Self emulsifying drug delivery system: norfloxacin model drug

Noor Abdulkareem; Mohanad Naji Sahib

doi:10.12688/f1000research.141057.1

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Research Article

Self emulsifying drug delivery system: norfloxacin model drug

[version 1; peer review: 1 approved with reservations, 2 not approved]

Noor Abdulkareem ¹, Mohanad Naji Sahib²

PUBLISHED 20 Oct 2023

Author details Author details

¹ Department of Pharmaceutics, Mustansiriyah University, Baghdad, Iraq
² Faculty of Pharmacy, Al-Turath University College, Baghdad, Iraq

Noor Abdulkareem
Roles: Conceptualization, Data Curation, Formal Analysis, Funding Acquisition, Investigation, Methodology, Project Administration, Resources, Software, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing

Mohanad Naji Sahib
Roles: Conceptualization, Formal Analysis, Funding Acquisition, Investigation, Methodology, Project Administration, Resources, Software, Supervision, Validation, Visualization, Writing – Review & Editing

OPEN PEER REVIEW

REVIEWER STATUS

Abstract

Background

Norfloxacin is a synthetic antibacterial fluoroquinolone that is poorly water soluble and active against a wide spectrum of gram-positive and gram-negative aerobic bacteria. The goal of this work was to create a self-nanoemulsion (SNE) as a colloidal dispersed drug delivery system for increasing norfloxacin dissolving rate, while also assuming intestinal lymphatic transport participation for such a nano-size system that would increase norfloxacin oral bioavailability.

Methods

Depending on the solubility of norfloxacin in various components, several formulations of liquid SNEDDS of the antibiotic were created using oleic acid (oil), tween20 (surfactant), and PEG200 (co-surfactant). To assess the presence of a nanoemulsion region, phase diagram was generated at various oil: surfactant: co-surfactant ratios.

Results

The in-vitro dissolution profile suggested an optimum norfloxacin SEDD formulation (F1) comprised of oleic acid (10%), tween 20 (45%), and PEG200 (45%), as opposed to commercially available traditional tablets.

The F1 formula exhibited thermodynamic stability with a zeta potential of +60.78mV and a droplet size of 57.4nm. The F1 formula revealed an improved dissolving profile as compared to the commercial Tablet of norfloxacin.

Conclusion

Based on the findings, this study indicated that preparing norfloxacin as a liquid self-nanoemulsifying system improved the solubility and drug release of norfloxacin counteract the inconsistent bioavailability of the commercial tablet.

Keywords

Norfloxacin , nanoemulsion , self nano-emulsifying drug delivery system (SNEDDS)

Corresponding author: Noor Abdulkareem

Competing interests: No competing interests were disclosed.

Grant information: The author(s) declared that no grants were involved in supporting this work.

Copyright: © 2023 Abdulkareem N and Sahib MN. 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: Abdulkareem N and Sahib MN. Self emulsifying drug delivery system: norfloxacin model drug [version 1; peer review: 1 approved with reservations, 2 not approved]. F1000Research 2023, 12:1380 (https://doi.org/10.12688/f1000research.141057.1) First published: 20 Oct 2023, 12:1380 (https://doi.org/10.12688/f1000research.141057.1) Latest published: 20 Oct 2023, 12:1380 (https://doi.org/10.12688/f1000research.141057.1)

Introduction

Self-emulsifying drug delivery systems (SEDDS) are isotropic homogeneous pre-concentrate mixes of oil, surfactant, co-surfactant, and drug that, when gently agitated in an aqueous media, rapidly produce fine oil-in-water (o/w) emulsions.¹ SEDDS improve the oral bioavailability of the medicine by enhancing its solubility and keeping it spread in small globules of oil during its passage through the gastrointestinal system.² Also, bioavailability will be improved as a result of avoiding the first pass effect that when bile acids are present, lingual and pancreatic lipases activate on the oily phase of the SEDDS, resulting in the creation of emulsified mono-glycerides, diglycerides, and fatty acids and the generation of intestinal mixed micelles. As these mixed micelles travel through the enterocytes, they produce chylomicrons, they can route the medication into lymphatic pathways instead of blood vessels.³ Because the diameter of the emulsion droplets generated ranges from nanometers to several microns, self-emulsify drug delivery systems are classified as self-nano-emulsifying (SNEDD) and self-micro-emulsifying (SMEDD).⁴

Norfloxacin (NOR) is a second generation fluoroquinolone. This broad-spectrum antibacterial drug is widely used to treat a variety of infection disorders involving the gastrointestinal or genitourinary systems.⁵^,⁶

Norfloxacin’s chemical name is 1-ethyl-6-fluoro-4-oxo-7-piperazin-1-yl-1H-quinoline-3-carboxylic acid. It has a very low solubility in water (0.28 mg/mL), and its color is a very light yellow. NOR is very basic in nature (pKa 6.39) and has an empirical log P value of 1.47. Additionally, the clinical effectiveness of this BCS class IV medication is affected by its poor bioavailability (30%), protein binding value (15%), and about 30% of drug excreted unaltered.⁷ There are a few attempts to improve the pharmaceutical properties of NOR such as dispersible tablets, extended-release matrix tablets, gastro-retentive floating tablets, cyclodextrin-containing suspension, solid lipid nanoparticles, suspensions, gastro-retentive floating microspheres, and sustained release alginate micro-beads.

The goal of this project is to develop norfloxacin as an oral self-emulsifying liquid formulation that will improve solubility and thus bioavailability.

Methods

Materials

Norfloxacin, coconut oil, mineral oil, olive oil, corn oil, spearmint oil and castor oil from Hangzhou Hyper chemicals (China). Oleic acid, clove oil and methanol were purchased from G.C.C., (UK). PEG 400, propylene glycol were obtained from CDH (India). PEG200, tween (20 and 80), span (20 and 80) were obtained from Thomas baker (India).

Determination of saturated solubility of norfloxacin

The saturated solubility of norfloxacin in various oils, surfactants, and co-surfactants was determined. The oils that were used were (coconut oil, mineral oil, olive oil, oleic acid, corn oil, spearmint oil, clove oil, castor oil). Surfactants and co-surfactants (tween 20, 80, span 20, 80) (PEG200, 400, PG). In order to assess the solubility, an excess amount of norfloxacin powder was added to 5ml of each excipient (oil, surfactant, and co-surfactant) contained in small, firmly sealed glass tubes. After 3 days in a shaking water bath at (25±0.5)°C, the tubes were centrifuged at a rate of 3000 rpm for twenty minutes, and the supernatant layer was filtered with a 0.45 m syringe filter. Methanol was used to dilute the samples. A UV-visible spectrophotometer (Biotech Engineering Management Co) is utilized in order to determine solubility. The measurement was carried out in triplicate.⁸^,⁹

Construction of pseudo-ternary phase diagrams

Pseudoternary phase diagrams for oil (oleic acid), surfactant (tween20) and co-surfactant (PEG200) represented as Smix were developed. Water was obtained at room temperature using the water titration technique, and each of them represents a side of the triangle. Several Smix (1:1, 1:2, 1:3, 1:4 and 2:1, 3:1, 4:1) ratios of surfactant and co-surfactant were utilized, and oil to particular Smix ratios (ranging from 0.5:9.5 to 9.5:0.5) were prepared.¹⁰^,¹¹

Development of a liquid self-emulsifying drug delivery system (SEDD)

To manufacture norfloxacin liquid self-emulsifying drug delivery (SEDD) formulations, a vortex mixer was used to combine norfloxacin (400 mg) with oleic acid oil, tween 20, and PEG200 (Smix) in a screw-capped glass vial. The mixture was then warmed in a water bath for half an hour at 50°C to induce homogeneity.¹² The (28) produced formulae’ components are shown in Table 1.

Table 1. The components of the liquid SEDD formulation of norfloxacin.

Formula code	Smix ratio	Oleic acid %	Tween 20%	PEG 200%
F1	1:1	10%	45%	45%
F2	1:2	10%	30%	60%
F3	1:3	10%	22.5%	67.5%
F4	1:4	10%	18%	72%
F5	2:1	10%	60%	30%
F6	3:1	10%	67.5%	22.5%
F7	4:1	10%	72%	18%
F8	1:1	20%	40%	40%
F9	1:2	20%	26.70%	53.30%
F10	1:3	20%	20%	60%
F11	1:4	20%	16%	64%
F12	2:1	20%	53.30%	26.70%
F13	3:1	20%	60%	20%
F14	4:1	20%	64%	16%
F15	1:1	30%	35%	35%
F16	1:2	30%	23.30%	46.70%
F17	1:3	30%	17.5%	52.5%
F18	1:4	30%	14%	56%
F19	2:1	30%	46.70%	23.30%
F20	3:1	30%	52.5%	17.5%
F21	4:1	30%	56%	14%
F22	1:1	40%	30%	30%
F23	1:2	40%	20%	40%
F24	1:3	40%	15%	45%
F25	1:4	40%	12%	48%
F26	2:1	40%	40%	20%
F27	3:1	40%	45%	15%
F28	4:1	40%	48%	12%

Evaluation of prepared norfloxacin SEDD

Robustness to dilution

The liquid SEDDS formulations were diluted in two separate 1000 ml beaker with deionized water and 0.1 N HCl (50, 100, 250, and 1000 times) to mimic in vivo environments. The diluted systems were shaken with the aid of a magnetic stirrer to ensure complete homogeneity and done at 37°C to simulate body temperature.¹³

These systems were kept at room temperature for 24 hours before being visually examined for signs of phase separation, drug precipitation, and droplet coalescence.¹⁴

Investigating the thermodynamic stability

Centrifugation test

The SEDDS formulations were centrifuged at 3500rpm for 20 minutes to check for phase separation, creaming, or cracking.¹⁵ Following the centrifugation test, the formulations that succeeded will be put to another thermodynamic test.¹⁶

Heating-cooling cycle (H/C cycle)

The stabled formulas were subjected to six cycles of heating and cooling at two different temperatures (4°C and 45°C). Formulas would stay at each temperature for at least 48 hours. The formulas that did not show any phase separations or creaming were subjected to freeze-thraw cycles.¹⁷

Freeze-thaw cycles

Stable SE formulas were subsequently subjected to freezing and thawing (-20°C and 25°C). They were carried out in three cycles, each lasting 48 hours.¹⁸

Self-emulsification time and dispersibility test

The addition of liquid self-emulsify formulas to 500 mL of 0.1N HCl under gentle magnetic stirring was visually observed. Emulsification time was established as the amount of time needed for the prepared formulations to completely disperse and form an emulsion. When a transparent homogenous system was attained. The in-vitro efficiency of the liquid SEDDS formulations was examined visually. It is believed that the creation of clear SEDD occurs best within a minute, since prolonged times result in a milky look.¹⁹ As indicated by the grade mentioned in Table 2.²⁰

Table 2. Grades for SEDD visual observation.

Grade	Time required for self-emulsion formation	Appearance
A	in 1 minute	transparent or rapid blue-tinged
B	in 1 minute	White-blue
C	After about 2 minutes	It becomes a pale blue-white, almost the color of milk.
D	More than 2 minutes	An ash emulsion with a dull, somewhat greasy look.
E	More than two minutes	Large oil droplets on the surface, indicating poor or no emulsification.

Determination of drug content

Using a UV spectrophotometer, the drug content of the chosen formulations (F1, F2, F5, F6, F8, F13) that passed the previously indicated characterisation tests was determined. In a 100 mL volumetric flask, a known amount of norfloxacin-SEDDS was accurately measured. The flask was then filled with methanol and sonicated for around 15 minutes to ensure full drug dissolution. The solution was appropriately filtered via a 0.45-micrometer membrane, diluted, then tested for drug concentration with a UV-spectrophotometer at 278 nm.²¹^–²⁴

Size of globules and polydispersity index (PDI)

The droplet size investigation was carried out using a dynamic light scattering approach, which examines the variance in light scattering caused by particle Brownian motion. Light scattering was measured at room temperature at a 90° angle of laser scattering.²⁵

The liquid norfloxacin-self emulsify formulation was diluted hundred times (0.25mL from each formula in 25 mL) with filtrated distilled water and gently agitated with a magnetic stirrer to generate a fine emulsion. The diluted emulsion was poured in a disposable cuvette in the sample chamber to analyze droplet size and PDI.²⁶

In-vitro drug release study of norfloxacin SNEDDS

Dissolution apparatus-II was used to establish in-vitro drug release profiles of SEDDS formulae as well as norfloxacin tablet. The medium was 750 ml of acetate buffer pH,⁴ and the test was carried out using stirring paddles at a speed of 50 rpm and at a temperature of 37°C. The dialysis bag approach was used for drug release investigations to obtain true amounts of free drug without interference with unreleased drug from the formula.²⁷ Aliquots (5 ml) of samples were obtained at 5,10,15,20,30,45,60 minute intervals. To maintain a sink condition, the same quantities of new dissolving medium (ph4) were replaced. The amount of drug dissolved was filtered and measured with a UV-vis spectrophotometer at 278 nm.²⁸

Zeta potential determination

The zeta potential analyzer was used to examine the best liquid SEDD formulation (F1) (Brookhaven instrument). The zeta potential value indicates the repulsive forces between the droplets.²⁹^,³⁰ The aqueous dispersion of the produced SE formula was made in the same manner as in the section of globule size measurement.

Results and discussion

Determination of norfloxacin saturated solubility

The solubility of norfloxacin in different oils, surfactants, and co-surfactants was determined as showen in Table 3. To find suitable vehicles with a high solubilizing ability for norfloxacin. The importance of maximum drug solubility is first and mainly an optimization of drug loading capacity. Second, drug precipitation is avoided during dilution, and the final volume of SEDDS is reduced, making it acceptable for oral administration.³¹ At last, while storage, the whole system’s stability will improve.

Table 3. Saturated solubility of norfloxacin in various oils, surfactants, and co-surfactants; (mean±SD).

vehicle	Solubility (mg/ml)
Oil
coconut oil	5.60±0.30
mineral oil	3.74±0.53
olive oil	22.64±0.24
oleic acid	76.42±0.23
corn oil	11.70±0.26
spearmint oil	10.63±0.36
cloves oil	22.30±0.18
castor oil	15.75±0.09
surfactant
tween 20	49.66±0.36
span 20	3.29±0.17
tween 80	14.42±0.46
span 80	4.38±0.29
Co-surfactant
PG	28.54±0.09
PEG200	71.42±1.78
PEG400	52.58±2.23

The solubility of norfloxacin in different oils is as follows: oleic acid >olive oil >clove oil >castor oil >corn oil > spearmint oil >coconut oil >mineral oil.

As oleic acid had the maximum solubility for norfloxacoin, it was chosen as the oil phase of SEDDS.

The solubility of norfloxacin in various surfactants reveals that the maximum solubility was observed in tween 20 (non-ionic surfactant with HLB values = 16.7),³² which was chosen as the best surfactant.

Norfloxacin solubility was also investigated in several co-surfactants that are critical for interfacial film flexibility and decreasing interfacial tension.³³

The medication had a low solubility in PG, but the maximum solubility was seen in PEG200, thus it was chosen.

Pseudo-ternary phase diagram construction

It was observed from phase diagrams in Figure 1 that increasing the ratio of surfactant to co-surfactant in Smix from 1:1 to 2:1 or 3:1 improved the nanoemulsion shaded area. Moreover, there was a reduction in nanoemulsion area at a Smix 4:1 ratio. The reason for the increased clarity of the emulsions produced as Smix increased was a decrease in the total system’s free energy. Thus, smaller emulsion droplet size reflects a formulation with greater visual clarity. On the other hand, a further increase in Smix may facilitate water breakthrough oil globule, resulting in their disruption and more oil globules released into the aqueous phase.³⁴ In addition, as the co-surfactant (PEG200) concentration increased (1:2, 1:3, and 1:4), the nanoemulsion area decreased in comparison to the 1:1 ratio, which was attributed to the decrease in surfactant (tween 20) concentration from 50% in the 1:1 ratio to 20% in the 1:4 ratio confirming the fact that the surfactant has a primary role by being adsorbed on the surface of oil droplets to provide the essential barrier for the formation of o/w emulsion while the co-surfactant serves as an adjuvant by giving flexibility to the formed barrier film, further lowering the interfacial tension.³⁵ These results concurred with that observed by different studies on self-nanoemulsification.³⁶^–³⁸

Figure 1. Diagram exhibiting the pseudo-ternary phases of oleic acid, Smix (tween20:PEG200), and deionized water.

The optimum o/w nano-emulsion area was produced with a low oil: Smix ratio (1:9, 2:8, 3:7, 4:6) because it provided superior stability and a smaller droplet size; this result was consistent with the data.³⁹ As a result, these oil: Smix ratios were chosen for further investigation. Furthermore, raising the oil concentration reduced the nanoemulsion region, which might be due to increased interfacial tension and decreased efficacy of surfactant and cosurfactant to overcome it.

Development of a liquid self-emulsifying drug delivery system (SEDD)

Based on pseudoternary phases diagram,twenty-eight liquid SEDD formulae were produced utilizing various tween 20: PEG200 (Smix) ratios of 1:1, 1:2, 1:3, 1:4, 2:1, 3:1, and 4:1, and oil: Smix ratios of 1:9, 2:8, 3:7, and 4:6. All of the produced formulations underwent a visual assessment of their appearance and other physical characteristics.

The twenty-eight anhydrous formulae that were synthesized had a uniform, clear yellow color and exhibited no evidence of phase separation or drug precipitation.

Characterization of the prepared Liquid SEDDS of norfloxacin

Robustness to dilution

The SEDDS must be able to resist dilution without exhibiting any phase separation or drug precipitation in order to be employed as a drug delivery vehicle, and diluting SEDDS formulations up to 1000 times with all of the abovementioned diluents can mimic the in-vivo conditions.⁴⁰ As shown in Table 4, the majority of reconstituted formulations demonstrated good emulsion stability, as evidenced by the preservation of their appearance with no evidence of drug precipitation or phase separation in all dilution media after 24 hr of storage at room temperature. This suggests that such systems may be suitable for oral administration, as they have a high probability of maintaining their emulsified state throughout their passage in the GIT with no phase separation.⁴¹

Table 4. The results of the robustness to dilution study for norfloxacin SEDDS of various formulations.

Formula no.	Stability in 0.1hcl	Stability in D.W.	Robustness to dilution
F1	✓	✓	STABLE
F2	✓	✓	STABLE
F3	✓	✓	STABLE
F4	✓	✓	STABLE
F5	✓	✓	STABLE
F6	✓	✓	STABLE
F7	✓	✓	STABLE
F8	✓	✓	STABLE
F9	✓	✓	STABLE
F10	✓	✓	STABLE
F11	✓	✓	STABLE
F12	✓	✓	STABLE
F13	✓	✓	STABLE
F14	✓	✓	STABLE
F15	✗	✗	UNSTABLE
F16	✗	✗	UNSTABLE
F17	✗	✗	UNSTABLE
F18	✗	✗	UNSTABLE
F19	✓	✓	STABLE
F20	✓	✓	STABLE
F21	✓	✓	STABLE
F22	✗	✗	UNSTABLE
F23	✗	✗	UNSTABLE
F24	✗	✗	UNSTABLE
F25	✗	✗	UNSTABLE
F26	✓	✓	STABLE
F27	✓	✓	STABLE
F28	✓	✓	STABLE

Several formulations failed this test and became turbid and unstable after 24 hours, possibly due to a low concentration of tween 20 in these formulations that if the formulation comprises water-soluble co-surfactant, precipitation is frequent and can be prevented by raising the surfactant concentration.⁴² In addition, the low concentration of Tween 20 was insufficient to emulsify the high oil content, particularly when it was partially replaced with PEG200. Yet, as the concentration of surfactant rises, both surfactant and co-surfactant exert their functions correctly.

Furthermore, modifying the pH and content of the aqueous phase had no effect on the emulsion characteristics.⁴⁰

It was also noted that as the concentration of oil increases, the formulation’s stability decreases.⁴³

Thermodynamic-stability studies

The SE formulations were visually evaluated after being subjected to centrifugation and abrupt temperature changes, including the heating-cooling cycle and the freezing-thawing cycle.

The observations of the thermodynamic stability investigation for several formulations of norfloxacin SEDDS were displayed in Table 5.

Table 5. Thermodynamic analysis of the chosen SEDD formulas.

Formula code	Centrifugation test	Heating-cooling test	Freeze-thrawing cycles test
F1	✓	✓	✓	PASSED
F2	✓	✓	✓	PASSED
F3	✓	✓	✓	PASSED
F4	✓	✗	-	FAILED
F5	✓	✓	✓	PASSED
F6	✓	✓	✓	PASSED
F7	✓	✓	✓	PASSED
F8	✓	✓	✓	PASSED
F9	✓	✓	✓	PASSED
F10	✓	✓	✓	PASSED
F11	✓	✗	-	FAILED
F12	✓	✓	✓	PASSED
F13	✓	✓	✓	PASSED
F14	✓	✗	-	FAILED
F15	✗	-	-	FAILED
F16	✗	-	-	FAILED
F17	✗	-	-	FAILED
F18	✗	-	-	FAILED
F19	✓	✓	✓	PASSED
F20	✓	✓	✓	PASSED
F21	✗	-	-	FAILED
F22	✓	✗	-	FAILED
F23	✗	-	-	FAILED
F24	✗	-	-	FAILED
F25	✗	-	-	FAILED
F26	✓	✗	-	FAILED
F27	✓	✗	-	FAILED
F28	✗	-	-	FAILED

The formulations were visually assessed for signs of phase separation, cracking, or creaming. The results show that most of the formulations passed all three tests and were stable. However, some formulations failed one or more tests, indicating instability. The failed formulations may be prone to phase separation or other forms of instability upon storage or transportation.

Self-emulsification time and dispersibility test

The majority of the tested formulae had a short self-emulsification time, demonstrating their capacity to make emulsion efficiently and simply.

Table 6 shows the results of different grades of microemulsion and the measured self-emulsification times created by twenty-eight formulations with varying Smix ratios and oil proportions. The previously indicated visual grading method was utilized to evaluate the in-vitro performance of the tested formulae.

Table 6. The dispersibility grade and self-emulsification time of liquid norfloxacin-loaded self-emulsion.

Formula code	Emulsification time (second)	Emulsification grade
F1	22	A
F2	27	A
F3	51	B
F4	48	C
F5	26	A
F6	30	A
F7	32	B
F8	39	A
F9	45	B
F10	51	B
F11	52	C
F12	32	B
F13	35	A
F14	39	B
F15	55	B
F16	49	C
F17	>120	D
F18	>120	D
F19	52	B
F20	51	C
F21	55	B
F22	58	B
F23	65	C
F24	>120	D
F25	>120	D
F26	57	B
F27	55	B
F28	60	B

The study of emulsification time and visual observations revealed that six formulations achieved self-emulsification times of 1 minute with a clear appearance and were certified as grade A (the best) liquid SEDDS. It was also discovered that in formulas F1,F8,F15,F22 containing oil: Smix ratios of 1:9, 2:8, 3:7, 4:6 respectively, keeping Smix ratios of 1:1 as the oil to Smix ratio increased, the process of emulsification slowdown, so when fixing Smix and increasing in oil content leads to a gradual increase in emulsification time. However, increasing the concentration of tween 20 resulted in a significant decrease in emulsification time, as well as improved uniformity and bluish color nature of the microemulsion, improving the spontaneity of emulsification.

The ability of surfactants to improve formation of an emulsion and dispersion by lowering the oil-aqueous interfacial tension may explain why higher surfactant concentration was related with shorter self-emulsification time.⁴⁴

This implies that emulsification efficiency is determined by selecting the appropriate oil ratio as well as the appropriate Smix ratio that provided the optimum emulsification capability, rate, and stability.⁴⁵

Drug content

The drug content of the selected formulae is provided in Table 7. The drug content of norfloxacin SEDDS formulations was meeting USP requirements and falling within an acceptable range (85%-115%). These findings indicate that there was no drug precipitation in the developed formulations and that norfloxacin was homogeneous and stable in SEDDS vehicles.⁴⁶

Table 7. The drug content of the chosen SEDD formulations.

Formulae code	Drug content percent %
F1	99.41±0.54
F2	98.40±0.68
F5	99.19±0.47
F6	99.09±0.49
F8	98.59±0.07
F13	98.25±0.58

Measurement of the globules size and polydispersity index (PDI)

The experimental results of globule size and PDI measurement for norfloxacin-nanoemulsion in distalled water were presented in Table 8. At a constant Smix ratio, it was discovered that increasing the oil% with a subsequent decrease in the quantity of surfactant and co-surfactant in the mixture resulted in a slight increase in globule size. The explanation might be due to a lack of surfactants and co-surfactants that can localize at the oil/water interface of a droplet to reduce interfacial tension and stabilize the system.⁴⁷

Table 8. The globule size and PDI of norfloxacin SNE dispersed in deionized water.

Formula code	Particle size (PS)	Polydispersity index (PDI)
F1	57.4±1.730	0.351
F2	124.2±1.548	0.210
F5	99.5±1.073	0.005
F6	86.7±1.781	0.395
F8	173.1±1.782	0.396
F13	144.3±1.837	0.447

Droplet size distribution is an important issue to consider when developing SMEDDS. The lower the PDI value, the narrower the droplet size distribution, indicating uniformity, homogeneity, and mono-dispersion of the formulated self-nanoemulsion, as well as long term stability.⁴⁸ All SEDDS formulae had low PDI values, indicating that oleic acid globules were dispersed within the formulation and confirmed its homogeneity.³⁴^,⁴⁹^–⁵²

In-vitro drug release study of norfloxacin SEDDS

Figure 2 depicts the in-vitro release profiles of the produced formulations and the norfloxacin tablet in PH⁴ dissolving media over 1 hour. At the end of 1 hour, the majority of tested SNEDDS formulae demonstrated a consistently better release rate than the tablet. The rapid spontaneous emulsification capabilities of SNEDDS, as well as the formation of small globules with a high surfactant content upon dilution, may explain the increased in-vitro release rate and extent.⁵³

Figure 2. In-vitro norfloxacin release from prepared liquid SNEDD formulations and norfloxacin tablet.

As compared the release from the formulation with constant oil% w/w and an increase in Smix, a clear decrease in norfloxacin releasing rate was seen because high Smix may cause drug sequestration inside micelles or oil droplets.²⁹ It was discovered that increasing the co-surfactant yielded the highest dissolution rate. The reason for this is that co-surfactant works as a solubilizer, providing high thermodynamic activity of norfloxacin and therefore facilitating dissolution.⁴⁷^,⁵⁴

When drug release was compared between optimum liquid SEDD formula of norfloxacin (F1) and norfloxacin commercial Tablet in ddsolver; the F1 formula showed a difference than tablet (f₁ = 15.25, If (f₁) ∈ [0-15], this means the reference formula is similar to tested formulations) higher release than the commercial Tablet as shown in Figure 3, and this is related to the ability of F1 to form spontaneous nano-emulsion.

Figure 3. Comparative in-vitro norfloxacin release profile from the liquid SEDD formula (F1) and commercial Tablet.

Zeta potential determination

According to the thumb rule, the zeta potential is an essential predictor of the nanoparticle stability in dispersion medium when the result between (-5 mV to +5 mV) suggests quick agglomeration and the result between (-20 mV to +20 mV) gives short-term stability. Levels of zeta potential between (-30 mV) to (+30 mV) suggest moderate stability, while values in the range (-60 mV) to (+60 mV) indicate excellent stability in the formulation.⁵⁵ The calculated zeta potential for the best liquid SEDD formula F1 was +60.78, as showen in Figure 4 indicating excellent stability.

Figure 4. Zeta potential of F1 of self emulsifying drug delivery system.

Conclusions

An oral administration of spontaneous dosage form of norfloxacin that can produce in-situ nano-emulsion in the gastrointestinal tract providing a stable SEDDS that may increase drug absorption and bioavailability was successfully developed for the first time. Norfloxacin liquid dosage form is also required since a number of individuals, particularly pediatric and geriatric patients, have difficulties swallowing solid dosage forms.

Data availability

Underlying data

Zenodo: pseudoternary phase diaghram.xlsx https://doi.org/10.5281/zenodo.8219346.⁵⁶

Zenodo: RELEASE OF DRUG.xlsx, https://doi.org/10.5281/zenodo.8219350.⁵⁷

Zenodo: saturated solubility.xlsx, https://doi.org/10.5281/zenodo.8219352.⁵⁸

Zenodo: RELEASE.xlsx, https://doi.org/10.5281/zenodo.8216275.⁵⁹

Zenodo: ph 4.xlsx, https://doi.org/10.5281/zenodo.8216277.⁶⁰

Zenodo: drug content.xlsx, https://doi.org/10.5281/zenodo.8216279.⁶¹

Zenodo: methanol.xlsx, https://doi.org/10.5281/zenodo.8216283.⁶²

Extended data

‐ f1 Particle size. https://doi.org/10.5281/zenodo.8216249
‐ f2 particle size. https://doi.org/10.5281/zenodo.8216267
‐ f5 particle size. https://doi.org/10.5281/zenodo.8216261
‐ f6 particle size. https://doi.org/10.5281/zenodo.8216259
‐ f8 particle size. https://doi.org/10.5281/zenodo.8216269
‐ f13 particle size. https://doi.org/10.5281/zenodo.8216273
‐ ddsolver. https://doi.org/10.5281/zenodo.8219340

Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).

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58. Abdulkareem NM, Sahib MN: saturated solubility. [Dataset]. 2023. Publisher Full Text
59. Abdulkareem NM, Sahib MN: RELEASE. [Dataset]. 2023. Publisher Full Text
60. Abdulkareem NM, Sahib MN: ph 4. [Dataset]. 2023. Publisher Full Text
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62. Abdulkareem NM, Sahib MN: methanol. [Dataset]. 2023. Publisher Full Text

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Author details Author details

¹ Department of Pharmaceutics, Mustansiriyah University, Baghdad, Iraq
² Faculty of Pharmacy, Al-Turath University College, Baghdad, Iraq

Noor Abdulkareem
Roles: Conceptualization, Data Curation, Formal Analysis, Funding Acquisition, Investigation, Methodology, Project Administration, Resources, Software, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing

Mohanad Naji Sahib
Roles: Conceptualization, Formal Analysis, Funding Acquisition, Investigation, Methodology, Project Administration, Resources, Software, Supervision, Validation, Visualization, 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.

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Abdulkareem N and Sahib MN. Self emulsifying drug delivery system: norfloxacin model drug [version 1; peer review: 1 approved with reservations, 2 not approved]. F1000Research 2023, 12:1380 (https://doi.org/10.12688/f1000research.141057.1)

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https://doi.org/10.5256/f1000research.154468.r238464

This could have been a good study if the approach had been different.
Moreover, norfloxacin has been discontinued in the US due to safety concerns. Why then would one want to produce a product for geriatrics and pediatric patients ... Continue reading

This could have been a good study if the approach had been different.
Moreover, norfloxacin has been discontinued in the US due to safety concerns. Why then would one want to produce a product for geriatrics and pediatric patients if it is not considered safe to use in its current commercial products?
Overall, the following remarks are important:

Major language editing is furthermore necessary.
The authors do not write coherently. They, for example, start off in the abstract with indicating that “the goal of this work was to create a self-nanoemulsion (SNE)…”. They then move on (Abstract, Methods) to stating that “…several formulations of liquid SNEDDS of the antibiotic were created..”. After this, they indicate, still in the Abstract (Results) that “The in-vitro dissolution profile suggested an optimum norfloxacin SEDD formulation…”. During the whole document they change between SNEDDS, SMEDDS, SEDDS, etc. At the end one is wondering what the actual aim was as well as what was actually obtained.
The authors use the words “formula” and “formulae”, instead of “formulation” or “formulations”, which are rather used to express mathematical relationships or rules expressed in symbols. I suggest rather using “formulation” or “formulations” to indicate that certain preparations were manufactured or formulated.
They provide a table (Table 1) to show the different formulations that were prepared and then provide a “Formula code” that was listed from F1 to F28. From here on, they only indicate, for example, “F1” or “F1, F8, F15, F22” to show differences in results obtained. However, this is extremely difficult to then try and discern which formulation is which. The reader constantly needs to revert back to the table in an attempt to establish how the different formulations differed in excipients – which in itself is a mission. They should rather use more specified codes when referring to the different formulations, for example: 1:1(O10T45P45) – F1.
The authors used 55 References in an attempt to show the novelty of their work, however, 51% of these references are older than 10 year; 45.5% are between 5–10 years; and only 1.8% may be considered more relevant references. References 56–62 are self-referencing documents – datasets.
Numerous references were also not correctly referenced.

Abstract:

Major language editing is suggested.
Why is the goal to increase the dissolving rate of norfloxacin? Should the aim not be to enhance the dissolution of this drug?
Please explain how oral bioavailability will be improved. It is claimed in the Abstract that lymphatic transport occurs, however, nothing is explained in the Introduction.
The “Method” part does not explain the methods used in this study. It only indicates that formulations were “created”, however, the preparation method or testing methods are not even mentioned.
The “Results” part is only recognizing a single experiment, i.e., dissolution results, and it just mentions the one formulation’s zeta potential, not confirming why one formulation may be claimed as optimum.
The “Conclusion” part is questionable. See explanation under “Conclusion”.

Introduction:

Major language editing is suggested,it does not directly link with the aim of this study.
Single sentence paragraphs are furthermore found in this section.
The authors state: “SEDDS improve the oral bioavailability…” – this is a dangerous statement as it has not been proven in all cases. Rather indicate that “It has been found in several studies that SEDDSs can improve oral bioavailability”.
Also, the authors claim that the first pass effect is avoided when using SEDDS. This is NOT true at all! To avoid the first pass effect, the whole dosage should be absorbed by means of the lymphatic system, which does not occur. Only some of the dissolved drug will enter into the lymphatic system, rendering most of the drug exposed to first pass metabolism.
It is stated that due to the difference in diameter of the emulsion droplets generated, the emulsions are classified into two self-emulsifying drug delivery systems. It is actually three different systems. Also, the classification is not ONLY based on droplet size.
Abbreviations are given without defining them first (e.g., BCS).
Abbreviations that were provided are not used throughout the paper (e.g., NOR). Why use it then?
In this section it is stated that the “goal of this project is to develop norfloxacin as an oral self-emulsifying liquid formulation that will improve solubility and thus bioavailability”. This statement differs from the Abstract. What is the actual aim here? Self-nanoemulsifying or self-emulsifying drug delivery system? Be consistent! Secondly, was bioavailability tested? If not, do not make such a statement.

Methods:

Again, major language editing is suggested.
In the “Materials” part it is indicated that certain oils were selected. However, nowhere is it explained where these oils were used and in what concentrations they were included in the formulations. Were these oils combined? Were only some of them used? This is a major concern.
More concerning is that the authors only indicate the oleic acid content of the different formulations. Did they extract only the oleic acid content? Or did they only show the oleic acid content of the different oils used in the formulations? If they included the oils in the formulations, they should then have considered the total content of the oils as the other fatty acids will most definitely have significant influence on all of the experimental results.

Was their method of analysis validated? Nothing is stated. Why was UV- visible spectroscopy used for solubility determination? The generally used method is HPLC-analysis.

Construction of pseudo-ternary phase diagrams: It is suddenly indicated that oleic acid is the oil phase. How did this transpire? What is Smix? This abbreviation is again not defined. The different ratios are confusing and are not well explained.
Development of a self-emulsifying drug delivery system (SEDD): Why is a vortex mixer used? SEDDSs are supposed to form naturally with only mild agitation.

What is this oleic acid oil?
Why were the formulations heated to 50⁰C? How will this induce homogeneity? Body temperature is only 37⁰C and it is at this temperature that SEDDSs need to self-assemble for the formulation to be considered optimum. Heating the formulations to a temperature significantly higher than body temperature will notably increase the kinetic energy, which in turn, will significantly change the formulation’s self-emulsification ability. This method is clearly not appropriate, and the claim of acceptable self-emulsification ability cannot stand.

Evaluation of prepared norfloxacin SEDD: First, this heading does not form part of the methodology, which it should. Next, the abbreviation, SEDD, is not a standard abbreviation.
Robustness to dilution: Now a different abbreviation (SEDDS) is used. This is also not the standard method used to test robustness to dilution. Why was deionized water used? It is stated that it was used to mimic in vivo environments. Which in vivo environment was mimicked? Again, why were the systems shaken, and this time with a magnetic stirrer? The authors claim that they wanted to obtain complete homogeneity. If you take measures to obtain homogeneity, how can you then claim that formulations that formed naturally, are indeed homogeneous? At what pH were the experiments conducted at? The pH of the formulations is very important as it will determine the ionization and subsequently the solubility of the drug (which is cationic) and there may even be some complexation occurring as the other excipients used are all anionic in character. What about mouth feel and taste – pH plays an important role here as well. Why was the pH not determined?

Table 1 is very confusing – what oils, named in the materials section, were used?

Investigating the thermodynamic stability: Again, an abbreviation is given that is not used anywhere else (H/C cycle). They also now refer to “stabled formulas”. Which of the formulations were considered stable? And why?
Freeze-thaw cycles: What are SE formulas?
Self-emulsification time and dispersibility test: Why was 500 ml used? What was the pH of the media and of the formulations? At what temperature was this study conducted? What was the stirring rate? What apparatus was used for this study? Did the authors even test spontaneous self-emulsification? It is indicated that: “When a transparent homogenous system was attained, the in-vitro efficiency of the liquid SEDDS formulations was examined visually. It is believed that the creation of clear SEDD occurs best within a minute, since prolonged times result in a milky look.” First, was the time it took to form a homogenous dispersion noted? The authors stated that only when a transparent homogenous system was attained, did they visually examine the formulations. What if no transparency was attained then?

Table 2: This table used is NOT correct and NO reference is indicated for this table. The frequently used table (see below) indicates that grading is done based on the time it took for self-emulsification to occur. It furthermore differentiates between appearance after certain times. Thus, grading is concerned with emulsion formation and not color formation. It is NOT based (as claimed by the authors) on the fact “that prolonged times result in a milky look”.
https://f1000research.s3.amazonaws.com/supplementary/141057/93f5b5b0-9220-4ef3-9d78-8b6949b8b794.png

Czajkowska-Kośnik A, et. al. 2015 (Ref 1)
(Example)

Determination of drug content: What is meant with “a known amount of norfloxacin-SEDDS was accurately measured”? How much methanol was added? Again, was the method validated? Why was HPLC not utilized? This method does not differentiate between dissolved drug incorporated in the SEDDSs (i.e., drug content in SEDDS) and undissolved drug that is not really part of the formulation. The % encapsulation efficiency (%EE) should rather have been tested. As this method is written here, it indicates that this experiment did not test drug content, it tested the accuracy of the analyst that measured the ingredients.
Size of globules and polydispersity index (PDI): Why use the words globules and droplets interchangeably? Why was “the diluted formulations agitated with a magnetic stirrer to generate a fine emulsion”? This manipulates the formulation and the true droplet size is therefore not measured. This is NOT an accurate experiment!
In-vitro drug release study of norfloxacin SNEDDS: Now suddenly the formulations are referred to as SNEDDS. Why again vary between what type of SEDDS was obtained? Why were dissolution studies done in 750 ml and with an acetate buffer at pH 4? This is NOT the standard volume or pH simulation of the stomach where the SEDDSs need to form?
Zeta potential determination: This should actually form part of the initial characterization experiments. Again, now the authors refer to: SE formula. It is furthermore stated that: “The aqueous dispersion of the produced SE formula was made in the same manner as in the section of globule size measurement.” Nothing is stated in the mentioned section on how this formulation was “made”. The formulation was diluted and agitated…which is not a correct method!

Results and discussion:

Major Language and technical editing necessary.
Determination of norfloxacin saturated solubility: Drug loading was not tested in this study. Why mention it then? Again, %EE should have been tested. What is meant with the sentence: “At last, while storage, the whole system’s stability will improve.”? Clarify. Do not use 1 sentence paragraphs. Why were the HLB-values of the oils, surfactants, and co-surfactants not a consideration? – only the HLB-value for Tween 20 was given, which is very high. Did you establish the required HLB-value for the oil and relate it to the amount of surfactant and co-surfactant included?
Pseudo-ternary phase diagram construction: None of the results in this section are clearly displayed. Figure 1 is not of a good quality, and one cannot discern between the “Smix” ratios referred to in-text. Also, it seems that the first pseudo-ternary phase diagram is incorrectly defined as “Smix(4:1); or was the two diagrams switched. These diagrams do not correlate to what is attempted to be explained in-text. No additional information is provided in the figure caption. Also, in-text the authors refer to “Smix from 1:1 to 2:1 or 3:1…”, however, on the figure it is: “Smix(4:1); Smix(1:2); Smix(1:3); Smix(1:4). This should be clarified.

Furthermore, the authors indicate that: “The reason for the increased clarity of the emulsions produced as Smix increased was a decrease in the total system’s free energy.” This is an unsubstantiated statement. No evidence is provided, and the free energy was not tested. Where is the proof (maybe include referencing as well)? When you increase the surfactant/co-surfactant ratio, there is a danger that you are moving into not creating emulsions, but rather moving into a multiphase dimension or even a bicontinuous dispersion phase.
I also do not agree with the statement that when the co-surfactant concentration is increased, the nanoemulsion area decreases. Co-surfactants are specifically added to be able to decrease the surfactant concentration without limiting the self-emulsification area. I do believe that the hydrophilicity of the surfactants/co-surfactants played a significant role here. The statements on why improved nano-emulsions form when the oil concentration is decreased, is nothing new and quite logic.

Development of a liquid self-emulsifying drug delivery system (SEDD): Based on what did you choose the 28 formulations? What is meant by “anhydrous formulae”? Should it not rather be emulsion-concentrate?
Characterization of the prepared liquid SEDDS of norfloxacin: Again, what is meant by: “…and diluting SEDDS formulations up to 1000 times with all of the abovementioned diluents can mimic the in-vivo conditions”? How does deionized water and a 1000 times dilution mimic in-vivo conditions? Also, in Table 4 abbreviations are given that have not been defined. Then, 0.1hcl vs 0.1 N HCl? Do the different “Formula no.” in Table 4 correlate with formulations previously given in Table 1? No explanation of Table 4 is given. Why does one “want to maintain their emulsified state throughout their passage in the GIT with no phase separation”? Where should this drug be absorbed? You also did not test this in different pH-ranges.

Then did you actually test if the surfactant and co-surfactant exert their functions correctly? How was this established? One cannot make such a statement if it was not tested or backed by ample evidence.
Again, one sentence paragraphs.
It is stated: “Furthermore, modifying the pH and content of the aqueous phase had no effect on the emulsion characteristics”. Nothing was included in the methodology that the pH of the environment was varied. No pH-values were even provided. When and how was this tested?
“It was also noted that as the concentration of oil increases, the formulation’s stability decreases.” – This statement is nowhere clearly explained.
The section on “Thermodynamic stability studies” is poorly written and vague – “some formulations passed….some formulations failed…”.
In the section on “Self-emulsification time and dispersibility test”, please explain what is meant by: “to make emulsion efficiently and simply.”
Then, the authors now suddenly refer to the formulations as microemulsions. Why?
The authors state: “This implies that emulsification efficiency is determined by selecting the appropriate oil ratio as well as the appropriate Smix ratio that provided the optimum emulsification capability, rate, and stability.” They did not attempt to further explain or discuss this statement. Also, was stability tested? No suggestions are given as to how to go about selecting the appropriate ratios. The reader is therefore not wiser.

Drug content: The reason why the drug content of all the formulations complies with the USP standards, is that the method used is wrong. There would not have been any drug precipitation as “The flask was then filled with methanol and sonicated for around 15 minutes to ensure full drug dissolution. The solution was appropriately filtered via a 0.45-micrometer membrane, diluted, then tested for drug concentration.”. – Full drug dissolution was ensured; an unspecified amount of methanol was used; and the solution was filtered. No distinction between drug dissolved in the oil phase and drug in the aqueous phase is made.
Measurement of the globules size and polydispersity index (PDI): The authors have misspelled “distilled water”; and they are now again referring to “nanoemulsion”.

Please explain the difference between “globule size” (in-text) and “particle size (PS)” in Table 8. There is no consistency in the terms used.
Suddenly, “SMEDDS” is used again….and then in the following sentence, “SEDDS”…
Why was F1 chosen as the “optimum” formulation? Although F2 and F5, for example, depicted slightly larger droplet sizes, the %RSDs are smaller as well as their PDIs. Their dissolution profiles furthermore do not significantly (it seems) differ from F1.

In-vitro drug release study of norfloxacin SEDDS: The results indicated in the figures included, are not clearly distinguishable. The timeline on the graphs is poorly measurable. On Figure 2, the “chart title” was not defined. On Figure 3 it is indicated in the “chart title”: “Mean dissolution profiles with SD”. Does SD stand for “standard deviation”? If so, no SD was indicated on the graph. How many samples per formulation were measured as the “mean dissolution profiles” are indicated. Why are the %RSDs not provided? On the y-axis it is stated that the “fraction dissolved” was measured. Fractions are given as: “0.1–1.0. This is “percentage” measured. Additionally, no distinct values for dissolution studies are given. The figures do not even conform (vary significantly in view). Also, Figure 2 depicts “SNEDDS” and Figure 3, displays “SEDD” in their individual captions.

The initial dissolution rate was not measured. Therefore, no conclusion can be made regarding the release/dissolution rate.
It was stated: “The rapid spontaneous emulsification capabilities of SNEDDS, as well as the formation of
small globules with a high surfactant content upon dilution, may explain the increased in-vitro release rate and extent.” – Please explain your reasoning. No in-depth discussion is provided.
Not wanting to go into too much detail, the following two sentences are contradictory: “As compared the release from the formulation with constant oil% w/w and an increase in Smix, a clear decrease in norfloxacin releasing rate was seen because high Smix may cause drug sequestration inside micelles or oil droplets.²⁹ It was discovered that increasing the co-surfactant yielded the highest dissolution rate.” – Also, no statistics on this were available.
Very important, the method for determining the F₁ dissolution (dissimilarity) factor is NOT described in the methodology. It is not even properly described in this section. No references are provided on this subject.
How many points were used to compare the formulations? When was 85% of the drug released from one of the formulations? Also, the F₁ dissolution (dissimilarity) factor methodology indicates that a restriction is placed, i.e., if two dissolution profiles are to be considered similar and bioequivalent, f₁ should be between 0 and 15. Please note, these values do not consider decimal values. Thus, f₁-values should be rounded off to the nearest whole number. Subsequently, your tested f₁-value should be rounded off to 15 (15.25), rendering these two dissolution profiles, similar. Your whole argument, that your formulation is considered or deemed superior to the commercial tablet product, is invalid.The conclusion is inappropriate.

Zeta potential determination: They talk about “a thumb rule”. Who provided this rule? They claim that the zeta potential is indicative of short term, moderate, as well as excellent stability. These terms are not properly defined. The authors do provide a reference (55). However, this reference was incorrectly referenced, as nowhere in this paper is it stated that: “According to the thumb rule, the zeta potential is an essential predictor of the nanoparticle stability in dispersion medium when the result between (-5 mV to +5 mV) suggests quick agglomeration and the result between (-20 mV to +20 mV) gives short-term stability. Levels of zeta potential between (-30 mV) to (+30 mV) suggest moderate stability, while values in the range (-60 mV) to (+60 mV) indicate excellent stability in the formulation.⁵⁵”.

This should be explained.
Also, the figure provided to indicate the “excellent stability” of the “best formula”, is very unclear and can even be left out. This figure does not provide any additional and/or interesting information.
Again, what were the pH-values of the different formulations? This would most definitely have had an influence on the solubility of the drug as well as the zeta potential of the formulations as stated.
Conclusion:

The authors claim that a “spontaneous dosage” form was developed. What is this?
They also claim that this dosage form can produce “in-situ nano-emulsion in the gastrointestinal tract providing a stable SEDDS that may increase drug absorption….” First, this was not tested in a human participant; secondly, stability was not tested in this environment; and third, they claim that drug absorption may be increased. How can drug absorption be increased? This should be explained in detail! If they stated that drug solubility was probably increased, which could lead to more dissolved drug being available for absorption, it would have made sense, but claiming that absorption itself is enhanced, is taking it too far.
In the Conclusion part of the Abstract, the authors stated that their formulation “counteract the inconsistent bioavailability of the commercial tablet.” Please include a reference that indicates “inconsistent bioavailability”. Although this drug is poorly bioavailable after absorption, it is still absorbed fast. "Absorption of norfloxacin is rapid following single doses of 200 mg, 400 mg and 800 mg. At the respective doses, mean peak serum and plasma concentrations of 0.8, 1.5 and 2.4 μg/mL are attained approximately one hour after dosing.” (Tablets Noroxin (Norfloxacin) Merck Sharp & Dohme. USA: FDA. September 2008.) Therefore, poor/inconsistent bioavailability is not due to poor/irregular absorption, and no formulation will change the bioavailability.
The conclusion is inappropriate.

Is the work clearly and accurately presented and does it cite the current literature?

No
Is the study design appropriate and is the work technically sound?

No
Are sufficient details of methods and analysis provided to allow replication by others?

No
If applicable, is the statistical analysis and its interpretation appropriate?

No
Are all the source data underlying the results available to ensure full reproducibility?

No
Are the conclusions drawn adequately supported by the results?

No

References

1. Czajkowska-Kośnik A, Szekalska M, Amelian A, Szymańska E, et al.: Development and Evaluation of Liquid and Solid Self-Emulsifying Drug Delivery Systems for Atorvastatin.Molecules. 2015; 20 (12): 21010-22 PubMed Abstract | Publisher Full Text

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: Developing drug delivery systems; SEDDS; SMEDDS; SNEDDS; lipophilic drug delivery; natural oils; Tuberculosis; improving drug delivery

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.

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Reviewer Report 25 May 2024

Asif Nawaz, Gomal University, Dera Ismail Khan, Khyber Pakhtunkhwa, Pakistan

Approved with Reservations

https://doi.org/10.5256/f1000research.154468.r232537

Current research focus on enhancing the solubility of norfloxacin using SEDD.
The following points should be considered before publication.
1. add latest references in introduction part.
2. Intro part need more informations like problems associated with low ... Continue reading

Current research focus on enhancing the solubility of norfloxacin using SEDD.
The following points should be considered before publication.
1. add latest references in introduction part.
2. Intro part need more informations like problems associated with low solubility of drug.
3. why tween 20 used unto 45%?? any reference for this concentration.
4.Results section needs more discussion.
5. Conclusion should be revised.

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?

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?

Partly
Are the conclusions drawn adequately supported by the results?

No

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: Nanotechnology, Transdermal Drug Delivery

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.

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Reviewer Report 27 Mar 2024

Himanshu Paliwal, Department of Pharmaceutics, Sanjivani College of Pharmaceutical Education and Research, Kopargaon, Maharasthra, India

Not Approved

https://doi.org/10.5256/f1000research.154468.r250875

I recommend rejection of manuscript because of porrly written manuscript with number of scientific inaccuracies, basic grammatical mistakes, unclear description about the methodology, and vague discussion about the results.
In particular, the following issues were observed:
1. Abstract: Abbreviations ... Continue reading

I recommend rejection of manuscript because of porrly written manuscript with number of scientific inaccuracies, basic grammatical mistakes, unclear description about the methodology, and vague discussion about the results.
In particular, the following issues were observed:
1. Abstract: Abbreviations should be used appropriately, For eg. SNEDDs, SEDD or SNE are given in abstract itself. Choose one of these to describe the formulation and use it consistently throughout the manuscript.
2. Introduction: The section is poorly written with limited information, and further following points can be looked upon:
a) Support the statement by citing some recent researches where first pass effect was avoided successfully.
b) Authors need to be careful while using abbreviation SNEDD for self-nanoemulsifying and similarly for SMEDD.
c) Can author explain differences between SNEDD and SMEDD. especially how preconcentrates can exclusively form SMEDD and SNEDD upon administration.
d) Section 2 of introduction can be combined with section 3
e) The summary of study should be discussed more comprehensively.

3. Methods
a) Construction of Pseudoternary phase diagram:
The reason behind conducting phase diagram should be discussed.
Water titration technique was not properly explained or rather wrongly explained. Correct the sentences and expand appropriately to make it understandable for the readers.
b) Development of a liquid self-emulsifying drug delivery system (SEDD): How can authors justify the use of SEDDS for delivery of high concentration of drug (400 mg).
Did authors checked appropriate emulsification capacity after loading of drug?
c) Evaluation of prepared norfloxacin SEDD: SEDDS or SEDD, Please decide and use it throughout the manuscript.
Table 1: Units should be indicated in bracket, then no need use it within each cell

Figure 1: Justification is required to explain very low nanoemulsion region for all the components even though authors reported high stability upon emulsification.

Results and discussion
a) Pseudo-ternary phase diagram construction:
"The optimum o/w nano-emulsion area was produced with a low oil: Smix ratio (1:9, 2:8, 3:7, 4:6) because it provided superior stability and a smaller droplet size; this result was consistent with the data." Is it low oil:Smix ratio, or higher Smix as compared to oil?
b) Development of a liquid self-emulsifying drug delivery system (SEDD): Visual assessment of preconcentrates or emulsified form of SEED
c) In-vitro drug release study of norfloxacin SEDDS: The details regarding commercial tablet used for the comparison with SEDDS should be included.
Also, the reason for using the tablet for comparison with SEDDS should also be indicated.
Why pure drug suspension was not considered for comparison?

Figure 3: The graph legends should be consistent with their description in Figure caption and discussion.

Is the work clearly and accurately presented and does it cite the current literature?

No
Is the study design appropriate and is the work technically sound?

No
Are sufficient details of methods and analysis provided to allow replication by others?

No
If applicable, is the statistical analysis and its interpretation appropriate?

No
Are all the source data underlying the results available to ensure full reproducibility?

No
Are the conclusions drawn adequately supported by the results?

Partly

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: Lipid-based drug delivery system, and Pulmonary drug delivery systems

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.

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Himanshu Paliwal, Sanjivani College of Pharmaceutical Education and Research, Kopargaon, India
Asif Nawaz, Gomal University, Dera Ismail Khan, Pakistan
Joe Viljoen, North-West University, Potchefstroom, South Africa

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Reviewer Report

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01 Aug 2024 | for Version 1

Joe Viljoen, North-West University, Potchefstroom, South Africa

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Not Approved

This could have been a good study if the approach had been different.
Moreover, norfloxacin has been discontinued in the US due to safety concerns. Why then would one want to produce a product for geriatrics and pediatric patients if it is not considered safe to use in its current commercial products?
Overall, the following remarks are important:

Major language editing is furthermore necessary.
The authors do not write coherently. They, for example, start off in the abstract with indicating that “the goal of this work was to create a self-nanoemulsion (SNE)…”. They then move on (Abstract, Methods) to stating that “…several formulations of liquid SNEDDS of the antibiotic were created..”. After this, they indicate, still in the Abstract (Results) that “The in-vitro dissolution profile suggested an optimum norfloxacin SEDD formulation…”. During the whole document they change between SNEDDS, SMEDDS, SEDDS, etc. At the end one is wondering what the actual aim was as well as what was actually obtained.
The authors use the words “formula” and “formulae”, instead of “formulation” or “formulations”, which are rather used to express mathematical relationships or rules expressed in symbols. I suggest rather using “formulation” or “formulations” to indicate that certain preparations were manufactured or formulated.
They provide a table (Table 1) to show the different formulations that were prepared and then provide a “Formula code” that was listed from F1 to F28. From here on, they only indicate, for example, “F1” or “F1, F8, F15, F22” to show differences in results obtained. However, this is extremely difficult to then try and discern which formulation is which. The reader constantly needs to revert back to the table in an attempt to establish how the different formulations differed in excipients – which in itself is a mission. They should rather use more specified codes when referring to the different formulations, for example: 1:1(O10T45P45) – F1.
The authors used 55 References in an attempt to show the novelty of their work, however, 51% of these references are older than 10 year; 45.5% are between 5–10 years; and only 1.8% may be considered more relevant references. References 56–62 are self-referencing documents – datasets.
Numerous references were also not correctly referenced.

Abstract:

Major language editing is suggested.
Why is the goal to increase the dissolving rate of norfloxacin? Should the aim not be to enhance the dissolution of this drug?
Please explain how oral bioavailability will be improved. It is claimed in the Abstract that lymphatic transport occurs, however, nothing is explained in the Introduction.
The “Method” part does not explain the methods used in this study. It only indicates that formulations were “created”, however, the preparation method or testing methods are not even mentioned.
The “Results” part is only recognizing a single experiment, i.e., dissolution results, and it just mentions the one formulation’s zeta potential, not confirming why one formulation may be claimed as optimum.
The “Conclusion” part is questionable. See explanation under “Conclusion”.

Introduction:

Major language editing is suggested,it does not directly link with the aim of this study.
Single sentence paragraphs are furthermore found in this section.
The authors state: “SEDDS improve the oral bioavailability…” – this is a dangerous statement as it has not been proven in all cases. Rather indicate that “It has been found in several studies that SEDDSs can improve oral bioavailability”.
Also, the authors claim that the first pass effect is avoided when using SEDDS. This is NOT true at all! To avoid the first pass effect, the whole dosage should be absorbed by means of the lymphatic system, which does not occur. Only some of the dissolved drug will enter into the lymphatic system, rendering most of the drug exposed to first pass metabolism.
It is stated that due to the difference in diameter of the emulsion droplets generated, the emulsions are classified into two self-emulsifying drug delivery systems. It is actually three different systems. Also, the classification is not ONLY based on droplet size.
Abbreviations are given without defining them first (e.g., BCS).
Abbreviations that were provided are not used throughout the paper (e.g., NOR). Why use it then?
In this section it is stated that the “goal of this project is to develop norfloxacin as an oral self-emulsifying liquid formulation that will improve solubility and thus bioavailability”. This statement differs from the Abstract. What is the actual aim here? Self-nanoemulsifying or self-emulsifying drug delivery system? Be consistent! Secondly, was bioavailability tested? If not, do not make such a statement.

Methods:

Again, major language editing is suggested.
In the “Materials” part it is indicated that certain oils were selected. However, nowhere is it explained where these oils were used and in what concentrations they were included in the formulations. Were these oils combined? Were only some of them used? This is a major concern.
More concerning is that the authors only indicate the oleic acid content of the different formulations. Did they extract only the oleic acid content? Or did they only show the oleic acid content of the different oils used in the formulations? If they included the oils in the formulations, they should then have considered the total content of the oils as the other fatty acids will most definitely have significant influence on all of the experimental results.

Was their method of analysis validated? Nothing is stated. Why was UV- visible spectroscopy used for solubility determination? The generally used method is HPLC-analysis.

Construction of pseudo-ternary phase diagrams: It is suddenly indicated that oleic acid is the oil phase. How did this transpire? What is Smix? This abbreviation is again not defined. The different ratios are confusing and are not well explained.
Development of a self-emulsifying drug delivery system (SEDD): Why is a vortex mixer used? SEDDSs are supposed to form naturally with only mild agitation.

What is this oleic acid oil?
Why were the formulations heated to 50⁰C? How will this induce homogeneity? Body temperature is only 37⁰C and it is at this temperature that SEDDSs need to self-assemble for the formulation to be considered optimum. Heating the formulations to a temperature significantly higher than body temperature will notably increase the kinetic energy, which in turn, will significantly change the formulation’s self-emulsification ability. This method is clearly not appropriate, and the claim of acceptable self-emulsification ability cannot stand.

Evaluation of prepared norfloxacin SEDD: First, this heading does not form part of the methodology, which it should. Next, the abbreviation, SEDD, is not a standard abbreviation.
Robustness to dilution: Now a different abbreviation (SEDDS) is used. This is also not the standard method used to test robustness to dilution. Why was deionized water used? It is stated that it was used to mimic in vivo environments. Which in vivo environment was mimicked? Again, why were the systems shaken, and this time with a magnetic stirrer? The authors claim that they wanted to obtain complete homogeneity. If you take measures to obtain homogeneity, how can you then claim that formulations that formed naturally, are indeed homogeneous? At what pH were the experiments conducted at? The pH of the formulations is very important as it will determine the ionization and subsequently the solubility of the drug (which is cationic) and there may even be some complexation occurring as the other excipients used are all anionic in character. What about mouth feel and taste – pH plays an important role here as well. Why was the pH not determined?

Table 1 is very confusing – what oils, named in the materials section, were used?

Investigating the thermodynamic stability: Again, an abbreviation is given that is not used anywhere else (H/C cycle). They also now refer to “stabled formulas”. Which of the formulations were considered stable? And why?
Freeze-thaw cycles: What are SE formulas?
Self-emulsification time and dispersibility test: Why was 500 ml used? What was the pH of the media and of the formulations? At what temperature was this study conducted? What was the stirring rate? What apparatus was used for this study? Did the authors even test spontaneous self-emulsification? It is indicated that: “When a transparent homogenous system was attained, the in-vitro efficiency of the liquid SEDDS formulations was examined visually. It is believed that the creation of clear SEDD occurs best within a minute, since prolonged times result in a milky look.” First, was the time it took to form a homogenous dispersion noted? The authors stated that only when a transparent homogenous system was attained, did they visually examine the formulations. What if no transparency was attained then?

Table 2: This table used is NOT correct and NO reference is indicated for this table. The frequently used table (see below) indicates that grading is done based on the time it took for self-emulsification to occur. It furthermore differentiates between appearance after certain times. Thus, grading is concerned with emulsion formation and not color formation. It is NOT based (as claimed by the authors) on the fact “that prolonged times result in a milky look”.
https://f1000research.s3.amazonaws.com/supplementary/141057/93f5b5b0-9220-4ef3-9d78-8b6949b8b794.png

Czajkowska-Kośnik A, et. al. 2015 (Ref 1)
(Example)

Determination of drug content: What is meant with “a known amount of norfloxacin-SEDDS was accurately measured”? How much methanol was added? Again, was the method validated? Why was HPLC not utilized? This method does not differentiate between dissolved drug incorporated in the SEDDSs (i.e., drug content in SEDDS) and undissolved drug that is not really part of the formulation. The % encapsulation efficiency (%EE) should rather have been tested. As this method is written here, it indicates that this experiment did not test drug content, it tested the accuracy of the analyst that measured the ingredients.
Size of globules and polydispersity index (PDI): Why use the words globules and droplets interchangeably? Why was “the diluted formulations agitated with a magnetic stirrer to generate a fine emulsion”? This manipulates the formulation and the true droplet size is therefore not measured. This is NOT an accurate experiment!
In-vitro drug release study of norfloxacin SNEDDS: Now suddenly the formulations are referred to as SNEDDS. Why again vary between what type of SEDDS was obtained? Why were dissolution studies done in 750 ml and with an acetate buffer at pH 4? This is NOT the standard volume or pH simulation of the stomach where the SEDDSs need to form?
Zeta potential determination: This should actually form part of the initial characterization experiments. Again, now the authors refer to: SE formula. It is furthermore stated that: “The aqueous dispersion of the produced SE formula was made in the same manner as in the section of globule size measurement.” Nothing is stated in the mentioned section on how this formulation was “made”. The formulation was diluted and agitated…which is not a correct method!

Results and discussion:

Major Language and technical editing necessary.
Determination of norfloxacin saturated solubility: Drug loading was not tested in this study. Why mention it then? Again, %EE should have been tested. What is meant with the sentence: “At last, while storage, the whole system’s stability will improve.”? Clarify. Do not use 1 sentence paragraphs. Why were the HLB-values of the oils, surfactants, and co-surfactants not a consideration? – only the HLB-value for Tween 20 was given, which is very high. Did you establish the required HLB-value for the oil and relate it to the amount of surfactant and co-surfactant included?
Pseudo-ternary phase diagram construction: None of the results in this section are clearly displayed. Figure 1 is not of a good quality, and one cannot discern between the “Smix” ratios referred to in-text. Also, it seems that the first pseudo-ternary phase diagram is incorrectly defined as “Smix(4:1); or was the two diagrams switched. These diagrams do not correlate to what is attempted to be explained in-text. No additional information is provided in the figure caption. Also, in-text the authors refer to “Smix from 1:1 to 2:1 or 3:1…”, however, on the figure it is: “Smix(4:1); Smix(1:2); Smix(1:3); Smix(1:4). This should be clarified.

Furthermore, the authors indicate that: “The reason for the increased clarity of the emulsions produced as Smix increased was a decrease in the total system’s free energy.” This is an unsubstantiated statement. No evidence is provided, and the free energy was not tested. Where is the proof (maybe include referencing as well)? When you increase the surfactant/co-surfactant ratio, there is a danger that you are moving into not creating emulsions, but rather moving into a multiphase dimension or even a bicontinuous dispersion phase.
I also do not agree with the statement that when the co-surfactant concentration is increased, the nanoemulsion area decreases. Co-surfactants are specifically added to be able to decrease the surfactant concentration without limiting the self-emulsification area. I do believe that the hydrophilicity of the surfactants/co-surfactants played a significant role here. The statements on why improved nano-emulsions form when the oil concentration is decreased, is nothing new and quite logic.

Development of a liquid self-emulsifying drug delivery system (SEDD): Based on what did you choose the 28 formulations? What is meant by “anhydrous formulae”? Should it not rather be emulsion-concentrate?
Characterization of the prepared liquid SEDDS of norfloxacin: Again, what is meant by: “…and diluting SEDDS formulations up to 1000 times with all of the abovementioned diluents can mimic the in-vivo conditions”? How does deionized water and a 1000 times dilution mimic in-vivo conditions? Also, in Table 4 abbreviations are given that have not been defined. Then, 0.1hcl vs 0.1 N HCl? Do the different “Formula no.” in Table 4 correlate with formulations previously given in Table 1? No explanation of Table 4 is given. Why does one “want to maintain their emulsified state throughout their passage in the GIT with no phase separation”? Where should this drug be absorbed? You also did not test this in different pH-ranges.

Then did you actually test if the surfactant and co-surfactant exert their functions correctly? How was this established? One cannot make such a statement if it was not tested or backed by ample evidence.
Again, one sentence paragraphs.
It is stated: “Furthermore, modifying the pH and content of the aqueous phase had no effect on the emulsion characteristics”. Nothing was included in the methodology that the pH of the environment was varied. No pH-values were even provided. When and how was this tested?
“It was also noted that as the concentration of oil increases, the formulation’s stability decreases.” – This statement is nowhere clearly explained.
The section on “Thermodynamic stability studies” is poorly written and vague – “some formulations passed….some formulations failed…”.
In the section on “Self-emulsification time and dispersibility test”, please explain what is meant by: “to make emulsion efficiently and simply.”
Then, the authors now suddenly refer to the formulations as microemulsions. Why?
The authors state: “This implies that emulsification efficiency is determined by selecting the appropriate oil ratio as well as the appropriate Smix ratio that provided the optimum emulsification capability, rate, and stability.” They did not attempt to further explain or discuss this statement. Also, was stability tested? No suggestions are given as to how to go about selecting the appropriate ratios. The reader is therefore not wiser.

Drug content: The reason why the drug content of all the formulations complies with the USP standards, is that the method used is wrong. There would not have been any drug precipitation as “The flask was then filled with methanol and sonicated for around 15 minutes to ensure full drug dissolution. The solution was appropriately filtered via a 0.45-micrometer membrane, diluted, then tested for drug concentration.”. – Full drug dissolution was ensured; an unspecified amount of methanol was used; and the solution was filtered. No distinction between drug dissolved in the oil phase and drug in the aqueous phase is made.
Measurement of the globules size and polydispersity index (PDI): The authors have misspelled “distilled water”; and they are now again referring to “nanoemulsion”.

Please explain the difference between “globule size” (in-text) and “particle size (PS)” in Table 8. There is no consistency in the terms used.
Suddenly, “SMEDDS” is used again….and then in the following sentence, “SEDDS”…
Why was F1 chosen as the “optimum” formulation? Although F2 and F5, for example, depicted slightly larger droplet sizes, the %RSDs are smaller as well as their PDIs. Their dissolution profiles furthermore do not significantly (it seems) differ from F1.

In-vitro drug release study of norfloxacin SEDDS: The results indicated in the figures included, are not clearly distinguishable. The timeline on the graphs is poorly measurable. On Figure 2, the “chart title” was not defined. On Figure 3 it is indicated in the “chart title”: “Mean dissolution profiles with SD”. Does SD stand for “standard deviation”? If so, no SD was indicated on the graph. How many samples per formulation were measured as the “mean dissolution profiles” are indicated. Why are the %RSDs not provided? On the y-axis it is stated that the “fraction dissolved” was measured. Fractions are given as: “0.1–1.0. This is “percentage” measured. Additionally, no distinct values for dissolution studies are given. The figures do not even conform (vary significantly in view). Also, Figure 2 depicts “SNEDDS” and Figure 3, displays “SEDD” in their individual captions.

The initial dissolution rate was not measured. Therefore, no conclusion can be made regarding the release/dissolution rate.
It was stated: “The rapid spontaneous emulsification capabilities of SNEDDS, as well as the formation of
small globules with a high surfactant content upon dilution, may explain the increased in-vitro release rate and extent.” – Please explain your reasoning. No in-depth discussion is provided.
Not wanting to go into too much detail, the following two sentences are contradictory: “As compared the release from the formulation with constant oil% w/w and an increase in Smix, a clear decrease in norfloxacin releasing rate was seen because high Smix may cause drug sequestration inside micelles or oil droplets.²⁹ It was discovered that increasing the co-surfactant yielded the highest dissolution rate.” – Also, no statistics on this were available.
Very important, the method for determining the F₁ dissolution (dissimilarity) factor is NOT described in the methodology. It is not even properly described in this section. No references are provided on this subject.
How many points were used to compare the formulations? When was 85% of the drug released from one of the formulations? Also, the F₁ dissolution (dissimilarity) factor methodology indicates that a restriction is placed, i.e., if two dissolution profiles are to be considered similar and bioequivalent, f₁ should be between 0 and 15. Please note, these values do not consider decimal values. Thus, f₁-values should be rounded off to the nearest whole number. Subsequently, your tested f₁-value should be rounded off to 15 (15.25), rendering these two dissolution profiles, similar. Your whole argument, that your formulation is considered or deemed superior to the commercial tablet product, is invalid.The conclusion is inappropriate.

Zeta potential determination: They talk about “a thumb rule”. Who provided this rule? They claim that the zeta potential is indicative of short term, moderate, as well as excellent stability. These terms are not properly defined. The authors do provide a reference (55). However, this reference was incorrectly referenced, as nowhere in this paper is it stated that: “According to the thumb rule, the zeta potential is an essential predictor of the nanoparticle stability in dispersion medium when the result between (-5 mV to +5 mV) suggests quick agglomeration and the result between (-20 mV to +20 mV) gives short-term stability. Levels of zeta potential between (-30 mV) to (+30 mV) suggest moderate stability, while values in the range (-60 mV) to (+60 mV) indicate excellent stability in the formulation.⁵⁵”.

This should be explained.
Also, the figure provided to indicate the “excellent stability” of the “best formula”, is very unclear and can even be left out. This figure does not provide any additional and/or interesting information.
Again, what were the pH-values of the different formulations? This would most definitely have had an influence on the solubility of the drug as well as the zeta potential of the formulations as stated.
Conclusion:

The authors claim that a “spontaneous dosage” form was developed. What is this?
They also claim that this dosage form can produce “in-situ nano-emulsion in the gastrointestinal tract providing a stable SEDDS that may increase drug absorption….” First, this was not tested in a human participant; secondly, stability was not tested in this environment; and third, they claim that drug absorption may be increased. How can drug absorption be increased? This should be explained in detail! If they stated that drug solubility was probably increased, which could lead to more dissolved drug being available for absorption, it would have made sense, but claiming that absorption itself is enhanced, is taking it too far.
In the Conclusion part of the Abstract, the authors stated that their formulation “counteract the inconsistent bioavailability of the commercial tablet.” Please include a reference that indicates “inconsistent bioavailability”. Although this drug is poorly bioavailable after absorption, it is still absorbed fast. "Absorption of norfloxacin is rapid following single doses of 200 mg, 400 mg and 800 mg. At the respective doses, mean peak serum and plasma concentrations of 0.8, 1.5 and 2.4 μg/mL are attained approximately one hour after dosing.” (Tablets Noroxin (Norfloxacin) Merck Sharp & Dohme. USA: FDA. September 2008.) Therefore, poor/inconsistent bioavailability is not due to poor/irregular absorption, and no formulation will change the bioavailability.
The conclusion is inappropriate.

Is the work clearly and accurately presented and does it cite the current literature?

No
Is the study design appropriate and is the work technically sound?

No
Are sufficient details of methods and analysis provided to allow replication by others?

No
If applicable, is the statistical analysis and its interpretation appropriate?

No
Are all the source data underlying the results available to ensure full reproducibility?

No
Are the conclusions drawn adequately supported by the results?

No

References

1. Czajkowska-Kośnik A, Szekalska M, Amelian A, Szymańska E, et al.: Development and Evaluation of Liquid and Solid Self-Emulsifying Drug Delivery Systems for Atorvastatin.Molecules. 2015; 20 (12): 21010-22 PubMed Abstract | Publisher Full Text

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

Developing drug delivery systems; SEDDS; SMEDDS; SNEDDS; lipophilic drug delivery; natural oils; Tuberculosis; improving drug delivery

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.

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Reviewer Report

2 Views

25 May 2024 | for Version 1

Asif Nawaz, Gomal University, Dera Ismail Khan, Khyber Pakhtunkhwa, Pakistan

2 Views Cite this report Responses(0)

Approved With Reservations

Current research focus on enhancing the solubility of norfloxacin using SEDD.
The following points should be considered before publication.
1. add latest references in introduction part.
2. Intro part need more informations like problems associated with low solubility of drug.
3. why tween 20 used unto 45%?? any reference for this concentration.
4.Results section needs more discussion.
5. Conclusion should be revised.

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?

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?

Partly
Are the conclusions drawn adequately supported by the results?

No

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

Nanotechnology, Transdermal Drug Delivery

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.

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Reviewer Report

8 Views

27 Mar 2024 | for Version 1

Himanshu Paliwal, Department of Pharmaceutics, Sanjivani College of Pharmaceutical Education and Research, Kopargaon, Maharasthra, India

8 Views Cite this report Responses(0)

Not Approved

I recommend rejection of manuscript because of porrly written manuscript with number of scientific inaccuracies, basic grammatical mistakes, unclear description about the methodology, and vague discussion about the results.
In particular, the following issues were observed:
1. Abstract: Abbreviations should be used appropriately, For eg. SNEDDs, SEDD or SNE are given in abstract itself. Choose one of these to describe the formulation and use it consistently throughout the manuscript.
2. Introduction: The section is poorly written with limited information, and further following points can be looked upon:
a) Support the statement by citing some recent researches where first pass effect was avoided successfully.
b) Authors need to be careful while using abbreviation SNEDD for self-nanoemulsifying and similarly for SMEDD.
c) Can author explain differences between SNEDD and SMEDD. especially how preconcentrates can exclusively form SMEDD and SNEDD upon administration.
d) Section 2 of introduction can be combined with section 3
e) The summary of study should be discussed more comprehensively.

3. Methods
a) Construction of Pseudoternary phase diagram:
The reason behind conducting phase diagram should be discussed.
Water titration technique was not properly explained or rather wrongly explained. Correct the sentences and expand appropriately to make it understandable for the readers.
b) Development of a liquid self-emulsifying drug delivery system (SEDD): How can authors justify the use of SEDDS for delivery of high concentration of drug (400 mg).
Did authors checked appropriate emulsification capacity after loading of drug?
c) Evaluation of prepared norfloxacin SEDD: SEDDS or SEDD, Please decide and use it throughout the manuscript.
Table 1: Units should be indicated in bracket, then no need use it within each cell

Figure 1: Justification is required to explain very low nanoemulsion region for all the components even though authors reported high stability upon emulsification.

Results and discussion
a) Pseudo-ternary phase diagram construction:
"The optimum o/w nano-emulsion area was produced with a low oil: Smix ratio (1:9, 2:8, 3:7, 4:6) because it provided superior stability and a smaller droplet size; this result was consistent with the data." Is it low oil:Smix ratio, or higher Smix as compared to oil?
b) Development of a liquid self-emulsifying drug delivery system (SEDD): Visual assessment of preconcentrates or emulsified form of SEED
c) In-vitro drug release study of norfloxacin SEDDS: The details regarding commercial tablet used for the comparison with SEDDS should be included.
Also, the reason for using the tablet for comparison with SEDDS should also be indicated.
Why pure drug suspension was not considered for comparison?

Figure 3: The graph legends should be consistent with their description in Figure caption and discussion.

Is the work clearly and accurately presented and does it cite the current literature?

No
Is the study design appropriate and is the work technically sound?

No
Are sufficient details of methods and analysis provided to allow replication by others?

No
If applicable, is the statistical analysis and its interpretation appropriate?

No
Are all the source data underlying the results available to ensure full reproducibility?

No
Are the conclusions drawn adequately supported by the results?

Partly

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

Lipid-based drug delivery system, and Pulmonary drug delivery systems

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.

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Self emulsifying drug delivery system: norfloxacin model drug

Abstract

Background

Methods

Results

Conclusion

Keywords

Introduction

Methods

Materials

Determination of saturated solubility of norfloxacin

Construction of pseudo-ternary phase diagrams

Development of a liquid self-emulsifying drug delivery system (SEDD)

Table 1. The components of the liquid SEDD formulation of norfloxacin.

Evaluation of prepared norfloxacin SEDD

Robustness to dilution

Investigating the thermodynamic stability

Table 2. Grades for SEDD visual observation.

Determination of drug content

Size of globules and polydispersity index (PDI)

In-vitro drug release study of norfloxacin SNEDDS

Zeta potential determination

Results and discussion

Determination of norfloxacin saturated solubility

Table 3. Saturated solubility of norfloxacin in various oils, surfactants, and co-surfactants; (mean±SD).

Pseudo-ternary phase diagram construction

Figure 1. Diagram exhibiting the pseudo-ternary phases of oleic acid, Smix (tween20:PEG200), and deionized water.

Development of a liquid self-emulsifying drug delivery system (SEDD)

Characterization of the prepared Liquid SEDDS of norfloxacin

Table 4. The results of the robustness to dilution study for norfloxacin SEDDS of various formulations.

Thermodynamic-stability studies

Table 5. Thermodynamic analysis of the chosen SEDD formulas.

Self-emulsification time and dispersibility test

Table 6. The dispersibility grade and self-emulsification time of liquid norfloxacin-loaded self-emulsion.

Drug content

Table 7. The drug content of the chosen SEDD formulations.

Measurement of the globules size and polydispersity index (PDI)

Table 8. The globule size and PDI of norfloxacin SNE dispersed in deionized water.

In-vitro drug release study of norfloxacin SEDDS

Figure 2. In-vitro norfloxacin release from prepared liquid SNEDD formulations and norfloxacin tablet.

Figure 3. Comparative in-vitro norfloxacin release profile from the liquid SEDD formula (F1) and commercial Tablet.

Zeta potential determination

Figure 4. Zeta potential of F1 of self emulsifying drug delivery system.

Conclusions

Data availability

Underlying data

Extended data

References

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