Impact of Impurities on Crystallization and Product Quality: A Case Study with Paracetamol
Round 1
Reviewer 1 Report
The manuscript reports a systematic and comprehensive study on the effects of impurities on crystallization and prodcut quality of paracetamol. The study is well designed, the paper is clearly structured and well written, the topic nicely fits the journal scope. Experiments and analysis appear to be robust. Therefore I would like to recommend the paper for publication as it is. However, I would like to suggest to consider to include an error analysis or error bars, e.g., to Fig. 3, 4, 7
Author Response
We thank reviewer 1 for their kind comments on our work. We have added error bars denoting the standard deviation of our data points to figures 3, 4 and 7, although in many cases the error bars are smaller than the data point.
Reviewer 2 Report
In my opinion, the manuscript presents very interesting and comprehensive research on the effect of acetanilide and metacetamol on the crystallization of paracetamol and the quality of the final product, which is extremely important in the pharmaceutical industry. The chosen techniques are of high standard and adequately describe the analysed problems. The use of Technobis Crystal16 instrument for the study of paracetamol crystallization with impurities is an innovative approach.
Unfortunately, this problem has already been largely described in the previous publication of the Authors. Even the Figure 5 and Figure 11 of the previous work are identical. Another disadvantage of this work is the lack of consideration of the influence of the mixture of impurities on the crystallization of paracetamol and the lack of analysis of the ternary phase diagrams. Such an analysis would be of great interest to the reader. The authors use the acronym PSD, but I have not found its development anywhere (particle-size distribution?).
This work may be accepted for publication in Crystals under certain conditions. Authors should heed my above remarks.
Author Response
In my opinion, the manuscript presents very interesting and comprehensive research on the effect of acetanilide and metacetamol on the crystallization of paracetamol and the quality of the final product, which is extremely important in the pharmaceutical industry. The chosen techniques are of high standard and adequately describe the analysed problems. The use of Technobis Crystal16 instrument for the study of paracetamol crystallization with impurities is an innovative approach.
Unfortunately, this problem has already been largely described in the previous publication of the Authors. Even the Figure 5 and Figure 11 of the previous work are identical. Another disadvantage of this work is the lack of consideration of the influence of the mixture of impurities on the crystallization of paracetamol and the lack of analysis of the ternary phase diagrams. Such an analysis would be of great interest to the reader. The authors use the acronym PSD, but I have not found its development anywhere (particle-size distribution?).
The binary phase diagram/Tamman triangle plot for paracetamol and acetanilide in Figure 5 has not been previously reported. Inclusion of previous data in Figure 5 was to enable a direct side by side comparison between these two impurity systems. Whilst this is referenced in the text (page 11, line 352) to add clarity about this overlap, we have added some text to the abstract, as well as clearer referencing to in the caption of Figure 5.
Indeed, studying a mixture of impurities on crystallisation would be an attractive addition to this study, at the time this was deemed out of scope for our objectives. As one can imagine, once mixtures of impurities are introduced, the study and models become complex, and we have decided to keep this separate from the work presented.
We apologise for the omission of a definition of the acronym PSD, the reviewer is correct with particle-size distribution, and we have added this definition to the text (Page 14, Line 445).
This work may be accepted for publication in Crystals under certain conditions. Authors should heed my above remarks.
We thank reviewer 2 for their kind and constructive comments.
Reviewer 3 Report
This manuscript studies the influence of acetanilide and metacetamol on the crystallization and product quality of paracetamol. The manuscript is well written and the experimental work and analysis were performed clearly and objectives were well met. I recommend publication of this manuscript after the authors have addressed the following points:
- Page 11, Figure 5(d), based on the linear regression equation, XACE-axis intercept should be ~-0.05. Please check.
- Page 10, second paragraph, should be Xi,P not Xi,F?
- Page 17, lines 564-565, the recycling of mother liquor may lead to impurity buildup even though it could improve product recovery.
- It would interesting as part of future work to perform a more detailed analysis on how metacetamol is incorporated into the crystal lattice of paracetamol.
Author Response
This manuscript studies the influence of acetanilide and metacetamol on the crystallization and product quality of paracetamol. The manuscript is well written and the experimental work and analysis were performed clearly and objectives were well met. I recommend publication of this manuscript after the authors have addressed the following points:
- Page 11, Figure 5(d), based on the linear regression equation, XACE-axis intercept should be ~-0.05. Please check.
The reviewer is correct, and the typo has been corrected.
- Page 10, second paragraph, should be Xi,P not Xi,F?
The reviewer is correct, and the typo has been corrected.
- Page 17, lines 564-565, the recycling of mother liquor may lead to impurity buildup even though it could improve product recovery.
We had overlooked this aspect of adding a mother liquor recycle in our manuscript. This has been added to the text as indicated, including an appropriate reference (number 36).
- It would interesting as part of future work to perform a more detailed analysis on how metacetamol is incorporated into the crystal lattice of paracetamol.
This would be a very nice future extension of the study presented, and we thank the reviewer for their constructive feedback.
Reviewer 4 Report
The article is devoted to the study of the problem of crystallization of the known drug paracetamol in the presence of impurities in the form of related compounds - acetanilide and metacetamol. At the same time, it is assumed that the conclusions made in the work can be extended to a wider range of compounds with pharmaceutical value.
When reading the article, there is a double impression. On the one hand, the authors have meticulously carried out painstaking and comprehensive research work with a detailed analysis of both the initial product and the characteristics of its behavior, and the products of its interaction with two impurities chosen as models in this case. All obtained results were confirmed by a complex of physicochemical methods, including measurements of solubility, HPLC, powder X-Ray diffraction, DSC, optical microscopy. The applicability of these methods and methods of extracting structural, dimensional, and quantitative characteristics of systems from experimental data are shown. References to related and own literary data are provided.
On the other hand, throughout almost the entire article, the feeling of Deja Vu does not leave - somewhere I have already seen and read it all, and certain conclusions of the work are found in the early works of the authors themselves and research works of other scientific groups. Acquaintance with the literary references given by the authors and other well-known works on this topic, and there are quite a few of them even recently, really leads me to the conclusion that the bulk of the information given by the authors in the abstract and conclusion, in one form or another, is already found as in publications from the list in the article, and in other similar ones.
The inclusion in this article of a microscopic image of the paracetamol- acetanilide system (p. 14, Fig. 8c), which is absolutely identical to the micrograph given by the authors in their previous published work [S. J. Urwin, G. Levilain, I. Marziano, J. M. Merritt, I. Houson and J. H. ter Horst, , Org. Process Res. Dev., 2020, 24, 1443-1456], p. 1450, fig. 7b] even more adjusts to a similar mood. Actually, in that work, some fragments of the conclusions of the cited work are already given. For example, in the previous work, the authors indicate a decrease in the content of acetanilide to 0.80 mol%, and in the work under review, this value slightly decreased to 0.79 mol%.
Unfortunately, in such a voluminous and well-developed study, in my opinion, the goal-setting of the work and its novelty have disappeared, although it certainly exists. I find it interesting, at least, observation of the transition of the polymorphic form of paracetamol 1 to form 2 at significantly lower levels of metacetamol, which is an obvious novelty. However, it does not figure in either the abstract or the conclusion.
In addition, section 3.2.1. on crystal purity, discussion on 9-10 pages is rather confusing and unnecessarily complicated. At least for a specialist who is close to this area of research, but is not completely immersed in it, reading and acquaintance with this part does not give pleasure.
The choice of compounds used and mentioned as impurities in the preparation of paracetamol raises several questions. There are a number of compounds in the literature that have been attributed to the presence of this API in the synthesis. For example, in work 29 from the list of references, the presence of two other related compounds in paracetamol, 4-nitrophenol and 4'-chloroacetanilide, which differ from those considered in this article, is considered the most problematic and important impurities. Other work focuses on the presence of p-acetoxyacetanilide impurities in paracetamol [Prasad, K.V .; Ristic, R.I .; Sheen, D.B .; Sherwood, J.N. Int. J. Pharm. 2001, 215, 29–44].
Moreover, in [McGregor, L., Rychkov, DA, Coster, PL, Day, S., Drebushchak, VA, Achkasov, AF, Nichol, GS, Pulham, CR, Boldyreva, EV, CrystEngComm, 17 (32), (2015), pp. 6183-6192], additionally, the existence of polymorphic form 2 of metacetamol is shown, i.e. this requires a modification of the consideration of the contribution of this compound, taking into account its polymorphism. And this range of potential impurities is greatly increasing, leading to some doubts about the productivity of existing methods for the synthesis of paracetamol. Maybe something needs to be changed there, and not try to analyze the presence of every possible impurity. It might make sense to analyze the total number of possible related compounds in paracetamol, the general reasons for their appearance in the sample in the form of impurities, and possible ways of removing them. It seems to me that this would greatly brighten this study if the authors critically assessed this area, being undoubtedly experts in it. Although this, of course, does not apply to comments but rather wishes.
In general, the article is quite within the framework of the problems that are considered in the journal Crystals, and may well take a worthy place in a number of its publications.
However, I believe that this article can be published in the journal Crystal only after a significant correction of the Abstract, the goal-setting part of the article, and its Conclusions. As it stands, virtually every sentence of the Abstract and Conclusion can be successfully challenged in terms of the novelty of these results.
The rest of the remarks boil down to the need to correct the typos encountered in the text, for example, page 3. line 117 crystals (3), page 8 line 236 - m-3 instead of m-3 s-1, fused reference numbers on page 2, lines 85, 87, 88, and semantic abbreviations in some sentences.
Author Response
The article is devoted to the study of the problem of crystallization of the known drug paracetamol in the presence of impurities in the form of related compounds -acetanilide and metacetamol. At the same time, it is assumed that the conclusions made in the work can be extended to a wider range of compounds with pharmaceutical value.When reading the article, there is a double impression. On the one hand, the authors have meticulously carried out painstaking and comprehensive research work with a detailed analysis of both the initial product and the characteristics of its behavior, and the products of its interaction with two impurities chosen as models in this case. All obtained results were confirmed by a complex of physicochemical methods, including measurements of solubility, HPLC, powder X-Ray diffraction, DSC, optical microscopy. The applicability of these methods and methods of extracting structural, dimensional, and quantitative characteristics of systems from experimental data are shown. References to related and own literary data are provided.On the other hand, throughout almost the entire article, the feeling of Deja Vu does not leave -somewhere I have already seen and read it all, and certain conclusions of the work are found in the early works of the authors themselves and research works of other scientific groups. Acquaintance with the literary references given by the authors and other well-known works on this topic, and there are quite a few of them even recently, really leads me to the conclusion that the bulk of the information given by the authors in the abstract and conclusion, in one form or another, is already found as in publications from the list in the article, and in other similar ones.The inclusion in this article of a microscopic image of the paracetamol-acetanilide system (p. 14, Fig. 8c), which is absolutely identical to the micrograph given by the authors in their previous published work [S. J. Urwin, G. Levilain, I. Marziano, J. M. Merritt, I. Houson and J. H. ter Horst, , Org. Process Res. Dev., 2020, 24, 1443-1456], p. 1450, fig. 7b] even more adjusts to a similar mood. Actually, in that work, some fragments of the conclusions of the cited work are already given. For example, in the previous work, the authors indicate a decrease in the content of acetanilide to 0.80 mol%, and in the work under review, this value slightly decreased to 0.79 mol%.Unfortunately, in such a voluminous and well-developed study, in my opinion, the goal-setting of the work and its novelty have disappeared, although it certainly exists. I find it interesting, at least, observation of the transition of the polymorphic form of paracetamol 1 to form 2 at significantly lower levels of metacetamol, which is an obvious novelty. However, it does not figure in either the abstract or the conclusion.In addition, section 3.2.1. on crystal purity, discussion on 9-10 pages is rather confusing and unnecessarily complicated. At least for a specialist who is close to this area of research, but is not completely immersed in it, reading and acquaintance with this part does not give pleasure.
The study presented here is an extension of our previous work, and whilst we acknowledge that there is a small overlap, the objective of this work is unique. In our previous paper, we proposed a general impurity rejection workflow based on identifying the impurity incorporation mechanism, exemplified by a number of crystalline compounds / impurity combinations, whereas here we look at the impact of different impurity concentrations on the crystallisation process of the compound paracetamol and all the possible effect on product quality. The connection between the two pieces of work is highlighted in the final paragraph of the discussion (page 18, lines 586-590).
The polymorphic transition to paracetamol form 2 was mentioned in the abstract, in lines 17-18, as well as the conclusion (page 18, lines 596-597), and the surprising nature of this due to the lower metacetamol concentrations was described on page 12, lines 382-384. We have added some text to the abstract to clarify the novelty.
2The choice of compounds used and mentioned as impurities in the preparation of paracetamol raises several questions. There are a number of compounds in the literature that have been attributed to the presence of this API in the synthesis. For example, in work 29 from the list of references, the presence of two other related compounds in paracetamol, 4-nitrophenol and4'-chloroacetanilide, which differ from those considered in this article, is considered the most problematic and important impurities. Other work focuses on the presence of p-acetoxyacetanilide impurities in paracetamol [Prasad, K.V .; Ristic, R.I .; Sheen, D.B .; Sherwood, J.N. Int. J. Pharm. 2001, 215, 29–44].Moreover, in [McGregor, L., Rychkov, DA, Coster, PL, Day, S., Drebushchak, VA, Achkasov, AF, Nichol, GS, Pulham, CR, Boldyreva, EV, CrystEngComm, 17 (32), (2015), pp. 6183-6192], additionally, the existence of polymorphic form 2 of metacetamol is shown, i.e. this requires a modification of the consideration of the contribution of this compound, taking into account its polymorphism. And this range of potential impurities is greatly increasing, leading to some doubts about the productivity of existing methods for the synthesis of paracetamol. Maybe something needs to be changed there, and not try to analyze the presence of every possible impurity. It might make sense to analyze the total number of possible related compounds in paracetamol, the general reasons for their appearance in the sample in the form of impurities, and possible ways of removing them. It seems to me that this would greatly brighten this study if the authors critically assessed this area, being undoubtedly experts in it. Although this, of course, does not apply to comments but rather wishes.In general, the article is quite within the framework of the problems that are considered in the journal Crystals, and may well take a worthy place in a number of its publications. However, I believe that this article can be published in the journal Crystal only after a significant correction of the Abstract, the goal-setting part of the article, and its Conclusions. As it stands, virtually every sentence of the Abstract and Conclusion can be successfully challenged in terms of the novelty of these results.
We thank reviewer 4 for their thorough review of our work, and we are happy they can appreciate the novelty in the study we have presented. To increase the clarity of the novelty in the paper for the readers, we have added some clarifying sentences to both the abstract and conclusion as suggested. This also helps address the reviewer’s previous comment on differentiating this study from our previous one.
With paracetamol being one of the most used medicines in the world, there are many known synthetic routes, and hence many impurities we could have chosen for our study. We specifically chose impurities which are most structurally similar to the API itself, as these tend to be the most difficult ones to deal with when designing a crystallisation process. Of course, we have studied a relatively simple system here, but our methodology in this work could be taken and applied to any number of products in industrial product development.
The rest of the remarks boil down to the need to correct the typos encountered in the text, for example, page 3. line 117 crystals (3), page 8 line 236 -m-3 instead of m-3 s-1, fused reference numbers on page 2, lines 85, 87, 88, and semantic abbreviations in some sentences
The errors on page 3, line 117, has been removed. The “s-1” missing from the units of J on page 8, line 236, has been added to the text. We have thoroughly checked the text for typographical errors and corrected those which we have found.
Regarding the fused reference numbers on page 2, we have referenced our manuscript following the guidelines set by Crystals, and cannot find the problem the reviewer is alluding to.
Round 2
Reviewer 2 Report
I am not entirely convinced of the authors' explanation regarding the repeated content of their previous publication. I understand that, once mixtures of impurities are introduced, the study and models become more complex and difficult to explain. And the authors did not do it. So, I have mixed feelings.
Reviewer 4 Report
In general, I am satisfied with the corrections made by the Authors of the article, although I am more satisfied with their responses to my comments. In particular, it is the phrase about the use in this work of the previously developed technique for identifying the mechanism of inclusion of impurities, in my opinion, would be desirable in the introduction of the article.
The work can be published as presented, but subject to the following comments:
- I assume that the inclusion in this article of a micrograph of the paracetamol-acetanilide system (p. 14, fig. 8c), previously published by the authors in [S. J. Urwin, G. Levilain, I. Marziano, J. M. Merritt, I. Houson and J. H. ter Horst, Org. Process Res. Dev., 2020, 24, 1443-1456] may infringe the journal's copyright (© 2020 American Chemical Society). Therefore, it is necessary to slightly change this picture or provide a link to the above publication and the ACS journal permission;
- when I pointed to the solidly written reference numbers on page 2, lines 85, 87, 88, I meant the following: according to the requirements of Crystal journal, “In the text, reference numbers should be placed in square brackets [], and placed before the punctuation; for example [1], [1-3] or [1,3]”.
