The aim of this study was to investigate the use of inclusion complexation technique employing
Any drug from a given dosage form to be absorbed must be present in the form of solution at the site of absorption. Low aqueous solubility is one of the major problems encountered during formulation development of new chemical entities especially in the process of generic product development. More than 40% of new chemical entities developed in pharmaceutical industry are practically insoluble in water. Various techniques are used for the enhancement of the solubility of poorly soluble drugs including physical and chemical modifications of drug like particle size reduction, crystal engineering, salt formation, solid dispersion, use of surfactant, hydrotropy, cosolvency, use of surfactants, and complexation [
For the inclusion complex formation, different methods were employed such as physical mixture, kneading, coevaporation, and lyophilisation techniques. The concept of mouth dissolving drug delivery system emerged from the desire to provide patient with more conventional means of taking their medication. It is difficult for many patients to swallow tablets. Hence, they do not comply with prescription, which results in high incidence of noncompliance and ineffective therapy. A mouth-dissolving drug delivery system, in most cases, is a tablet that dissolves or disintegrants in the oral cavity without the need of water or chewing [
Candesartan cilexetil was a gift sample from Hetero Drugs Pvt. Ltd. (Hyderabad).
The physical mixture of candesartan cilexetil with
Inclusion complex was prepared by dissolving 1 : 1, 1 : 3, and 1 : 5 molar ratios of
Candesartan cilexetil and
Phase solubility studies were carried out according to the method reported by Higuchi and Connors. An excess of candesartan cilexetil was added to 10 mL portions of distilled water, each containing variable amount of
100 mg of drug
The XRD patterns of drug,
1H nuclear magnetic resonance spectra were recorded on AMX400 NMR spectrometer. Chemical shifts (
Candesartan-
Formulation table for ODT’s using complexes prepared by kneading method.
Formulations | Ingredients (mg) Total tablet weight = 150 mg | ||||||||
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Candesartan- |
Mannitol | Low HPC | Crospovidone | Croscarmellose sodium | Sodium starch glycolate | Aspartame | Aerosil | Talc | |
F1 | 82 | 49 | 5 | — | — | — | 5 | 3 | 6 |
F2 | 82 | 46.5 | 7.5 | — | — | — | 5 | 3 | 6 |
F3 | 82 | 44 | 10 | — | — | — | 5 | 3 | 6 |
F4 | 82 | 49 | — | 5 | — | — | 5 | 3 | 6 |
F5 | 82 | 46.5 | — | 7.5 | — | — | 5 | 3 | 6 |
F6 | 82 | 44 | — | 10 | — | — | 5 | 3 | 6 |
F7 | 82 | 49 | — | — | 5 | — | 5 | 3 | 6 |
F8 | 82 | 46.5 | — | — | 7.5 | — | 5 | 3 | 6 |
F9 | 82 | 44 | — | — | 10 | — | 5 | 3 | 6 |
F10 | 82 | 49 | — | — | — | 5 | 5 | 3 | 6 |
F11 | 82 | 46.5 | — | — | — | 7.5 | 5 | 3 | 6 |
F12 | 82 | 44 | — | — | — | 10 | 5 | 3 | 6 |
The prepared granules were evaluated for angle of repose, bulk density, tapped density, Hausner’s ratio, and Carr’s compressibility index [
Twenty tablets were selected at random and individually weighed, and the average weight was calculated. The uniformity of weight was determined according to pharmacopoeial specifications.
Hardness is the tensile strength of tablets expressed in kg/cm2, which was determined using Monsanto hardness tester. Preweighed sample of tablets was placed in the friabilator (Roche Friabilator) and operated for 100 revolutions. Tablets were dusted and reweighed.
Percentage friability was calculated by using the formula
Five tablets from each formulation were selected randomly, crushed and mixed. From the mixture powder equivalent to 10 mg of candesartan, cilexetil was weighed and dissolved in 100 mL of 5% PEG 400 in distilled water. The resulting solution was filtered through Whatman filter paper no. 41, diluted suitably, and the absorbance of the resulting solution was measured spectrophotometrically at 232 nm using distilled water as blank. Experiments were carried out thrice, and average percentage drug content was considered.
Drug content was estimated by the formula
The disintegration time for all formulations was carried out using tablet disintegration test apparatus. Six tablets were placed individually in each tube of disintegration test apparatus, and discs were placed. The water was maintained at a temperature of 37° ± 2°C, and time taken for the entire tablet to disintegrate completely was noted.
A tablet is placed on piece of tissue paper that was folded twice and kept in a petri dish (internal diameter = 6.5 cm) containing 6 mL of water, and the time for complete wetting is measured. The wetted tablet is then weighed, and the water absorption ratio,
The selected formulations were closely packed in aluminum foils and then stored at 40°C ± 2°C/75% RH ± 5% in stability chamber for 6 months and evaluated for their physical appearance, drug content, percent friability, and
All the complexes were subjected to
FTIR was performed for the pure drug
FTIR spectra. (a) FTIR spectra of candesartan cilexetil, (b) FTIR spectra of
One of the most classic applications of DSC analysis is the determination of the possible interactions between a drug entity and the excipients in its formulations. When guest molecules are included in CD cavities, their melting, boiling, glass transition, and sublimation points shift to different temperatures or disappear. Figures
DSC thermograms. (a) DSC Thermogram of candesartan cilexetil, (b) DSC Thermogram of
Inclusion complexes between candesartan cilexetil and
Analyzing the phase solubility profiles, it was observed that the increase of candesartan cilexetil solubility in the system was due to due to molecular interaction with
Phase solubility curve.
The XRD results were in good agreement with the thermal analysis data. X-ray diffraction patterns in Figure
X-ray diffractograms. (a) X-ray diffractogram of candesartan cilexetil, (b) X-ray diffractogram of
Mass spectroscopic studies were carried out to find out the molecular weight of candesartan cilexetil-
Mass spectral studies. (a) Mass spectrum of candesartan cilexetil-
The 1H-NMR chemical shift for each proton of candesartan cilexetil and
NMR spectra. (a) NMR spectra of candesartan cilexetil, (b) NMR spectra of
Candesartan cilexetil-
Formulation table for ODT’s using complexes prepared by lyophilisation method.
Formulations | Candesartan- |
Mannitol | Low HPC | Crosspovidone | Cross carmellose sodium | Sodium starch glycolate | Aspartame | Aerosil | Talc |
---|---|---|---|---|---|---|---|---|---|
F13 | 82 | 49 | 5 | — | — | — | 5 | 3 | 6 |
F14 | 82 | 46.5 | 7.5 | — | — | — | 5 | 3 | 6 |
F15 | 82 | 44 | 10 | — | — | — | 5 | 3 | 6 |
F16 | 82 | 49 | — | 5 | — | — | 5 | 3 | 6 |
F17 | 82 | 46.5 | — | 7.5 | — | — | 5 | 3 | 6 |
F18 | 82 | 44 | — | 10 | — | — | 5 | 3 | 6 |
F19 | 82 | 49 | — | — | 5 | — | 5 | 3 | 6 |
F20 | 82 | 46.5 | — | — | 7.5 | — | 5 | 3 | 6 |
F21 | 82 | 44 | — | — | 10 | — | 5 | 3 | 6 |
F22 | 82 | 49 | — | — | — | 5 | 5 | 3 | 6 |
F23 | 82 | 46.5 | — | — | — | 7.5 | 5 | 3 | 6 |
F24 | 82 | 44 | — | — | — | 10 | 5 | 3 | 6 |
The precompression parameters for the all 24 formulations were carried out, and the results were shown in Tables
Precompression parameters of prepared granules (F1 to F12).
Formulation code | Bulk densitya (g/mL) | Tapped densitya (g/mL) | Hausner’s ratioa | Carr’s indexa (%) | Angle of reposea ( |
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Precompression parameters of prepared granules (F13 to F24).
Formulation code | Bulk densitya (g/mL) | Tapped densitya (g/mL) | Hausner’s ratioa | Carr’s indexa (%) | Angle of reposea ( |
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The weights of all tablet formulations ranged between 137 and 161 mg (Table
Postcompression parameters for prepared orodispersible tablets.
Formulation code | Weight variationa (mg) | Friabilitya (%) | Hardnessa (kg/cm2) | Percentage drug contenta |
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The hardness of all formulations was determined, and the results were shown in Table
The percentage friability of all the formulations was found to be not more than 0.7%, which is well within the limit of less than 1%. The results of friability indicated that the tablets were mechanically stable.
The drug content studies for all 24 formulations were carried out by a validated method using 5% PEG 400 in distilled water and was found to be in the range of 98.14%–100.28% of candesartan cilexetil, and the results were shown in Table
Wetting time of the formulations was determined, and all the formulations showed wetting time of 90 to 210 seconds. Water absorption ratio of all the formulations was calculated using the equation, and all the formulations showed good water absorption ratio from 72.58 to 81.42. Wetting time of the dosage form is related to contact angle. Lower wetting time implies a quicker disintegration time (Table
Evaluation parameters of orodispersible tablets.
Formulation code | Wetting time (sec)a | Disintegration time (sec)a |
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IR spectral studies.
Sample | Wave number (cm−1) | Observation |
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Candesartan cilexetil | 3083.38 | C–H aromatic stretch |
3335.62 | N–H secondary stretch | |
1718.26 | C=O stretch | |
1248.86 | C–N stretch and CH3 rock | |
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3612.12 | –OH groups |
2934.34 | CH2 stretch | |
1205.21 | Asymmetric C–O–C stretch | |
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Inclusion complexes prepared by kneading method | 3321.65 | N–H secondary stretch |
3645.24 | –OH groups | |
1710.34 | C=O stretch | |
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Inclusion complexes prepared by lyophilisation | 3346.87 | N–H secondary stretch |
1705.46 | C=O stretch | |
2921.41 | CH2 stretch |
The prepared orodispersible tablets were evaluated for their
Graph showing drug release from formulations F12 and F24.
The accelerated stability studies of orodispersible tablets were performed as per the ICH guidelines to investigate whether the orodispersible tablets are affected during storage conditions. Optimized formulations F12 and F24 were kept at 40 ± 2°C with
In the present study, complexes of candesartan cilexetil with
The authors report no conflict of interests.
The authors wish to thank Gokula Education Foundation, Bangalore, for providing necessary facilities to carry out the research work. The authors wish to thank the Indian Institute of Science (IISc), Bangalore, for carrying out DSC, NMR, and XRD studies.