N Damodharan et al.

/ Journal of Pharmacy Research 2012,5(1),333-337

Research Article ISSN: 0974-6943

Available online through www.jpronline.info

Preparation and Evaluation of solid dispersion of Candesartan cilexetil

N Damodharan* and Navya Ghanta. Department of pharmaceutics, SRM College of Pharmacy, SRM Nagar, Kattankulathur,Chennai-603203, Tamilnadu, India.

Received on:20-09-2011; Revised on: 15-10-2011; Accepted on:10-12-2011 ABSTRACT

The current study was aimed to enhance the solubility of poorly soluble drug Candesartan cilexetil using solid dispersion technology and thereby improving its dissolution characteristics. Solid dispersions were formulated by using carriers like polyethylene glycol 6000(hydrophilic polymer), polyvinylpyrrolidone K 30(hygroscopic polymer) and Gelucire 50/13(amphiphilic surfactant) in different drug-to- carrier ratios by solvent evaporation and melting method. The prepared solid dispersions were characterized using differential scanning calorimetry, powder X-ray diffraction and solubility studies. Based on solubility data three drug-to-carrier combinations, polyethylene glycol (1:5), polyvinylpyrrolidone K 30 (1:5) and Gelucire 50/13 (1:1) were selected to formulate into a capsule dosage form equivalent to 8mg of the drug. The capsules were evaluated for its physical parameters like weight variation, disintegration, drug content and in-vitro dissolution studies. Results of dissolution studies showed rapid release of drug from solid dispersions when dispersed in polyvinylpyrrolidone K 30 when compared with pure drug and other formulations. The dissolution profile of chosen capsule was compared with the marketed product and the formulated capsule showed better release profile than the marketed product. Thus solid dispersion technique can be used successfully for enhancement of solubility and dissolution characteristics of Candesartan cilexetil. Key words: Candesartan cilexetil, Solid dispersion, Differential scanning calorimetric studies, Powder X-ray diffraction studies, Dissolution, Carriers. INTRODUCTION The progress in treatment of diseases has been evident within upsurge in development of new drugs. An estimated 40% of new chemical entities discovered by the pharmaceutical industry today are poorly soluble or lipophilic compounds. The solubility issues complicating the delivery of these new drugs also affect the delivery of many existing drugs. The enhancement of oral bioavailability of such poorly water soluble drugs remains one of the most challenging aspects of drug development [1]. The development of solid dispersions in 1961 by Sekiguchi and Obi as a practically viable method to enhance bioavailability of poorly water soluble drugs overcame the limitations of previous approaches such as salt formation, solubilization by cosolvents and particle size reduction [2]. The term solid dispersion refers to a group of solid products consisting of at least two different components, generally a hydrophilic matrix and a hydrophobic drug. The matrix can be either crystalline or amorphous [3]. Candesartan cilexetil is a prodrug which is hydrolyzed into Candesartan during absorption from the gastro intestinal tract. Candesartan is a selective AT1 subtype angiotensin II receptor antagonist. It is indicates for the treatment of hypertension. Candesartan blocks the vasoconstrictor and aldosterone secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in many tissues such as vascular smooth muscle and adrenal gland (www.drugbank showing Candesartan cilexetil/ca). Candesartan cilexetil is practically insoluble in water leading to poor dissolution and variable bioavailability upon oral administration. The main objective of this work is to investigate the possibility of improving the solubility and dissolution rate of Candesartan cilexetil by preparing solid dispersions with

various carriers like polyethylene glycol 6000, polyvinylpyrrolidone K 30 and Gelucire 50/13 in different ratios. MATERIALS AND METHODS Materials Candesartan cilexetil was supplied by Dr. Reddys laboratory and polyethylene glycol 6000 from Viswaat chemicals, polyvinylpyrrolidone K 30 from BASF India and Gelucire 50/13 from Gate fosse. All other chemicals and reagents used were of analytical grade. Methods Solubility studies It was carried out to determine solubility of Candesartan cilexetil in presence of various carriers like polyethylene glycol 6000, poloxamer 188, polyvinylpyrrolidone K 30, Gelucire 50/13, hydroxy propyl methyl cellulose etc. This was done by dissolving excess amount of drug in flasks containing different concentrations of carriers in different ratios (1:0.25, 1:1, 1:5) in distilled water. The flasks were shaken thoroughly at 200rpm and kept aside for 48hours. The suspensions were filtered and absorbance was measured at 254nm after dilution. From these studies carriers like polyethylene glycol 6000, polyvinylpyrrolidone K 30, Gelucire 50/13 was chosen as they showed better solubility. These drug-to-carrier ratios were used for preparation of solid dispersions (Table 1).

Table 1: Solubility data of the drug using different carriers

S.no Polymer

*Corresponding author.
Dr. N.Damodharan, M.Pharm., Ph.D. Professor and Head, Department of Pharmaceutics, SRM College of Pharmacy, Kattankulathur-603203, India.
1 2 3 4 5 6 7 8 Poloxamer 188 Polyvinylpyrollidone K30 Gelucire 50/13 Hydroxypropyl Methyl Cellulose Polyethylene Glycol 4000 Polyethylene Glycol 6000 Hydroxy Propyl Cellulose Mannitol

Drug:polymer ratios 01:00.3 1:01 1:05 0.0003 0.0011 0.0078 0.0011 0.0006 0.001 0.0003 0.0003 0.0007 0.0007 0.03 0.0002 0.0009 0.0005 0.0004 0.0003 0.0008 0.0005 0.0292 0.0001 0.0004 0.0004 0.0003 0.0001

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Preparation of Solid Dispersion[4] Solid dispersions of Candesartan cilexetil were prepared by melting and solvent evaporation method. In melting method, required quantity of the drug with polyethylene glycol 6000, polyvinylpyrrolidone K 30 and Gelucire 50/13 were prepared separately in 3 different ratios 1:0.25, 1:1, 1:5, mixed well in a china dish and heated up to a temperature just beyond the melting points of the carriers. The mixture was poured on a tile and cooled. The resulted solidified mass was pulverized and passed through sieve # 30[5]. In solvent evaporation method, required quantity of the drug with polyethylene glycol 6000, polyvinyl pyrrolidone K 30 and Gelucire 50/13 were prepared separately in 3 different ratios 1:0.25, 1:1, 1:5, dissolved separately in acetonitrile. Solvent was removed by evaporation under reduced pressure. The mass was dried in an oven, pulverized and passed through sieve # 30.

Figure 1: X-ray powder diffraction studies of Candesartan cilexetil and carriers Journal of Pharmacy Research Vol.5 Issue 1.January 2012 333-337

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EVALUATION OF SOLID DISPERSIONS Powder X-Ray Diffraction[6] To investigate the polymorphic transitions and the influence of carriers on these transformations during preparation of solid dispersion and the phase identification of a crystalline material lattice spacings were measured by Xray diffraction. The physical state of Candesartan cilexetil in different samples was evaluated and X-ray diffractograms were recorded using BRUKER P XRD instrument. Standard runs using a 40 kV voltage, a 40mA current and a scanning rate of 0.020min-1. The diffraction patterns of the pure drug exhibits its characteristic peaks at various diffracting angles indicating the crystalline nature where as solid dispersion of polyvinylpyrrolidone K 30 and Candesartan cilexetil exhibits a diffraction spectrum not showing any detectable peaks, which indicates the presence of drug mostly in amorphous form. The other two solid dispersions drug: polyethylene glycol 6000 and drug: Gleucire50/13 showed diffraction peaks which were matching to that of pure drug indicating the presence of drug in crystalline form (Figure-1). Differential Scanning Calorimetry Thermal investigations of solid dispersion were performed by using Perkin Elmer. In an aluminum pan, 3-6 mg of sample was placed and crimped with a lid containing a pin hole and kept in the DSC unit along with a similar pan as a reference. The sample was heated at 100 c /min from temperature range of 10-3000 C. The experiment was performed under nitrogen flow, at a scanning rate 100C/min. DSC scans of various solid dispersion of Candesartan cilexetil were taken. Figure-2 reports the thermograms of solid dispersions of drug/Gelucire 50/ 13, drug and Gelucire 50/13. The DSC curve of pure Candesartan cilexetil exhibited a single endothermic peak at 1650 c corresponding to the melting of the drug and the sharp peak indicates its crystallinity. The DSC curve of Gelucire 50/13 exhibited a single endothermic peak at 450 c corresponding to the melting of the polymer. Thermal profiles of solid dispersion showed the melting peaks of Gelucire 50/13 at 450 c and drug at 1650 c indicating the drug crystalline form. Figure-3 reports the thermograms of solid disperisons of drug/polyethylene glycol 6000, drug and polyethylene glycol 6000. Solid dispersions of drug and polyethylene glycol 6000 showed melting peaks of drug at 1690 c and polyethylene glycol 6000 at 610 c indicating that the drug still exists in crystalline form. But in both polyethylene glycol 6000 and Gelucire 50/13 the intensity of the peak was reduced indicating that the drug crystallinity got reduced in solid dispersions. Figure-4 reports the thermograms of solid dispersions of drug/polyvinylpyrrolidone K 30, drug and polyvinyl pyrollidone K 30. Polyvinylpyrollidone K 30 always showed a broad endotherm due to the presence of residual moisture ranging from 800 C to 1200 C. Solid dispersions of drug and polyvinyl pyrollidone K 30 showed broad endotherm but the drug melting point was no longer observed. It could be attributed to the destruction of crystal lattice, because of progressive amorphization or dissolution into the carrier[7]. This indicates the conversion of drug into amorphous form and confirms that the drug no longer exists in crystalline form. Solubility studies of solid dispersions Solid dispersions produced using polyethylene glycol 6000, polyvinylpyrrolidone K 30, Gelucire 50/13 as carriers in three different ratios were checked for their solubility. According to the drug polymer ratio required quantity of solid dispersion was weighed along with sodium lauryl sulphate (50 mg) and Figure 3: DSC curves of Polyethylene glycol 6000. added to 10 ml of demineralized water and maintained at 37o c and shaken in a Rota shaker for 48 hours at 200 rpm[8]. The samples were filtered using 0.45m pvdf filters and analyzed using HPLC at 254 nm. From these studies three formulations were selected and they include drug + polyethylene glycol 6000 (1:5), drug + polyvinylpyrrolidone K 30 (1:5) and drug + Gelucire 50/13 (1:1) (Table 2).

Table 2: Solubility Studies of formulated solid dispersions

S.NO Drug+Polymer Conc of drug (mg/ml) 01:00.3 1:01 1:05 0.0692 0.13172 0.09632 0.1021 0.15928 0.05593 SLS 50 mg 50mg 50mg

1 2 3

Drug+Polyethylene Glycol 6000 0.05852 Drug+Polyvinylpyrollidone k 30 0.12096 Drug+Gelucire 50/13 0.06629

Figure 2: DSC curves of Gelucire.

Figure 4: DSC curves of Polyvinylpyrollidone K 30.

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Capsule preparation and characterization [9] To each dose of prepared solid dispersions of polyethylene glycol 6000, polyvinylpyrrolidone K 30 and Gelucire 50/13 at selected ratios, 50mg of sodium lauryl sulphate was added and the formulated solid dispersions equivalent to 8 mg of drug were filled in size 3 capsules [10]. Composition of different formulations of Candesartan cilexetil is given in Table 3. Results of dissolution studies indicated rapid and fast dissolution of Candesartan cilexetil, about 85% within 60 minutes from solid dispersion when dispersed in polyvinylpyrrolidone K 30 (F-1). In case of formulation F-2(with drug and polyethylene glycol 1:5) showed 53.2% within 60 minutes, formulation F-3(with drug and Gelucire 50/13 1:1) showed 16.5% and pure drug 0.6%. The fast and rapid dissolution of drug from solid dispersion containing polyethylene glycol as carrier is due to presence of drug in amorphous form. X-ray diffraction and differential scanning calorimetric studies revealed that crystalline nature of Candesartan cilexetil in pure form was reduced in the solid dispersions. X-ray diffractograms and differential scanning calorimetric analysis confirms that the drug-to- carrier composition alters the crystallinity of the samples. Solid dispersions of drug when dispersed in polvinylpyrrolidone (1:5) converted the crystalline drug into amorphous form. When compared with the pure drug and with other formulations, the dissolution was found to increase in the following order: Formulation I > Formulation II > Formulation III > Drug Comparative dissolution profile, of different formulations of solid dispersions, and pure drug are shown in Figure-5. Formulation I is compared with that of marketed product and the release profile of Formulation I showed superior results from which 80% of the drug is released within 15 minutes (Figure-6). Hence the formulated solid dispersion capsules can be prescribed for the treatment of hypertension. The solubility of Candesartan cilexetil was successfully increased by using solid dispersion technology. It demonstrated the usefulness of solid dispersions in enhancing the solubility of drug.

Table 3: Formulations of Candesartan celexitil

S.No Formulations F-1 (polyvinyl pyrollidone K30) (1:5) 8 40 50 F-2 F-3 (polyethylene (GELUCIRE 50/13) glycol 6000) (1:5) 8 40 50 (1:1) 8 8 50

1 2 3 4

Drug: polymer ratios Drug (mg) Polymer (mg) Sodium lauryl sulphate (mg)

Prepared capsules were evaluated for weight variation, disintegration, drug content uniformity and in-vitro dissolution studies. Drug content uniformity Amount of solid dispersion equivalent to 8 mg of the drug was dissolved in mobile phase (Mixture of buffer (0.02M mono basic potassium, acetonitrile, triethylamine in the ratio of 40:60:0.2, pH adjusted to 6.0 using phosphoric acid) and analyzed for drug content using HPLC at 254nm. In-vitro dissolution studies were carried out in USP type II paddle apparatus using 500 ml demineralized water maintained at 370.5oc. 10ml aliquots of samples were withdrawn at different time intervals and replaced using drug free dissolution media. The samples were analyzed using HPLC and the percentage of drug dissolved at different time intervals was plotted against time. The drug release profiles of formulated capsules were compared with the pure drug and with the marketed product [11]. RESULTS AND DISCUSSION Solid dispersions showing better solubility were formulated into capsule dosage form and evaluated for its parameters. All the parameters were within the specified limits. Weight variation was within the I.P limits (10%). The time taken for the capsules to disintegrate was evaluated in all the formulations and found to be in the range of 8-9minutes which was within I.P limits (within 15 minutes for uncoated tablet). The drug content analysis of Candesartan cilexetil in all the formulations was found to be 98.9% w/w (Table 4). It indicates that the drug is uniformly dispersed and the methods used in the study appear to be reproducible for preparation of solid dispersions.

Table 4: Drug content uniformity

Solid Dispersion Drug: Carrier Amount of solid dispersion (mg) 98 98 66 Expected amount of drug (mg) 8 8 8 % of drug estimated by HPLC

Figure-5: Comparative dissolution profile of different formulations and drug

Drug-polyethylene glycol 6000 Drug-polyvinyl pyrollidone K 30 Drug-gelucire50/13

1:05 1:05 1:01

98.2 99.7 98.8

In-vitro dissolution studies are performed for all the three formulations (Table 5). Table 5: Dissolution studies
S.NO Time in min Percentage drug released F-1 F-2 F-3 80.2 82.1 85.6 86.5 84.9 43.2 46.9 49.1 51.7 53.2 13.4 14.5 14.9 15.4 16.5 API 0.1 0.1 0.1 0.1 0.6 marketed 16.6 17.1 18.5 19.9 21.2

1 2 3 4 5

15 30 45 60 Recovery

Figure-6: Comparative Dissolution Profile of Marketed Product and Formulation-I Journal of Pharmacy Research Vol.5 Issue 1.January 2012 333-337

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CONCLUSION Candesartan cilexetil used in the treatment of hypertension provide a better therapy and good patient compliance if solubility of drug is successfully increased by using solid dispersion technology. The result indicated that the solid dispersion of Candesartan cilexetil prepared by using polyvinylpyrrolidone K 30 as carrier is a reliable and scalable approach for the enhancement of oral bioavailability. REFERENCES
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Source of support: Nil, Conflict of interest: None Declared

Journal of Pharmacy Research Vol.5 Issue 1.January 2012

333-337