Chemical decomposition

Overview
Oxidation

Hydrolysis
Loss of activity
photolysis Toxic
Decomposition process

Isomerization

Polymerization
Hydrolysis
 These are functional
groups which are
liable to undergo
hydrolysis
Beberapa fakta mengenai
Hidrolisis
1. Reaksi hidrolisis menyerang ikatan
nucleophilic yang tidak stabil oleh air dalam
sediaan obat bentuk larutan.
2. Reaksi melibatkan group laktam terjadi lebih
cepat diikuti oleh ester, amida dan imida.
3. Reaksi ini selalu mengikuti orde pertama
4. Reaksi ini terjadi pada semua larutan yang
disebut Solvolysis.
5. Reaksi ini dikatalis oleh H3O+ dihasilkan ion
logam valensi 2, Hidrolisis ion (protolisis),
panas, cahaya, Larutan, konsentrasi obat
yang tinggi.
4
Hydrolysis
 The most common degradation pathway
 Catalyzed by
 Hydrogen ions (acid-catalysis)
 Hydroxyl ions (base-catalysis)
 Species found in buffers (acid-base
catalysis)
Hydrolysis-stabilization strategies

 Liquid formulation
 Formulated in Optimum pH
 Reducing the drug solubility
 Complex formation between drugs and
added compound
 Addition of surfactant (depending on
location where drugs are incorporated in the
micellar form)
 cosolvency
 Preparation of solid dosage form
Metoda Peningkatan Stabilitas
1. Sedapat mungkin dihindari kontak
dengan air.
2. pH, jika memungkinkan secara
fisiologis, larutan obat harus
diformulasikan sedekat mungkin ke pH
stabilitas optimumnya.
3. Jenis pelarut. Penggantian air sebagian
atau seluruhnya dengan pelarut yang
konstanta dielektriknya lebih rendah.

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4. Kompleksasi. Laju hidrolisis dapat
dipengaruhi oleh pembentukan
kompleks.
5. Surfaktan. Surfaktan nonionik,
kationik, dan anionik dapat
menstabilkan obat terhadap katalis
basa.
6. Modifikasi Struktur kimia.
7. Mengurangi kelarutan dengan cara
pembentukan garam atau esternya
yang sukar larut.

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Oxidation
 The second common after hydrolysis
 Removal of electropositive atom, radical
or electron
 Addition of electronegative atom or
radical
 Process: autooxydation (w/o
catalysation) and involving chain
process
Oxidation-chain process
Step Influenced by Product

Initiation Light, heat, metals X·+RH R·+XH

(Fe, Cu as trace
amount in buffer)

Propagation O2, light R·+O2 ROO·

ROO·+RH ROOH+R·
ROO· (peroxides) and ROOH
antioxidant
(hydroperoxide) = photolabile
Form: OH· and RO· (highly
reactive)
Termination ROO·+ROO· stable product
ROO·+R· stable product
R·+R· stable product
Drugs susceptible to oxydation
 Carbon-carbon double bonds (steroids,
sterols
 Polyunsaturated fatty acids vegetable
oil
 Faktor-faktor yang mengkatalisis laju oksidasi :
1. Adanya oksigen
2. pH
3. temperatur
4. logam berat
5. cahaya (Photolisis)

 Beberapa jenis golongan obat yang mudah teroksidasi:

1. Golongan katekolamine, terutama yang memiliki ggs OH pada
cincin aromatisnya seperti adrenalin
2. Golongan fenolik, seperti : Phenylephrine, morphine
3. Phenotiazine, seperti Klorpromazine, promethazine
4. Golongan alkena, terutama yang memiliki ikatan rangkap
5. Steroid
6. Golongan trisiklik
7. Thiols, yang mempunyai ggs R-SH seperti Captopril
8. Miscellanpus, ex: amfoterisin B, Tetrasiklin, Furosemide.

12 Oksidasi
Oxidation-stabilization
strategies
 Replacing O2 with N2 or CO2 gas inside
the primer package
 Addition of antioxidant: BHA, (please
find at least other 5 antioxidant on your
own)
 Addition a metal chelator? Please give
an example?
 Avoid high storage temperature
 The protection given by antioxidant is
owing to its property of more readily
oxidized than the drug
 Antioxidants interrupt the propagation
step
Isomerisation
Drug Optical isomers

Enzimatic
pH dependent
Photochemical degradation
 Degradation because of light (sunlight
or artificial light such as fluorescent
light)
 Result
 Loss of activity
 Alter the physicochemical properties
 discoloration, dissolution rate, precipitation,
viscosity change
Photochemical degradation
 Example of drug: folic acid, ascorbic
acid, hydrocortisone, ribovlavin
 Photodegradation can be attributed to
the photolability of excipient
 Final formulation is required to be
assessed
Photochemical degradation
 Occurs when λ of light is within the λ range of
absorption of drug (direct or sensitized reaction)
 And then drug absorbs the radiation and degrades
 Photoreactivity can occur when the drug is already
applied (light penetration to skin or eye blood
circulation)
 Result: toxicity (when the light induce the reaction between
drug and endogenous substance. This reaction may lead to
the formation of ROS)
 Photosensitive excipient can increase the chance of
photodegradation ( sensitized reaction) due to its
capability to transfer the absorbed energy
Expected to photodegradation
 Carbonil
 Nitroarimatic
 N-oxide
 Arile halides
 Alkenes
 Polyenes
 Sulfides
Photochemical reaction step in
two stages
 primary reaction
 due to the absorption of a photon (does
not depend on the temperature)
 Result in the formation of intermediate
(radicals, radical ions)
 Secondary reactions
 Reaction of intermediate to form a final
product
 can react through ‘dark’ reactions
O2 influence
 strongly influence the degradation
 Can add to a photoexcited molecule
(drug) leading to oxidation products
 A photoexcited molecule (e.g. drug) can
transfer its energy to ground state
oxygen leading to the formation of
singlet oxygen (highly reactive)
Photostability study
 Stability studies of the drug substance
in the final preparation
 Drug materials are either white or
colored
 Always include exposure to both UV-
and visible radiation to cover all
possible degradation reactions
Photochemical degradation-strategies to
minimize

 Put into a colored container

 Amber container can exclude light of λ
470 nm
 Store in the dark
 Coating the tablet with UV absorbing
material (vinyl acetate containing
oxybenzone)
Polymerization
 Binding of identical drug molecules
 Result: antigenic compound
Question-case study
 Dimer aminopencilline is formed during storage in the
aqueous formulation. Dimerization occurs by cleavage the β-
lactam bond and the open ring reacts with the side chain of
the second aminopenicilline molecule.

Question:
1. Think what is the pathway of degradation? Is oxidation being
the important issue?
2. Do you thing that the degradation compound is harmless?
3. What is the strategy to improve the stability?
4. What is the analytical tool can we use to measure the
degradation product?
 What is ROS?
 Why can ROS formation cause toxicity?