Research Articles

2019  |  Vol: 5(4)  |  Issue: 4 (July- August)  |  https://doi.org/10.31024/ajpp.2019.5.4.19
Preparation and evaluation of gastroretentive hydrogel beads of Cefdinir by ionotropic gelation method

M. Y. Khalifa1*, M. A. Saleem2, Shaikh Siraj N.1, Huzaifa Patel3

1Department of Pharmaceutics, Ali-Allana College of Pharmacy Akkalkuwa, Nandurbar, Maharashtra, India-425415

2Department of Pharmaceutics, Luqman College of Pharmacy, Gulbarga Karnataka, India

3Department of Pharmaceutics, Jamia College of Pharmacy Akkalkuwa, Nandurbar, Maharashtra, India-425415

*Address for Correspondence:

M. Y. Khalifa

Asst. Professor, Ali-Allana College of Pharmacy Akkalkuwa, Nandurbar, and Maharashtra, India


Abstract

Objective: The purpose of the present study was to develop and evaluate gastroretentive hydrogel beads of Cefdinir using polymers like Sodium alginate and Sodium CMC by ionotropic gelation method using Calcium carbonate or sodium bicarbonate as a gas forming agent. Materials and Methods: Twelve formulated beads evaluated physically in terms of surface morphology, bead size, entrapment efficiency, floating characteristics, Fourier transform infrared spectroscopy, in vitro swelling, and in vitro drug release and stability studies.  Results: The surface morphology revealed that the prepared beads are spherical, having rough and dense surface with microscopic cracks and wrinkles on the surface. According to nature of coagulation medium the shape of beads was changed. Formulations F5 shows higher drug entrapment efficiency (i.e. 94.60%) suggesting that the ionotropic gelation method is effective for the entrapment of Cefdinir. All the beads formulation remained float throughout the study up to 24 h with the range of 62.25-96.40% suggesting that calcium carbonate and sodium bicarbonate can be used as buoyant. All the beads show good swelling up to 12 hrs in 0.1 N HCL. The swelling followed values in order of sodium carboxy methyl cellulose > sodium alginate. The in vitro drug release indicated that increase the concentration of gas forming agent increase the drug release and drug release followed values in order of sodium alginate > sodium CMC. Also increase in concentration of the polymer resulted in decreased drug release. Conclusion:  It can be concluded that the floating beads of cefdinir can be prepared by using CaCOand NaHCO3as buoyant along with hydrogel forming polymer like sodium alginate and sodium carboxy methylcellulose as a release modifier for improved oral bioavailability of Cefdinir.

Keywords: Cefdinir, ionotropic gelation, gas forming agent, oil entrapment, sodium alginate, sodium carboxy methyl cellulose


Introduction

It is widely known that gastric residence time is one of the important factors affecting the drug bioavailability of pharmaceutical dosage forms. Variable and short gastric emptying time can result in incomplete drug release from the drug delivery system above the absorption zone (stomach or upper part of small intestine), leading to a diminished efficacy of the administered dose (Sungthongjeen et al., 2006). One of the most feasible approaches for achieving a prolonged and predictable drug delivery profile in the GI tract is to control the gastric residence time. Dosage forms with a prolonged gastro retentive dosage forms will provide us with new and important therapeutic options. Gastroretentive systems can remain in the gastric region for several hours and hence significantly prolong the gastric residence time of drugs. Prolonged gastric retention improves bioavailability reduces drug waste (Shaikh et al., 2016). It has applications also for local drug delivery to the stomach and proximal small intestines. Gastroretention helps to provide better availability of new products with new therapeutic possibilities and substantial benefits for patients (Sharma et al., 2011). . During the last few years, most popular approach of Gastroretention is floating drug delivery systems .Among these, the use of floating hydrogel beads is the simplest approach.

Cefdinir is a semi-synthetic third generation oral antibiotic in the cephalosporin family of antibiotics. Cefdinir is used to treat a wide variety of bacterial infections. It has biological half-life of 1.5h so, administration of drug is six times per days for acute and sub-acute conditions, its having 35-54%% of bioavailability. It exhibits lower bioavailability when given in conventional dosage forms due to diminished absorption and degradation in lower part of the GIT. So there is need to prepare gastroretentive hydrogel beads of cefdinir to increase its bioavailability & therapeutic efficacy (Chandra et al., 2018).

Materials and methods

Materials

Cefdinir was purchased from Rajesh chemical Mumbai (India), Sodium alginate, Sodium carboxy methyl cellulose, Calcium chloride, Aluminium chloride, Calcium Carbonate, sodium bicarbonate, (SD Fine Chem Ltd., Mumbai). All other chemicals were of analytical grade.

Formulation of gastroretentive beads

In the first scheme the Cefdinir beads were prepared by using single polymer like sodium alginate (3%) and sodium Carboxymethyl cellulose (3%). For the preparation of sodium alginate and sodium Carboxymethyl cellulose solution; the polymer was dissolved in distilled water and the gas forming agent such as CaCO3, NaHCO3 was added to the solution with levels from 1:0.5 to 1:1 (alginate: gas forming agent w/w) the formulation composition are shown in table 1. The resulting solution was dropped through a 20G syringe needle into 1% CaCl2 or 2% AlCl3. The solution containing suspended beads were kept overnight and then filtered, washed twice with 500 ml distilled water. The beads were dried at room temperature for 48 hrs and were stored in desiccators (Yellanki et al., 2010).

Table 1. Formulation table for floating beads of Cefdinir by ionic gelation method

Ingredients

Formulation Code

F1

F2

F3

F4

F5

F6

F7

F8

F9

F10

F11

F12

 

Cefdinir

1

1

1

1

1

1

1

1

1

1

1

1

 

Na. Alginate

3

3

3

3

3

3

3

3

-

-

-

-

 

Na. CMC

-

-

-

-

-

-

-

-

2.5

2.5

2.5

2.5

 

NaHCO3

1

1

1.5

1.5

-

-

-

-

1

1.5

-

-

 

CaCO3

-

-

-

-

1.5

1.5

3

3

-

-

1.5

3

 

CaCl2

1

-

1

-

1

-

1

-

-

-

-

-

 

AlCl2

-

2

-

2

-

2

-

2

2

2

2

2

 

Characterization of floating beads

Fourier-transformation infrared (FTIR) spectroscopy

Fourier Transformation Infrared spectra of pure drug, polymer and drug loaded floating beads were obtained in KBr pellets at moderate scanning speed between 4000-200 cm-1 in a Perkin-Elmer Fourier Transformation Infrared Spectroscope (Hrsoliya et al., 2012).

Determination of bead diameter size

Particle size of the prepared beads was determined using an optical microscope fitted with the stage and an ocular micrometer. Twenty dried beads were measured for calculating the mean diameter of beads. The result is expressed as the mean diameter (mm) ± standard deviation (Pasparakis et al., 2002).

Drug content and Entrapment efficiency

The drug content and entrapment efficiency of prepared beads was determined by method of extraction of drug present in beads. The dried beads (100mg) were taken and extracted in 100 mL of 0.1N HCl (pH 1.2) for 24 hours. Then the dispersion of beads was sonicated for 30 min and the solution was filtered through a 0.45 µm filter. The concentration of drug present in filtrate determined spectrophotometrically at 287 nm (UV-2450, Shimadzu, Japan). Each determination was made in triplicate. The drug content and entrapment efficiency of prepared beads was determined by putting value in given below formula (Varshosaz et al., 2007).

In-vitro buoyancy

The floating abilities of the beads were determined using USP paddle apparatus (50 rpm,37 ±0.2 °C, 900 ml, 0.1N HCl). 50beads were placed in the medium; the time to float and duration of floating (floating time) were measured by visual observation. The percentage of floating pellets was calculated by the following equation: (Chandra et al., 2018).

Swelling Study

Beads were studied for swelling characteristics. Sample from drug-loaded beads were taken, weighed and placed in wire basket Beads were studied for swelling characteristics. Sample from drug-loaded beads were taken, weighed and placed in wire basket of USP dissolution apparatus II. The basket containing beads was placed in a beaker containing 900 ml of HCl solution (pH 1.2) maintained at 37±0.5°C. After12hours the beads were removed from their respective swelling media and weighed after drying the water on the surface of the beads using filter paper (Singhal et al., 2010; Hari, 2010; Sriamornsak, 2007). Then the swelling index was calculated and represented as percent.

Scanning electron microscopy (SEM)

Morphological examination of the surface and internal structure of the dried Calcium alginate beads was carried out using a scanning electron microscope (JEOL JEM-1200 EX II, Japan) equipped with secondary electron detector at an accelerating voltage of 10 kV. The samples were coated with gold to a thickness of about 30 nm in a vacuum evaporator. The internal structure of beads was examined by cutting them with a steel blade (Shaikh et al., 2018).

In-vitro drug release studies

Release studies were performed in triplicate using the USP basket method at 100 rpm and 37±0.5°Cin 1000 mL of test medium (i.e., SGF). Approximately 50 beads were used for each experiment. The samples are withdrawn at specific time interval and assayed spectrophotometrically at the wavelength of maximum absorbance. The percentage of the drug release is calculated with respect to the drug content of the beads. The drug content is expressed as the percentage of drug encapsulated in a unit weight of beads. The experiments are carried out in triplicate and the results averaged (Chaturvedi et al., 2012; Piyakulawat, 2007; Bhattarai, 2011).

Results and discussion

Fourier-transformation infrared (FTIR) spectroscopy

Figure 1. FTIR of formulation blends

 

 

 

The drug-polymer interaction was studied using FTIR spectroscopy for selected combination of drug with different polymers used.  The FTIR spectra obtained is illustrated in figure 1. The IR spectrum of cefdinir give absorption peak at 3271 cm-1 due to Alkene groups (=C–H stretching) with absorption peak at 1710 cm-1 and 1544-1756cm-1 due to Ketone groups (-C=O). The IR spectrum of the F1 and F5 containing sodium alginate exhibit a broad hump around 3346cm-1 to 3242 cm-1 corresponds to -OH of the -COOH. Strong absorption peak is observed at1641cm-1. The IR spectrum of sodium alginate show a broad hump due to presence of O-H group along with C=O absorption peak. The IR spectrum of F9 and F12 containing sodium CMC gives broad hump at 3170cm-1.

Particle size determination and visual analysis of cefdinir beads

Table 2. Particle size determination and visual analysis

Formulation code

Particle size (mm)

(mean ± SD) (n = 20)

Shape

Colour

F1

0.99 ± 0.04

Spherical

Off white

F2

1.37 ± 0.08

Spherical with tail

Off white

F3

1.41 ± 0.06

Spherical

White

F4

1.58 ± 0.07

Spherical with tail

Off white

F5

1.32 ± 0.05

Spherical

White

F6

0.88 ± 0.04

Spherical with tail

Off white

F7

1.32 ± 0.05

Spherical

Off white

F8

1.98 ± 0.07

Spherical

Off white

F9

0.98 ± 0.03

Spherical with tail

Yellow

F10

1.06 ± 0.04

Spherical

White

F11

1.43 ± 0.06

Spherical with tail

Light Yellow

F12

1.69 ± 0.02

Spherical

Off white

Figure 2. Photograph showing prepared floating beads

 

 

 

The particle size of beads is represented in table 2.The sizes of beads were influenced by the orifice of the needle, extrusion rate and concentration of polymer. The mean particle size of sodium alginate beads prepared by ionotropic gelation method (F1-F8) was between 0.88 to 1.98mm and sodium CMC beads prepared by ionotropic gelation method (F9-F12) were between 0.98 to 1.69mm.The sodium alginate and sodium CMC beads prepared with calcium chloride were spherical and the beads prepared with aluminum chloride were spherical with tail.

Drug entrapment efficiency and floating study

Table 3. Drug entrapment efficiency and floating study

Formulation code

%Drug Entrapment (mean ± SD) (n = 3)

Floating lag time (min.)

Floating time (hrs)

Percentage floating (mean ± SD) (n = 3)

F1

88.28 ± 0.28

< 1

> 12

88.34 ± 0.84

F2

90.36 ± 0.08

< 1

> 12

89. 60 ± 0.65

F3

78.66 ± 0.78

< 1

> 12

79.92 ± 0. 34

F4

84.24 ± 0.17

< 1

> 12

82.24 ± 0. 87

F5

94.60 ± 1.05

< 1

> 12

96.42± 1.02

F6

93.19 ± 0.34

< 1

> 12

91.69 ± 0.31

F7

93.10 ± 0.76

< 1

> 12

95.24± 0.30

F8

89.90 ± 1.30

< 1

> 12

87.32 ± 0.98

F9

68.75 ± 0.78

< 2

> 12

66.95 ± 0.14

F10

62.25 ± 1.40

< 2

> 12

64.74 ± 1.04

F11

69.89 ± 1.37

< 2

> 12

68.00 ± 1.72

F12

67.28 ± 0.90

< 2

> 12

70.80 ± 0.87

The results of entrapment efficiency are presented in table 3. The mean drug entrapment efficiency (DEE) of sodium alginate beads prepared by ionotropic gelation method (F1-F8) was between 78.66 to 94.60% and sodium CMC beads (F9-F12) was between 62.25 to 69.89%. The floating ability of prepared beads was evaluated along with dissolution studies. The beads containing gas forming agent (F1-F12) sank immediately and float with lag time not more than 2min in 0.1 N HCl (pH 1.2), and % floating was between 64.74-96.42%, floating ability of CaCO3 was higher than NaHCO3as a gas forming agent was observed.

In vitro swelling data of Cefdinir beads

Table 4.   In vitro swelling data of Cefdinir beads (F1-F6)

Time (hrs)

Swelling Index

F1

F2

F3

F4

F5

F6

1

68.8

51.87

55.3

48.91

53.27

45.42

2

95.32

75.23

92.29

71.36

82.845

64.36

3

169.96

110.59

167.2

119.2

127.82

108.25

4

210.02

139.95

195.41

145.41

178.1

124.26

5

295.15

201.31

271.37

191.32

205.43

155.28

6

321.74

272.67

302.11

259.41

249.59

233.84

7

338.52

296.03

329.69

271.4

266.95

250.21

8

362.24

310.39

340.01

292.11

280.99

262.91

Figure 3. In vitro swelling data of Cefdinir beads (F1-F6)

 


Table 5.   In vitro swelling data of Cefdinir beads (F7-F12)

Time (hrs)

Swelling Index

F7

F8

F9

F10

F11

F12

1

49.97

41.27

78.8

71.91

63.27

64.43

2

73.23

65.845

105.32

101.36

92.845

84.31

3

118.59

97.82

179.96

172.2

137.82

128.25

4

140.95

151.1

250.02

218.41

198.12

184.26

5

204.31

201.43

315.15

299.32

225.43

275.29

6

275.67

229.595

346.74

330.41

259.59

293.84

7

296.03

241.985

358.52

347.4

266.98

318.26

8

309.39

269.38

394.24

369.11

279.99

312.18

 

Figure 4. In vitro swelling data of Cefdinir beads (F7-F12)

 

The swelling data of sodium alginate and sodium carboxy methyl cellulose beads are represented in Table 4-5 and illustrated in Figure 3-4. All the formulations showed good swelling in pH 1.2 HCL.

Scanning electron microscopy (SEM)

The surface morphology of prepared beads was studied by scanning electron microscopy. External and internal surfaces of beads formulation F4, are shown in Fig. 5. The sodium alginate and sodium CMC beads prepared with calcium chloride were spherical and the beads prepared with aluminum chloride were spherical with tail. External surface was smooth with slightly rougher surface/shrinkage which could be due to drying. In the drug loaded beads the internal surface is slightly sponge like which is due to the drug and rate controlling polymer are uniformly dispersed in the polymer matrix.

Figure 5. SEM study of F4 formulation

 

In-vitro drug release studies

In-vitro drug release studies of cefdinir from floating beads were performed in 0.1 N HCL for 12 hours using USP Type I dissolution test apparatus.The in vitro release data was represented in Table 6-7 and illustrated in Fig.6-7.The in vitro release of cefdinir was mainly affected by nature and amount of polymer, swelling behaviour of the polymers.

Table 6. In vitro drug release data of Cefdinir beads (F1-F6)

Time (hrs)

Cumulative % Drug Release

F1

F2

F3

F4

F5

F6

1

1.6

1.65

1.91

2.95

1.4

1.86

2

4.25

2.7

5.25

5.65

2.75

3.02

3

12.56

8.57

12.56

14.68

8.56

10.57

4

32.12

33.66

31.12

35.89

31.12

34.96

5

38.94

42.4

44.94

54.02

40.94

44.8

6

46.72

52.58

56.72

70.94

46.72

55.61

7

58.88

64.3

68.88

80.78

56.88

67.43

8

63.76

76.17

80.76

88.25

62.76

76.17

9

76.36

83.15

86.36

90.47

74.36

84.19

10

80.58

85.12

90.58

92.35

81.58

87.28

11

83.33

88.41

92.33

94.12

83.33

88.46

12

88.02

89.61

93.89

94.98

84.23

88.56

Figure 6. In vitro drug release data of Cefdinir beads (F1-F6)


Table 7. In vitro drug release data of Cefdinir beads (F7-F12)

Time (hrs)

Cumulative % Drug Release

F7

F8

F9

F10

F11

F12

1

2.56

4.2

2.06

2.86

1.2

1.54

2

6.5

7.96

3.56

4.2

3.4

2.56

3

13.31

16.8

12.57

10.57

6.86

5.25

4

38.12

38.16

24.06

34.96

10.96

12.56

5

51.04

62.64

40.87

44.8

22.8

36.12

6

66.72

76.34

52.61

55.61

41.32

48.94

7

79.23

84.58

64.98

67.43

62.4

64.72

8

88.02

92.84

76.4

76.72

70.98

78.44

9

90.34

94.3

80.34

84.06

79.35

87.76

10

92.88

96.21

86.22

92.76

84.5

88.36

11

93.86

97.06

88.76

94.47

87.32

89.68

12

94.47

98.14

89.36

96.34

86.12

92.33

Figure 7. In vitro drug release data of Cefdinir beads (F7-F12)

 

Conclusion

A successful attempt has been made to formulate floating alginate and sodium CMC beads of Cefdinir by ionotropic gelation method. From the results of FT-IR, it can be concluded that there is no interaction between the drug and the polymers used. The formulation F8 shows highest release of Cefdinir 98.14% over a period of 12 hrs with excellent floating properties. Hence, the floating beads of Cefdinir can be prepared by using CaCO3 and NaHCO3 as buoyant along with hydrogel forming polymer like sodium alginate and sodium carboxy methylcellulose as a release modifier for improved oral bioavailability of Cefdinir.

Conflicts of interest: Not declared.

References

Bhattarai RS, Dhandapani NV, Shreshtha A. 2011. Drug delivery using alginate and chitosan bead: an overview. Chronicles of young scientists 2(4):192-196.

Chaturvedi S, Sharma PK, Tyagi VS. 2012. Comparison of emulsification and ionic gelation method of preparation of mucoadhesive microsphere. The Pharma Innovation 1(5):1-10.

Hari BN, Brahma RA, Samyuktha RB.2010. Floating drug delivery of Nevirapine as a gastroretentive system. Journal of Young Pharmacist, 2(4):350-355.

Hrsoliya MS, Patel VM, Pathan JK, Ankit C, Meenakshi P, Ali M. 2012.  Formulation of floating microspheres of ritonavir by cross linking-effect of NaHCO3 as gas forming agent. International Journal of Pharmaceutical & Biological Archive, 3(1):108-111.

Mishra B, Rajanikanth PS. 2007. Preparation an in vitro characterization of gellan based floating beads of acetohydroxamic acid for eradication of H. pylori. Acta Pharmaceutica, 57:413-427.

Piyakulawat P, Praphairaksit N, Chantarasiri N, Muangsin N. 2007. Preparation and evaluation of chitosan/carrageenan beads for controlled release of sodium diclofenac. AAPS PharmSciTech, 8 (4):E1-E11.

Chandra S, Sowndarya K, Kumar SH, Suresh R, Sangeetha S, Tamilselvan A. 2018. Formulation and Evaluation Studies of Floating Drug Delivery  System Containing Cefdinir antibiotic.  International Journal of Advanced Pharmaceutical Sciences, 1(4):130-176.

Shaikh S, Molvi KI. 2016. Current trends in gastroretentive floating bioadhesive drug delivery system. International Journal of Pharmacy and Pharmaceutical Research, 6(1):356-67.

Shaikh S, Shaikh S, Khan GJ, Pathan S. 2018. Formulation and Characterization   of Mucoadhesive Microsphere of Gliclazide HCL. Journal of Drug delivery and Therapeutics, 8(4):117-125.

Sharma S, Nanda A, Singh L. 2011. Gastroretentive Drug Delivery System: An Overview. International Journal of Research in Pharmaceutical and Biomedical Sciences 2(3):954-958.

Singhal P, Kumar K, Pandey M, Saraf SA. 2010. Evaluation of acyclovir loaded oil entrapped calcium alginate beads prepared by ionotropic gelation method. International Journal of Chemtech Research, 2(4):2076-2085.

Sriamornsak P, Sungthongjeen S, Puttipipatkhachorn S. 2007. Use of pectin as a carrier for intragastric floating drug delivery: carbonate salt contained beads. Carbohydrate Polymers, 67:436-445.

Sungthongjeen S, Paeratakul O, Limmatvapirat S, Puttipipatkhachorn S. 2006. Preparation and in vitro evaluation of a multiple-unit floating drug delivery system based on gas formation technique. International Journal Pharmacy, 324:136–143.

Varshosaz J, Tabbakhian M, Zahrooni M. 2007. Development and characterization of floating microballoons for oral delivery of Cinnarizine by a factorial design. Journal of Microencapsulation, 24(3):253-262.

Yellanki SK, Nerella NK. 2010. Stomach-specific drug delivery of riboflavin using floatinalginate beads. International Journal. Pharm. Pharmaceutical Sciences, 2(2):160-163.

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