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Journal of Nanomaterials
Volume 2016, Article ID 6909085, 9 pages
http://dx.doi.org/10.1155/2016/6909085
Research Article

Synthesis of Cefixime and Azithromycin Nanoparticles: An Attempt to Enhance Their Antimicrobial Activity and Dissolution Rate

1Department of Pharmacy, Sarhad University of Science and Technology, Peshawar, Pakistan
2Department of Chemistry, University of Malakand, Chakdara, Dir (Lower), Khyber Pakhtunkhwa 18000, Pakistan

Received 17 June 2016; Revised 22 September 2016; Accepted 10 October 2016

Academic Editor: Victor M. Castaño

Copyright © 2016 Farhat Ali Khan et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

In this study cefixime and azithromycin nanoparticles were prepared by antisolvent precipitation with syringe pump (APSP) and evaporator precipitation nanosuspension (EPN) methods. The nanoparticles were characterized by XRD, FTIR, SEM, and TGA. X-ray diffraction pattern of cefixime samples showed the amorphous form, while azithromycin samples showed crystalline form. The FTIR spectra of parental drugs and synthesized nanoparticles have no major structural changes detected. The SEM images showed that nanoparticles of both drugs have submicron sized and nanosized particles. TGA analyses showed that above 30°C the decomposition of cefixime samples starts and their weight gradually decreases up to 600°C, while, in case of azithromycin, 30°C to 250°C, very small changes occur in weight; from above 250°C decomposition of the sample took place to a greater extent. The antibacterial activities of raw drugs and prepared samples of nanoparticles were determined against Staphylococcus aureus, Shigella, E. coli, and Salmonella typhi by agar well diffusion method. Every time the nanoparticles samples showed better results than parental drugs. The dissolution rates of raw drugs and prepared nanoparticles were also determined. The results were always better for the synthesized nanoparticles than parental drug.

1. Introduction

Cefixime belongs to third generation cephalosporin’s antibiotic drugs. It has been extensively used for the diagnosis of infections like pharyngitis, otitis media, gonorrhea, lower respiratory tract infections such as bronchitis, and urinary tract infections. It shows antibacterial activity by interfering with bacteria peptidoglycan synthesis after binding to the β-lactam-binding proteins [1, 2]. Cefixime is considered as a low solubility and low permeability cephalosporin antibacterial drug. It is soluble in dimethyl sulfoxide (DMSO), dimethyl formamide (DMF), ethanol, and methanol but insoluble in water [3]. Low solubility of drug affects bioavailability [4]. Due to low solubility of cefixime, its bioavailability is only 30–50% of an oral dose absorbed and shows maximum peak serum concentrations within 2–6 hours [5].

Azithromycin is a semisynthetic macrolide antibiotic. It is chemically related to erythromycin and clarithromycin. It is effective against a wide variety of bacteria such as Haemophilus influenzae, Streptococcus, Pneumoniae, Mycoplasma pneumoniae, Staphylococcus aureus, Mycobacterium avium, and many others. Azithromycin prevents bacteria from growing by interfering with their ability to make proteins. Due to differences in the way proteins are made in bacteria and humans, the macrolide antibiotics do not interfere with production of proteins in humans. It is an unusual antibiotic in that it stays in the body for quite a while (has a longer half-life) allowing for once a day dosing and for shorter treatment courses for most infections [6]. Azithromycin is absorbed rapidly after oral administration with a bioavailability of about 36%. It has a variable effect with food. It is also as a poorly water-soluble drug [7].

Several latest drugs are of low water solubility and low dissolution rates. Their solubility and dissolution rate can be enhancing by reducing particle size [8, 9]. Reducing the size of particles will enhance surface area, which can increase the rate of dissolution in aqueous like body fluids [1012]. The dissolution rate is directly proportional to exposed surface area to medium used in dissolution [13]. The small size of nanoparticles means that they have different physicochemical and physiological properties compared to larger particles, such as reduced light scattering, improved stability to gravitational separation and aggregation, faster diffusion rates, higher solubility, and higher penetration rates through biological barriers. The high surface/volume ratio increases the importance of the properties of the surface molecules over the bulk molecules [14, 15].

For the preparation of nanoparticles two different strategies are used. These are top-down approach in which larger size particles break down into nanoparticles and bottom-up approach in which smaller particles build up together up to nanosize. In general, more energy is required in the top-down methods as compared to the bottom-up methods [16]. Milling and homogenization are two common top-down approaches in which coarse particles are broken down into small particles [17, 18]. In contrast, the “bottom-up” approaches, such as antisolvent precipitation, supercritical fluid technology, and spray freezing into liquid, are seldom employed. In comparison to milling and high pressure homogenization, some “bottom-up” techniques, like antisolvent precipitation, are quite simple, cost effective, and easy for scaling up [19, 20].

Solvent/antisolvent precipitation is the most used bottom-up methods for the preparation of nanoparticles. For preparation of lipid nanoparticles spontaneous emulsification method is used. It is used for the preparation of food ingredients nanoparticles. It is mostly used for the preparation of very small size particles with managed sizes, shapes, and physical conditions. It is a good process, in which there is no requirement of specific apparatus and complex working setting, the expenditures are comparatively less, the process might simply be handled up, and the threat of test is appreciably lesser as compared to top-down method [21]. This method is also used in pharmaceutical industry [22]. Nanoparticles are more effective for drug delivery, especially for highly hydrophobic agents, and can increase their low water solubility and dissolution rate [23].

To exploit the importance of reduced size particles in drug dissolution and bioavailability, the aims of this study were to enhance dissolution rate, bioavailability, and antibacterial activity of selected drugs by the preparation of reduced size particles with the help of solvent/antisolvent precipitation method.

2. Materials and Method

2.1. Nanoparticles Preparation

Antisolvent precipitation with syringe pump (APSP) and evaporator precipitation nanosuspension (EPN) methods were used for the preparation of cefixime and azithromycin nanoparticles.

In ASP method, saturated solutions of both cefixime and azithromycin were prepared in 50 mL of methanol and ethanol, respectively. The syringe was filled with the original drug solution which was immediately introduced at a definite flow rate (2 mL/min) into the antisolvent (deionized water) of certain volume with stirring rate (9,000 rpm). Three different ratio (1 : 10, 1 : 15, and 1 : 20) volumes of saturated drug solutions were mixed with the solution of deionized water. In samples (cefixime) A and B the solvent to antisolvent ratios were 1 : 10 and 1 : 15, respectively, while in case of azithromycin samples F, G, and H the solvent to antisolvent ratios were 1 : 10, 1 : 15, and 1 : 20, respectively. After stirring the resulting mixtures were evaporated quickly using a rotary evaporator to obtain nanoparticles.

In the EPN process, like the ASP method we prepared saturated solutions of both cefixime and azithromycin in the same solvents using the same volume. The solutions were quickly added to hexane (antisolvent), resulting in the formation of nanosuspensions. The nanosuspensions were achieved by repaid evaporation of the solvent and antisolvent, with the help of vacuum pump using a rotary evaporator. The solvent to antisolvent ratios 1 : 10, 1 : 15, and 1 : 20 (v/v) were used in different experiments. In cefixime samples C, D, and E the solvent to antisolvent ratios were 1 : 10, 1 : 15, and 1 : 20, respectively, while in case of azithromycin samples I, J, and K the solvent to antisolvent ratios were 1 : 10, 1 : 15, and 1 : 20, respectively.

Characterizations of prepared nanoparticles were done using standard characterization techniques: SEM, FTIR, TGA, and XRD.

The antibacterial spectra of the novel preparations were determined by agar well diffusion method.

2.2. Dissolution Study

USP standard dissolution apparatus having six vessels for dissolution was used to perform the dissolution study. UV-VIS spectrophotometer was used to determine the absorbance of all solutions.

Standard cefixime trihydrate, azithromycin, and prepared nanoparticles, methanol, potassium dihydrogen phosphate (KH2PO4), and sodium hydroxide (NaOH) used in dissolution study were of analytical grade. According to US Pharmacopeia, 68 gm of monobasic potassium phosphate (KH2PO4) was dissolved in 10 liters of water. 7.2 pH was adjusted with 1 N sodium hydroxide (NaOH) solution.

About 22.38 mg of cefixime trihydrate, equivalent to about 20 mg and 20 mg of azithromycin, was weighted and transferred into volumetric flasks of 10 mL capacity. After this 10 mL of methanol was added to dissolve it, with help of buffer solution volume was made up to 100 mL and shaken well. Five mL of the solution from this was taken, diluted with 100 mL buffer solution, and mixed very well.

Each vessel of dissolution apparatus was filled with 900 mL of phosphate buffer solution having pH 7.2 and setting the temperature of the system to 37°C ± 0.5°C. Samples were added to dissolution vessels and the apparatus operated at 100 RPM. After 5, 10, 20, 30, and 45 minutes, 5 mL of solutions was taken from each vessel and then filtered. 100 mL volumetric flask was taken and 5 mL of filtrate which was taken out was added to volumetric flask. 0.1 mL of methanol was added to it and volume was made up to 100 mL with buffer solution and shaken well. The absorbance of samples and reference standard solutions were determined in UV-VIS spectrophotometer at wavelength 288 nm against the blank solution. Following formula was used to calculate the percentage of drug release:

3. Result and Discussion

In this study 5 samples of cefixime and 6 samples of azithromycin nanoparticles were prepared by APPS and EPN methods [24] and were given arbitrary names A, B, C, D, E, F, G, H, I, J, and K. Samples A, B, F, G, and H were prepared by APSP method, while C, D, E, I, J, and K were prepared by EPN method. The nanoparticles characterizations were done by XRD, FTIR, SEM, and TGA.

3.1. X-Ray Diffractometry

X-ray diffraction of pure drug shows crystalline shapes of cefixime with sharp peak from 9.05° 2θ to 26.45° 2θ, a characteristic of cefixime [25]. Diffused peak patterns of XRD show the amorphous form of a solid [26]. The diffraction patterns of raw drug and samples A, B, C, D, and E are given in Figure 1. From the figure it is evident that diffraction patterns of pure cefixime are sharp, while samples A, B, C, D, and E show diffuse pattern which indicates that nanoparticles of samples A, B, C, D, and E were in the amorphous form.

Figure 1: XRD pattern of cefixime samples.

The characteristic X-ray diffraction pattern of azithromycin shows that the main peak occurred in about 10° and other important peaks appear at about 6°, 9.5°, 12°, 15.5°, 16.5°, 17.5°, and 18.8° [7], which means that most of their peaks occurred in between 9° and 20°. Comparing the XRD patterns of samples F, G, H, I, J, and K with that of pure drug (Figure 2) it was concluded that no characteristic changes occur in their XRD patterns of prepared nanoparticles and pure drugs. It means that crystallinity of prepared nanoparticles remains unchanged.

Figure 2: XRD pattern of azithromycin samples.
3.2. FTIR Spectroscopy

The spectrum of raw cefixime showed different peaks at 3292 cm−1 (N-H stretching), 2947 cm−1 (C-H stretching), 1668 cm−1 (C-O stretching, CONH), 1337 cm−1 (C-N stretching, aromatic), 1591 cm−1 (ring, stretching vibrations), 1772 cm−1 (C-O stretching, COOH), 746 cm−1 (C-H, bending), and 1543 cm−1 (C-C stretching). The pattern observed was similar to that already reported in literature [27]. The FTIR photographs have been shown in Figure 3. The FTIR spectra of pure cefixime absorption peak at 3300 cm−1, 2960 cm−1, 1670 cm−1, 1770 cm−1, 1310 cm−1, 1560 cm−1, 1770 cm−1, and 1540 cm−1; in the case of cefixime nanoparticles sample A, these distinctive peaks were located at 3400 cm−1, 2900 cm−1, 1681 cm−1, 1338 cm−1, 1589 cm−1, 1770 cm−1, 744 cm−1, and 1539 cm−1, respectively; in the case of cefixime nanoparticles sample B, these distinctive peaks were located at 3500 cm−1, 2900 cm−1, 1668 cm−1, 1338 cm−1, 1558 cm−1, 1770 cm−1, 732 cm−1, and 1539 cm−1; in the case of cefixime nanoparticles sample C, these distinctive peaks were located at 3350 cm−1, 2900 cm−1, 1668 cm−1, 1338 cm−1, 1558 cm−1, 1770 cm−1, 732 cm−1, and 1539 cm−1, respectively; in the case of cefixime nanoparticles sample D, these distinctive peaks were located at 3500 cm−1, 2900 cm−1, 1668 cm−1, 1338 cm−1, 1608 cm−1, 1770 cm−1, 727 cm−1, and 1539 cm−1, respectively; in the case of cefixime nanoparticles sample E, these characteristic peaks were located at 3550 cm−1, 2900 cm−1, 1668 cm−1, 1338 cm−1, 1608 cm−1, 1770 cm−1, 731 cm−1, and 1539 cm−1, respectively. From the figure it is clear that there were no significant differences between the spectrum of pure cefixime and samples A, B, C, D, and E spectrum which means that no major structural changes occur in cefixime nanoparticles.

Figure 3: FTIR spectrum of cefixime samples.

The FTIR patterns of azithromycin pure drug and prepared samples have been presented in Figure 4. The principal peaks of FTIR spectra of azithromycin at 1721 cm−1, 1188 cm−1, and 1052 cm−1 have been observed [7]. In sample F, these peaks were located at 1716.56 cm−1, 1165 cm−1, and 1053.13 cm−1, in sample G, these peaks were located at 1718.58 cm−1, 1166.93 cm−1, and 1049.28 cm−1, in sample H these peaks were located at 1720.20 cm−1, 1166.93 cm−1, and 1049.28 cm−1, in sample I these peaks were located at 1729.50 cm−1, 1166.93 cm−1, and 1049.28 cm−1, in sample J these peaks were located at 1724.36 cm−1, 1165.00 cm−1, and 1053.13 cm−1, and in sample K these peaks were located at 1724.36 cm−1, 1165.00 cm−1, and 1053.13 cm−1, respectively. From the result it can be concluded that the structural integrity and nature of all sample have not been changed like those of the raw drug and no significant changes occur in their spectra.

Figure 4: FTIR spectrum of azithromycin samples.
3.3. SEM Study

Morphology of nanoparticles of cefixime was determined by SEM. The SEM images show that nanoparticles have amorphous submicron sized and nanosized particles. The results have been shown in Figure 5. The particles sizes of the prepared nanoparticles were from 13.0 to 85 nm.

Figure 5: SEM images of cefixime nanoparticles of samples.

From azithromycin SEM images (Figure 6), it was concluded that the prepared azithromycin nanoparticles have no regular shapes. Also it was observed that the particles sizes were of submicron and nanoparticles level. The particles sizes of the prepared azithromycin nanoparticles were from 11.0 to 89 nm.

Figure 6: SEM images of azithromycin nanoparticles of samples.
3.4. Thermal Gravimetric Analysis

The thermal gravimetric analysis of samples A, B, C, D, and E is shown in Figure 7 which gives us information about the weight loss of cefixime nanoparticles samples A, B, C, D, and E upon increasing temperature. To decompose, the samples were heated from 30°C to 600°C, above 30°C the decomposition of samples starts, and their weight decreases gradually up to 600°C.

Figure 7: TGA photograph of cefixime nanoparticles samples.

Thermal gravimetric analyses TGA of samples F, G, H, I, J, and K results were shown in Figure 8. The result of the figure indicated that by increasing the temperature of samples from 30°C to 250°C very small changes occur in weight of the samples, while from above 250°C decomposition of the samples took place to a greater extent and up to 600°C. From this it can be concluded that prepared nanoparticles were an anhydrous form because no significant loss of weight occurs in 30°C up to 250°C. Similar conclusions were also reported previously [28, 29].

Figure 8: TGA photograph of azithromycin nanoparticles samples.
3.5. Antimicrobial Activities of Raw and Nanoparticles Samples of Cefixime against Bacterial Strains

The antibacterial activities of raw drug and prepared samples of nanoparticles were determined against Staphylococcus aureus, Shigella, E. coli, and Salmonella typhi.

The mean values of zone diameter of inhibition of nanosamples and raw drug of cefixime against Salmonella typhi are shown in Table 1. The results showed that the antimicrobial activities of nanoparticles samples A, B, C, and D were higher than raw drug, while in case of sample E, the antibacterial spectrum of the original drug and that of sample were similar.

Table 1: Zone of inhibition of nanoparticles and raw cefixime drug against Salmonella typhi.

Zone of inhibition of nanoparticles and raw azithromycin against Salmonella typhi were determined and it was found that prepared nanoparticles of azithromycin were greater than raw azithromycin. The results were shown in Table 2.

Table 2: Comparison of zone of inhibition of samples and raw drug against Salmonella typhi.

Against the E. coli bacteria strain, the mean values of zone diameter of inhibition of samples from A to E and that of raw drug are shown in Table 3. The results show that the antimicrobial activities of all nanoparticles samples were higher than that of raw drug.

Table 3: Zone of inhibition of nanoparticles and raw drug against E. coli.

The means diameter zones of inhibition of samples F, G, H, I, J, and K raw azithromycin drug were compared and it was found that nanoparticles of azithromycin were greater than diameter of inhibition zone of the sample as compared to raw drug. The results were shown in Table 4.

Table 4: Comparison of zone of inhibition of samples and raw drug against E. coli.

The mean values of zone diameter of inhibition of samples and raw drug against Staphylococcus aurous strain are shown in Table 5. The result shows that the antimicrobial activities of the prepared nanoparticles samples were higher than that of raw drug.

Table 5: Zone of inhibition of nanoparticles and raw drug against Staphylococcus aureus.

The mean values of diameter zone of inhibition of samples F, G, H, I, J, and K were compared with that of raw drug; it was concluded that zones of inhibition were greater than that of raw drug which showed that antimicrobial activities of prepared azithromycin nanoparticles were greater activities as compared to raw azithromycin drug. The results were shown in Table 6.

Table 6: Comparison of zone of inhibition of nanoparticles with raw drug against Staphylococcus aureus.

Against Shigella, the mean values of zone diameter of inhibition of samples of raw are shown in Table 7. The results of nanoparticles were higher than that of raw drug.

Table 7: Zone of inhibition of nanoparticles and raw drug against Shigella.

The mean values of zone of inhibition diameter of samples F, G, H, I, J, and K and zone of inhibition diameter of raw drug against Shigella bacterial strain are shown in Table 8 which indicated that the antimicrobial activities of nanoparticles were greater than that of raw drug.

Table 8: Comparison of zone of inhibition of nanoparticles with raw drug against Shigella.
3.6. Dissolution Study of the Samples

About 23 mg, which was equivalent to 20 mg of samples, was used while determining the dissolution rates of the samples. After every 5 minutes 5 mL samples from the dissolution apparatus were withdrawn and their absorbency was measured. The absorbance was found to increase with passage of time. At 30 minutes the dissolution of nanoparticles and raw cefixime had been calculated and then their dissolution rates were compared. Samples A, B, C, D, and E and raw cefixime showed 90.169%, 94.86%, 87.82%, 90.047%, 90.169%, and 59.643%, respectively (Figure 9). Similarly, the prepared samples of azithromycin named F, G, H, I, J, and K showed 76.23%, 86.40%, 71.15%, 96.56%, 81.23%, and 76.23% dissolution rates, respectively, while the raw drug showed 55.91% dissolution rate (Figure 10). The data clearly indicates considerable increase in dissolution rate of the prepared cefixime and azithromycin nanoparticles compared to raw drugs. The increase in dissolution rate of the synthesized nanoparticles can be ascribed to decrease in size of the nanoparticles which leads to increase in both dissolution and solubility of the drugs [814].

Figure 9: Comparative dissolution of prepared cefixime nanoparticles and raw cefixime.
Figure 10: Comparative dissolution of prepared azithromycin nanoparticles and raw.

4. Conclusions

Considerable reductions in the size of the nanoparticles up to submicron and nanoscale level were successfully achieved. The nanoparticles samples exhibited better results than parental drugs against Staphylococcus aureus, Shigella, E. coli, and Salmonella typhi. The synthesized nanoparticles were found to show better dissolution rate than raw drugs. Hence, reduction in size of the parental drug resulted in enhanced antimicrobial activity and improved dissolution rate.

Competing Interests

The authors declare that they have no conflict of interests.

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