Solubility and dissolution improvement of

ketoprofen by emulsification ionic gelation

Cite as: AIP Conference Proceedings 1927, 030024 (2018); https://doi.org/10.1063/1.5021217
Published Online: 09 February 2018

Revika Rachmaniar, Deby Tristiyanti, Syarif Hamdani, and Afifah

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© 2018 Author(s).
 Solubility and Dissolution Improvement of Ketoprofen by
Emulsification Ionic Gelation
Revika Rachmaniar1, a), Deby Tristiyanti1, b), Syarif Hamdani2, c) and Afifah1, d)
1
Department of Pharmaceutics, Indonesian School of Pharmacy,
2
Department of Pharmacochemistry, Indonesian School of Pharmacy,
Jl. Soekarno-Hatta No. 354, Bandung, West Java 40266, Indonesia
a)
Corresponding author: revikarachmaniar@stfi.ac.id
b)
debytristiyanti@stfi.ac.id, c)syarifhamdani@stfi.ac.id, d)afifahdermaga@gmail.com

Abstract. Ketoprofen or [2-(3-benzoylphenyl) propionic acid] is non-steroidal anti-inflammatory (NSAID) and an

analgesic which has high permeability and low solubility. The purpose of this work was to improve the solubility and
dissolution of poorly water-soluble ketoprofen prepared by emulsification ionic gelation method and utilizing polymer
(chitosan) and cross linker (tripolyphosphate, TPP) for particles formulation. The results show that increasing pH value
of TPP, higher solubility and dissolution of as-prepared ketoprofen-chitosan was obtained. The solubility in water of
ketoprofen-chitosan with pH 6 for TPP increased 2.71-fold compared to untreated ketoprofen. While the dissolution of
ketoprofen-chitosan with pH 6 of TPP in simulated gastric fluid without enzyme (0.1 N HCl), pH 4.5 buffer and
simulated intestinal fluid without enzyme (phosphate buffer pH 6.8) was increased 1.9-fold, 1.6-fold and 1.2-fold
compared to untreated ketoprofen for dissolution time of 30 minutes, respectively. It could be concluded that chitosan
and TPP in the emulsification ionic gelation method for ketoprofen preparation effectively increases solubility and
dissolution of poorly water-soluble ketoprofen.

INTRODUCTION
Solubility and dissolution are critical properties because it estimates for the poor solubility of active
pharmaceutical ingredient serves it for pharmacological profiling. Ionic gelation is one of various methods that
increase solubility, dissolution, absorption as having large surface area; avoids risk of toxicity; decreases dosing
frequency for patient; enhances bioavailability; increases therapeutic effect. It is based on the ability of
polyelectrolytes to cross link in the presence of counter ions to form hydrogel beads. It is capable of extensive
gelation and swelling in gastrointestinal fluids and releases the drug through controlled polymer relaxation. The
hydrogel beads are produced by dropping a drug-loaded polymeric solution into the aqueous solution of polyvalent
cations [1].
Natural polymers are used as drug carriers in ionic gelation because of their biocompatibility and
biodegradability. One of common natural polymer is chitosan. Chitosan can be simply fabricated to various
morphologies including micro particles. Properties of chitosan-based drug delivery systems can be controlled by
forming a polyelectrolyte-anionic complex. Chitosan contains free positively charged amine groups and forms
structure by linking with the counter ions and induce gelation by cross linking. The counter ion of chitosan is the
negatively charged phosphate group of tripolyphosphate (TPP). TPP is a non-toxic multivalent anion that form
hydrogel beads through ionic interaction with the positively charged amine groups of chitosan. Chitosan-TPP
complex is the most important drug delivery hydrogel beads [1-4].
Emulsification ionic gelation is an advanced method in ionic gelation with the combination of oily phase and
emulsifier. This method is useful for microparticles forming as an effective delivery carrier [1, 3-4]. Factors
affecting emulsification ionic gelation method are polymer and crosslinking electrolyte concentration, temperature,

The 1st International Conference and Exhibition on Powder Technology Indonesia (ICePTi) 2017
AIP Conf. Proc. 1927, 030024-1–030024-6; https://doi.org/10.1063/1.5021217
Published by AIP Publishing. 978-0-7354-1619-2/$30.00

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gas forming agent concentration, drug concentration, polymer concentration, time of cross linking and pH of
crosslinking solution [1,5].
Ketoprofen [2-(3-benzoylphenyl) propionic acid] is a nonsteroidal anti-inflammatory drug (NSAID) with an
analgesic and antipyretic properties indicated for the symptomatic treatment of pain and inflammation. Its
mechanism of action is associated with peripheral cyclooxygenase-1(COX-1) and cyclooxygenase-2(COX-2)
inhibition, which reduces the synthesis of prostaglandins and thromboxane precursors. However, its efficacy is
countered by side effects of gastrointestinal irritation, short biological half-life (t1/2 = 2.1 h) and high frequency of
dosing (2-4 times daily) [6-9]. Ketoprofen has low bioavailability due to high permeability and low solubility [10-
11]. These properties of ketoprofen have limited design of dosage forms for various administration. Alternative
dosage form to improve the properties in this study was microparticles by emulsification ionic gelation.
The purpose of this work is to improve the solubility and dissolution of poorly water-soluble ketoprofen prepared
by emulsification ionic gelation method by utilizing chitosan as polymer and TPP with various pH as cross linker for
particles formulation. Surface morphology, functional group, solubility and dissolution of as prepared ketopofen-
chitosan-TPP particle were investigated.

EXPERIMENT

Preparation of Ketoprofen-Chitosan-TPP by Emulsification Ionic Gelation

Each batch of microparticles was prepared loading fixed of ketoprofen (1 g) in 96% ethanol and chitosan (1 g) in
4% acetic acid. Accurately weighed mixture of ketoprofen and chitosan was dispersed by using the homogenizer
Heidolph Silent Crusher M at speed of 10.000 rpm. TPP solution (15 mL) adjusted by using 2 N hydrochloric acid
to pH 2, pH 4 and pH 6. TPP solution (15 mL) and VCO (25 mL) constantly were added into mixture of ketoprofen-
chitosan while stirring using homogenizer at a speed of 10.000 rpm for 45 minutes. Ketoprofen-chitosan-TPP were
washed with benzene and then filtered by Whatman No. 1 filter paper on Buchner funnel. Particles were collected
and dried at temperature of 70oC for 24 hours.

Characteristics of Particles
Untreated ketoprofen and ketoprofen-chitosan-TPP particles were characterized by means of fourier transform
infrared spectroscopy (FT-IR) Thermo Scientific Nicolet iS5 spectrophotometer to characterize functional groups
and scanning electron microscopy (SEM) Phenom FEI to characterize surface morphology.

Solubility Studies
Untreated ketoprofen and ketoprofen-chitosan-TPP particles (equivalent to 20 mg of ketoprofen) were added to
50 ml of water, shaked at speed of 400 rpm for 24 h at temperature of 25±0.5 °C. The sample was filtered through a
membrane filter 0.4 5 μm then determined by UV spectrophotometer Shimadzu at a wavelength of 260 nm.

Dissolution Studies
Untreated ketoprofen and ketoprofen-chitosan particles (equivalent to 50 mg of ketoprofen) was determined by
dissolution tester apparatus type II Flight RC-3 at 50 rpm. Dissolution studies was performed at 37±0.5 °C with 900
ml 0.1 N HCl, pH 4.5 buffer and pH 6.8 phosphate buffer. At predetermined intervals, 5 ml of medium was sampled,
filtered, then determined by UV spectrophotometer at a wavelength of 260 nm.

RESULTS AND DISCUSSIONS

The result obtained from FTIR is displays in Fig. 1 indicates that emulsification ionic gelation did not damage
the structure of ketoprofen. FTIR spectrum revealed the pattern spectrum of ketoprofen-chitosan-TPP pH 2, pH 4
and pH 6 similar to chitosan at 3741.09, 3743.98 and 3747.97 cm-1 exhibits the NH3+ group, respectively. FTIR
spectrum revealed the pattern spectrum of ketoprofen-chitosan-TPP pH 2, pH 4 and pH 6 similar to ketoprofen at

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1741.23, 1742.96 and 1743.05 cm-1 corresponds to the carboxylic C=O group, respectively. Ketoprofen-chitosan-
TPP exhibit the shift of carboxylic C=O group to the larger wavenumber due to intermolecular hydrogen bonding
between ketoprofen and chitosan. FTIR spectrum revealed the pattern spectrum of ketoprofen-chitosan-TPP pH 2,
pH 4 and pH 6 at 1554.77, 1556.22 and 1557.02 cm-1 respectively which indicate the cross linking of a negative
charge phosphate (PO-) of TPP to a positive charge amino group (R-NH3+) of chitosan. It is observed that particle
formation of ketoprofen-chitosan-TPP has occurred [12].

FIGURE 1. FTIR spectrum of ketoprofen-chitosan-TPP pH 2, ketoprofen-chitosan-TPP pH 4, ketoprofen-chitosan-TPP pH 6,

Ketoprofen, Chitosan and TPP

Scanning electron micrograph of untreated ketoprofen, ketoprofen-chitosan-TPP pH 2, pH 4 and pH 6 showed

that the major particles were rod shaped as shown in Fig. 2. Ketoprofen-chitosan-TPP has smaller particles than
untreated ketoprofen, but they aggregate because of the influence pH value of TPP and hygroscopic properties of
chitosan. Ion interaction between chitosan and TPP was obtained at low pH value of TPP (acidic), phosphate ion of
TPP interacts with NH3+ of chitosan. Acidic condition of emulsification ionic gelation process makes high ionic
interaction strength which causes aggregation. Deprotonate by hydroxyl ion was obtained at high pH value of TPP
(alkaline), hydroxyl ion and phosphate ion of TPP compete to interact with NH3+ of chitosan. Alkaline conditions of
emulsification ionic gelation process lead to low ionic interaction strength. Furthermore, chitosan powder is a stable
material at room temperature, although it is hygroscopic after drying and it causes ketoprofen-chitosan-TPP particles
get attached to each other to produce inhomogeneous particles as shown in Fig. 2.

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 FIGURE 2. SEM image of (a) untreated ketoprofen (b) ketoprofen-chitosan-TPP pH 2 (c) ketoprofen-chitosan-TPP pH 4
(d) ketoprofen-chitosan-TPP pH 6

The solubility in water for ketoprofen-chitosan-TPP at pH 2, pH 4 and pH 6 increased significantly as displayed

in Table 1 where the increase of 2.23-, 2.46- and 2.71-fold higher than the solubility of untreated ketoprofen,
respectively. Increasing the pH value of TPP leads to less bonding of cross linking so that release of ketoprofen
occurs more easily. Additional chitosan in ketoprofen may cause increasing on solubility because it is polymer
which forms hydrogen bonding between ketoprofen and chitosan. This hydrogen bonding can be seen in Fig. 1.
Upon water dissolved, amine groups of the chitosan become protonated, resulting in a positively charged (R-NH3+)
and chitosan salts that are soluble in water; the solubility is affected by the degree of deacetylation [13]. Ratio of
surface area and volume of ketoprofen-chitosan-TPP affects solubility also. Ratio of surface area and volume of
ketoprofen-chitosan-TPP are greater because the particle size are smaller than untreated ketoprofen. The large
surface area of particles makes contact with water so that they have higher solubility than untreated ketoprofen.
TABLE 1. Solubility of ketoprofen, ketoprofen-chitosan-TPP pH 2, pH 4 and pH 6
Sample Solubility (µg/ml)
Untreated Ketoprofen 183.70
Ketoprofen-chitosan-TPP pH 2 408.99
Ketoprofen-chitosan-TPP pH 4 451.04
Ketoprofen-chitosan-TPP pH 6 497.08

Based on guidance for industry, waiver of in vivo bioavailability and bioequivalence studies for immediate-
release solid oral dosage forms based on a biopharmaceutical classification system (BCS), the dissolution study used
900 ml HCl in accordance with simulated gastric fluid without enzymes, acetate buffer in accordance with simulated
fluid among gastric and intestinal, phosphate buffer in accordance with simulated intestinal fluid without enzymes

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and 37±0.5°C of temperature in accordance with the temperature of the human body [14]. The dissolution profiles of
untreated ketoprofen and ketoprofen-chitosan-TPP are illustrated in Fig. 3.

(a) (b)

(c)
FIGURE 3. Dissolution profile of untreated ketoprofen, ketoprofen-chitosan-TPP pH 2, pH 4 and pH 6 in (a) 0.1 N HCl, (b) pH
4.5 acetate buffer, (c) pH 6.8 phosphate buffer

The dissolution of ketoprofen-chitosan-TPP were increased in 0.1 N HCl, pH 4.5 acetate buffer and pH 6.8
phosphate buffer compared to untreated ketoprofen for dissolution time of 30 minutes as displayed in Table 2.
TABLE 2. Percentage of Dissolved Ketoprofen in 30 minutes in dissolution medium
Dissolved Ketoprofen (%)
Dissolution Medium Untreated Ketoprofen- Ketoprofen- Ketoprofen-
Ketoprofen chitosan-TPP pH 2 chitosan-TPP pH 4 chitosan-TPP pH 6
0.1 N HCl 45.86 61.67 94.94 89.14
pH 4.5 acetate buffer 58.50 90.25 97.26 95.82
pH 6.8 phosphate buffer 77.54 97.49 99.57 94.68

Ketoprofen-chitosan-TPP were dissolved more than 85% in 30 minutes in the dissolution medium. Ketoprofen-
chitosan-TPP were dissolved higher than untreated ketoprofen because chitosan as hydrophilic polymer forms
hydrogen bonding between ketoprofen and chitosan and the large surface area of particles can make contact with the
dissolution medium.
Ketoprofen-chitosan-TPP have high dissolution rate at 15 minutes which are dissolved more than 85% in pH 4.5
buffer and phosphate buffer. It is because ketoprofen more dissolved at alkaline medium. After emulsification ionic

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gelation process, ketoprofen-chitosan-TPP particles get smaller particle size supporting high dissolution rate in those
medium. It permits ketoprofen-chitosan-TPP can be formulated as dosage form for drug delivery system in intestinal
fluid compared to gastric fluid.
Sampling during the dissolution process was performed using filter to prevent the particles that is not completely
dissolved to pass through, clogging of filters during sampling can affect the accumulative ketoprofen release on
time. So, at that point the accumulative ketoprofen release was decreased.
The use of chitosan and TPP in preparation of ketoprofen by emulsification ionic gelation is potential to improve
solubility in water and dissolution in gastric and intestinal fluid and permits the formulation of dosage form and drug
delivery system.

CONCLUSION
The solubility in water and dissolution in simulated gastric and intestinal fluid of ketoprofen-chitosan-TPP was
increased compared to untreated ketoprofen. The increasing pH value of TPP, the higher solubility and dissolution
of as-prepared ketoprofen-chitosan-TPP was obtained. Emulsification ionic gelation method and utilizing chitosan
as polymer and TPP as cross linker successfully increases the solubility and dissolution of ketoprofen and permits
the formulation of dosage form and drug delivery system in intestinal fluid.

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