantity attributes of the final formulation.
Comment
- Description of preparation of the formulation in chapter 2.2.2. is not very clear and confuses the reader. Especially since only in the results chapter are the names 'wet granulation' for the F6 formulation and 'direct compression' for the F7 formulation mentioned. Description in chapter 2.2.2. should be reworded.
Answer
According to the reviewer’s comment, in the section 2.2.2., we added: “All the formulations were prepared by direct compression, except the formulation F6, which is prepared by wet granulation.”
Comment
- There is no assessment of the influence of the composition on tabletability.
Answer
We would like to the reviewer for this comment. In the section 3.1. we added: “We would like to underline that in all cases, tabletability was achieved without observing any visual defects, i.e., capping or lamination. The shape of the tablets after compression and during storage was decided.”
Comment
- In part of the discussion, I miss a comparison of the impact of the tableting method and the overall composition.
Answer
According to the reviewer’s comment, in the last paragraph of the discussion section, we added: “As mentioned above, all the formulations were prepared by direct compression, except formulation F6, which is prepared by wet granulation. The different processes may also play a key role in the interactions between the excipients and the OME and/or between the excipients because they have an impact on the thermal history of the materials used. Last but not least, this thermal history and the presence of the binding liquid in the process of the wet granulation may be responsible for the release of OME at the dissolution studies, as indicated in the literature [53-55].”
We also added three new references:
Park, J.H.; Kwon, D.Y.; Heo, J.Y.; Park, S.H.; Park, J.Y.; Lee, B.; Kim J.H.; Kim, M.S. Effect of Drug Carrier melting points on drug release of dexamethasone-loaded microspheres. Tissue Eng Regen Med 2017, 14(6):743-753.
Park, J.H.; Kang, H.J.; Kwon, D.Y.; Lee, B.K.; Lee, B.; Jang, J.W.; Chun, H.J.; Kim, J.H.; Kim, M.S. Biodegradable poly(lactide-co-glycolide-co-ε-caprolactone) block copolymers - evaluation as drug carriers for a localized and sustained delivery system.J Mater Chem B. 2015;3(41):8143-8153.
Park, J.H.; Lee, B.K.; Park, S.H.; Kim, M.G.; Lee, J.W.; Lee, H.Y.; Lee, H.B.; Kim, J.H.; Kim, M.S.; Preparation of Biodegradable and Elastic Poly(ε-caprolactone-co-lactide) Copolymers and Evaluation as a Localized and Sustained Drug Delivery Carrier.Int J Mol Sci. 2017; 21;18(3):671.
Round 2
Reviewer 3 Report
Comments and Suggestions for AuthorsAccept in present form
