Development and evaluation of drug-cyclodextrin-polymer ternary system of Cefuroxime axetil to enhance the solubility and dissolution efficiency
Ashok T. Jadhav1, Kishorkumar B. Burade1, Deepak A. Kulkarni2,3,
Sanjay S. Pekamwar2, Shweta S. Kulkarni4
1Government College of Pharmacy, Karad, 415124, Maharashtra, India.
2School of Pharmacy, SRTM University, Nanded, 431606, Maharashtra, India.
3Srinath College of Pharmacy, Bajajnagar, Waluj, Aurangabad, 431136, Mahararashtra, India.
4Dr. D. Y. Patil Institute of Pharmaceutical Sciences and Research, Pimpri, Pune, 411018, Maharashtra, India.
*Corresponding Author E-mail: ashokambu@gmail.com
ABSTRACT:
Cefuroxime axetil (CA) is BCS class II drug and has 55% absolute oral bioavailability due to poor aqueous solubility hence the present work is an attempt to enhance the solubility and hence dissolution of CA by inclusion complexation with natural Cyclodextrins (CDs). The complexation efficiency of Cyclodextrin is low and hence large amount of CDs are required to solubilize small amount of poorly water-soluble drug. To overcome this limitation the hydrophilic polymers were used to improve the complexation efficiency of cyclodextrin through the formation of ternary complexes. In association with water soluble polymers like Polyvinyl Pyrrolidone (PVP) and Hydroxy Propyl Methyl Cellulose (HPMC) the complexation potential CDs (β-CD and HP-β-CD) was found to be improved which was analyzed by comparative evaluation of binary (drug: cyclodextrin) and ternary system (drug:cyclodextrin:polymer). Binary and ternary complexes were prepared by lyophilization method. On the basis of physicochemical characterization techniques like TLC, FTIR, DSC, and XRPD, the complex formation between CA, CD and water-soluble polymers was confirmed. The dissolution rate studies were also carried out in order to assess the in-vitro performance of complexes. Drug-HP-β-CD-HPMC lyophilized system showed higher solubility and dissolution rate as compared to other systems.
KEYWORDS: Cefuroxime axetil (CA), Cyclodextrins (CDs), Ternary complex, Hydroxy Propyl Methyl Cellulose (HPMC), Polyvinyl Pyrrolidone (PVP).
INTRODUCTION:
Since aqueous solubility is one of the crucial factor influencing drug absorption from the GIT, many newly discovered compounds exhibits low oral bioavailability. Because, the oral route is convenient method for administration of drug as compare to any other method. Therefore, in the novel oral drug delivery system enhancement of oral bioavailability is generating interest now a days and different strategies are employed by the researchers to increase the dissolution of lipophilic drug like particulate drug delivery, solid dispersion, complexation with cyclodextrins etc1.
Due to limited solubility and limited use of cyclodextrins various synthetic cyclodextrins are synthesized which are having higher water solubility as compared to natural cyclodextrin and researcher are in a condition to reduce the dose of cyclodextrin. And it also found that addition of third phase or component like L-arginine, Water soluble polymer like sodium carboxymethylcellulose, (NaCMC), hydroxymethylcellulose (HPMC), Polyvinyl-pyrolidone K-30 ,K-25 (PVP), Polyethylene-glycol-4000 and polyethylene glycol 6000 (PEG) at low concentration leads to significant increase in solubility as well as complexation ability of cyclodextrin which also lead to decrease in dose of cyclodextrin2.
The addition of small amount of a water soluble polymer to an aqueous complexation medium, followed by heating the medium in an autoclave, can significantly increase stability constant of drug-CD complexes by formation of ternary complexes or co-complexes. Thus these polymers improve complexing abilities of CDs by increasing apparent stability constant of drug-CD binary complex and hence drug availability in aqueous CD solutions. This also helps to reduce the dose of cyclodextrin in pharmaceutical dosage forms3.
It has been observed that there is increase in stability constant (Kc) upon addition of water soluble polymer, it shows that they are able to interact in different way with Drug-CDs binary complexes depending upon their structure. Since polymer can establish different interaction with CD and Drug molecule such as hydrogen bond, Vander Walls dispersion forces or hydrophobic bonds. Combined use of CD and water soluble polymer shows synergistic increasing effect of aqueous solubility of drug4.
On addition of water soluble polymer increases solubility and also leads to increase in permeability of drug as well as CDs for example in case of eye preparations such as eye drops, at the cornea the polymers may adhere to the surface. This promotes the release of drug molecules from the CD inclusion complexes into the solution leading to high concentration of drug at the corneal surface resulting in permeability enhancement. And also leads to modulation in drug release from the hydroxypropyl methylcellulose gel which gives controlled release property of drug along with increased permeation. Thus, not only oral but also topically effective formulations can be developed by using Drug-Cyclodextrin-polymer ternary complexes5.
Recent works have shown that the presence of various auxiliary substances such as cellulose derivatives, water-soluble polymers, hydrotropic compounds, surfactants, co-solvents, and the like, can significantly affect cyclodextrin complexation. For example, small amphiphilic molecule such as ethanol and propylene glycol can reduce cyclodextrin complexation by acting as competing guest molecule. Likewise, lipophilic preservative molecule or surfactants have been shown to displace drug molecules from the cyclodextrin cavity6.
Fig. 1: Structure of β-Cyclodextrin
In contrast, enhanced complexation can be obtained by formation of ternary complexes (or co-complexes) between a drug molecule, CD molecule and a third component. For instance, the addition of certain low molecular weight acids/ Hydroxy acids can enhance cyclodextrin solubilization of base drugs by an order of magnitude through the formation of drug-acid-CD ternary complexes7. Basic amino acids can be used for ternary CD complexation of acidic drugs, due to their potential ability to simultaneously interact with both the drug, by salt formation, and CD, via hydrogen bonding. Similarly, addition of small amounts of various water-soluble polymers to the aqueous complexation medium (accompanied by sonication and autoclaving of the suspensions) can significantly increase the cyclodextrin complexation efficiency by increasing the stability constant (Kc) of drug-CD complex8.
MATERIAL AND METHODS:
Materials:
Cefuroxime axetil was received as a gift sample from Ranbaxy Pharma Pvt. Ltd., Devas Madhya Pradesh, β-cyclodextrin and HP-β-cyclodextrin was received from Alembic Pharma. Baroda, HPMC was received from Colorcon Pharma, Goa, PVP-K-30 was received from Hi media Labs.
Phase solubility studies:
Optimization of hydrophilic polymers
Solubility studies were carried out to optimize the concentration of PVP and HPMC. An excess amount of Cefuroxime Axetil was added to 10ml aqueous solutions containing PVP (0, 0.1, 0.25, 0.5 %w/v) or HPMC (0, 0.1, 0.25, 0.5 %w/v) in series of 25 ml stoppered glass tubes. These suspensions were equilibrated at room temperature by mechanical stirring for 48 h. and then filtered using Whatman filter paper (No.40). The filtered samples were suitably diluted and assayed for Cefuroxime Axetil content by UV spectrophotometer9.
Phase solubility of binary and ternary systems:
Phase solubility studies were performed for both binary and ternary systems at room temperature according to the method of Higuchi and Connors. An excess amount of Cefuroxime Axetil was added to 10ml distilled water containing increasing concentrations of β-CD and HP-β-CD (0-30 mm) in the presence or absence of a fixed amount of PVP (0.5%w/v) and HPMC (0.1%w/v) in series of 25 ml stoppered glass tubes10.
For binary and ternary system, the suspensions were equilibrated at room temperature by mechanical stirring for 48 hr. All suspensions were then filtered using Whatman filter paper (No.40). The filtered samples were suitably diluted and assayed for Cefuroxime Axetil content by UV spectrophotometry against blank prepared in the same concentration of β-CD, β-CD-PVP and β-CD-HPMC. And HP-β-CD, HP-β-CD-PVP and HP-β-CD-HPMC. The experiments were performed in triplicate11.
The phase solubility diagram was constructed by plotting the dissolved Cefuroxime Axetil concentration against the respective concentration of β-CD and HP-β-CD. The binding constants for both binary and ternary systems (Kc) were calculated from the phase solubility diagram using its slope and intercept values12.
Physical binary and ternary mixtures:
Equimolar mixtures were prepared by homogeneously blending exactly weighed amounts of previously sieved Cefuroxime Axetil and β-CD and HP-β-CD by geometric dilution method until homogeneous mixture is obtained. For ternary PMs The optimized ratio of PVP-K-30 and HPMC were added13.
Lyophilized (LPh) binary and ternary products:
For binary product, equimolar amounts of β-CD,HP-β-CD and Cefuroxime Axetil were dissolved in water and methanol respectively. The two solutions were sonicated for 15 min. and mixed for 2 hrs.at 500C.The resultant clear solution was taken in a plastic beaker and freezed at -220C in a deep freezer. Then the mixture was lyophilized. The temperature was set and maintained at -400C for 12hrs until sample was completely dry. Vacuum up to 0.01mpa was kept throughout the freeze drying processes14.
For ternary products, equimolar amounts of β-CD, HP-β-CD and Cefuroxime Axetil were dissolved in 0.5%w/v of PVP solution or 0.1%w/v of a HPMC solution and in methanol respectively. The resultant solution was mixed and sonicated for 15 min. The clear solution was frozen and then freeze dried as above. The systems D-β-CD, D- β-CD-PVP and D- β-CD-HPMC system was designated as A1, A2 and A3 respectively while D-HP-β-CD, D- HP-β-CD-PVP and D-HP-β-CD-HPMC systems were designated as B1, B2 and B3 respectively. All the dried products were sieved and fractions smaller than 100μm were used for further study15.
Characterization of binary and ternary systems:
Saturation solubility:
Excess amount of complexes were stirred in distilled water at 37°C for 48 hrs in screw-capped tubes in incubator shaker. The suspensions were periodically filtered with a Whatman filter paper no. 40 to provide the sample solutions. These sample solutions were suitably diluted and analyzed using Shimadzu-1700 UV/VIS Spectrophotometer at 281nm16.
UV Spectral shift study:
Fresh solution of Cefuroxime Axetil (10µg/ml) and various formulations were prepared in distilled water and scanned in the range of 200-400nm using the Shimadzu-1700 UV/Visible Spectrophotometer. The UV absorbance of each sample was corrected for solvent background against respective polymer solution without the drug. The change in the wavelength and absorbance after complexation was noted17.
Percentage drug content study:
The amount of drug available in system is determined by ether wash and chloroform wash method. Fixed amount of prepared system is added to 20 ml of both ether and chloroform. The drug was extracted from the system by occasional shaking the suspension for 20-30 min. the suspension were filtered and the filtrate was evaporated. The amount of drug was calculated after reconstituting the residue with 1:1 methanol water system and absorbance was measured at 281 nm using double beam UV spectrophotometer18.
Thin layer chromatographic analysis:
The study was carried out by using Silica gel G as coating substance with mixture of chloroform: Ethyl acetate: Glacial Acetic Acid: Water (4:4:4:1) as mobile phase. The quantity of the Drug and Binary and ternary system equivalent to 0.10 gm of Cefuroxime axetil was dissolved in mobile phase and spotted over the plate and run the mobile phase with drug and formulation on TLC plate. After removal of plate allow it to dry in air for 15min. & kept in saturated iodine chamber. Rf value of Drug obtained was compared with the Rf value of the prepared Binary and ternary system of Cefuroxime axetil19.
Fourier transforms Infrared (FTIR) spectrophotometer:
Infrared analysis of samples was carried out using FTIR spectrophotometer (Jasco FTIR- 401, Japan). After mixing 1-2mg of sample with dry potassium bromide and the samples were examined at transmission mode over wave number range of 4000 to 400cm-1 20.
X-ray powder diffraction (XRPD):
X-ray diffraction patterns of different samples were recorded on diffractometer. The samples were irradiated with mono-chromatized CuKα radiation and analyzed between 5-60ºC 2θ. The scanning rate (2θ /min-1) was set at 100C/min21.
Differential scanning calorimetry (DSC):
DSC thermograms of the pure drug, and lyophilized powder samples of different preparation were studied on a TA instrument model SDT-2960, USA. DSC measurements were performed at a heating rate of 10ºC/min from 25 to 250ºC using aluminum sealed pan. The sample size was 5-10mg for each measurement. During the measurement, the sample cell was purged with nitrogen gas22.
In-vitro drug release study:
The release rate studies of Cefuroxime Axetil, alone and from binary and ternary systems (complex and physical mixtures) were performed in 0.07 N HCl, 100mg of drug or drug equivalent were added to 900 ml of 0.07 N HCl in USP Apparatus II set at 37±0.20C and rotated at 55rpm. 5 ml of sample was withdrawn at regular intervals maintaining sink condition and filtered. The sample was suitably diluted and the absorbance of the resultant solution was measured at 281nm.The percent drug released from the complex was determined from the calibration curve23. The dissolution pattern of binary system was compared with that of pure drug and physical mixture while dissolution pattern of ternary system was compared with pure drug as well as binary system24.
RESULTS AND DISCUSSION:
Phase solubility studies:
For optimization of water soluble polymer phase solubility is carried out in aqueous solution of polymer. It has been reported that water soluble polymers like PVP, HPMC shows solubilizing effect towards various drugs by forming water-soluble complexes. In this study initial increase in drug solubility was observed, but it was rapidly followed by plateau Fig. 1. In case of PVP drug solubility showed a fast and sharp increase upto a maximum value at a polymer concentration of 0.5%w/v. Since this value was almost constant even though PVP concentration was increased, 0.5%w/v was considered as the optimum concentration for PVP. In a similar way optimum concentration for HPMC was found to be 0.1%w/v. These concentrations were used for further studies25.
Phase solubility of binary and ternary systems:
The phase solubility studies diagram obtained with β-CD and HP-β-CD with and without water soluble polymers (PVP and HPMC) is shown in Fig. 1 It displayed AL type equilibrium phase solubility diagram for both binary and ternary systems showing that Cefuroxime Axetil solubility increase linearly as a function of CD concentration and the soluble complexes formed were without occurrence of precipitation in the range of CD concentration which was used. As the slope value for binary system in this diagram was less than 1, it was possible to assess 1:1 stiochiometry and calculate stability constant of binary drug-β-CD and HP-β-CD complex using equation of Higuchi and Connors26.
Fig. 1: Phase solubility of binary and ternary systems
The stability constant (Kc) values of binary and ternary systems and drug solubility ratio values in solutions of different composition are shown in Table 1 .The addition of water soluble polymers to the CD solution did not change resulted on increase in stability constants (Kc). Apparent stability constants of Cefuroxime Axetil with binary and ternary systems under study increased in the order of D-HP-β-CD-HPMC > D-HP-β-CD-PVP > D-β-CD-HPMC > D-β-CD-PVP> D-HP-β-CD > D-β-CD Increase in stability constant of ternary systems as compared to binary indicates increase in complexation efficiency of cyclodextrin27.
Table 1: Phase solubility of binary and ternary systems
System |
Regression coefficient |
Slope |
Intercept (10-6) |
Binding const. Kc |
KTS /KBS• |
Solubility ratio SCD+pol/ SCD* |
D-βCD |
0.9920 |
0.0035 |
0.9 |
390 |
---- |
----- |
D-βCD-PVP |
0.9896 |
0.0036 |
0.9 |
401 |
1.02 |
1.81 |
D-βCD-HPMC |
0.9904 |
0.0033 |
0.9 |
368 |
0.98 |
14.68 |
D-HPβCD |
0.9932 |
0.0034 |
0.8 |
426 |
---- |
----- |
D-HPβCD-PVP |
0.9963 |
0.0039 |
0.9 |
435 |
1.02 |
5.68 |
D-HPβCD-HPMC |
0.9970 |
0.0039 |
0.8 |
489 |
1.14 |
14.58 |
Characterization of binary and ternary systems:
Saturation solubility:
Both binary and ternary systems showed enhancement in solubility as compared to pure drug alone.
Order of increasing solubility:
D-HP-β-CD-HPMC > D-HP-β-CD-PVP > D-β-CD-HPMC > D-β-CD-PVP> D-HP-β-CD > D-β-CD (Table 2)
Table 2: Saturation solubility of binary and ternary systems
Sr. No: |
System |
Saturation solubility (mg/ml) |
01 |
Pure Drug |
0.42 |
02 |
A1 |
0.78 |
03 |
A2 |
1.42 |
04 |
A3 |
11.57 |
05 |
B1 |
0.90 |
06 |
B2 |
5.13 |
07 |
B3 |
13.17 |
Percentage drug content study:
Percentage drug content was found to be in the range of 96.85 to 98.78 which shows uniform distribution of drug in both binary and ternary systems.
TLC studies:
The Rf values for Cefuroxime Axetil and complexes are given in Table 3.The decreased value of Rf shows interaction between Drug, β-CD and polymers.
Table 3: TLC studies
System |
Rf value |
Drug |
0.61 |
A1 |
0.57 |
A2 |
0.56 |
A3 |
0.57 |
B1 |
0.55 |
B2 |
0.58 |
B3 |
0.59 |
Fourier transforms Infrared spectrophotometer interpretation:
A peak at 1685.34 cm-1 occurred at higher wave number indicating an amide group usually (1695.34 cm-1 to 1630 cm-1 . In the complex this is shift to lower frequency with change in intensity suggesting change in the environment of C=O group associated with the amide moiety. The presence of absorption bends at 1249 cm-1 indicating aromatic ether are seen in drug and binary and ternary system suggesting there is slight change in environment of this moiety. Thus absorption bends at 1985.34 cm-1 and 1772.64 cm-1 are attributed to stretching vibration of the amide carbonyl in the ester and carboxylic acid (Fig. 2).The slight shifting of absorption bend for the carbonyl group of the amide to lower frequency can be attributed to the breakdown of the inter molecular hydrogen bond associated with crystalline drug molecule and formation of hydrogen bonding of monomeric drug with CD28.
Fig. 2: FTIR interpretation of A1, A2, A3 and B1, B2, B3 system
X-ray powder diffraction (XRPD) interpretation:
XRPD graphs are shown in Fig. 3 for pure drug, Cyclodextrins, polymers, physical mixture and prepared binary and ternary system.XRPD Pattern of the Lyophilized Ternary system of Cefuroxime axetil, HPBCD and HPMC shows all peaks which are appeared in individual XRPD Pattern. The XRPD Pattern of the Lyophilized Ternary system has completely different patterns in which there is significant difference in characteristic peaks of Cefuroxime axetil, thus confirming the existence of new compounds.There is difference in d-values between the XRPD Spectra of Cefuroxime axetil and the prepared binary and ternary system referring the crystal habit modification and change in the intensity of peaks which indicate different arrangement of the molecules hence confirming the development of different polymorphic forms. Thus results show that Cefuroxime axetil are completely in entrapped in the cyclodextrin cavity by d-spacing, Peak intensity and 2θ conform that the ternary system have crystalline structure29.
Fig. 3: XRPD interpretation of A1, A2, A3 and B1, B2, B3 system
Differential scanning calorimetry (DSC) interpretation:
To characterize the prepared formulations DSC studies of Cefuroxime Axetil and Optimized formulations were performed. The DSC curve of pure Cefuroxime Axetil exhibits a peak at an onset temperature of 241.75 0C, due to its melting point. In both Formulations B1 and B3 melting endothermic peak of Cefuroxime Axetil was not observed which indicates there is complex formation in binary and ternary system (Fig. 4)30.
Fig. 4: Differential scanning calorimetry (DSC) interpretation of optimized formulations
In-vitro drug release study:
The dissolution curves of Cefuroxime Axetil from binary and ternary systems and the relevant dissolution data are presented in Fig.5 and Table 4which exhibited better dissolution properties than drug alone. A marked increase in dissolution rate of pure drug was evident in binary and ternary systems and can be attributed to both improvements in drug wettability and formation of readily soluble complexes in the dissolution medium. As for the other systems, the increase in dissolution rate was higher for the ternary systems than respective binary compositions, especially for lyophilized preparations. D-HP-β-CD-HPMC ternary system was found to exhibit faster dissolution profile as compared to other systems. The increase in the dissolution rate of drug in case of ternary systems as compared to binary system might be related to enhancement of complexation efficiency and solubilizing effect of cyclodextrin in the presence of water-soluble polymers31.
Table 4: Comparative % Release of type -A and type-B formulations
Sr. No. |
Time (Min) |
% Cumulative Drug release |
||||||
API |
A1 |
A2 |
A3 |
B1 |
B2 |
B3 |
||
1 |
10 |
48.68 |
52.29 |
54.45 |
55.32 |
54.45 |
55.83 |
60.16 |
2 |
20 |
49.88 |
57.57 |
61.06 |
63.67 |
64.53 |
64.54 |
68.91 |
3 |
30 |
54.95 |
66.14 |
69.65 |
69.67 |
70.54 |
70.55 |
75.81 |
4 |
40 |
59.78 |
70.07 |
75.34 |
76.23 |
76.23 |
76.24 |
81.53 |
5 |
50 |
62.67 |
76.62 |
86.27 |
88.03 |
83.34 |
85.09 |
88.93 |
6 |
60 |
65.85 |
84.17 |
92.30 |
95.64 |
94.84 |
97.90 |
98.54 |
Fig. 5: Comparative % Release of type -A and type-B formulations
CONCLUSION:
The present work is an attempt in order to enhance the solubility and hence dissolution of CA by inclusion complexation with natural CDs. But the complexation efficiency of cyclodextrins is low and hence large amount of CDs are required to solubilize small amount of poorly water-soluble drug. Combined use of cyclodextrin and hydrophilic polymers greatly improved drug solubility and dissolution rate because of enhanced complexation efficiency of cyclodextrin. Thus the association of hydrophilic polymers to drug-CD systems would offer a promising drug delivery system having the great advantage of reducing dose of the drug and the amount of cyclodextrin needed.
ACKNOWLEDGEMENT:
The authors sincerely acknowledge the support of Government College of Pharmacy, Karad, Maharashtra, India for providing all the amenities and environment to execute this work.
CONFLICT OF INTEREST:
The authors declare no conflict of interest.
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Received on 25.12.2020 Modified on 18.02.2021
Accepted on 12.04.2021 © RJPT All right reserved
Research J. Pharm.and Tech 2022; 15(2):779-786.
DOI: 10.52711/0974-360X.2022.00130