Kalyanwat R et al.

/ Pharmacie Globale (IJCP) 2011, 5 (09)

Available online at www.pharmacie-globale.info

ISSN 0976-8157

Research Article

PHARMACIE GLOBALE INTERNATIONAL JOURNAL OF COMPREHENSIVE PHARMACY

STUDY OF ENHANCEMENT OF DISSOLUTION RATE OF CARBAMAZEPINE BY SOLID DISPERSION

Renu Kalyanwat*1, Stuti Gupta1, Rajendra Kr Songara1, Dolly Jain1 and Sushma Patel2
1School 2Department

of Pharmaceutical Sciences, Jaipur National University, Jaipur, Rajasthan, India. of Pharmaceutical Sciences, M L S University, Udaipur, Rajasthan, India.

Received: 28 January 2011; Revised: 12 March 2011; Accepted: 28 April 2011; Available online: 5 May 2011

ABSTRACT

The purpose of this study is to enhance the dissolution rate of carbamazepine by solid dispersion. This solid dispersion of carbamazepine was prepared by modified solvent evaporation method. Two types of superdisintegrants croscarmellose sodium and sodium starch glycolate were incorporated. Then prepared different batches of solid dispersion were evaluated by drug content determination, saturation solubility study and dissolution study. Thus dissolution rate of carbamazepine was found to be increasing with superdisintegrant addition. Keywords: Carbamazepine, croscarmellose sodium, sodium starch glycolate, dissolution apparatus, UV spectrophotometer.

INTRODUCTION

Many potential drug candidates are characterized by a low oral bioavailability. Often poor drug dissolution/solubility rather than limited permeation through the epithelia of the gastrointestinal tract are responsible for low oral bioavailability.1 So all drugs, regardless of their administration route, must exhibit at least limited aqueous solubility for therapeutic efficiency. There are various methods to enhance the solubility for example salt formation, micronizing, complexation and solid dispersion formation.2 The principles for improving the dissolution properties of drugs by solid dispersion techniques are particle size reduction, alteration in crystalline morphology and intimately mixing the drug with hydrophilic excipients.3 Furthermore, no energy is required to break up the crystal lattice of a drug during dissolution process and improvement in drug solubility and wettability due to surrounding hydrophilic carriers. Reduction or absence of aggregation and agglomeration may also contribute to increased dissolution.4 The methods used to prepare SDs include solvent evaporation method5, melting method6, melt-solvent method7, kneading method8, co-precipitation method9, spray drying method10, gel entrapment technique11 modified solvent evaporation method12 and Coprecipitation with supercritical fluid13. Carbamazepine is an anticonvulsant drug. It is practically insoluble in water.14 Several attempts have been made to increase the dissolution rate or bioavailability of carbamazepine. In the current research, a modified solvent
*Corresponding Author: Renu Kalyanwat School of Pharmaceutical Science, Jaipur National University, Jaipur, Rajasthan, India. Contact no: +91-9462099521 Email: renu198324@gmail.com

evaporation method was used to prepare solid dispersions of carbamazepine. This method requires the dissolution of the drug in organic solvent at its saturation solubility with continued stirring for some time.12 Solid dispersion technique has already been employed for improving solubility of nimesulide, ketoprofen, celecoxib, albendazole and nifedipine.15

MATERIALS AND METHODS

Chemicals and Reagents Carbamazepine was supplied as a gift sample by Sun Pharmaceuticals Pvt Ltd, croscarmellose sodium was supplied as gift sample by Deys medical Store and sodium starch glycolate was purchased from SD fine chemicals Pvt Ltd India. All the reagents used were of analytical grade. Preparation of physical mixtures Physical mixture of carbamazepine with croscarmellose sodium containing six different weight ratio (1:0.5, 1:1, 1:3, 1:5, 1:7, 1:9) were prepared separately. Carbamazepine and CCS were accurately weighed, pulverized and then mixed thoroughly by light titration for 5 min in a glass mortar until homogenous mixture was obtained. Similarly physical mixture of carbamazepine with sodium starch glycolate containing six different weight ratio (1:0.5, 1:1, 1:3, 1:5, 1:7, 1:9) were prepared. Preparation of solid dispersions Modified solvent evaporation method: Solid dispersions of carbamazepine in croscarmellose sodium containing six different weight ratios (1:0.5, 1:3, 1:5, 1:7, and 1:9) were prepared by modified evaporation method. Accurately weighed amount of carbamazepine was dissolved in acetone at its saturation solubility. Polymer was suspended in sufficient amount of water. The carbamazepine solution was poured at once into polymer suspension. The entire solution was evaporated at 50C. It Pharmacie Globale (IJCP), Vol. 02, Issue 05

Kalyanwat R et al. / Pharmacie Globale (IJCP) 2011, 5 (09)

was stored in desiccators for 48 hours. Similarly solid dispersions of carbamazepine in sodium starch glycolate containing six different weight ratios (1:0.5, 1:3, 1:5, 1:7, 1:9) were prepared by modified evaporation method. Evaluation of Carbamazepine solid dispersion Carbamazepine content: The content of carbamazepine in each physical mixture (CCS/SSG) was determined using UV-spectroscopy. Accurately weighed physical mixture equivalent to 10mg of carbamazepine was transferred to 100ml of volumetric flask and diluted to 100ml with water and sonicated for 30 mins for complete solubilization of drug. Solution was filtered with filter paper. One ml of this solution was taken and its absorbance was measured spectrophotometrically. Concentration of carbamazepine was determined using calibration curve of drug in water. (Table 1) Table 1. Drug content in physical mixture
S No 1 2 3 4 5 6 7 8 9 10 11 12 Physical Mixture (PM) PMCCS(1:0.5) PMCCS(1:1) PMCCS(1:3) PMCCS(1:5) PMCCS(1:7) PMCCS(1:9) PMSSG(1:0.5) PMSSG(1:1) PMSSG(1:3) PMSSG(1:5) PMSSG(1:7) PMSSG(1:9) Drug Content (%) 97.23 98.40 96.65 98.54 96.20 95.26 98.57 97.65 97.47 98.81 98.65 97.65

Table 3. Solubility of carbamazepine in physical mixtures in water and simulated gastric fluid without enzymes
S No Sample Solubility of carbamazepine (mg/ml) Water 1 2 3 4 5 6 7 8 9 10 11 12 13 Drug PMCCS(1:0.5) PMCCS(1:1) PMCCS(1:3) PMCCS(1:5) PMCCS(1:7) PMCCS(1:9) PMSSG(1:0.5) PMSSG(1:1) PMSSG(1:3) PMSSG(1:5) PMSSG(1:7) PMSSG(1:9) 0.3 0.5 0.52 0.54 0.55 0.58 0.62 0.44 0.48 0.50 0.51 0.54 0.58 Simulated gastric fluid without enzyme 0.3 0.42 0.43 0.44 0.44 0.45 0.47 0.32 0.33 0.34 0.35 0.35 0.36

Table 4. Solubility of carbamazepine in solid dispersions in water and simulated gastric fluid without enzymes
S No Sample Solubility of carbamazepine (mg/ml) Water 1 2 3 4 5 6 7 8 9 10 11 12 13 Drug SDCCS(1:0.5) SDCCS(1:1) SDCCS(1:3) SDCCS(1:5) SDCCS(1:7) SDCCS(1:9) SDSSG(1:0.5) SDSSG(1:1) SDSSG(1:3) SDSSG(1:5) SDSSG(1:7) SDSSG(1:9) 0.3 1.36 1.41 1.48 1.55 1.57 1.6 1.34 1.4 1.46 1.54 1.56 1.58 Simulated gastric fluid without enzyme 0.3 1.35 1.4 1.46 1.52 1.54 1.56 1.32 1.38 1.44 1.5 1.52 1.54

The content of carbamazepine in each solid dispersion (CCS/SSG) was determined using UV-spectroscopy. Accurately weighed solid dispersion equivalent to 10mg of carbamazepine was transferred to 100ml of volumetric flask and diluted to 100ml with water and sonicated for 30 mins for complete solubilization of drug. Solution was filtered with filter paper. One ml of this solution was taken and its absorbance was measured spectrophotometrically. Concentration of carbamazepine was determined using calibration curve of drug in water. (Table 2) Table 2. Drug content in solid dispersion
S No 1 2 3 4 5 6 7 8 9 10 11 12 Solid Dispersion (SD) SDCCS(1:0.5) SDCCS(1:1) SDCCS(1:3) SDCCS(1:5) SDCCS(1:7) SDCCS(1:9) SDSSG(1:0.5) SDSSG(1:1) SDSSG(1:3) SDSSG(1:5) SDSSG(1:7) SDSSG(1:9) Drug Content (%) 97.65 98.55 96.75 96.80 95.26 98.35 97.66 97.54 98.80 96.87 98.21 97.59

Dissolution rate studies: In-vitro dissolution studies of carbamazepine, physical mixtures(CCS or SSG) and solid dispersions prepared by modified solvent evaporation method in 1:0.5, 1:1, 1:3, 1:5, 1:7 and 1:9 weight ratios were performed. The sample of 5 ml was withdrawn at regular intervals of 5 minutes by pipette. The volume withdrawn was replaced by fresh volume of dissolution medium (water or stimulated gastric fluid without enzymes) to maintain constant volume of medium. The filtered samples were analysed spectrophotometrically. The amount of carbamazepine released was determined using respective calibration curves. Table 5. In-vitro dissolution profile of carbamazepine and physical mixture of carbamazepine in water
Sample Drug PMCCS(1:0.5) PMCCS(1:1) PMCCS(1:3) PMCCS(1:5) PMCCS(1:7) PMCCS(1:9) PMSSG(1:0.5) PMSSG(1:1) PMSSG(1:3) PMSSG(1:5) PMSSG(1:7) PMSSG(1:9) 20.01 24.75 24.77 24.80 24.85 24.86 24.90 24.5 24.55 24.6 24.66 24.70 24.75 %cumulative carbamazepine release 15min 30min 45min 60min 90min 120min 39.82 49.71 49.75 49.80 49.83 49.85 49.95 49.48 49.54 49.62 49.65 49.7 49.72 40.24 74.80 74.82 74.85 74.88 74.9 74.92 74.5 74.52 74.6 74.65 74.7 74.75 40.71 96.55 96.65 96.7 96.74 96.8 96.85 95.45 95.62 95.78 95.77 95.8 96.0 40.72 96.74 96.75 96.76 96.77 96.82 96.9 95.5 95.65 95.8 95.81 95.85 96.21 41.22 96.85 96.76 96.78 96.79 96.84 96.21 95.56 95.7 95.82 95.85 95.92 96.25

Saturation solubility studies: The saturation solubilities of drug, physical mixtures and solid dispersions in water and simulated gastric fluid without enzymes were evaluated. For this drug was incorporated in 7ml water in successive amounts till it was being completely dissolved. It was stirred occasionally at 37C for 24hours. Then the solution was filtered and concentration of drug was determined by UV spectrophotometer. Following the same method saturation solubility of drug, physical mixtures and solid dispersions in simulated gastric fluid without enzymes was determined (Table 3 & 4)

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Table 6. In-vitro dissolution profile of carbamazepine and solid dispersion of carbamazepine in water
Sample Drug SDCCS(1:0.5) SDCCS(1:1) SDCCS(1:3) SDCCS(1:5) SDCCS(1:7) SDCCS(1:9) SDSSG(1:0.5) SDSSG(1:1) SDSSG(1:3) SDSSG(1:5) SDSSG(1:7) SDSSG(1:9) %cumulative carbamazepine release 15min 30min 45min 60min 90min 120min 20.01 39.82 40.24 40.71 40.72 41.22 80.25 92.25 96.31 96.45 97.20 97.45 81.50 92.75 97.10 97.45 97.65 97.65 82.25 93.40 97.50 97.55 97.65 97.85 83.12 94.25 97.78 97.80 97.80 98.05 84.25 95.32 98.0 98.12 98.15 98.45 85.25 96.21 98.12 98.18 98.50 98.65 79.45 91.85 95.25 96.38 97.05 97.28 79.55 92.18 96.85 97.4 97.45 97.55 80.45 93.16 97.35 97.52 97.6 97.74 81.45 94.18 97.70 97.75 97.78 97.90 82.25 95.22 97.85 97.95 98.05 98.36 83.21 96.14 98.05 98.10 98.25 98.57

Figure 1. In-vitro dissolution profile of carbamazepine and physical mixture of carbamazepine in water
120
%cumulative carbamazepine release

100 80 60 40 20 0
Drug

%cumulative carbamazepine release 15min %cumulative carbamazepine release 30min

PMCCS(1:0.5) PMCCS(1:1) PMCCS(1:3) PMCCS(1:5) PMCCS(1:7) PMCCS(1:9) PMSSG(1:1) PMSSG(1:3) PMSSG(1:5) PMSSG(1:7) PMSSG(1:0.5) PMSSG(1:9)

%cumulative carbamazepine release 45min %cumulative carbamazepine release 60min %cumulative carbamazepine release 90min %cumulative carbamazepine release 120min

7 Sample

10

11

12

13

Figure 2. In-vitro dissolution profile of carbamazepine and solid dispersion of carbamazepine in water
120 100

Table 7. In-vitro dissolution profile of carbamazepine and physical mixture of carbamazepine in simulated gastric fluid without enzyme
Sample Drug PMCCS(1:0.5) PMCCS(1:1) PMCCS(1:3) PMCCS(1:5) PMCCS(1:7) PMCCS(1:9) PMSSG(1:0.5) PMSSG(1:1) PMSSG(1:3) PMSSG(1:5) PMSSG(1:7) PMSSG(1:9) %cumulative carbamazepine release 15min 30min 45min 60min 90min 120min 20.01 39.82 40.24 40.71 40.72 41.22 24.25 49.25 74.28 92.65 92.70 92.75 24.32 49.35 74.30 92.85 92.90 92.95 24.40 49.38 74.35 93 93.5 93.65 24.42 49.4 74.4 93.54 93.65 93.68 24.45 49.45 74.42 93.65 93.70 93.72 24.48 49.47 74.45 94 94.25 94.30 24.10 49.10 73.2 92.50 92.55 92.58 24.20 49.23 73.4 92.74 92.8 92.85 24.25 49.35 73.45 92.91 92.95 92.96 24.28 49.4 73.75 93 93.21 93.24 24.30 49.46 74.25 93.54 93.58 93.6 24.40 49.87 74.25 93.84 93.9 93.92

%cumulative carbamazepine release

80 %cumulative carbamazepine release 15min %cumulative carbamazepine release 30min 60 %cumulative carbamazepine release 45min %cumulative carbamazepine release 60min %cumulative carbamazepine release 90min 40 %cumulative carbamazepine release 120min

20

SDSSG(1:1)

SDSSG(1:3)

SDSSG(1:5)

SDSSG(1:7)
12

SDCCS(1:1)

SDCCS(1:3)

SDCCS(1:5)

SDCCS(1:7)

SDCCS(1:9)

SDCCS(1:0.5)

7 Sample

SDSSG(1:0.5)

10

11

13

Figure 3. In-vitro dissolution profile of carbamazepine and physical mixture of carbamazepine in simulated gastric fluid without enzyme
100

%cumulative carbamazepine release

90 80 70 60 50 40 30 20 10 0

SDSSG(1:9)

Drug

%cumulative carbamazepine release 15min %cumulative carbamazepine release 30min %cumulative carbamazepine release 45min %cumulative carbamazepine release 60min %cumulative carbamazepine release 90min %cumulative carbamazepine release 120min

PMSSG(1:1)

PMSSG(1:3)

PMSSG(1:5)

PMSSG(1:7)
12

PMCCS(1:1)

PMCCS(1:3)

PMCCS(1:5)

PMCCS(1:7)

PMCCS(1:9)

Table 8. In-vitro dissolution profile of carbamazepine and solid dispersion of carbamazepine in simulated gastric fluid without enzyme
Sample Drug SDCCS(1:0.5) SDCCS(1:1) SDCCS(1:3) SDCCS(1:5) SDCCS(1:7) SDCCS(1:9) SDSSG(1:0.5) SDSSG(1:1) SDSSG(1:3) SDSSG(1:5) SDSSG(1:7) SDSSG(1:9) %cumulative carbamazepine release 15min 30min 45min 60min 90min 120min 20.01 39.82 40.24 40.71 40.72 41.22 75.10 90.75 94.25 95.21 95.54 96.14 76.22 90.82 95.21 96.22 96.50 96.74 77.30 90.9 96.15 96.75 97 97.2 78.25 91.24 96.50 96.75 96.8 97.3 79.25 92.25 97.15 97.35 97.45 97.51 80.25 93.25 97.34 97.45 97.52 97.6 75.05 90.55 94.08 95.15 95.52 96.10 76.12 90.78 95.12 96.15 96.45 96.60 77.24 90.78 96.12 96.50 96.85 97.15 78.20 91.20 96.42 96.25 96.78 97.28 79.20 92.15 96.0 97.18 97.20 97.45 80.15 93.24 97.30 97.32 97.35 97.54

PMCCS(1:0.5)

7 Sample

PMSSG(1:0.5)

10

11

13

Figure 4. In-vitro dissolution profile of carbamazepine and solid dispersion of carbamazepine in simulated gastric fluid without enzyme
120 100

%cumulative carbamazepine release

80 %cumulative carbamazepine release 15min %cumulative carbamazepine release 30min 60 %cumulative carbamazepine release 45min %cumulative carbamazepine release 60min %cumulative carbamazepine release 90min %cumulative carbamazepine release 120min 40

20

SDCCS(1:0.5)

SDCCS(1:1)

SDCCS(1:3)

SDCCS(1:5)

SDCCS(1:7)

SDCCS(1:9)

SDSSG(1:1)

SDSSG(1:3)

SDSSG(1:5)

SDSSG(1:7)
12

7 Sample

SDSSG(1:0.5)

10

11

13

CONCLUSION

RESULTS AND DISCUSSION

Drug content in physical mixture and solid dispersion was found to range from 95.26% to 98.81%. Solubility/ dissolution profile of the pure drug, physical mixture and solid dispersion were compared and an increase in dissolution of drug was found in physical mixture and solid dispersion in comparison to pure drug. (Figure 1, 2, 3 & 4)

As the concentration of superdisintegrants was increased an increase in solubility/dissolution profile of carbamazepine in medium was found. It may be due to the wicking and swelling properties of superdisintegrants in the medium. Croscarmellose sodium superdisintegrant showed better dissolution profile of carbamazepine from solid dispersion than sodium starch glycolate superdisintegrant. It may be due to more swelling and wicking ability of croscarmellose sodium. Dispersions. I J Pharm. 2002; 249:45-58. 2. Aulton; Design of Dosage Forms. Aultons Pharmaceutics The design and Manufacture of Pharmacie Globale (IJCP), Vol. 02, Issue 05

REFERENCES

1. Verheyen S, Blaton N and Kinget R, Van Den Mooter G; Mechanism of Increased Dissolution of Diazepam and Temazepam from Polyethylene glycol l6000 Solid

SDSSG(1:9)

Drug

PMSSG(1:9)

Drug

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3.

4. 5.

6.

7.

8.

9.

Medicines. Hungary: Churchill Livingstone, 2007; 1011. Williams R O, Taft D R and Conville J T M; Advanced Drug Formulation Design to Optimize Therapeutic Outcomes. New York:Informa Health Care,2007; 454486. Muhammad J H; Pharmaceutical Solid Dispersion Technology. New York: Lancaster, 2001; 13-81. Okonogi S and Puttipipatkhachorn S; Dissolution Improvement of High drug- loaded Solid Dispersion. AAPS Pharm Sci Tech. 2006; 7:52. Kalaiselven R, Mohanta G P, Kannan K, Manna P K and Manavalan R; Studies on Mechanism of Enhanced Dissolution of Albendazole Solid Dispersions with Crystalline Carriers. Indian J Pharm Sci. 2006; 68:599607. Patel M M and Patel D M; Fast Dissolving Valdecoxib Tablets Containing Solid Dispersion of Valdecoxib. Indian J Pharm Sci. 2006; 68:222-225. Chaulang G, Patil K, Ghodke D, Khan S and Yeole P; Preparation and Characterization of Solid Dispersion Tablet of Furosemide with Crospovidone. Research J Pharm and Tech. 2008; 4:386-389. Nokhodchi A, Talari R, Valizadeh H and Jalali M B; An Investigation on the Solid Dispersions of

Chlordiazepoxide. International Journal of Biomedical Science.2007; 3:210-216. 10. Vanshiv S D, Rao MRP, Sonar G S, Gogad V K and Borate S G; Physicochemical Characteization and Invitro Dissolution of Domperidone by Solid Dispersion Technique. Indian J Pharm Educ Res.2009; 43:86-90. 11. Bhise S B and Rajkumar M; Effect of HPMC on Solubilty and Dissolution of Carbamazepine Form III in Simulated Gastrointestinal Fluids. Asian Journal of Pharmaceutics.2008; 2:38-42. 12. Rane Y, Mashru R, Sankalia M and Sankalia J; Effect of hydrophilic swellable polymers on dissolution enhancement of carbamazepine solid dispersions studied using response surface methodology. AAPS Pharm Sci Tech. 2007; 8:27-30. 13. Moneghini M, Kikic I, Voinovich D, Perissutti B and Filipovic-grcic J; Processing of carbamazepine-PEG 4000 solid dispersions with supercritical carbon dioxide: preparation, characterization and in-vitro dissolution. Int. J. Pharm. 2001; 222:129-138. 14. Indian Pharmacopoeia Ministry of Health and Family Welfare 1996; 137. 15. Prajapati ST, Gohel MC and Patel LD; Studies to enhance dissolution properties of carbamazepine. Indian J Pharm Sci; 2007; 69: 427-430.

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