Evaluation of Dissolution Enhancement of Aprepitant Drug in Ternary Pharmaceutical Solid Dispersions with Soluplus^® and Poloxamer 188 Prepared by Melt Mixing

Round 1

Reviewer 1 Report

This is a well planned and performed study. Few comments to improve the scientific quality of the manuscript.

(1) The authors should justify the drug and polymer proportions chosen in the solids dispersions in relation to the size of the drug doses used clinically. What would be an optimum drug content of an APT solid dispersion dosage form?

(2) Details on how EDAX measurements were conducted should be reported.How drug nanocrystals were analyzed without interference from the polymer matrix?

(3) Drug release does not appear to be controlled by matrix erosion, as the authors concluded. As the difficult to dissolve part of the system is the hydrophobic drug, drug release should be controlled by drug particles dissolution. This is the reason why drug release falls with drug content, i.e. with the size of the drug particles, in the matrix. A Hixson Crowell dissolution model should better describe obtained release data. In any case, it is difficult to make a reliable analysis of drug release mechanism when at the first sampling time point drug release is higher than 70% (Figure 11).

Author Response

This is a well planned and performed study. Few comments to improve the scientific quality of the manuscript. (1) The authors should justify the drug and polymer proportions chosen in the solids dispersions in relation to the size of the drug doses used clinically. What would be an optimum drug content of an APT solid dispersion dosage form? (2) Details on how EDAX measurements were conducted should be reported.How drug nanocrystals were analyzed without interference from the polymer matrix? (3) Drug release does not appear to be controlled by matrix erosion, as the authors concluded. As the difficult to dissolve part of the system is the hydrophobic drug, drug release should be controlled by drug particles dissolution. This is the reason why drug release falls with drug content, i.e. with the size of the drug particles, in the matrix. A Hixson Crowell dissolution model should better describe obtained release data. In any case, it is difficult to make a reliable analysis of drug release mechanism when at the first sampling time point drug release is higher than 70% (Figure 11). General Comment: This is a well-planned and performed study. Few comments to improve the scientific quality of the manuscript. Authors Reply: We thank the reviewer for his/her nice comments. Comment 1: The authors should justify the drug and polymer proportions chosen in the solids dispersions in relation to the size of the drug doses used clinically. What would be an optimum drug content of an APT solid dispersion dosage form? Authors Reply: Based on Emend SmPC there are several strengths starting from 40mg/dose up to 125mg/dose. Hence, in the case of 90/10 SD the lowest total dose weight will be 360mg and the highest total dose will be 1125mg, quantities that are acceptable for per os administration. Clarifications are given in the revised manuscript. Comment 2: Details on how EDAX measurements were conducted should be reported.How drug nanocrystals were analyzed without interference from the polymer matrix? Authors Reply: Details are given in the revised manuscript. Comment 3: Drug release does not appear to be controlled by matrix erosion, as the authors concluded. As the difficult to dissolve part of the system is the hydrophobic drug, drug release should be controlled by drug particles dissolution. This is the reason why drug release falls with drug content, i.e. with the size of the drug particles, in the matrix. A Hixson Crowell dissolution model should better describe obtained release data. In any case, it is difficult to make a reliable analysis of drug release mechanism when at the first sampling time point drug release is higher than 70% (Figure 11). Authors Reply: We thank the reviewer for his/her suggestion and we agree that it is difficult tricky to have a reliable fitting model when 70% of the API is released in the first sampling point. However, since our approach fits perfectly the obtained results, we fill that the approach followed may adequately describe APT’s release mechanism.

Reviewer 2 Report

As a Pharmaceutical Chemistry, I always like to see the chemical structure of the drug when possible. The authors mentioned the presence of two polymorphs of the API in Wide Angle X-ray Diffractometry (WAXD) Analysis. Do authors know how much of each polymorph was present in the formulation and if that ratio is reproducible? Furthermore, is there solubility data available bor individual polymorphs since polymorphs can differ significantly in dissolution, thus affecting the bioavailability.

Author Response

As a Pharmaceutical Chemistry, I always like to see the chemical structure of the drug when possible. The authors mentioned the presence of two polymorphs of the API in Wide Angle X-ray Diffractometry (WAXD) Analysis. Do authors know how much of each polymorph was present in the formulation and if that ratio is reproducible? Furthermore, is there solubility data available bor individual polymorphs since polymorphs can differ significantly in dissolution, thus affecting the bioavailability. Thessaloniki 5/10/2019 Dear Editor We would like to thank both -You and Reviewers- for the time spending on the evaluation of our paper and the helpful/accurate comments and valuable suggestions. In the following, you can find our responses –one by one answer to the reviewer comments- and changes that we have included in the revised manuscript with red colour taking into account all reviewers suggestions. Reviewer #1: General 1: As a Pharmaceutical Chemistry, I always like to see the chemical structure of the drug when possible. Authors Reply: We agree with the reviewer that the paper looks nicer when the chemical structures are presented, however, both API and used excipients are widely known and hence, we have decided not to include their chemical structure in manuscript. Comment 2: The authors mentioned the presence of two polymorphs of the API in Wide Angle X-ray Diffractometry (WAXD) Analysis. Do authors know how much of each polymorph was present in the formulation and if that ratio is reproducible? Authors Reply: The determination of the ratio of each polymorph in the prepared formulations was outside of the scope of the present manuscript. Comment 3: Furthermore, is there solubility data available bor individual polymorphs since polymorphs can differ significantly in dissolution, thus affecting the bioavailability. Authors Reply: According to published data (US20100298327A1) “crystalline Form I of aprepitant has been shown to have a lower solubility (0.9±0.1 mg/ml) when compared with Form II (1.3±0.2 mg/ml)”, however the evaluation of API’s polymorph solubility in the prepared SDs was outside of the scope of the present paper. Sincerely Yours Dimitrios Bikiaris Professor

Round 2

Reviewer 1 Report

Following authors revisions, the manuscript could now be accepted for publication.

Author Response

Following authors revisions, the manuscript could now be accepted for publication. We would like to thank the reviewer for his accurate comments, which increased the overall value of the revised manuscript and also for his final decision to accept the paper for publication.

Reviewer 2 Report

As a Pharmaceutical Chemistry, I always like to see the chemical structure of the drug when possible. Authors Reply: We agree with the reviewer that the paper looks nicer when the chemical structures are presented, however, both API and used excipients are widely known and hence, we have decided not to include their chemical structure in manuscript. 

The whole point of my comment was to avoid Google searching the drug structure...

Comment 2: The authors mentioned the presence of two polymorphs of the API in Wide Angle X-ray Diffractometry (WAXD) Analysis. Do authors know how much of each polymorph was present in the formulation and if that ratio is reproducible? Authors Reply: The determination of the ratio of each polymorph in the prepared formulations was outside of the scope of the present manuscript. 

Since the manuscript deals with solubility enhancement and solubility also depend upon the polymorph present, it is very relevant to know the contribution from each polymer! What if the ratio of the polymorphs changes during the next batch preparation, the dissolution profile of the formulation will not be the same. This also begs the question, how reproducible these results are when compared with various batches, if made?

Comment 3: Furthermore, is there solubility data available bor individual polymorphs since polymorphs can differ significantly in dissolution, thus affecting the bioavailability. Authors Reply: According to published data (US20100298327A1) “crystalline Form I of aprepitant has been shown to have a lower solubility (0.9±0.1 mg/ml) when compared with Form II (1.3±0.2 mg/ml)”, however the evaluation of API’s polymorph solubility in the prepared SDs was outside of the scope of the present paper. Sincerely Yours Dimitrios Bikiaris Professor.

As mentioned above, prior knowledge of the solubility profile of the drug and its polymorphs helps to assess the clear effect of formulation on the dissolution phenomenon...

Author Response

The whole point of my comment was to avoid Google searching the drug structure... The drug structure is included in the revised manuscript as per reviewer suggestion. Since the manuscript deals with solubility enhancement and solubility also depend upon the polymorph present, it is very relevant to know the contribution from each polymer! What if the ratio of the polymorphs changes during the next batch preparation, the dissolution profile of the formulation will not be the same. This also begs the question, how reproducible these results are when compared with various batches, if made? The initial content of form II crystals in the raw material (API) was about 6%. After SD preparation the same form II content was obtained in all cases. This was added in the revised manuscript. As mentioned above, prior knowledge of the solubility profile of the drug and its polymorphs helps to assess the clear effect of formulation on the dissolution phenomenon... As was mentioned in our previous replay according to published data (US20100298327A1) “crystalline Form I of aprepitant has been shown to have a lower solubility (0.9±0.1 mg/ml) when compared with Form II (1.3±0.2 mg/ml)”. Taking into account that in all SDs form II is about 6%, we do not expect any effect to dissolution profiles of this small percentage.

Round 3

Reviewer 2 Report

The revised manuscript can now be accepted in the present form...

Author Response

The revised manuscript can now be accepted in the present form... Many thanks