ISSN 0975-2366

DOI:https://doi.org/10.31838/ijpr/2020.12.03.011
Research Article

Preformulation Studies of Nifedipine

J. SRINIVASARAO1, PROF. C. GOPINATH2
SM pharmaceuticals Sdn. Bhd.; Sungai petani; Malaysia
JNTUA OTRI; Anantapur; Andhra Pradesh; India.
Email: srinivasaraoj14@gmail.com
Received: 24.01.20, Revised: 09.02.20, Accepted: 21.03.20

ABSTRACT
The preformulation studies deals with physical; chemical properties of Nifedipine for the generation of bi-layer
heterogeneous tablets formulation development studies. Solubility studies for saturated solutions were carried out
over the pH range of 1.2-6.8. The solubility of Nifedipine in water at 37°C was 436.3mg/L. Further the solubility is
not affected significantly (P < 0.05) in the buffer solutions in a pH range of 1.2 to 6.8. The PSD histograms represents
the presence of Dv (50) 7.18µm; Dv (90) 19.3µm µm particles of Nifedipine. From the p-XRD studies; the
diffraction line profiles are 2θ values for diffraction peaks at 11.7504°, 11.9178°, 12.9763° confirms to form D for
Nifedipine. By the UV-Visible; FTIR; NMR and Mass spectroscopy studies Characterized to Nifedipine. The DSC
thermo gram conforms to of Nifedipine at 172.77°C. The Assay content results of three APIs were within 99%-
101%. The Nifedipine contains nitro phenyl pyridine, nitroso phenyl pyridine analogues, and methyl 3-amino but-2-
enoate is <0.1% with >99.9% purity and all other unknown impurities were not detected in the drug substance. The
compatibility of binary mixtures of drug and excipients, stored at 40°C ± 2°C/ 75% ± 5% RH for 1 month was
assessed and the % results of Assay and impurities from initial period to after 30th day not have significant difference;
P<0.01. The preformulation results conforms, the Excipients PVP K-30; Croscarmellose Sodium; HPMC K-15/E-5,
Carbomer 974p, Ethyl cellulose, Xanthan gum, ZnO, and SiO2 were compatible with Nifedipine and selected for
development of control release bilayer tablets.
Key words: Preformulation studies; DSC studies; NMR Studies; FTIR Studies; p-XRD studies

INTRODUCTION channel blocker, chemically defined as Dimethyl

The oral route is the most preferred, accepted, 2,6-dimethyl-4-(2-nitrophenyl)-1,4-
desirable route for administrating therapeutically dihydropyridine-3,5-dicarboxylate [4]
. Peak
active agents for systemic effects over the different plasma concentration is achieved after 6 hours.
routes of administration are available for the Linear pharmacokinetic profile is over the dose of
delivery of drugs as it is a convenient, safe, good 30-180mg [5]. It is bio transformed in the liver by
patient compliance and adaptable to cytochrome P450 system. 60 to 80% of absorbed
accommodate more drugs. Even for sustained drug is excreted in urine as highly water-soluble
release formulations have been investigated for dormant metabolites and 5-15% is in biliary
oral route of administration because of flexibility emission. The Elimination half-life is 7hours [6].
in designing dosage forms. The Nifedipine was
selected taking into account of their
physicochemical, and biopharmaceutical
properties. all recent clinical guidelines still
considered ACE inhibitors, Thiazides, Calcium
channel antagonists and are as primary treatment
for organization of hypertension [1]. The
combination drug therapy at lower dose is
recommended to permit medications of different
mechanism of action, to complement each other
and mutually effectively lower the blood pressure Figure 1: Typical Chemical structure of
than the highest doses of the individual [2]. The Nifedipine
primary intention of release drug delivery is to
make sure safety and to improve efficacy of drugs MATERIALS
in addition to patient compliance [3]. Nifedipine is The active pharmaceutical ingredient Nifedipine
dihydropyridine chemical class selective Calcium BP procured from Unique Chemicals, Gujarat,

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 Preformulation Studies of Nifedipine
India; The Excipients namely Polyvinylpyrrolidone
K-30 BP; Croscarmellose Sodium BP; Hydroxy
propyl methyl cellulose K-15 and E-5 BP,
Carbomer 974P BP, Ethyl cellulose BP, Xanthan
gum BP, Zinc oxide BP, and colloidal silicon di
oxide were donated by SM Pharmaceuticals SDN
BHD, Malaysia.
Formic acid, Hydrochloric acid, Sodium
Hydroxide, Potassium di-hydrogen phosphate, Di
Potassium hydrogen phosphate, Sodium di-
hydrogen phosphate, Sodium Lauryl sulphate
analytical grade chemicals and Methanol,
Acetonitrile HPLC Grade solvents were purchased
from Merck, Mumbai.
The reference materials Nifedipine BPCRS # 2997
was procured from British Pharmacopoeia. The
impurity standards of Nifedipine impurity A CRS #
1(nitro phenyl pyridine analogue), Nifedipine
impurity B CRS # 2(nitroso phenyl pyridine
analogue) for peak identification were procured
from European Pharmacopoeia.
EQUIPMENT / INSTRUMENTS
The sophisticated instruments HPLC; Model:
2689; Make: Waters; UPLC; Model: H-Class;
Make: Waters; UV –Visible Spectrophotometer;
Model: UV 2600; Make: Shimadzu; Semi Micro
Balance; Model: GR202; Make: AND Company
Limited; Analytical Balance; Model: AL 204;
Make: Mettler Toledo; Stability chamber; Model:
TH 400 S/G; Make: Thermolab; Differential
Scanning Calorimeter; Model: Q20; Make: TA
Instruments; Particle size analyser; Model:
Mastersizer 3000; Make: Malvern Panalytical Ltd;
FTIR spectrometer; Model:Alpha; Make: Bruker;
Nuclear Magnetic Resonance Spectrometer
500MHz; Model: ECZ400S/L1; Make: JEOL; X-
ray diffractometer (p-XRD); Model: Aeris; Make:
Malvern Panalytical Ltd; pH meter; Model: 827 pH
Lab; Make: Metrohm; Magnetic Stirrer; Model:
MS7-H550-S; Make: DLab; LC-MS; Model: SQD-
2; Make: Waters; UPLC-MS/MS; Model: Xevo TQ-
S; Make: Waters; Burrel Scientiphic wrist action
laboratory shaker; Model: 75; Make: Fisher;
Halogen Moisture Analyzer Model: HS153; Make:
Mettler Toledo.
METHODS
The Physico-Chemical properties of drug
substances have a great impact on the selection of
controlled release formulation and manufacturing
process. The physico-chemical characteristics of
Nifedipine, and Drug and individual Excipient
72 | International Journal of Pharmaceutical Research | Jul - Sep 2020 | Vol 12 | Issue 3
compatibility studies were carried out. The
excipients used were; Hydroxy propyl methyl
cellulose K-15 and E-5, Carbomer 974p, Ethyl
cellulose, Polyvinylpyrrolidone K-30;
Croscarmellose Sodium; Xanthan gum, Zinc
oxide, colloidal silicon di oxide
Solubility studies
A significant Physical-chemical property
of a drug candidate is solubility, particularly
aqueous solubility. A drug should have aqueous
solubility for therapeutic effectiveness in the PH
range of 1 to 8. The drug must be in solution form
to enter into systemic circulation, to exert
therapeutic effect. The solubility studies were
conducted by using UV –Visible
Spectrophotometer; UV1900; Shimadzu. The
solubility of Nifedipine, Enalapril maleate, and
Hydrochlorothiazide were determined in distilled
water; 0.1N hydrochloric acid PH1.2; 0.1N
hydrochloric acid PH1.2 with 1% w/v sodium lauryl
sulfate; acetate buffer pH 3.0, 4.0, and phosphate
buffers pH 5.0 and 6.8 phosphate buffer. The PH
of all media were verified by using pH meter; 827
pH Lab; Metrohm. Precisely measured volume of
each solvent was poured in screw-capped glass
vials followed by addition of excess drug. The
glass vials were sealed and positioned on a
mechanical shaker at 37 °C for 24 hours.
Thereafter aliquots were withdrawn, centrifuged,
and filtered. The filtrates were diluted and
absorbance was recorded using UV–Visible
Spectrophotometer.
Particle size distribution
Particle size considerably affects several quality
parameters such as solubility, lack of grittiness,
content uniformity, rate of dissolution, and
ultimately bioavailability. Various methods to
determine the particle size comprise cascade
impaction, laser holography, microscopy, sieving,
sedimentation rate, light energy diffraction.
Particle size distribution studies of Nifedipine was
carried out on a particle size analyser; Master sizer
3000; Malvern. Laser diffraction technique was
employed to measure size distribution of powder
particles in a dry dispersion apparatus. Based on
distribution data, the particle size of powder was
defined by various means like D (3, 2) D (4, 3),
and the maximum particle size was measured by
percentiles as Dv10, Dv50, Dv90.
 Preformulation Studies of Nifedipine

Crystallinity and Polymorphism using FTIR spectrometer; Alpha; Bruker with ATR
Crystallinity and polymorphism are one of the accessory. Obtained spectra were the average of
important features of preformulation studies. 16 scans at a resolution of 4 cm−1
Crystals and polymorphs are characterized by
microscopy, thermal analysis and X-ray diffraction Nuclear Magnetic
techniques. Importance of identification of shape Resonance (NMR) Spectroscopy
of crystals and its internal structure can affect the 1
H and 13C NMR spectra were run on NMR
solubility and stability. Powder X-ray diffraction (p- instrument 500MHz; ECZ400S/L1; JEOL
XRD) technique is a powerful nondestructive equipped with 1H and 13C operating at 500 MHZ
technique for recognition of polymorphic forms of using tetra methyl silane (TMS) as an internal
sample and provides specific pattern for a given standard. About 10 mg and 30 mg of Nifedipine
form. The pattern appeared as a fingerprint of pure drug for H1 NMR and C13 NMR were taken
phase and is represented as a plot of relative or individually into a clean NMR tube and diluted
absolute intensity verses the angular parameter with the deuterated di methyl sulfoxide (DMSO-
2θ. The P-XRD pattern is a record of diffracted d6) and the spectra were scanned by using below
intensity of a crystalline sample in one instrument parameters as given in the Table 1.
dimensional as a function of diffraction angle. The
diffraction studies of Nifedipine, Enalapril maleate
Table 1: Nuclear Magnetic
and Hydrochlorothiazide, each containing
Resonance (NMR) spectroscopy Conditions
500mg, were conducted on an X-ray
diffractometer; Aeris; Malvern H1- NMR instrument C13- NMR instrument
Panalytical.Goniometer was used to maintain the Parameters Parameters
angle and rotate the sample p- XRD patterns were
X-Domain Proton X-Domain Carbon-13
recorded using following scan parameters:
X-Points 16384 X-Points 32768
A. Target material Cu
B. Voltage 40 Kv Offset 7ppm X-Offset 100 ppm
C. Current 15 mA. X-Sweep 18ppm X-Sweep 250 ppm
D. Angular parameter 2θ 2º to 50º at a step X-Pre scans 1 X-Pre scans 4
size of 0.022º Solvent DMSO-D6 Solvent DMSO-D6
E. Length of 2θ 3.02 BF or S. Exp 0.30 Hz BF or S. Exp 2.0 Hz
F. Scan time 36s Relaxation delay 2 sec Relaxation delay 2 sec
G. Specimen length 10mm Pulse 45 Degree Pulse 30 Degree
H. Temperature 25ºC Scans 16
I. CuKαα radiation 1.5418Å.
J. K-β 1.392, Liquid chromatography–Mass Spectrometry
K. K-α2/K-α1 0.5 (LC-MS)
Mass analysis and detection for pure drug
CHARACTERIZATION Nifedipine was carried out using LC-MS system;
UV-Visible Spectroscopy SQD-2; Waters equipped with electron spray
The UV spectra of APIs were scanned using a UV ionization operated in combined mode. The
spectrophotometer; UV-2600; Shimadzu. mobile phase used was 5mM ammonium acetate
Standard stock solution of Nifedipine was in water and acetonitrile in a ratio of 20:80 in
prepared individually by dissolving 30mg in 100 Isocratic method at a flow rate of 0.2ml/min. Run
ml methanol. 30ppm standard solution was time was 3min. The optimized source dependent
prepared by suitable dilution of stock solution with conditions were as follows.
the same solvent and scanned in the range of Desolvation gas flow- 1000 L/hr
200-400nm to determine the wavelength of • Cone gas flow - 25L/hr
maximum absorbance.
• Capillary Voltages - 3.5 kV
• Cone Voltage- 50 V
Fourier Transformed-Infrared (FT-IR)
• Desolvation temperature - 350°C
Spectroscopy
Infrared spectra covering the region of 4000 to
650cm-1 were conducted for Nifedipine pure drug

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 Preformulation Studies of Nifedipine

Thermal Analysis by Differential Scanning Table 3: Typical MS conditions for related

Calorimetric substance quantification
Thermal properties of pure drugs were analyzed
by using differential scanning calorimeter; TA Parameter Setting
Instruments; Q-20 V24.11 Build 124. 2.08mg of Mode ESI +
the sample was weighed and placed on the
thematically sealed pan; an empty pan was used Capillary voltage 2.5 kV
for blank. Now keep both the pans on respective Cone voltage 20 V
slots. Then samples were heated by maintaining a
temperature range of 20 to 350°C at a ramped Collision Energy Ramp 15 – 45 V
temperature of 10 °C / min, using nitrogen at a (MSMS experiment)
flow rate of 50 mL/min for maintaining the inert Source temperature o
120 C
atmosphere.
Desolvation Temperature o
350 C
Quantitative Assay Content
The content of Nifedipine was determined by Desolvation Gas Flow 650 L hr
UPLC H-Class with PDA detector; Make: Waters
using Acquity UPLC BEH C18; 1.7µm; 2.1mm I.D x
Table 4: Typical gradient elution program for
50mm Length (Make: Waters) previously
related substance quantification
stabilized at 40ᴼC with 0.5mL per minute flow rate
of 0.1%v/v formic acid in water as buffer; a Time Flow
mixture of Methanol and acetonitrile in a ratio of %A %B Curve
(min) (mL/min)
10:90 v/v from the gradient table 2. The standard
and sample solution was prepared with a 0 0.4 98 2 -
concentration of 30µg/mL of Nifedipine in 0.5 0.4 98 2 6
methanol followed by make up the dilutions with
aqueous buffer containing 0.1% v/v formic acid. 7 0.4 60 40 6
The chromatography is carried with 1.0µL 8 0.4 98 2 11
injection volume; detection of analytes was
measured at 254nm. 10 0.4 98 2 11

Drug- Excipients Compatibility Studies

Table 2: Typical liquid chromatography
This is an important feature of pre formulation
gradient program
studies used to evaluate the impact of excipients
Time Line A Line B on physical and chemical stability, dissolution and
(minutes) (%buffer v/v) (%Solventv/v) ultimately bioavailability of the formulation. FT-IR
0.0 95 5 Spectroscopy, DSC studies for the physical
0.5 95 5 mixture, and Accelerated Stability studies for
1.2 70 30 binary mixture of pure drug and individual
2.0 50 50 excipients were performed to assess the
compatibility of excipients with Nifedipine. The
3.0 95 5
blend was mixed and filled in Type I glass vials
4.0 95 5
(open vials & vials sealed with rubber stopper) and
Quantitative Estimation of Related Substance were stored in Stability chamber; Model: TH 400
The impurities related to Nifedipine were S/G (Make: thermo lab) at 40ºC + 2 ºC / 75%
quantified by using UPLC H-Class equipped with R.H for 1 month. The stored compatibility mixtures
Tandem mass spectrometer detector (MS/MS); were tested individually by UPLC, HPLC analysis to
Waters using Acquity UPLC BEH C18; 1.7µm; assess the drug substance purity and impurity
2.1mm I.D x 50mm Length; Waters previously profile.
stabilized at 40ᴼC with 0.4mL per minute flow rate
of 0.1%v/v formic acid in water as buffer; RESULTS AND DISCUSSION
Methanol and acetonitrile in a ratio of 10:90 v/v Solubility studies
from the gradient table 4 with mass spectrometric Solubility studies for saturated solutions were
conditions as given in the table 3. carried out over the pH range of 1.2-6.8. The

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 Preformulation Studies of Nifedipine

data of the solubility studies are shown in table 5.
The solubility of Nifedipine in water at 37°C is
436.3mg/L. Further the solubility is not affected
significantly (P > 0.05) in the buffer solutions in a
pH range of 1.2 to 6.8. From the table 5, it is seen
that Nifedipine is having limited solubility <
450mg/Lower the entire pH range studied.
According to the Biopharmaceutical Classification
System (BCS), Nifedipine is a Class II compound
with low solubility and high permeability. The
absorbance of Nifedipine in 0.1N Hydrochloric
acid and 1% Sodium lauryl sulfate media is in
between 0.4212 to 0.9664 abs from Figure 2
solubility graphs and these absorbance values are
significantly greater than from all other media.
The representing solubility graphs are shown in
Figure 2.

Table 5: Solubility data of Nifedipine

Sr. Nifedipine
Name of Solubility Media
No Solubility (mg/L)
1 Water 436.3
2 0.1N HCl, pH 1.2 462.2
3 0.1NHCl, pH 1.2 + 1% SLS 471.4
3 Acetate buffer, pH 3.0 456.3
4 Acetate buffer, pH 4.0 453.1
5 Phosphate buffer, pH 5.0 451.6
6 Phosphate buffer, pH 6.8 447.3
7 0.1N Sodium hydroxide 434.5

1.2000
Water
1.0000
0.1N HCl; pH 1.2
0.8000
0.1N HCl, pH 1.2
0.6000 + 1%SLS
0.4000 Acetate buffer pH
3.0
0.2000 Acetate buffer pH
4.0
0.0000
0.00 100.00 200.00 300.00 400.00 500.00
Concentration (mg/L)

Figure 2: Typical Solubility graph for Nifedipine

Particle size distribution study represented in the Figure 3 conforms the presence
The study was carried out by using laser diffraction of Dv (10) 1.67µm; Dv (50) 7.18µm; Dv (90)
method on Master sizer 3000 particle size 19.3µm and Dv (95) 23.9 µm particles in
analyzer. The Nifedipine PSD histogram crystalline power by dry dispersion technique.

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 Preformulation Studies of Nifedipine

Figure 3: Typical PSD Histogram for Nifedipine

X-Ray diffraction studies atoms and/or molecules do not possess a

The main characteristics of diffraction line profiles
are 2θ position, peak height, peak area, and
shape (characterized by, e.g., peak width, or
asymmetry, analytical function, and empirical
representation). A crystalline structure of
Nifedipine implies that the structural units (i.e. the
unit cells) are repeated in a long-range order. The
distinguishable crystal lattice. From the diffract
graph represented in Figure 4, the diffraction line
profiles are 2θ values for diffraction peaks are at
8.0627°, 10.4088°, 11.7504°, 11.9178°,
12.9763°, 13.3525°, 14.6803°,16.1915°
confirms to form D solid phase.

Figure 4: Pattern of X- ray Diffraction of Nifedipine

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 Preformulation Studies of Nifedipine

CHARACTERIZATION 200nm to 400nm. The 30ppm of Nifedipine

UV-Visible Spectroscopy standard solution is prepared in methanol. The ƛ-
The UV spectra of APIs were scanned by using the max values observed at 235 nm and at 329nm
Shimadzu UV-2600 instrument in a range of from the figure 5.

Figure 5: Typical UV Spectrum for Nifedipine

Fourier Transformed Infrared Spectroscopy
The FT-IR spectrum of Nifedipine pure drug from
the Figure 6 shows characteristic peaks which
consist of a broad peak at 3332 cm-1 indicating
the >N-H stretching ( pyridine moiety), the
absorption peaks at 1529cm-1 is due to (N-O)
asymmetric stretching, and at 1349 cm-1 is due to
(N-O) symmetric stretching ( Aryl- nitro), at 1680
cm-1 is due to >C=O stretch (ester group), at
1227 cm-1 is due to C-O stretch, at 2953cm-1,
2996 cm-1 are due to C–H stretching and
absorption at 1623 cm-1 representing ring
breathing band (pyridine).

Figure 6: Typical FTIR Spectrum for Nifedipine

Nuclear Magnetic Resonance Spectroscopy
Chemical shift values are reported on the δ scale
in ppm relative to TMS (δ 0.00) as internal
standard. The 1H NMR spectrum of compound
from figure: 7 shows chemical shift values in the
region of 7.68 to 7.24ppm corresponding to
protons at C-3, C-5, C-4, and C-6 of phenyl
group. The Prominent signals at 5.66ppm
ascribed to -CH proton and at 5.72ppm to -NH
proton of the dihydropyridine ring. The singlet
observed at 2.34ppm represents methyl group at
C-2, and C-6 on the dihydropyridine ring. The
spectrum also displays a singlet at 3.59ppm
attributable to methoxy group at C-3, and C-5 of
the dihydropyridine ring. Chemical shifts values
assigned to various protons are listed in Table: 7.

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 Preformulation Studies of Nifedipine

The 13CNMR spectrum from figure 8, reveals
chemical shift values in between 123.8ppm to
132.7ppm assigned to carbons of phenyl group.
The signal at 34.5ppm attributed to C-4 carbon.
The signal at 51.0ppm was assigned to two
methoxy group. The chemical shift value at
19.5ppm ascribed to two methyl group. The signal
observed at 103.7ppm was assigned to
quaternary carbons of C-3 andC-5. The chemical
shift values at 142.0 and144.7 ppm was assigned
to quaternary carbons of C-2 and C-6. The signal
at 167.5ppm assigned to carbon atoms of two
keto group. Chemical shifts values assigned to
various carbons are listed in Table: 8. Finally,
H1/C13–NMR spectra confirms to Nifedipine
Chemical Structure.

Table 7: 1HNMR chemical shift values for Nifedipine

Position Group δ H(ppm)
2 and 6 CH3 2.34 (s, 6H)
3 and 5 OCH3 3.59(s, 6H)
1 NH 5.72(s, 1H)
4 CH 5.66(s, 1H)
3’ of phenyl CH 7.68 (dd, 1H, J=8.3 Hz, 1.4Hz)
5 ‘of phenyl CH 7.51 (dd, 1H, J=8.3 Hz, 1.4Hz)
4 ‘of phenyl CH 7.45 (td, 1H, J=7.6 Hz, 1.4Hz)
6’ of phenyl CH 7.24(m,1H)

Table 8: 13CNMR chemical shift values for Nifedipine

Position Type of δ C (ppm)
Carbon
C- 2 and C-6 CH3 19.5
C- 4 CH 34.5
C-3 and C-5 OCH3 51.0
C-3 and C-5 qC 103.7
C-3 ‘ CH 123.8
C-4 ‘ CH 127.0
C-5 ‘ CH 131.0
C-1 ‘ C 132.7
C- 2 qC 142.0
C- 6 qC 144.7
C-3 and C-5 C=O 167.5

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 Preformulation Studies of Nifedipine

Figure 7: 1HNMR spectrum for Nifedipine

Figure 8: 13CNMR spectrum for Nifedipine

Mass Spectrometry negative ionization mode, based on this,

The molecular ion provides the molecular mass of conformed that the molecular weight of Nifedipine
the analyte. The molecular ion masses for is 346.3 as in the mass spectrum shown in Figure
Nifedipine was predicted in ES combined mode. 9.
The molecular ion (M-1) -detected at m/z 345.2 in

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 Preformulation Studies of Nifedipine

Figure 9: Typical Mass spectrum for Nifedipine

Thermal Analysis by Differential Scanning
Calorimetric
The differential scanning calorimeter (DSC) is a
fundamental tool in thermal analysis. Melting is an
endothermic process, requiring the absorption of
heat. The temperature remains constant during
melting despite continued heating from 20 to
350°C with a rate of 10°C/min. The DSC thermo
gram of Nifedipine from the Figure 10, the peak
was observed at 172.77°C and the onset value is
171.27°C represents the characteristic
endothermic peak of Nifedipine and energy
required for melting is 111.2J/g.

Figure 10: Typical DSC graph for Nifedipine

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 Preformulation Studies of Nifedipine

Assay Content and Related Substances
The purity of Nifedipine by UPLC is >99.8%. The
% of impurities A and B and other impurities by
UPLC-MS/MS are <0.1% and <0.01%
respectively and results are shown in Table 9.
Drug-Excipients Compatibility studies
To meet the target product profile, tablet
excipients with appropriate functionality were
assessed. Based on scientific and prior
knowledge, the chosen excipients had been used
successfully for a roller-compacted formulation.
The FT-IR spectra of the Nifedipine and excipients
were overlaid to identify probable chemical
interaction between them. The FT- IR spectra of
HPMC E5 and HPMC E15 show stretching
vibrations of the hydroxyl group at 3445cm-1 and
3455cm-1. Both the polymers show bending
vibrations of hydroxyl group at same wavelength
that is 1644 cm-1, as well as aliphatic stretching
of C-H appear at 2905cm-1. Characteristic
absorption bands of C-O in C-O-C group of
glucose molecules of HPMC E5 and E15 observed
at 1059cm-1 and 1060cm-1 and both polymers
show at C–H bending at 1337 cm–1.
The spectrum of ethyl cellulose shows
characteristic absorption bands for C-O stretching
vibration in the C-O-C linkage of glycoside bonds
is at 1052 cm–1 and C–H stretching bands at
2890 cm–1 and 2980 cm–1. The absorption at
1369 cm–1 corresponds to C–H bending.
The FT IR spectrum of Xanthan gum exhibits a
prominent absorption band at 3400 cm-1 is due to
OH groups interacting with a water molecule, the
absorption peak at 1692cm-1 is ascribed to C=O
stretching of esters, and at 1615cm-1 is for COO-
stretching vibration. The absorption band at
1052cm-1 corresponds to the C-O stretching of C-
O-C glycoside linkage bonds. Compared to the
absorption bands from each component, it was
observed that the FT-IR spectrum of Nifedipine
showed a superposition of peaks from the
excipients, indicated that there were no
intermolecular interactions between them from
Figure 11.
The thermal profile of Xanthan gum discloses a
melting point in between 90-120ºC, the
endothermic peak observed for Xanthan gum at
100.2ºC. While the drug melting peak is quite
visible in the physical mixture of Nifedipine and
Xanthan gum (1:1) thermogram at 173.5ºC,
Therefore the thermograms of the physical mixture
showed that no interaction between Nifedipine
and Xanthan gum. The thermograms of pure
Nifedipine and Xanthan gum /Nifedipine mixture
are shown in the Figure 12
In the physical mixture (1:1) thermogram, the drug
melting peak still appears at 173.5ºC, indicating
that there was no physiochemical interaction
between Nifedipine and HPMC. The thermograms
of pure Nifedipine and Nifedipine /HPMC mixture
are shown in the Figure 13.
The DSC thermogram of pure Nifedipine shows a
sharp endothermic peak at 172.7ºC and a similar
endothermic peak was observed at 173.5ºC for
the controlled release granules of Nifedipine
indicated that all selected excipients were
compatible with Nifedipine.
The Assay result from Table 9 for Nifedipine is
greater than 99% and the relative standard
deviation is <1.0% from the initial results to 30th-
day results. The calculated confidence interval at
95% level from descriptive statistics is 0.21,
represents no significant change in the assay
results from the initial. The related impurities
Nifedipine nitrophenyl pyridine analogue
(impurity A), Nifedipine Nitroso phenyl pyridine
analogue (impurity B) were <0.1% from entire
study intervals.

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 Preformulation Studies of Nifedipine

Figure 11: Overlay FT-IR spectra for Nifedipine and Excipient

Figure 12: DSC thermogram for Nifedipine and Nifedipine and Xanthan gum mixture

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 Preformulation Studies of Nifedipine

Figure 13: DSC thermogram for Nifedipine and Nifedipine and HPMC mixture

Table 6: Compatibility results of Nifedipine API and Nifedipine with Excipients Mixture

Condition % Impurities
Assay
Mixture Name at 40°C/75%RH A B Any other
(%)
Time period (%) (%) impurity (%)
Initial (0 Hour) 99.8 0.03 0.04 BDL (<0.01%)
7th Day 99.7 0.03 0.05 BDL (<0.01%)
Nifedipine API
15th Day 99.9 0.04 0.06 BDL (<0.01%)
30th Day 99.6 0.06 0.07 BDL (<0.01%)
Nifedipine + Initial (0 Hour) 99.7 0.04 0.05 BDL (<0.01%)
HPMC K-15 7th Day 99.8 0.03 0.04 BDL (<0.01%)
15th Day 99.6 0.05 0.07 BDL (<0.01%)
30th Day 99.8 0.04 0.06 BDL (<0.01%)
Nifedipine + Initial (0 Hour) 99.6 0.06 0.06 BDL (<0.01%)
Carbomer 934P 7th Day 99.5 0.05 0.07 BDL (<0.01%)
15th Day 99.8 0.05 0.07 BDL (<0.01%)
30th Day 99.7 0.06 0.05 BDL (<0.01%)
Nifedipine + Initial (0 Hour) 99.4 0.04 0.05 BDL (<0.01%)
HPMC E-5 7th Day 99.6 0.03 0.06 BDL (<0.01%)
15th Day 99.7 0.06 0.04 BDL (<0.01%)
30th Day 99.5 0.05 0.07 BDL (<0.01%)
Nifedipine + Initial (0 Hour) 99.6 0.06 0.06 BDL (<0.01%)
Colloidal silicon 7th Day 99.8 0.04 0.05 BDL (<0.01%)
dioxide 15th Day 99.4 0.05 0.06 BDL (<0.01%)
30th Day 99.6 0.06 0.07 BDL (<0.01%)
Nifedipine + Initial (0 Hour) 99.7 0.06 0.08 BDL (<0.01%)
Ethyl cellulose 7th Day 99.8 0.05 0.04 BDL (<0.01%)
15th Day 99.4 0.07 0.04 BDL (<0.01%)
30th Day 99.5 0.07 0.05 BDL (<0.01%)
Nifedipine + Initial (0 Hour) 99.6 0.04 0.03 BDL (<0.01%)
PVP K-30 7th Day 99.5 0.06 0.07 BDL (<0.01%)
15th Day 99.8 0.06 0.05 BDL (<0.01%)
30th Day 99.7 0.07 0.04 BDL (<0.01%)
Nifedipine + Initial (0 Hour) 99.7 0.06 0.07 BDL (<0.01%)
7th Day 99.8 0.05 0.04 BDL (<0.01%)

83 | International Journal of Pharmaceutical Research | Jul - Sep 2020 | Vol 12 | Issue 3

 Preformulation Studies of Nifedipine

Crosscormellose 15th Day 99.6 0.03 0.06 BDL (<0.01%)

sodium 30th Day 99.5 0.04 0.06 BDL (<0.01%)
Nifedipine + Initial (0 Hour) 99.6 0.04 0.05 BDL (<0.01%)
Xantham Gum 7th Day 99.7 0.03 0.03 BDL (<0.01%)
15th Day 99.8 0.05 0.04 BDL (<0.01%)
30th Day 99.6 0.06 0.07 BDL (<0.01%)
Nifedipine + Initial (0 Hour) 99.5 0.06 0.07 BDL (<0.01%)
red ferric oxide 7th Day 99.6 0.08 0.05 BDL (<0.01%)
15th Day 99.4 0.06 0.06 BDL (<0.01%)
30th Day 99.3 0.04 0.06 BDL (<0.01%)
Nifedipine + Initial (0 Hour) 99.4 0.06 0.07 BDL (<0.01%)
Zinc oxide 7th Day 99.3 0.07 0.08 BDL (<0.01%)
15th Day 99.6 0.06 0.05 BDL (<0.01%)
30th Day 99.7 0.04 0.06 BDL (<0.01%)
*BDL: Below detection limit

CONCLUSION excipients were compatible with Nifedipine and

Pre formulation play a significant part in the
selection of drug candidate, formulation
components, and drug product manufacturing
process. Pre formulation studies give directions for
design of formulation in choice of drug form,
excipients and composition. Physical structure
helps in adjustment of biopharmaceutical and
pharmacokinetic properties. Pre formulation
studies on Nifedipine have been performed. The
water solubility of nifedipine is 436.3mg/L.
According to the Biopharmaceutical Classification
System (BCS), Nifedipine is a Class II compound
with low solubility and high permeability. The PSD
of Nifedipine indicated that it is a crystalline
powder.
X-ray diffraction pattern of Nifedipine diffraction
peaks confirms the D form solid state. The
chemical structure of nifedipine was confirmed by
UV-Visible Spectroscopy, FT-IR Spectroscopy, NMR
Spectroscopy, Mass Spectrometry and melting
point was determined by thermal analysis by DSC.
The solid-state stability by FT-IR, DSC, accelerated
stability studies in presence of tablet excipients has
been conducted. The FT-IR overlay spectral studies
indicated that there were no intermolecular
interactions between Nifedipine and selected
excipients. In the DSC thermograms of physical
mixture, and DSC graph of Nifedipine controlled
release granules, the drug melting peak was quite
visible confirms that no physiochemical interaction
between Nifedipine and excipients. Accelerated
stability studies of blend at 40ºC + 2 ºC / 75%
R.H for 1month, the % purity of Nifedipine is >
99% and % of Nifedipine impurities A and B with
in prescribed limits. Therefore, the selected
employed to assist in the preparation of controlled
release granules of this therapeutic agent and
further development of anti-hypertensive bilayer
tablets.
Acknowledgements
This research was sponsored and supported by
M/s SM Pharmaceuticals Sdn. Bhd, Malaysia for
procuring Materials, Chemicals, Reference
Materials, and for their valid support for testing of
samples of the research study.
Ethical Clearance
This part of research work has not carried on any
animal or Human, and this work was carried on
chemical and instrumental analysis.
Source of Funding
This research was in part of my Ph. D research
work and the funding was sourced from SM
Pharmaceuticals Sdn Bhd, Malaysia.
Conflict of Interest
The SM Pharmaceuticals Sdn Bhd, Research and
Development Centre had no association in the
writing of the manuscript as well as in the decision
to submit the article for publication. The authors
have indicated that they have no competing
interest regarding the content of this article
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