FORMULATION AND EVALUATION OF NIMODIPINE BY SOLID DISPERSION

WITH SUITABLE CARRIER

ABSTRACT
Nimodipine is as acting calcium channel blocker used to treat chronic angina, vasospastic
angina and hypertension. In present research work an attempt has been made to prepared of
nimodipine with increased rate of dissolution may leads to increase bioavailability.
Formulation of complex of poorly soluble nimodipine prepared by the solid dispersion with
different ratio (1:1), (1:2), (1:3) PVP K30, PEG-4000, and PEG-6000 using solvent
evaporation method. Solid dispersion was characterized for IR, DSC an in vitro dissolution
studies. FTIR study revealed that drug was stable in solid dispersions. The drug content was
found to be high and uniformly distributed in the all formulation. The in vitro dissolution
studies carried using USP type XXVII (paddle) type dissolution apparatus. The prepared
dispersion showed marked increase in the dissolution rate of Nimodipine than that of pure
drug. The dispersion with PVP K30 (1:3) by solvent evaporation method showed faster
dissolution rate (99.4%) as compared to other dispersion with PEG 4000 and PEG 6000
whichever prepared by solvent evaporation method. It concluded that dissolution of the
Nimodipine could be improved by the solid dispersion and PVP K30 based solid dispersion
was more effective in enhancing the dissolution.

Keyword: Nimodipine, solid dispersion, PEG4000, PEG6000, PVP K30, dissolution









INTRODUCTION
Nimodipine is a 1,4-dihydropyridine calcium channel blocker. Nimodipine is a poorly water-
soluble drug and has a low bioavailability and limited clinical efficacy. For low
solubility/high permeability drugs, dissolution plays an important role in their absorption
Recently, for the purpose of improving oral bioavailability, a variety of techniques have been
used to enhance the solubility in water and in biological fluids at physiological pH values,
such as salt formation, solubilization, particle size reduction, solid dispersion, self-dispersing
lipid formulations and the use of inclusion compounds based on cyclodextrin The increase in
dissolution rate from solid dispersions can be attributed to one or a combination of the
following factors: a reduction of particle size of the drug, a solubilizing effect on the drug by
the water soluble carrier, enhancement of the wettability and dispersibility of the drug by the
carrier material, and the possible formation of a metastable dispersion that has a greater
solubility resulting in a faster dissolution rate. Carriers used in the formation of solid
dispersions are PEG4000, PEG6000 and PVPK30. Polymers are freely soluble in water and
are available in various molecular weights. The molecular size of both polymers favors the
formation of interstitial solid solutions. The purpose of our study was to formulate the
nimodipine solid dispersions using solvent evaporation method employing freely water-
soluble carriers, PEG-4000, PEG6000 and PVP K30 and to evaluate the effect of the
polymers on the dissolution rate of the drug.

MATERIALS AND METHODS
Materials
Nimodipine powder was received as gift sample from USV labs Mumbai. PEG4000,
PEG6000 and PVPK30 were procured from Chemdyes corp., Rajkot. All other chemicals
used are of analytical grade.
Preparation of solid dispersions in drug and various polymer ratios
Solid dispersions of Nimodipine were prepared at various polymer weight ratios by solvent
evaporation method. Amount of carrier was varied keeping amount of Nimodipine constant
(1:1, 1:2, 1:3). Accurately weighed amount of Nimodipine & PVP, PEG are dissolved in the
methanol respectively. Then this solution was placed on the hot plate at 60 C with magnetic
stirring until the solvent evaporates. The solid dispersion prepared above was scrapped, dried,
and was passed through sieve no.60 and stored in the dessicator until further use.


Table:1 Formulation of solid dispersion











Drug Content
Nimodipine content of the complexes was estimated by UV spectrophotometric method.
Nimodipine from accurately weighed samples was extracted into methanol and the extracts
were suitably diluted with 0.1N HCl and assayed for nimodipine content by measuring the
absorbance at 319 nm using 0.1N HCl as blank.
FT-IR Studies
Structural changes and lack of a crystal structure can lead to changes in bonding between
functional groups which can be detected by infrared spectroscopy. The FT-IR spectrum was
obtained by using FT-IR Spectrophotometer.
Differential Scanning Calorimetry
DSC is a thermo analytical technique in which the difference in the amount of heat required
to increase the temperature of a sample and reference are measured as a function of
temperature. Both the sample and reference are maintained at nearly same temperature
throughout the experiment.
IN VITRO DISSOLUTION
The dissolution study was carried out using USP XXVII Apparatus I. The dissolution
medium was 900ml of phosphate buffer with a PH of 6.8 kept at 37 10c. The solid
dispersions containing of Nimodipine was taken in a muslin cloth and tied to the rotating
paddle kept in the basket of dissolution apparatus, the paddle was rotated at 50 rpm. Samples
of 5ml were withdrawn at specified time intervals and analyzed spectrophotometrically at
319nm using Shimadzu 1700 UVvisible spectrophotometer, the samples withdrawn were
replaced by fresh buffer solution. Each preparation was tested in triplicate and the mean
values were calculated.
RESULTS AND DISCUSSION
Batch
Code
Composition Method Ratio
SD1 Nimodipine+ PVP-K30 Solvent evaporation 1:1
SD2 Nimodipine + PVP-K30 Solvent evaporation 1:2
SD3 Nimodipine + PVP-K30 Solvent evaporation 1:3
SD4 Nimodipine+ PEG 4000 Solvent evaporation 1:1
SD5 Nimodipine+ PEG 4000 Solvent evaporation 1:2
SD6 Nimodipine+ PEG 4000 Solvent evaporation 1:3
SD7 Nimodipine+ PEG 6000 Solvent evaporation 1:1
SD8 Nimodipine+ PEG 6000 Solvent evaporation 1:2
SD9 Nimodipine+ PEG 6000 Solvent evaporation 1:3
FTIR Studies
The FTIR spectra of the physical mixture of the formulations (Nimodipine, PVPK30, PEG
4000, PEG 6000) were compared with the FTIR spectra of the pure drug. FTIR spectroscopic
studies conducted for possible drug carrier interaction. FTIR spectra of pure drug & solid
dispersion indicated no significant evidence of chemical interaction between drug and carrier.
This confirms the stability of drug with its solid dispersion shown in figure 1.

Figure: 1 IR Spectrum of A) Nimodipine B) Nimodipine + PVP K30 SD C) Nimodipine +
PEG4000 SD D) Nimodipine + PEG6000 SD. prepared by solvent evaporation method

Differential scanning calorimetry

Figure: 2 DSC thermograms of, A) Pure Nimodipine B) Nimodipine+PVPK30 C)
Nimodipine+PEG4000 D) Nimodipine + PEG6000
DSC thermo grams for pure drug and physical mixture were obtained. The thermogram of
pure drug exhibited the single endothermic peak at around 198C as the drug melting point
lies around 180-195C.In case of physical mixture of drug with carrier, the drug peak was
shifted to lower temperature of 195C with reduced intensity which may be due to baseline
shift and an additional peak at 152C observed due to presence of carrier. Baseline shifts may
be caused by changes in sample weight, heating rate or the specific heat of the sample. A
change in specific heat often occurs after the sample has gone through a transition such as
crystallization or melting.

EVALUATION OF SOLID DISPERSION
DRUG CONTENT
The highest percent drug content was observed with PVP-K30 solid dispersion in ratio 1:3
(SD3) (99.4%) as compared to PEG-4000 and PEG6000 The in vitro drug release was
increased in the manner of pure drug <PEG-4000<PEG-6000< PVP-K30.
Table: 2 Drug content for different Solid Dispersion
Formulation code
% Drug release
Nimodipine
52.5 0.06
SD1 94.1 0.05
SD2 95.9 0.05
SD3 99.4 0.03
SD4 84.4 0.01
SD5 89.4 0.05
SD6 94.3 0.01
SD7 84.7 0.02
SD8 85.3 0.05
SD9 95.8 0.03

IN-VITRO DRUG RELEASE STUDY

The dissolution profile of solid dispersion of Nimodipine with prepared by different carrier
by solvent evaporation method was summarized in Table 3 The percentage of dissolved drug
increased substantially when formulated as solid dispersion compared with the nimodipine
alone.

Table: 3 comparison of cumulative % drug release of different SD


Figure: 3 Comparative in vitro release profile of different formulation




0
20
40
60
80
100
120
0 20 40 60 80 100
SD1
SD2
SD3
SD4
SD5
SD6
SD7
SD8
SD9
Cumulative % drug released* SD
TIME
(min)
NMD*
SD1 SD2 SD3 SD4 SD5 SD6 SD7 SD8 SD9
0 00 00 00 00 00 00 00 00 00 00
15
6.35

3.61
20.2

1.37
22.8

2.35
24.7

2.3
8.9

1.67
11.2

1.21
12.5

1.55
10.5

1.55
13.5

0.6
18.2

2.68
30
17.98

2.20
44.18

1.79
47.8

2.18
50.13

1.7
19.03

0.28
20.14

2.25
21.55

1.35
28.09

0.78
28.24

0.78
31.60

1.79
45
29.88

4.10
73.28

2.05
74.13

0.52
76.46

2.21
31.04

2.02
33.15

3.41
36.67

2.64
43.73

1.45
42.73

0.45
46.33

2.27
60
42.8

4.50
92.8

0.16
93.02

0.28
98.83

1.58
45.35

1.65
47.84

1.63
48.38

1.02
61.46

1.67
60.46

1.35
65.36

0.17
75
58.03

1.10
93.8

1.38
93.24

0.25
98.93

0.9
65.06

0.79
67.10

1.22
69.63

1.62
78.3

3.24
78.3

3.24
81.14

1.25
90
58.35

2.50
93.99

0.5
94.02

1.24
99.88

0.29
80.41

0.18
83.54

0.37
84.22

1.19
92.06

1.11
90.5

1.78
95.48

0.9
From the results shown above it was clear that PVP K 30 has greater potential to dissolve
nimodipine than PEG 4000 and PEG 6000. This phenomenon was attributed to higher degree
of hydrophilicity of PVP K 30.During dissolution of the solid dispersion the polymer creates
a microenvironment which prevents the amorphous drug from recrystallization after being
dissolved in the dissolution medium. It was not surprising that the maximum release increases
with the increase of carrier concentration. From dissolution profile of all complexes,
formulation prepared with solvent evaporation method using different carrier. In 1:3 ratio
(SD3) has greater cumulative % drug release among different complex.
CONCLUSION
Solid dispersions of Nimodipine prepared by solvent evaporation method showed highest
invitro dissolution enhancement as compared to pure Nimodipine and dispersions prepared
by physical mixture and cogrinding method. The Invitro results of formulations SD3
revealed that an increase dissolution accompanied by an increase in the amount of
Nimodipine dissolved. Finally it can be concluded that improved drug dissolution achieved
by formulating Nimodipine as solid dispersion systems with PVP K30 (1:3).
ACKNOWLEDGEMENT
The authors gratefully acknowledge the principal and assistant professor, Shri Satsangi
Saketdham Ram Ashram Group of Institutions, Faculty of Pharmacy, Vadasma, Gujarat for
providing necessary facilities to carry out this research work.