Formulation and Evaluation of Candesartan Cilexetil Fast Dissolving Tablets using Inclusion Complexes

 

Siva Prasad Sunkara*, Vidyadhara Suryadevara, Sowjanya Lakshmi Bathula,

Sandeep Doppalapudi, Pavan Kumar Padarthi, Viswanadh Kunam

Chebrolu Hanumaiah Institute of Pharmaceutical Sciences, Chandramoulipuram,

Chowdavaram, Guntur, Andhra Pradesh, India – 522019

 

ABSTRACT:

In the present investigation, an attempt was made to improve the dissolution rate and bioavailability by inclusion complexes using Candesartan cilexetil and β-cyclodextrin. Solid dispersions were prepared by physical mixing, co-evaporation and kneading methods using Candesartan Cilexetil and β-cyclodextrin in 1:1 ratio. The complexes were evaluated for phase solubility, drug content and drug release. The drug release study was carried out using phosphate buffer pH 6.8 as dissolution medium. The inclusion complexes prepared by solvent evaporation method showed rapid drug release when compared to physical mixing and kneading methods. The optimized complexes were further formulated as fast dissolving tablets using superdisintegrants like sodium starch glycolate (SSG) and croscarmellose sodium (CCS) in varying ratios by direct compression method. Various pre and post compression parameters were evaluated for the granules and all were found to be in specified Indian Pharmacoepial limits. Dissolution profiles showed that the formulation C6 with 15% w/w of CCS as superdisintegrant showed rapid drug release when compared to other formulations. FTIR and DSC analysis of pure drug and optimized formulation revealed no major interactions between the drug and polymers. Model independent techniques including similarity factor, dissimilarity factor and dissolution efficiency were applied for comparison of dissolution profiles. Thus it was concluded that fast dissolving tablets of Candesartan cilexetil showed enhanced dissolution rate.

 

 

INTRODUCTION:

The therapeutic effectiveness of a drug depends upon the bioavailability and ultimately upon the solubility of drug molecules. Solubility and dissolution rate are important parameters to achieve the desired concentration of drug in the systemic circulation, so that the required pharmacological response will be elicited. Currently only 8% of new drug moieties have both high solubility and permeability¹.

 

Various techniques for the improvement of solubility of poorly water-soluble drugs include micronization; formation of inclusion complexes with Cyclodextrin, formation of amorphous drug and formation of solid dispersions with hydrophilic carriers have been utilized². Inclusion complexes are formed by the insertion of the non-polar molecule or the non-polar region of one molecule into the cavity of another molecule or host molecules. The most commonly used host molecules are Cyclodextrin. Three naturally occurring are α, β, and γ Cyclodextrin. Cyclodextrin consist of (α-1,4) linked α- D- glucopyranose units and contain a somewhat lipophilic central cavity and a hydrophilic outer surface. Due to the chair conformation of the glucopyranose units, the Cyclodextrin are shaped like a truncated cone. In aqueous solutions, Cyclodextrin are able to form inclusion complexes with many drugs by taking up a drug molecule or more frequently some lipophilic moiety of the molecule, into the central cavity. For the inclusion complex formation, different methods were employed such as physical mixing, Co-evaporation, Kneading method and Lyophilisation techniques³. The fast dissolving or disintegrating dosage forms are well established in the management of pain, inflammation, vomiting, headache and hypertension. Valuable research reports for formulation of FDT’s are available and also various technologies for improving dissolution property of poorly soluble drugs have been documented to enhance bioavailability following oral absorption^4,5. Candesartan cilexetil (CAN) is an angiotensin receptor blocker indicated in the treatment of essential hypertension. CAN is a white to off-white powder with a molecular weight of 610.67. It is partially insoluble in water and sparingly soluble in methanol.  The absolute bioavailability for Candesartan cilexetil is about 40% when CAN is given as a solution and about 14% when given as tablets. A peak plasma concentration of Candesartan cilexetil occurs about 3-4hrs after oral doses as tablets⁶. The aim of the work is to enhance the solubility, dissolution rate and oral bioavailability of poorly soluble Candesartan cilexetil by formulating it as inclusion complexes using various techniques employing β-cd⁷. Further the prepared complexes were formulated as fast dissolving tablet using various superdisintegrants in different concentrations.

 

MATERIALS AND METHODS:

Candesartan Cilexetil was obtained as a gift sample from M/s Mylan Laboratories Pvt. Ltd., Hyderabad. Cyclodextrin was procured from Yarrow chem Ltd., Mumbai. SSG and CCS were obtained from S.D. Fine Chem. Ltd., Mumbai.

 

Phase–Solubility Studies:

Phase–solubility studies were carried out according to the method reported by Higuchi and Connors⁸. It permits the evaluation of the affinity between the carrier and drug in aqueous solution and to know the stable inclusion complex. Excess amounts of Candesartan cilexetil containing various concentrations of β-cd (2-10mm) were added respectively into conical flasks with 10 ml of 6.8 pH phosphate buffer. These flasks were shaken at 25°C for 48 hrs and then the contents were filtered through a Whatmann filter paper. The filtrate was diluted and assayed for Candesartan cilexetil content by using spectrophotometer at 225nm. The apparent stability constants were calculated from the phase solubility diagrams and according to following equation;

                Slope

Ks = ––––––––––––––––––

           Intercept (1 – slope)

 

Preparation of Candesartan cilexetil inclusion complexes:

All the binary mixtures were prepared by physical mixing, co-evaporation and kneading methods in 1:1 molar ratio of drug and β-cd on the basis of the results obtained from phase solubility studies⁹. In physical mixing method, known quantity of Candesartan cilexetil and β-cd were mixed well in 1:1 molar ratio by mortar and pestle, passed through sieve no. 80 and hermetically sealed¹⁰. In Solvent evaporation or co-evaporation method, Candesartan cilexetil and β-cd were mixed in 1:1 molar ratio with suitable solvent. The mixture was then evaporated at 40-50^ºC and passed through sieve no. 80^11. In kneading method, β-cd was triturated with little amount of water or hydro alcoholic solutions and converted into a paste. Then drug was added, kneaded for 1h and passed through sieve no.80.

 

In Vitro Dissolution Studies for Candesartan cilexetil–β cd Complexes:

Dissolution studies on prepared inclusion complexes were performed in a calibrated 8 station dissolution test apparatus (LABINDIA DS8000) equipped with paddles (USP apparatus II) employing 900ml of 6.8pH phosphate buffer as dissolution medium. The paddles were operated at 50 rpm and temperature was maintained at 37 ± 1ºC throughout the experiment. The samples (5ml) were withdrawn at 5, 10, 15, 20, 30 and 45 minutes and replaced with equal volumes of same dissolution medium to maintain the constant volume throughout the experiment. The amount of the drug dissolved was estimated by ELICO double beam U.V spectrophotometer at 225nm. The dissolution studies on each formulation were conducted in triplicate and various parameters were calculated.

 

Development of Candesartan cilexetil Tablets from Inclusion Complexes:

Candesartan cilexetil tablets with inclusion complex (equivalent to 32mg of drug) were prepared by direct compression method. The superdisintegrants (Sodium Starch Glycolate and Croscarmellose sodium) in varying concentrations (5-15%) were used to prepare the tablets. The materials were individually weighed; the powder mixture was then lubricated with 1% talc and magnesium stearate. To minimize the processing variables all batches of tablets were compressed, under identical condition.  The quantity of cyclodextrin taken was based on molecular weight of Candesartan.

 

The powder blends were evaluated for flow properties such as angle of repose, compressibility index and Hausner’s ratio. The compressed tablets were further evaluated for their physical parameters such as weight uniformity, hardness, friability, drug content, and in vitro dissolution studies¹².

 

In vitro dissolution studies of Candesartan cilexetil Fast Dissolving Tablets:

Dissolution studies on each tablet formulation were performed in a calibrated 8 station dissolution test apparatus (LABINDIA DS8000) equipped with paddles (USP apparatus II) employing 900ml of 6.8pH phosphate buffer as dissolution medium. The paddles were operated at 50rpm and temperature was maintained at 37 ± 1ºC throughout the experiment. The samples (5 ml) were withdrawn at 5, 10, 15, 20 and 30 minutes and replaced with equal volume of same dissolution medium to maintain the constant volume throughout the experiment. Samples with drawn at various time intervals were suitably diluted with same dissolution medium and the amount of the drug dissolved was estimated by ELICO double beam U.V spectrophotometer at 225nm. The dissolution studies on each formulation were conducted in triplicate.

 

Characterization Studies:

Based on the dissolution studies, the optimized formulation C6 was selected and Fourier Transfer Infrared (FTIR) and Differential Scanning Calorimeter (DSC) studies were performed to observe the drug and excipient interactions.

 

Comparison of Dissolution Profiles:                                                                                                                                          

Model independent approach was applied for comparison of dissolution profiles. The dissolution profiles comparison was done using difference factor (f1) and similarity factor (f2) to compare the dissolution profile of prepared Candesartan FDT’s with marketed tablet formulation with all time points included in the invitro dissolution studies. Dissimilarity and similarity factor was calculated and two dissolution profiles are considered similar when the f2 value is 50 to 100¹³.

 

Statistical Analysis:

Formulation C6 was found to be optimized based on the dissolution profiles, similarity and dissimilarity factors. For each time, five samples were withdrawn at different time intervals and then were tested the significant difference between all prepared FDT’s and marketed tablet formulation. Statistical analysis was done using INSTAT graph pad software (Version 5.0). Comparison between the dissolution data of various formulations of FDT’s were made with one way analysis of variance (ANOVA) followed by Dunnett’s test. ANOVA was applied for comparison of the above samples having different variance levels. In all the tests, the criterion for statistical significance was p <0.05^14,15.

 

Accelerated Stability Studies:

Accelerated stability studies was performed out on formulation C6 as prescribed by International Council for Harmonisation of technical requirements for registration of pharmaceuticals for human use (ICH) guidelines at temperature of 40±2ºC, ambient humidity and at room temperature. After this period, the FDTs were analyzed for drug content, friability, hardness, and invitro dissolution studies.

 

RESULTS AND DISCUSSION:

Phase-Solubility Studies:

The solubility curve obtained from the phase solubility studies were classified as the AL type according to Higuchi and Connors, which suggests that a water soluble complex was formed in solution. Phase solubility studies were performed in 6.8 pH phosphate buffer showed a linear increase in solubility with increasing concentration of β-cd. The stability constant, Ks were found to be 468 M^-1 & 685 M^-1 indicating the formation of 1:1 stable complex. So, this is selected for preparation of inclusion complexes.

 

Development of Candesartan cilexetil inclusion complexes:

Inclusion complexes were prepared by physical mixing, co-evaporation and kneading methods using β-cd, in 1:1 ratio and found to be stable and suitable for increasing the dissolution rate of Candesartan cilexetil. The drug content of prepared inclusion complex was found to be in the range of 30.6 – 31.8mg.

 

The invitro dissolution studies were performed for prepared inclusion complexes in 6.8 pH phosphate buffer. It was found that the inclusion complex prepared by physical mixing, kneading method and solvent evaporation methods released the drug rapidly when compared to pure drug. Past studies revealed the usage of microspheres has enhanced the rate of dissolution of Candesartan¹⁶. T₅₀ and DE_30% for pure drug was found to be more than 45 and 25 mins respectively. T₅₀ and DE_30% for inclusion complexes prepared by physical mixing method (CPM), co-evaporation method (CS) and kneading method (CK) was found to be in 32 mins and 28.31%, 16 min and 41.61% and 23min and 35.6% respectively.

 

CPM: Candesartan cilexetil inclusion complexes prepared by physical mixing method, CS: Candesartan cilexetil inclusion complexes prepared by co-evaporation method, CK: Candesartan cilexetil inclusion complexes prepared by kneading method. Mean ± SEM (n=3). Two way ANOVA followed by Dunnett’s test **p < (0.0001) compared with pure drug.

 

Table 1: Dissolution parameters of Candesartan cilexetil and β-cd Complexes prepared by Various Methods

Inclusion complex	T50 (min)	DE30%	Zero order		First order		Hixson crowell
			R2	K (mg/min)	R2	K (min-1)	R2	K (mg1/3)
Pure drug	45	20.32	0.8120	1.82	0.865	0.010	0.9012	0.09
CPM	30	28.3	0.896	1.89	0.9675	0.031	0.9102	0.05
CS	16	41.6	0.9561	1.41	0.9968	0.07	0.9665	0.03
CK	23	35	0.9128	1.68	0.9862	0.05	0.924	0.17

CPM: Candesartan cilexetil inclusion complexes prepared by physical mixing method, CS: Candesartan cilexetil inclusion complexes prepared by co-evaporation method, CK: Candesartan cilexetil inclusion complexes prepared by kneading method

 

Development of Candesartan cilexetil Tablets from Inclusion Complexes:                                                                

From the prepared inclusion complexes, fast dissolving tablets were prepared by using superdisintegrants SSG and CCS in different concentrations (5-15%) by direct compression method.

 

Table 2: Composition of Candesartan cilexetil FDTs using β-cd Inclusion Complex by Co-evaporation Method

Ingredients (mg/Tablet)	C1	C2	C3	C4	C5	C6
CS	64	64	64	64	64	64
Sodium starch glycolate	10	20	30	-	-	-
Croscarmellose sodium	-	-	-	10	20	30
Micro crystalline cellulose	122	112	102	122	112	102
Talc	2	2	2	2	2	2
Magnesium stearate	2	2	2	2	2	2
Total weight (mg)	200	200	200	200	200	200

 

CS: Candesartan cilexetil inclusion complexes prepared by co-evaporation method

 

The flow properties such as angle of repose and compressibility index evaluated for various tablet formulations and were found to exhibit good flow characteristics. The angle of repose values obtained for various formulations in the range of 14.24-25.45⁰ and Carr’s index in the range of 12.78-17.45%. Hausner’s ratios for various formulations were in the range of 1.19-1.25. The direct compression process was found to be suitable for compressing the tablet formulations as fast dissolving tablets. All the batches of tablets were compressed under identical conditions to minimize processing variables. Tablet formulations were further evaluated for physical parameters. All the tablet formulations were found to be stable and meeting I.P specified limits for weight uniformity, friability, drug content and dispersion time.

 

The drug release of tablet formulations in the presence of various superdisintegrants were in the order of CCS>SSG. The dissolution parameters were compared with that of marketed Candesartan oro-dispersible tablet. It was found that the tablet formulation C6, with CCS as superdisintegrants showed the rapid drug release when compared to marketed formulation. These were further confirmed by similarity factor (f2) and difference factor (f1) studies. In vitro dissolution parameters such as first order rate constant and Hixson–Crowell constant were calculated for all formulations. Most of the formulations were found to release the drug by first order kinetics, which indicated by R² values in the range of 0.92 to 0.99. T₅₀, and DE_30% for the formulation C6, prepared by Solvent evaporation method with 15% CCS was found to be in 6.5 mins and 75.9 %. Many studies have been performed which shows the formulation of solid dispersions enhances solubility of poorly water soluble drugs ^{17, 18, 19}. Past works have proved the usage of sodium starch glycolate in solubility enhancement ^{20, 21, 22}. Previous studies used a mixture of various polymers along with kneading and lyophilization techniques. ²³

 

Results are expressed as Mean ± SEM (n=3). The data was analyzed using two way analysis of variance (ANOVA) followed by Dunnett’s test ***p < (0.0001) compared with Marketed Formulation.

 

Results are expressed as Mean ± SEM (n=3). The data was analyzed using two way analysis of variance (ANOVA) followed by Dunnett’s test ***p < (0.0001) compared with Marketed Formulation

Table 3: In- vitro Dissolution Parameters of Candesartan cilexetil Fast Dissolving Tablets

Formulations	T50(min)	DE 30%	Zero order		First order		Hixson crowell
			R2	K(mg/min)	R2	K(min-1)	R2	K(mg1/3)
C1	11.5	39.1	0.944	1.10	0.988	0.044	0.911	0.099
C2	9.8	45	0.888	1.29	0.9813	0.058	0.951	0.089
C3	7.9	47	0.841	1.41	0.9721	0.0759	0.805	0.080
C4	7.3	38.6	0.813	1.90	0.9783	0.0539	0.869	0.075
C5	7	46.9	0.814	1.13	0.9513	0.0616	0.828	0.073
C6	6.5	75.9	0.772	1.36	0.9878	0.091	0.910	0.0690
Marketed Formulation	20.31	15.2	0.912	1.25	0.852	0.056	0.901	0.021

 

Comparison of Dissolution Profiles:

Bioavailability and bioequivalence study guidance for oral dosage forms describes the model independent mathematical approach as proposed by Moore and Flanner for calculating a dissimilarity factor (f1) and a similarity factor (f2) of dissolution across a suitable time interval. The similarity factor (f2) (where 0 ≤ f2 ≤ 100 and (f2)  ≥ 50% implies dissolution profiles are similar) is a function of mean differences and does not take into account the differences in dissolution within the test and reference batches. The (f2)  and (f1)  factors indicated that formulation C6 exhibited similar dissolution profiles with more than 63 as (f2) value are highly comparable with the standard formulation. In general, the fast dissolving tablets should release more than 90% of drug in 10 to 15 minutes. The prepared formulations of Candesartan (C6) has met this criteria. Past studies also revealed that preparation of inclusion complexes using β-cd has enhanced the solubility of poorly water soluble drugs^24,25.

 

Characterization Studies:

FTIR studies were performed for pure drug and optimized formulation. The results revealed that there was no major interaction between the drug and polymers. Candesartan cilexetil pure drug exhibited sharp peaks at 2941.08cm^-1 and 1613.44cm^-1, indicating the presence of Aliphatic CH Stretching and C-C Stretching. For C6, sharp peaks were observed at 2941.01cm^-1 and 1613.25cm^-1, indicating the presence of Aliphatic CH stretching and C-C stretching. DSC thermo graphic studies were carried out on Candesartan cilexetil pure drug and optimized formulation C6. These studies exhibited sharp endothermic peak at 170.6⁰C for Candesartan cilexetil pure drug and sharp endothermic peak at 172.49⁰C for the optimized formulation C6. A slight change in peaks with a minute change in temperature was observed. The results revealed that there was no major interaction between the drug and polymers at respective temperatures.

 

(A) Candesartan Cilexetil Pure Drug

 

 

(B) C6 Optimized Formulation

 

 

(A) Candesartan Cilexetil Pure Drug

 

 

(B) C6 Optimized Formulation

 

Accelerated Stability Studies:

The optimized formulation C6 was subjected to accelerated stability studies as per ICH guidelines after storage under different conditions. Physical parameters and drug release studies were carried out on these formulations. From the results, it was observed that there were no significant changes in physical parameters and drug release even after stability studies at various storage conditions, and thus indicating that the formulation was stable.

 

CONCLUSION:

Based on the above studies, it may be concluded that it is possible to increase the dissolution rate of poorly soluble drug Candesartan by preparing it in the form of solid dispersions with β-cd. Of all the methods employed for the preparation of solid dispersions, co-evaporation method exhibited rapid drug release when compared to pure drug and other two methods. The fast dissolving tablet C6 prepared by using CCS in 15%w/w was found to be optimal because of its superior performance in enhancing the dissolution of Candesartan cilexetil. Therefore, it can be concluded that the aqueous solubility of poorly drugs can be significantly improved by utilizing the solid dispersion technique with the help of β-cds.

 

ACKNOWLEDGEMENTS:

The authors express their gratitude to Mylan pharma Ltd., Hyderabad for providing gift sample of Candesartan cilexetil. The authors are thankful to the management of Chebrolu Hanumaiah Institute of Pharmaceutical Sciences, Guntur for providing the facilities to carry out the research work.

 

ABBREVIATIONS:

CAN-Candesartan Cilexetil, CCS-Croscarmellose sodium, CD-Cyclodextrin, DDS-Drug Delivery Systems, FDT-Fast Dissolving Tablets, FTIR-Fourier Transform Infra Red,  β-cds-Beta Cyclodextrin, I.P-Indian Pharmacopoeia, K_s-Stability constant, RPM-Rotations per minute, SD-solid dispersions, T_50min-Time required for 50% drug release (in minutes), D.E _30% -Dissolution Efficiency.

 

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

 

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Accepted on 21.09.2019           © RJPT All right reserved

Research J. Pharm. and Tech 2020; 13(2):751-757.