Download formulation, evaluation and in vitro dissolution performance of

Acta Poloniae Pharmaceutica ñ Drug Research, Vol. 73 No. 4 pp. 1037ñ1043, 2016
ISSN 0001-6837
Polish Pharmaceutical Society
FORMULATION, EVALUATION AND IN VITRO DISSOLUTION
PERFORMANCE OF ENALAPRIL MALEATE SUSTAINED RELEASE
MATRICES: EFFECT OF POLYMER COMPOSITION AND VISCOSITY GRADE
AAMNA SHAH1, GUL M. KHAN2, HANIF ULLAH3, KAMRAN AHMAD KHAN1,
KALEEM ULLAH3 and SHUJAAT A. KHAN3*
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, Dera Ismail Khan, Pakistan
2
Department of Pharmacy, Quaid-i-Azam University, Islamabad, Pakistan
3
Department of Pharmacy COMSATS Institute of Information Technology, Abbottabad 22060, Pakistan
1
Abstract: The present study aimed at developing the sustained release matrix tablets of enalapril maleate and
evaluating the effect of polymer concentration and viscosity grade on drug release. The sustained release
enalapril maleate tablets were successfully formulated by direct compression method using nonionic cellulose
ethers HPMC K15, HPMC K100 and HPC polymers either alone or in combination. In-vitro drug release study
was carried out in phosphate buffer (pH 6.8) for a period of 24 h following USP dissolution apparatus II i.e.,
paddle apparatus. Model dependent approaches like zero-order, first order, Higuchiís model and KorsmeyerPeppas model were used to assess drug release from various formulations. All the three polymers alone or in
combination sustained the drug release. The drug release characteristics from HPMC and HPC polymer followed zero order release kinetics except for 45% concentration of all polymers alone or in combination where
by the drug release followed Higuchiís model. In all cases, the drug release mechanism was both diffusion as
well as erosion.
Keywords: enalapril maleate, HPMC, HPC, sustained release, viscosity grades
Different types of sustained release (SR) formulations have been formulated for improving clinical efficacy of active pharmaceutical ingredients
(APIs) and patient compliance. The SR oral dosage
forms have been documented for improvement in
therapeutic efficacy and maintenance of steady state
plasma concentration of drug (1). Nonionic cellulose ethers and hydroxypropylmethyl cellulose
(HPMC) have been extensively considered for the
purpose of formulating oral SR formulations. Such
hydrophilic and water soluble polymers are wellliked due to their broad regulatory acceptance, cost
effectiveness and flexibility in order to get a desired
drug release profile (2). HPMC always finds preference in formulation of hydrophilic matrices due to
cost effectiveness, choice of viscosity grades, nonionic nature, robust mechanism and utilization of
existing conventional equipment and methods (3). It
has been most extensively employed as a gel forming agent in the formulations of controlled release,
semisolid, liquid and solid dosage forms. Variation
in viscosity grades, polymer concentration and the
addition of various excipients to the matrices can
alter the release of drug (4).
HPC is used as film coating agent or tablet
coating agent at a 5% (w/w) concentration.
Similarly, HPC in a concentration of 15-35% (w/w)
is used for the preparation of SR, controlled release
(CR) and extended release (ER) dosage forms.
Additionally HPC in a concentration of 2-6% is used
as tablet binder in both dry and wet granulation
processes used for tablet manufacturing (5).
Enalapril is angiotensin-converting enzyme
(ACE) inhibitor that is administered orally. It undergoes in vivo hydrolysis to form its bioactive metabolite. Biotransformation most likely takes place in the
liver. Biotransformation beyond bio-activation is
not observed in human (6). Enalapril maleate (EM)
is considered as effective candidate for SR dosage
forms due to its gastric absorption, high water solubility and shorter half-life (7). Foods do not affect its
bioavailability. It is primarily excreted through renal
* Corresponding author: e-mail: [email protected]
1037
1038
AAMNA SHAH et al.
route. It reduces blood pressure (BP) by lessening
systemic vascular resistance. The reduction in BP is
not associated with reflex tachycardia. Moreover,
there is slight increase in cardiac output without any
impairment in cardiovascular reflexes (8).
Direct compression (DC) is the most inexpensive, fast, and simple method for the preparation of
SR tablet formulations (9). Moreover, it does not
change the physical nature of the drug. It is most
commonly used in the formulation of crystalline
powders due to good cohesive properties (10). DC
can be effectively used for drugs sensitive to moisture and humidity as this technique do not require
water and any other solvent (9).
MATERIALS AND METHODS
Materials
Disodium hydrogen orthophosphate and potassium dihydrogen phosphate were procured from
Guideís Corporation (Pvt.), Ltd., Islamabad.
Sodium hydroxide and hydrochloric acid (37%) was
purchased from Merck, Germany, EM was supplied
as a gift by Warrick Pharmaceuticals, Islamabad.
Lactose and magnesium stearate were procured
from BDH Chemical Ltd., England. PVP K-30,
Talc, AvicelÆ (PH-102 and PH-200) were procured
from Guideís Corporation (Pvt.) Ltd., Islamabad.
Moreover, Methocel K100M Premium, Methocel K
15 and HPC (Dow Chemicals Co. Midland USA)
were supplied as a gift by Allied Pharmaceuticals,
Islamabad. All the chemicals were used as such
without any further purification.
Compositions and preparation of enalapril
maleate matrix tablets
SR matrix tablets of EM were formulated using
Methocel K15, Methocel K100 and HPC in different
drug to polymer ratio i.e., D : P ranging from 4 : 3 to
4 : 10. Moreover, they were also used concomitantly in some formulations and their combined effect
on drug release profile was observed. Lactose MH
and Lactose SD, Avicel 102 and 200, magnesium
stearate, talcum powder and PVP K-30 were used as
excipients. Formulations pattern using HPMC K15,
HPMC K100 and HPC alone or in combination are
shown in Table 1.
Direct compression technique was used for the
preparation of tablets. This method is used for drugs
or substances with crystalline form and having good
cohesive and compressibility properties. For tablet
preparation Methocel K-15, Methocel K-100M premium and HPC were used as polymers. In this
method drug, polymer and all the excipients except
magnesium stearate were thoroughly mixed with
one another and geometrically blended in pestle and
mortar for 5-10 min. The mixture was passed
through sieve number 24 followed by addition of
magnesium stearate and mixed for 2 min. Again, the
mixture was passed through sieve number 24. The
powder mixture was compressed using rotary tableting machine (ZP-19, Lahore, Pakistan). Eight mm
flat punches were used for tablet preparation. The
batch size selected for each formulation was 300
tablets while the compression weight was 200 mg
per tablet. The compositions of all formulations are
shown in Table 1.
Table 1. Compositions of various formulations (F1-F12).
Composition (mg) per tablet (200 mg)
Code
HPC
Methocel
K15
Methocel
K100
Drug :
Polymer
Lactose
Drug
Talc
Magnesium
stearate
PVPK30
F1
30
--
--
4:3
92.68
52.32
10
5
10
F2
60
--
--
4:6
62.68
52.32
10
5
10
F3
90
--
--
4:9
32.68
52.32
10
5
10
F4
--
30
--
4:3
92.68
52.32
10
5
10
F5
--
60
--
4:6
62.68
52.32
10
5
10
F6
--
90
--
4:9
32.68
52.32
10
5
10
F7
--
--
30
4:3
92.68
52.32
10
5
10
F8
--
--
60
4:6
62.68
52.32
10
5
10
F9
--
--
90
4:9
32.68
52.32
10
5
10
F10
10
10
10
4:3
92.68
52.32
10
5
10
F11
20
20
20
4:6
62.68
52.32
10
5
10
F12
30
30
30
4:9
32.68
52.32
10
5
10
1039
Formulation, evaluation and in vitro dissolution performance of
Table 2. Mathematical models applied to formulations.
Kinetic model
Zero-order kinetics
W = k1 t
Higuchi kinetics
W = k2 t1/2
First order kinetics
ln (100 - W) = ln 100 ñ k3 t
Korsmeyer-Peppas equation
Mt / M8 = k4 tn
Table 3. Physical properties of formulations.
Formulation
Weight (mg)
Thickness (mm)
Friability (%)
Hardness (kg/cm2)
Average
SD (±)
Average
SD (±)
Average
SD (±)
F1
203.6
2.836
3.0
0.07
0.19
8.1
0.152
F2
203.2
3.553
3.1
0.05
0.17
7.5
0.217
F3
202.3
2.584
3.3
0.07
0.15
6.8
0.295
F4
202.8
2.44
3.3
0.05
0.25
8.9
0.109
F5
203.4
3.627
3.5
0.07
0.19
7.7
0.336
F6
203.2
3.293
3.6
0.07
0.13
6.4
0.179
F7
203.7
3.860
3.4
0.09
0.11
7.1
0.123
F8
202.8
2.440
3.6
0.04
0.08
6.6
0.152
F9
202.8
3.293
3.7
0.07
0.04
5.4
0.144
F10
202.3
2.214
3.5
0.08
0.13
7.6
0.219
F11
204.6
3.718
3.6
0.07
0.10
6.4
0.192
F12
202.8
3.327
3.7
0.08
0.08
5.6
0.261
Physical evaluation of prepared formulations
After tablet preparation, tablets were evaluated
by applying various official tests according to USP.
Dimensional test which was applied on tablets
include thickness, while the QC test include weight
variation, friability and hardness test. For weight
variation test, 20 tablets were taken and weighed
individually using the electronic weighing balance
(AX-120, Shimadzu, Japan). Then, average weight
of all the 20 tablets was calculated. According to
USP, the individual weight of not more than 2
tablets should vary from average weight by not more
than 5%. For hardness test, 10 tablets were selected
randomly and their hardness/average breaking
strength was tested using the hardness tester (PTB3112, Germany). USP acceptable limit of hardness
is 5-10 kg/cm2. For friability test, 10 pre-weighed
tablets were taken and placed in friabilator (FB0606, Curio, Lahore, Pakistan). The friability apparatus was turned on for 100 revolutions at 25 rpm
and the tablets were weighed again. The % friability
was then calculated using the equation:
W1 ñ W2
Friability (%) = ñññññññññ
× 100
(1)
W1
USP limit of friability is less than 0.8% w/w.
For dimensional test, 10 tablets were selected randomly for checking tablet thickness using the digital
Vernier caliper (China). The USP acceptable range
for thickness is 2-4 mm for the tablets having diameter of 4-13 mm.
In vitro drug release studies
In vitro drug release test of controlled release
matrix tablets of EM was performed on prepared
tablets in accordance with the ìDissolution
Procedureî described by USP applying Apparatus 2
and involving use of Paddle Dissolution System.
Pharma test dissolution apparatus (DT/7-13372,
Germany) was used for the study. Phosphate buffer
solution of pH 6.8 was used as dissolution medium.
Volume of the medium was 900 mL, temperature
was maintained at 37 ± 1OC while rotating speed of
paddles was 50 rpm. The test was performed on six
tablets from each batch. The drug release pattern
was evaluated by taking 5 mL samples at specific
time interval of 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 18
and 24 h. The samples collected were filtered
through Whatman filter paper or through filter mem-
1040
AAMNA SHAH et al.
brane having pore size of 0.45 µm and then analyzed
with UV-visible spectrophotometer (7200, Cecil,
England) at λmax of 206 nm. The analysis of dissolution data was performed using various kinetic models i.e., zero order release kinetics, first order release
kinetics, Higuchi and Korsmeyer-Peppas models.
Drug release kinetics
The data obtained from the dissolution studies
were fitted into the mathematical models shown in
Table 2.
In these equations, ëWí represents the percent
drug released at time ëtí compared with total amount
of drug present in tablets. k1, k2 and k3 are rate constants depending upon the models. Mt/M∞ designates
fractional drug release form the matrix tablet into
the dissolution medium. Diffusion exponent ëní
characterizes the release mechanism of drug. The
mechanism of drug release was elucidated by calculating the value of ëní from the dissolution data
obtained from the initial 60% release. If the ëní
value is greater than 0.43 and less than 0.85 then,
release of drug is anomalous or non-Fickian, while
if value of ëní is greater than 0.85 then, in that case
release kinetics is super case-II transport.
RESULTS
Physical evaluation of prepared formulations
The weight variation test was performed for all
formulations (F1-F12) and results were found to be
in the range of 202.3 ± 2.584 mg to 204.6 ± 3.718
mg (Table 3). No tablet deviate from the official
limit, which is 5% for 200-250 mg tablet. Thus, all
formulations were within limits and passed the
weight variation test. The friability tests performed
for the formulations (F1-F12), were in the range of
0.04 to 0.25%, which fall within the limit of standard (less than 0.8%). The thickness was carried out
according to the procedure. The thickness of the
tablets ranges from 3.0 ± 0.07 to 3.8 ± 0.08 mm. The
hardness for all formulations ranged from 5.6 ±
0.261 to 8.1 ± 0.154 kg/cm2, which showed that
hardness was within the limits.
The release profile from SR tablet matrices of
EM using different polymers i.e., HPMC K100,
HPMC K15 and HPC in varying drug to polymer
ratio are shown in Figure 2. As shown in Figure 2,
the release profile for formulation (F1) with 15% of
HPC was extended to about 99% of drug in 12 h.
The drug release was found to be about 91% for
Figure 1. Physical properties of formulations F1-F12: A. Weight (mean ± SD), B. Thickness (mean ± SD), C. Friability (%), D. Hardness
(mean ± SD)
1041
Formulation, evaluation and in vitro dissolution performance of
Table 4. Drug release kinetics.
Determination coefficient (R2)
Zero-order
First-order
Higuchi
Korsmeyer-Peppas
Value of n for
Korsmeyer-Peppas
F1
0.905
0.803
0.778
0.966
0.638
F2
0.959
0.702
0.877
0.94
0.838
F3
0.942
0.664
0.982
0.99
0.903
F4
0.951
0.749
0.846
0.988
0.741
F5
0.985
0.541
0.947
0.987
0.833
F6
0.917
0.681
0.982
0.994
0.95
F7
0.959
0.68
0.862
0.966
0.765
F8
0.982
0.724
0.978
0.973
0.862
Formulation
F9
0.91
0.772
0.978
0.973
0.994
F10
0.981
0.566
0.926
0.99
0.843
F11
0.984
0.789
0.984
0.984
0.933
F12
0.96
0.821
0.995
0.941
0.855
Figure 2. Drug release profile of all formulations (F1-F12)
30% (F2) and 72% for 45% of HPC (F3) in 12 h,
respectively.
In case of HPMC K15, the formulation with
15% of HPMC K15 (F4) extended drug release
and about 99% of drug was released in about 12 h.
Therefore, for obtaining further extended release
profile, the concentration of polymer was
increased and proportional decrease in percent
drug release was observed. The formulation with
30% (F5) and 45% of HPMC K15 (F6) released
about 88% of drug and 62% of drug in 12 h,
respectively.
Similarly, the formulation with 15% of HPMC
K100 (F7), the release profile was extended, however, the release extent was higher than the desired
results and about 96% of drug release was observed
in about 12 h. And the formulation with 30% of
HPMC K100 (F8) released about 77% of drug in 12
1042
AAMNA SHAH et al.
h. The formulation with 45% of HPMC K100 (F9)
released 55% of drug in 24 h.
When assessed combination of all the three
polymers in equal ratios, the drug release in 12 h,
was 92, 72 and 52% for 15, 30 and 45% of polymers
blend, respectively. Moreover, the polymer blend
retarded the drug release more efficiently than that
of polymer used alone in the same corresponding
ratios (15, 30 and 45%).
The release rate of drug was reduced significantly when HPMC K100, HPMCK 15 and HPC
were used in combination.
Drug release kinetics
Table 3 represents the results of in vitro drug
release kinetic models applied to the sustained
release matrix tablets of EM using HPMC K15,
HPMC K100, HPC and all these three polymers in
combination. Drug release from HPC, HPMC K15
and HPMC alone as well as in combination followed
zero order at concentration of 15% and 30%, whereas at concentration of 45% all three polymers alone
or in combination followed Higuchiís model. The
value of ëní in Korsmeyer-Peppas equation was
observed to be greater than 0.45 for all the prepared
formulation which indicates that all the formulations
were exhibiting non-Fickian or anomalous drug diffusion. The drug release mechanisms followed by all
formulations was found to be the combination of two
mechanisms i.e., diffusion and erosion (Table 4).
DISCUSSION
In order to mimic the physiological conditions
of lower GIT, all the formulations were subjected to
drug release studies in phosphate buffer (pH = 6.8)
for 24 h. HPMC K100 showed more efficient drug
release retardant property than HPMC K15 due to
relatively higher viscosity, good gelling characteristics and strong linking capacity of HPMC K100.
Furthermore, the slow release profile observed with
combination of polymers may be due to the high
concentration of polymers, high viscosity, strong
cross linking and high molecular weight achieved.
The swelling of matrix tablets were detected
during the dissolution process. HPMC is well
known for swelling controlled release mechanism
and hydrophilic drug are released from this polymer
by diffusion process (2). The hydration of polymer
is the reason for swelling of tablets. Glass transition
temperature of the polymer is reduced as compared
to the temperature of the dissolution medium due to
swelling of the tablets. The dissolution solvent
exerts stress on the polymeric chains due to which
there occurs relaxation effect within polymeric
chains. This relaxation effect, in turn, increases distance among the polymeric chains. In hydrated
polymer the molecular volume of polymer is
increased that reduces the free volume due to the
presence of microspores, which is observed clearly
as shift in the drug release mechanism. Other
researchers also observed similar type of results in
their studies (11).
In all cases, an increase in polymer concentration retarded the drug release from the matrices.
This might be due to the reasons that an increase in
the concentration of polymer and drug to polymer
ratio lags the release of drug while reducing the
amount of polymer and D : P ratio enhance the drug
release from the polymeric matrices (11).
Moreover, an increase in concentration and/or
viscosity grade of polymer may lead to an increase
in gel viscosity upon absorption of water, which acts
as a barrier to diffusion that, in turn, may lead to a
decrease of the diffusion coefficient. Thus, the drug
release may be retarded. The gel barrier also provides hindrance to the penetration of water thus preventing the wetting of tablet core. Consequently, the
tablet disintegration is hindered, which further sustains the drug release (12).
CONCLUSION
The SR tablet matrices of EM were successfully formulated using HPC and different viscosity
grades of HPMC. As evident from in vitro drug
release studies, the drug release was retarded by
increasing viscosity grade or quantity of polymer as
well as changing the type of polymer. The findings
of this study obviously documented that matrix
tablets of HPC and HPMC are a promising and effective drug delivery tool for once daily administration
of enalapril maleate. The analysis of the release profiles in the light of distinct kinetic models led to the
conclusion that the drug release characteristics from
HPMC polymer matrices follows zero order kinetics
except for 45% of all polymers alone or in combination where the drug release was following Higuchiís
model. In all cases, the mechanism of drug release
was both diffusion as well as erosion.
REFERENCES
1. Padhy S.K., Sahoo D., Acharya D., Mallick J.,
Patra S.: Am. J. Pharm. Tech. Res. 3, 689
(2013).
2. Nair A.B., Vyas H., Kumar A.: J. Basic Clin.
Pharmacol. 1, 71 (2010).
Formulation, evaluation and in vitro dissolution performance of
3. Rogers, T.L.: Hypromellose, in Handbook of
Pharmaceutical Excipients. Rowe R.C.,
Sheskey P.J., Quinn M.E. Eds., 6th edn. pp.
326-329, Pharmaceutical Press, London 2009.
4. Tiwari S.B.,Siahboomi A.R.R.: Drug.Deliv.
Tech. 9 (7), 20 (2009).
5. Edge S., Kibbe A.H., Shur J.: Lactose,
Monohydrate, in Handbook of Pharmaceutical
Excipients. Rowe R.C., Sheskey P.J., Quinn
M.E. Eds., 6th edn., p. 364-369, Pharmaceutical
Press, London 2009.
6. Lokesh B.V.S., Naidu S.R.: J. Adv. Sci. Art. 2,
34 (2007).
7. Sekhar C.Y., Prasanna V.T., Mohan P.,
Sagarika T.: Int. J. Adv. Pharm. Sci. 1, 308
(2010).
1043
8. Davies R.O., Gomez H.J., Irvin J.D., Walker
J.F.: Br. J. Clin. Pharmacol. 18 (Suppl. 2), 215S
(1984).
9. Gohel M.C., Jogani P.D.: J. Pharm. Pharm. Sci.
8, 76 (2005).
10. Dokala G.K., Pallavi C.: Int. J. Res. Pharm.
Biomed. Sci. 4, 155 (2013).
11. Khan G.M., Zhu J.B.: J. Med. Sci. 1, 361
(2001).
12. Murtaza G., Ullah H., Khan S.A., Mir S., Khan
A.K. et al.: Trop. J. Pharm. Res. 14, 219 (2015).
Received: 18. 08. 2015