Mechanistic investigation of food effect on disintegration ... · importance of viscosity Asma...

BIOPHARMACEUTICS & DRUG DISPOSITIONBiopharm. Drug Dispos. 33: 403–416 (2012)Published online 11 August 2012 in Wiley Online Library(wileyonlinelibrary.com) DOI: 10.1002/bdd.1798

Mechanistic investigation of food effect on disintegration anddissolution of BCS class III compound solid formulations: theimportance of viscosity

Asma Radwana, Gordon L. Amidonb, and Peter Langgutha,*aInstitute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, GermanybCollege of Pharmacy, The University of Michigan, Ann Arbor, MI 48109-1065, USA

*CorrespJohannE–mail:

Copyrig

ABSTRACT: A negative food effect, i.e. a decrease in bioavailability upon the co-administration ofcompounds together with food, has been attributed particularly with high solubility/low permeabilitycompounds (BCS class III). Different mechanisms have been proposed including intestinal dilutionleading to a lower concentration gradient across the intestinal wall as well as binding of the activepharmaceutical ingredient to food components in the intestine and thereby decreasing the fraction ofthe dose available for absorption. These mechanisms refer primarily to the compound and not to thedosage form. An increase in viscosity of the dissolution fluid will in particular affect the absorption ofBCS type III compounds with preferential absorption in the upper small intestine if the API release isdelayed from the dosage form. The present study demonstrated that the increase in viscosity of thedissolution medium, following ingestion of a solid meal, may drastically reduce disintegration anddissolution. For that purpose the viscosity of the standard FDA meal was determined and simulatedby solutions of HPMC in buffer. Asmodel formulations, three commercially available tablets containingtrospium chloride, a BCS class III m-cholinoreceptor antagonist was used. Trospium chloride drugproducts have been described to undergo a negative food effect of more than 80% following ingestionwith food. The tablets showed prolonged disintegration times and reduced dissolution rates in viscousmedia, which could be attributed to changes in the liquid penetration rates. The effect was particularlysignificant for film-coated tablets relative to uncoated dosage forms. The results show the necessity ofconsidering media viscosity when designing in vitro models of drug release for BCS type III drugformulations. Copyright © 2012 John Wiley & Sons, Ltd.

Key words: tablet disintegration; food effect; bioavailability; tablet dissolution; viscosity

Introduction

Food viscosity is one of the physiological parametersthat can affect oral drug absorption [1]. Most of thestudies that addressed the influence of viscosity ondrug absorption demonstrate a reciprocal rela-tionship between drug absorption and gastricviscosity [1–4]. In particular, drug products withlow bioavailability are addressed, for which

ondence to: Institute of Pharmacy and Biochemistry,es Gutenberg University, Mainz, [email protected]

ht © 2012 John Wiley & Sons, Ltd.

reduced postprandial absorption may lead to treat-ment failure and reduced therapeutic efficacy [5].

Different theories have been proposed toexplain the mechanisms behind this food viscosityeffect: (i) an inhibition of gastric emptying and/ormodification of intestinal transit time [6,7]; (ii) aslower diffusion of drug molecules in the viscouslumen towards the intestinal membrane [6]; (iii) areduction in the disintegration rate of the drugformulation under viscous conditions [8–11]; (iv) areduction in drug dissolution rate [4,6,9].

Previous studies examining drug dissolution anddisintegration under viscous conditions showedreduced dissolution and disintegration rates [12–15],

Received 17 March 2012Revised 3 June 2012Accepted 3 July 2012

404 A. RADWAN ET AL.

e.g. a reduction in the intrinsic dissolution rate byreduced diffusivity of benzoic acid in solutions ofuncharged polymers according to the Stokes-Einstein equation [12]. Eshra et al. explained thereduction in ketoprofen absorption in humans bya retarding effect of food on the dissolution anddiffusion rates of the dissolved drug [4]. Khouryet al. reported reduced dissolution kinetics ofhydrocortisone acetate in dilute polymeric HPMCsolutions, which act as a diffusion barrier [16]. Yet,there are also data showing that tablet disintegra-tion, for example in canine stomach in the fed state,can be influenced by a viscosity-independentmechanism, i.e. a formation of a film coat aroundthe dosage form [10,11]. Anwar et al. state that theviscosity plays an important role in delayed tabletdisintegration in milk [8]. Paroj�cić et al. havereported reduced disintegration and dissolutionrates of paracetamol tablets in viscous solutions ofHPMC K4M. This was attributed to the poorerwetting of the tablet surface and reduced hydrody-namic shear stress [9].Ingestion of foodstuffs containing water soluble

fibres has been demonstrated to elevate the luminalviscosity by several orders of magnitudes [17–20].Digesta viscosity, assessed in vivo using Echo planarmagnetic resonance imaging,was found to lie in therange of 300–4000 mPa�s. The viscosity of gastricaspirates from healthy volunteers was reported torange from 200–2000 mPa�s immediately after foodingestion [21]. The average intestinal contentviscosity values of rats fed with an oat based mealwas found to lie in the range of 199–370 mPa�s[22]. Although ingestion of a high viscosity mealincreases the apparent viscosity of the stomachcontents, digesta viscosity is reduced by rapidgastric dilution and increased luminal motility.The intake of highly viscous meals has been associ-ated with strong gastric secretions. The volume ofgastric secretions produced within 80 min inresponse to locust bean gum meal ingestion hasbeen evaluated to be in the range of 95–157 ml[21,23]. Shear conditions within GI are anotherimportant factor affecting the luminal viscosity.However, little is known on the shear rate thatexists in the GI tract and there is no single standard-ized method to measure it. The motility within theGI tract varies considerably with location and mealcomposition. This makes the interpretation andevaluation of gastric viscosity data difficult [20].

Copyright © 2012 John Wiley & Sons, Ltd.

Likewise, not even the effect of gastric dilution onthe viscosity of an FDA standard meal at differentshear rates has been reported.

The Biopharmaceutics Classification System(BCS) may be used to predict the type of foodeffect to be expected for the different classes ofdrugs. For BCS Class III drugs (high solubility, lowpermeability), a negative food effect is most likelyto occur [24]. For example, trospium chloride, whichbelongs to this group, has a systemic availability ofapproximately 10% following oral administration.The first-pass effect is negligible since thecompound has little affinity for CYP or phase IIenzymes, thus poor permeability can be maderesponsible for its poor bioavailability [25]. Reducedbioavailability of trospium has been reported by theconcomitant intake of a high fat meal, with an AUCvalue 86% lower than that obtained when it wasadministered in the fasted state [26].

A food effect is important to be considered inthe early stages of drug development and in vitrodissolution methods may be helpful in thisrespect. Most of the in vitro models described inthe Pharmacopeias, however, are not suitable forpredicting the effect of food on drug release.Compendial media, such as simulated gastricfluid (SGF) and simulated intestinal fluid (SIF)are not representative of the GI environment inthe fed state, particularly with respect to mediaviscosity. In an attempt to better predict the potentialof food on drug absorption, various physiologicallyadapted media have been proposed. These systemsconsider factors related to media pH and compo-sitions, such as bile salt, lipolytic enzymes andphospholipids contents. However, these media lackthe physiological basis from a viscosity point ofview [27]. Several media, such as milk and EnsureW

Plus, have been proposed to simulate the postpran-dial gastric conditions [28]. However, the viscosityof these media may not reflect the change in thegastric viscosity after meal intake; therefore, theymay not be suitable to predict viscosity-derivedfood effects. Only a few studies have so faraddressed viscosity aspects in developing suchmedia [29]. The effect of viscosity changes due tothe dilutional process by gastric secretion has notbeen simulated. Yet, for better in vitro assessmentof in vivo performance, it is essential to develop adissolution medium that adequately reflects thepostprandial viscous conditions in the GI tract.

Biopharm. Drug Dispos. 33: 403–416 (2012)DOI: 10.1002/bdd

405MECHANISM OF FOOD EFFECT FOR BCS CLASS III PRODUCT

In this manuscript an in vitro model that ispredictive for the viscosity effect following inges-tion of a standardmeal is proposed. The rheologicalbehaviour of a homogenized standard meal recom-mended by FDA prior to and following dilution ischaracterized in order to design a representativeviscosity-adjusted dissolution medium to simulatefed conditions.Solutions containing different concentrations of

VEAs were applied to understand the mechanismof drug release under viscous conditions; HPMCand guar gum polymeric solutions were selectedto investigate the impact of the nature and structureof the VEA on the drug release process. The in vitrodata are interpreted in light of the negative foodeffect encountered following the oral administra-tion of solid dosage forms of a BCS III compoundin vivo and gastrointestinal simulation technologyis applied to establish in vitro/in vivo relationships.

able 1. Concentrations of different viscosity enhancing agentssed in the study

olymer1 Concentration of solution

PMC E4M (pH4.6, 6.8) 0.5%, 1%, 1.4%, 1.5%, 1.75%, 2%uar gum (pH 6.8) 0.25%, 0.5%, 0.75%

Concentration expressed as w/v.

Materials and Methods

Materials and dosage forms

Trospium chloride was obtained from Midas(Ingelheim, Germany), methyl hydroxypropylcellulose E4M (Methocel E4M premium) fromSynopharm (Germany). Guar gum, sodiumhydroxide and potassium dihydrogen phosphatewere purchased from Sigma Aldrich (Germany).Sodium acetate dihydrate was obtained from CarlRoth (Germany). Three commercially availabletrospium chloride tablet formulations were inves-tigated: SpasmolytW, SpasmexW and TrospiW.SpasmolytW and SpasmexW are film-coated tablets,whereas, TrospiW is a conventional tablet. TrospiW

was kindly donated from Medac (Germany),SpasmexW was obtained from Dr R. Pfleger(Germany) and SpasmolytW from Madaus(Germany).

Media composition

Various types of release media were used, differingin: (i) pH: 0.05 M acetate buffer pH 4.6 (USP), andsimulated intestinal fluid (SIF) pH 6.8 preparedfrom 6.8 g KH2PO4, 0.2 MNaOHand distilledwaterto 1000 ml. These media were used to simulate thefasted state under different pH (reference media);(ii) Viscosity: HPMC was added to SIF pH 6.8 and


acetate buffer pH 4.6 in different concentrations torepresent the viscous fed state under various pHconditions. Table 1 lists the HPMC concentrationschosen to be used throughout the study. Guargum was added to SIF in different proportions toprovide information on the effect of the type ofviscosity enhancing agent (VEA), e.g. its polymerstructure on drug release process.

Viscosity determination

As a starting point for determining the suitableviscosity range for the different dissolution mediato be used throughout this study and to designsuitable media to simulate the viscous conditionsin the fed state, the rheological profile of an FDAhomogenized standard meal before and afterdilution was characterized. The composition ofthis standard meal was: 2 slices of toast withbutter, 2 eggs fried in butter, 2 strips of bacon, 4ounces of hash brown potatoes, 8 ounces of wholemilk [30]. Altered food viscosity through dilutionby GI secretions was mimicked by diluting thehomogenized standardmealwith different volumesof water. The FDA diet (460 ml), recommendedto be co-administered with 240 ml of water, wasmixed thoroughly using a Waring blender andthe initial viscosity of this homogenized food wasdetermined. The diet was then diluted with 100 mlof water and the viscosity was reanalysed. Thedilution process was repeated once before thefinal viscosity was measured to yield a final volumeof 900 ml.

To ascertain the concentrations of the differentVEAs required for achieving viscosity similar tothat of the homogenized meal and its dilutions,the rheological profiles of the different agentswere constructed.

All viscosity measurements were performedin triplicate on a rotational rheometer RV 12(HAAKE, Germany) using the MV DIN Sensorsystem at 37 �C. Viscosity values used for viscous

Tu

P

HG

1



media characterization in this study weredetermined at a shear rate of 1.29 s-1.

Simulation of gastric viscosity in the fed state

Matching the viscosity of the FDA homogenizedmeal can be designed by dissolving VEAs in SIFand acetate buffer and adjusting their rheologicalprofiles to the standard meal. As the viscosity ofthe GI fluids is changing over time due to thedilution process, this process was simulated bythe gradual addition of non-viscous dissolutionmedia at different time intervals. The rate ofdilution process was adjusted based on previousin vivo studies to 130 ml/h [21].

Solubility determination

Equilibrium solubility of trospium chloride invarious media was determined at 37 �C. An excessamount of the drug was added to 3 ml of theinvestigated media, which was kept in a shakerincubator maintained at 37 �C for 24 h. Thereafter,the solutions were filtered and assayed spectropho-tometrically at 210 nm. Solubility determinationswere performed in duplicate.

Density determination

The density of the different solutions used wasdetermined byweighing a 50ml pycnometer beforeand after filling it with the investigated solution.The difference in the mass of the pycnometer wasdivided by its volume and yielded the densityvalue. Density determination was performed intriplicate at 37 �C.

Determination of the osmotic pressure

The osmotic pressure of the different dissolutionmedia was determined using a vapour pressureosmometer (Wescor, Germany), calibrated withstandard solutions of known osmolality.

Water uptake

Water uptake into trospium tablets was studied asa function of the viscosity of the penetrating liquidusing the Enslinmethod. The tabletwas placed on asintered glass filter connected to a horizontal grad-uated capillary containing the liquid. The volumeof water taken up by the tablet was measured by


noting the change in the capillary reading withtime. The results are reported as the mean� SD ofthree measurements.

Disintegration

The USP test without disks was employed toassess the media viscosity effect on the tabletdisintegration rate, using a tablet disintegrationtester (PharmaTest, Germany). All the tests werecarried out in 800 ml of the various media at 37�C using six tablets, one per vessel, for each test.Individual disintegration times were noted andthe mean� SD reported. The disintegration studywas performed in different media differing in pHand viscosity: SIF and acetate buffer were usedas reference test media, corresponding to fastedstate viscosity, whereas HPMC solutions (pH 4.6and 6.8) and guar gum solutions (pH 6.8) wereused to simulate the fed states.

Drug release

The dissolution study of trospium tablets in simpleand viscous media was performed in a rotatingpaddle apparatus II (PharmaTest, Germany) using900 ml of media at 50 rpm. All the experimentswere conducted at 37 �C. Five ml samples werewithdrawn at predetermined time intervals 5, 15,30, 45, 60, 90 and 120 min, filtered, properly dilutedand assayed UV-photometrically (lamda 20photometer, PerkinElmer,USA) at 210 nm. Followinganalysis, dissolution versus time profiles in differentmedia were constructed.

Intrinsic dissolution

The intrinsic dissolution was measured using theUSP rotating disk method at 50 and 75 rpm in aUSP apparatus II (PharmaTest, Germany) at 37 �C.Approximately 250 mg of pure trospium chloridewas compressed under a pressure of 20 kN forcefor 30 s using a 0.8 mm diameter die (WoodApparatus, Pharma Test, Germany) into disks of0.5 cm2 surface area for intrinsic dissolutionmeasurements using a hydraulic press (PaulWeber,Germany). The disks were dedusted withcompressed air to remove any loose particles. Thedies were then placed into a holder that wasimmersed into the dissolutionmedium; the distanceof the compressed drug disk from the bottom of the


igure 1. Viscosities of homogenized FDA meal without andith subsequent dilution with different volumes of water

100, 200, 300 ml) at differing shear rates


dissolution vessel was maintained at 2.5 cm. Allintrinsic dissolutionmeasurements were performedin triplicate.For low viscosity media, 900 ml of dissolution

medium was added to the dissolution vessel. Forhighly viscous media, 500 ml of media was usedin order to obtain sufficient concentrations foraccurate absorbance measurement.At appropriate time intervals 4 ml samples

were withdrawn for analysis. When 500 ml ofmedium was used the dissolution medium wasreplaced after every sampling. Withdrawn sampleswere not replaced when 900 ml medium was used.Samples were withdrawn every 2 min for lowviscosity media; the time interval of sampling mayreach 10 min for highly viscous media until sevendata points had been collected.The concentration of trospium in solution was

determined as described above. The intrinsic disso-lution rate (amount dissolved per unit area) wasdetermined from the slope of the linear relationshipbetween the amounts dissolved versus time

Gastrointestinal simulation

Gastrointestinal simulation (GastroPlusW Ver. 7.0)was used to simulate the effects of the decreaseddissolution rates on plasma concentration–timeprofiles. Simulations were performed for a 60 mgdose of trospium chloride. Peff was set to 0 for thestomach compartment and to 0.3 � 10-5 cm/sfor duodenum, jejunum 1 and jejunum 2 com-partments, respectively. For ileum 1 and ileum 2a Peff of 0.1 � 10-4 cm s-1 was set and for ileum3, caecum and ascending colon, a Peff value of0 was set. The solubility of trospium chloride wasset to 670 mg/ml and its diffusion coefficient to0.8 � 10-7 cm2/s. Simulations were performedusing the cumulative dissolution of trospium inSIF as input for the fasted state and in 1.4% HPMCfor the fed state, respectively. A two-compartmentdisposition function as described in reference [31]was used to describe the disposition parameters oftrospium following i.v. dosing.

Statistical analysis

Differences between two groups were tested forsignificance using ANOVAwith a value of p< 0.05as the significance level. Similarity in dissolutioncurves was tested by the f2-statistic where an


f2 value between 50 and 100 suggests that twodissolution profiles are similar.

Results

Determination of viscosity

The rheological profile of the standard homogenizedFDA meal revealed pseudoplastic behaviour, i.e.the viscosity decreased with an increase in theshear rate (Figure 1). Furthermore, a reduction insolution viscosity after dilution was observed.Progressive dilution of the diet reduced theviscosity from an initial 2500 mPa�s to 466 mPa�sat a low shear rate of 1.29 s-1 (Figure 2). Theseobservations are in accordance with previousinvestigations [29]. Marciani has attributed arapid reduction in digesta viscosity in his studiesfrom 11000 to 2000 mPa�s after the intake of aviscous meal to its gastric dilution [23].

Based on the above results, three levels ofmedia viscosity can be defined to represent thelow (15–20 mPa�s), medium (100–120 mPa�s) andhigh (1300–1350 mPa�s) viscous conditions of GIcontents. Rheograms of different concentrationsof HPMC (at pH 4.6 and 6.8) and guar gum solu-tions have been constructed. The mean viscositiesof the solutions used in this study are presented inTable 2. The concentrated HPMC solutions arefound to exhibit pseudoplastic flow behaviour.

Fw(


Figure 2. Rheology plots of HPMC solutions in comparison with FDA meal


The 0.5% HPMC solution showed certain devia-tion from the Newtonian flow at low shear rates,while at higher shear rates the flow pattern wasNewtonian. There was a small reduction of theviscosity of HPMC solutions under pH 4.6compared with pH 6.8. The flow characteristicsof guar gum solutions followed pseudoplasticbehaviour, which is in agreement with previousstudies [32].

Simulation of gastric viscosity in the fed state

By comparing the rheological profiles of differentconcentrations of HPMC solutions with that ofthe FDA standard meal, the rheogram of 1.4%

Table 2. Physicochemical characteristics of trospium chloride solutwere performed once. For solubility, the means of n= 2–3 and the i

Media Viscosity Z(cP) at 1.29 s-1 Density (g

SIF 1 0.9970.1 N HCl 1 0.9910.5% HPMC (pH=6.8) 20 0.9931% HPMC (pH=6.8) 100 0.9982% HPMC (pH=6.8) 1300 1.004Acetate buffer 1 0.9900.5% HPMC (pH=4.6) ND 0.9911% HPMC (pH=4.6) ND 0.9942% HPMC (pH=4.6) 900 0.9970.25% guar (pH=6.8) 15 0.9980.5% guar (pH=6.8) 140 0.9980.75% guar (pH=6.8) 1350 0.998

ND, not determined.


(w/v) HPMC solution approximates the homoge-nized FDA standard meal (Figure 2). Guar gumrheograms were much inferior in simulating theviscosities of the standardized meal.

For the simulation of the dilution process, theaddition of 200 ml of the non-viscous media to700 ml of 1.4% HPMC viscous solution would bereasonably consistent with the dilution factorpreviously reported in the literature [21].

Solubility and density determinations

The results of the density and the solubility deter-minations of trospium chloride in the differentmedia are presented in Table 2. Trospium solubility

ions in different media. Except for solubility, determinationsndividual values or the standard deviations are reported

/ml) Solubility (g/ml) Osmotic pressure (mmol/kg)

0.786� 0.021 950.696 (0.703, 0.689) 1880.667� 0.029 1150.537 (0.540, 0.533) 1250.415 (0.420, 0.410) 2000.765 (0.759, 0.770) 740.658 (0.624, 0.693) 820.559 (0.568, 0.550) 84

ND 860.787 (0.770, 0.803) 1050.636 (0.643, 0.628) 1060.515 (0.520, 0.510) 109


Figure 3. Disintegration times of various trospium chlorideproducts in different disintegration media. The effects ofincreasing media viscosity on disintegration times were in allcases significant (p< 0.05), whereas the effect of change of pHfor HPMC solutions at the same concentrations of VEA wasinsignificant (p> 0.05). *pH 6.8; **pH 4.6


was high, as expected for a charged compound. Itssolubility decreased in the presence of the differentVEA, this may be attributed to a competitionbetween both the hydrophilic VEA molecules andthe solute molecules for the solvent. This reductionin the solubility can be considered as one of thefactors influencing the dissolution process, albeitits effect is probably limited. There was no apparenteffect of pH on trospium solubility in viscousHPMC media when comparing results at pH 4.6and 6.8, respectively.

Effect of osmotic pressure

The osmotic pressure of the different dissolutionmedia is depicted in Table 2. Only small differencesin the osmotic pressure with concentration of VEAswere observed in HPMC and guar solutions,probably since their molecular weight is high.

Water uptake

Since water uptake is the preliminary step in thedisintegration mechanism, its characterization isimportant towards a better understanding of drugrelease. A linear relationship between wateruptake and time was observed (data not shown).The water uptake rate was calculated from theslope of the plot. The results are shown in Table 3.It can be seen that water uptake into the differ-

ent tablets was reduced by the addition of theVEA, and was accompanied by prolonged lagtimes. A significant reduction in the water uptakerate appeared by increasing the concentration ofthe polymer. Furthermore, differences in lag timescan be observed. Longer lag times are reportedfor coated tablets (SpasmexW and SpasmolytW)compared with the uncoated tablet (TrospiW).

Table 3. Water uptake rates and lag times by tablets (mean� SD, n

Media Spasmolyt

Rate *10-3 (ml/min) T lag (min) Rate*10-3 (m

SIF 8.0� 1.05 1.0� 0 6.4� 00.5% HPMC 1.9� 0.08 12.0� 6.5 3.4� 01% HPMC 0.5� 0.01 16.0� 6.9 0.7� 02% HPMC 0.3� 0.10 28.0� 1.4 0.4� 00.25% guar 6.5� 0.30 3.5� 0.7 6.3� 00.5% guar 1.0� 0.10 13.3� 0.6 1.6� 00.75% guar 0.5� 0.05 42� 16.0 0.5� 0


Disintegration study

The average disintegration times are shown inFigure 3. The results clearly demonstrate thepotential for media viscosity to significantly delaytablet disintegration. In non-viscous media, allinvestigated products exhibited fast disintegration.The disintegration times under viscous conditionswere significantly prolonged for the three formula-tions (p< 0.05). Disintegration times in 1.4%HPMCwere increased from an average value of 3.5 min inSIF to 18, 22 and 35 min for TrospiW, SpasmexW andSpasmolytW, respectively. The change of pH atidentical concentrations of VEA did not signifi-cantly affect disintegration times.

Differences in the behaviour of the three formula-tions in the different mediawere obvious (Figure 4).

= 3–5)

Spasmex Trospi

l/min) T lag (min) Rate *10-3 (ml/min) T lag (min)

.01 1.0� 0.1 8.5� 0.48 0.8� 0.28

.17 14.0� 3.6 3.3� 0.06 5.3� 1.15

.08 17.0� 1.4 0.7� 0.07 14.8� 3.70

.01 25.0� 2.1 0.4� 0.02 22.0� 2.12

.39 11.5� 6.4 5.1� 0.40 1.8� 1.04

.10 14.3� 3.2 1.2� 0.07 6.3� 2.08

.02 23� 1.4 0.4� 0.01 10.5� 2.12


Figure 4. Relationship between water uptake into tablets andtablet disintegration times


The uncoated tablet (TrospiW) was least affected byan increase in the viscosity of the media. Filmcoated tablets, on the other hand, showed compara-tively longer disintegration times. Furthermore, itwas noted that both film-coated tablets did notbehave in a similar manner. For SpasmolytW

relatively longer disintegration times in viscousmedia were measured compared with SpasmexW.There was a good, although nonlinear, correlationbetween water uptake into the tablets and disinte-gration rates (Figure 4), an observation thatconfirms the results reported by Anwar et al. [9]who reported a good correlation between the liquidpenetration rate into the tablet and the resultingdisintegration times. The increase inmedia viscosityafter food ingestion is not the only explanation fordelayed disintegration of trospium chloride tablets;film formation around the tablet was suggested byAbrahmsson as another explanation [11].

Dissolution study

The in vitro dissolution of the different trospiumformulations was investigated in the differentmedia. Figure 5a–c illustrates the dissolution profilesfor the three products in the presence and absence ofthe different VEAs at various concentrations.The rates of drug release under simulated fasting

conditions were faster compared with simulatedfed conditions. Under simulated fasting conditions,the different products containing trospium chloridewere completely dissolvedwithin 15min, reflecting


the very rapid tablet disintegration and thehigh solubility of the drug substance. A viscosityincrease in the media resulted in a decrease in thedissolution of trospium from the different formula-tions in a concentration dependent manner. F2similarity factors were generally less than 50, indi-cating significant differences in the dissolutionprofiles at various viscosities. Drug release fromthe different formulations in 1.4% HPMC, whichhas a viscosity similar to the FDA standard meal,was reduced to less than 50%. In 2% HPMCsolutions, dissolution was very slow, i.e. less than20% of the drug was dissolved within 120 min.These findings are in agreement with the resultpreviously obtained by Parojcic et al. who observeda delay in the dissolution and disintegration rates ofparacetamol tablets in viscous media [9]. In guargum enhanced viscous media, similar findings,though not identical, were observed. Equiviscoussolutions of different VEAs thus resulted in differ-ent dissolution patterns. At high viscosities, thedissolution profiles in HPMC appeared to bereduced compared with those in equiviscoussolutions of guar gum.

Reducing the pH of the dissolution media wasfound to exert no effect on the drug releasepatterns from the investigated tablets at HPMCconcentrations above 1% (similarity factors> 50).However, at lower HPMC concentrations, changingthe pH showed significant effects on the dissolutionprocess. Figure 6a–c illustrates the pH effect on drugrelease profiles for the three tablets in the viscousHPMC solutions. In SIF media pH 6.8, completedrug release was observed within 15 min, whereas,at a lower pH acetate buffer 4.6, the total percentageof drug release was reduced to 86%.

In general, good correlations were obtainedbetween disintegration times and dissolutionrates in viscous media (Figure 7). It is evident thatthe lower dissolution rates observed in viscousmedia reflect the prolonged disintegration andthe reduced liquid penetration rates.

Intrinsic dissolution

The results from the intrinsic dissolution experi-ments are shown in Table 4. The IDR of the drugwas found to be affected by the viscosity of themedia. The intrinsic dissolution rate is inverselyproportional to the viscosity of the medium. Thus


Figure 5. (a) Dissolution profiles for SpasmolytW in viscous HPMC and guar solutions at pH 6.8, 50 rpm in USP-2 apparatus. In allcases values for f2 were< 50. Mean� SD, n=3. (b) Dissolution profiles for SpasmexW in viscous HPMC and guar solutions at pH6.8, 50 rpm in USP-2 apparatus. In all cases values for f2 were< 50. Mean� SD, n=3. (c) Dissolution profiles for TrospiW in viscousHPMC and guar solution at pH 6.8, 50 rpm in USP-2 apparatus. In all cases values for f2 were< 50. Mean� SD, n=3


Copyright © 2012 John Wiley & Sons, Ltd. Biopharm. Drug Dispos. 33: 403–416 (2012)DOI: 10.1002/bdd

Figure 6. (a) Effect of pH on dissolution of trospium from SpasmolytW tablets in solutions with differing viscosities. Only atconcentrations of HPMC< 1.0% f2 factors were< 50. Mean� SD, n= 3. (b) Effect of pH on dissolution of trospium from SpasmexW

tablets in solutions with differing viscosities. Only at concentrations of HPMC <1.0% f2 factors were< 50. Mean� SD, n= 3.(c) Effect of pH on dissolution of trospium from TrospiW tablets in solutions with differing viscosities. Only at concentrationsof 2% HPMC the f2 factor was equal to 63. Mean� SD, n=3


Copyright © 2012 John Wiley & Sons, Ltd. Biopharm. Drug Dispos. 33: 403–416 (2012)DOI: 10.1002/bdd

Figure 7. Relationship between dissolution and disintegrationtimes for various products of trospium chloride

igure 8. Simulated and predicted plasma concentration–timerofiles for trospium in fasted and fed states in humans


the addition of HPMC at a low concentrationreduces the dissolution rate. A similar trend isobserved in the guar gum solution. The IDRis found to increase with increasing agitationintensity from 50 rpm to 75 rpm. This can beattributed to the decreased diffusion layer thicknessresulting in increased mass transport from thematrix surface.

Gastrointestinal simulation of the effect of decreasein dissolution rate on plasma concentration versustime profiles and fraction absorbed

The results of the gastrointestinal simulation areshown in Figure 8. The model described the exper-imental plasma concentration–time profile quitewell in the fasted state and it also predicts a severedecrease in the fed state. However, the decrease in

Table 4. Intrinsic dissolution rates for trospium chloride atdifferent agitation rates (mean� SD, n=3)

MediaRexp75rpm

(mg/cm2min)R exp50 rpm

(mg/cm2min)

SIF 17.5� 0.81 15.5� 0.600.1 N HCl 17.7� 0.35 15.3� 0.700.5% HPMC 14.2� 0.44 10.2� 1.061.0% HPMC 9.4� 0.75 6.5� 0.302.0% HPMC 3.9� 0.04 2.2� 0.170.25% guar gum 17.9� 0.97 13.6� 0.460.5% guar gum 11.8� 1.25 5.9� 0.680.75% guar gum 4.8� 0.16 1.0� 0.13


Fp

plasma concentrations in the presence of foodwas somewhat underestimated. For example, thepredicted Cmax was 1.7 ng/ml by the model,whereas the average measured Cmax was only 0.6ng/ml. This demonstrates that additional factorsof unknown mechanism may contribute to thenegative food effect of trospium and need to beinvestigated further.

Discussion

It is evident that increasing the media viscosity hada profound influence on drug disintegration anddissolution. This effect was found to be mediatedmainly through the water penetration process.

Water uptake is the initial step in the disintegrationprocess, thus factors affecting liquid penetrationinto the tablet will affect its disintegration rate.The Washburn equation can be used to describethe critical parameters influencing liquid penetra-tion into the tablet [33]. According to this equation,liquid uptake into non-disintegrating poroustablets is adversely affected by the viscosity of thepenetrating liquid. Although the equation is oflimited applicability here, since the tablet is disinte-grating and porosity is changing with time, aninverse relation between liquid viscosity and itspenetration rate into tablets is suggested, whichmay explain the reduced water uptake by tabletsin highly viscous media.



These findings suggest an impact of gastricviscosity on drug release and bioavailability.Media having viscosity similar to that of theFDA standard meal showed reduced dissolutionand disintegration rates.The differences observed in the disintegration

and dissolution behaviour between equiviscousHPMC and guar gum polymeric solutions can berelated to the chemical structure of the polymerchain. Guar gum is a branched polymer withcompact structure, whereas HPMC chains arelinear structures offering more resistance to drugand water diffusivity.C* (coil overlap concentration) is a characteristic

concentration for each polymer, above which thecoils of the polymer chains begin to overlap andentangle with one another leading to an abruptincrease in viscosity and decrease in solute diffusiv-ity. Drug dissolution can be significantly decreasedat concentrations above C* through reduced diffu-sivity [34]. The C* for HPMC has been determinedpreviously to be 0.57% [35] This may help toexplain the significant difference in drug dissolu-tion between 0.5% and 1% HPMC solutions. TheC* value for guar gum was found to be 0.2% [34].The concentrations of guar gum used in this studywere beyond this value. Reduced diffusivity inviscousmedia could explain the low liquid penetra-tion rates and the subsequent prolonged disintegra-tion times and reduced dissolution profiles.There is a good correlation between water pene-

tration rate into tablet, disintegration time anddissolution rate in different viscous media. TheSIF medium showed the fastest penetration ratesand exhibited the shortest disintegration times.Polymeric solutions exhibit slower rates of fluidpenetration into tablets, and slower disintegration.The prolonged disintegration times may be respon-sible for the reduced dissolution profiles observedin viscous media.The overall effect was more pronounced for film

coated tablets, which could be explained by theswelling of the HPMC coat layer surroundingthe tablet, acting as a barrier for the diffusion ofthe solvent and drug molecules in and out of thetablet and offering a longer diffusional pathlength. Differences between coated and uncoatedtablets can be observed, that may be attributedto the variation in the coating thickness andexcipients included that were not obvious by


using SIF as media for disintegration or dissolu-tion. These findings are supported by previousreports. Galia reported the slow dissolution offilm coated pandol tablets in milk compared withnon-coated acetaminophen tablets, which was asattributed to a chemical interaction between milkand tablet excipients [28].

In the present study, the role of viscosity onthe drug release process has been assessed. It isevident that food viscosity can delay drug dissolu-tion and tablet disintegration. This is of particularimportance for solid dosage forms containing BCSclass III compounds that may undergo preferen-tial absorption in the upper small intestine. Adelay in drug release will supply the dissolveddrug distal to the absorption site, thus reducingthe fraction of absorbed drug and sometimes thetherapeutic efficacy.

Media viscosity should be considered foradequate prediction of food effect on drug release.Previous models were not physiologically relevantto the actual fed state from the viscosity point ofview. In this study 1.4% HPMC solutions aresuggested for the simulation of the postprandialconditions of the GI tract but further work isneeded for establishing in vitro/in vivo correlation.

Conclusion

The results suggest that food viscosity plays animportant role in the dissolution process of BCSclass III drugs. Changes in disintegration timesmay be responsible for the different dissolutionprofiles observed in these different media. Changesin media viscosity can significantly influence thedisintegration times of tablets through changes inliquid penetration rates.

Various media have been proposed for simula-tion of the fed state; however, these media did notreflect the viscosity conditions within the GI tract.In the present study, the addition of a viscosityenhancing agent for more accurate simulation ofthe fed conditions is suggested. Viscosity is shownto be an important factor affecting dissolutionand disintegration of dosage forms – thus whendefining a dissolution medium to simulate thepostprandial state, viscosity should be consideredas a relevant factor.



Acknowledgements

This research was supported by grants from theGerman Academic Exchange Service (DAAD) toA.R. and the Humboldt Foundation to G.L.A.

Conflict of Interest

The authors report no conflict of interest.

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