Ir aqi J.Pha rm.Sc i., Vol.15 (2 ) ,2006 Ac ce lerated Stability of Ib upr ofen Micr oc aps ules 37 Effect of Temperature on the Stability and Release Profile of Ibuprofen Microcapsules Issraa R. Abed Al- Rahman *1 *De pa rtme nt o f Pharm aceu tic s, College of Pha rm acy, Baghda d un iversity, Bag hdad - Iraq. Abstract The s tability and releasing profile of 2:1 core: wa ll ratio ibuprofen mic roc apsules prepa red by aqueous coa cerva tion (gelatin and ac acia polymers coa t) and an orga nic coace rvation methods (ethyl c ellulose a nd sodium alginate polymers c oat) in weight equivalent to 300mg drug, we re studied using different storage tempe ra tures 40°C, 50°C ,60°C and refrigerator tempe ra ture 4°C in an ope ned a nd closed containe r for three months (re leas ing profile) and four months (s tability s tudy).It wa s found that, the se ibuprofen mic rocapsules we re stable with e xpira tion da tes of 4.1 a nd 3.1 yea rs for aqueous and an organic method res pec tive ly.Aqueous prepa red ibuprofe n microcapsules were found more stable than those microcaps ules prepa red by organic method with activation ene rgy (Ea) 4804.8 c al/mol a nd 5033.6 ca l/mol of a drug respec tive ly.The releasing perce ntage of ibuprofen for all microcapsules prepa red by both me thods was decreased as the storage te mperatures increased, exce pt for mic rocapsules prepared by a que ous me thod, whic h were found to be the same at 25-40°C as the standard one which stored at 25°C temperature, on the other hand , as the te mperature decrease d to 4°C (refrige ra tor ) of a n open and c losed conta iner ,the amount of drug de te cted in microparticles is increased. These differe nces in the amount of drug re leased may be re ferred to the c hange in physica l prope rties in polymer coa ts or in the amount of drug de te cted in a whole microca psules. Keyword: Ibuprofe n Mic rocapsules , Storage Tempe ra ture, Stability. الخالصة كبسوالت رة ل مت دراسة تأثير درجات الحرا رة مختلفة ت را ي درجات ح وفين ف اليبوبر م٬ ° ٥۰,م °٦۰(ا حرارة ) م° ٤۰ عها في درجة رى بوض ق (م°٤واخ غل واألخر م وح على ثباتية وطريقة تحرر مادة )في وعائين مفت ن المائية ) ۱ :۲ (األيبوبروفين من النسبة ريقتي جالتين والصمغ (للكبسوالت المجهرية المحضرة بالط غلفة بمادتي ال الم وية )العربي وم (والطريقة العض عادل ) لسليلوز األثيل والجينيت الصودي ن لمدة ۳۰۰بوزن ي وبروفي ثالثة ملغم من مادة األيب واء راسة ثباتية الد ر لد ربعة اشه وا واء رة .اشهر لدراسة تحرر الد ريه المحض كبسوالت المجه سبة من ال كان ثباتية تلك الن مدى صالحية ك واضحا مع ن ريقتي منهمابالط ريقتين المائية و العضوية على التوالي ۱.۳ و ۱.٤ل ولقد وجد أن .سنوات للط مائية أكثر ثباتية بسبب وجود المادة المصلبة للغالف هايد(الكبسوالت المجهرية المغلفة بالطريقة ال مالدي زيد من ) الفور التي ت جات رة منخفضة كان ذلك واضحا أيضا من خالل قلة كفاءة التغليف وقابلية تحمله للحرارة العالية أو الرطوبة مع در را ح واء زيئات الد حفيز ج ؤدي .طاقة ت ن تلك الكبسوالت عند زيادة درجات حرارة الخزن ت من جانب أخر وجد أن تحرر الدواء م رات الفزياوية التي تحدث في الم غي ود ذلك الى الت كس بانخفاض درجات الحرارة ويع ى الع ادة الى قلة في سرعة التحرر وعل ن من الكبسوالت المجهرية المخزونة عند وبروفي وفين والمشابهة لتحرر األيب كبسوالت المجهرية لأليبوبر م °۲٥المغلفة لل ها في نفس تلك الدرجة زن مائية ال تتغير ,عند خ ريقة ال مجهرية المحضرة بالط كبسوالت ال كما لوحظ تحرر الدواء من ال . م°٤۰- ۲٥ مقارنة للنسبة األصلية عند الدرجة 1corresp ond in g author ema il issraap har m @yah oo.com Rece ived 3-5-2006 Accepted 1 3-12-20 06 Ir aqi J.Pha rm.Sc i., Vol.15 (2 ) ,2006 Ac ce lerated Stability of Ib upr ofen Micr oc aps ules 38 In troduction: Microenca psula tio n technique prov id es a go od tool to protec t the drug from environmenta l factors (te mperature , humid ity, light, o xygen) by imp ro ving its s ta bility thro ugh e nc lo sing of s mall drug pa rticles of liquid s, s olids or gas es by a n inta ct s he ll(1,2). Acc elerated s ta bility stud y at e le va te d te mpe ra ture s is an impo rta nt stud y whic h indica te s the effec t of te mpe rature o n che mical stab ility of microc aps ules as we ll a s the ir physica l p rop erties (3) . Che mic ally b y pred ic ting the ra te of drug d eco mpos ition a fter exp erime ntally ev aluating the v elocity co nsta nt o f a pa rticular re ac tion, the amount of a ctive drug pres ent at any time and expiration d ate c ould b e de te rmine d the s pe cific manor in whic h the ra te of rea ctio n va ries with the c onc entration of the reac ta nts (3,4). The Arrhenius eq uation reve als the e ffec t of te mpe ra ture o n an obs erve d rate co ns ta nt b y affe cting the mo le cular motio n thro ugh de te rmining the Arrhenius a ctiv atio n e ne rgy (Ea) , whic h is the minimum kinetic e ne rgy that a molec ule must p oss es s in order to undergo rea ctio n (4) . The physica l e ffe ct of te mpe ra ture , o n microca psule s by a ltering the glas s transitio n te mpe ra ture (Tg) of mic ros pheres polymers co at ; is a na rrow te mpe ra ture ra nge o ver which mic roc ap sule s polymer rev ersibly change from phase to phas e w hich oc curs in amo rp hous polymers and in a morpho us c hains pa rtly c rystalline polymers, for exa mple Tg of pure glyco lide -L-lac tide (PLGA) polymer of microca psule wa ll was found to be 49 oC at which the rmo -rev ersible ge la tion in which the lo ng and fle xible p olymer c hains tend to bec ome entangle d and attra ct e ac h o ther by sec ondary side cha in forces , this phys ic al cha nges in microc ap sules p olyme r cause an alte ring in the diffus ion o f the d rug fro m mic ro cap sule s wall by affe cting the d riving fo rc es of p hysico-chemica l po te ntia l grad ie nt and transpo rt parame ters(5,6). On the other hand , protein microc ap sules stored at 4oC o ve r the c ourse of 2 8 d ays produced physica l c hange s in shap e or inte grity of microca ps ules that a ffec te d the re le asing behavior of these s pheres (7). Aim of the work To stud y the effe ct of different storage te mpe ra ture s o n the s ta bility (kinetic study) and re le asing profile of 2:1 ib uprofen mic ro cap sule s prepa re d b y aqueous (gelatin and a ca cia co at) and organic metho ds (sod ium alginate a nd e thylcellulos e polyme r c oat)(8). Ma terials and Methods Ibup ro fe n powd er SDI, Iraq. Gelatin granula ted (Fluka A-G, CH-94 70 Buchs, Switzerla nd). Ethylcellulose , Chlo roform, Methanol a nd Etha nol 96%, (BDH Che mic al Ltd, England). Phe no phtha line S olutio n, Calcium Chlorid e, Sod ium a lginate (Judex la boratory regents , Sud bury, Midd le s, Engla nd). S odium hydroxide , Po ta ss ium dihyd ro gen phos pha te (E-Me rk, Da rmstadt, We st Germany). Formalde hyde so lution (Ho pkin a nd Eilliams Ess ex, England ). Aca cia, Is oprop ano l (Ried el De - Haen AG, S eelze Hannov er, Ge rma ny). Pre paration of Ib upr ofen Microc aps ules Ib uprofen microcapsules were prep ared freshly using a queous metho d (co mplex coacerva tion phase separa tion) a nd o rganic metho d as shown in sc he me 1 and 2 respec tive ly (8): Ir aqi J.Pha rm.Sc i., Vol.15 (2 ) ,2006 Ac ce lerated Stability of Ib upr ofen Micr oc aps ules 39 Ge la tin (2%) w/w Ib uprofen + Acac ia (2%) w/w 40 0C 40 0C Mix with s tirring at 25 0 r.p.m adjust to pH 4 Se t a s ide for 50 minutes with stirring (4 00C) Add 10 ml forma ldehyde (5%) with s tirring for 10 minute s Co ol d own to 5 0C filte r Resuspend ed in isop ropa nol Filte r dry (roo m te mp.) Sche me -1- Pre pa ra tion o f ibuprofe n microcaps ules by aque ous me tho d. Ibuprofen + Na -a lginate (2%) Ethylc ellulose in c hloroform (20 %) 40 0C roo m temp erature Mix Dropp ing into 1% calcium c hloride so lution Dry in o ven a t 6 00C Sche me -2- Pre pa ration of ibuprofe n microca ps ules by org anic me thod. Ir aqi J.Pha rm.Sc i., Vol.15 (2 ) ,2006 Ac ce lerated Stability of Ib upr ofen Micr oc aps ules 40 Ass ay o f Micr oca psules content 0 .4 50gm of 2: 1 core : wa ll ibup ro fe n microca psule s p re pared by a que ous and orga nic metho d (eq . to 207 mg (6 9%) a nd 26 1 mg (87%) ib uprofen rec ep tive ly) was extrac te d in 5 0ml o f methano l, 0.4ml o f pheno phthaline so lution a s indicato r was a dde d, the n titra te d against 0.1M s odium hydro xide until a re d co lo r was o btaine d, b la nk titration was carrie d out, and a mount of d rug co ntent was determine d ,eac h 1 ml of 0.1M NaOH is equiv alent to 20.63 mg of C13H18O 2 (9,10). Deter minatio n of micr ocapsules pr operties Microenca psulatio n yield and encapsula tion efficiency of 2:1 co re : wall ra tio ib uprofen mic ro ca psules prepared b y aq ueous and organic metho d we re es tima te d us ing the fo llowing e xp ress io ns . Actual wt. of mic ro cap sule s ga ined Mic ro enc ap sula tion yie ld = x 10 0 (%) The oretic al wt. of mic roc ap sule s Ac tual drug lo ad ing Enc ap sulation e fficienc y = x 10 0 (%) The oretic al drug load ing Effec t of tempera ture on s tability of ibupro fe n microca psu les : The e ffec t of different storage te mpe ra ture s on the d egra dation rate of the selec ted formula 2: 1 c ore: wa ll ra tio ibup ro fe n mic ro cap sule s prepa re d by a que ous and o rganic me thod wa s stud ie d. The stud y wa s d one by incub ated the prepa re d mic ro ca psule s in a n amb er co lo re d glas s c ontaine rs at diffe re nt te mpe ra ture s (6 0oC, 50 oC, 40oC) a nd 4oC of refrigera tor in an o pened a nd clos ed c onta iners fo r 4 months. Samples of mic ro ca psule s of both prep aratio n metho ds (aqueous and o rganic ) in we ight of 652 mg and 517 mg re spe ctively eq uivalent to 300 mg ib up rofe n we re taken at des ired time intervals (e very month) and a ss aye d fo r the co ntent o f drug ac cording to the p ro ced ure mentioned b efore fo r stab ility s tudy. The e ffec t of te mper atur e on the diss olutio n be havio r of ibu pro fe n mic ro cap sules : In vitro drug relea se from 2:1 co re : wall ratio ib uprofen mic ro cap sule s sa mples using b as ket method in we ight equiv alent to 300 mg d rug of both prep aratio n metho ds wa s stud ie d us ing U. S. P d is so lution a ppa ra tus with 900 ml of pH6.8 pho sphate buffer at 37 oC  1 and stirring s pe ed 15 0 r.p.m. At a pprop riate time inte rv als 5ml s amp le wa s withdrawn, filte re d, and me as ured sp ec trop hotome trica lly at λmax 264 nm. This as sa y w as re pea te d for three months , ino rd er, to study the effe ct o f diffe re nt storage temperature (4 0oC, 50 oC, 60oC), 4oC ope ned co ntaine r a nd clos ed one ) o n the re le ase profile of ibup ro fe n fro m s elected fo rmula o f bo th method s. Results a nd Disc ussion Micr oc aps ules c onten ts Microencap sula tion yie ld a nd enca psula tion efficiency of 2 :1 co re : wall ra tio ib uprofen mic ro cap sule s prep ared b y aq ue ous and organic me thod we re ca lc ulated a s sho wn in ta ble 1. TT aa bbllee (( 11)) MMiicc rroo cc aa ppss uullee ss CCoo nnttee nn ttss oo ff 22 :: 11 CCoo rree ttoo WWaa llll RRaa tt iioo IIbb uupp rr oo ffee nn MMiicc rroo cc aa ppss uu llee ss PPrree ppaa rree dd bbyy AAqquuee oo uuss aa nndd OO rr gg aa nn iicc MMee tthh oo dd.. (2 :1) co re : wall ra tio D rug Amo unt (gm) Coa t (gm) M icro e nca ps ulation yie ld Pe rce nt yie ld D rug loa ding (mg ) Encapsul - atin efficien cy (%) Gel- atin Aca- cia Ethylcellu - lose N a- Algina te T heoretical (gm ) Actual (gm ) Theoretical (m g) Actual (mg) Aq ueo us ly prepared ra tio 8 2 2 - - 12 8 6 7 300 207 69 Orga nicly prepared ra tio 8 - - 2 2 12 1 1.7 97.5 300 261 87 Ir aqi J.Pha rm.Sc i., Vol.15 (2 ) ,2006 Ac ce lerated Stability of Ib upr ofen Micr oc aps ules 41 Effe ct o f elevated temp era tu re o n stability of ib upr ofen micr oca ps ule s F igures (1) and (2 ) sho w the c hange in the lo g % rema ining o f ibup ro fe n versus time at different eleva ted te mperature 40oC, 50 oC, 60oC.The obtaine d profile s were linear fo r bo th 2: 1 c ore :wall ra tio ibup ro fe n mic ro cap sule s prepa re d b y a que ous a nd o rganic metho d indica ting that ibuprofen de grad atio n fo llowe d first ord er kinetics. The s lo pe o f this line arity wa s de te rmine d and the ca lc ulated rate co ns ta nts are s umma rize d in ta bles 2 a nd 3 for b oth metho ds , resp ec tive ly. Arrhe nius plots are shown in figure s (3 ) and (4 ) .The ra te c ons tants (K) at 2 5oC o btained from the plot were 2.13 x 10-3 mo nth-1 a nd 2.8 1 x 10-3 mo nth-1 for aqueo us and orga nic metho d re spe ctively. -3 -2.5 -2 -1.5 -1 -0.5 0 2.9 3 3.1 3.2 3.3 3.4 3.5 (1/T)x10-3 L o g K 1.982 1.986 1.99 1.994 1.998 2.002 0 1 2 3 4 Time (month ) lo g % re m a in in g 40 c 50 c 60 c 1.977 1.982 1.987 1.992 1.997 2.002 0 1 2 3 4 5 Time (month ) L o g % re m a in in g 40 c 50 c 60 c -3 -2.5 -2 -1.5 -1 -0.5 0 2.9 3 3.1 3.2 3.3 3.4 (1/T) *10-3 lo g ( k) Figure (1): Acce le ra te d bre akdown of ibupro fe n in 2 :1 co re : wall ratio mic roc apsules at diffe re nt e le va te d te mpe ra ture s us ing aqueo us formula Figure (3): Arrhe nius plot for es timatio n s he lf life o f ib uprofe n microca psule s us ing 2:1 c ore : wall ratio pre pare d by (Aque ous me thod) Figure (4 ): Arrhe nius plot for e stima tion she lf life o f ibuprofe n micro ca psule s using 2 :1 c ore : wall ra tio pre pare d by (Organic me tho d) Figure (2): Acce le rate d bre akdown o f ibuprofe n in 2:1 co re : wall rat io mic roc aps ules at diffe re nt e le va te d te mpe ratures using orga nic fo rmula Ir aqi J.Pha rm.Sc i., Vol.15 (2 ) ,2006 Ac ce lerated Stability of Ib upr ofen Micr oc aps ules 42 TTaa bbllee ((22)):: DDee gg rraa ddaa tt iioo nn RRaa ttee CCoo nn ss ttaa nn ttss (( KK)) oo ff IIbbuu pprr oo ffee nn MMiicc rroo ccaa pp ss uu llee ss UUss iinngg 22 :: 11 CCoo rree :: WWaa llll RRaa tt iioo aa tt DDiiffff ee rree nntt TTee mmppee rr aa tt uurree ss (( AAqquuee oo uu ss MMee tt hhoo dd )) Ta ble (3): Deg radatio n Rate Constants (K) of Ibupro fe n Mic rocaps ule s Using 2 :1 Co re : Wall Ra tio at Diffe re nt Te mpe ratures (Orga nic Me thod). Te mpe rature K ( Mont h-1) 40oC 4.67 x 1 0-3 50oC 5.77 x 1 0-3 60oC 7.59 x 1 0-3 Sinc e the de grada tion o f the d rug follow ed first order kine tic (stra ight line ), the expiration d ate co uld be c alcula te d by the following e qua tion:- t10% = c25 o K 0.104 (4). It was eq ua l to 4 .1 years (Aque ous ) and 3.1 ye ars (Orga nic). While the Arrhenius a ctiv atio n e ne rgy (Ea) w as c alcula te d fro m the slop e of Arrhe nius plots .It wa s fo und to be 480 4.8 ca l/mol and 5 03 3.6 cal/mol res pe ctiv ely. The ab ove res ults indica te d tha t, the microsp heric partic le s pre pa re d from gelatin and aca cia co at (aq ueo us me thod) were more stab le be ca use of p re se nce of c ro ss linking agent (formalde hyde) (11), as we ll as , ac tiv atio n energy was les s than tha t of orga nic metho d (12), which is in c ons istent with the res ults obta ined by S iv akumar-P A w ho found that the stab ility o f ibup ro fe n lipo so pmes increas ed b y us ing a cros slinking a gent(13). The other manifes ta tio ns o f ge ne ra l ap pea ra nc e like color o f microca ps ules we re not c hange d afte r 4 mo nths for b oth formulas . Effe ct of tempe ra tur e on the diss olutio n be havio r of ibu pro fe n mic ro cap sules : Figures 5 and 6 ind ic ate tha t no la rgely difference wa s ap pe ared in the releas ing profile of a ll s tore d ib uprofen mic roc ap sule s of bo th metho ds at 60 oC, 5 0oC, 40oC), 4oC in an ope ned and c lose d co ntainer (refrigerator) after one mo nth in co mpariso n with s tand ard 2:1 core: wall ratio ib up rofe n mic ro sp heres prepa re d by aq ue ous and o rganic method stored at ro om temperature(14) ,while a fter sec ond and third mo nths , the re le asing behavior o f microca ps ules for bo th me thods was c le arly c hange d a s shown in figure s 7, 8 and 9,10 for aq ueo us and o rganic metho d, re spe ctively. Te mpe rature K (Month-1) 40 oC 3.96 x 10 -3 50 oC 4.75 x 10 -3 60 oC 6.45 x 10 -3 0 20 40 60 80 100 120 15 30 4 5 60 7 5 90 1 05 S td 600C 500C 400C 40C c lose % d ru g r e le a se d 40C op en Figure (5 ): The re le asing be havior of 2 :1 core : wall rat io ibuprofe n microc aps ules pre pare d by aqueo us me tho d store d at diffe re nt te mpe ratures afte r one month us ing 6.8pH o f phosphate buffe r Fig ure (6): The re le as ing be havior of 2 :1 core : wa ll ratio ibuprofe n micro ca psule s pre pa re d by organic me thod store d at diffe re nt te mpe rature s after one mo nt h using 6 .8 pH of phos phate buffe r. Ir aqi J.Pha rm.Sc i., Vol.15 (2 ) ,2006 Ac ce lerated Stability of Ib upr ofen Micr oc aps ules 43 F igures 7 a nd 8, illus tra te the re le as ing be hav io r of 2: 1 co re : wall ratio ibup ro fe n microca psule s prepa re d by aqueo us metho d stored a t 40 oC in which the re le ase of the d rug was the same as the s tand ard one . The sa me re sult wa s obta ined by Ca ro l-AS, he found that the releas e of tryptophan and theo phylline fro m gel mic roc ap sules stored at 25oC and 40oC re maine d uncha nged(15). On the other hand, microc aps ules s tore d at 50oC and 60oC provide d lo wer relea se o f drug due to re mova l of s olve nt, de nse r pe riphery (v is cous bounda ry) of microc aps ules (16), b ut when the te mperature of storage d ec re ase d to 4oC of refrige ra to r of an ope n a nd close conta iner, the releas e of ibuprofen increa sed bec ause of physica lly changes in the integrity of microc aps ules s ha pes whic h be came more spheric al with s moo th s urfa ce that pro vided la rger s urfa ce area with p orous s urfa ce a fter comp le tion of s ta bility stud y(17,18). Also , microca psule s stored in a n o pen conta iner pro vide d highe r relea se of ib uprofen than c lo sed o ne d ue to pres enc e of humidity in the refrigerator environment that mad e the gelatin swe ll fas te r in the d is solution med ia with ra pid diffusion of the drug from the te xture of the gel(10). The results o btained from figure 9 a nd 1 0 sho wed the d elay in re le as ing p rofile of ib uprofen from micro ca psule s pre pa re d by organic metho d when the tempe ra ture of storage inc re as ed from 40 oC to 6 0oC d ue to te nde nc y o f microca ps ules to s tic king which was reve rs ible afte r co oling to roo m te mpe ra ture . The slightly dec re ase d of disso lutio n rate and the s ticking phe no mena could b e exp la ined by c ha nge in the po lymer film d ue to its low gla ss tra ns ition temp erature, which could be a dditio na lly red uce d by disso lv ed ib uprofen mo le cules in a dditio n, storage a t higher tempe ra ture a llowe d e thyl cellulos e film to b ec ome more dense d ue to curing effect as it was re po rted for eudragit L10 0-5 5 po lymer(19). In s pite of increas ing the re le as e of ib uprofen from micro ca psule s pre pa re d by organic me thod when s to re d a t re frigerator te mpe ra ture in co mparison with standard 2: 1 core: wall ratio s tored at ro om tempe ra ture , the re le ase o f drug fro m mic roc ap sules s tored in an op en c onta iner a t 4 oC s howe d lo wer re le ase of d rug at firs t 15 -3 0 minutes b ec aus e of some amorphous ibuprofen in the s olid d is persion proba bly re acte d with the p olymer by c atalytic action o f water vap or d uring storage(20). 0 20 40 60 80 100 120 15 30 45 60 75 90 105 St d 60 0 C 50 0 C 40 0 C 4 0 C ope n 4 0 C cl ose 0 20 40 60 80 100 120 15 30 45 60 75 90 105 St d 60 0 C 500 C 40 0 C 4 0 C o p en 4 0 C clo se % d ru g r e le a se d Fig ure (7): Dissolutio n be havior o f ibuprofe n mic roc apsules pre pare d by a que ous me thod store d at diffe re nt te mpe ratures us ing pho sphate buffe r pH 6.8 a fte r 2 nd mo nth of storage. Fig ure (8): Dissolution be hav io r of ibuprofe n microc aps ules pre pare d by aque ous me thod s to re d a t diffe re nt te mpe ratures after third mo nt h o f stora ge us ing p hos pha te buffe r pH 6 .8 Ir aqi J.Pha rm.Sc i., Vol.15 (2 ) ,2006 Ac ce lerated Stability of Ib upr ofen Micr oc aps ules 44 Conclusion 2:1 c ore : wa ll ratio ib uprofen mic roc ap sule s prepa re d by b oth aqueo us a nd orga nic metho d were sta ble with s helf life o f 4.1 a nd 3.1 ye ars. All physica l changes a ffec te d the re le as ing be hav io r of this ratio o ccurred at d ifferent storage tempe ra ture were re vers ib le o n le av ing thes e formulas at 25oC in tightly c lo se d conta iner. 2:1 core: wall ratio ib uprofen microc ap sules prepa re d by a que ous method can b e stored at a te mpe ra ture 2 5-40oC without altering its stability o r the releas e profile . Refe renc es 1. Uddin, M.S., Ha wlader, M.N., Zhu ,H.J ., Mic roencapsula tion o f ascorbic a cid; e ffec t of process va ria bles on product charac te ris tics Journal Microe ncaps ul., 200 1; 18, P .1 99- 209 . 2. Berto lini, A.C., Siani, A.C., Grosso ,C.R., Stability o f mono terpenes e ncaps ulated in g um Ara bic by sp ra y drying, J-Agric-Foo d-Che m., 200 1;49,780-5. 3. Ismat A. Hamid, Industrial p harmac y, 197 5; 2 01 -204. 4. Alfre d Ma rtin, The p hysica l p ha rma cy,; 4th editio n; 1993,313 -3 14 . 5. We n, I., Ki mbe rly, W.A., Ki ne tic and ther modyna mic mo deling of the formation of polyme ric mic rosp heres using solve nt extraction /evapo ra tion ,Jo urna l of co ntrolle d re lease, 1995; 3 7, 187 -198. 6. Yo shio ka,S.,Aso ,Y.,Kojima,S., Drug re lease fro m poly dl- lactide mic rosp heres controlled by ga ma – irradiation ,Journal of controlled release , 1995 ; 37 , 263-267. 7. Ma gee ,G.A., Ha lb ert,G.W., Wil mott, N., Effec t of process variables o n the in v itro degra da tion of p ro te in microspheres , Journal of c ontrolled re lease ,19 95;37 ,1 1-19. 8. Iss raa, R.A., P repa ra tion of ib up rofe n mic ro ca psules as a s us ta ined re le ase s olid dosage form, Thesis , Colle ge of p harmac y, Unive rs ity of Baghda d ,2000. 9. European pharmacopoeia [Disk], Ib uprofen, France , 1998. 10. Britis h pharmac opoeia, Vo l. 1 and 2, 199 3; P .305,3 01. 11. Chowd hury, S.R., Mukherje e, P. K., Mic roencapsula tion of ib uprofen by c omple x coace rvatio n tec hnique, East-P harm, 19 95; 38[Mar], 137-138 . 12. Nguyen, M.T., He ndrick, M., Mo del studies o n the s tability of folic acid a nd 5- methyl tetra hyd ro fo lic a cid de grada tio n during thermal trea tme nt in co mbina tion with high h ydros tatic pressure , J-Agric –Fo od- Che m, 20 03; 21[May], 51 , 33 52-7. 13. S ivakumar, P.A., Mythily , S., Liposome ib uprofen co njuc ate a nd the rele ase cha racteristics o f ibuprofen, Indian-Drugs, 199 4;31[Dec], 568- 573. 14. El-Bary, A.A.,El-Naba rawi, M.A., Moha med ,M.I., Prop io nic acid deriv atives fro m their d osage forms , Drug-De r-Ind-Pha rm. 199 8; 2 4, 439 -45. Figure (9 ): Dissolution be hav io r of ibuprofe n micro ca psule s pre pare d by organic me thod store d at diffe re nt te mpe ratures afte r 2 nd month of s to rage using 6.8 pH p hos phate buffe r. Figure (10): Dissolut io n be havior o f ibuprofe n micro ca psule s pre pare d by organic me thod store d a t diffe re nt te mpe ra tures afte r 3rd mo nth of s to rage using 6 .8 phos phate buffe r. Ir aqi J.Pha rm.Sc i., Vol.15 (2 ) ,2006 Ac ce lerated Stability of Ib upr ofen Micr oc aps ules 45 15. Charala mbos , G.V.,Da vid, G.D., Carol,A.S ., Zero-order rele ase from b ip ha sic polyme r hydrogels, Jo urna l of co ntrolle d re lease ,1995;34, 185-192 . 16. We n, I.L., Kmbe rly, W.A., Predic tion of peptide-lo ade d PLGA mic rosp he res p repa re d by solve nt e xtra ction/evap oratio n metho d ,J ournal o f co ntro lled release , 19 95;37 , 1 99- 214. 17. Rajes h, R.D., Ra je sh, H.P., Fac to rial effe ct of p ro cess paramete rs o n pharmace utical characte ristics and s tability stud y o f P LGA microca ps ules co ntaining wa te r-so luble drug, PLGA microsheres , 2 004 ;1 -1 4. 18. Davidson, I.G., La gne r,E.J .,Re lease mec hanism of ins ulin e ncaps ulated in trehalose es te r de riva tive microcapsules delivere d v ia inhalation ,Int.-J- Pharm., 20 03; 26[Mar],25 4, 211 -22. 19. We ib , G., Kno ch,A., Micro encapsula tio n of ibup ro fe n by a co acervation process us ing eud ra git L1 00-55 as an e nteric polyme r, Drug develop ment and ind ustria l pha rmacy, 19 93; 19, 2751-2764. 20. Ma koto,O.,Mika,O.,Hygroscooic sta bility and d isso lution p rope rties of spray-d ried s olid dispe rsion o f furo se mid e with e ud ra git, Journal of pharmac eutica l s ciences ,19 93; 82,32 -3 8.