ABSTRACT
The pu pose o his esea ch was o pe o m a g anulome i-
cal and low p ope ies s udy o a mo phine polyme ic com-
plex and de e mine he in luence o 3 a iables—pa icle
size o complex, pH alue, and ionic s eng h o he dissolu-
ion medium—on he dissolu ion beha io . The mo phine-
Eud agi L complex was p oduced in aqueous medium om
mo phine hyd ochlo ide sa u a ed solu ion and Eud agi L
30D dilu ed un il 12% w / ol and pa ially neu alized
(40%). To de e mine he heological beha io o he com-
plex, se e al heological es s we e de eloped: bulk and
apped densi ies, Hausne a io, angle o epose, and low
a e. The esul s co esponding o he echnological s udy
sugges ha he 100- o 250-µm ac ion can be conside ed
as ee lowing powde . In ela ion o he dissolu ion beha -
io o he complex, he esul s indica e ha he ionic s eng h
has been de ec ed as he mos in luencing ac o when al-
ues below physiological condi ions a e used. In conclusion,
no echnological p oblems o he p oduc ion o u he
solid dosage o ms a e expec ed. Fu he mo e, no changes
in he dissolu ion p o iles o he complex ha e been de ec -
ed when ionic s eng h alues a e inside he physiological
ange.
KEYWORDS:mo phine-Eud agi complex, heology, disso-
lu ion medium, dissolu ion medium, pH.
INTRODUCTION
Mo phine gi en egula ly by mou h is ecommended
h oughou he wo ld o he managemen o se e e pain in
cance pa ien s when less-e ec i e d ugs a e no longe ade-
qua e. Mo eo e , con olled elease o al mo phine sys ems
o e he clinical ad an age o less equen dosing, wi h an
inc ease in quali y o li e o pa ien s wi h ch onic pain
equi ing epea ed-dose opioid analgesia.1
Eud agi L 30D was used as a ca ie o p epa e mo phine
polyme ic complexes in o de o ob ain con olled elease
sys ems by a eac ion be ween he d ug and he polyme ,
yielding a chemical d ug-polyme in e ac ion. The complex-
a ion echnique used has been pa en ed by Uni e si y o
Se ille.2In his echnique, he ac ylic esin is pa ially dilu -
ed and neu alized. The polyme in i s sodium sal o m
eac s wi h he added d ug o ob ain a p ecipi a e— he mo -
phine complex. Se e al p elimina y s udies we e ealized
o e his ini ial complex. A hyd ogen bond in e ac ion was
epo ed be ween mo phine and Eud agi .3The in i o dis-
solu ion beha io was s udied.4,5 The ob ained esul s4,5
indica ed ha he e should be ano he ac o , as well as pH,
in luencing he dissolu ion p o iles. Finally, a p eclinical
s udy was pe o med in a s. The esul s indica ed ha his
complex had a ma ked analgesic e ec om 30 minu es o
8 hou s.6
In u he s udies, se e al modi ica ions on he ini ial p epa-
a ion echnique we e pe o med in o de o op imize he
elabo a ion p ocess o complexes.7So, c i ical ac o s a ec -
ing he de elopmen o he p oposed eac ion we e es ab-
lished, and pa ame e s such as mo phine con en (pe cen age
w /w o mo phine-HCl in he complex), mo phine en ap-
men (pe cen age w /w o mo phine-HCl inco po a ed in o
he complex, wi h espec o he o al amoun o d ug added
o he eac ion medium), and weigh e iciency (pe cen age
o he o al weigh o he subs ances employed [d ug plus
excipien s] ha is ans o med in complex) we e e alua ed.
These pa ame e s ha e been desc ibed p e iously.7
Conside ing he expe imen al condi ions assayed, he bes
e iciency complexa ion was yielded by using Eud agi L
12D 40% neu alized and adding mo phine necessa y o
eac wi h he 54% ca boxylic acid/ca boxyla e g oups o he
polyme (35% d ug excess wi h espec o he s oichiome ic
d ug amoun co esponding o he 40% neu alized g oups).
So, his complex has been selec ed o con inue u he s ud-
ies. Conside ing he p e iously epo ed esul s, in he p es-
en wo k a mo e de ailed s udy has been pe o med o e his
selec ed complex.
The aim o he p esen s udy is as ollows: (1) o ca y ou a
g anulome ical and low p ope ies s udy o he p e iously
indica ed complex, and (2) o de e mine he in luence o 3
a iables o e he dissolu ion beha io : pa icle size o com-
plex, pH alue, and ionic s eng h o he dissolu ion medium.
These 2 las ac o s a e pa icula ly impo an conside ing
ha he complex is based on he in e ac ion be ween Eud agi
and mo phine by means o hyd ogen bonds3so i can be
po en ially sensi i e o pH and ionic s eng h a ia ions.
1
Co esponding Au ho : Ma ia Angeles Holgado,
Depa amen o de Fa macia y Tecnología Fa macéu ica,
Facul ad de Fa macia, Uni e sidad de Se illa, c/ P o eso
Ga cía González nº 2, 41012 Se illa, Spain. Tel: 0034 95
551624. Fax: 0034 95 556726. Email: [email p o ec ed].
In Vi o E alua ion o a Mo phine Polyme ic Complex: Flowabili y Beha io
and Dissolu ion S udy
Submi ed: Feb ua y 11, 2004; Accep ed: June 4, 2004.
Me cedes Fe nández-A é alo,1Jose a Al a ez-Fuen es,1Ana I uin,1and Ma ia Angeles Holgado1
1Depa amen o de Fa macia y Tecnología Fa macéu ica, Facul ad de Fa macia, Uni e sidad de Se illa.
AAPS Pha mSciTech 2004; 5 (3) A icle 39 (h p://www.aapspha msci ech.o g).
AAPS Pha mSciTech 2004; 5 (3) A icle 39 (h p://www.aapspha msci ech.o g).
2
MATERIALS AND METHODS
Ma e ials
The ollowing ma e ials we e used: mo phine hyd ochlo ide
(Alcalibe , Mad id, Spain); Eud agi L 30D (Degussa,
Ba celona, Spain); sodium hyd oxide (Aco a ma, Ta asa,
Spain); McIl aine’s ci ic acid-phospha e ( o ob ain se e al
pH alues: 2.2, 4.0, 6.0, and 8.0) (Pan eac Química,
Ba celona, Spain); sodium chlo ide, me hanol (high pe -
o mance liquid ch oma og aphy [HPLC] g ade), and
diammonium hyd ogen phospha e (Me ck, Ba celona,
Spain).
P epa a ion o Mo phine Complexes
The mo phine-Eud agi L complex was elabo a ed in aque-
ous medium om mo phine hyd ochlo ide sa u a ed solu ion
and Eud agi L 30D (30% w / ol). Acco ding o p e ious
esul s,7 he polyme was dilu ed o 12% w / ol and pa ially
neu alized (40%). The amoun o mo phine hyd ochlo ide
added was calcula ed o eac wi h he 54% ca boxylic/ca -
boxyla e g oups o he polyme (35% d ug excess wi h
espec o he s oichiome ic d ug amoun co esponding o
he 40% neu alized g oups). The ob ained whi e solid was
hen sepa a ed by il a ion and d ied in an o en (model 204,
Selec a, Ba celona, Spain). A e c ushing (cu ing me hod,
Moulinex, Mad id, Spain), he p oduc was oppo unely
sie ed (model Vib o, Re sch, Haan, Ge many).
Pa icle Size Dis ibu ion
In o de o de e mine he size pa icle dis ibu ion o he com-
plex and o selec he op imum c ushing ime, a g anulome -
ical s udy was de eloped a e se e al imes o pul e iza ion
(40, 60, 120, and 180 seconds). A sie e me hod (Re sch) was
used o ob ain di e en powde ac ions.
To cha ac e ize he size pa icle dis ibu ion o di e en pow-
de s ob ained, p obi uni s we e calcula ed as ollows:
whe e Xindica es size pa icle and µ, mean pa icle size.
Pa icle P ope ies and Bulk Flow
To de e mine he heological beha io o he complex, se e -
al heological es s we e de eloped8:
•Bulk densi y (ρ0): 25 g o powde complex was
pou ed in o a glass measu ing cylinde (SBS-model
Vol-1), measu ing he ini ial olume occupied (V0).
•Tapped densi y (ρ1250): he same cylinde wi h he
powde was hen au oma ically apped 1250 imes
(cons an olume), measu ing he inal olume
occupied.
•Hausne a io (HR) and pe cen age o comp essibil-
i y (%C): used as dimensionless pa ame e s; hese
pa ame e s we e calcula ed acco ding o he ela ion
be ween apped and bulk densi ies. The equa ions
used we e he ollowing:
•Angle o epose (°): i has been used as indi ec
me hod o quan i ying powde lowabili y; his
measu emen was pe o med using 10 g o he pow-
de in s udy and a unnel desc ibed in Real
Fa macopea Española.8
•Flow a e (g/s): he simples me hod o de e mining
powde lowabili y di ec ly is o measu e he a e a
which he powde discha ges om a unnel; 50 g o
he powde in s udy was added o he unnel
desc ibed abo e. The ime pe iod o he ma e ial o
low h ough his unnel was de e mined. Di iding
he discha ged powde mass by his ime yields a
low a e ha can be used o quan i a i e compa i-
son o di e en powde s.
Quan i ica ion o he Mo phine
An HPLC me hod was chosen o quan i ying mo phine:
Hi achi HPLC sys em manage (F ank u , Ge many), pump
L-7100, manual injec o 77251, diode a ay de ec o L-7455,
in e phase D-7000, column Me ck Alusphe 100 RP-selec
B, 5 µm pa icle size, 12.5 cm × 4 mm inne diame e (ID).
A low a e o 1 mL/min was employed, and he a iable
wa eleng h de ec o was se a 273 nm. The selec ed mobile
phase was me hanol/pu i ied wa e /diammonium phospha e
50:50:0.01 ol/ ol/w . The alida ion o he ch oma og aph-
ic me hod, in e ms o linea i y, p ecision, and accu acy was
desc ibed in a p e ious s udy.7
In Vi o Dissolu ion S udy
The in i o dissolu ion s udy was pe o med a 37°C ± 0.5°C
in he Uni ed S a es Pha macopeia (USP) 26 baske appa a-
us (model D-6, Tu u G au, Ta asa, Spain) a a speed o 50
pm o e 4 hou s. Samples o 200 mg o mo phine polyme -
ic complex, placed by hand in colo less lock-cap gela in cap-
sules, we e assayed in iplica e, using 700 mL o dissolu ion
medium. A p ede e mined ime in e als, samples we e
assayed by HPLC.
% C=
ρ
1250 -
ρ
0
ρ
1250
× 100 (3)
HR =
ρ
1250
ρ
0
(2)
P obi = X-
µ
SD + 5 (1)
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To cha ac e ize he dissolu ion beha io o he complex, he
in luence o 3 a iables o e he dissolu ion cha ac e is ics
(pa icle size o complexes, pH alue, and ionic s eng h o
he dissolu ion medium) was de e mined.
S a is ical Analyses
S a is ical analyses we e pe o med on a ea unde he cu e
(AUC) alues ob ained om di e en dissolu ion p o iles.
The di e ences be ween g oups we e analyzed using a
S uden -Newman-Keuls es ollowing signi ican main
e ec s o ea men by analysis o a iance (ANOVA).
S a is ical signi icance was accep ed a he 5% le el (P< .05).
RESULTS AND DISCUSSION
Size Pa icle Dis ibu ion
Tables 1, 2, 3, and 4 show da a ob ained in ela ion o size
pa icle dis ibu ion o each c ushing ime. A loga i hmic
no mal dis ibu ion was ound. The good i ing ob ained
indica es ha his model p o ides an adequa e cha ac e iza-
ion o he size pa icle dis ibu ion o he complex.
On he o he hand, Figu e 1 shows he size pa icle dis ibu-
ion as a unc ion o se e al c ushing imes. As can be
obse ed, he quan i a i e da a co esponding o he mean
pa icle size o each c ushing ime a e as ollows:
•40 seconds: µ = 54.90 µm (SD = 71.05 µm)
•60 seconds: µ = 46.54 µm (SD = 70.90 µm)
•120 seconds: µ = 30.68 µm (SD = 36.15 µm)
•180 seconds: µ = 28.30 µm (SD = 24.03 µm)
Powde pa icle size is a c i ical ac o o ake in o accoun
when solid dosage o ms a e elabo a ed. In his case, he con-
ol o his pa ame e is c ucial as he ob ained mo phine
complex will be p ocessed o ob ain o al con olled elease
o ms. So, he pa icle sizes o he powde p oduc may be
de ined du ing p e o mula ion s udies o a oid p oblems du -
ing p oduc ion.
Figu e 1 shows ha a e ei he 40 o 60 seconds o c ushing
ime, he ob ained pa icula e size dis ibu ion is simila ,
being 50 o 150 µm he majo i y ac ion. O e 120 seconds
o c ushing, he <50 µm ac ion inc eases signi ican ly. This
impo an dec emen in he pa icle size can p oduce impo -
an e ec s o e he echnological and biopha maceu ical
p ope ies o he p oduc .
Table 1. Pa icle Size Cha ac e iza ion o he Complex
A e 40 Seconds C ushing*
Size Pa icle
(µm) % w /w
%
Accumula ed P obi
< 50 16.6 16.6 4.006
50 - 150 57.9 74.5 5.643
150 - 250 21.8 96.3 6.751
250 - 350 2.6 98.9 7.326
350 - 450 0.8 99.7
> 450 0.3 100
*µ = 55.12 µm; SD = 61.35 µm; 2= 0.9950.
Table 2. Pa icle Size Cha ac e iza ion o he Complex
A e 1 Minu e o C ushing*
Size Pa icle
(µm) % w /w
%
Accumula ed P obi
< 50 41.6 41.6 4.798
50 - 150 56.2 97.8 7.054
150 - 250 1.7 99.5 7.326
250 - 350 0.3 99.7
350 - 450 0.2 99.9
> 450 0.1 100
*µ = 45.99 µm; SD = 69.35 µm; 2= 0.9886.
Table 3. Pa icle Size Cha ac e iza ion o he Complex
a e 2 minu es o C ushing*
Size Pa icle
(µm) % w /w
%
Accumula ed P obi
< 50 23.2 23.2 4.261
50 - 150 60.1 83.3 5.954
150 - 250 12.3 95.6 6.751
250 - 350 1.9 97.5 6.881
350 - 450 1.3 98.2 7.326
> 450 1.2 100
*µ = 30.68 µm; SD = 36.15 µm; 2= 0.9934.
Table 4. Pa icle Size Cha ac e iza ion o he Complex
a e 3 Minu es o C ushing*
Size Pa icle
(µm) % w /w
%
Accumula ed P obi
< 50 38.2 38.2 4.695
50 - 150 57.0 95.3 6.645
150 - 250 3.9 99.2 7.326
250 - 350 0.5 99.6
350 - 450 0.2 99.8
> 450 0.2 100
*µ = 26.61 µm; SD = 31.70 µm; 2= 0.9456.
Figu e 1. Pa icle size dis ibu ion a e se e al c ushing
imes.
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Fo u he s udies, 2 g anulome ical ac ions (<100 µm
and 100-250 µm) will be used o p oduce able s based on
mo phine complex, in o de o s udy he in luence o mean
pa icle size o he complex o e he biopha maceu ical
beha io o he able s.9Figu e 2 shows he pe cen age
(w /w ) o hese ac ions in he complex powde as a unc-
ion o c ushing ime. On he basis o he ob ained esul s, 40
seconds o c ushing ime was selec ed because his ime p o-
ides he highes p opo ions o hese 2 g anulome ical ac-
ions. Mo eo e , his sho ime allows o (1) educing he
ene gy consump ion du ing he milling p ocess, and (2)
dec easing he exposu e o he complex solid o damage si -
ua ions du ing he ope a ion (eg, hea , ib a ion).
Pa icle P ope ies and Bulk Flow
The heological s udy was pe o med using he complex
powde ob ained a e 40 seconds o c ushing ime. The ol-
lowing g anulome ical ac ions we e used: 0 o 250, 0 o
100, and 100 o 250 µm. Table 5 shows bulk and apped den-
si ies da a ob ained o each g anulome ical ac ion. The
highe di e ences obse ed be ween alues o bo h densi ies
a e ound in he <100 µm and <250 µm ac ions, indica ing
he p esence o bigge in e pa icula spaces in compa ison
wi h he 100 o 250 µm ac ion.
HR and %C, angle o epose, and low a e da a ob ained a e
shown in Table 6. Acco ding o HR and %C, he be e lowa-
bili y co esponds o 100 o 250 µm ac ion. I s %C < 18%
(Ca ’s index) indica es good low ( ee lowing powde s)
and i s HR ≈1.2 shows ha his powde has low in e pa ic-
ula ic ions.
Acco ding o hese esul s, i can be concluded ha bo h
g anulome ical ac ions (<100 µm and 100-250 µm) exhib-
i adequa e heological p ope ies.
As a unc ion o hese esul s, i can be concluded ha o u -
he s udies, no heological p oblems in he elabo a ion o he
mo phine o al deli e y sys ems a e expec ed.
Dissolu ion S udy o he Complex
In luence o he Pa icle Size o he Complex O e he
Dissolu ion Beha io
Pu i ied wa e as dissolu ion medium was used. The dissolu-
ion p o iles ob ained as a unc ion o pa icle size o complex-
es a e showed in Figu e 3. In o de o compa e and o e alua e
hese dissolu ion da a, a ma hema ical model independen o
he dissolu ion p ocess was used.10 This model es ablishes 2
compa ison ac o s: he di e ence ac o (ƒ1) and he simila i-
y ac o (ƒ2). These ac o s a e easily calcula ed and p o ide a
simple measu e o simila i y be ween pai s o dissolu ion p o-
iles bu do no p o ide in o ma ion on indi idual ba ches.
The di e ence ac o (ƒ1) is he pe cen age di e ence
be ween 2 dissolu ion p o iles a each ime in e al:
whe e R indica es he eleased amoun o d ug o e e ence
o mula ion; and T , he eleased amoun o d ug o es
o mula ion.
ƒ1= [Σ(( | R - T | ) / ΣR )] × 100 (4)
Figu e 2. Pa icle size dis ibu ion a e se e al c ushing
imes.
Table 5. Bulk and Tapped Densi ies (g/mL) o Each G anulome ical F ac ion Indica ed*
Size Pa icle ρρ0(g/mL) SD CV (%) ρρ1250 (g/mL) SD CV (%)
< 250 µm 0.630 0.003 0.725 0.842 0.005 0.968
100 - 250 µm 0.614 0.007 1.170 0.744 0.009 1.220
< 100 µm 0.583 0.006 1.096 0.782 0.006 0.769
*CV indica es he coe icien o a ia ion.
Table 6. Hausne Ra io, Pe cen age o Comp essibili y, Angle o Repose, and Flow Ra e (g/s) Co esponding o he Pa icle
Sizes Indica ed*
< 250 µm 100 - 250 µm < 100 µm
%C HR °g/s %C HR °g/s %C HR °g/s
Mean 25.17 1.34 21.46 17.61 17.41 1.21 22.17 34.02 25.46 1.34 22.84 14.38
SD 1.12 0.02 4.096 4.44 0.95 0.01 1.26 2.42 0.83 0.02 3.35 0.22
CV (%) 4.46 1.50 19.09 25.18 5.47 1.14 5.70 7.12 3.24 1.12 14.64 4.96
%C indica es pe cen age o comp essibili y; HR, Hausne a io; (°), angle o epose; and CV indica es coe icien o a ia ion.
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I he dissolu ion p o iles a e supe imposed, ƒ1 eaches a
alue o 0, whe eas he ac o alue inc eases when he di -
e ences be ween dissolu ion p o iles also inc ease.
The simila i y ac o can be calcula ed using he ollowing
exp ession:
whe e nindica es he numbe o expe imen al da a.
F om a p ac ical poin o iew, alues o ƒ1be ween 0 and 15
and ƒ2be ween 50 and 100 can be conside ed as supe im-
posed dissolu ion p o iles.
Table 7 shows he ob ained esul s co esponding o he com-
pa ison be ween he ac ions (<250 µm, <100 µm, and <250
µm, 100-250 µm). I can be obse ed ha he e a e no any
di e ences among he ob ained dissolu ion p o iles. So, he
dissolu ion cu es can be conside ed as supe imposed. In his
sense, he ac o “pa icle size” can be ob ia ed o he ol-
lowing sec ions.
In luence o he Ionic S eng h o he Dissolu ion Medium
This s udy was pe o med wi h he ac ion <250 µm o he
complex. A McIl aine’s ci ic acid-phospha e bu e solu ion
was used as dissolu ion medium o i a pH alue o 5.0, so
as o ob ia e any possible in e e ence due o he dissolu ion
o polyme (soluble abo e pH 5.5). App op ia e dilu ions o
se e al amoun s o NaCl we e added in o de o ob ain di -
e en alues o ionic s eng h: 0.001, 0.005, 0.01, 0.05, and
0.2 M. NaCl was used because sodium is epo ed as he
mos common ion in he uppe gas oin es inal ac (GIT).11
In a p e ious s udy,5se e al in i o dissolu ion s udies o
mo phine complex a pH cons an alues we e de eloped.
In ha s udy, he dissolu ion a e o he complex a pH 1.2
was su p isingly high conside ing he pH-dependen solu-
bili y o Eud agi L. These esul s would indica e he p es-
ence o ano he ac o , di e en om pH, in luencing he
dissolu ion beha io o he complex. Taking in o accoun
ha he in e ac ion be ween mo phine and Eud agi is by
means o hyd ogen bonds,3 he ionic s eng h o he disso-
lu ion medium should be conside ed as an impo an in lu-
encing ac o on he dissolu ion beha io o he mo phine
complex.
The expe imen al da a we e i ed o Ko smeye Equa ion12:
whe e Q /Q
∞
is he d ug- eleased a io a di e en imes; KK,
is he Ko smeye cons an ; and n, is a pa ame e ha de ines
he elease mechanism.
Figu e 4 shows he dissolu ion p o iles ob ained as a unc ion
o ionic s eng h o dissolu ion medium. Table 8 shows he
kine ic s udy da a o he same cu es. In all cases, a signi i-
can and posi i e e ec o ionic s eng h can be obse ed. As
a unc ion o KK alues ob ained, he highe he medium
ionic s eng h is, he highe he d ug dissolu ion a e is. I is
Q / Q
∞
= KK· n(6)
ƒ2= 50 × log {[1 / (1 + (Σ (R - T )2 ) / n)]½× 100} (5)
Figu e 3. Release p o iles o mo phine complex as a unc-
ion o pa icle size.
Table 7. Compa a i e S udy o ƒ1and ƒ2Values
Co esponding o he Pa icle Sizes Indica ed*
Pa icle Size F ac ions ƒ1ƒ2
<250 µm / <100 µm 11.00 73.61
<250 µm / 100-250 µm 8.28 76.15
*The di e ence ac o is ƒ1and he simila i y ac o is ƒ2.
Figu e 4. Release p o iles o mo phine complex as a unc-
ion o ionic s eng h.

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concluded ha he ac o “ionic s eng h” exe s a g ea in lu-
ence o e he dissolu ion beha io o he complex.
As shown in Figu e 4, ionic s eng h alues g ea e han 0.01
esul ed in no signi ican changes in d ug elease (P> .05).
This inding implies ha he e mus be a c i ical alue o
ionic s eng h o e which his ac o exe s no u he e ec
on mo phine elease om he complex. Ne e heless, om a
biopha maceu ical poin o iew, i can be concluded ha
changes o ionic s eng h wi hin physiological ange o GIT
(ionic s eng h ange, 0.11-0.14) will no a ec he in i o
pe o mance o he mo phine complex.13,14 The e o e, ionic
s eng h may no be conside ed as a con ibu ing ac o o
any indi ec ood e ec s, and he polyme ic complex can be
basically ega ded as a sys em independen o ionic s eng h
unde no mal physiological condi ions.
The elease exponen na di e en le els o ionic s eng h
was almos unchanged, which cla i ied ha he ionic s eng h
does no signi ican ly modi y he elease mechanism o he
complex.
In luence o he pH Value o he Dissolu ion Medium
Se e al McIl aine’s ci ic acid-phospha e bu e solu ions
we e used o ob ain di e en pH alues (2.2, 4.0, 6.0, and
8.0). In a i s s ep o his s udy and o ob ia e he in luence
o ionic s eng h, all he dissolu ion media we e i ed o an
ionic s eng h alue o 0.005. A ac ion o <250 µm o he
complex was used o his s udy.
Figu e 5 shows he dissolu ion p o iles ob ained as a unc ion
o pH alue, and Table 9 shows he kine ic s udy da a o he
same cu es. As a unc ion o KK alues, o e pH > 4, he
highe he medium pH alue is, he highe he d ug dissolu-
ion a e is. Signi ican di e ences (P< .05) we e ob ained.
The pos hoc analysis indica ed ha hese p o iles belong o
3 homogeneous subse s (pH alues 6, 8, and 2.2-4). This si -
ua ion is caused by he pH-dependen solubili y o he poly-
me ( he solubili y o Eud agi L 30D begins a pH > 5.5. So,
unde hese ionic s eng h condi ions, below physiological
alues, he e is a clea in luence o pH dissolu ion medium
o e he elease p o iles o he complex.
Ne e heless, a comple e elease o mo phine is no eached,
e en wi h he highes pH alue (pH = 8). This ci cums ance
can be due o he ac ha , al hough Eud agi is a pH-depend-
en polyme , he concen a ion o ions (0.005) is a away om
he physiological ange.13 I can be deduced ha he e mus be
a minimum ionic s eng h alue o achie e a comple e elease
o mo phine om his polyme ic complex. The e o e, and ak-
ing in o accoun he na u e o d ug-polyme in e ac ion (based
on hyd ogen bonds), i should be concluded ha he impac o
ionic s eng h on he elease beha io o he complex is mo e
impo an han he pH o he dissolu ion medium.
In o de o ealize he s udy unde physiological condi ions,
in a second s ep o his s udy, he same expe imen s we e pe -
o med using an ionic s eng h alue o 0.1. Figu e 6 and
Table 10 show he ob ained kine ic s udy da a. As can be
seen, a comple e elease o mo phine is eached a he end o
he assay, e en wi h he lowes pH alue (pH = 2.2).
Signi ican di e ences (P< .05) we e ob ained. The pos hoc
analysis indica ed ha hese di e ences co espond o pH =
8. This ci cums ance is ela ed o he ac ha unde physio-
logical ionic s eng h condi ions, he in luence o pH appea s
only a alues allowing a high dissolu ion a e o he poly-
me . This ci cums ance indica es again he ma ked in luence
o he ionic s eng h o e he elease p ocess o his complex,
in compa ison wi h he o me s udy.
Unde physiological condi ions o ionic s eng h, he e is a
di ec ela ion be ween he pH alue o he dissolu ion medi-
um and he elease a e o he p ocess.
Table 8. Kine ic S udy Da a Using he Ko smeye
Equa ion as a Func ion o Ionic S eng h*
Ionic S eng h (M) nKk 2
0.001 0.343 0.090 0.998
0.005 0.410 0.108 0.999
0.01 0.412 0.140 0.998
0.05 0.410 0.155 0.993
0.2 0.477 0.112 0.997
*pH = 5.0.
Figu e 5. Release p o iles o mo phine complex as a unc-
ion o pH (ionic s eng h alue o 0.005).
Table 9. Kine ic S udy Da a Using he Ko smeye
Equa ion as a Func ion o pH*
pH nKk 2
2.2 0.4727 0.0575 0.9994
4.0 0.4678 0.0607 0.9993
6.0 0.4997 0.0695 0.9980
8.0 0.3890 0.1460 0.9998
*Ionic s eng h alue o 0.005 M.
AAPS Pha mSciTech 2004; 5 (3) A icle 39 (h p://www.aapspha msci ech.o g).
7
CONCLUSION
The e o e, conside ing he expe imen al s udied condi ions,
he ionic s eng h has been iden i ied as he mos in luencing
ac o . Mo eo e , i can be concluded ha (1) a comple e
elease o mo phine om he complex is achie ed unde
physiological condi ions o ionic s eng h, independen o he
pH alues, and (2) conside ing physiological condi ions,
changes o ionic s eng h do no imply any modi ica ions o
he elease p o ile o d ug om he polyme ic sys em.
In conclusion, 40 seconds has been de e mined o be sui able
c ushing ime in o de o ob ain 2 conc e e g anulome ical
ac ions (<100 µm and 100-250 µm). The ac ion 100-250
µm can be conside ed as ee lowing powde . Thus, i can be
concluded ha no echnological p oblems in he elabo a ion
o u he solid dosage o ms a e expec ed. In ela ion o he
s udy o he dissolu ion beha io o he complex, i has been
ound ha he ac o “ionic s eng h” exe s a g ea in luence
o e he dissolu ion beha io o he complex when i s alues
a e below physiological condi ions.
ACKNOWLEDGEMENTS
The p esen s udy is pa o a Eu opean esea ch p ojec ( e -
e ence numbe 1FD97–0624-C04). The polyme Eud agi L
30D is a gi om Degussa (Ba celona, Spain).
REFERENCES
1. Wo ld Heal h O ganiza ion. Cance Pain Relie . Gene a, Swi ze land:
WHO; 1986.
2. Rabasco AM, Fe nández-A é alo M, Al a ez-Fuen es J, Holgado MA,
Ca aballo I, in en o s. Sis ema de libe ación con olada de mo ina y
o os á macos solubles en agua po complejación con sus ancias
polimé icas. Spanish pa en P9401748. Augus 1, 1994.
3. Al a ez-Fuen es J, Fe nández-A é alo M, Holgado MA, Ca aballo I,
Lle a JM, Rabasco AM. Mo phine polyme ic cop ecipi a es o con-
olled elease: elabo a ion and cha ac e iza ion. D ug De Ind Pha m.
1994;20:2409-2424.
4. Al a ez-Fuen es J, Fe nández-A é alo M, Holgado MA, Ca aballo I,
Lle a JM, Rabasco AM. Cha ac e iza ion o mo phine polyme ic cop e-
cipi a es: a biopha maceu ical s udy. Pha mazie. 1994;49:834-839.
5. Al a ez-Fuen es J, Holgado MA, Ca aballo I, Fe nández-A é alo M,
Rabasco AM. In luence o he pH alue o he dissolu ion medium on he
elease p o iles o a mo phine polyme ic complex. D ug De Ind Pha m.
1997;23:553-559.
6. Al a ez-Fuen es J, Fe nández-A é alo M, Holgado MA, e al.
P eclinical s udy o a con olled elease o al mo phine sys em in a s. In
J Pha m. 1996;139:237-241.
7. Fe nández-A é alo M, Ca aballo I, Millán M, e al. Op imisa ion o a
complexa ion p ocess as a new me hod o ob aining a con olled mo -
phine deli e y sys em. STP Pha ma Sci. 2002;12:334-336.
8. Real Fa macopea Española. 2nd ed. Minis e io de Sanidad y
Consumo: Mad id, Spain; 2002.
9. I uin A, Al a ez Fuen es J, Holgado MA, Fe nández A é alo M.
In luence o pa icle size o mo phine polyme ic complex o e he
elease beha io o able s. Pape p esen ed a : Eu opean Con e ence on
D ug Deli e y and Pha maceu ical Technology; May 10-12, 2004;
Se illa, Spain.
10. Lin Ju H, Liaw SJ. On he assessmen o simila i y o d ug dissolu-
ion p o iles: a simula ion s udy. D ug In J. 1997;31:1273-1289.
11. Lindhal A, Ungell AL, Knu son L, Lenne nas H. Cha ac e iza ion o
luids om he s omach and p oximal jejunum in men and women.
Pha m Res. 1997;14:497-502.
12. Ko smeye RW, Gu ny R, Doelke E, Bu i P, Peppas NA.
Mechanism o solu e elease om po ous hyd ophilic polyme s. In J
Pha m. 1983;15:25-35.
13. Bon e oni MC, Rossi S, Fe a i F, S a ik E, Peña-Rome o A,
Ca amella C. Fac o ial analysis o he in luence o dissolu ion medium
on d ug elease om ca ageenan-dil iazem complexes. AAPS
Pha mSciTech. 2000;1(2):E15.
14. Mu X, Tobyn MJ, S ani o h JN. In luence o physiological a iables
on he in i o d ug elease beha io o a polysaccha ide ma ix con-
olled- elease sys em. D ug De Ind Pha m. 2003;29:19-29.
Figu e 6. Release p o iles o mo phine complex as a unc-
ion o pH (ionic s eng h alue o 0.1).
Table 10. Kine ic S udy Da a Using he Ko smeye
Equa ion as a Func ion o pH*
pH nKk 2
2.2 0.4831 0.1092 0.9993
4.0 0.4772 0.1380 0.9987
6.0 0.4881 0.1602 0.9994
8.0 0.4567 0.1924 0.9996
*Ionic s eng h alue o 0.1 M.