DRUG

STABILITY
Ungsari Rizki Eka P., M.Sc.,
Apt.
 DECARBOXYLATION
OXIDATION
HYDROLYSIS

DEGRADATION
PATHWAYS
DEHYDRATION

ISOMERIZATION
PHOTOLISIS
POLYMERIZATION
 DEGRADATION
HYDROLISIS PATHWAYS
Hydrolysis indicates cleavage of chemical bonds by the addition of water.
Hydrolysis is one of the most common drug degradation reactions, even in
solid dosage forms in the presence of moisture, and the most common
substrates are those that contain the acyl group:
 ASIL
DEGRADATION PATHWAYS

• Gugus asil merupakan gugus yang ada pada

setiap asam karboksilat dan derivatnya.
• Semua interkonversi antara asam karboksilat
dan derivatnya terjadi dalam satu mekanisme
umum yaitu PENYERANGAN NUKLEOFILIK
pada GUGUS ASIL.

* Nukleofil (Nu) : reagen yang membentuk ikatan kimia

terhadap partner reaksinya. Berupa spesies
(ion/molekul) yang tertarik kuat ke sebuah daerah yang
bermuatan positif pada sesuatu yang lain.
DEGRADATION PATHWAYS
 HYDROLYSIS OF HOMATROPINE IN AQUEOUS
SOLUTION ??

Homatropine is an ester that undergoes hydrolysis in aqueous solutions.

Samples were collected and the homatropine concentration at various time
points calculated:
Time (h) [Homatropine] (M) Ln [Homatropine] (M)
1.4 0.026 ?
3.0 0.024 ?
6.0 0.021 ?
9.0 0.018 ?
12 0.015 ?
17 0.012 ?
The following values can then be

calculated from the graph:

The first-order rate constant = k1 = ?

The half-life = t1/2 = ?

The shelf-life = t90 = ?

Uji stabilitas dipercepat pada skala laboratorium, dilakukan
pada Parasetamol 120 mg dalam larutan aquadest 60 mL. Bila
reaksi mengikuti kinetika reaksi orde 1. Hitung umur simpan
sediaan tersebut, bila disimpan pada suhu 25oC.

Suhu Waktu (menit) Kadar Suhu Waktu Kadar

parasetamol (menit) parasetamol
(ppm) (ppm)

40oC 0 57,6 60oC 0 57,6

30 56,2 30 54,93
60 54,8 60 52,53
90 51,33 90 50,26
120 52,13 120 48,4
150 50,8 150 46,26
180 49,6 180 44,13
50oC 0 57,6
30 55,93
60 54,46
90 53
120 51,6
150 50,2
180 48,93
 HYDROLISIS
DEGRADATION PATHWAYS
EXAMPLE
Esters Aspirin, alkaloids
Dexmethasne sodium phosphate
Nitroglycerin

Lactones Pilocarpine
Spironolactone

Amides Chloramphenicol

Lactams Penicillins
Cephalosporins
Imides Glutethimide
Malonic ureas Barbiturates
 DEGRADATION PATHWAYS
HYDROLISIS SOLUTION?
• The formulation of the drug at pH of optimum
stability
• Addition of non-water solvent
• Controls moisture content
• Drugs are made in solid dosage form
 HYDROLISIS??
DEGRADATION PATHWAYS

Kloramfenikol palmitat
DEGRADATION PATHWAYS
DEGRADATION PATHWAYS
 OXIDATION
DEGRADATION PATHWAYS
Oxidation is a loss of electrons or an increase in the oxidation
state and reduction is a gain in electrons or a decrease in the
oxidation state. Redox reaction is an electron transfer process :

Reduced form Oxidized form + ne-

Oksidasi adalah peningkatan bilangan oksidasi.

Reduksi adalah penurunan bilangan oksidasi.

Oksidasi menjelaskan pelepasan elektron dari

sebuah molekul, atom, atau ion.
Reduksi menjelaskan penambahan elektron dari
sebuah molekul, atom, atau ion.
OXIDATION
DEGRADATION PATHWAYS
Dapat berupa reaksi tunggal atau
reaksi komplementer
Pada senyawa senyawa organik terutama ditentukan oleh
jumlah ikatan atom karbon terhadap oksigen dan dapat terjadi
bertahap.
Oksidasi
CH4  CH3OH  CH2O  CHOOH  OCO
Reduksi
OXIDATION
DEGRADATION PATHWAYS
Example : ascorbic acid, ergotamine, morphine, captopril,
prednisone, vitA, D, E.

The rate of oxidative degradation of ascorbic acid is at its maximum

at the pKa value at which [AH2] = [AH-], suggesting the following degradation
mechanism:
DEGRADATION
VIT C PATHWAYS
 UJI STABILITAS DIPERCEPAT INJEKSI
VITAMIN C, (mengikuti orde-1) :
Suhu Suhu(˚K) b K log K 1/T
40 313 0.000361 0.000831 -3.080 0.0031948
50 323 0.000394 0.000907 -3.042 0.003095975
60 333 0.00063 0.00145 -2.88 0.00300300

Hitung umur simpan pada suhu 25C

OXIDATION OF CAPTOPRIL ?
DEGRADATION T90 PATHWAYS
at 25C??
*first orde reaction
 DEGRADATION
OXIDATION PATHWAYS
OF CAPTOPRIL
 DEGRADATION
AUTO-OXIDATION PATHWAYS
Autoxidation (auto-oxidation) is a complex oxidation mechanism that
proceeds through a free radical chain process. It is a common degradation
mechanism for unsaturated fats, but a number of drugs containing
carboncarbon double bonds also undergo autoxidation.

In general, the free radical chain process consists of three steps :

 DEGRADATION
AUTO-OXIDATION PATHWAYS
The rancidification of fat, which gives a distinct rancid smell (due to the
formation of volatile aldehydes and ketones), is an example of
autoxidation:
 DEGRADATION PATHWAYS
OXIDATION

SOLUTION?
1. EKSLUSI OKSIGEN
2. PENGATURAN pH LARUTAN
3. PROTEKSI THD CAHAYA
4. PENGGUNAAN BAHAN PENGKELAT
5. PENGGUNAAN ANTIOKSIDAN
 DEGRADATION PATHWAYS
1. EKSKLUSI OKSIGEN

Pengusiran oksigen dari dalam sediaan obat.

1. Pengusiran oksigen pada pelarut.

2. Pengusiran oksigen dari bahan,
3. Pengusiran oksigen saat mengemas.
 DEGRADATION PATHWAYS
2. PENGATURAN pH LARUTAN

Bentuk terionkan dari senyawa obat akan

lebih cepat mengalami oksidasi.

Sehingga obat-obat yang mudah terion

seperti asam askorbat, akan lebih cepat
teroksidasi pada pH netral dan alkalis.
 DEGRADATION PATHWAYS
3. PENGGUNAAN BAHAN PENGKELAT

Bentuk terionkan dari senyawa obat akan

lebih cepat mengalami oksidasi.

Contoh : etilendiamin tetraasetat (EDTA),

asam sitrat.
PENGGUNAAN ANNTIOKSIDAN
DEGRADATION
Contoh PATHWAYS
: BHA, BHT, propil galat

propil galat
PENGGUNAAN ANNTIOKSIDAN
DEGRADATION PATHWAYS
ISOMERIZATION
• Isomerization is a degradation process in which a drug degrades to form a
product with an identical chemical formula (i.e., isomers).
• Isomers have the same chemical composition but a different configuration
or structure and possess different physicochemical properties.

For example,
the natural L-ascorbic acid has antiscorbutic activity, but the synthetic D-
ascorbic acid does not. Both, however, have antioxidant properties.

STEREOISOMERS
ISOMERS
STRUCTURAL
ISOMERS
STEREOISOMERS
 STRUCTURAL
ISOMERS

L-(2)-Epinephrine (l-adrenaline or 4-[(1R)-

1-hydroxy-2-(methylamino)
ethyl]benzene-1,2-diol) has one chiral
center. In aqueous solutions, epinephrine
undergoes specific acid catalyzed
racemization.
 DEGRADATION
STRUCTURAL PATHWAYS
ISOMERS

Structural isomers (constitutional isomers) have the same molecular

formula, but the atoms are arranged in a different way. For example, n-
propanol (propan-1-ol) and isopropanol (propan-2-ol) are structural
isomers with the same molecular formula (C3H8O) but different
physicochemical properties, like boiling point and density. Propanol and
isopropanol are position isomers. Tautomers are also structural isomers
but they are readily interconverted by a chemical reaction called
tautomerization.
PHOTOLISIS
berarti: dekomposisi oleh cahaya

misal:
Sodium nitroprusside yang diberikan secara infusi intravena
untuk terapi hipertensi akut, jika larutan terlindung dari
cahaya, maka akan stabil selama setidak-tidaknya 1 tahun;
jika terekspos terhadap cahaya ruangan, maka masa
simpannya hanya 4 jam.
 Efek Temperatur terhadap Kecepatan
Reaksi
Persamaan Arrhenius

 k = konstanta laju reaksi

A = faktor frekuensi (terjadinya tabrakan karena adanya
energi)
Ea = energi aktivasi (energi yang digunakan untuk
tabrakan)
 R = tetapan gas = 1,987 kkal/mol
 T = ºC + 273 (ºK)
 Bentuk logaritma
persamaan Arrhenius

 Persamaan ini dapat digunakan untuk

menghitung:
 Energi aktivasi (dari slope-nya)
 k pada suhu yang berbeda
 Menghitung kadaluwarsa karena dapat dicari k pada
suhu kamar
 Plot Arrhenius merupakan hubungan antara
log k dengan 1/T