Formulation and Evaluation of Mesalazine Solid Dispersion

 

Chapalamadugu Ugandhar*

Al-Ameen College of Pharmacy, Bangalore, Karnataka.

*Corresponding Author E-mail: ugandhar.ch1@gmail.com

 

ABSTRACT:

A simple technique of solid dispersion was used in the present investigation. Solid dispersions of mesalazine was prepared by using different carriers such as HPMC K15M and peg 6000. Various solid dispersions were prepared as described in the methodology.  Solid state and drug polymer interactions were carried out by UV studies, these studies revealed that drug and polymer were compatible. The dissolution was carried out by USP, basket method. From the results, formulation PEG-1:2 (drug:polymer-1:2) released 87.7%  of drug within 8 hours . All the other formulations released were formulated such that they showed enhanced dissolution rate   with PEG and HPMC in different ratios.  In-vitro release indicated that the solid dispersion containing PEG-1:2 had better dissolution profile when compared with others. 

 

KEYWORDS: Solid dispersion, PEG, HPMC, dissolution

 


INTRODUCTION:

The term solid dispersion defined as “A dispersion of one or more active ingredients in an inert carrier or matrix in the solid state prepared by the melting, solvent or melt solvent method.

 

SELECTION OF CARRIERS:

It is important that the carries chosen for the solid dispersion system should be readily soluble in water.

 

IDEAL PROPETIES OF CARRIERS USED FOR SOLID DISPERSION5:

The carriers used for preparing solid dispersions should be

§  Soluble in water (Insoluble in case of sustained action            solid dispersion).

§  Non toxic.

§  Physiologically inert.

§  Have a relatively low pressure.

§  Physically and chemically complete with the drug.

§  Thermally stable up to its melting point.

 

E.g.:

Citric acid, Succinic acid, Bile acid, Sterols, and polymers like PVP and PEG etc.

 

METHOD OF PREPARATION6:

There are three general methods of preparation via

1)    Melting method

2)    Solvent method

3)    Melt-solvent method

 

1)    MELTING METHOD:

In this method the physical mixture of drug and water soluble carrier were heated directly until it is melted, which was then cooled, and solidified rapidly in an ice bath under rigorous stirring. To facilitate faster solidification, the homogenous melt is poured in the form of a thin layer on to a stainless steel plate and cooled by following air or water on the opposite side of the plate. This modification was employed by Goldberg et. al.7; the final mass is pulverized and sieved.

              

·      The simplicity and economy.

·      Super saturation of drug in a system can often be obtained by quenching the melt rapidly from a high temperature.

 

Under such conditions the solute molecule is arrested is arrested in the solvent mixture by instantaneous solidification process. Often system is found to harden more rapidly if kept at 370C or higher temperatures.

 

DISADVANTAGE:

Decomposition or evaporation of drug or carriers as fusion occurs usually at higher temperatures.

 

REMEDIAL MEASURES:

·      Evaporation can be avoided if the physical mixture is heated in a sealed container.

·      Melting under vacuum or blanket of inert gases like N2 may be employed to prevent oxidation of the drug.

 

2)    SOLVENT METHOD:

In the solvent method, solid dispersions are prepaid by dissolving of two solid Components in a common solvent, followed by evaporation of the solvent. More commonly, solvent is removed by evaporation under reduced pressure at different temperatures. The process uses organic solvent as the agent to intimately mix the drug and carrier to prepare solid dispersion.

 

ADVANTAGE:

The thermal decomposition of drug or carriers can be prevented because of the low temperatures required for the evaporation of organic solvents.

 

DISADVANTAGES:

The higher cost of preparation, the difficulty in completely removing the solvent and the difficulty of reproducing crystal forms.

 

3)    MELT-SOLVENT METHOD9:

The drug is first dissolved in a solvent and then the solution is incorporated directly into the melt of the carrier. This method has advantages of both melting and solvent methods although it is limited to drugs with low therapeutic dose. A liquid drugs such as methyl salicylate, Vitamin-E, clofibrate could be formulated as solid dosage from by mixing it with melted liquid of PEG-6000 and cooling the mixture.

 

MECHANISM OF INCREASED DISSOLUTION RATE5:-

§  Reduction of particle size.

§  Increased wettability in dissolution medium.

§  Increased dispersability in dissolution medium.

§  Formation of metastable dispersion.

§  Formation of high energy states, amorphous states.

§  Formation of soluble complex in micro environment.

 

 

MATERIALS AND METHODS:

PREPARATION OF SOLID DISPERSIONS BY SOLVENT EVAPORATION TECHNIQUE4:

The solid dispersions of mesalazine were prepared by the solvent evaporation technique. The weighed amount of the drug was dispersed in a given volume of polymer methanol solution of required concentration. These were stirred for 15 min to ensure homogenous mixing. The dispersion was then evaporated to dryness. Two size fractions- the particle which passed through sieve #40 and #60 and particles which passed through sieve #60 but retained on #80 were subjected for in-vitro dissolution performance. The drug is mixed with two different carriers such as HPMC, PEG  in 1:2 and 1:3 (drug: carrier) ratios.

TABLE-1: FORMULATION OF SOLID DISPERSION OF MESALAZINE

 

S. no

Formulation

Quantity of ingredients used (mg)

Drug

Carrier

Ratio

1

HPMC

100

200

1:2

2

PEG

100

200

1:2

3

HPMC

100

300

1:3

4

PEG

100

300

1:3

 

Evaluation of sustained Release Solid Dispersion:

1. Drug content uniformity:

The drug content uniformity was carried for solid dispersion system in the phosphate buffer pH 7.4.

 

Method:

Calibration curve.

 

2. Dissolution rate study:

Dissolution of mesalazine from various solid dispersion was studied by using phosphate buffer ph 7.4. Dissolution of mesalazine in pure form and various solid dispersion was studied by using USP XXIII dissolution rate test apparatus (serwell electronics) employing a bosket stirrer. A sample of solid dispersion equivalent to 100 mg. A temperature of 37±0.5oC was maintained throughout the experiment. 5 ml of sample of dissolution medium were withdrawn at known time interval and analyzed for mesalazine content by measuring the absorbance at 231 nm. The volume withdrawn was replaced with fresh quantity of dissolution medium. Percent of mesalazine dissolved at various times was calculated and plotted against time.

 

RESULTS AND DISCUSSION:

Standard Calibration Curve of Mesalazine:

Standard calibration curve of mesalazine was determined by plotting absorbance against concentration at 231 nm, it follows the Beer’s law. Results were tabulated in table no 2 and plotted in figure 1. The r2 and slope were found to be 0.9988 and 0.0419.

 

Evaluation of Sustained release solid Dispersion:

Drug content uniformity:

To ensure the uniform dispersion of formulation, drug content studies were carried out in triplicate by random sampling using phosphate buffer pH 7.4. Results revealed that has been uniformly distributed which lies wit in the prescribed limits of IP, the results were show in table no 2.

 

TABLE-2:DRUG CONTENT OF SOLID DISPERSION OF MESALAZINE

S. No.

Solid dispersion

Drug Polymer Ratio

% Drug content

1

HPMC

1:2

1:3

90.4

91.25

2

PEG

1:2

1:3

97.6

90.52

 

 


TABLE-3:IN VITRO DISSOLUTION PROFILE OF PURE DRUG

S. no

Time

Absorbance

Concentration

Amount present in 900ml

Cumulative%  of release

1

5min

0.0476

1.134

10.206

10.260

2

10min

0.0963

2.293

20.637

20.637

3

15min

0.2423

5.770

51.930

51.930

4

30min

0.3247

7.732

69.588

69.588

5

1hr

0.3984

9.487

85.383

85.383

6

2hr

0.4214

10.035

90.315

90.315

 

TABLE-4:  IN VITRO DISSOLUTION PROFILE OF HPMC(1:2)

S. no

Time

Absorbance

Concentration

Amount present in 900ml

Cumulative % of release

1

5min

0.01429

0.3403

3.0627

3.0627

2

10min

0.01887

0.4493

4.0437

4.0437

3

15min

0.02196

0.5229

4.7061

4.7061

4

30min

0.03642

0.8672

7.8048

7.8048

5

1hr

0.07987

1.9057

17.1510

17.1510

6

2hr

0.09654

2.2990

20.6910

20.6910

7

3hr

0.10920

2.6005

23.4045

23.4045

8

4hr

0.1987

4.7319

42.5872

42.5872

9

5hr

0.2542

6.0608

54.5472

54.5472

10

6hr

0.3387

8.0660

72.5940

72.5940

11

7hr

0.3709

8.8328

79.4950

79.4950

12

8hr

0.3926

9.3496

84.1464

80.1464

 

TABLE-5:IN VITRO DISSOLUTION PROFILE OF HPMC(1:3)

S. no

Time

Absorbance

Concentration

Amount present in 900ml

Cumulative % of release

1

5min

0.0132

0.2933

2.6387

2.6387

2

10min

0.0156

0.3731

3.3579

3.3579

3

15min

0.0203

0.4846

4.3614

4.3614

4

30min

0.0345

0.8230

7.4070

7.4070

5

1hr

0.0547

1.3040

11.7360

11.7360

6

2hr

0.0746

1.7787

16.0083

16.0083

7

3hr

0.0987

2.3519

21.1671

21.1671

8

4hr

0.1829

4.3556

39.2004

39.2004

9

5hr

0.2082

4.9582

44.6238

44.6238

10

6hr

0.3142

7.4825

67.3425

67.3425

11

7hr

0.3678

8.7590

78.8310

78.8310

12

8hr

0.3696

8.8018

79.2162

79.2162

 

TABLE-6: IN VITRO DISSOLUTION PROFILE OF PEG (1:2)

S. no

Time

Absorbance  

Concentration

Amount present in 900ml

Cumulative    % of release

1

5min

0.0324

0.771

6.943

6.0943

2

10min

0.0395

0.940

8.455

8.455

3

15min

0.0467

1.112

10.009

10.009

4

30min

0.0678

1.614

14.526

14.526

5

1hr

0.0747

1.778

16.010

16.010

6

2hr

0.0912

2.171

19.546

19.546

7

3hr

0.1243

2.960

26.640

26.640

8

4hr

0.1812

4.315

38.836

38.836

9

5hr

0.2012

4.791

43.123

43.123

10

6hr

0.2814

6.701

60.312

60.312

11

7hr

0.3442

8.196

73.772

73.772

12

8hr

0.3948

9.420

84.780

87.780

 

 

TABLE-7: IN VITRO DISSOLUTION PROFILE OF PEG (1:3)

S. No

Time

Absorbance   

Concentration

Amount present in 900ml

Cumulative  % of release

1

5min

0.0212

0.5048

4.5432

4.5432

2

10min

0.0345

0.8216

7.3944

7.3944

3

15min

0.0591

1.4079

12.6711

12.6711

4

30min

0.0627

1.4931

13.4379

13.4379

5

1hr

0.0752

1.7908

16.1172

16.1172

6

2hr

0.0814

1.9385

17.4465

17.4465

7

3hr

0.0912

2.1718

19.5462

19.5462

8

4hr

0.0987

2.3505

21.1545

21.1545

9

5hr

0.1089

2.5934

23.3406

23.3406

10

6hr

0.2987

7.1134

64.0200

64.0200

11

7hr

0.3012

7.1729

64.1511

64.1511

12

8hr

0.3897

9.2805

83.2540

81.2540

 


In vitro dissolution studies:

The in vitro release studies were carried out for all formulations using USP XXIII type I apparatus and   phosphate buffer pH 7.4 was used as the dissolution medium.

 

The in vitro drug release of pure drug was shown in table 3 and graphically represented as % cumulative release against time profile the graph was shown in figure1. The dissolution profile of solid dispersions was compared with pure drug. Data’s obtained has been graphically represented as % cumulative release against time profile. The graphs were shown in figure 2. The data of these studies were shown in table 3 to 7. It was found that the drug release was 90.3%. In case of HPMC solid dispersion, the drug release was 80.14% for 1:2 ratio at 8 hours, 79.21% for 1:3 at 8 hours.

 

FIGURE-1: DISSOLUTION PROFILE OF MESALAZINE PURE DRUG

 

FIGURE-2:  DISSOLUTION PROFILE OF SOLID DISPERSION OF MESALAZINE

In case of PEG solid dispersion, the drug release was 87.7% for 1:2 at 8 hours, 81.25% for 1:3 at 8 hours.

 

It concludes that PEG (1:2) had shown better sustained release rate when compared with other formulations.

 

REFERENCES:

1.       Chiou W1, Rieglman’s, Pharmaceutical application of Solid Dispersion system.  Journal of Pharmaceutical sciences 191; 60; 1281 – 1284.

2.       Udapa N, Tatwanadi SV, Gode Kd. Pharmaceutical Solid Dispersion.  The Eastern Pharmacist 1985; 12; 45 – 54.

3.       Madhu K, Vdnere, Encyclopedia of Pharmaceutical technology Vol.3, 1990, 337-351.

4.       Ruckmani K, Muneera MS, “Enhancement of solubility and dissolution of Carbamazipine by PEG-6000”, The Eastern Pharmcist, 2000 Jun;117-118

5.       Chowdhary K.P.R et al., prepared Mucoadhesive tablets of Mesalamine and its solid dispersions in HPMC and HPC were investigated with a view to design sustained release tablets of Mesalamine-2001.

6.       “Therapeutic Drugs” Volume 2:, C. Dollery (Ed), Churchill Livingstone London, UK,     1991,pp.25 - 27.

7.       Goldberg H, Gibaldi M, Increasing dissolution rates and gastrointestinal absorption of drug via solid dispersion and eutectic mixture of chloramphenicol-urea system. J Pharm Sci 1966;55;581-584

8.       The British Pharmacopoeia, The Pharmaceutical Press, London, UK, 2008, pp.1003 – 1004.

9.       Cristina, Flego, et al. Dissolution rate of Griseofluvin from solid dispersion with poly vinly methy1 ether maleic acid. Drug Dev Ind Pharm 1988; 14(9): 1185-1187

 

 

 

Received on 25.03.2012       Modified on 05.04.2012

Accepted on 06.04.2012      © RJPT All right reserved

Research J. Pharm. and Tech. 5(6): June 2012; Page 809-812