SATBILITAS KIMIA OBAT

Drs.i nyoman kadjeng widjaja

drug
instability

loss of drug

reduction
of
potency

poor
product
quality

Identification of
the product(s)
formed provides a
better
understanding of
the mechanism(s)
of these chemical
reactions as well
as other valuable
information

loss of
drug potency

various
pathways

only one
quantitating
drug loss

penicillins

acidic pH

rearrange

penicillenic
acids
reactive intermediates
allergenicity of penicillins

The drug
may
degrade

to
xic
co s
lo ub
r
o r st a
od nce
or

??
degradants

Exp.1.
DEGRADANT

Cholinesterase
Reactivator
Organophosphorous
pesticides

Exp.2.
DEGRADANT

Fanconi
syndrom
e

The drug
may
degrade
th
es e p
un th ro
ac eti du
ce ca ct
pt lly
ab
le

??
degradants

Adrenalin, stimulan of
sympathetic nervous system

a highly colored red

route of drug administration

was via a nasal spray

acceptability of a
drug substance that degraded to volatile,
odor-producing, sulfur-containing degradant.
Even minor degradation of the drug produced
an unacceptable odor.
This was of specific concern
because one intended

Drug substances used

as pharmaceuticals
have diverse molecular structures
and are,
therefore, susceptible
to many and variable
degradation pathways

Degradation pathways
include hydrolysis,
dehydration,
isomerization and
racemization,
elimination, oxidation,
photodegradation, and
complex interactions
with excipients and
other drugs

design of stability studies

earliest stages
of drug development

minimize
chemical
degradation

Parenteral products
(contact with water)
solid dosage forms,
(moisture)

hydrolysis

Hydrolysis is
often the main
degradation pathway
for drug substances
having ester and
amide functional
groups
within their
structure.

procaine,
aspirin,
chloramphenicol,
atropine,and
methyl-phenidate

Ester bond
a carboxylic acid
and
various alcohols

carbamic,
sulfonic,
and sulfamic acids
and
various alcohols

These ester compounds

are primarily hydrolyzed
through
nucleophilic attack
of hydroxide ion or water
at the este

The degradation rate depends on

the substituents R1 and R2,
in that electron-withdrawing groups enhance hydrolysis
whereas electron-donating groups
inhibit hydrolysis

 Carboxylic acid esters that are susceptible to hydrolysis are

shown include ethylparaben, benzocaine, procaine, oxathiin
carboxanilide , aspirin, atropine, scopolamine, methylphenidate,
meperidine, steroid esters such as hydrocortisone sodium
succinate and methylprednisolone sodium succinate, and
succinylcholine chloride.
Ethylparaben and benzocaine are very similar in structure; both
have a para electron-donating group and both are ethyl esters.
Therefore, information about the reactivity of one of them could be
the basis for predicting the stability of the other.
Similarly, ester group hydrolysis in atropine should be similar in
rate and pH dependency to that in scopolamine.

 Is it not reasonable to expect the hydrolysis of

methylprednisolone sodium succinate to be similar to
that of hydrocortisone sodium succinate?
Therefore, if one is presented with a new drug
substance containing a hydrolyzable ester moiety, it
should be possible, using appropriate literature
examples of similar drugs, to make a good estimate of
the sensitivity of the ester group to hydrolysis.
Apparent rate constants for the hydrolysis of various
carboxylic acid esters are shown in Table 2 for the
comparison of their reactivities. As these values were
obtained under different conditions of temperature, pH,
ionic strength, and buffer species, they are for rough
comparison only.
Nevertheless, they do point out the role that structure
plays in the relative reactivity of the ester bond.

Other Esters.
Carbamic acid esters such as chlorphenesin carbamate and carmethizole,
shown in Scheme 7, are known to undergo hydrolysis in strongly acidic and
neutral-to-alkaline solutions, respectively. The two carbamate ester
groups in carmethizole undergo hydrolysis at significantly different rates
owing in large part to completely different mechanisms.The first
carbamate group is cleaved by more of an elimination reaction via
carbonium formation whereas the second carbamate linkage appears to
hydrolyze via a normal hydrolysis mechanism.

Cyclodisone, a sulfonic acid ester, and sulfamic acid 1,7-heptanediyl

ester ,a sulfamic acid ester, have been reported to hydrolyze in the neutralto-alkaline pH range (Scheme 8). Both hydrolyze via carbon-oxygen
bond cleavage rather than sulfur.oxygen bond cleavage. Representative
sulfonic esters and sulfamic esters susceptible to hydrolysis.

Phosphoric acid esters such as hydrocortisone disodium phosphate and

echothio-phate iodide are known to hydrolyze (Scheme 9).

Although nitric esters such as nitroglycerin and nicorandil undergo

hydrolysis, nitroglycerin is relatively stable (Scheme 9).

 Amide bonds are commonly found in drug molecules. Amide bonds

are less susceptible to hydrolysis than ester bonds because the
carbonyl carbon of the amide bond is less electrophilic (the
carbon-to-nitrogen bond has considerable double bond character)
and the leaving group, an amine, is a poorer leaving group
(Scheme 10).
Figure 3 shows the structure of acetaminophen, chloramphenicol,
lincomycin, indomethacin, and sulfacetamide, all of which are
known to produce an amine and an acid through hydrolysis of
their amide bonds; moricizine, a derivative of phenothiazine, which
undergoes hydrolysis of its amide bonds followed by oxidation; and
HI-6, a bis(pyridimium)aldoxime having an amide bond, which
exhibits fast hydrolysis in concentrated aqueous solutions owing
to the acidifying effect of a strongly acidic oxime group.

-Lactam
-Lactam antibiotics such as penicillins and cephalosporins, which
are cyclic amides or lactams, undergo rapid ring opening due to
hydrolysis. Ring opening of the -lactam group has been reported
or penams, such as, benzylpenicillin, ampicillin, amoxicillin,
carbenicillin,phenethicillin,and methicillin (Scheme 11),
For cephems, such as cephalothin cefadroxil, cephradine, and
cefotaxime (Scheme12). These drug substances have both a
lactam and an amide bond in their molecular structure, the
former being considerably more susceptible to hydrolysis
cephalothin and cefotaxime are also acetoxy esters, and opening
of their lactam ring competes with hydrolysis of the ester bond.
Decomposition products produced by hydrolysis of penam and
cephem -lactams are still reactive and undergo various side
reactions

For example, condensation products were formed upon

hydrolysis of cefaclor, and dimeric products were detected upon
hydrolysis of loracarbef, as shown in Scheme 13, as well as of
ampicillin.
Cycloserine, which can be considered a cyclic amide, undergoes
opening of its isoxazolidone ring due to hydrolysis in acidic
media, as shown in Scheme 14. Like loracarbef and ampicilllin, it
also undergoes self-condensation.
The reactivity of these amides toward hydrolysis depends on the
substituents R1, R2, and R3 (Scheme 10), as shown in Table 3.
The -lactam antibiotics, including penicillins and cephalosporins,
undergo surprisingly facile hydrolysis compared to other amides.
The most likely contributors to this facile hydrolysis are electronic
factors, the relief of ring strain (a four-membered ring coupled to a
five- or six-membered ring), and the lower double bond character
between the carbonyl carbon and the amide nitrogen

 Barbiturates, hydantoins, and imides contain functional groups

related to amides but tend to be more reactive.
Barbituric acids such as barbital, phenobarbital, amobarbital,
and metharbital undergo ring-opening hydrolysis, as shown in
Scheme 15.
Decomposition products formed from these drug substances are
susceptible to further decomposition reactions such as
decarboxylation. The hydrolysis rates of these substances
depend on the substituents R1, R2, and R3.

 For some allylbarbituric acids, the effects of these substituents on

hydrolysis rates can be explained in terms of Hammett.s value. As
shown in Scheme 16, the hydantoin allantoin is susceptible to
hydrolysis,
and the imide bonds
in and (+)-1,2-bis(3,5dioxopiperazinyl-l-yl)propane are hydrolyzed by parallel and
successive reactions. The reactivity of the imide groups is
intramolecularly affected by the tertiary amine groups in its structure.
This conclusion was drawn from the observation that model
compound A .As shown in Scheme 16, the hydantoin allantoin is
susceptible to hydrolysis, and the imide bonds in and (+)-1,2bis(3,5-dioxopiperazinyl-l-yl)propane are hydrolyzed by parallel
and successive reactions. In the case of , the reactivity of the
imide groups is intramolecularly affected by the tertiary amine
groups in its structure. This conclusion was drawn from the
observation that model compound A

OKSIDASI
FOTOLISIS
Oxidation is a well-known chemical degradation pathway for
pharmaceuticals. Oxygen, which participates in most oxidation
reactions,
is
abundant
in the
environment
to which
pharmaceuticals are exposed, during either processing or longterm storage. Oxidation of ascorbic acid (Scheme 44) was
reported as early as 1940, and many factors affecting ascorbic
acid oxidation have been discussed, including the role of metal
ions

 Oxidation mechanisms for drug substances depend on the chemical

structure of the drug and the presence of reactive oxygen species
or other oxidants.
Catechols such as methyl-dopa and epinephrine are readily
oxidized to quinones, as shown in Scheme 45.

 5-Aminosalicylic acid undergoes oxidation and forms

quinoneimine, which is further degraded to polymeric compounds
(Scheme 46).

 Ethanolamines such as procaterol

compounds (Scheme 47),

are oxidized to

formyl

 Thiols such as 6-ercaptopurine, captopril, and derivative of

thiocarbamic acid) are oxidized to disulfides (Scheme 48)

 Phenothiazines such as promethazine are oxidized via complex

pathways and yield various products (Scheme 49)

 polyunsaturated molecules such as vitamin A, as well as other

polyenes such as ergocalciferol, cholecalciferol, fumagillin, and
filipin, are susceptible to oxidation

 Spiradoline is susceptible to oxidative degradation, resulting in the

formation of an imidazolidine ring in addition to hydrolysis of the
amide bond (Scheme 51)

 Sulfur atoms are becoming more common in new drug candidates

and present a particular challenge owing to their propensity to
oxidize to the corresponding sulfoxides and ultimately sulfones
(Scheme 52)

Photodegradation
Photodegradation has been reported for a large number of drug
substances. The mechanisms for these reactions are generally
very complex. As exemplified by chloroquine and primaquine,
shown in Schemes 53 and 54, respectively, photodegradation
generally yields numerous products through complex pathways.
Photodegradation is often accompanied by oxidation in the
presence of oxygen. Thus, drug substances such as Fumagillin,
phenothiazines, and cholecalciferol,whose oxidation was described
in the previous section, are degraded to different products in the
presence and absence of light.

 Representative photodegradation routes for drug substances

include dehydrogenation of nifedipine, reserpine,and nicardipine
(Scheme 55)

 dehydrogenation accompanied by transmutation of a nitro group

in nimodipine (Scheme 56)

 Rearrangement of chlordiazepoxide (Scheme 58)

 In addition, the following photoinduced degradation reactions

have been reported:
hydrolysis of mefloquine, furosemide, (Scheme 59);
elimination of hydrogen halide from meclofenamic acid (Scheme
60);
oxidation of a hydroxyl group of 2 l-cortisol tert-butylacetate and
a-[(dibutylamino)methy1]-6,8-dichloro-2-(3,4-dichlorophenyl)-4quinoline methanol (Scheme 61); and rearrangement of
benzydamine (Scheme 62).
Oxidation of menadione is enhanced by light (Scheme 63)