Int J Pharm Pharm Sci, Vol 9, Issue 9, 115-121,Original Article



Department of Pharmaceutics, College of Pharmacy, Al-Bayan University, Baghdad, Iraq

Received: 22 Mar 2017 Revised and Accepted: 13 Jul 2017


Objective: This study was designed to improve the solubility and biological activity of class II drug clarithromycin (CLA) by utilizing the nanotechnology as a novel drug delivery system.

Methods: Bismuth sulfide (Bi2S3) nanoparticles were synthesized using chemical co-precipitation technique, while the loading of clarithromycin (CLA) with bismuth sulfide (Bi2S3) nanoparticles was achieved using incorporation method. The loading process, as well as particle size reduction, were evaluated using x-ray diffraction (XRD), furrier transformed infrared (FTIR) and atomic force microscopy (AFM). In vitro release study was performed using USP paddle apparatus type II in phosphate buffer solution pH 7.4. Disc diffusion method was the technique used to test the antibacterial activity of CLA before and after loading process.

Results: Loading of CLA with Bi2S3 nanoparticles was accomplished successfully accompanied with particle size reduction within nano range as measured by AFM. In vitro release study showed a significant* increase in solubility and dissolution profile of CLA after loading process, which was also proven using XRD that indicate transformation from crystalline into more soluble amorphous structure. Susceptibility test displayed significant* potentiation of antibacterial activity at all tested concentrations against gram+ve bacteria Staphylococcus aureus and Bacillus subtilis after loading of CLA with Bi2S3 nanoparticles, while gram ve bacteria E. coli showed no response for CLA before and after loading process.

Conclusion: The solubility, as well as the antibacterial activity of CLA, were improved significantly* after preparation of nanotechnology based drug delivery system through the utilization of metal nanoparticles, Bi2S3, as nanocarriers for CLA.

Keywords: Nanotechnology, Clarithromycin (CLA), Bismuthsulfide (Bi2S3) nanoparticles


Clarithromycin (CLA) is a semisynthetic antibacterial macrolide antibiotic that inhibits synthesis of a protein of bacteria, it binds to the 50S ribosomal subunit of susceptible organisms and therefore prevents translocation of aminoacyl transfer RNA and inhibition of protein synthesis [1]. CLA is used for respiratory tract infection, skin soft tissue infection, Chlamydia infection, acute maxillary sinusitis, helicobacter pylori infection, tonsillitis, pharyngitis, chronic bronchitis and pneumonia [2]. According to biopharmaceutical classification system (BCS), CLA belongs to class II which means the drug had low solubility of 0.33 mg/ml [3] and high permeability and therefore to overcome bioavailability problems, nanotechnology has been utilized [4]. This low aqueous solubility results in a slow rate of dissolution after oral administration and thereby the low amount of drug in solution and low absorption in addition to first pass metabolism and pH dependent solubility of CLA, all these factors lead to low bioavailability (not more than 50%) [5].

This is the reason for assigning class II drugs of BCS as having dissolution rate limited absorption [6]. The application of nanotechnology as a novel approach for drug delivery was the scope for the elaboration of physiochemical and performance of many drugs in the recent years, where nanotechnology is the understanding and control of matter at nearly 1 to 100 nm dimensions [7, 8]. Nanotechnology has numerous medical applications as a therapeutic drug delivery system as well as in the development of the treatment for a variety of diseases and disorders [9]. Nanotechnology can increase the efficacy of drugs and thereby reducing doses number and decreasing the risk of side effect and toxicity [10]. Many types of nanoparticles have been utilized as carriers for drugs to improve their pharmaceutical and biological properties known as nanocarriers, for example, liposomes, niosomes, nanotube, nanocrystal, micelles and other materials [11, 12]. Inorganic nanoparticles are a part of nanomaterials used as nanocarriers and defined as particles of metal, metal oxide or metallic composition presenting with at least one length scale in the range of nanometer. Because of their very small nano-size scale, these nanostructures appeared with significantly improved and diverse physical, chemical, and biological properties [12, 13]. Bismuth sulfide (Bi2S3) is a member of inorganic nanoparticles that have been utilized in this study as the nanocarrier for clarithromycin. Bismuth sulfide (Bi2S3) nanoparticles used medically in computed tomography (CT) imaging [14]. The aim of the following study was to prepare and evaluate a nanotechnology based drug delivery system as a novel drug delivery system to improve and advance the pharmaceutical (particularly solubility) and/or biological (antimicrobial spectrum) properties of low soluble class II drugs. CLA was the model drug for this study as it belongs to class II drugs in the biopharmaceutical classification system (BCS).



Clarithromycin (CLA) JIANGSU YEW PHARMACEUTICAL Co. Limited (China); sodium sulfide (Na2S. XH2O) THOMAS BAKER Co. Limited (India); bismuth nitrate Bi (NO3)3.6H2O Qualikems Fine Chem Co. Ltd. (India); acetone C3H6O Sigma Chemical Co. Limited (USA); dimethyl sulfoxide (DMSO) Loba Chemie Pvt. Ltd (India).


Synthesis of bismuth sulfide (Bi2S3) nanoparticles

Chemical co-precipitation method was the technique used to synthesize Bismuth sulfide (Bi2S3) nanoparticles and involve the titration (10 drops per min) of 0.1 M of disodium sulfide Na2S.10H2O aqueous solution onto 0.1 M of bismuth nitrate Bi (NO3)3.6H2O aqueous solution with special conditions (vigorous stirring at 1100 rpm and heating at 80 °C) using a magnetic stirrer (Dragon Lab, USA). When dropping was started, the color of the aqueous solution of bismuth nitrate was changed from white into black color. After finishing the titration, stirring was continued vigorously at 1100 rpm and temperature the temperature was hold constant at 80 °C for 3 h. The resulted black sticky product of Bi2S3 nanoparticles was then filtered and washed using deionized water before being dried using silica gel containing desiccators [15].

3Na2S+2Bi(NO3)3 → Bi2S3+6NaNO3

Loading of clarithromycin with Bi2S3 nanoparticles

Loading of CLA with Bi2S3 nanoparticles was performed in the last step of Bi2S3 nanoparticles synthesis (incorporation method) which involves the addition of the drug in the last step of nanoparticles synthesis before the titration of sodium sulfide has been completed, where 0.1 M of CLA added using acetone as a solvent. When titration completed, the stirring was continued for 3-4 h and finally filtered, washed using deionized water to be desiccated and collected [16, 17].

Characterization techniques of CLA loaded Bi2S3 nanoparticles

X-ray diffraction (XRD)

XRD instrument (Shimadzu, Japan) was utilized to detect the effect of loading process of Bi2S3 nanoparticles on the nature and lattice property of CLA.

Hence, XRD was performed for CLA before and after loading process. Instrument was equipped by the use of Cu-Ka radiation of λ = 1.54060 Ǻ and voltage 40 Kv with electrical current of 30 mA. A range of 0 to 60 degrees with axis θ-2θ was applied and scanning speed of 5 °/min [18].

Fourier transform infra-red spectroscopy (FTIR)

The nature of functional groups of CLA was characterized before and after loading with Bi2S3 nanoparticles by the use of FTIR instrument (Shimadzu Japan) to detect whether loading process cause any chemical modification of the drug. FTIR was used with spectroscopy (4000-500 cm-1) and using potassium bromide disc [19].

Atomic force microscopy (AFM)

Shape, particle size and size distribution of unloaded CLA and CLA after loading with Bi2S3 nanoparticles were characterized by the use AFM instrument (Augestrom advance Inc., USA)[20]. Solid powdered samples were dissolved using methanol and then few drops were poured separately on a silica glass plate and left to dry at room temperature residue on the plate to be scanned using AFM instrument [21].

Drug entrapment efficiency, loading and yield percentages [22-24]

The entrapment efficiency percent of the entrapped CLA was calculated using the following equation:

The loaded CLA with Bi2S3 nanoparticles percent was calculated as follow:

While the yielded drug percent by Bi2S3 nanoparticles was calculated using equation below:

Fig. 1: FTIR of (A) unloaded clarithromycin (CLA) and (B) clarithromycin (CLA) loaded bismuth sulfide (Bi2S3) nanoparticles

In vitro drug release study

The in vitro release of CLA from Bi2S3 nanoparticles was accomplished by the use of paddle apparatus, USP type II rotating (Copley, UK), at 37+0.5 °C and rotating speed of 100 rpm. An equivalent 100 mg of CLA loaded with Bi2S3 nanoparticles and 100 mg of unloaded CLA samples were dispersed each separately in 500 ml phosphate buffer solution with a pH 7.4. Samples of 5 ml were withdrawn at programmed time intervals and replaced with the same volume of phosphate buffer fresh media after each withdrawal. The withdrawn samples were then filtered and CLA content was determined spectrophotometrically using UV-Visible spectrophotometer (Shimadzu, Japan) at 210 nm, each experiment was analyzed in triplicate [25, 26].

Antibacterial susceptibility test

Disc diffusion method was the technique used and it was achieved for CLA loaded Bi2S3nanoparticles in comparison with unloaded CLA and blank Bi2S3 nanoparticles. The test was performed against two types of gram+ve bacteria (Staphylococcus aureus and Bacillus subtilis) and one type of gram–ve bacteria (E. coli) using serial diluted concentrations (500, 250, 125 and 62.5 µg/ml) of unloaded CLA and an equivalent concentration of CLA loaded with Bi2S3 nanoparticles. Dimethyl sulfoxide (DMSO) was the solvent used to prepare samples and Muller Hinton agar was the culture medium used where each sample was cultured for 24 h at 37 °C [27-29].

Statistical analysis

The experiments were performed in triplicates and the quantitative data comparison for biologic activity of CLA was analyzed using one-way and two-way ANOVA tests, while Student T-Test was used for of quantitative data comparison of in vitro release. Results were expressed as mean±standard deviation. SPSS package for windows (version 13, SPSS Inc., Chicago, IL, USA) was the used statistical analysis program and the statistical significance for each test (P value) adapted was less than 0.05.


Fourier transform infra-red spectroscopy (FTIR)

FTIR spectrum of unloaded CLA (fig. 1 A) displayed bands for multiple hydroxyl groups (OH) in the backbone structure at the range (3469–3419 cm-1), while bands at 1730 cm-1and 1691 cm-1assign to the two carbonyl groups of ester and ketone respectively. Aliphatic groups (CH3 and CH2) appeared in the expected stretching area (asymmetrical and symmetrical) in the range (2974-2781 cm-1), while the finger prints area showed the bending bands of the drug. The FTIR spectrum of loaded CLA withBi2S3 nanoparticles (fig. 1 B) displayed the same functional groups for unloaded CLA with small shifting.

X-ray diffraction (XRD)

The x-ray spectrum of unloaded CLA (fig. 2A) showed sharp narrow intense diffraction peaks with high multiplicity, this indicates the highly crystalline structure of the unloaded drug. After loading of CLA with Bi2S3 nanoparticles, the x-ray (fig. 2 B) was diffracted with non-intense nor-sharp diffraction peaks giving arise to crystal lattice transformation into amorphous drug molecules.

Fig. 2: XRD of (A) unloaded clarithromycin (CLA) and (B) clarithromycin (CLA) loaded bismuth sulfide (Bi2S3) nanoparticles

Atomic force microscopy (AFM)

Average particle sizes images (2 and 3-dimensional images) determined by AFM for CLA before (fig. 3A) and after (fig. 3B) loading with Bi2S3 nanoparticles were found 116.17 and 95.5 nm respectively, indicating particle size reduction of CLA after loading process. Particle size distribution was also detected using AFM instrument and displayed more symmetrical (pyramidal shaped) as well as the more fine distribution of CLA particles after loading on Bi2S3 nanoparticles (fig. 4 A) than that of unloaded CLA (fig. 4B).

Drug entrapment efficiency, loading and yield percentages

The entrapped drug percent for CLA was found 98.79%, while the percent of the loaded drug with Bi2S3 nanoparticles was found 92.66%. The yielded drug percentage was found 65.88%.

In vitro drug release study

The in vitro release pattern of CLA from Bi2S3 nanoparticles (fig. 5 B) in phosphate buffer solution with pH 7.4and showed significantly* improved solubility and dissolution profile after loading with Bi2S3 nanoparticles when compared with the dissolution profile of unloaded drug (fig. 5 A). Where after 120 min CLA completely (100%) released from Bi2S3 nanoparticles while unloaded CLA dissolution profile showed only 30% dissolution of the drug.

Fig. 3: AFM (2 and 3 D) images of (A) unloaded clarithromycin (CLA) and (B) clarithromycin (CLA) loaded bismuth sulfide (Bi2S3) nanoparticles

Fig. 4: AFM particle size distribution of (A) unloaded clarithromycin (CLA) and (B) clarithromycin (CLA) loaded bismuth sulfide (Bi2S3) nanoparticles

Fig. 5: In vitro profile of (A) unloaded clarithromycin (CLA) and (B) clarithromycin (CLA) loaded bismuth sulfide (Bi2S3) nanoparticles. Data represent mean (n=3)+SD

Antibacterial susceptibility test

The susceptibility test of CLA (table 1) before and after loading process with Bi2S3 nanoparticles showed significantly* increased antibacterial activity at all concentrations used against gram +ve bacteria Staphylococcus aureus and Bacillus subtilis after loading withBi2S3 nanoparticles. While the test against gram -ve bacteria Escherichia coli showed no antibacterial activity, nor for unloaded CLA did neither for loaded drug at all test concentrations.

Table 1: Antibacterial activity of unloaded clarithromycin (CLA), clarithromycin (CLA) loaded bismuth sulfide (Bi2S3) nanoparticles and blank bismuth sulfide (Bi2S3) nanoparticles represented as inhibition zone in milliliter (mm)

Sample Staphylococcus aurous Bacillus subtilis Escherichia coli
Concentration µg/ml
62.5 125 250 500 62.5 125 250 500 62.5 125 250 500
Dimethyl sulfoxide (DMSO) _ _ _ _ _ _ _ _ _ _ _ _
Blank bismuth sulfide (Bi2S3) nanoparticles _ _ _ _ _ _ _ _ _ _ _ _
Unloaded clarithromycin (CLA) 21 22 22 24 18 20 21 23 _ _ _ _
Clarithromycin (CLA) loaded bismuth sulfide (Bi2S3) nanoparticles 31 33 35 38 32 34 34 35 _ _ _ _


Nanoparticles of Bi2S3 were synthesized and loaded successfully with CLA, the loading process was achieved physically by attractive or physical complex formation without any chemical reaction between Bi2S3 nanoparticles and CLA. FTIR spectra of CLA before and after loading process as comparative showed similar main functional groups of CLA with small shifting after loading with Bi2S3 nanoparticles indicating the physical complex creation without any chemical reaction [30]. The particle size reduction of the prepared loaded CLA assessed by AFM device approve the nano-sized particles of CLA after loading process with accompanied alterations in its physical and pharmaceutical properties of the very small produced particles, where the in vitro release and dissolution profile study showed significantly* enhanced solubility of CLA after loading with Bi2S3 nanoparticles, this enhanced solubility might be a result of particle size reduction within nano-range (1-100 nm) and thereby increased effective surface area of exposed drug particles to the dissolution medium and significantly* enhanced solubility which in turn lead to increase in absorption and bioavailability of already poor soluble drug, CLA [31, 32]. Another explanation of enhanced solubility was attributed to the transformation of CLA particles from the highly crystalline low soluble structure into amorphous highly soluble molecules [33-36]. This alteration in the morphism of molecules was detected using X-ray instrument which displayed narrow intense sharp diffraction peaks of unloaded crystalline CLA, while after loading process with Bi2S3 nanoparticles the diffracted peaks were diminished and the sharp peaks were disappeared. The high loading, entrapment efficiency and yield percentages (92.66%, 98.79% and 65.88%) give an indication of the effective and uniform process of CLA loading with Bi2S3 nanoparticles as well as excellent compatibility between the drug and Bi2S3 nanoparticles without chemical degradation or cross interaction between them.

The highly loaded and entrapped CLA to Bi2S3 nanoparticles give evidence of enough drug being carried by Bi2S3 nanoparticles to the targeted site and hence the desired biologic activity will be obtained. Disc diffusion method used to test the antibacterial activity was achieved against gram+ve bacteria Staphylococcus aurous and Bacillus subtilis and showed significantly* increased activity at all serially diluted concentrations used. This potentiation of biologic activity could be attributed to the enhanced penetration rate of reduced nano-sized particles into pathogenic bacteria and thereby enhanced the effective concentration of CLA within bacteria and potentiating activity [37-39].

This increased activity might be utilized to decrease number and amount of conventional dosage form doses to decrease potential side effects and increase patient compliance. The reduction in particle size of CLA molecules might also cause a huge increase in effective exposed surface area of drug particles to the microorganism membrane resulting in enhanced penetration and activity [40, 41]. The enhanced solubility of loaded CLA with Bi2S3 nanoparticles can bring CLA into solution faster than that of unloaded drug and thereby enhanced available CLA for absorption into the blood stream and increased bioavailability which can reach targeted area with high concentration [42, 43]. E. coli showed no response to both, unloaded and loaded CLA.


The utilization of nanotechnology as a novel drug delivery system for poorly soluble class II drug clarithromycin (CLA), give rise for a significantly* increase in the solubility and in the antibacterial activity after loading with Bi2S3 nanoparticles as effective nanocarriers. The increased antibacterial activity and solubility (hence absorption and bioavailability) of CLA after loading process give rise to decrease the number of doses and drug content per dose to avoid side effect and enhance patient compliance.


Author is grateful to Al-Bayan University for their support and encouragement. Special thank for the central service lab/College of Science for performing the analytical methods in this study.


This study was self-funded and was written, achieve experimental and analytical work and revised by the author.


The author declare no conflicts of interest. The author alone are responsible for the content and writing of the paper.


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How to cite this article

  • Mustafa R Abdulbaqi. Preparation and evaluation of clarithromycin loaded bismuth sulfide (Bi2S3) nanoparticles utilizing nanotechnology as a novel drug delivery system. Int J Pharm Pharm Sci 2017;9(9):115-121.

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Nanotechnology, Clarithromycin (CLA), Bismuthsulfide (Bi2S3) nanoparticles





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International Journal of Pharmacy and Pharmaceutical Sciences
Vol 9, Issue 9, 2017 Page: 115-121

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Mustafa R. Abdulbaqi
Department of , College of Pharmacy, Al-Bayan University, Baghdad, Iraq

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