Effect on Drug Release profile of Meclizine Hydrochloride by using various Dissolution Media

 

Rahul Rajge, Vishal Mahanur, Mukund Tawar

Department of Pharmaceutics, P.R. Pote Patil College of Pharmacy Amravati – 444604.

*Corresponding Author E-mail:  rajgerahul88@gmail.com

 

ABSTRACT:

The present work was carried out to study the probable interactions of commonly used beverages on the release characteristics of Meclizine HCl sustained release tablet dosage form. Studies were carried out to evaluate the alterations in disintegration time and in-vitro dissolution profiles of Meclizine HCl from the tablets. All the studies indicated that the time required for disintegration of Meclizine HCl tablets is more with the modified immersion media as compared with that in water. At the end of the study it was revealed that more than 82% of Meclizine HCl from tablets MF1 was released in Distilled Water and other modified dissolution media except Coffee, Aerated Cola Drink, Non-Aerated Soft Drink and hence, the tablets failed the USP acceptance criteria in water and other dissolution modified media. In Coffee, Aerated Cola Drink, Non-Aerated Soft Drink having passed the USP acceptance criteria. All the three brands of Meclizine HCl viz. MF1, MF2 and MF3 failed to comply with the USP criteria for percentage drug release within 8 h in distilled water.

 

KEYWORDS: Meclizine HCl, Antihistamine, Dissolution, Concomitant Consumptions, Beverages.

 

 


INTRODUCTION:

Often patients are counselled to take medications, especially those for pain-relief, with milk to minimize the gastric irritation. Moreover, the patients may consume the medicines with one or more of the other beverages including the health drinks with complex compositions1. It is known incontrovertible fact that there's an excellent variation within the quantity and therefore the regimen followed for consumption of those beverages. There are possibilities of probable interactions between any of the components of these beverages and the formulation ingredients including the drug candidate itself.

 

In view of this, the present study has been designed to assess the effects of concomitant consumption of commonly consumed beverages on the release characteristics of immediate release and sustained release products of Meclizine Hydrochloride. This would help to generate useful data on potential risk or benefits of such co-administration2.

 

Meclizine Hydrochloride is that the hydrochloride salt sort of meclizine, an artificial piperazine with anti-emetic, sedative and histamine H1 antagonistic properties. Meclizine hydrochloride blocks the H1 histamine receptor and prevents the symptoms that are caused by histamine activity on capillaries, bronchial and gastrointestinal smooth muscles, including vasodilation, increased capillary permeability, broncho-constriction, and spasmodic contraction of gastrointestinal smooth muscles3-5.

 

MATERIALS AND METHODS:

Meclizine Hydrochloride was obtained as a gift sample from Exmed Pharmaceuticals, Gujarat. The various marketed formulation of Meclizine hydrochloride was also purchased from the local market. The various dissolution medium was purchased from the local market. All other chemicals and reagents used were of analytical grade.

 

Standard Calibration Curve:

From solution having concentration 100μg/ml aliquots of 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5 and 5ml were pipette out into 10ml volumetric flasks. The volume was made up to the mark with Phosphate buffer 6.8 to get the final concentration of 5, 10, 15, 20, 25, 30, 35, 40, 45 and 50 μg/ml respectively6. The absorbance of each concentration was measured at 235nm.

 

FTIR of Pure Drug and Tablet:

The FT-IR of pure drug and marketed tablet formulation was carried out in order to check any difference in the peaks. The FT-IR study was carried out by using the conventional potassium bromide dispersion technique. A 10-20mg of drug was mixed uniformly with potassium bromide and filled into cavity of sample holder and an IR spectrum was noted using FTIR spectrophotometer7.

 

Standardization of Marketed Tablet Formulation:

The standardization of marketed formulation was performed by testing the hardness and diameter and thickness of the tablet. The hardness test was carried out by using the Monsanto hardness tester and the dimensions of the tablet were measured by using digital vernier caliper.

 

Method of preparation of beverages:8-10

Milk:

Commercial brand of toned milk was used for preparation of the modified medium. The milk was boiled using liquefied petroleum gas burner. From this 120ml milk was measured using measuring cylinder. To this, two tea spoons (8.185g) of sugar were added.

 

Tea:

Commercially available family mixture of tea was used for preparation of decoction. For this, about 100 ml of water was boiled on LPG burner. To this boiling water, two tea spoons (8.185g) of sugar was added and stirred with stainless steel spoon followed by one tea spoon (1.581g) of tea powder. The boiling of decoction was continued for 10 min along with stirring was discontinued and the vessel was covered with lid for 5 minutes. The decoction was filtered through stainless steel kitchen strainer and to it 25ml of previously boiled milk (40-45°C) was added.

 

Coffee:

Commercially available coffee granules were used for preparation of coffee decoction. For this, about 65ml of water was boiled on liquefied petroleum gas burner. To this boiling water, two tea spoons (8.025g) of sugar was added and stirred with stainless steel spoon followed by addition of one tea spoon (1.621g) of coffee granules. The boiling of decoction was continued for 10 min further the heating was disconnected and the decoction was stirred using stainless steel spoon. To this clear brown hot coffee, 65ml milk (40-42°C) was added. Final volume of single serve was 120ml.

 

Aerated Cola Drink:

Commercial brand of cola drink was used for preparation of the modified medium. The single serve 250ml of the drink measured using measuring cylinder was used.

 

Non-Aerated Soft Drink:

Commercial brand of mango drink was used for preparation of the modified medium. The single serve 250ml of the soft drink measured using measuring cylinder was used.

 

Plain Buttermilk:

Plain buttermilk was prepared freshly from the commercial available curds. It stored at cool temperature (8-15°C). Total quantity of curds of one pack i.e. 200g was transferred into 500ml beaker using stainless steel spoon and was churned (5-10 min) using mechanical stirrer. To this, 40ml of water (30-35°C) was added in small portions with continues stirring. The temperature of buttermilk was noted.

 

Spiced Buttermilk:

Commercial brand of ready to drink Spiced buttermilk was used. The single serve of 120ml was measured using measuring cylinder.

 

Standardization of Prepared Beverages:

All the readymade and processed beverages were standardized for pH, temperature, colour, flavor, taste, volume of single serve and were observed for presence or absence of foam.

 

Preparation of Modified Immersion and Dissolution Media Using Standardized Beverages:

The immersion media were used for conducting disintegration test and dissolution medium for tablets of Meclizine HCl.

 

Preparation of Modified Immersion and Dissolution Media:

The total volume of immersion medium and dissolution medium as per IP/USP is 800 and 900ml respectively. For this, 120ml of boiled milk was added to 900ml of distilled water. For tea 120ml of boiled tea was added 900ml of distilled water. For coffee 120ml of boiled coffee was added to 900ml of distilled water. For aerated drink 250ml of cola was added to 900ml of distilled water. For the non-aerated drink 250ml of mango drink was added to 900ml of distilled water.  For plain buttermilk 120ml of buttermilk was added to 900ml of distilled water. For spiced buttermilk 120ml of Spiced buttermilk was added to 900ml of distilled water.

 

Evaluation of the Modified Immersion Media and Dissolution Media:11-15

Organoleptic Properties:

Organoleptic properties viz. color and odor of beverages were noted by subjective perception. Color was noted by visual observation, odor was checked for peculiarity.

 

pH:

The pH of each modified medium was noted immediately after preparation using Digital pH meter previously calibrated with pH of 4 and 6.8.

 

Test for Temperature Equilibration of Neat Beverages:

For this, each of the neat beverages stored at respective temperature of serving were added in required quantities separately into the sufficient volume of distilled water contained in the vessel of disintegration test apparatus. The temperature of water in the thermostatically controlled bath was maintained at 37±2°C. So that, the temperature of distilled water contained in vessel of disintegration test was 37±2°C.

 

Effect of Food Weight on Disintegration Time of Tablets:

To simulate the effect of the food weight on the disintegration time of tablets, a USP disk (3.5g) was placed flat on the top of each tablet.

 

In-vitro Drug Release: 

The drug release study was carried out using USP XXII type II (paddle) apparatus by using distilled water and other modified media. The temperature of 37±0.5°C was maintained throughout the study. The paddles were rotated at 50RPM. The samples were withdrawn at regular intervals and the same amount of dissolution media was added to the dissolution chamber to maintain the sink conditions. The withdrawn sample was then analyzed at 235nm on UV spectrophotometer.

 

Kinetics Study:

The kinetic drug-release data were analyzed according to zero order, first order, Higuchi, Kosmeyer-Peppas. The acceptable equation was chosen on the idea of goodness of fit test16.

 

Comparative Evaluation of Dissolution Profiles of Meclizine HCl tablet by a Model-Independent Method:

For the determination of equivalence of dissolution data in distilled water and modified dissolution media approaches recommended by FDA guideline documents were referred and the model-independent approach based on the calculation of similarly (f2) factor, the main advantage of the f2 equation is that it provides a simple way to compare the data. Nevertheless, this equation does not account for the variability or correlation structure of the data and it is sensitive to the number of points used. In this study, a model-independent approach was used in which the dissolution profiles of one drug in two different dissolution media i.e. distilled water and each of modified dissolution media were compared using the fit factor17-19.

 

RESULTS AND DISCUSSION:

Standard Calibration Curve:

From the scanning of Meclizine HCl in buffer solution, it was concluded that the λ max of Meclizine HCl was 235 nm. From the standard calibration curve it was found that Meclizine HCL obeys the beer’s- lambert’s law in the range of 10 -50 µg/ml. The equation of linear line was found to be, y= 0.0143X + 0.379, R2 = 0.997. Correlation coefficient (R2) value indicates the linear correlation between concentration and absorbance.

 

Figure 1: Standard Calibration Curve of Meclizine HCL

 

FTIR Study:

From the FTIR study of the pure drug and the marketed formulation revealed that there was no formation, modification or disappearance of any kind of peak in the functional groups.

 

Standardization of Marketed Tablet:

The diameter of the marketed tablet was found to be in the range of 9.04±0.052 - 9.43±0.01mm, the thickness of the tablet was found to be it the range of 3.94±0.024 - 4.20±0.012mm and the hardness of the tablet was found to be in the range of 7.98±0.031 - 8.96±0.042kg/cm3.


 

Fig 2: FTIR of pure drug Meclizine Hydrochloride

 

Fig 3: FTIR of Marketed Formulation

 


Organoleptic Study of Neat Beverages and pH study:

The organoleptic properties of neat beverages are varying depending upon their composition. The neat beverages were evaluated for colour (visual observation) and odor test. Among all the seven beverages the aerated cola drink was found to be strongly acidic.

 

Table 1: Organoleptic and pH Study

Sr. No.

 Code for Beverage

Colour

Odor

pH

1.

Distilled water

-

-

7-7.2

2.

Milk

White

Milky

6.81-6.84

3.

Tea

Brown

Strong astringent

6.6-6.72

4.

Coffee

Brown

Strong bitter

6.18-6.24

5.

Aerated cold drink

Blackish brown

Strong cola

2.4-2.5

6.

 Non-aerated soft drink

Yellow

Fruity

3.15-3.25

7.

 Plain buttermilk

Milky white

Acidic

4.72-4.82

8.

Spiced buttermilk

Milky white

Acidic

4.61-4.69

 

Temperature Equilibration Efficacy of Neat Beverages:

The observation of temperature equilibration studies revealed that the cold beverages took relatively lesser time to equilibrate with temperature of 37±2°C after dilution with distilled water (to make up the volume for disintegration or for in vitro dissolution) than the hot beverages despite the volume of one serving added for the later was lesser (120ml) than in case of cold beverages (250ml). This is due to the fact that the temperature gradient of cold beverages was relatively lesser than that of the hot beverages.

 

Organoleptic Properties of Modified Immersion and Dissolution Media: 

The optimized beverages were evaluated for colour (visual observation) and odor test. Among all the seven beverages the aerated cola drink was found to be strongly acidic.


 

Table 2: Organoleptic Properties of Modified Immersion and Dissolution Media

Sr. No.

Media code

Colour

Flavor

Initial pH

Final pH

1

Distilled water

-

-

7-7.2

7-7.2

2

Milk

White

Milky

6.81-6.84

6.92-6.98

3

Tea

brownish

Strong

6.6-6.72

7.1-7.15

4

Coffee

brownish

Strong

6.18-6.24

6.68-6.78

5

Aerated cold drink

blackish brown

Strong

2.4-2.5

2.6-2.7

6

CMZ

yellowish

Fruity

3.15-3.25

3.28-3.33

7

Plain buttermilk

Milky white

Acidic

4.72-4.82

5.71-5.80

8

Spiced Buttermilk

Milky white

Acidic

4.61-4.69

5.51-5.20

 

Table 3: Disintegration Time

Sr. No.

Immersion media code

Disintegration time (min)

(mean ± SD) (MF1)

Disintegration time (min)

(mean ± SD) (MF2)

Disintegration time (min)

(mean ± SD) (MF3)

Without disc

With disc

Without disc

With disc

Without disc

With disc

1

Distilled water

18.15±0.010

18.14±0.014

15.42±0.025

15.32±0.15

8.25±0.036

8.20±0.15

2

Milk

20.12±0.040a

20.63±0.41b

18.17±0.025a

18.12±0.064a

10.00±0.064a

9.96±0.42a

3

Tea

19.48±0.030a

19.40±0.19a

16.56±0.051a

16.62±0.38a

9.15±0.026a

8.89±0.28b

4

Coffee

20.38±0.030a

20.28±0.17a

17.33±0.052a

17.29±0.20a

10.12±0.060a

9.87±0.32a

5

Aerated cold drink

19.43±0.036a

19.35±0.037a

17.13±0.032a

16.68±0.31a

9.23±0.058a

8.96±0.37b

6

Non-aerated soft drink

21.08±0.060a

20.80±0.39a

18.37±0.025a

18.30±0.15a

10.09±0.02a

10.01±0.47a

7

Plain buttermilk

20.05±0.066a

19.64±0.34a

18.09±0.020a

17.88±0.42a

9.27±0.020a

8.93±0.39b

8

Spiced buttermilk

20.13±0.025a

19.80±0.21a

18.14±0.026a

18.10±0.31a

9.15±0.030a

9.10±0.21b

n=3, a Significant, p < 0.01, using one-way ANOVA, b Not significant

 


Effect on Disintegration Time:

The trend for disintegration time of tablet formulation MF1 in different immersion media was Non-Aerated Soft Drink > Coffee > Spiced Buttermilk > Milk > Plain Buttermilk > Tea > Aerated Cola Drink >Distilled Water and was significantly greater than that in the distilled water. In the presence of USP disk, the time required to disintegrate the tablets is less in all the media as compared to that without disk except in milk having slight increase in the disintegration time. The effect of food was significant in all the immersion media except in milk. The trend for disintegration time of tablet formulation MF2 in different immersion media was Non-Aerated Soft Drink > Milk > Spiced Buttermilk > Plain Buttermilk > Coffee > Aerated Cola Drink > Tea > Distilled Water and was significantly greater than in distilled water.

 

In the presence of USP disk, the time required to disintegrate the tablets is less in all media as compared to that without disk except in TEA where slight increase in the disintegration time was observed. The effect of food was significant in all the immersion media. The tablets of DS3 indicated significant increases in time for disintegration in all the modified immersion media as compared to those observed in water. The trend for disintegration time of tablet formulation MF3 in different immersion media was Coffee > Non-Aerated Soft Drink > Milk > Plain Buttermilk > Aerated Cola Drink > Spiced Buttermilk > Tea > Distilled Water.

 

In-vitro release profiles of tablet of brands MF1, MF2 and MF3:

At the end of 8 h, more than 82% of Meclizine hydrochloride from tablets MF1 was released in distilled water and other modified dissolution media except Coffee, Aerated Cola Drink, Non-Aerated Soft Drink and hence, the tablets failed the USP acceptance criteria in water and other dissolution modified media. In coffee, aerated cola drink, non-aerated soft drink having passed the USP acceptance criteria. The in vitro release of Meclizine hydrochloride in water at the end of 8 h was highest as compared to other modified media. The in vitro release profile of Meclizine hydrochloride from tablets MF1 exhibited release of more than 80% of drug in 8 h in all media except tea, aerated cola drink and non-aerated soft drink. Time required reaching peak concentration of Meclizine hydrochloride varied between 7-8 h for all dissolution profiles. The f2 values indicated that the profiles of Meclizine hydrochloride from MF1 in milk and spiced buttermilk could be considered similar with that in distilled water while all other profiles were dissimilar. At the end of 8 h, more than 82% of Meclizine hydrochloride from tablets MF2 was release in distilled water and other modified dissolution media except coffee, aerated cola drink, non-aerated soft drink, plain buttermilk, spiced buttermilk and hence, the tablets failed the USP acceptance criteria in water and other dissolution modified media. In coffee, aerated cola drink, non-aerated soft drink, plain buttermilk and spiced buttermilk having passed the USP acceptance criteria. The in vitro release of Meclizine hydrochloride in water at the end of 8 h was highest as compared to other modified media. The in vitro release profile of Meclizine hydrochloride from tablets MF2 exhibited release of more than 80% of drug in 8 h in all the media except tea, aerated cola drink, non-aerated soft drink, plain buttermilk and spiced buttermilk.


 

Table 4: In-vitro Study of tablets in Different Media

Medium

Time (hours)

MF1

MF2

MF3

% DR

RSD

f2 value

% DR

RSD

f2 value

% DR

RSD

f2 value

Distilled water

8

90.21

1.09

-

99.54

0.94

-

93.56

0.89

-

Milk

8

86.38

1.01

58.15

85.37

2.68

34.00

91.52

0.75

43.84

Tea

8

44.36

6.59

23.53

43.4

1.73

13.64

49.65

1.75

15.66

Coffee

8

80.03

0.99

33.80

80.18

1.36

26.58

77.76

2.85

36.11

Aerated cold drink

8

65.17

1.15

40.47

63.7

2.58

22.59

68.14

1.90

33.22

Non-aerated soft drink

8

72.52

1.28

45.41

68.24

1.79

25.32

73.28

1.35

36.02

Plain Buttermilk

8

85.88

1.04

41.03

67.99

3.83

23.62

58.34

6.29

31.91

Spiced Buttermilk

8

87.86

6.64

64.12

68.1

0.75

60.38

59.69

2.01

55.13

 

Fig 4: % Cumulative Drug Release of MF1 in Different Media

 

 

Fig 5: % Cumulative Drug Release of MF2 in Different Media

 

 

Fig 6: % Cumulative Drug Release of MF3 in Different Medium


 

Effect of Medium:

All the three brands followed the same trend of percentage drug release in milk, tea, cola and Mazza. Plain buttermilk and spiced buttermilk had the same trend of release for all the three brands. The modified medium containing tea had drastically reduced the percentage of drug released from all the three brands and it also did not comply with the USP criteria for release of Meclizine hydrochloride in 8 h. All the three brands followed altogether different trend of release of drug from the modified dissolution medium containing coffee release from three brands.

 

Comparative kinetics of release of Meclizine hydrochloride from SR tablets MF1, MF2 and MF3:

The best fit model for release profiles of Meclizine hydrochloride from sustained release (MF1, MF2 and MF3) tablets was consistent for tea, cola plain buttermilk and spiced buttermilk. However, great variation in kinetics was depicted for all other media including water for three SR brands of Meclizine hydrochloride. All the formulations when tested for kinetic study revealed that the drug release follow first order kinetics with the drug release model of kosmeyer’s paper.

 

CONCLUSION:

With the modern lifestyle the medication may often be consumed with, before or after the natural or synthetic beverages including aerated cola drinks or fruit juices. Hence, present work was carried out to study the probable interactions of commonly used beverages on the release characteristics of Meclizine hydrochloride from sustained release tablet dosage forms. The findings of the present study do suggest that a cognizance must be taken of such potential of these beverages where in both the onset and duration of action of drug is altered. Such interaction may especially change the risk to benefit ratio of programmed delivery and/or offset the benefits of smartly designed formulations which make use of speciality additives for spatial and temporal positioning of drug. These studies have much broader utility in terms of how the knowledge generated is employed for clinical study design and dosing regimen recommendations. Moreover, these findings also suggest the need for a regulatory approach to gauge the potential for dose dumping or sub therapeutic dose delivery from formulation and manufacturing process information and classification of products into “vulnerable” and “rugged” categories being developed.

 

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Received on 02.02.2021            Modified on 28.04.2021           

Accepted on 05.06.2021      ©Asian Pharma Press All Right Reserved

Asian Journal of Pharmacy and Technology. 2021; 11(3):191-197.

DOI: 10.52711/2231-5713.2021.00031