Design and Characterization of Sustained Released Alginate Beads of Meclizine Hydrochloride

 

Wajid Ahmad*, Rihan Jawed

Department of Pharmaceutics, Institute of Pharmacy, Angola, Turkey.

*Corresponding Author E-mail: wajidahmad806@gmail.com

 

ABSTRACT:

The objective of present study was to prepare alginate beads of antihistamine meclizine hydrochloride for sustain release action. The alginate beads were prepared by employing sodium alginate as a polymer with sodium carboxymethyl cellulose and chitosan hydrochloride as release retardant. The method of preparation employed was ionotropic gelation. The prepared beads were seen having the drug release rate of 98.34% of A4 batch and 99.02% of B4 batch in the time period of 12hrs. The maximum percent drug content of 94.72±0.06%   was found in A4 batch. From the results it can be seen that A4 batch was found to be optimum as it was having maximum drug content and maximum amount of drug release in the predicted time period of 12hrs. The microbeads of meclizine hydrochloride by using ionotropic gelation method were prepared successfully employing various polymers in different concentrations. The prepared microbeads can be a better alternative than various other sustained release dosages forms.

 

KEYWORDS: Meclizine hydrochloride, Ionotropic Gelation, Anti-Histamine, Microbeads, Antiemetics.

 

 


INTRODUCTION:

The Oral Route of administration is one of the precise routes of administration having more patient reception or expediency. Sustained release technology has emerged as a crucial new field within the development of pharmaceutical dosage form. Sustained release systems consist of any drug delivery system that attains slow release of drug over an extended phase of time. More accurately, sustained drug delivery can be defined as “Sustained drug action at a predetermined rate by preserve a relatively stable, effective drug level in the body with affiliated minimization of unwanted effects.

 

In sustained release dosage forms, an adequate amount of drug is initially made obtainable to the body to cause a desired pharmacological effect1. The residual fraction is released occasionally and is required to maintain the maximum early pharmacological activity for some enviable period of time in surplus of time expected from usual single dose2-3.

 

Meclizine HCl (MZ HCl) is a first- generation antihistamine of the piperazine group. Meclizine is structurally and biologically alike to buclizine, cyclizine, and hydroxyzine, but has a little half-life of 6 hrs. It is utilized as an antivertigo/antiemetic agent, particularly within the prevention and treatment of nausea, vomiting, and dizziness related to kinetosis. It showed anticholinergic, central nervous system depressant, and local anesthetic effects. Its antiemetic and antivertigo property is not fully understood, but its central anticholinergic effect is somewhat responsible. The medicine downcast labyrinth excitability and vestibular stimulation, and it may influence the medullary chemoreceptor trigger zone4-5.

 

MATERIALS AND METHODS:

Meclizine Hydrochloride was obtained as a gift sample from Exmed Pharmaceuticals. Sodium CMC was obtained as procured from S.D. Fine Chem, Mumbai. Chitosan Hydrochloride was procured from Yarrowchem, Mumbai. Sodium Alginate was procured from S.D. Fine Chem, Mumbai. Calcium chloride was procured from Rankem Mumbai. All others reagents and chemicals were used as obtained and were of analytical grade.

 

Drug – Excipients Interaction Study:

Infra- red spectra matching approach was used for the detection of any possible chemical and physical interaction between the drug and the excipients. A physical mixture (1:1) of drug and polymer was prepared and mixed with suitable quantity of salt. About 100mg of this mixture was compressed to form a transparent pellet using a hydraulic press at 2 tons’ pressure6-7. It was scanned from 4000 to 150 cm-1 in FT-IR spectrophotometer. The IR spectrum of the physical mixture was compared with the standard value of pure drug and excipients and it was matched for any disappearance of any peak to detect any of interaction between the drug and excipients.

 

DSC Study:

Exactly weighed 5 to 6mg samples were hermetically sealed in aluminum crucible and heated at constant rate of 10oC/min over a temperature range of 40oC to 300oC. Inert atmosphere was maintained by purging nitrogen gas at a flow of fifty ml/min8.

 

Standard Calibration Curve:

About 100mg of pure drug was dissolved in pH 6.8 phosphate buffer in a 100ml volumetric flask and made up to 100ml with the same. Aliquots from this stock solution were taken, and dilutions were done using phosphate buffer to obtain concentrations of 2, 4, 6, 8, and 10µg/ml. Absorbance of these solutions were measured at 230nm by UV Spectrophotometry9.

 

Preparation of Microbeads:

As Meclizine hydrochloride is water insoluble drug so, for preparing sustained release microbeads the emulsion of pure drug was prepared by employing light liquid paraffin and sodium alginate. By this the beads will get better buoyancy which will enhance its floating time.  Sodium CMC and chitosan hydrochloride both were used as released modifiers. Accurately weighed required amount of Meclizine hydrochloride was taken with required amount of sodium alginate. In a motar pestle required amount of liquid paraffin was taken and the mixture of drug and sodium alginate was incorporated and an emulsion was prepared by adding required amount of water. Required quantities of Sodium CMC and chitosan hydrochloride were dissolved in required amount of water in different beakers. Both the solutions of drug and polymer were mixed with continuous stirring and kept aside for 1hr for degassing. The solution was then incorporated into a 4% solution of calcium chloride. The prepared beads were stirred until the beads are cured. The prepared beads were then filtered and washed with distilled water and dried in a petri plate for 24hrs at room temperature10-12. The beads were then collected and evaluated for various parameters.

 

Table 1: Formulation Chart of Meclizine Hydrochloride Microbeads

Batch

Drug (mg)

Sodium Alginate (%)

Sodium CMC (%)

Chitosan Hydrochloride (%)

CaCl2 (%)

A1

25

1

2.5

-

4

A2

25

1.5

2

-

4

A3

25

1.75

1.5

-

4

A4

25

2

1

-

4

B1

25

1

-

2.5

4

B2

25

1.5

-

2

4

B3

25

1.75

-

1.5

4

B4

25

2

-

1

4

 

Evaluation Parameters:

Micromeritics Properties:

The prepared microbeads were evaluated for their Micromeritics properties such as Tap density, Bulk density, Carr’s index, Hausner’s Ratio, Angle of repose.

 

Tap Density:

Tapped density of prepared microbeads was determined by the tapping method. Accurately weighed quantity of microbeads from each batch was transferred in to a 10 ml measuring cylinder. After observing the prevailing volume of microbeads, the tapping was continuing on a tough surface till no progressive modification in the volume was noted and therefore the tapped density were calculated 13.

                           Mass of microbeads

Tap Density: -------------------------------------

                  Volume of microbeads after tapping

 

Bulk Density:

It is the quantitative relation between a given mass of a powder and its bulk volume. Bulk density of the formulated microbeads was calculated by pouring about 2 g of formulated microbeads in a clean measuring cylinder, and initial volume was measured 14. The bulk density was calculated by the subsequent equation:

                         Mass of microbeads in gram

Bulk Density: -------------------------------------

                       Volume of microbeads in cm3

 

Carr’s Index:

The Carr’s index of the powder is a direct measure of the potential powder arch or bridge strength and stability. It is calculated by the following formula:

 

                                Tap Density – Bulk Density × 100

Carr’s Index: ------------------------------------------------                                                            

                                           Tap Density

 

 

                                       Hausner’s Ratio - Tap Density

Hausner’s Ratio: ---------------------------------------------

                                            Bulk Density

 

Angle of Repose:

The flow property of floating microbeads is usually estimated by determining the angle of repose. The angle of repose of microbeads was determined by using a fixed funnel on a burette stand employing fixed funnel method. The microbeads were allowed to freely fall through the fixed funnel until apex of conical pile formed just touched the tip of the funnel 15. The angle of repose (θ) decided consistent with the subsequent formula:

                    Height of Pile

Tan θ =    ---------------------------

                 Radius of Pile

 

Drug Entrapment Efficiency:

Accurately weighed beads (10mg) were transferred to a beaker containing 10ml Phosphate buffer pH 6.8 and the mixture was allowed to stand for 24 hours. The contents of the beaker were stirred for 1-2 hours using a magnetic stirrer for complete breakage of the beads, followed by filtration using what man filter paper. The amount of drug (x) in a single batch of beads was then estimated in the filtrate by measuring the absorbance at 215nm using U.V.-visible spectrophotometer16-17. Drug Entrapment efficiency was then calculated by following formulae:

 

% Entrapment efficiency = (x /T)*100

Where,

x = Actual quantity of drug present in beads and

T=Theoretical quantity of drug added during preparation

 

Swelling Index:

Accurately weighed beads of each preparation were taken in a beaker containing 10 ml of phosphate buffer of pH 6.8 and 1.2, and then allowed to stand at room temperature for 6 hr. The excess liquid adhered to the surface of the beads was removed by blotting with paper and therefore the swollen beads were weighed. Each experiment was carried out in triplicate 18. The swelling index of the beads was calculated by using the formula:

 

SI= (Ws-Wd)/Wd

 

Were,

Ws= weight of swollen beads and

Wd= weight of dried beads

Percentage Yield:

Percentage yield of prepared microbeads formulation was determined by weighing the microbeads after drying 19. The actual weight of microbeads was divided by the full weight of all the non-volatile parts used for the preparation of microbeads and is calculated by the subsequent formula:

 

                                          Actual Weight of microbeads × 100

Percentage Yield = ---------------------------------------------------

                                             Total Weight of microbeads

 

Bead Size Determination:

Beads size of the alginate beads was determined using an optical microscope using a compound microscope. A standard stage micrometer was wont to calibrate the optical micrometer.

 

Loose surface crystal study (LSC):

This study was conducted to calculate any amount of drug present on the surface of the microbeads or that might which have leaked from the beads which showed immediate release in dissolution media. Quantities of approximate 100mg of microbeads were taken in a measuring cylinder and 100ml of phosphate buffer (pH 7.4) was added into it as simulating the dissolution media. The samples were shaken vigorously for 15min in a mechanical shaker20. The amount of drug leached out from the surface was analyzed spectrophotometrically at 230nm.

 

Surface Morphology:

The surface morphology of the prepared microbeads was determined by the scanning electron microscopy (SEM). The samples for SEM were prepared by sprinkling the microbeads on a double adhesive tape which stuck to a stub. The stubs were then coated with platinum underneath an argon atmosphere employing a gold sputter module in an exceedingly high vacuum evaporator.

 

In vitro drug release:

In-vitro release studies of prepared beads were carried out to 900ml of 0.1 N HCl (pH 1.2). The test was carried out in 0.1 N HCl for 2 h, and then using phosphate buffer for the remaining time (pH 7.4) using USP- XXII apparatus at 100rpm, maintained at a temperature of 37±5˚C for a period up to 12 hrs. At each time interval 5 ml of sample was withdrawn for the study and at the same time 5ml of fresh dissolution media was added to maintain sink condition21. The withdrawn samples were suitably diluted and measured the absorbance spectrophotometrically at 230nm.

 

Kinetics Study:

The drug release data were fitted to zero order (cumulative % drug release versus time), first order (log of cumulative % drug retained versus time), and Higuchi models (cumulative % drug released versus square root of time) and Korsmeyer-Peppas model (log% of cumulative drug release Vs log of time) to calculate the kinetics of drug release and determine the release mechanism of the drug from the prepared floating microbeads of meclizine hydrochloride22.

 

RESULTS AND DISCUSSIONS:

FT-IR Spectroscopy:

In the test of drug – excipients interaction it was found that there was no physical and chemical interaction between the drug and polymers. It was seen that there was no disappearance or formation of any new peaks in the results. Therefore, it was found that all the materials used were compatible with each other.

 

DSC Study:

From the DSC study it was revealed that the pure drug and the optimized formulation does not shows any significant change in the melting point and the drug does not shows any type of change in temperature. Therefore it was concluded that the drug was compatible with the polymers and it was not having any type of compatibility.


 

 

Figure 1: a) FTIR of Pure Drug. b) FTIR of Optimized Formulation


 


Figure 2: a) DSC of Pure Drug. b) DSC of Optimized Formulation

 


Standard Calibration Curve:

The standard calibration curve of meclizine hydrochloride was performed with a λ max of 230nm on the UV spectrophotometer and the results were drawn on the excel sheet which gave the equation of y = 0.042x + 0.004 and R˛ = 0.998. This shows that the equation is linear and it follows the beer lamberts law.

 

Micromeritics Properties:

The results of the Micromeritics properties of the prepared microbeads shows tap density in the range of 0.591±0.72 - 0.923±0.06, bulk density in the range of 0.389±0.04 - 0.865±0.17, carr’s index and hausner’s ratio in the range between 3.8 - 34.08 and 1.04 - 1.52. The angle of repose was reported between 14.860±0.47 - 49.280±0.25. From all these parameters it can be concluded that the prepared beads were having better to good flow properties.

 

Figure 3: Standard Calibration Curve of Meclizine Hydrochloride in Phosphate Buffer of pH 6.8

 

Table 2 Micromeritics Properties of the prepared Microbeads

Batch No.

Tap Density (gm/cm3)

Bulk Density (gm/cm3)

Carr’s Index

Hausner’s Ratio:

Angle of Repose.

Pure Drug

0.501±0.04

0.181±0.03

22.66

1.28

24.560±0.22

A1

0.803±0.36

0.741±0.04

7.7

1.08

19.500±0.25

A2

0.827±0.02

0.795±0.36

3.8

1.04

20.250±0.71

A3

0.923±0.06

0.865±0.17

6.2

1.06

15.670±0.06

A4

0.843±0.58

0.798±0.29

5.3

1.05

18.780±0.02

B1

0.872±0.12

0.825±0.07

5.3

1.05

16.850±0.08

B2

0.909±0.07

0.862±0.03

5.1

1.05

14.860±0.47

B3

0.591±0.72

0.389±0.04

34.08

1.52

49.280±0.25

B4

0.785±0.28

0.656±0.14

16.47

1.20

27.570±0.74

 


Evaluation Parameters:

From the various evaluation parameters it was seen that the percentage entrapment efficiency of batches A1 – A4 was between 80.35±0.07 - 92.68±0.82, percentage yield was in the range of 82.24±0.08 - 89.38±0.25, percent drug content was found to be between 91.24±0.06 - 94.72±0.06, particle size was found to be between 1183 – 1254 mm. From the evaluation parameters of batches B1 – B4 it was seen that the percentage entrapment efficiency was found to be the range of 83.73±0.06 - 96.49±0.67, the percentage yield of batches B1-B4 was found to be in range of 78.47±0.67 - 80.20±0.28, the percentage drug content was found to be 88.18±0.03 - 94.24±1.17, the particle size was found to be 973 -1017 mm, the percentage of loose surface crystal was found to be 0.14 - 0.21. The maximum drug content of 94.72±0.06 was found to be in the batch of A4.


 

Table 3 Evaluation Parameters of Microbeads

Batch No.

Entrapment Efficiency (%)

Percentage Yield (%)

Drug Content (%)

Particle Size (mm)

Loose Surface Crystal (%)

A1

91.25±0.25

89.38±0.25

92.88±0.62

1215

1.110

A2

80.35±0.07

85.64±0.03

91.68±0.52

1254

1.945

A3

84.75±0.03

86.12±0.72

91.24±0.06

1183

4.301

A4

92.68±0.82

82.24±0.08

94.72±0.06

1214

4.341

B1

88.46±0.41

79.36±0.67

89.43±0.03

973

0.14

B2

79.81±0.21

79.20±0.28

90.09±0.05

997

0.15

B3

96.49±0.67

78.47±0.67

94.24±1.17

1006

0.21

B4

83.73±0.06

80.20±0.28

88.18±0.03

1017

0.19

 


Swelling Ratio:

The swelling ratio of the prepared beads in the different solutions was totally different and variable. The swelling ratio of the beads in the pH of 6.8 was found to be in the range of 1723 – 2541. The swelling ratio of beads in the pH1.2 was found to be between 153 – 244.

 

Table 4: Swelling ratio at different pH

Sr. No.

Formulation Code

Swelling Ratio

pH 6.8

pH 1.2

1

A1

1723

186

2

A2

1731

198

3

A3

1734

218

4

A4

1759

220

5.

B1

1910

172

6.

B2

2185

153

7.

B3

2381

244

8.

B4

2541

213

 

In-vitro Dissolution Study:

From the % cumulative drug release study of the batches of A1-A4 the release of drug was found to be in the range of 2.241-98.34% and from the batches of 0.203-99.02% in the time span of 12 hours respectively. Form the details it was seen that the formulation of A4 was having the highest rate of drug release i.e. of 98.34% and the drug release of the batch B4 was 99.02%. The drug release of these batches was found to be maximum when compared with all other batches. So, therefore the batch of A4 and B4 was found to be optimized as the drug release of these batches was maximum when compared with the other batches.

 

Figure 4: In-vitro Drug Release of A1 –A4 Formulation.

 

Figure 5: In-vitro Drug Release of B1 –B4 Formulation

 

Kinetics Study:

All the release data was fitted into various kinetic models like, zero order, first order, Higuchi, and Korsmeyer-Peppas, in order to find out order and mechanism of drug release from microbeads. Determined the order of release of drug from the selected batch of microbeads by graphical method from the dissolution data, a graph was plotted with % drug release remaining Vs time to find out zero order release. The value of ‘n’ gives a manifestation of the release mechanism; when n = 1, the release rate is independent of time (zero-order) (case II transport), n = 0.5 for Fickian diffusion and when 0.5 < n <1.0, diffusion and non-Fickian transport are implicated. Lastly, when n > 1.0 super case II transport is apparent. Regression coefficient and ‘n’ were calculated the value showed that value of ‘n’ was 1.351 for and 0.491 for, the prepared micro beads exhibited zero order kinetics followed by super case –II transport.

 

Surface Morphology:

Surface morphology study was performed in order to check the surface properties of the prepared beads. From the surface morphology study it was seen that the prepared beads were having a rough surface and surface cracks.

 

Figure 6: Surface Morphology of the Optimized Formulation A4

 

CONCLUSION:

The microbeads of meclizine hydrochloride were prepared using sodium alginate and release retardants sodium CMC and chitosan hydrochloride. From the evaluation parameters it was seen that the batch of A1 – A4 and B1 – B4 were prepared by using various concentration of polymers and it was found that batch A4 and B4 was found to be optimized formulation as the drug release rate in the time period of 12hrs and the percent drug content was more than compare with other batches. From the above study it can be seen that the microbeads of meclizine hydrochloride can be successfully prepared by employing ionotropic gelation method.

 

REFERENCES:

1.     Malviya VR, Pande SD, Bobade NN. Preparation and Evaluation of Sustained Release Beads of Zolmitriptan Hydrochloride. Research Journal of Pharmacy and Technology. 2019; 12(12): 5972-6.

2.     Menon TV, Sajeeth CI. Formulation and evaluation of sustained release sodium alginate microbeads of carvedilol. Research Journal of Pharmacy and Technology. 2013;6(4):392-7.

3.     Malviya VR, Pande SD. Road CKN. Preparation ad Evaluation of Zolmitriptan Hydrochloride Lozenge. J Pharma Res. 2019; 8(8): 624-9.

4.     Malviya V, Thakur Y, Gudadhe SS, Tawar M. Formulation and evaluation of natural gum based fast dissolving tablet of Meclizine hydrochloride by using 3 factorial design 2. Asian Journal of Pharmacy and Pharmacology. 2020; 6(2): 94-100.

5.     Sivakumar R, Narayanan N, Rajendran NN. Bioadhesive Microbeads of Ketoprofen for Controlled and Site Specific Delivery. Research Journal of Pharmacy and Technology. 2011; 4(3): 385-8.

6.     Malviya V, Ladhake V, Gajbiye K, Satao J, Tawar M. Design and Characterization of Phase Transition System of Zolmitriptan Hydrochloride for Nasal Drug Delivery System. International Journal of Pharmaceutical Sciences and Nanotechnology. 2020 May 31; 13(3): 4942-51.

7.     Malviya VR, Tawar MG. Preparation and Evaluation of Oral Dispersible Strips of Teneligliptin Hydrobromide for Treatment of Diabetes Mellitus. International Journal of Pharmaceutical Sciences and Nanotechnology. 2020 Jan 31; 13(1): 4745-52.

8.     Masareddy RS, Rananaware SD, Patil BR. Preparation and Characterization of Rabeprazole Gastroretentive Drug Delivery System by Ionotropic Gelation Technique. Research Journal of Pharmacy and Technology. 2010; 3(2): 526-9.

9.     Malviya V, Manekar S. Design, Development and Evaluation of Aceclofenac and Curcumin Agglomerates by Crystallo Co-Agglomeration Technique. Research Journal of Pharmacy and Technology. 2021 Mar 18;14(3):1535-41.

10.   Jaiswal M, Lanjhiyana SK. Fabrication and Evaluations of Dual Crosslinked Mesalamine containing Pectin-Chitosan gel micro beads for controlled and targeted colon delivery. Research Journal of Pharmacy and Technology. 2018;11(11):4797-804.

11.   Malviya V. Preparation and Evaluation of Emulsomes as a Drug Delivery System for Bifonazole. Indian Journal of Pharmaceutical Education and Research. 2021 Jan 1;55(1):86-94.

12.   Roy H, Balaiah S, Kumar TV. Design and In-vitro Evaluation of Cefuroxime axetil floating Microbeads for Treatment of acute Bacterial caused Chronic Bronchitis. Research Journal of Pharmacy and Technology. 2018;11(6):2276-82.

13.   Chauhan SB, Singh V, Chauhan R. Enteric coated Microbeads as a Potential Delivery System for improved probiotic effect of Lactobacillus rhamnosus GG. Research Journal of Pharmacy and Technology. 2019;12(12):6049-56.

14.   Chengaiah B, Alagusundaram M, Ramkanth S, Chetty CM. Self emulsifying drug delivery system: a novel approach for drug delivery. Research Journal of Pharmacy and Technology. 2011;4(2):175-81.

15.   Gnanaprakash K, Shekhar KB, Chetty C. A review on floating drug delivery system of H2 receptors. Research Journal of Pharmacy and Technology. 2011;4(4):502-9.

16.   Putney SD, Burke PA. Improving protein therapeutics with sustained-release formulations. Nature Biotechnology. 1998 Feb;16(2):153-7.

17.   Leroux JC, Allémann E, De Jaeghere F, Doelker E, Gurny R. Biodegradable nanoparticles—from sustained release formulations to improved site specific drug delivery. Journal of Controlled Release. 1996 May 1;39(2-3):339-50.

18.   Takahara J, Takayama K, Nagai T. Multi-objective simultaneous optimization technique based on an artificial neural network in sustained release formulations. Journal of Controlled Release. 1997 Nov 10;49(1):11-20.

19.   Lee HJ, Riley G, Johnson O, Cleland JL, Kim N, Charnis M, Bailey L, Duenas E, Shahzamani A, Marian M, Jones AJ. In vivo characterization of sustained-release formulations of human growth hormone. Journal of Pharmacology and Experimental Therapeutics. 1997 Jun 1;281(3):1431-9.

20.   Ankit B, Rathore RP, Tanwar YS, Gupta S, Bhaduka G. Oral sustained release dosage form: an opportunity to prolong the release of drug. IJARPB. 2013 Jan 1;3(1):7-14.

21.   Malviya V, Pande S. Development and Evaluation of Fast dissolving Film of Fluoxetine hydrochloride. Research Journal of Pharmacy and Technology. 2021 Oct 31;14(10):5345-50.

22.   Hilton AK, Deasy PB. In vitro and in vivo evaluation of an oral sustained-release floating dosage form of amoxycillin trihydrate. International Journal of Pharmaceutics. 1992 Oct 10;86(1):79-88.

 

 

 

Received on 08.11.2021        Modified on 04.04.2022

Accepted on 10.06.2022   ©AandV Publications All Right Reserved

Res.  J. Pharma. Dosage Forms and Tech.2022; 14(3):199-205.

DOI: 10.52711/0975-4377.2022.00032