Miguel An ónio Pi es de Ma os
De elopmen o o al able s
con aining Nico andil
Disse ação do 2º Ciclo de Es udos conducen e ao g au de
Mes e em Tecnologia Fa macêu ica
T abalho ealizado sob a o ien ação do
P o esso Dou o Domingos Fe ei a e
P o esso Dou o Sé gio Simões
Ou ub o 2014
ii
Disclaime
The pa ial ep oduc ion o his hesis is au ho ized o esea ch pu poses only, by
w i en decla a ion o he au ho , o which is commi ed.
iii
Acknowledgmen s
Ag adeço aos meus o ien ado es P o esso Dou o Domingos Fe ei a e
P o esso Dou o Sé gio Simões oda a ajuda e apoio p es ados.
Um mui o ob igado ao P o esso Dou o Paulo Cos a pela disponibilidade,
comen á ios e ajuda.
Es e abalho con ou com a colabo ação da Bluepha ma, Indús ia Fa macêu ica S.A. que
disponibilizou as suas ins alações, equipamen os e ecu sos pa a
a execução do abalho expe imen al.
Deixo um econhecimen o sen ido pela colabo ação, ajuda e sob e udo paciência, aos
meus colegas, Alice U bano, José Miguel, Pa ícia Sil a, Paulo An unes e Síl ia Vicen e.
Ag adeço, de o ma especial, à Cláudia Sil a, pela amizade.
Pa a a minha amília, pelo apoio de oda a ida e pa a os meus Amigos, po semp e me
e em incen i ado a con inua .
Pa a a minha a ó ma e na.
A odos, mui o Ob igado.
i
Dedicado à Luísa.

i
De elopmen o o al able s con aining Nico andil
ii
Abs ac
The de elopmen o any d ug p oduc is always guided by he goal o designing a
p oduc which complies wi h de ined speci ica ions a elease and ha is able o main ain
i s physic-chemical p ope ies and s abili y wi hin accep able limi s du ing i s shel -li e.
The e o e, he compliance wi h he p inciples o Quali y, Sa e y and E icacy depends on a
me iculous and planned pha maceu ical de elopmen wo k.
The p esen wo k ocused on he o mula ion o a s able Nico andil o al able
dosage o m, h ough a ca e ul e alua ion and choice o he D ug Subs ance, he
excipien s and selec ion o an op imized manu ac u ing p ocess.
C i ical ac o s a ec ing Nico andil s abili y we e discussed and e alua ed unde a
isk managemen s a egy conside ing hei impo ance o he s abili y o he d ug p oduc .
Selec ion o excipien s was done h ough a DS/excipien s compa ibili y s udies and
single and o al impu i ies we e quan i ied by HPLC analy ical echnique, o selec hose
who showed be e chemical s abili y.
De elopmen o he o mula ion aimed o p oduce 10mg Nico andil able s, by di ec
comp ession o a homogeneous powde mix u e and was conduc ed along ou ials.
Finished p oduc pha maceu ical pe o mance and chemical s abili y a e a h ee
mon hs sho e m s abili y s udy, in ICH condi ions, was e alua ed and compa ed wi h a
e e ence d ug p oduc .
S a is ical e alua ion o he mul iple pa ame e s sugges s ha , in his pe iod, he e
a e no signi ican di e ences be ween es and e e ence, ei he in pha maceu ical
pe o mance o chemical s abili y.
Key wo ds:
Nico andil, pha maceu ical de elopmen , o al able s, s abili y.
iii
De elopmen o o al able s con aining Nico andil
ix
Resumo
O desen ol imen o de qualque medicamen o de e se o ien ado pa a a ob enção
de um p odu o que cump a com as especi icações de inidas à da a do ab ico e que
man enha as suas p op iedades ísico-químicas e de es abilidade den o de limi es
acei á eis du an e o seu ciclo de ida. Po isso o cump imen o dos p incípios de
Qualidade, Segu ança e E icácia depende de um me iculoso planeamen o do
desen ol imen o a macêu ico.
O abalho ap esen ado e e como obje i o o desen ol imen o de uma o mulação
es á el de comp imidos de Nico andil, a a és de uma c i e iosa ca a e ização da
subs ância a i a, de uma escolha undamen ada de excipien es e de um p ocesso
o imizado de ab ico.
Os a o es c í icos que a e am a es abilidade do Nico andil o am discu idos e
a aliados no âmbi o de uma análise de isco, conside ando a sua ele ância pa a a
es abilidade do p odu o acabado.
A seleção de excipien es oi ei a eco endo a es udos de compa ibilidade des es
com a subs ância a i a, usando a quan i icação das impu ezas indi iduais e o ais
eco endo à écnica analí ica de HPLC, pa a seleciona os que indicia am melho
compa ibilidade.
O desen ol imen o da o mulação e e como obje i o a p odução de comp imidos
con endo 10mg de Nico andil, po comp essão di e a de uma mis u a de pós homogénea
e é cons i uído po 4 e apas.
A a aliação dos comp imidos incidiu sob e o desempenho a macêu ico e sob e a
es abilidade química após um es udo de es abilidade ab e iado de 3 meses em
condições ICH. Os esul ados des a a aliação o am compa ados com um p odu o de
e e ência.
A a aliação es a ís ica dos dados ge ados suge e que, nes e pe íodo de empo, não
exis em di e enças signi ica i as en e o p odu o es e e o de e e ência, que a ní el de
desempenho a macêu ico, que a ní el da es abilidade.
Key wo ds:
Nico andil, desen ol imen o a macêu ico, comp imidos o ais, es abilidade.
De elopmen o o al able s con aining Nico andil
x i
Table 35. T ial #1. Quan i a i e composi ion o es mix u es ................................. 86
Table 36. T ial #1. Comp ession es s esul s ........................................................ 87
Table 37. T ial #1. Table cha ac e iza ion esul s .................................................. 89
Table 38. T ial #2. Quan i a i e composi ion o es mix u es ................................. 92
Table 39. T ial #2. Mix u e lowabili y and mix u e cha ac e iza ion esul s ............ 93
Table 40. T ial #2. Blend homogenei y ................................................................... 93
Table 41. T ial #2. 10mg able s cha ac e iza ion esul s ....................................... 94
Table 42. T ial #3. Quali a i e composi ion ............................................................ 96
Table 43. T ial #3. P ocess summa y able ............................................................ 97
Table 44. T ial #3. Mix u e cha ac e iza ion esul s .............................................. 100
Table 45. T ial #3. Mix u e homogenei y esul s ................................................... 102
Table 46. T ial #3. Table s cha ac e iza ion esul s .............................................. 102
Table 47. Manu ac u ing pa ame e s o be es ed on ial #4 ................................ 103
Table 48. T ial #4. Quan i a i e composi ion ........................................................ 104
Table 49. T ial #4. Mix u e homogenei y esul s ................................................... 106
Table 50. T ial #4. Table s cha ac e isa ion esul s .............................................. 107
Table 51. T ial #4. Uni o mi y o dosage uni ........................................................ 108
Table 52. Final isk assessmen on DS a ibu es ................................................ 110
Table 53. Final isk assessmen on excipien s a ibu es ...................................... 111
Table 54. Final isk assessmen on manu ac u ing p ocess ................................. 112
Table 55. 10min dissolu ion Tukey HSD esul s ................................................... 115
Table 56. 15min dissolu ion Tukey HSD esul s ................................................... 116
Table 57. 30min dissolu ion Tukey HSD esul s ................................................... 117
Table 58. Tes s pe o med du ing s abili y s udy .................................................. 118
Table 59. Summa y o s abili y esul s o es o mula ion (30N) ........................... 119
Table 60. Summa y o s abili y esul s o es o mula ion (60N) ........................... 120
Table 61. TPP o es p oduc conclusion ............................................................. 129

De elopmen o o al able s con aining Nico andil
x ii
Ac onyms
API
-
Ac i e pha maceu ical ing edien
aw
-
Wa e ac i i y
cGMP
-
Cu en Good Manu ac u ing P ac ices
CPP
-
C i ical P ocess Pa ame e
CQA
-
C i ical Quali y A ibu es
CU
-
Con en Uni o mi y
DS
D ug Subs ance
FDA
-
Food and D ug Adminis a ion
FTIR
-
Fou ie T ans o ma e In a Red
GIT
-
Gas oin es inal ac
ICH
-
In e na ional Con e ence on Ha moniza ion
KF
Ka l Fische ( o al wa e de e mina ion)
N
New on
NA
-
No applicable
ND
-
No de ec ed
NIR
-
Nea -in a ed
NMT
No mo e han
Ph. Eu .
-
Eu opean Pha macopoeia
QTPP
-
Quali y Ta ge P oduc P o ile
RH
-
Rela i e humidi y
RSD
Rela i e S anda d De ia ion
SSG
-
Sodium s a ch glycola e
Tg
-
Glass ansi ion empe a u e
TPP
-
Ta ge P oduc P o ile
udl
-
Unde de ec ion limi
USP
-
Uni ed S a es Pha macopeia
Wa e (u.p.)
-
Ul a pu e wa e
XRPD
-
X- ay powde di ac ion
De elopmen o o al able s con aining Nico andil
x iii
De elopmen o o al able s con aining Nico andil
1
In oduc ion
De elopmen o o al able s con aining Nico andil
2
De elopmen o o al able s con aining Nico andil
In oduc ion
3
1. Theo y and e iew o he li e a u e
Solid o al dosage o ms and especially able s o o al adminis a ion, a e he mos
common pha maceu ical dosage o m (1). Vi ually ubiqui ous, o al able s, despi e i s
appa en simplici y, demand a ca e ul esea ch and de elopmen p ocess un il being
launched in o ma ke . Table s, as well as any d ug p oduc , go h ough a design p ocess
un il i assumes i s inal shape. This design p ocess is called pha maceu ical
de elopmen .
The pu pose o he pha maceu ical de elopmen is o demons a e, h ough he
compila ion o scien i ic e idences, ha he achie emen o a speci ic o mula ion o he
dosage o m, composed by he d ug subs ance (DS) and speci ic excipien s and i s
manu ac u ing p ocesses, obus and sui able o he in ended use (2).
The in o ma ion and knowledge gained om pha maceu ical de elopmen s udies
include a a iable numbe o es o mula ions wi h di e en composi ions and
manu ac u ing p ocess ials using di e en p ocess pa ame e s. All o his da a p o ide
scien i ic knowledge o suppo he es ablishmen o he design space, speci ica ions, and
manu ac u ing con ols. Conce ning he pha maceu ical de elopmen , wo majo
sequen ial s ages ha e an impo an ole in d ug de elopmen : p e- o mula ion, whe e he
DS is s udied and es ed and he o mula ion, whe e he dosage o ms is de ined.
1.1. P e- o mula ion and o mula ion
The de elopmen o any d ug p oduc equi es an ex ensi e chemical and physical
cha ac e iza ion o he DS and excipien s, which is he basis o se a p ope s a egy o
he de elopmen p ocess (3). The pu pose o p e- o mula ion and o mula ion is o ga he
knowledge on he DS, excipien s, manu ac u ing p ocess and inished d ug p oduc o
demons a e he desi ed pha maceu ical pe o mance, has p edic able he apeu ic
esponse and s abili y o he inal d ug p oduc h oughou i s li e cycle. In o he wo ds, i
means i has o demons a e he necessa y quali y, sa e y and e icacy p ope ies and s ill
be able o be manu ac u ed a an indus ial scale.
P e- o mula ion is he i s s age whe e he DS p ope ies a e in es iga ed and
whe e hose which can ha e an impac on he o mula ion design a e iden i ied and
s udied, such as: c ys allini y, solubili y, chemical and physical s abili y and polymo phism
(4).
In his s age i is also necessa y o e alua e and selec adequa e excipien s o
ensu e an op imal pe o mance o he d ug p oduc . Al hough, selec ing excipien s is no a
s aigh o wa d p ocess, since i mus be demons a ed ha hey a e chemical and

De elopmen o o al able s con aining Nico andil
In oduc ion
4
physically compa ible wi h he DS. This issue is o u mos impo ance since i is di ec ly
ela ed o he s abili y and quali y o he inal d ug p oduc (5, 6).
1.2. S abili y o d ug p oduc s
DS and d ug p oduc s abili y is an issue o majo impo ance since i is a well-
ecognized cause o poo d ug p oduc quali y, sa e y and e icacy (7-9).
A d ug p oduc can only emain in ma ke while i s quali y p o ile comply wi h
pha macopoeial s anda ds and manu ac u e speci ica ions, which ha e been p e iously
app o ed by egula o y agencies. These speci ica ions allow he es ablishmen o he
shel -li e pe iod (10).
S abili y o d ug p oduc s is di ec ly ela ed o pa ien sa e y. I is manda o y o
p esen enough e idences o d ug p oduc s abili y o egula o y au ho i ies o achie e
ma ke au ho iza ion. On he o he hand, s abili y o he d ug p oduc is also ela ed o
economic success.
Ul ima ely, ins abili y o DS and d ug p oduc s will cause many ad e se eac ions on
pa ien s due o he p esence o deg ada ion p oduc s and/o low e icacy, due o loss o
po ency. F om he egula o y poin o iew, pa ien sa e y is he eason why DS and d ug
p oduc s abili y a e highly egula ed h ough in e na ional s anda ds and guidelines which
helps o gua an ee he necessa y quali y s anda ds o he DS and d ug p oduc p io o
ma ke en y.
By las , i a d ug p oduc wi h s abili y issues en e s ma ke i will mos likely be
subjec o p oduc ecalls, bad publici y, low expi y da e and high cos s, ei he di ec o
indi ec , o pha maceu ical companies.
E en ually, e e y single d ug p oduc will chemically and physically change along i s
li ecycle, since chemical and physical in e ac ions a e una oidable. The e o e, de eloping
a d ug p oduc mus ake in o conside a ion s a egies o gua an ee p oduc s abili y and
compliance wi h speci ica ions as long as possible.
A d ug p oduc is a complex sys em o med by molecules o DS and excipien s.
These molecules ha e speci ic s uc u es and o ganic g oups ha will dic a e he physical
and chemical p ope ies o he aw ma e ials ha hey o igina e bu also he p ope ies o
he inished d ug p oduc .
These in e ac ions a e also in luenced by ex e nal ac o s such as empe a u e,
humidi y, ligh o oxygen, manu ac u ing p ocess, packaging ma e ial and anspo and
s o age condi ions.
The main consequence associa ed wi h d ug p oduc s abili y is he inc eased le el
o oxici y ha deg ada ion p oduc s b ing o he pa ien s and he e o e pha maceu ical
De elopmen o o al able s con aining Nico andil
In oduc ion
5
companies a e bound o pe o m and epo s abili y s udies on hei d ug p oduc s (8, 9,
11). These s abili y s udies a e pe o med ini ially du ing he pha maceu ical de elopmen
s age bu also along he p oduc li e ime, while i emains on ma ke .
The ini ial s abili ies s udies will se e o p opose an expi y da e, o in o he wo ds o
de ine he ime du ing which he d ug p oduc complies wi h i s c i ical quali y a ibu es
and is wi hin he de ined speci ica ions. On he o he hand, ollow up s abili y s udies and
long e m s udies will se e o moni o and suppo he p e iously de ined expi e da e.
When add essing he s abili y o d ug p oduc s i is necessa y o speci y ha his can
be chemical, physical and mic obiological s abili y (9).
Chemical s abili y is o majo impo ance and can be e alua ed and quan i ied
h ough analy ical p ocedu es using di e en echniques. Iden i y, assay and impu i y
le els a e manda o y pa ame e s o be e alua ed, since hese pa ame e s a e he ones
ha can change unde se e al ac o s, as al eady men ioned, bu also due o in e ac ions
be ween DS (i mo e han one a e p esen in he d ug p oduc ) and be ween DS and
excipien s.
Many chemical eac ions a e p omo ed due o ca alys s subs ances p esen in he
excipien s, wa e molecules o mic o-en i onmen al pH. These chemical eac ions can
cause DS deg ada ion, h ough mechanisms such as hyd olysis, oxida ion, educ ion,
deca boxyla ion, ing clea age, polyme iza ion, polymo phic changes and pho olysis, only
o men ion a ew common examples (9). All o hese po en ial deg ada ion pa hways lead
o he appea ance o deg ada ion p oduc s ela ed o a po en ial inc ease in p oduc
oxici y. This is why i is also necessa y o achie e an adequa e knowledge o he
deg ada ion p ocess and o iden i y he deg ada ion p oduc s o med (11).
O he ac o s ha in luence he chemical s abili y a e, o example, empe a u e,
ligh , oxygen and excipien s p esen on he o mula ion o he d ug p oduc , among o he s.
Mechanical s eng hs like p essu e/compac ion o ces, milling and g inding may also
a ec chemical as well as physical s abili y o he DS and d ug p oduc s (9).
Physical s abili y is ela ed o he physical p ope ies o he DS and excipien s o
al e a ions on hese along d ug p oduc shel li e. Physical s abili y is ela ed o d ug
p oduc p ope ies ha a ec i s e icacy, such as solubili y, dissolu ion, disin eg a ion,
esis ance o c ushing, iabili y, wa e con en , polymo phic changes and
c ys alline/amo phous ansi ions (7, 12). Bioa ailabili y is, he e o e, dependen on his
ype o s abili y, since hese p ope ies a e ela ed o he in i o pe o mance o he d ug
p oduc .
Mic obiological s abili y, al hough less c i ical in solid o al dosage o ms han in o he
pha maceu ical o ms, such as liquids o semi solids, mus be moni o ed along he long
De elopmen o o al able s con aining Nico andil
In oduc ion
6
e m s abili y s udy o ensu e ha p ope limi s, de ined by compendial speci ica ions, a e
espec ed.
In e na ional guidelines a e he s anda d in o ma ion sou ce o p ope ly conduc a
s abili y s udy which is essen ial o demons a e ha a p oduc emains wi hin allowed
impu i y le els. I is gene ally accep ed by egula o y agencies a dec ease up o 95% o
he labelled DS amoun du ing shel li e o a d ug p oduc , al hough, shel li e is mainly
dic a ed by he le el o deg ada ion p oduc s (13). The In e na ional Con e ence on
Ha moniza ion, h ough i s impu i y guidelines (10, 14), speci ies he epo ing,
iden i ica ion, and quali ica ion h esholds o impu i ies in d ug p oduc s. A limi be ween
0.1% - 1% o o al and single deg ada ion p oduc s is usually he in e al in which he
iden i ica ion o quali ica ion is manda o y (13).
The s abili y assessmen o d ug p oduc s can be done using se e al s a egies.
Since i is no p ac ical o pe o m an on-going (o long e m) s abili y e alua ion du ing
p oduc de elopmen , i became necessa y o speed up es ing imes h ough accele a ed
s abili y s udies in s anda dized condi ions. These s udies a e o en ca ied ou bo h on he
DS and d ug p oduc s a empe a u es om 25ºC up o 40°C, unde ela i e humidi y
condi ions om 60% o 75% (15, 16) and du ing a de ined pe iod o ime. These ype o
s udies a e also known as iso he mal s ess es ing (IST) (17).
ICH long e m, in e media e and accele a ed condi ions o hese s udies a e de ined
in in e na ional guidelines and a e 25ºC/60%RH, 30ºC/65%RH and 40ºC/75%RH (16).
Al hough he p edic ion o shel li e can be based on s udies unde accele a ed
condi ions, da a a he ecommended s o age empe a u e a e gene ally equi ed o
suppo he ac ual shel li e o ma ke ed p oduc s and o con i m he esul s o he
accele a ed s abili y p ocess (16), howe e , he use o s a is ics applied o he eal ime
da a should allow ex ension o shel -li e (18). A simple ex apola ion can be done o
p edic shel -li e by conside ing ha he shel li e de e mined a 40°C/75%RH is abou
one- ou h o ha a oom empe a u e.
1.2.1. Solid s a e s abili y
Solid s a e eac ions a e mo e complex and ake longe han eac ions which ake
place in solu ion s a e because in he solid s a e he e a e less numbe o molecula
con ac s be ween d ug and excipien molecules and he e a e also mul iple phase
eac ions which makes eac ions in he solid s a e mo e di icul o in e p e (19).
These ype o eac ions can also be s udied h ough he inc ease o empe a u e
and humidi y. Highe alues o hese wo ac o s accele a e he speed a which
deg ada ion eac ions ake place, which on i s u n inc ease he amoun o deg ada ion
De elopmen o o al able s con aining Nico andil
In oduc ion
7
p oduc s. Such s a egy allows he quan i ica ion o hese p oduc s on sho e ime, which
o he wise would ake unp ac ical ime o appea . The pu pose o hese s udies is o ha e
an indica ion o s abili y h ough da a ex apola ion, assuming ha he deg ada ion
mechanism a highe empe a u es and ela i e humidi y le els is he same as ha a
25°C.
1.2.2. Tempe a u e
Iso he mal s ess es ing o deg ada ion o samples a cons an highe empe a u es
is kind o s ess condi ion commonly used o compa ibili y s udies (13, 20). I is based on
he assump ion ha he kine ics o deg ada ion eac ions ollows A henius kine ics, which
s a es he eac ion a e dependence on empe a u e (13). Howe e , his need no o be
he case and a non-linea A henius plo may be an indica ion o change o deg ada ion
mechanism as he empe a u e is inc eased.
Ex apola ion o shel li e is based on he assump ion ha a solid-s a e eac ion
ollows A henius kine ics and ha an ac i a ion ene gy de e mined a highe
empe a u es can be used o calcula e he a e and shel li e a oom empe a u e. The
assump ion is alid i he eac ion a highe empe a u es also occu s a oom empe a u e
and ollows he same deg ada ion pa hway and no i ele an deg ada ion p oduc s a e
o med meanwhile (18).
A shi in he p ima y deg ada ion p ocesses is o en indica ed by he appea ance o
addi ional impu i y peaks in he HPLC analysis o changes in he e en ion ac o (R )
alues ha a e an indica ion o in e ac ion o decomposi ion. Some au ho s s a e ha i no
in e ac ion is obse ed a 50 o 60ºC, especially in he p esence o mois u e and ai , none
can be expec ed a lowe empe a u es (21).
The e o e, usually mo e han one s essed condi ion is chosen o de e mine i he
deg ada ion eac ions obse ed a ele a ed empe a u es migh be he ones which ha e
such high ac i a ion ene gies ha hey occu only unde pha maceu ically i ele an
condi ions.
1.2.3. Wa e Con en and Hyg oscopici y
Mois u e p esen in dosage o ms may come om se e al sou ces: bulk ac i e
pha maceu ical ing edien (API), excipien s, manu ac u ing p ocesses and en i onmen al
condi ions (9). The mechanisms o wa e in e ac ion in solid s a e a e ela ed o he wa e
molecule cha ac e is ics. Wa e is a molecule wi h pa icula cha ac e is ics hanks o he
hyd ogen bonds i can o m wi h o he molecules. Hyd ogen bond is a ype o elec os a ic
o ce ha ules wa e p ope ies in i s physical s a es and also i s in e ac ions wi h solids.
De elopmen o o al able s con aining Nico andil
In oduc ion
14
Table 1. Risk anking sys em
Low
B oadly accep able isk. No u he in es iga ion is needed.
Medium
Risk is accep able. Fu he in es iga ion may be needed o educe he isk.
High
Risk is unaccep able. Fu he in es iga ion is needed o educe he isk.
The isk assessmen ool links ma e ial a ibu es and c i ical p ocess pa ame e s
(CPP) o d ug p oduc C i ical Quali y A ibu es (CQA’s) o co ela e and e alua e he
po en ial impac ha each pa ame e will ha e on hem. CQA’s a e physical, chemical,
biological o mic obiological p ope ies ha should be wi hin an app op ia e limi , ange o
dis ibu ion, o ensu e he desi ed p oduc quali y. CQAs a e gene ally associa ed wi h he
d ug subs ance, excipien s, in e media es (in-p ocess ma e ials) and d ug p oduc (2).
Addi ionally, (CPP) a e p ocess pa ame e whose a iabili y has an impac on a c i ical
quali y a ibu e and he e o e should be moni o ed o con olled o ensu e he p ocess
p oduces he desi ed quali y.
Risk assessmen is ypically pe o med ea ly in he pha maceu ical de elopmen
p ocess and is upda ed du ing de elopmen when ma e ials, p ocess and p oduc
knowledge is ob ained.
Despi e being a use ul ool ha helps o suppo scien i ically s ong p oduc
dossie s o egula o y au ho i ies i is no always app op ia e o necessa y o use a o mal
isk managemen p ocess. The use o in o mal isk managemen p ocesses (using
empi ical ools and/o in e nal p ocedu es) can also be conside ed accep able.
P io o he s a o he de elopmen p ocess i was necessa y o de ine he a ge
p o ile so ha a isk assessmen and isk managemen s a egies could be de ined (31).
Gene ally, a Ta ge P oduc P o ile (TPP), de ines he p oduc a ibu es and i is
o en exp essed p ima ily in clinical e ms, bu should also include he pha maceu ical,
echnical, egula o y and comme cial/ma ke ing a ibu es equi ed o he p oduc . The
TPP is based on he ideal p oduc cha ac e is ics, which a e conside ed o be desi able.
Fo he p oduc de elopmen p ocess he Quali y Ta ge P oduc P o ile (30) (QTPP)
was selec ed based on he e e ence p oduc cha ac e is ics, as i ela es o he quali y,
sa e y and e icacy, as well as on he DS cha ac e is ics. QTPP is a p ospec i e summa y
o he quali y cha ac e is ics o a d ug p oduc ha ideally will be achie ed o ensu e he
desi ed quali y, aking in o accoun sa e y and e icacy o he d ug p oduc .
Fo he pu pose o his wo k, he po en ial c i ical quali y a ibu es (CQAs) we e
e alua ed conside ing he DS, excipien s and d ug p oduc cha ac e is ics ha can ha e
an impac on d ug p oduc quali y. Once iden i ied i was possible o e alua ed and con ol
hese cha ac e is ics.

De elopmen o o al able s con aining Nico andil
In oduc ion
15
Addi ionally, p oduc and p ocess design should be s a ed as ea ly as possible,
while iden i ying c i ical pa ame e s and p ocess moni o ing and con ol helps o co ec ly
guide p oduc de elopmen .
The selec ion o an adequa e manu ac u ing p ocess was based on all he
in o ma ion ga he ed and suppo ed by a isk assessmen used du ing all s ages o he
de elopmen o iden i y po en ial high isk o mula ion and p ocess pa ame e s so ha a
con ol s a egy could be implemen ed.
Based on he de elopmen layou a ange o o mula ion and p ocess a iables we e
de ined as obus ness limi s inside which a ia ions a e accep ed wi hou comp omising
quali y sa e y and e icacy o he d ug p oduc .
These CQA a e conside ed p io i ies in he isk assessmen e alua ion. Fo his
p oduc , assay, deg ada ion p oduc s, dissolu ion, con en uni o mi y (CU), wa e con en
and ha dness o able s a e iden i ied as CQA’s ha ha e he po en ial o be impac ed by
he o mula ion and/o p ocess a iables can in luence p oduc s abili y.
Quali y a ibu es ha a e no conside ed c i ical, such as able s physical a ibu es,
will be e alua ed acco ding o compendial s anda ds and e e ence p oduc
cha ac e is ics.
4. Nico andil
4.1. Backg ound
Nico andil is a DS p oduced o he i s ime in 1984 by Chugai Pha maceu ical
Co®. L d. Japan (32), company ha s ill owns he ma ke ing igh s o Nico andil. Chugai
Pha maceu ical has licensed i s p oduc ion o companies such as Me ck® and Sano i-
A en is® unde he names o Danco ®, Iko el® and Sigma ®, among o he b and names.
Nico andil ma ke sales ep esen se e al millions o eu os in he las 5 o 10 yea s in
Japan and ac oss 11 coun ies h oughou Asia and Eu ope.
Nico andil became a widely used an i-angina he apeu ic agen since i s launch in
Japan in 1984 and in Eu ope in 1994. E e since and a e yea s o clinical expe ience
wo ldwide, he sa e y eco d o Nico andil con inues o gi e physicians a eliable sou ce o
solu ions o ea his majo pa ien g oup (33) inc easing he impo ance o his DS in he
ea men o ca dio ascula diseases due o he minimum e ec s on he dynamics o
ca dio ascula ci cula ion and on ca diac unc ions (34). When adminis e ed wice-daily
he dosage o Nico andil ensu es 24 hou s con ol (35) and p o ides an e ec i e and
ole able he apy o pa ien s wi h angina, ei he as mono he apy in up o 80% o pa ien s
(36) bu also in combina ion wi h o he an i-angina he apies, wi hou in e ac ions o an
inc ease in ad e se eac ions (37).
De elopmen o o al able s con aining Nico andil
In oduc ion
16
Nico andil is a ni a e de i a i e o nico inamide (nico inamide es e ) ha has a dual
mechanism o pha macological ac ion (38) and belongs o a g oup o medicines called
asodila o s.
Nico andil widens he co ona y blood essels o inc ease he blood supply o he
hea hence elie ing angina e ec s. This e ec is caused by i s ni a e g oup which
p omo es enous elaxa ion h ough s imula ion o guanyla e cyclase (39).
Ano he e ec o Nico andil is he widening o sys emic blood essels. This means
ha he o al pumping e o o he hea is educed (40). This e ec is done h ough he
opening o po assium channels caused by he nico inamide ing (41). The combined
ac ion imp o es co ona y blood low o pos -s eno ic egions, educes p eload and a e
load and imp o es he oxygen balance in he myoca dium.
This cha ac e is ically pha macological ac ion makes Nico andil sui able o he
p e en ion and long e m ea men o ch onic s able angina pec o is and educ ion o he
isk o acu e co ona y synd omes in pa ien s wi h ch onic s able angina.
The common ini ial o al dose is 10mg wice daily, inc eased as necessa y o a
maximum o 30mg wice daily. Bioa ailabili y is abou 75% o 80%. Nico andil is apidly
and well abso bed om he gas o in es inal ac bu ood can dec ease he a e o
abso p ion. Fi s -pass me abolism is no signi ican and Nico andil molecule is only sligh ly
bound o plasma p o eins.
Maximum plasma concen a ions a e achie ed in 30 o 60 minu es a e in ake and
a e di ec ly ela ed o he dosage in ake. Me abolism occu s mainly by de-ni a ion o he
molecule h ough i s side chain. A second deg ada ion mechanism occu s h ough
p oduc ion o N-(2-hyd oxye hyl)-nico inamide e en ually o ming nico inic acid.
Fu he me abolisa ion o hese p oduc s leads o he o ma ion o wa e and i amin
B complex subs ances. Less han 20% o an adminis e ed dose is exc e ed in he u ine as
me aboli es. Less han 2% o he dose is exc e ed ia he bilia y ou e and 10% o he
dose can be ound in plasma bu is apidly elimina ed. The main phase o elimina ion has
a hal -li e o abou 1 hou .
4.2. Reac ion and Deg ada ion Mechanisms
Nico andil molecule ep esen s a challenge o he o mula ion scien is due o i s
p ope ies which a e dic a ed by i s idimensional molecula s uc u e (42), c ys alline
la ice and composi ion in o ganic g oups, which u ns i in a s able molecule when
unp ocessed (43) bu highly uns able once i is p ocessed and included in a d ug p oduc
o mula ion (44, 45).
De elopmen o o al able s con aining Nico andil
In oduc ion
17
Nico andil molecule, as highligh ed on Figu e 1, has ou o ganic g oups: a py idine
ing (#1), an amide g oup (#2), a seconda y amine g oup (#3) and a ni a e g oup (#4).
Figu e 1. Nico andil o ganic g oups
The molecula s uc u e o Nico andil does no p esen chi al ca bon a oms o
isome ism and acco ding o cu en knowledge i has no known polymo phs.
Nico andil molecule adop s a olded con o ma ion, which is s abilized by
in amolecula Van de Walls con ac s be ween he ca bonyl g oup oxygen a om and he
ni ogen a om in he ni o g oup. In e molecula hyd ogen bonds and sho con ac s a e
obse ed (42).
Besides he molecula olded con o ma ion, Nico andil is a anged in a c ys alline
pa e n so ha he Ni ogen a oms o he py idine ings a e close oge he wi h he a oms
o C-CH2ONO2 neighbo ing g oup, a a dis ance 0.3367 nm, less han he sum o he an
de Waals adii o C and N (0.3484 nm) (42). Plo a oms app oaching Ni ogen and
Ca bon a oms can be ega ded as he eac ion cen e .
This molecula s uc u e and con o ma ion, as illus a ed in Figu e 2 (adap ed om
e e ence 32), de e mines i s majo deg ada ion pa hway and he p esence o subs i uen s
s ongly in luences i s eac i i y.
Figu e 2. C ys alline packing iew o Nico andil
De elopmen o o al able s con aining Nico andil
In oduc ion
18
Nico andil, as a ni a e es e , mainly decomposes h ough a hyd olysis eac ion
which s a s in he ni o es e bond (46). Besides his, he elec on wi hd awing unc ional
g oup close o he es e bond which makes i a candida e o nucleophilic a ack by
hyd oxide ions. This explains i s s ong deg ada ion in p esence o wa e o high ela i e
humidi y en i onmen s.
Since amide bonds (also p esen in Nico andil molecule) a e less suscep ible o
hyd olysis han es e bonds (because he ca bonyl ca bon o he amide bond is less
elec ophilic due o he double bond o he Ca bon-Ni ogen) and he lea ing g oup, (an
amine) is a poo lea ing g oup, he i s clea age, occu s in he es e bond, eleasing his
way, he ni a e ion.
These deg ada ion eac ions in aqueous solu ion ollows a i s o de kine ic eac ion
ei he in alkaline o acid en i onmen al hough i is as e in alkaline pH o igina ing an
in e media e p oduc wi h an UV abso p ion spec a nea 335nm (47). The e a e se e al
known deg ada ion p oduc s iden i ied (Figu e 3).
Figu e 3. Nico andil main deg ada ion p oduc s
De elopmen o o al able s con aining Nico andil
In oduc ion
19
The hyd olysis eac ion o Nico andil s a s by he o ma ion o an in e media e
molecule (3-(4,5-dihyd o-2-oxazolyl) py idine)) (48) (Figu e 4).
Figu e 4. Hyd olysis eac ion o Nico andil
This eac ion has been u he elucida ed (47) and explains he o ma ion o he
Ni a e ion (Figu e 5).
Figu e 5. Hyd olysis o Nico andil and Ni a e o ma ion
Along wi h he o ma ion o he in e media e molecule (II), he ni a e ion is also
o med. This eac ion e ol es in o he o ma ion o one o he majo deg ada ion p oduc s,
N-(2-hyd oxye hyl) nico inamide, when he in e media e compound eac s wi h wa e
(Figu e 6).
Figu e 6. In e media e compound o ma ion

De elopmen o o al able s con aining Nico andil
In oduc ion
20
F om his in e media e compound (III) nico inic acid (V) and N-(2-hyd oxye hyl)
nico inamide (IV) a e o med, depending on condi ions (47) (Figu e 7).
Figu e 7. Deg ada ion eac ions sequence om in e media e compound
Besides hese known deg ada ion impu i ies, Nico andil has been desc ibed in a
esea ch pape as a molecule ha pa icipa es in solid s a e qua e niza ion polyme iza ion
eac ions (49).
The p oposed s uc u e o he dime o med h ough his eac ion is shown on
Figu e 8.
Figu e 8. Nico andil dime
Fu he polyme iza ion is possible h ough he addi ional bonds be ween Nico andil
molecules, o ming addi ional deg ada ion p oduc s. Nico andil molecules can o m
dime s, ime s and e ame s, which ha e been desc ibed as deg ada ion p oduc s in
B i ish Pha macopoeia (2014) Nico andil able s monog aph ( e ised).
The polyme iza ion eac ion o ms polyme ic compounds be ween 40ºC and 70ºC
which a e soluble in wa e and insoluble in o ganic sol en s.
The gene al polyme iza ion eac ion is shown on Figu e 9 (adap ed om e e ence
34).
Figu e 9. Nico andil polyme iza ion eac ion
De elopmen o o al able s con aining Nico andil
In oduc ion
21
I has been desc ibed ha his deg ada ion is no as s ong in acidic en i onmen s
as i is in alkaline en i onmen s (41, 43, 46, 50), p obably due o he low pKa o
Nico andil.
Ano he ac o ha is associa ed wi h inc eased deg ada ion is he damage induced
on he c ys al la ice o Nico andil. Such damage can be induced by common ope a ions
associa ed wi h he manu ac u e o solid dosage o ms such as milling, g inding o
able ing.
The dis up ion o he c ys alline con o ma ion is linked wi h a change in he ee
ene gy a he su ace o he c ys alline s uc u e (su ace ene gy) which means ha mo e
ene gy is a ailable o pa icipa e o ini ia e deg ada ion eac ions (9, 51, 52).
4.3. C i ical D ug Subs ance a ibu es
Conside ing he p e ious in o ma ion and bibliog aphic sea ch, DS a ibu es we e
selec ed and discussed ega ding hei c i ic le el (Table 2).
Table 2. C i ical D ug Subs ance a ibu es assessemen
DS a ibu es
Jus i ica ion
Is i a CQA?
Pa icle size
dis ibu ion
Pa icle size dis ibu ion is a c i ical a ibu e since i can nega i ely in luence
blend homogenei y, solubili y, dissolu ion and con en uni o mi y o able s.
Yes
Hyg oscopici y
Hyg oscopici y is a p ope y ela ed o p oduc s abili y since Nico andil is
sensi i e o high mois u e le els. Hyg oscopic ma e ials adso b mois u e om he
en i onmen in o he o mula ion inc easing he wa e molecules amoun s
a ailable o eac ion. Since Nico andil is no hyg oscopic his pa ame e is no
conside ed a CQA.
No
Solubili y
Nico andil is e e ed in manu ac u e ’s CoA as spa ingly soluble. Solubili y is a
c i ical a ibu e since i can nega i ely a ec dissolu ion and assay, he e o e his
pa ame e mus be e alua ed.
Yes
Wa e con en
Wa e con en is a c i ical a ibu e since high le els o wa e on he componen s
and d ug p oduc migh induce highe deg ada ion a es. Since Nico andil
p esen s low wa e con en his pa ame e is no a CQA.
No
Chemical s abili y
Nico andil is an uns able molecule when p ocessed and blended wi h o he
subs ances. Fo mula ion de elopmen mus be designed conside ing he ac o s
ha can p omo e deg ada ion o Nico andil.
Yes
Flowabili y
Flow p ope ies o he componen s o a o mula ion ob ained by di ec
comp ession a e always c i ical a ibu es and equi e u he es ing.
Yes
Polymo phism
Nico andil has no known polymo phs, he e o e his pa ame e is no conside ed
c i ical.
No
De elopmen o o al able s con aining Nico andil
In oduc ion
22
5. Re e ence P oduc
The e e ence d ug p oduc (RP) ma ke ed is an uncoa ed, whi e, ound, wi h
ace ed edges, weighing app oxima ely 100mg and 200mg o al able wi h a label
indica ion o 10mg and 20mg o Nico andi, espec i ely.
Acco ding o he public li e a u e (53) he quali a i e and quan i a i e o mula ion o
he RP is desc ibed in Table 3.
Table 3. Quali a i e and quan i a i e composi ion o Re e ence P oduc
Quali a i e o mula ion
Quan i a i e o mula ion
Nico andil
10%
Manni ol
76%
Co n s a ch
1%
C osca mellose sodium
5%
S ea ic acid
8%
Nico andil RP has a shel li e o 18 mon hs when s o ed in a d y place below 25ºC
and each blis e s ip should be used wi hin 30 days o opening. P ima y packaging is
composed o ha d empe ed aluminium oil/ (Polyamide/aluminium/PVC) blis e s ips
con aining 10 able s. Each able inside he blis e is linked o a ound disk wi h a
desiccan agen (silica gel) placed on one side o he blis e , as can be seen on Figu e 10.
Figu e 10. P ima y packaging ma e ial o Nico andil 10mg e e ence p oduc
This ype o design allows he con ol o mois u e inside each blis e pocke al hough
once one able is emo ed all o he will be exposed o ai due o he communica ion
channels linking each pocke . A de ailed physical and chemical cha ac e iza ion o he RP
is desc ibed in he p e- o mula ion sec ion.
De elopmen o o al able s con aining Nico andil
In oduc ion
23
6. Pa en landscape
The pha maceu ical indus y is p oli ic in gene a ing in ellec ual p ope y. The
p o ec ion o such in ellec ual p ope y is done h ough pa en s. A pa en is an exclusi e
igh g an ed o an in en ion (in ellec ual p ope y) and las s gene ally o a pe iod o
wen y yea s. Pa en s a e e i o ial igh s and only applicable in he coun y o g oups o
coun ies in which a pa en has been illed o g an ed in acco dance wi h he law o ha
coun y o acco ding o he pa en ea y es ablished be ween g oups o coun ies (54).
Pa en s can be issued, o example, o e DS, d ug p oduc s o manu ac u ing p ocesses.
Pa en s a e a aluable sou ce o in o ma ion no only o a oid in ingemen o hi d pa ies
in ellec ual p ope y bu also because i desc ibes p e ious wo k which is help ul o guide
al e na i e, no el y app oaches o o mula e a d ug p oduc .
Wi h he pu pose o collec suppo in o ma ion o he p esen wo k on Nico andil
o mula ions and s abili y, a pa en sea ch was conduc ed and he selec ed documen s
s udied a e desc ibed on Table 4.
Table 4. Lis o pa en s selec ed o e alua ion
O ice
Numbe
Ti le
Da e
USPTO
4,200,640
Ni ic Es he o N-(2-hyd oxye hyl) Nico inamide
and Pha maceu ical Use.
29 Ap 1980
USPTO
4,803,213
Me hod Fo P oduc ion o S able
Nico andil P epa a ion.
07 Feb 1989
USPTO
4,822,808
Me hod Fo P oduc ion o S able
Nico andil P epa a ion.
18 Ap 1989
EPO
0 574 221 B1
Pha maceu ical S able
Fo mula ions o Nico andil.
15 Dec 1993
EPO
1 001 773 B1
O al Solid Pha maceu ical Composi ions Con aining
Nico andil Fo a Modula ed Release and he
P ocess o hei P epa a ion.
06 Feb 2002
Nico andil syn hesis is disclosed in pa en USPTO 4,200,640. Addi ionally, his
pa en also p oposes a ew o mula ions o solid o al dosage o ms con aining Nico andil
o suppo ha his compound can be o mula ed in o di e en pha maceu ical
o mula ions.
Some examples o Nico andil o mula ions p oposed a e desc ibed on Table 5.
De elopmen o o al able s con aining Nico andil
Aims o he S udy
30
Table 6. Ta ge P oduc P o ile p oposal o he inished p oduc (con .)
Pa ame e
Ta ge p oposal
Jus i ica ion
Is i a
CQA?
Table shape
Round, bicon ex
Size and shape a e no c i ical a ibu es.
Table s dimensions chosen a e simila o he RP.
No
Table
dimensions
7 mm
Sco e and
embossing
None
Sco e and embossing a e no c i ical a ibu es. Table di isibili y is
possible in he 10mg s eng h al hough such pu pose alls ou side
he scope o his wo k.
No
Colou and
appea ance
Whi e
Colo and appea ance a e no c i ical a ibu es al hough hey a e
a long e m s abili y indica o o physical incompa ibili ies and
should be e alua ed.
No
Weigh
100mg
Table weigh can a ec sa e y and e icacy since i is ela ed o
he uni o mi y o dosage uni . Weigh is simila o he 10mg
s engh able o he RP. Since i is a compendial ou ine es o
able s i is no conside ed a c i ical a ibu e o he scope o his
wo k bu mus be ne e hless e alua ed.
No
F iabili y
NMT 1.0% w/w
Compendial ou ine es o able s. Since able ha dness is a
c i ical quali y a ibu e, iabili y mus be moni o ed o a oid loss o
s uc u al in eg i y o able s du ing handling and anspo .
Requi es close moni o ing.
No
Disin eg a ion
Table s should
disin eg a e in mo e
han 20s and less
han 10 minu es
Compendial ou ine es o able s. Disin eg a ion ime has an
impac on dissolu ion p o ile and hence on e icacy and
bioequi alence o he d ug p oduc . Requi es close moni o ing.
No

De elopmen o o al able s con aining Nico andil
31
Ma e ials and Me hods
De elopmen o o al able s con aining Nico andil
32
De elopmen o o al able s con aining Nico andil
Ma e ials and Me hods
33
1. Ma e ials
1.1. Reagen s
All eagen s used we e o Analy ical Pu pose (AP) g ade o HPLC g ade. The
me hod o p epa a ion is he ollowing:
Mobile phase A o HPLC analysis: p epa ed wi h Wa e (u.p.):THF:TEA:TFA
(989:3:5:3, / ). Also used as a sol en o he p epa a ion o samples o HPLC analysis.
Mobile phase B o HPLC analysis: p epa ed wi h Wa e (u.p.):THF:TEA:TFA
(979:8:5:8, / ).
THF: e ahyd o u an; TEA: ie hylamine; TFA: i luo oace ic acid. (all om Me ck®)
HCl 0,1N: Se ed as dissolu ion media and was p epa ed by dilu ing 8.28mℓ o
uming HCL 37% pe 1 li e o wa e R1. Con i ma ion o pH was done using a calib a ed
pH me e .
0.05 M Phospha e bu e solu ion pH 4.5: Used as bu e solu ion in dissolu ion
media and solubili y es ing. P epa ed acco ding o Ph. Eu . 4.4.3 by dissol ing 6.80g o
po assium dihyd ogen phospha e R (Me ck®) in 1000.0 mℓ o wa e R. The pH o he
solu ion is 4.5.
Phospha e bu e solu ion pH 7.0 R1: Used as bu e solu ion in dissolu ion media
and solubili y es ing. P epa ed acco ding o Ph. Eu . 4.4.3 by mixing 250mℓ o 0.2M
po assium dihyd ogen phospha e R (Me ck®) and 148.2 mℓ o an 8 g/l solu ion o sodium
hyd oxide R (Me ck®). Adjus he pH i necessa y. Dilu e o 1000 mℓ wi h wa e R.
1.2. Excipien s
Excipien s ha we e used du ing p e- o mula ion and o mula ion s udies a e lis ed
in Table 7. These a e iden i ied by hei chemical name, b and names and supplie .
1 Wa e R. See Ph. Eu . o de ini ion and speci ica ion.
De elopmen o o al able s con aining Nico andil
Ma e ials and Me hods
34
Table 7. Lis o excipien s used du ing de elopmen
Non-p op ie a y name
B and name and g ade
Supplie
Isomal
GalenIQ® 721
Beneo Pala ini ®
P egela inized S a ch
S a ch 1500® LM
Colo con®
Sodium s a ch glycola e
Vi as a ® PSF
JRS Pha ma®
Sodium algina e
Kel one®
FMC Biopolyme ®
S ea ic acid
Dub Mic olub® 50
S ea ine ie Dubois®
Mic oc is alline cellulose
A icel® PH102
FMC Biopolyme ®
Anhyd ous Colloidal Silicon dioxide
Ae osil® / Syloid® AL1-FP
E onik ® / G ace®
Manni ol, ine powde
Pea li ol C25®
Roque e Pha ma®
Manni ol, coa se g ade
Pea li ol SD 200®
Roque e Pha ma®
C osca mellose sodium
AcDiSol®
FMC Biopolyme ®
C ospo idone
Kollidon CL®
BASF®
Sample p epa a ion o compa ibili y s udies
Bina y and composi e mix u es o Nico andil wi h excipien s we e p epa ed by
weighing sepa a ely each componen in o 5mℓ glass ials o pe i dishes whe e hey we e
mixed oge he wi h o a ion mo emen s and he use o a spa ula. Componen s we e
added in a 1:1 p opo ion. Wi h he pu pose o e alua ing he e ec o comp ession on he
compa ibili y wi h excipien s, Nico andil was comp essed wi h each excipien in a
hyd aulic p ess wi h 0,5 on o ce and 5 on o ce du ing 30s o 5min. Compac s we e
pul e ized using mo a and pes le and he esul ing powde was p epa ed acco ding o
he me hod desc ibed in he sample p epa a ion o HPLC. Samples we e p epa ed once
and eplica es we e aken om he sou ce mix u e and analyzed.
P e- o mula ion and Fo mula ion de elopmen s udies
In Table 8 a lis o he equipmen used can be ound. All equipmen used we e
calib a ed by a ce i ied en i y. Analy ical scales we e e i ied ega ding esponse in he
wo king ange be o e each use. All equipmen esponses we e conside ed adequa e a
he ime o usage.
De elopmen o o al able s con aining Nico andil
Ma e ials and Me hods
35
Table 8. Equipmen used
Equipmen
Manu ac u e
pH me e inoLab pH Le el 2P
WTW
Analy ical balances
( ange: 0 – 210g; sensi i i y: 0,01mg)
Me le Toledo XS205
Module AR402 mo o d i e adap ed wi h a uni e sal gea
and double cone mixe
E weka®
Pu elab Ul a Elga
(ul a pu e wa e sou ce)
Enk o ®
Hea ing/ D ying o en
Memme ®
Vacuum hea ing o en
He aeus® Ins umen s Vacu he m
Pelle p ess and dies o FTIR
Specadie Sys em
Specac®
Clima e chambe s
(25ºC/60%; 30ºC/65%; 40ºC/75%)
Fi oclima® D1200 Pha ma
Vo sch®
HPLC sys ems
VWR Hi achi Eli e Lach om and Shimadzu
LC2010C sys ems wi h column o en (se
up a 25ºC) and pho odiode a ay de ec o
2. Me hods
P e- o mula ion and o mula ion s udies mus be necessa ily suppo ed by analy ical
me hods o e alua e he pe o mance and cha ac e is ics o he es p oduc s along he
way.
Analy ical me hods mus be de eloped and alida ed o demons a e ha such
me hods a e adequa e o i s pu pose and ha he esul s ob ained a e eliable and
ep oducible on he wo king ange de ined. Me hod alida ion a e manda o y acco ding o
cGMP and ex ensi ely documen ed h ough in e na ional guidelines (55, 56).
Se e al pa ame e s a e commonly de e mined du ing analy ical me hod
de elopmen and alida ion: selec i i y/speci ici y, linea i y in he wo king ange, p ecision
( epea abili y, in e media e p ecision and ep oducibili y), accu acy, s abili y o solu ions,
de ini ion o he de ec ion and quan i ica ion limi s.
The p esen wo k used dissolu ion, UV and HPLC me hods de eloped and alida ed
in-house acco ding o in e na ional guidelines (ICH) and he accep ance c i e ia used o
e alua e me hod alida ion can be consul ed in he Annex sec ion. Calcula ion o mulas
used in he quan i ica ion a e desc ibed in he Annex sec ion. Whene e Ph. Eu . is
e e ed as compendial sou ce, e sion 7.0 is o be conside ed.

De elopmen o o al able s con aining Nico andil
Ma e ials and Me hods
36
2.1. S a is ical analysis
S a is ical analysis was done using IBM Co p. SPSS S a is ics e sion 22.0.
Dissolu ion es s we e compa ed by one-way ANOVA and Tukey HSD pos -hoc
es s. Fo each sample g oup, a no mali y es was de e mined using he Shapi o-Wilk
s a is ic and o de e mine he homogenei y o a iance a Le ene’s es was used. A alue
o p<0.05 was conside ed signi ican o all es s.
S abili y assessmen was done by e alua ing mul iple a iables associa ed wi h he
chemical and physical s abili y o he dosage o m. The chosen s a is ical ool o his ype
o da a analysis was he clus e analysis (57). A Two S ep clus e ing echnique based on
he be ween g oups linkage clus e ing me hod was used (58). C i e ion o he clus e ing
was he Schwa z’s Bayesian C i e ion (BIC) and he numbe o clus e s was de e mined
au oma ically. Measu emen be ween da a in e als was done using he squa ed
Euclidean dis ance. Samples we e au oma ically s anda dized by he so wa e (Figu e 11).
Figu e 11. Clus e ing e alua ion pa ame e s
2.2. Solubili y
Solubili y, in pha maceu ical e ms, is he maximum amoun o a DS ha can be
dissol ed in a sol en in a gi en condi ion (59). The solubili y o a DS is one o he mos
impo an p ope ies ha needs o be assessed ea ly in he de elopmen p ocess.
The bioa ailabili y o an o ally adminis e ed d ug depends p ima ily on i s solubili y
in he gas oin es inal ac and i s pe meabili y ac oss cell memb anes. This o ms he
basis o he biopha maceu ical classi ica ion sys em (BCS) (60, 61) which can be used o
es ablish in i o / in i o co ela ions be ween d ug p oduc s. The solubili y de e mina ion
also suppo s analy ical me hod de elopmen since a DS needs o be in he solu ion s a e
o be quan i iable and p o ides in o ma ion on he o mula ion de elopmen i he e is he
need use manu ac u ing p ocesses o excipien s ha can imp o e solubili y.
Solubili y o Nico andil in pu i ied wa e was de e mined acco ding o he Ph. Eu .
Sec ion 5.11. – Cha ac e s sec ion in monog aphs. Solubili y es is done in se e al
De elopmen o o al able s con aining Nico andil
Ma e ials and Me hods
37
sequen ial s eps. The i s s ep consis s in weighing 100mg o he Nico andil in a
s oppe ed ube adding 0.1mℓ o he sol en . This solu ion is hen shake igo ously o
1min and placed in a cons an empe a u e a 25.0 ± 0.5ºC o 15min. I he DS is
comple ely dissol ed i is conside ed e y soluble (S>100mg/0.1mℓ). In he case o he DS
is no comple ely dissol ed he dissolu ion p ocedu e is epea ed by adding o he sample
mo e 0.9mℓ ( o al 1mℓ) mo e o he sol en . This p ocedu e is epea ed in sequence wi h
addi ional olumes o 10, 30, 100, 1000 and 10000mℓ un il all DS is dissol ed.
Acco ding o he o al olume added he DS is classi ied in e ms o solubili y
acco ding o Figu e 12.
Figu e 12. Solubili y classi ica ion acco ding o Ph. Eu .
2.3. Dissolu ion
Dissolu ion is he dynamic p ocess by which DS is dissol ed in a de ined sol en
and i is cha ac e ized by he a e a which i dissol es e sus ime. In i o dissolu ion
es ing se es many pu poses: i guides he o mula ion and p oduc de elopmen p ocess
owa d op imiza ion; o assess BA/BE s udies; o moni o d ug p oduc pe o mance du ing
s abili y es ing o quali y con ol elease, o example. One o he equi emen s o conduc
an app op ia e dissolu ion es is o use a su icien olume o dissolu ion medium, which
should be able o dissol e he expec ed amoun o d ug eleased om a d ug p oduc .
2.3.1. Sink condi ions e alua ion
Acco ding o he Ph. Eu . sink condi ions a e me o a DS when 3 o 10 imes i s
solubiliza ion olume a e abo e he sa u a ion olume. Nico andil sink condi ions we e
assessed in h ee dissolu ion media co e ing he ele an physiological pH o he GIT (pH
anging om 1.1 o 7.0) and conside ing ha Nico andil is a spa ingly soluble DS,
he e o e, a dissolu ion olume o 900mℓ is p e e ed.
Conside ing ha he highes s eng h ma ke ed is 20mg, maximum concen a ion in
a 900mℓ dissolu ion essel would be 0.0222mg/mℓ. Assuming ha i e imes his
De elopmen o o al able s con aining Nico andil
Ma e ials and Me hods
38
concen a ion is enough o demons a e sink condi ions, hen i mo e han 0.111mg/mℓ
can be dissol ed in he bu e solu ions hen sink condi ions can be demons a ed.
Sink condi ions es ing was done in duplica e by weighing app oxima ely 5.8mg o
Nico andil in o a 50mℓ olume ic lask. To demons a e solubili y, samples we e analysed
in UV spec opho ome y agains a s anda d solu ion a e p ope dilu ion ( inal
concen a ion: 0.022mg/mℓ). S anda d solu ion was p epa ed by accu a ely weighing
app oxima ely 22.2mg o Nico andil in o a 200mℓ olume ic lask and dilu ing 4mℓ o his
solu ion in o a 20mℓ olume ic lask ( inal concen a ion: 0.022mg/mℓ). The esul s a e
p esen ed in Table 9.
Table 9. Nico andil sink condi ions assessmen
Dissolu ion media es ed
Calcula ed solubili y
(mg/mℓ)
Wo king concen a ion
/ max solubili y a io
HCl 0.1N
0.1176 (+ 0.03)
18.7%
Phospha e bu e pH 4.5 (Ph. Eu .)
0.1152 (+ 0.03)
19.1%
Phospha e bu e pH 7.0 (0.025M) (Ph. Eu .)
0.1174 (+ 0.03)
18.7%
Resul s indica e ha he wo king concen a ion is less han 20% o he calcula ed
solubili y in all dissolu ion media es ed which means ha sink condi ions a e me and ha
Nico andil can be solubilized a leas i e imes, i s highes ma ke ed s eng h (20mg) in
900mℓ dissolu ion olume.
Unde he Biopha maceu ical Classi ica ion Sys em (BCS), Nico andil can be
conside ed as a Class 1 DS since i is highly pe meable and highly soluble acco ding o
he BCS s anda ds which s a e ha when mo e han he highes s eng h is soluble in
250mℓ o less he DS is conside ed highly soluble. In his case i has been demons a ed
ha Nico andil solubili y is mo e han 20mg/250mℓ = 0.08mg/mℓ.
2.3.2. Dissolu ion condi ions
The selec ion o he dissolu ion medium conside ed ha as an immedia e elease
o mula ion Nico andil mus be quickly dissol ed in he gas ic luids so ha i can be
p omp ly eady o abso p ion. A sui able dissolu ion media o his pu pose is HCl 0.1N.
Expe imen al dissolu ion was ca ied ou in a calib a ed Va ian VK 7000 wi h Ca y
50 spec opho ome e complying wi h Ph. Eu . (2.9.3) speci ica ions (appa a us 2). Ini ial
equipmen se up conside s 900 mℓ o HCl 0.1 N (pH 1.1 + 0.05) in each o he six
dissolu ion essels. The empe a u e o he media was 37.0  0.5ºC. A he s a o he
es one able is weighed and placed in each dissolu ion essel unde 50 pm s i ing a e.
De elopmen o o al able s con aining Nico andil
Ma e ials and Me hods
39
Dissolu ion samples we e collec ed au oma ically and analyzed by UV
spec opho ome y a 262nm wa eleng h in 1.0cm qua z cells, agains a e e ence
s anda d, a he beginning o he dissolu ion es (blank measu emen ) and a 5 minu es
in e al un il 30minu es.
Re e ence s anda d was p epa ed by weighing accu a ely 22.4mg app oxima ely o
Nico andil wo king s anda d in o a 200mℓ olume ic lask and dissol ing wi h HCl 0.1N.
A e wa ds 2.0mℓ a e dilu ed in a 20mℓ olume ic lask. Concen a ion o he inal
e e ence solu ion is 0.011mg/mℓ.
2.4. Ul a iole spec oscopy
UV me hod is a as and simple me hod ha can be used in DS quan i ica ion and
iden i ica ion. The i s s ep ha needs o be aken when choosing UV analysis is o selec
a sui able wa eleng h showing an adequa e abso bance ange, a which Nico andil can
be quan i ied, his can be done by acing a spec a o he DS solu ion along he UV ange
and e alua ing he exis ing peaks.
A s anda d solu ion o Nico andil was p epa ed a he concen a ion o 0.022mg/mℓ
in h ee dissolu ion media/bu e s: HCl 0.1N, phospha e bu e pH 4.5 (Ph. Eu .) and
0.025M phospha e bu e pH 7.0 (Ph. Eu .) and analysed in UV using 1cm qua z cells.
Nico andil DS solu ion p esen s a maximum abso bance peak a ound 262nm as can be
seen in Figu e 13, which is sui able o he quan i ica ion o Nico andil based on UV
spec opho ome y.
Figu e 13. Nico andil UV spec a in di e en pH
De elopmen o o al able s con aining Nico andil
Ma e ials and Me hods
46

De elopmen o o al able s con aining Nico andil
47
Resul s and Discussion
De elopmen o o al able s con aining Nico andil
48
De elopmen o o al able s con aining Nico andil
Resul s and Discussion
49
1. P e- o mula ion s udies
1.1. DS cha ac e iza ion
Two majo sou ces o in o ma ion ega ding chemical and physical pa ame e s and
o he p ope ies o he DS a e he manu ac u e ’s Ce i ica e o Analysis (CoA) and
compendial sou ces such as he majo Pha macopoeias. The in o ma ion con ained in
hese e e ences a e he i s in o ma ion a ailable on DS and con ains impo an
in o ma ion ha can be used as a s a poin o p e- o mula ion s udies.
Nico andil is he in e na ional non-p op ie a y name o N-[2-(ni oxy)-e hyl]-3-
py idineca boxamide (chemical name) o N-(2-hyd oxye hyl)-nico inamide ni a e es e
and is a DS desc ibed in he Japanese Pha macopoeia (69). I s molecula o mula is
C8H9N3O4 and has a ela i e molecula weigh o 211.18. Nico andil is a DS ha is eely
soluble in me hanol, e hanol (99.5%) and glacial ace ic acid. I is soluble in ace ic
anhyd ide, spa ingly soluble in wa e and sligh ly soluble in e he . I is poo ly soluble in
e hyl e he o benzene.
Nico andil mel s and decomposes be ween 89° and 94°C and has an abso p ion
coe icien E1% (1cm, max 262 nm, H2O) o 161-175 AU. The pH o 1% aqueous solu ion
is 5.7 - 5.8 and i s pKa is 3.18.
Nico andil is a non-hyg oscopic subs ance, s able in he c ys alline o m when
s o ed a abou 5°C (+ 3°C) in a well-closed con aine (69), al hough i is no s able a
oom empe a u e o in p esence o humidi y. When in aqueous solu ion i is highly
uns able a oom empe a u e.
Nico andil is a whi e o o whi e c ys alline powde wi h a so consis ency. I is
possible o obse e lumps and agg ega es (Figu e 14) which can each app oxima ely 6 o
8cm in hei maximum leng h, al hough can be easily sca e ed.
The e a e also ha d, small size agg ega es, no la ge han a couple o millime es
which a e di icul o sca e , e en using manual o mechanical sie ing.
De elopmen o o al able s con aining Nico andil
Resul s and Discussion
50
Figu e 14. Bulk appea ance o Nico andil
A common ope a ion in he pha maceu ical indus y, used in he manu ac u e o
solid o mula ions, is powde sie ing. When ying o sie e Nico andil by hand h ough a
mesh size o 0.500mm and 0.710mm o sca e he la ge and small agg ega es, i was
no iced ha bulk powde was di icul o pass h ough bo h meshes. Wi hou he aid o
mechanical aids i migh be di icul o sie e bulk powde o sca e agg ega es, p obably
due o Nico andil pa icle cha ac e is ics. These la ge and small agg ega es a e an
indica ion ha an adequa e powde blend homogenei y h ough d y blending ope a ions
migh be di icul o achie e.
To u he e alua e pa icle mo phology mic oscopic isualiza ion was pe o med.
Th ee Nico andil ba ches (#1, #2 and #3) we e obse ed using an op ical mic oscope
acco ding o he me hod desc ibed in he Ma e ials and Me hods sec ion (op ical
mic oscopy).
Figu e 15 and Figu e 16 show ep esen a i e images o Nico andil pa icles om
h ee ba ches a di e en magni ica ions.
De elopmen o o al able s con aining Nico andil
Resul s and Discussion
51
Figu e 15. Nico andil op ical mic oscopy. Ba ches #1 and #2
Figu e 16. Nico andil op ical mic oscopy. Ba ch #3
Pa icles can be desc ibed, gene ally, as sho columna pa icles while a small pa
a e pla e shaped. The e is ba ch a iabili y ega ding pa icle cha ac e is ics since o he
pa icle shapes a e obse ed in ba ches #2 and #3. In hese cases pa icles ha e acicula
shape and a majo po ion a e sho columna pa icles.

De elopmen o o al able s con aining Nico andil
Resul s and Discussion
52
Pa icles a e anslucen wi h sha p edges and ha e a smoo h su ace, al hough wi h
de ec s, such as c acks. Images also show he mic oscopic pa icle agglome a ion ha
can be obse ed on he small ha d clus e s.
The e ec o g inding on he pa icles can also be obse ed. Pa icles lose hei o m
and appea o be smashed and his beha iou is sugges i e o a b i le c ys al.
Bi e ingence, which is an indica ion o c ys allini y, was also obse ed.
1.1.1. Solubili y
Solubili y was de e mined in duplica e samples. In bo h cases i was necessa y o
add up o 10mℓ o pu i ied wa e o 100mg o powde ed Nico andil o achie e comple e
solubilisa ion. Nico andil is he e o e conside ed spa ingly soluble in wa e .
1.1.2. Appa en densi y
Nico andil appa en densi y was de e mined and e alua ed (Hausne a io and
Comp essibili y Index), acco ding o Ph. Eu ., in i e ba ches, as desc ibed in he
Ma e ials and Me hods sec ion. The a e age and s anda d de ia ion esul s (  ) o i e
ba ches a e shown in Table 10.
Table 10. Appa en densi y esul s o Nico andil
Pa ame e
Ba ch #1
Ba ch #2
Ba ch #3
Ba ch #4
Ba ch #5
Bulk densi y (g/mℓ)
0.263 (+ 0.01)
0.422 (+ 0.01)
0.435 (+ 0.01)
0.304 (+ 0.01)
0.247 (+ 0.01)
Tapped densi y (g/mℓ)
0.381 (+ 0.01)
0.530 (+ 0.01)
0.550 (+ 0.01)
0.358 (+ 0.01)
0.314 (+ 0.01)
Hausne a io
1.45
1.26
1.26
1.18
1.27
Comp essibili y Index
30.97%
20.33%
20.87%
14.9
21.32
Powde low e alua ion
Ph. Eu . (2.9.36)
“Poo ”
“Passable”
“Passable”
“Fai ”
“Passable”
In e p e a ion o powde low ook in o accoun ha his powde o ms lumps which
c ea e la ge emp y spaces inside he glass ube. E en hough classi ied as Poo and
Passable, acco ding o he esul s shown, Nico andil seems o ha e bad low p ope ies.
1.1.3. Flowabili y
In all i e ba ches es ed Nico andil did no low eely h ough he 25 mm nozzles. I
equi es cons an mechanical aid o main ain powde low, hus low h ough 15mm and
10mm nozzles was no pe o med, as i was assumed ha powde would no low h ough
a smalle hoppe . In wo ba ches (#4 and #5) powde did no low h ough 25mm nozzle.
Resul s exp ess he a e age ime and s anda d de ia ion esul s (  ) ha powde
akes o go h ough he hoppe and a e indica ed on Table 11.
De elopmen o o al able s con aining Nico andil
Resul s and Discussion
53
Table 11. Flowabili y esul s o Nico andil.
Time (s) / 100g
Nozzle: 25 mm
Ba ch #1
Ba ch #2
Ba ch #3
Ba ch #4
Ba ch #5
N
3
3
3
3
3
 
4.9 s ( 0.38)
7.9 s ( 0.67)
9.5 s ( 0.90)
Does no low
Does no low
RSD (%)
7.76 %
11.24 %
9.48%
Minimum
4.6 s
7.5 s
8.6 s
Maximum
5.3 s
8.7 s
10.4 s
Figu e 17 illus a es he low pa e ns (25mm nozzle) o bulk Nico andil. Mass o
powde is indica ed in he Y axis (m [g ]) and ime in he X axis ( (s)). Th ee ba ches a e
indica ed (ba ches #1, #2 and #3, om le o igh ), hose in which powde low could be
eco ded. Resul s show he i egula low which was s a ed and kep by he use
mechanical aids.
Figu e 17. Nico andil low pa e n
Resul s o appa en densi y and powde low sugges ha he di icul powde low o
Nico andil, despi e being p esen in a 10% a io, mus be compensa ed du ing o mula ion
wi h an adequa e a io o excipien s wi h good low p ope ies since powde low can
in luence blend homogenei y, which is a c i ical issue du ing o mula ion, especially in a
powde blend o di ec comp ession, ha can ha e a la ge impac on inished p oduc
quali y a ibu es.
1.1.4. Wa e con en
Nico andil has a low wa e con en . Resul s o Ka l Fische om he Ce i ica e o
Analysis indica e an a e age wa e con en le el by Ka l Fische i a ion me hod o 0.06%
(n=8 + 0.03) wi h a es speci ica ion o NMT 0.1%.
De elopmen o o al able s con aining Nico andil
Resul s and Discussion
54
1.1.5. Pa icle size dis ibu ion
Nico andil pa icle size dis ibu ion was de e mined by lase di ac ion me hod
acco ding wi h he p ocedu e desc ibed in Ma e ials and Me hods sec ion. Conside ing he
esul s o powde densi y, lowabili y esul s and pa icle cha ac e is ics, pa icle size
dis ibu ion by analy ical sie ing was no possible o pe o m, so o ob ain an accu a e
esul o he pa icle size dis ibu ion his me hod was used.
The alues ob ained on h ee ep esen a i e ba ches o Nico andil a e summa ized
on Table 12.
Table 12. PSD esul s o Nico andil by lase di ac ion
F ac ion
Ba ch #1
d10
10.36 µm
d50
38.78 µm
d90
89.04 µm
F ac ion
Ba ch #2
d10
9.56 µm
d50
25.69 µm
d90
52.01 µm
F ac ion
Ba ch #3
d10
7.38 µm
d50
23.28 µm
d90
52.72 µm
Pa icle size dis ibu ion shown e e s o h ee ba ches used du ing pha maceu ical
de elopmen . Fo compa ison pu poses addi ional ba ches we e es ed ega ding pa icle
size and he esul s a e desc ibed in Table 13 ( alues in mic a).
F om a o al o nine ba ches es ed i is possible o obse e ha Nico andil pa icle
size dis ibu ion has a high ba ch o ba ch a ia ion.
De elopmen o o al able s con aining Nico andil
Resul s and Discussion
55
On a e age, 90% o he pa icle sizes a e below 90µm app oxima ely, al hough
highe alues go up o 198.6 mic on and as low as 43.0 mic on. The a e age size o he
pa icles is 29.7µm and 10% o he pa icles a e no la ge han 9.3µm.
Table 13. Nico andil pa icle size dis ibu ion
F ac ions (µm)
d10
d50
d90
A e age (n=9)
9.3 (+4.5)
29.7 (+11.1)
90.3 (+49.2)
min
2.6
16.0
43.0
max
14.8
53.3
198.6
1.1.6. Assay and impu i y con en by HPLC
On Table 14, assay and impu i ies esul s ob ained by HPLC analysis a e
summa ized. This da a is ep esen a i e o nine DS ba ches analysed and has been
compiled o compa ison pu poses. F om each ba ch wo samples we e p epa ed and
analysed (see sample p epa a ion o HPLC in Ma e ials and Me hods sec ion).
Table 14. Assay and impu i ies esul s o Nico andil
Pa ame e
Resul
Assay
100.06% (+ 0.97%)
Rela ed subs ances
Ni a e
0.0673% (+ 0.01%)
N-(2-hyd oxye hyl)-Nico inamide
0.0453% (+ 0.02%)
Imp. A
0.0205% (+ 0.01%)
Imp. B
0.0205% (+ 0.01%)
Imp C
0.0028% (+ 0.00%)
Single unknown impu i y
0.0108% (+ 0.00%)
To al impu i ies
0.17% (+ 0.03%)
Known impu i ies s anda ds we e analysed and hei peaks iden i ied as shown on
Figu e 18. Fo compa ison pu poses a blank and an excipien s solu ion ch oma og ams
we e added. I is possible o obse e ha Ni a e (#1) impu i y elu es a ound 4min and is
de ec ed and quan i ied a 215nm (see HPLC me hod desc ip ion in ma e ials and
me hods sec ion).
Nex known impu i y ha elu es is nico inic acid (#2) a ound 5min), ollowed by N-(2-
hyd oxye hyl)-nico inamide (#3) a ound 7min and 2-aminoe hylnico ina e (Impu i y A) (#4)
a ound 9min. Impu i y #5, me hyl-nico ina e, is a syn hesis impu i y ha elu es a ound
23min. Nico andil peak (#6) elu es a ound 28min and in he g adien phase o he analysis
polyme ic impu i ies s a o elu e, i s , impu i y B (dime ) (#7) a ound 42min and la e
impu i y C (#8), a ound 53min.
De elopmen o o al able s con aining Nico andil
Resul s and Discussion
62
Figu e 20. RP 10mg a e age dissolu ion p o ile
HPLC assay and impu i y esul s a e summa ized in Table 18.
Table 18. Re e ence P oduc assay and impu i y esul s
T ade Name
Danco
Adanco
Ba ch
5459920
5437234
Assay (n=2)
95.9% (+ 1.35)
95.6% (+ 0.81)
Rela ed subs ances (n=2)
Ni a e
0.5888% (+ 0.01)
0.5391% (+ 0.00)
Nico inic Acid
0.0016% (+ 0.00)
ND
N-2-hyd oxye hyl-nico inamide
0.0167% (+ 0.00)
0.0174% (+ 0.00)
Impu i y A (2-aminoe hyl nico ina e)
0.0869% (+ 0.01)
0.0820% (+ 0.00)
Impu i y B (Dime )
0.3705% (+ 0.00)
0.3660% (+ 0.00)
Impu i y C (T ime )
0.1021% (+ 0.00)
0.1245% (+ 0.00)
Single unknown impu i y
0.0441% (+ 0.00)
0.0329% (+ 0.00)
To al impu i ies
1.37%
1.30%

De elopmen o o al able s con aining Nico andil
Resul s and Discussion
63
1.4. Excipien s Sc eening
A i s selec ion o excipien s was made based on bibliog aphic da a ela ed wi h
hei physical and chemical p ope ies o disca d hose p one o eac wi h he o ganic
g oups o Nico andil and hence accele a e decomposi ion p ocess, o example,
excipien s con aining c ys alline wa e , ha be disca ded om a possible o mula ion., o
hose which cha ac e is ics would no be adequa e o he a ge immedia e elease solid
o al dosage o m.
An ini ial sc eening was based on p e ious s udies published (70-75) on he
de elopmen o o al dosage o ms o Nico andil. Mos o he pape s ound we e ela ed
wi h he de elopmen o modi ied elease o mula ions ins ead o immedia e elease,
which is he aim o he p esen s udy.
On Table 19 he e is a compila ion o he excipien s p e iously used in o mula ions
o Nico andil ound on li e a u e. I desc ibes excipien unc ionali y, e e ences o he
s udies in which hey we e used, applica ion o such excipien s and decision on whe he o
use o u he s udies and co esponding da a ha jus i ies such decision.
Excipien s iden i ied as “po en ial candida e” e e o excipien s ha migh be
ad an ageous o he s abili y o he o mula ion and we e selec ed o addi ional s udies.
Excipien s excluded a e hose ha by hei cha ac e is ics do no seem o be app op ia e,
due o ei he hei o ganic g oups ha can be a sou ce o deg ada ion o by o he
cha ac e is ics ha we e no conside ed p e e en ial.
Table 19. Excipien s conside ed o be used in a Nico andil o mula ion
Excipien
Common
unc ion
Re e ences
Decision
Jus i ica ion
Isomal
Diluen / ille
Po en ial
candida e
Can be
es ed
Non hyg oscopic excipien sui able o as disin eg a ing
able s on di ec comp ession o mula ions. Chemically
s able, low eac i i y and low hyg oscopici y.
Sodium s a ch
glycola e
Disin eg an
(2 - 8%)
Po en ial
candida e
Can be
es ed
Ve y hyg oscopic excipien al hough on a as disin eg a ion
able migh be necessa y o achie e an adequa e dissolu ion
a e.
C ospo idone
Disin eg an
(2% - 5%)
Po en ial
candida e
Can be
es ed
Hyg oscopic excipien al hough on a as disin eg a ion able
migh be necessa y o achie e an adequa e dissolu ion a e.
Mic oc ys alline
Cellulose
Diluen
Disin eg an
(74)
Can be
es ed
Excipien widely used in di ec comp ession o mula ions wi h
se e al g ades and pa icle sizes a ailable.
Manni ol
Diluen / ille
(10% - 90%)
(72, 75)
Can be
es ed
Non hyg oscopic excipien . I has been used in p e ious
wo ks on Nico andil o mula ions (51).
P e-geli ied
S a ch
Table binde in
di ec
comp ession
o mula ions
Table disin eg an
(2% - 10%)
(75)
Can be
es ed
Hyg oscopic excipien wi h high wa e con en al hough has
low wa e ac i i y (76, 77) he e o e, i will equilib a e slowe
when exposed o mois u e condi ions and may, p e e en ially,
bind he mois u e, p e en ing in e ac ion o wa e wi h o he
componen s ac ing as mois u e sca enge (78).
De elopmen o o al able s con aining Nico andil
Resul s and Discussion
64
Table 19. Excipien s conside ed o be used in a Nico andil o mula ion (con inue)
Excipien
Func ion
Re e ences
Decision
Jus i ica ion
C osca mellose
sodium
Disin eg an
(0.5% - 5.0%)
(75)
Can be
es ed
Hyg oscopic excipien . I s e icacy migh be educed when
used wi h o he hyg oscopic excipien s in a able o mula ion.
Sp ay d ied
Lac ose
Reducing suga
(73)
Excluded
As a educing suga i will likely eac wi h he seconda y
amine g oup p esen in Nico andil.
Sodium
bica bona e
Alkalizing agen
(73)
Excluded
Sodium bica bona e is an alkalizing excipien s and highe pH
on a solid ma ix has been desc ibed as a ac o ha
inc eases deg ada ion a e o Nico andil.
HPMC
(K4M, K15,
K100M, K200M)
Binde
Film coa ing
Ma ix o
ER/MR
(70, 72-74)
Excluded
Hyd oxyp opyl me hylcellulose is an excipien used in o al
p oduc s, p ima ily a able binde , in ilm-coa ing and as a
ma ix o use in ex ended- elease able o mula ions hence i
is no sui able o a as dissolu ion p o ile on an immedia e
elease solid dosage o m ob ained by di ec comp ession.
Cu ina HR®
ER/MR agen
lub ican
(72)
Excluded
This excipien o ms a ma ix ha delays Nico andil
dissolu ion hence i is no sui able o an immedia e elease
o mula ion.
E hyl cellulose
ER/MR agen
(70)
Excluded
The main use o e hyl cellulose in o al o mula ions is as a
hyd ophobic coa ing agen o able s and g anules. This
excipien o ms a ma ix ha delays Nico andil dissolu ion
hence i is no sui able o an immedia e elease o mula ion.
Chi osan
ER/MR agen
(71)
Excluded
Chi osan is a mul ipu pose excipien in solid o al o mula ions
ha include con olled d ug deli e y applica ions,
mucoadhesi e and apid elease dosage o ms. Al hough, his
excipien o ms a ma ix ha delays Nico andil dissolu ion
hence i is no sui able o an immedia e elease o mula ion,
besides i has eac i e hyd oxyl and amino g oups and is
hyg oscopic.
Sodium algina e
Table
disin eg an and
binde
(71, 74)
Can be
es ed
This excipien is used as a lub ican and has been e e ed as
a possible imp o emen on Nico andil s abili y due o i s
compac ion p ope ies.
Eud agi ® L101,
Eud agi ® RSPO
Film coa ing
Ma ix o
ER/MR
(70, 72, 73)
Excluded
Eud agi ® a e a class o excipien s known as
polyme hac yla es which a e p ima ily used in o al capsule
and able o mula ions as ilm-coa ing agen s, en e ic
coa ings and sus ained elease o mula ions. This excipien is
no sui able o an immedia e elease solid dosage o m
ob ained by di ec comp ession.
ER/MR: ex ended elease/modi ied elease
De elopmen o o al able s con aining Nico andil
Resul s and Discussion
65
Table 19. Excipien s conside ed o be used in a Nico andil o mula ion (con inue)
Excipien
Func ion
Re e ences
Decision
Jus i ica ion
Dibasic calcium
phospha e
Diluen
(70)
Excluded
The su ace o milled anhyd ous dibasic calcium phospha e is
alkaline (2) and consequen ly i should no be used wi h d ugs
ha a e sensi i e o alkaline pH.
Glyceyl
Behena e
Lub ican
(1.0% - 3.0%)
Po en ial
candida e
Can be
es ed
Glyce yl dibehena e is a mix u e o diacylglyce ols, mainly
dibehenoylglyce ol, and a iable quan i ies o mono- and
iacylglyce ols. I is an excipien ha has been desc ibed (79)
has ha ing good binding p ope ies, i does no a ec able
ha dness and is una ec ed by mixing o p oduc ion
pa ame e s.
Colloidal silica
dioxide
Glidan
(0.1% - 1.0%)
(70, 72-74)
Can be
es ed
Used in solid o al dosage o ms mainly as glidan o imp o e
low p ope ies o powde . Hyg oscopic excipien al hough due
o i s a ini y o wa e i can ac as a mois u e sca enge .
Fuma ic acid
Acidic agen .
(72, 74, 80)
Excluded
Fuma ic acid has been desc ibed as compa ible wi h Nico andil
al hough his excipien has been used on wo condi ions: 2ºC-
8ºC and 25ºC/60% RH: These esul s do no gua an ee ha a
highe empe a u es o humidi y his compa ibili y wi h
Nico andil is main ained. Pa en in o ma ion e e s a s able
Nico andil o mula ion using uma ic acid. Since his excipien
has al eady been used i is no going o be conside ed o
u he s udies.
Magnesium
s ea a e
Lub ican
(70, 74)
Excluded
The p esence o a me allic ca ion migh ac as a ca alys on
deg ada ion eac ions.
Calcium
s ea a e
Lub ican
(75)
Excluded
Calcium s ea a e is a mix u e o calcium sal s o di e en a y
acids consis ing mainly o s ea ic acid and palmi ic acid wi h
mino p opo ions o o he a y acids. I con ains calcium oxide
which migh be a ac o ha p omo es Nico andil deg ada ion.
Since he e a e o he al e na i es, Calcium s ea a e is no a
p e e ed lub ican .
S ea ic acid
Lub ican
(72, 74, 75)
Can be
es ed
S ea ic acid is a p e e ed lub ican and one o he excipien s
ha can ha e a s abiliza ion e ec on Nico andil by p o ec ing
he c ys alline s uc u e unde comp ession o ces. This
excipien is also p esen in he e e ence p oduc and desc ibed
in Nico andil pa en al hough i is men ioned he use o a non-
mic onized g ade. Selec ed s ea ic acid o compa ibili y s udies
was a mic onized g ade.
Talc
Glidan , diluen ,
lub ican
(72)
Excluded
Talc is no a p e e ed lub ican since lub ican s based on long
alipha ic a acid chains ha e been desc ibed as ha ing a
s abilisa ion e ec on Nico andil c ys alline s uc u e.
The in o ma ion con ained on Table 19 helped o selec g oups o excipien s
acco ding o hei unc ional class ha migh be ad an ageous o a solid o al o mula ion
con aining Nico andil.
To achie e a dissolu ion p o ile simila o he e e ence p oduc , which is an
immedia e elease o mula ion, a as disin eg a ion mus be ensu ed, hence disin eg an
class excipien s mus be added o he o mula ion such as sodium s a ch glycola e,
c osca mellose sodium and c ospo idone.
An excipien wi h glidan p ope ies such as anhyd ous colloidal silica migh be used
o imp o e powde lowabili y i necessa y due o he poo low p ope ies o Nico andil.
Rega ding lub ican s, glyce yl behena e and s ea ic acid we e conside ed o
compa ibili y es ing.
De elopmen o o al able s con aining Nico andil
Resul s and Discussion
66
1.5. Compa ibili y S udies
Compa ibili y s udies o Nico andil wi h selec ed excipien s was done using High
P essu e Liquid Ch oma og aphy o assess chemical incompa ibili y wi h excipien s
h ough he quan i ica ion o single and o al impu i y le els. Compa ibili y s udies we e
done using bina y mix u es on a a io o 1:1 o Nico andil wi h excipien s and u he
s udies we e pe o med using combina ions o excipien s wi h Nico andil.
Be o e s a ing he compa ibili y s udies i was necessa y o e alua e he e ec o
selec ed deg ada ion condi ions on Nico andil DS alone o es ablish he single (known and
unknown) and o al amoun o impu i ies ac oss di e en condi ions.
The choice o hese condi ions is impo an since Nico andil molecule, as men ioned
be o e, is sensi i e o bo h empe a u e, humidi y and comp ession o ces.
I is impo an o e alua e which a e he adequa e deg ada ion condi ions o he wise
i migh be possible ha oo ha sh condi ions will cause he appea ance o deg ada ion
p oduc s ha will no appea du ing p oduc shel li e. Se e al published s udies, including
pa en s, e e a wide ange o empe a u e and humidi y condi ions used du ing Nico andil
deg ada ion s udies (45, 51, 80).
Fo he compa ibili y s udies pe o med in his wo k maximum empe a u e selec ed
o deg ada ion s udies was 60ºC since i seems ha o highe empe a u es deg ada ion
o Nico andil is no longe ele an excep o o ced deg ada ion s udies. Rega ding
humidi y a wide alues ange was e alua ed, s a ing wi h 0% ela i e humidi y ( acuum
chambe un il 80% RH.
Nico andil samples we e p epa ed by weighing app oxima ely 100mg o DS di ec ly
in o glass ials ha a e hen placed in he deg ada ion chambe s in he di e en
condi ions es ed (Table 20) o 8 hou s. Condi ions #1, #2 and #3 we e used since hey
a e ICH deg ada ion condi ions o long e m, in e media e and accele a ed s abili y
s udies co espondingly and samples we e placed in open ials in clima e chambe s.
Condi ion #4 was used o e alua e empe a u e alone, sample was placed inside a
closed ial in a acuum o en. Condi ion #5 was p epa ed o e alua e he e ec o low
mois u e and highe empe a u e. Sample was placed in a closed con aine wi h desiccan
(silica gel) and humidi y was moni o ed using a calib a ed Tempe a u e and Humidi y
da aloge . Condi ion #6 was ob ained by placing an open ial in a desicca o wi h a
sa u a ed sal solu ion o po assium chlo ide. Condi ion #7 was ob ained by adding 10% o
pu i ied wa e (w/w) o he Nico andil sample and placing i in o a sealed ial.
Fo compa ison pu poses he HPLC esul s o non-deg aded Nico andil was added.
De ails on empe a u e and humidi y used as well as esul s a e shown on able Table 20.
De elopmen o o al able s con aining Nico andil
Resul s and Discussion
67
1.5.1. Deg ada ion condi ions o Nico andil
Table 20. Deg ada ion condi ions o Nico andil
Condi ion
#1
#2
#3
#4
#5
#6
#7
DS
S anda d
(con ol)
Tempe a u e
25ºC
30ºC
40ºC
60ºC
60ºC
60ºC
60ºC
Rela i e humidi y
60%
65%
75%
0%
40%
80%
Wa e
added
Assay (n ≥ 2)
101.08%
(+ 0.13%)
101.54%
(+ 0.50%)
102.24%
(+ 1.52%)
100.46%
(+ 0.16%)
100.32%
(+ 0.04%)
96.57%
(+ 0.10%)
67.21%
(+ 2.02%)
100.60%
(+ 0.43%)
Impu i ies (n ≥ 2)
Known
Ni a e
0.0642%
(+ 0.01%)
0.0571%
(+ 0.00%)
0.0642%
(+ 0.01%)
0.1523%
(+ 0.02%)
0.1849%
(+ 0.08%)
0.5649%
(+ 0.10%)
5.9907%
(+ 0.50%)
0.0673%
(+ 0.01%)
A
0.0433%
(+ 0.01%)
0.0439%
(+ 0.00%)
0.0499%
(+ 0.01%)
0.0337%
(+ 0.01%)
0.1643%
(+ 0.12%)
0.5602%
(+ 0.05%)
5.1487%
(+ 0.03%)
0.0453%
(+ 0.02%)
B
0.0218%
(+ 0.01%)
0.0236%
(+ 0.01%)
0.0206%
(+ 0.00%)
0.1328%
(+ 0.03%)
0.0807%
(+ 0.02%)
0.8748%
(+ 0.25%)
11.0327%
(+ 0.51%)
0.0205%
(+ 0.01%)
C
0.0025%
(+ 0.00%)
0.0063%
(+ 0.00%)
0.0080%
(+ 0.02%)
0.0425%
(+ 0.02%)
0.0278%
(+ 0.00%)
0.1184%
(+ 0.20%)
3.1804%
(+ 0.22%)
0.0028%
(+ 0.00%)
Unkn.
1
0.0150%
(+ 0.00%)
0.0138%
(+ 0.00%)
0.0166%
(+ 0.01%)
0.0225%
(+ 0.01%)
0.0357%
(+ 0.01%)
0.1835%
(+ 0.25%)
3.2489%
(+ 0.31%)
0.0107%
(+ 0.00%)
2
0.0099%
(+ 0.00%)
0.0091%
(+ 0.01%)
0.0110%
(+ 0.00%)
0.0145%
(+ 0.00%)
0.0195%
(+ 0.00%)
0.0386%
(+ 0.10%)
1.5887%
(+ 0.14%)
0.0075%
(+ 0.01%)
3
<0.01%
<0.01%
<0.01%
0.0158%
(+ 0.01%)
0.0151%
(+ 0.00%)
<0.01%
(+ 0.10%)
1.3863%
(+ 0.15%)
<0.01%
(+ 0.01%)
To al impu i ies
0.16%
(+ 0.01%)
0.17%
(+ 0.01%)
0.19%
(+ 0.03%)
0.43%
(+ 0.10%)
0.56%
(+ 0.23%)
2.38%
(+ 0.28%)
32.27%
(+ 0.88%)
0.17%
(+ 0.03%)
The esul s ob ained seem o indica e ha in he ICH deg ada ion condi ions he e is
no a clea indica ion o deg ada ion in he ime pe iod es ed (8h). Al hough when
empe a u e and humidi y ises, Nico andil s a s o deg ade as e . The e ec o
empe a u e alone can be e alua ed in condi ion #4. A high empe a u e only deg ada ion
a e is highe han condi ion #3 (40ºC/75% RH) which is a sign o he impo an ole o
empe a u e has on Nico andil deg ada ion a e. Addi ionally, i is possible o obse e ha
impu i ies B and C a e associa ed wi h a empe a u e inc ease (condi ion #4) a he han
humidi y inc ease ( alues in bold) On he o he hand, impu i y A is mo e ela ed o
humidi y inc ease (condi ion #5) a he han on empe a u e inc ease ( alue on bold).
A he same empe a u e (60ºC) bu inc easing he ela i e humidi y, he e is an
indica ion ha deg ada ion inc eases judging by he esul o o al impu i ies inc eases.
S ill keeping he empe a u e a 60ºC bu doubling he ela i e humidi y le el (condi ion
#6), inc ease in o al impu i ies is no o ious wi h app oxima ely 4.5 imes olds jump, which
migh sugges ha empe a u e and humidi y can ha e a syne gis ic e ec on he
deg ada ion o Nico andil ( alues in bold).
The addi ion o wa e o Nico andil sample (condi ion #7) caused an ex ensi e
deg ada ion and esul s he e is no ele ance in e alua ing hese esul s, since impu i ies
gene a ed a e so high ha he a ia ions in hei p o ile a e unlikely o be signi ican .

De elopmen o o al able s con aining Nico andil
Resul s and Discussion
68
On Figu e 21 and Figu e 22 i is possible o obse e he impu i y peaks in condi ions
#5 and #6.
Figu e 21. Nico andil deg ada ion ch oma og am (condi ion 5)
Figu e 22. Nico andil deg ada ion ch oma og am (condi on 6)
Despi e being ela i ely s able a egula empe a u e and humidi y condi ions, o
example 25ºC/60%, when le unp ocessed (no in he p esence o excipien s o subjec ed
o mechanical s ess (45), he e is a ange o empe a u e and humidi y we e Nico andil
deg ades wi h pha maceu ical ele ance. Fo highe empe a u e and humidi y, he
deg ada ion seems o be so ex en ha has li le signi icance o he e alua ion o
excipien s compa ibili y. Conside ing hese esul s he deg ada ion condi ions migh need
De elopmen o o al able s con aining Nico andil
Resul s and Discussion
69
o be adap ed depending on he excipien es ed, ne e heless condi ions 25ºC/60%,
40ºC/75% and 60ºC/80% a leas o 8h, seems o be app op ia ed deg ada ion
condi ions.
Besides he e alua ion o he deg ada ion condi ions on Nico andil, i seems o be
ele an o e alua e also he how he DS beha es unde mechanical s ess (g inding,
milling and compac ion o ces). The pu pose o hese es s was o simula e he e ec s ha
he DS would go h ough du ing he manu ac u e o he inal dosage o m.
1.5.2. E alua ion o mechanical s ess on Nico andil
A mechanical p ocess o educe he la ge and small pa icle agg ega es p esen on
Nico andil bulk powde will likely be necessa y o ensu e blend homogenei y. Two
p ocesses can be used o his end, sie ing using an oscilla ing ba mechanism o o ce
he powde blend h ough a mesh o a milling p ocess using a o a ing mill in blade
con igu a ion. Mechanical p ocessing has been desc ibed, as p e iously men ioned, as
sou ce o impu i y inc ease due o he damage o he c ys alline s uc u e caused by
impac o ces which, on i s u n, causes mo e en opy in he s uc u e and mo e ee
ene gy a ailable o be used in deg ada ion eac ions.
To e alua e he e ec o bo h ypes o mechanical s essing ha can po en ially can
be used du ing manu a u ing, Nico andil was milled and sie ed. These wo ypes o
pa icle educ ion me hods ha e been selec ed since hey a e common echniques used in
he p oduc ion o pha maceu ical dosage o ms. On he o he hand, he pu pose was also
o compa e he e ec o an a i ion me hod (sie ing) wi h a cu ing me hod on he
c ys allin s uc u e.
Milling ials we e done using an F ewi Hamme wi a a o o speed o 60000 pm
(blade con igu a ion) and sie ing was done using an oscilla ing ba sie e a ached o an
E weka AR402 module a a speed o 134 pm. Mesh sizes used in bo h expe imen s we e
0.50mm. To al impu i ies and assay esul s (a e age n≥3) a e shown on Table 21.
De elopmen o o al able s con aining Nico andil
Resul s and Discussion
70
Table 21. E ec o milling and sie ing on he impu i y p o ile o Nico andil
Comp ession o ce
Milling
Sie ing
Be o e deg ada ion
Assay
99.52%
(+ 1.10%)
99.05%
(+ 2.16%)
To al impu i ies
0.23%
(+ 0.25%)
0.20%
(+ 0.07%)
Impu i y A
0.1499%
(+ 0.15%)
0.0586%
(+ 0.03%)
Impu i y B
0.0142%
(+ 0.01%)
0.0113%
(+ 0.01%)
Impu i y C
0.0015%
(+ 0.00%)
0.0000%
(+ 0.00%)
A e deg ada ion
60ºC / 80% RH
( ime = 8h)
Assay
95.48%
(+ 8.28%)
96.38%
(+ 4.09%)
Impu i y A
0.1489%
(+ 0.09%)
0.2022%
(+ 0.12%)
Impu i y B
0.0989%
(+ 0.09%)
0.1960%
(+ 0.12%)
Impu i y C
0.0284%
(+ 0.02%)
0.0347%
(+ 0.04%)
To al impu i ies
0.63%
(+ 0.43%)
1.13%
(+ 0.81%)
Samples we e analysed be o e being deg aded a 60ºC and 80%RH and a e . The
o al impu i y le el seems o be highe when an oscilla ing ba sie ing p ocess is used
p obably due o a highe ic ion done on he Nico andil bulk powde ha migh cause a
highe s uc u al damage.
On Figu e 23 and Figu e 23a, a PXRD di ac og am o Nico andil samples sie ed
and milled is ep esen ed along wi h Nico andil DS (no p ocessed).
Figu e 23. Nico andil di ac og am o sie ied and milled samples
De elopmen o o al able s con aining Nico andil
Resul s and Discussion
71
Figu e 23a. De ailed iew o iden i ied a ea o igu e 22
Gene ally, di ac og ams ma ch a e e y peak which means ha amo phiza ion is
no de ec ed. The e is al hough a change on he milled sample (poin s 1 and 2) wi h he
appea ance o wo ex a peaks. This migh be due o a con aminan du ing sample
p epa a ion. Conside ing he o al di ac og am and he consis ency o he emaining
peaks i is unlikely he occu ence o a change on he c ys alline s uc u e.
By compa ing in de ail he peak shape (Figu e 22a), i is possible o obse e ha o
he p ocessed samples he peaks a e sligh ly wide ha he unp ocessed samples which
means ha mo e ac u e si es (smalle c ys alline g ain) a e p esen , which is cohe en
wi h he induced mechanical s ess.
1.5.3. E alua ion o compac ion on Nico andil
To assess he impac on Nico andil c ys alline s uc u e o he compac ion o ces
du ing able ing, a comp ession es was done on Nico andil. This es was e alua e by he
o al impu i ies le el a e a deg ada ion s age. Samples we e p epa ed by compac ing he
DS on a p ess using di e en compac ion p essu es and di e en imes o comp ession.
Samples we e di ided in wo comp ession o ces: 0.5 on, applied du ing 30s and 2min
and 5 on applied du ing 30s and 2min. Assay and impu i ies esul s we e quan i ied and
a e p esen ed on Table 22.
De elopmen o o al able s con aining Nico andil
Resul s and Discussion
78
1.6. Excipien s selec ion
The excipien s o be included in he inal o mula ion we e p elimina y selec ed
acco ding o a a ionale desc ibed on Table 29. Op imized quali a i e o mula ion will be
discussed du ing o mula ion de elopmen .
Table 29. Lis o excipien s selec ed o o mula ion de elopmen s age
Componen s
Func ion
Ra ionale
Isomal (GalenIQ 721®)
Diluen / ille
Fo mula ion main componen . Isomal compa ibili y esul s
sugges ha i has he po en ial o s abilize Nico andil molecule.
Sodium S a ch Glycola e
(Vi as a PSF®)
Binde /
disin eg an
S a ch p egela inized has a mois u e sca enging p ope y and
low wa e ac i i y which can be used as an ad an age on a
mois u e sensi i e o mula ion.
Maize s a ch
(S a ch 1500® low mois u e
g ade)
Disin eg an
Despi e being a hyg oscopic excipien his disin eg an could be
used o accele a e he dissolu ion p o ile. A low mois u e g ade
will be used. The e a e no indica ion o he use o such s a ch
g ade on he pa en s.
S ea ic acid
(Dub Mic olub 50®
mic onized)
Lub ican
This lub ican has been iden i ied as a po en ial s abiliza ion
agen o he compac ion o ces ha he Nico andil c ys al su e s
du in able ing. Addi ionally, s ea ic acid has been desc ibed as
a p e e ed lub ican in o mula ions con aining S a ch 1500®
(79). A mic onized g ade will be used du ing o mula ion
de elopmen . Pa en s desc ibe he use o a non-mic onized
g ade o s ea ic acid.
1.6.1. Excipien s desc ip ion and cha ac e iza ion
A his poin i was necessa y o ga he addi ional in o ma ion on he excipien s
p ope ies, which is desc ibed he ea e .
 Isomal - GalenIQ 721®
Isomal is he only polyol p oduced om suc ose and is a mix u e o hyd ogena ed
mono and disaccha ides whose p incipal componen s a e he disaccha ide alcohols
1-O-α-D-glucopy anosyl-D-manni ol dihyd a e and 6-O-α-D-glucopy anosyl-D-so bi ol.
I appea s as a whi e o almos whi e powde o g anula o c ys alline subs ance
and has good he mal and chemical s abili y due o i s s able glycosidic bond. I does no
go h ough b owning eac ions and does no possess educing g oups and he e o e i is
no expec ed o eac wi h o he aw ma e ials in a o mula ion. Isomal is non-hyg oscopic
and a 25ºC does no signi ican ly abso b addi ional wa e up o a ela i e humidi y o
85%. As an e ec o he low hyg oscopici y, able s p oduced wi h Isomal a e mo e s able
han able s con aining o he suga based diluen s.
This excipien is used in a a ie y o pha maceu ical p epa a ions including di ec
comp ession and we g anula ion p ocesses o he p oduc ion o able s. Se e al g ades

De elopmen o o al able s con aining Nico andil
Resul s and Discussion
79
o Isomal ma ke ed unde he b and name o GalenIQ® a e a ailable, al hough, ype 721
is an excipien especially designed o di ec comp ession due o i s highe solubili y which
p oduces good disin eg a ion esul s and has he desi able compac ion p ope ies,
he e o e g ade 721 is he g ade chosen o be used in o mula ion de elopmen .
Since i is a diluen Isomal will be he majo componen he e o e i is expec ed o
in luence he mix u e lowabili y and compac ion p ope ies.
The compac ion p ope ies o he di e en ypes o Isomal a e desc ibed in he
li e a u e (81-83). E alua ion by Heckel plo analysis showed ha Isomal exhibi s plas ic
beha io and unde goes elas ic eco e y p ima ily in he die (82). This means ha he
de o ma ion beha io is simila o so bi ol and manni ol, bu di e s om he de o ma ion
beha io o o he polyols such as xyli ol and lac i ol, which a e mainly b i le ma e ials. I
has an excellen lowabili y, does no s ick o able ing ools and o e s a good
compac abili y.
Comp ession o Isomal wi hou lub ica ion is di icul and may cause die wall
s icking, capping and lamina ion. When Isomal is p esen in a o mula ion he addi ion o
a lub ican is ecommended.
 Sodium S a ch Glycola e - Vi as a PSF® low mois u e g ade
Sodium s a ch glycola e is a subs i u ed de i a i e o po a o s a ch, ice s a ch,
whea o co n. Sodium s a ch glycola e is he sodium sal o ca boxyme hyl e he and
appea s as a ine, e y hyg oscopic, whi e o o -whi e, as eless, odo less, ee lowing
powde . I can be used in di ec comp ession o we g anula ion o mulas. Disin eg an
p ope ies and mechanism o ac ion a e widely desc ibed in he li e a u e.
The usual concen a ion employed in a o mula ion is be ween 2% and 8%, wi h he
op imum concen a ion abou 4%. SSG has been desc ibed as no sensi i e o he con en
o lub ican excipien s in a able o mula ion and also o he amoun o comp ession o ce
applied du ing able ing.
Sodium s a ch glycola e used was Vi as a PSF g ade om JRS Pha ma which is a
special g ade wi h low me hanol con en especially sui ed o alcohol and mois u e
sensi i e ac i es.
 Maize s a ch - S a ch 1500®, low mois u e g ade
Whi e o sligh ly yellow, mode a ely coa se o ine ee lowing, odou less and wi h a
sligh cha ac e is ic as e powde . Pa ial p e-gela iniza ion p o ides s a ch wi h i s unique
p ope ies. Low mois u e g ade co n s a ch has been physically modi ied wi h wa e
De elopmen o o al able s con aining Nico andil
Resul s and Discussion
80
con en below 7% and can be di ec ly comp essed in o able s. S a ch 1500 LM has
imp o ed low and comp ession cha ac e is ics playing mul iple unc ions o binde ,
disin eg an , low-aid and sel -lub ican in di ec comp ession o mula ions.
The addi ion o S a ch also helps he mix u e lows well and dec eases he amoun
o lub ican agen s needed due o he sel -lub ican p ope ies o p egela inized s a ch.
The low mois u e g ade is specially designed o be used wi h mois u e sensi i e DS which
helps on he long e m p oduc s abili y (78).
Besides his cha ac e is ic, also showed less abso p ion a es o mois u e compa ed
o common disin eg an s such as sodium c osca melose and sodium s a ch glycola e. In
his s udy, i was also sugges ed ha s a ch 1500 has an inhibi ing e ec on wa e ac i i y
(o equilib ium ela i e humidi y exp essed in pe cen age) wi hin he o mula ion and
e a ding mois u e in e ac ion wi h he DS.
The same a ionale is used o jus i y he inclusion o s a ch 1500 since i should
p e e en ially bind mois u e and dec ease he a e a which he equilib ium ela i e
humidi y equilib a es wi h he en i onmen .
 S ea ic Acid - Dub Mic olub 50, mic onized
The USP32–NF27 desc ibes s ea ic acid as a mix u e o s ea ic acid and palmi ic
acid, de ining he con en o s ea ic acid as no less han 40.0% and he sum o he wo
acids as no less han 90.0%. S ea ic acid is a ha d, whi e o ain ly yellow-colo ed,
somewha glossy, c ys alline solid wi h he appea ance o lea le s o a whi e o yellowish
whi e powde . I has a sligh a -like odo and as e. S ea ic acid is widely used in o al
o mula ions as a able and capsule lub ican . I is insoluble in wa e , soluble in alcohols
and a sol en s. Mic onized g ade o s ea ic acid was used o p omo e an in ima e con ac
wi h emaining pa icles so ha upon able ing comp ession o ces a e de ia ed om he
Nico andil c ys als.
1.7. Excipien s isk assessmen
The second pa o he isk assessmen ocus on he excipien s a ibu es and was
pe o med o e alua e he impac ha each componen could ha e on he d ug p oduc
CQA’s.
Conside ing he excipien s selec ion ollowing he p e- o mula ion s udies an
analysis on po en ial isk ha each excipien selec ed could b ing in o he o mula ion and
p ocess was done and is desc ibed on Table 30. The in o ma ion con ained on his able
lis s he o mula ion componen s and add esses each one ollowing a p ocedu e ha
De elopmen o o al able s con aining Nico andil
Resul s and Discussion
81
akes in o accoun ma e ials p ope ies, bibliog aphic esea ch and cha ac e is ics ha can
ha e an impac on he inished p oduc quali y a ibu es.
Table 30. Risk assessmen e alua ion on excipien s
D ug P oduc
CQAs
GalenIQ 721®
(Isomal )
amoun
Maiz s a ch
(S a ch 1500® LM)
amoun
Vi as a PSF ®
(Sodium s a ch glycola e)
amoun
DUB Mic olub 50
(S ea ic acid)
amoun
Assay
Medium
Low
Low
Medium
Deg ada ion
P oduc s
Low
Low
High
Low
Dissolu ion
Medium
Medium
Medium
High
Wa e con en
Low
Medium
High
Low
Ha dness
High
Medium
Low
Low
The jus i ica ion o he isk assessmen o each excipien is desc ibed on Table 31.
Table 31. Ra ionale on isk assessmen e alua ion o o mula ion excipien s
D ug P oduc
CQA’s
Ra ionale
Risk
e alua ion
Fo mula ion Va iables: GalenIQ 721® (Isomal ) amoun
Assay
Isomal ep esen s he majo po ion o he o mula, he e o e, i can ha e a s ong
in luence on he low p ope ies o he blend and hence i s homogenei y. This, in u n, can
impac able uni o mi y o dosage and hence able assay. On he o he hand since his
pa icula ype o Isomal is especially designed o di ec comp ession o mula ions, i s low
and densi y p ope ies makes his excipien sui able o his o mula ion. This a iable
needs u he e alua ion.
The isk is
medium
Deg ada ion
P oduc s
Since Isomal has a low wa e con en and has low eac i i y i s in luence is no expec ed o
be dele e ious o he DS as p e iously sugges ed by compa ibili y s udies.
The isk is
low
Dissolu ion
Isomal ep esen s he majo po ion o he o mula, which can impac a a g ea ex en he
compac ion p ope ies o he blend. This, in u n, can impac dissolu ion p o ile. On he
o he hand since his pa icula ype o Isomal is especially designed o di ec
comp ession o mula ions, i s low and densi y p ope ies makes his excipien sui able o
his o mula ion. This a iable needs u he e alua ion.
The isk is
medium
Wa e con en
Isomal ep esen s he majo po ion o he o mula and his can impac a a g ea ex en
he wa e con en o he o mula ion. Since Isomal has a low wa e con en and has low
eac i i y i s in luence is no expec ed o be dele e ious o he DS as p e iously sugges ed
by compa ibili y s udies.
The isk is
low
Ha dness
Isomal ep esen s he majo po ion o he o mula and his can impac a a g ea ex en
he compac ion p ope ies o he blend. This, in u n, can impac able ha dness and cause
DS ins abili y. This a iable needs u he e alua ion.
The isk is
high
De elopmen o o al able s con aining Nico andil
Resul s and Discussion
82
Table 30. Ra ionale on isk assessmen e alua ion o o mula ion excipien s (con .)
D ug P oduc
CQA’s
Ra ionale
Risk
e alua ion
Fo mula ion Va iable: S a ch 1500® LM amoun .
Assay
In he ecommended amoun anges, s a ch i is no likely o impac able assay.
The isk is low
Deg ada ion
P oduc s
Due o s a ch p ope ies and he demons a ed compa ibili y, his excipien is expec ed o
ha e a s abili y p omo e e ec on Nico andil DS.
The isk is low
Dissolu ion
S a ch can impac dissolu ion due o i s unc ional p ope ies. The amoun used mus be
e alua ed o gua an ee dissolu ion p o ile simila i y o he RP.
The isk is
medium
Wa e con en
Despi e ha ing a wa e con en ha can each 5%, s a ch p ope ies u ns his excipien
in o a wa e sca enge inside a able ma ix. Ne e heless, compa ibili y s udies al eady
pe o med sugges low in e ac ion wi h Nico andil.
The isk is
medium
Ha dness
S a ch is also known o i s binding p ope ies. In he ange o ecommended amoun s.
Comp ession ials should be pe o med o e alua e able pe o mance.
The isk is
medium
Fo mula ion Va iable: Vi as a PSF® (Sodium s a ch glycola e) amoun .
Assay
This excipien is no expec ed o in luence he assay alues o he d ug p oduc .
The isk is low
Deg ada ion
P oduc s
SSG is e y hyg oscopic which can ha e a nega i e impac du ing p ocessing since i
has he abili y o adso b mois u e om ai . Wa e con en is a known ac o ha
inc eases ins abili y o he DS and he d ug p oduc . Fu he s udies should be
pe o med.
The isk is
high
Dissolu ion
SSG le el can impac he disin eg a ion ime and, ul ima ely, dissolu ion p o ile. Since
one o he goals is o ma ch as close as possible he RP dissolu ion p o ile a disin eg an
migh be needed in he o mula. Ne e heless, conside ing he emaining componen s
and he p esence o s a ch, his excipien mus be u he e alua ed.
The isk is
medium
Wa e con en
SSG has a high wa e con en alue. Despi e being p esen in a small amoun , i s
hyg oscopic na u e i is necessa y o u he e alua e his componen .
The isk is
high
Ha dness
This excipien is no expec ed o in luence he able ha dness.
The isk is low
Fo mula ion Va iable: S ea ic acid 50 amoun .
Assay
In he ecommended amoun le els and by a oiding o e lub ica ion s ea ic acid has low
in luence on powde blend low, he e o e i is unlikely o impac able assay and CU.
The isk is
medium
Deg ada ion
P oduc s
This excipien has been iden i ied as a po en ial p omo e o s abili y by dec easing he
comp ession o ce on Nico andil able s. Compa ibili y s udy did no indica e any
e idence o a possible in e ac ion wi h he DS.
The isk is low
Dissolu ion
O e -lub ica ion o excessi e lub ican may e a d dissolu ion p o ile.
The isk is
medium
Wa e con en
This excipien is no expec ed o in luence o al wa e con en o he d ug p oduc .
The isk is low
Ha dness
This excipien is no expec ed o in luence he able ha dness.
The isk is low
De elopmen o o al able s con aining Nico andil
Resul s and Discussion
83
2. Fo mula ion de elopmen
The goal o his sec ion is o desc ibe he sequence o es s and esul s ha led o
he p oduc ion a d ug p oduc based on he CQA and TPP de ined on he Aims o he
s udy sec ion (Table 6).
The o mula ion de elopmen encompasses he p oduc ion o powde blend o
di ec comp ession and he p oduc ion o 10mg Nico andil ound able s wi h 7mm in
diame e , wi hou sco es o embossing. By di ec comp ession i should be unde s ood as
he p ocess by which able s a e manu ac u ed by di ec ly comp essing powde blends o
he ac i e ing edien and sui able excipien s.
The choice o he manu ac u ing p ocess is dic a ed by he s abili y cha ac e is ics o
Nico andil. The known s abili y issues immedia ely ule ou aqueous based we
g anula ion, d y g anula ion o any o he p ocess ha induces a physical o m change on
he pa icles o p omo es excessi e mechanical s ess on i s c ys alline s uc u e.
The manu ac u ing s a egy o o mula e Nico andil able s will be, he e o e, he
p oduc ion o a powde blend o di ec comp ession.
Di ec comp ession is a manu ac u ing p ocess in which a powde blend o he DS
and adequa e excipien s is comp essed di ec ly a e he blending ope a ion. Di ec
comp ession p esen s challenges ela ed mainly o he pa icle size o he se e al
componen s, al hough shape and densi y also play impo an oles (84). I hese
pa ame e s a e su icien ly di e en be ween each o he he powde blend will end o
p esen di icul low and pa icle seg ega ion phenomena is likely o occu . This poses a
h ea o he blend homogenei y and able con en uni o mi y. Despi e being appa en ly a
simple and s aigh o wa d manu ac u ing p ocess, o mula ing a d ug p oduc based on
di ec comp ession equi es ca e ul e alua ion o DS and excipien s physical p ope ies o
ob ain a powde blend wi h adequa e low p ope ies o allow he powde blend o low
uni o mly no only in o he able ing machine bu also in o a die ca i y whe e i will be
comp essed in o a i m compac , o able .
The endency o a powde mix u e o o m a uni o m blend o o seg ega e is also
dependen on physical p ope ies such as cohesi eness, pa icle size and shape o
densi y (1). The homogenei y o he inal blend depends on o he pa ame e s such as he
ope a ing design, DS concen a ion and aw ma e ials cha ging sequence as well as
blende ill le el, mixing ime and mixing speed.

De elopmen o o al able s con aining Nico andil
Resul s and Discussion
84
2.1. Manu ac u ing p ocess isk assessmen
Be o e s a ing he o mula ion de elopmen a isk assessmen was done
conside ing ha he inal pu pose was o p oduce a powde blend o di ec comp ession.
The majo ope a ions in such manu ac u ing s eps a e powde blending, lub ica ion and
able ing. C i ical poin s which can ha e po en ial impac on inished p oduc CQA’s and
he co esponding isk assessmen a e lis ed on Table 32.
Table 32. Risk assessmen e alua ion ela ed wi h he manu ac u ing p ocess
P ocess s ep
Assessmen
Risk
e alua ion
Blending
Loading
componen s
and DS
sie ing.
Due o PSD o Nico andil his s ep should be done wi h he DS p e iously sie ed
gen ly by hand h ough a 1mm mesh size o sca e la ge agg ega es.
The isk is
low
Bending s ep
Blending wi h Isomal should be done in wo s eps o dilu e he blend geome ically.
Dilu ion and blending ime a e c i ically ela ed o DS homogenei y in he blend.
The isk is
medium
Milling s ep
Milling s ep is done o gua an ee ha he DS can be p ope ly blended wi h he
componen s.
The isk is
high
Lub ica ion
Lub ican s a e no mally used in low amoun s and a e associa ed wi h de-mixing i
o e blended. Fo he p omo ion o an adequa e lub ican dis ibu ion his should be
sie ed by hand h ough a 0,710mm mesh size pa ially dilu ed wi h a blend po ion.
The isk is
medium
Final mix u e
Powde blend will be used o p oduce 10mg able s. Blend cha ac e is ics mus be
e i ied be o e able ing.
The isk is
medium
Table ing
Comp ession
o ce
Comp ession o ce (main comp ession and p e-comp ession) can in luence
p oduc pe o mance since i is ela ed o c i ical quali y a ibu es o he able s
such as esis ance o b eaking, disin eg a ion, iabili y and dissolu ion p o ile.
Addi ionally, comp ession o ce has been associa ed also wi h inc ease in p oduc
ins abili y.
The isk is
low
Table ing
speed
Table ing was done conside ing only one speed.
The isk is
low
Table
cha ac e is ics
Table s cha ac e is ics a e an indica ion o p oduc quali y and o e all comp ession
p ocess e iciency. Cha ac e is ics should mee a ge p oduc p o ile de ined
ini ially.
The isk is
medium
2.2. Fo mula ion de elopmen s udies
Fo mula ion de elopmen was di ided in ou ials which s a ed by e alua ing i s
componen s. Each o hese componen s a e iden i ied as o mula ion a iables wi h
po en ial isk as de ined on Table 31. The pu pose o he o mula ion de elopmen was o
de ine an op imized manu ac u ing p ocess able o p oduce a homogeneous powde
blend o di ec comp ession and o p oduce 10mg Nico andil able s.
Table 33 summa izes he de elopmen p ocess and b ie ly desc ibes he a ionale
associa ed wi h each s ep.
De elopmen o o al able s con aining Nico andil
Resul s and Discussion
85
Table 33. Summa y o o mula ion ials
T ial
Numbe
Numbe o
ba ches
p oduced
Desc ip ion
#1
5
P oduc ion o a Nico andil powde blend o es he in luence o sodium s a ch
glycola e on he disin eg a ion imes o 10mg able s o assess i s ele ance on
he o mula ion.
#2
3
P oduc ion o a Nico andil powde blend using di e en amoun s o S a ch 1500
PG LM g ade o e alua e he e ec on 10mg able s p ope ies.
#3
2
De elopmen and op imiza ion o he blending p ocess. In oduc ion and
e alua ion o milling ials. P oduc ion and cha ac e iza ion o Nico andil 10mg
able s and e alua ion o he comp ession p ocess.
#4
1
P oduc ion and cha ac e iza ion o Nico andil blend and 10mg able s in a 1kg
ba ch size. P oduc ion o samples o s a a 3 mon hs s abili y s udy. De ini ion
o he inal manu ac u ing p ocess, c i ical p ocess pa ame e s, isk assessmen
and inal p oduc speci ica ions.
The amoun o excipien s o be used was based on echnical bibliog aphy (79)
ega ding hei commonly accep ed amoun anges and is desc ibed on Table 34. Tes
ega ding changes in he quan i a i e composi ion o es o mulas will be done inside
hese anges.
Table 34. Common amoun s o selec ed excipien s
Componen
Func ion
% in he
o mula ion
Jus i ica ion
Nico andil
DS
10%
Ta ge p o ile
GalenIQ 721®
(Isomal )
Diluen , ille
> 25%
Handbook o Pha maceu ical
Excipien s.
P oduc echnical li e a u e.
S a ch 1500® LM
(P egela inized s a ch, low mois u e)
Binde ,
disin eg an
2% - 20%
Handbook o Pha maceu ical
Excipien s.
P oduc echnical li e a u e.
Vi as a PSF® g ade
(Sodium s a ch glycola e, low mois u e g ade)
Disin eg an
2% - 8%
Handbook o Pha maceu ical
Excipien s.
P oduc echnical li e a u e.
Dub Mic oLub 50
(S ea ic acid, mic onized)
Lub ican
1% - 3%
Handbook o Pha maceu ical
Excipien s.
De elopmen o o al able s con aining Nico andil
Resul s and Discussion
86
2.2.1. T ial #1
Aim: The pu pose o he ial #1 was o assess i sodium s a ch glycola e (SSG) a
e y hyg oscopic excipien is necessa y on he o mula ion and o which ex en i s
p esence in luences he disin eg a ion imes and he dissolu ion p o ile conside ing ha
s a ch, selec ed o be included on he o mula ion, also has a disin eg an ac ion on he
p oposed amoun . SSG has been iden i ied as a high isk o mula ion a iable and
equi es u he e alua ion ega ding he necessi y o be included in he o mula ion. T ial
#1 was designed o assess he in luence o SSG and is composed o i e es mix u es
wi h a iable SSG amoun s.
Manu ac u ing p ocess: The selec ed manu ac u ing p ocess conside s he
p oduc ion o i e 150g powde blends using a d y blend p ocess o di ec comp ession.
Blending ope a ion was done manually using a PE plas ic bag. The p ocess s a ed by
mixing he DS wi h SSG and S a ch 1500 LM. This p e-blend was mixed in he bag du ing
3 min and sie ed by hand h ough 0,710mm sie e. Isomal was added and blended o an
addi ional 3 min. S ea ic acid was dilu ed wi h wo pa s o he mix u e and hand sie ed
h ough a mesh size o 0,5mm and inco po a ed in he powde blend. The inal mix u e
was blended o 1 min. This mix u e was used o p oduce able s in an 8 s a ions lab scale
Ronchi® au oma ic comp essing machine using 7mm ound, bicon ex punches wi hou
b eak line o embossing.
The composi ion o he es mix u es is desc ibed on Table 35.
Table 35. T ial #1. Quan i a i e composi ion o es mix u es
Componen s
Fo mula ion
#1
Fo mula ion
#2
Fo mula ion
#3
Fo mula ion
#4
Fo mula ion
#5
Nico andil
10%
10%
10%
10%
10%
GalenIQ 721®
(Isomal )
75%
73%
71%
67%
63%
S a ch 1500® PG LM
(P e-gelela inized s a ch)
10%
10%
10%
10%
10%
Vi as a PSF®
(Sodium s a ch glycola e, low
mois u e)
0%
2%
4%
8%
12%
Dub Mic oLub 50
(S ea ic acid, mic onized)
5%
5%
5%
5%
5%
To al
100%
100%
100%
100%
100%
De elopmen o o al able s con aining Nico andil
Resul s and Discussion
87
Va iable amoun s o SSG we e used main aining ixed he amoun s o he emaining
componen s excep Isomal which was used o compensa e he a iable amoun s o SSG.
Tes #1 does no con ain SSG and se es as con ol sample. Tes s #2, #3 and #4 ha e
a iable quan i ies o SSG, 2%, 4% and 8% which a e he minimum, op imal and
maximum ecommended amoun s in he li e a u e. Tes #5 con ains 12% SSG-PSF.
S a ch 1500® LM was inco po a ed in he ini ial o mula ion as 10% since i is he
maximum amoun ecommended o disin eg an ac ion while main aining binde
p ope ies.
The lub ican agen , s ea ic acid 50 mic onized, was used in he amoun o 5%
based on in o ma ion e ie ed om pa en da a ha indica es s ea ic acid as an excipien
ha can help o dec ease he comp ession o ces o e Nico andil du ing able ing.
Resul s:
Blending ope a ions we e di icul due o he ac ha bulk Nico andil is ha d o sie e
alone. This is due o he la ge and small agg ega es p esen in he bulk DS ha canno be
sca e ed by simple d y blending ope a ions. In ac , using a manual sie ing s ep h ough
a 1.0 o 0.710mm mesh sizes, Nico andil powde alone, wi hou he use o an excipien as
a sie ing adju an , e-agglome a es a e he sie ing. A p e-blend was pe o med wi h
S a ch o p omo e Nico andil dilu ion and o aid he subsequen sie ing s ep.
A e he p oduc ion o he powde blend, he able s we e manu ac u ed by di ec
comp ession and we e cha ac e ized. To e alua e he esponse o he powde blend o
compac ion o ce, comp ession ials wi h inc easing o ces we e pe o med. Comp ession
se ings a e indica ed wi h alues: #150, #125, #100, #75 and #50. Each alue ep esen s
he dis ance in millime es be ween he main comp ession olls on he comp ession
machine. Lowe alues mean smalle dis ances and hence a highe comp ession o ce is
applied be ween punches. On Table 36 a e shown he esul s (n=20) o ha dness es ing.
Table 36. T ial #1. Comp ession es s esul s
Comp ession se ing
(Main comp ession o ce)
Tes #1
Tes #2
Tes #3
Tes #4
Tes #5
Table ha dness ( + σ)
#150
27 N (+ 2)
23 N (+ 3)
25 N (+ 2)
20 N (+ 2)
14 N (+ 2)
#125
46 N (+ 5)
56 N (+ 6)
50 N (+ 8)
44 N (+ 9)
35 N (+ 10)
#100
115 N (+ 11)
104 N (+ 7)
104 N (+ 4)
89 N (+ 4)
60 N (+ 9)
#75
120 N (+ 8)
110 N (+ 11)
107 N (+ 6)
97 N (+ 6)
75 N (+ 4)
#50
127 N (+ 9)
114 N (+ 9)
107 N (+ 9)
102 N (+ 10)
84 N (+ 9)
De elopmen o o al able s con aining Nico andil
Resul s and Discussion
94
Table s we e p oduced wi h wo di e en comp ession o ces: se ing #125 and #105
o e alua e a ge , low and high able ha dness. Resul s om able cha ac e iza ion a e
p esen ed on Table XX: T ial #2 10mg cha ac e iza ion. Cha ac e iza ion es s we e
pe o med acco ding o he me hodology desc ibed in he Ma e ials and Me hods sec ion,
esul s a e summa ized in Table 41.
Table 41. T ial #2. 10mg able s cha ac e iza ion esul s
Mix u e numbe
Tes #1
Tes #2
Tes #3
Tes #1
Tes #2
Tes #3
Comp ession se ing
#125
#105
Ha dness
60 N
55 N
29 N
100 N
97 N
85 N
F iabili y
0.37%
0.39%
0.40%
0.22%
0.23%
0.36%
Dissolu ion (% a 30min)
100.8%
99.7%
100.7%
101.2%
98.5%
99.1%
Disin eg a ion
Time (n=6)
Fi s :
(mm:ss)
3:30
3:27
2:40
4:05
4:00
2:40
Las :
(mm:ss)
4:15
3:40
3:10
4:25
4:20
3:10
Table weigh
(n=10)
A e age
99.8
100.5
98.6
100.9
99.5
99.82
min
97.3
99.5
97.6
98.0
97.9
97.10
max
102.3
101.3
99.3
102.5
101.2
102.7
RSD
1.35%
0.62%
0.61%
1.47%
1.28%
2.10
Table
hickness
(n=10)
(mm)
2.59
2.62
2.62
2.51
2.50
2.51
RSD (%)
0.97%
0.49%
0.39%
1.44%
0.76%
0.75%
When compa ed wi h ial #1, able s wi hou SSG-PSF ( es mix u e #1) ha e highe
ha dness o he same comp ession o ce used. The e ec on disin eg a ion imes when
SSG PSF inc eases is e iden and i can be concluded ha his excipien s is accele a ing
as expec ed he disin eg a ion ime.
Reducing s a ch om 10% o 5% ( om ial #1 o ial #2) seems o p oduce able s
wi h highe ha dness o he same comp ession o ce applied.
On Figu e 28 and Figu e 29 dissolu ion p o iles a e shown and compa ed wi h he
RP.

De elopmen o o al able s con aining Nico andil
Resul s and Discussion
95
Figu e 28. T ial #2. Dissolu ion p o iles o able s om mix u es 1, 2 and 3
Figu e 29. T ial #2. Dissolu ion p o iles o able s om mix u e 1 and RP
When compa ing he dissolu ion p o iles i is possible o obse e ha able s
p oduced om ial #2 mix u e a e simila o he dissolu ion p o ile o bo h RP ba ches
(Figu e 29) and able s p oduced om mix u e #2 and #3 show slowe dissolu ion a es.
De elopmen o o al able s con aining Nico andil
Resul s and Discussion
96
2.2.3. T ial #3
Aim: The pu pose o ial #3 was o p oduce a powde blend using a milling s ep o
p omo e op imal blend homogenei y and o p oduce and cha ac e ize able pe o mance.
Du ing DS cha ac e iza ion i was no iced ha bulk Nico andil p esen ed la ge, so and
s icky agglome a es. P e ious ials con i med ha Nico andil will ha dly blend wi h
excipien s wi hou he use o a mechanical p ocess. E en in a smalle scale,
agglome a ion is p esen and i is possible o obse e small and ha d g ain like
agglome a es ha would unlikely be sca e ed by simple d y blending ope a ions.
Since i became necessa y o sca e hese agglome a ions and mic oscopic
agg ega es, a milling s ep was in oduced in he manu ac u ing p ocess. As al eady
sugges ed by p e o mula ion es s a milling seems o induce less damage on Nico andil
c ys alline s uc u e han he oscilla ing ba sie ing p ocess which causes mo e ic ion
(Table 21).
Manu ac u ing p ocess: The selec ed manu ac u ing p ocess conside s he
p oduc ion o one 500g powde blend using a d y blend p ocess o di ec comp ession.
Blending ope a ion was done using a double cone blende . The i s aw ma e ial o be
added o he bin is Isomal (10%), nex Nico andil ollowed by S a ch 1500 PG LM g ade
o p omo e an in ima e con ac by s a ch pa icles. This sequence allows a geome ic
dilu ion o Nico andil. This p e-blend was mixed and a e wa ds he emaining amoun o
Isomal was added ollowed by ano he mixing s ep. By las , he mix u e can be lub ica ed
wi h s ea ic acid 50 mic onized p e iously dilu ed wi h wo pa s o he mix u e and hand
sie ed h ough a mesh size o 0,5mm. Blend homogenei y was assessed by collec ing 4
samples om app oxima ely equidis an poin s on he bin using a hie p obe in he p e-
blend (be o e lub ica ion) an in he inal blend. Table s we e p oduced in an 8 s a ions lab
scale Ronchi® au oma ic comp essing machine.
The composi ion o he mix u e is desc ibed on Table 42.
Table 42. T ial #3. Quali a i e composi ion
Componen s
Quan i a i e composi ion
Nico andil
50g
10%
GalenIQ 721®
(Isomal )
375g
75%
S a ch 1500® PG LM
(P e-gelela inized s a ch)
5g
10%
Dub Mic oLub 50
(S ea ic acid, mic onized)
2.5g
5%
To al
500g
100%
De elopmen o o al able s con aining Nico andil
Resul s and Discussion
97
An op imal blending p ocess can be achie e by es ing di e en blend imes and
sampling powde blend o assess con en homogenei y.
The i s blending ope a ion was done in 5 minu es in e als un il 15 minu es o al
blending ime was eached. A each in e al he mix u e was inspec ed o he exis ence o
lumps o agg ega es.
The same p ocedu e was epea ed a e he milling s ep whe e di e en o o
speeds we e es ed. Two addi ional blending s eps ollowing a geome ic dilu ion
p ocedu e we e es ed. A his s age, in bo h s eps a e milling a mix u e homogenei y
was pe o med. Lub ica ion ime was also es ed wi h di e en blending imes and a he
end mix u e homogenei y, low p ope ies, pa icle size dis ibu ion, densi y and wa e
con en was de e mined.
The able s ob ained om his mix u e we e also s udied ega ding physical
p ope ies and dissolu ion.
Manu ac u ing p ocess sequence, se ings, con olling and equipmen used a e
desc ibed on Table 43:
Table 43. T ial #3. P ocess summa y able
S age
Machine/Desc ip ion
Se ings
Con olling
Blending
(P e Blend)
E weka module
Speed: 34 pm
Double cone blende
Check o a ion speed
Mixing s ep #1
5 min
+ 5 min ( o al 10min)
+ 5 min ( o al 15min)
Check blending ime
Visual inspec ion
Hamme wi
Speed: o be de ined
Mesh size: o be
de ined
Visual inspec ion
PSD
Blending
(Blend)
E weka module
Speed: 34 pm
Double cone blende
Check o a ion speed
Mixing s ep #2
5 min
+ 5 min ( o al 10min)
+ 5 min ( o al 15min)
Check blending ime
Mix u e homogenei y
Mixing s ep #3
10 min
+ 10 min ( o al 20min)
+ 5 min ( o al 25min)
Check blending ime
Mix u e homogenei y
Blending
(Final Blend)
Sie e
( o sie e s ea ic acid)
0.500 mm
Check sie e size and
in eg i y
E weka module
Speed: 34 pm
Double cone blende
Check o a ion speed
Mixing s ep #4
(lub ica ion)
3 min
+ 2 min ( o al 5min)
+ 3 min ( o al 8min)
Mix u e homogenei y
Flowabili y
Powde densi y
PSD
Comp ession
Ronchi 8 s a ion o a y
p ess
Lab scale able ing
machine
Main comp ession: o
be de ined
P e-comp ession: o
be de ined
Filing: o be de ined
Ha dness
Disin eg a ion ime
F iabili y
Dissolu ion
De elopmen o o al able s con aining Nico andil
Resul s and Discussion
98
The nex lowcha summa izes he manu ac u ing s eps aken.
De elopmen o o al able s con aining Nico andil
Resul s and Discussion
99
Du ing he ini ial blending s ep i was possible o obse e la ges agglome a es o
Nico andil in he powde blend a e e y 5 minu es in e al. A he end o he 15min
blending ime some smalle size agglome a es emained sca e ed in he powde blend.
This mix u e was milled a di e en speeds wi hou he use o a mesh. Samples we e
analysed ega ding PSD o each speed es ed. The esul s a e shown in Figu e 30 we e i
is possible o obse e he a ia ion on he PSD (mic a) wi h he inc ease in he milling
speed (x1000 o a ions pe minu e).
Figu e 30. PSD esul s o milling ials
Only a highe speeds i is possible o educe pa icle agg ega es ha become
e ained on 1mm sie e (squa e ma ke s). These agg ega es a e o med by Nico andil
pa icles and i s p esence can comp omise blend homogenei y.
Since i is no possible o comple ely elimina e g ain like pa icles e en using
maximum speed an addi ional es was pe o med using his ime a mesh size o 0,6mm.
The esul s a e exp essed on Figu e 31 using he same ep esen a ion as in Figu e
30.

De elopmen o o al able s con aining Nico andil
Resul s and Discussion
100
Figu e 31. PSD esul s o milling ials (wi h mesh)
Using a 0,60mm mesh du ing milling helped o educe he small Nico andil
agg ega es e en a slowe speed (squa e ma ke ) as is sugges ed on Figu e 31. To his
milled powde blend Isomal was added and blended in wo s eps. This ac ion is done o
geome ically dilu e he ini ial powde blend acco ding o he manu ac u ing p ocess
desc ibed. The inal mix u e was cha ac e ized. The esul s a e desc ibed on Table 44.
Table 44. T ial #3. Mix u e cha ac e iza ion esul s
Tes
P e blend
Final blend
Densi y
Bulk
0,583
0,570
Tapped
0,757
0,735
Hausne
Ra io
1,30
1,29
Comp essibili y
Index
22,92
22,4
E alua ion
Passable
Passable
Flowabili y
(Time (s) /
100g )
Nozzle (mm)
25
15
10
25
15
10
A e age (s)
6,5
16,5
NP
6,2
14,5
NP
S . De (s)
0,10
3,42
NP
0,10
3,20
NP
RSD (%)
1,55%
20,72%
NP
1,30%
18,50%
NP
Powde blend p esen s a passable low cha ac e is ic. Flow h ough hoppe (25mm)
was cons an and s eady al hough when using a 15mm hoppe low was mo e di icul and
i egula . When 10mm hoppe was used powde did no low.
Final mix u e pa icle size dis ibu ion by analy ical sie ing was de e mined (Figu e
32.
De elopmen o o al able s con aining Nico andil
Resul s and Discussion
101
Figu e 32. T ial #3. Mix u e pa icle size dis ibu ion
This powde blend is cha ac e ized by a low pa icle size wi h 50% o he pa icles
bellow 182mic a.
Blend homogenei y was de e mined using he in house UV me hod as desc ibed in
Ma e ials and Me hods sec ion. Powde blend was sampled in six poin s di ec ly in o a
200mℓ olume ic lask acco ding o he diag am on Figu e 33.
Figu e 33. T ial #3. Mix u e sampling diag am
Each sampling poin was measu ed 4 imes. A e age and ela i e s anda d
de ia ion esul s a e summa ized in Table 45.
De elopmen o o al able s con aining Nico andil
Resul s and Discussion
102
Table 45. T ial #3. Mix u e homogenei y esul s
S age
Time
Assay
RSD
Blending s ep
#2
5 min
100.45%
2.64%
10 min
100.86%
1.30%
15 min
100.58%
0.98%
Blending s ep
#3
10 min
99.59%
3.35%
20 min
101.06%
2.09%
25 min
99.01%
1.20%
Final mix u e
3 min
101.19%
1.58%
5 min
101.56%
0.96%
8 min
100.16%
0.88%
Resul s sugges ha homogenei y imp o es wi h longe p ocessing imes judging by
he esul s o ela i e s anda d de ia ion. Lub ica ion s ep does no seem o p omo e de-
mixing wi h longe blending imes.
The inal powde sampled was comp essed in o 10mg able s using di e en
comp ession o ces. Cha ac e iza ion esul s a e summa ized on Table 46.
Table 46. T ial #3. Table s cha ac e iza ion esul s
Comp ession se ing
#105
#115
#125
#135
Weigh (n=10)
100mg
100mg
100mg
100mg
Ha dness
61N
45 N
40 N
18 N
Disin eg a ion
ime
Fi s
3min 43s
4min 15s
2min 48s
3min 21s
3min 30s
3min 57s
2min 19s
3min 16s
Las
F iabili y
0.23%
0.38%
0.41%
0.59%
Dissolu ion (%)
96.9%
(0.62%)
No pe o med
100.5%
(1.08%)
No pe o med
Comp ession se ing #125 and #105 p oduced able s wi h an a e age o 40N and
61N espec i ely which we e used o a dissolu ion es (Figu e 34).
De elopmen o o al able s con aining Nico andil
Resul s and Discussion
103
Figu e 34. T ial #3. 61N and 40N able s dissolu ion es
Conside ing he esul s ob ained in his ial, he p ocess pa ame e s included on
Table 47 will be es ed on an inc ease powde blend amoun .
Table 47. Manu ac u ing pa ame e s o be es ed on ial #4
S age
Machine/Desc ip ion
Se ings
Blending
(P e Blend)
E weka module
Speed: 34 pm
Double cone blende
Mixing s ep #1
10min
Hamme wi
Speed: o be de ined
Mesh size: o be de ined
Blending
(Blend)
E weka module
Speed: 34 pm
Double cone blende
Mixing s ep #2
10min
Mixing s ep #3
15min
Blending
(Final Blend)
Sie ing s ep
( o sie e s ea ic acid)
0.500 mm
E weka module
Speed: 34 pm
Double cone blende
Mixing s ep #4
(lub ica ion)
5min
Comp ession
Ronchi 8 s a ion o a y p ess
Lab scale able ing machine
Main comp ession: o be de ined
P e-comp ession: o be de ined
Filing: o be de ined
Se ing o milling and comp ession o ce will be de ined a he end o T ial #4,
depending on he ou come.
De elopmen o o al able s con aining Nico andil
Resul s and Discussion
110
Table 52. Final isk assessmen on DS a ibu es
D ug P oduc
CQA’s
Ra ionale
Risk
e alua ion
DS A ibu es: Pa icle Size Dis ibu ion
Assay
Th oughou he de elppmen wo k all assay esul s complied wi h expec ed esul s. Milling ials
pe o med on powde mix u es also did no indica e any assay p oblems. The isk was educed om
medium o low.
Low
Deg ada ion
P oduc s
The e we e no indica ion ha PSD could nega i ely a ec DS s abili y. The isk was educed om
medium o low.
Low
Dissolu ion
All dissolu ion es s pe o med showed as dissolu ion p o ile. These esul s suppo he low isk
assignmen ela ing dissolu ion and pa icle size dis ibu ion. The isk was educed om medium o
low.
Low
Wa e con en
DS PSD is an in insic phsical p ope y which is no ela ed wi h he wa e con en o he d ug
p oduc . Du ing de elopmen wo k desc ibed no e idences ha e been ound ha could ela e his
wo pa ame e s. The isk was unchanged.
Low
Ha dness
PSD o he DS does no seem o ha e ele an in luence on able ha dness esul s, mainly due o
he emaning componen s o he o mula in which cha ac e is ics ha e much mo e weigh on he
comapc ion p ope ies o he powde blend. The isk was unchanged.
Low
DS A ibu es: Solubili y
Assay
Th oughou he de elppmen wo k all assay esul s complied wi h expec ed esul s. Sink condi ions
ha e been demosn a ed o comply wi h pha macopoeial s anda ds. The isk was unchanged.
Low
Deg ada ion
P oduc s
The e is no indica ion ha solubili y can nega i ely a ec DS s abili y. The isk was unchanged.
Low
Dissolu ion
All dissolu ion es s pe o med showed as dissolu ion p o ile. These esul s suppo he low isk
assingnmen ela ing dissolu ion and solubili y. The isk was educed om medium o low.
Low
Wa e con en
The e is no ela ionship be ween solubili y and wa e con en . The isk was unchanged.
Low
Ha dness
Solubili y o he DS does no seem o ha e ele an in luence on able ha dness esul s. The isk
was unchanged.
Low
DS A ibu es: Chemical S abili y
Assay
Nico andil s abili y is a majo issue when o mula ing a d ug p oduc wi h his molecule. A ca e ull
moni o ing o aw ma e ials p ope ies, manu ac u ing p ocess and packaging is necessa y o a oid
excessi e exposu e o he DS and d ug p oduc o condi ions ha can p omo e deg ada ion
eac ions. The isk was educed om high o medium.
Medium
Deg ada ion
P oduc s
Dissolu ion
E en a accele a ed condi ions he Nico andil able s main ain a as dissolu ion beha iou .
Ne e heless addi ional s abili y da a seems o be necessa y o u he in es iga e dissolu ion
pe o mance. The isk was educed om high o low.
Low
Wa e con en
Wa e con en and ela i e humidi y mus be ca e ully moni o ed o a oid excessi e exposu e o
wa e . The isk was educed om high o medium.
Medium
Ha dness
Table ha dness mus be kep a a minimum possible o educe he a nega i e e ce on c ys alline
s uc u e o Nico andil. The isk was educed om high o medium.
Medium
DS A ibu es: Flowabili y
Assay
Flow p ope ies do no seem o be in luencing assay esul s. The isk was educed om medium o
low.
Low
Deg ada ion
P oduc s
DS low p ope ies a e no di ec ly ela ed o d ug p oduc impu i y le el. The isk was unchanged.
Low
Dissolu ion
Flowabili y o he DS has been p ope ly compensa ed du ing o mula ion de elopmen and had no
isible impac on dissolou ion p o ile. The isk was educed om medium o low.
Low
Wa e con en
DS low p ope ies a e no di ec ly ela ed o d ug p oduc wa e con en . The isk was unchanged.
Low
Ha dness
DS low p ope ies a e no di ec ly ela ed o able ha dness o o an ex en ha equi es u he
e alua ion. The isk was unchanged.
Low

De elopmen o o al able s con aining Nico andil
Resul s and Discussion
111
3.1.2. Excipien s
Table 53. Final isk assessmen on excipien s a ibu es
Fo mula ion
Va iables
D ug P oduc
CQA’s
Ra ionale
Risk
e alua ion
GalenIQ 721®
(Isomal )
Assay
Isomal seems o be an adequa e componen (diluen ) on he
o mula ion. Resul s do no seem o indica e any nega i e e e c on d ug
p oduc CQA’s. All pa am e s isk has been educed o Low le el.
Low
Deg ada ion
P oduc s
Low
Dissolu ion
Low
Wa e con en
Low
Ha dness
Low
S a ch 1500®
LM
Assay
This excipien does no seem in luence he assay esul s. The isk was
educed om medium o low.
Low
Deg ada ion
P oduc s
A low mois u e g ade was used on he o mula ion al hough i seems
ha addi ional s udies migh be necessa y o e alua e he e ec o
s a ch on he p oposed concen a ions on he o mula ion. The isk has
been inc eased om low o medium.
Medium
Dissolu ion
Despi e he binding / disin eg an p ope ies o s a ch i seems ha
addi ional s udies migh be necessa y o e alua e he e ec o s a ch on
he p oposed concen a ions on he dissolu ion beha iou on he long
e m s abili y. The isk was unchanged.
Medium
Wa e con en
A low mois u e g ade was used on he o mula ion al hough i seems
ha addi ional s udies migh be necessa y o e alua e he e ec o
s a ch on he po posed concen a ions on he o mula ion. The isk was
unchanged.
Medium
Ha dness
This compone does no seem o nega i ely in luence able ha dness.
The isk was educed om medium o low.
Low
S ea ic acid
50
Assay
S ea ic acid does no seem o ha e a nega i e e ec o on any o he
CQA’s o he d ug p oduc . All pa am e s isk has been educed o Low
le el.
Low
Deg ada ion
P oduc s
Low
Dissolu ion
Low
Wa e con en
Low
Ha dness
Low
De elopmen o o al able s con aining Nico andil
Resul s and Discussion
112
3.1.3. Manu ac u ing p ocess
Table 54. Final isk assessmen on manu ac u ing p ocess
P ocess s ep
Assessmen
Con ol s a egy
Risk
e alua ion
Blending
Loading
componen s
and DS sie ing.
Due o PSD o Nico andil his s ep should be done
wi h he DS p e iously sie ed gen ly by hand h ough
a 1mm mesh size o sca e la ge agg ega es.
Nico andil should be added in be ween S a ch and
SSG-PSF g ade o p omo e a be e DS dis ibu ion.
A simple isual inspec ion is
adequa e o e i y ha mos o DS
agg ega es ha e been sca e ed.
No impac on inal blend
homogenei y is expec ed.
Low
5 min. bending
s ep
Blending s ep in oduced o p epa e he p e-mix u e
o he milling s ep.
A simple isual inspec ion is
adequa e o e i y ha he
esul ing blend appea s o ha e
he DS sca e ed. No impac on
inal blend homogenei y is
expec ed.
Low
Milling s ep
Milling s ep is done o gua an ee ha he DS can be
p ope ly blended wi h he o he componen s. In he
se ings used.
Milling speed: 30 o 60 pm
(x1000).
Mesh size: 0,60mm.
Low
Addi ion o
Isomal and 30
min blending
s ep
Blending wi h Isomal should be done in wo s eps o
dilu e he blend geome ically. Dilu ion and blending
ime a e c i ically ela ed o DS homogenei y in he
blend.
Mix u e homogenei y mus be
pe o med be o e lub ica ion s ep
o e i y DS homogenei y and he
need o addi ional blending ime.
Low
Addi ion o
lub ican and
5min blending
s ep
Lub ican s a e no mally used in low amoun s and a e
associa ed wi h de-mixing i o e blended. To p omo e
an adequa e lub ican dis ibu ion his should be
sie ed by hand h ough a 0,710mm mesh size
pa ially dilu ed wi h a blend po ion.
Mix u e homogenei y mus be
pe o med o e i y DS
homogenei y.
Low
Final mix u e
Powde blend will be used o p oduce 10mg able s.
Blend cha ac e is ics mus be e i ied be o e able ing.
Mix u e homogenei y mus be
pe o med o e i y DS
homogenei y. Addi ionaly, blend
cha ac e iza ion mus be
pe o med.
Low
Table ing
Comp ession
o ce
Comp ession o ce (ei he main comp ession and p e-
comp ession) can in luence p oduc pe o mance
since i is ela ed o c i ical quali y a ibu es such as
esis ance o b eaking, disin eg a ion, iabili y and
dissolu ion p o ile. Addi ionaly, comp ession o ce has
been associa ed also wi h inc ease in p oduc
ins abili y.
Comp ession o ces mus be low
enough o ob ain able s wi h
desi able cha ac e is ics.
Low
Table ing speed
Table ing was done conside ing only one speed.
Check able ing speed.
Low
Table
cha ac e is ics
Table s cha ac e is ics a e an indica ion o p oduc
quali y and o e all comp ession p ocess e iciency.
Cha ac e is ics should mee a ge p oduc p o ile
de ined ini ially.
IPC should be done a egula
in e als du ing manu ac u ing
p ocess.
Low
De elopmen o o al able s con aining Nico andil
Resul s and Discussion
113
3.2. Simila i y assessmen
To assess he in luence o s abili y condi ions and ime on he dissolu ion
pe o mance, esul s we e s a is ically e alua ed a di e en imes (10, 15 and 30min).
S a is ical analysis used is desc ibed in he Ma e ials and Me hods sec ion. Dissolu ion
p o iles we e plo ed by compa ing able s wi h he same ha dness along he ime and also
be ween di e en condi ions agains wo ba ches o he RP, al hough o he pu pose o
e alua ion and o de ec di e ences o pe o mance be ween he wo ha dness s a is ical
e alua ion conside s all samples.
On Figu e 37, he dissolu ion p o iles o 30N samples s o ed a 25ºC/60% RH and
40ºC/75% RH du ing he 3 mon hs s abili y s udy and wo ba ches o he RP a e shown.
Figu e 37. A e age dissolu ion p o iles o 30N able s s RP
On Figu e 38, he dissolu ion p o iles o 60N samples s o ed a 25ºC/60% RH and
40ºC/75% RH du ing he 3 mon hs s abili y s udy and wo ba ches o he RP a e shown.
De elopmen o o al able s con aining Nico andil
Resul s and Discussion
114
Figu e 38. A e age dissolu ion p o iles o 60N able s s RP
E alua ion o he dissolu ion p o iles o 30N able s samples show ha dissolu ion
a e dec eased in he 40ºC/75% RH a e 1 mon h (T1M) and 3 mon hs (T3M) and he
dissolu ion p o ile in hese wo condi ions is e y app oxima e. As o he 25ºC/60% RH
condi ion, p o iles seem o be also e y simila and almos ma ch he ini ial ime (T0).
Conside ing ha he p oduc s ill exhibi s a as dissolu ion p o ile i migh be possible o
assume ha all DS is eleased and solubilized be o e he s omach emp ying ime (30min).
E alua ion o he dissolu ion p o iles o 60N able s samples show ha dissolu ion
a e dec eased a e 1 mon h (T1M) in bo h deg ada ion condi ions. A e 3 mon hs (T3M)
a 40ºC/75% RH he p o ile is equi alen o he one a T1M in he same condi ion.
Ne e heless, he p oduc s ill shows a as dissolu ion p o ile so i migh be possible o
assume ha all DS is eleased and solubilized be o e he s omach emp ying ime (30min)
e en a he end o he sho e m s abili y s udy.
To e alua e simila i y o dissolu ion p o iles a s a is ical compa ison o he esul s o
dissol ed amoun s a 10, 15 and 30min was done. These esul s allow o conclude ha
he e a e some s a is ical di e ences in he compa ison imes al hough in e ms o
pha maceu ical pe o mance hese di e ences a e no likely o ha e an impac on he
biological a ailabili y o he DS in he bloods eam.
De elopmen o o al able s con aining Nico andil
Resul s and Discussion
115
Conside ing ha he disin eg a ion imes a e unde 5min and o disca d he
a iabili y induced by his physical phenomenon, dissolu ion p o iles we e compa ed a
10min, 15min and 30min. A 10min, able s a e ully disin eg a ed so we assume ha
pe o mance is now dic a ed by dissolu ion beha io only, which is in luenced, on i s u n,
by he solubili y o he DS. Dissolu ion a 15 minu es was also used o compa ison
pu poses o e alua e di e ences o he RP which demons a es a e y as dissolu ion
p o ile (87).
A 10 minu es he samples can be di ided in ou g oups wi h s a is ical di e ences
be ween hem (subse s 1 o 4) as desc ibed in Table 55. To e alua e hese di e ences a
box plo ep esen a ion is shown, whe e i is possible o obse e ha all samples a
40ºC/75% RH s and aside he emaining samples (Figu e 39). When compa ing wi h bo h
ba ches o he RP i is possible o conclude ha dissolu ion da a a 10min is s a is ically
simila o he 30N able alues in he 25ºC/60% RH in all ime poin s, while he emaining
samples p esen signi ica e di e ences om he RP.
Figu e 39. Box plo o dissolu ion esul s a 10min 30N and 60N s RP
Table 55. 10min dissolu ion Tukey HSD esul s
Samples
Subse o alpha = 0.05
1
2
3
4
L #2 60N T1M 40_75
65.0897
L #2 30N T3M 40_75
69.2589
69.2589
L #2 60N T3M 40_75
69.5887
69.5887
L #2 30N T1M 40_75
70.7537
L #2 60N T1M 25_60
81.8686
L #2 60N T0M
84.6200
L #2 60N T3M 25_60
85.5925
L #2 30N T1M 25_60
90.6523
L #2 30N T3M 25_60
91.5079
L #2 30N T0M
93.2803
RP 54599 20
94.3667
RP 54372 34
95.0167
Signi icance
0.063
0.994
0.233
0.081

De elopmen o o al able s con aining Nico andil
Resul s and Discussion
116
The nex c i ical poin analyzed was a 15minu es. In his ime he samples can be
di ided in i e g oups wi h s a is ical di e ences be ween hem (subse s 1 o 5) as
desc ibed in Table 56, al hough mo e samples a e s a is ically simila o he RP. To
e alua e hese di e ences a box plo ep esen a ion is shown, whe e i is possible o
obse e ha all samples a 40ºC/75% RH s ill s and aside he emaining samples (Figu e
40). When compa ing wi h bo h ba ches o he RP i is possible o conclude ha
dissolu ion da a a 15min is s a is ically simila o he 30N and 60N able alues in he
condi ion 25ºC/60% RH in all ime poin s, while he emaining samples p esen signi ica e
di e ences om he RP. This sugges ha he di e ences caused in he dissolu ion p o ile
by inc eased ha dness a e ading away.
Figu e 40. Box plo o dissolu ion esul s a 15min 30N and 60N s RP
Table 56. 15min dissolu ion Tukey HSD esul s
Samples
Subse o alpha = 0.05
1
2
3
4
5
L #2 60N T1M 40_75
77.9595
L #2 30N T3M 40_75
82.1284
L #2 60N T3M 40_75
83.9882
83.9882
L #2 30N T1M 40_75
85.9201
92.3188
L #2 60N T1M 25_60
94.4833
94.4833
L #2 60N T0M
94.9304
94.9304
L #2 60N T3M 25_60
95.5000
95.5000
L #2 30N T1M 25_60
95.5478
95.5478
L #2 30N T3M 25_60
96.9107
L #2 30N T0M
97.7784
RP 54599 20
98.0175
RP 54372 34
99.0234
Signi icance
1.000
0.872
0.842
0.165
0.087
De elopmen o o al able s con aining Nico andil
Resul s and Discussion
117
The las ime poin analyzed was a 30minu es. In his ime he samples can be
di ided in h ee g oups wi h s a is ical di e ences be ween hem (subse s 1 o 3) as
desc ibed in Table 57. 30min dissolu ion Tukey HSD esul sThe g aphic ep esen a ion o
hese di e ences is shown on a box plo , whe e i is possible o obse e ha RP samples
a e di e en om all o he samples excep o 30N able s a 3 mon hs in he 40ºC/75%
RH samples.
This is due o he ac ha he RP does no each 100% dissolu ion a 30 minu es
dissolu ion ime and ins ead has 95% (Figu e 41).
Figu e 41. Box plo o dissolu ion esul s a 30min 30N and 60N s RP
Table 57. 30min dissolu ion Tukey HSD esul s
Samples
Subse o alpha = 0.05
1
2
3
RP 54599 20
94.4833
L #2 30N T3M 40_75
95.4480
RP 54372 34
95.5333
L #2 60N T3M 40_75
97.1925
97.1925
L #2 60N T1M 40_75
99.0176
99.0176
L #2 30N T1M 40_75
99.1605
99.1605
L #2 30N T3M 25_60
99.9335
99.9335
L #2 60N T1M 25_60
99.9547
99.9547
L #2 60N T3M 25_60
100.3397
L #2 30N T0M
100.4654
L #2 60N T0M
100.6020
L #2 30N T1M 25_60
100.9409
Signi icance.
0.141
0.124
0.615
As men ioned be o e hese di e ences ha e less impo ance since all dissolu ion
p o iles a e s ill e y as which means ha DS is comple ely dissol ed be o e 30min. In
p ac ical e ms, hese esul s sugges ha he bioequi alence be ween es able s should
be he same as he RP.
De elopmen o o al able s con aining Nico andil
Resul s and Discussion
118
3.3. S abili y assessmen
Conce ning he sho e m s abili y he selec ed es s o e alua e p oduc s abili y
and pha maceu ical pe o mance we e: DS assay, impu i y assessmen (single known and
o al), dissolu ion, disin eg a ion ime, ha dness and wa e con en (KF). Table 58
summa izes he esul s ob ained a each ime and in each condi ion.
Dissolu ion and Wa e Con en (KF) we e no pe o med o he in e media e
condi ion a 1 mon h and 3 mon hs since he in o ma ion ga he ed om hese wo poin s
was no conside ed necessa y aking in o accoun he d ug p oduc pe o mance
cha ac e is ics.
I is assumed ha long e m (25ºC/60%RH) and accele a ed condi ions
(40ºC/75%RH) a e ep esen a i e o d ug p oduc s abili y and he esul s ob ained a
hose ime poin s can be used o assess pe o mance in in e media e condi ions,
acco ding o in e na ional guidelines on s abili y (16) and ma ixing and b acke ing (88).
In case o any odd esul s in disin eg a ion imes and wa e con en a ex eme
condi ions, in e media e samples would be analyzed.
Table 58. Tes s pe o med du ing s abili y s udy
Tes s o
pe o m
T0
T1M
T3M
25ºC/60%RH
30ºC/65%RH
40ºC/75%RH
25ºC/60%RH
30ºC/65%RH
40ºC/75%RH
Assay
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Impu i ies
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Disin eg a ion
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Dissolu ion
Yes
Yes
No
Yes
Yes
No
Yes
Wa e con en
Yes
Yes
No
Yes
Yes
No
Yes
Resis ance o
c ushing
Yes
Yes
Yes
Yes
Yes
Yes
Yes
S abili y es ing was pe o med on 10mg Nico andil able s packed in Alu-Alu blis e .
This packaging ma e ial is a special designed mul ilaye ed ul a-high ba ie lamina e ilm
wi h a polyole in sealan laye inco po a ing mois u e sca enging agen / desiccan in he
inne laye o he aluminum oil. Table s in he blis e a e he e o e in con ac wi h a
su ace ha adso bs mois u e om he ai inside he pocke .
Table 59 and Table 60 p esen s he o e all esul s o 30N and 60N es p oduc ,
co espondingly. Pa ame e s e alua ed we e assay, known and unknown impu i ies, o al
impu i ies, disin eg a ion, dissolu ion, wa e con en (KF) and able ha dness.
De elopmen o o al able s con aining Nico andil
Resul s and Discussion
119
Table 59. Summa y o s abili y esul s o es o mula ion (30N)
Pa ame e
Tes ing poin (mon h) / esul s
T0
T1M
T3M
RP
30N
25ºC/60% RH
30ºC/65% RH
40ºC/75% RH
25ºC/60% RH
30ºC/65% RH
40ºC/75% RH
RP
30N
RP
30N
RP
30N
RP
30N
RP
30N
RP
30N
Assay
96.9%
101.05%
98.7%
101.21%
96.9%
100.25%
88.60%
94.01%
96.3%
100.44%
94.70%
103.81%
85.80%
85.36%
Nico inic acid
ND
ND
ND
ND
ND
ND
ND
< 0.1%
ND
ND
ND
ND
≤ 0.1%
< 0.1%
N-(2 hyd oxye hyl)
Nico inamide
ND
< 0.1%
ND
< 0.1%
ND
< 0.1%
≤ 0.1%
< 0.1%
ND
ND
ND
ND
≤ 0.1%
< 0.1%
Imp A
≤ 0.1%
< 0.1%
≤0.1%
< 0.1%
≤ 0.1%
< 0.1%
0.16%
0.1005%
≤ 0.1%
0.1507%
≤ 0.1%
0.1123%
0.32%
0.0221%
Imp B
0.20%
< 0.1%
0.37%
0.2547%
0.45%
0.3702%
0.68%
1.0113%
0.42%
0.4657%
0.47%
0.5530%
0.53%
1.3454%
Imp C
0.21%
< 0.1%
≤0.1%
< 0.1%
0.29%
0.1331%
0.55%
0.6055%
0.26%
0.0331%
0.35%
0.3292%
0.58%
1.1240%
Ni a e
NP
0.0903%
NP
0.1348%
NP
0.2116%
NP
1.2876%
NP
0.3833%
NP
0.7985%
NP
4.2523%
Single unknown imp.
≤ 0.1%
0.03%
≤0.1%
0.02%
≤ 0.1%
0.03%
0.30%
0.64%
≤ 0.1%
0.07%
≤ 0.1%
0.25%
0.36%
0.68%
To al impu i ies
(excep Ni a e)
0.41%
0.23%
0.37%
0.43%
0.74%
0.67%
1.90%
2.93%
0.68%
0.83%
0.82%
1.35%
2.60%
3.91%
Disin eg a ion
2min 50s
3 min 15s
3min 05s
3min 30s
2min 00s
2min 29s
3min 10s
3min 30s
1min 00s
1min 18s
NP
1min 25s
1min 42s
3min 55s
4min 35s
1min 10s
1min 33s
2min 55s
3min 45s
1min 20s
1min 45s
3min 59s
4min 43s
2min 35s
2min 56s
4min 09s
4min 50s
Dissolu ion
98%
100.6%
98%
98.6%
98%
NP
97%
97.9%
99%
98.5%
98%
NP
95%
93.7%
Wa e con en (KF)
0.3%
2.1%
0.2%
2.2%
0.2%
2.5%
0.2%
2.8%
0.3%
2.0%
0.3%
2.0%
0.3%
1.9%
Resis ance o
c ushing
61 N
29N
56 N
30N
66 N
34N
64 N
45N
NP
31N
NP
37N
NP
46N
De elopmen o o al able s con aining Nico andil
126

De elopmen o o al able s con aining Nico andil
Conclusions
127
1. Gene al conclusions
The p esen wo k desc ibed he p e- o mula ion and o mula ion de elopmen ha
led o he p oduc ion o 10mg able s o Nico andil by di ec comp ession o a
homogeneous powde blend. The manu ac u ing p ocess has been demons a ed o be
able o p oduce a inished p oduc ha p esen s adequa e pha maco echnical
cha ac e is ics and p esen s pe o mance cha ac e is ics simila o he e e ence p oduc .
Nico andil is highly sensi i e o mois u e and compac ion o ces, eaching high
deg ada ion a es when included in a o mula ion, which is po en ia ed a inc eased
empe a u es.
A h ee mon hs sho e m s abili y s udy was pe o med. Va ious c i ical p ope ies
we e assessed and compa ed o he e e ence d ug p oduc . E alua ion o he esul s o
he es ed pa ame e s sugges ha o e he ime pe iod o he s udy, no ele an
di e ences in e ms o pe o mance and s abili y be ween he es p oduc and he
e e ence d ug p oduc we e obse ed. Despi e his analysis, i is clea ha due o he
uns able na u e o Nico andil, ICH accele a ed condi ions migh no be adequa e o
suppo expi y da e o he inished p oduc . Ne e heless, esul s ob ained on he RP also
indica e he same deg ada ion end.
The main p inciples ha guided his wo k we e:
1. De ailed esea ch on a ailable scien i ic bibliog aphy and pa en s in o de o
collec in o ma ion ha could be used o op imize he de elopmen p ocess.
2. De ini ion o a Ta ge P oduc P o ile and he C i ical Quali y A ibu es o he
d ug p oduc o de ine a de elopmen s a egy.
3. Applica ion o a isk managemen ool du ing he de elopmen p ocess.
4. Cha ac e iza ion and e alua ion o he DS p ope ies be o e manu ac u e.
5. Ca e ul selec ion and cha ac e iza ion o excipien s in o de o maximize
Nico andil s abili y.
6. Selec ion o adequa e p ocess pa ame e s o a oid unnecessa y isks linked
o s abili y issues o he DS.
7. Selec ion o a packaging ma e ial cons i u ing an e ec i e ba ie agains
mois u e.
De elopmen o o al able s con aining Nico andil
Conclusions
128
The main achie emen s o his wo k can be summa ized as he ollowing:
1. A simple and obus manu ac u ing p ocess, ad an ageous o indus ial
p oduc ion, was designed and i was demons a ed ha i allows he
p oduc ion o a homogeneous powde blend wi h adequa e lowabili y and
comp essibili y.
2. Table s wi h adequa e pha maco echnical p ope ies and con en uni o mi y
can be ob ained by di ec comp ession o he powde blend.
3. Fo mula ion seems o p o ec Nico andil wi hin an in e al o comp ession
o ces (up o 60 N).
This wo k also demons a ed ha he con ol s a egy applied on he manu ac u ing
p ocess was adequa e o gua an ee he compliance wi h he quali y a ge s de ined.
I is possible o conclude also ha speci ic con ol s a egies mus be ollowed, such
as:
1. The ini ial p ope ies o he DS mus be ca e ully e alua ed. Cha ac e is ics such
as wa e con en , ini ial impu i y le els and PSD mus be speci ied and ba ches
no complying wi h speci ica ions mus be ejec ed o manu ac u e.
2. Excipien s mus be also con olled ega ding c i ical pa ame e s, like wa e
con en and PSD.
3. En i onmen al condi ions on manu ac u e a eas mus be adjus ed, meaning ha
i is ecommended ha empe a u e should be kep a leas bellow 25ºC and
ela i e humidi y le els should be as low as possible.
4. Table s should ha e a s o age condi ions es ic ion conside ing he sensi i i y o
Nico andil. I can be ecommended ha able s should be s o ed bellow 25ºC
and p o ec ed om mois u e sou ces.
F om he ini ial a ge p oduc p o ile i is possible o conclude ha all equi emen s
ha e been achie ed. Table 61 p esen s he ini ial TPP and compa es each pa ame e wi h
he ob ained d ug p oduc .
De elopmen o o al able s con aining Nico andil
Conclusions
129
Table 61. TPP o es p oduc conclusion
Pa ame e
TPP
Conclusion
Dosage o m and ou e o
adminis a ion
O al able
Pha maceu ical de elopmen achie ed he
p oduc ion o o al able s.
Dosage design
Immedia e elease.
Dissolu ion esul s demons a e an immedia e
elease p o ile.
Dosage s eng h
10mg
Assay and con en uni o mi y demons a e
compliance wi h a ge s engh .
Assay
100% w/w label claim.
Complies. (Table 59)
Impu i y le el
Known impu i ies: NMT 0.5%
Unknown impu i ies: NMT 0.2%
S abili y has been demons a ed o be
s a is ical simila wi h RP in he end o he
sho e m s abili y s udy. Accele a ed
condi ions e ealed o be unadequa e o he
es ablishmen o an expi y da e due o ou o
speci ica ion esul s, al hough he RP exhibi ed
he same end.
Dissolu ion
Ve y as dissolu ion p o ile
(Q +5%) > 85%, 15min.
Dissolu ion esul s showed ha mo e han 85%
o DS is solubilized a e 15minu es. (Figu e
36)
Wa e con en
As low as possible.
Tes p oduc exhibi s highe wa e con en ha
RP p obably due o s a ch. (Table 50)
Ha dness
(Resis ance o c ushing)
As low as possible main aining
minimum compendial s anda ds
o o al able dosage o m.
P oposed speci ica ion is
20N – 60N
10mg able s ha e been p oduced wi h
adequa e pha maco echncal p ope ies. (Table
50)
Table shape
Round, bicon ex
Complies
Table dimensions
7 mm
Sco e and embossing
None
Complies
Colou and appea ance
Whi e
Complies
Weigh
100mg
Complies (Table 50)
F iabili y
NMT 1.0% w/w
Complies (Table 50)
Disin eg a ion
Table s should disin eg a e in
mo e han 20s and less han 10
min.
Complies (Table 50)
De elopmen o o al able s con aining Nico andil
Conclusions
130
De elopmen o o al able s con aining Nico andil
131
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