Formulation and Evaluation of Taste Masked Sustained Release Dosage Form of Metformin Hydrochloride Using Indion Resin

 

Bhoyar PK1*, Biyani DM2, Shahare HV1, Ikhar PK1,Borkar VS1

1S.S.D.J. College of Pharmacy, Neminagar Chandwad, Dist: Nashik (Maharashtra) India.

2S.K.B.College of Pharmacy, New Kamptee, Dist: Nagpur (Maharashtra). India.

 

ABSTRACT

Sustained release formulation of metformin hydrochloride (MTHCL) presents significant challenges due to its poor inherent compressibility, high dose and high water solubility. Thus formulating MTHCL into an sustained dosage form would provide slow release. But, it is bitter in taste and taste should be masked to formulate it in a palatable form. So in the work undertaken, an attempt was made to sustained the release as well as to mask the bitter taste by complexation technique using strong cation-exchange resin, Indion 254 and Indion 264 (Polyacrylic hydrogen with carboxylic functionality).The drug loading onto ion-exchange resin was optimized for mixing time, activation, effect of pH, mode of mixing, ratio of drug:resin and temperature.The resinate was evaluated for micromeritic properties, taste masking and characterized by X-Ray diffraction study and IR. Using resinate sustained release tablets were formulated using Hydoxy propyl methyl cellulose (K100M: HPMC) as binder and microcrystalline cellulose(MCC) as diluent.The tablets were evaluated for hardness, thickness,friability,drug content, weight variation and invitro drug release.Tablets thus formulated (Batch B-6) provided sustained release of drug over a period of time 10 hours with First order kinetics. The release of MTHCL from resinate controls the diffusion of drug molecules through the polymeric material into aqueous medium.The results showed that MTHCL was successfully taste masked and formulated into an sustained dosage form as an alternative to conventional tablet.

 

KEY WORDS: Metformin hydrochloride, Sustained release, Taste masking, Indion (254,264).

 

INTRODUCTION

In the present study Metformin Hydrochloride was chosen as a model drug. It is an oral antidiabetic biguinide preparation. It is used in the treatment of type 2 diabetes (NIDDM), type 1 diabetes (IDDM).1-2 It is very strongly bitter drug. Ion exchange resins are water insoluble cross linked polymers containing salt forming group in repeating position on polymer chain. The unique advantage of ion exchange resins for complexation is due to the fixed positively or negatively charged functional groups attached to water insoluble polymer backbones. These groups have an affinity for oppositely charged counter ions, thus absorbing the ions into the polymer matrix. Since most of drugs posses ionic sites in their molecules, the resin charge provides means to loosely bind such drugs. The binding is an equilibrium process, resulting in continuous desorption or elution of drug from the resin as drug is absorbed into the body.3-4 Several authors have reported to use ion exchange resinate matrices to controlled the release of variety of drugs.5-7

 

Administration of a drug orally having bitter taste with acceptable level of palatability is a challenge to the pharmacist in the present world, especially in pediatric and geriatric formulation.8-9 The complex of cationic drug and strong cation exchange resin does not break at the pH of saliva i.e. 6-7 with cation concentration of 40 meq/lit. This implies that while passing through mouth, the drug remains in the complex form, thereby imparting no bitter taste in the mouth.


In the present work strong cation exchange resins i.e. Indion 254, Indion 264 were employed. in order to get the sustained release profile of metformin hydrochloride.

 

MATERIALS AND METHODS:

Materials:

Metformin hydrochloride–IP was a Gift sample from Zim Laboratories (Nagpur, India). Indion 254, Indion 264 were obtained from Ion Exchange India Ltd. (Mumbai, India). MCC and HPMC (K100M) was obtained from Lobachemie (Mumbai, India).

 

Preparation of drug resin Complex (Resinate): 10-12

Resinates were prepared by Batch process. An accurately weighed amount of drug (100 mg) was dissolved in 100 ml of distilled water. Then ion exchange resin (100 mg) was added and stirred on a magnetic stirrer. Resinate thus formed was filtered and washed with copious amount of deionised water to remove any uncomplexed drug. It was then dried at 50oc and the drug content was determined spectrophotometrically at 233.5 nm. 

 

Determination of drug content in the resinate: 13

Accurately weigh,100 mg drug equivalent resinate, added to 100 ml of 0.1N  HCl and stirred for 5 hours. Then the suspension was filtered, further dilutions were made & the drug content was determined at 233.5 nm using 0.1N HCl as a blank.

 

Optimization of Metformin hydrochloride–Indion resin complexation:

The drug loading on to resin was optimized for various parameters such as mixing time, activation, effect of pH, mode of mixing, ratio of drug:resin and effect of temperature.

 

Table 1: Formulation Design

Ingradients

Formulations

B-1

B-2

B-3

B-4

B-5

B-6

Indion 254

Resinate

524*

524

524

-

-

-

Indion 264

Resinate

-

-

-

542*

542

542

MCC

(PH 102)

54

42

30

36

24

12

HPMC

(K100M)

48

60

72

48

60

72

Mg. Stearate

12

12

12

12

12

12

Talc

12

12

12

12

12

12

Total

650

650

650

650

650

650

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

* Containing 300 mg of drug

 

Optimization for mixing time on drug loading:11

Separate batches of indion 254 and indion 264 (100mg) were soaked in 100 ml of distilled water in a beaker and about 100mg of drug was added and stirred  for 5 hrs and the drug content was determined as mentioned previously.

 

Effect of activation of resin on drug loading:

Resins were washed with distilled water and subsequently with 1N HCl. The resins were rewashed with water until neutral pH was reached. Drug: resin complexes were prepared by placing 100mg of acid-activated resins, in a beaker containing 100 ml distilled water and about 100mg of drug and stirred for 5 hrs & drug content was determined. Similarly, alkali activation of all resins were performed, replacing 1 N HCl with 1 N NaOH.

 

Effect of pH, mode of mixing, ratio of drug: resin and temperature on drug loading: 10-12                           

For optimization of pH, weighed, 100 mg of drug was added to 100mg of activated Resins in 100 ml of distilled water. The pH of solutions were adjusted at 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0 and 6.5 and stirred for 5 hrs and the drug content was determined. For optimization of mode of mixing, Rotary shaker & Magnetic stirrer were used. All activated resins (100mg) in 100 ml of distilled water and about 100mg of drug. The pH were adjusted at 3.5 & drug content was determined. For ratio of drug:resin, three batches were prepared containing drug-resin in the ratio of 1:1, 1:2, 1:3. The pH was maintained at 3.5.The solution was stirred for 5 hrs. To study the effect of temperature, separate batches were prepared containing drug-resin in the ratio of 1:1 was taken. The pH was maintained at 3.5 and were stirred at 300C,350C,400C,450C,500C,600C,700C and  the drug content was determined .

 

Evaluation of micromeritic properties of resinates:14-16

The different properties of resinates like shape, flow properties, bulk density, tap density, packing ability were studied.

 

Characterization of resinate:

Infrared (IR) study:

FT-IR spectrum of the drug, resin and resinate were recorded over the wave no 4000 to 400 cm-1 on Jasco Dispersive type FT-IR spectrophotometer using the KBr disc technique .Then the spectra were comparatively analysed for drug interaction.  

 

X-ray diffraction study:

The drug, resins and resinate was subjected to X-ray diffraction study for the confirmation of complex formation.

 

Taste evaluation of solid drug: resin complex:

Drug resin complex (1:1) was subjected to sensory evaluation by a panel of nine members using time intensity method. Sample equivalent to 100 mg was held in mouth for 10 sec. Bitterness was recorded instantly and then after 20,30,40,50 and 60 minutes. The evaluation was performed by classifying bitter taste into five classes. Level 0: No bitter taste is sensed, 1: Acceptable bitterness, 2: Slightly bitterness, 3: Moderately bitterness Level 4: strongly bitterness. Descriptive statistics mean and standard deviation were calculated for all variables. Paired t test was applied using INSTAT software. Value p< 0.05 has been considered as statistical significant level.

 

Formulation of tablets:

Resinates of drug (dose of drug 300mg) were formulated into tablet by wet granulation technique using MCC and HPMC (K100M). Required quantity of resinate, HPMC (K100M) and MCC were blended in geometric fashion, deionised water was added to powder blend, disperse thoroughly in order to get the weight mass. The damp mass was then shift through sieve no-22 to obtain granules. The granules obtained were lubricated and compressed into tablet on tablet machine. (Table.1).

Evaluation of tablets:17-19

Tablets were evaluated for various official and nonofficial specifications.Thickness measured with the help of vernier caliper in micrometer. The hardness of the tablets were measured with monsanto hardness tester.

For drug content uniformity,20 tablets were weight and crushed. Weight accurately to get 10 mg drug equivalent resinate powder and transferred it to 100 ml of 0.1 N HCl. This suspension was stirred on a magnetic stirrer for 5 hrs. The suspension was then filtered and the drug content was determined at 233.5 nm by making suitable dilutions.

 

Table 2: Micromeritic properties of  resinates*

Character

Indion 254

resinate

Indion 264

resinate

Shape

Irregular

Irregular

Angle of repose

33.00

0.3233

Bulk density (gm/cm3)

0.7552

0.6944

Tap density (g/cm3)

0.7812

0.7352

Carr's index (%cc)

5.888

0.5549

Housner ratio

1.0625

1.058

 

 

 

 

 

 

 

 

 

 

 

* Average of three determinations

 

Table 3: Volunteers 0pinion test for Metformin hydrochloride before and after taste masking (n=9)

Time

(sec.)

Before

taste masking

Mean±SD

After taste

masking with

Indion 254

Mean±SD

After taste

masking with

Indion 264

Mean±SD

10

4.0±0.00**

0.2±0.44**

0.2±0.44**

20

3.3 ±0.50**

0.1±0.33**

0.1±0.33**

30

2.55±0.52**

0

0

40

2.0±0.50**

0

0

50

1.77±0.44**

0

0

60

1.22 ±0.44**

0

0

 

 

 

 

 

 

 

 

 

 

 

 

P<0.0001**

 

In-vitro release studies:

Tablets formulated with resinates were subjected to in-vitro dissolution studies using USP type II apparatus (paddle type) at 100 rpm with temperature of 370c ± 0.50 C. Dissolution was carried in 900 ml simulated gastric fluid for 2 hour and for further 8 hours in simulated intestinal fluid.20,21 After 1 hour interval, 5 ml dissolution medium was withdrawn by pipette. The samples withdrawn were diluted to 50 ml with buffer and filtered. The filtered samples were analyzed at 233.5 nm.

Drug release models:

 

The drug release data of Batch B-6 was fitted in various release kinetic equations such as Zero Order, First order, Matrix, Peppas, Hix.Crow.

 

RESULT AND DISCUSSION:

Optimization of Metformin hydrochloride-Indion resin complexation:

Metformin hydrochloride was loaded on ion exchange resin by batch process. Complexation is essentially a process of diffusion of ions between the resin and surrounding drug solution. As reaction is equilibrium phenomenon, maximum efficacy is best achieved in batch process .11

 

Complexation between drug and resin increase up to optimum time and then remain almost constant. It was found to be optimum after 5 hrs of mixing in all the resins investigated. Highest drug binding on resin was achieved when activated with 1N HCl. The drug loading was found to be 25.61±0.52, 25.32±0.49 for indion 254 and 264 respectively. After activation with acid treatment, the exchangeable ion on the resin is H+. Relative selectivity of H+ is least than other ionic form and therefore it increases percent complexation. Maximum drug loading on the resin occurs at pH 3.5; a maximum of 30.79±0.73, 29.75±1.16 for indion 254 and 264 respectively. As pH increases above 3.5, percentage of drug loading decreases. This may be due to fact that the fraction of metformin hydrochloride (pKa –11.5) protonation decreases as the pH increases and reduces the interaction with the resin.11- 22 Complexation was found to be optimum in case of stirring, a maximum of 30.79±0.67, 29.75±0.64 for indion 254 and 264 and in case of shaking 25.27±0.54, 24.67±0.86 for indion 254 and 264 respectively. This finding may indicate the significant involvement of van der waals forces taking place along with drug exchange during complexation. 23 Drug resin in the ratio of 1:1 gives optimum loading. The drug loading was found to be 30.78±0.53, 29.75±0.35 for indion 254 and 264 respectively. Increase in the amount of resin increases the amount of drug adsorbed from the solution but decreases the drug content per 100 mg of resinates. Maximum drug loading on the resin occurs at a temperature of 600C; a maximum of 58.31±0.74, 56.18±0.74 for indion 254 and 264 respectively. Increased temperature during complexation increases ionization of drug and resin. Higher temperatures tend to increase the diffusion rate of ions by decreasing the thickness of exhaustive exchange zone. 24

 

Evaluation of physical properties of resinates:

The different micromeritic properties resinates like shape, flow properties, bulk density, tap density, packing ability were studied (Table:2).The results showed that the resinates have good flow properties and packing abilities.

 

Evidence of complex formation:

Infrared (IR) study:

FT-IR spectra of drug shows peak for amino group at 1028 cm -1  wave number which is absent in FT-IR spectra of drug : resin complexes of indion 254 and 264 resinate. This gives evidences of complex formation.Figure:1.

 

 

X-ray diffraction study:

The X-Ray Diffraction study of drug shows highly crystalline nature. Resins indion 254 and indion 264 showed amorphous nature and the resinates showed noncrystalline characteristics. This might be because of entrapment of drug molecule in the polymer matrix of the resins. From all the evidences it can be concluded that the drug resinate was a chemical complex (Figure:2). Studies have shown that the molecules of the entrapped drug changes from crystalline to amorphous state.25

 

Panel evaluation of taste:

Panel of 9 members using time intensity method determined the threshold bitterness value. From majority of volunteers it was found that 100 mg/ml was the threshold concentration of bitter taste of metformin hydrochloride (Table:3). 


Table 4: Evaluation of physical characteristics of tablets (Batch B1-B6)

Evaluation parameters

Formulations

B-1

B-2

B-3

B-4

B-5

B-6

Hardness (kg)

4.11±0.64

4.25±0.63

4.51±0.36

4.21±0.68

4.41±0.32

4.53±0.35

Thickness (mm)

7.55±1.57

7.56±0.63

7.16±1.23

7.53±0.93

7.26±0.35

7.21±0.46

Friability (%w/w)

0.63

0.58

0.53

0.54

0.49

0.44

Drug Content (%w/w)

97

96.68

99

98.1

97.22

99

% Weight variation

3.45 ±0.7

4.04 ±0.6

1.43 ±0.4

2.08±1.6

2.78±0.5

1.23±0.2

 

 

Table 5: Cumulative % of drug release from tablets(Batch B-1-B-6)

Time

(Hrs) 

Dissolution

Medium 

Cumulative  drug release (Mean±S.D.,n=3 )

B-1

B-2

B-3

B-4

B-5

B-6

1

1.2 PH Buffer

25.05±

0.48

25.15±

0.48

23.34±

2.59

24.55±

0.59

23.32±

2.48

22.73±

0.47

2

1.2 PH Buffer

 

44.16±

0.92

43.30±

1.54

39.61±

1.45

42.95±

2.48

40.88±

1.48

39.56±

0.48

3

6.8 PH Buffer

 

55.24±

1.49

55.26±

0.58

54.79±

1.49

54.82±

0.48

53.52±

0.48

53.3±

0.48

4

6.8 PH Buffer

 

65.83±

0.83

63.64±

1.49

63.62±

0.59

64.99±

1.39

63.88±

0.49

63.79±

1.49

5

6.8 PH Buffer

 

74.96±

1.58

73.73±

1.32

72.84±

0.59

74.63±

0.49

73.73±

0.95

71.97±

1.49

6

6.8 PH Buffer

 

82.39±

0.58

82.08±

2.48

78.99±

0.48

81.12±

0.49

80.92±

0.83

79.16±

0.49

7

6.8 PH Buffer

 

90.96±

1.49

89.95±

1.40

85.86±

0.94

86.12±

0.37

84.91±

1.49

83.18±

0.49

8

6.8 PH Buffer

 

91.07±

0.49

95.17±

0.91

92.77±

0.87

91.96±

1.40

89.74±

2.54

85.96±

0.58

9

6.8 PH Buffer

 

 

 

 

 

93.86±

1.48

89.75±

1.46

10

6.8 PH Buffer

 

 

 

 

 

 

92.37±

1.47


 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Figure 1: FT-: IR spectra of A. Metformin hydrochloride, B. Indion 254 resin,                                

 C.Indion-254 resinate, D Indion 264 resin, E. Indion-264 resinate.

 

Fig. 2: X-Ray Diffraction pattern of A. Metformin hydrochloride, B. Indion 254 resin,C. Indion-254 resinate, D Indion 264 resin, E. Indion-264 resinate.

 

Formulation of sustained release tablet using resinate:

The batches of controlled formulations were designed, using higher and lower concentration of HPMC (K100M)  and MCC (PH-102) and other excipients and compressed into tableting machine.    

 

Evaluation of tablets:

The prepared batches (B1-B6) of tablets were evaluated for various official and non-official parameters. Tablets were obtained of uniform weight due to uniform die fill with acceptable variations as per IP specifications, i.e.below 7.5 %.The hardness of tablets for each formulation was between 4-5 kg/cm2 .Average thickness was found to be in the range of 6 to 8 mm. Friability below 1% was an indication of good mechanical resistance of the tablets. The uniformity of drug content was found to be 96%-99% w/w which was within acceptable limits. Results are shown in Table 4.

 

In-vitro drug release:

Results of the invitro release studies of various formulations designed and manufactured are presented in Table No 5 and are shown in Figure.3.The result showed that, in case of  indion 254 resinate, more than 95 % of drug released from tablets formulation with HPMC (K100M) in 8 to 10 % concentration within 7-8 hrs(Batch B1,B2). By addition of 12% HPMC does not affect the drug release significantly (Batch B-3). This may be due to rapid disintegration of tablets in dissolution medium because of larger particle size of indion 254 resinate. In case of indion 264 resinate tablets (Batch B-4, B-5) with 8-10 % HPMC, more than 93 % of the drug released within 8-9 hrs. Addition of 12 % HPMC, more than 92 % of drug released from tablet for 9 to 10 hrs (Batch B-6).This may be because of strong binding properties of HPMC which binds the fine particles of resinate. The drug release from these tablets was simply due to slow erosion and ion exchange. The B-6 formulation shows precise sustained release of metfomin hydrochloride with first order kinetics.

 

Fig. 3: Cumulative % of drug release from tablets (Batch B-1-B-6)

 

CONCLUSION:

Metformin hydrochloride a bitter drug could be successfully sustained released and taste masked using ion exchange resins. The process of sustained release was optimized with respect to parameters like mixing time, activation, effect of pH, mode of mixing, ratio of drug: resin and temperature. The resinate was evaluated for micromeritic properties, taste masking and characterized by IR and X-Ray diffraction study. Tablets thus formulated with Indion 264 and 12% HPMC (K100M) (Batch B-6) provided sustained release of drug over a period of time 10 hours. The release of MTHCL from resinate controls the diffusion of drug molecules through the polymeric material into aqueous medium. The B-6 formulation shows precise sustained release of metfomin hydrochloride and follows first order kinetics. Hence it was concluded that, formulation B-6 was selected as best formulation.

 

ACKNOWLEDGEMENT:

The author wish to thanks Zim pharmaceuticals Pvt.Ltd (kalmeshwar),Nagpur,India for providing the gift sample of Metformin hydrochloride.The authors wish to thanks Ion-Exchange India ltd. Mumbai,India for providing Indion resin samples and University department of  Physics, Nagpur, India for providing X-Ray diffraction facility.

 

REFERENCES:

1.       Hermann LS,Melender A. Biguanides: Basic aspects and Clinical use. Wiley, New  York.1992.

2.       Tucker GT,Casey C,Phillips PJ. Metformin kinetics in health subjects and in patients with diabetes mellitus. Br.J. Cli.Pharmacology.1981;12(2):235-246.

3.       Hughes L.Ion exchange resinates-Technology behind the mystery. Pharmaceutical  Technology.2005; 17(4):38-42.

4.       Borodkin S,Yunker MH.Interaction of amine drugs with a polycarboxylic acid ion-exchange resin. J. Pharm.Sci. 1970;59(4):481-486.

5.       Raghunanthan Y,et al. Sustained release drug delivery system. I: Coated ion-exchange resin system for Phenylpropanolamine and other drugs. J Pharm Sci. 1981; 70:379-383.

6.       Wolf O, Antitussive effect of Noscapine Hydrochloride sulphonated cross-linked polystyrene resin. J.Pharm.Sci.1965;54 (4):1058.

7.       Manek SP, Kamat VS. Indion CRP-244 and Indion CRP-254 resins as  sustained release and taste masking agents.Ind.J.Pharm.Sci.1981;(43):209-212.

8.       Glen M. Taste masking in oral pharmaceuticals. Pharm.Technol.1994;18(4):84-98.

9.       Gowthamarajan K, ,et al.Pop the bitter pills:Taste masking technologies for bitter  drugs.Resonance.2004;25-32.

10.    Avari J G, Bhalekar M.Cation exchange resin for taste masking and rapid  dissolution of Sparfloxacin.Indian Drugs.2004;41(1):19-23.

11.    Pisal S, et al. Molecular Properties of ciprofloxacin-indion 234 complexes.   AAPSPharmaSciTech.2004;5(4):1-8    

12.    Quality control methods for medicinal plants.World Health Organization.1998:38- 40.

13.    Schacht EH. Controlled Drug Delivery .Stephen.D.Bruck, Florida.1983.

14.    Banker G.S, Anderson N.R.Theory and Practice of Industrial Pharmacy. Liberman and Kingies, Philadelphia.1987.

15.    Mahajan H S,et al. Mouth dissolving tablets of  sumatriptan succinate. Indian Drugs.2004; 41(10):592-598.

16.    Cooper J,Gunn C. Powder flow and compaction..In Carter. Tutorial Pharmacy. New Delhi.1986: 6th ed: pp.211-233.

17.    Lachman L.Liebermann H A.The Theory and Practice of Industrtial Pharmacy. Mumbai: Varghese Publishing House;1987: 4 th ed:pp.293.

18.    United State Pharmacopoeia: 23: United State Pharmacopoeial Con.Inc:1987;323.

19.    Rawlins E A.Bentley’s Textbook of Pharmaceutics. London:Cassell and  Collier Macmillan, London.1977.

20.    Indian Pharmacopoeia, Controller of Publication of India.New.1996:4th ed:pp.82-84.

21.    Anonymous,British Pharmacopoeia.1993;61-79.

22.    Bhalekar M,et al. Cation exchangers in pharmaceutical formulations. Indian  J.Pharma.Educ.2004; 38(4):184-188.

23.    Glasstone S, Lewis D. Elements of Physical Chemistry. Macmillan  and Company, London.1960.

24.    Frank D, Koebel B. Some like it hot, some like it cold. Water Quality.2000; 54:54-57.

25.    Akkaramonkolporn P. Molecular properties of propranolol hydrochloride prepared as drug-resin complexes. Drug Dev Ind Pharm.2001; 27:359-364.

 

 

 

Received on 26.04.2009

Accepted on 10.05.2009     

© A&V Publication all right reserved

Research Journal . of Pharmaceutical Dosage Forms  and Technology. 1(1): July.-Aug. 2009, 49-54