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Jurnal Biofarmasetika dan Farmakokinetika 2017

THE EFFECT OF DISOLUTION DEPENDS TO PARTICLE SIZE OF


METAMPIRON AND ASCORBIC ACID DRUGS

Andre Mahesa, Dapid Caniago, Indah Putri Ramadhany, Merina Septia, Sandy Yoga
R, Septia Nurhaliza, Suryani, Ulfa Salyanti

Pharmacy, Faculty of Mathematics and Natural Sciences,

Sriwijaya University, Indralaya

Email: farmasiunsri2015@gmail.com

ABSTRACT

The comparable dissolution test is a test that can be used to ascertain the equivalence and
properties of drug products. The dissolution test was performed in a dissolution medium with
pH adjusted to in vivo conditions at pH 1.2; 4,5; and 6.8. Generic drugs that must be tested
wrong equivalence of metampiron and viatamin C. Antalgin or metampiron is one of the
painkillers (analgesics) which belongs to the non-steroidal anti-inflammatory group (AINS)
while Vitamin C is classified as an antioxidant. The aim of this study was to determine the
equivalence of dissolution profiles that were analyzed with the parameters of f1, f2, and
DE70 between antalgin and vitamin C to the innovator in pH 4.5 acetate buffer media.
Dissolution test was carried out according to USP 32-NF 27 using a type 2 test at 37 0,50C
with a rotation speed of 50 rpm. Analysis of the results used to determine the dissolution
profile equation is the difference factor (f1), similarity factor (f2), and dissolution efficiency
(DE70) and determination of levels of antalgin and vitamin C. The results of this study
conclude that samples with equivalence profiles dissolution comparable analyzed with the
parameters of f1, f2, and DE70 to the innovator product in pH 4.5 acetate buffer media
between sample A (Antalgin) and sample B (Vitamin C) showed a significant difference of
each test tablet with significance> 0.005. However this does not degrade the quality and
quality of the test sample.

Keywords: Antalgin, vitamin C, differential dissolution, difference factor (f1), similarity


factor (f2), and dissolution efficiency (DE70).

Pharmacy, Faculty of Mathematics and Natural Sciences,Sriwijaya University, Indralaya 2017


Jurnal Biofarmasetika dan Farmakokinetika in 2017

PRELIMINARY release of the active ingredient from the dosage


The drug is a substance intended for form is usually determined by the velocity of
humans to reduce or eliminate pain, inhibit or the active ingredient dissolved from the whole
prevent the disease that attacks it. The drug dosage form or fractions or particles derived
given to the patient must go through many from the dosage form itself. The rate of
processes in the body. And the drug ingredients dissolution of the active substance from the
given in any way must also have water polar state or from its preparation is defined as
solubility for therapeutic efficacy (Voight, the number of active substances which are
1984). dissolved per unit of time under conditions
Dissolution is defined as the process by between the solid-liquid surface, the
which a solid enters the solvent to produce a temperature and the composition of the frozen
solution simply. Dissolution is a process medium. The rate of dissolution provides
whereby a dissolved solid is principally information about the process profile to the
controlled by the affinity between a solid and a solution per unit time (Syukri, 2002).
solvent. The solubility of an active substance is The dissolution rate is directly
very important. That is because the availability proportional to the surface area of the solid
of a drug depends on the ability of the material, the diffusion coefficient, and is
substance to dissolve into the solvent before it directly proportional to the decrease in
is absorbed into the body (Syukri, 2002). concentration at any given time. This
In the pharmaceutical field, knowledge dissolution rate is also inversely proportional to
of the speed of dissolution or solubility is the thickness of the diffusion layer. The release
needed to help him choose a suitable solvent of the active agent of a drug drug product is
medium for drugs or combinations of drugs, strongly influenced by the physicochemical
helping to overcome certain difficulties arising properties of the active agent the dosage form,
from the time of pharmaceutical preparation (in in which the release of the active agent is
the pharmaceutical field), and further acting as determined by its dissolving velocity in the
a standard or a test of purity (Astuti, 2008). surrounding medium (Martin, 1993).
The release of the active substance of a Dissolution test is very useful because it
drug product is strongly influenced by the is a limiting factor in drug absorption.
physicochemical properties of the active Dissolution test is used to prove compliance
ingredient and the dosage form. The with compendial specification and is a
availability of the active ingredient is usually requirement in drug registration. The solution is
determined by the rate at which the active also used in product development and stability
substance is released from its dosage form. The testing as part of product specification. Factors

Pharmacy, Faculty of Mathematics and Natural Sciences,Sriwijaya University, Indralaya 2017


Jurnal Biofarmasetika dan Farmakokinetika in 2017

affecting the dissolution rate of a drug of the gastrointestinal tract. The drug enters into the
preparations are grouped into related factors on solution of its solid form. If the drug is not
the chemical physics properties of the drug, coated with the polymer, the solid matrix also
factors related to drug formulations, factors disintegrates into other granules and granules
associated with the dosage form, the breaking down into fine particles of
corresponding factors in the dissolution test, disintegration, disintegration and dissolution
and the related factors in dissolution testing can take place simultaneously by releasing a
parameters ie solubility and surface area drug from the form in which the drug is
Shargel, 1998). administered (Voight, 1984)
Factors that may affect the dissolution rate
of an intermediate include temperature, METODE PENELITIAN
viscosity, pH, stirring, particle size, A. Tools and Materials
polymorphism, and surface properties of the The tools required in this lab are
substance. With increasing temperature it will dissolution test devices (stirer paddle),
increase the solubility of a substance. pH spectrophotometer, waterbath, beaker
greatly affects the solubility of acidic glass, test tube, volume pipette, micro
substances and weak bases. Substances that are pipette, cuvette and stopwatch.
weak base will be more easily dissolved when The ingredients used in this lab are
in the acidic atmosphere, while the weak acid conventional tablet preparations
will more easily dissolve in an alkaline (tablets, tablets and granules),
atmosphere. The smaller the particle size, the metampiron tablets and vitamin C,
greater the surface area of the substance will aquadest, SIF, SGF, acetate buffer pH3,
accelerate the solubility of the substance. 4.5, 6, phosphate buffer pH 5.8 in syrup
Polymorphism or the surface properties of the simplex and pure active ingredient.
samgat affect the solubility of polymorphisms
B. Work Procedures
such as the internal structure of different
1. Weigh the weight of the dosage.
substances, will affect the solubility of the
2. Prepare into a glass beaker containing
substance in which the stable crystal will be
500 ml of medium (SIF and SGF).
more easily soluble in its stable form (Astuti,
3. Place the beaker glass over the magnetic
2008).
stirer at 37oC and insert the spin bar into
The intrinsic dissolution rate is the rate at
the center of the glass beaker.
which a solid dissolves within a solvent in a
4. Insert the weighed preparations into the
quantitative range. When a tablets of other
glass beaker and then turn on the stirrer
dosage forms are included in the

Pharmacy, Faculty of Mathematics and Natural Sciences,Sriwijaya University, Indralaya 2017


Jurnal Biofarmasetika dan Farmakokinetika in 2017

simultaneously with the stopwatch. Tablet


5. Take 5 mlsediaan every minute to 0, 5, wak Kada Kadar Fakto Juml Fakto %pelepa AUC
tu r (%) (mg/ r ah r san
10, 15, 30 and 60. ml) korel total disol
asi usi
6. Restored 5 ml dissolved media liquid 0 2,15 0,012 0,000 5,37 0,067 1,79 ~
25 5 43 5 9
into glass beaker to keep the sink condition. 5 2,27 0,027 0,000 6,82 0,022 2,27 10,1
39 3 98 5 7 5
7. Perform titration process with Iodine 10 4,46 0,046 0,001 11,1 0,037 3,71 14,9
12 1 87 51 1 5
pentiter substance then record the volume. 15 6,26 0,062 0,003 15,6 0,052 5,21 32,3
20 6 12 53 1 0
Measurements are performed as much as 30 7,82 0,078 0,004 19,5 0,065 6,51 87.9
75 2 68 84 1
60 9,15 0,091 0,006 22,8 0,076 7,62 211,
three times the replication and then 82 5 51 81 2 95
calculate the percentile of the tested
material. Relation of time Vs % Concentration

B. HASIL DAN PEMBAHASAN Tablet


A. Asam Askorbat (Vitamin C) 12 y = 0.119x + 2.9761
R = 0.8269
Granul 10
8
wa Kad Kada Fakto Jum Fakt %pelep AUC 6
ktu ar r r lah or asan Kadar (%)
4
(%) (mg/ korek tota disol
ml) si usi 2
0 1,56 0,01 0,000 3,90 0,01 1,3 ~ 0
55 56 312 0 30 0 50 100
5 1,76 0,01 0,000 4,40 0,01 1,4 6,90
12 76 664 0 46
10 2,54 0,02 0,001 6,35 0,02 2,11 8,94 Kapsul jelek
39 54 172 1 11 25
15 4,28 0,04 0,002 10,8 0,03 3,56 14,1 wak Kada Kadar Faktor Juml Fakt %pelepa AUC
55 20 028 02 56 925 tu r (%) (mg/ korela ah or san
30 5,47 0,05 0,003 13,7 0,04 4,57 60,9 ml) si total disol
92 49 126 28 57 75 usi
60 7,63 0,07 0,004 17,0 0,06 6,35 163, 0 1,565 0,015 0,000 3,9 0,01 1,3 ~
18 63 652 75 35 8 5 65 312 3
5 2,348 0,023 0,000 5,85 0,01 1,95 8,12
2 48 78 95 5
Grafik Hubungan Waktu Vs %Kadar 10 5,870 0,058 0,001 14,6 0,04 4,89 87,1
6 70 48 76 83
15 6,683 0,065 0,003 16,3 0,05 5,44 25,8
3 33 25 35 44 25
Granul 30 8,023
2
0,080
23
0,004
85
28,0
62
0,06
68
6,68 90,0

y = 0.1043x + 1.7924 60 10,23 0,102 0,006 25,5 0,08 8,52 228


10
R = 0.937 38 33 89 81 52
8
6
Relation of time Vs % Concentration
4 Kadar (%)
2
0
0 50 100

Pharmacy, Faculty of Mathematics and Natural Sciences,Sriwijaya University, Indralaya 2017


Jurnal Biofarmasetika dan Farmakokinetika in 2017

15 4,92 0,049 0,0002 12,2 0,024 2,4 9,7

Kapsul jelek 30 6,82 0,068


04
0,0003
5
17 0,034 3,4
5
43,
4 5
15 y = 0.1351x + 3.086 60 9,35 0,093 0,0005 23,3 0,046 4,6 120
R = 0.8093 26 5
10

5 Kadar (%)
Relation of time Vs % Concentration
0
0 50 100
Granul
Kapsul bagus 10 y = 0.1043x + 1.7924
R = 0.937
8
wak Kada Kadar Faktor Juml Fakt %pelepa AUC
tu r (%) (mg/ korela ah or san 6
ml) si total disol 4 Kadar (%)
usi
0 1,369 0,013 0,000 3,4 0,01 1,13 ~ 2
8 6 272 13 0
5 2,938 0,029 0,000 7,32 0,02 2,44 8,92
3 3 858 5 44 5 0 50 100
10 5,087 0,050 0,001 12,7 0,04 4,23 16,6
9 8 87 01 23 75
15 7,004 0,070 0,003 17,5 0,05 5,83 25,1 Tablet
8 0 27 0 83 5
30 8,574 0,085 0,004 21,4 0,07 7,14 97,2 wak Kad Kadar Fakto Juml Fakto %pelepa AU
0 7 98 25 14 75 tu ar (mg/ r ah r san C
60 10,74 0,107 0,007 26,7 0,08 8,91 240, (%) ml) kore total disol
33 4 12 8 91 75 ksi usi
0 2,81 0,028 0 7 0,014 1,4 ~
5 3,72 0,037 0,185 9,435 0,018 1,8 8
10 5,13 0,051 0,44 13,19 0,026 2,6 11
Grafik Hubungan Waktu Vs %Kadar
15 5,41 0,054 0,71 14,21 0,028 2,8 13,5
30 7,52 0,075 1,085 19,83 0,039 3,9 50,2
5 5
Kapsul Bagus 60 9,14 0,091 1,54 24,29 0,048 4,8 130,
5
15 y = 0.1462x + 3.0298
R = 0.8474
10 Grafik Hubungan Waktu Vs %Kadar

Kadar (%)
5

0 Tablet
0 50 100 y = 0.119x + 2.9761
15 R = 0.8269

B. Metampiron (Antalgin) 10
Granul Kadar (%)
5
wak Kad Kadar Faktor Juml Fakto %pelepa AU
tu ar (mg/ koreks ah r san C 0
(%) ml) i tota disol
0 50 100
usi
0 1,63 0,017 0 4,25 0,000 0,85 ~
85
5 2,32 0,023 0,0004 5,75 0,011 1,1 4,8 Kapsul jelek
6 75
10 3,02 0,03 0,0001 7,5 0,015 1,5 8,5 wak Kad Faktor Kada Jumla Fakt %pelep AU
06 tu ar Koreksi r h or asan C

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Jurnal Biofarmasetika dan Farmakokinetika in 2017

(%) (mg/ total disol

0 1,6 0,00003
ml)
0,016 4,000
usi
0,00 0,8 ~
Kapsul Bagus
1 4 11 32 8 y = 0.1462x + 3.0298
5 2,6 0,00000 0,026 6,500 0,01 1,3 5,2 15
R = 0.8474
0 052 0 52 3 5
10 4,5 0,00009 0,045 11,25 0,02 2,2 8,7 10
0 5 0 095 2 5
15 5,4 0,0117 0,054 13,26 0,02 2,6 12 Kadar (%)
1 1 17 6 5
30 7,0 0,0131 0,070 17,58 0,03 3,51 45,
3 3 3 51 82 0
60 9,6 0,0150 0,096 24,08 0,04 4,81 124
0 50 100
3 3 5 81 ,8

Relation of time Vs % Concentration

Kapsul jelek
DISCUSSION
12
y10
= 0.1351x + 3.086 This experiment discusses the speed of
R = 0.8093 dissolution. The goal is to know the ability of
8 Kadar (%)
6 the drug to escape from its dosage form and
4 Linear
(Kadar (%)) dissolve in body fluids. The speed of
2
0 dissolution is defined as the speed of the
0 50 100
dissolved active agent of all forms of the

Kapsul bagus dosage / fraction / particle derived from the


form itself. The release of the active substance
wak Kad Kadar Fakto Jumla Fakt %pelepa AUC
tu ar (mg/ r h total or san is essential because the availability of the drug
(%) ml) korek disol
si usi
depends on the ability of the substance
0 1,61 0,016 0,000 4,000 0,008 0,8 ~
32 32
5 2,60 0,026 0,000 6,500 0,013 1,3 5,25
dissolved into the solvent medium before it is
84 84
10 4,50 0,045 0,001 11,25 0,022 2,2 8,75
absorbed into the body to allow the drug to
74 74
15 5,41 0,054 0,002 13,50 0,027 2,7 12,2 enter the bloodstream and produce a
1 82 282 5
30 7,03 0,070 0,004 17,50 0,035 3,5 46,5 therapeutic effect.
3 22 42
60 9,63 0,096 0,006 24,00 0,048 4,8 1243 Dissolution is the process of releasing a
3 14 614 ,5
chemical substance or drug compound from a
solid preparation into a particular medium. The
Grafik Hubungan Waktu Vs %Kadar
drug must definitely have good destructive
power and dissolution rate relatively quickly
enough. Dissolution rate as the amount of
solute from solid dosage form in a given
medium as a function of time. It may also be
interpreted as the speed of the drug solution of

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Jurnal Biofarmasetika dan Farmakokinetika in 2017

pharmaceutical preparations or granules or Particle size, the smaller the particle size the
particles as a result of the fractional dosage surface area of the substance will increase so
forming the drug after contact with the liquid that will accelerate the solubility of a
medium. In the case of tablets are usually substance.
interpreted as mass transfer, ie the rate of drug In addition to these factors are also factors that
release or the degree of solubility of the drug affect the rate of dissolution of drugs in vitro,
substance from the preparation tablet to the among others: the physical properties of
receiving medium. chemical drugs, the physical properties of
The speed of dissolution of a substance can be chemical drugs have a major effect on kinetics
affected by several factors including decline. The effective surface area can be
temperature. The higher the temperature will enlarged by reducing the particle size. The
increase the solubility of substances that are dissolution rate will increase because the
endothermic will also increase the price of the solubility occurs on the surface of the solute.
coefficient of the substance. Polymorphism and Solubility Drugs in water also affect the rate of
the surface properties of substances, dissolution. Salt-shaped drugs, generally more
polymorphisms and surface properties of soluble than acid-free and free-drug. The drug
substances will greatly influence the solubility may form polymorphic, ie the existence of
of a substance, the presence of polymorphisms several different dissolution kinetics, although
such as the internal structure of different it has the identical chemical structure.
substances, will affect the solubility of . This causes the amount of the drug to become
substances in which metastable crystals will be discolored to less and also affects the amount
more soluble than their stable forms. Given the of drug absorbed. Device factors and
surfactant and the surface properties of the environmental conditions of the different
hydrophobic substances, it will cause the devices used in the dissolution test will cause
surface tension between the particles to differences in drug dissolution rates. The speed
decrease so that the substance is easily of stirring will affect the speed of drug
moistened and more soluble. The viscosity dissolution, the faster the stirring then the
viscosity of the decreased solvent will also medium movement will be faster so it can
increase the solubility of a substance. The pH increase the speed of dissolution. In addition,
greatly influences the solubility of this acidic or temperature, viscosity and media composition,
weak base substance. The weakly alkaline will as well as sampling may also affect the speed
be more soluble if present in acidic atmosphere of drug dissolution. The particle size may affect
while the weak acid will be more easily the dissolution of the drug because the smaller
dissolved if it is in alkaline atmosphere. particle size the easier the solute in the solvent

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medium, and vice versa particle size or surface minute 15 at 2.7% minute to 30 by 3.5% and at
area of a substance will be a more difficult drug minute 60 by 4.8%. For ugly capsules in 0
dissolved in the solvent, there are four types of minutes 0.8%, at 5 mins by 1.3%, at 10 minutes
sample doses used; tablets, granules, capsules by 2.2%, at 15 minutes by 2.6%, 30 minutes by
in good shape, and capsules that are in bad 3.51 % and at minute 60 amounted to 4.81%.
condition. The first step in this experiment was For tablet in minute 0 equal to 1,4%, at minute
to test by inserting into four types of antalgin 5 equal to 1,8%, at minute 10 equal to 2,6%, at
preparations and vitamin c into buffer pospat, minute 15 equal to 2,8%, minute 30 to 3,9% ,
then on sampling of 5 ml in minutes to 0, 5, 10, and pda minute to 60 equal to 4.8%. For
15, 30 and 60 minutes. , the sample is taken granules in 0 minutes 0.85%, at 5% at 1.1%, at
from the previous sampling in titration using 10 minutes at 1.5%, at 15 minutes by 2.4%, 30
iodo-iodimetric titration. minutes by 3.4% and at 60 minutes by 4.6%.
The sample of the drug used was vitamin c From the data it is known that the sample of
and antalgin which in vitamin c got percent of vitamin c is better release than antalgin where
drug release for good capsule at minute 0 equal in general the sequence is dissolved from
to 1,13%, at minute 5 equal to 2,44%, at minute granules, tablets, bad capsules and good
10 equal 4,23%, in the 15th minute of 5.83%, capsules.
the 30th minute was 7.14% and in the 60th
minute it was 8.99%. for ugly capsule obtained
percentage of release at minute 0 equal to CONCLUSION

1,3%, at minute 5 equal to 1,95%, at minute 10 This experiment used antalgin and vitamin C to
equal to 4,89%, at minute 15 equal to 5,44%, find out the dissolution rate that is influenced
minute 30 6.68% and pda minute 60 amounted by factors that influence the particle size. The
to 8.52%. For tablet in minute 0 equal to particle size may affect the dissolution of the
1,79%, at minute 5 equal to 2,27%, at minute drug because the smaller the particle size the
10 equal to 3,71%, at minute 15 equal to 5,21% easier it becomes the solute in the solvent
to 30 by 6.51% and at minute 60 amounted to medium, and vice versa the larger the particle
7.62%. For granule at minute 0 1,3%, at minute size or surface area. Substances will then
5 equal to 1,40%, at minute 10 equal to 2,71%, become increasingly difficult soluble drugs in
at minute 15 equal to 3,56%, minute to 30 the solvent. In general the sequenced order
equal to 4,57% and in the 60th minute 6.35%. starts from granules, tablets, bad capsules and
In the antalgin sample there was a percentage good capsules.
of drug release for good capsule in 0 minutes at
0.8%, at 5 min by 1.3%, at 10 min by 2.2%, at

Pharmacy, Faculty of Mathematics and Natural Sciences,Sriwijaya University, Indralaya 2017


Jurnal Biofarmasetika dan Farmakokinetika in 2017

REFERENCES

Astuti, K. 2008, Analisis Farmasi, Yogyakarta,


UGM Press, Indonesia

Martin. 1993, Farmasi Fisika Dalam Ilmu


Farmasetik, Jakarta, UI Press,
Indonesia.

Shargel, C. 1998, Biofarmasetika dan


Farmakokinetika Terapan Edisi II,
UNAIR Press, Surabaya, Indonesia.

Syukri. 2002, Biofarmasetika, Yogyakarta, UII


Press, Indonesia,

Voight, R. 1984, Buku Pelajaran Teknologi


Farmasi, UGM Press, Yogyakarta,
Indonesia.

Pharmacy, Faculty of Mathematics and Natural Sciences,Sriwijaya University, Indralaya 2017