Forecasting in vivo pharmacokinetics of metformin HCl floating beads using Gastroplus® PBPK

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Among the available therapeutic options, Metformin hydrochloride is a key medication, particularly for those who cannot effectively manage the condition through changes in diet and lifestyle alone. This research aimed to predict their in vivo parameters from an in vitro release study by developing a physiologically based pharmacokinetic (PBPK) model by using Gastroplus® software. Methods Sodium alginate-based MH floating beads were prepared by dissolving different concentrations of sodium alginate in deionized water, incorporating MH (1 g) and calcium carbonate (1.5 mg) as a gas-forming agent, and mixing at 200 rpm. The air-free dispersion, achieved through 30 minutes of sonication, was dropped into a 5% w/v calcium chloride solution containing 5% v/v isopropyl alcohol via a syringe for cross-linking and bead formation. Beads were cured in the solution for 30 minutes to enhance mechanical strength, then filtered, washed, and air-dried for 24 hours, ensuring uniformity and stability for controlled drug delivery and the prepared beads were evaluated for their entrapment efficiency %, morphology, floating property and in vitro release Ultimately, using Gastroplus® software, to predict the pharmacokinetic profile of in vitro release results. Results Entrapment efficiency exhibited acceptable values, and the beads were smooth, and rounded in shape for all formulations. The beads remained afloat during the release study; the release study revealed that F1 to F5 showed asymptotic slow-release, while F6 and F7 gave shorter release times. The prediction of absorption indicated highest MH absorption was in the jejunum, then the duodenum. Conclusion The prepared Beads had promising pharmacokinetic parameters and C max was close to MH modified released tablet. 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F1000Research 2025, 14 :140 ( https://doi.org/10.12688/f1000research.159438.2 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. Close Copy Citation Details Export Export Citation Sciwheel EndNote Ref. Manager Bibtex ProCite Sente EXPORT Select a format first Track Share ▬ ✚ Research Article Revised Forecasting in vivo pharmacokinetics of metformin HCl floating beads using Gastroplus® PBPK [version 2; peer review: 1 approved, 2 approved with reservations] Sura Zuhair Mahmood https://orcid.org/0000-0003-0007-8441 1 , Nora Zawar Yousif https://orcid.org/0000-0002-6025-506X 1 , Masar Basim Mohsin Mohamed https://orcid.org/0000-0001-9601-4180 1 Sura Zuhair Mahmood https://orcid.org/0000-0003-0007-8441 1 , Nora Zawar Yousif https://orcid.org/0000-0002-6025-506X 1 , Masar Basim Mohsin Mohamed https://orcid.org/0000-0001-9601-4180 1 PUBLISHED 09 Sep 2025 Author details Author details 1 Pharmaceutics Department, Pharmacy College, Mustansiriyah University, Baghdad, Iraq Sura Zuhair Mahmood Roles: Conceptualization, Data Curation, Funding Acquisition, Investigation, Methodology, Project Administration, Resources, Visualization Nora Zawar Yousif Roles: Data Curation, Formal Analysis, Funding Acquisition, Investigation, Resources, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing Masar Basim Mohsin Mohamed Roles: Conceptualization, Data Curation, Formal Analysis, Funding Acquisition, Investigation, Project Administration, Resources, Software, Supervision, Validation, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing OPEN PEER REVIEW DETAILS REVIEWER STATUS Abstract Background Diabetes mellitus type II is expected to impact a large population worldwide. Among the available therapeutic options, Metformin hydrochloride is a key medication, particularly for those who cannot effectively manage the condition through changes in diet and lifestyle alone. This research aimed to predict their in vivo parameters from an in vitro release study by developing a physiologically based pharmacokinetic (PBPK) model by using Gastroplus ® software. Methods Sodium alginate-based MH floating beads were prepared by dissolving different concentrations of sodium alginate in deionized water, incorporating MH (1 g) and calcium carbonate (1.5 mg) as a gas-forming agent, and mixing at 200 rpm. The air-free dispersion, achieved through 30 minutes of sonication, was dropped into a 5% w/v calcium chloride solution containing 5% v/v isopropyl alcohol via a syringe for cross-linking and bead formation. Beads were cured in the solution for 30 minutes to enhance mechanical strength, then filtered, washed, and air-dried for 24 hours, ensuring uniformity and stability for controlled drug delivery and the prepared beads were evaluated for their entrapment efficiency %, morphology, floating property and in vitro release Ultimately, using Gastroplus ® software, to predict the pharmacokinetic profile of in vitro release results. Results Entrapment efficiency exhibited acceptable values, and the beads were smooth, and rounded in shape for all formulations. The beads remained afloat during the release study; the release study revealed that F1 to F5 showed asymptotic slow-release, while F6 and F7 gave shorter release times. The prediction of absorption indicated highest MH absorption was in the jejunum, then the duodenum. Conclusion The prepared Beads had promising pharmacokinetic parameters and C max was close to MH modified released tablet. READ ALL READ LESS Keywords Ionic gelation; Na alginate, gastroretentive, effervescent system, multiple units, in silico Corresponding Author(s) Nora Zawar Yousif ( [email protected] ) Close Corresponding author: Nora Zawar Yousif Competing interests: No competing interests were disclosed. Grant information: The author(s) declared that no grants were involved in supporting this work. Copyright: © 2025 Mahmood SZ et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite: Mahmood SZ, Yousif NZ and Mohsin Mohamed MB. Forecasting in vivo pharmacokinetics of metformin HCl floating beads using Gastroplus® PBPK [version 2; peer review: 1 approved, 2 approved with reservations] . F1000Research 2025, 14 :140 ( https://doi.org/10.12688/f1000research.159438.2 ) First published: 28 Jan 2025, 14 :140 ( https://doi.org/10.12688/f1000research.159438.1 ) Latest published: 09 Sep 2025, 14 :140 ( https://doi.org/10.12688/f1000research.159438.2 ) Revised Amendments from Version 1 The following changes have been made: For Abstract: improved the aim of the abstract, introduction: changing phrases in the introduction and replacing references with more recent ones, adding new references regarding the limitations in the previous study. Methods: the references were updated in Formulation of beads, Percentage of entrapment efficiency %:, Floating properties (Buoyancy lag time and duration of buoyancy), In silico modelling for metformin absorption. In addition, new references with clarifications were added in results and discussion sections: in percentage of yield, Floating properties (buoyancy lag time and duration of buoyancy). igure 2 changes in the title, and the image scale resolution is adjusted according to the suggestion. Figure 4 changes in the title. igure 6 changes in the figure y-axis titles as per reviewer request, addition of future perspective and limitation sections, at last the conclusion has been adjusted. The following changes have been made: For Abstract: improved the aim of the abstract, introduction: changing phrases in the introduction and replacing references with more recent ones, adding new references regarding the limitations in the previous study. Methods: the references were updated in Formulation of beads, Percentage of entrapment efficiency %:, Floating properties (Buoyancy lag time and duration of buoyancy), In silico modelling for metformin absorption. In addition, new references with clarifications were added in results and discussion sections: in percentage of yield, Floating properties (buoyancy lag time and duration of buoyancy). igure 2 changes in the title, and the image scale resolution is adjusted according to the suggestion. Figure 4 changes in the title. igure 6 changes in the figure y-axis titles as per reviewer request, addition of future perspective and limitation sections, at last the conclusion has been adjusted. See the authors' detailed response to the review by Sagar Salave See the authors' detailed response to the review by Anuj Garg READ REVIEWER RESPONSES Introduction According to International Diabetes Federation (IDF) in 2021, approximately 537 million individuals worldwide about (10.5%) of the global population, especially those aged 20–79 years are living with diabetes, this number is growing to be increased within a few upcoming decades. 1 Several protocols guide to treatment of diabetes mellitus II, and Metformin hydrochloride (MH) is one of the medicines used in the treatment, especially for those who cannot control the illness with nutrition and lifestyle alone. Many studies also covered the use of MH in obesity treatment, as bulky cohort studies showed the significant weight loss associated with MH therapy. 2 MH has a favourable clinical response with few negative consequences since MH does not cause hypoglycemia at any tolerable dose. Some challenges arose upon MH prolonged therapy, such as the high dose of 0.5 to 3 g per day. Also, the MH biological half-life is 1.5-3 h with low bioavailability. Moreover, MH was correlated to the drugs that demonstrated a narrow absorption window, as the proximal small intestine is the primary site of MH absorption. Hence, developing controlled-release dosage forms of MH by selecting the gastroretentive technology was the solution to embrace the previous issues. 3 Numerous approaches and dosage forms enable prolonged residence in the stomach; even so, floating bead units are considered for gastric retention in this study. Beads are unique spherical microcapsules serving drug encapsulation within the bead’s core that permits slow release. Multiple floating bead units accomplish the goal of developing gastroretentive drug delivery systems by sustaining drug release and prolonging stomach residence. Compared to single unit preparations, multiparticulate unit systems have significant merits, notably uniform dispersion in the gastrointestinal tract (GIT), unvarying drug absorption, reduced inter- and intra-individual variability, less potential for dose dumping, and improved flow property. 4 , 5 Former studies investigated multiple unit floating beads, such as Yasir Mohd et al prepared combined Na alginate and pectin multiple unit floating beads to prolong the MH release for up to 12 hr by emulsification gelation technique. 6 Also, Singh A. et al developed metformin floating microsphere using Eudragit RS 100 controlling polymer, thus providing a sustained release pattern up to 12 hr. 7 Byungsuk K. et al, a sustained-release non-effervescent floating matrix tablet was prepared using a simple and efficient direct compression of spray-dried granules containing metformin hydrochloride to prolong the release of MH for 24 hr. 8 Recently, MH was prepared as a core-shell hydrogel and nanoparticles to retain and sustain the release. 9 , 10 The goal of this research mainly involves the use of Gastroplus ® software (version 9.8.2, SimulationPlus Inc., Lancaster, CA, USA) to obtain a model for MH that helped to predict pharmacokinetic parameters for the in vitro release study for the first time in MH multiple unit floating beads. The same goal was used to gain in vivo prediction for the in vitro release using Gastroplus ® software for metoclopramide HCl 11 and sildenafil. 12 This research marks our initial utilization of GastroPlus ® software to predict in vivo pharmacokinetic parameters from in vitro data for metformin bead formulations, while previous studies focused on MH simulation using Gastroplus ® software for further scopes, including expecting the outcome of 1000 mg tablet clinically. 13 Also, a PBPK model of 850 mg metformin HCl for healthy and renal impaired sick patients was used to investigate the parameters that described renal dysfunction. 14 , 15 Moreover, Dahan et al improved in silico metformin model to study absorption after the shortening of gastrointestinal segments by bypass surgery, which is highly recommended for obese type II diabetic patients. 16 The PBPK model depends on several equations embedded within the Gastroplus that control the dissolution, absorption, and other physiological processes within the body of humans or animals. Building PBPK models needs many inputs that are related to the physical properties of the compounds, in addition to the information that specifies the drug metabolism and permeability. The output of this process is the ability to predict the in vivo data of the interested compound. 17 Methods Materials Na alginate was purchased from Fine chem limited, and the Metformin hydrochloride was kindly gifted from Samara Drug Industry (Iraq). Calcium chloride (99.89%), Calcium carbonate, and isopropyl alcohol were purchased from BDH, Ind., England (as listed in Table 1 ). Table 1. List of reagents. Reagent Amount Catalogue number Calicum carbonate 1 kg 22313.294 Calicium chloride 250 gm 22300.233 Isopropyl alcohol 500 ml 0918-500 ML Methods Formulation of floating beads Different concentrations of sodium alginate solution were prepared for use in the MH floating beads formulation, as shown in Table 2 . Each solution was made by using a magnetic stirrer to dissolve the appropriate amount of Na alginate in 100 ml of deionized water with gentle strirring. An alginate solution containing 1 gm MH and 1.5 mg calcium carbonate as a gas-forming agent was mixed well by stirring at a constant speed 200 rpm at room temperature. All remaining air bubbles in the dispersion were removed using a sonicator for 30 minutes. The resulting dispersion was introduced to a 100 ml solution of 5% (w/v) calcium chloride (fused) in isopropyl alcohol 5% v/v (isopropyl alcohol is used as dispersing agent and cross-linking agent, so might be these properties play an important role in uniform bead formation) at room temperature via a 23-gauge syringe needle. 5 The mechanical strength of the beads was improved by leaving them in the curing solution for 30 minutes. The beads went through many rounds of filtration and washing with water, after which they were air-dried for 24 hours. 18 Table 2. Composition of MH alginate floating Beads. Formulation code Na alginate ( gm ) F1 1 F2 1.5 F3 2 F4 2.5 F5 3 F6 0.25 F7 0.5 * Each formulation contains MH, CaCO 3 , and CaCl 2 equal to 1 gm, 1.5 gm, 5 gm, and respectively. Percentage of yield The percentage of yield depends on the ratio of polymer and gas forming agent, which the following formula can calculate 19 : % Yeild = ( Calculated yield / Theoretical yield ( Polymer + Drug ) × 100 Percentage of entrapment efficiency % Fifty milligrams of MH beads were crushed and added to a 100 ml solution of 0.1 N HCl pH 1.2 to be filtered after 24 hr of incubation with constant stirring; then MH was analyzed using a UV/VIS spectrophotometer (UV Spectrophotometer, 1601, Shimadzu, Japan) at 233 nm, the maximum wavelength and dilution of the filtrate with 0.1N HCl pH 1.2. The following equation was used to calculate the entrapment efficiency. The individual batch should be examined for drug content in triplicate. 20 Entrapment efficiency % = ( Actual drug content / theoretical drug content ) × 100 Floating properties (Buoyancy lag time and duration of buoyancy) Buoyancy lag time starts from the beads’ introduction into the medium until their buoyancy to the surface of the dissolution vessel, and the buoyancy duration means the time for which the beads constantly float on the surface of the medium. Both tests were performed during the in vitro release study by visual observation. Buoyancy lag time was determined by weighing equivalent to 500 mg of MH beads and placing them into a dissolution vessel paddle type containing 900 ml of 0.1 N HCl, pH 1.2 at 37 ± 0.5°C at 50 rpm. 21 All the determinations were conducted in triplicate. In vitro release study In vitro , release study investigations were carried out using a USP Dissolution apparatus Type II. The dissolution medium was 900 ml of simulated gastric fluid 0.1 N HCl (pH 1.2) at 37±0.5 o C. A sufficient quantity of beads equivalent to 500 mg of MH was placed in the dissolution medium. The paddle speed was limited to 50 rpm, and 5 ml samples were taken and replaced with fresh medium hourly for up to 12 hr. The withdrawal samples were analyzed using a UV/VIS spectrophotometer (UV Spectrophotometer, 1601, Shimadzu, Japan) at 233 nm. Morphological examination The selected beads were viewed under a Field Emission Scanning Electron Microscope (FESEM) (Inspect TM F50, FEI company, USA). The surface of the beads and their cross sections were coated with gold-palladium under an argon atmosphere using a gold sputter module in a high vacuum evaporator. Fourier Transmittance Infrared (FTIR) Shimadzu- 8300, Japan FT-IR spectroscopy was utilized for Na alginate, MH as powder, and the selected drug-loaded beads were milled and then put in a KBr press. The spectra were taken from 4000 to 400 cm −1 . In silico modeling for metformin absorption The Gastroplus ® software (version 9.8.2, SimulationPlus Inc., Lancaster, CA, USA ‘ SLP Cloud Access /acadmic access ’ helped construct an MH model to gain a prediction of in vivo pharmacokinetic parameters for in vitro multiple unit beads release data. Table 3 presents input parameters related to MH physicochemical and pharmacokinetic properties taken from the literature and/or in silico estimated. The constructed model relies on divided segments of the gastrointestinal tract according to Advanced Compartmental Absorption and Transient (ACAT) model composed of the following: stomach, duodenum, jejunum 1 and 2, ileum 1-3, caecum and ascending colon. The model construction depended on 500 mg of each intravenous bolus and immediate–release oral tablet of MH. The GetData Digitizer version 2.26.0.2 software was used to extract metformin 500 mg of intravenous and oral immediate-release tablet data of healthy individuals aged 42 and weighing 63.4 kg, which was the base of the PBPK. 22 The clearance values shown in Table 3 were obtained by applying the PKPlus software module to 500 mg intravenous metformin and clarified a three-compartmental model. Table 3. Input parameters used in n the compound window of GastroPlus as (*) and (**) values were predicted by ADMET predictor in addition to PKPlus in Gastroplus® software (version 9.8.2, Simulation Plus, Inc., Lancaster, CA, USA), respectively. Parameter Input Reference Dose 500 mg Molecular weight 129.17 g/mol * Dosage form Immediate release tablet Log P at pH -1 -0.82 * Solubility at pH 12.9 134.78 mg/ml . 14 Diffusion Coefficient 1.14 x 10 −5 cm 2 /s * Drug particle density 1.2 g/ml * Effective permeability 0.032 cm/s x 10 −5 . 28 Clearance a 30.828 L/h * Clearance a 0.48625 L/h/kg * K12 b 0.70212 1/h ** K21 b 0.76947 1/h ** K13 b 0.21387 1/h ** K 31 b 0.001192 1/h ** V2 c 0.4317 L/kg ** V3 c 84.893 L/kg ** OCT1 d km g 1.47 mM . 24 OCT1 d Vmax h 396 pmol/min/mg protein . 24 OCT2 d km 0.99 mM . 24 OCT2 d Vmax 1444 pmol/min/mg protein . 24 MATE1 e km 0.78 mM . 29 MATE1 e Vmax 4.46 nmol/min/mg protein . 15 MATE-K2 e km 1.98 mM . 29 MATE-K2 e Vmax 1.69 nmol/min/mg protein . 15 PMAT f km 1.32 mM . 15 PMAT f Vmax 27 pmol/min/mg protein . 26 a Cl donates as clearance. b k12, k 21, k13 and k31 donate as elimination phase constants of 3 compartmental model. c V2 and V3 donates volume of distribution. d OCT 1 and OCT 2 denote organic cation transporters. e MATE1 and MATE2-K donate the multidrug and toxin extrusions. f PMAT donates Plasma Membrane Monoamine Transporter. g km donate the measurements of the affinity of the substrate for the transporter. h Vmax denote maximum rates of metabolism. As MH was classified III according to the Biopharmaceutical classification system (BCS), which is water soluble with low permeability; 23 hence, the PBPK model was set as permeability limited. MH was reported as a substrate for the organic cation transporters (OCTs), which are influx transporters starting with OCT1, primarily found in the human liver, and OCT2 transporters are located mainly in the kidney. Thus, these two transporters were included in the PBPK model. Nonetheless, the OCT3 were not included the simulation of the MH model as they showed low affinity to MH and its expression in the region of the human small intestine. 24 Efflux transporters the multidrug and toxin extrusions (MATE1 and MATE2-K) were MH substrate as the MATE1 expression is mainly in the liver and kidney cells membrane. The kidney cell’s membrane is the prominent place of MATE2-K. 25 In addition, Plasma Membrane Monoamine Transporter (PMAT) identified affinity for MH uptake and expressed in the human small intestine. All the km and Vmax values of the transporters are presented in Table 3 . In the prediction process after model building, many inputs were added, starting with beads in vitro release results were entered with a change of gastric physiological emptying time to the floating beads time, and the (controlled release) CR gastric was chosen as the input of the dosage form. The predicted model verification was by using the error percentage equation 26 , 27 : % PE = ( Observed − calculated ) Observed × 100 Results and Discussion Beads formulation The ionotropic gelation method was effective in preparing the multiparticulate bead with all conditions used, such as stirring rate, the temperature of preparation and the percentage of calcium chloride solution. All the formulations in Table 2 successfully and visually showed beads and collected to be stored for further investigations. Percentage of yield All beads were subjected to the yield percentage test to assess the effect of the bead’s content, primarily the Na alginate, and the results are shown in Table 4 . The results found that the increase in Na alginate concentration (F6, F7, F1-F4) increased the percentage yield of produced beads. This finding was similar to Singh et al finding of floating microspheres of famotidine. 30 This means the increased Na alginate amount helped in better bead formulations, as viscosity enhancement may result in improved crosslinking and consequently efficient bead formation. 31 Except for F5 the percentage of yield was diminished, this may be related to the formation of a thicker solution that acts as a barrier to form beads easily. The same inference was observed by previous researcher Tønnesen HH. 32 Table 4. The percentage of yield and entrapment efficiency of MH beads. Code of beads formulation %yield Entrapment efficiency F1 73%± 0.56 60%±0.011 F2 75%±0.63 68%±0.065 F3 77%±0.11 70%±0.045 F4 90%±0.45 79%±0.023 F5 85%±0.21 69%±0.105 F6 70%±0.51 75%±0.230 F7 72%±0.54 80%±0.124 Percentage of entrapment efficiency % An important consideration when designing new bead formulations is how effectively they hold the drug. Table 4 shows that all formulations (F1-F7) showed acceptable entrapment efficiency percent %, referring that Na alginate polymer concentrations are satisfactory for enclosing the drug in bead formulations, a similar finding was noticed in Abbas et al. ’s work of enalapril floating microspheres as a controlled release dosage form. 33 Despite the small differences in entrapment efficiency values of all bead formulations, this might be attributed to the layers of Na alginate that were formed, which led to a decrease in the inbox of MH. Floating properties (buoyancy lag time and duration of buoyancy) It was essential for the current study to investigate the floating property, which was one of the study goals. All the formulations of beads floated without delay. This could be explained by the fact that an increase in Na alginate concentration leads to a robust matrix of the strong gel and increases diffusion path length for the gas, thus effectively entrapping generated gas bubbles, 34 except F6, which contains the lowest amount of the polymer (0.250 gm) consequently, a weaker gel matrix can be formed resulting in a lag time of 30 min, however, collectively the formulas remained floated for the whole release study time. This finding is comparable to what was observed with floating alginate beads of curcumin. 35 In vitro drug release The MH release from beads was required to compare the drug release profile from different bead formulations, and the results are illustrated in Figure 1 . The MH release was higher with a lower Na alginate amount, as in F6 and F7. The gelation process is based on the formation of tights between the guluronic acid residues in Na alginate and CaCl 2, which might increase as the Na alginate concentration increases, thus resulting in prolonged drug release, as was noticed with the rest of the prepared formulations, this observation was justified by Mandal et al either. 36 Also, it was clear from Figure 1 that the bead formulations F1, F2, F3, F4 and F5 exhibited very similar release profiles and around 80 % MH was released gradually after 12 hours, while F6 and F7 released the MH after 6 hr and 8 hr, respectively. Figure 1. The in vitro release study in 0.1 N HCl pH 1.2 as each release profile represents an average triplicate ±SD for each bead formulation. Morphological examination The F4 (representative beads of F1, F2 and F3), F6 and F7 were selected for morphological examination and FTIR. The morphological investigation by FESEM gives an idea about the shape and the surfaces of the formed bead. Figure 2 reveals that the beads are rounded in shape, suggesting that the concentrations of the polymer were satisfactory for bead formation, the beads apparently exhibit smoother surfaces as the concentration of Na alginate increases as in F4 in comparison to F6 and F7; this may be due to the higher density of crosslinked polymer matrices at the surface. The inside of the beads, as it appears in cross-sectional view, didn’t show distinguished morphology. A similar finding was noticed by Voo Wang-Ping et al . 37 Visually, the bead diameter of F4, F6 and F7 was around 1mm, as exhibited in the first left column of Figure 2 . The same value of the diameter (1mm) was obtained in a different study prepared alginate beads. 38 Figure 2. (A) Field emission scanning electron microscopy (FESEM) micrographs for the surface view as the magnification bars are 1mm and 30 μm for F4, F6 and F7 bead formulations, (B) (FESEM) microimages for cross-sectional view, magnification bar is 5 μm for F4, F6 and F7 bead formulations. Fourier transmittance infrared (FTIR) To understand the interactions between molecules formulating beads, FTIR was applied. The FTIR spectrogram of MH, as presented in Figure 3(A) , showed similar peaks to the previous study of MH spectrogram, as the peaks at 3367 cm -1 , 3300 cm -1 and 1580 cm -1 associated with the distinct group of N-H asymmetric stretching, N-H symmetric stretching and N-H bending, respectively. 39 Also, the Na alginate spectrogram showed a peak at 1619 cm -1 , which is the position of the carbonyl group of Na alginate beads. 40 Figure 3(B) demonstrates beads F4, F6 and F7 spectrograms emphasizing a peak deviation associated with the carbonyl group to 1629 cm -1 , as this might refer to Na alginate molecules binding with calcium ions that helped to arrange and build the beads. 41 The N-H asymmetric stretching, N-H symmetric at 3367 cm −1 and 3300 cm −1 overlaid with OH region of the hydroxyl group of sodium alginate as it hard to tell if physical interaction happened in the spectrograms of F4, F6 and F7 related to the mentioned groups; however, MH might physically interact at N-H group as there is a shift of the band at 1580 cm −1 to a lower region. Although it is not inconclusive, it can indicate the hydrogen bondings. Figure 3. The whole FTIR spectrograms in Figure A represent the full range spectrograms for F4, F6, F7, pure drug, Na alginate, and CaCO 3 ; Figure B indicates carbonyl group shifting in F4, F6, and F7. Metformin absorption in silico model The parameters as an outcome of the in silico simulation that assisted in building a physiological model relied on the physicochemical and pharmacokinetic information are presented in Table 5 . Also, the constructed model parameters Cmax, Tmax, AUC 0-inf, and AUC 0-t were validated, as screened in Figure 4 , depending on the error percentage of observed and calculated data. The acceptance of %PE is valid as the calculated values do not double the observed values or the fold error value is not doubled. 42 The model showed a very acceptable error in percentage, as shown clearly in Table 5 . Table 5. The predicting and observed values of metformin pharmacokinetic parameters of Gastroplus ® for 500 mg oral immediate-release tablet. Pharmacokinetic parameters Observed Calculated % PE Cmax a (μg/mL) 1.44 1.5021 -4.312 Tmax b (h) 2 1.92 4 AUC c 0-∞ (μg-h/mL) 8.8805 8.9842 -1.16 AUC 0-t (μg-h/mL) 8.2756 8.5212 -2.9 a Cmax denotes maximum serum concentration. b Tmax, the time required to reach maximum concentration. c AUC donates area under the curve, the negative values of %PE mean the predicted are >than observed. Figure 4. 500 mg oral immediate tablet physiological model as the bold line represents calculated and the dotted line represents the observed values. Moreover, Figure 5A demonstrates that absorption does not take place in the stomach, whereas the maximum MH absorption occurred in jejeunum 1, followed by the duodenum and jejeunum 2, and then almost nowhere else. Similarly, as the prediction results revealed, the MH multiple unit floating gastroretentive drug delivery system exhibited no stomach absorption site. 11 Also, the fraction absorbed (total availability) was 23.9, of Metformin IR of the model, as seen in Figure 5A , which was close to 27%, the predicted fraction absorbed that was found by the Dahan study. 16 Consequently, Figure 5B indicates that F1 to F5 beads formulas provided high stomach amounts following their floating duration and showed a gradual with slight differences decrease in MH amount within 12 hrs representing its floating duration, while F7 showed a drastic decrease in the stomach amount of MH within the first hour of simulation time. Additionally, F6 presented a gradual reduction in the amount of MH in the stomach within simulation time. These outcomes referred that these gastroretentive multiple unit floating beads play an essential role in restricting the MH release rate in the site-specific region, which in turn guarantees the release of MH into the appropriate absorption site and, thus, may improve the bioavailability. Figure 5. Predicting data, Figure A: The regional absorption of the 500 mg MH selected gastroretentive multiple unit floating beads; Figure B: The MH amount retained in the stomach for 12 h, as IR represents the immediate release tablet and the blue curve denotes F1, F2, F3, F4, and F5 in Figure B. In the same figure, for comparison purposes, immediate-release kinetic was taken from an immediate-release tablet of 500 mg of MH that showed (rapid MH decline). 43 The simulating curves of plasma concentration-time as in Figure 6 parameters reveal that F1-F5 exhibit low Cmax with non-declining curves, thus referring to the gastroretentive property of slow-release MH multiple unit floating beads. At the same time, F6 and F7 showed a higher Cmax, as F7 showed a decline in the curve; this might be attributed to the total released amount of MH in the stomach. However, the floating period was persistent during the in vitro release study. Interestingly, the US Food and Drug Administration revealed the pharmacokinetics parameters of a 500 mg extended-release tablet, as its Cmax was 0.6 μg/ml, which was close to the Cmax of 0.449 μg/ml of F7. 44 Taking this into account, the MH simulation helped to decide the better formulation of floating beads that achieved the aim of this study. Figure 6. Predicted plasma concentration-time curves of MH multiple unit beads. Future perspective During drug development, the bridge between the drug characteristics and in vivo behaviour of pharmacokinetics can be achieved by the vital in silico tool (PBPK). In recent decades, the in silico tool has been widely applied to different drug delivery systems and different routes of administration, including oral, inhaled, transdermal, ophthalmic, and complex injectable products, for small drug molecules to more complex therapeutics. The results of the simulation have provided important insights into the PK behaviours of new dosage forms, which strongly support drug regulation. 45 In the current research the future perspective involves optimization and development of the prepared dosage form, taking into consideration the specific physiological parameters for instance, age, weight and renal function, these factors may require dose adjustment or altered regimens, especially in certain population including elderly, renal and hepatic impatient. In addition, the physiology changes related to diabetes mellites such as the gastrointestinal motility and pH changes, or cancer-associated alteration in pH due to the tumour microenvironment, or changes related to gastrectomy or ulcer affecting drug solubility and absorption process. Consequently, these considerations could be integrated to develop personalized PBPK and enhance the predictive capability of the models, leading to more precise simulations for drug absorption and disposition, correspondingly paving the way for personalised medicine with patient-specific modelling, eventually enhancing therapeutic efficacy and safety. Furthermore, The Gastroplus may take the lead toward enhanced IVIV correlation by establishing robust IVIVC models that aid in the transition from laboratory findings to clinical applications reducing the dependence on prevalent in vivo studies. Limitation More accurate results are expected to be produced through the use of the PBPK modelling in drug delivery at high speed. Though recently, many limitations have impeded this goal. The PBPK will not catch the interindividual variability due to genetic differences, comorbidities, or concurrent medications which have an impact on drug absorption and metabolism. Conclusion This study aimed to develop a method for MH to create multi-unit beads utilized for gastroretentive purposes. Numerous tests were applied, including percentage yield, entrapment efficiency percent, floating property, and the in vitro release study. All prepared beads floated for their corresponding release time and showed different release patterns. Gastroplus ® , a software, was used to acquire fruitful models of MH. In silico results based on in vitro release and floating property demonstrated that F1-F5 beads with high stomach MH amount supported the progressive reduction in MH released amount within simulation time, whereas F6 showed a rapid decline in the stomach amount corresponding to the faster MH release. The interesting formulation F7 exhibited a gradual decrease in MH amount and established a close Cmax to the 500 mg extended-release tablet. Furthermore, the Gastroplus ® software simulation found the highest MH absorption location in jejunum 1, followed by the duodenum. The utilization of GastroPlus ® in PBPK modelling provides an influential platform for the design and optimization of bead-based drug delivery systems, paving the way for more effective and personalized therapeutic strategies and enhancement in IVIV correlation. Contributor role Conceptualization: Sura Zuhair Mahmood, Nora Zawar Yousif and Masar Basim Mohsin Mohamed Data Curation: Sura Zuhair Mahmood, Nora Zawar Yousif and Masar Basim Mohsin Mohamed Formal Analysis: Nora Zawar Yousif and Masar Basim Mohsin Mohamed Funding Acquisition: Sura Zuhair Mahmood, Nora Zawar Yousif and Masar Basim Mohsin Mohamed Investigation: Sura Zuhair Mahmood, Nora Zawar Yousif and Masar Basim Mohsin Mohamed Methodology: Sura Zuhair Mahmood Project Administration: Sura Zuhair Mahmood, Nora Zawar Yousif and Masar Basim Mohsin Mohamed Resources: Sura Zuhair Mahmood, Nora Zawar Yousif and Masar Basim Mohsin Mohamed Software: Masar Basim Mohsin Mohamed Supervision: Masar Basim Mohsin Mohamed Validation: Masar Basim Mohsin Mohamed Visualization: Sura Zuhair Mahmood, Nora Zawar Yousif and Masar Basim Mohsin Mohamed Writing – Nora Zawar Yousif and Masar Basim Mohsin Mohamed Writing – Review & Editing: Nora Zawar Yousif and Ethics and consent Not applicable. Data availability Underlying data Zenodo:Forecasting in vivo pharmacokinetics of metformin HCl Floatin g beads using Gastroplus ® PBPK ( https://zenodo.org/records/14197021 ). 46 This project contains the following files: • FTIR of Metformin.xlsx • the last one inshallah.xlsx • the raw data of release and gastroplus.xlsx Extended data Zenodo • The raw data of amount in stomach https://zenodo.org/records/15692145 47 • FTIR Metformin figure https://zenodo.org/records/15692151 48 • Plasma time figure formulation https://zenodo.org/records/15692186 49 • Regional Absorption https://zenodo.org/records/15692198 50 • Release Metformin figure https://zenodo.org/records/15692204 51 • Metformin in vivo Data https://zenodo.org/records/15692171 52 Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0). Acknowledgements The researchers would like to express their gratitude to SimulationPlus Inc. (located in Lancaster, California, United States) for providing them with access to the Gastroplus ® software (version 9.8.2). The authors also thank Pharmacy College - Mustansiriyah University ( https://www.uomustansiriyah.edu.iq/ ) for their support. References 1. Hossain MJ, Al-Mamun M, Islam MR: Diabetes mellitus, the fastest growing global public health concern: Early detection should be focused. Health Sci. Rep. 2024; 7 (3): e2004. PubMed Abstract | Publisher Full Text | Free Full Text 2. McDonagh MS, Selph S, Ozpinar A, et al. : Systematic review of the benefits and risks of metformin in treating obesity in children aged 18 years and younger. JAMA Pediatr. 2014; 168 (2): 178–184. PubMed Abstract | Publisher Full Text 3. Salunke P, Rane B, Bakliwal S, et al. : Floating microcarriers of an antidiabetic drug: Preparation and its in-vitro evaluation. J. Pharm. Sci. Technol. 2010; 2 : 230–240. 4. 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Daemi H, Barikani M: Synthesis and characterization of calcium alginate nanoparticles, sodium homopolymannuronate salt and its calcium nanoparticles. Scientia Iranica. 2012; 19 (6): 2023–2028. Publisher Full Text 42. Park M-H, Shin S-H, Byeon J-J, et al. : Prediction of pharmacokinetics and drug-drug interaction potential using physiologically based pharmacokinetic (PBPK) modeling approach: A case study of caffeine and ciprofloxacin. Korean J. Physiol. Pharmacol. 2017; 21 (1): 107–115. PubMed Abstract | Publisher Full Text | Free Full Text 43. Food U, Administration D: Glucophage ® (metformin hydrochloride tablets)/Glucophage XR ® (metformin hydrochloride extended release tablets). NDA 20-357/S-031 and NDA 21-202/S-016. 2008. 44. Cheng C-L, Lawrence XY, Lee H-L, et al. : Biowaiver extension potential to BCS Class III high solubility-low permeability drugs: bridging evidence for metformin immediate-release tablet. Eur. J. Pharm. Sci. 2004; 22 (4): 297–304. PubMed Abstract | Publisher Full Text 45. Wang W, Ouyang D: Opportunities and challenges of physiologically based pharmacokinetic modeling in drug delivery. Drug Discov. Today. 2022; 27 (8): 2100–2120. PubMed Abstract | Publisher Full Text 46. Mahmood SZ, Yousif NZ, Mohamed MBM: Forecasting in vivo pharmacokinetics of metformin HCl Floating beads using Gastroplus ® PBPK. [Data set]. Zenodo. 2024. Publisher Full Text 47. Mahmood SZ, Yousif NZ, Mohamed MBM: Amount in stomach. Zenodo. 2025. Reference Source 48. Mahmood SZ, Yousif NZ, Mohamed MBM: fTIR metformin figure. Zenodo. 2025. Reference Source 49. Mahmood SZ, Yousif NZ, Mohamed MBM: Plasam time figures formulations. Zenodo. 2025. Reference Source 50. Mahmood SZ, Yousif NZ, Mohamed MBM: Regional Absorption. Zenodo. 2025. Reference Source 51. Mahmood SZ, Yousif NZ, Mohamed MBM: Release metformin figure. Zenodo. 2025. Reference Source 52. Mahmood SZ, Yousif NZ, Mohamed MBM: Metformin in vivo data. Zenodo. 2025. Reference Source Comments on this article Comments (0) Version 2 VERSION 2 PUBLISHED 28 Jan 2025 ADD YOUR COMMENT Comment Author details Author details 1 Pharmaceutics Department, Pharmacy College, Mustansiriyah University, Baghdad, Iraq Sura Zuhair Mahmood Roles: Conceptualization, Data Curation, Funding Acquisition, Investigation, Methodology, Project Administration, Resources, Visualization Nora Zawar Yousif Roles: Data Curation, Formal Analysis, Funding Acquisition, Investigation, Resources, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing Masar Basim Mohsin Mohamed Roles: Conceptualization, Data Curation, Formal Analysis, Funding Acquisition, Investigation, Project Administration, Resources, Software, Supervision, Validation, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing Competing interests No competing interests were disclosed. Grant information The author(s) declared that no grants were involved in supporting this work. Article Versions (2) version 2 Revised Published: 09 Sep 2025, 14:140 https://doi.org/10.12688/f1000research.159438.2 version 1 Published: 28 Jan 2025, 14:140 https://doi.org/10.12688/f1000research.159438.1 Copyright © 2025 Mahmood SZ et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Download Export To Sciwheel Bibtex EndNote ProCite Ref. Manager (RIS) Sente metrics Views Downloads F1000Research - - PubMed Central info_outline Data from PMC are received and updated monthly. - - Citations open_in_new 0 open_in_new 0 open_in_new SEE MORE DETAILS CITE how to cite this article Mahmood SZ, Yousif NZ and Mohsin Mohamed MB. Forecasting in vivo pharmacokinetics of metformin HCl floating beads using Gastroplus® PBPK [version 2; peer review: 1 approved, 2 approved with reservations] . F1000Research 2025, 14 :140 ( https://doi.org/10.12688/f1000research.159438.2 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS track receive updates on this article Track an article to receive email alerts on any updates to this article. TRACK THIS ARTICLE Share Open Peer Review Current Reviewer Status: ? Key to Reviewer Statuses VIEW HIDE Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Version 2 VERSION 2 PUBLISHED 09 Sep 2025 Revised Views 0 Cite How to cite this report: Nawaz M and Rehman S. Reviewer Report For: Forecasting in vivo pharmacokinetics of metformin HCl floating beads using Gastroplus® PBPK [version 2; peer review: 1 approved, 2 approved with reservations] . F1000Research 2025, 14 :140 ( https://doi.org/10.5256/f1000research.183289.r414010 ) The direct URL for this report is: https://f1000research.com/articles/14-140/v2#referee-response-414010 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 30 Sep 2025 Murryam Nawaz , Pharmacy, Riphah Interntional University, Islamabad, Islamabad Capital Territory, Pakistan Sadia Rehman , Riphah International University, Islamabad, Pakistan Approved with Reservations VIEWS 0 https://doi.org/10.5256/f1000research.183289.r414010 Summary of the Article: The manuscript reports the fabrication of metformin hydrochloride (MH) floating beads using an ionotropic gelation technique with alginate and cross-linking via CaCl₂. Seven formulations were prepared and evaluated for yield, entrapment efficiency, floating behavior, and ... Continue reading READ ALL Summary of the Article: The manuscript reports the fabrication of metformin hydrochloride (MH) floating beads using an ionotropic gelation technique with alginate and cross-linking via CaCl₂. Seven formulations were prepared and evaluated for yield, entrapment efficiency, floating behavior, and in vitro drug release. The optimized formulation was characterized by FTIR, FESEM, and swelling studies. To translate in vitro findings into in vivo performance, a physiologically based pharmacokinetic (PBPK) model was constructed using GastroPlus®. The model incorporated known metformin transporter interactions (OCT1/2, MATE1/2, PMAT) while excluding OCT3. Simulation outcomes were compared to reported pharmacokinetic profiles of immediate-release tablets, and the authors suggest that the floating beads offer enhanced gastro-retentive behavior and absorption. The manuscript also includes a limitation and future perspective section, highlighting personalized PBPK approaches. Overall Assessment: The study addresses a clinically relevant problem — improving the delivery of MH, a first-line drug for type II diabetes, through gastroretentive floating beads combined with PBPK modeling. The topic is interesting and potentially useful for pharmaceutical formulation and predictive modeling research. However, the presentation lacks clarity, the statistical analysis is weak, and the PBPK model validation is insufficient. While the manuscript has merit, it requires major revision before it can be considered scientifically sound. Major Comments: Entrapment efficiency, yield, and in vitro release data are presented as mean ± SD, but no statistical comparisons (ANOVA, t-tests) are performed between formulations. Without significance testing, it is unclear whether differences between formulations are meaningful. The PBPK model is validated against only one dataset (500 mg IR tablets). Sensitivity analysis on transporter inclusion/exclusion (especially OCT3) should be considered or at least justified more thoroughly. Table 2 (formulation composition) appears incomplete in the submitted version. Full details of polymer concentrations, curing times, and number of replicates should be included for reproducibility. Raw dissolution data with error bars should be presented. The conclusion that PBPK modeling “confirms” enhanced absorption of MH beads is overstated whereas, the evidence only suggests a potential improvement. Authors should moderate their claims and align conclusions more closely with the presented data. Abstract should be more concise — clearly state aim, methods, key results, and conclusion. Literature review needs updating with recent studies (2019–2024) on metformin gastroretentive systems and PBPK applications. Checklist Answers with Justifications: Is the work clearly and accurately presented and does it cite the current literature? Partly – The structure is clear, but language issues obscure meaning. References are somewhat outdated; more recent citations are needed. Is the study design appropriate and is the work technically sound? Partly – The bead fabrication and PBPK approach are appropriate. However, the PBPK validation is weak and statistical rigor is lacking. Are sufficient details of methods and analysis provided to allow replication by others? Partly – Important details (full formulation table, replicate numbers, raw data) are missing, limiting reproducibility. Is the statistical analysis and its interpretation appropriate? Partly – Basic descriptive statistics are given, but no comparative statistical analysis has been applied. Are all the source data underlying the results available to ensure full reproducibility? Partly – Key raw data and details are not provided in sufficient depth. Are the conclusions drawn adequately supported by the results? Partly – Conclusions are generally in line with results, but claims of enhanced absorption should be toned down given the limited validation. Is the work clearly and accurately presented and does it cite the current literature? Partly Is the study design appropriate and is the work technically sound? Partly Are sufficient details of methods and analysis provided to allow replication by others? Partly If applicable, is the statistical analysis and its interpretation appropriate? Partly Are all the source data underlying the results available to ensure full reproducibility? Partly Are the conclusions drawn adequately supported by the results? Partly Competing Interests: No competing interests were disclosed. Reviewer Expertise: Pharmaceutical technology, formulation development, drug delivery systems, emulsions, suspensions, hydrogels, nanogels, nanoparticles. We confirm that we have read this submission and believe that we have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however we have significant reservations, as outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Nawaz M and Rehman S. Reviewer Report For: Forecasting in vivo pharmacokinetics of metformin HCl floating beads using Gastroplus® PBPK [version 2; peer review: 1 approved, 2 approved with reservations] . F1000Research 2025, 14 :140 ( https://doi.org/10.5256/f1000research.183289.r414010 ) The direct URL for this report is: https://f1000research.com/articles/14-140/v2#referee-response-414010 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Views 0 Cite How to cite this report: Salave S. Reviewer Report For: Forecasting in vivo pharmacokinetics of metformin HCl floating beads using Gastroplus® PBPK [version 2; peer review: 1 approved, 2 approved with reservations] . F1000Research 2025, 14 :140 ( https://doi.org/10.5256/f1000research.183289.r412668 ) The direct URL for this report is: https://f1000research.com/articles/14-140/v2#referee-response-412668 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 17 Sep 2025 Sagar Salave , National Institute of Pharmaceutical Education and Research, Ahmedabad, India; Pharmaceutical Chemistry, The University of Kansas (Ringgold ID: 4202), Lawrence, Kansas, USA Approved VIEWS 0 https://doi.org/10.5256/f1000research.183289.r412668 Authors have made significant ... Continue reading READ ALL Authors have made significant changes in the revised manuscript Competing Interests: No competing interests were disclosed. Reviewer Expertise: Drug delivery, formulation development, Nanomedicine, vaccines I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Salave S. Reviewer Report For: Forecasting in vivo pharmacokinetics of metformin HCl floating beads using Gastroplus® PBPK [version 2; peer review: 1 approved, 2 approved with reservations] . F1000Research 2025, 14 :140 ( https://doi.org/10.5256/f1000research.183289.r412668 ) The direct URL for this report is: https://f1000research.com/articles/14-140/v2#referee-response-412668 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Version 1 VERSION 1 PUBLISHED 28 Jan 2025 Views 0 Cite How to cite this report: Garg A. Reviewer Report For: Forecasting in vivo pharmacokinetics of metformin HCl floating beads using Gastroplus® PBPK [version 2; peer review: 1 approved, 2 approved with reservations] . F1000Research 2025, 14 :140 ( https://doi.org/10.5256/f1000research.175161.r364759 ) The direct URL for this report is: https://f1000research.com/articles/14-140/v1#referee-response-364759 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 15 Apr 2025 Anuj Garg , Institute of Pharmaceutical Research, GLA University, Mathura, Uttar Pradesh, India Approved with Reservations VIEWS 0 https://doi.org/10.5256/f1000research.175161.r364759 In the present research work, the authors have developed floating beads containing metformin and forecast the plasma concentration using Gastroplus software on the basis of previous in vivo results and in vitro results performed in the present study. ... Continue reading READ ALL In the present research work, the authors have developed floating beads containing metformin and forecast the plasma concentration using Gastroplus software on the basis of previous in vivo results and in vitro results performed in the present study. The author describes the methodology appropriately and well written in the manuscript. However, the references are not upto date and most of the cited references are before 2020. Moreover, the objective of this study was to develop floating beads which seems to be very old method and various studies have been already published for the same objective to formulate floating beads. One of the paper is as follow: Nayak, A., Jain, S. K., & Pandey, R. S. (2011 [Ref-1]). Controlling release of metformin HCl through incorporation into stomach specific floating alginate beads. Molecular pharmaceutics , 8 (6), 2273-2281. The interpretation of results should be discussed in depth to explain the possible reason behind the results. Is the work clearly and accurately presented and does it cite the current literature? Partly Is the study design appropriate and is the work technically sound? Yes Are sufficient details of methods and analysis provided to allow replication by others? Yes If applicable, is the statistical analysis and its interpretation appropriate? Partly Are all the source data underlying the results available to ensure full reproducibility? No source data required Are the conclusions drawn adequately supported by the results? Yes References 1. Nayak A, Jain SK, Pandey RS: Controlling release of metformin HCl through incorporation into stomach specific floating alginate beads. Mol Pharm . 2011; 8 (6): 2273-81 PubMed Abstract | Publisher Full Text Competing Interests: No competing interests were disclosed. Reviewer Expertise: Drug delivery, Pharmacokinetics I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Garg A. Reviewer Report For: Forecasting in vivo pharmacokinetics of metformin HCl floating beads using Gastroplus® PBPK [version 2; peer review: 1 approved, 2 approved with reservations] . F1000Research 2025, 14 :140 ( https://doi.org/10.5256/f1000research.175161.r364759 ) The direct URL for this report is: https://f1000research.com/articles/14-140/v1#referee-response-364759 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Author Response 11 Sep 2025 Sura Zuhair Mahmood , Pharmaceutics Department, Pharmacy College, Mustansiriyah University, Baghdad, Iraq 11 Sep 2025 Author Response In the present research work, the authors have developed floating beads containing metformin and forecast the plasma concentration using Gastroplus software on the basis of previous in vivo results and ... Continue reading In the present research work, the authors have developed floating beads containing metformin and forecast the plasma concentration using Gastroplus software on the basis of previous in vivo results and in vitro results performed in the present study. The author describes the methodology appropriately and well written in the manuscript. However, the references are not up-to-date and most of the cited references are before 2020. Moreover, the objective of this study was to develop floating beads which seems to be very old method and various studies have been already published for the same objective to formulate floating beads. Thank you for your valuable comments and observations. We have updated most of the references to ensure they are more current. While we acknowledge that the method used is established and considered an old technique, we believe it remains highly reproducible and capable of yielding reliable results. Furthermore, previous studies have not addressed the prediction of in vivo pharmacokinetics based on in vitro release data using this specific approach, which we believe adds novelty to our work, and this was referred to in the introduction section One of the paper is as follows: Nayak, A., Jain, S. K., & Pandey, R. S. (2011 [Ref-1]). Controlling release of metformin HCl through incorporation into stomach specific floating alginate beads. Molecular pharmaceutics , 8 (6), 2273-2281. Kindly refer to the introduction and reference sections, which were changed to more recent ones as per your request The interpretation of results should be discussed in depth to explain the possible reasons behind the results Thank you for pointing this out. The revised version now includes a more detailed explanation and is highlighted within the result section. In the present research work, the authors have developed floating beads containing metformin and forecast the plasma concentration using Gastroplus software on the basis of previous in vivo results and in vitro results performed in the present study. The author describes the methodology appropriately and well written in the manuscript. However, the references are not up-to-date and most of the cited references are before 2020. Moreover, the objective of this study was to develop floating beads which seems to be very old method and various studies have been already published for the same objective to formulate floating beads. Thank you for your valuable comments and observations. We have updated most of the references to ensure they are more current. While we acknowledge that the method used is established and considered an old technique, we believe it remains highly reproducible and capable of yielding reliable results. Furthermore, previous studies have not addressed the prediction of in vivo pharmacokinetics based on in vitro release data using this specific approach, which we believe adds novelty to our work, and this was referred to in the introduction section One of the paper is as follows: Nayak, A., Jain, S. K., & Pandey, R. S. (2011 [Ref-1]). Controlling release of metformin HCl through incorporation into stomach specific floating alginate beads. Molecular pharmaceutics , 8 (6), 2273-2281. Kindly refer to the introduction and reference sections, which were changed to more recent ones as per your request The interpretation of results should be discussed in depth to explain the possible reasons behind the results Thank you for pointing this out. The revised version now includes a more detailed explanation and is highlighted within the result section. Competing Interests: No competing interests were disclosed. Close Report a concern Respond or Comment COMMENTS ON THIS REPORT Author Response 11 Sep 2025 Sura Zuhair Mahmood , Pharmaceutics Department, Pharmacy College, Mustansiriyah University, Baghdad, Iraq 11 Sep 2025 Author Response In the present research work, the authors have developed floating beads containing metformin and forecast the plasma concentration using Gastroplus software on the basis of previous in vivo results and ... Continue reading In the present research work, the authors have developed floating beads containing metformin and forecast the plasma concentration using Gastroplus software on the basis of previous in vivo results and in vitro results performed in the present study. The author describes the methodology appropriately and well written in the manuscript. However, the references are not up-to-date and most of the cited references are before 2020. Moreover, the objective of this study was to develop floating beads which seems to be very old method and various studies have been already published for the same objective to formulate floating beads. Thank you for your valuable comments and observations. We have updated most of the references to ensure they are more current. While we acknowledge that the method used is established and considered an old technique, we believe it remains highly reproducible and capable of yielding reliable results. Furthermore, previous studies have not addressed the prediction of in vivo pharmacokinetics based on in vitro release data using this specific approach, which we believe adds novelty to our work, and this was referred to in the introduction section One of the paper is as follows: Nayak, A., Jain, S. K., & Pandey, R. S. (2011 [Ref-1]). Controlling release of metformin HCl through incorporation into stomach specific floating alginate beads. Molecular pharmaceutics , 8 (6), 2273-2281. Kindly refer to the introduction and reference sections, which were changed to more recent ones as per your request The interpretation of results should be discussed in depth to explain the possible reasons behind the results Thank you for pointing this out. The revised version now includes a more detailed explanation and is highlighted within the result section. In the present research work, the authors have developed floating beads containing metformin and forecast the plasma concentration using Gastroplus software on the basis of previous in vivo results and in vitro results performed in the present study. The author describes the methodology appropriately and well written in the manuscript. However, the references are not up-to-date and most of the cited references are before 2020. Moreover, the objective of this study was to develop floating beads which seems to be very old method and various studies have been already published for the same objective to formulate floating beads. Thank you for your valuable comments and observations. We have updated most of the references to ensure they are more current. While we acknowledge that the method used is established and considered an old technique, we believe it remains highly reproducible and capable of yielding reliable results. Furthermore, previous studies have not addressed the prediction of in vivo pharmacokinetics based on in vitro release data using this specific approach, which we believe adds novelty to our work, and this was referred to in the introduction section One of the paper is as follows: Nayak, A., Jain, S. K., & Pandey, R. S. (2011 [Ref-1]). Controlling release of metformin HCl through incorporation into stomach specific floating alginate beads. Molecular pharmaceutics , 8 (6), 2273-2281. Kindly refer to the introduction and reference sections, which were changed to more recent ones as per your request The interpretation of results should be discussed in depth to explain the possible reasons behind the results Thank you for pointing this out. The revised version now includes a more detailed explanation and is highlighted within the result section. Competing Interests: No competing interests were disclosed. Close Report a concern COMMENT ON THIS REPORT Views 0 Cite How to cite this report: Salave S. Reviewer Report For: Forecasting in vivo pharmacokinetics of metformin HCl floating beads using Gastroplus® PBPK [version 2; peer review: 1 approved, 2 approved with reservations] . F1000Research 2025, 14 :140 ( https://doi.org/10.5256/f1000research.175161.r364754 ) The direct URL for this report is: https://f1000research.com/articles/14-140/v1#referee-response-364754 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 18 Feb 2025 Sagar Salave , National Institute of Pharmaceutical Education and Research, Ahmedabad, India; Pharmaceutical Chemistry, The University of Kansas (Ringgold ID: 4202), Lawrence, Kansas, USA Not Approved VIEWS 0 https://doi.org/10.5256/f1000research.175161.r364754 Authors need to revise the manuscript thoroughly as per the below comments: Major comments: 1. Improve the abstract 2. Improve the introduction section, and discuss recent studies with limitations instead of just an overview for ... Continue reading READ ALL Authors need to revise the manuscript thoroughly as per the below comments: Major comments: 1. Improve the abstract 2. Improve the introduction section, and discuss recent studies with limitations instead of just an overview for better comparison 3. The author needs to discuss results in detail rather than just observations Minor comments: 1. Correct annotations throughout the manuscript (eg. Figures) 2. Figure 6, please correct Y-axis label 3. Include scale bar in SEM images 4.. Write a future perspective of the current study 5.. What are the limitations of this study Is the work clearly and accurately presented and does it cite the current literature? Yes Is the study design appropriate and is the work technically sound? Partly Are sufficient details of methods and analysis provided to allow replication by others? Partly If applicable, is the statistical analysis and its interpretation appropriate? Partly Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? Yes Competing Interests: No competing interests were disclosed. Reviewer Expertise: Drug delivery, formulation development, Nanomedicine, vaccines I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Salave S. Reviewer Report For: Forecasting in vivo pharmacokinetics of metformin HCl floating beads using Gastroplus® PBPK [version 2; peer review: 1 approved, 2 approved with reservations] . F1000Research 2025, 14 :140 ( https://doi.org/10.5256/f1000research.175161.r364754 ) The direct URL for this report is: https://f1000research.com/articles/14-140/v1#referee-response-364754 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Author Response 11 Sep 2025 Sura Zuhair Mahmood , Pharmaceutics Department, Pharmacy College, Mustansiriyah University, Baghdad, Iraq 11 Sep 2025 Author Response 1. Improve the abstract The aim of the abstract has been revised to improve clarity. 2. Improve the introduction section, and discuss recent studies with limitations instead of ... Continue reading 1. Improve the abstract The aim of the abstract has been revised to improve clarity. 2. Improve the introduction section, and discuss recent studies with limitations instead of just an overview for better comparison Thank you for your careful reading and valuable feedback. Yes, the highlighted parts of the introduction were improved by changing the aim of the study and referring to the limitations in the other previous studies regarding metformin HCl formulations. 3. The author needs to discuss results in detail rather than just observations Yes, this change has been implemented and highlighted in the results of the revised version. Minor comments: 1. Correct annotations throughout the manuscript (eg. Figures) The annotations have been revised accordingly, especially in Figures 2 and 4 2. Figure 6, please correct the Y-axis label Yes, it is done 3. Include a scale bar in SEM images Yes, included in the image 4. Write a future perspective of the current study Done, and it is highlighted in the revised version 5. What are the limitations of this study The limitation was written at the end of the revised version 1. Improve the abstract The aim of the abstract has been revised to improve clarity. 2. Improve the introduction section, and discuss recent studies with limitations instead of just an overview for better comparison Thank you for your careful reading and valuable feedback. Yes, the highlighted parts of the introduction were improved by changing the aim of the study and referring to the limitations in previous studies regarding metformin HCl formulations. 3. The author needs to discuss results in detail rather than just observations Yes, this change has been implemented and highlighted in the result of the revised version. Minor comments: 1. Correct annotations throughout the manuscript (eg. Figures) The annotations have been revised accordingly, especially in Figures 2 and 4 2. Figure 6, please correct the Y-axis label Yes, it is done 3. Include a scale bar in SEM images Yes, included in the image 4. Write a future perspective of the current study Done, and it is highlighted after the end of the revised version 5. What are the limitations of this study The limitations were written at the end of the revised version 1. Improve the abstract The aim of the abstract has been revised to improve clarity. 2. Improve the introduction section, and discuss recent studies with limitations instead of just an overview for better comparison Thank you for your careful reading and valuable feedback. Yes, the highlighted parts of the introduction were improved by changing the aim of the study and referring to the limitations in the other previous studies regarding metformin HCl formulations. 3. The author needs to discuss results in detail rather than just observations Yes, this change has been implemented and highlighted in the results of the revised version. Minor comments: 1. Correct annotations throughout the manuscript (eg. Figures) The annotations have been revised accordingly, especially in Figures 2 and 4 2. Figure 6, please correct the Y-axis label Yes, it is done 3. Include a scale bar in SEM images Yes, included in the image 4. Write a future perspective of the current study Done, and it is highlighted in the revised version 5. What are the limitations of this study The limitation was written at the end of the revised version 1. Improve the abstract The aim of the abstract has been revised to improve clarity. 2. Improve the introduction section, and discuss recent studies with limitations instead of just an overview for better comparison Thank you for your careful reading and valuable feedback. Yes, the highlighted parts of the introduction were improved by changing the aim of the study and referring to the limitations in previous studies regarding metformin HCl formulations. 3. The author needs to discuss results in detail rather than just observations Yes, this change has been implemented and highlighted in the result of the revised version. Minor comments: 1. Correct annotations throughout the manuscript (eg. Figures) The annotations have been revised accordingly, especially in Figures 2 and 4 2. Figure 6, please correct the Y-axis label Yes, it is done 3. Include a scale bar in SEM images Yes, included in the image 4. Write a future perspective of the current study Done, and it is highlighted after the end of the revised version 5. What are the limitations of this study The limitations were written at the end of the revised version Competing Interests: No competing interests were disclosed. Close Report a concern Respond or Comment COMMENTS ON THIS REPORT Author Response 11 Sep 2025 Sura Zuhair Mahmood , Pharmaceutics Department, Pharmacy College, Mustansiriyah University, Baghdad, Iraq 11 Sep 2025 Author Response 1. Improve the abstract The aim of the abstract has been revised to improve clarity. 2. Improve the introduction section, and discuss recent studies with limitations instead of ... Continue reading 1. Improve the abstract The aim of the abstract has been revised to improve clarity. 2. Improve the introduction section, and discuss recent studies with limitations instead of just an overview for better comparison Thank you for your careful reading and valuable feedback. Yes, the highlighted parts of the introduction were improved by changing the aim of the study and referring to the limitations in the other previous studies regarding metformin HCl formulations. 3. The author needs to discuss results in detail rather than just observations Yes, this change has been implemented and highlighted in the results of the revised version. Minor comments: 1. Correct annotations throughout the manuscript (eg. Figures) The annotations have been revised accordingly, especially in Figures 2 and 4 2. Figure 6, please correct the Y-axis label Yes, it is done 3. Include a scale bar in SEM images Yes, included in the image 4. Write a future perspective of the current study Done, and it is highlighted in the revised version 5. What are the limitations of this study The limitation was written at the end of the revised version 1. Improve the abstract The aim of the abstract has been revised to improve clarity. 2. Improve the introduction section, and discuss recent studies with limitations instead of just an overview for better comparison Thank you for your careful reading and valuable feedback. Yes, the highlighted parts of the introduction were improved by changing the aim of the study and referring to the limitations in previous studies regarding metformin HCl formulations. 3. The author needs to discuss results in detail rather than just observations Yes, this change has been implemented and highlighted in the result of the revised version. Minor comments: 1. Correct annotations throughout the manuscript (eg. Figures) The annotations have been revised accordingly, especially in Figures 2 and 4 2. Figure 6, please correct the Y-axis label Yes, it is done 3. Include a scale bar in SEM images Yes, included in the image 4. Write a future perspective of the current study Done, and it is highlighted after the end of the revised version 5. What are the limitations of this study The limitations were written at the end of the revised version 1. Improve the abstract The aim of the abstract has been revised to improve clarity. 2. Improve the introduction section, and discuss recent studies with limitations instead of just an overview for better comparison Thank you for your careful reading and valuable feedback. Yes, the highlighted parts of the introduction were improved by changing the aim of the study and referring to the limitations in the other previous studies regarding metformin HCl formulations. 3. The author needs to discuss results in detail rather than just observations Yes, this change has been implemented and highlighted in the results of the revised version. Minor comments: 1. Correct annotations throughout the manuscript (eg. Figures) The annotations have been revised accordingly, especially in Figures 2 and 4 2. Figure 6, please correct the Y-axis label Yes, it is done 3. Include a scale bar in SEM images Yes, included in the image 4. Write a future perspective of the current study Done, and it is highlighted in the revised version 5. What are the limitations of this study The limitation was written at the end of the revised version 1. Improve the abstract The aim of the abstract has been revised to improve clarity. 2. Improve the introduction section, and discuss recent studies with limitations instead of just an overview for better comparison Thank you for your careful reading and valuable feedback. Yes, the highlighted parts of the introduction were improved by changing the aim of the study and referring to the limitations in previous studies regarding metformin HCl formulations. 3. The author needs to discuss results in detail rather than just observations Yes, this change has been implemented and highlighted in the result of the revised version. Minor comments: 1. Correct annotations throughout the manuscript (eg. Figures) The annotations have been revised accordingly, especially in Figures 2 and 4 2. Figure 6, please correct the Y-axis label Yes, it is done 3. Include a scale bar in SEM images Yes, included in the image 4. Write a future perspective of the current study Done, and it is highlighted after the end of the revised version 5. What are the limitations of this study The limitations were written at the end of the revised version Competing Interests: No competing interests were disclosed. Close Report a concern COMMENT ON THIS REPORT Comments on this article Comments (0) Version 2 VERSION 2 PUBLISHED 28 Jan 2025 ADD YOUR COMMENT Comment keyboard_arrow_left keyboard_arrow_right Open Peer Review Reviewer Status info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Reviewer Reports Invited Reviewers 1 2 3 Version 2 (revision) 09 Sep 25 read read Version 1 28 Jan 25 read read Sagar Salave , National Institute of Pharmaceutical Education and Research, Ahmedabad, India; The University of Kansas (Ringgold ID: 4202), Lawrence, USA Anuj Garg , GLA University, Mathura, India Murryam Nawaz , Riphah Interntional University, Islamabad, Pakistan Sadia Rehman , Riphah International University, Islamabad, Pakistan Comments on this article All Comments (0) Add a comment Sign up for content alerts Sign Up You are now signed up to receive this alert Browse by related subjects keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 Rehman S et al. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 30 Sep 2025 | for Version 2 Murryam Nawaz , Pharmacy, Riphah Interntional University, Islamabad, Islamabad Capital Territory, Pakistan Sadia Rehman , Riphah International University, Islamabad, Pakistan 0 Views copyright © 2025 Rehman S et al. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved With Reservations info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Summary of the Article: The manuscript reports the fabrication of metformin hydrochloride (MH) floating beads using an ionotropic gelation technique with alginate and cross-linking via CaCl₂. Seven formulations were prepared and evaluated for yield, entrapment efficiency, floating behavior, and in vitro drug release. The optimized formulation was characterized by FTIR, FESEM, and swelling studies. To translate in vitro findings into in vivo performance, a physiologically based pharmacokinetic (PBPK) model was constructed using GastroPlus®. The model incorporated known metformin transporter interactions (OCT1/2, MATE1/2, PMAT) while excluding OCT3. Simulation outcomes were compared to reported pharmacokinetic profiles of immediate-release tablets, and the authors suggest that the floating beads offer enhanced gastro-retentive behavior and absorption. The manuscript also includes a limitation and future perspective section, highlighting personalized PBPK approaches. Overall Assessment: The study addresses a clinically relevant problem — improving the delivery of MH, a first-line drug for type II diabetes, through gastroretentive floating beads combined with PBPK modeling. The topic is interesting and potentially useful for pharmaceutical formulation and predictive modeling research. However, the presentation lacks clarity, the statistical analysis is weak, and the PBPK model validation is insufficient. While the manuscript has merit, it requires major revision before it can be considered scientifically sound. Major Comments: Entrapment efficiency, yield, and in vitro release data are presented as mean ± SD, but no statistical comparisons (ANOVA, t-tests) are performed between formulations. Without significance testing, it is unclear whether differences between formulations are meaningful. The PBPK model is validated against only one dataset (500 mg IR tablets). Sensitivity analysis on transporter inclusion/exclusion (especially OCT3) should be considered or at least justified more thoroughly. Table 2 (formulation composition) appears incomplete in the submitted version. Full details of polymer concentrations, curing times, and number of replicates should be included for reproducibility. Raw dissolution data with error bars should be presented. The conclusion that PBPK modeling “confirms” enhanced absorption of MH beads is overstated whereas, the evidence only suggests a potential improvement. Authors should moderate their claims and align conclusions more closely with the presented data. Abstract should be more concise — clearly state aim, methods, key results, and conclusion. Literature review needs updating with recent studies (2019–2024) on metformin gastroretentive systems and PBPK applications. Checklist Answers with Justifications: Is the work clearly and accurately presented and does it cite the current literature? Partly – The structure is clear, but language issues obscure meaning. References are somewhat outdated; more recent citations are needed. Is the study design appropriate and is the work technically sound? Partly – The bead fabrication and PBPK approach are appropriate. However, the PBPK validation is weak and statistical rigor is lacking. Are sufficient details of methods and analysis provided to allow replication by others? Partly – Important details (full formulation table, replicate numbers, raw data) are missing, limiting reproducibility. Is the statistical analysis and its interpretation appropriate? Partly – Basic descriptive statistics are given, but no comparative statistical analysis has been applied. Are all the source data underlying the results available to ensure full reproducibility? Partly – Key raw data and details are not provided in sufficient depth. Are the conclusions drawn adequately supported by the results? Partly – Conclusions are generally in line with results, but claims of enhanced absorption should be toned down given the limited validation. Is the work clearly and accurately presented and does it cite the current literature? Partly Is the study design appropriate and is the work technically sound? Partly Are sufficient details of methods and analysis provided to allow replication by others? Partly If applicable, is the statistical analysis and its interpretation appropriate? Partly Are all the source data underlying the results available to ensure full reproducibility? Partly Are the conclusions drawn adequately supported by the results? Partly Competing Interests No competing interests were disclosed. Reviewer Expertise Pharmaceutical technology, formulation development, drug delivery systems, emulsions, suspensions, hydrogels, nanogels, nanoparticles. We confirm that we have read this submission and believe that we have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however we have significant reservations, as outlined above. reply Respond to this report Responses (0) Nawaz M and Rehman S. Peer Review Report For: Forecasting in vivo pharmacokinetics of metformin HCl floating beads using Gastroplus® PBPK [version 2; peer review: 1 approved, 2 approved with reservations] . F1000Research 2025, 14 :140 ( https://doi.org/10.5256/f1000research.183289.r414010) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/14-140/v2#referee-response-414010 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 Salave S. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 17 Sep 2025 | for Version 2 Sagar Salave , National Institute of Pharmaceutical Education and Research, Ahmedabad, India; Pharmaceutical Chemistry, The University of Kansas (Ringgold ID: 4202), Lawrence, Kansas, USA 0 Views copyright © 2025 Salave S. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Authors have made significant changes in the revised manuscript Competing Interests No competing interests were disclosed. Reviewer Expertise Drug delivery, formulation development, Nanomedicine, vaccines I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. reply Respond to this report Responses (0) Salave S. Peer Review Report For: Forecasting in vivo pharmacokinetics of metformin HCl floating beads using Gastroplus® PBPK [version 2; peer review: 1 approved, 2 approved with reservations] . F1000Research 2025, 14 :140 ( https://doi.org/10.5256/f1000research.183289.r412668) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/14-140/v2#referee-response-412668 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 Garg A. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 15 Apr 2025 | for Version 1 Anuj Garg , Institute of Pharmaceutical Research, GLA University, Mathura, Uttar Pradesh, India 0 Views copyright © 2025 Garg A. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (1) Approved With Reservations info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions In the present research work, the authors have developed floating beads containing metformin and forecast the plasma concentration using Gastroplus software on the basis of previous in vivo results and in vitro results performed in the present study. The author describes the methodology appropriately and well written in the manuscript. However, the references are not upto date and most of the cited references are before 2020. Moreover, the objective of this study was to develop floating beads which seems to be very old method and various studies have been already published for the same objective to formulate floating beads. One of the paper is as follow: Nayak, A., Jain, S. K., & Pandey, R. S. (2011 [Ref-1]). Controlling release of metformin HCl through incorporation into stomach specific floating alginate beads. Molecular pharmaceutics , 8 (6), 2273-2281. The interpretation of results should be discussed in depth to explain the possible reason behind the results. Is the work clearly and accurately presented and does it cite the current literature? Partly Is the study design appropriate and is the work technically sound? Yes Are sufficient details of methods and analysis provided to allow replication by others? Yes If applicable, is the statistical analysis and its interpretation appropriate? Partly Are all the source data underlying the results available to ensure full reproducibility? No source data required Are the conclusions drawn adequately supported by the results? Yes References 1. Nayak A, Jain SK, Pandey RS: Controlling release of metformin HCl through incorporation into stomach specific floating alginate beads. Mol Pharm . 2011; 8 (6): 2273-81 PubMed Abstract | Publisher Full Text Competing Interests No competing interests were disclosed. Reviewer Expertise Drug delivery, Pharmacokinetics I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. reply Respond to this report Responses (1) Author Response 11 Sep 2025 Sura Zuhair Mahmood, Pharmaceutics Department, Pharmacy College, Mustansiriyah University, Baghdad, Iraq In the present research work, the authors have developed floating beads containing metformin and forecast the plasma concentration using Gastroplus software on the basis of previous in vivo results and in vitro results performed in the present study. The author describes the methodology appropriately and well written in the manuscript. However, the references are not up-to-date and most of the cited references are before 2020. Moreover, the objective of this study was to develop floating beads which seems to be very old method and various studies have been already published for the same objective to formulate floating beads. Thank you for your valuable comments and observations. We have updated most of the references to ensure they are more current. While we acknowledge that the method used is established and considered an old technique, we believe it remains highly reproducible and capable of yielding reliable results. Furthermore, previous studies have not addressed the prediction of in vivo pharmacokinetics based on in vitro release data using this specific approach, which we believe adds novelty to our work, and this was referred to in the introduction section One of the paper is as follows: Nayak, A., Jain, S. K., & Pandey, R. S. (2011 [Ref-1]). Controlling release of metformin HCl through incorporation into stomach specific floating alginate beads. Molecular pharmaceutics , 8 (6), 2273-2281. Kindly refer to the introduction and reference sections, which were changed to more recent ones as per your request The interpretation of results should be discussed in depth to explain the possible reasons behind the results Thank you for pointing this out. The revised version now includes a more detailed explanation and is highlighted within the result section. View more View less Competing Interests No competing interests were disclosed. reply Respond Report a concern Garg A. Peer Review Report For: Forecasting in vivo pharmacokinetics of metformin HCl floating beads using Gastroplus® PBPK [version 2; peer review: 1 approved, 2 approved with reservations] . F1000Research 2025, 14 :140 ( https://doi.org/10.5256/f1000research.175161.r364759) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/14-140/v1#referee-response-364759 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 Salave S. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 18 Feb 2025 | for Version 1 Sagar Salave , National Institute of Pharmaceutical Education and Research, Ahmedabad, India; Pharmaceutical Chemistry, The University of Kansas (Ringgold ID: 4202), Lawrence, Kansas, USA 0 Views copyright © 2025 Salave S. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (1) Not Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Authors need to revise the manuscript thoroughly as per the below comments: Major comments: 1. Improve the abstract 2. Improve the introduction section, and discuss recent studies with limitations instead of just an overview for better comparison 3. The author needs to discuss results in detail rather than just observations Minor comments: 1. Correct annotations throughout the manuscript (eg. Figures) 2. Figure 6, please correct Y-axis label 3. Include scale bar in SEM images 4.. Write a future perspective of the current study 5.. What are the limitations of this study Is the work clearly and accurately presented and does it cite the current literature? Yes Is the study design appropriate and is the work technically sound? Partly Are sufficient details of methods and analysis provided to allow replication by others? Partly If applicable, is the statistical analysis and its interpretation appropriate? Partly Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? Yes Competing Interests No competing interests were disclosed. Reviewer Expertise Drug delivery, formulation development, Nanomedicine, vaccines I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. reply Respond to this report Responses (1) Author Response 11 Sep 2025 Sura Zuhair Mahmood, Pharmaceutics Department, Pharmacy College, Mustansiriyah University, Baghdad, Iraq 1. Improve the abstract The aim of the abstract has been revised to improve clarity. 2. Improve the introduction section, and discuss recent studies with limitations instead of just an overview for better comparison Thank you for your careful reading and valuable feedback. Yes, the highlighted parts of the introduction were improved by changing the aim of the study and referring to the limitations in the other previous studies regarding metformin HCl formulations. 3. The author needs to discuss results in detail rather than just observations Yes, this change has been implemented and highlighted in the results of the revised version. Minor comments: 1. Correct annotations throughout the manuscript (eg. Figures) The annotations have been revised accordingly, especially in Figures 2 and 4 2. Figure 6, please correct the Y-axis label Yes, it is done 3. Include a scale bar in SEM images Yes, included in the image 4. Write a future perspective of the current study Done, and it is highlighted in the revised version 5. What are the limitations of this study The limitation was written at the end of the revised version 1. Improve the abstract The aim of the abstract has been revised to improve clarity. 2. Improve the introduction section, and discuss recent studies with limitations instead of just an overview for better comparison Thank you for your careful reading and valuable feedback. Yes, the highlighted parts of the introduction were improved by changing the aim of the study and referring to the limitations in previous studies regarding metformin HCl formulations. 3. The author needs to discuss results in detail rather than just observations Yes, this change has been implemented and highlighted in the result of the revised version. Minor comments: 1. Correct annotations throughout the manuscript (eg. Figures) The annotations have been revised accordingly, especially in Figures 2 and 4 2. Figure 6, please correct the Y-axis label Yes, it is done 3. Include a scale bar in SEM images Yes, included in the image 4. Write a future perspective of the current study Done, and it is highlighted after the end of the revised version 5. What are the limitations of this study The limitations were written at the end of the revised version View more View less Competing Interests No competing interests were disclosed. reply Respond Report a concern Salave S. Peer Review Report For: Forecasting in vivo pharmacokinetics of metformin HCl floating beads using Gastroplus® PBPK [version 2; peer review: 1 approved, 2 approved with reservations] . F1000Research 2025, 14 :140 ( https://doi.org/10.5256/f1000research.175161.r364754) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/14-140/v1#referee-response-364754 Alongside their report, reviewers assign a status to the article: Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions Adjust parameters to alter display View on desktop for interactive features Includes Interactive Elements View on desktop for interactive features Competing Interests Policy Provide sufficient details of any financial or non-financial competing interests to enable users to assess whether your comments might lead a reasonable person to question your impartiality. 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