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Manuscript Number:
Pramod J Hurkadale
Professor, Dept. of Pharm Sci, KLE, Belagavi Karnataka, India
pramodh@kleuniversity.edu
He is active in the field of chemistry and drug delivery
Avinash S Dhake
Principal, SMBT College of Pharmacy, Nasik, Maharashtra, India
asdhake@yahoo.co.in
Prof Dhake is an active researcher in the field of polymer chemistry
dr B Narasimhan
Principal, Department of Pharmaceutical Sciences, Maharishi dayanand
university, Rohtak, India
naru2000us@yahoo.com
Prof is an active researcher in pharmaceutical chemistry
Opposed Reviewers:
Cover Letter
To
The Editor
Dear Sir
Please find the attached manuscript entitled “Synthesis and Characterization of Diclofenac and
Ibuprofen Conjugate with Polyvinyl Alcohol” by Pooja Kumari, Jyoti Mundlia, Munish Ahuja for
publication in your esteemed journal. It is an original unpublished work and is not under
consideration elsewhere.
Thanking You
Yours Sincerely
E-mail: munishahuja17@yahoo.co.in
Responses to Technical Check Results
Sir, the keywords have been reduced to five in the manuscript as per your advice.
2. Please submit full affiliation (department, institution, city and country) and email addresses
of four potential Referees.
The full affiliation including department, institution, city, country and email addresses
of the potential reviewers have been updated.
*
Address for Correspondence
Prof. Munish Ahuja,
Department of Pharmaceutical Sciences,
GJUS&T, Hisar-125001
Email: munishahuja17@yahoo.com
Phone: 91-01662-263515
1
ABSTRACT
In this study, conjugation of carboxyl groups of diclofenac or ibuprofen with hydroxyl groups
of polyvinyl alcohol was carried out employing dicyclohexylcarbodiimide and
dimethylaminopyridine as coupling agents. The polyvinyl alcohol-drug conjugates were
characterized by Fourier-transform infra red spectroscopy, 1H-Nuclear magnetic resonance
spectroscopy, differential scanning calorimetry, X-ray diffraction and scanning electron
microscopy investigations. Conjugation of diclofenac to polyvinyl alcohol was found to
diminish its viscosity by 5% while ibuprofen conjugation led to 46% fall in the viscosity of
polyvinyl alcohol. Polyvinyl alcohol-ibuprofen conjugates showed amphiphilic properties
and its critical aggregation concentration as determined by dynamic light scattering was
found to be 13 µg/ml. The results of hydrolysis studies of conjugates carried out in phosphate
buffer (pH 7.4) revealed the presence of 0.16 g and 0.33 g of diclofenac and ibuprofen in
respective conjugates. Further, the kinetic analysis of hydrolysis data of the conjugates
indicated that the hydrolysis of conjugates followed first-order kinetics with hydrolysis rate
constant of 6.21x10-2 and 2.76 x10-2 h-1 for hydrolysis of ibuprofen and diclofenac
respectively. Thus, conjugation of diclofenac and ibuprofen to polyvinyl alcohol appears to
be a promising drug delivery stratergy.
2
1. Introduction
3
Diclofenac, 2-[2-(2,6-dichloroanilino)phenyl]acetic acid is a poorly water soluble NSAID. It
is weakly acidic with pKa value of 4.15 and possesses analgesic and anti-pyretic properties. It
acts by reducing the arachidonic acid bioavailability and thus leads to reduction in
intracellular concentrations of free arachidonate in leukocytes [10]. It has an awful taste and
causes gastric irritation [11].
In the present work, carboxyl groups of ibuprofen and diclofenac have been conjugated with
hydroxyl group of PVA employing carbodiimide chemistry to prepare esters. Further, the
PVA drug conjugates have been characterized by spectral, thermal, microscopic, and
hydrolysis studies.
2.1. Material
Polyvinyl alcohol was procured from S D Fine-Chem Limited (Mumbai, India). Pure
diclofenac sodium (99.6%) and ibuprofen (98%) were obtained as gift samples from Coax
Bioremedies, (Hisar, Haryana) and Aventis Pharma Limited (Ankleshwar, India),
respectively. 1,3–dicyclohexylcarbodiimide (DCC), 4-dimethylaminopyridine (DMAP) and
dialysis cellulose tubing membrane (molecular weight cut-off 14,000) were obtained from
Sigma–Aldrich (Bangalore, India). Dimethyl sulphoxide (DMSO), potassium dihydrogen
orthophosphate and dialysis closure clips were procured from Hi-Media Laboratories Pvt.
Ltd. (Mumbai, India). Sodium hydroxide pellets were purchased from Thomas Baker
(Mumbai, India). Deionized water was used throughout the reaction process. All chemicals
used were of reagent grade.
2.2. Synthesis of Polyvinyl alcohol and ibuprofen conjugate (PVA-IBU) and diclofenac
conjugate (PVA-DCF)
4
flask, followed by addition of DCC (80 mg) and DMAP (30 mg) under nitrogen blanket. The
reaction was stirred for 1 h at 60-65 °C. After 1 h, the solution of PVA prepared above was
slowly added through the side neck of double neck flask and the reaction was allowed to
continue for 6 h under nitrogen atmosphere. The product was filled into dialysis tubing (14
kDa cut-off molecular weight) and subjected to dialysis against DMSO for 24 h and 3 days
against deionized water to remove unreacted reagents. The product so obtained was kept at -
75 °C for 3 h followed by freeze drying using laboratory model lyophilizer (Alpha 2-4 LD
Plus, Martin Christ, Germany) for 24 h at -75 °C and 0.0010 mbar for 24 h.
The infrared spectra of IBU, PVA, DCF, PVA-DCF and PVA-IBU conjugate samples were
recorded employing diffuse reflectance accessory (DRS-8000A) using FTIR
-1
spectrophotometer (IR, Affinity-I, Shimadzu, Japan) in the range of 4000-400 cm . The
sample was diluted to 1% of the KBr powder and placed into the sample plate of the diffuse
reflectance accessory.
The UV absorption spectra of DCF, IBU, PVA-DCF and PVA-IBU conjugate were recorded
by scanning the aqueous solutions (0.1%, pH-7.4) of IBU, DCF, PVA-DCF and PVA-IBU
conjugate in the range of 200-800 nm in the UV- vis-NIR spectrophotometer (Cary 5000,
Varian, Netherland).
Differential scanning calorimetric analysis of IBU, PVA, DCF, PVA-DCF and PVA-IBU
samples were carried out using differential scanning calorimetric (DSC 25, TA instruments,
California, USA). The samples were crimped in standard aluminium pan and heated at
constant rate of 10 °C/min over a temperature range of 35-205 °C. The analysis was
performed under nitrogen purge of 50 ml/min and with base purge of 350 ml/min.
The sample X-ray diffractograms of PVA, DCF, IBU, PVA-DCF and PVA-IBU were
recorded using X-ray diffractometer (Miniflex 2, Rigaku, Japan) from 10-80o diffraction
5
angle (2θ) with a scanning speed of 0.05 min-1 at room temperature under the measurement
conditions: source, nickel filtered Cu-Kα radiation: voltage 30 kV; Current 15mA.
1
H-NMR spectroscopic analysis of IBU, PVA, DCF, PVA-IBU and PVA-DCF conjugate was
carried out in using DMSO-d6 as a solvent at 25 °C NMR spectrophotometer (Bruker Ascend,
400 MHz, Switzerland). The tetramethylsilane was used as internal standard.
The morphological features of DCF, IBU, PVA, PVA-IBU and PVA-DCF were studied in
scanning electron microscope (ZEISS, EVO18, China) by coating the samples with gold and
placing them on sample holder with double adhesive carbon tape. The photomicrographs
were recorded at an accelerating voltage of 20 kV at different magnifications.
2.3.8. Viscosity
The viscosity of aqueous solutions (1.4% w/v) of PVA, PVA-DCF and PVA-IBU was
studied using Ostwald viscometer in triplicate at room temperature (25 °C).
Five milliliters of buffered aqueous solutions (0.2% w/v, pH 7.4) of PVA-DCF and PVA-IBU
conjugate were placed in a cellulose membrane dialysis tubing (cut off 14 kDa). The dialysis
tubing was closed securely using dialysis closure clips. The dialysis bag was suspended in 10
ml of phosphate buffer (pH-7.4) maintained at 37 °C using sinkers. An aliquot of 2.5 ml
sample was withdrawn and analyzed at various time intervals over 96 h study period. The
contents of the DCF and IBU in withdrawn samples was determined spectrophotometerically
by measuring the absorbance at 276 nm and 264 nm, respectively (Cary 5000, Varian,
Netherland).
6
3. Results and Discussion
Diclofenac was precipitated from its sodium salt by acidification of its solution. The
precipitated diclofenac was purified and its conversion to acid form was confirmed by
melting point determination as diclofenac has a melting point of 183 °C while its sodium salt
melts at 283 °C (13). Conjugation of the hydroxyl groups of polyvinyl alcohol (PVA) with
the carboxylic groups of DCF/IBU in mixed solvent system was carried out utilizing
carbodiimide chemistry. The PVA-DCF conjugate was observed to be white colored,
odorless and obtained in a % yield of 80.97% while the PVA-IBU conjugate was
light orange colored, odorless and obtained in a % yield of 74.61%. The product so formed
was analyzed by TLC using precoated silica plates. The chromatogram of PVA-DCF
conjugate was developed using chloroform:toluene (7:3) as the solvent system. The Retention
factor (Rf) values of diclofenac, PVA and the conjugate were obtained to be 0.87, 0.81 and
0.71 respectively. On the other hand, for developing chromatogram of PVA-IBU conjugate n-
hexane, ethyl acetate and glacial acetic acid (7.5:2.5:0.5) were used as the solvent system.
The Rf values of IBU, PVA and the PVA-IBU conjugate were observed to be 0.69, 0.73 and
0.76 respectively.
The reaction between PVA and DCF/IBU has been illustrated in the scheme below:
The conjugation of DCF and IBU with polyvinyl alcohol were characterized by UV,
FT-IR and 1H-NMR spectral analysis.
Fig. 1(a) and (b) compares the UV spectra of DCF with PVA-DCF conjugate and IBU
with PVA-IBU solution in phosphate buffer (pH- 7.4) respectively. The DCF solution shows
a λmax at 276 nm while the PVA-DCF conjugate shows a λmax at 279 nm. Similarly, the
spectra of IBU presents an absorption maxima at 264 nm while the PVA-IBU conjugate
shows a λmax at 274 nm. Thus, the conjugation of IBU or DCF to PVA causes a red shift in
their absorption spectra [12].
FT- IR spectrosopy
7
Fig. 2 displays the FT-IR spectra of PVA, DCF, PVA-DCF, IBU and PVA-IBU. In
spectra of PVA, a band appearing at 3369.89 cm-1 can be assigned to the O-H stretching in
PVA. The peak appearing at 2947.44 cm-1 may be ascribed to C-H symmetric stretching of
CH2 while the characteristic vibration band appearing at 1123.67 cm-1 is assigned to C-O
stretching. The stretching occurring at 1241.67 cm-1 is ascribed due to C-C group. In spectra
of DCF, the band with medium intensity appearing at 3330.16 cm-1 is contributed by the N-H
stretching while the peak appearing at 3080.83 cm-1 can be ascribed to the aromatic C-H
stretching. The O-H moiety in the carbonyl functional group shows a stretch at 2992.61cm-1.
Also, peaks of very high intensities appearing at 1693.53 cm-1, 1581.34 cm-1, 857.88 cm-1 are
due to C=O stretch, C-C stretch and C-Cl stretch respectively. In PVA-DCF conjugate, the
peak appearing at 3331.51 cm-1 can be ascribed to the N-H stretching while the peak
appearing at 1737.89 cm-1 is due to C=O stretch which confirms the transition of carboxylate
into ester by conjugation. The peaks appearing at 1581.34 cm-1, 1145.14 cm-1 and 857.66 cm-1
indicates the presence of C-C stretch, C-O-C stretch and C-Cl stretch due to DCF
respectively.
In the spectra of IBU, the broad band appearing between 3331.7 cm-1 and 2944 cm-1 is
due to the overlapping contribution of OH moiety in the carbonyl functional group, aromatic
CH2 stretch, CH3 asymmetric stretch, respectively. The peak appearing at 2733.56 cm-1 can be
ascribed to CH2 symmetric stretch. The intense band appearing at 1714.75 cm-1 is due to the
C=O stretching in the carbonyl functional group. Also, peak appearing at 1555.65 cm-1
indicates the presence of aromatic C-C stretch while the band of strong intensity observed at
768.73 cm-1 is due to the CH2 rocking vibration. In spectra of PVA-IBU conjugate, the peak
appearing at 1737.89 cm-1 due to C=O stretch confirms the transition of carboxylate into ester
by conjugation. The peak appearing at 1662.60 cm-1 may be ascribed to aromatic C-C
stretching while the C-O-C stretching appearing at 1241.73 cm-1 indicates the esterification
reaction.
1
H-NMR spectroscopy
Fig 3 depicts the 1H-NMR spectrums of PVA, IBU, PVA-IBU, DCF and PVA-DCF
were carried out in DMSO-d6. In 1H-NMR spectrum (fig. 3 c) of PVA, the triplet peak
observed at 1.33-1.43 ppm is ascibed to the protons of methylene (-CH2). The characteristic
peaks visible at 4.48 ppm and 3.184-3.189 ppm can be contributed to the protons of hydroxyl
(-OH-) and methane (-CH-) groups, respectively. The 1H-NMR spectra of IBU (fig. 3 a)
8
showing characteristic doublet peaks at 7.09-7.11 ppm and 7.18-7.20 ppm which belong to
the protons of the phenyl ring. On the other hand, there appears one multiplet peak at 1.76-
1.86 ppm and three doublet peaks at 0.85-0.87 ppm and 2.41-2.42 ppm which corresponds to
the protons on the propyl entity. Also, a characteristic singlet peak at 12.33 ppm can be
attributed to the protons of carboxylic acid group. The spectrums of IBU shows characteristic
signals at 3.60-3.65 ppm and at 1.34-1.36 ppm which can be assigned to the protons of
propanoic acid in the main chain.
The 1H-NMR spectra (fig. 3d) of PVA-IBU conjugate shows two characteristic
multiplet peaks occurring at 7.04-7.18 ppm due to the protons of the aromatic ring of the
conjugate which indicate the presence of IBU in the conjugate. A doublet and a triplet peak at
1.34 ppm and 3.50-3.64 ppm can be ascribed to the protons of -CH2 and –CH moiety,
indicating the presence of PVA in the conjugate. The disappearance of hydroxyl peaks of the
polymer and the carboxylic peak of IBU indicates that conjugation went through
esterification reaction. The disappearance of this peak in the PVA-IBU conjugate reflects that
the COO-1 was the reaction site and vanishing of this moiety indicates the formation of the
conjugate. During earlier study, a large number of peaks and the enlargement of the peaks in
1
H-NMR spectra of polymers was attributed to the occurrence of repeated monomer units
having different chemical environments [14].
The 1H-NMR spectrum of DCF (fig. 3b) shows characteristic doublet peak at 6.30-
6.28 ppm and 7.52-7.54 ppm and triplet peak at 7.18-7.24 ppm ranges which belongs to the
aromatic protons of the phenyl ring respectively. Moreover, protons of N-H entity shows
characteristic singlet peak 3.71 ppm. On the other hand, there appears two doublet peaks at
6.85-6.89 ppm and 7.5-7.9 ppm which corresponds to the protons to methine (-CH-) entities
in the N-H attached to 2.6-dichlorophenyl ring respectively. Also, a characteristic singlet
peak at 12.69 ppm can be attributed to the protons of carboxylic acid group. In the NMR
spectra of PVA-DCF conjugate (fig. 3e) the two doublet peaks appearing at 1.33-1.45 ppm
belongs to the protons of CH2 while the triplet peak appearing at 3.29-3.39 ppm corresponds
to the protons of C-H entity. The disappearance of the carboxylic peak of DCF clearly
indicates esterification reaction between PVA and DCF has taken place [14].
Fig. 4 displays the respective DSC thermograms of PVA, IBU, PVA-IBU, DCF and
PVA-DCF. In the thermal curve of PVA, a broad endotherm occurs at 139.35 °C with
9
enthalpy of 195.35 J/g. The thermogram of IBU shows endothermic peak at 77.47 °C with
enthalpy of 132.80 J/g. The second endothermic peak appears at 181.16 °C with enthalpy of
24.149 J/g. The characteristic thermal curve of PVA-IBU shows three endotherms at 93.90
°C, 143.69 °C, and 185.49 °C with enthalpies of 160.65 J/g, 1.4870 J/g, 28.762 J/g
respectively. So, the shift in the endothermic peaks and appearance of one more peak in the
thermogram of PVA-IBU indicate formation of the conjugate.
The thermogram of DCF shows an endothermic transition peak at 180.49° C with heat
flow of 117.77 J/g. The endotherm peaks of PVA-DCF appears at 101.89 °C and at 179.59
°C with heat flow of 114.25 J/g and 18.408 J/g with their respective onset temperatures at
54.24 °C and 154.19 °C. Thus, the shift in endotherms and the appearance of one more
endothermic peak in the thermogram of PVA-DCF indicate conjugate formation.
Fig. 5 compares the diffraction spectrum of PVA, IBU, DCF, PVA-DCF and PVA-
IBU conjugate. The diffractogram of PVA shows the presence of diffusion pattern
characteristic of semi-crystalline substances with diffraction peaks at 14.42°, 17° and 19.6°
(2θ) [15]. The diffraction curve of IBU is typical of crystalline substances with characteristic
peaks at 12.1°, 16.46°, 17.52°, 19.36°, 19.84°, 21.96°, 20° and 22.14° (2θ). The diffraction
spectra of PVA-IBU conjugate presents the characteristic diffraction peaks at 14.34°, 16.26°,
19.5° and 25.1° (2θ), which indicate the increase in crystallinity of PVA on conjugation with
IBU.
Fig. 6 (a-b) shows scanning electron micrographs of IBU. The micrograph images
reveal polyhedral shaped crystals of IBU with granular surface. Further the micrograph
images (fig. 6c) shows the presence of smooth surface on PVA while the surface of PVA-
IBU conjugate is striated (fig. 6d) with presence of plate shaped structure which is somewhat
consistent with the XRD study pattern. Fig. 6 (e-f) shows scanning electron micrographs of
10
DCF. The micrograph images reveal needle shaped crystals of DCF with smooth surface.
Fig.6 (g) indicates the presence of striated and rough grannular surface of PVA-DCF
conjugate.
The viscosity of PVA-IBU, PVA and PVA-DCF conjugate solutions was determined
using Ostwald viscometer. Aqueous solutions of PVA, PVA-DCF and PVA-IBU conjugate
for the concentration 1.4% (w/v) was used as PVA (1.4% w/v) is commonly used as vehicle
for ophthalmic solutions. The viscosity of PVA, PVA-DCF and PVA-IBU conjugate
solutions was determined to be 2.066, 1.955 centipoises (cps) and 1.111 centipoises (cps) at
25 °C respectively. Thus, 46.22% fall in viscosity of PVA was observed on conjugation with
IBU while only a little change (i.e. 5.37%) in the viscosity of PVA was observed on
conjugation with DCF.
The PVA-drug conjugate release the drug by hydrolysis of the ester bond between
PVA and IBU/DCF. The hydrolysis study of PVA-IBU and PVA-DCF conjugates was
carried out in phosphate buffer (pH-7.4) in dialysis membrane so that the hydrolyzed drugs
permeate out of the dialysis bag containing the PVA-drug conjugate. The results of
hydrolysis studies of PVA-IBU conjugate (fig. 8b) revealed that all the ibuprofen was
11
released by hydrolysis in the 72 h. Further on the basis of the results of hydrolysis studies, the
PVA-IBU conjugate was determined to contain 0.33 g of ibuprofen/gram of conjugate.
On the other hand, PVA-DCF conjugate (fig. 8a) was observed to release almost whole
of the drug within 96 h. The hydrolysis studies unveiled that 1 g of PVA-DCF conjugate
contained 0.16 g of DCF. On subjecting the data of release of drugs via hydrolysis for kinetic
modeling, the value of R2 for zero, first, Higuchi’s Square root and Korsemeyer-Peppas
kinetics was found to be 0.708, 0.934, 0.880 and 0.885 respectively while for PVA-IBU
conjugate, the corresponding R2 for zero, first, Higuchi’s Square root and Korsemeyer-
Peppas kinetics was found to be 0.809, 0.988, 0.933 and 0.942 respectively. Thus, the results
of hydrolysis study indicated that PVA-IBU and PVA-DCF conjugates release IBU and DCF
respectively by hydrolysis following first order kinetics. Further the value of first order rate
constant K for IBU and DCF was found to be 0.06218 h-1 and 0.027636 h-1 respectively [17].
Conclusion
In the present study poorly water soluble, non-steroidal anti inflammatory drugs diclofenac
and ibuprofen were conjugated to the hydrophilic polyvinyl alcohol by esterification of their
carboxyl groups with the hydroxyl groups of polyvinyl alcohol utilizing carbodiimide
coupling chemistry. The formation of conjugates was confirmed by FTIR and 1H-NMR
spectral analysis. The conjugation of ibuprofen to polyvinyl alcohol exerted a significant fall
in its viscosity while no such effect was observed in the case of diclofenac conjugation.
Similarly, conjugation of hydrophobic ibuprofen to hydrophilic polyvinyl alcohol imparted
amphiphilic properties on the conjugate, but diclofenac conjugate did not show the
amphiphilic behavior. The results of hydrolysis studies which indicated that the conjugation
of ibuprofen to polyvinyl alcohol was achieved to a greater extent than that of diclofenac to
polyvinyl alcohol, support the findings of viscosity and critical aggregation behavior studies.
However by optimizing the reaction parameters a higher degree of conjugation can be
achieved. In conclusion, the conjugates of diclofenac and ibuprofen with polyvinyl alcohol
appear to be promising drug delivery system for further in vivo studies and development of a
suitable dosage form.
Acknowledgement
The authors express gratitude to Department of Science & Technology, Govt. of India for
providing financial assistance to Jyoti Mundlia under DST-PURSE programme.
12
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13
[13] C. M. Adeyeye, P.K. Li, Diclofenac sodium, Analytical profiles of drug substances, ed.
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[15] N.A. Peppas, D. Tennenhouse, Semicrystalline poly(vinyl alcohol) films and their blends
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14
Cl
OH
O
NH
OH O
Cl
Diclofenac acid + Ibuprofen
OH n
Polyvinyl alcohol
DCC/DMAP
60-65 °C
N2 atmosphere
HC CH2 H
H2C C O
n n
O O C
Cl Cl
Polyvinyl alcohol-
diclofenac conjugate
15
Fig. 1. UV spectrum of (a) DCF, PVA-DCF and (b) IBU, PVA-IBU conjugate
16
Fig. 2. FTIR spectra of PVA, IBU, PVA-IBU, DCF and PVA-DCF
17
Fig.3. 1H-NMR spectra of: a- PVA, b- IBU, c- PVA-IBU, d- DCF and e-PVA-DCF
18
Fig. 4. DSC themograms of PVA, IBU, PVA-IBU, DCF and PVA-DCF
19
Fig.5. X-ray diffractogram of PVA, IBU, PVA-IBU, DCF and PVA-DCF
20
Fig.6. Scanning electron micrograph showing (a) shape, (b) surface of IBU (c) surface of
PVA (d) shape of PVA-IBU (e) shape, (f) surface of DCF (g) shape of PVA-DCF
21
Fig. 8. In-vitro release profile of (a) PVA-IBU and (b) PVA-DCF conjugate
22