Review Reports

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

In this paper the in vitro dissolution of ibuprofen-loratadine FDC oral supension to commercial formulations was investigated.

The study is interesting. However, in my opinion a major revision of the manuscript is necessary. It is necessary to study some parts of the manuscript in more depth.

More precisely:

 

1. The experimental work seems rather limited to me. If possible, I would add some more measurements or tests.
2. Introduction: it needs to be expanded, deepened and updated. Furthermore, only 6 of the 15 references cited in the introduction are from the last 5 years.
3. The structural formulas of ibuprofen and loratadine must be added and the reason for the "acidic and basic natures of ibuprofen and loratadine", as written in several parts of the manuscript, must be explained. For example, “pKa of 4.4” for ibuprofen, which group are you referring to? It must also be explained why “loratadine is a weak basic compound”.
4. Page 3, the equation 2 is written in a confusing manner and it is difficult to read.
5. Table 1. Accuracy in terms of % recovery, for Ibuprofen “99.6-100.18”, to be corrected to “99.6-100”. Idem page 7, line 200, “100.18 percent”.
6. There is a problem of significant figures and errors expressed as standard deviations (SD). For example, page 5, line 150, “67.5 ± 3.21 %”, It can't be indicated like that: 67.5±3.2 %”, or 67.50±3.21 %”. Page 5, line 163, “54.8 ± 3.27 %”. Similarly, in Table 2, “43 ± 2.61”, “92 ± 2.61”, “25.5 ± 2.88”, “47.5 ± 3.27”, “67.5 ± 3.21”. In Table 3, “54.8 ± 3.27”, “42 ± 2.53”, “84 ± 2.97”.

Author Response

Comments of reviewer 1:

In this paper the in vitro dissolution of ibuprofen-loratadine FDC oral suspension to commercial formulations was investigated.

The study is interesting. However, in my opinion a major revision of the manuscript is necessary. It is necessary to study some parts of the manuscript in more depth.

More precisely:

Comments 1: The experimental work seems rather limited to me. If possible, I would add some more measurements or tests.

Response 1: We appreciate your recommendation. We assessed the FDC suspension using additional dissolution characteristics, such as percent drug release at early time points (Q₁₅ and Q₃₀), time required to reach 50% and 90% release (T₅₀ and T₉₀), and dissolution efficiency (DE%), in addition to calculating the similarity (f₂) and difference (f₁) factors. These measurements guarantee an adequate comparison with the commercial reference products by offering a more thorough evaluation of drug release kinetics and overall formulation performance. (as presented in line numbers: 21-22, 133-172, 250-264, 298-308).

Comments 2: Introduction: it needs to be expanded, deepened and updated. Furthermore, only 6 of the 15 references cited in the introduction are from the last 5 years.

Response 2: We appreciate the reviewer's feedback. To further clarify why loratadine and ibuprofen should be used in a pediatric FDC, the introduction has been revised and broadened. Pediatric formulation issues, the significance of in vitro dissolution for drug performance prediction, and the optimization of dissolution conditions for combination products are highlighted in the new text. In order to rectify out-of-date citations and include current literature, recent references have been added. (as seen in line numbers: 52-54, 58-60, 79-84).

Comments 3: The structural formulas of ibuprofen and loratadine must be added and the reason for the "acidic and basic natures of ibuprofen and loratadine", as written in several parts of the manuscript, must be explained. For example, “pKa of 4.4” for ibuprofen, which group are you referring to? It must also be explained why “loratadine is a weak basic compound”.

Response 3: We are thankful to the reviewer for insightful feedback. The structural formulae for loratadine and ibuprofen have been included (Figure 1). Loratadine is slightly basic because of a tertiary amine nitrogen that takes up a proton in acidic environments, boosting solubility; ibuprofen is acidic because of its carboxylic acid (–COOH) group, which has a pKa of about 4.4 and ionizes at higher pH, increasing solubility. These additions support the selection of dissolution media and shed light on the physicochemical basis of their dissolution behavior. (as seen in line numbers 65-75).

Comments 4: Page 3, the equation 2 is written in a confusing manner and it is difficult to read.

Response 4: We agree to the reviewer and are thankful for pointing out the problem in Equation 2. The equation has now been rewritten in a way that is easy to understand. To guarantee correctness and readability, formatting, mathematical symbols, and space have been adjusted. other equation of the manuscript was also cross-checked and corrected accordingly. (as shown in line numbers 133-172).

Comments 5: Table 1. Accuracy in terms of % recovery, for Ibuprofen “99.6-100.18”, to be corrected to “99.6-100”. Idem page 7, line 200, “100.18 percent”.

Response 5: We agree to the reviewer. Table 1's ibuprofen accuracy values have been updated from "99.6–100.18" to "99.6–100." Similarly, "100.18 percent" has been changed to "100 percent" in the comparable text on page 7, line 200, and every other instance in the document.

Comments 6: There is a problem of significant figures and errors expressed as standard deviations (SD). For example, page 5, line 150, “67.5 ± 3.21 %”, It can't be indicated like that: 67.5±3.2 %”, or 67.50±3.21 %”. Page 5, line 163, “54.8 ± 3.27 %”. Similarly, in Table 2, “43 ± 2.61”, “92 ± 2.61”, “25.5 ± 2.88”, “47.5 ± 3.27”, “67.5 ± 3.21”. In Table 3, “54.8 ± 3.27”, “42 ± 2.53”, “84 ± 2.97”.

Response 6: We appreciate the reviewer for drawing attention to the problem with significant figures and standard deviations (SD). To guarantee uniformity in important data, the manuscript has been amended, including Tables 2 and 3 and the pertinent language on page 5. To reflect proper precision and rounding, all results now follow the correct format.

Reviewer 2 Report

Comments and Suggestions for Authors

The conclusions of the study demonstrate a robust validation of two HPLC–UV methods capable of simultaneously quantifying loratadine and ibuprofen in dissolution testing of a fixed-dose combination (FDC) suspension. Compliance with ICH Q2(R2) criteria for accuracy, precision, and linearity strongly supports the analytical reliability of the developed methods. Moreover, the observation of similar release profiles between the FDC suspension and the corresponding commercial products—confirmed by f₁ values below 15 and f₂ values above 50—further substantiates the in vitro equivalence of the formulations assessed. The selection of dissolution media, namely phosphate buffer at pH 7.2 and 0.1 N HCl at pH 3, is well justified by the acid–base characteristics of the two active pharmaceutical ingredients, thereby enhancing the physiological relevance of the assay. Overall, the findings suggest that the developed suspension exhibits dissolution behavior comparable to that of the reference formulations and represents a potentially more patient-friendly option for the concurrent management of allergic, inflammatory, and pain-related conditions.

Comments for author File: Comments.pdf

Author Response

 Although the study provides a solid analytical validation and demonstrates satisfactory dissolution similarity between the FDC suspension and the reference products, several aspects could be strengthened to further enhance the robustness and applicability of the findings.

Comments 1: Broader dissolution conditions and media

The dissolution assessment was performed in two media representing acidic and neutral environments. Including additional biorelevant media—such as FaSSIF or FeSSIF—could offer a more comprehensive understanding of drug release under physiological fed and fasted states, especially considering the pH-dependent solubility of loratadine and the dissolution-limited absorption of ibuprofen.

Response 1: We value the reviewer's insightful comments. Figure 1 includes the structural formulas for ibuprofen and loratadine. Because of its carboxylic acid (–COOH) group, which has a pKa of about 4.4 and ionizes at higher pH to increase solubility, ibuprofen is acidic. Because loratadine's tertiary amine nitrogen can take up a proton in acidic conditions, making it more soluble, loratadine is slightly basic. (line numbers: 65-74). Ibuprofen dissolution was tested using USP monograph media (phosphate buffer pH 7.2) with slight adjustments to account for their different features, while loratadine media (0.1 N HCl, pH 3.3) was developed locally. Separate media were used to provide discriminative and reliable in vitro evaluation because it is not possible to appropriately measure simultaneous release in a single medium due to the different acid-base characteristics of the two drugs.

Comments 2: Characterization of particle size and physical stability

Since dissolution of suspensions is strongly affected by particle size distribution and physical stability over time, incorporating systematic evaluation of particle size, zeta potential, and sedimentation behavior would add value. These parameters are critical for pediatric suspensions, where uniform dose delivery is essential.

Response 2: We are thankful to the reviewer's feedback. We recognize that zeta potential, sedimentation behavior, particle size distribution, and general physical stability are significant variables that can affect suspension effectiveness, especially in pediatric formulations where consistent dosage delivery is essential. The in vitro dissolution comparison and the development of an HPLC technique for the FDC suspension were the main objectives of the current research. Therefore, it was outside the scope of this work to systematically evaluate particle size and physical stability requirements.

 

 

Comments 3: Evaluation of potential API–API and API–Excipient interactions

Although the dissolution data suggest no significant interaction between ibuprofen and loratadine, complementary solid-state analyses (e.g., DSC, XRPD, FTIR) could provide more direct evidence of physicochemical compatibility and exclude subtle interactions not detectable through dissolution testing alone.

Response 3: We appreciate the reviewer's insightful recommendation. Complementary solid-state tests were carried out to directly demonstrate physicochemical compatibility even if the dissolution results showed no obvious interaction between ibuprofen and loratadine. To evaluate possible API–API and API–excipient interactions, DSC and FTIR analyses were carried out on the powders. These analyses supported the formulation ingredients' compatibility by confirming that there were no apparent physicochemical interactions. A different publication that has already been submitted for review contains a detailed examination of particle size and other physical stability characteristics (data not shown here; no API–API or API–excipient interactions were observed).

Comments 4: In Vitro–In Vivo correlation considerations

The study stops at dissolution testing. Establishing at least a preliminary discussion of the potential for IVIVC, or conducting in vivo work in a later phase, would strengthen claims regarding therapeutic equivalence, particularly in pediatric populations where pharmacokinetic variability is significant.

Response 4: We value the reviewer's important recommendation. We agree that, especially for pediatric formulations, in vitro–in vivo correlation (IVIVC) considerations are crucial. A brief mention about the possibility of IVIVC research is included in the Discussion section, even though the current study only evaluated in vitro dissolution (see line numbers: 312-315).

Comments 5: Long-Term stability of the FDC suspension

Given that suspensions may undergo viscosity changes, sedimentation, flocculation, or degradation, a stability study—chemical, physical, and microbiological—would be essential to ensure that dissolution performance remains consistent throughout the product’s shelf life.

Response 5: We appreciate the reviewer's insightful feedback. The FDC suspension has already undergone a thorough long-term stability study during which the product showed adequate stability. However, these stability data could not be included in the current work because they are part of a different publication that has been finalized and submitted for review. The comparative in vitro dissolution performance is the primary emphasis of the current manuscript; the complete stability results will be accessible after the companion article is published.

 

Comments 6: Impact of excipients and formulation variables

A more detailed examination of how excipient concentration, viscosity modifiers, or wetting agents influence dissolution and API compatibility could improve understanding of formulation robustness. This is particularly relevant for FDC products combining drugs with different solubility classes.

Response 6: We appreciate the reviewer's insightful comment. Using a Box–Behnken design, the effects of important formulation variables were comprehensively studied during product development. Citric acid, sodium carboxymethyl cellulose, and glycerin were analyzed as independent factors while the amounts of other excipients were kept constant. This optimization showed that the chosen excipient levels produced an appropriate pH, viscosity and density without negatively impacting API compatibility or dissolution performance. The current article, which focuses on comparative dissolution specifically, does not include these findings because they are reported in a separate manuscript that has been submitted for review.

Comments 7: Consideration of palatability and acceptability for pediatric use

Since the formulation is intended for children, incorporating sensory acceptability or palatability assessment would strengthen the claim that the FDC suspension is patient-friendly.

Response 7: We appreciate the reviewer emphasizing the significance of acceptability and palatability in pediatric formulations. Although the HPLC method development, validation, and in vitro dissolution assessment of the FDC suspension were the main objectives of the current study, the updated Conclusion acknowledges the importance of patient-friendly characteristics. Future research will assess palatability and acceptability to guarantee adherence and convenience of administration. The revised statement now suggests that the FDC suspension may be appropriate for pediatric use (as seen in line number 334-336).

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

All my suggestions were accepted. I recommend publishing the manuscript on Liquids in this form.

Reviewer 2 Report

Comments and Suggestions for Authors

The authors have undertaken an excellent revision and have duly incorporated the suggestions and corrections provided.