Dissolution testing of solid dosage forms is well-established as a standard technique to assess drug release from tablets and capsules. It is currently the most useful in vitro method for assuring batch-to-batch uniformity, and is a valuable quality control procedure for comparing release profiles of different batches of finished products.peer-reviewe

Farrugia, Claude

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No 6 Summer 2002    thechronic✱ill         17Flow-ThroughDissolutionTestingA comparisonwith stirred beaker methodsClaude A. Farrugia B.Pharm.(Hons.) Ph.D.(UIC)Lecturer, University of Malta, Msida, MaltaE-mail: claude.farrugia@um.edu.mtDissolution testing of solid dosage forms is well-established asa standard technique to assess drug release from tablets andcapsules. It is currently the most useful in vitro method forassuring batch-to-batch uniformity, and is a valuable qualitycontrol procedure for comparing release profiles of differentbatches of finished products.1Keywords: dissolution testing, flow-through apparatusThe earliest dissolution apparataincluded Pernarowski’s basketdissolution assembly2 and Poole’spaddle design.3 Until recently, officialdissolution testing methods were basedentirely on modifications of these staticmodels. However, these methods sufferfrom a number of disadvantages4 andthe need for a new official dissolutiontest was recognised, resulting in theintroduction of the flow-throughdissolution apparatus in the UnitedStates Pharmacopeia5 and the BritishPharmaceopoeia.6Basic Design ofDissolution ApparataThe traditional dissolution apparataare based on a stirred-tank staticsystem model, where the drug isdissolved in a relatively large, fixedvolume of dissolution mediumcontained in a cylindrical vessel with ahemispherical bottom. The vessel ispartially immersed in a suitable waterbath to maintain the temperature ofthe medium at 37OC. A forcedconvection type of agitation isaccomplished by means of a stirring,rotating or oscillating device, generallya motor-driven paddle or wire-meshbasket. Discrete samples areperiodically withdrawn from thedissolution medium and analysed.In flow-through methods, theassembly consists of a reservoir andpump for the dissolution medium, athermostatically-controlled flow-through cell and a water bath thatmaintains the dissolution medium at37OC (Figure I). The pump is separatedfrom the dissolution unit in order toshield the latter against vibrationsoriginating from the pump. The cell ismade of transparent and inert material,and is mounted vertically with a screenand filter system that prevents escapeof undissolved particles from the top ofthe cell. The bottom cone is usuallyfilled with small 1-mm glass beads withone 5-mm bead positioned at the apexto protect the fluid entry tube. Thedosage form under investigation isplaced on the beads or on a wire carrierinside the cell and a continuous flow ofthe dissolution medium from thereservoir is forced upwards through thecell by the pump. The dissolution fluidis usually collected in a separatereservoir as it leaves the dissolutioncell; fractions are removed at specifiedintervals and analysed.Comparison of the flow-through method with staticvolume dissolution testing.The advantages and disadvantagesof the flow-through method are listedin Table I. Three particularly importantissues warrant further discussion.1. Flow characteristicsof the dissolution mediumOne of the factors responsible forthe inherent lack of homogeneity in thebeaker methods results from theagitation methods. Agitating the liquidby stirring with a wire mesh basket or apropeller creates a certain degree ofturbulent solvent flow, which causes avariable shear rate of solvent transferover the surface of the particles,resulting in excessive variations in theindividual rates of dissolution. Themovement of solute over any particlewill depend on the position of theparticle in the vessel and the characterof the stirring process at each positionNo 6 Summer 2002    thechronic✱ill         18within the container. The latter variesmarkedly with the geometry of thevessel, the volume of the liquid, andthe speed and form of motion createdby the agitator.4 The apparatus thusintroduces an inherent variability intothe dissolution process, which isextrinsic to the product under study.This can result in a lack ofreproducibility, and consequently, thesesystems have to be greatlystandardised, reducing investigativeflexibility.The objective of the flow-throughdesign was to expose the dosage formto a homogeneous, non-turbulent,laminar flow, devoid of the problemsassociated with a stirring mechanism.However, achieving this goal can alsobe problematic, since both the natureof the pump7,8 and, to a greater extent,the flow rate9,10 can affect the patternof flow inside the cell. Thus in earlierdesigns, at high flow rates, a column ofsolvent moved rapidly upwards andrandomly dispersed after striking theupper screen and filter holder, withwidespread turbulence. The drugparticles resided in eddies within thistype of flow, resulting in decreaseddissolution rates. On the other hand, atrelatively low flow rates, while thesolvent entering the chamber hadlaminar characteristics, after strikingthe upper screen some of the solventreturned to the bottom of the cell, withlaminar or turbulent characteristics,creating an undesirable two-directionalflow. The best results were thusobtained with intermediate flow rates;within a certain range of flow rates, thedissolution rate was found to varylogarithmically with the flow rate.9 Therange of useful flow rates was increasedwhen a bed of glass beads was added tothe cell to act as dampers.102. Liquid VolumeIn the beaker methods, the liquidvolume must be fixed beforehand; twomajor considerations require that theliquid volume be a large one.a) Dissolution rate is directlyproportional to the concentrationgradient between the saturationsolubility concentration at thesolid/liquid interface, and thesolute concentration in the bulk ofthe system. Since the formerconcentration remains constant, itis important that the bulk soluteconcentration be kept as low aspossible in order to maintain arelatively constant concentrationgradient. This is achieved bydissolving the dosage form in alarge volume of medium.4b) In all beaker methods the drugconcentration in the liquid increasesfrom zero up to either thesaturation limit or theconcentration which corresponds tothe completely dissolved drugamount. This concentration increaseis different from the in vivo processin which the dissolved material isremoved continuously from thedissolution medium by absorption.In order to improve the chances ofachieving good in vitro-in vivocorrelations in this area, dissolutionprocesses must be studied bymethods in which the liquid acts asa perfect sink, that is, theconcentration never exceeds 10-20% of the saturation. The need fora perfect sink necessitates using arelatively large volume of solvent.4While the rate of agitation shouldbe kept low in order to establishmeaningful in vitro-in vivo correlationsand to detect subtle differencesbetween formulations, low agitation ofa high volume system results in poorhomogeneity, and the samplewithdrawn for analysis might not berepresentative of the whole system. Arelatively high rate of agitation is thusrequired, accentuating the lack ofhomogeneity in flow patternsmentioned previously. Thus, there is aninherent disagreement existing in thesesystems between the requirements forhomogeneity, large volumes, and lowTable I: Advantages anddisadvantages of the flow-through dissolution apparatusAdvantages:• Laminar flow characteristics overa wide range of solvent flow rates• Infinite sink ideal for lowsolubility drugs• Differential rather thancumulative time profile ofdissolved drug concentration• Dwell time of dosage form inmedium is minimal, reducing riskof drug degradation• pH modification of dissolutionmedium is easy• Samples for analysis easilyobtained without alteringdissolved drug concentrationDisadvantages:• Large volumes of media requiredto maintain flow rate• Risk of clogging of filters• Validation of flow rate duringtesting is difficultFigure I: Schematic representationof a flow-through dissolution apparatus.No 6 Summer 2002    thechronic✱ill         191. Chattaraj SC, Kanfer I. ‘The Insertion Cell’: Anovel approach to monitor drug release fromsemi-solid dosage forms. Int J Pharm1996;133:59-63.2. Pernarowski M, Woo W, Searl R. Continuousflow apparatus for the determination ofdissolution characteristics of tablets andcapsules. J Pharm Sci 1968;57:1419-21.3. Poole J. Some experiences in the evaluationof formulation variables in drug availability.Drug Inform Bull 1969;3:8-16.4. Tingstad JE, Riegelman S. Dissolution ratestudies I: Design and evaluation of acontinuous flow apparatus. J Pharm Sci1970;59:692-6.5. United States Pharmacopeia. The UnitedStates Pharmacopeia 23rd Revision. Rockville,MD: The United States PharmacopeialConvention, Inc.; 1995. p. 1791-6.6. British Pharmacopoeia Commission. TheBritish Pharmacopoeia, 1993. London, U.K.:Her Majesty’s Stationery Office; 1993. p.A160-2.References7. Lerk CF, Zuurman K. The influence ofpulsation on the dissolution ratemeasurements in column type apparatus. JPharm Pharmacol 1970;22:319-20.8. Langenbucher F, Benz D, Kurth W, Möller H,Otz M. Standardized flow-cell method as analternative to existing pharmacopoeialdissolution testing. Pharm Ind1989;51:1276-81.9. Tingstad J, Gropper E, Lachman L, Shami E.Dissolution rate studies III: Effect of typeand intensity of agitation on dissolutionrate. J Pharm Sci 1973;62:293-7.10. Tingstad J, Dudzinski J, Lachman L, Shami E.Dissolution rate studies IV: Solvent flowpatterns in a column-type apparatus. JPharm Sci 1973;62:1527-30.11. Bolhuis GK, Lerk CF, Zuurman K. Comparisonof the accuracy of different types ofdissolution rate methods. Pharm Weekbl1973;108:49-53.the major advantage of the open flow-through apparatus is that perfect sinkconditions can be maintained withoutthe use of large vessels, whilemaintaining relatively low degrees ofagitation.3. Data GenerationThe beaker methods are based onthe concept of a fixed volume and thusproduce data expressed as an integralfunction, since the dissolved moleculesare accumulating in the solution. Onthe other hand, since the flow-throughtechnique continuously exposes thedosage form to fresh solvent, datageneration occurs non-cumulatively ina differential form.4 Consequently, thebeaker methods produce averagedissolution rates at best, making itdifficult to detect subtle but possiblyimportant differences in formulations,which are more readily detected in thedata generated by the flow-throughapparatus.Comparative studiesfor the assessment of theflow-through apparatusThe first comparative evaluations ofthe flow-through apparatus relative toother apparata were performed in the1970’s.11,12 More recently, acollaborative study involving fourSwedish laboratories compared thedissolution of the USP salicylic acidcalibrator tablet in the USP paddleapparatus and in a flow-throughsystem.13The results indicated a betterreproducibility over a wide range offlow rates for the flow-through methodthan the paddle method. However, asimilar study performed by the samegroup in 1989 using the USPprednisolone calibrator tablets yieldedconflicting results.14 Nevertheless thelatter study showed the flow-throughapparatus to be sensitive toformulation behaviour, and also capableof discriminating between differentcontainers in the same batch - a factorof extreme importance for tablets ofdrugs which are sensitive to storageconditions, such as prednisolone. It wasthus concluded that, in spite of thevariability between the dissolutionmethods, the flow-through apparatuscould be considered as capable as thebeaker methods in generating reliabledata, an assessment confirmed by theScandinavian laboratories in asubsequent study using the sparinglysoluble drug phenacetin.15ConclusionThe official apparata all have theirinherent advantages and disadvantagesand are thus ideal for dissolutiontesting of different systems. While theconventional stirred beaker apparataare most suited for dissolution testingof immediate-release dosage forms ofdrugs with good solubilitycharacteristics, the flow-throughapparatus, whilst suitable for mostsolid dosage forms, yields maximumbenefit in evaluating the dissolution ofpoorly-soluble drugs, primarily due tothe fact that the system provides aninfinite sink similar to thatencountered under physiologicalconditions.  ✱12. Bathe RV, Häfliger O, Langenbucher F,Schönleber D. In vitro comparison of thebeaker, the rotating basket and the columndissolution-rate methods. Pharm Acta Helv1975;50:3-10.13. Nicklasson M, Wennergren B, Lindberg J,Persson C, Ahlgren R, Palm B et al. Acollaborative in vitro dissolution study usingthe flow-through method. Int J Pharm1987;37:195-202.14. Wennergren B, Lindberg J, Nicklasson M,Nilsson G, Nyberg G, Ahlgren R et al. Acollaborative in vitro dissolution study:Comparing the flow-through method with theUSP paddle method using USP prednisonecalibrator tablets. Int J Pharm1989;53:35-41.15. Nicklasson M, Orbe A, Lindberg J, Borgå B,Magnusson A-B, Nilsson G et al. Acollaborative study of the in vitro dissolutionof phenacetin crystals comparing the flowthrough method with the USP paddlemethod. Int J Pharm 1991;69:255-64.

Flow-through dissolution testing : a comparison with stirred beaker methods

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Flow-through dissolution testing : a comparison with stirred beaker methods

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