EFFECT OF PARTICLE SIZE OF MICRO AND NANO IBUPROFEN dissolution rate

IBUPROFEN TABLET IN THAT MAKE

BY DRY GRANULATION

Sheila Aprida Eka Putri, inding Kusmayadi, Fahjar Prisiska

Faculty of Pharmacy and Science, University of Muhammadiyah Prof. Dr. Hamka,

Jakarta

Abstract

Ibuprofen is one of a class of anti-inflammatory drugs (NSAIDs) are widely used as an analgesic,
anti-inflammatory and antipyretic. The dissolution rate or speed of the drug dissolves relatively
insoluble in water has long been a problem in the pharmaceutical industry. Ibuprofen including a
model compound Biopharmaceutical Classification System (BCS) II, high permeability low
solubility. The study aims to improve the dissolution rate by reducing the particle size.
Implementation of this study begins by minimizing the particle size by using the tools of high
enery miling (HEM) E3D (LIPI) to be a nano particle size. Then compressed into a tablet that size
smaller then crushed into granules and then compressed into tablets kambali back and test the
disintegration time, uniformity of weight, weight diversity, fragility and physical visits tablets.
These results indicate that ibuprofen tablet which has a particle size of microparticles and
nanoparticles are not so have differences, but at the micro tablet has absorption value reaches
100%. Dimna uptake results in micro-reaching 106.67% with the initial uptake value padamenit
to 5 was 39.05% and the absorbance at only 60 minutes to reach 88.65% in early absorption value
at only 5 minutes to 16.54%.

Keywords: Ibuprofen, microparticles, nanoparticles, dissolution rate.

PRELIMINARY

Ibuprofen is one of the drugs poorly soluble in water and showed poor solubility, because it
has a hydrophobic structure (and Bushra Aslam, 2010; Mansouri, et al., 2011). In addition
ibuprofen has a high cohesiveness power resulting in poor flowability (Bushra and Aslam, 2010).
Ibuprofen is one of a class of anti-inflammatory drugs (NSAIDs) are widely used as an analgesic,
anti-inflammatory and antipyretic.

The dissolution rate or speed of the drug dissolves relatively insoluble in water has long been
a problem in the pharmaceutical industry. Ibuprofen including a model compound
Biopharmaceutical Classification System (BCS) II, high permeability low solubility (Sofwan,
2013) .In some medications, dissolution is a step pacesetters onset of action and therapeutic

1
activities, therefore an attempt to improve the dissolution of a drug is often necessary (Nugroho ,
et al., 2010).
Factors that affect the rate of dissolution one of which is a particle size. Effect of drug particle
size on the rate of dissolution and bioavailability comprehensively demonstrated by the drugs
gastrointestinal absorption rate is limited by the dissolution and particle size reduction generally
increase the rate of absorption and bioavailability of total. The dissolution rate is proportional to
the surface area of the active substance. Because the surface area increases with a decrease in
particle size (Siregar, 2010).
Steps can be taken to increase the rate of dissolution one is to reduce the particle size of
ibuprofen in the micro and nano scale. Size of particles thus often referred to as nanoparticles.
Nanoparticles described as the formulation of a dispersed particle in the nanometer size or scale
of thousandths of a micron. Particle size limitation is certain for this system there are differences
because of nanoparticles on different drug delivery systems with nanoparticle technology in
general. In some sources said that the new nanoparticles show distinctive properties in diameter
under the 1-1000 nm, but this limit is difficult to achieve for a system of nanoparticles as drug
delivery systems. Drug nanoparticles in general should contain sufficient amounts of drug within
the matrix of the particles of each item, so it requires a relatively large size compared to the non-
pharmaceutical nanoparticles. Nevertheless generally remains agreed that the nanoparticles are
particles having sizes below 1 micron (Sofwan, 2013).
Microparticles and nanoparticles may be obtained by various methods such as crushing
(crushing), grindin (milling), spray drying (spray drying) and freeze drying (freeze drying)
(Mansouri, et al., 2011). The most common method is the media mill which is a particle size
reduction technology and proven reliability (Sofwan, 2013).
Based upon the description above, will be examined on the particle size variation in perfomed
tablet formulations of ibuprofen and its influence on the dissolution rate

research methodology

Tool

The tools used in this study include analytical balance, high energy milling (HEM) E3D
(LIPI) with grinding media such as ceramic balls diameter of 2 mm, scanning electron microscopy,

2
particle size distribution, tapped density tester, calipers, millimeter scrub, hardness tester ,
Friability tester, desintegrant tester, disolution tester, UV-vis spectrophotometer.
material

The materials used in this study include micronized Ibuprofen, Ibuprofen raw stsandar,
Polivinivirolidon (PVP), talc, Mg. Stearate, Lactose, distilled water, alcohol 96%, NaOH,
KH2PO4.
Preparation of nanoparticles of ibuprofen
Enter ibuprofen and ceramic balls diameter of 2 mm, with a ratio of 1gram ibuprofen and
10 balls kramik put in a room (chamber) and close the chamber, and means of high energy milling
(HEM) E3D with a speed of 1400rpm for 30 hours. Measuring particle size Particle size analyzer
(PSA) (Sofwan 2013).
Particle size analyzer (PSA)
Measurements were made after powder particles with pelanetari ballmilling diperkeci to
measure nano particles, then immediately in measuring nanoparticles, Before analysis, the drug
suspension is diluted with pure water as much as 0.2 mg / ml. then read immediately to prevent
precipitation. (Mansouri, et al., 2011)
Determination of the maximum wavelength ibuprofen
Make a stock solution of Ibuprofen was prepared by dissolving 100 mg of Ibuprofen in 100
mL of phosphate buffer at pH 7.2 in order to obtain concentration. Taken from the mother liquor
then added 5 mL of phosphate buffer pH 7.2 in 25 mL. Ibuprofen solution uptake was measured
at a wavelength of 264 nm using a UV-VIS spectrophotometer. Then made to the wavelength
absorption curve (Clarke's, 1986).
Preparation of the calibration curve ibuprofen
Make a standard solution of Ibuprofen in phosphate buffer pH 7.2 was made at a
concentration of 90, 180, 270, 360, 450μg / ml, which is obtained from the calculation of the
maximum wavelength. Then the absorption determined at the maximum wavelength (Syofyan et
al 2015).
Preparation of granules
Weigh weight ibuprofen and pvp sesusai listed tat teble, input into a homogeneous mix
container, weigh primogel, Talcum, mg stearate and lactose sesuasi with tables. Then enter
primogel, Talcum, mg stearate and lactose into the container stir homogeneous. A mixture was

3
made using the slug punch with a diameter of 2.5 cm large with high pressure. Results slug then
destroyed and sieved with a sieve (mesh no.18).
Evaluation of properties of the granules.
Table 2 Formula Ibuprofen Tablet
material FI FII Function
microns 40% - Active
ibuprofen
nano - 40% substance
PVP 3% 3% fastener
Pimogel 4% 4% crusher
Talk 1% 1% lubricants
mg stearate 1% 1% lubricants
lactose ad 100% ad 100% filler
Description: weight of 500mg per tablet, made two formula and every formula is made 500tab.
flow time
A simple cover in place it in the outlet funnel and filled with granules are weighed first,
the 100,0gram. When the cover is opened, then record the time it takes the granules to come out.
By dividing the mass of the granules with the powder exit time (gram / sec). Syaratan flow time
was 100.0 grams of ≤ 10min (Siregar 2010).
Test the angle of repose
A total of 100.0 grams of granules are fed into a funnel which has been closed. The granules
were left mengalirbebas funnel. Allow the granules fall onto graph paper block. Then will form a
stable cone and formed an angle of inclination, and then calculated the angle silence (Siregar
2010). Dwell angle values range from 250 to 450, with low value menunjaukan better
characteristics.

compressibility test
The granules are put into a measuring cup 100 ml, 100 ml measured up high. Then the
granules diketukan with tapped density tester beats 500 times 3 times treatment. Then note the
volume of the granules after the tap and weighed (Siregar 2010).
Table 1. Terms compressibility

4
 % Compressibility flow properties
5-15 Very well
12-16 Good
18-21 Good
25-32 Bad
33-38 Very bad
> 40 Very bad

Test granule distribution

Weighed 100.0 grams of granules, and then put into a sieve mesh sieve terraced with no
18, 20, 24, 30, 40. Then the sieving machine is turned on at a frequency of 30 Hz for 25 minutes.
Then weighed the weight of the granules retained on each sieve (Lachman et al. 1994).
tabletting
The granules that have been evaluated and then printed using a tablet printer engine. Next
do the evaluation
Tablet evaluation
Test weight uniformity
Twenty tablets were weighed entirely carefully calculated weighted average. Weighed one
at a tablet, compared with the average weight of the tablet. Terms uniformity of tablet weight
assigned to tablets with a weight of more than 300 mg is no more than 2 tablets whose weight
deviates from the weighted average of greater than 5% and no one tablet was the weight deviates
from a weighted average of more than 10 % (Anonymous, 1995).

Tablet hardness test

Ten tablets were tested, one by one placed on the anvil hardness testing machine figures
shown on a scale showed tablet hardness in units of Kg. Good tablet hardness is (4-8) Kg (Lachman
dkk.1994)
Tablet friability test
Tablets are to be tested as many as 10 tablets, first cleaned of dust and weighed carefully.
Tablets are then inserted into friabilator, and played as many as 100 rounds for 4 minutes, so the

5
rotation speed of 25 rpm. When finished, remove the tablet from the appliance, clean of dust and
weigh it carefully. Then calculated the percentage loss of weight before and after treatment. Tablet
considered good when the fragility of ≤ 0.5 to 1% (Lachman et al 1994).

𝑊0−𝑊1
% Brittleness = × 100% .................................................. .. (4)
𝑊0

Information: W0 = Weight of the tablet before entered into the tool

W1 = Weight of tablet after inserted into the tool
disintegration
The tablet to be tested (for 6 tablets) is inserted into each tube, closed with a cover and the
baskets are raised and lowered in the medium of water with a temperature of 37 ° C. In another
monograph mentioned medium was simulated gastric solution (gastric fluid). Disintegration time
is calculated based on the most recent tablet destroyed. Terms of disintegration time for the tablet
is not coated≤ 15 minutes, for a sugar-coated tablets and coated nonenterik less than 30 minutes,
while for enteric coated tablet should not be destroyed within 60 minutes.
diversity weight
Weigh sesakma 10 tablets one by one and calculate the average weight - the average. Of
the Promised assay, were obtained as yangtertera in each - each monograph, calculate the amount
of active ingredient from each - each of 10 tablets with active substance is distributed
homogeneously assumption (Anonymous 1995).
assay
Take 20 tablets at random, weighed and determine the average weight. The twenty tablets
in crushed to a powder, then weighed sesakma 100mg equivalent. Furthermore dissolved in
phosphate buffer pH 7.2 in 100ml. Then pipette in 1 ml and dissolved in phosphate buffer pH 7.2
in 10 ml. Absorbance at the maximum wavelength with uv sepektrofotometer tool.
dissolution
The dissolution test using a model of type 2 with 60 rpm, dissolution medium 900ml of
phosphate buffer pH 7.2 and 60 minutes. Procedures done fixing the amount of C13H18O2,
dissolved by measuring absorbance of test solution filtrate, Juka need to dilute with dissolution
and absorption media ibuprofen BPFI standard solution in the same medium at a wavelength of

6
approximately 264nm absorbance maksumum. Tolerance within 60 minutes should dissolve not
less than 80% (Q) C13H18O2, from the amount listed on the label. (Anonymous 1995).