M PHARM IV SEM DISSERATION RESEARCH WORK

FORMULATION AND EVALUATION OF BILAYER TABLETS OF

NEBIVOLOL HCL AND NATEGLINIDE

Presented By Under the Guidance Of

G. Navaneetha Dr.G.Ganesh Kumar M.Pharm.,Ph.D
Rg.No:636221886011 Professor and HOD
Department of Department of Pharmaceutics
Pharmaceutics

SRIKRUPA INSTITUTE OF PHARMACEUTICAL SCIENCES

VILL- VELLIKATTA, DIST- SIDDIPET,TELANGANA
OCTOBER 2023 01
 CONTENTS

 Introduction
 Literature review
 Drug profile
 Aim ,objective and plan of work
 Materials
 Formulation
 Evaluation
 Result & Discussion
 Conclusion
 References

02
 INTRODUCTION

The goal of any drug delivery systems is to provide a therapeutic amount of drug
to the proper site in the body to achieve promptly and then maintain the desired
drug concentration.
Two aspects are most important to drug delivery, namely spatial placement and
temporal delivery of a drug. Spatial placement related to targeting drug to a specific
organ or tissue. While temporal delivery refers to controlling the rate of drug
delivery to the target tissue.
BILAYER TABLET
A type of multilayered tablet in which instead of single tablet two layers were
formulated by which two incompatible drugs can also be combined together in same
formulation.

03
 Advantage:
 Frequency of drug administration is reduced.
 The Patient compliance can be improved, and drug administration can be made more convenient.
 Blood level oscillation characteristic of multiple dosing of conventional dosage forms is reduced,
because a more even blood level is maintained.
 Implicit in the design of sustained release forms, is that the amount of drug Administered can be reduced,
thus maximizing availability with a minimum dose.
 The safety margin of high-potency drugs can be increased, and the incidence of both local
and systemic adverse side effects can be reduced in sensitive patients.

 DISADVANTAGES :
 Administration of sustained release medication does not permit the
prompt termination of therapy.
 The physician has less flexibility in adjusting dosage regimens. This is fixed by the dosage form regimen.
 Sustained release forms are designed for the normal basis of average drug biologic half-lives. Consequently,
disease states that alter drug disposition, significant patient variation, so forth are not accommodated.
 Economically more costly processes and equipment are involved in manufacturing many
sustained release forms

04
 LITERATURE REVIEW
• 24Biswajit Biswal et al., (2011) were studied on designing
floating Bilayer tablet of Trimetazidine Dihydrochloride
by dry granulation method. Theformulated
tablets were evaluated for weight variation, hardness,
friability, drug content, floating lag time, total
buoyancy time and in vitro release studies. He reported
that the combination of low viscosity polymer
and high viscosity polymer would increase the
release rate.

• 25Rubina Reichal et al., (2011) were developed the

floating tablet of Nateglinide by direct compression
technique by using various viscosity grades of HPMC k4M,
HPMC K100 and Carbopol 934P to
prolong the gastric residence time
and to increase the drug bioavailability.
•
05
• 26Gaur et al., (2011) were designed the floating tablet of Nebilol
HCl by optimizing gas generating agent to improve the buoyancy time.
He found that increasing concentration of sodium bicarbonate results in
bursting effect.

• 27Padmavathy et al., (2011) were studied on formulating

floating tablet of Oflaxacin using HPMC by wet granulation
technique. She reported that the drug release rate decreased as the
concentration of high viscosity polymer increased.

06
• 30Garg shiv kumar et al., (2011) were studied on
Gastroretentive floating tablet of Aceclofenac by using
HPMC K4M, HPMC K15M by direct compression
method. He found that drug release rate decreased in
order of HPMC K grade < HPMC E grade with
increasing macromolecular weight, the degree of
entanglement of the polymer chain increase.So,
the mobility of the macromolecules in the fully
swollen system decreased this leads to decreased drug
diffusion and decreased drug release with increase in
molecular weight.

• 31Madhu soodan Sharma et al., (2011) designed

the floating tablet of Cefpodoxime proxetil by
employing different viscosity grades of HPMC
K4M,K15M,K100M at different drug to polymer
ratio. He reported that the different viscosity
grades in different ratio would effect the drug release.
•
07
• 32Laxmi goswami,et al., (2011) fabricated Bilayer Floating Tablet of
Nebilol HCl and Pioglitazone was done by direct compression using
polymers like hydroxyl propyl methyl cellulose(HPMC),Carbopol,
Polyvinylpyrrolidone to facilitate immediate release of pioglitazone
and sustained release of Nebilol HCL. The formulated tablets remain
buoyant over a period of 12-20 hrs and released more than 80% of
drug in study period.

• 33Dinesh kumar et al., (2010) formulated the Bilayer tablet of

Raniditine by direct compression method. HPMC K100, HPMC K4M,
HPMC E-15 were used as gel forming agents and sodium bicarbonate
are used as gas generating agent. The formulated tablets were
evaluated for weight variation, drug content, floating lag time and
duration of floating. The results shows that good floating property and
sustained release character.

• 34Ajay Bagherwal et al., (2010) studied on formulating Ciprofloxacin

HCl floatingtablet by dry granulation method. The
formulated tablets were characterized for weight variation,
hardness, friability, drug content, floating lag time, total buoyancy time
and in vitro dissolution study. From the release studies it was
concluded that increase in polymer concentration decreases the
release rate

08
 DRUGPROFILE

3.1.NEBIVOLOL HYDROCHLORIDE:
3.1.1 DRUG PROFILE:
Nebivolol is a beta blocking agent used to treat hypertension and aid in the managemnent
of heart failure.
Drug category : Beta blocker
Chemical name : [iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-
methanol, monohydrochloride
Brand : Bystolic
Molecular formula :C22H26ClF2NO4
Description:
Molecular weight : 441.9g/mol
Solubility : soluble in the water(<1mg /ml at 25c), ethanol (10mM),DMSO(88g/ml)at
25c), methanol, and DMF.
Melting point : 219-222C
Protein binding : 98%
Half Life : 12-19 hrs
Bioavailability : 12-96%

FIG NO : Chemical structure of Nebivolol Hcl

09
 MECHANISM OF ACTION:

Nebivolol is a highly selective beta-1 adrenergic receptor antagonist with weak beta-2
adrenergic receptor antagonist activity. Blocking beta-1 adrenergic receptors by d-nebivolol
leads to decreased resting heart rate, exercise heart rate, myocardial contracility, systolic
blood pressure, and diastolic blood pressure. The selectivity of d-nebivolol limits the
magnitude of beta blocker adverse effects in the airways or relating to insulin
sensitivity.Nebivolol also inhibits aldosterone, and beta-1 antagonism in the
juxtaglomerular apparatus also inhibits the release of renin. Decreased aldosterone leads to
decreased blood volume, and decreased renin leads to reduced vasoconstriction.l-nebivolol
is responsible for beta-3 adrenergic receptor agonist activity that stimulates endothelial
nitric oxide synthase, increasing nitric oxide levels; leading to vasodilation, decreased
peripheral vascular resistance, increased stroke volume, ejection fraction, and cardiac
output.The vasodilation, reduced oxidative stress, and reduced platelet volume and
aggregation of nebivolol may lead to benefits in heart failure patients.

10
Aim and objectives :

Aim :

Aim of the present work is to formulate and evaluate bilayer tablets of nebivolol a
and Nateglinide thrugh its incorporation of an oral dosage form that is able to
release nebivolol immediately as well as sustained realease of neteglinide for 12 hrs
to enhance the oral bioavaliability of nateglinide

OBJECTIVES :

The main objective of this work was formulation of bilayer tablet composed of two
different classes of drug
Helps in separating the two incompatible substances in which one layer is
immediate release as loading dose and second layer is controlled/ suastained release
as maintainance dose.
Delayed release dosage form is designed to relaese the drug at a time other than
promptly after administraion.

11
 PLAN OF WORK :

 1. Selection of drug and polymers.

1. 2. Authentification and pre-formulation studies.
A. Determination of melting point.
B. FT-IR Spectroscopic studies to authentify the drug molecule.
C. FT-IR Spectroscopic studies to detect the drug- excipient compatibility.
D. Analytical method development
o Preparation of standard stock solution of drug.
o Preparation of simulated gastric fluid (SCF) pH 1.2, simulated intestinal fluid
(SIF) pH 7.2.
o Construction of calibration curve.
3. 3. Formulation and development
A. Non-aqueous Wet Granulation Method.
B. Characterization of prepared Granules.
o Angle of repose
o Bulk density
12
o Tapped density
o Carr's index (% compressibility)
o Hausner's ratio
C. Compression of granules
D. Coating of tablets
4. Evaluation tests
E. Weight variation test.
F. Thickness test.
G. Hardness test.
H. Friability test.
I. Drug content uniformity test.
J. In vitro drug release studies in SGF (pH 1.2) for 2 hours, SIF (pH 6.8) for
3 hours and SIF (pH 7.2) for 3 hours.
5.To utilize the dissolution data to gain insight into the kinetics and
mechanism of drug release from compression coated tablets.
6. Stability testing of tablets using ICH accelerated stability conditions
for 3 months. 13
 MATERIAL
S
S.NO Materials Manufacturer
Gift sample obtained from force India pharmaceuticals,
1 Nateglinide Chennai.

Gift sample obtained from force India pharmaceuticals,

2 Nebivolol
3 HPMC K4M
4 HPMC E-5
5 HPMC E-15
6 Carbopol
7 Sodium Bicarbonate
8 Citric Acid
9 Povidone
Di Calcium
10 Phosphate
Chennai.
Hi Pure fine industries, Chennai
Hi Pure fine industries, Chennai
Hi Pure fine industries, Chennai
Loba chemie Private Ltd, Mumbai
Nice chemicals Private Ltd, Kerala
Nice chemicals Private Ltd, Kerala
Nice chemicals Private Ltd, Chennai
Nice chemicals Private Ltd, Kerala

11 Magnesium stearate Nice chemicals Private Ltd, Kerala

12 Talc Nice chemicals Private Ltd, Kerala

14
 Formulation of floating Bilayer Tablet

The floating Bilayer tablet was prepared by direct compression

method. Steps involved in Bilayer Tablet Preparation:

• Filling of immediate release layer of Nebivolol granules in to dies

• Slightly compressed the immediate release layer of Nebivolol granules

• Ejection of upper punch

• Addition of floating sustained release layer of Nateglinide granules over

the
immediate release granules
• Increasing the compression force and compressed both the layer

• Ejection of floating Bilayer tablet

15
Preparation of Floating Nateglinide Sustained Release (SR):

Drug ( nataglinide+ polyemer (HPMC K4M,HPMC E-5, HPMC E-15

Gas generating agents (Sodium bicarbonate + citric acid)

Dry granules were passed through the mesh no 44

Mixed with magnesium stearate, talc

Compression

Preparation of Nebivolol immediate release (IR):

Drug (Nebivolol+Crospovidone+Dicalcium phosphate (filler) + coloring

Agent dry granules were passed through a mesh no 44

Mixed with magnesium stearate and talc

Compression

16
 Formulation of Floating Bilayer tablet of Nateglinide SR and Nebivolol IR

Formulation code (amount per tablet in mg)

S.No Ingredients
C1 C2 C3 C4 C5 C6 C7 C8 C9
1 Nateglinide 60 60 60 60 60 60 60 60 60
2 HPMC K4M 50 100 150 - - - 150 100 50
3 HPMC E-15 150 100 50 50 100 150 - - -
4 HPMC E-5 - - - 150 100 50 50 100 150
Sodium
5 100 100 100 100 100 100 100 100 100
Bicarbonate
6 Citric Acid 50 50 50 50 50 50 50 50 50
7 MCC 40 40 40 40 40 40 40 40 40
Total weight 450 450 450 450 450 450 450 450 450
8 Nebivolol 5 5 5 5 5 5 5 5 5

9 Crospovidone 10 10 10 10 10 10 10 10 10

Dicalcium
10 30 30 30 30 30 30 30 30 30
Phosphate
Magnesium
11 3 3 3 3 3 3 3 3 3
Stearate
12 Talc 2 2 2 2 2 2 2 2 2
Total weight 500 500 500 500 500 500 500 500 500
 EVALUATIO
N

EVALUATION PARAMETER:
Trial batches of different formulations of individual tablets (sustained and
immediate) and Bilayer tablets were prepared and evaluated for the
following parameters.

Evaluation of granules: • Physical evaluation of tablet

• Bulk Density • Weight variation
• Tapped Density • Thickness
• Angle of Repose • Hardness
• Carr’s Index • Friability
• Hausner’s Ratio • Swelling index
• Floating lag time
In-Vitro drug release study • Total buoyancy time
• Invitro dissolution studies • Drug content

Stability studies (As per ICH guidelines)

18
 RESULTS AND DISCUSSION

Preformulation studies

Description
• Nateglinide : White to off white crystalline powder
• Nebivolol : White crystalline powder

Drug- Excipient Compatibility Studies by FT-IR analysis

Drug-Excipient compatibility was carried out by FT-IR analysis. Initially the IR
spectrum of pure drug, Nateglinide HCl and Nebivolol and excipients like HPMC
K4M, HPMC E-5 and HPMC E-15 was obtained. After that various admixtures of
drug with other excipients like Nateglinide HCl, Nebivolol, HPMC K4M, HPMC E-
5 and HPMC E-15 were prepared and IR spectra were obtained. The obtained spectra
of physical admixtures were observed for major peaks and recorded.

19
 Table No: IR Spectral
assignment of Nebivolol

S.N Wave Assignment

o number(cm-1)
1 3370.34 N-H stretching

2 2939.25 C-H
stretching(Aromatic)

3 2358.9 C-H
stretching(Aliphatic)
4 1692.87 C=O stretching
5 1445.72 C=N stretching
6 1347.41 S=O stretching
7 1282.45 C-N stretching
8 1160.05 C=C stretching Fig : IR Spectral assignment of
Nebivolol
9 874.55 C-H outplane
bending

20
 Table No: IR Spectral assignment of
Nateglinide

S.no Wavenumber (cm-1) Assignment

1 3173.06 N-H stretching

2 2687.1 C-H stretching

3 1629.52 C=O stretching

4 1573.03 C-N stretching

5 1168.15 C-C stretching

6 931.12 C-H out plane

bending
Fig : IR Spectral assignment of
Nateglinide

21
Table No: IR Spectral assignment of
HPMC E-5

S.N Wavenumber Assignment

o (cm-1)
1 3409.65 O-H stretching (primary
amine)
2 2916.15 C-H stretching
3 2077.56 C-H stretching
(Aliphatic)

4 1641.82 C=O stretching

(Isomeric
carbonyl)

5 1377.17 C-O bend

6 1058.73 C-C bend Fig: IR Spectral assignment of
7 601.89 C-H out of plane HPMC E-5

22
 Table No : IR Spectral assignment of
HPMC K-4M

S.No Wave number (cm-1) Assignment

1 3409.65 O-H stretching (primary amine)

2 2916.15 C-H stretching

3 2077.56 C-H stretching (Aliphatic)

C=O stretching (Isomeric

4 1641.82 carbonyl)

5 1377.17 C-O bend

6 1058.73 C-C bend

7 601.89 C-H out of plane

Fig : IR Spectral assignment of HPMC K-

4M

23
 Fig : IR Spectral assignment of HPMC K-
4M

S.N Wave number (cm- Assignment

o 1)

1 3276.88 N-H stretching

2 3167.52 O-H stretching
3 2939.64 C-H stretching
4 1685.78 C=O stretching
5 1450.19 C=N stretching
6 1351.27 C=C stretching
C-H out
7 931.12
plane Fig : IR Spectral assignment of physical
bending
mixture –I

24
 Table No: IR Spectral assignment of physical mixture
–II (Nateglinide HCl+Nebivolol+HPMCE-5)

S.N Wavenumber (cm- Assignment

o 1)
1 3294.93 N-H stretching
2 3157.52 O-H stretching
3 2944.64 C-H stretching
4 1442.18 C=N stretching
5 1354.98 C=C stretching
6 1065.36 C-N bend
Fig: IR Spectral assignment of physical
7 936.8 C-H out of mixture –II
plane

25
 Table No: IR Spectral assignment of
physical mixture –III
(Nateglinide HCl+Nebivolol+HPMCE-15)

S.N Wavenumber (cm-1) Assignment

o
1 3294.93 N-H stretching
2 3157.52 O-H stretching

3 2944.64 C-H stretching

4 1442.18 C=N stretching

5 1354.98 C=C stretching
6 1065.36 C-N bend

7 936.8 C-H out of plane Fig: IR Spectral Assignment of Physical

Mixture –III

26
 Table No : 30IR Spectral assignment of
physical mixture –IV
(Nateglinide HCl+Nebivolol+HPMCE-
15)

S.N Wavenumber (cm- Assignment

o 1)

1 3294.93 N-H
stretching
2 3157.52 O-H
stretching
3 2944.64 C-H
stretching
4 1442.18 C=N
stretching
5 1354.98 C=C
stretching Fig : IR Spectral Assignment of Physical
6 1065.36 C-N bend Mixture –IV

7 936.8 C-H out of

plane
27
Kinetic Analysis of Pemigatinib Release Data
Drug Release Kinetic Analysis

To elucidate the mode and mechanism of drug release, the C3 data from the
invitro release study was applied in different mathematical models and was
interpreted in the form of graphical presentation and evaluated by correlation
coefficient (R2) represented in Table... Drug release data for optimized
formulation C3was fitted into various kinetic equations to find out the order and
mechanism of drug release. Various release kinetics curves. The highest degree of
correlation coefficient determines the suitable mathematical model that follows
drug release kinetics. The drug release follows zero order kinetics, which ideal
for any drug delivery system. From the above comparison, it was found that
Higuchi square root model showed second higher degree of correlation
coefficient (R2) than other models. Hence, drug release profile of Bilayer tablets,
follows diffusion mechanism. Also, the model Korsmeyer-Peppas power law
equation states the type of diffusion, which was evaluated by value, n which is
greater than 0.966 which implies that the drug release from the system follow
Super case II transport.

28
Invitro drug release order kinetics for optimized C3 formulation

Zero Order Release of Optimized

Formulation C3
120 y = 6.119x + 2.234
R² = 0.932

100
cumulative %drug release

80

60
Zero order
Linear (Zero order)
40

20

0
0 2 4 6 8 10 12
Time (hrs)

Fig: Zero order plot for the optimized formulation C3

of Bilayer tablets
29
 First Order Release of Optimized
Formulation C3
2.500
Log Cumulative % drug

y = -0.071x + 2.420
2.000 R² = 0.894
remaining

1.500

1.000 First order

Linear (First order)
0.500

0.000
0 2 4 6 8 10
Time (hrs)

Fig: First order plot for the optimized formulation C3

of Bilayer tablets

Higuchi Model Release of Optimized

Formulation C3
80 y = 28.53x - 11.05
R² = 0.872
cumulative %drug released

60

40
Higuchi
20 Linear (Higuchi)

0
0.000 0.500 1.000 1.500 2.000 2.500 3.000
-20
SQRT of Time

Fig: Higuchi Model plot for the optimized formulation C3

of Bilayer tablets
30
 Kors-Peppas Model Release of Optimized
Formulation C3
80 y = 78.78x + 1.057
log cumulative %drug release

70 R² = 0.931
60
50
40
Kors-peppas
30
20 Linear (Kors-peppas)
10
0
0.000 0.200 0.400 0.600 0.800 1.000
log time

Fig: Korsmeyer Peppas Model plot for the optimized formulation C3

of Bilayer tablets

Table: Release kinetics of optimized formulation C3 of Bilayer tablets

Korsmeyer-
Zero Order First Order Higuchi
Formulation Peppas
Code

R2 n R2 n R2 n R2 n

C3 0.932 6.119 0.894 -0.071 0.872 28.53 0.931 78.78

31
From the above results it is apparent that the regression coefficient value closer to unity in
case of zero order plot i.e.0.32 indicates that the drug release follows a zero order
mechanism. This data indicates a lesser amount of linearity when plotted by the first order
equation. Hence it can be concluded that the major mechanism of drug release follows zero
order kinetics.

Further, the translation of the data from the dissolution studies suggested possibility of
understanding the mechanism of drug release by configuring the data in to various
mathematical modeling such as Higuchi and Korsmeyer- Peppas plots. Further the n value
obtained from the Korsmeyer-Peppas plots i.e. 0.931 indicating non-Fickian (anomalous)
transports thus it projected that delivered its active ingredient by coupled diffusion and
erosion.

32
CONCLUSION

• Bilayer tablets of Nateglinide and Nebivolol containing sustained release

layer and immediate release layer were successfully formulated. Release
was found to follow zero, krossmayer–peppas models. All the formulation
batches tested for physical parameters like weight variation, hardness,
friability and drug content, all were found to be within the USP limits. The
optimized formulations were found to be stable at all the stability conditions.
During stability studies, no significant variation in drug release was observed,
indicating that formulation batch C3 was stable over the chosen condition
for 3 months. The optimized formulation C3 showed better drug release
profile Combination of HPMC K4M and HPMC E5 is an interesting
polymer mixture for the preparation of SR matrix tablet.

33
 Referances:

• 1. Lee V.H. and Robinson J.P., Sustained and

Controlled Release Drug Delivery System,
• Marcel Dekker, New York, 1978: 7-11.
• 2. Lee V.H. and Robinson J.P, Controlled Drug Delivery,
Marcel Dekker, New York,
• 1987: 5
• 3. Vyas S.P. and Roop.K.Khar, Controlled Drug
Delivery Concepts and Advances,
• Vallabh prakasham, Delhi 1st edition; 2002: 3-7.
•
• 4. Lachmann.L; Lieberman.H.A., The Theory and Practice
of
• Industrial Pharmacy,
Varghese publishing house, Mumbai, 3rd
• edition; 1987: 430- 431.
• 5. Brahmankar, D.M. and sunil B.Jaiswal., Biopharmaceutics
and pharmacokinetics
a
• Treatise, Vallabh prakasham, Delhi 1st edition; 2002:347-
352
•
34
• 6. Siepmann, J.; Kranz, H.; Bodmeier, R., HPMC Matrices for Controlled
Drug Delivery: A New Model Combining Diffusion, Swelling and Dissolution
Mechanisms of Predicting the Release Kinetics, Pharm Res, (16) 1999 : 1748 –
1756.
•
• 7. Martindale, The Complete Drug References, 33rd edition,931-962.
•
• 8. Viazquez, M.T., Perel-Marcos, B., Gomez-Amoza, J.L.,
Martiner – Pache Cho. R, Souto, C., Concheiro A., A Influence of
Technological Variables on Release of Drugs from Hydrophilic Matrices,
Drug Dev Ind Pharm, (18) 1992: 1355-1375.
•
• 9. Mithal B.M., A Textbook of Pharmaceutical
formulation, Vallabh prakasham, Delhi, 6th edition;2004: 5-7.
•
• 10. Leon Lachmann, Herbert A.Lieberman, Joseph L. Kanic, Text
Book of Pharmaceutical Dosage Forms (Tablets), Varghese publishing
house, Mumbai 3rd edition; 2002: 447-449.

35