INTRODUCTION:

Iron is an essential element¹ and hence its deficiency should be treated before it results in iron deficiency anaemia, the most commonly observed anaemia². Iron deficiency is caused because of inadequate iron intake, increased iron requirement during growth and pregnancy period, and conditions involving chronic blood³.

Treatment of iron deficiency with iron supplementation is better than balanced nutrition alone which is not adequate and difficult to follow strictly^{4, 5}.

Different types of conventional Ferrous or Ferric iron products are available for the treatment of iron deficiency, and among these, Ferrous Sulphate is preferred as Ferric preparations are having poor bioavailability due to poor solubility of Ferric iron in alkaline media and for the absorption through duodenal enterocytes, Ferric iron needs to be converted into Ferrous iron which is absorbed through carrier protein, divalent metal transporter 1(DMT1)¹. But conventional products cause gastrointestinal side effects which reduce the tolerance and adherence to the prescribed treatment and require prolonged treatment duration of months to recover deficient iron⁶ hence sustained release of Ferrous Sulphate had statistically significant lower side effects incidences compared to other Ferrous Sulphate products by reducing the release of the entire dose of iron into the gastrointestinal region⁷. Further gastroretentive sustained release drug delivery systems for drugs with an absorption window in the stomach improve the bioavailability of these drugs⁸ and Ankush Sharma et al. have proved that for the iron with his research on gastroretentive high-density pellets lodged with zero-valent iron nanoparticles⁹. Dosage forms that can be retained in the stomach are called Gastroretentive dosage forms and can be developed by different approaches like floating, high density, mucoadhesive, expandable, superporous hydrogel, magnetic, and other delayed gastric emptying systems^{10, 11}. Amongst the multiple-unit dosage forms which are advantageous over a single unit^{12, 13}, pellets offer both industrial and clinical benefits. Pellets prepared by extrusion and spheronization, a compression type of pelletization technique involves control of both process and formulation variables which affect the final properties of pellets ¹⁴. Non-Effervescent floating drug delivery systems with instant floatation overcome the possible problem of premature evacuation due to lag time before floating, related to gas generating systems, and can be formulated using low-density fatty materials or highly swellable polymers ^15-17. Dashrath Patel et al. found that a combination of Gelucire^®43/01 and ETHOCEL^TMpolymer showed the desired floatability and sustained drug release¹⁸.

This research study aimed to develop gastroretentive floating pellets of Dried Ferrous Sulphate by extrusion spheronization technique.

MATERIALS AND METHODS:

Materials:

Dried Ferrous Sulphate was purchased from Qualikems Fine Chem Pvt. Ltd, India. Gelucire^® 43/01 was gifted by Gattefosse India Pvt. Ltd., India. HPMC K4M, K100M, K200M, and ETHOCEL^TM 100 cps were gifted by Colorcon Asia Pvt. Ltd., India. Polyvinyl pyrrolidone K-30 was purchased from Himedia laboratories Pvt. Ltd., Mumbai. All other chemicals used were of analytical grade.

Methods:

Preliminary Screening of formulation polymers by trial and error:

Formulation polymers significantly affect pellets processing and characteristics and hence important to identify suitable polymers and their quantities. The formulation data of these batches are presented in (Table 1).

It is evident from the literature that spheronization speed and time both parameters significantly affect the pellet's properties and were considered significant process parameters.¹⁴Formulation polymers were selected based on the average size of pellets, roundness as a pellet shape indicator, floatability, and % cumulative drug release as important evaluation parameters. All the batches were extruded at 120 RPM speed through a 16# perforated stainless steel screen and spheronization at 2000 RPM for 5 minutes on a cross-hatched plate. PVP K-30 was added in 5 %W/W of dry mix amount in all formulations as a solution in a solvent system. Batches T1 to T5 and T6 to T11 were formulated with a solvent system containing a 1:1 ratio of IPA: Deionized water and IPA respectively. Batch T11 was formulated with 44# size of ETHOCEL^TM 100 cp.

Batch optimization with experimental design:

Central composite design- CCD as a response surface method was selected to check the effect of multiple factors¹⁹. Spheronization speed and time as process and concentration of Gelucire^®43/01 and ETHOCEL^TM 100 cp as formulation, variables were defined as factors. Average pellet size and roundness were selected separately as response variables 1 and 2 respectively. Data were statistically analyzed by applying analysis of variance (ANOVA) at level 0.5 (α =1.682) using Design Expert^® 11.

Preparation of Dried Ferrous Sulphate matrix pellets by extrusion spheronization:

Pellets were prepared using a laboratory scale basket-sieve type extruder (Cronimach, India. Volume capacity of 314 cm³) and spheronizer (Cronimach, India. Volume capacity of 1074 cm³) as per the following procedure: 1) All the dry ingredients(80#) weighed and mixed in ascending order of their weight, in a polybag for 10 minutes. 2) Gelucire^® 43/01 was taken in a dry and clean mortar and melted at 43⁰C on a thermostatic heating mantle. A mixture of dry material from the previous step was added to the melted Gelucire^® 43/01 and kneaded for 5 minutes by maintaining the mixture in a warm condition to avoid hard lump formation (In all formulations, the polymers were varied in terms of ratio to the drug).

Table 1: Preliminary Trial batches with Gelucire^®43/01, HPMC K4M/K100M/K200M, ETHOCEL^TM 100cp.

Ingredients(g)	Batch Code
	T1	T2	T3	T4	T5	T6	T7	T8	T9	T10	T11
Dried Ferrous Sulphate	5	5	5	5	5	5	5	5	5	5	5
HPMC K4M	5	-	-	-	-	-	-	-	-	-	-
HPMC K100M	-	5	-	-	-	-	-	-	-	-	-
HPMC K200M	-	-	5	10	5	-	-	-	-	-	-
Gelucire^®43/01	5	5	5	10	5	5	7.5	10	5	7.5	9
ETHOCEL^TM 100 cp	-	-	-	-	5	5	7.5	10	7.5	5	8

The kneaded mass was wetted with an Isopropyl alcohol or 50 % mixture of Isopropyl alcohol in deionized water and kneaded for 5 minutes. 3) The resultant wet mass was then extruded at 120 RPM speed, through a radial metal sieve(16#). Extrudates were collected and transferred to Spheronizer.4) Extrudates were spheronized at a specific speed and time, using a bottom Cross-hatched, 12 cm diameter with a grid height of 1 mm, grid width of 1 mm, and groove width of 2 mm friction plate. Pellets were collected and spread over a paper sheet, in a tray and air-dried at ambient conditions for 3 hours. Dried pellets were stored in airtight bags and were characterized for different parameters.

Characterization of pellets:

a) Average pellet size:

Pellet average pellet size was measured by the sieving method using a set of British Standard brass sieves, in a sieve shaker (Singhla Scientific Industries, India).

b) Pellets shape:

The shape of the pellets was measured in terms of roundness (ratio of inscribed to circumscribed diameter) using a microscope ((OLYMPUS, CX33) and calibrated eyepiece micrometer scale. Fifty pellets were selected randomly from the 8# to 22# sievesand the average was recorded for each batch^{14, 20}.

c) Drug content:

Pellets equivalent to 150 mg of Dried Ferrous Sulphate were powdered, dispersed in deionized water, stirred on a magnetic stirrer, filtered through a 0.45 µm membrane filter, and diluted suitably with deionized water. The diluted sample (0.5 ml) was mixed with O-Phenanthroline standard reagent (0.8 ml) in presence of Sodium acetate trihydrate solution (0.2 ml) and made to 10 ml with deionized water. The red colour complex formed which was analyzed using a UV visible spectrophotometer at 510 nm wavelength²¹.

d) In-vitro drug release study and Drug release kinetics:

Cumulative % drug release in 0.1 N HCl dissolution media, maintained at 37⁰C temperature, for every 1 hour till 12 hours was checked using USP type 2 paddle dissolution apparatus (VEEGO, VDA-8D) at 50 RPM paddle speed. Pellets(22#) equivalent to 150 mg dose of Dried ferrous Sulphate were added to the dissolution medium, 5 ml sample was withdrawn and replaced with a fresh dissolution medium at each sampling point. Samples were filtered, mixed with Sodium acetate trihydrate solution and O-Phenanthroline standard reagent, and analyzed using a UV visible spectrophotometer at 510 nm wavelength²¹. The data of an optimized std run was checked for the mechanism and kinetics of drug release, mathematically with zero order, first order, Higuchi, Hixon Crowell cube root, and Korsmeyer-Peppas models²².

e) Floating lag time and Floating duration:

During the drug release study, floating lag time was measured as the time required for pellets to reach the surface from the bottom of the dissolution flask if settled. The floating duration was observed as the total time during which the pellets remained on the surface of the dissolution media²³.

f) Accelerated stability studies:

The effect of environmental conditions on the quality attributes of the optimized formulation was checked with a stability study carried out as per the ICH guideline²⁴, after 3 months of storage in an airtight HDPE bottle at 30⁰C ± 5⁰C temperature and 65 ± 5 % relative humidity. The formulation contained Gelucire^® 43/01 which melts at 43⁰C and hence real-time stability study conditions were selected.

RESULT:

Preliminary Screening of formulation polymers:

Evaluated data on average pellet size, roundness, floating lag time and floating duration, % drug content, and % drug release for preliminary batches are presented in (Table 2 and Figure 1).

Table 2: Pellets characterization data of preliminary trial batches

Batch Code	Average Pellet size (µm± SD) (n=3)	Roundness ±SD (n=50)	Floating behaviour	Floating lag time (minute) ±SD (n=3)	% Drug content ± SD (n=3)	% Drug release at 1 hour % ± SD (n=3)
T1	824 ± 30	0.85 ± 0.04	Partial Floating	8 ± 1	99 ± 2.5	99.2 ± 1.5
T2	842 ± 35	0.93± 0.03	Partial Floating	10 ± 1.5	99 ± 1.2	98 ± 3.5
T3	861 ± 40	0.8± 0.04	Partial Floating	15 ± 1	98.6 ± 3.5	96 ± 1.5
T4	904 ± 28	0.85± 0.04	Partial Floating	18± 1	99.7 ± 1.5	99.5 ± 0.5
T5	714 ± 35	0.75± 0.04	Floating	Zero	100 ± 2.8	94.6 ± 0.4
T6	751 ± 25	0.85 ± 0.03	Floating	Zero	100. 1.2	42 ±1.5
T7	755 ± 20	0.92 ± 0.03	Floating	Zero	100 ± 0.9	30.3 ±1.1
T8	785 ± 25	0.95± 0.02	Floating	Zero	99.7 ±1.1	14.4 ± 0.7
T9	573 ± 20	0.4 ± 0..02	Floating	Zero	99. 6 ± 2.1	76.7 ± 2.2
T10	1700 ± 50	0.99 ± 0.04	Floating	Zero	100 ± 1.9	8.7 ± 0.2
T11	872 ± 35	0.93± 0.02	Floating	Zero	101 ± 0.9	31.6 ± 0.2

These data indicated the influence of formulation ingredients and their concentration on pellets characteristics. The type of wetting solvent system also depends on the formulation composition. Based on the desired criteria, batch T11 formulation was considered for further optimization.

Figure 1. % Cumulative Drug release comparison of preliminary batches T6 to T11

Batch optimization with experimental design:

The response data obtained for each experimental run under CCD were fitted to an ANOVA Quadratic model to generate a mathematical polynomial equation as Y= b₀ + Σb_nx_n(n=1-4) + Σb_n(n=5-8)x²_{n(n=1-4)) +}b₉x₁x₂ + b₁₀ x₁x₃ + b₁₁x₁x₄ + b₁₂x₂x₃ + b₁₃ x₂x₄ + b₁₄ x₃x_4,where Yis the response_,b₀is intercept_,x_n indicate main effect, x² indicate square effect, x_nx_n indicate interactive effect and b_n represent regression coefficient for a particular effect.

A polynomial equation for coded terms was generated for the average pellet size response Y₁as

Y₁= 1874.05 + 367.762A +183.73B+151.221C-417.709D-182.584AB-149.125AC+114.625BC + 263.137BD -361.375CD-147.47A²-102.568 C²-130.146D² and A polynomial equation generated for pellet shape response Y₂was, Y₂=0.888+0.107A+ 0.065C-0.083D-0.127AB+0.034AD-0.026BC+ 0.058BD-0.099CD-0.053A²+0.016B²-0.012C²-0.032D²

A, B, C, and D are variable factors. (P-values less than 0.05 indicate model terms are significant). 3 D response surface curves were generated (Figure 2) elucidating the effect of independent factors on response variables.

Figure 2: (A) 3 D response surface curve of average pellet size against spheronization time and speed (B) 3 D response surface curve of roundness against spheronization time and speed (C) Overlay plot at different spheronization time and speed at a fixed concentration of Gelucire^®43/01 and ETHOCEL^TM 100 cp

For the optimization, Gelucire^® 43/01 and ETHOCEL^TM 100 cp were varied, each at 3 levels of 1.6:1, 1.7:1, 1.8:1, and 1.4:1, 1.5:1, 1.6:1 respectively in terms of ratio to a drug (5 g). Factors with their coded and decoded levels, the formulation design matrix, and response data of all 21 std run batches are presented in (Table 3).

Table 3: Experimental batches with response data as per Central Composite Design (3 levels, 4 factors, rotatable, α=1.68)

Std run	A: Spheronization Time (minute) -1=3, 0=4, 1=5, -1.682=2.32, 1.682 =5.68	B: Spheronization Speed (RPM) -1=2000, 0=2125, 1=2250,1.682=1915, 1.682 =2335	C: Gelucire^®43/01 Concentration (g) -1=8, 0=8.5, 1=9, -1.682=7.66, 1.682 =9.34	D: ETHOCEL^TM100cp Concentration (g) -1=7, 0=7.5, 1=8, -1.682=6.66, 1.682 =8.34	Response Y1: Average pellet size (µm ± SD) (n=3)	Response Y₂: Roundness ± SD (n=50)
1	1	1	1	-1	2360 ± 0	0.95 ± 0.03
2	1	1	-1	-1	1520 ± 50	0.65± 0.03
3	1	-1	1	1	868 ± 30	0.93± 0.02
4	-1	1	-1	1	1265 ± 45	0.85± 0.04
5	1	-1	-1	1	1932 ± 80	0.92± 0.04
6	-1	-1	1	-1	2150 ± 90	0.93± 0.02
7	-1	1	1	1	1256 ± 50	0.73± 0.03
8	-1	-1	-1	-1	1172 ± 40	0.55± 0.02
9	-1.68179	0	0	0	830 ± 25	0.55± 0.02
10	1.68179	0	0	0	2067± 85	0.91± 0.04
11	0	-1.68179	0	0	1742 ± 60	0.9± 0.03
12	0	1.68179	0	0	2360 ± 0	0.95± 0.02
13	0	0	-1.68179	0	1183 ± 30	0.75± 0.03
14	0	0	1.68179	0	1968 ± 85	0.94± 0.02
15	0	0	0	-1.68179	2200 ± 100	0.93± 0.02
16	0	0	0	1.68179	795 ± 30	0.65± 0.03
17	0	0	0	0	1890 ± 75	0.88± 0.04
18	0	0	0	0	1950 ± 70	0.9± 0.03
19	0	0	0	0	1830 ± 55	0.88± 0.04
20	0	0	0	0	1920 ± 80	0.9± 0.04
21	0	0	0	0	1800 ± 60	0.9± 0.03

Drug content, drug release study, and release mechanism of experimental batches under CCD:

All 21 std run batches were observed with immediate floating and floated throughout 12 hours of the drug release study. Only those batches were presented (Figure 3), in which the average pellet size was obtained from 759 to 1300 µm and std run 3 was found with all desired criteria. During mathematical modeling, drug release data of std run 3 were found best fitted to Higuchi and Korsmeyer-Peppas models. Based on the higher (0.9989) R² and lower MSE (0.9459) values, the Korsmeyer-Peppas model was considered which indicated kKP and n values as 29.9 and 0.48 respectively.

Accelerated stability studies:

Drug content, % Cumulative drug release, and floating behaviour of std run 3 were checked after the stability study storage period and these parameters were not significantly deviated from the values before the stability study. Average drug content (% ± SD, n=3) was found 101 ± 0.9 and 100 ± 1.9 before and after the stability study respectively. Pellets floated immediately and throughout the drug release study.

DISCUSSION:

Preliminary trial batches of pellets with various polymers were evaluated to understand the effect of these polymers and their concentration on micromeritics, floating, and release properties of pellets. The Floatability of a dosage form in a gastric fluid depends on the average density of the dosage form which should be less than the density of a gastric⁸ and can be lowered using low-density hydrophobic lipid Gelucire^®43/01 or swellable HPMC polymers. Hydrophobic ETHOCEL^TM 100 cp has been used in sustained-release formulations and gastroretentive formulations due to its release retarding effect¹⁸. In the Extrusion-spheronization technique, Gelucire^®43/01 as a lipid binder, facilitates pelletization and therefore was selected as a primary ingredient in formulation development¹⁸.

The average pellet size and roundness of pellets were increased with an increased amount of Gelucire^®43/01(Batch T4, T8, and T10) and decreased with a decreased amount of Gelucire^®43/01(Batch T5 and T9). Formulation batches with HPMC had shown partial floating and failed to sustain the drug release while batches with a combination of ETHOCEL^TM and Gelucire^®43/01 had shown immediate floating and sustained release (Figure 1). The desired release profile was observed in batches T8 and T11. An equal ratio of polymers and Gelucire^®43/01 balance the pellet size and roundness (T4 and T8) but a little higher ratio of Gelucire^®43/01 to ETHOCEL^TMgrade can effectively retard the drug release (Batch T11). The effect of increased concentration of Gelucire^®43/01on pellet shape can be attributed to its lubricating effect of lipid nature and effect on pellet size due to softness of the mass during spheronization resulting in multiple layering of pellets¹⁸. The drug content of all the batches was within the limit indicating uniformity in mixing. Batch T11 was formulated with 44# size powder of ETHOCEL^TM 100 cp to check the acceptability of this powder grade which eliminated the fine particle requirement of this polymer and result data indicated that desired pellets criteria can be obtained with the formulation composition of batch T11 and was selected for further optimization with a ratio of Gelucire^®43/01 to the drug between 1.8:1 to 1.6:1 and ETHOCEL^TM 100 cp to the drug between 1.6:1 to 1.4:1.

Formulation optimization was done based on statistical analysis using the CCD of the experiment. As per the polynomial equation of average pellet size, all individual factors except the concentration of ETHOCEL^TM 100 cp significantly increased pellet size while the increased concentration of ETHOCEL^TM 100 cp decreased the pellet size. Figure 2A and Figure 2B suggested that at the central point level (median concentration) of polymers, lower average pellet size was observed at any speed range selected in the design and better roundness at low speed for longer spheronization time respectively. As per the polynomial equation of pellet roundness, spheronization time, and concentration of Gelucire^®43/01 significantly increased roundness hence improving pellet shape. Interactive coefficients indicated the positive and negative effects of combined factors. These observations suggested that all the factors are required to be kept in a suitable range to get desired pellet size and shape. The overlay plot in Figure 2C graphically demonstrates design space in terms of the operating range of all four independent factors. When the concentration of both the polymers is on the upper level in the formulations, desired pellet size in a range of 855 to 1350 µm and pellet shape with roundness in the range of 0.8 to 0.95 would be obtained when spheronization speed was maintained between 4.5 to 5 minutes at 2000 to 2125 RPM spheronization speed. The experimental results of average pellet size 868 µm and roundness-0.93 obtained for std run were not significantly different than the predicted response values of 920 µm and 0.92 respectively, which confirmed the predictability and validity of the model. Figure 3 shows the % cumulative drug release profile of the batches in which size 22# pellets were obtained. A similar size was selected for the drug release study to exclude the effect of pellet size on drug release.

It was found that the % cumulative drug release in pellets was influenced by the pellet shape and the total % of Gelucire^®43/01 in the formulation. Round pellets with minimum surface area compared to irregular shape pellets reduced drug release and increased Gelucire^®43/01 amount further retarded drug release. Pellet’s shape and hence drug release in pellets depended on formulation composition along with the speed and time of the spheronization process. Based on the result data, std run batch 3 was concluded as an optimized batch of gastroretentive Dried Ferrous Sulphate pellets which indicated that the increased Gelucire^®with increased time of spheronization at low speed improved pellet shape which yielded sustained drug release¹⁸. Hydrophobicity and low density of polymers contributed to the immediate and prolonged floating of all 21 std run formulations. Korsmeyer-Peppas values of kKp and n confirmed the drug release by diffusion through pore formation²² and it was in agreement with the experimental observation as pellets size was not changed significantly during the drug release study. The optimized formulation was found stable for 3 months under study conditions²⁴.

Figure 3: % Cumulative drug release comparison of Batch Std 3,4,7,8,9,13 and 16

CONCLUSION:

Sustained-release gastroretentive floating Dried Ferrous Sulphate pellets with desired pellet size and better roundness using the extrusion-spheronization technique was successfully developed and optimized by combining ETHOCEL^TM 100 cp with Gelucire^®43/01 at specific spheronization time and speed as per the CCD matrix. Based on the result data, standard run batch 3 was concluded as an optimized batch which contained Gelucire^®43/01 to drug and ETHOCEL^TM 100 cp (44#) to a drug in a ratio of 1.8:1 and 1.6:1 respectively, extruded and then spheronized at 2000 RPM for 5 minutes and which yielded round pellets with 868 µm average pellet size and sustained release of iron for 12 hours. This developed iron formulation would be beneficial to improve bioavailability and overall utilization of iron and hence reducing total treatment duration in patients with iron deficiency.

CONFLICT OF INTEREST:

The authors of this research study declared no conflict of interest in publishing the work.

ACKNOWLEDGMENTS:

The authors acknowledge Colorcon Asia Pvt. Ltd., India, and Gattefosse India Pvt. Ltd. for their help in providing the excipients. We are thankful to Zydus Lifesciences Ltd., Ahmedabad for the FTIR study.

REFERENCES:

1. Muñoz M, et al. Disorders of iron metabolism. Part 1: Molecular basis of iron homoeostasis. Journal of Clinical Pathology. 2011 Dec 20; 64(4): 281–86. doi:10.1136/jcp.2010.079046

2. World Health Organization. Nutritional Anaemias : Tools for Effective Prevention. World Health Organization. 2017. Available on https://apps.who.int/iris/bitstream/handle/10665/259425/9789241513067-eng.pdf?sequence=1

3. Wang J, et al. Novel Iron-Whey Protein Microspheres Protect Gut Epithelial Cells from Iron-Related Oxidative Stress and Damage and Improve Iron Absorption in Fasting Adults. Acta Haematologica. 2018 Feb 1; 138(4): 223–32. doi: 10.1159/000480632

4. Serati M, Torella M. Preventing complications by persistence with iron replacement therapy: a comprehensive literature review. Current Medical Research and Opinion. 2019; 35(6): 1065–72. 10.1080/03007995.2018.1552850.

5. Moriarty-craige SE, et al. Multivitamin-mineral supplementation is not as efficacious as iron supplementation in improving hemoglobin concentrations in nonpregnant anemic women living in Mexico. American Society for Clinical Nutrition. 2004; 80(3): 1308–11.

6. Muñoz M, et al. The safety of available treatment options for iron-deficiency anemia. Expert Opinion on Drug Safety. 2018; 17(2): 149–59. doi:10.1080/14740338.2018.1400009. Available from: http://dx.doi.org/10.1080/14740338.2018.1400009

7. Santiago P. Ferrous versus ferric oral iron formulations for the treatment of iron deficiency: A clinical overview. The Scientific World Journal. 2012. doi:10.1100/2012/846824

8. Haridwar Lodh, et al. Floating Drug Delivery System: A Brief Review. Asian Journal of Pharmacy and Technology. 2020; 10(4): 255-64. doi: 10.5958/2231-5713.2020.00043.4

9. Sharma A, et al. Development and Characterization of Gastroretentive High-Density Pellets Lodged With Zero Valent Iron Nanoparticles. Journal of Pharmaceutical Sciences. 2018; 107(10): 1-11. doi:10.1016/j.xphs.2018.06.014

10. Gunjan L. Zope, et al. Glimpse of Floating Drug Delivery in Pharmaceutical Formulations: A Review. Research Journal of Pharmaceutical Dosage Forms and Technology. 2016; 8(2): 147-53. doi: 10.5958/0975-4377.2016.00019.7

11. Shaik. Mohammad Farooq, et al. Floating Drug Delivery Systems: An updated Review. Asian Journal of Pharmaceutical Research. 2020; 10(1): 39-47. doi: 10.5958/2231-5691.2020.00009.X

12. Sarika S. Lokhande. Recent Trends in Development of Gastro-Retentive Floating Drug Delivery System: A Review. Asian Journal of Research in Pharmaceutical Sciences. 2019; 9(2): 91-6. doi: 10.5958/2231-5659.2019.00014.6

13. A.V.S. Hima Bindu, et al. Padmalatha. Floating Drug Delivery System: An Overview. Asian Journal of Research in Pharmaceutical Sciences. 2021; 11(4): 295-300. doi: 10.52711/2231-5659.2021.00046

14. Michie H, et al. The influence of plate design on the properties of pellets produced by extrusion and spheronization. International Journal of Pharmaceutics. 2012; 434(1–2): 175–82. doi: 10.1016/j.ijpharm.2012.05.050

15. Singh BN, Kim KH. Floating drug delivery systems : an approach to oral controlled drug delivery via gastric retention. Journal of Controlled Release. 2000; 63: 235–59. PII: S0168-3659(99)00204-7

16. Mali Hanmant S., et al. A Review on Floating and Mucoadhesive Drug Delivery System. Asian Journal of Pharmacy and Technology. 2021; 11(3): 225-30. doi: 10.52711/2231-5713.2021.00037

17. Vinod Matole, et al. A Brief Review on Gastro-Retentive Drug Delivery Systems. Research Journal of Pharmaceutical Dosage Forms and Technology. 2021; 13(1): 62-65. doi : 10.5958/0975-4377.2021.00011.2

18. Patel DM, et al. Floating Granules of Ranitidine Hydrochloride-Gelucire 43/01: Formulation Optimization Using Factorial Design. AAPS PharmSciTech. 2007; 8(2): E1-7.

19. Mavani Prakash, et al. Design, Development and Optimization Aceclofenac Effervescence tablets by Central Composite Design. Research Journal of Pharmaceutical Dosage Forms and Technology. 2015; 7(1): 15–20.

20. Lee D. Experimental investigation of laser ablation characteristics on nickel-coated beryllium copper. Metals (Basel). 2018; 8(4): 8–20. doi:10.3390/met8040211

21. University of Kentucky. Molecular Absorption Spectroscopy: Determination of iron with 1,10-Phenanthroline. Analytical Chemistry Laboratory. 2005; 5: 30–4. Available from: http://www.chem.uky.edu/Courses/che226/Labs/05-Fe_Absorption-2005Fa

22. Smita S. Aher, et al. Formulation and Evaluation of Controlled Release Matrix Tablet of Albuterol Sulphate. Asian Journal of Research in Pharmaceutical Sciences. 2016;6(4):223-9. doi: 10.5958/2231-5659.2016.00031.X

23. B. Ranga Nayakulu, et al. Formulation and evaluation of floating matrix tablet of Losartan for gastro-retentive drug delivery. Asian Journal of Pharmacy and Technology. 2016; 6(2): 85-90. doi: 10.5958/2231-5713.2016.00012.X

24. ICH Q1A(R2). International Conference on Harmonization (ICH). Guidance for industry: Q1A(R2) Stability Testing of New Drug Substances and Products. ICH Harmonised Tripartite Guideline. 2003; 4(February):24.

Received on 23.11.2022 Modified on 17.03.2023

Research J. Pharm. and Tech 2024; 17(4):1851-1857.

DOI: 10.52711/0974-360X.2024.00294