formulation and evaluation of dual drug delivery of irbesartan and hydrochlorothiazide with ph ...

16 Pages·2015·0.69 MB·English

WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES
Tanuja et al. World Journal of Pharmacy and Pharmaceutical Sciences
SJIF Impact Factor 5.210
Volume 4, Issue 12, 519-534 Research Article ISSN 2278 – 4357

FORMULATION AND EVALUATION OF DUAL DRUG DELIVERY

OF IRBESARTAN AND HYDROCHLOROTHIAZIDE WITH PH
INDEPENDENT SYSTEM

P. Tanuja1*, R. Shireesh Kiran1, A. Pratyusha, V. Uma Maheswara Rao

Department of Pharmaceutices, CMR College of Pharmacy, Kandlakoya (v), Medchal Road,
Hyderabad – 501401, T.S, India.

ABSTRACT
Article Received on
07 Oct 2015, The main objective of the present study was to formulate and evaluate

Revised on 28 Oct 2015, Dual drug tablets of Irbesartan and Hydrochlorothiazide with pH
Accepted on 17 Nov 2015
independent system by direct compression technique. Irbesartan is an

angiotensin receptor and Hydrochlorothiazide is a diuretic with short

*Correspondence for
half-life (3-4 hrs & 6-14hrs respectively) with a bioavailability of 70-

Author

90% orally. The drugs identity were confirmed by UV spectroscopy.
P. Tanuja
Department of The polymers used to sustain the drug release are Guar gum, Xanthan

Pharmaceutices, CMR gum, HPMC and ethyl cellulose. The compatibility studies between the

College of Pharmacy,
drug and the polymer were studied using the FT-IR spectroscopy and
Kandlakoya (v), Medchal
were found to be compatible. Preformulation parameters like tapped
Road, Hyderabad –
density, bulk density, Carr’s index, Hausner’s ratio, compressibility
501401, T.S, India.
index, angle of repose were studied and the results were found to be
within the limits. Using the above polymers, formulations F1 to F7 were manufactured by
direct compression technique and the tablets were evaluated for their thickness, hardness,
friability, weight variation and content uniformity test. The in vitro drug release studies were
performed in Phosphate buffer of pH 1.2 and 6.8 using USP type-II dissolution apparatus.
From the dissolution studies it was found that F6 formulation was best since it release
minimum amount of drug (6.8%) initially and maximum drug (100%) at the end of 9hrs.The
F6 formulation was subjected to stability studies for about 3months as per ICH guidelines and
found to be stable.
KEYWORDS: Angiotensin receptor; Diuretics; Irbesartan; Hydrochlorothiazide, pH
independent, Dual drug action.
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INTRODUCTION
Irbesartan is an angiotensin receptor blocker (ARB) used mainly for the treatment of
hypertension (Wright.et.al-2007). It competes with angiotensin II for binding at the AT1
receptor subtype. Unlike ACE inhibitors, ARBs do not have the adverse effect of dry cough.
The use of ARBs is pending revision due to findings from several clinical trials suggesting
that this class of drugs may be associated with a small increased risk of cancer.

A thiazide diuretic often considered the prototypical member of this class. It reduces the
reabsorption of electrolytes from the renal tubules. This results in increased excretion of
water and electrolytes, including sodium, potassium, chloride and magnesium. It has been
used in the treatment of several disorders including edema, hypertension, diabetes insipidus,
and hypoparathyroidism (HCTZ-2015).

MATERIAL AND METHODS
Tab. No. 1: Materials.
S.No. Drug/Excipients Source
1 Irbesartan Arthi drugs, Mumbai.
2 Hydrochlorothiazide Arthi drugs, Mumbai
3 HPMC Fmc. USA
4 Citric acid ISP USA
5 Tartaric acid Signet Mumbai
6 Dicalcium phosphate Signet Mumbai
7 Magnesium stearate Signet Mumbai
8 Microcrystalline cellulose pH 102 Weiming Pharmaceuticals

Tab. No.2: Instruments/Equipments.
S.No. Name of the Instrument/Equipment Make
1 Single stroke tablet compression machine Model-CMS, Cadmach
3 Friabilator USP EF-2, Electro Lab
4 Hardness tester Pfizer
5 Digital vernier scale Mitutoyo, Japan
6 Bulk Density apparatus Veego
7 Mettler Balance model-AE-160, Mettler, Switzerland.
8 pH meter Digisun electronics
10 Disintegration tester USP Electro Lab
11 FT-IR model-FTIR-SHIMADZU
12 KBr-Dye Model-15.011, PERKIN-LMER.
13 Dissolution apparatus Model-TDT-06 USP(XXI) sisco.
14 UV spectrophotometer Model-UV-1371

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METHODOLOGY
Preformulation studies
Solubility
A semi quantitative determination of the solubility was done by adding the solute in small
incremental amounts to the fixed volume of the solvent. After each addition, the system is
vigorously shaken and examined visually for the undissolved solute particles. When some
solute remains undissolved the total amount added up to the point served as a good and rapid
estimate of solubility.

Determination of pH and Log P
A 4% W/V solution of Irbesartan was prepared using methanol. The pH of the corresponding
solution was recorded.

Log P
The calculations are based on the structural formulae of compounds the Log P was
determined by using Pallas software.

Determination of densities
Apparent bulk density
The bulk density, was determined by transferring the accurately weighed sample of powder to
the graduated cylinder. The initial volume and weight was noted. Ratio of weight of the
sample was calculated by using the following formulae.
Bulk density = Weight / bulk volume.

Tapped density
Weighed powder sample was transferred to a graduated cylinder and was placed on the tap
density test apparatus, was operated for a fixed number of taps. The tapped density was
determined by the following formula:
Tap density = Weight / Tapped volume.

Percentage compressibility
Based on the apparent bulk density and the tapped density, the percentage compressibility of
the bulk drug was determined by the following:
% Compressibility = Tapped bulk density - Initial bulk density / Tapped density x 100.

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Sieve analysis
10 gm of the drug sample was placed for 10 min on the mechanical sieve shaker. % retained
on the mechanical sieve was analysed.

Moisture content
A 5 gm of the pure Irbesartan was transferred in to an aluminum plate and the moisture was
determined at 600C. The moisture content was determined using sartorins apparatus.

Drug excipient compatibility studies
Compatability of the drug with excipients (HPMC, Dicalcium phosphate, Citric acid, Tartaric
acid and Magnesium stearate) used to produce pH independent formulation was established
by IR spectral analysis.

IR spectral analysis of pure drug, pure drug with the excipients was carried out. This study
was carried out to detect any changes on chemical constitution of the drug after combining it
with the excipient.

The drug and excipients were mixed in a ratio of 1:1 placed in a petri dish and kept in a hot
air oven at 450C for 15 days. The samples were taken for FT-IR study.

Preparation of pH independent formulation
Direct compression
100 mg of the drug and the excipients were passed through sieve # 60, lubricants were added
by geometrical dilution followed by through mixing for 20 min. The prepared mass was
compressed by using 13 mm flat faced punches in a controlled environment to get the
average weight of 270 mg tablets.7 formulations were prepared by using different
concentrations of disintegrants. The compressed formulations were shown in the following
table.

Preparation of matrix tablets
For IR layer (Irbesartan) by direct compression method
Step1: Weigh the all ingredient in required quantity
Step2: Transfer all ingredients into a mortar triturate for 10 minutes until, to get fine powder
and sieve the material. (#60)
Step3: then transfer the material into blender for proper distribution of drug in blend for
10minutes.
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Step 4: then addition of lubricant mix well.
Step5: Perform the micromeritic properties (Precompression studies).
Step 6: Compression.

For SR layer (Hydrochlorthiazide) by wet granulation process All the tablets, each containing
mg of Hydrochlorthiazide were prepared by wet granulation method. The manufacturing
process involves following steps they were
1) Sifting: Drugs, polymers (HPMC K100M&ethyl cellulose) and diluents were sifted
through 40 mesh sieve (stage 1).
2) Binder preparation
3) Granulation

a) Dry mixing: The drug and diluent after stage 1 were mixed well to ensure the
uniformity of premix blend. Several drug –diluent premixes were then mixed with
the selected ratio of polymer (s) previously shifted through sieve no 40 for 5 min.
b) Granulation: Granules were prepared by adding step 2 in step 3a and the wet mass pass
through sieve no.18.
c) Drying: The produced Irbesartan granules were dried at 55°C ± 5°C for 1 hour in a hot-air
oven.
4) Sizing: Dried granules were passed through 20 mesh sieve.
5) Lubrication: These granules were blended with lubrication mixture (magnesium stearate
and talc) for 5min in polythene bag.
6) Compression: After the lubrication granules were compressed using 16 station rotary
tabletting machine, equipped with flat-faced, round punches of 10-mm diameter.

Tab. No:-3. Formulation of the Irbesartan and Hydrochlorothiazide.

Formulation Series
Ingredients (mg) F-1 F-2 F-3 F-4 F-5 F-6 F-7
Irbesartan 50 50 50 50 50 50 50

Hydrochlorothiazide 50 50 50 50 50 50 50
Citric acid - 12.5 25 37.5 - - -
Tartaric acid - - - - 12.5 25 37.5

HPMC 75 75 68.75 62.5 75 68.75 62.5

Dicalcium phosphate 93 80.5 74.25 68 80.5 74.25 68
Magnesium stearate 2 2 2 2 2 2 2
Total 270 270 270 270 270 270 270

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The drug polymer ratio was developed to adjust drug release as per theoretical release profile
and to keep total weight of tablet constant for all the fabricated batches under experimental
conditions of preparations. The total weight of the matrix tablets was with different drug,
polymer ratios like 10%, 15%, 20%, 1:1. The various polymers used were HPMC K100M
and Ethyl cellulose. Diluent like MCC (water-insoluble) was used for the preparation of
matrix tablets.

Evalution of blend and tablets
Bulk density
Apparent bulk density was determined by pouring presieved drug-excipient blend in to
graduated cylinder and measuring the volumeweight ―as it is‖.

Tapped density
It was determined by placing a graduted cylinder, containing a known mass of drug –
excipient blend, on mechanical tapping apparatus, which was operated for a fixed no. of
taps untill the powder bed volume has reached a minimum. Using the weight of a blend in a
cylinder and this volume, the tapped density was computed.

Angle of repose
Angle of repose was determined by using funnel method. Powder was poured from funnel,
that can be raised vertically until a maximum cone height, h, was obtained. Diameter Powder
of heap, D, was measured. The repose angle, θ, was calculated by the formula Tan θ = 2h/D.

Powder flow properties
One of the ways of measurement of free flowing powder is compressibility as computed from
density of the powder. It was calculated by using the formulae.
% Compressibility = (ρ ρ )/ρ
t- o t

Where ρ = Tapped density, ρ = Bulk density.
t o

EVALUATION OF TABLETS
The formulated tablets were evaluated for the following parameters.

Tablet physical appearance
Prepared pH independent tablets were evaluated for smoothness and absence of cracks, chips,
and other undesirable characteristics.
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Weight variation
Twenty tablets were selected from formulated tablets at random and the average weight was
calculated, individual tablet weights were compared with the average weight. Not more than
two individual weights deviate from the average weight by more than the percentage shown
in the table.

Friability
Friability of the tablet was checked by using Roche friabilator. This device Subjects a number
of tablets to the combined effect of the abrasion and shock by utilizing a plastic chamber that
revolves at 25 rpm dropping at a distance of 6 inches with each revolution. Preweighed
samples of tablets were placed in the friabilator, which was then operated for 100 revolutions.
Tablets were deducted and reweighed

Hardness
Pfizer hardness tester was used for the determination of the hardness. For each formulation 6
tablets were determined.

Thickness
Thickness of the tablets was determined using digital Vernier calipers. 5 tablets from each
formulation and average was calculated.

KINETIC DATA ANALYSIS
Zero-Order Kinetics
Zero order as cumulative amount of Percentage drug released vs. time.
C = K t
0

Where K0 is the zero-order rate constant expressed in units of concentration/time and t is the
time in hours. A graph of concentration vs. time would yield a straight line with a slope equal
to K0 and intercept the origin of the axes.

First order kinetics
First order as log cumulative percentage of log (%) cumulative drug remaining vs time.
Log C = Log Co − kt / 2.303

Where, C0 is the initial concentration of drug
k is the first order constant
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t is the time

Higuchi Model
Higuchi’s model as cumulative percentage of drug released vs square root of time.
Q = K t1/2

Where K is the constant reflecting the design variables of the system and t is the time in
hours. Hence, drug release rate is proportional to the reciprocal of the square root of time.

Hixon crowell erosion equation
Hixson-Crowell cube root law, as the cube root of percentage drug remaining vs. time
correlated the release from systems with polymer erosion/dissolution resulting in a change in
surface area and diameter of particles or tablets.
Q 1/3 – Q1/3 = k t
0 t HC

Where, Qt is the amount of drug released in time t
Q0 is the initial amount of the drug in the tablets
k is the rate constant for the Hixson-Crowell rate equation
HC

Korsmayer Peppas equations
Korsmeyer et al (1983) derived a simple relationship which described drug release from a
polymeric system. To find out the mechanism of drug release, first 60% drug release data was
fitted in Korsmeyer–Peppas model.
M / M = Ktn
t ∞

Table.4: Diffusion Exponent and Solute Release Mechanism for Cylindrical Shape.

Diffusion exponent (n) Overall solute diffusion mechanism
0.45 Fickian diffusion
0.45 < n < 0.89 Anomalous (non-Fickian) diffusion

0.89 Case-II transport
n > 0.89 Super case-II transport
Dissolution studies
Dissolution rate was studied by using USP type II paddle apparatus at 50 rpm. Phosphate
Buffer of pH 6.8, was used as dissolution media. Temperature was maintained at 370 C 
0.50C. Aliquots of dissolution media was with drawn at specific time intervals and it was
filtered. Same amount of the fresh dissolution media was replaced. The filtered solution was
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determined for drug content spectrometrically at 272 nm. Dissolution rate studies was carried
for all designed formulations.

Stability studies
Selected formulations were subjected to stability studies as per I.C.H guidelines.

Following conditions were used for stability testing
 250C/60% RH analyzed every month for a period of three months.
 300C/60% RH analyzed every month for a period of three months.
 400C/75% RH analyzed every month for a period of three months.

RESULTS AND DISCUSSION
PREFORMULATION STUDIES
Results of the Preformulation studies of Irbesartan and hydrochlorothiazide are shown in the
following table:
Table 5: PREFORMULATION RESULTS.
S. No. Parameters Observations
Freely soluble in acetone,
1 Solubility soluble in methanol & alcohol,
practically insoluble in water
Determination of the pH, pH of 2.43
2 and Log P Log P is 4.08

i. Apparent bulk density Apparent bulk density—11g/ml
ii. Bulk density Bulk density—10 g/ml
3 % Compressibility 37.35%
# 40=32.2%
# 60= 42.3%
4 Sieve analysis
# 100 = 58.1%
# 120 =86.2 %
5 Moisture content 1.08% w/w

Table.6: Evaluation of the blend.
Formulations 5min 10min 15min
F1 33.97 64.37 96.25
F2 37.54 64.37 92.38
F3 39.33 60.79 98.56
F4 42.43 59 85.82
F5 50.06 87.61 97.34
F6 51.98 89.21 98.32
F7 51.23 85.82 99.13
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Evaluation of the blend
The Blend was evaluated for the tapped density, bulk density, % compressibility and angle of
repose. The results are summarized in the tabular form.

Evaluation of pH independent tablets
Physical characterization
The all formulations showed have no spots. And all the formulations are round and spherical
shaped.

Weight variation
All the formulations were complying with weight variation test.
Hardness
All the formulations were comply with hardness. Hardness of all the tablets was found to be
in the range of 2.5 to 3.6 Kg/cm2.

Table.7: Evaluation of the physical parameters of pH independent formulation.

Formulation Bulk density Tapped density Powder flow Angle of
Code (g/ml) (g/ml) properties Repose
F-1 0.543 0.64 15.625 28.89
F-2 0.523 0.645 17.32 28.95

F-3 0.45 0.523 18.758 27.12

F-4 0.432 0.435 14.21 26.79

F-5 0.542 632 14.28 24.36

F-6 0.51 0.576 12.986 24.25

F-7 0.324 0.38 14.731 26.02

Table.8: Drug profile study of sustain release Hydrochlorothiazide.
S.No. Conc.(g/ml) Absorbance at 272 nm
1 0 0
2 5 0.009
2 10 0.016
3 15 0.024
4 20 0.031
5 25 0.038
6 30 0.045
7 35 0.055
8 40 0.067
9 45 0.076
10 50 0.085
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