International Journal of Innovative Pharmaceutical...

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 Samples (5 ml) withdrawn at a time interval of 0, 0.50, 1, 2, 6, 12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.

mailto:[email protected]




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.




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




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




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




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



3 Pump RPM 25-35







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



3 Pump RPM 25-35







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




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




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




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




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.

REFERENCE

1. Shaji J., Chadawar V., Talwalkar P., Multiparticulate Drug Delivery System, The

Indian Pharmacist, June 2007, 6: 21-28.

2. Preparing Modified Release Multiparticulate Dosage Forms With Eudragit Polymers,

Pharma Polymers, November 2002, 9: 2-3.

3. Gajdos, B.,. Rotary granulators - Evaluation of process technology for pellet production

using factorial design 1984. Drugs Made Ger. 27: 30-36.

4. Tang E. S.K., Chan L.W., Heng P.W.S, Coating of Multiparticulates for Sustained

Release, Amer J Drug Delivery 2005: 3: 17-28.

5. Tang E. S.K., Chan L.W., Heng P.W.S, Coating of Multiparticulates for Sustained

Release, Amer J Drug Delivery 2005: 3: 17-28.

6. Ozturk. A.G., Ozturk. S.S, Palsson. B.O, Wheatley. T.A, Dressman. J.B.,

Mechanism of release from pellets coated with an ethyl cellulose-based film.

Journal of Controlled Release,1990: 14,203.

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