Preformulation: Solubility, dissociation or ionization constant (pKa), and partition co-efficient Course name: Pharmaceutics II Course code: PHRM 308 Section Semester: !a"" 0# S$%MITTE& TO: &r' Su(ia Is"am Chair)erson &e)artment o( Pharmac* S$%MITTE& %+: Sami*a ,honda-er Rinta .I&: 0#0/3/00/0182 ,a3i Mashreha Mahmud .I&: 0#0/#/00/01#2 Tah-i4 Ahsan .I&: 0#0/#/00/05 2 S*ed Sha(i6ur Rahaman .I&: 0#0/#/00/0012

East 7est $ni8ersit* Su4mission date: 0th No8em4er9 0#


Page number


Introduction Solubility Intrinsic solubility Importance of intrinsic solubility Ho to impro!e solubility #issociation or ionization constant (pKa) in preformulation pKa #etermination Henderson-Hesselbalc% e&uations Partition coefficient Importance of partition coefficient #ru( absorption, distribution and e)cretion #ru( desi(n ,iop%armaceutics -onclusion /eference

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)re(ormu"ation studies are initiated' &urin: the )re(ormu"ation )hase9 the )h*sica" and chemica" )ro)erties o( the acti8e )harmaceutica" in:redient .API2 are determined' The :ained -no;"ed:e on the API is necessar* (or the se"ection o( the ri:ht sa"t or )o"*mor)hic (orm and this he")s in the desi:n and de8e"o)ment o( the dosa:e (orm'Pre(ormu"ation inc"udes man* sta:es .<achman et a"9 #==02' Here the so"u4i"it*9 dissociation constant .),a2 and )artition coe((icient .<o: P2 are discussed ;hich are re6uired (or API characteri3ation .Nan>;ade9 0# 2'

So"u4i"it* is the mass o( so"ute that disso"8es in a s)eci(ic mass or 8o"ume o( so"8ent at a :i8en tem)erature' !or e?am)"e # :m o( NaC" disso"8es in '08@m" o( ;ater at 5AC' The so"u4i"it* o( a mo"ecu"e in 8arious so"8ents is determined as a (irst ste)' This in(ormation is 8a"ua4"e in de8e"o)in: a (ormu"ation .%ha8in9 0##2' Im)ortance o( so"u4i"it*: So"u4i"it* is one o( the most im)ortant )h*sicochemica" )ro)erties studied durin: )harmaceutica" )re(ormu"ation 4ecause it a((ects the 4ioa8ai"a4i"it* o( the dru:9 the rate o( dru: re"ease into the disso"ution medium9 and conse6uent"*9 the thera)eutic e((icac* o( the )harmaceutica" )roduct .Nan>;ade9 0# 2' !or "i6uid dosa:e (orm de8e"o)ment9 accurate so"u4i"it* data are essentia" to ensure the ro4ustness o( the (inished )roduct' !or so"id dosa:e (orms9 so"u4i"it* data are im)ortant in determinin: i( an ade6uate amount o( dru: is a8ai"a4"e (or a4sor)tion Bin 8i8o’' I( a com)ound has a "o; a6ueous so"u4i"it*9 it ma* 4e su4>ect to disso"ution rate/"imited or so"u4i"it*/"imited a4sor)tion ;ithin the :astrointestina" .GI2 residence time .<o4en4er: et a"9 0002' Determination of solubility in preformulation: So"u4i"it* is usua""* determined in a 8ariet* o( common"* used so"8ents and some oi"s i( the mo"ecu"e is "i)o)hi"ic'The so"u4i"it* o( a materia" is usua""* determined 4* the e6ui"i4rium so"u4i"it* method9 ;hich em)"o*s a saturated so"ution o( the materia"9 o4tained 4* stirrin: an e?cess o( materia" in the so"8ent (or a )ro"on:ed )eriod unti" e6ui"i4rium is achie8ed' This method is -no;n as e6ui"i4rium so"u4i"it* method' Common so"8ents used (or so"u4i"it* determination are as (o""o;s: #' 7ater ' G"*co"s (or e?am)"e9 )o"*eth*"ene :"*co"s9 )ro)*"ene :"*co"9 :"*cerin and sor4ito"

3' A"coho"s (or e?am)"e eth*" a"coho"9 methano"9 4en3*" a"coho" and iso)ro)*" a"coho" 1' Sur(actants (or e?am)"e t;eens and )o"*sor4ates 5' Ce:eta4"e oi"s "i-e castor oi"9 )eanut oi" and sesame oi" @' %u((ers at 8arious )Hs .%ha8in9 0##2'

Table: Sho;in: the a))ro?imate so"u4i"ities o( )harmaco)eia" and nationa" (ormu"ar* su4stances are indicated 4* the descri)ti8e terms' .A""audin9 0# 2 Intrinsic solubility (C₀)1: Intrinsic so"u4i"it* is de(ined as the ma?imum amount o( so"ute disso"8ed in a :i8en amount so"8ent under standard conditions o( tem)erature9 )ressure and )H' 7hen the )urit* o( the dru: sam)"e can 4e assured9 the so"u4i"it* 8a"ue o4tained in acid (or a ;ea- acid or a"-a"i (or a ;ea- 4ase can 4e assumed to 4e intrinsic so"u4i"it*' In sim)"e ;ords the so"u4i"it* o( a )ure ;ea- acid in acid or ;ea- 4asic dru: under a"-a"ine conditions in the intrinsic so"u4i"it*' The intrinsic so"u4i"it* o( a ;ea- acid is the "o;est o4ser8ed so"u4i"it* ;hen the )H o( the medium is more than t;o units 4e"o; the ),a o( the dru:' The intrinsic so"u4i"it* o( a ;ea- 4ase is the "o;est o4ser8ed so"u4i"it* ;hen the )H o( the medium is more than t;o units a4o8e the ),a o( the dru: .%ha8in9 0##2' Importance of intrinsic solubility: #' &isso"ution: Man* dru:s are (ormu"ated as so"utions or added in )o;der or so"ution (orm to "i6uids such as in(usion ("uid or in>ections in ;hich the* must disso"8e and remain in so"ution (or a :i8en )eriod o( time' ' %ioa8ai"a4i"it*: &ru:s must 4e in a dis)ersed (orm in the so"ution 4e(ore the* can 4e a4sor4ed across the 4io"o:ica" mem4ranes'

3' Rate o( dru: re"ease 4* di((usion: !or so"id dosa:e (orms such as ta4"ets9 ca)su"es or e8en dru:s that ha8e )reci)itated (rom so"ution9 the disso"ution o( the dru: is necessar* 4e(ore it can 4e re"eased (rom the dosa:e (orm (or it to 4e a4sor4ed' 1' Thera)eutic e((icac*: these (actors discussed a4o8e ;i"" u"timate"* determine ho; e((ecti8e the dru: ;i"" 4e ;hen administered .<achman et a"9 #==02' How to improve solubility: So"u4i"it* ma* 4e im)ro8ed ;ith the addition o( an acidic or 4asic e?ci)ient' !or e?am)"e9 so"u4i"i3ation o( as)irin ma* 4e increased 4* addition o( an a"-a"ine 4u((er' Genera" methods o( increasin: the so"u4i"it* are: #' Addition o( co/so"8ent9 (or e?am)"e9 ;ater9 a"coho"9 :"*cerin ' Addition o( com)"e?in:a:ent9 (or e?am)"e9 ca((eine9 E&TA 3' Chemica" modi(ication o( the dru: 1' )H ad>ustment 5' Addition o( sur(actant9 (or e?am)"e9 s)an9 t;een9 S<S .%ha8in9 0##2' Poor so"u4i"it* has issues not on"* ;ith (ormu"atin: the dru:D it a"so im)oses )ro4"ems in e8a"uatin: the )h*sicochemica" )ro)erties o( the mo"ecu"e itse"(' An a6ueous so"u4i"it* o( #0m:E< or more is re6uired o8er )H ran:e o( #/0 to achie8e ade6uate a4sor)tion o( a dru: (rom the intestines' A so"u4i"it* o( "ess than #m:Em< su::ests the need (or (ormin: a sa"t o( the dru: es)ecia""* (or ta4"ets and ca)su"es .PointCross Inc'9 0##2'

#issociation or ionization constant (pKa) in preformulation
The dissociation or ioni3ation constant is one o( the most im)ortant characteristics o( a )harmaceutica" chemica" moiet* ;hich has to 4e estimated ;ith accurac*' The ),a is amon: the )arameters that ha8e to 4e estimated ;ith accurac*9 irres)ecti8e o( so"u4i"it* constraints .&oria9 0##2'The ),a 8a"ues o4tained (or the se"ected dru:s are com)ared ;ith the "iterature 8a"ues'It is re6uired to understand the site o( a4sor)tion9 distri4ution to 8arious or:ans and e?cretion o( dru:s'),a is a"so he")(u" in screenin: sa"ts9 de8e"o)in: )re/c"inica" and c"inica" (ormu"ation F19 59 @G' It is a"so use(u" in de8e"o)in: ana"*tica" methods9 "i-e HP<C .PointCross Inc'9 0##2' pKa Determination: ),a can 4e determined 4* the (o""o;in: methods:  Henderson/Hesse"4a"ch e6uations

 $C/CIS' S)ectra  Potentiometric titration  So"u4i"it* measurements  HP<C techni6ues  Ca)i""ar* 3one e"ectro)horesis  !oamin: acti8it* .Ra8ichandiran et a"9 0##2 Henderson Hesselbalc! e"uations: The ),a is the ne:ati8e "o:arithm o( the e6ui"i4rium constant .,a2 o( the acid/4ase reaction o( the com)ound o( interest .%ha8in9 0##2' &etermination o( the dissociation constant (or a dru: ca)a4"e o( ioni3ation ;ithin a )H ran:e o( # to #0 is im)ortant since so"u4i"it*9 and conse6uent"* a4sor)tion9 can 4e a"tered 4* orders o( ma:nitude ;ith chan:in: )H' The Henderson/Hasse"4a"ch e6uation )ro8ides an estimate o( the ioni3ed and un/ioni3ed dru: concentration at a )articu"ar )H .A""audin9 0# 2' !or acidic com)ounds: )H H ),a I "o: .Fioni3ed dru:GEFun/ioni3ed dru:G2 !or 4asic com)ounds: )H H ),a I "o: .Fun/ioni3ed dru:GEFioni3ed dru:G2 ),a o( a com)ound is thus a measure o( dru: un/ioni3ed at a certain )H ),a H /"o: ,a9 ;here ,a is the acidit* or ioni3ation constant o( a ;ea- acid' !or a ;ea- 4ase9 ,a H ,;E,49 ;here ,; is the ionic )roduct o( ;ater.,;HFH3OIG ? FOH/G2 and ,4 is the 4asicit* or ioni3ation constant o( the ;ea- .%ha8in9 0##2' #t!er met!ods: There are man* e?)erimenta" methods used (or determinin: the ),a as mentioned a4o8e' Sim)"e (ittin: o( the )H/so"u4i"it* )ro(i"e can 4e used i( so"u4i"it* measurements ha8e a"read* 4een made at mu"ti)"e )H 8a"ues' &i((erent methods are a8ai"a4"e to determine the ),a o( dru:s9 such as )otentiometr*9 s)ectro)hotometr* and so"u4i"it* methods F1G' The )otentiometric titration and s)ectrometric method are common"* used and ;ide"* acce)ted techni6ues F1G' Poor so"u4i"it* o( the com)ounds ham)ers traditiona" )otentiometric methods

F#G' This method can 4e a))"ied on"* (or com)ounds ha8in: so"u4i"it* :reater than #00 JM' S)ectro)hotometric methods can 4e a))"ied to the com)ounds ha8in: so"u4i"it* e8en # JM' Ho;e8er9 this method is "imited to mo"ecu"es ha8in: chromo)hores at ioni3ation center9 ;hich sho;s s)ectra" dissimi"arit* at )rotonated and de)rotonated (orm .Ra8ichandiran et a"9 0##2' The im)ortance o( ),ain 4io"o:ic s*stems needs to )reser8e a re"ati8e"* constant en8ironment9 inc"udin: contro" o8er the )H o( the or:anismKs ("uids' One ;a* to achie8e this is throu:h the use o( L4u((ersL M a 4u((er is a com)ound ;hich due to its acid/4ase chemistr* reacts to chan:es in the en8ironment to )reser8e a near constant )H that is near the ),a o( the 4u((erin: com)ound .Nan>;ade9 0# 2' Thus9 the acid dissociation constant .),a2 is a use(u" )h*sicochemica" )arameter to e8a"uate the e?tent o( ioni3ation o( (unctiona" :rou)s re"ated to )H9 o(ten o( 8ita" si:ni(icance to understand the )harmaco-inetic and )harmacod*namic 4eha8ior o( a dru: su4stance .A8dee( and Testa9 0# 2'

Partition coefficient
Partition coe((icient .oi"E;ater2 is a measure o( a dru:Ns "i)o)hi"icit* and an indication o( its a4i"it* to cross ce"" mem4ranes' It is de(ined as the ratio o( the concentration o( unioni3ed dru: in oi" )hase ;ith the concentration o( the unioni3ed dru: in the a6ueous )hase9 at e6ui"i4rium .<achman et a"9 #==02' PoE; H .Coi"EC7ater2 e6ui"i4rium !or series o( com)ounds9 the )artition coe((icient can )ro8ide an em)iric hand"e in screenin: (or some 4io"o:ic )ro)erties' !or dru: de"i8er*9 the "i)o)hi"icEh*dro)hi"ic 4a"ance has 4een sho;n to 4e a contri4utin: (actor (or the rate and e?tent o( dru: a4sor)tion' A"thou:h )artition coe((icient data a"one does not )ro8ide understandin: o( in 8i8o a4sor)tion9 it does )ro8ide a means o( characteri3in: the "i)o)hi"icEh*dro)hi"ic nature o( the dru:'Since 4io"o:ica" mem4ranes are "i)oida" in nature9 the rate o( dru: trans(er (or )assi8e"* a4sor4ed dru:s is direct"* re"ated to the "i)o)hi"icit* o( the mo"ecu"e .<achman et a"9 #==02' Importance of partition coefficient: Partition coe((icient is im)ortant (or the (o""o;in: (actors/ #2 &ru: a4sor)tion9 distri4ution and e?cretion 2 &ru: desi:n

32 %io)harmaceutics 1) Dru$ absorption% distribution and e&cretion: <i)o)hi"icit* a((ects the (o""o;in: as)ects o( the dru:/ I' So"u4i"it*: I( )artition coe((icient increases then accordin: to the )artition coe((icient ratio discussed )re8ious"*9 the concentration o( the unioni3ed dru: in the oi" )hase increases' This indicates that;ith increase in )artition coe((icient9a6ueous so"u4i"it* decreases and "i)id so"u4i"it* increases and 8ice 8ersa' II' Mem4rane )ermea4i"it*: I( )artition coe((icient increases9 "i)o)hi"icit* increases so mem4rane )ermea4i"it* increases' III' A4sor)tion )otentia": 7ith increase in )artition coe((icient9 "i)id so"u4i"it* increases so a4sor)tion across the "i)oida" mem4rane increases and hence a4sor)tion )otentia" increases .!o"-ers et a"9 0032' IC' P"asma )rotein 4indin:: I( )artition coe((icient increases9"i)o)hi"icit* increases ;hich in turn increases the dru:s tendenc* to 4ind ;ith )"asma )rotein' Increase in )"asma )rotein 4indin: "essens the amount o( dru: enterin: the tar:et tissues and ce""s' C' Tissue distri4ution: A(ter a4sor)tion into the s*stemic circu"ation the 4"ood distri4utes the dru: to tissues' The 4"ood carries the dru: throu:h the "i8er (or he)atic (irst )ass meta4o"ism' I( the dru: is hi:h"* "i)o)hi"ic then ;hi"e )assin: throu:h the "i8er it ma* :et de)osited in the adi)ose tissues .(at ce""s2 in the "i8er9 resu"tin: in si:ni(icant decrease in tissue distri4ution o( dru:' CI' Rena" or he)atic c"earance: (or rena" and he)atic c"earance o( the dru:9 it must ha8e "o;er )artition coe((icient 8a"ues .<achman et a"9 #==02' The )artition coe((icient o( a dru: is de)endent on its ioni3ation state and there(ore on )H' On"* unioni3ed dru: ;ith su((icient "i)id so"u4i"it* is a4sor4ed across the 4io"o:ica" mem4rane and into the s*stemic circu"ation' Po"ar dru:s or ioni3ed dru:s are h*dro)hi"ic in nature and so are )oor"* a4sor4ed into the s*stemic circu"ation' &ru:s ;ith "o; )artition coe((icient 8a"ue ha8e hi:her a6ueous so"u4i"it* and are una4"e to cross the "i)id 4io"o:ica" mem4rane' <i)id so"u4"e dru:s ;ith hi:h )artition coe((icient 8a"ue ha8e "o; a6ueous so"u4i"it* and are a4"e to cross the "i)id 4arrier and reach the s*stemic circu"ation'

&ru:s ;ith )artition coe((icient 8a"ue 4et;een # and3 are ;e"" a4sor4ed' Those ;ith )artition coe((icient 8a"ue "ess than 3 or :reater than @ ha8e )oor trans)ort characteristics' Hi:h"* non/)o"ar dru:s ha8e )oor trans)ort across mem4ranes due to their tendenc* to reside in the "i)o)hi"ic re:ions .(orm a de)ot2 o( mem4ranes' Hi:h"* )o"ar com)ounds sho; )oor 4ioa8ai"a4i"it* 4ecause the* are una4"e to )enetrate the "i)id mem4rane 4arriers .<achman et a"9 #==02' Com)ounds ;ith a 4a"ance 4et;een )ermea4i"it* and trans)ort across the mem4rane sho; the 4est ora" 4ioa8ai"a4i"it*' !or o)timum a4sor)tion9 the dru: shou"d ha8e su((icient a6ueous so"u4i"it* to disso"8e in the :astrointestina" tract at the site o( a4sor)tion and "i)id so"u4i"it* shou"d 4e hi:h enou:h to (aci"itate the )enetration o( the dru: across the "i)ioda" mem4rane and into the s*stemic circu"ation' The hi:her the 8a"ue o( the )artition coe((icient the :reater is the "i)o)hi"icit* o( the dru: and 8ice 8ersa' &ru:s ha8in: 8a"ues o( PoE; much :reater than # are c"assi(ied as "i)o)hi"ic9 ;hereas those ;ith )artition coe((icients much "ess than # are indicati8e o( a h*dro)hi"ic dru:' A"thou:h it a))ears that the )artition coe((icient ma* 4e the 4est )redictor o( a4sor)tion rate9 the e((ect o( disso"ution rate9 ),a9 and so"u4i"it* on a4sor)tion must not 4e ne:"ected .!o"-ers et a"9 0032' '( Dru$ desi$n: <i)o)hi"icit* can 4e e?)"oited in desi:nin: certain dru:s to either increase their duration o( action9 tar:et a )articu"ar or:an or to reduce their to?icit*' !or e?am)"e9 most centra" ner8ous s*stem .CNS2 actin: dru:s ha8e hi:h )artition coe((icient 8a"ues ma-in: them 8er* "i)o)hi"ic and there4* the dru:s are a4"e to cross the 4"ood 4rain 4arrier to e?ert their anesthetic e((ect 4ecause the* remain "ar:e"* in unioni3ed (orm .Nan>;ade9 0# 2' )( *iop!armaceutics: Accordin: to %io)harmaceutics C"assi(ication S*stem .%CS2 dru: su4stances are c"assi(ied as: • • • • C"ass I M Hi:h )ermea4i"it* and hi:h so"u4i"it* C"ass II M Hi:h )ermea4i"it* and "o; so"u4i"it* C"ass IIIM <o; )ermea4i"it* and hi:h so"u4i"it* C"ass IC M <o; )ermea4i"it* and "o; so"u4i"it* .!o"-ers et a"9 0032'

!&A Centre (or &ru: E8a"uation and Research .C&ER2 de(ines these dru: 4oundaries as: I' II' Hi:h"* so"u4"e: 7hen the hi:hest dose stren:th is so"u4"e in 50m" ;ater o8er a )H ran:e o( # to 0'5' Hi:h"* )ermea4"e: 7hen the e?tent o( a4sor)tion in humans is determined to 4e :reater than =0O o( an administered dose 4ased on mass 4a"ance or in com)arison to an intra8enous re(erence dose' III' Ra)id"* disso"8in:: 7hen :reater than 85O o( the "a4e"ed amount o( dru: su4stance disso"8es ;ithin 30 minutes usin: $SP a))aratus I or II in a 8o"ume "ess than =0 m" o( 4u((er so"utions .!o"-ers et a"9 0032'

Pre(ormu"ation studies on a ne; dru: mo"ecu"e )ro8ide use(u" in(ormation (or su4se6uent (ormu"ation o( a )h*sicochemica""* sta4"e and 4io)harmaceutica""* suita4"e dosa:e (orm' Thorou:h )re(ormu"ation ;or- is the (oundation o( de8e"o)in: e((icatious and economica" (ormu"ations'


A""audin9 P'M'S' . 0# 2 A Re8ie; on Pre(ormu"ation Studies on &ru:s' International +ournal of on ,!armaceutical -esearc! and Development(1.529 @1/01 A8dee(9 A' and Testa9 %' . 00 2 Ph*sicochemica" )ro(i"in: in dru: research: a 4rie( sur8e* o( the state/o(/the/art o( e?)erimenta" techni6ues' Cell .ol /ife 0ci' 5=: #@8#M#@8=' %ha8in9 C' . 0##2 ,reformulation ,arameters pKa and 0olubility FOn"ineG A8ai"a4"e (rom: htt):EEm*)harma:uide'comE;)'''EPre(ormu"ationO 0Parameters'))t No8em4er 0# G' &oria9 M' C' C' . 0##2 Dosa$e 1orm Desi$n: ,!armaceutical and 1ormulation Considerations FOn"ineG A8ai"a4"e (rom: htt):EEima:es'rashie"a 8'mu"ti)"*'mu"ti)"*content'com FAccessed #8th No8em4er 0# G' !o"-ers9 G'9 Han 8an de9 7'9 Hans9 <'9 Artursson9 P'9 Mannho"d9 R'9 and ,u4in*i9 H' . 0032'Dru$ *ioavailability : 2stimation of 0olubility% ,ermeability% 3bsorption and *ioavailability (.et!ods and ,rinciples in .edicinal C!emistry)(7einheim9 7i"e*/CCH' <achman9 <' <ie4erman9 H' A'9 and ,ani:9 P' <' .#==0) T!e T!eory and ,ractice of Industrial ,!armacy(3rd edn' Mum4ai9 Car:hese Pu4"ishin: House' <o4en4er:9 R'9 Amidon9 G'<' and Cieira M' . 00029 0olubility as a /imitin$ 1actor to Dru$ 3bsorption( In: &ressman P% and <ennernas H .eds'29 Ora" &ru: A4sor)tion9 Prediction and Assessment' Ne; +or-9 Marce" &e--er9 Inc' Nan>;ade 0# G' PointCross Inc' . 0##29 Dru$ Development 4uide% ,reformulation: 0olubility determination FOn"ineG A8ai"a4"e (rom:





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