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International Journal o/Pharmaceutics. 28 1986) 229-238Elsevier

229

IJP 00956

Studies on tableting properties of lactose. IV. Dissolution anddisintegration properties of different types of crystalline lactoseH.V. van Kamp , G.K. Bolhuis r, K.D. Kussendrager * and C.F. Lerk

Luhorato~vfor hartmceutrcal Technology and Dupeming, University of Groningm, 9713 A W Gronrn,qen or~d DMV, P. 0. Box 13. 5460 BA Veghel The Nether1und.y)

(Received August 26th. 1985)(Accepted October 8th. 1985)

Key words: tablets - a-lactose monohydrate - anhydrous a-lactose - P-lactose - dissolution -disintegrationSummary

In this study the relationship between the dissolution properties of different types of crystalline lactose and the disintegratton oftablets, containing these lactoses. was investigated. Tablets, compressed from either a-lactose monohydrate or crystallized Ij-lactosedisintegrated very quickly in water, as a result of rapid liquid uptake and fast dissolution of the bonds. Tablets compressed fromanhydrous a-lactose did not disintegrate at all when brought into contact with water. but dissolved during the disintegrationprocedure. This effect, which was shown to be caused by poor water penetration into the tablets. is attributed to a combination ofboth small pore diameters and precipitation in the pores of dissolved anhydrous a-lactose as a-lactose monohydrate. in the course ofthe penetration process. This precipitation is an effect of the smaller initial solubility of a-lactose monohydrate compared with that ofanhydrous a-lactose. The same phenomenon could be seen for tablets containing roller-dried p-lactose when they were compressed athigh forces. In this case the poor disintegration of the tablets is attributed to the combination of the presence of about 2Os0, anhydrousn-lactose in roller-dried p-lactose and the small pore diameters in the tablets.

From a pharmaceutical point of view, lactose isprobably the most widely used diluent in tabletformulations. Lactose is a disaccharide, producedby isolation from cows milk, in which the con-centration is about 4.6 . The most common, com-mercially available form is a-lactose monohydrate.It is generally used in powdered form as a filler fortablets, prepared by means of wet granulationtechniques. Sieved crystalline fractions of a-lactoseCorrespondence: G.K. Bolhuis, Laboratory for PharmaceuticalTechnology and Dispensing, University of Groningen, Ant.Deusinglaan 2, 9713 AW Groningen, The Netherlands.

monohydrate, like the 100 mesh quality, have ex-cellent flow properties and for that reason a-lactosemonohydrate is used in direct compression sys-tems (Gillard et al., 1972; Bolhuis and Lerk, 1973).However, the moderate binding properties needthe incorporation of a good dry binder (Delattreand Jaminet, 1974; Lerk et al., 1974). The bindingproperties of hydrous lactose could be improvedby spray-drying (Gunsel and Lachman, 1963) orby conversion into a granulated form (Tablettose)(Shangraw et al., 1981).

Another form of lactose, which has been espe-cially designed for direct compression is anhydrouslactose (Batuyios, 1966). The commonly used typeis anhydrous lactose with a high P-content. The

0378-5173/86/ 03.50 0 1986 Elsevier Science Publishers B.V. (Biomedical Division)

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commercial products consist of a granulation ofextremely fine crystals, produced by roller-drying,subsequent breaking up and sieving (Shangraw etal., 1981). The resultant particle structure presentsa large surface for binding, resulting in good com-pressibility. The flow properties of the rather irreg-ular particles were found to be less than optimum,however (Bolhuis and Lerk, 1973). A product thathas been marketed recently is anhydrous lactosewith a high a-content. It is prepared by dehydra-tion of a-lactose monohydrate (Lerk et al., 1983).In comparison with anhydrous lactose having ahigh /?-content, the anhydrous product having ahigh a-content has about the same binding proper-ties. Due to its more regular form and smallerparticle size distribution, however, it has betterflow properties (Bolhuis et al., 1985).

Although the binding and flow properties of thedifferent types of lactose have been studied exten-sively, little attention has been paid to the effect ofthe presence of lactose on the disintegration timeof tablets. As there are great differences betweenthe initial solubilities of different kinds of lactose(Van Kreveld, 1969) and since it is known thatexcipients with a high water solubility are able toincrease the disintegration time of tablets (Lerk etal., 1979; Graf et al., 1982), it could be expectedthat the choice of the lactose would have a markedeffect on tablet disintegration.The first three studies in this series were dealingwith the consolidation and binding properties ofdifferent types of crystalline lactose (Vromans etal., 1985a and b; De Boer et al., submitted forpublication).

The aim of this work was to study the relationbetween the dissolution properties of differenttypes of crystalline lactose and the disintegrationof the tablets made.

Materials and MethodsMaterials

The lactoses used were: (i) cY-lactose monohy-drate 100 mesh (a/p ratio 96.5 : 3.5); (ii)anhydrous a-lactose (DCLactose 30) (a/j3 ratio82.5 : 17.5); (iii) crystallized (anhydrous) P-lactose(a//I ratio 3 : 97); and (iv) roller-dried (anhy-

drous) P-lactose (DCLactose 21) (a/p ratio19 : 81).

The crystallized P-lactose was prepared bycrystallization from a saturated lactose solution byevaporation at boiling temperature. After additionof hot glycerol and filtration of the crystals atabout lOOC, the crystals were washed subse-quently with ethanol and acetone and dried. Theother types of lactose were commercial products,supplied by DMV, Veghel, The Netherlands. Al-cohol Eur.Ph. and methylcellulose 400 mPasEur.Ph. were obtained from Lamers and Inde-mans, s-Hertogenbosch, The Netherlands. Drieddimethylsulfoxide pro analysis quality was sup-plied by E. Merck, Darmstadt, F.R.G.Methods

a/j? ratio. The a/p ratio of the lactose wasdetermined according to the GLC method of Bumaand Van der Veen (1974).

Initial solubility. The initial solubility of thedifferent types of lactose was determined by pour-ing 150 g of a-lactose or 225 of P-lactose by meansof a vibrating feeder in a 600 ml beaker containing300 g of water of 37 + 0.5C, which was stirredwith a high speed mixer at 600 rpm. The dissolvedfraction was determined refractometrically.

Preparation of tablets. Tablets were preparedby manually introducing 500 mg of the lactoseinto a 13 mm die of a punch and die assembly,mounted between the plates of a hydraulic press(Hydro Mooi, Appingedam, The Netherlands). Thetablets were compressed at a specific load withboth a compression and a decompression rate of 2kN/s. The die was prelubricated by compressionof a magnesium stearate tablet.

Tablet porosity and pore volume. Tablet poros-ity and pore volume were calculated from thetablet weight and volume and the density of thematerial, as measured with an air comparisonpycnometer (model 930, Beckman Instruments,Fullerton, CA).

Crushing strength and disintegration time. Thecrushing strength of the tablets was measured,using a motorized instrument (model E-2, Dr. K.Schleuninger, Zurich, Switzerland). The data givenare the mean of at least 5 tablets. The disintegra-tion time was measured, using the Eur.Ph. proce-

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dure without disks. If not otherwise stated, waterwas used as a test fluid. Other disintegration mediaused were: dried dimethylsulfoxide, alcohol and a1% methylcellulose solution in water, having aviscosity of 51 t 1 mPas. The data given are themean of the disintegration time of 5 individualtablets.

Penetration of liquid into the tablets. Alcoholpenetration into the tablets was performed at 0Cas described earlier (Lerk et al., 1979). Thepenetration data given are the mean of at least 5measurements. Water penetration measurementswere performed, using a recently developed com-puterized method, described in an earlier paper(Van Kamp et al., 1986). The tests were performedat 20 k 0SC. The data are given with a relativestandard deviation and are the mean of at least 3deter~nations.

esults

Fig. 1 shows initial solubility profiles for differ-ent types of lactose powders. The figure shows ahigher dissoIution rate and initial solubility for theproducts consisting mainly of &lactose when com-pared to the products with a high o-content. Theinitial solubility of anhydrous a-lactose is higherthan that of a-lactose monohydrate but decreasesafter reaching a maximum. Of the /34actoses, thehighest initial solubility was found for roller-dried

roller driedplactose

crystallizedplactose

anhydrous a-lactose -n-lactose monohydrate

20 40 60 80 100 120timefsl

Fig. 1. Initial solubility profiles of different types of crystallinelactose powder in water of 37&0SC.

P-lactose. It should be noticed, however, that thesolubilities shown here are initial solubilities. Dueto mutarotation of lactose in aqueous sotution, thefinal solubility of all Iactose types (in the mutaro-tated form) will be the same.

Table 1 gives the crushing strength and disin-tegration time of tablets from four types of lactose,compressed at four force levels. Both anhydrousa-lactose and roller-dried P-lactose can be com-pressed into harder tablets at a specific load thantablets compressed from a-lactose monohydrate orcrystallized &lactose. Likewise, Table 1 shows agreat difference between the disintegration proper-ties of tablets compressed from the different prod-ucts. A fast disintegration time of less than 1 mincan be seen in the case of tablets containing a-lactose monohydrate or crystallized &lactose, evenwhen compressed at the highest force level. Tabletsfrom roller-dried fl-lactose showed only a fastdisintegration when compressed at low forces.Tablets from anhydrous a-lactose exhibited muchlonger disintegration times, even when their higher

TABLE 1CRUSHING STRENGTH AND DISrNTEG~TION TIMEIN WATER OF TABLETS COMPRESSED FROM DIFFER-ENT TYPES OF CRYSTALLINE LACTOSE AT 4 COM-PRESSION FORCE LEVELS

Compression Crushing Disinte.force (kN) strength gration

(kn) time (s)a-lactose monohydrate 5

102040

Anhydrous a-lactose 5102040

Crystallized j&lactose 5102040

Roller-dried p-lactose 5102040

cl.02.25.69.44.31.9

15.0:, 20.0

0.81.04.37.83.06.1

10.9> 18.9

78

1428

600610690698

45

13422143

205350

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TABLE 2POROSITY, CALCULATED PORE VOLUME, VOLUMETRIC ALCOHOL UPTAKE AT 0C AND VOLUMETRIC WATERUPTAKE AT 20C OF TABLETS, COMPRESSED FROM DIFFERENT TYPES OF CRYSTALLINE LACTOSE AT 4COMPRESSION LEVELSType of lactose anddensity (g/cm7)a-Lactose monohydrate ( = 1.545)

Anhydrous e-lactose ( p = 1.565)

Crystallized P-lactose (p = 1.59)

Roller-dried &lactose (p = 1.59)

Compression Porosityforce (kN) (%)

5 24.510 18.720 13.640 9.2

5 26.110 19.620 13.140 7.5

5 21.710 16.320 11.140 7.3

5 28.510 22.420 15.740 9.6

Calculated Volumetric Volumetrifpore alcohol watervolume (cm) uptake (cm) uptake (ems)0.104 0.092 0.1800.074 0.068 0.1820.051 0.049 0.1810.033 0.043 0.1590.113 0.095 0.1350.078 0.078 0.1160.048 0.058 0.0250.026 0.044 0.0190.087 0.081 0.1100.062 0.057 0.1070.040 0.040 0.1040.025 0.026 0.0970.127 0.102 0.2600.091 0.073 0.2510.059 0.055 0.0770.034 0.045 0.018

crushing strength levels are taken into account.Moreover, the disintegration time of these tabletswas hardly if at all dependent on the compressionforce used. There is also a difference in disintegra-tion behaviour: tablets compressed from anhydrouscY-lactose showed, in contrast to tablets com-pressed from the other lactoses, a dissolution ratherthan a real disintegration. For tablets containingroller-dried &lactose, the disintegration behaviourwas dependent on the compression force used.Tablets compressed at 5 or 10 kN showed a ratherrapid disintegration, tablets compressed at 20 kNdisintegrated when dissolution was almost com-pleted and only a small core was left, and tabletscompressed at 40 kN did not disintegrate at all butdissolved completely.

Table 2 gives porosity data, calculated porevolume and volumetric alcohol and water uptakeof the tablets mentioned in Table 1. The porositiesof tablets compressed at a specific load do notdiffer very much in the case of cu-lactose. As to thep-lactoses a higher porosity was found in the caseof the roller-dried product in comparison with the

crystallized form. The rather good similarity be-tween the calculated pore volumes and the volu-metric alcohol uptake indicates that in all thetablets a large majority of the pores could bereached by the penetrating liquid. Figs. 2 and 3

Fig. 2. Alcohol penetration into tablets compressed from a-lactose monohydrate (open symbols) and anhydrous a-lactose(closed symbols), respectively. Compression force: 5 kN (0.0);10 kN A, A): 20 kN (0, ; 40 kN (y, v).

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Fig. 3. Alcohol penetration into tablets compressed from crys-tallized /3-lactose (open symbols) and roller-dried p-lactose(closed symbols), respectively. Compression force: 5 kN 0, 0);10 kN A, A); 20 kN (D, w); 40 kN (v, v).

show rates of alcohol penetration into the tablets.A linear relation was found between the square ofthe volumetric liquid uptake and the time for allthe tablets investigated.

In contrast with alcohol, great differences be-tween calculated pore volume and volumetric up-take were found when water was used as penetrat-ing liquid (see Table 2). For tablets consisting ofcu-lactose monohydrate or crystallized /?-lactose,the water uptake was found to be much largerthan the calculated pore volumes. For tablets com-pressed from anhydrous a-lactose, the penetrated

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water volume was only higher than the calculatedpore volume in the case of tablets compressed atlow forces. The water uptake decreased, however,at increasing compression forces down to valuesbelow the calculated pore volume. For roller-driedP-lactose the volumetric water uptake was muchhigher than the calculated pore volume when thetablets were made at low compression forces. Atthe highest compression force, the measured wateruptake was, however, lower than the calculatedpore volume.

Fig. 4 shows water penetration profiles of thetablets. In the case of a-lactose monohydrate (Fig.4a) or crystallized &lactose (Fig. 4c) it can be seenthat an increase in compression force causes aninitial retardation of the penetration rate into thetablets. This effect can also be seen for roller-driedP-lactose at the lowest compression forces. Fortablets from anhydrous a-lactose or roller-dried/3-lactose, water uptake was poor and incompletewhen high compression forces were used (Fig. 4band d).

In Table 3 the disintegration times in differentmedia of tablets compressed from a-lactose mono-hydrate and anhydrous cY-lactose, respectively, arementioned. The disintegration time of tablets froma-lactose monohydrate in dried dimethylsulfoxidewas much longer than that in water. The disin-tegration behaviour of tablets containing anhy-drous a-lactose in dimethylsulfoxide was similar tothat of tablets compressed from the hydrous formand was strongly dependent on the compression

TABLE 3DISINTEGRATION TIME OF TABLETS COMPRESSED FROM a-LACTOSE MONOHYDRATE AND ANHYDROUSe-LACTOSE, RESPECTIVELY. IN DIFFERENT MEDIA

Compressionforce (kN)

Disintegration time(s) in:Water Dimethyl-sulfoxide Alcohol 1% Methyl-cellulose

solutiona-Lactose monohydrate 5 I 70 > 1800 80

10 8 175 > 1800 9520 14 625 > 1800 100

Anhydrous a-lactose 5 600 105 > 1800 80010 610 410 > 1800 89020 690 1050 > 1800 870

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300700I a

I1 2 3 4 5

time minl -300

I C

41 2 3 4 5

time min) -

b

430 I1 2 3 4 5

time min) -300 d

0 ,1 2 3 4 5

time minl+Fig. 4. Water penetration into tablets compressed from different types of crystalline lactose. (a) a-Lactose monohydrate; (b)anhydrous a-lactose; (c) crystallized P-lactose; (d) roller-dried P-lactose. Compression force: (1) 5 kN; (2) 10 kN; 3) 20 kN; (4) 40kN.

force used. This in contrast to the disintegrationtime in water, which was dependent on the com-pression force. Using alcohol as a disintegrationmedium, none of the tablets investigated showeddisintegration. In a viscous medium, 1% methylcel-lulose in water with aBviscosity of 51 mPas, all thedisintegration times showed an increase whencompared with those in water.

DiscussionThe far longer disintegration times in water of

tablets from anhydrous a-lactose and from roller-dried P-lactose compressed at high forces, whencompared to those of tablets from a-lactose mono-hydrate or crystallized /3-lactose (Table 1) corre-spond qualitatively with the differences in water

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penetration into the respective tablets (Table 2 andFig. 4). The high water uptake, which is muchlarger than the calculated pore volumes of tabletsfrom a-lactose monohydrate or crystallized p-lactose and from roller-dried p-lactose tabletsmade at low compression forces may be caused bydissolution of lactose at binding places and at porewalls during the penetration process. This resultsin wider pores or even a partial opening of thetablets. This process gives rise to an increase inpore volume during penetration, just as it wasfound in previous research (Lerk et al., 1979) fortablets containing the highly soluble spray-drieddextrose. The kink in the penetration curves (Fig.4a, c and d) can be explained by the observationof a sudden widening of the tablet structure. Thismay be caused by the dissolution of the bondsafter an initial slow penetration into the smallpores. The incomplete water penetration intotablets. being composed of anhydrous a-lactose orroller-dried /?-lactose compressed at high forcelevels, is consistent with the observation that thesetablets did not disintegrate into smaller particlesas in the case of other lactoses but dissolvedduring disintegration. The high water uptake ofthese tablets, compressed at low compression forcescan most probably be attributed to an increase indiameter of the pores that are situated at theoutside of the tablets. This is caused by the dis-solution of the highiy soluble lactoses. The shorterdisintegration time of tablets from roller-dried @-lactose compressed at 40 kN, in comparison withtablets containing anhydrous a-lactose (Table 1) isa consequence of the higher initial solubility ofroller-dried &lactose.

The differences in water penetration and theconsequent differences in disintegration behaviouramong the tablets compressed from different typesof lactose should be explained by differences inthe properties of these laetoses. These propertiesinclude the amount and the strength of the inter-particulate bonds, the compression behaviour, inparticular the resultant porosity and pore size dis-tribution as well as the initial solubility and theresulting increase in viscosity of the solution.

Differences in amount and strength of interpar-ticulate bonds may be derived from the crushingstrength data in Table 1. It can be seen that the

disintegration time of tablets from anhydrous (Ylactose with a low crushing strength was muchlonger than that of tablets from other lactoses witha comparable hardness. It was shown in previouswork (Vromans et al., 1985b) that the crushingstrength of different types of crystalline lactosewas only related to the pore surface area, createdduring compression, and hence on the extent offragmentation. For this reason it may be assumedthat the nature of the bonds of all the lactosesinvestigated is the same. Although this nature ofthe bonds is not exactly known, it may be assumedthat they are lactose bonds which easily dissolvewhen they come into contact with water. It can beseen from Table 1 that tablets from cu-lactosemonohydrate, which has the lowest initial solubil-ity of the lactoses tested, disintegrated in a shorttime, even when compressed at a high force. Henceit can be seen that the binding properties of thedifferent lactoses are not important factors con-tributing to the differences in the disintegrationbehaviour found.

An increase in viscosity of the penetrating liquid,caused by the dissolution of tablet material duringpenetration can retard water uptake. This was alsoshown in previous work (Lerk et al., 1979) in thecase of tablets containing spray-dried dextrose.The solubility of the lactoses is lower, however,than that of dextrose and the viscosity of saturatedand even that of super-saturated lactose solutionsare relatively low (Buma, 1980). Moreover, oftablets containing crystallized P-lactose a higherviscosity may be expected than of tablets contain-ing anhydrous cY-lactose. The reason is that crystal-lized &lactose has a higher initial solubility (Fig.1). It was shown, however, that water penetrationinto the tablets from crystallized &lactose pro-ceeded faster and in a more complete way (Fig. 4band c). The effect of a viscous fluid on tabletdisintegration was demonstrated by performingthe disintegration test in a 1% methylcellulosesolution in water, having a viscosity of 51 + 1mPas. The data in Table 3 show that an increasein viscosity of the disintegration medium delaystablet disintegration of all tablets tested. It can beseen, however, that the effect of the viscosity ofthe penetrating liquid is too small to be responsi-ble for the great differences in disintegration times

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of tablets compressed from the different types oflactose (Table 1).

Differences in the mean pore size of the lactosetablets investigated will affect the rate of liquidpenetration. The linear relation found between thesquare of volumetric alcohol uptake and time (Figs.2 and 3) are in accordance with Washburns equa-tion (Washburn, 1921). This was to be expectedbecause the lactoses are insoluble in alcohol sothat the bonds are not loosened during thepenetration process and the pore structures remainconstant (Lerk et al., 1979). The slower rate ofpenetration into tablets containing anhydrous CY-lactose in comparison with the hydrous product(Fig. 2) indicates that anhydrous a-lactose tabletshave smaller pores. These differences in pore sizedistribution correspond with the results obtainedby mercury porosimetry in previous research (Lerket al., 1983; Vromans et al., 1985b). The dif-ferences referred to were attributed to a stronglyincreased fragmentation of anhydrous a-lactoseduring compression. Fig. 3 indicates that there areonly small differences in the mean pore size oftablets compressed from the /3-lactoses. The ex-istence of different pore sizes cannot be responsi-ble, however, for the incomplete water penetrationinto tablets from anhydrous a-lactose or roller-dried P-lactose, compressed at high forces. This isobvious when the alcohol uptake of tablets froma-lactose monohydrate. compressed at 20 kN, iscompared with that of tablets from anhydrousa-lactose, compressed at 10 kN (Fig. 2). In spite ofa faster alcohol penetration into the anhydrousa-lactose tablets, the water penetration was muchslower and less complete than that of tablets com-pressed from a-lactose monohydrate (Fig. 4a and

TABLE 4QUANTITY OF DISSOLVED LACTOSE, MEASURED IM-MEDIATELY OR WITH 2 MIN DELAY AFTER AD-DITION OF WATER. DESCRIPTION IN THE TEXT

Quantity of dissolved lactose g)Suction Suctionimmediately after 2 m n

a-Lactose monohydrate 1.5 1.8Anhydrous a-lactose 4.5 3.5

b). Likewise, in the case of fi-lactose, the dif-ferences in water penetration into the tablets (Fig.4c and d) cannot be explained by differences inpore sizes (Fig. 3).

In conclusion, the viscosity of the penetratingliquid and the differences in pore size of tablets ofthe lactoses investigated do not fully explain theincomplete and slow water uptake and the lack ofdisintegration of tablets containing anhydrous (Ylactose and tablets containing roller-dried /3-lactosecompressed at high forces. Hence there must beanother factor which has a deleterious effect onwater penetration into these tablets. It may beassumed that this factor is the difference in initialsolubility of the different types of lactose in water,which can be seen from Fig. 1. The deviatingdissolution behaviour of anhydrous cy-lactose iscaused by the fact that the anhydrous product willbe immediately converted into the hydrate formwhen it is in solution (Van Kreveld, 1969). For thisreason the solubility of anhydrous a-lactose showsa maximum and will decrease very soon as a resultof the lower solubility of a-lactose monohydrate.During water penetration into tablets or into apowder bed only a limited amount of water comesinto contact with the solid. When this solid isanhydrous a-lactose, after a rapid initial dissolu-tion, cu-lactose monohydrate will precipitate inconsequence of its lower initial solubility. Thisphenomenon can be easily seen by the solidifica-tion of a given quantity of anhydrous a-lactosepowder, when it is moistened with water. Theeffect can be demonstrated quantitatively by pour-ing 20 g of water on 10 g of lactose on a 34 mmG3 glass filter and varying the time between wateraddition and suction. For the experiment the liquidwas sucked immediately and after 2 min, respec-tively, dried by evaporation and weighed quantita-tively. Table 4 shows the resultant weight of thedissolved and precipitated lactose. In the case ofa-lactose monohydrate, the dissolved quantity oflactose increased, as was to be expected, whenfiltration was carried out after a waiting time of 2min. In the case of anhydrous a-lactose. however.there was an opposite effect: if the solution wassucked directly, the lactose content in the filtratewas higher than when the solution was suckedafter 2 min. This indicates that a part of the

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dissolved anhydrous a-lactose has precipitated inthe powder bed as cu-lactose monohydrate. It maybe assumed that the same phenomenon also occursin tablets containing anhydrous cY-lactose: duringwater penetration, the anhydrous product exhibitsa fast dissolution and will be converted into a-lactose monohydrate, which partially precipitates.This precipitation can have a marked effect onwater penetration into small pores where thepenetration rate is low, so there is more time todissolve lactose. Moreover, small pores will first bestopped up by the precipitation of &-lactosemonohydrate, resulting in incomplete penetrationof water into the tablet and in incomplete tabletdisintegration. In dimethylsulfoxide both ol-lactosemonohydrate and anhydrous a-lactose are soluble.The solubilities at 37C are 6.0% and 0.6%. respec-tively. In contrast to what happens in water, aconversion of anhydrous cY-lactose into the hy-drous form is not possible in dried dimethylsulfo-xide. For this reason, a precipitation of cu-lactosemonohydrate during the penetration of dimethyl-sulfoxide will not occur. This establishment corre-sponds with the disintegration times in dimethyl-sulfoxide (Table 3), where a similar and compres-sion pressure-dependent disintegration behaviourwas found for both types of cu-lactose. The longerdisintegration times for tablets from anhydrouscu-lactose in comparison with tablets of the hy-drous form can be explained by their higher crush-ing strengths (Table l), smaller mean pore sizes(Fig. 2) and lower solubility in dimethylsulfoxide.

The poor water uptake and rather long disin-tegration time of tablets from roller-dried &lactosecompressed at high forces, may be caused by boththe presence of small pores in the tablets and thepresence of about 20% anhydrous ar-lactose in thesubstance, which can precipitate in the hydrousform during water penetration.

In conclusion, it was shown that unlubricatedtablets, compressed from either a-lactose monohy-drate or crystallized /3-lactose, disintegrate veryquickly in water as a result of rapid liquid uptakeand fast dissolution of the bonds. Tablets fromanhydrous cu-lactose do not disintegrate at all whenbrought into contact with water. They dissolveduring the disintegration process. This effect whichis caused by bad water penetration into the tablets,

is attributed to a combination of small pore diam-eters and precipitation of dissolved anhydrous cylactose as a-lactose monohydrate in the course ofthe penetration process. The same phenomenoncan be seen for tablets containing roller-dried p-Iactose when they are compressed at high forces.The results of an investigation on the effect ofboth lubricants and disintegrants on the disin-tegration and drug dissolution of tablets contain-ing different types of lactose will be presented in afuture publication.

The authors are indebted to Drs. H. Vromansfor the valuable discussions about this work.

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Bolhuis, G.K., Reichman, G., Lerk, CF., Van Kamp. H.V. andZuurman. K., Evaluation of anhydrous a-lactose, a newexcipient in direct compression. Drug. Dev. Ind. Pharm., 11(1985) 1657-1681.

Buma, T.J., Viscosity and density of concentrated lactose solu-tions and of concentrated cheese whey. Neth. Milk Dairy J.,34 (1980) 65-68.

Buma, T.J. and Van der Veen, H.K.C., Accurate specific opti-cal rotations of lactose, and their dependence on tempera-ture. Neth. Milk Dairy J.. 28 (1974) 175-185.

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Gillard, J., Delattre, L., Jaminet. F. and Roland, M., Etude desparametres influencant lecoulement des agents diluantsutihses en compression directe. J. Pharm. Belg., 27 (1972)713-742.

Graf, E., Ghanem, A.H. and Mahmoud, H., Studies on theDirect Compression of Pharmaceuticals. Part 8: Role ofliquid penetration and humidity on tablet formulations.Pharm. Ind.. 44 (1982) 200-203.

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