Chapter 1 presents general information on tableting and is an introduction to the other chapters. Chapter 2 covers the mechanism of action of tablet disintegrants, in particular modern super disintegrants. The results indicate that when the tablets contain a slightly swelling but hydrophilic disintegrant, the penetration of water into tablets is the controlling step in the process of disintegration. Consequently tablet disintegration is strongly affected by the presence of a hydrophobic lubricant. ... Zie: Summar

Kamp, Herman Vincent van

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University of GroningenOptimization of the formulation of fast disintegrating tabletsKamp, Herman Vincent vanIMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:1987Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Kamp, H. V. V. (1987). Optimization of the formulation of fast disintegrating tablets. s.n.CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 24-12-2025SI'MMARfChapter 1 presents general information on tableting and is an introductionto the other chapters.Chapter 2 covers the mechanism of action of tablet disintegrants, inparticular modern super disintegrants. The results indicate that when thetablets contain a slightly swelling but hydrophilic disintegrant, thepenetration of water into tablets is the controlling step in the process ofdisintegration. Consequently tablet disintegration is strongly affected bythe presence of a hydttophobic lubricant. When the tablets contain stronglyswelling disintegrants, a chain reaction of disruption of the tabletstructure is the dominant factor in the process of disintegration, since thedisruption proceeds from the outside to the inside of the tablet. In thiscase, the process of disintegration is hardly influenced by hydrophobiclubricants.In Chapter 3, the design of an improved method for the measurement ofliquid uptake by tablets or loose powders is presented. The apparatusdescribed enables easy, fast and reproducible measurement of both wateruptake and penetration rate into particulate systems. Water uptake profileso f  t ab le t s  compressed  fnom d i f f e ren t  f i l l e r -b inde rs  o r  f i l l e r -binder / disintegrant mixtures , both unlubricated and lubricated , clearly showthe effect of the nature of the filler-binder, the presence of the lubricantand the swelling capacity of the disintegrant on the disintegrationproperties of the tablets. The results indicate, that this method can beused for characterization of tablet excipients and may be helpful inunderstanding the disintegration mechanism.Chapter 4 describes the use of the improved method of measuning waterpenetration for the investigation of the effect of variation in molecularstructure (degree of crosslinking and carboxymethylation) of 28experimental sodium starch glycolates. The results presented show theexistence of a pronounced relation between molecular structure and purityo f  t he  28  p roduc ts  and  the i r  su i t ab i l i t y  as  a  d i s i n teg ran t .Carbox5rmethylation of potato starch resulted in an increased solubilityaccompanied by increased values for swelling capacity and viscosity whenbrought into contact with water. Crosslinking of the substituted productsresulted, however, in a decrease in solubility, swelling properties andviscosity. The water uptake capacity of carboxlrmethylated starches wasstrongly increased at low levels of crosslinking followed by a decrease at ahighen degree of crosslinking. Proper combination of carbox5nnethylationand crosslinking of potato starch enabled the production of a sodiumstarch glycolate with optimal disintegration properties, as wasdemonstrated in two directly compressible tablet systems. Moreover,purification of the sodium starch glycolates enhanced their disintegrationefficiency.Although in most chapters of this thesis properties of tablets studied, weret29prepared by direct compression, an exception was made in Chapter 5. Herethe tablets were made by wet granulation with lactose as filler, gelatin asbinder, magnesium stearate as lubricant and a disintegrant. The propertiesof the tablets could be markedly improved, when the disintegrant potatostarch (20%) was replaced by a much lower concentration (4eo) of aninso lub le  super  d is in tegran t ,  such as  sod ium s tarch  g lyco la te  o rcrospovidone. The incorporation of a partially water soluble low substitutedsodium carboxymethylcellulose, which causes a viscous barrier in thetablets when it comes in contact with water, was shown to be deleteriousfor both tablet disintegration and drug release.In contrast to potato starch, the position of the super disintegrants(intragranular, extragranular or equally distributed) had hardly any effecton the tablet properties. The improved properties of the tablets containinginsoluble super disintegrants, when compared to tablets with potato starch,results from the use of a much lower concentration of disintegrant, but inparticular due to the difference of the effect of magnesium stearate onthe disintegration capacity of the slightly swelling potato starch ancl thestrongly swelling super disintegrants. The latter, even in the presence ofthe liquid penetration inhibiting hydrophobic magnesium stearate, causes achain reaction of opening the tablet, starting at the outside and resultingin fast disintegration.In Chapter 6 the relation between the dissolution propertíes of differenttypes of crystalline lactose and the disintegration of tablets, containingthese lactoses, is described. Tablets, compressed from either a-lactosemonohydrate or crystallized B-lactose disintegrate very quickly in water, asa result of rapid liquid uptake and fast loosening of the bonds. Tablets,compressed from anhydrous a-lactose, when brought into contact withwater, did not disintegrate at all, but dissolved during the disintegrationtest. The effect, which was shown to be caused by poor water Fenetrationinto the tablets, was attributed to a combination of small pore diametersand precipitat ion of the dissolved anhydrous cr- lactose as c-lactosemonohydrate in the pores of the tablets during the penetration process.This precipitation is an effect of the lower initial solubiLity of a-lactosemonohydra te ,  compared to  tha t  o f  anhydrous  c - Iac tose .  The samephenomenon could be seen for tablets containing roller-dried B-lactosewhen they were compressed at high forces. In this case the poordisintegration of the tablets is attributed to the combination of thepresence of about 20% anhydrous cr-lactose in roller-dried B-lactose and thesmall pore diameters in the tablets.In Chapter 7 the effects of both the presence of a Iubricant and theaddition of disintegrants on the crushing strength, disintegration time anddrug release of tablets compressed from the different types of crystallinelactose were investigated. The addition of 0.5eo magnesium stearate to a-lactose monohydrate, anhydrous a-lactose and rol ler-dried B-lactose,respectively, reduced the crushing strength, disintegration velocity anddrug dissolution rate of tablets compressed from these excipients. Thedecrease of the crushing strength was larger for tablets of o-lactosemonohydrate or anhydrous a-lactose than for tablets of roller-dried B-1 3 0lactose. The effect oa disintegrant on disigreatly on the typeFor  c - lac tose  moncunlubricated, the adincrease in disintegrThis effect could eas.a highly swelling disthe tablet.For tablets compress(the lubricant had a rdissolution rate, bec,the disintegration teabout  20% anhydrocompressed at a lowcou ld  be  enhancedcrospovidone, whichthe tablets.In Chapters 8, 9 ancis described. A tablei.e. act ive componentprevious chapters seThe composition oftrial and error. Thisthe best formulationmight be helpful in sJconcomitant mathemaivariables. The indeprmixtures of the chosevariables are the prresponses of interes'response as a functicbe  combined graphcomposition satisfyin6designs has been givsupported by a practIn Chapters 9 and 10studied according to'lactose monohydrate,were investigated. Tlcroscarmellose sodiuneffect of the disintelfrom the filler-bindecontour plots of thesuper disintegrantsf i l l e r -b inders .  In  rexperiment was perfolactose. The effect of both the presence of a lubricant and the addition ofa disintegrant on disintegtpation time and drug dissolution velocity dependedgreatly on the tytrre of lactose used.For a-lactose monohydrate tablets, which disintegrated quickly whenunlubricated, the addition of 0.59o magnesium stearate caused a significantincrease in disintegration time and a decrease in drug dissolution rate,This effect could easily be counteracted, however, by the incorporation ofa highly swelling disintegrant which enhanced the water penetration intothe tablet.For tablets compressed from anhydrous cr-lactose or roller-dried B-lactose,the lubricant had a relatively small effect on disintegration time and drugdissolution rate, because these tablets dissolved from the outside duringthe disintegration test. For roller-dried B-lactose tablets, which containabout 20% anhydrous c-lactose and for anhydrous o-lactose tablets,compressed at a low load, the disintegration and drug dissolution ratecould be enhanced by the incorporation of a disintegrant such ascrospovidone, which enabled a rapid progress of the penetration front inthe tablets.In Chapters 8, 9 and 10 the systematic optimization of tablet formulationsis described. A tablet formulation always consists of different ingredients:i .e. act ive component, f i l ler-binders, disintegrants, lubricants etc..  In theprevious chapters several of these excipients were discussed.The composition of pharmaceutical formulations is often approached bytrial and enor. This is a time consuming and unreliable method of findingthe best formulation. Optimization by means of an experimental designmight be helpful in shortening experimenting time. Such a design with theconcomitant mathematical models, reveals effects and interactions of thevariables. The independent variables are the different compositions of themixtures of the chosen ingredients (drug and excipients). The dependentvariables are the properties (responses) of the formulations. When allresponses of interest have been expressed in models that describe theresponse as a function of the composition of the mixture, the models canbe combined graphically or mathematically to find the most optimumcomposition satisfying all demands. An introduction to the use of mixturedesigns has been given in Chapter 8 which consists of a theoretical partsupported by a practical example: optimizing a simple placebo formulation.In Chapters 9 and 10 some basic formulations for direct compression werestudied according to this systematic approach. In Chapter g mixtures of a-lactose monohydrate, roller-dried p-lactose and microcrystalline cellulosewere investigated. Three different disintegrants, sodium starch glycolate,croscarmêllose sodium and crospovidone were tested at a level of 4%. Theeffect of the disintegrants on the properties of the tablets, compressedfrom the filler-binder mentioned, was evaluated by superimposing thecontour plots of the different tablet responses. It was found that all thesuper disintegrants investiga.ted were effective in this combination off i l ler-binders. In order to evaluate drug dissolut ion rate an extraexperiment was performed, in which oxazepam was used as test drug, The131results showed that a proper combination of excipients, based on theapplied optimization technique, resulted in tablets with a fast release ofoxazepam.In Chapter 10 the properties of formulations based on lactoses are testedin the same way. The lactoses used were: o-lactose monohydrate, roller-dried B-lactose and spray-dried lactose. The three disintegrants used inChapter 9, were also tested in these formulations, As could be expectedfrom the results of Chapter ?, crospovidone was the most effectivedisintegrant. Moreover the release of the test drug (hydrochtorothiazide)from the crospovidone containing tablets was very fast for all thedifferent lactose combination.The experimental design combined with the mathematically modelling of thedata is an aid to the formulator to get thorough knowledge of thepossibilities of a combination of certain excipients. When experiments aredesigned in this way, a well validated product can be obtained.132In Hoofdstuk 1 wor<tabletteren. Dit hoolhoofdstukken.In Hoofdstuk 2 wordldie het uiteenvallenduiden erop dat, wardesintegratiemiddelsnelheidsbepalende seen tablet wordt danfoob smeermiddel. l!rsuperr  desintegra 'hydrofobe smeermiddeeltjes van het desopengebroken, zodatdaar het desintegratin de totale desintegIn Hoofdstuk 3 wor,opname van vloeistofbeschreven apparahoeveelheid opgenomeen bepaald systeem,is de wateropnamê vtab le t t e ren  van  rdesintegratiemiddelstearaat. De resultavan de aard van hetgratiemiddel en de aworden de desintegrkan geconcludeerd w<voor de karakterisverkrijgen van meerIn Hoofdstuk 4 worwaterpenetratie uit Imoleculaire struktuurexperi.mentele natritduidelijke relatie tevan die experimente.de sinte gratierniddel.de oplosbaarheid inzwelvermogen en eende gesubstitueerde poplosbaarheid, de zlgecarboxlrmethyleerddoor een geringe ma

Optimization of the formulation of fast disintegrating tablets

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Optimization of the formulation of fast disintegrating tablets

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