IMPROVEMENT OF SOLUBILITY AND DISSOLUTION RATE OF CANDESARTAN CILEXETIL BY SOLID DISPERSION IN POLYVINYL PYRROLIDONEHTML Full Text
Received on 09 November, 2013; received in revised form, 26 December, 2013; accepted, 23 March, 2014; published 01 April, 2014
IMPROVEMENT OF SOLUBILITY AND DISSOLUTION RATE OF CANDESARTAN CILEXETIL BY SOLID DISPERSION IN POLYVINYL PYRROLIDONE
Vishal S. Katti, Atul M. Kadam*, Sandip M. Honmane, Shitalkumar Patil, Sachin Patil and Kiran Bhamare
Department of Pharmaceutics, Ashokrao Mane College of Pharmacy, Peth-Vadgaon, Kolhapur– 416112, Maharashtra, India
ABSTRACT: The aim of the present study was to characterize solid dispersion (SD) of Candesartan cilexetil (CC) prepared with polyvinyl pyrrolidone K30 (PVP) for enhancing its solubility and bioavailability. The SDs of Candesartan was prepared by solvent evaporation method. The prepared SDs were evaluated for saturation solubility, practical yield, drug content, and in vitro dissolution study, IR-Spectroscopy, X-ray powder diffractometry (XRD) and differential scanning calorimetry (DSC). The dissolution rates of SDs prepared with PVP was much faster than the pure CC and physical mixtures (PM). The data from the XRD showed that drug was crystalline in bulk and in PM. Significant change in melting peak in DSC thermograms of SDs revealed amorphization. SDs showed marked increase in the solubility of CC with increasing carrier concentration. At the highest ratio of carriers the drug solubility was enhanced about 6-folds for SD in PVP. The dissolution rate was increased with increasing carrier concentration at pH 6.5. XRD data revealed a remarkable interaction between the CC and the carrier that enhanced drug dissolution. The 1:4 ratios were sufficient for conversion of Candesartan to amorphous form.
Solid dispersion, Carrier, Candesartan cilexetil, Solubility, X-ray diffraction
INTRODUCTION:In pharmaceutical Candesartan cilexetil (CC) is marketed as the angiotensin II receptor antagonist; CC is indicated for the treatment of hypertension and congestive heart failure. Thus, while ACE inhibitors are still considered first-line therapy in research and development an increasing number of drug candidates are poorly water soluble. The solubility and dissolution may become rate limiting factors for effective bioavailability of such drugs upon oral administration 1.
In congestive heart failure, CC can be used in combination with an ACE inhibitor to achieve improved mortality and morbidity. It is quickly and fully bioactivated by ester hydrolysis to form the active Candesartan during absorption from the gastrointestinal (GI) tract 2, 3, 4.
The use of a prodrug form increases the bioavailability of CC. Despite this, absolute bioavailability is relatively low at 15% (CC tablets) to 40% (CC solution). IC50 of this drug is 15 µg/kg. It is described as BCS Class II drug 5. Water-insoluble drugs show low absorption and poor bioavailability thus there is a need of an improvement in solubility of Class II drug formulations 6. CC show low and erratic oral bioavailability due to poor dissolution of the drug in the fluids of the gastrointestinal tract (GIT). An enhancement of the dissolution rate of water-insoluble drug remains one of the most challenging tasks of drug development, because it can increase drug oral bioavailability. It is well established that, the solubility and the bioavailability of poorly water soluble drugs can be improved by converting these drugs into an amorphous state 7.
Several methods such as freeze-drying 8 spray drying 9, 10, melting and quench-cooling 11, melt extrusion and mechanical activation (milling) 12 have been reported to successfully prepare amorphous forms of drugs. Formulation of SDs is another strategy used to increase the solubility and dissolution rate of drugs 13.
The SD technique for water-insoluble drugs provides an efficient solution to improve the dissolution rate of a drug 14. According to Chiou and Riegelman, SD of one or more active ingredients in an inert carrier or matrix, where the active ingredients could exist in finely crystalline, solubilized or amorphous state. Reported literatures indicate that polymeric carriers have been employed for enhancing the aqueous solubility of insoluble drugs 1. Drugs when molecularly dispersed in polymeric carriers, may achieve the highest levels of particle size reduction and surface area enhancement, which result in improved dissolution rates 15.
Polymers such as polyethylene glycol (PEG) and Polyvinyl Pyrrolidone (PVP) have been extensively used as carriers for dispersions due to their low melting point and hydrophilic nature 16. Methods used to produce SDs include melting method, solvent method and solvent wetting method. However, the melting method has limitations that occur incomplete miscibility between drug and carrier due to the high viscosity of a polymeric carrier in the molten state. Thermally unstable drugs can be degraded due to the requirement of relatively high preparation temperatures 17.
In literature first reported application of solvent evaporation method was preparation of SDs of β-carotene with carrier PVP using chloroform as common solvent 18. Basically, solvent evaporation method involves two steps (i) preparation of a solution containing both matrix material or carrier and drug and (ii) the removal of the solvent resulting in the formation of the solid mass 17.
Nature of the solvent used and the rate and temperature of evaporation are critical factors that can affect the formed mass 19. One of the unique features of this method is that thermal decomposition of the drugs can be prevented as low temperature is required for the removal of the organic solvents 20. Till date solvent evaporation method has been reported for valdecoxib 21, carbamazepine 22, fexofenadine hydrochloride 23, and glibenclamide 24, etc.
The literature reported reveals the successful application of this method for improvement in dissolution of poorly water soluble drugs. Manimaran et al., in 2010, prepared the SD of glibenclamide by the solvent evaporation method using PVP, PEG and POLO as hydrophilic carrier. In this study, hydrophilic carriers enhanced the solubility of glibenclamide to a varying degree. All SDs increased dissolution rate compared to pure glibenclamide 25.
Although use of SD has been reported frequently in the field of pharmaceuticals, only few SD systems are used commercially 17. CC is rapidly absorbed after oral administration but since it has poor aqueous solubility its dissolution rate is very low 6.
In this study, we used solvent evaporation method to prepare the SDs of CC using different concentrations of PVP. Methanol was used because it is common solvent for CC and carriers. The physicochemical properties of different systems were determined from DSC and XRD studies.
In addition, the effect of carrier concentration on dissolution properties of CC in SDs was investigated.
MATERIALS AND METHOD: A gift sample of Candesartan cilexetil (CC) was supplied by Alembic Research Centre, Baroda, India. PVP K-30 and Methanol were purchased from S.D. Fine Chemicals, India. All other chemicals used were of analytical grade.
Solubility: The solubility tests of drug sample were carried out in different solvents (aqueous and organic) according to United States Pharmacopeia. The results were then compared with standard.
Estimation of Candesartan Cilexetil: Contents of CC were estimated by UV Spectrophotometric method by measuring the absorbance at 256 nm in water: methanol (1:1). The method was validated for linearity, accuracy, precision and interference. The method obeyed Beers law in the concentration range of 2-10 μg/mL (r = 0.9995).
Preparation of PMs and SDs: Physical mixtures of CC with PVP at 1:2, 1:4 weight ratio of CC: carrier were prepared by blending with trituration for 10 min followed by sieving (500 μm).The prepared mixtures were then filled in glass bottles, sealed and stored in a dessicator until further use.
SD Compositions were selected based on literature reviewed. SDs of CC was prepared at various weight ratios by solvent evaporation method. Amount of carrier was varied keeping amount of CC constant (1:2, 1:4). Accurately weighed amount of CC & PVP are dissolved in the methanol and water respectively. The clear solution was obtained when both the solutions were mixed; Tween 20was added the as a surfactant to same. Then this solution was placed on the hot plate at 60 °C with magnetic stirring until the solvent evaporates. The solid dispersion prepared above was scrapped, dried, and was passed through sieve no.60 and stored in the dessicator until further use.
Practical Yield and Drug Content: Generally, percentage practical yield (% PY) is calculated to know about the efficiency of any method, thus it helps in selection of appropriate method of production. SDs were weighed to determine practical yield and % PY was calculated. SDs equivalent to 10mg of CC were accurately weighed and dissolved in 10 mL of methanol. The solution was filtered, diluted suitably and drug content was determined from absorbance at λ max 256 nm by spectrophotometric method from the following equation.
Practical mass (Solid Dispersion)
PY (%) = X 100
Theoretical mass (Drug +carrier)
Saturation Solubility: An excess amount of drug sample (CC) was added to 1.5 mL of both Water and phosphate buffer pH 6.5 containing 0.7% Tween 20 separately. Thesamples were shaken for 48 hrs at 37°C in a horizontal orbitalshaker.
The supernatant was filtered through a Milliporefilter (pore size 0.45 μm). Accurately measured 0.5 mL ofthe filtrate was immediately diluted and analyzed spectrophotometrically using UV-visible spectrophotometer (UV-1700, Shimadzu AS, Japan) at 256 nm after suitable dilution. For determination of saturation solubility of prepared SD, excess quantity of SD was added separately to 1.5 mL of both water and phosphate buffer (pH 6.5) containing 0.7% Tween 20 and then saturation solubility was also measured in the same way. All experiments were conducted in triplicate.
FT-IR Studies: Structural changes and lack of a crystal structure can lead to changes in bonding between functional groups which can be detected by infrared spectroscopy. The FT-IR spectrum was obtained by using FT-IR Spectrophotometer-Jasco. The samples were previously grinded and mixed with Potassium Bromide at 1:100 ratio respectively. The scanning range was 4000-400 cm-1.
DSC Analysis: Differential scanning calorimetry (DSC) studies were carried out using Mettle-Toledo DSC 821 instrument. Indium and zinc standards were used to calibrate the DSC temperature and enthalpy scale. The powdered samples (5 mg) are hermetically sealed in aluminum crucibles and heated at a constant rate of 10°C/min over a temperature range of 25–250°C. Inert atmosphere was maintained by purging nitrogen gas at flow rate of 30 mL/min. Results were obtained in triplicates for each sample.
XRD Analysis: XRD studies have been widely used to understand crystallinity of solids. The XRD patterns were recorded on X-ray diffractometer (PW 1729, Philips. Netherlands). Samples were irradiated with monochromatized Cu-Ka radiation (1.542 A˚) and analyzed from 50 to 500 2θ. The voltage and current used were 30 kV and 30 mA, respectively. The X-ray diffraction procedure to estimate the degree of crystallinity was based upon the measurement of the total scattering and the scattering from the crystalline region of formulations
In vitro Dissolution Studies: The USP dissolution test type II apparatus (Electrolab TDT- 06 N, India) was used. Amount of samples equivalent to 10 mg of drug were dispersed into the dissolution vessel containing 900 mL of phosphate buffer pH 6.5 containing 0.75% of Tween 20 at 37°C. and stirred at 50 rpm. Samples were withdrawn periodically, filtered and replaced with a fresh dissolution medium. After filtration through 0.45 μm microfilter, concentration of CC was determined spectrophotometrically at λ max 256 nm. All experiments were carried out in triplicate.
Stability studies: Stability studies of the prepared SDs were carried out at two different storage conditions, Room temperature (RT) and Refrigerated (RF i.e. 2–8°C) for 3 months. Three batches for both formulations were used for each condition. Assay was carried out one month time interval to determine the chemical stability of CC. To determine the drug content of formulation with amount equivalent to 2.5 mg of CC was dissolved in methanol, diluted appropriately, filtered and absorbance of resulting solution was measured spectroscopically at 256 nm.
RESULTS AND DISCUSSION: Percent practical yield and drug content in prepared SDs of (1:2), (1:4) ratio was in the range of 83.44% - 91.64% and 94.82% - 96.33%, respectively. Composition containing CC: PVP at ratio 1:4 showed highest percentage yield and drug content.
Solubility Determination: The aqueous solubility of a drug is a prime determinant of its dissolution rate and absorption. CC is practically insoluble in water and slightly soluble in phosphate buffer pH 6.5 at room temperature. The solubility of CC in phosphate buffer pH 6.5 was markedly increased in presence of PVP. The solubility of CC in phosphate buffer pH 6.5 was found to be 147 μg/mL at 37°C±0.5ºC. Formulated SD 1:2, 1:4 shows 597±0.85 μg/mL and 893 μg/mL in phosphate buffer pH 6.5, respectively. In general, the increase in solubility of CC is 4 fold and 6 fold when SD formulated as 1:2 and 1:4 respectively with PVP.
The results of solubility study revealed that solubility increases with increase in concentration of carrier. Reasons for this might be improved wettability and porosity, decreased primary particle size and partial amorphization of drug in dispersed state compared to raw crystals of CC 26. Enhanced solubility and dissolution rate of CC in SD prepared using PVP could be attributed to the chemical structure of highly water soluble PVP.
PVP has amphiphilic structure and ability to form monomolecular micelles by changing configuration in solution. At higher concentration, these monomolecular micelles associate to form aggregates of varying size, which have the ability to solubilize drug 27. Results indicated that solubility of Candesartan increases with increase in concentration of PVP.
FT-IR Studies: FT-IR spectroscopic studies conducted for possible drug carrier interaction. FT-IR spectra of pure drug & solid dispersion indicated no significant evidence of chemical interaction between drug and carrier. This confirms the stability of drug with its solid dispersion shown in figure 1.
FIGURE 1: IR SPECTRUM OF PURE CC, PM OF CC AND PVP (1:4), SD 1:2, SD 1:4
Differential Scanning Calorimetry: The thermogram of pure CChas shown a sharp endotherm at 169.29°C corresponding to its melting point. This sharp endothermic peak signifies crystalline nature of pure CC. The endothermic peak at 156.3ºCis characteristic melting peak of PVP.
In thermogram ofSDs 1:2 and 1:4, endothermic peak was observed at 153.97°C and 153.69°C respectively withthe loss of its sharp appearance. The broadening and shifting of peak towards the left side shows the partial conversion of pure crystalline CC into its amorphous form.
The absence of melting peak corresponding to melting of drug was supported by XRD studies. The results suggested that CC is dispersed completely into carrier. Thermograms of CC, PVP and their PM and SDs are shown in figure 2. The differences in the thermal behavior of CC in the form of PM and SDs suggested the amorphization of drug dependent of the ratio of the carrier used when prepared as SDs. The thermal analysis indicated decrease in crystallinity of CC in presence of higher proportions of carriers. All PM and SDs in PVP exhibited endothermic peaks due to the fusion of PVP. This revealed the existence of carriers in the crystalline state that was consistent with the appearance of diffraction peaks in the corresponding XRD pattern.
FIGURE 2: DSC THERMOGRAMS OF CANDESARTAN, PVP, PM AND THEIR DIFFERENT SYSTEMS
XRD Analysis: XRD studies were carried out to study transformations in the state of drug in its PMs and SDs. XRD patterns for different systems are shown in figure 3 for CC-PVP systems, respectively. The diffraction spectrum of pure CC showed that the drug is highly crystalline powder and possesses sharp peaks at 9.86°, 17.04°, and 23.21° at 2° θ. This corresponds to the crystalline form polymorph of CC. Characteristic peaks of PVP appeared at 13.68°, 19.24°, 23.32° and 27.37°2 at 2°θ. PVP showed no prominent peaks.
All the principles peaks from PVP were present in their PMs, but with lower intensities. In the case of the PM, diffractograms were simply the sum of pure components and no interaction could be detected between them particularly at lower ratio (1:2). In case of PM of CC- PVP system at 1:4 ratio, there was a decrease in the intensity of CC but the major peaks remained at the same positions.
The intensity of peaks reflected their mutual concentration. The decrease in the intensity of the diffractogram in case of the SD appeared at 1:2 ratio and the peaks of CC disappeared completely at 1:4 ratio. It could be attributed to the coating of its crystal lattice, because upon evaporation of solvent residual carrier forms a coat around crystals. There was no peak shifting associated to the carriers in PMs indicating formation of an insertion type solid where drug molecules found place inside the structure of the carrier without or with a limited deformation of the original crystal lattice. This is common in mixtures of polymeric carriers with small amounts of low molecular weight drugs. In case of SDs, the intensity of the peaks of CC diminished with the increase in polymer ratio. These observations revealed that the amount of PVP is sufficient to dissolve the CC completely. The amorphization of CC was observed in the SD of CC -PVP at 1:4 ratio, than its PM at same ratio. The results indicated that conversion of crystalline CC into amorphous by different degrees. The reduced peak intensities in XRD patterns clearly indicate that the CC appears amorphous 28.
FIGURE 3: XRD DIFFRACTOGRAMS OF CC, PVP, PM AND THEIR DIFFERENT SYSTEMS
In vitro Dissolution study: Drug release studies were carried out in phosphate buffer pH 6.5 shown in Figure 4. Blending of CC with carriers in the form of PMs or SDs could enhance the release of CC. The faster dissolution rate of PMs compared to pure drug was observed and it could be attributed to the improvement of wettability of CC particles due to the presence of highly hydrophilic molecular components. Dissolution rates for SDs were greater than those for PMs and CC alone. In the dispersed state CC get entrapped into the hydrophilic coat of carriers and its crystallinity changes with change in its physicochemical properties 29. PVP changed crystalline CC to amorphous CC enhancing the dissolution rate. This observation is supported by the XRD studies of the SDs. The amount of CC dissolved after 60 min of CC, PMs and its SDs in PVP prepared at different drug: carrier ratios as shown in Table 1. The highest amount of drug dissolved after time period was 36.55%, 56.78% form pure CC and PM respectively. In case of SDs of the carriers used the amount of 1:2, 1:4 drug dissolved was 69.25%, 87.12% respectively.
TABLE 1: THE PERCENT DRUG DISSOLUTION AFTER 60 MIN OF CC, PM AND ITS SDS IN PVP PREPARED BY SOLVENT EVAPORATION METHOD AT DIFFERENT DRUG: CARRIER RATIOS
|Time (Min)||% Drug Release|
|Pure drug||PM||SD (1:2)||SD (1:4)|
FIGURE 4: DISSOLUTION PROFILES OF CC AND CC - PVP SYSTEMS IN PHOSPHATE BUFFER pH 6.5
Stability studies: The stability of prepared SDs observed was satisfactory at both conditions for 3 months as active content was more than 95% in all cases. Although the active contents are above 95%, it follows a decline order with time so its storage should be maintained at refrigerated condition (Table 2).
Thus, it can be concluded that the stability of CC was not affected due to heating and the formulation was stable for 3 months. Further studies are needed to prove long term stability of the formulation and to find out reasons for the decline order.
TABLE 2: % DRUG CONTENT OF SDS AT VARIOUS STABILITY STORAGE CONDITIONS
|Stability Condition||Formulation||% Drug content ±SD|
|Room Temperature||SD (1:2)||99.69±0.73||98.19±0.28||97.26±0.69||96.29±0.25|
CONCLUSION: The study demonstrates that dispersions of CC into water-soluble carriers change the crystallinity of CC relative to the type and the amount of the carrier. The formation of CC -PVP SD almost completely destroys the crystallinity of the drug and represents a suitable modification for improving its solubility. Decrease in agglomeration of particles, increase in wettability and decrease in crystallinity of the drug contributes to faster dissolution rate. Preliminary results from this work indicate that preparation of CC SDs by solvent evaporation method using hydrophilic polymer carrier PVP could be a promising approach to improve solubility and dissolution rate of CC. The higher ratio of PVP (1:4) tested in this study was sufficient for conversion of CC to amorphous form.
ACKNOWLEDGEMENT: The authors express their gratitude to Alembic Research Centre, Baroda, India, for providing Candesartan as gift sample for this research work.
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How to cite this article:
Katti VS, Kadam AM, Honmane SM, Patil S, Patil S and Bhamare K: Improvement of solubility and dissolution rate of Candesartan cilexetil by Solid Dispersion in Polyvinyl pyrrolidone.Int J Pharm Sci Res 2014; 5(4): 1550-56.doi: 10.13040/IJPSR.0975-8232.5(4).1550-56
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Vishal S. Katti, Atul M. Kadam*, Sandip M. Honmane, Shitalkumar Patil, Sachin Patil and Kiran Bhamare
Department of Pharmaceutics, Ashokrao Mane College of Pharmacy, Peth-Vadgaon, Kolhapur– 416112, Maharashtra, India
09 November, 2013
26 December, 2013
23 March, 2014
01 April, 2014