Controlled Release of Cefixime using Sodium Carboxymethyl Cellulose Polymer

 

Kawther Abd Alwahid Abdulhameed*, Nadeerah Abdulhameed Salih

Department of Chemistry, College of Abn ALhaythem for Science, University of Baghdad, Iraq

 

ABSTRACT:

Environmentally benign and efficient route of synthesis of PAA-g-SCMC was prepared via irradiation (800W) using modified household microwave alone (without using initiator). PAA-g-SCMC polymer before and after loading with the drug was confirmed on FT-IR spectrophotometer and SEM. SCMC polymer was also used to extend the release of antibiotic namely, Cefixime.  Buffer solutions of pH 7.2 and 1.2 were used as the medium for the release of drug to simulate the pH media of small intestine and stomach respectively. We used UV-visible spectrophotometer fo imbibing measuring solution of antibiotic for Cefixime respectively at 285nm. The antibiotic release was done at different temperature (25⁰C, 37⁰C). Generally, there lease was increased at pH 7.2 and temperature at 37⁰C. The results obtained from the grafted polymers were better than the non grafted polymers concerning the controlled release of the drug.

 

 

 

INTRODUCTION:

Pharmacotherapy can be defined as the treatment and prevention of sickness by means of chemically or biologically origin drugs. It ranks among the most important methods of medical treatment, in addition to surgery, physical treatment, radiotherapy, and psychotherapy [1]

 

Carboxylmethyl cellulose (CMC) is a cellulose derivative with carboxyl methyl groups (-CH2-COOH) bound to some of the (OH) groups of the glucopyranose monomers that make up the cellulose backbone. It is often used as its sodium salt [2].  Sodium carboxylmethyl cellulose is shown in Figure 1

 

 

Figure 1: The Chemical Structure of Sodium Carboxymethyl Cellulose [3].

 

Cefixime is Molecular weight = 453.45 Chemical Formula is: C₁₆H₁₅N₅O₇S₂ [4].  Figure: 2. Show the structural formula. Cefixime is active against infections of the otitis medi, respiratory tract infections caused by susceptible bacteria. It also is used for treating urinary tract infections and sexually transmitted disease as well as in obstructive lung disease.

 

 

Figure: 2 Chemical Structure of Cefixime

 

MATERIALS AND METHODS:

AA (Acrylic acid), SCMC (Sodium Carboxyl Methyl Cellulose), PAA-g-SCMC (Poly Acrylic Acid grafted Sodium Carboxyl Methyl Cellulose), Cefixime (The drug), aluminum chloride, deionized water, KCl, NaH₂PO₄, HCl, NaOH, Ethanol, and Acetone.

 

Preparation of beads from polymer solution:

The beads prepared by ionic Gelation method by aluminum chloride as cross-linking factor [6]. Download drug from the polymer carried out by the puffiness equilibrium method.  Dissolving 5% w/v of polymer in (D.W) than reflux in gentle heat. The aqueous solution of polymer was mixing with the Specific quantity of antibiotic and blended homogeneously with the stirrer, the solution was centrifuged for 30 min to get rid of any air bubbles that may be appeared during the stirring processes. mixture added to the drop wise via 20 gauge hypodermic needle fitted with a 50 ml inject into 6%  w/v  gelling aqueous solution agents (AlCl3), being stirred at 200 rpm for 10 min. The beads removed after the elation period of 30 min., The beads filtered by corrosion resistant stainless steel sieve (pore size: 0.25 mm) then washed by (D.W) many times to become free from un-reacted ions, dried at 40º C  to 10 hrs, as shown dried beads in Figure 3.

 

 

Figure 3: The beads prepared after drying

 

UV-via Scanning and calibration curve for Cefixime:

The calibration curve of Cefixime for determination of its concentration in the release process carried out by preparing a stock solution of the one antibiotic in a certain volume of deionized water. From this solution diluted concentration of drug preparation and it absorbance recorded by UV- visible spectrophotometer. The calibration curves obtained by plotting absorbance versus concentration. The scan analysis drug illustrated in Figure:4. the reading   of absorbance and concentration of drug tabulated in Table 1. The calibration curve of Cefixime illustrated in Figure 5.

 

Figure 4: UV-visible scan analysis of Cefixime

 

Table 1: The readings of absorbance and conc. For Cefixime.

 

 

Figure 5: Calibration Curve of Cefixime. (The absorbance at lmax 285 nm)

 

Preparation of buffer solutions:

Prepared two solutions in pH = 1. 2 and7. 2prepared for kinetics experiments. The buffer solutions of   pH= 1.2 prepared by mixing 50ml of 0.2 mol from potassium chloride solution with 85 ml from 0.2 mol hydrochloric acid solution in the volumetric flask, volume completed to 200 ml with (D.W). The buffer solution of pH = 7. 2 prepared similarly method by mixing 28 ml of 0.2 mol from NaH₂PO₄ solution and 72ml of 0.2 mol from Na₂HPO₄ solution into 200 ml volumetric flask, volume completed with (D.W) [7].

 

Synthesis of PAA-g-SCMC:

Specific amounts of SCMC (2% w/v) dissolved in (D.W) to allowed to stir for 2 hrs to remove any air bubbles. Then the certain amount of acrylic acid (AA) added to the solution and allowed to stir for 10 minutes. The mixture was put in a round-bottomed flask with the magnetic bar, the flask was then set in a modified household microwave equipped with the condenser at 800 W for 10 min. The product was taken out and cooled to room temperature. Then to neutralize acrylic acid groups, appropriate amounts of NaOH (1M) added until reaching pH = 9. The product precipitated by acetone, then the product dried at 45°C for 10 hrs [8] SEM image of PAA-g-SCMC beads after drying show in Figure: 6

 

 

Figure 6: SEM image of PAA-g-SCMC beads after drying.

 

Antibiotics release kinetic experiments:

The drug release experiments, carried out on dried polymer beads after it has been loaded with the drug. The beads transfer to the volumetric flask (1 liter) then mixing with 500ml of buffer solution certain pH and temperature. The system stirred continuously at the constant speed in 80 rpm in bath water and shake.  At certain time intervals (30 min), take 3 ml of solution from the flask and transfer to volumetric flask 5 ml, then completed by fresh buffer solution, to keep the volume constant. The collected samples analyzed to assess the concentration of drug by UV-Vis spectrophotometer at λ max = 285 nm for Cefixime. The concentration of drug released determined after 24 hr which is M∞. The release experiments were done at pH = 7. 2 and pH = 1. 2 at temperatures 25 and 37°C.

 

Drug release from SCMC:

In this study, SCMC has also been used as the drug carrier for Cefixime in pH = 1.2 and pH = 7.2 at 25 °C as SCMC (1 gm polymer/20 ml D.W.). The following results have been obtained in Table: 2 and 3, we show UV-visible Scan of Cefixime release from SCMC in figure 7.

 

Figure 7: UV- visible Scan of Cefixime release from SCMC

 

Table 2: Cefixime release from SCMC at pH= 1.2 at 25°C. (Load= 0.1gm drug, 1 gm polymer/20 ml D.W).

Reading No.	Time (min)	Abs (at 285nm)	Conc. of drug release (mg/ml)	Mt/M∞	% drug release
1	30	0.339	5.13×10-3	0.196	19.6
2	60	0.882	8.69×10-3	0.329	32.9
3	90	0.956	17.0×10-3	0.583	58.3
4	120	1.053	18.87×10-3	0.639	63.9
5	150	1.065	19.00×10-3	0.709	70.9
6	180	1.066	19.1×10-3	0.718	71.8
7	210	1.071	19.22×10-3	0.720	72.0
8	240	1.073	19.30×10-3	0.722	72.2
9	270	1.077	19.42×10-3	0.727	72.7
10	300	1.078	19.44×10-3	0.729	72.9

 

 

Table 3: Cefixime release from SCMC at pH= 7.2 at 25°C,(load = 0.1gm drug , 1 gm polymer/20ml D.W).

Reading No.	Time (min)	Abs (at 285nm)	Conc. of drug release (mg/ml)	Mt/M∞	% drug release
1	30	0.488	8.00×10-3	0.292	29.2
2	60	0.929	16.49×10-3	0.601	60.1
3	90	1.198	21.50×10-3	0.790	79.0
4	120	1.245	22.50×10-3	0.823	82.3
5	150	1.265	22.61×10-3	0.827	82.7
6	180	1.276	23.01×10-3	0.841	84.1
7	210	1.282	23.24×10-3	0.852	85.2
8	240	1.288	23.32×10-3	0.853	85.3
9	270	1.300	23.60×10-3	0.862	86.2
10	300	1.304	23.62×10-3	0.865	86.3

 

Drug release from PAA-g-SCMC

In this study, PAA-g-SCMC has been used as the drug carrier for Cefixime at pH 1.2 and pH 7.2 at 25 of and 37^oC the following results have been obtained in Table: 4,5,6 and 7

 

Table 4: Cefixime release from PAA-g-SCMC at 25°C and pH= 1.2, (load = 0.05 gm drug, 0.5 gm polymer/20 ml D.W).

Reading No.	Time (min)	Abs (at 285nm)	Conc. of drug release (mg/ml)	Mt/M∞	% drug release
1	30	0.089	3.32×10-4	0.015	1.5
2	60	0.184	2.2×10-3	0.102	10.2
3	90	0.255	3.6×10-3	0.167	16.7
4	120	0.302	4.42×10-3	0.200	20.0
5	150	0.391	6.14×10-3	0.283	28.3
6	180	0.465	7.87×10-3	0.358	35.8
7	210	0.550	9.57×10-3	0.436	43.6
8	240	0.665	11.87×10-3	0.540	54.0
9	270	0.774	14.01×10-3	0.639	63.9
10	300	0.896	16.5×10-3	0.750	75.0
11	330	0.920	16.9×10-3	0.772	77.2
12	360	0.926	17.11×10-3	0.777	77.7

 

Table 5: Cefixime release from PAA-g-SCMC at 37 °C and pH= 1.2, (load = 0. 05 gm drug / 0.5 gm polymer/20 ml D.W).

Reading No.	Time (min)	Abs (at 285nm)	Conc. of drug release (mg/ml)	Mt/M∞	% drug release
1	30	0.139	1.2×10-3	0.042	4.2
2	60	0.199	2.4×10-3	0.081	8.1
3	90	0.309	4.5×10-3	0.152	15.2
4	120	0.429	6.8×10-3	0.229	22.9
5	150	0.558	9.3×10-3	0.311	31.1
6	180	0.745	12.9×10-3	0.438	43.8
7	210	0.861	15.0×10-3	0.606	60.6
8	240	1.228	22.2×10-3	0.752	75.2
9	270	1.417	25.8×10-3	0.863	86.3
10	300	1.513	27.7×10-3	0.924	92.4
11	330	1.517	27.8×10-3	0.926	92.6
12	360	1.519	27.9×10-3	0.927	92.7

 

Table 6: Cefixime release from PAA-g-SCMC at 25 °C and pH =7.2(load=0.05gm drug / 0.5 gm polymer/20 ml D.W

Reading No.	Time (min)	Abs (at 285nm)	Conc. of drug release (mg/ml)	Mt/M∞	% drug release
1	30	0.171	1.91×10-3	0.079	7.9
2	60	0.271	3.82×10-3	0.157	15.7
3	90	0.369	5.71×10-3	0.235	23.5
4	120	0.404	6.38×10-3	0.262	26.2
5	150	0.552	9.23×10-3	0.380	38.0
6	180	0.622	10.5×10-3	0.435	43.5
7	210	0.698	12.0×10-3	0.496	49.6
8	240	0.798	13.9×10-3	0.574	57.4
9	270	0.935	16.6×10-3	0.683	68.3
10	300	1.036	18.5×10-3	0.764	76.4
11	330	1.169	21.1×10-3	0.869	86.9
12	360	1.207	21.8×10-3	0.899	89.9

 

Table 7: Cefixime release from PAA-g-SCMC at 37 °C and pH =7.2,(load=0.05gmdrug/0.5gmpolymer/20ml D.W).

Reading No.	Time (min)	Abs (at 285nm)	Conc. of drug release (mg/ml)	Mt/M∞	% drug release
1	30	0.185	2.17×10-3	0.089	8.9
2	60	0.301	4.4×10-3	0.191	19.1
3	90	0.420	6.6×10-3	0.291	29.1
4	120	0.571	9.6×10-3	0.417	41.7
5	150	0.631	10.0×10-3	0.467	46.7
6	180	0.719	12.0×10-3	0.541	54.1
7	210	0.759	13.2×10-3	0.574	57.4
8	240	0.875	15.4×10-3	0.671	67.1
9	270	1.044	18.7×10-3	0.814	81.4
10	300	1.122	20.0×10-3	0.879	87.9
11	330	1.170	21.1×10-3	0.919	91.9
12	360	1.178	21.2×10-3	0.926	92.6

 

 

Figure 8: UV- visible scan of Cefixime Release from PAA-g-SCMC.

 

RESULTS:

FT-IR Characterization:

FT-IR spectrum of SCMC shows in Figure 9. The peaks at 3313 and 3184 cm ̵ ¹ assigned to the stretching vibration for 2o and 1o group of (O-H) respectively. The peak at 2916 cm ̵ ¹ groups the stretching vibration for aliphatic C-H. The peak at 1602 cm ̵ ¹ due function group for C=O in COO¯ groups. The peak at 1442 and 1317 cm ̵ ¹ are assigned to symmetrical stretching vibration of COO¯ groups. While the peak shows in 1066 cm ̵ ¹ is for stretching vibration group ether C-O-C [9].

 

The FT-IR of Cefixime Figure 10, the peak at 3295 cm ̵ ¹ it is the absorption of primary amines NH₂ Figure 10. The C-H of the aromatic as well as aliphatic functionalities observed at 3211, 3140, 2978 and 2945 cm ̵ ¹. function group for C=O absorption peak for the carboxylic acid increase to an overlapping absorption of two carboxylic acids functional groups and shown at 1776 cm ̵ ¹, but C=O for amide both cyclic imides and amide are seen at 1664 cm ̵ ¹. These observations are in concurrence with the structure of the drug molecule. represent the FTIR of SCMC blended with Cefixime Figure 11, the broad peaks in position of hydroxyl and amine or amide groups represent the overlap between functional groups of Cefixime and SCMC, suggesting that, this formulation is not a reaction product but it is a mixture of the drug and the polymer, these results have been found to be identical with recent studies.

 

 

Figure 9: FT-IR Spectrum of SCMC.

 

Figure 10: FT-IR Spectrum of Cefixime.

 

 

Figure 11: Spectrum FT-IR for SCMC loaded with Cefixime

 

Kinetic release study of antibiotic from polymer beads:

To study the mechanism for drug release antibiotic from SCMC network hydrogen, data release fitted to an empirical equation of (Korsmeyer and Peppas) [11].

 

Mt/M∞ = K tⁿ (1-3) or ln Mt/M∞ = ln k + n ln t (2-3).

 

Where Mt, M∞ are amounts of drug release at time t and ∞ correspondingly to k is a dynamical consistent and n is dispersion proponent that can be similar to the drug transporting system. Parameters k and n obtained by plotting the experimental values of ln Mt/M∞ versus ln t and fitting the data to the straight line. Parameter n was obtained from the slope of this plot, whereas parameter k was obtained from the intersection at ln t = 0. An equivalent of n = 0.45 indicates Fickian (case I) release n > 0.45 but n < 0.89 for non-Fickian (irregular)absolution; and n > 0.89 demonstates extra case II type of absolution. Case II generally refers to corrosion of the polymeric chain and irregular transportation (non-Fickian) attributed to an aggregation of both dispersion and corrosion controlled-drug discharge. The antibiotic entangled in the SCMC beads after dissolution of both the drug and SCMC in the deionized water then crosslinked by draining the mix into trivalent cation result (Al⁺³).

 

Release of Cefixime from SCMC beads:

The released Cefixime concentration was estimated from the calibration curve of Figure 5, Figure 12 showed the premise kinetic of Drug a Cefixime from SCMC in pH =1.2 at 25°C, The equilibrium reached at 150 min.

 

Figure 12: Kinetics premise of drug Cefixime from SCMC beadsat pH =1.2, 25 °C with shaking speed 80 rpm

 

Figure 13 represents the plot of in Mt / M∞ vs. ln time of premise of drug Cefixime from SCMC beads in pH = 1.2, the premise kinetic drug Cefixime from SCMC beads and the application of (Korsmeyer- Peppas) linear equation was shown in figure 14 and Figure 15 respectively. It is obvious from Figure 16 that the Cefixime release at pH =7.2 was faster than at pH =1.2, where the equilibrium reached within 100 min

 

 

Figure 13: Plot of ln Mt\M∞ vs. ln t of premise drug Cefixime from beads of SCMC in pH =1.2 at 25 °C

 

 

Figure 14: Premise kinetics drug Cefixime from beads of SCMC in pH =7.2 at temperature 25°C with shaking speed 80 rpm.

 

 

Figure 15: Plot of in Mt\M∞ vs. ln t of premise Cefixime from beads SCMC in pH =7.2, temperature 25 °C.

Figure: 16 for the premise Cefixime from beads SCMC in different pH at temperature 25°C, it reveals that antibiotic premise was higher at pH= 7.2.

 

 

Figure 16: premise kinetics Cefixime from beads SCMC in different pH, at temperature 25°C with shaking speed 80 rpm.

 

This behavior may be due to the FCGs within the polymer chains. These groups are present as non-ionized that are connected With each other by (H.B.) hydrogen bonds, at pH= 1.2, this causes a decrease in the free space within polymeric matrix which hinder the premise Cefixime on the other hand, the free carboxyl groups at pH =7.2 are mostly in ionized form, therefore, the number of hydrogen bonds are small and increasing with no effect. This causes an increase in free space within the polymeric matrix support the premise drug Cefixime [9].

 

Entrapment of drug:

Transport mechanism in swelling polymeric beads is generally contributed by numerous factors such as kinetic constant (k), diffusion exponent(n), correlation coefficient (r²) and entrapment efficiency or encapsulation efficiency (EE%)

 

EE% = [ Practical drug content.  Theoretical drug content ]  100.

The encapsulation efficiency represents the percentage of encapsulated drug with respect to the total drug introduced into the polymer solution. The encapsulation efficiency was increased with decrease in solubility of polymer

 

Table 8 showed the parameters obtained from the application of Krosomyer-Peppas (K-P equation) kinetic equation. It has shown that Cefixime release from SCMC beads at pH 1.2 and pH 7.2 have n>0.5 (0.839 and 0.778 respectively)

 

Table 8: the parameters of the K-P equation for the release of Cefixime From SCMC beads.

Polymer	Drug	T	pH	n	k	r²	EE%
SCMC	Cefixime	25 °C	1.2	0.839	11.4 x10¯³	0.967	13.7
		25 °C	7.2	0.778	22.2 x 10¯³	0.946	14.3

 

 

FT-IR Characterization of PAA-g-SCMC

From the FT-IR spectrum of SCMC Figure 9 it has been observe that, the peak at 3313 cm ̵ ¹ and higher belong to stretching vibration of 2⁰ O-H (diols), the broad peak at 3184 cm ̵¹ is due to the stretching vibrations of 1⁰ O-H (CH2OH). Smaller peaks at 2916 cm ̵¹ are assigned to the C–H stretching vibrations. The band at 1066 cm ̵ ¹ is attributed to the C–O–C stretching vibration. The peak at 1602 cm ̵ ¹ is due to asymmetrical stretching vibrations of COO‾ groups. The peaks at 1442 cm ̵ ¹ and 1317 cm ̵ ¹ are assigned to symmetrical stretching vibrations of COO− groups. In the case of PAA-g-SCMC as shown in Figure 17, 1⁰ O–H broad peak is absent. This confirms 1⁰ O–H as the grafting site. If the grafting would have been thermally induced, then ‘C–C’ bond would have cleaved to generate the free radical site for grafting (as ‘C–C’ bond is weaker than ‘O–H’ bond). But microwave effect excites the more polar ‘O–H’ bond, leading to its cleavage resulting in the free radical site for grafting. This vanishing of 1⁰ O–H broad peak due to grafting is the first ever experimental proof presented of the involvement of microwave effect (not thermal effect) as the cause of grafting in microwave initiated synthesis of graft copolymers. The peak centered at 3443 cm ̵ ¹ is due to stretching vibration of 2⁰ O–H (diols). Smaller peaks at 2916 cm ̵ ¹ and 2854 cm ̵ ¹ are assigned to the C–H stretching vibrations. The band at 1022 cm ̵ ¹ is attributed to the C–O–C stretching vibrations. The peak at 1734 cm−1 is due to C=O stretching vibration. The peak at 1600 cm ̵ ¹ is due to asymmetrical stretching vibrations of COO¯ groups. Smaller peaks at 1419 cm ̵ ¹ and 1327 cm ̵ ¹ are a assigned to symmetrical stretching vibration of COO¯ group, and so to say that these results have been found to be identical with recent studies.

 

 

Figure 17: FT-IR Spectrum of PAA-g-SCMC.

 

FT-IR Characterization of PAA-g-SCMC beads loaded with Cefixime:

Figure 18 shows the FT-IR of PAA-g-SCMC loaded with Cefixime. The characteristic peaks of PAA-g-SCMC were found at 3414, 1734,1631 and 1066 cm ̵ ¹ as shown in Figure 17. The characteristic peaks of Cefixime were found at 3295, 3211, 3140, 2810 and 1668 cm ̵ ¹, as shown in Figure 10 The characteristic peaks of PAA-g-SCMC loaded with Cefixime, shows that no extra peaks observed in the FT-IR spectrum. The FT-IR absorption band in cm ̵ ¹ of the Cefixime and the polymer was found to be similar. This established that the drug and all the polymers used in the study showed no interaction and indicated that they were compatible with each other.

 

 

Figure 18: FT-IR Spectrum PAA-g-SCMC loaded with Cefixime.

 

REFERENCES:

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3.       Mahewicz T.G., Kirk T.J., Othmer Concise of Chemical Technology, 4 ed., Wiley, New York, 1999: 368.

4.       Adam D., Hostalek U., Troster K., 5-day cefixime therapy for bacterial pharyngitis and/or tonsillitis, 1995.

5.       National Committee for Clinical Laboratory Standards, Approved Standard: Performance Standards for Antimicrobial Disk Susceptibility Tests (M2-A3), December, 1984.

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9.       Mudhusudana K., Malikarjuna B., Krishna K.S.V., Prabhakar M.N., Chowdoji K. and Subha M.C.S., Preparation and characterization of pH sensitive Poly (vinyl alcohol)/Sodium Carboxy methyl Cellulose IPN microspheres for in vitro release studies of an anti-cancer drug. Polym. Bull. 68 (7), 2012: 1905-1919.

10.     Raghavendra, Rao NG., Pentewar Ram, Thube Ketan, Suryakar VB., Formulation and in vitro evaluation of gastric oral floating tablets of cefixime for controlled release, Research Journal of Pharmaceutical, Biological and Chemical Sciences, 2010.

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Received on 08.09.2018          Modified on 10.11.2018

Accepted on 24.12.2018        © RJPT All right reserved