Stabilitas bahan obat

Overview
In this chapter we will:
Identify those classes of drugs that are particularly susceptible to chemical
breakdown and examine some of the precautions that can be taken to minimise
the loss of activity
Look at how reactions can be classified into various orders, and how we can
calculate the rate constant for a reaction under a given set of environmental
conditions
Look at some of the factors that influence drug stability
Examine methods for accelerating drug breakdown using elevated temperatures
and see how to estimate drug stability at the required storage conditions from
these measurements.
Key oint
rugs may break down in solution and also in the solid state !for example, in tablet or
powder form".
It is often possible to predict which drugs are likely to decompose by looking for
specific chemical groups in their structures.
#he most common causes of decomposition are hydrolysis and oxidation, but
loss of therapeutic activity can also result from isomerisation, photochemical
decomposition and polymerisation of drugs.
It is possible to minimi$e breakdown by optimising the formulation and storing
under carefully controlled conditions.
The chemical breakdown of drugs
The main ways in which drugs break down are as follows:
Hydrolysis
Drugs containing ester, amide, lactam, imide or carbamate groups are susceptible to
hydrolysis.
Hydrolysis can be catalysed by hydrogen ions (specific acid catalysis) or hydroxyl ions
(specific base catalysis).
olutions can be stabilised by formulating at the pH of maximum stability or, in some
cases, by altering the dielectric constant by the addition of non!a"ueous sol#ents.
Oxidation
$xidation in#ol#es the remo#al of an electropositi#e atom, radical or electron, or the
addition of an electronegati#e atom or radical.
$xidati#e degradation can occur by autooxidation, in which reaction is uncatalysed and
proceeds "uite slowly under the influence of molecular oxygen, or may in#ol#e chain
processes consisting of three concurrent reactions: initiation, propagation and
termination.
%xamples of drugs that are susceptible to oxidation include steroids and sterols,
polyunsaturated fatty acids, phenothia&ines, and drugs such as sim#astatin and polyene
antibiotics that contain con'ugated double bonds.
(arious precautions should be taken during manufacture and storage to minimise
oxidation:
The oxygen in pharmaceutical containers should be replaced with nitrogen or carbon
dioxide.
)ontact of the drug with hea#y!metal ions such as iron, cobalt or nickel, which catalyse
oxidation, should be a#oided.
torage should be at reduced temperatures.
*ntioxidants should be included in the formulation.
Isomerisation
+somerisation is the process of con#ersion of a drug into its optical or geometric isomers,
which are often of lower therapeutic acti#ity.
%xamples of drugs that undergo isomerisation include adrenaline (epinephrine:
racemisation in acidic solution), tetracyclines (epimerisation in acid solution),
cephalosporins (base!catalysed isomerisation) and #itamin * (cistrans isomerisation).
Photochemical decomposition
%xamples of drugs that degrade when exposed to light include phenothia&ines,
hydrocortisone, prednisolone, ribofla#in, ascorbic acid and folic acid.
,hotodecomposition may occur not only during storage, but also during use of the
product. -or example, sunlight is able to penetrate the skin to a depth sufficient to cause
photodegradation of drugs circulating in the surface capillaries or in the eyes of patients
recei#ing the drug.
,harmaceutical products can be ade"uately protected from photo!induced decomposition
by the use of colouredglass containers (amber glass excludes light of wa#elength . /01
nm) and storage in the dark. )oating tablets with a polymer fi lm containing ultra#iolet
absorbers has been suggested as an additional method for protection from light.
!"# $i%rolisa
1.1. Furosemide
= 4-chloro-2-(furan-2-ylmethylamino)- 5-sulfamoylbenzoic acid
2.3. 4icotinamide
5 niacinamide 5 nicotinic acid amide 5 (itamin ,, 5 6!pyridinecarboxamide
1.3. Procainamide= 4-amino-N-(2-diethylaminoethyl) benzamide
Gugus laktam:
Core structure of enicillins (to) and cehalosorins (bottom). !-lactam rin" in red.
#enzylenicillin (enicillin $)= (2S%5R%&R)-3%3-dimethyl-'-o(o-&-(2-henylacetamido)-4-thia-1-
azabicyclo)3.2.*+hetane-2-carbo(ylic acid
,mo(icillin = (2S%5R%&R)- &--)(2R)-2-amino- 2-(4-hydro(yhenyl)- acetyl+amino.- 3%3-dimethyl- '-o(o- 4-
thia- 1-azabicyclo)3.2.*+hetane- 2-carbo(ylic acid
Cephalosporin C= (7R,0R)!6!8(*cetyloxy)methyl9!0!:8(;R)!;!amino!;!
carboxypentanoyl9amino<!=!oxo!;!thia!2!a&abicyclo8/.3.19oct!3!ene!3!carboxylic acid

)efoxitin 5 (6S,7R)-4-(carbamoyloxymethyl)-7-methoxy--oxo-7-!("-thiophen-"-ylacetyl)amino#-$-thia-1-
a%abicyclo!4.".&#oct-"-ene-"-carboxylic acid
&lav'lani( a(i% ) (2R%5R%Z)-3-(2-hydro(yethylidene)-'-o(o-4-o(a-1-aza-bicyclo)3.2.*+hetane-2-
carbo(ylic acid
*'+'s ,-i%e.
)ycloheximide 5 /!8(3R)!3!8(2S,6S,;S)!6,;!Dimethyl!3!oxocyclohexyl9!3!
hydroxyethyl9piperidine!3,7!dione
Cyclohe(imide is an inhibitor of rotein biosynthesis in eu/aryotic or"anisms%
roduced by the bacterium Streptomyces griseus. Cyclohe(imide e(erts its e0ect by
interferin" 1ith the translocation ste in rotein synthesis (mo2ement of t1o t34,
molecules and m34, in relation to the ribosome) thus bloc/in" translational
elon"ation. Cyclohe(imide is 1idely used in biomedical research to inhibit rotein
synthesis in eu/aryotic cells studied in vitro (i.e. outside of or"anisms). 5t is
ine(ensi2e and 1or/s raidly. 5ts e0ects are raidly re2ersed by simly remo2in" it
from the culture medium.
/hali%o-i%e = (RS)-2-(2%&-dio(oieridin-3-yl)-1H-isoindole-1%3(2H)-dione
/hali%o-i%e is a sedati2e dru" introduced in the late 165*s that 1as used to treat
mornin" sic/ness and to aid slee.
)2+
5t 1as sold from 165' until 16&1% 1hen it 1as
1ithdra1n after bein" found to be a terato"en - a cause of birth defects.
)3+
7odern
uses of thalidomide (trademar/ed as /halo-i%% accordin" to 89, :ran"e #oo/)
include treatin" multile myeloma in combination 1ith de(amethasone%
)4+
and
erythema nodosum lerosum% 1ith strict controls on its use to re2ent birth defects.
)
Captan = (6aR,0aS)!3!8(trichloromethyl)sulfanyl9!6a,/,0,0a!tetrahydro!2H!isoindole!2,6(3H)!
dione
Captan is the name of a general use pesticide (>?,) that belongs to the phthalimide class of
fungicides. Though it can be applied on its own, )aptan is often added as a component of other
pesticide mixtures. +t is used to control diseases on a number of fruits and #egetables as well as
ornamental plants. +t also impro#es the outward appearance of many fruits, making them brighter
and healthier!looking. )aptan is utili&ed by both home and agricultural growers and is often
applied during apple production. )aptan is cited as >roup @3, a probable human carcinogen by
the %,*.
839
)23H2;4$6 5 3,3!dimethyl!3,6!dihydro!2!ben&ofuran!0!yl methylcarbamate
5 )arbofuran, -uradan, )urater
Carbo'uran is one of the most toxic carbamate pesticides. +t is marketed under the trade names
Furadan, by -A) )orporation and Curater, among se#eral others. +t is used to control insects
in a wide #ariety of field crops, including potatoes, corn and soybeans. +t is a systemic
insecticide, which means that the plant absorbs it through the roots, and from here the plant
distributes it throughout its organs where insecticidal concentrations are attained. )arbofuran
also has contact acti#ity against
pests.
(eosti)mine = 3--)(dimethylamino)carbonyl+o(y.-N,N,N-trimethylbenzenaminium
(eosti)mine (*rosti)min, +a)osti)min) is a parasympathomimetic that acts as a re#ersible
acetylcholinesterase inhibitor.
0# O1si%asi
teroid
)holesterol 5 (21R,26R)!21,26!dimethyl!20!(7!methylheptan!3!yl)!
3,6,/,0,=,B,22,23,2/,2;,27,20!dodecahydro!2H!cyclopenta8a9phenanthren!6!ol
)holesterol is re"uired to build and maintain membranesC it modulates membrane fluidity o#er
the range of physiological temperatures. The hydroxyl group on cholesterol interacts with the
polar head groups of the membrane phospholipids and sphingolipids, while the bulky steroid and
the hydrocarbon chain are embedded in the membrane, alongside the nonpolar fatty!acid chain of
the other lipids. Through the interaction with the phospholipid fatty!acid chains, cholesterol
increases membrane packing, which reduces membrane fluidity.
8B9
+n this structural role,
cholesterol reduces the permeability of the plasma membrane to neutral solutes,
8219
protons,
(positi#e hydrogen ions) and sodium ions.
8229
Dithin the cell membrane, cholesterol also functions in intracellular transport, cell signaling and
ner#e conduction. )holesterol is essential for the structure and function of in#aginated ca#eolae
and clathrin!coated pits, including ca#eola!dependent and clathrin!dependent endocytosis. The
role of cholesterol in such endocytosis can be in#estigated by using methyl beta cyclodextrin
(AE)D) to remo#e cholesterol from the plasma membrane. Fecently, cholesterol has also been
implicated in cell signaling processes, assisting in the formation of lipid rafts in the plasma
membrane. Gipid raft formation brings receptor proteins in close proximity with high
concentrations of second messenger molecules.
8239
+n many neurons, a myelin sheath, rich in
cholesterol, since it is deri#ed from compacted layers of chwann cell membrane, pro#ides
insulation for more efficient conduction of impulses.
8269
Dithin cells, cholesterol is the precursor molecule in se#eral biochemical pathways. +n the li#er,
cholesterol is con#erted to bile, which is then stored in the gallbladder. @ile contains bile salts,
which solubili&e fats in the digesti#e tract and aid in the intestinal absorption of fat molecules as
well as the fat!soluble #itamins, *, D, %, and H. )holesterol is an important precursor molecule
for the synthesis of #itamin D and the steroid hormones, including the adrenal gland hormones
cortisol and aldosterone, as well as the sex hormones progesterone, estrogens, and testosterone,
and their deri#ati#es.
839
ome research indicates cholesterol may act as an antioxidant.
82/9
)holic acid 5 6,0,23!trihydroxy!21,26!dimethylhexadecahydro!2H!cyclopenta8a9phenanthren!
20!yl)pentanoic acid
$ther names: 6I,0I,23I!trihydroxy!;E!cholanoic acid
2ro+esterone ) Pre"n-4-ene-3%2*-dione
2ro+esterone also /no1n as 23 (re"n-3-ene-3%2*-dione) is a C-21 steroid
hormone in2ol2ed in the female menstrual cycle% re"nancy (suorts gestation)
and embryo"enesis of humans and other secies
3. 5somerisasi
;etracycline = (4S%&S%12aS)-4-(dimethylamino)-3%&%1*%12%12a-entahydro(y-
&-methyl-1%11-dio(o-1%4%4a%5%5a%&%11%12a-octahydrotetracene-2-carbo(amide
= &
22
$
24
4
2
O
<


,estosterone = (=R,BS,21R,26S,2/S,20S)! 20!hydroxy!21,26!dimethyl! 2,3,7,0,=,B,22,23,2/,2;,27,20!
dodecahydrocyclopenta8a9phenanthren!6!one
,estosterone is a steroid hormone from the androgen group and is found in mammals, reptiles,
829

birds,
839
and other #ertebrates. +n mammals, testosterone is primarily secreted in the testicles of
males and the o#aries of females, although small amounts are also secreted by the adrenal
glands. +t is the principal male sex hormone and an anabolic steroid.
+n men, testosterone plays a key role in the de#elopment of male reproducti#e tissues such as the
testis and prostate as well as promoting secondary sexual characteristics such as increased
muscle, bone mass, and the growth of body hair.
869
+n addition, testosterone is essential for health
and well!being
8/9
as well as the pre#ention of osteoporosis.
8;9
$n a#erage, in adult human males, the plasma concentration of testosterone is about 0!= times as
great as the concentration of adult human femalesJ plasma,
879
but as the metabolic consumption of
testosterone in males is greater, the daily production is about 31 times greater in men.
8098=9

-emales also are more sensiti#e to the hormone.
%stradiol 5 (20E)!estra!2,6,;(21)!triene!6,20!diol
5stra%iol -e%i(ation
%strogen is marketed in a number of ways to address issues of hypoestrogenism. Thus, there are
oral, transdermal, topical, in'ectable, and #aginal preparations. -urthermore, the estradiol
molecule may be linked to an alkyl group at )20 (sometimes also at )6) position to facilitate the
administration. uch modifications gi#e rise to estradiol acetate (oral and #aginal applications)
and to estradiol cypionate (in'ectable).
$ral preparations are not necessarily predictably absorbed, and are sub'ect to a first pass through
the li#er, where they can be metaboli&ed, and also initiate unwanted side effects. Therefore,
alternati#e routes of administration that bypass the li#er before primary target organs are hit ha#e
been de#eloped. Transdermal and trans#aginal routes are not sub'ect to the initial li#er passage.
%thinylestradiol, the most common estrogen ingredient in combined oral contracepti#e pills, is a
more profound alteration of the estradiol structure.
%thinylestradiol5 2B!nor!20I!pregna!2,6,;(21)!trien!31!yne!6,20!diol
-terol .
E!itosterol 5 20!(;!%thyl!7!methylheptan!3!yl)!21,26!dimethyl!3,6,/,0,=,B,22,23,2/,2;,27,20!
dodecahydro!2H!cyclopenta8a9phenanthren!6!ol
$ther names: 33,36!Dihydrostigmasterol, tigmast!;!en!6!ol, E!itosterin
*lone and in combination with
similar phytosterols, E!sitosterol
reduces blood le#els of cholesterol,
and is sometimes used in treating
hypercholesterolemia.
8medical citation needed9
E!itosterol inhibits cholesterol absorption in the intestine.
839
Dhen the sterol is absorbed in the intestine, it is transported by lipoproteins and incorporated
into the cellular membrane.
869
,hytosterols and phytostanols both inhibit the uptake of dietary and
biliary cholesterol, decreasing the le#els of GDG and serum total cholesterol. @ecause the
structure of E!sitosterol is #ery similar to that of cholesterol, E!sitosterol takes the place of
dietary and biliary cholesterol in micelles produced in the intestinal lumen.
8/9
This causes less
cholesterol absorption in the body.
-ti)mastanol 5 (6E)!tigmastan!6!olC (6E,;I)!tigmastan!6!olC E!itostanolC DihydrositosterinC
DihydrositosterolC Dihydro!E!sitosterolC -ucostanolC pinastanolC 3/I!%thylcholestanol
-ti)mastanol (sitostanol) is a phytosterol found in a #ariety of plant sources. imilar to sterol
esters and stanol esters, stigmasterol inhibits the absorption of cholesterol from the diet.
8
2oly'nsat'rate% 6atty a(i%s
O-e+a78
$mega!6 fatty acids, polyunsaturated
97:inolei( a(i% ;<:<= )cis, cis-6%12-:ctadecadienoic acid= C1<=32:2
NK6 fatty acids that are important in human physiology are I!linolenic acid (2=:6, nK6C *G*),
eicosapentaenoic acid (31:;, nK6C %,*), and docosahexaenoic acid (33:7, nK6C DH*). These
three polyunsaturates ha#e either 6, ;, or 7 double bonds in a carbon chain of 2=, 31, or 33
carbon atoms, respecti#ely. *s with most naturally!produced fatty acids, all double bonds are in
the cis!configuration, in other words, the two hydrogen atoms are on the same side of the double
bondC and the double bonds are methylene interrupted, i.e., there are two single bonds between
each pair of ad'acent double bonds.
Chemical structure of alha-linolenic acid (,>,)% an essential n?3 fatty acid%
(1<@3A6c%12c%15c% 1hich means a chain of 1< carbons 1ith 3 double bonds on
carbons numbered 6% 12% and 15). ,lthou"h chemists count from the carbonyl
carbon (blue numberin")% hysiolo"ists count from the n (B) carbon (red
numberin"). 4ote that% from the n end (dia"ram ri"ht)% the Crst double bond
aears as the third carbon-carbon bond (line se"ment)% hence the name Dn?3D.
;his is e(lained by the fact that the n end is almost ne2er chan"ed durin"
hysiolo"ic transformations in the human body% as it is more ener"y-stable% and
other carbohydrates comounds can be synthesized from the other carbonyl end%
for e(amle in "lycerides% or from double bonds in the middle of the chain.
Chemical structure of eicosaentaenoic acid (EP,).
Chemical structure of docosahe(aenoic acid (9=,).
O-e+a7>
$mega!7 fatty acids, polyunsaturated
7:inoleni( a(i% ;*:<= ) all-cis-&%6%12-octadecatrienoic acid= C1<=3*:2
O-e+a7?
$mega!B fatty acids, mono! and polyunsaturated
:leic acid = (6Z)-:ctadec-6-enoic acid= C1<=34:2
Phenothiazine= thiodihenylamine% dibenzothiazine% dibenzoarathiazine% 1*H-
dibenzo-)b%e+-1%4-thiazine% P;F= C12=64G
;urunannya@
Chlorromazine ) 3-(2-chloro-1*H-henothiazin-1*-yl)-N%N-dimethyl-roan-1-amine= &1'$16&l 42S

)hlorproma&ine works on a #ariety of receptors in the central ner#ous system, producing
anticholinergic, antidopaminergic, antihistaminic, and weak antiadrenergic effects. @oth the
clinical indications and side effect profile of ),L are determined by this broad action: its
anticholinergic properties cause constipation, sedation, and hypotension, and help relie#e nausea.
+t also has anxiolytic (anxiety!relie#ing) properties. +ts antidopaminergic properties can cause
extrapyramidal symptoms such as akathisia (restlessness, aka the JThora&ine shuffleJ where the
patient walks almost constantly, despite ha#ing nowhere to go due to mandatory confinement,
and takes small, shuffling steps) and dystonia. +t is known to cause tardi#e dyskinesia, which can
be irre#ersible.
839
+n recent years, chlorproma&ine has been largely superseded by the newer
atypical antipsychotics, which are usually better tolerated, and its use is now restricted to fewer
indications. +n acute settings, it is often administered as a syrup, which has a faster onset of
action than tablets, and can also be gi#en by intramuscular in'ection. +( administration is #ery
irritating and is not ad#isedC its use is limited to se#ere hiccups, surgery, and tetanus.
869

,erphena&ine 5 3!8/!86!(3!chloro!21H!phenothia&in!21!yl) propyl9pipera&in!2!yl9ethanol5 C32/37Cl (60 -

,erphena&ine is used to treat psychosis (e.g. in schi&ophrenics) and the manic phases of bipolar
disorder. ,erphena&ine effecti#ely treats the positi#e symptoms of schi&ophrenia, such as
hallucinations and delusions, but its effecti#eness in treating the negati#e symptoms of
schi&ophrenia, such as flattened affect and po#erty of speech, is unclear. %arlier studies found the
typical antipsychotics to be ineffecti#e or poorly effecti#e in the treatment of negati#e symptoms,
8/9
but two recent, large!scale studies found no difference between perphena&ine and the atypical
antipsychotics.
8;9
+n low doses it is used to treat agitated depression (together with an antidepressant). -ixed
combinations of perphena&ine and the tricyclic antidepressant amitriptyline in different
proportions of weight exist (see %trafon below). Dhen treating depression, perphena&ine is
discontinued as fast as the clinical situation allows.
8citation needed9
,erphena&ine has no intrinsic
antidepressi#e acti#ity. e#eral studies show that the use of perphena&ine with fluoxetine
(,ro&ac) in patients with psychotic depression is most promising, although fluoxetine interferes
with the metabolism of perphena&ine, causing higher plasma le#els of perphena&ine and a longer
half!life. +n this combination the strong antiemetic action of perphena&ine attenuates fluoxetine!
induced nausea and #omiting (emesis), as well as the initial agitation caused by fluoxetine. @oth
actions can be helpful for many patients.
,erphena&ine has been used in low doses as a JnormalJ or JminorJ tran"uili&er in patients with a
known history of addiction to drugs or alcohol, a practice which is now strongly discouraged.
879
8citation needed9
,erphena&ine has sedating and anxiolytic properties, making the drug useful for the treatment of
agitated psychotic patients and, in high doses (up to 211 mg per day), for patients with life!
threatening (febrile) catatonia, a state in which the patients are extremely agitated, but unable to
express themsel#es. +n this situation perphena&ine may be used together with electrocon#ulsi#e
therapy and correction of electrolytes and fluids in the body.
* #aluable off!label indication is the short!time treatment of hyperemesis gra#idarum, in which
pregnant women experience #iolent nausea and #omiting. This problem can become se#ere
enough to endanger the life of the unborn. *s perphena&ine has not been shown to be teratogenic
and works #ery well, it is sometimes gi#en orally in the smallest possible dose.
Gim2astatin= (1S%3R%'S%<S%<aR)-<--2-)(2R%4R)-4-hydro(y-&-o(otetrahydro-2H-yran-2-yl+ethyl.-3%'-
dimethyl-1%2%3%'%<%<a-he(ahydronahthalen-1-yl 2%2-dimethylbutanoate= &25$3<O5

;he rimary uses of sim2astatin is for the treatment of dysliidemia and the
re2ention of cardio2ascular disease.
)1+
5t is recommended to be used only after
other measures such as diet% e(ercise% and 1ei"ht reduction ha2e not imro2ed
cholesterol le2els suHciently.
)1+
2olyene anti-y(oti(s% sometimes referred to as olyene antibioti(s% are a class
of antimicrobial olyene comounds that tar"et fun"i.
)1+
;hese olyene antimycotics
are tyically obtained from some secies of Streptomyces bacteria. ;he olyenes
bind to er"osterol in the fun"al cell membrane and romote lea/iness 1hich may
contribute to fun"al cell death. ,mhotericin #% nystatin% and natamycin are
e(amles of olyene antimycotics. 2olyene anti-y(oti(s% sometimes referred to
as olyene antibioti(s% are a class of antimicrobial olyene comounds that tar"et
fun"i.
)1+
;hese olyene antimycotics are tyically obtained from some secies of
Streptomyces bacteria. ;he olyenes bind to er"osterol in the fun"al cell membrane
and romote lea/iness 1hich may contribute to fun"al cell death. ,mhotericin #%
nystatin% and natamycin are e(amles of olyene antimycotics.
<-hoteri(in @
4ystatin
4atamycin
8# ,so-erisasi
(R)-(I)->-Einehrine or (R)-(I)->-adrenaline =(R)-4-(1-hydro(y-
2-(methylamino)ethyl)benzene-1%2-diol= &6$134 O3
*drenaline is used to treat a number of conditions including: cardiac arrest, anaphylaxis, and
superficial bleeding.
8239
+t has been used historically for bronchospasm and hypoglycemia, but
newer treatments for these, such as salbutamol, a synthetic epinephrine deri#ati#e, and dextrose,
respecti#ely, are currently preferred.
8239
;etracycline = (4S%&S%12aS)-4-(dimethylamino)-3%&%1*%12%12a-entahydro(y-
&-methyl-1%11-dio(o-1%4%4a%5%5a%&%11%12a-octahydrotetracene-2-carbo(amide
= &
22
$
24
4
2
O
<

(itamin * 5(3%,/%,7%,=%)!6,0!Dimethyl!B!(3,7,7!trimethyl!2!cyclohexen!2!yl)!3,/,7,=!
nonatetraen!2!ol 5 (Fetinol) 5C31/610