Ir aq i J.Pharm.Sc i., Vol.15 (1 ) ,2006 1 Formulation and Clinical Evaluation of Orphenadrine citrate as a Plain Tablet Abdul Karim F. Jumaa,Alaa A.Abdulrasool and Hikmet A.Al – Dujali Received 5-8-2001 Accepted 11-6-2002 ABSTRACT Orphenadrine is an anticholinergic ,antimuscarinic , ce ntrally acting skeletal mus cle re la xa nt .It pres ents in the fo rm of c itrate and HCl sa lts which a re use d in tre atment of the symptoms o f mild P arkins on's d is eas e and also it is use d as a djuva nt with othe r drugs in the therap y . Many trials were mad e to fo rmula te Orp henadrine c itra te as a p la in tab le t using we t granulation or dire ct c ompres sion tec hniq ue in o rd er to get a s atis factory formula through s tudying the e ffec t of va rious fa ctors such a s bind ers , diluents and disintegra nts type s . The b est fo rmula wa s ob ta ined by using Po ly Vinyl P yro lidine (PVP ) as a b inder also the res ults indica te d that starch a nd mannito l ga ve a cce ptab le p hys ical prope rties to the ta blets whe n they we re us ed as diluents . At the s ame time , the results s ho wed that Avice l which wa s us ed a s a disintegra nt ga ve an ac cep table disintegra tion and d is so lution time in co mparison with the reference ta blet DISIP AL . In a dditio n , the se lected formula wa s us ed to stud y the effe ct of me thod of incorpo ra tion of d is integrant on the p hysical prope rties of ta blets .It w as found that the intragra nula r incorpo ra tion re sulted in a s ho rter disintegra tion a nd d is so lution times .The sta bility of Orphenadrine citra te p re pa red ta blets wa s also studied up on storage at 50C, 60C and 70C fo r fo ur mo nths .The drug was fa irly stab le a nd the e xpiratio n date for the p re pared ta blet wa s co nside re d to b e equal for 5 yea rs .On the othe r ha nd , the res ults of c linica l study on p atie nts suffering fro m P arkins on's dis eas e indica te d that pa tients w ith tre mor (re gula r rhythmic os cilla tion o f extremities es pe cially hand and finge r ) a nd mild symptoms o f Pa rkinso n's dise as e showed a good re spo ns e to the p re pa re d ta blets , b ut it had no effe ct on p atie nts of dys tonia ( fixed upwa rd gaze , ne ck twisting ,clenc hing jaw s ) and akinesia ( slow down of move ment of volunta ry musc le and d iffic ulty o f initia tion o f mov eme nt ). The ov erall re sults of this s tudy indica te that the d rug can b e prepa re d as tablets , which fit the re quireme nts of Britis h Pharmaco poe ia since the prepa re d tablets gave s atisfac to ry res ults . - :الخالصة Orpheفينادرين روألا na drine) ( يوجد على شكل . هو عقار مضاد إلفراز الكولين ويعمل كمسترخي مركزي للعضالت الهيكلية ة األخـرى     أمالح السترات  والهايدروكلورايد حيث يستخدمان في عالج األعراض البسيطة لمرض باركنسون أو مساعد مـع األدوـي اجراء العديد من المحاوالت للحصول على صبغة تركيبية مقبولة لسترات االورفينادرين كأقراص سريعة  تم. المستخدمة في العالج  واد الرابطـة ٬ المـواد     التحرر باستعمال طريقة الحبيبيات الرطبة او الكبس المباشر من خالل دراسة تأثير العديد من العوامل مثل  الـم . المضافة و المواد المحطمة أو المفتتة  ة  ) PVP( أن أفضل النتائج قد تم الحصول عليها باستخدام مادة البولي فانييل بايروليدين  ى أن     . كمادة رابـط ائج إـل كمـا أشـارت النـت .النشا والمانيتول يعطيان خصائص فيزيائية مقبولة لألقراص عند استخدامها كمواد مخففة  المستخدم كمادة مفتتة أعطى زمن تفتت وتحرر مقبول مقارنة ) Avicel( سيل في نفس الوقت أظهرت النتائج بان السليلوز ألمجهري افي واص    ) حبوب ديسبال ( بالمصدر  ى الـخ ة عـل اضافة الى هذا  التركيبية المختارة قد استخدمت لدراسة تأثير طريقة اضافة المادة المفتـت م دراسـة    . دى الى زيادة في سرعة التفتت والذوبان حيث وجد بان ادخال المادة المفتتة ضمن الحبيبات ا. الفيزياوية لألقراص  كـذلك ـت عقار مسـتقرًا  حيث كان ال. م لمدة اربعة اشهر  70م ٬  60م ٬  50استقرارية الدواء عند خزن الحبوب في درجات حرارة مختلفة  ارات نتائج الدراسة السريرية على من جهة اخرى ٬ اش. المحضرة هو خمس سنوات  صالنتهاء مفعول األقرا وان التاريخ  الذي اعتمد  المرضى الذين يعانون من مرض الباركسون بان المرضى الذين لديهم ارتعاش وبعض االعراض البسيطة لمرض باركنسون اظهروا  ر إلى أن نتائج هذه الدراسة تشي. المرضى الذين بعانون من ضعف المقوية  ىاستجابة جيدة للتركيبة المختارة ولكن ليس لها تأثير عل طالما أن الحبوب المحضرة أعطت  يإمكانية تحضير العقار على شكل حبوب كجرعة دوائية صلبة مطابقة لموصفات الدستور البريطان .نتائج مقبولة  Depar tme nt of Pharmaceutics,College of Pharmac y , Un iversity of Baghd ad , Bag hdad-Ir aq Ir aq i J.Pharm.Sc i., Vol.15 (1 ) ,2006 2 INTRODUCTION The s ke le ta l mus cle re la xa nts are group of co mpounds us ed to re liev e sp as ticity & ab normally high mus cle tone (1,2 ) .The y produce their effe cts by action on central ne rv ous sys tem (CNS) ,howe ver , the ir mec hanism o f action not yet unders to od . The re a re ma ny theo ries , which explain the mec hanism of ac tion o r the c linic al us es of mus cle re la xa nts .One of thes e theories is that they red uce s ke le ta l mus cle sp as m , p os sibly thro ugh a n a trop ine like central a ctio n o n ce re bra l moto r centers o r on the me dulla but they do not ha ve a na lges ic activity that co ntribute to the ir effec ts in pa tie nts with skeletal musc le s pa sm (3) . Anticholinergic drugs (Antimus ca rinic drugs ) were the most effe ctive drugs for tre atment of Pa rkinson's dise ase for mo re tha n a c entury , this is b y bloc king Ac etyl c ho line rec eptors o f the CNS , there by partia lly re dress ing the imba la nc e crea te d b y dec re as ing d op aminergic ac tivity (4) , howe ver , the intro duc tion of the dop ame nic drugs ( Le vo dop a & dec arboxylas e inhibitors ) ha s re le ga te d anticholinergics to a suppo rtive role in the trea tme nt of the diso rde r . Nov erthle ss , the a nticho line rgric drugs are still use ful for p atie nts with minimal s ympto ms as patients unable to to le ra te le vop dop a be cause o f side effec ts o r contra indications , fo r thos e who are not benefite d by lev odo pa (5) & for patients w ho ha d parkins onia n symptoms ind uce d by antips yc hotic drugs (6 , 7) . Orp henad rine citra te is white or a lmost white , o dorle ss or a lmo st odo rles s , c rystalline pow der with a bitte r ta ste & fo llowe d b y se ns atio n of numbness . It me lts in the ra nge of 1 34 C to 1 38 C (8) . Soluble 1 in 7 0 of wa te r , s lightly s oluble in etha nol ; practically insoluble in chlo roform and e ther (9) .It s ho uld b e stored in tight & light re sista nt c onta iners (10) . CH2  COOH m E C Nme HO C COOH CH2  COOH N,N d ime tly [ 2 – ( 2 – methylbe nzhydoxy ) ethyl ] amine dihyyd -roge n c itrate (11) .C18H23NO.C 6H6O7 with M.wt of 46 1.5 gm . Orp henadrine citrate is us ed for symptoma tic tre atment of P arkins on's dise as e (11) ,to relieve p ain due to sp as m o f vo luntary mus cle (12) and as an a lterna tiv e to quinon in trea tme nt of noc tura l leg cramps (13) .Orp he ndrine ma y also be use d in vertigo in patient with s po ntane ous ve stib ular d is ea se (14) , and it may b e comb ined with halope rido l in trea tme nt o f chro nic schizop hrenic pa tient (15) or with p arace tamol in trea tment of Myo lgia (14) . Orphenadine is contraind ic ated in p atie nt with glauco ma (17),e lde rly pe op le (18) a nd with antac id (19) .Its o verdo se is trea te d with physo stigmine (20) o r tetra hyd ro amino crine (21) . on the othe r ha nd , Orphenadrine intoxica tion is po te ntiated by etha no l(22) and its use may cause de pe nde nce (23) . Orp henad rine citra te pre se nts as a n oral tab le t extend ed releas e of 100 mg unde r the tra de name of NORFLEX  and p arente al injec tion o f 30 mg/ml (a mpoule of 2 ml ) und er the trad e na me of BanF LEXand NORFLEX . Also Orphenadrine c itrate is fo und in comb inatio n such a s ; NORF LEX  oral p la in ta blet whic h co ntains Orphena drine citrate 25 mg , as pirin 38 5 mg and caffeine 30 mg ; and Myogesic  whic h co ntains Orphe nad rine citrate 35 mg and pa rac etamo l 4 50 mg(24) . This stud y wa s c arried out to fo rmula te Orp hendrine citrate as a tab le t do sa ge form , thro ugh prep aring d iffe re nt formulas , and comp aring them with reference tablets . Als o the effect of excipients type (bind ers , disintegrants and dilue nts ) o n phys ic al pro pe rtie s of the tablet was s tudied in ad dition to the e ffec t o f inc orporation method of disintegrants . Furthe rmo re , the s electe d formula , which fitte d the s ta nd ard req uire ments ,was thoroughly inves tigated for its exp iration da te and c linica l e ffec ts . EXP ERIMENTAL PART :- Materials - Orphe nad rine citrate p owde r.(Dar AL Dawa , Amman , J orda n ), S ta rc h , Mannito l (Me rk , Darmstad t ,Germa ny ) , Microc rystalline cellulose (Av ic el PH101 , F MC c orporation , Pennys ylva nia , USA ), Polyv inyl pyro lidine (PVP ,K30),Etha nol ,Hydroc hloric Ac id (HCl) , Carboxy methylc ellulose s od ium s alt (CMC) , Is oprop yl alchoho l ,(BDH Chemica ls Ltd, ,poo l, England ),Magnes ium s trea ra te , (Ba rloc hes ,GMBH, Germany), Acac ia arabique ,Dextros e , Talc.(Rie del – De – HAEN AG See lze – Hanno ver , Germany ),Dib asic ca lc ium phos pha te (Emc omp re ss ,Ed ward Mend ell Co., USA ), Explota b (AVEBA, Veendo m ,Ne therla nds ),DISIPAL ta blets as a re fe re nce (Ya mano uc hi P harma Ltd. , UK). c c Ir aq i J.Pharm.Sc i., Vol.15 (1 ) ,2006 3 Formulation of Or phenadrine citrate Tablets Diffe re nt formulas (Ta ble I ) were prep ared to find the mos t sa tis fa ctory fo rmula using wet granulatio m te ghniq ue e xce pt formula 7 whic h was prep ared by direct comp re ss io n te chnique , in whic h the d rug and e xc ipie nts ( excep t lubricant )were d ry b le nde d for at le as t 5 minutes a nd then mixture wa s co mpress ed into tab le ts us ing F 3 Ma nes ty ta blet ma chine with a s ingle 7 mm normal co nca ve p unc he s . In c as e of us ing wet granula tio n method , the fo llowing p ro ced ure was fo llowe d : afte r 5 minutes dry blend ing of drug & excipients , the bind er so lution was ad ded to the formula grad ually in the mixing morta r until a sa tisfac tory wetting was achie ve d (Ba ll te st ).The wet mas s wa s then gra nula te d thro ugh a siev e no. 10 a nd dried in a tra y ove n at 4 5C for 30 minute s. The granule s were then reduced in s ize and ho moge nize d b y pa ssing them through a siev e no .1 6. A kno wn weight of the granules was the n mixed with s pec ified amo unt of disinte grant extra – granularly for 10 minutes in we ll clos ed c ontaine r a nd the n mixed with magnes ium stea ra te (200 me sh in size )fo r 2 minutes . The fina l mixture was c omp re ss ed. Physical Parame ter Measureme nt of Or phenadrine Tablets Hardne s s :- The ha rdnes s of Orphe nad rine citrate tablets we re me as ured us ing Monsanto and Erweka hardne ss tes te rs no rma l ra nge betwee n & 8 kg(24) . We ig ht Va riatio n :It was d etermined for a ll pre pa re d formulas by ta king 20 tab le ts , weighe d individually and the ave ra ge we ight is calcula ted .For the ta blets to be ac ce ptable by not more tha n 2 of the 20 tab le ts ma y differ from the a verage weight b y not mo re than 7.5% a nd no tab le t may diffe r by more than double the pe rc ent (25). Friability Te st : The friab ility o f ta blets was perfo rmed us ing Ro che fria bila to r and Erweka frib ilator fo r 4 minute s at 25 r.p .m by weighing 10 tablets the n place them inside the tes ter for 4 minutes and weigh them again .The difference in weight s hould not exc ee d 1% . Dis inte gratio n Time : The d is inte gration time was meas ured using U.S.P disintegra tion app aratus . It co nsis ts of a b as ket rack ass emb ly c ontaining s ix o pen – e nde d glass tubes with a 10 –mes h s creen on the bottom .The ba sket was immersed in an app ro priate fluid (0.1N HCl ) a t 37 C .The bas ke t rack wa s raised a nd lowe rd a t a rate of 30 stoc ke s pe r minute(25) . Ta ble (1) Sche dule of Diffe re nt Formulations o f Orphe nadrine Citrate as a Pla in Table t Q.S = s ufficie nt quantity , X=amount of Av ice l ,Y= a mount of Sta rc h ,D=amo unt o f De x tros e , M =amo unt of Ma nnitol , E= amount o f Explo ta b ,S = amount o f Starch (disinte grant )… Ma te rials For mula No. 1 2 3 4 5 6 7 8 9 Orphenadrin e .citrate (mg) 75 75 75 75 7 5 75 75 7 5 75 P VP10%w/v in e thanol Q.S Q.S Q.S Q.S Q.S Avicel pH101 X X X X X X Starch Y Y Y Y 0.5Y Y Y Mg.ste arate 1.5 1.5 1.5 1.5 1 .5 1.5 1.7 1 .5 1.5 De xtro se D Ac acia 2 0% Q.S Ma nnitol M Explotab E Starch (disinte grant) S Emcomp re ss 68.5 Starch pas te Q.S CMC Q.S To ta l we ight 15 0 150 15 0 150 1 50 15 0 150 1 50 15 0 Ir aq i J.Pharm.Sc i., Vol.15 (1 ) ,2006 4 Diss olutio n Te s t : The USP Ba sket Me thod (26) was use d to s tudy the relea se o f the drug from the prepa re d ta ble ts a nd from the re fe re nc e ta blet DIS IP AL  (Yamano uc hi) . The studie s were c arried out in shie ld ed app aratus to protec t the solution of d rug from light us ing 900 ml of 0.1N HCl s olution as the diss olutio n med ium a t 37C with a c ons tant stiring s pee d of 5 0 r.p.m (26,27) .Samp le s were withdrawn at five minutes interva l for o ne hour . The sa mple volume was replac ed immed ia te ly b y a fres h 0.1N HCl . The sa mples were filte re d b y microfilte r a nd ana lyze d sp ectrophotome trically at its max 264 nm (28) . Assay for total Orphe nadr ine c itrate pre sent in the Table ts Pre paration of standard :15 0 mg of p ure Orp he nad rine c itrate was diss olve d in 75 ml 0.1N HCl , shaken for 1 5 minutes and filtered , then the volume was co mpleted to 10 0 ml with 0.1N HCl . A s amp le o f 20 ml was taken and diluted to 100 ml with 0 .1 N HCl . The a bso rb anc e of the diluted so lution wa s de te rmine d spe ctrophotome tric ally a t its max which is 2 64 nm(28) . Ass ay o f the Pre pare d Ta ble ts : 20 ta blets of Orp he nad rine c itra te we re triturated and a n ac curate weight e quiv alent to 0.15 gm of Orp he nad rine c itrate was ad ded to 75 ml of 0.1N HCl , shaken for 15 minutes and filte re d .The fina l vo lume was co mpleted to 100 ml with 0 .1 N HCl The ab sorba nce of diluted s olutio n wa s de te rmine d sp ectrophotome trically at 2 64 nm , and the qua ntity of drug p er tablet wa s ca lc ulated ac co rding to the follo wing eq uation : Tes t /S td .  10 0 =% Orphe na drine c itrate pres ent in ta blet (29) . Kinetic Study Effec t o f te mpe ra ture o n Orp henadrine citra te ta blets was s tudied b y storing so me ta blets of the se le cted formula (1) a t diffe re nt te mpe ra ture s ( 50 C 60 C 7 0 C ) fo r four months .Sa mples of tablets were taken at des ired time intervals a nd as sa ye d fo r co ntents of Orp henad rine citrate a cc ording to the metho d mentio ned be fo re .The fria bility , disintegra tion a nd diss olutio n time we re als o che cked at the end of four mo nths , and organoleptic prope rties we re a lso examine d . STATISTICAL ANALYSIS Stude nts t – tes t was us ed to e xa mine the difference in the me an of the res ults of parame ters te sted . A p – v alue of le ss than 0.05 was conside re d signific ant . PRELIMINARY CLINICAL STUDY The s elec te d pre pa re d fo rmula (1) in ad dition to DISPAL we re give n to sev en pa tients suffering fro m tre mor (legs a nd a rm ) , stiffnes s and auto nomic d ysfunction which a re clinic al symp toms o f Pa rkinson's dise ase .They were also given to thre e pa tie nts with dys to nia , a t the s ame time the stud y was d one using p la ceb o tab le ts . The treatme nt was fo llowe d up to three months with a dos e of one ta blet 3 times da ily . The stud y wa s do ne in Nahrain Co llege of Medicine Tea ching Hosp ita l to de termine the c linica l symptoms and the c linica l pa ra meters us ed to ass es the therapy . RESULTS and DISCUSSION : Effect of Binder Type Different formulas (1,3 ,8 and 9 ) we re prepa re d to s tudy the e ffec t of b inde r type on the hardnes s , fria bility , d is integration and disso lutio n times as s hown in tab le (2) a nd fig Ta ble (2) Effec t of Binde r Type on the Hardne ss , ,Friability , D is inte gra tion Time a nd Diss olutio n Time of the S uggeste d Orphe na drine Citra te Formu la in Co mparis on with t he Refe re nce Table t S uggested fo rmula T yp e of bin de r Hardness (k g) F riab ility (%) Disintegratio n T ime(min) Disso lut ion T ime(min)to 1 00 % 1 1 0% P VP 8.25 0 .5 39 5 20 3 2 0%Ac acia Mu cilage 7 0 .7 6 20 8 1 0% S ta rc h p aste 5 1 .1 5 15 9 5 % CMC 3 2 .8 4 30 D IS IP AL R eferen ce 10 25 Ir aq i J.Pharm.Sc i., Vol.15 (1 ) ,2006 5 Fig .1 :Effec t o f binde r on the re lease o f Orphe nadrine fro m p re pare d fo rmulas in comparis on with the refe re nce table t DIS IPAL Fig. 2 : Effec t o f dilue nt on the re lease of Orphe nadrine from pre pare d fo rmu la s in co mparison wit h the re fe re nce table ts DIS IPAL in 0 .1 N HCl and 37 C The re sults o btaine d indica te that us ing different type s of b inders affe ct the p hys ical prope rties and the re le as e of drug . For example , fo rmula 1 in whic h PVP wa s us ed a s a bind er , s ho wed a go od ha rd ne ss (8.25kg) , friability (0 .5 %),disinte gratio n time (5 mins .) and diss olutio n time up to 1 00% (2 0 mins. ) in co mparison with the reference tablet DISPAL .This may be d ue to the us e of P VP in e thanol which has the sa me v is co sity a s P.V.P in water(30 ) .Als o hydgros cop ic ity of PVP p re vents the ta blet from be ing ha rd er with age (31) . Formula 3 , whic h utilize s ac acia mucila ge in water a s a bind er ,showed go od hardnes s (7 kg), ac ce ptable friability (0 .7 %) , disintegra tion time (6mins .) a nd diss olutio n time up to 1 00% (20mins .) in comp aris on with the re fe re nc e tab le t DISPAL.The se may b e due to the fac t that gum ac ac ia ge nerally produce hard gra nule s but witho ut p rod uc ing ta blets of inc re asing hardne ss (31) . F ormula 8 which c ontains starch p aste a s a bind er , sho wed rea so nab le hardness (5 kg) and disintegra tion time of (5mins .)with una cc eptab le fria bility (1 .1 %) and fa st disso lutio n time up to 1 00% (1 5mins .) .This may be d ue to the p ro perty o f sta rc h p as te , which forms ge ne ra lly s oft and brittle ta blets(31) . Finally fo rmula 9 in which CMC. was used as a b inde r , s howe d lo w hardness (3 kg)and unacc epta ble friability (2.8%)w ith an acc ep ta ble disinte gratio n time (4 mins.)and lo ng disso lutio n time (30mins.)s ince CMC. sod ium is visco sity controller ,it is c onc eivab le that it forms a highly visc id s ys te ms that re sist dilution by disso lutio n fluid which might imp ede drug releas e(32). Effect of Diluent Type Formulas 1 ,2 ,4 a nd 7 were us ed to study the effe ct of diluent type o n the hardnes s , fria bility ,d is integration and diss olutio n times of the p re pa re d ta blets . Tab le (3) s hows the e ffe ct o f diluent type on physica l prope rties of the p re pared tab le ts , while fig (2) sho ws the releas e of Orp henad rine c itrate from the p rep ared tab le ts (formula 1,2,4 and 7 ) in comp aris on with the re fe re nce ta blets DISIP AL . Formula 1 in which s ta rc h was use d as d ilue nt gav e a good hardnes s(8.25kg), friab ility (0 .5 39%) , disintegra tio n (5min) and disso lutio n time up to 1 00% (20min) . Formula 2 which co ntains dextro se a s a diluent ,showe d a goo d friab ility (0 .1 %), hardnes s (7kg) and d is inte gration time ( 4 mins.) but long d is so lution time (40mins .), although brown sp ots was s ee n o n the ta blet afte r a while whic h ma y be due to the inte ra ctio n o f dextros e w ith a mines ( Orphenadrine )(30) . Fo rmula 4 in which mannito l was use d as a diluent , gave a good fria bility(0.5%), hardne ss (7.25 kg), disintegra tion time (6 mins.),with a rea so nab le disso lutio n time (35mins.). This ma y be due to non – hygro sco picity of ma nnitol (30). Formula 7 ,which was prep ared by dire ct comp re ss io n tec hniq ue , s ho wed a we ight variatio n .This is bec ause of po or flo w of powd er in sp ite o f p re se nce of Emco pmres s .Also it s ho wed una cc eptab le fria bility (1 .1%) and hardne ss (3kg)with a rapid disintegra tion time (50-se c) and d is so lution time of 20 min . Effect of Disintegr ant Effe c t of Dis inte grant Type Formulas 1,5 and 6 were utilize d to s tudy the effe ct of d is inte grant typ e on phys ic al prope rties of the prepa re d ta blets as sho wn in ta ble (4 ) and fig (3) . 0 50 100 0 10 20 30 40 Time (m in ) P e rc e n t o f D ru g R e le a s e d formula 9 DISIPAL formula 1 formula 3 formula 8 0 50 100 150 0 20 40 60 Tim e (min ) P e rc e n t o f D ru g R e le a s e d formula2 formula4 DISIPAL formula 1 formula 7 Ir aq i J.Pharm.Sc i., Vol.15 (1 ) ,2006 6 Ta ble (3) Effe ct of Dilue nt o n the Physica l Prope rtie s o f Orphe nadrine Citrate Plain Tab le ts Ta ble (4) Effec t of Dis inte grant Type on the Physical Prope rties o f Pre pa re d Orphe nadrine ta ble ts Fig. 3 : The effe ct o f disinte g ra nts ty pe on the re lease o f Orphe nadrine in co mparis on with the re fe rence table ts DISIPAL  Formula 5 , in whic h Explotab (lo w s ub stitute d ca rb oxymethyl starch (32) ) was us ed as a disintegra nt s ho wed a relatively low hardnes s (4 kg) with a n a cc eptab le friab ility (0 .1 %), disintegra tion time (5mins .) a nd diss olutio n time (25 mins.) , ho weve r , its diss olutio n profile showe d no signific ant diffe re nce with fo rmula 6 fig(3) (p – va lue > 0.05 ). This is ma y be d ue to Explotab prop erties sinc e its gra nule s abs orb water ra pidly and swe ll but do not b re ak . In general , the s welling granule s re main intac t , c aus ing disintegra tion witho ut b ursting (unlike sta rc h ) and conse que ntly relea se of the solub le starch frac tion .This might le ad to increas e the visco sity a nd de lay moisture pe ne tration into the ta blet (29) . Formula 6 showe d a goo d fria bility (0 .0 1%) , disintegra tion time (4mins .) a nd d is so lution time (3 0mins.), with re la tive ly lo w hardnes s(3.5kg) .This may b e due to the fa ct that ta blets co ntaining high amo unt or conce ntra tion o f starch a re o fte n s oft a nd may be difficult to dry (33) . Formula 1 in which Avicel  was use d as disinte grant , showe d a goo d hardness (8.25kg)and fria bility (0.5%) with an a cc eptab le d is integration time (5 mins.),and a fas t diss olution time (2 0mins .). This is be cause Avicel is a super disintegra nt which is highly p orous ,with strong " wic king" te nde nc ie s (23) ,this will allo w wa ter to e nter the ta blets matrix by mea ns of c apilla ry forces which brea ks the hydrogen bo nding be tween adjac ent bundles of c ellulo se microc rystals(33) Effe c t of Mo de of Incorporation of Dis inte grant Formula 1 , was us ed to study the e ffec t of metho d of inc orporation of d is integrant .It was prepa re d b y thre e metho ds of incorpo ra tion , they we re : e xtra graunlar 1, intragra nula r 1b , and c omb inatio n of b oth type s 1c .The da ta a re displayed in fig (4) and ta ble (5 ). Formula No . Diluent Type Hardness(kg) Friability (%) Disintegra tion time (mi n) Dissolutio n Time (min) to 100% 1 Starch 8 .25 0 .539 5 20 2 Dextrose 7 0.1 4 40 4 Ma nnitol 7.5 .5 6 35 7 Emcompre ss 3 1.1 0.5 20 Fo rmula No. Diluent Typ e Hardnes s(kg) Friability (%) Dis integration ti me (mi n) Dissolutio n Time (min)to1 00% 1 Av icel 8.25 0.53 9 5 20 5 Exp lo tab 4 0 .1 5 25 6 Starch 3 .5 0 .01 4 30 0 10 20 30 40 50 60 70 80 90 100 0 5 10 15 20 25 30 TIME (MIN.) P e rc e n t o f D ru g R e le a s e d formula 1 formula 5 formula 6 disipal Ir aq i J.Pharm.Sc i., Vol.15 (1 ) ,2006 7 1.984 1.986 1.988 1.99 1.992 1.994 1.996 1.998 2 2.002 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 Tim(month) lo g p e rc e n t re m a in in g 50 60 70cc c Fig. 4 : Effe ct o f mode of inc orporatio n of dis inte grant on the re lease of Orphe ndrine fro m pre pa re d formulas Table ( 5 ) A Comparis on Be twee n the Effect of Me thod of Inc orporatio n of Dis inte gra nt Extra or Intra or Combina tion o f Both Fo rmula No. Dis integrant Loc ation Ha rd ness (kg) F riab ility(%) Dis inte gratio n Time (mi n) Disslutio n Time (mi n) to 100% I Avice l Extra 8.25 0 .539 5 2 0 Ib Avice l intra 3 0.1 3 1 9 Ic Avicel Extra & intra 3.5 0.15 4 1 5 The res ults s ho wed that fas ter disinte gratio n (3 mins.)and sho rte r diss olution time (1 0mins .)for formula 1b c omp ared with tha t of fo rmula 1c a nd formula 1. This is in a greeme nt with Gordon et al(34). who state d that inco rpo ra tion of s upe r d is inte grant in the intra gra nula r pha se re sulted in fas ter tablet diss olutio n than did inc orporating it in the extragra nular phase o r bo th p ha ses . Bas ed o n the ov erall results ; it se ems tha t formula 1 and 5 are the p ro mis ing formulas co mpared with the re fe re nc e ta ble t DISPAL .Sinc e both of them showe d goo d d is integration and diss olutio n times . Ho wev er , rega rd ing the ec ono mic p art of p rod uc tion a nd the cos t of mannito l (33) , fo rmula 5 was e xclud ed . Kine tic Study The stability of fo rmula 1 which wa s chos en a s the promising formula wa s stud ie d at d iffe re nt te mpe ra ture s ( 50 , 60 a nd 70 C ) for four months . The degra da tion of Orphe na drine citra te follows first order kinetic sinc e stra ight line s were o btaine d when the lo garithm of pe rc ent re maining o f Orphe na drine citrate wa s plotte d ve rs us time ( fig.5) . The de grad atio n ra te c ons tants (K) fo r d ifferent te mpe rature s were ca lc ulated from the slop es o f the lines a s shown in table (6) . Ta ble (6 ) Ra te Co ns tants of De grada tion (K) of Orphe nadrine Citrate (formula 1) a t Diffe re nt Te mpe rature s Te mpera ture C K(mon th -1) 50 1.010-3 60 1 .41310-3 70 1 .99510-3 Fig .5 : Acce le rate d bre akdown of Orphe nadrine citra te a t diffe re nt e levate d te mpe rature s (fo rmula 1) 0 50 1 00 0 10 20 3 0 Tim e ( m in ) P e rc e n t o f D ru g R e le a s e d fo rm ula I fo rm ulaI fo rm ula 1 b c Ir aq i J.Pharm.Sc i., Vol.15 (1 ) ,2006 8 To c omp ute the expec te d e xpiratio n d ate (t10%), Arrhenius plot was ma de to p re dict the K25C as shown in fig (6). utilizing the fo llowing equatio n : 0 .1 04 t10 =  K25C Howe ver , the c alculate d t10% wa s lo ng ,so its co nside rd to be equal for 5 ye ars .In ad dition , at the end o f fo ur months , no c ha nge in physica l p rop erties of the prepa re d ta blets wa s se en . Fig .6 Arrhe nius plot for e xpiration date e stima tion o f Orphe nadrine citra te (formula 1) RELIMINARY CLINICAL STUDY The res ults o f this stud y as indica te d in tab le (7 ) sho wed fiv e out o f se ven p atie nts ha d a goo d re spo ns e to the drug a fter o ne we ek of trea tme nt fo r the se lected formula 1 a s well as the re fe re nc e ta blets DISPAL , while the re st two p atie nts showed d ifferent behav ior . i.e , one had no res po nse to the d rug and the o ther sho wed s id e effe cts such a s ha lluc inatio n and blurre d v is io n a fter o ne da y o f trea tme nt , therefore the the ra py was sto ppe d , o n the other hand , the drug s howe d no effe ct on patients with dystonia as with the plac ebo ta blets . CONCLUSION Fro m all previous experimenta l work one can conclud e tha t be st b inder is PVP in ethanol since it is c he ap , a va ilab le , co mpress ible and comp atible with drug . Starch a nd Ma nnitol a re the b es t diluents b ut we prefer using starch bec ause of its low co st . Av ic el is a goo d disintegra nt s ince it is c ompres sible , highly porous giving a good disintegra ting time although it is relative ly e xpe ns iv e .F ormula 1 is the most sa tisfac to ry formula in co mparison with the reference tab le ts DISIPAL.and the t10% was c onsidered to b e equal for 5 yea rs . Ta ble (7) Clin ic al Responses to pre pare d Orphe nadrine ta ble ts and the re fe re nce P atie nt Age (yea r) Se x Chief co mplaint Past tre atmen t Duration ne w tre atmen t Dose No te s 1 6 0 Ma le Tre mor Pa rkizol sina met One d ay 13 Pa tie nt de velop ha llucination and b lurred vis io n stop tre atment after one do se o nly 2 4 0 Ma le Tre mor No 2 wee ks 13 Mod erate res ponse 3 5 0 Fe male Tre mor Sina met 2 mo nths 13 Go od re sp ons e 4 5 9 Ma le Tre mor No 3 mo nths 13 Go od re sp ons e 5 3 0 Female Tre mor No 1wee k 13 No res ponse 6 4 0 Fe male Tre mor a nd rigidity Pa rkizol Sina met a rtane 1 month 13 Go od re sp ons e 7 4 5 Ma le Tre mor No 2 wee ks 13 Mod erate res ponse 8 1 1 Fe male Dys to nia No 3 wee ks 13 No res ponse 9 1 5 Ma le Dys to nia No 1 month 13 No res ponse 10 3 0 Ma le Dys to nia No 2 wee ks 13 No res ponse % respo nse to Tre mor 71 .4 % side effect 14 .2 8 % resp onse to dystonia 0.0 No te : The diffe re nce be twe e n g ood & mode ra te re s ponse s is re late d to the e x amine r - 4 - 3 . 8 - 3 . 6 - 3 . 4 - 3 . 2 - 3 - 2 . 8 - 2 . 6 - 2 . 4 - 2 . 2 - 2 0 1 2 3 4 1 / T * 1 0 0 0 lo g k ( m o n th -1 ) Ir aq i J.Pharm.Sc i., Vol.15 (1 ) ,2006 9 REFERENCES 1. 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