Formulation development and investigation of ibuprofen controlled

release tablets with hydrophilic polymers and the effect of co-

excipients on drug release patterns

Syed Umer Jan1*, Gul Majid Khan2 and Izhar Hussain3

1
Department of Pharmacy, University of Balochistan, Quetta, Pakistan
2
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan
3
Department of Pharmacy, COMSATS Institute of Information Technology, Abbottabad, Pakistan

Abstract: The aim and objective of the present study was to formulate and evaluate controlled release polymeric tablets
of Ibuprofen with determinations of formulation factors using various grades and types of polymer Ethocel i.e. Ethocel
Standard 10P; 10FP, 100P and100FP for their release rates and release patterns in suitable media and also the mechanism
involved in the release of drug from the matrices. The effect of several co-excipients was also studied on the drug release
rates and patterns of Ibuprofen from the polymeric matrices. Ibuprofen-Ethocel CR tablets were prepared at three
different D: P ratios i.e. 10:1, 10:2 and 10:3. The effects of co-excipients were studied only in formulations having D: P
ratio of 10:3. In vitro drug release studies of Ibuprofen-Ethocel controlled release matrix tablets were carried out in
phosphate buffer pH 6.8 using Pharma Test Dissolution Apparatus adopting Rotating Basket Method according to USP.
Different kinetic models were applied to the release data of test formulations in order to investigate the release
mechanism of drug from the controlled release matrix tablets. The release patterns of Ibuprofen-Ethocel CR matrices
were compared with reference conventional Ibuprofen tablets and Ibuprofen SR tablets. F2 similarity factor was applied
to the test formulations and reference standard to compare their similarities. The drug formulations studied exhibited
satisfactory release results.

Keywords: Ibuprofen, ethocel premium and fp premium polymers, direct compression, controlled release tablets, release
kinetics, co-excipients.

INTRODUCTION drug to polymer ratio that increases the drug’s release rate
from the cellulose matrices (Ford et al., 1985, Mitchell et
Sustained release and controlled release drug delivery al., 1993, Shekar et al., 2010).
systems have gained great advancement in the world of
medicine in the recent years. The release rate of drug Ibuprofen is a propionic acid derivative and belongs to
from the site of absorption into the systemic circulation is non-steroidal anti-inflammatory drugs commonly known
controlled by the use of polymers in controlled delivery as (NSAIDS). Ibuprofen is used for various chronic
systems and is used mainly in oral preparations such as inflammatory diseases like arthritis, primary
tablets and capsules. The particulate form of these dysmenorrhea and fever etc. Generally Ibuprofen acts as
polymers combines with the particles of the drug and thus vasodilator, causing dilation of coronary arteries and
controls the release rate of the drug from its moiety or some other blood vessels. Ibuprofen is a core medicine in
matrix tablets in a constant manner and for specific time WHO’s “Essential Drugs List” that serves as a list of
period either preferably up to 24 hours. The drug plasma minimum medical needs for a basic health care system
level is maintained to an optimum range in controlled (WHO Essential Drugs List, 2006).
drug delivery systems so as to reduce the toxicities (Vert
et al., 1991). MATERIALS AND METHODS

The drug release rate is directly influenced by several Ibuprofen (BDH Chemical Ltd., Pool, England),
factors in controlled drug delivery systems that are monobasic potassium phosphate, NaoH, CMC, HPMC,
directly related to both physical and chemical properties Starch (Merk, Germany), Ethocel Standard 10 and 100 P
of the drugs and its dosage form. These factors are mainly and FP premium, Methocel KM100 Premium EP (Dow
polymers associated and show a tremendous influence in Chemical Co., Midland, USA), Pharma Test Dissolution
drug release from the polymeric tablets. These factors Apparatus (D 63512, Hainburg, Germany), UV-Visible
include polymer’s amount used, its molecular weight, Spectrophotometer (Shimadzu, Japan), Hardness Tester
particle size and concentration. The most important (TB24, Germany), Friability Tester (Erweka TA3R,
amongst these is the concentration of polymer and the Germany).

*Corresponding author: e-mail: [email protected]

Pak. J. Pharm. Sci., Vol.25, No.4, October 2012, pp.751-756 751
Formulation Development and Investigation of Ibuprofen

Standard calibration curve of Ibuprofen Development of Ibuprofen CR tablets

For standard curve of Ibuprofen, first of all stock solution As given in Table 2, 200 mg of Ibuprofen tablets with
was prepared by taking 20 mg of Ibuprofen in 100 ml several types and grades of Ethocel (Ethocel Standard 10
solvent (phosphate buffer pH 6.8) in a volumetric flask. and 100 Premium and FP Premium) were developed at
The drug was dissolved in the solvent by ultra sonifier. several drugs to polymer ratios i.e. 10:1, 10:2 and 10:3. In
Four different dilutions were prepared of the stock this formulation Lactose was used as a filler and
solution (0.1 mg/ml) having concentrations, 0.05 mg/ml, magnesium stearate was used a lubricant. Co-excipients
0.025 mg/ml, 0.0125 mg/ml and 0.0062 mg/ml were added to several formulations to see their effect on
respectively. These prepared dilutions were then analyzed drug release rates from polymeric tablets. The
by UV-Visible Spectrophotometer (Shimadzu, Japan) at formulations having co-excipients, 30% of the filler was
264 nm. The values of absorbance are given in table 1 replaced by three co-excipients CMC, HPMC and Starch.
below. The values of absorbance were plotted against To develop CR tablets of Ibuprofen, the polymer and drug
concentrations and a slope was developed as given in were mixed using pestle and mortar and filler was added
fig. 1. to this mixture. The mixture was passed through 30 mm
sieve. After sieving lubricant was added to the sieved
Table 1: Concentration vs Absorbance of Ibuprofen mixture and was again passed through the same mesh
S. No. Concentration Absorbance screen twice. The final mixture was compressed to tablets
1. 0.1 mg/ml 0.567 by single punch machine (Erweka AR100, Germany).
2. 0.05 mg/ml 0.277
3. 0.025 mg/ml 0.125 Physical characterization
4. 0.0125 mg/ml 0.0626 After the compression of Ibuprofen CR tablets, they were
5. 0.00625 mg/ml 0.0312 evaluated for physical tests including hardness, friability,
dimensional and disintegration tests. The hardness tests
were performed by Hardness tester (TB24, Germany).
Friability of the tablets was performed by Friability Tester
(Erweka TA3R, Germany). All the tablets were evaluated
for disintegration tests by using Disintegration Apparatus
(Hainburg, Germany). The dimensional tests were
performed with the help of vernier caliper.

In vitro release studies and the drug release kinetics

Pharma Test Dissolution Apparatus (D 63512, Hainburg
Germany) was used for the in vitro drug release studies of
Ibuprofen. The method adopted for in vitro release studies
Fig. 1: Standard curve of Ibuprofen. was USP Method-1 (Rotating Basket Method), using

Table 2: Formulation of 200 mg CR tablets of Ibuprofen

D:P Ratio Drug Polymer Filler ( Lactose) Lubricant Co-excipients
200 mg Ibuprofen -Ethocel matrices
10 Premium
0.5 %
10 FP Premium
10:1 100mg 10 mg 89 mg ------
100 Premium
1 mg
100 FP Premium
10 Premium
10 FP Premium
10:2 100mg 20 mg 79 mg 1 mg ------
100 Premium
100 FP Premium
10 Premium
10 FP Premium
10:3 100 mg 30 mg 69 mg 1 mg ------
100 Premium
100 FP Premium
200 mg Ibuprofen -Ethocel matrices having Co-excipients ( CMC, HPMC, Starch)
10 Premium
0.5 % 30 % of filler
10:3 100mg 10 FP Premium 30 mg 48.3 mg
100 Premium & FP 1 mg 20.7 mg
752 Pak. J. Pharm. Sci., Vol.25, No.4, October 2012, pp.751-756
 Syed Umer Jan et al.

phosphate buffer pH 6.8 as a dissolution solvent. ± 0.19 kg/cm2 which were within the USP range (5-10
Temperature of the dissolution solvent was maintained at kg/cm2). The average thickness of the tablets was 2.595 ±
a constant temperature of 37± 0.1ºC and rotating speed of 0.002 mm which was also within the USP limits (2-4
the baskets was kept constant at 100 rpm. At specific time mm). The average friability of all the formulations were
intervals, samples were withdrawn from the dissolution 0.133% ± 0.016 which was also within the USP limits
solvent and were immediately replaced by fresh solvent (< 0.8%). In order to find out the release mechanism of
which was already stored at the same temperature. The drug from the CR tablets, the in vitro release profiles were
samples were filtered through membrane filters and were fitted in five different kinetic models as mentioned above.
analyzed by using UV spectrophotometer at 264 nm to In these kinetic models the Korsmeyer Pappas equation
calculate their absorbances. These absorbances were fitted best fits the dissolution data. In Korsmeyer Pappas
in regression line equation obtained from the standard equation an (n) value demonstrates the way by which the
calibration curve and the concentration of drug dissolved drug is released from the matrix tablets. The value of (n)
in the solvent was calculated. greater then 0.5 shows that the drug is released from the
matrix tablets by non-Fickian, diffusion or nearly Zero
Drug release kinetics for matrix tablets of each order release mechanism. The in vitro study results of all
formulation was calculated by the following five kinetic the Ibuprofen CR formulations with/without co-excipients
models. showed that the (n) value was greater then 0.5 which
clearly indicate the diffusion a non-Fickian or nearly Zero
order release mechanism.
Zero-order Kinetics W=K1t (Xu and Sunada, 1995) (1)

First-Order Kinetics In (100-W)= In100 – K2t (2) As shown in fig 2, the release of drug from the test
formulations were significantly reduced thus extends the
(Xu and Sunada, 1995) release profiles of the drug. The time of drug release was
Higuchi-Kinetics W=K4t1/2 (Higuchi T, 1963) (3)
extended up to 16 hours of Ibuprofen with Ethocel
standard Premium polymers i.e. Ethocel standard 10 and
Hixson-Crowell (100-W)1/3= 1001/3- K3t (Xu and (4) 100 Premium at a drug to polymer ratio of 10:1, but in
Kinetics Sunada, 1995) case of Ibuprofen with FP Premium grades of Ethocel
(Ethocel standard 10 and 100 FP Premium) the effect was
Korsmeyer-Peppas Mt/M ∞=K5 tn (Ritger and (5) more prominent and a cumulative release was up to 80%.
Equation Peppas, 1987) This could be due to the fine particle size of FP grades of
Ethocel which delays the release of drug from polymeric
Where k1-k4 = drug release constant, W = percent release tablets which confirms the findings of (Khan and Zhu,
of drug at time t, Mt/M∞ = fractional release of drug into 2001 and Jan et al., 2011 and 2012) in which similar
dissolution solvent and N = diffusion exponent which results were found. Similarly when Ibuprofen was
shows the mechanism of drug release from the matrix formulated with various grades and types of Ethocel at a
tablets. drug to polymer ratio of 10:2, the release of drug was
more reduced as compared to formulations with D: P ratio
Similarity factor f2 of 10:1 and more then 90% of the drug was released in 19
Similarity factor f2 was adopted by FDA Center for Drug hours for Ibuprofen formulations with Premium grades of
Evaluation and Research (CDER, 1997) to compare Ethocel and 75% drug was released from Ibuprofen
different dissolution profiles. Its value ranges between 50 formulations with FP grades of polymer. This effect of
and 100, the values smaller then 50 shows dissimilarity could be due to the reason that increasing the
between the different dissolution profiles. concentration/amount of polymer in drug to polymer
ratios reduces the drug release and extends the time of
f2 = 50Log {[1+1/n Wt ∑nt=1 (Rt-Tt) 2] -0.5 ×100} drug release. Similar extension of drug release time was
found in Ibuprofen-polymer CR formulations prepared at
Where n = number of pull points, Wt = optional weight D:P ratio of 10:3 in which the commutative drug release
factor, Rt = reference profile at time (t) and Tt = test from Ethocel Premium matrices were found to be 98% in
profile at same time t. 24 hours of time duration and 64% drug release was
found in formulations with FP Premium matrices. The
comparative release profiles of Ibuprofen-Ethocel
RESULTS matrices prepared at D: P ratio 10:2, release profiles of
reference standard (conventional Ibuprofen immediate
All the tablets were evaluated for physical appearance and release tablets) and Ibuprofen SR tablets are given in fig 5
tests and were found to be with in the USP limits. The bellow.
physical appearance was smooth and fair and was shiny.
The average hardness of all the test formulations was 6.63

Pak. J. Pharm. Sci., Vol.25, No.4, October 2012, pp.751-756 753

Formulation Development and Investigation of Ibuprofen

DISCUSSION
Effect of co-excipients on drug release profiles
The effect of several co-excipients was elucidated on
Ibuprofen-Ethocel CR formulations with D:P ratio of 10:3
in order to obtain desirable properties and release profiles.
These co-excipients include CMC, HPMC and Starch. Fig
6 shows the effect of CMC on the release profiles of
Ibuprofen from controlled release matrix tablets. It could
be observed that the addition of CMC to CR formulations
enhances the release of drug from the formulations
irrespective whether the formulation is with Premium
Fig. 2: Release profile of Ibuprofen from Ethocel standard grade of Ethocel or FP grade of Ethocel. The drug from
10P;10FP,100P,100FP at D:P ratio of 10:1. CR formulations with Ethocel Premium polymer was
released in 8 hrs instead of 24 hrs and following the same
patterns the release of drug from Ethocel FP formulations
was in 10 hrs. This effect could be due to the reason that
when formulations with CMC are exposed to water then
the CMC absorbs water from the external surroundings
and become swallowed and the internal osmotic pressure
is increased due to which the tablets bursts and release the
drug into the surroundings. The addition of HPMC and
Starch to the CR formulations also enhances the release of
drug from the CR formulations which could be observed
from the figs. 6, 7, 8 and 9. Starch and HPMC are also
Fig. 3: Release profile of Ibuprofen from Ethocel standard water swell able excipients in nature thus leads to the
10P;10FP,100P,100FP at D:P ratio of 10:2. rupturing of dosage form on exposure to water and
releasing the drug loaded on them (Khan and Zhu,
2001and Shefaat Ullah Shah et al.,2011 and 2012).

Fig. 4: Release profile of Ibuprofen from Ethocel standard

10P;10FP,100P,100FP at D:P ratio of 10:3.
Fig. 6: Release profile of Ibuprofen from Ethocel standard
10 Premium at D:P ratio of 10:3 containing co-excipients
CMC, HPMC and Starch.

Fig. 5: Comparative release profiles of Ibuprofen from

Conventianal formulation, Ibuprofen SR tablet and Fig. 7: Release profile of Ibuprofen from Ethocel standard
Ethocel standard10P;10FP,100P,100FP at D:P ratio of 10FP Premium at D:P ratio of 10:3 containing co-
10:2. excipients CMC, HPMC and Starch.
754 Pak. J. Pharm. Sci., Vol.25, No.4, October 2012, pp.751-756
 Syed Umer Jan et al.

Ibuprofen CR tablets
S. D:P Co- F2
with different grades of
No Ratio excipients values
Ethocel
5 Ethocel 10 Premium 10:2 - 44.76
6 Ethocel 10FP Premium -do- - 46.99
7 Ethocel 100 Premium -do- - 44.58
Ethocel 100FP
8 -do- - 45.78
Premium
9 Ethocel 10 Premium 10:3 - 44.78
10 Ethocel 10FP Premium -do- - 43.99
11 Ethocel 100 Premium -do- - 43.71
Ethocel 100FP
12 -do- - 46.65
Premium
Fig. 8: Release profile of Ibuprofen from Ethocel standard 13 Ethocel 10P Premium -do- CMC 59.08
100 Premium at D:P ratio of 10:3 containing co- 14 Ethocel 10FP Premium -do- CMC 58.98
excipients CMC, HPMC and Starch. 15 Ethocel 100P Premium -do- CMC 59.45
Ethocel 100FP
16 -do- CMC 58.19
Premium
17 Ethocel 10P Premium -do- HPMC 66.66
18 Ethocel 10FP Premium -do- HPMC 66.88
19 Ethocel 100P Premium -do- HPMC 66.91
Ethocel 100FP
20 -do- HPMC 64.90
Premium
21 Ethocel 10P Premium -do- Starch 64.98
22 Ethocel 10FP Premium -do- Starch 65.67
23 Ethocel 100P Premium -do- Starch 65.35
Ethocel 100FP
24 -do- Starch 64.96
Premium

Fig. 9: Release profile of Ibuprofen from Ethocel standard CONCLUSION

100FP Premium at D:P ratio of 10:3 containing co-
excipients CMC, HPMC and Starch. The results obtained from the different parameters of
Ibuprofen-Ethocel controlled release matrix tablets
Similarity factor f2 showed that the investigated types and grades of polymer
The f2 similarity factor was applied to all the test Ethocel could be successfully used to prepare rate
preparations and was compared with reference standard controlled matrix tablets of Ibuprofen. This investigative
formulation which was obtained from the local market as study also showed that the FP Premium grades of polymer
Ibuprofen SR tablet. In comparing the release profiles of Ethocel could more efficiently extend the drug release
test formulations with reference standard, the values of profiles as compared to Premium grades of Ethocel. The
CR formulations without co-excipients were less then 50 three co-excipients successfully enhanced the drug release
(range 50-100) which clearly indicates the difference in profiles with CMC being the more efficient co-excipient
the release profiles of test with that of reference standard in nature.
formulations, while the values for the formulations with
co-excipients were larger then 50 which indicates that the REFERENCES
release profiles of test formulations have resemblance
with that of reference standard because the reference Centre for Drug Evaluation and Research (1997). US
standard was an SR formulation. The values of f2 Department of Health and Human Services, Food and
similarity factor are given in table 3. Drug Administration. Guidance for Industry:
Table 3: F2 values applied to CR tablets of Ibuprofen- Dissolution Testing of Immediate Release Solid Dosage
Ethocel. Forms.
Ford JL, Rubenstein MH and Hogan JE (1985).
S.
Ibuprofen CR tablets
D:P Co- F2
Formulation of sustained release promethazine hydro-
with different grades of chloride tablets using hydroxypropylmethylcellulose
No Ratio excipients values
Ethocel matrices. Int. J. Pharm., 24: 327-338.
1 Ethocel 10 Premium 10:1 - 45.07 Higuchi T (1963). Mechanism of Rate of Sustained-
2 Ethocel 10FP Premium -do- - 46.12 Action Medication. Theoretical Analysis of Rate of
3 Ethocel 100 Premium -do- - 43.56 Solid Drugs Dispersed In Matrices. J. Pharm. Sci., 52:
Ethocel 100FP
4 -do- - 45.55 1145-1149.
Premium

Pak. J. Pharm. Sci., Vol.25, No.4, October 2012, pp.751-756 755

Formulation Development and Investigation of Ibuprofen

Jan SU, Khan GM, Khan KA, Rehman A and Khan H vitro evaluation of ofloxacin-ethocel controlled release
(2011). In vitro release pattern of Ketoprofen using matrix tablets prepared by wet granulation method:
ethyl cellulose ether derivatives. J. Appl. Pharm., Influence of co-excipients on drug release rates. Pak. J.
Pharm. Sci., 24(3): 255-261.
01(03): 149-158.
Shah SU, Khan GM, JAN SU, Shah KU, Hussain A,
Jan SU, Khan GM, Khan H, Rehman A, Khan KA, Shah Khan H and Khan KA (2012). Development of novel
SU, Shah KU, Badshah A and Hussain I (2012). diclofenac potassium controlled release tablets by wet
Release pattern of three new polymers in Ketoprofen granulation technique and the effect of co-excipients on
controlled-release tablets. Afr. J. Pharm. & Pharmacol., in vitro drug release rates. Pak. J. Pharm. Sci., 25(1):
6(9): 601-607. 161-168.
Khan GM and Zhu JB (2001). Evaluation of Ethocel Shekar BC, Kiran RS and Babu BN (2010). Design and
Premium ethyl cellulose derivatives with different evaluation of sustained release monolithic matrix
molecular weighs as controlled release matrix forming tablets of tramadol hydrochloride. IJPI, 1(1): 1-11.
functional polymers for Ibuprofen. The Sciences, 1: Vert M, Li S and Garreau H (1991). More About the
361-367. Degradation of LA/GA-derived Matrices in Aqueous
Mitchell K, Ford JL, Armstrong DJ, Elliot PNC, Hogan Media. J. Control. Release, 16: 15-26.
JE and Rostron C (1993). The influence of substitution WHO (2006). Model List of Essential Medicines (PDF).
type on the performance of methyl cellulose and World Health Organization. March 2005.
hydroxy propyl methyl cellulose in gels and matrices. http://whqlibdoc.who.int/hq/2005/a87017_eng.pdf.
Int. J. Pharm., 100: 143-154. Retrieved 2006-03-12. Acessed at 12 December, 2010.
Ritger RL and Peppas NS (1987). A simple equation for Xu GJ and Sunada H (1995). Influence of formulation
disposition of solute release II: Fickian and anomalous changes on drug release kinetics from hydroxypropyl
release from swellable devices. J. Control Release, 5: methylcellulose matrix tablets. Chem. Pharm. Bull., 43:
37-42. 483-487.
Shah SU, Shah KU, JAN SU, Ahmad K, Rehman A,
Hussain A and Khan GM (2011). Formulation and in

756 Pak. J. Pharm. Sci., Vol.25, No.4, October 2012, pp.751-756