Metronidazole is a broad spectrum antibiotic. It is sparingly soluble in water but has oral bioavailability of 93-95%. So solid dispersions (SDs) containing metronidazole was prepared in different ratios (1:1, 1:2 and 1:5) and using different carriers like dextrose, citric acid, polyethylene glycol (PEG-4000) and polyvinylpyrrolidone (PVP). Fusion or melting method was used for SD containing dextrose and citric acid and Solvent evaporation method was used for SD containing PVP and PEG-4000. The solubility studies revealed that solubility of metronidazole was enhanced to manifolds. Best result was exhibited when drug carrier ratio is in the order of 1:5&gt;1:2&gt;1:1. Among the different carriers, the solubility and dissolution was increased to maximum in case of PVP and PEG and almost 100 % drug released within 1 hour. The development of solid dispersions was further confirmed by DSC and XRD

Kashyap, Neha

Madan, Kirtika Madan

Mayle, Shalini

Sambhakar, Sharda

Singh, Bishambar

Singh, Monalisha

English

International Journal of Drug Delivery

  
 
International Journal of Drug Delivery 5 (2013) 94-98 
http://www.arjournals.org/index.php/ijdd/index 
 
Original Research Article 
             
Solid dispersions: A tool for improving the solubility and dissolution of 
metronidazole 
    Sharda Sambhakar1, Bishambar Singh2, Kirtika Madan1, Monalisha1, Neha Kashyap1, Shalini Mayle1 
 
 
*Corresponding author: 
 
 Sharda Sambhakar 
 
1Department of Pharmacy, Banasthali 
University, Niwai, Tonk (Rajasthan)-
304022, India 
2PHTI, SMS Medical Collage, Jaipur 
(Rajasthan)-302017, India 
 
 
 
 
A b s t r a c t  
Metronidazole is a broad spectrum antibiotic. It is sparingly soluble in water but has oral 
bioavailability of 93-95%. So solid dispersions (SDs) containing metronidazole was prepared in 
different ratios (1:1, 1:2 and 1:5) and using different carriers like dextrose, citric acid, polyethylene 
glycol (PEG-4000) and polyvinylpyrrolidone (PVP). Fusion or melting method was used for SD 
containing dextrose and citric acid and Solvent evaporation method was used for SD containing 
PVP and PEG-4000. The solubility studies revealed that solubility of metronidazole was enhanced to 
manifolds. Best result was exhibited when drug carrier ratio is in the order of 1:5>1:2>1:1. Among 
the different carriers, the solubility and dissolution was increased to maximum in case of PVP and 
PEG and almost 100 % drug released within 1 hour. The development of solid dispersions was 
further confirmed by DSC and XRD. 
Keywords: Solid Dispersions; polyvinylpyrrolidone (PVP); Metronidazole 
Introduction 
Metronidazole, an anti-amoebic drug, is a prototype nitroimidazole 
derivative. It has broad spectrum of activity and acts by disrupting 
the DNAÊs helical structure, thereby inhibiting the bacterial nucleic 
acid synthesis and eventually results in bacterial cell death. It is 
active against protozoa, including Giardia lsmblia, anaerobic 
bacteria like helicobacter pylori, streptococci, spirochetes etc. 
Metronidazole is sparingly soluble in water but has oral 
bioavailability of 93-95%. It is extensively metabolized by liver. The 
work presented deals with enhancing the solubility of 
metronidazole by solid dispersion approach. Since the solid 
dispersions are easy to prepare, less time consuming, also the 
carriers used here are cheap and easily available [1]. 
Materials and Method 
Metronidazole was purchased from Alembic Pharmaceuticals Ltd 
(India). Dextrose, polyvinyl pyrrolidone (PVP), citric acid, 
polyethylene glycol-4000 (PEG), ethyl alcohol, acetone, chloroform 
were purchased from S.D. Fine Chemicals Ltd. (India). All other 
chemicals and reagents are of AR grade. 
Preparation of Solid Dispersions of Metronidazole 
The solid dispersions of metronidazole with PVP and PEG-4000 
were made by Solvent Evaporation method [2]. The physical 
mixtures of metronidazole with carriers (PVP and PEG-4000) in 
molar ratios of 1:1, 1:2 and 1:5 were added to the common  
 
 
solvents (chloroform+acetone in 1:1 ratio). The solvent was 
evaporated in water bath at 400Cwith continuous stirring. The 
resultant residue was dried in vaccum for 3 hours and stored in 
dessicator for overnight. The dried mass was grinded and passed 
through sieve no.44. 
The solid dispersions of metronidazole with citric acid and dextrose 
were made by Melting method [1]. The physical mixtures of 
metronidazole with carriers (citric acid and dextrose) in molar ratios 
of 1:1, 1:2 and 1:5 were taken in preheated china dish and heated 
until melted, thereby dispersing the drug in molten carrier. The 
molten mass was then cooled immediately by putting the mass on 
ice. The resultant residue was dried in vaccum for 3 hours and 
stored in desiccators for overnight. The dried mass was grinded 
and passed through sieve no.44. 
 
Characterization of Solid Dispersions 
Physical Appearance 
The prepared solid dispersions were analyzed for their colour and 
appearance using simple microscope. 
Solubility Studies 
The saturation solubility studies of different solid dispersions were 
determined. Excess of solid dispersions were taken in conical 
flasks and placed on mechanical shaker for 24 hours, until 
ISSN: 0975-0215 
  
This work is licensed under a Creative Commons Attribution 3.0 License.  
Sambhakar et al. International Journal of Drug Delivery 5 (1) 94-98 [2013] 
 
PAGE | 95 |
 
 
equilibrium is reached. The solubility was then analyzed using UV-
VIS spectrophotometer (LABINDIA UV 3000) at λmax of 276 nm, 
by making suitable dilutions. 
Dissolution Studies 
In-vitro dissolution studies of metronidazole and the various solid 
dispersions were performed on USP Type II (Labindia DS 8000) 
Dissolution Test Apparatus in 0.1M HCl with a constant 
temperature of 370C and a speed of 50 rpm. Aliquotes were 
withdrawn at predetermined time intervals, and absorbance was 
measured at 276 nm, using UV-VIS spectrophotometer [10]. 
 
X-ray powder diffraction  
 
(XRPD): X-ray powder diffraction (XRPD) patterns were recorded 
on an X-diffractometer (Phillip PW 1130/00 diffractometer, 
Netherland), employing Cu K_radiation source operating at 30 mA 
and 40 kV. Samples were scanned from 6 to 40Ĉ 2θ at a scanning 
rate of 0.02Ĉ 2θ s-1[6]. 
 
Differential Scanning Colorimetry  
DSC curve for pure metronidazole and their various solid 
dispersions (in different ratios) were taken and were compared [6]. 
Result and Discussions 
Various solid dispersions were analyzed for their physical 
appearance as shown in Table1. 
 
       Table1: Physical appearance of various solid dispersions. 
        
Dextrose and citric acid they results in the precipitation of drug in 
amorphous/granular form in SD. While the PVP and PEG results in 
the formation of glassy and waxy solid mass [12]. Saturation 
solubility study was performed for various solid dispersions and 
was compared with the solubility of pure drug as shown in Table 2. 
 
Table 2: Solubility data for various solid dispersions of Metronidazole 
 
S.No. Solid Dispersions Method of Preparation Solubility (μg/ml) Increase in solubility
(in folds) 
1 MTZ-dextrose  1:1 SD Fusion/melting 1046.88 2
2 MTZ-dextrose  1:2 SD Fusion/melting 968.013 2
3 MTZ-dextrose  1:5 SD Fusion/melting 1767.265 4
4 MTZ-Citric acid 1:1 SD Fusion/melting 3223.319 7
5 MTZ-Citric acid 1:2 SD Fusion/melting 3453.201 8
6 MTZ-Citric acid 1:5 SD Fusion/melting 4139.423 10 
7 MTZ-PVP 1:1 SD Solvent Evaporation 19983.098 46 
8 MTZ-PVP 1:2 SD Solvent Evaporation 34271.028 79 
9 MTZ-PVP 1:5 SD Solvent Evaporation 75490.65 147 
10 MTZ-PEG 1:1 SD Solvent Evaporation 4722.046 11 
11 MTZ-PEG 1:2 SD Solvent Evaporation 5970.605 14 
12 MTZ-PEG 1:5 SD Solvent Evaporation 106513.667 245 
 
From solubility studies, it was found that among different carriers, 
PVP & PEG showed the maximum increase in solubility. This was 
probably due to the increased wettability, dispersibility and 
solubilization effect of polymers and surfactants. The solubility and 
dissolution rate increases as the amount of carrier increases 
(1:5>1:2>1:1). The solubility and dissolution also increases (Table 
3) in case of dextrose and citric acid, because the solid dispersions 
result in the precipitation of drug in amorphous form, with 
decreased particle size. The dissolution rate was enhanced due to 
high surface area of the solid dispersions [12].  
Further the carrier material also retards any agglomeration of 
particles, additionally sometimes solid dispersions results in 
metastable state, which has high solubility and hence faster 
dissolution rate. 
Also, the presence of a small amount of soluble carrier in the 
crystalline lattice of the poorly soluble drug may also produce a 
dissolution rate faster than the pure compound with similar particle  
 
 
 
 
S. No. Solid Dispersions Appearance
1 Drug + PVP complex Glassy and orange in color
2 Drug + PEG complex waxy and off-white in color
3 Drug+Citric acid 
complex 
granular and pale in color
4 Drug + Dextrose 
complex 
granular and off-white in 
color 
Sambhakar et al. International Journal of Drug Delivery 5 (1) 94-98 [2013] 
 
PAGE | 96 |
 
 
                            Table 3: Dissolution data for various solid dispersions of metronidazole 
Time 
(min) 
Percentage Drug Release 
MTZ MTZ-dextrose SD MTZ-citric acid SD MTZ-PVP SD MTZ-PEG SD
1:1 1:2 1:5 1:1 1:2 1:5 1:1 1:2 1:5 1:1 1:2 1:5
10 13.7
1μ2 
13.81
μ2 
25.56
μ2 
50.54
μ3 
21.32
μ3 
49.27
μ1 
53.36
μ2 
93.99
μ1 
96.99μ
2 
99.1
μ4 
26.98
μ2 
80.01
μ3 
72.9μ1
20 24.7
μ3 
25.6μ
1 
36.5μ
3 
66.5μ
3 
33.7μ
2 
63.2μ
2 
68.4μ
3 
99.39
μ2 
99.79μ
1 
99.9
μ3 
40.2μ
1 
93.4μ
3 
85.23μ
2 
30 38.3
μ2 
40.13
μ3 
52.2μ
1 
78.2μ
2 
49.4μ
3 
75.5μ
3 
79.8μ
2 
99.88
μ3 
99.987
μ1 
99.9
μ3 
57.6μ
3 
99.57
μ3 
97.5μ3
40 47.1
μ3 
51.2μ
2 
59.4μ
4 
88.9μ
3 
56.8μ
2 
85.5μ
2 
9.7μ3 99.88
μ2 
99.987
μ4 
99.9
μ2 
62.8μ
2 
99.89
μ2 
99.51 
μ3 
50 55.8
μ2 
57.8μ
2 
69.88
μ2 
96.8μ
2 
69.8μ
2 
92.9μ
4 
97.15
μ5 
99.88
μ2 
99.987
μ3 
99.9
μ2 
75.3μ
3 
99.9μ
3 
99.898
μ4 
60 72.3
μ1 
75.1μ
4 
80.13
μ3 
98.45
μ3 
80.1μ
1 
97.7μ
2 
99.18
μ3 
99.88
μ2 
99.987
μ3 
99.9
μ2 
83.7μ
3 
99.9μ
3 
99.89μ
2 
 
size. This may be due to a small number of the neighboring drug 
molecules holding the dissolving drug molecule after the rapid 
dissolution of neighboring water soluble carrier [19]. 
Also, there is usually a relatively strong chemical bonding between 
the solute and the solvent in solid solution, while the lattice energy 
in the glass solution is expected to be much less because of its 
similarity with the liquid solution. Similarly the dissolution rate from 
an amorphous or glassy solid is usually faster than crystal form of 
same chemical identity. Therefore, if everything is equal, then the 
dissolution rate of drugs in the glass solution should be 
theoretically faster than that in the solid solution. Apart from the 
predicted reasons, combination and miscellaneous mechanisms 
also exists. 
 
Figure 1: DSC curves of metronidazole with PEG-4000.                Figure 2: DSC curves of metronidazole with PVP 
 
 
(A) Pure MTZ                    (B) 1:1 MTZ-PEG SD                        (A) Pure MTZ                      (B) Pure PVP  
(C) 1:2 MTZ-PEG SD       (D) 1:5 MTZ-PEG SD                          (C) Physical mixture             (D) 1:1 MTZ-PVP SD 
                                                                                             (E) 1:2 MTZ-PEG SD                (F) 1:5 MTZ-PEG SD 
  
 
 
 
 
Sambhakar et al. International Journal of Drug Delivery 5 (1) 94-98 [2013] 
 
PAGE | 97 |
 
 
 
Figure 3: XRD patterns for metronidazole-PEG SD.              Figure 4: XRD patterns for metronidazole-PVP SD. 
 
 
(A) Pure MTZ                   (B) Pure PEG                                      (A) Pure MTZ                   (B) Pure PEG 
(C) Physical mixture         (D) 1:1 MTZ-PEG SD                         (C) Physical mixture         (D) 1:1 MTZ-PVP SD 
(E) 1:2 MTZ-PEG SD       (F) 1:5 MTZ-PEG SD                          (E) 1:2 MTZ-PVP SD      (F) 1:5 MTZ-PVP SD  
 
 
The DSC and XRD data were also taken to confirm the formation 
of solid dispersions and also to know the mechanism of solubility 
and dissolution enhancement. This further confirms the 
amorphization and dispersibility of drug within the carrier matrix. 
 
Conclusions 
 
Thus from the above study we can conclude that water soluble 
carriers can be extensively used for their potential for improving the 
solubility of sparingly and poorly soluble drugs, which can further 
results in improving the bioavailability of many drugs. 
Acknowledgements 
We are very thankful to Alembic Pharmaceuticals Ltd (India) for 
providing us a gift sample of metronidazole and also to various 
departments of Banasthali University for carrying out the necessary 
research work. 
 
Authors Contribution 
SS supervised the students for the preparation and analysis of 
complexes. BS worked on the preparation of manuscript. KM 
prepared and analyzed the MTZ-Dextrose complexes, ML worked 
on MTZ-Citric acid complexes, NK on MTZ-PVP complexes and 
SM on MTZ-PEG complexes. 
 
Conflict of interest 
The authors have no conflict of interest. 
 
 
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Solid Dispersions: A tool for improving the Solubility and Dissolution of Metronidazole

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Solid Dispersions: A tool for improving the Solubility and Dissolution of Metronidazole

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