JURNAL FARMASI SAINS DAN KOMUNITAS, May 2020, 8-19  Vol. 17 No. 1 
p-ISSN 1693-5683; e-ISSN 2527-7146 

doi: http://dx.doi.org/10.24071/jpsc.002034 

*Corresponding author: Rahmah Elfiyani 

Email: rahmahelfiyani@uhamka.ac.id 

THE INFLUENCE OF -CYCLODEXTRIN CONCENTRATIONS AS LIGANDS ON 

INCLUSION COMPLEXES TO INCREASE THE SOLUBILITY OF IBUPROFEN  

 

Rahmah Elfiyani*), Anisa Amalia, Alvin Integra  

 

Faculty of Pharmacy and Science, University of Muhammadiyah Prof. DR HAMKA, Klender-
Jakarta Timur, 13460, Indonesia 

Received August 12, 2019; Accepted January 21, 2020 

 

 

ABSTRACT  

Ibuprofen is a compound with low solubility but high permeability in water. One method to 

improve the ability of a substance to dissolve in water is through the formation of inclusion 

complexes. This study aims to obtain ratio between ibuprofen and -cyclodextrin which results in 

inclusion complex with an optimal amount of dissolved ibuprofen. The inclusion complex was 
made using solvent evaporation method with molar ratio variations of 1: 1, 1: 2, 1: 3, 1: 4 and 1: 

5. The results of the inclusion complex were characterized by X-ray diffraction, FTIR, SEM, and 
DTA. The solubility test was carried out using three different media; they are pH solution 7.4; pH 

solution 1.5; and distilled water. The solubility test results showed no increase on the ibuprofen 
solubility of the inclusion complex within medium solutions of pH 7.4 and pH 1.5 whereas in 

aquades medium there was an increase in the inclusion complex solubilit y compared to pure 

ibuprofen. Based on the results, it can be concluded that inclusion complex with molar ratio of 1: 
1 shows optimal amount of dissolved ibuprofen compared to other ratio variations in aquadest 

medium. 
 

Keywords: β-cyclodextrin; ibuprofen; inclusion complexes; solvent evaporation. 

 
 

INTRODUCTION 
In a study conducted by Octavia et al. 

(2015), it was found that pure ibuprofen 

could not be dissolved for more than 70% in 
30 minutes. Such compound requires a 

method to increase its solubility to improve 
the bioavailability of drugs (Yasir et al. 

2010). Other studies investigating the 

increase of ibuprofen solubility have been 
carried out in the form of solid dispersion by 

the methods of solvent evaporation and 
melting dispersion (Gupta et al., 2011). This 

study uses relatively toxic organic solvents 

which will leave residue on the results of 
ibuprofen solid dispersion. 

Another way to improve the solubility 
of drugs that are difficult to dissolve in water 

is through the inclusion complex, through 

which can improve the speed of dissolution, 
absorption, bioavailability, and chemical 

stability of the drug (Loftsson & Brewster, 

1996). Inclusion complex is a form of 
inserting non-polar compounds (substrates) 

into a container of another compound 

(ligand) (Ketan et al., 2012). -cyclodextrin 
compound is one of cyclodextrin types that 

can be used as a ligand in the formation of 

inclusion complex. It is because -

cyclodextrin has relatively large cavity 
diameter of up to 6Å and good water 

solubility of 1 part in 20 parts of water 
(Rowe et al., 2012). 

Based on the explanation above, this 

research will produce an inclusion complex 

with a variation of ibuprofen:-cyclodextrin 

ratio using the solvent evaporation method 
due to an increase in ibuprofen solubility. 

The purpose of this study is to obtain ratio of 

ibuprofen:-cyclodextrin which produces 

inclusion complex with an optimal amount of 
dissolved ibuprofen.    

http://dx.doi.org/10.24071/jpsc.002034


Jurnal Farmasi Sains dan Komunitas,2020, 17(1), 8-19 

The Influence of -cyclodextrin Concentrations as… 9 

METHODS 
The materials used in this study are 

ibuprofen (Hubei granules-biocause 

pharmaceutical), β-cyclodextrin (BaoJi 
GuoKang Bio-Technology), alcohol, 

aquadest, KCl (Merck), HCl (Merck), 

KH2PO4 (Merck), and NaOH (Merck). In 
addition, the instruments used in this study 

include X-ray diffractometer (Pan Analytical 
empryren), DTA (Mettler Toledo), UV-VIS 

spectrophotometer, SEM (SEM-eds JEOL 

JED350), FTIR spectrophotometer (Agilent), 
magnetic stirrer (Power MS-H-Pro), rotary 

evaporator (Butchi), and sieving (Retsch AS 
200 digits CA).  

 

Production of inclusion complex 
 The inclusion complex was made into 5 

formulas by varying the molar ratio between 

ibuprofen:-cyclodextrin which were 1: 1; 1: 

2; 1: 3; 1: 4 and 1: 5 (Table 1). Ibuprofen 
was dissolved in 50 ml of ethanol (M1) while 

β-cyclodextrin was dissolved in 50 ml of hot 

water (60°C) (M2). After that, the M2 clear 
solution was put into M1 clear solution and 

stirred using a magnetic stirrer at 300 rpm for 
30 minutes. The turbid solution is then 

evaporated (170 bar, 150 rpm, temperature 

40°C). The dried powder formed was sieved 
using a mesh of 100, then dried in a 

desiccator for 3 hours (Priotta, 2015).  

Characterization of inclusion complexes 

 Infrared spectra of ibuprofen, β-

cyclodextrin and inclusion complexes were 
recorded using FT-IR spectrophotometer by 

KBr pellet method. Measurements were 
made at wavenumbers 400 - 4000 cm-1 

(Hiremath et al, 2008). 

 DTA would characterize the solid-state 

interaction of the inclusion complex, -

cyclodextrin and, ibuprofen. The sample 
used was approximately 5 mg of ibuprofen, 

β-cyclodextrin, and inclusion complex at 
warming temperatures from 30 to 400 °C 

with a heating speed of 10 °C / minute (Ma 

et al., 2012). 
 XRD patterns of Ibuprofen, β-

cyclodextrins and inclusion complexes were 
recorded using X-ray diffractometer with Cu 

anode tube at 5-700 / 2θ intervals. The 

sample was placed on a plate-shaped holder 
made of aluminum. Diffractogram would be 

read automatically on the computer (Asih II, 
2011). 

 Particle morphology was observed 

using SEM. The powder sample (ibuprofen, 
β-cyclodextrin, inclusion complex) was 

placed in an aluminum sample holder and 
coated with gold with thickness of 10 nm. 

Samples were then observed for the 

enlargement of SEM devices. The voltage 
was set at 20 kV and the current was 12 mA 

(Octavia et al, 2015). 

 

Solubility test 

 A total of 100 mg of standard ibuprofen 
and inclusion complex results were dissolved 

into 20 ml of ethanol each, put into a 100 ml 
volumetric flask and dissolved with the 

medium (buffer pH 1.5/ distilled water) until 

the boundary mark. It was stirred using a 
magnetic stirrer at a speed of 150 rpm for 15 

minutes. A sample of 10 ml was taken and 
filtered with a 0.45 µm filtrate membrane. 

Absorption was measured at maximum 

wavelength using spectrophotometer. The 
solubility test was also carried out on solvent 

buffer pH 7.4 without the addition of ethanol 
to help to dissolve ibuprofen. 

 

DATA ANALYSIS 
 Solubility test data on dissolved 

ibuprofen levels were analyzed using non-
parametric analysis of Friedman because the 

data were not normally distributed and were 

not homogeneous.   

Tabel 1. Formula of Inclusion Complex 

 F 1 F 2 F 3 F 4 F 5 

β-cyclodextrine (g)  283,75 567,5  851,25  1135 1418,75 

Ibuprofen (g) 51,55 51,55 51,55 51,55 51,55 



Jurnal Farmasi Sains dan Komunitas,2020, 17(1), 8-19 
 

   Rahmah Elfiyani et al. 10 

RESULTS AND DISCUSSION 

FTIR 
 The results of FTIR characterization from 

ibuprofen, β-cyclodextrin and inclusion 

complexes can be seen in Figure 1 and Table 
2. Inclusion complexes showed the presence 

of β-cyclodesktrin and ibuprofen groups. In 
formula 1 there were wavelengths of 1701.5 

cm-1 and 1459.3 cm-1 which were the peaks in 

ibuprofen, a slight shift in wavelength from 
1461 cm-1 to 1459 cm-1 (Barmi et al., 2018). 

In formula 2, a shift in wavelength from 
3283.8 to 3280.1 belonged to β-cyclodextrin 

(Silverstein et.al., 1981), but there was no 

aromatic peak of ibuprofen. The wavelength of 

ibuprofen aromatic group was not seen in 
formulas 3, 4 and 5 as well. Carboxylic group 

wavelength shift from 1701.5 to 1735.1 
belonged to ibuprofen in formula 3, formula 4 

and formula 5. This indicated a weak 

interaction between ibuprofen and β-
cyclodextrin (Hiremath et al., 2008). From 

these results, it was known that there was a 
shift in wavelength and appearance of 

ibuprofen, and wavelengths of -cyclodextrin 
which indicated an interaction between 

ibuprofen and -cyclodextrin  

. 
Tabel 2. Wave Number of FTIR 

 Distance wave number (cm-1) -cyclodextryn (cm-1) 

(O-H) 2500-3300 3263,3 
(C-H) aromatis  1000-1275 1099,6 

(C-O) alcohol dan fenol  1000-1300 1077,2 
 Distance wave number (cm-1) Ibuprofen (cm-1) 

(C=O) carboxylic acid  1701 1701.5 

(C=C) aromatic  1461 1460 
 Distance wave number (cm-1) Inclusion complex (cm-1)  

O-H 2500-3300 3265-3280,1 
C-H 1000-1275 1104.1 

C-O 1000-1300 1079.1 

C=O carboxylic acid 1701 1701.5-1735.1 
(C=C) aromatic  1461 1459 

Figure 1. IR Spectrum of ibuprofen, -cyclodextrin and inclusion complex.



Jurnal Farmasi Sains dan Komunitas,2020, 17(1), 8-19 
 

 

The Influence of -cyclodextrin Concentrations as… 11 11 

X-ray Diffractometry 
 It can be seen in Figure 2. In formula 1, 
the inclusion complex was formed due to the 

bonding of ibuprofen and -cyclodextrin so 
that the peaks in formula 1 and formula 2 were 

not too many. With the increase on the number 

of -cyclodextrin, the peaks were increasingly 

visible until formula 5, but did not cover the 
peak of ibuprofen. The diffraction pattern 

formed from formula 1 to formula 5 was 

increasingly seen approaching -cyclodextrin 
diffraction pattern with increasing peaks 

similar to -cyclodextrin. This signifies that 
ibuprofen molecule has entered the structure 

of -cyclodextrin cavity so that it looks 

dominant -cyclodextrin diffractogram (Rini 
et al., 2015). The decrease in height of peak 

intensity indicates a change in the structure so 

that the results of the inclusion complex are 
amorphous (Pamudji et al., 2014; Barmi et al., 

2018). 

 
 

 

 

 



Jurnal Farmasi Sains dan Komunitas,2020, 17(1), 8-19 
 

  Rahmah Elfiyani et al. 12 

 

 

 
Figure 2. XRD result of ibuprofen, -cyclodextrin and inclusion complex.  

 

Differential Thermal Analysis  

 Formula 1 and formula 2 showed an 
endothermic process at a temperature of 

2900°C - 3200°C. Endothermic changes can 
occur due to oxidation of organic compounds 

(Setabudi et al., 2012). However, formula 3 

experienced an exothermic process at a 
temperature range of 2940°C - 3020°C and at 

that temperatures there was a change in mass. 
Meanwhile, in formula 4 and formula 5, 

exothermic process was directly followed by 

endothermic process. Exothermic process 
usually occurs due to the formation of crystals 

during the heating process which is often 
referred to solidification. 

In all results (Figure 3) on inclusion 

complex, dehydration which usually occurs at 
temperatures of around 1000°C is absent this 

time due to the disappearance of ibuprofen 

melting point. Ibuprofen loses its peak because 

it has entered the cavity of -cyclodextrin so 

that it does not show endothermic points at 
these adjacent temperatures (Hirameth 2008; 

Manca et al., 2005). 
 

Scanning Electron Microscope 

 The results of pure ibuprofen 
examination showed a long cylindrical rod 

shape while -cyclodextrin was seen as a lump 
with a rough and irregular texture. In the 

results of inclusion complex, all formulas 
appear to have no form that resembles 

ibuprofen and -cyclodextrin. In fact, almost 
all are irregular in shape (Figure 4). 

 



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The Influence of -cyclodextrin Concentrations as… 13 

 

 
 

 

 
 

 
 

 

 
 

 
 

 

 
 

 
 

 

 
 

 
 

(a) 

 

 
 

 

 
 

 

 
 

 
 

 

 
 

 
 

 

 
 

 
 

 

 
 

(b) 



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  Rahmah Elfiyani et al. 14 

 

 
 

 

 
 

 
 

 

 
 

 
 

 

 
 

 
 

 

 
 

 
 

 

(c) 

 

 
 

 

 

 
 

 
 

 

 
 

 
 

 

 
 

 
 

 

 
 

 
 

(d) 



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The Influence of -cyclodextrin Concentrations as…  15 

 

 
 

 

 
 

 
 

 

 
 

 
 

 

 
 

 
 

 

 
 

 
 

 

(e) 

 

 
 

 

 
 

 

 
 

 
 

 

 
 

 
 

 

 
 

 
 

 

 
 

(f) 



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  Rahmah Elfiyani et al. 16 

 

 
 

 

 
 

 
 

 

 
 

 
 

 

 
 

 
 

 

 
 

 
 

 

(g) 
Figure 3. DTA result: (a) Formula 1, (b) Formula 2, (c) Formula 3, (d) Formula 4, (e) Formula 5, (f) ibuprofen, (g) -

cyclodextrin. 

   
Formula 1     Formula 2 

 

   
Formula 3     Formula 4 

 
Figure 4. SEM results 



Jurnal Farmasi Sains dan Komunitas,2020, 17(1), 8-19 

The Influence of -cyclodextrin Concentrations as… 17 

   
Formula 5     -cyclodextrin 

 

 
ibuprofen 

Figure 4. SEM results (Continued) 

 

Solubility Test  
 One of the most common methods in 

evaluation inclusion complexation is phase 

solubility. A phase solubility diagram is 
constructed by plotting the molar 

concentration of dissolved solute found on the 
vertical axis against the concentration of 

complexing agent added on the horizontal 

axis. Two general types of phase solubility 
profiles are generated; Type A where soluble 

complexes are formed, and Type B where 
complexes of limited solubility are formed 

(Higuchi & Connors, 1965).   

 The results (Figure 5) show that the 

addition of -cyclodextrin to the inclusion 

complex at solution of pH 7.4 and pH 1.5 
follows the type BI diagram which means that 

there is no increase in the solubility of 

ibuprofen with the addition of -cyclodextrin 

at ratios of 1: 1, 1: 2, 1: 3, 1: 4, and 1: 5. As 
with the aquadest medium, there is an increase 

in the solubility of ibuprofen in formula 1 
(ratio 1: 1) compared to pure ibuprofen, and 

the solubility type follows type Bs diagram.  

Curve Bs shows the formation of a complex 
that increases the total solubility of the 

compound (similar to type A diagram). More 
addition of complexing agents producing 

solubility of the complex is reached. As 

additional compound goes into solution, some 
solid complexes precipitate. Further addition 

of complexing agents beyond point z results in 
depletion of the compound from solution by 

complex formation. Curve BI is interpreted 

similarly except that the complex formed is so 
insoluble that no increase in solubility is 

observed (Mosher & Thompson, 2007). 
Statistical analysis of the solubility test results 

shows that sig ˂ 0.05 based on which it can be 

concluded that the 2 variables (ratio of 

ibuprofen:-cyclodextrin and the type of 

medium) generate different solubility results 

 



Jurnal Farmasi Sains dan Komunitas,2020, 17(1), 8-19 
 

 

  Rahmah Elfiyani et al. 18 

 
Figure 5. Solubility phase diagram of inclusion complexes  

CONCLUSION 
The inclusion complex is not able to 

increase the solubility of ibuprofen within 
solution medium of pH 7.4 and pH 1.5. 

Meanwhile, in the aquadest medium, the 

formation of inclusion complexes can increase 
the solubility of ibuprofen at ratio of 1: 1. 

 

ACKNOWLEDGMENT 
This research was supported by a grant 

from the LEMLITBANG UHAMKA 
(Research and Development Institute of 

Muhammadiyah Prof. DR HAMKA 
University) with contract number of 

247/F.03.07/2019. 

 

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