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Decomposition Kinetics of Levofloxacin: Drug-Excipient Interaction

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The present study is focused on the thermal decomposition of Levofloxacin in the absence and presence of different excipients (sodium starch glycolate, magnesium stearate, microcrystalline cellulose and lactose using Thermogravimetry (TG). Fourier Transform Infra Red Spectroscopy (FTIR) and Differential Scanning Calorimetry (DSC) were used to study the possible drug – excipient interaction. It has been shown that the interaction of the first three excipients (sodium starch glycolate, magnesium stearate, and microcrystalline cellulose) with Levofloxacin is physical in nature. Lactose was shown to decrease the degradation temperature to a maximum extent. This indicates a strong chemical interaction between the drug and lactose. The activation energies in the former case were found almost similar but deviated considerably in the latter case.
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Z. Phys. Chem. 2020; 234(1): 117–128
Jan Nisar*, Mudassir Iqbal, Munawar Iqbal, Afzal Shah,
Mohammad Salim Akhter, Sirajuddin, Rafaqat Ali Khan,
Israr Uddin, Luqman Ali Shah and Muhammad Sufaid Khan
Decomposition Kinetics of Levofloxacin:
Drug-Excipient Interaction
https://doi.org/10.1515/zpch-2018-1273
Received July 31, 2018; accepted February 21, 2019
Abstract: The present study is focused on the thermal decomposition of
Levofloxacin in the absence and presence of different excipients (sodium starch
glycolate, magnesium stearate, microcrystalline cellulose and lactose using
Thermogravimetry (TG). Fourier Transform Infra Red Spectroscopy (FTIR) and
Differential Scanning Calorimetry (DSC) were used to study the possible drug –
excipient interaction. It has been shown that the interaction of the first three
excipients (sodium starch glycolate, magnesium stearate, and microcrystalline
cellulose) with Levofloxacin is physical in nature. Lactose was shown to decrease
the degradation temperature to a maximum extent. This indicates a strong chemi-
cal interaction between the drug and lactose. The activation energies in the former
case were found almost similar but deviated considerably in the latter case.
Keywords: drug-excipient interaction; excipients; kinetic analysis; levofloxacin;
thermal decomposition.
*Corresponding author: Jan Nisar, National Centre of Excellence in Physical Chemistry,
University of Peshawar, Peshawar 25120, Pakistan, e-mail: pashkalawati@gmail.com
Mudassir Iqbal, Luqman Ali Shah and Muhammad Sufaid Khan: National Centre of Excellence
in Physical Chemistry, University of Peshawar, Peshawar 25120, Pakistan
Munawar Iqbal: Department of Chemistry, The University of Lahore, Lahore, Pakistan
Afzal Shah: Department of Chemistry, College of Science, University of Bahrain, Sakhir 32038,
Bahrain; and Department of Chemistry, Quaid-i-Azam University, Islamabad 45320, Pakistan
Mohammad Salim Akhter: Department of Chemistry, College of Science, University of Bahrain,
Sakhir 32038, Bahrain
Sirajuddin: National Centre of Excellence in Analytical Chemistry, University of Sind, Jamshoro,
Pakistan
Rafaqat Ali Khan: Department of Chemistry, COMSATS Institute of Information Technology,
Abbottabad 22060, Pakistan
Israr Uddin: Department of Otorhinolaryngology, Khyber Medical College Peshawar, Peshawar,
Pakistan
118 |J. Nisar et al.
1Introduction
Levofloxacin is an antibiotic used to treat bacterial infection [1–3]. In order to
make it appropriate for administration for treatment of a specific infection it is
blended with a suitable excipient which is normally an inert substance. Excipient
not only improves the drug manufacturing properties and facilitates its admin-
istration but also helps in stabilizing the drug against environmental degrada-
tion [4, 5]. Excipients are always considered to be inert, however, some recent
reports revealed toxicity issues of some common excipients especially in pae-
diatric formulations [6, 7]. Any adverse interaction between drug and excipient
affects the chemical nature of drug and ultimately disturbs the efficiency of drug
against the disease [8–10]. Identification of such reactions and finding out suit-
able safety information for the same would ensure wellbeing of the patients. Var-
ious research groups are involved worldwide for improving drug delivery system.
Saleem et al. [11] used microemulsion formulation for the preparation of nanopar-
ticles of levofloxacin and the fluorescence results supported controlled release of
drug. Baratam and Vijayaratna [12] formulated matrix tablets using hydroxypropyl
methylcellulose with sodium bicarbonate as gas generating agent for sustained
drug delivery of levofloxacin hemihydrate. Asha et al. [13] developed a novel type
of Levofloxacin tablets formulation which was observed to dissolve more swiftly
as compared to standard dosage form. Most recently Chavada et al. [14] employed
an absorption-factor spectrophotometric method for simultaneously determin-
ing azithromycin and levofloxacin in their binary mixtures and the pharmaceu-
tical formulations were observed with no interfering from excipients. Nguyen
et al. [15] reported a simple extractive spectrophotometric method for the deter-
mination of fluoroquinolones in some pharmaceutical products and the proposed
method was found suitable for quantification of fluoroquinolones in pharmaceu-
tical formulations. Mullapudi and Dheram [16] reported an ultraviolet photolysis
decomposition method for the determination of fluoride in fluorine containing
pharmaceuticals and the proposed method was found suitable for routine anal-
ysis of fluoride in organofluorine-containing drugs. Moreover, numerous authors
reported levofloxacin interaction with excipients at ambient temperature taking
into account pH of the blood, UV/Vis light interaction and role of the solvent
[17–23]. El-Megharbel et al. [24] reported synthesis of in-situ copper(II) complexes
of some quinolone in binary solvent and observed that the burst release along
with decreased longitudinal relaxivity can be achieved under acidic environment.
However, to the best of our knowledge Sadeek and El-Shwiniy [25] were the first
to study the decomposition kinetics of levofloxacin metal complexes using Coats–
Redfern and Horowitz–Metzger methods, and the thermodynamic data revealed
Decomposition Kinetics of Levofloxacin |119
thermal stability of all the complexes, therefore, further kinetics investigation is
required for the interaction of levofloxacin with the excipients.
The most important aim of kinetic studies of chemical reaction is to determine
the kinetic parameters [26–29]. These parameters help in predicting the stabil-
ity of different chemical species. The kinetics parameters for a solid substance
are calculated by heating it at isothermal and non-isothermal conditions. Under
isothermal condition kinetic parameters are determined by using the well known
Arrhenius equation, while in case of non-isothermal method, the kinetic parame-
ters are determined by Ozawa Flynn Wall and various other methods. Ozawa Flynn
Wall method was derived from the linear estimation based on the integral calculus
from Arrhenius equation [30–34].
It is interesting to study the degradation of drug at marketing temperatures.
Moreover, the accelerated processes are used for the data collection at elevated
temperatures. Chemical reaction increases at higher temperature. At higher tem-
perature enough energy is provided to break the chemical bond and decompo-
sition starts at that temperature [35, 36]. Therefore, the aim of this work is to
study the kinetics of thermal degradation of levofloxacin in presence of different
excipients using thermogravimetry. FTIR spectra and DSC were also used to study
the possible drug – excipient interaction. The study will help in determination of
compatibility behavior of the drug with different excipients.
2Experimental
2.1 Materials
Levofloxacin has chemical formula C18H20FN3O4·1/2H2O and molecular weight
370.38 g/mol. The drug was purchased from Zhejiang Jingxin Pharmaceutical
China. The excipients microcrystalline cellulose, sodium starch glycolate, lactose
and magnesium stearate were purchased from Allied chemical Karachi.
2.2 Methods
2.2.1 Preparation of the binary mixture
The levofloxacin and all the four excipients were grinded separately in a mortar
till fine powder is formed and then they were mechanically mixed in the ratio of
1:1 (w/w) for further analysis.
120 |J. Nisar et al.
2.2.2 Thermogravimetrical analysis
All the pyrolysis experiments were performed in nitrogen atmosphere
(20 mL/min) in the temperature range 30–600 °C at heating rates of 7.5, 10,
12.5 and 15 °C/min using TG/DTA (Perkin Elmer, USA). The thermograms thus
recorded were interpreted for kinetics study using Ozawa Flynn Wall method.
2.2.3 Dierential scanning calorimetry
The experiments were performed on a Mettler Toledo (Thermo) under nitrogen
atmosphere (20 mL/min). For standard DSC experiments, sample between 5 and
10 mg was heated in the temperature range 25–500 °C at 10 °C/min. Prior to
experiment the equipment was calibrated and the experiments were carried out
in absence and presence of excipients.
2.2.4 Fourier transform infra red spectroscopy
For FTIR analysis, Schimadzue, IR Prestige-21 and FTIR-8400 were used. The drug
alone and with excipients was mixed with IR grade KBr and grinded well using
pestle and mortar. The samples were then scanned in the region 4000–400 cm1.
3Results and discussion
3.1 Kinetic study and thermal behavior of levofloxacin
The weight loss curves (TG) and derivative of weight loss (DTG) of pure lev-
ofloxacin in the absence of excipient at a heating rate of 10 °C/min registered
during the performed pyrolysis are shown in Figure 1. As expected, due to its uni-
form structure, the drug degradation appears to be a single step process (single
degradation peak) with water evaporation at 70 °C while the DTG graph shows the
maximum degradation temperature at 376 °C. The TGA curve indicates that lev-
ofloxacin is thermally stable up to 255 °C and successive mass loss occurs between
255 and 600 °C.
Figure 2a–e exposes TG curves obtained at heating rates 7.5, 10, 12.5 and
15 °C min1for pure levofloxacin and with excepients. It is evident from the
curves that when the heating rate is low, equilibrium is accomplished rapidly
with rise in temperature. However, when the heating rate is high, equilibrium is
delayed which causes shifting of the curve to high temperature [37, 38].
Decomposition Kinetics of Levofloxacin |121
Fig. 1: TGA/DTG curves of pure Levofloxacin in dynamic nitrogen atmosphere (20 mL min1)
and heating rate 10 °C min1.
The activation energy for dynamic study of drug was calculated using Ozawa
Flynn Wall equation [39–41].
ln(β)=lnAαE
Rg(α)5.331 1.052 E
RT (1)
The plot of ln βversus 1/T depicted in Figure 3 was used for calculation of
activation energy. The plots exhibit quite good correlation. The activation energy
was determined as 118.05 kJ/mol for the pure levofloxacin thermal decomposition.
Table 1 shows the activation energies of Levofloxacin alone and with the excipi-
ents using Ozawa’s equation. The table shows that no significant difference in
activation energy is observed for the pure drug using non-isothermal method and
these values are relatively close to each other except lactose. This shows that the
degradation for these entire binary mixture take place in the same temperature
range. The small difference in activation energies in the presence of excipients
shows stability and suitability of the drug for formulation. The small activation
energy determined for the combination of the drug with lactose shows the strong
chemical interaction of the drug with excipient making the drug non-compatible
for solid formulation with this specific excipient.
3.2 Fourier transform infra red spectroscopy
FTIR is an easy, fast and accurate method for assessing drug–excipient
compatibility [42]. The IR analysis of levofloxacin, levofloxacin-sodium starch
122 |J. Nisar et al.
Fig. 2: (a) TG curves of pure Levofloxacin obtained at heating rates 7.5, 10, 12.5 and
15 °C min1. (b) TG curves of the mixture of Levofloxacin with Sodium starch glycolate
obtained at heating rates 7.5, 10, 12.5 and 15 °C min1. (c) TG curves of the mixture of Lev-
ofloxacin with Magnesium stearate obtained at heating rates 7.5, 10, 12.5 and 15 °C min1.
(d) TG curves of the mixture of Levofloxacin and Microcrystalline cellulose obtained at heating
rates 7.5, 10, 12.5 and 15 °C min1and (e) TG curves of the mixture of Levofloxacin and Lactose
obtained at heating rates 7.5, 10, 12.5 and 15 °C min1.
glycolate, levofloxacin-magnesium stearate, levofloxacin-microcrystalline cel-
lulose and levofloxacin-lactose were performed and the spectra obtained are
presented in Figure 4a and b. The levofloxacin FTIR characteristic absorption
Decomposition Kinetics of Levofloxacin |123
Fig. 3: Ozawa Flynn Wall plots at various conversions for the degradation of levofloxacin.
Tab. 1: Activation energy (Ea) values obtained for Levofloxacin in absence and presence of
various excipients by non-isothermal study using Ozawa-Flynn-Wall method.
Sample Activation Energy (kJ mol1)
Levofloxacin 118.05
Levofloxacin/magnesium stearate 94.11
drug/sodium starch glycolate 94.14
Levofloxacin/microcrystalline cellulose 95.77
Levofloxacin/lactose 39.93
peaks were obtained for the –OH group of the –COOH moiety at around
3261.4 cm1and –CO peak near 1725.1 cm1. The aromatic C–H peaks are
also observed in the range 2900–3000 cm1[43]. The main functional bands
of the above mixtures were appeared at different regions. The C–N stretch-
ing at 1236 cm1, C–H aromatic stretching at 1473 cm1, the 1630 and 1600
pair absorption bands may be related to the carbonyl and C=C moiety inside
the levofloxacin, O–H absorption band at 1630 cm1, stretching of CH2at
2929 cm1were observed for all mixtures of the drug and excipients. In
case of lactose an additional new band due to O–H stretching at 3642 cm1
can be seen in Figure 4b. This shows chemical interaction of levoflaxcin
and lactose. This chemical interaction between levofloxacin and excipient
makes lactose as undesirable for the formulation of solid dosage as only
124 |J. Nisar et al.
Fig. 4: (a and b) FTIR spectra of levofloxacin and 1:1 physical mixtures of drug/sodium starch
glycolate, drug/magnesium stearate, drug/microcrystalline cellulose and drug/lactose.
physical interaction is desired, while chemical interaction completely changes
the pharmo kinetics of the drug.
3.3 Dierential Scanning Calorimetry
Figure 5 exposes DSC curves of drug, excipient and drug–excipient mixtures.
The DSC curve for pure levofloxacin exhibited a small endothermic peak at
around 95 °C due to the dehydration of the levofloxacin. Two sharp endothermic
peaks around 190–200 °C are also observed corresponding to its melting point
[44]. These second and third events were reported as the melting of α,βand γ
Decomposition Kinetics of Levofloxacin |125
Fig. 5: DSC curves of Levofloxacin and Excipients alone and Levofloxacin with excipients;
A–Levofloxacin, B–Sodium starch glycolate, C–Magnesium stearate, D–Lactose, E–
Microcrystalline cellulose, F–Levo +Sodium starch glycolate, G–Levo +Magnesium stearate,
H–Levo +Lactose, I–Levo +Microcrystalline cellulose.
levofloxacin polymorphs [45]. Additionally, an exothermic event was observed
due to crystallization of αor βforms from the melted γform [46]. These observa-
tions were in agreement with the documented DSC thermogram for levofloxacin
in literature under the same heating rate 10 °C/min [47, 48]. The endother-
mic peak at around 95 °C peak was observed to disappear for the mixtures
of levofloxacin-magnesium stearate and levofloxacin-microcrystallinecellulose.
This shows that the metal cations present in magnesium stearate in the form of
126 |J. Nisar et al.
magnesium bind themselves to levofloxacin resulting into disappearing of the
endothermic peak. Moreover, microcrystalline cellulose as chelating agent also
exhibits the same property. The results show one exothermic peak at 120–130 °C.
Lactose showed two endothermic peaks around 50 and 260 °C, respectively. The
two transitions in lactose correspond to water loss and lactose melting, respec-
tively. So, the new endothermic peaks appeared around 125 °C and the second
at 165 °C indicate the presence of lactose in the mixture [49], and the lower
activation energy observed for the combination of the drug with lactose is indica-
tive of the fact that some chemical interaction may exist between the drug and
lactose.
4Conclusions
In the present work the activation energies under non-isothermal condition
were determined for the thermal decomposition of levofloxacin and the acti-
vation energy was determined as 118.05 kJ/mol. The stability and compatibil-
ity were studied by using TG/DTG, DSC and FTIR techniques. The compatibility
of levofloxacin with sodium starch glycolate, magnesium stearate, microcrys-
talline cellulose and lactose were investigated and it was observed that the first
three excipients showed good compatibilitywith levofloxacin while lactose exhib-
ited incompatibility due to chemical interaction with the drug. From the results
it can be concluded that a physical interaction exists between the drug and
sodium starch glycolate, magnesium stearate, microcrystalline cellulose, where
as a chemical interaction is evident between the drug and lactose.
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Microemulsions (μEs) are being exploited as a potential route for yielding an extensive range of nanoparticles of different chemical nature, shapes and sizes. Nanodrugs offer new avenues for structuring better “drug delivery systems”. In this study, an oil‐in‐water (o/w) μE formulation comprising N‐butyl acetate/polysorbate 80/ethanol/water was developed for the preparation of nanoparticles of fluoroquinolone antibiotics (FLQ‐NPs). A pseudoternary phase diagram was mapped at constant surfactant/cosurfactant (1:2), revealing improved and high loading of FLQs in an optimum μE formulation. The as‐formulated μE showed high loading of FLQs as; levofloxacin (4.20 wt.%), ciprofloxacin (3.16 wt.%), moxifloxacin (2.53 wt.%), gatifloxacin (1.36 wt.%), ofloxacin (0.70 wt.%). Fourier transform IR analysis indicated good compatibility of each FLQ drug with μE excipients. However, dynamic light scattering showed an increase in the average particle size of the μE on drug loading, indicating the accumulation of FLQ at interface layer of the micelle. Additionally, lyophilized levofloxacin (a selected antibiotic) showed long‐term stability, amorphous morphology and improved dissolution rate, inspected by scanning transmission electron microscopy, X‐ray diffraction and electronic spectroscopy, respectively. Moreover, fluorescence measurements suggested the interfacial vicinity of levofloxacin within the μE domain, which may support controlled release of drug during systemic circulation.
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In order to overcome the challenges of the solid unit dosage forms, Fast Dissolving Tablets (FDT) or orally disintegrating tablets (ODT) has emerged as alternative oral dosage forms. These novel types of tablets have the ability to dissolve more rapidly when compared to standard solid dosage forms. The main objective of the present study was to develop Oral dispersible tablet formulation containing 150mg of Levofloxacin for the treatment of a number of infections including infection of Joints and bones, respiratory tract infections, urinary tract infections, skin structural infections and typhoid fever etc. In our study, it was observed that all the values of pre-compression and post-compression studies were within the limits.
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Captopril (CAP) was the first commercially available angiotensine-converting enzyme (ACE) inhibitor. In the anti-hypertensive therapy is considered the selected drug has to be therapeutically effective together with reduced toxicity. CAP is an antihypertensive drug currently being administered in tablet form. In order to investigate the possible interactions between CAP and excipients in tablets formulations, differential scanning calorimetry (DSC) and thermogravimetric (TG) analysis completed by X-ray powder diffraction (XRPD) and Fourier transform infrared spectroscopy (FTIR) were used for compatibility studies. A possible drug-excipient interaction was observed with magnesium stearate by DSC technique.
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