IJRPC 20, (3) Chowdry et l. ISSN: 223 278 INTERNATIONAL JOURNAL OF RESEARCH IN PHARMACY AND CHEMISTRY Aville online t www.ijrpc.com Reserch Article A FACTORIAL STUDY ON THE EFFECTS OF β CYCLODEXTRIN AND POLOXAMER 407 ON THE SOLUBILITY AND DISSOLUTION RATE OF PIROXICAM Chowdry KPR*, Sury PRK nd Vur Sirish University College of Phrmceuticl Sciences, Andhr University, Viskhptnm, Andhr Prdesh, Indi. *Corresponding Author: prof.kprchowdry@rediffmil.com ABSTRACT The ojective of the study is to evlute the individul nd comined effects of β cyclodextrin (βcd), surfctnt (Poloxmer 407) on the soluility nd dissolution rte of piroxicm, BCS clss II drug in series of 2 2 fctoril experiments. The soluility of piroxicm in four selected fluids contining βcd nd Poloxmer 407 s per 2 2 fctoril study ws determined. The individul nd comined effects of βcd nd Poloxmer 407 in enhncing the soluility of piroxicm were highly significnt (). βcd nd Poloxmer 407 lone gve n increse of.08 nd 2.03 fold respectively in the soluility of piroxicm nd cominedly they gve.97 fold increse in the soluility of piroxicm. Solid inclusion complexes of piroxicm βcd were prepred with nd without Poloxmer 407 y kneding method s per 2 2 fctoril design. The individul min effects of βcd nd Poloxmer 407 nd their comined effect in enhncing the dissolution rte (K ) nd dissolution efficiency (DE 30) of piroxicm were highly significnt (). βcd nd Poloxmer 407 lone gve respectively 5.5 nd 3.34 fold increse in the dissolution rte of piroxicm nd cominedly they gve mrkedly higher enhncement (20.2 fold) in the dissolution rte of piroxicm. βcd nd Poloxmer 407 lone gve respectively 3.26 nd 3.08 fold increse in the dissolution efficiency (DE 30) of piroxicm nd cominedly they gve mrkedly higher enhncement (5.55 fold) in the dissolution efficiency (DE30) of piroxicm. Comintion of βcd with Poloxmer 407 gve much higher enhncement in the dissolution rte nd efficiency (DE 30) of piroxicm thn is possile with them individully. Hence comintion of βcd nd Poloxmer 407 is recommended to enhnce the dissolution rte of piroxicm. Key words: Piroxicm, β Cyclodextrin, Poloxmer 407, Dissolution rte, Fctoril Study. INTRODUCTION Aout 95% of the newly developed orgnic drugs elong to clss IΙ under BCS nd exhiit low nd vrile orl iovilility due to their poor queous soluility. They re prcticlly in solule in wter nd queous fluids. As such their orl sorption is dissolution rte limited nd they require enhncement in soluility nd dissolution rte 60
IJRPC 20, (3) Chowdry et l. ISSN: 223 278 for incresing their orl iovilility. Among the vrious pproches complextion with cyclodextrins hs gined good cceptnce in recent yers in industry for enhncing the soluility nd dissolution rte of poorly solule drugs. Cyclodextrins (CDs) re cyclic torusshped molecules with hydrophilic outer surfce nd lipophilic centrl cvity which cn ccommodte vriety of lipophilic drugs. As consequence of inclusion process mny physicochemicl properties such s soluility, dissolution rte, stility nd iovilility cn e fvourly ffected,2. Cyclodextrins hve een receiving incresing ppliction in phrmceuticl formultion in recent yers due to their pprovl y vrious regultory gencies 3,4. Poloxmer 407 is polyethylene oxide polypropylene oxidepolyethylene oxide trilock copolymer of nonionic nture nd is used s soluilising gent 57. Though cyclodextrin complextion nd use of surfctnts such s Poloxmer 407 for enhncing the soluility nd dissolution rte of poorly solule drugs hve een investigted individully, no reports re ville on their comined use in enhncing the soluility nd dissolution rte of poorly solule drugs. The ojective of the present investigtion is to evlute the individul min effects nd comined (or interction) effects of β cyclodextrin (βcd) nd surfctnt (Poloxmer 407) on the soluility nd dissolution rte of piroxicm from CD complexes in 2 2 fctoril experiment. Piroxicm, widely prescried nti inflmmtory nd nlgesic drug elongs to clss II under BCS nd exhiit low nd vrile orl iovilility due to its poor queous soluility nd needs enhncement in soluility nd dissolution rte for incresing its orl iovilility. In fctoril experiments the effects of severl fctors of vrition re studied nd investigted simultneously, the tretments eing ll the comintions of different fctors under study. In these experiments n ttempt is mde to estimte the effects of ech of the fctors nd lso the interction (or comined) effects, i.e., the vrition in the effect of one fctor s result to different levels of other fctors. EXPERIMENTAL Mterils Piroxicm ws gift smple from M/s. Ntco Phrm Ltd., Hyderd. βcyclodextrin ws gift smple from M/s. Cerestr Inc., USA. Methnol (Quligens) nd Poloxmer 407 were procured from commercil sources. Estimtion of Piroxicm An UV spectrophotometric method sed on the mesurement of sornce t 333 nm in 0. N Hydrochloric cid of ph.2 ws used for the estimtion of piroxicm. The method ws vlidted for linerity, ccurcy, precision nd interference. The method oeyed Beer s lw in the concentrtion rnge of 00 µg/ml. When stndrd drug solution ws repetedly ssyed (n=6), the reltive error nd coefficient of vrince were found to e 0.75% nd.25% respectively. No interference y the excipients used in the study ws oserved. Soluility determintion Excess drug (50 mg) ws dded to 5 ml of ech fluid tken in 25 ml stoppered conicl flsk nd the mixtures were shken for 24 h t room temperture (28± o C) on Rotry Flsk Shker. After 24 h of shking, 2 ml liquots were withdrwn t 2 h intervl nd filtered immeditely using 0.45 µ disk filter. The filtered smples were diluted suitly nd ssyed for piroxicm y mesuring sornce t 333 nm. Shking ws continued until two consecutive estimtions re the sme. The soluility experiments were replicted four times ech (n=4). Preprtion of PiroxicmCD complexes Solid inclusion complexes of piroxicm βcd were prepred in :2 rtio with nd without Poloxmer 407 (2%) y kneding method. Piroxicm, βcd nd Poloxmer 407 were triturted in mortr with smll volume of solvent consisting of lend of wter: methnol (:). The thick slurry formed ws kneded for 45 min nd then dried t 55 o C until dry. The dried mss ws powdered nd sieved to mesh No. 20. Dissolution rte study The dissolution rte of piroxicm s such nd from βcd complexes prepred ws studied in 900 ml of 0. N hydrochloric cid using Disso 2000 (Lindi) 8sttion dissolution test pprtus with pddle stirrer t 50 rpm. A temperture 37± o C ws mintined 602
IJRPC 20, (3) Chowdry et l. ISSN: 223 278 throughout the study. Piroxicm or piroxicm CD complex equivlent to 20 mg of piroxicm ws used in ech test. Smples of dissolution medi (5ml) were withdrwn through filter (0.45µ) t different intervls of time, suitly diluted nd ssyed for piroxicm t 333 nm. The smple of dissolution fluid withdrwn t ech time ws replced with fresh fluid. The dissolution experiments were replicted three times ech (n=3). RESULTS AND DISCUSSION The individul min effects nd comined (interction) effects of βcd (Fctor A) nd Poloxmer 407 (Fctor B) on the queous soluility of piroxicm were evluted in 2 2 fctoril experiment. For this purpose, two levels of βcd (0, 5mM) nd two levels of Poloxmer 407 (0, 2%) were selected in ech cse nd the corresponding four tretments involved in the 2 2 fctoril study re purified wter (), wter contining 5 mm βcd (); wter contining 2% Poloxmer 407 (); wter contining 5 mm βcd nd 2% Poloxmer 407 (). The soluility of piroxicm in the ove mentioned four fluids ws determined (n=4) nd the results re given in Tle. The queous soluility of piroxicm ws mrkedly enhnced y βcd nd Poloxmer 407 lone nd in comintion. The soluility dt were sujected to Anlysis of vrince (ANOVA) to find out the significnce of min individul nd comined effects of βcd nd Poloxmer 407 on the soluility of piroxicm. The results of ANOVA re shown in Tle 2. The individul nd comined effects of βcd nd Poloxmer 407 in enhncing the soluility of piroxicm were highly significnt (). βcd nd Poloxmer 407 lone gve n increse of.08 nd 2.03 fold respectively in the soluility of piroxicm nd cominedly they gve.97 fold increse in the soluility of piroxicm. To evlute the individul nd comined effects of βcd nd Poloxmer 407 on the dissolution rte of piroxicm, solid inclusion complexes of piroxicm βcd were prepred with nd without Poloxmer 407 s per 2 2 fctoril design. For this purpose two levels of βcd (0 nd : 2 rtio of drug : CD) nd two levels of Poloxmer 407 ( 0 nd 2%) were selected nd the corresponding four tretments involved in the 2 2 fctoril study were piroxicm pure drug (); piroxicm βcd (:2) inclusion inry complex (); piroxicm Poloxmer 407 (2%) inry mixture (); piroxicm βcd (:2) Poloxmer 407 (2%) ternry complex (). The CD complexes were prepred y kneding method. All the solid inclusion complexes of piroxicm βcd Poloxmer 407 prepred were found to e fine nd free flowing powders. Low coefficient of vrition (c.v.) vlues (< %) in the percent drug content indicted uniformity of drug content in ech tch of solid inclusion complexes prepred. The dissolution rte of piroxicm lone nd from βcd complexes prepred ws studied in 0.N hydrochloric cid. The dissolution of piroxicm followed first order kinetics with r (correltion coefficient) ove 0.90. Dissolution efficiency (DE 30) vlues were clculted s suggested y Khn 8. The dissolution prmeters re given in Tle3. The dissolution of piroxicm ws rpid nd higher in the cse of ll piroxicm βcd complexes prepred when compred to piroxicm s such. The dissolution rte (K ) vlues were sujected to ANOVA to find out the significnce of the min nd comined effects of βcd nd Poloxmer 407 on the dissolution rte of piroxicm. The results of ANOVA re shown in Tles 45. ANOVA indicted tht ll the individul min effects of βcd nd Poloxmer 407 nd their comined effect in enhncing the dissolution rte (K ) nd dissolution efficiency (DE 30) of piroxicm were highly significnt (P < 0.0). βcd nd Poloxmer 407 lone gve respectively 5.5 nd 3.34 fold increse in the dissolution rte of piroxicm nd cominedly they gve mrkedly higher enhncement (20.2 fold) in the dissolution rte of piroxicm. Similrly βcd nd Poloxmer 407 lone gve respectively 3.26 nd 3.08 fold increse in the dissolution efficiency (DE 30) of piroxicm nd cominedly they gve mrkedly higher enhncement (5.55 fold) in the dissolution efficiency (DE 30) of piroxicm. Thus the results of the study indicted tht comintion of βcd with Poloxmer 407 gve much higher enhncement in the dissolution rte nd efficiency (DE 30) of piroxicm thn is possile with them individully. Hence comintion of βcd nd Poloxmer 407 is recommended to enhnce the dissolution rte of piroxicm, BCS clss II drug. 603
IJRPC 20, (3) Chowdry et l. ISSN: 223 278 Tle : Soluility of Piroxicm in Vrious Fluids s per 2 2 Fctoril Study Fluids (Code s per 2 2 Fctoril Experiment) Distilled wter () Wter contining 5 mm βcd () Wter contining 2% Poloxmer () Wter contining 5mM βcd nd 2% Poloxmer () Soluility (mg/ml) (n=4) (x± sd) 0.79±0.004 0.93±0.008 0.364±0.02 0.352±0.037 Increse in Soluility (Numer of Folds).08 2.03.97 Tle 2: ANOVA of Soluility Dt of Piroxicm in vrious fluids s per 2 2 Fctoril Study (βcd Poloxmer 407) Source of Vrition D.F S.S M.S.S FRtio Significnce Totl 5 0.24 0.008 Tretment 3 0.9 0.040 83.98 0.004 0.004 7.869 P < 0.05 0.8 0.8 250.369 0.008 0.008 6.867 Error 2 0.006 0.0005 F0.0 (, 2) = 9.33; F0.05 (, 2) = 4.75 ; F0.0 (3, 2) = 5.95; F0.05 (3, 2) = 3.49 Tle 3: Dissolution Rte nd DE 30 of Piroxicm βcd Poloxmer 407 Complex Systems prepred s per 2 2 Fctoril Study Tretment* Averge K (n=3) (x± sd) Increse in K (Numer of Folds) Averge DE30 (n=3) (x± sd) Increse in DE30 (Numer of Folds) 0.0±0.0 3.5±0.04 0.059±0.7 5.5 0.29±0.0 3.26 0.036±0.004 3.34 9.70±0.09 3.08 0.22±0.48 20.2 7.52±0.04 5.55 *: piroxicm pure drug; : piroxicm βcd (:2) inclusion inry complex; : piroxicm Poloxmer 407 (2%) inry mixture; : piroxicm βcd (:2) Poloxmer 407 (2%) ternry complex Tle 4: ANOVA of Dissolution Rte (K ) of Piroxicm βcd Poloxmer 407 Complex Systems prepred s per 2 2 Fctoril Study Source of Vrition D.F S.S M.S.S FRtio Significnce Totl 0.079 0.007 Tretment 3 0.078 0.026 576.297 604
IJRPC 20, (3) Chowdry et l. ISSN: 223 278 0.8 0.025 0.068 0.8 0.025 0.068 2602.84 553.472 503.64 Error 8 0.00036 0.00005 F0.0 (, 8) =.26; F0.05 (, 8) = 5.32; F0.0 (3,8) = 7.59 ; F0.05 (3,8) = 4.07 Tle 5: ANOVA of DE 30 Dt of Piroxicm βcd Poloxmer 407 Complex Systems prepred s per 2 2 Fctoril Study Source of Vrition Totl Tretment D.F S.S M.S.S FRtio Significnce 3 35.073 30.244 3.566 42.246 203.20 28.643 03.45 3.566 42.246 203.20 7.328 5.908 235.66 336.646 P < 0.05 Error 8 4.82884 2.69 F0.0 (, 8) =.26; F0.05 (, 8) = 5.32 ; F0.0 (3,8) = 7.59 ; F0.05 (3,8) = 4.07 CONCLUSION The individul nd comined effects of βcd nd Poloxmer 407 in enhncing the soluility of piroxicm were highly significnt (). βcd nd Poloxmer 407 lone gve n increse of.08 nd 2.03 fold respectively in the soluility of piroxicm nd cominedly they gve.97 fold increse in the soluility of piroxicm. The individul min effects of βcd nd Poloxmer 407 nd their comined effect in enhncing the dissolution rte (K) nd dissolution efficiency (DE 30) of piroxicm were highly significnt (). βcd nd Poloxmer 407 lone gve respectively 5.5 nd 3.34 fold increse in the dissolution rte of piroxicm nd cominedly they gve mrkedly higher enhncement (20.2 fold) in the dissolution rte of piroxicm. Comintion of βcd with Poloxmer 407 gve much higher enhncement in the dissolution rte nd efficiency (DE 30) of piroxicm thn is possile with them individully. Hence comintion of βcd nd Poloxmer 407 is recommended to enhnce the dissolution rte of piroxicm. REFERENCES. Fromming KH nd Szejtli J. Cyclodextrins in Phrmcy, Kluwer Acdemic Pulictions, Dordrecghi. 994;20. 2. Duchene D nd Woussidjewe D nd Dumitriu S. Polyscchrides in Medicl Applictions. Mrcel Dekker, New York. 996;575 602. 3. Thompson DO. Cyclodextrins Enling Excipients. Their present nd Future Use in Phrmceuticls, Crit Rev Ther Drug Crrier Syst. 997; 4 ():04. 4. Hedges AR. Industril Applictions of Cyclodextrins. Chem Rev. 998; 98: 2035 2044. 5. Ptel TB, Ptel LD, Ptel TB, Mkwn SH nd Ptel TR. Formultion nd Chrcteriztion of Solid dispersions Contining Glienclmide. Int J Phrm Phrmceuticl Sci. 200;2:38 4. 6. Pore Y, Vys V, Sncheti P, krekr P nd Shh M. Physicochemicl Chrcteriztion of Solid Dispersion Systems of Tdlfil with Poloxmer Act Phrm. 2009;59 (4): 45346. 7. Dumortier G, Grossiord JL, Agnely F nd Chumeil JC. A review of Poloxmer 407 Phrmceuticl nd Phrmcologicl Chrcteristics. Phrmceuticl Reserch. 2006; 23 (2):27092728. 8. Khn KA. The Concept of Dissolution Efficiency. J Phrm Phrmcol. 975; 27: 4849. 605