In vitro evaluation of a morphine polymeric complex: flowability behavior and dissolution study

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) AAPS Pha mSciTech 2004; 5 (3) A icle 39 (h p://www.aapspha msci ech.o g). 3 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. AAPS Pha mSciTech 2004; 5 (3) A icle 39 (h p://www.aapspha msci ech.o g). 4 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. AAPS Pha mSciTech 2004; 5 (3) A icle 39 (h p://www.aapspha msci ech.o g). 5 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. AAPS Pha mSciTech 2004; 5 (3) A icle 39 (h p://www.aapspha msci ech.o g). 6 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.