Dissolution Technologies MAY Introduction rally disi - PDF document

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 Introduction rally disintegrating tablets contain a widevariety of pharmaceutical actives coveringmany therapeutic categories,and can beparticularly good applications for pediatric andgeriatric treatments.The time for disintegration of Table 1 The development of dissolution methods fororally disintegrating tablets is comparable to the Dissolution Testing of Orally Disintegrating TabletsJames Klancke Sr.Director,Analytical Development,CIMA LABS INC,Brooklyn Park,MN Abstract Orally disintegrating tablets (ODT) are solid dosage forms that disintegrate in the oral cavity leaving aneasy-to-swallow residue.The disintegration times are generally less than one minute.For orally disinte- Table 1.Some Commercial Orally Disintegrating Tablet Products ProductODT Company/Partne r Alavert Loratadine ODTCIMA/Wyeth Consumer HealthBenadryl RediTabsR.P.Scherer/Schering-PloughTempra FirsTabsCIMA/Mead Johnson Excedrin QuickTabsEthypharm/BMSMaxalt MLTR.P.Scherer/Merck NuLevCIMA/Schwarz PharmaRemeron SolTabsCIMA/Organon Zomig ZMTand RapimeltCIMA/Astra ZenecaZyprexa ZydisR.P.Scherer/Eli Lilly 
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\f\n\b approaching or exceeding one gram and containing rela-tively dense particles may produce a mound in the dissolu-tion vessel,which can be prevented by using higher paddlespeeds.These two situations expand the suitable range to 25 75 rpm.The USP 1 basket apparatus may have certain appli-cations for orally disintegrating tablets,but is used lessfrequently due to the physical properties of these tablets.Specifically,tablet fragments or disintegrated tablet massesmay become trapped on the inside top of the basket at thespindle where little or no effective stirring occurs,yieldingirreproducible dissolution profiles. Taste-Masking Drives Dissolution Taste-masking of bitter or objectional-tasting drugsubstances is critical for any orally-adminstered dosageform,including suspensions and chewable tablets.Lesscommonly,active pharmaceutical ingredients to be incor-porated are tasteless and do not require taste-masking.Thetaste-masking aspect greatly influences dissolution methoddevelopment,specifications,and testing.Several factorsinfluence dissolution profiles of orally disintegrating tabletsthat contain taste-masked actives.Drug particle coatingscan vary in thickness,and certain polymer coatings have pH-dependent solubility such as methacrylates which influencedissolution profiles.Surface wettability of these particles isdependent on composition and may also be dependent onthe process by which they were manufactured.There are multiple approaches to taste-masking andcoating which have applicability to orally disintegratingtablets and must be understood by method developmentpersonnel.A drug solution or suspension can be applied to asubstrate followed by polymer coating,or the drug particlesmay be coated directly.Alternatively,granulation of the drugwith certain excipients followed by polymer coating canachieve taste-masking.Certain taste-mask coatings are pH-independent,while others are pH-sensitive.The coatingscan dissolve,swell,or become permeable during the disso-lution test depending on the selected media.Coating forcontrolled-release,where taste-masking is a given,can alsobe used and incorporated into fast-dissolve dosage formssince compression forces are low and the controlled-releaseparticles remain intact.If the drug is tasteless or very lowdose,direct blend of bulk drug substance into fast-dissolvematrix is straightforward,and the dissolution profile is influ-enced primarily by properties of the drug substance.The disintegration time of orally disintegrating tablets in adissolution vessel is generally less than thirty seconds andtherefore not an important factor in the resulting dissolu-tion profile in terms of discrimination.The discrimination isbased on taste-masked coating and the active ingredientitself.Since orally disintegrating tablets are of low density,floating particles may be observed even after completetablet disintegration has taken place.The disintegrationtime of an ODT is obvious to patients and product develop-ment specialists,so in-vivo and in-vitro times are oftencompared during the development process.This fast disin-tegration makes it very important to observe how the tabletfragments and particles are behaving during the dissolutiontest compared to conventional tablets,which typicallydisplay much less breakup at the bottom of the vessel earlyin the test.As with all solid oral dosage forms,dissolution serves as acontrol test.The same is true for taste-masked bulk drug.Batch-to-batch consistency can be assured,and dissolutiondata on the taste-masked drug is frequently predictive ofdissolution of the tableted product.The USP 2 paddle appa-ratus at 50-100 rpm is suitable for dissolution testing oftaste-masked drug as well.The media used for the taste-masked drug should match that of the finished product tomaximize the value of the test.There are certain cases whereit may be advantageous to use increased paddle speed fortaste-masked drug in order to better match the orally disin-tegrating tablets profile.Dissolution as a stability test fortaste-masked drug is indicative of performance of coatingover time and is a meaningful test in stability programs.Shelf-life (for bulk warehousing) specifications shouldmatch the release specifications.Dissolution of taste-masked bulk drug is an important testmethod for both product development and quality control. Q -type specifications are not applicable since it is notrepresentative of finished dosage unit (but rather is ahomogenous sample).It is appropriate to use the meanvalue obtained from 6 or 12 vessels.The % drug releasedcalculation is based directly on assay value of material ratherthan label claim,and UV analysis of the sample pulls isgenerally suitable.Filtration is important due to undissolvedparticles present during sampling.An example of thedependence of dissolution on taste-mask coating thicknessfor bulk,taste-masked pseudoephedrine HCl particles isshown in Figure 1 (page 8) Relative assessment of taste using a neutral pH media isused to establish approximate baseline for early timepointdissolution value.The delay in drug release only needs to belong enough to pass through the oral cavity,followed by fastand complete release as for any immediate release dosageform.A simulated ideal profile is shown in Figure 2 (page 8). The assessment is also monitored during scale-up toassure that the taste-masking attributes are maintained.In 7 Dissolution   

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 Orally Disintegrating Tablets É continued development,a target specification can be set for taste-masked drug to assure acceptable/consistent taste.HPLC is often required to analyze dissolution aliquots dueto presence of UV-absorbing components,specificallyflavors and sweeteners.Excipient to drug ratios may behigher since the formulation is designed to have good tasteand mouthfeel,decreasing signal of the drug to background(excipients) in the UV.In general,the approach to dissolution for orally disinte-grating tablets has similarities to conventional tablets.Disso-lution is key to orally disintegrating tablets productdevelopment,and taste-masking approaches dictate exper-imental dissolution plan.Due to the nature of these formula-tions,there is generally an additional level of complexity indevelopment and analysis. Nomenclature Notes Orally Disintegrating Tablets terminology adapted by theNomenclature and Labeling committee at USP.[DRUG] Orally Disintegrating Tablets is the generalform of nomenclature for tablets that disintegraterapidly or instantly in the oral cavity.Itis the name to beused where immediate-release is characteristic of theswallowed particles;i.e.,drug release is that which isobserved also for conventional compressed tablets thatare not formulated specifically to release drug at someother time interval,and the Immediate-Release termi-nology does not appear in the name. References 1.AC Liang and LH Chen,Fast-dissolving intraoral drugdelivery systems,Expert Opin.Ther.Patents,11(6),20012.Y Morita,Y Tsusima,M Yasui,R Termoz,J Ajioka,and KTakayama,Evaluation of Disintegration Time of RapidlyDisintegrating Tablets via a Novel Method Utilizing aCCD Camera,Chem.Pharm.Bull.,50(9) 1181-1186,20023.S Schiermeir,and PC Schmidt:Fast dispersible ibupro-fen tablets,Eur.J.Pharm Sci.15 295-305,20024.M Siewert,J Dressman,C Brown,and V Shah,FIP/AAPSGuidelines for Dissolution/In Vitro Release Testing ofNovel/Special Dosage Forms,Dissolution Technologies,February 2003 Figure 2. Figure 1.