Solid State Stability

8/9/2019 Solid State Stability

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SOLID STATE STABILITY


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Stabilitas padatan

Fisika Transformasi Polimorfik

Kristalisasi, perubahan bentuk polimorf, interaksi

dengan eksipien, interaksi dengan lembab,

kontaminasi.

KimiaoAkibat perubahan pada intramolekular atau intermolekularo Reaksi Hydrolysis, oxidation, photolysis


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Stabilitas fsika

Stability of amorphous form

greatly depends on how is it prepared.

rystalli!ation abo"e Tg

Presen#e of residual #rystallinity $defe#t sites%

#an be sour#e for nu#leation

&n general, grinding'milling produ#es least stable

amorphous form


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(tability of the #rystalline state Polymorphi# transformation and sol"ation'desol"ation

biggest problems

(tability of polymorphi# form may depend upon

temperature

Presen#e of moisture #an promote polymorphi# and

pseudopolymorphi# transformations

Polymorphi# and pseudopolymorphi# #hanges are often

obser"ed upon s#aling up a pro#ess

Stabilitas fsika


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Stability of the crystalline stateFour steps to a solid*state rea#tion

+. oosening of mole#ules at the rea#tion site *

ne#essary distortion of rea#tion #a"ity

-. )ole#ular #hange * breaking and forming of

#hemi#al bonds

. (olid*solution formation * rea#tant and produ#t

both present in #rystal

/. (eparation of produ#t * produ#tion of new

produ#t #rystals.)ole#ular mobility 0 #an be enhan#ed by presen#e

of defe#t sites.ommon rea#tions in the solid state in#lude

hydrolysis, oxidation, and photolysis

Stabilitas kimia


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Stability of the crystalline state

Topo#hemi#al postulate 1

2rea#tions in #rystals o##ur with a minimum of atomi#

and mole#ular mo"ement3

Reaction Kinetic

4 Rea#tion kineti#s in solid state mu#h more#ompli#ated than in solution4 5u#leation*based me#hanisms #ommonly used

EquationsRelating toDecomposition

in the Solid

Stabilitas kimia


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SI!LEST DE"O!OSITIO# ODES O$!%RE SOLIDS

Solid is placed in a &acuum '

e(posed b) tempe*atu*eI Solid solid + solid

II Solid solid + liquid

III Solid liquid + liquid

I, Solid solid + gas, Solid liquid + gas

,I Solid gas + gas

REA"TIO# -I#ETI"S


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$akto*./akto* )angmempenga*uhi deg*adasi

obat padat

01 -elembaban21 Eksipient

31 -eke*asan tablet

41 ate*ial kemasan


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Crystalline State and Polymorphism in SolidDrugs

The chemical stabilit) o/ solidd*ugs is a5ected b) thec*)stalline state o/ the d*ug1

D*ugs in the c*)stalline stateha&e lo6e* g*ound.state /*eeene*g) and e(hibit highe* 7 G

and8 the*e/o*e8 slo6e* *eacti&it)1


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Crystallization of AmorphousDrugs

Attempts a*e o/ten made to /o*mulate poo*l)6ate*.soluble d*ugs in thei* amo*phous state8because the solubilit) o/ amo*phous mate*ialsis gene*all) highe* than that o/ c*)stalline state

Because o/ the lo6e* /*ee ene*g) o/ thec*)stalline state8 amo*phous substances tendto change to thei* mo*e the*mod)namicall)stable c*)stalline state 6ith time1

The*e/o*e8 c*)stalli9ation o/ amo*phous d*ugsubstances ma) occu* du*ing long.te*msto*age and ma) lead to d*astic changes in the*elease cha*acte*istics o/ the d*ug


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Formation and Growth ofCrystals

olecules in a c*)stal8 and the c*)stalsthemsel&es8 should not be conside*ed static

d*ug substances and e(cipients in solid dosage/o*ms8 such as tablets and g*anules8 ma)

*ec*)stalli9e o* sublime onto the su*/ace o/ thedosage /o*m du*ing sto*age1

So.called :6hiske*; c*)stalli9ation

obse*&ed in tablets o/ ethen9amide and ca5eine

anhThis c*)stalli9ation 6as enhanced in po*ous

tablets and at highe* tempe*atu*es1

Tablets containing lactose and mannitole(cipients ha&e been sho6n to /o*m 6hiske*s


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Polymorphism/Transitions in CrystallineStates

!ol)mo*phs a*e di5e*ent c*)stalline /o*ms o/ thesame d*ug1

Because these /o*ms ha&e di5e*ent /*ee ene*g)

o* chemical potentials8 depending on

tempe*atu*e conditions8 t*ansitions bet6eenpol)mo*phs occu*1

!ol)mo*phic t*ansitions du*ing sto*age ma) alte*c*itical p*ope*ties o/ d*ugs because the solubilit)and dissolution *ate o/ d*ug substances

gene*all) &a*) 6ith changes in thei* c*)stalline/o*m1

$*om a sto*age pe*specti&e8 tempe*atu*e andhumidit) a5ect pol)mo*phic t*ansitions1


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Polymorphism

an) d*ug substances e(hibit pol)mo*phismEach c*)stalline state has a di5e*ent g*ound.state

/*ee.ene*g) le&el and a di5e*ent chemical*eacti&it)

E( < Solid.state h)d*ol)sis o/ ca*bama9epine /*omneedle.shaped c*)stals 6ith a highe* "*)stallineo*de* is /aste* than that o/ beam.shaped andp*ismatic /o*ms

Reacti&it) o/ ca*bama9epine to light also depends

on the c*)stalline /o*m o/ the d*ugDi5e*ences in *eacti&it) among di5e*ent

c*)stalline /o*ms ha&e also been *epo*ted /o*photodeg*adation o/ /u*osemide1


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The stabilit) o/ d*ugs in thei*amo*phous /o*m is gene*all) lo6e*

than that o/ d*ugs in thei* c*)stalline/o*m8 because o/ the highe* /*ee.ene*g) le&el o/ the amo*phous state1

Dec*eased chemical stabilit) o/ solidd*ugs b*ought b) mechanicalst*esses such as g*inding is due to achange in c*)stalline state

A *elationship bet6een the stabilit)and g*inding time 6as att*ibuted tothe inc*eased solubilit)


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E5ect o/ g*inding time on the deg*adation o/ aspi*in insuspension at 4=>"1


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Eet of !oisture and"umidity on Solid Drugs

The e5ect o/ moistu*e andhumidit) on the deg*adationkinetics o/ asco*bic acid8 thiamine

salts8aspi*in8 &itamin A and*anitidine h)d*ochlo*ide has been*epo*ted1

oistu*e pla)s t6o p*ima*) *oles incatal)9ing chemical deg*adation


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mechanism

6ate* pa*ticipates in the d*ug deg*adationp*ocess itsel/ as a *eactant8 leading toh)d*ol)sis1 deg*adation *ate is di*ectl) a5ectedb) the concent*ations o/ 6ate*8 h)d*onium ion8o* h)d*o(ide ion

6ate* adso*bs onto the d*ug su*/ace and /o*ms amoistu*e.so*bed la)e* in 6hich the d*ug isdissol&ed and deg*aded1

?ate* adso*ption ma) also change the ph)sical

state o/ d*ugs8 the*eb) a5ecting thei* *eacti&it)1Thus8 6ate* a5ects d*ug deg*adation indi*ectl)

b) p*o&iding a /a&o*able en&i*onment /o*deg*adation


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The mechanisms /o* these e5ectso/ 6ate* a*e dete*mined b) theph)sical state o/ 6ate*

molecules1$o* e(ample8 /o* d*ugs that /o*m

h)d*ates8 6ate* o/ c*)stalli9ation

is t*apped in the c*)stals and8gene*all)8 cannot pa*ticipate inchemical *eactions1


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E5ect o/ g*inding on the deg*adation o/ ampicillin t*ih)d*ate du*ingsto*age at 4=>"1 @*inding time8 =8 8 0 min 8 3= min 8C= min02= min78 0= min1


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!oisture Adsorption

oistu*e adso*ption du*ing sto*age canalso a5ect the ph)sical stabilit) o/pha*maceuticals8 leading to changes insuch p*ope*ties as appea*ance and

dissolution *ate1Adso*ption o/ moistu*e is go&e*ned b)

the ph)sical p*ope*ties o/ the d*ugsubstance and e(cipients1

$o* e(ample8 the adso*ption o/ moistu*eb) aspi*in c*)stals 6as enhanced b)adding h)d*ophilic e(cipients


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Eet of e#ipients

E(amples< the accele*ating e5ect o/ talc on the

h)d*ol)sis o/ thiamine h)d*ochlo*ide

po6de*s the accele*ating e5ect o/ magnesium

stea*ate on discolo*ation o/ tabletscontaining amines and lactose

the e5ect o/ talc impu*ities8stea*icacid8and calcium succinate on thedeg*adation o/ aspi*in tablets1


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E(cipients

e(cipients ma) pa*ticipate di*ectl) indeg*adation as *eactants8 such as addition*eactions 6ith d*ugs1

E(cipients ma) also e(hibit catal)9ing

e5ects to6a*d d*ug deg*adation Fe(1 thenucleophilic catal)sis e5ect o/ suga*s Fsuchas glucose and suc*oseG and amines on thedeg*adation o/ este* o* amide d*ugsG

Othe* mechanisms include the e5ect o/moistu*e p*esent in e(cipients8

the e5ect o/ pH changes caused b)e(cipients


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Eksipient

Bebe*apa eksipient dilapo*kanmeningkatkan kecepatan deg*adasisepe*ti

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Solid State Stability

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