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Der Pharmacia Sinica, 2011, 2 (5):169-181
ISSN: 0976-8688
CODEN (USA): PSHIBD
Enhancement of Dissolution rate and stability study of Ofloxacin
Solid dispersion
Pintu K De1*, Basudev Sahana2 and Soumen Rakshit2
1
Department of Pharmaceutics, Dr. B. C. Roy College of Pharmacy and Allied Health Sciences,
Dr. Megnad Saha Sarani, Bidhannagar Durgapur, W.B. INDIA
2
Institute of Pharmacy, Jalpaiguri, Govt. of West Bengal, Jalpaiguri, W.B., India
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ABSTRACT
In case of relatively insoluble drugs i.e., the drugs having solubility less than 1%, the rate of dissolution
is usually the rate determining step in the overall absorption process to become bioavailable. However
for relatively soluble drugs i.e., the drugs having intrinsic dissolution rate more than 1mg/cm2/min, the
permeability of the drug may become the rate determining step. Poor solubility causing potential bioabsorption problems unless the dosage forms are specially designed. Solid dispersion is the dispersion of
the drug in a biologically inert matrix. The objective of the present study was to enhance the dissolution
rate of Ofloxacin by making a molecular dispersion of drug in the polymeric matrix of Polyethylene
Glycol-6000. Solid dispersion of Ofloxacin was prepared following fusion and solvent evaporation
techniques. The drug polymer interaction was studied by Differential Scanning Calorimetry (DSC) and
Fourier Transform Infrared Spectroscopy (FTIR), which revealed the absence of major interactions in
both the methods. Dissolution study of the solid dispersions shows the enhancement of dissolution rate of
Ofloxacin. After 15 minutes of study only 65% of the pure drug is dissolved in the aqueous medium
whereas at the same time 98% dissolution was observed with the formulation of solid dispersion in
presence of a surfactant. Among the two methods; considering the absence of interaction and higher rate
of dissolution the solvent evaporation technique is found most suitable to enhance the dissolution rate and
consequently the bioavailability of the drug. The stability study of the formulations as per ICH guideline
Q1A in stability chamber both at intermediate and accelerated conditions ascertained that the
formulations are stable at wide range of storage conditions.
Key words: Solid dispersion, Ofloxacin, FTIR, DSC, TGA.
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INTRODUCTION
Ofloxacin is a synthetic fluoroquinolone broad spectrum antimicrobial agent for oral
administration. It acts by inhibiting bacterial DNA gyrase enzyme which is required for DNA
replication and thus causes bacterial lysis. The solubility characteristics of ofloxacin at room
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temperature, as defined by USP is sparingly to slightly soluble in aqueous solutions with pH 7
(solubility falls to 4 mg/mL).
The rate and extent of absorption of an orally administered drug are dependent upon two
independent processes, its dissolution characteristics in an aqueous medium and its permeability
characteristics across the gastric or intestinal mucosa. Ideally for optimum absorption a drug
should have sufficient aqueous solubility to dissolve in the fluids at absorption site and lipid
solubility high enough to facilitate partitioning in the lipoidal membrane and into the systemic
circulation.
Solubility values are useful in a candidates early development are those in distilled water, 0.9%
Nacl, 0.01M Hcl, 0,1M Hcl and 0.1M NaoH, all at room temperature as well as at pH 7.4 buffer
at 37°C. Drug’s having limited solubility (<1% means 10mg/ml) over the pH range 1-7 at 37°C,
often exhibit potential bioabsorption problem unless dosage forms are specially designed. If the
intrinsic dissolution rate was greater than 1mg/cm2/min then absorption was unimpeded.
Dissolution rates less than 0.1mg/cm2/min were likely to give dissolution rate limited absorption.
This tenfold difference in dissolution rate translates to a lower limit for solubility of 1mg/ml.
Solubility less than 1mg/ml indicates the potential bioabsorption problems unless the dosage
forms are specially designed. Solubility profiles are not predictors of biological performance but
do provide rationale for more extensive in-vivo studies and formulation development prior to
drug evaluation in humans.
Table1. Carriers for Solid Dispersions
Sr. No.
1
2
3
4
5
Chemical Class
Examples
Acids
Citric acid, Tartaric acid, Succinic acid
Sugars
Dextrose, Sorbitol, Sucrose, Maltose, Galactose, Xylitol
Polyvinylpyrrolidone, PEG-4000, PEG-6000, Carboxymethyl cellulose,
Polymeric
Hydroxypropyl cellulose, Guar gum, Xanthan gum, Sodium alginate,
Materials
Methyl cellulose, HPMC, Dextrin, Cyclodextrins, Galactomannan
Polyoxyethylene stearate, Poloxamer, Deoxycholic acid, Tweens and
Surfactants
Spans, Gelucire 44/14, Vitamine E TPGS NF
Miscellaneous Pentaerythritol, Urea, Urethane, Hydroxyalkyl xanthines
Up to 40 per cent of new chemical entities discovered by the pharmaceutical industry today are
poorly soluble or lipophilic compounds. . The various techniques are available for enhancement
of solubility. Solid dispersion is one of the most promising approaches for solubility
enhancement. The solid dispersion approach to reduce particle size and therefore increase the
dissolution rate and absorption of drugs was first recognized in 1961[1]. It improves dissolution
rate by reducing particle size, higher porosity, drug is in amorphous state, improving wettability
and hence improves bioavailability of poorly water soluble drugs. The term “solid dispersions”
refers to the dispersion of one or more active ingredients in an inert carrier in a solid state,
frequently prepared by the melting (fusion) method, solvent method, or fusion solvent-method
[2]. Novel additional preparation techniques have included rapid precipitation by freeze drying
[3], often in the presence of amorphous hydrophilic polymers and also using methods such as
melt extrusion [4]. The most commonly used hydrophilic carriers for solid dispersions include
polyvinylpyrrolidone [5,6] polyethylene glycols [7], Plasdone-S630 [8]. Many times surfactants
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may also used in the formation of solid dispersion. Surfactants like Tween-80, Docusate sodium,
Myrj-52, Pluronic-F68 and Sodium Lauryl Sulphate used [8].
The solubility of etoposide [9], Felodipine [10], itraconazole [11], aceclofenac [12], valdecoxib
[13], celecoxib [14], Ketoprofen [15] can be improved by solid dispersion using suitable
hydrophilic carriers.
MATERIALS AND METHODS
Materials
Ofloxacin was received as a gift sample from Cadila Health Care Ltd.(Ahmedabad, India); PEG6000 (Hydroxyl number 16-23, Molecular weight 5000-7000, Melting range 60-63° C), was
purchased from Merck, Mumbai, India. Chloroform was procured from Ranbaxy Laboratories
Limited, SAS Nagar, India. Other materials used in this study like Tween-80 are of analytical
grade.
Preparation of Ofloxacin Solid Dispersions
Two commonly used methods have been followed for preparation of ofloxacin solid dispersion.
1) Hot Melt Method and 2) solvent evaporation method.
Hot Melt Method
Ofloxacin and PEG-6000 mixture of different composition (10 & 20% drug load) were melted in
crucible in a muffle furnace at 257°c and rapidly cooled in a refrigerator. The solid residue was
powdered and sifted through Sieve no.100 and stored in desiccators prior to use.
Solvent Evaporation Method
The drug, Ofloxacin and the polymer, Polyethylene glycol 6000 (PEG 6000) have been dissolved
together in a common solvent i.e. chloroform. After evaporation of solvent the formulation were
kept in desiccators containing activated silica gel and dried to constant weight. The dried product
was powdered and sifted through Sieve no.100 and stored in desiccators prior to use for further
evaluation.
Table2: Different formulations of Ofloxacin solid dispersion
FORMULATION CODE
F-1
F-2
F-3
F-4
COMPOSITION
10% drug in polymer
20% drug in polymer
Drug: polymer=5:5 in chloroform
Drug: polymer: surfactant (tween 80) =5:5:1.in chloroform.
METHOD
Fusion
Fusion
Solvent evaporation
Solvent evaporation
Drug-polymer compatibility study
The physicochemical interactions between Ofloxacin and the polymer (PEG 6000) used in the
formulation of solid dispersion were studied using Fourier transform infrared spectroscopy
(FTIR). The infrared spectra were recorded in the FTIR (Perkin Elmer) instrument in the wave
length region between 4400 and 600cm-1 by KBr pellet method. The spectra obtained for pure
drug, polymer and different solid dispersion formulations were compared.
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Fig.4 FTIR Spectra of the pure drug, Ofloxacin.
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Fig.5 FTIR Spectra of Formulation F1 prepared by fusion method containing 10% drug.
Fig.6 FTIR Spectra of Formulation F3 prepared by solvent evaporation method, drug to polymer ratio 5:5.
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Fig.7 FTIR Spectra of A) Pure Ofloxacin, B) Formulation F1, C) Formulation F2 D) Formulation F3 E)
Formulation F4 F) PEG-6000
Fig.8 DSC curve of pure Ofloxacin
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Fig.9 DSC curve of Fomulation F1 prepared by fusion method containing 10% drug.
Fig.10 DSC Curve of Formulation F3 prepared by solvent evaporation method drug to polymer ratio 5:5.
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Fig.11 DSC curve to compare the thermogram of pure ofloxacin with the formulation F1 and F3
Fig.12 TG Analysis of Pure ofloxacin with the formulation F1 and F3
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Thermal Analysis
A differential scanning calorimeter (DSC) [DSC60, SHIMADZU Corporation, Japan] is used
under nitrogen gas flow of 60mL/min, at a heating rate of 5°c/min. the samples were sealed in an
aluminum pan. A sample of 2-3mg was accurately weight was subjected to DSC run over the
temperature range 40-350°c. The temperature was calibrated using pure indium with a melting
point of 156.6°c. an empty pan was used as a reference.
Stability Study
The stability study of the formulations was done according to ICH guideline Q1A in stability
chamber. The stability study was performed at intermediate and accelerated conditions in closed
containers at specific storage conditions (Table 3). In both cases samples were analyzed for drug
content at 0, 3 and 6 months to find out the effect of temperature and humidity on product
stability.
Table3 Different stability study condition according to the ICH guideline
Study
Intermediate (IM)
Accelerated (AC)
Storage condition
30°c ± 2°c/65% RH ± 5% RH
40°c ± 2°c/75% RH ± 5% RH
Minimum time period
6months
6 months
Sampling interval
0, 3 & 6 months
0, 3 & 6 months
Table 4 Drug content analysis after stability study of intermediate (IM) and accelerated (AC) conditions
Formulation
F1
F2
F3
F4
0 months
IM
AC
98.6 98.6
97.5 97.5
99.3 99.3
99.7 99.7
3 months
IM
AC
98.4 98.5
97.5 97.3
99.0 99.1
99.6 99.4
6 months
IM
AC
98.2
98.4
97.3 97.04
99.05 98.6
99.01 97.9
Dissolution Study of Ofloxacin Solid Dispersions:
100 mg equivalent weight of pure ofloxacin was taken for each formulation and dissolution study
was done in 6 stages USP Apparatus II (rotating paddle type). 900ml of distilled water was taken
as dissolution medium. The temperature was maintained at 37±0.5°c. stirring speed was adjusted
to 75 rpm. 5ml sample was withdrawn at 05 minutes interval and same volume of distilled water
was added to it. Then all the samples are measured in U.V Spectrophotometer (Shimadzu UV1700) at 280nm against appropriate blank.
RESULTS AND DISCUSSION
The IR spectra of pure ofloxacin (Fig.4) showed the presence of principal peaks responsible for
different functional groups. The wave number 3044 cm-1 is due to stretching vibration of
hydroxyl group and intermolecular hydrogen bond; 1714 cm-1 due to stretching vibrations of
C=O group of acids; 1622 cm-1 due to N-H bending vibration; 1550 cm-1 due to the presence of
alkyl groups; 1407 cm-1 due to stretching vibration of methylene group in benzoxazine; 1351 cm1
due to hydroxyl bending vibration; 1200 cm-1 and 1240 cm-1 due to C-O-C stretching
vibration; 1011 cm-1 due to C-F stretching. The presence of all these peaks gives confirmation
about the purity of the drug. The FTIR spectra of the formulation F1 which was prepared by
fusion method containing 10% drug in the polymer PEG-6000 showing the absence of the certain
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principal peaks (Fig.5) like 1550, 1407, 1011cm-1.Whereas almost all the peaks were present in
FTIR spectra of formulation F3 (Fig6) which was prepared by solvent evaporation method
containing equal ratio of drug and polymer. Fig.7 shows the FTIR spectra of PEG-6000(A);
Formulation F2 (B); pure drug, Ofloxacin (C); Formulation F1 (D); Formulation F3 (E);
Formulation F4 (F) all together in the same scale for better understanding of appearance,
disappearance or shifting of IR peaks. From the above observation it can be concluded that there
are no interaction in the process of formulation by solvent diffusion method although a minor
interaction was observed in fusion method.
Fusion is one of the effective method for preparing solid dispersion, but when the drug is melted
alone or in combination of the polymer PEG-6000, the color of the formulation gradually
become yellowish brown from white, this may be due to physical degradation at the temperature
above 150°c [16]. Whereas the color of the solidified mass prepared by solvent evaporation
technique (F3) does not change.
Thermal analytical techniques like Thermal Gravimetric Analysis (TGA) and DSC are
potentially very useful in determining the stability and the presence of very low level of
impurity. Also through DSC curve we can detect the different crystalline form of the same drug
and the ratio of each polymorph. In DSC the difference in energy input (∆H) required to
maintain the sample temperature is measured with respect to a thermally inert reference
substance. ∆H is plotted against the temperature (T). In TGA the change in the experimental
mass is measured as the temperature is increased at a predetermined rate. Percentage weight
remaining of the compound is plotted against temperature (T). Comparison of TGA curve
(Fig.12) shows almost same rate of change in the mass of the experimental formulations (F1 and
F3) like pure Ofloxacin. Hence it can be ascertained that both the formulations contain the intact
drug in unchanged form. The DSC curve of pure ofloxacin shown in fig.8 exhibited a sharp
endothermic peak at 269.12°c corresponding to its melting [16]. The DSC curve of solid
dispersion F1 (Fig.9) prepared by fusion method showed the absence of the endothermic peak
corresponding to the melting of ofloxacin but it shows a sharp endothermic peak at67.32°c which
is corresponding to the melting of PEG-6000. The DSC curve of solid dispersion F3 (Fig.10)
prepared by solvent evaporation method showed the presence of both the endothermic peaks at
261°c and at 66.27°c which are corresponding to the melting of ofloxacin and PEG-6000
respectively. Comparisons of endothermic peaks of DSC curve (Fig.11) of pure ofloxacin along
with the formulations F-1 and F-3 shows the absence of interaction and presence of drug in
unchanged form.
All the formulations (F1 to F4) were kept at intermediate and accelerated conditions (Table3) in
stability chamber in the closed container. A portion of the sample was taken out at 0, 3 and 6
months and interval and tested them for drug content. The result (Table 4) shows no significant
changes in appearance and also in drug content. The highest percentage of degradation was
observed in formulation F-4 after 6 months of storing in accelerated condition is found 1.89%.
Hence it can be said that the formulations are stable at wide variation in storage condition for
long time.
The in vitro drug release studies were performed in using 6stage dissolution test apparatus USP
type II (rotating paddle type). The release profile for all the five formulations were fitted to zero
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order kinetics (cumulative % drug release vs. time plot) in Fig.1, first order kinetics (log%
remaining to be released vs. time plot) in Fig.2 and in Higuchi model (cumulative % release vs.
square root of time plot) depicted in Fig.3. The results of release profile indicate that only 65%
of drug dissolved after 15 minutes of dissolution study with pure drug. But the dissolution study
of all solid dispersions of ofloxacin shows higher dissolution than the pure drug after a definite
time which indicates in enhancement of dissolution rate. If we compare the dissolution of solid
dispersions by fusion and solvent evaporation method; solvent evaporation method gives higher
dissolution (98%) rate as compared to fusion method (90%). In the fusion method as we increase
the drug load or decrease the polymer proportion the dissolution rate is further low as in F-2
(90%) as compared to F-1 (93%). The solid dispersions prepared by solvent evaporation method
and containing Tween-80 (F-4) as surfactant gives highest dissolution (98%) as compared to
dispersions without surfactant F-3 (96%). The drug release data was fit to different kinetic model
to understand the release mechanism. The linearity was found more comparatively in Higuchi
plot than zero or first order plot, and release mechanism may follow diffusion from solid
dispersion.
CONCLUSION
Solid dispersion of Ofloxacin can be prepared with Polyethylene Glycol 6000 by both Fusion
and Solvent Evaporation technique. Solid dispersion of Ofloxacin by both the above mentioned
methods increases the dissolution rate of Ofloxacin. The stability of the drug, ofloxacin is not
affected by any of the two methods and the formulations can be stored without any significant
degradation for long tome. Among two methods followed, highest dissolution was found with
the formulation prepared by solvent evaporation technique in presence of surfactant. Hence
preparation of solid dispersion of Ofloxacin can be useful in enhancing the dissolution and
improvement of the bioavailability of the drug.
Acknowledgements
The authors are highly indebted to Principal, Institute of Pharmacy Jalpaiguri, Govt. of West
Bengal. Authors are also thankful to Cadila Health Care Ltd., Ahmedabad, India for providing us
gift sample of pure drug, Ofloxacin.
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