Troubleshooting Low Potency Results in Solid Oral Dosage Forms: Is it the

Method or the Formulation?

SMPL! PR!PRTIO"#!$TR%TIO"
Carlos Lee Research Analytical, Pfizer Global Research and Development
Keywords: Accelerated olvent !"traction, A!, #icrowave Assisted !"traction, #A!, !"traction, ample
Preparation, A$tomated, pray Dried Dispersion, Low Potency %ablet
bstract
Low potency val$es are common occ$rrences in dr$& prod$ct 'PLC assays( Considerable time and reso$rces are
often committed to determine if the low potencies are method or form$lation related( %he need for increased
b$siness efficiency thro$&ho$t the dr$& development process re)$ires analysts to develop effective strate&ies to
)$ic*ly resolve or eliminate the method vs form$lation iss$e( +$mero$s tools are available to help rapidly
tro$bleshoot and resolve the method vs form$lation iss$e( %hese tools, if $sed appropriately,
can provide rapid resol$tion to the method vs form$lation debate and can also aid in the development of
rob$st,r$&&ed analytical methods for solid oral dosa&e forms(
Introduction
Low potency res$lts are relatively fre)$ent occ$rrences in dr$& prod$ct 'PLC assays( %hese low potency res$lts
are driven by several factors, most of which can be divided into two main cate&ories: form$lation and method( -ne
of the most common form$lation related factors involves entrapment of the AP. onto man$fact$rin& e)$ipment
and,or AP. stora&e containers,ba&s( !ntrapment iss$es are often common in low dose form$lations and are
$s$ally addressed by coatin& the e)$ipment with e"cipients prior to addition of AP., and,or
rinsin& AP. containers,ba&s with e"cipients to ens$re )$antitative transfer of the container,ba& contents( Another
form$lation related factor that can contrib$te to low potency val$es involves $nderchar&in& of the AP. d$rin& dr$&
prod$ct man$fact$re( /ei&hin& errors
and,or miscalc$lation of the AP. activity factor are often the so$rce of these low potency val$es( %he latter is more
prevalent when the AP. is a salt, whose co$nterion contrib$tes si&nificantly to the molec$lar wei&ht of the dr$&
s$bstance( e&re&ation is another form$lation
related factor that contrib$tes to low potency res$lts d$rin& assay of solid oral dosa&e forms( %his involves physical
separation or de0mi"in& of the AP. from e"cipients in the form$lation( e&re&ation may occ$r d$e to particle size
and,or flow differences between the AP. and e"cipients( e&re&ation often leads to s$per0potent and,or s$b0potent
solid oral dosa&e forms and contrib$tes to inhomo&eneity of the man$fact$red s$pplies(
%o f$lly $nderstand the many method related factors that can contrib$te to low potency res$lts, one needs to have
a clear $nderstandin& of the critical steps in the sample preparation e"traction 1P2!3 process( As shown in 4i&$re
5, the first critical step in the P2! process involves disinte&ration or dispersion of the solid oral dosa&e form to
create small &ran$les,particles( %his increase in s$rface area is then followed by tep 6, which involves dissol$tion
of the AP. in the dil$ent( 4actors that infl$ence these two critical steps will impact the rate and e"tent of e"traction
of the AP. from the tablet matri"( %wo s$ch factors are dissolvin& solvent selection and a&itation techni)$es( %hese
two factors contrib$te to the development of inefficient and inappropriate analytical methods for solid oral dosa&e
forms and sho$ld be caref$lly and thoro$&hly eval$ated when tro$bleshootin& low potency val$es(
.n this paper, effective strate&ies for tro$bleshootin& low potency res$lts in dr$& prod$ct 'PLC assays will be
disc$ssed( %hese strate&ies, which incl$de the $se of non0traditional e"traction techni)$es, can help to
si&nificantly red$ce the time it ta*es to tro$bleshoot low recovery res$lts, allowin& pro7ect timelines to be
maintained(
"on&Traditional SP'! Tools
Low potency val$es observed d$rin& 'PLC assays often lead to the proverbial method vs( form$lation debate
between analysts and form$lators( %he on$s is often on analysts to show that the low potency res$lts is or is not
method related( 8eca$se of the need to increase b$siness efficiencies and beca$se of ti&ht pro7ect timelines,
today9s analysts m$st $se effective strate&ies to )$ic*ly and effectively resolve or eliminate the method vs(
form$lation iss$e( %he application of non0traditional tools can help facilitate rapid tro$bleshootin& of low potency
res$lts and help identify the so$rce of these iss$es( %wo non0traditional P2! techni)$es that are very effective in
tro$bleshootin& low potency res$lts are 53 Press$rize 4l$id !"traction 1P4!3or Accelerated olvent !"traction
1A!3: and 63 #icrowave Assisted !"traction 1#A!3( %hese two techni)$es have received limited attention over
the last ;05< years as P2! techni)$es and little, if any: have been said abo$t their potential as tro$bleshootin&
tools for low potency res$lts 15, 6, =, >, ;, ?, @, A3(
P4! or A! is a techni)$e for e"tractin& solid and semi0solid samples at elevated temperat$res and press$res,
with or&anic and,or a)$eo$s solvents 1?0A3( #A! is similar to A! in that it facilitates e"traction of samples at
elevated temperat$res and press$res( 'owever, $nli*e in A!, e"tractions in #A! are performed in parallel and
therefore sample thro$&hp$t is hi&her( Additionally, $nli*e in A!, samples in #A! can be a&itated by stirrin&: a
*ey factor when analyzin& challen&in& solid oral dosa&e forms( 4$rthermore, the mechanism of heatin& in #A!
allows for faster heatin& of samples and therefore faster sol$bilization,e"traction of AP.s from solid oral dosa&e
forms 153(
((lication o) S! and M! as Low Potency Troubleshooting Tools
A! and #A! are potentially powerf$l screenin& tools for rapid tro$bleshootin& of low potency res$lts( %hese
essentially BinfiniteB e"traction techni)$es can help pinpoint the so$rce of low potency res$lts 0 #ethod or
4orm$lation relatedC /ith as little as 6 tablets and in less than 6> ho$rs, answers to the method vs form$lation
iss$e can be obtained( %he screenin& proced$re involves performin& e"traction, $sin& A! or #A!, on two tablets
at:
53 Ambient temperat$re 16;DC 0 ><DC3 and:
63 'i&h temperat$re 1@<DC 0 5<<DC3
%he sample dil$ent $sed in the dr$& prod$ct test proced$re, which &enerated the low potency res$lt, is $sed as the
e"traction solvent in the A! and #A! screen( %he e"tracted sample is dil$ted to vol$me, filtered and assayed by
the dr$& prod$ct test proced$re( %he recovery
data &enerated at the two e"treme temperat$re conditions are then cate&orized into one of three b$c*ets as shown
in %able 5( .nsi&ht into the so$rce of the low potency res$lts is capt$red in the e"treme ri&ht col$mn( 4or e"ample,
A!,#A! e"traction that res$lts in low recovery at low temperat$res, b$t )$antitative recovery at hi&h
temperat$res, s$&&est that the low potency res$lts are method related 18$c*et A3( %his is beca$se )$antitative
e"traction of the AP. at elevated temperat$res shows that there were no iss$es with the form$lation 0 all
the dr$& is present, b$t the analytical method was $nable to completely e"tract it from the solid oral dosa&e form(
%he res$lts from the A!,#A! st$dies also provide additional information to the analyst to help determine a fi" for
the analytical method( %he )$antitative
recovery obtained at elevated temperat$res s$&&ests that e"traction may be *inetically driven and that lon&er
e"traction and,or sample a&itation times may facilitate complete recovery of the analyte from the tablet matri"(
Alternatively, chan&in& the ratio of the or&anic and,or a)$eo$s composition of the dil$ent may also help to enhance
recovery of the analyte( %able 5 f$rther shows that low recovery at low temperat$res and similarly low recovery at
elevated temperat$res s$&&est that we have a form$lation related iss$e 18$c*et 83( .f all the dr$& was present in
the solid oral dosa&e form, e"traction at elevated temperat$res sho$ld show increased recovery over the low
temperat$re e"traction( %he fact that no chan&e in recovery was observed when compared to the low temperat$re
e"traction s$&&ests that the low assay res$lts may be form$lation and not method related( %he above info sho$ld
provide the analyst with s$fficient data and confidence to initiate disc$ssions with the form$lator abo$t potential
form$lation related iss$es that co$ld contrib$te to low assay res$lts( .n %able 5, 8$c*et C, we see that low
recovery at low temperat$res b$t increased recovery at elevated temperat$res is a bit more challen&in& to
decipher( %he res$lts do not clearly s$&&est a form$lation or
method related iss$e( .n cases li*e these, the analyst sho$ld ass$me that the low assay res$lts are method related
and consider the application of other non0traditional techni)$es to shed f$rther li&ht on the root ca$se of the low
potency res$lts( Additionally, the analyst sho$ld
thoro$&hly eval$ate AP. bio0pharmace$tical data, s$ch as sol$bility in the dil$ent and consider dr$&,e"cipient
interaction as a li*ely so$rce of the low recovery( !val$ation of the str$ct$re and physiochemical properties of the
AP. and e"cipients $sed in the form$lation sho$ld help the analyst in determinin& if dr$&,e"cipient interaction co$ld
be contrib$tin& to the low potency res$lts( Additional tools s$ch as differential scannin& calorimetry and,or solid
state +#R co$ld also be $sed to predict and,or eval$ate the form$lation for dr$&,e"cipient interaction(
!*am(le %ase Studies !m(loying S!#M! Screens
Case st$dies hi&hli&htin& the application of A!,#A! as screenin& tools to tro$bleshoot low potency res$lts are
shown in %ables 6 and =( .n %able 6, Compo$nd A, a Pfizer propriety 6;E pray Dried Dispersion 1DD3 ; m&A
tablet form$lation, showed $ne"pected low potency when eval$ated with the man$al e"traction method( %he A!
screen was applied to determine if the low potency res$lt was form$lation or method related( !"traction at low
temperat$res provided low recovery of the AP. from the tablet matri", while e"traction at elevated temperat$res
provided essentially )$antitative recovery of the AP.( %he above res$lts s$&&ested that the low potency res$lts
obtained with the man$al method co$ld not be form$lation related, as all the AP. was obvio$sly present within the
tablet matri" 18$c*et A3( %he res$lts were more li*ely method related, with *inetics possibly playin& a si&nificant
role( As shown in %able 6, increasin& the sha*e and sonication times from 5 ho$r and =< min$tes,
respectively, to 6 ho$rs and ?< min$tes, respectively, afforded )$antitative recovery of the AP. from the tablet
matri"( Additionally, chan&in& the sample preparation proced$re by $sin& water first, followed by the addition of
F;,; AC+,water, allowed for rapid and )$antitative e"traction of the AP. from the tablet matri"( %he initial $se of
water allowed for rapid disinte&ration of the tablet, which contained
appro"imately =E of the s$per disinte&rant, sodi$m starch &lycolate 1!"plotab3( Another e"ample which hi&hli&hts
the s$ccessf$l application of A!,#A! screen to tro$bleshoot low potency res$lts is shown in %able =( Compo$nd
8, another Pfizer propriety compo$nd, provided low recovery when the man$al method was applied( %ablets were
then eval$ated with A! at low temperat$re and hi&h temperat$re( Res$lts from the A! st$dies s$&&ested that
the low potency res$lts were form$lation rather than method related 18$c*et 83( %his is beca$se e"traction at
elevated temperat$res res$lted in no chan&e in percent recovery when compared to e"traction at lower
temperat$res( .f additional dr$& was present in the form$lation, an increase in recovery at elevated temperat$res
wo$ld be e"pected( /ith the above data in hand, the analyst was able to convince the form$lator that the low
assay res$lts were form$lation driven( $bse)$ent eval$ation of samples from the blender and mill showed
that dr$& was adherin& to walls of the blender and mill wall, confirmin& that the low assay res$lts were form$lation
driven( %he iss$e was remedied by first addin& e"cipients to coat the s$rfaces of the man$fact$rin& e)$ipment(
Assay of the reform$lated tablets res$lted in )$antitative recovery of the AP. from the matri", confirmin& that the
analytical method was s$itable for its intended p$rpose(
As the above e"amples indicate, A! and #A! have &reat potential to be s$itable screenin& tools for
tro$bleshootin& low potency res$lts( A! and #A! can provide insi&ht as to the so$rce of the low potency res$lts 0
leadin& to rapid resol$tion of the method vs form$lation
debate, with minim$m reso$rce b$rn( Additionally, if applied early in the method development phase, A! and
#A! can facilitate the development of rob$st and r$&&ed sample
preparation,e"traction proced$res for solid oral dosa&e forms( %his is beca$se A!,#A! can be $sed as
screenin& tools to determine if the initially selected e"traction solvent is s$itable for e"tractin& the AP. from the
tablet matri"( %his *ind of information can lead to rapid method development and validation and early confidence
as to the rob$stness and r$&&edness of the analytical method( %he proced$re for $sin& A!,#A! as a method
development screenin& tool is analo&o$s to the A!,#A! tro$bleshootin& screen proced$re described earlier( %he
difference is that an additional b$c*et 18$c*et D3 is added to %able 5 1%able >3( .f e"traction on two tablets provide
)$antitative recovery at both temperat$re e"tremes, the solvent $sed is s$itable for e"tractin& the AP. from the
tablet matri"( %he A!,#A! method development screen was $sed in the development of an analytical
method for Compo$nd C, a ; m&A immediate release tablet form$lation( %he dissolvin& solvent $sed in the AP.
assay,p$rity method was eval$ated to determine if it was a s$itable solvent for e"tractin& the AP. from the tablet
matri"( A!,#A! e"tractions were performed
on two Compo$nd C tablets at low and elevated temperat$res( %he samples were then dil$ted to nominal
concentration, filtered and assayed with the AP. 'PLC method( As shown in %able ;, )$antitative recovery was
obtained at both temperat$re e"tremes 18$c*et D3, s$&&estin& that the solvent is s$itable for e"tractin& the AP.
from the tablet matri"( /ith the above information, the analyst was able to develop and validate a s$itable 'PLC
method in less than 5 wee*, with minimal h$man and sample reso$rces(
%onclusions
Low potency res$lts are relatively fre)$ent occ$rrences in dr$& prod$ct 'PLC assays( %hese low potency res$lts
are either method or form$lation related( %he c$rrent dr$& development climate re)$ires analysts to )$ic*ly
tro$bleshoot and identify the so$rce of the low potency val$es, so that clinical s$pplies co$ld be reform$lated or
methods redeveloped to allow for timely release to s$pport the clinical st$dies( !fficient and effective
tro$bleshootin& re)$ires that the analysts apply appropriate strate&ies, incl$din& the $se of non0traditional sample
preparation,e"traction screenin& tools s$ch as A! and #A!(
c+nowledgements
%he a$thor wo$ld li*e to than* Karen Alsante for her review of this man$script and for her constr$ctive feedbac*(
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