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RESEARCH ARTICLE T.Nagendra et.al / IJIPSR / 3 (3), 2015, 164-175
Department of Pharmaceutics ISSN (online) 2347-2154
Available online: www.ijipsr.com March Issue 164
FORMULATION AND EVALUATION OF NICARDIPINE
HYDROCHLORIDE SUSTAINED RELEASE PELLETS
1T.Nagendra Babu*,
2K.Umasankar,
3P.Jaya Chandra Reddy
Department of pharmaceutics, Krishna Teja Pharmacy College, Chadalawada Nagar, Tirupati-
517501, INDIA
Corresponding Author
T.Nagendra
Department of Pharmaceutics,
Krishna Teja Pharmacy College, Tirupati,
Andhra Pradesh, INDIA
Email: [email protected].
Phone: +91 9666421159
International Journal of Innovative
Pharmaceutical Sciences and Research www.ijipsr.com
Abstract
The objective of the present study was to formulate and evaluate Nicardipine hydrochloride sustained
release pellets which correlates the standards of marketed product by using HPMC and Ethyl Cellulose
as polymers. And compare the in-vitro dissolution profiles of formulated pellets with various
concentrations of HPMC and Ethyl cellulose. The in vitro drug release studies were carried out in pH 6.8
using dissolution test apparatus II. The pellets were placed inside the 900 ml dissolution medium and
speed and paddle was set at 75 rpm. Samples (5 ml) withdrawn at a time interval of 0, 0.50, 1, 2, 6, 12
hours and same value of fresh medium were replaced. The samples were analysed for drug content pH
6.8 as blank at λ max 237 nm. The percentage drug release was plotted against time Compatibility study
of drug and polymers were conducted by employing FTIR Spectral studies. In this FTIR studies along
with drug, HPMC E5 and ethyl cellulose 7cps used. The order of drug release for optimised formulation
followed first order. And the mechanism of drug release is non-fickian diffusion governed by Higuchi.
In the drug loading stage total five formulations(F1,F2,F3,F4,F5) are formulated and in these F4 chosen
as optimized formulation because of its % yield and assay were within the limits.
Keywords: Nicardipine hydrochloride, HPMC, Ethyl Cellulose, Pellets, Higuchi, Non-fickian.
RESEARCH ARTICLE T.Nagendra et.al / IJIPSR / 3 (3), 2015, 164-175
Department of Pharmaceutics ISSN (online) 2347-2154
Available online: www.ijipsr.com March Issue 165
INTRODUCTION
Incorporating an existing medicine into a novel drug delivery system (NDDS) can significantly
improve its performance in terms of efficacy, safety and improved patient compliance. In the form
of a NDDS, an existing drug molecule can get new life, thereby increasing its market value and
competitiveness. Historically, the word pellet has been used by a number of industries to describe
a variety of agglomerates produced from diverse raw materials. Pellets can be defined as
agglomerates of fine powders or granules of bulk drugs and excipients. Multiparticulate dosage
forms are pharmaceutical formulations in which the active substance is present as a number of
small independent subunits with diameter of 0.05-2.00 mm [1]. To deliver the recommended total
dose, these subunits are filled into a capsule or compressed into a tablet [1,2] . They provide many
advantages over single-unit systems because of their small size. Multiparticulates are less
dependent on gastric emptying, resulting in less inter and intra-subject variability in
gastrointestinal transit time. They are also better distributed and less likely to cause local irritation
[3]. The pelletized products can improve the safety and efficacy of the active agent. Recently
much emphasis is being laid on the development of multiparticulate dosage forms in preference to
single unit systems because of their potential benefits such as increased bioavailability, reduced
risk of systemic toxicity, reduced risk of local irritation and predictable gastric emptying [4].
Pellets offer a great flexibility in pharmaceutical solid dosage form design and development. They
flow freely and pack easily without significant difficulties, resulting in uniform and reproducible
fill weight of capsules and tablets .Successful film coating can be applied onto pellets due to their
ideal spherical shape and a low surface area-to-volume ratio [5]. Pellets composed of different
drugs can be blended and formulated in a single dosage form. This approach facilitates the
delivery of two or more drugs, chemically compatible or incompatible, at the same sites or
different sites in the gastrointestinal tract. Even pellets with different release rates of the same
drug can be supplied in a single dosage form.
Sustained Release
Sustained released means that the drug will be released under first order kinetics.
Therefore if a drug starts out at 100mg and releases at a rate of 10% per unit time [6].
100mg --> 90mg --> 81mg --> 72.9 mg.
RESEARCH ARTICLE T.Nagendra et.al / IJIPSR / 3 (3), 2015, 164-175
Department of Pharmaceutics ISSN (online) 2347-2154
Available online: www.ijipsr.com March Issue 166
MATERIALS AND METHODS: List of Materials Used: Nicardipine hydrochloride,
Sugar sphres, Sodium lauryl sulphate, Inf-10, Lactose, Mannitol, Sucrose, Pvp K-30, Tween 80,
HPMC E5, Methylene dichloride, Iso propyl alcohol, Ethyl cellulose 7 cps, Di ethyl phthalate
Analytical Methods for Estimation of Nicardipine
The following analytical methods are reported for the estimation of Nicardipine
1. UV Spectroscopy
2. High Performance Liquid Chromatography
3. Reverse phase High performance Liquid Chromatography
4. Visible Spectroscopy.
In the present investigation UV .Spectrophotometer method was used for the estimation of
Nicardipine Hydrochloride
Assay
Standard preparation
Weigh accurately about 100 mg of Nicardipine hydrochloride working standard into 100 ml of
volumetric flask add 50 ml of Methanol,sonicate and shake well and dilute to volume with
Methanol. Mix well. Pipette 2 ml of this solution in to 100 ml volumetric flask dilute to volume
with distilled water and mix well.
Sample Preparation
Weigh accurately about 20 mg drug equivalent pellets in a 50 ml volumetric flask, add 10 ml of
Methanol, sonicate for 10 minutes. Cool and dilute to volume with Methanol. Filter the solution
through what man filter paper. Then take 2 ml of filtrate into 50 ml volumetric flask and dilute to
volume with distilled water. Measure the absorbance at 237 nm.
Calculation
Assay = Std.Wt 2 50 50 S.Abs P
100 100 S.Wt 2 Std.Abs
Std.Wt. = standard weight S.Wt. = sample weight
Std.Abs. = standard absorbance S.Abs= sample absorbance P= purity of substance
RESEARCH ARTICLE T.Nagendra et.al / IJIPSR / 3 (3), 2015, 164-175
Department of Pharmaceutics ISSN (online) 2347-2154
Available online: www.ijipsr.com March Issue 167
STANDARD CURVE FOR NICARDIPINE HYDROCHLORIDE
Table 1: Analytical profile for Fig.1: Standard curve
Nicardipine hydrochloride Nicardipine hydrochloride
Table 2: Formulation of Nicardipine Hydrochloride Pellets
NICARDIPINE HCl 22%W/W
BATCH SIZE 1KG
FORMULATION CODE F1 F2 F3 F4 F5
DRUG LOADING
NICARDIPINE HCL 0.22 0.22 0.22 0.22 0.22
SUGAR SPHERES 0.252 0.252 0.252 0.252 0.252
SLS 0.012 0.012 0.012 0.012 0.012
INF-10 0.005 0.01 0.02 0.03 0.025
LACTOSE 0.176 0.176 0.176 0.176 0.176
MANNITOL 0.175 0.175 0.175 0.175 0.175
SUCROSE 0.08 0.08 0.08 0.08 0.08
PVP K-30 0.004 0.004 0.004 0.004 0.004
TWEEN 80 0.002 0.002 0.002 0.002 0.002
P.WATER QS QS QS QS QS
THEORICAL YIELD 0.926 0.931 0.941 0.951 0.946
SEAL COATING
HPMC E5(3%) 0.028
MDC 0.18
IPA 0.132
THEORITICAL YIELD 0.974
SR COATING
EC 7CPS 0.50% 1% 1.50% 2% 2..5
EC 7CPS 0.005 0.01 0.015 0.02 0.025
DEP 0.001 0.002 0.003 0.004 0.005
IPA 0.26 0.52 0.78 1.067 1.334
MDC 0.08 0.16 0.24 0.328 0.411
THEORITICAL YIELD 0.98 0.986 0.992 0.998 1.004
Concentration
(µg/ml) Absorbance
0 0
5 0.09
10 0.185
15 0.273
20 0.368
25 0.457
RESEARCH ARTICLE T.Nagendra et.al / IJIPSR / 3 (3), 2015, 164-175
Department of Pharmaceutics ISSN (online) 2347-2154
Available online: www.ijipsr.com March Issue 168
FORMULATION OF NICARDIPINE HYDROCHLORIDE PELLETS
Nicardipine Hydrochloride Sustained Release Pellets: In this work, the method used for
preparing Nicardipine Hydrochloride sustained release pellets was powder layering followed by
solution/suspension-layering technique.
Solution / suspension-layering technique:
The three main steps followed in suspension layering technique to prepare sustained release
pellets of Nicardipine were,
1. Drug coating
2. Sub coating
3. Functional coating
1. Drug coating:
A coating solution containing appropriate concentration of drug, binder, and other excipients was
prepared. Then, the solution was sprayed on to the nonpareil seeds by using Wruster bottom spray
(FBP), by maintaining all appropriate parameters like spray rate, bed temperature, inlet
temperature, exhaust and RPM. Dried forms of coated pellets were obtained.
Samples were withdrawn at different areas and tested for content uniformity and assay.
Std.Wt. = standard weight S.Wt. = sample weight
Std.Abs. = standard absorbance S.Abs. = sample absorbance
P = purity of Nicardipine hydrochloride
Table 3: Process parameters during drug loading
S.No Name of the parameter Operation parameter
1 Inlet temp 50-60 °C
2 Exhaust Temp 48-52 °C
3 Pump RPM 25-35
4 Atomization air pressure 3.5-4.5 kg/cm2
5 Spray rate 80-250 gm/min
6 Drying Time 30 min
RESEARCH ARTICLE T.Nagendra et.al / IJIPSR / 3 (3), 2015, 164-175
Department of Pharmaceutics ISSN (online) 2347-2154
Available online: www.ijipsr.com March Issue 169
2. Sub coating
The calculated quantity of drug loaded pellets was taken into FBC bowl. After ensuring the
integrity of the apparatus the operation was started by setting the temperature, spray pressure,
spray rate etc. Coating was done by wurster coating method. Coating process was started
maintaining the temperature between 45-50°C and continued until the required weight gain and
coating of the material is achieved. After completing the process the pellets were allowed to dry
in the bowl itself by air blowing for 15 min. The critical parameters include bowl temperature and
spray rate. After drying the pellets were unloaded from the bowl and collected for sifting.
Sifting
The dried pellets were passed through the sieves 12# and 18#. The ups and downs of each sieve
were collected separately. Pellets retained on 18# are used for further process. Samples were
taken from each batch and subjected for assay and dissolution test.
Table 4: Process parameters during barrier coating
3. Functional coating:
After drug and seal coating this step plays most important role in sustaining the drug release. This
is also called as polymer coating, where a coating solution containing appropriate concentration
of polymer was prepared and sprayed on seal coated pellets. The coating solution was sprayed on
the pellets using same mechanism and by maintaining the appropriate parameters.The
development of present study was mainly based on the process of binding of drug to non-pareil
seeds and binding of polymer on to drug coated non-pareil seeds. During this process, a variety of
possible binders were used in order to bind the drug onto the NPS. The main aim was to sustain
the release of drug.
Sifting: The dried pellets were passed through the sieves 12# and 16#. The ups and downs of
each sieve were collected separately. Pellets retained on 16# are used for further process. Samples
were taken from each batch and subjected for assay and dissolution test.
S.No Name of the parameter Operation parameter
1 Inlet temp 45-50 °C
2 Exhaust Temp 40-45 °C
3 Pump RPM 25-35
4 Atomization air pressure 3.5-4.5 kg/cm2
5 Spray rate 80-250 gm/min
6 Drying Time 15 min
RESEARCH ARTICLE T.Nagendra et.al / IJIPSR / 3 (3), 2015, 164-175
Department of Pharmaceutics ISSN (online) 2347-2154
Available online: www.ijipsr.com March Issue 170
Table 5: Process parameters during sub coating
Preformulation Studies
Preformulation study is an investigation of physical and chemical properties of a drug substance
alone and when combined with excipients. It is the first step in the rationale development of
dosage form. The overall objective of preformulation study is to generate information useful to
the formulation development for a stable and bioavailable dosage forms. The use of
Preformulation parameters is to maximize the chances in formulating an acceptable, safe, efficient
and stable product.
Physical Drug Excipient Compatibility Studies
Excipients were important ingredients of almost all pharmaceutical dosage form. The successful
formulation of a stable and effective solid dosage form depends on the selection of excipients, so
it is necessary to know the inherent stability of the drug substance and possibility of interaction
with excipients. The physical compatibility studies were coupled with the stability studies at
higher temperature and humidity conditions.Physical observation of sample was done every week
for any color change or lumps formation and flow, for three months stored at 40oC/75% RH.
Table 6: Protocol for drug-excipients compatibility
Batch
no.
Drug-Excipients combination D:ERatio
1 Nicardipine hydrochloride alone -
2 Nicardipine hydrochloride + sls 1:5
3 Nicardipine hydrochloride +Inf-10 1:5
4 Nicardipine hydrochloride +lactose 1:5
5 Nicardipine hydrochloride + mannitol 1:5
6 Nicardipine hydrochloride +sucrose 1:5
7 Nicardipine hydrochloride +pvp k-30 1:5
S.NO Name of the parameter Operation parameter
1 Inlet temp 50-60 °C
2 Exhaust Temp 48-52 °C
3 Pump RPM 25-35
4 Atomization air pressure 3.5-4.5 kg/cm2
5 Spray rate 80-250 gm/min
6 Drying Time 30 min
RESEARCH ARTICLE T.Nagendra et.al / IJIPSR / 3 (3), 2015, 164-175
Department of Pharmaceutics ISSN (online) 2347-2154
Available online: www.ijipsr.com March Issue 171
Drug Release Kinetics
Data obtained from the in-vitro release studies were fitted to various kinetic equations such as
zero order, first order, Higuchi model and Korsmeyer- Peppas model
Zero order equation Q = Q0 – K0t ¾
First order equation In Q = In Q0 – K1t
Higuchi equation Q = K2t1/2
Korsmeyer - Peppas equation Q/Q0 = K tn
Where, K0 to K2 were release rate constan t s, Q/Q0 was fraction of drug released at tim e t, K
was a constant and n was diffusion constant that indicates general operating release mechanism .
For Fickian (diffusion controlled), n ≤ 0.5; for non- Fickian (anomalous) release, ‘n’ value is in
between 0.5 to 1.0; for zero order release, n=1.0; for super case transport II, n > 1.040.
EXPERIMENTAL RESULTS
Organoleptic Characters of Nicardipine Hcl
Table 7: Nicardipine Specifications
S.No. TEST SPECIFICATION RESULT
1
Description
Greenish yellow colour crystalline
powder
An off-white to
cream colored
crystalline
hygroscopic powder
2 Solubility Soluble in water and slightly soluble
in methanol Complies
3 Water Content
(by Karl-Fisher) NMT 3% 1% w/w
4 LOD by IR moisture analyzer, at 1050C 1.37 % w/w
5
Bulk density
Tapped density
Haussner’s Ratio
Carr’s/Compressibility Index
(%)
0.21 gm/ml
0.27 gm/ml
1.28
22
6 Melting Point 136-138 OC 136
oC
7 Assay on Anhydrous Basis
(Potentiometric) <98% and not more than 102% w/w 98.9%w/w
RESEARCH ARTICLE T.Nagendra et.al / IJIPSR / 3 (3), 2015, 164-175
Department of Pharmaceutics ISSN (online) 2347-2154
Available online: www.ijipsr.com March Issue 172
FTIR Scan of Nicardipine Hydrochloride
Table 8: FTIR Scan Of Nicardipine Hydrochloride
Fig 2: FTIR Scan of Nicardipine Hydrochloride
Table 9: FTIR spectrum of physical mixture (NicardipineHCl, HPMCE5 and ethyl
cellulose)
Fig 3: FTIR spectrum of physical mixture (NicardipineHCl, HPMC E5 and ethyl cellulose)
Wave number (cm-1
) Functional group
1356 NO2 stretching
3070 C-H stretching
1637 C=C stretching
3182 N-H stretching
1703 C=O stretching
Wave number (cm-1
) Functional group
1357 NO2 stretching
3064 C-H stretching
1633 C=C stretching
3182 N-H stretching
1701 C=O stretching
RESEARCH ARTICLE T.Nagendra et.al / IJIPSR / 3 (3), 2015, 164-175
Department of Pharmaceutics ISSN (online) 2347-2154
Available online: www.ijipsr.com March Issue 173
INFO: The FTIR spectra show the peaks in pure drug of Nicardipine hydrochloride are not
disutrubed in the mixture. So that it indicates they are compatible
Dissolution Data of Nicardipine Pellets
All values are expressed as mean ±S.D, n=3
Drug Release Comparison of Optimized Formulation F4 With Marketed Product
Fig 4: Drug Release Comparison of Optimized Formulation F4 with Marketed Product
Table 10: Dissolution Data Of Nicardipine Pellets
Assay:
Table 11: Assay values
Formulation F1 F2 F3 F4 F5
Assay 86% 80% 92% 95% 90%
DISSOLUTION PROFILE
% drug release
TIME(hr) F1 F2 F3 F4 F5 MARKETED
PRODUCT
0 0 0 0 0 0 0
0.5 40±0.09 25±0.12 22±0.05 17.03±0.07 15±0.05 18±0.07
1 56±0.08 55±0.09 38±0.13 29.47±0.09 44±0.06 30±0.14
2 98±0.08 73±0.04 55±0.11 48.71±0.23 69±0.06 49.5±0.08
6 -- 99±0.01 61±0.08 68.32±0.13 98±0.05 69.3±0.06
12 -- -- 73±0.16 86.29±0.15 -- 89±0.16
RESEARCH ARTICLE T.Nagendra et.al / IJIPSR / 3 (3), 2015, 164-175
Department of Pharmaceutics ISSN (online) 2347-2154
Available online: www.ijipsr.com March Issue 174
The limits of assay was 95% to 105%
The labeled Nicardipine concentration was22.0%
The F4 formulation was 20.9%(95%)
In-vitro dissolution studies
The release profiles of Nicardipine from pellet coated with ethyl cellulose. The entire pellet
disintegrates during the dissolution test, and no gel like structure remained, indicating complete
dissolution at different coating levels. As the coating level increased, the drug release decreased.
The reduction in the release rate with increasing coating level may be due to the increased
diffusional path length with increase in the thickness of the coat. The effect of coating level on
release of Nicardipine from pellets coated with ethyl cellulose. It was observed from the results
that the coating levels had a major effect on the ultimate rate of drug release and the duration of
the release. The entire pellet remained intact during the dissolution test, indicating that the ethyl
cellulose coating layer controlled the drug release. Generally, in dosage forms that have a water
insoluble polymer as the rate controlling membrane, since diffusion through the membrane
controls the overall release rate of the drug, the layer properties and geometry, such as coating
porosity, internal structure, and coating thickness, may be critical factors in determining the
release rate of drug
Kinetics of In-Vitro Dissolution:
The drug release for the optimized formulation (F4) followed first order kinetics shown in Figure
No.20,21 As the graph was drawn between the log % of drug unreleased verses time were found
to be linear. To ascertain the mechanism of drug release data was subjected to Higuchi shown in
Figure No22,23&Korsmayer,peppas equation shown in Figure No 24,25 From the regression
coefficients the plots shows highest linearity with first order followed by Higuchi model.
Determination of Assay:
The assay of Nicardipine Hydrochloride was determined by using UV-spectrophotometric
method. The result obtained within the specified limits(95%-105%).
CONCLUSION
The in-vitro dissolution studies of all formulations were carried out in simulated intestinal fluid
for 12 hours and the formulations met the standard results. Nicardipine HCl sustain released
pellets were formulated by solution layering technique by using HPMC E5 and Ethyl cellulose
RESEARCH ARTICLE T.Nagendra et.al / IJIPSR / 3 (3), 2015, 164-175
Department of Pharmaceutics ISSN (online) 2347-2154
Available online: www.ijipsr.com March Issue 175
7cps as polymers of release retarding. The preformulation studies of API were found to be within
limits. Those are bulk density, tapped density, compressibility index, hausner’s ratio and angle of
repose. The stability studies were conducted for optimized formulation (F4) as per ICH guidelines
at 250C±2/60±5% RH and 40
0C±2/75±5% RH for 3 months and no changes were observed. The
optimised formulation F4 had the similar dissolution properties with that of marketed formulation
The conclusion of this dissertation was by preparing the noval dosage forms like sustain released
pellet formulations, can improve the drug availability in the plasma for more than conventional
dosage forms.
ACKNOWLEDGEMENT
I express my deep sense of gratitude and indebtedness to my most respected teacher, research
guide and mentor, Mr. P. Jayachandra Reddy for his untiring guidance, unmitigated
encouragement, for inculcating confidence and for being a great source of inspiration and keen
interest in making this thesis a reality. It would not have been possible to achieve this goal
without his support, care and affection.
I express my sincere thanks to to Dr.K.Umasankar, M.Pharm, Ph.D,HOD, Krishna Teja
Pharmacy College,Tirupati for granting permission to carry out my research work in industry.
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