highly soluble drugs directly granulated by water...

Research ArticleHighly Soluble Drugs Directly Granulated byWater Dispersions of Insoluble EudragitD Polymers as a Part ofHypromellose K100M Matrix Systems

Eliška Maškovaacute12 Martina Naiserovaacute1 Katelina Kubovaacute1

Josef Mašek 2 Sylvie Pavlokovaacute1 Martina Urbanovaacute3 Jil- Brus3

Jakub VyslouDil 1 and David Vetchyacute 1

1Department of Pharmaceutics Faculty of Pharmacy University of Veterinary and Pharmaceutical Sciences BrnoBrno Czech Republic2Department of Pharmacology and Immunotherapy Veterinary Research Institute Brno Czech Republic3Institute of Macromolecular Chemistry Czech Academy of Sciences Praha Czech Republic

Correspondence should be addressed to Josef Masek masekvricz

Received 18 December 2018 Revised 4 February 2019 Accepted 13 February 2019 Published 5 March 2019

Academic Editor Sami M Nazzal

Copyright copy 2019 Eliska Maskova et alThis is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

The aim of the present study was to investigate the suitability of insoluble Eudragit water dispersions (NE NM RL and RS)for direct high-shear granulation of very soluble levetiracetam in order to decrease its burst effect from HPMC K100M matricesThe process characteristics ss-NMR analysis in vitro dissolution behavior drug release mechanism and kinetics texture profileanalysis of the gel layer and PCA analysis were explored An application of water dispersions directly on levetiracetam was feasibleonly in a multistep process All prepared formulations exhibited a 12-hour sustained release profile characterized by a reducedburst effect in a concentration-dependent manner No effect on swelling extent of HPMC K100M was observed in the presence ofEudragit Contrary higher rigidity of formed gel layer was observed using combination of HPMC and Eudragit Not only thetype and concentration of Eudragit but also the presence of the surfactant in water dispersions played a key role in the dissolutioncharacteristics The dissolution profile close to zero-order kinetic was achieved from the sample containing levetiracetam directlygranulated by the water dispersion of Eudragit NE (5 of solid polymer per tablet) with a relatively high amount of surfactantnonoxynol 100 (15) The initial burst release of drug was reduced to 804 in 30 min (a 642 decrease) while the total amountof the released drug was retained (9702)

1 Introduction

Drug delivery systems based on poly(acrylic acid) derivativesare highly suitable in order to provide time- andor site-controlled drug delivery within the gastrointestinal tract[1ndash5] Polymethacrylate copolymers (Eudragit) are widelyused either for controlled release film coatings or as matrixformers in common granulation techniques as well as indirect compression in oral pharmaceutical formulations [6ndash10]These polymers appear particularly attractive due to theirhigh chemical stability good compatibility properties and

a large variety of products with different physicochemicalcharacteristics present on the market [11ndash13]

Polymethacrylates are synthetic cationic anionic andneutral polymers of dimethylaminoethyl methacrylatesmethacrylic acid and methacrylic acid esters in varyingratios Their physicochemical properties are determined byfunctional groups Several different types are commerciallyavailable and they can be obtained as dry powder granulesan aqueous dispersion or an organic solution [6 9 14]

The insoluble types of polymers Eudragit RL and RSwith alkaline as well as Eudragit NE and NM polymers

HindawiBioMed Research InternationalVolume 2019 Article ID 8043415 13 pageshttpsdoiorg10115520198043415

2 BioMed Research International

with neutral groups enable controlled time release of theactive ingredient by pH-independent swelling [9 14] Theyare used in sustained release drug delivery separately or incombination with other poly(meth)acrylates (pH-dependentsoluble or insoluble type of Eudragit) [12 15] or withdifferently structured polymers very often with cellulosederivatives such as hypromellose (HPMC) [16 17]

The hydrophilic polymer selected for the present studywas hypromellose K100M (HPMC K100M) Hydrophilicpolymer matrix systems are widely used for designing oralsustained release delivery systems because of their flexibilityto provide the desirable drug release profile cost effective-ness and broad regulatory acceptance [16] The drug releasefrom HPMC polymer matrix especially the release of highlywater-soluble drugs formulated into HPMCmatrices may becharacterized by an initial burst effect because of the rapiddiffusion of the dissolved drug through the hydrophilic gelnetwork created on thematrix surfaceThe initial high releaserate may lead to drug concentration near or above the toxiclevel in vivo [18]

A combination of water-insoluble polymers with HPMCcould solve this problem as they decrease the penetration ofwater in the matrix leading to a decreased diffusion of thedrug and slower initial release The insoluble polymers thatcould be incorporated into theHPMCmatrices include insol-uble methacrylic acid copolymers (eg Eudragit NE 30D)and ammonio-methacrylate copolymers (eg Eudragit RL100 or PO RS 100 RS 30D) ethylcellulose (eg Ethocel orSurelease) cellulose acetate or polyvinyl acetate [9 19ndash24]To reduce the burst effect an ethanolic solution of EudragitRL 100 and RS 100 was added to a mixture of freely water-soluble drug nicorandilHPMC K4M [25]

As a more effective tool proved to be the application of aninsoluble polymer in a liquid formdirectly on the API (ActivePharmaceutical Ingredient) or APIinsoluble filler mixturecurrently the information on this issue is relatively limitedin the literature and available only for non-HPMC matrixsystems In the study published by Krajacic et al the slightlysoluble diclofenac sodium was successfully granulated withthe aqueous polymer dispersion of Eudragit NE 40D toobtain prolonged drug dissolution profiles from matriceswithout the burst release [26] Similarly Tabasi et al [27]described the granulation of the mixture of slightly solubletheophyllinelactose monohydratemicrocrystalline cellulose(PH 101) with a different concentration of Eudragit NE 30Dto investigate the dissolution behavior of prepared matricesOn the other hand burst effect of freely soluble drug diltiazemhydrochloride was reduced by applying Eudragit NM 30Don the druginsoluble microcrystalline cellulose (PH 101)blend in the ratio 11 during the high-shear granulation [28]Additionally Tsai et al [29] granulated conventional excip-ients such as lactose and dibasic calcium phosphate withthe Eudragit RS 30D Eudragit RL 30D and ethylcellulose(Surelease) Granulated excipients were directly compressedto fabricate sustained release captopril tablets

In our previous recently published studies focused onHPMC K4M matrices with a reduced burst effect we inves-tigated an application of water dispersions of insolubleEudragit polymers on a very soluble model API during

high-shear granulation It was concluded that there is nopossibility of applying them directly in one-step processdue to the creation of a highly sticky mass unsuitable forconsequent processing This problem was solved by theaddition of insoluble filler such as MCC or Neusilin US2to create a drugfiller mixture [30 31] Nevertheless thebehavior of the highly soluble API directly granulated withwater dispersions of insoluble Eudragit polymers has notbeen published yet The main aim of the present study wasto explore a near zero-order release of highly soluble modeldrug directly granulated by water dispersions of EudragitNENM RL and RS respectively fromhypromellose K100Mmatrix tablets Moreover the matrix systems were inves-tigated using gel layer investigation and multivariate dataanalysis The integral part of this study was a presentation ofdifficulties observed during the granulation process

2 Materials and Methods

21 Materials Levetiracetam was kindly donated by Zentivaks Prague Czech Republic HPMC K100M was procuredfrom Colorcon Limited Dartford Great Britain and themicrocrystalline cellulose (MCC) Avicel PH 102 was pur-chased from FMC Biopolymers Rockland United States ofAmerica Eudragit NE NM RL and RS in the form of 30water dispersions were received as a gift sample from EvonikRohmGmbHDarmstadt GermanyMagnesium stearatewasobtained from Peter Greven BadMunstereifel Germany andcolloid silica from Degussa Vicenza Italy All materials wereof European Pharmacopoeia (Ph Eur) quality

22 Methods

221 Preparation and Evaluation of Granules The granulesfrom themodel drug levetiracetam (particle size 14157plusmn 287120583m laser diffraction HELOS Sympatec Germany aqueoussolubility at 20∘C 104 g100 ml [32]) and 30 aqueousdispersion of four different insoluble Eudragit polymerswere prepared in a high-shear mixer (ROTOLAB ZanchettaS Salvatore Montecarlo Italy) The instrument settings wereas follows impeller pause time 0 s impeller working time300 s cycle time 300 s and impeller speed 1200 rpmThe granulation liquid (30 water dispersion of Eudragitpolymers) was manually added for the first 60 seconds thenthe mixture was granulated for 240 s at 1200 rpm The wetmass was passed through a 125 mm mesh sieve and thegranules were dried for 24 hours at 40∘C in a cabinet dryerAfter drying the granules were again passed through the 125mmmesh sieve

The amount of water dispersion used in the granulationprocess was limited by the absorption capacity of the drugwhich allowed an application of only a limited amount of a30 Eudragit water dispersion on the drug in individualsteps of the granulation process Set 25 including samplesNE25 NM25 RL25 and RS25 was prepared by the appli-cation of 139 69 and 70 g of water dispersion in three-stepgranulation Set 5 including samples NE5 NM5 RL5 andRS5 was prepared by the application of 139 69 70 88 100

BioMed Research International 3

Table 1 Composition of granules and the number of granulation steps

Samplelowast Drug (g) Eudragit 30D dispersion (g) No ofgranulation stepsNE (g) NM (g) RL (g) RS (g)

NE25 1000 277 - - - 3NE5 1000 557 - - - 6NM25 1000 - 277 - - 3NM5 1000 - 557 - - 6RL25 1000 - - 277 - 3RL5 1000 - - 557 - 6RS25 1000 - - - 277 3RS5 1000 - - - 557 6lowast25 and 50 mean the amount of solid Eudragit in the final tablets

and 90 g in a six-step granulation process The final granulecomposition is shown in Table 1 This multistep granulationhelped to avoid overwetting of the granulated mass

Three samples of approximately 1 g were taken from drygranules after last granulation step and they were evaluatedfor their humidity Each sample was put on the hangingpan of Moisture Analyzer HX 204 (Mettler-Toledo AGSwitzerland) and it was dried for 15 minutes at 105∘C by ahalogen radiator Sample weight was recorded continually byintegrated balance The total loss in weight was interpreted asmoisture content

The other excipients the hydrophilic polymer HPMCK100M the indifferent insoluble filler Avicel PH 102 mag-nesium stearate (25) and colloid silica (05) both forimproving granule flow properties were added extragran-ularly and the mixing procedure continued by a 3-axialhomogenizer Turbula (T2C WAB Basel Switzerland) foranother 10 min

The higher concentration of magnesium stearate thanusual (25) was chosen to improve flowability of tablet-ing mixtures otherwise exhibiting poor flow characteristicswithout magnesium stearate The same concentration wasused also in other experimental studies [33 34] Consideringthe excellent mechanical properties of matrix tablets (seelater) an often described weakening of the particle-particlebonding was not observed No effect of magnesium stearateon slow-down of dissolution profile was expected because theparticles of levetiracetam were not in direct contact with it inthe matrix structure

The prepared granules were evaluated according to PhEur 9 for flowability (Medipo Brno Czech Republic diame-ter of outflow opening 250 plusmn 001 mm) Hausner ratio (SVM102 Erweka Heusenstammen Germany)

222 Solid-State NMR Spectroscopy The 13C cross-polar-ization (CP) magic angle spinning (MAS) NMR spectra weremeasured at a spinning frequency of 11 kHz a B1(

13C) fieldnutation frequency of 625 kHz and contact time of 1 msand with the repetition delay of 7 s The 13C-detected T1(

1H)relaxation times were measured using a saturation-recoveryexperiment in which the initial train of 1H saturation pulseswas followed by a variable delay (001ndash15 s) The intensity of

the 1H spin-locking field in the frequency units was 80 kHzGlycine was used as an external standard to calibrate the 13CNMR chemical shift scales (17603 ppm) respectively Theexperiments were conducted at 295 K Frictional heating ofthe sample was compensated and the sample temperature wascalibrated using 207Pb chemical shift in Pb(NO3)2 [35]

223 Preparation and Evaluation of Matrix Tablets Hydro-philic matrix tablets of approximate weight 340 mg werecompressed using 10 mm-diameter lentiform-faced punches(Korsch type EK 0 Korsch Pressen Berlin Germany) Thecompaction force was 215 kN The composition of thematrix tablets is shown in Table 2 The reference sample (R)containing polymer MCC PH 102 instead the Eudragit wasprepared by direct compression

All tablets were evaluated according to Ph Eur 9 forweight uniformity (n = 20 analytical balance KERN 870-13 KERN amp Sohn Gmgh Germany) hardness (n = 10 C50Tablet Hardness ampCompression Tester Engineering SystemsNottingham Great Britain) and friability (n = 1 weight of65 g at 25 rpm for 4 min TAR 10 Erweka HeusenstammTAR 10 Germany) An YL 9100 high-performance liquidchromatograph (HPLC Young Lin Instrument) was usedto determine the levetiracetam content (n=10) Chromato-graphic separation was implemented in column Venusil XBPC18 (150 times 46 mm particle size 3 120583m) The mobile phasecontained 68 of 02 phosphoric acid and 32 methanolIn total the analysis took 5 minutes and the chromatogramswere detected at 220 nm The mobile phase flow rate was10 mlmin column temperature 27∘C and injection volumewas 20 120583l To confirm the stability of levetiracetam in matrixtablets the evaluation of the content was repeated again after12 months (condition 25∘C 60 of relative humidity) (datanot shown)

224 Determining Dissolution Profiles and Similarity FactorAnalysis The dissolution profiles of the prepared sampleswere determined by a 12-hours dissolution test with SOTAXAT7On-Line System (DonauLab Zurich Switzerland) usingthe paddle method at 50 rpm in 900ml of a phosphate buffer(pH 60 Ph Eur 9) at 37∘C The samples were withdrawn attimes 30min 60min and then each 1 hour and quantified for


Table 2 Composition of matrix tablets

SampleDrug HPMC K100M MCC PH 102 Eudragit

(mg) () (mg) () (mg) () (mg) ()Rd 1000 30 2167 65 167 50 - -NE25 1000 30 2167 ex 65 84 ex 25 83 25NE5 1000 30 2167 ex 65 - - 167 50NM25 1000 30 2167 ex 65 84 ex 25 83 25NM5 1000 30 2167 ex 65 - - 167 50RL25 1000 30 2167 ex 65 84 ex 25 83 25RL5 1000 30 2167 ex 65 - - 167 50RS25 1000 30 2167 ex 65 84 ex 25 83 25RS5 1000 30 2167 ex 65 - - 167 50exExtragranular excipients ddirect compression each sample contains 05 of Aerosil 200ex and 25 of magnesium stearate ex for better flowability andcompression feasibility

the released drug amount by HPLC according to the above-mentioned conditions Themean value of the drug release (n= 6) and the standard deviation (SD) for each tablet batchwere calculated

In order to compare the dissolution profiles of levetirac-etam similarity factors f 2 were calculated The similarityfactors were determined between the samples to examinethe effect of the Eudragit type and concentration on thedissolution profiles of themodel drugThedatawere analyzedby (1) for similarity factor f 2 [36 37]

1198912 = 50 times log[1 + (1119899)

119899sum119894=1

1003816100381610038161003816119877119894 minus 11987911989410038161003816100381610038162]minus05

times 100(1)

where n is the number of time points Ri and Ti are thedissolution data of reference and tested samples at time iThesimilarity factor value ranges between 0 and 100 When thesimilarity factor is equal to 100 the two profiles are identicalWhen it approaches 0 their dissimilarity increases Valuesbetween 0 and 50 express a statistically significant differencein dissolution curves On the other hand values ranging from50 to 100 confirm statistically significant similarity [37]

225 Drug Release Kinetics and Mechanism Analysis Themechanism and kinetics of drug release from matrix tabletswere studied by correlating the obtained dissolution datawith the following equations square root-time kinetics(zero-order equation first-order equation Higuchi modelKorsmeyer-Peppas equation Hixson-Crowell model and theBaker-Lonsdale model ([37ndash41])

226 Determination of Gel Layer Thickness and PenetrationForce The test consisted of each tablet being placed intoa holder made of polyvinylchloride (PVC) which coveredthe tablet and allowed the polymer to swell in only onedirection The gel layer thickness of the swelled matrices andpenetration force depicted by work performed as a functionof time weremeasured every hour under the same conditionsas the dissolution test in an off-line apparatus using a TextureAnalyser CT 3 (Brookfield Great Britain) for 6 hours [42]

After being pulled out of the dissolution vessel the tabletin the PVC mold was placed in the center of the testingplatform A TA39 cylinderrod probe (2 mm in diameter and30 mm depth) was used to determine these parameters Theprobe was moved towards the sample at a speed of 05 mmsThe measurement of the penetration depth and penetrationforce was started when a trigger load of 5 g was achieved(which corresponded to the contact of the probe with theedge of the gel layer)Themeasurement was terminated whena trigger load of 250 g was reached (corresponding to thecontact of the probe with a border between the hydrated gellayer and nonhydrated polymer in the core of matrix) Thenthe probe was automatically withdrawn from the gel layer ata speed of 10 mms [43] The obtained data were analyzedat a rate of 200 points per second using Texture Expertsoftware (Brookfield Great Britain) The mean value of thethree samples and SD for both parameters were calculated foreach individual time point

227 Characterization of Gel Layer by Cryo-Scanning ElectronMicroscopy (Cryo-SEM) The surface morphology of thematrix tablet NM25 was observed using a scanning electronmicroscope Hitachi SU8010 Japan The matrix tablets wereallowed to swell in a dissolution medium under the sameconditions as the dissolution test A special ceramic tablet-shaped container was used to restrict tablet swelling to onedirection the top surface of the tablet Tested tablets wereremoved from the vessels cross-sectioned and immediatelyfrozen in liquid nitrogen after 3 hours Finally the frozencross-sections were coated with PtPd and the structure andthe magnitude of the gel layer were observed on the cross-sections at -130∘C

228 Multivariate Data Analysis When comparing theeffects of a sample composition on selected variables ananalysis of variance (ANOVA) was employed to determinethe statistical significance (significant effect for cases wherethe p-value is less than the level of significance 120572 = 005and insignificance for p-value greater than 005)Thep-values


Table 3 Flow properties of final mixtures and characteristics of matrix tablets

Sample Hausner ratio Flowevaluation

Friability Hardness Average drugcontent Average weight

plusmn SD [] [119873] plusmn SD [] plusmn SD [mg] plusmn SDR 132 plusmn 001 Passable 015 816 plusmn 200 9595 plusmn 102 3387 plusmn 00018NE25 127 plusmn 002 Passable 013 921 plusmn 160 10058 plusmn 534 3453 plusmn 00028NE5 124 plusmn 001 Fair 006 892 plusmn 180 10484 plusmn 623 3472 plusmn 00029NM25 130 plusmn 000 Passable 010 863 plusmn 230 10357 plusmn 201 3403 plusmn 00025NM5 125 plusmn 001 Fair 038 877 plusmn 230 10554 plusmn 360 3389 plusmn 00028RL25 130 plusmn 002 Passable 008 927 plusmn 280 10398 plusmn 112 3417 plusmn 00033RL5 122 plusmn 000 Fair 006 946 plusmn 280 10343 plusmn 607 3394 plusmn 00040RS25 130 plusmn 001 Passable 010 968 plusmn 480 10397 plusmn 145 3454 plusmn 00034RS5 130 plusmn 000 Passable 006 880 plusmn 360 10656 plusmn 381 3455 plusmn 00046

are listed in parentheses for commented parameters in theDiscussion section

For visualization of the data structure and dependenciesamong the variables a PCA was carried out after the datastandardization Especially the sample comparison on thebasis of polymer type (reference Eudragit samples) andEudragit concentration was mainly examined The resultingmodel was built on the grounds of selected variables provid-ing a good correlation structure and explained variability Atotal of 7 variables were included in the analysis tablet hard-ness release exponent n for the Korsmeyer-Peppas kineticmodel designated as n (KPM) determination coefficient forzero-order kinetics R2 (0) and the amount of released drugin dissolution time 30 min (burst effect) 300 min (the timepoint when the penetration force including to PCA wasmeasured) and 720 min (the final time of the dissolutiontest) from the dataset time of 300 minutes was selectedbased on the most proven significant effects in ANOVAoutputs

The data analysis was performed with the aid of softwareR version R 343 [44]

3 Results and Discussion

31 Preparation and Flow Properties of the Granules Thegranules were prepared by the application of Eudragit NENM RL or RS 30 water dispersions (WD) as granulationliquids directly on the very soluble model drug levetiracetamin a high-shear mixer (Table 1) The addition of WD inone step was not achievable Huge overwetting due to APIsolubility and creation of strongly sticky mass unsuitablefor other use was observed [45] Therefore the granulesof Set 25 and Set 5 were made by a 3-step and a 6-stepprocess respectivelyThe procedure used proved to be a time-and energy-consuming process Compared to our previousresults the levetiracetammicrocrystalline cellulose mixture(100g 50g) was granulated under the same conditions by 277g of all types of Eudragit WD in 1-step and by 557 g ofEudragitNE or NM in 1-step and RL or RS in 2-step process[30] Even more Eudragit NE WD (1113 g) was applied onthe levetiracetamNeusilin US2 mixture (100g 100g) in our

experimental study published by Naiserova et al [31] Thusa conclusion can be clearly made that highly soluble APIcannot be directly granulated by WD of insoluble Eudragitpolymers in any technologically tolerable processThe reduc-tion in the number of granulation steps was achieved byapplying Eudragit WDs on the mixture of an API withan excipient exhibiting high water absorption capacity andspecific surface area in a manner dependent on its amount[46 47]

The moisture content in the dry granules after the lastgranulation step ranged from 058 to 093 with maximumSD 024 which proves that drying was complete Generallya moisture content of less than 2 indicates optimum dryingof granules [48]

The final prepared granules were characteristic of theirflowproperties according to Ph Eur 9 forHausner ratio (HR)(Table 3) The Hausner ratio for the reference sample R was132 for Eudragit samples it reached values from 122 to 130while the flow characteristic of the granules varied from fairto passable An improvement in the granule flow properties(HR) was observed after the addition of a higher Eudragitamount (compare Set 5 to Set 25) The higher proportion ofa binder used for the granulation process leads expectedly toan enlargement of the granule particle diameter resulting inbetter flow behavior [49]

32 Solid-State NMR Spectroscopy of the Granules The suc-cessful development and application of pharmaceutical soliddispersions (multicomponent formulations) also require pre-cise structural and physicochemical characterization as anystructural deviation from the expected architecture mayinduce undesired changes in physicochemical propertiesGenerally the structural transformations as well as thereduced size of crystallites or other domains have a sub-stantial impact on the system behavior Therefore studyingpolymer-drug interactions in solid dispersions and relatingthe chemical composition 3D architecture and physico-chemical properties to one another is a fundamental andchallenging step in the development of these pharmaceutical


Levetiracetam

13 CPMAS NMR

（3

O

ON

（2

(a)

(b)

(c)

(d)

(e)

150 100 50

ppm

1

23

4

56

7

8

1 23

45

67 8

Figure 1 13C CPMAS NMR spectra of (a) the neat levetiracetam(b) granules levetiracetam with Eudragit RS (c) levetiracetamwith Eudragit RL (d) levetiracetam with Eudragit NM (e)levetiracetam with Eudragit NE

solids In this regard solid-state NMR spectroscopy hasalready proven its remarkable potential

Following our previous structural investigations of arange of pharmaceutical systems the most suitable tech-niques of ss-NMR spectroscopy were applied to probechanges in the physical state and size of domains of leve-tiracetam depending on the presence of different polymerconformers (Eudragit NE NM RL or RS) In accordancewith our previous study [31] the recorded 13CCPMASNMRspectra of all the prepared granulate samples (Figure 1) clearlyconfirmed the structural and physicochemical stability oflevetiracetam As the recorded 13C CPMAS NMR signals oflevetiracetam are narrow and well separated with constantresonance frequencies regardless of the type of Eudragitused the active compound in the prepared solids dispersions(formulations) remains in the crystalline state and does notexhibit any phase transformations or significant increase instructural defects

Furthermore to estimate the size of domains of leve-tiracetam in the investigated granules we used the previouslydescribed experimental approach based on the measurementof 13C-detected 1H spin-lattice relaxation times (T1(

1H))As described previously the 1Hminus1H spin diffusion a fastmagnetization transfer over large distances taking placeduring the relaxation periods induces the equilibrationof 1H magnetization behavior of different nuclear spinsrepresenting different molecules or components To put itbluntly if the recorded T1(

1H) relaxation times of differentcomponents in amulticomponent system differ considerablythen the system is phase-separated with large domains thesize of which usually exceeds 100-500 nm On the contraryif the recorded T1(

1H) relaxation times of these componentsare similar or identical it means that the system is ratherhomogenous with the size of domains smaller than 10 nm[50ndash53] In general the rate of magnetization equilibrationreflects the extent of phase separation inmulticomponent andmultiphase systems

In our particular case the T1(1H) relaxation times

determined for neat levetiracetam (39 s) and Eudragitsamples (2 s) differ considerably This finding thus allows theapplication of the above-described experimental approach toprobe changes in the size of domains Thus subsequently werecorded the 13C-detected 1H spin-lattice relaxation timesfor both components (levetiracetam and Eudragit) for allthe prepared solid dispersions We found out that T1(

1H)relaxation times of levetiracetam slightly decreased to thevalues 35 35 27 and 30 s for the systems with EudragitNE5NM5 RL5 and RS5 respectively This finding indicates thatthe size of crystallites of levetiracetam is basically unaffected(or slightly reduced) by the presence of low amounts (ca 10) of Eudragit irrespective of the type of the polymer usedIn contrast as demonstrated in our previous contribution[31] higher amounts of polymer additives (ca 25 ) induce aconsiderable reduction in the size of domains as well as oflevetiracetam depending on of content Eudragit NE Dueto the very high solubility of the levetiracetam and a highamount of HPMC K100M in final tablets the change inparticle size can be considered as insignificant [54]

33 Characteristics of Matrix Tablets The results of friabil-ity hardness average drug content and average weight ofprepared matrix tablets are provided in Table 3 The resultsshow that all physical parameters of the compressed tabletswere within the permissible limits of Ph Eur The averageweight of the samples was within the range of 3387-3472mg The drug content ranged from 9595 to 10656 and themaximum change in the content of samples after 12 monthsof 232 confirmed the stability of API in the system (datanot shown) The matrices were pressed to the maximumhardness Based on the hardness value of the referencesample R (816 N) it is clear that the presence of Eudragitpolymer in the structure of the tablets led to an increase inthis parameter (863ndash968 N) This effect was evaluated asstatistically significant (ANOVA p lt 0001) In general theaddition of Eudragit polymers improved bonding amongparticles ([28 55]) After the exclusion of the reference sample


0102030405060708090

100

0 60 120 180 240 300 360 420 480 540 600 660 720Time [min]

R (SD max = 148) NE25 (SD max = 247)NE5 (SD max = 195) NM25 (SD max = 158)NM5 (SD max = 546)

Diss

olve

d am

ount

of d

rug

[]

(a)

0102030405060708090

100

0 60 120 180 240 300 360 420 480 540 600 660 720Time [min]

R (SD max = 148) RL25 (SD max = 501)RL5 (SD max = 238) RS25 (SD max = 311)RS5 (SD max = 489)

Diss

olve

d am

ount

of d

rug

[]

(b)

Figure 2 Release amount of levetiracetam from (a) formulation NM and NE and (b) formulation RL and RS during the dissolution tests incomparison with the reference sample (R) at pH 60

Table 4 Important characteristics of dissolution profiles and similarity factor analysis

SampleAverage burst effect

in 30 minTotal released drug

amountSimilarity factor

analysis f 2plusmn SD () to the R compared sampleR 2247 plusmn 032 10058 plusmn 148 -NE25 1608 plusmn 107 8932 plusmn 247 5974 NE25 NE5

7102NE5 804 plusmn 043 9702 plusmn 195 5255NM25 2023 plusmn 066 9358 plusmn 156 7103 NM25 NM5

7552NM5 1718 plusmn 062 8475 plusmn 546 6100RL25 1586 plusmn 089 8617 plusmn 369 7505 RL25 RL5

9284RL5 1370 plusmn 046 8957 plusmn 238 6986RS25 1494 plusmn 066 9648 plusmn 243 7238 RS25 RS5

4698RS5 861 plusmn 095 7747 plusmn 489 4405

from the analysis both parametersmdashthe type of Eudragitused (p lt 0001) and its concentration (p = 0002)mdashas well asthe interactions between them (p lt 0001) had a statisticallysignificant effect The friability varied between 006 and038

34 Dissolution Profiles Similarity Factor Analysis DrugRelease Mechanism and Multivariate Data Analysis Themain aim of this study was to adjust the 12-hour dissolutionprofile of very soluble model drug levetiracetam fromHPMCK100Mmatrices towards zero-order kinetics and to decreasethe burst effect by applying the WD of insoluble Eudragitpolymers directly to the API during the granulation pro-cessThe dissolution characteristics similarity factor analysisresults and the fittings of API release data to different kineticequations can be seen in Figure 2 Tables 4 and 5 respectively

The calculated PCA model was created for a comparisonof the reference sample R and samples with a different

type and concentration of Eudragit on the basis of fun-damentally important characteristics (tablet hardness drugrelease mechanism expressed as a release exponent n fromKorsmeyer-Peppas kinetic model release kinetics expressedas a determination coefficient R2 for zero-order kineticsdissolution characteristics in 30 300 and 720 minutes andpenetration force in 300 minutes) while maintaining goodcorrelation structure of data Obtained outputs are repre-sented in the PCA scores plot (Figure 3(a)) and PCA loadingsplot (Figure 3(b)) The amount of variability explained bythe first two principal components was high enough since itdescribed 785 of variability [56]

The PCA scores plot (Figure 3(a)) shows a dissimilaritybetween the reference sample R and Eudragit samplesComparedwith the reference sampleR a 10-642decreasein the burst release (see arrow dis(30 min) in Figure 3) anda 35-23 decrease in the total amount of levetiracemreleased from EudragitHMPC matrices during the 12-hourdissolution test were observed The influence of Eudragit


Table 5 Mathematical modelling and drug release kinetics from matrices

Model Higuchi Korsmeyer-Peppas

Zero-order First- order Hixson-

CrowellBaker-Lonsdale

Sample R2 R2 n R2 R2 R2 R2

R 09981 09989 04751 09023 09949 09934 09906NE25 09975 09982 05532 09228 09924 09902 09854NE5 09989 09882 06670 09579 09949 09944 09774NM25 09986 09990 04756 09162 09854 09930 09767NM5 09965 09998 05273 09121 09979 09895 09970RL25 09870 09960 06855 09124 09911 09771 09944RL5 09885 09963 07610 09223 09945 09817 09943RS25 09945 09962 06559 09248 09895 09892 09827RS5 09976 09835 06997 09473 09947 09919 09800

PC 2

(22

4)

PC 1 (561)

2

1

0

minus1

minus2

minus3 minus2 minus1 0 1 2 3

RS25 RL5

RL25

NE5

RS5

NM5

NE25

NM25R

(a)

PC 2

(22

4)

PC 1 (561)

06

04

02

00

minus02


dis (300 min)

dis (720 min)

dis (30 min)force (300 min)

hardness

n (KPM)

R2 (0)

(b)

Figure 3 PCA scores and loadings plot (a) PCA scores plot objects included in model reference sample R and Eudragit samples (b) PCAloadings plot variables included in model hardness release exponent n for the Korsmeyer-Peppas kinetic model n (KPM) coefficient ofdetermination for zero-order kinetics R2 (0) the amount of the released drug at time 30 min (burst effect) dissolution time 300min and 720min and penetration force for time point 300 min

incorporated into the matrix system is attributed to itsinsoluble character limiting the penetration of the dissolutionmedium [57 58] or to the creation of nonuniform polymerlayers on the API surface leading to a decrease in the surfacearea for drug release [59] Despite the high correlation withfirst-order kinetics (R2 gt 0985) all Eudragit samplesexhibited an improvement in fitting to zero-order kinetics(R2 gt 0912) in comparison to the reference sample R (R2 =0902) see arrow R2(ZO) in Figure 3

While the increasing Eudragit concentration inmatricesalways led to a further reduction in the burst effect the resultsdealing with the total amount of the released drug wereless unambiguous With a rising Eudragit concentrationan undesired decrease in the total amount of the released

drug was revealed in the NM and RS samples and thisphenomenonmakes them unsuitable for the desired purposeAlthough the dissolution profile of the sample RS5 exhibiteda very low burst effect (861) a total deflection of the curvefrom R can be observed (similarity factor f 2 RRS5 4405)An overall slow-down of the dissolution profile of the RS5sample (11987950 3372 plusmn 154 min) exhibiting high correlationwith zero-order kinetics (R2 = 0947 see Figure 3 R2(0))was probably caused by the low permeability of this cationicpolymer containing only 5 (ww) of trimethylammonioethyl methacrylate chloride with hydrophilic quaternaryammonium groups [60] On the other hand the sampleNM5 with the smallest reduction of the burst effect (1718)among the samples containing 5 of insoluble polymer


exhibited a significantly lower release rate of the drug inthe second half of the dissolution test (similarity factorf 2 RNM5 6100) Conversely a desired increase in thefinal amount of the released drug towards the referencesample R was revealed for the NE and RL samples whilethe Eudragit concentration in matrices increased Dueto its higher permeability (10 ww of trimethylammonioethyl methacrylate [60] the sample RL5 did not exhibit asatisfactory reduction in the burst effect at the beginning ofthe dissolution test (1370)Different behavior was recordedfor the NE5 sample The incorporation of 5 of EudragitNE resulted in the dissolution profile characterized by thelow burst release of very soluble levetiracetam (804) andits almost complete liberation from the matrix system during12 hours (9702) Therefore this formulation was morebeneficial over the sample RS5 which exhibited similarlylow burst effect but a significantly lower total drug releaseMoreover the determination coefficient R2 of sample NE5for zero-order kinetics (R2 = 0958) calculated from thesedata was the closest to 1 Although the obtained dissolutionprofile was similar to the reference sample R (similarity factorf 2 RNM5 5255) its behavior can be concluded as the bestfitting with the desired purpose It can be noticed that thesamples based on chemically identical polymer EudragitNEand NM (both defined as low permeable) [6] exhibited asignificantly differentmanner in drug release (see Figure 3(a)PCA scores plot arrow dis 30 min) This could be probablyexplained by the difference in the nature and content of theemulsifier While Eudragit NE 30 D contains nonoxynol100 in the concentration of 15 (wv) Eudragit NM 30D contains polyethylene glycol stearyl ether in less than ahalf of the concentration [6] The presence of surfactantnonoxynol 100 in the concentration of 15 could probablyincrease the low permeability of Eudragit NE polymericfilm inside the matrix and effectively facilitate the mediumpenetration not at the beginning but in the next course ofthe dissolution test [61] For completeness of informationit should be noted that WD of Eudragit RL and RS aresurfactant-free [14]

The mechanism of API release from HPMC K100Mmatrices was investigated based on mathematical modelling(Table 5) and PCA results (Figures 3(a) and 3(b) n(KPM))The dissolution data showed a good agreement with theKorsmeyer-Peppas model (R2 gt 0984) therefore the releaseexponent n could be used to predict the mechanism of thedrug release For sample R without Eudragit polymer nwas calculated to be 04751 This value close to 045 expect-edly confirmed the diffusion of drug molecules throughthe HPMC matrix as the predominant mechanism with alimited share of erosion This finding is in agreement withthe literature data reporting that the very soluble drug isprimarily released by the diffusion of the dissolved moleculeof API through the hydrated gel layer of hydrophilic swellingpolymers [62] including hypromellose matrix systems [63ndash66] The addition of insoluble Eudragit polymers led to anincrease in the release exponent n for all Eudragit samples(04756-07610) and supported the rising role of matrixerosion in a concentration-dependent manner as can be seen

in Figure 3 arrow n(KPM) This finding was also supportedby the fact that the determination coefficient R2 for Hixson-Crowell model (R2 gt 098) except for NM samples increasedwith a rising Eudragit concentration inmatrixThe presenceof diffusion as a predominant mechanism of the API releasewas also confirmed by the good correspondence of the datawith Higuchi (R2 gt 099) and Baker-Lonsdale model (R2 gt098)

35 Texture Profiling Gel Layer Dynamics of SwollenMatricesandCharacterization ofGel Layer byCryo-SEM Drug releasefrom hydrophilic matrices is controlled by the thickness andconsistency of the gel layer created on the surface influencingboth the burst effect at the beginning of the dissolution testand the overall dissolution profile [67] Gel layer formationand its dynamic as a function of time (gel layer thicknessand the rigidity of the gel) was measured by means of textureprofiling analysis [43 67 68] The gel layer thickness andpenetration force through the gel layer are represented as afunction of time in Figure 4

To verify the accuracy of the measurements the hydratedtablet of the NM25 sample was cross-sectioned and observedby the cryo-SEM technique after 3 hours of the dissolu-tion test (Figure 5(a)) The thickness of the gel layer wasin good accordance with the texture profile measurement(Figure 4(a)) Moreover cryo-scanning electron microscopicimages of the nonhydrated core and the surface of thegel layer were obtained (Figures 5(b) and 5(c)) As it isdemonstrated in Figures 4(a) and 4(c) the forming gel layerthickness was not significantly influenced by the Eudragitpresent in the studied formulations The result is quitedifferent from the results obtained by Naiserova et alwhere the presence of the insoluble Eudragit polymerssignificantly reduced the thickness of the gel layer of theHPMC K4MEudragit matrices at the beginning of thedissolution test [31] An explanation could be seen in theuse of the higher viscosity type of HPMC (K100M) whichprobably reduced the influence of Eudragit polymers onswelling properties of HPMC [69] However the gel layerof Eudragit samples exhibited higher values of penetrationforce necessary for its overcoming (see the penetration forceFigures 4(b) and 4(d))The creation ofmore rigid gel layers incomparison to the reference sample was probably responsiblefor the dissolution behavior of Eudragit samples Thisfinding was supported by PCAwhere the negative correlationof the penetration force (see Figure 3(b) arrow force 300min) and dissolution characteristic at 300 and 720 minutes(see Figure 3(b) arrow dis 300 min dis 720 min) can beobservedThepenetration force also exhibited concentration-dependent behavior and rose with the increasing Eudragitamount in tablets These findings were positively confirmedby the results from ANOVA (p lt 0001) As it can benoticed the reference sample R showed a more continuouscourse of gel layer thickness and the penetration force intime whereas the course of these parameters fluctuatedfor Eudragit formulations An explanation could be seenin a more extensive erosion process in samples containinga certain proportion of insoluble matter This could be


0

05

1

15

2

25

3

35

4

0 60 120 180 240 300 360Time [min]

R

NE25

NE5

NM25

NM5

Gel

layer

thic

knes

s [m

m]

(a)

032

034

036

038

040

042

044

046

048

30 60 90 120 150 180 210 240 270 300 330 360

Pene

trat

ion

forc

e [N

]

Time [min]R

NE25

NE5

NM25

NM5

(b)

0

05

1

15

2

25

3

35

4

0 60 120 180 240 300 360Time [min]

R

RL25

RL5

RS25

RS5

Gel

layer

thic

knes

s [m

m]

(c)

032

034

036

038

040

042

044

046

048

30 60 90 120 150 180 210 240 270 300 330 360

Pene

trat

ion

forc

e [N

]

Time [min]

R

RL25

RL5

RS25

RS5

(d)

Figure 4 Gel layer thickness and the penetration force through the gel layer of tested samples during 360minutes (a) (c) Set 25 SDmax 058mm Set 5 SDmax 031 mm (b) (d) Set 25 SDmax 002 N Set 5 SDmax 004 N

(a) (b) (c)

Figure 5 Surface gel layers of the matrix formulation NM25 by the cryo-SEM technique during the dissolution test with pH 6 after 3 hours(a) cross-section of surface gel layer (the gel layer marked with an arrow) (b) nonhydrated core of the tablet and (c) detail of the surface ofa gel layer


responsible for some step changes in the internal structureof the forming gel layer This result is in agreement withour previous study On the other hand the step changesin these characteristics were not as significant as when thelow viscosity type HPMC K4M was used as a matrix carrier[31]

4 Conclusion

The application of an insoluble type of Eudragit NE NMRL and RS in the form of water dispersions directly on a verysoluble drug levetiracetam during the high-shear granulationwas feasible only in a multistep granulation process It wasdemonstrated that not only the chemical structure of the usedinsoluble polymers played a role in dissolution behavior ofprepared formulations A key parameter could be seen alsoin the presence of surfactants in the used water dispersionsFrom this point of view the adjustment of the dissolutionprofile of very soluble drug towards zero-order kinetic (lowerburst effect and maximum of totally released API) wasachievable only from HPMC K100M matrices containingthe drug previously granulated by 30 water dispersionof Eudragit NE containing a relatively high amount ofsurfactant nonoxynol 100 (15)

Data Availability

All data supporting the findings of this study are includedwithin the article

Conflicts of Interest

The authors declare that they have no conflicts of interest

Acknowledgments

This work was supported by the following grant theMinistry of Education Youth and Sports OPVVV PO1project ldquoFITrdquo (Pharmacology Immunotherapy nanoToxicol-ogy) CZ02101000015 0030000495 and Czech Ministryof Agriculture grant MZE RO0518

References

[1] R Semde K Amighi M J Devleeschouwer and A JMoes ldquoStudies of pectin HMEudragit RLEudragit NEfilm-coating formulations intended for colonic drug deliveryrdquoInternational Journal of Pharmaceutics vol 197 no 1-2 pp 181ndash192 2000

[2] R I Moustafine V A Kemenova and G Van Den MooterldquoCharacteristics of interpolyelectrolyte complexes of eudragit E100 with sodium alginaterdquo International Journal of Pharmaceu-tics vol 294 no 1-2 pp 113ndash120 2005

[3] J Goole P Deleuze F Vanderbist and K Amighi ldquoNewlevodopa sustainedrelease floating minitablets coated withinsoluble acrylic polymerrdquo European Journal of Pharmaceuticsand Biopharmaceutics vol 68 no 2 pp 310ndash318 2008

[4] J Albers R Alles K Matthee K Knop J S Nahrup andP Kleinebudde ldquoMechanism of drug release from polymeth-acrylate-based extrudates and milled strands prepared by hot-melt extrusionrdquo European Journal of Pharmaceutics and Bio-pharmaceutics vol 71 no 2 pp 387ndash394 2009

[5] D Sauer A B Watts L B Coots W C Zheng and JW McGinity ldquoInfluence of polymeric subcoats on the drugrelease properties of tablets powder-coated with pre-plasticizedEudragit L 100-55rdquo International Journal of Pharmaceutics vol367 no 1-2 pp 20ndash28 2009

[6] S Thakral N K Thakral and D K Majumdar ldquoEudragit Atechnology evaluationrdquo Expert Opinion on Drug Delivery vol10 no 1 pp 131ndash149 2013

[7] F Lecomte J Siepmann M Walther R J MacRae and RBodmeier ldquoBlends of enteric and GIT-insoluble polymers usedfor film coating physicochemical characterization and drugrelease patternsrdquo Journal of Controlled Release vol 89 no 3 pp457ndash471 2003

[8] S U Schilling C D Bruce N H Shah A W Malick and JW McGinity ldquoCitric acid monohydrate as a release-modifyingagent in melt extruded matrix tabletsrdquo International Journal ofPharmaceutics vol 361 no 1-2 pp 158ndash168 2008

[9] R C Rowe P J Sheskey and M E Quinn Handbook ofPharmaceutical Excipients American Pharmacists AssociationWashington DC USA 6th edition 2009

[10] C N Patra R Priya S Swain G Kumar Jena K C Panigrahiand D Ghose ldquoPharmaceutical significance of eudragit areviewrdquo Future Journal of Pharmaceutical Sciences vol 3 no 1pp 33ndash45 2017

[11] V K Nikam K B Kotade V M Gaware et al ldquoEudragit aversatile polymer a reviewrdquoPharmacologyonline vol 1 pp 152ndash164 2011

[12] A Ceballos M Cirri F Maestrelli G Corti and P MuraldquoInfluence of formulation and process variables on in vitrorelease of theophylline from directly-compressed Eudragitmatrix tabletsrdquo Farmaco vol 60 no 11-12 pp 913ndash918 2005

[13] L Rodriguez O Caputo M Cini C Cavallari and R GrecchildquoIn vitro release of theophylline from directly-compressedmatrices containing methacrylic acid copolymers andor dical-cium phosphate dihydraterdquo Farmaco vol 48 no 11 pp 1597ndash1604 1993

[14] M Joshi ldquoRole of eudragit in targeted drug deliveryrdquo Interna-tional Journal of Current Pharmaceutical Research vol 5 pp 58ndash62 2013

[15] I OzguneyG Ertan andTGuneri ldquoDissolution characteristicsof megaloporous tablets prepared with two kinds of matrixgranulesrdquo Farmaco vol 59 no 7 pp 549ndash555 2004

[16] P R Radhika T K Pala and T Sivakumar ldquoFormulationand evaluation of sustained release matrix tablets of glipiziderdquoIranian Journal of Pharmaceutical Research vol 5 pp 205ndash2142009

[17] K Małolepsza-Jarmołowska A A Kubis and L Hirnle ldquoStud-ies on gynaecological hydrophilic lactic acid preparations part5 the use of eudragit E-100 as lactic acid carrier in intravaginaltabletsrdquo Die Pharmazie vol 58 no 4 pp 260ndash262 2003

[18] XHuang andC S Brazel ldquoOn the importance andmechanismsof burst release in matrix-controlled drug delivery systemsrdquoJournal of Controlled Release vol 73 no 2-3 pp 121ndash136 2001

[19] S B Tiwari and A R Rajabi-Siahboomi ldquoModulation of drugrelease from hydrophilic matricesrdquo Pharmaceutical TechnologyEurope vol 20 no 9 pp 24ndash32 2008


[20] A Rajabi-Siahboomi K Fegely C Young P Rege andassignee inventors BPSI Holdings LLC ldquoInventors BPSIholdings LLC assignee drug compositions containing con-trolled release hypromellose matricesrdquo United States patent US20070048377A1 2007

[21] A S Tatavarti K A Mehta L L Augsburger and S WHoag ldquoInfluence of methacrylic and acrylic acid polymers onthe release performance of weakly basic drugs from sustainedrelease hydrophilic matricesrdquo Journal of Pharmaceutical Sci-ences vol 93 no 9 pp 2319ndash2331 2004

[22] V Dias A Gothoskar K Fegely and A Rajabi-SiahboomildquoModulation of drug release from hypromellose (HPMC)matrices suppression of the initial burst effect paper pre-sented atTheAmerican association of pharmaceutical scientistsannual meeting and exposition San Antonio TX USA 2006rdquo

[23] C D Melia ldquoHydrophilic matrix sustained release systemsbased on polysaccharide carriersrdquo Critical Reviews in Thera-peutic Drug Carrier Systems pp 395ndash421 1991

[24] M B Uddin J A Chowdhury K R Azam and M KIslam ldquoInvestigation of the effects of different physicochemicalparameters on in vitro release kinetics of theophylline fromEudragit NE 30 and Eudragit RS 30D matrix tabletsrdquo Journal ofPharmaceutical Sciences and Research vol 2 no 4 pp 240ndash2462010

[25] K R Reddy S Mutalik and S Reddy ldquoOnce-daily sustained-release matrix tablets of nicorandil formulation and in vitroevaluationrdquo AAPS PharmSciTech vol 4 pp 480ndash488 2003

[26] A Krajacic and I G Tucker ldquoMatrix formation in sustainedrelease tablets possible mechanism of dose dumpingrdquo Interna-tional Journal of Pharmaceutics vol 251 no 1-2 pp 67ndash78 2003

[27] S H Tabasi VMoolchandani R Fahmy and S W Hoag ldquoSus-tained release dosage forms dissolution behavior prediction astudy of matrix tablets using NIR spectroscopyrdquo InternationalJournal of Pharmaceutics vol 382 no 1-2 pp 1ndash6 2009

[28] K Dvorackova R Kaledaite J Gajdziok et al ldquoThe develop-ment of eudragit5 NM-based controlled-release matrix tabletsrdquoMedicina vol 48 no 4 pp 192ndash202 2012

[29] T Tsai Y-P San H-O Ho J-S Wu and M-T Sheu ldquoFilm-forming polymer-granulated excipients as the matrix materialsfor controlled release dosage formsrdquo Journal of ControlledRelease vol 51 no 2-3 pp 289ndash299 1998

[30] K Kubova D Pecek K Hasserova et al ldquoThe influence ofthermal treatment and type of insoluble poly(meth)acrylates ondissolution behavior of very soluble drug from hypromellosematrix tablets evaluated bymultivariate data analysisrdquo Pharma-ceutical Development and Technology vol 22 no 2 pp 206ndash2172017

[31] M Naiserova K Kubova J Vyslouzil et al ldquoInvestigationof dissolution behavior HPMCeudragit5magnesium alumi-nometasilicate oral matrices based on NMR solid-state spec-troscopy anddynamic characteristics of gel layerrdquoAAPSPharm-SciTech vol 19 no 2 pp 681ndash692 2018

[32] U Klancar S Baumgartner I Legen et al ldquoDetermining thepolymer threshold amount for achieving robust drug releasefrom HPMC and HPC matrix tablets containing a high-doseBCS class i model drug in vitro and in vivo studiesrdquo AAPSPharmSciTech vol 16 no 2 pp 398ndash406 2014

[33] S Mantry N Ghimirey S Sharma and R Sharma ldquoFormu-lation design and in vitro characterization of sustained releasetablet of nifedipinerdquo UJPSR vol 2 no 1 pp 27ndash34 2016

[34] M R Atheequr B P Kumar and A Baha ldquoDevelopment andevaluation of sustained release tablets ofmebeverine hydrochlo-riderdquo Indian Journal of Research in Pharmacy andBiotechnologyvol 2 no 6 pp 1455ndash1459 2014

[35] J Brus ldquoHeating of samples induced by fast magic-anglespinningrdquo Solid State Nuclear Magnetic Resonance vol 16 no3 pp 151ndash160 2000

[36] J W Moore and H H Flanner ldquoMathematical comparison ofdissolution profilesrdquo International Journal of Pharmacology andPharmaceutical Technology vol 20 pp 64ndash74 1996

[37] P Costa and J M Sousa Lobo ldquoModeling and comparisonof dissolution profilesrdquo European Journal of PharmaceuticalSciences vol 13 no 2 pp 123ndash133 2001

[38] T Higuchi ldquoRate of release of medicament from ointment basescontaining drugs in suspensionrdquo Journal of PharmaceuticalSciences vol 50 pp 874-875 1961

[39] R W Korsmeyer R Gurny E Doelker P Buri and N APeppas ldquoMechanisms of solute release from porous hydrophilicpolymersrdquo International Journal of Pharmaceutics vol 15 no 1pp 25ndash35 1983

[40] A W Hixson and J H Crowell ldquoDependence of reactionvelocity upon surface and agitationrdquo Industrial amp EngineeringChemistry vol 23 no 8 pp 923ndash931 1931

[41] R W Baker and H K Lonsdale ldquoControlled release mech-anisms and ratesrdquo in Controlled Release of Biologically ActiveAgents A C Taquary and R E Lacey Eds pp 15ndash71 PlenumPress New York USA 1974

[42] H Li R J Hardy and X Gu ldquoEffect of drug solubility onpolymer hydration and drug dissolution from polyethyleneoxide (PEO) matrix tabletsrdquo AAPS PharmSciTech vol 9 no 2pp 437ndash443 2008

[43] D PecekM Stybnarova E Maskova P Dolezel M Kejdusovaand D Vetchy ldquoVyuzitı analyzy textury pri vyvoji a hodno-cenı matricovych tablet s prodlouzenym uvolnovanım lecivardquoChemicke Listy vol 108 pp 483ndash487 2014

[44] Core R Team ldquoR a language and environment for statisticalcomputing Vienna Austria R foundation for statistical com-putingrdquo httpswwwr-projectorg

[45] J Plazier-Vercammen D Dauwe and p p Brione ldquoPossibilityof the use of Eudragit RS as a sustained-release matrix agentfor the incorporation of watersoluble active compounds at highcentagesrdquo STP pharma sciences vol 7 pp 491ndash497 1997

[46] CMHentzschel A Sakmann andC S Leopold ldquoSuitability ofvarious excipients as carrier and coating materials for liquisolidcompactsrdquoDrug Development and Industrial Pharmacy vol 37no 10 pp 1200ndash1207 2011

[47] Neusilin ldquoGeneral Properties Neusilincomrdquo 2017 httpwwwneusilincomproductgeneral propertiesphp

[48] A Kuksal A K Tiwary N K Jain and S Jain ldquoFormulationand in vitro in vivo evaluation of extended- release matrixtablet of zidovudine influence of combination of hydrophilicand hydrophobic matrix formersrdquo AAPS PharmSciTech vol 7no 1 pp E1ndashE9 2006

[49] T P de Souza R Martınez-Pacheco J L Gomez-Amoza and PR Petrovick ldquoEudragit E as excipient for production of granulesand tablets from phyllanthus niruri L spray-dried extractrdquoAAPS PharmSciTech vol 8 no 2 pp E54ndashE60 2007

[50] O Policianova J Brus M Hruby et al ldquoStructural diversityof solid dispersions of acetylsalicylic acid as seen by solid-stateNMRrdquoMolecular Pharmaceutics vol 11 no 2 pp 516ndash530 2014


[51] M Urbanova M Gajdosova M Steinhart D Vetchy and JBrus ldquoMolecular-level control of ciclopirox olamine releasefrom poly(ethylene oxide)-based mucoadhesive buccal filmsexploration of structurendashproperty relationships with solid-stateNMRrdquo Molecular Pharmaceutics vol 13 no 5 pp 1551ndash15632016

[52] M Urbanova A Sturcova J Kredatusova and J Brus ldquoStruc-tural insight into the physical stability of amorphous sim-vastatin dispersed in pHPMA enhanced dynamics and localclustering as evidenced by solid-state NMR and Raman spec-troscopyrdquo International Journal of Pharmaceutics vol 478 no2 pp 464ndash475 2015

[53] K E Dempah J W Lubach and E J Munson ldquoCharacteriza-tion of the particle size and polydispersity of dicumarol usingsolid-state NMR spectroscopyrdquo Molecular Pharmaceutics vol14 no 3 pp 856ndash865 2017

[54] J L Ford M H Rubinstein and J E Hogan ldquoFormulationof sustained release promethazine hydrochloride tablets usinghydroxypropyl methylcellulose matricesrdquo International Journalof Pharmaceutics vol 24 no 2-3 pp 327ndash338 1985

[55] S I Badawy M M Menning M A Gorko and L G GilbertldquoEffect of process parameters on compressibility of granulationmanufactured in a high-shear mixerrdquo International Journal ofPharmaceutics vol 198 pp 51ndash61 2000

[56] C Reimann P Filzmoser RG Garret and R Dutter StatisticalData Analysis Explained Applied Environmental Statistics withR John Wiley amp Sons Chichester UK 2008

[57] C Karthikeyinis S Jayaprakash A Abirami and S M HalithldquoFormulation and evaluation of aceclofenac sodium bilayersustained release tabletsrdquo International Journal of ChemTechResearch vol 1 no 4 pp 1381ndash1385 2009

[58] S Azarmi J Farid A Nokhodchi S M Bahari-Saravi and HValizadeh ldquoThermal treating as a tool for sustained release ofindomethacin from eudragit RS and RLmatricesrdquo InternationalJournal of Pharmaceutics vol 246 no 1-2 pp 171ndash177 2002

[59] SMKhamanga andR BWalker ldquoDrug transportmechanismsfrom carbopoleudragit verapamil sustained-release tabletsrdquoDissolution Technologies vol 18 no 3 pp 30ndash38 2011

[60] B Skalsky and H U Petereit ldquoChemistry and applicationproperties of polymethacrylate systemsrdquo in Aqueous PolymericCoatings for Pharmaceutical Dosage Forms J W McGinity andL A Felton Eds pp 237ndash278 Informa Healthcare New YorkNY USA 3th edition 2008

[61] A Gopferich and G Lee ldquoThe influence of endogenous surfac-tant on the structure and drug-release properties of eudragitNE30D-matrixesrdquo Journal of Controlled Release vol 18 no 2pp 133ndash144 1992

[62] H Kojima K Yoshihara T Sawada H Kondo and K SakoldquoExtended release of a large amount of highly water-soluble dil-tiazem hydrochloride by utilizing counter polymer in polyethy-lene oxides (PEO)polyethylene glycol (PEG) matrix tabletsrdquoEuropean Journal of Pharmaceutics and Biopharmaceutics vol70 no 2 pp 556ndash562 2008

[63] D Baviskar R Sharma and D Jain ldquoModulation of drugrelease by utilizing pH-independent matrix system comprisingwater soluble drug verapamil hydrochloriderdquo Pakistan Journalof Pharmaceutical Sciences vol 26 no 1 pp 137ndash144 2013

[64] J T T Leskinen M A Hakulinen M Kuosmanen J Keto-lainen S Abrahmsen-Alami and R Lappalainen ldquoMonitoringof swelling of hydrophilic polymer matrix tablets by ultrasoundtechniquesrdquo International Journal of Pharmaceutics vol 404no 1-2 pp 142ndash147 2011

[65] M A Roni G Kibria and R Jalil ldquoFormulation and in vitroevaluation of alfuzosin extended release tablets using directlycompressible eudragitrdquo Indian Journal of Pharmaceutical Sci-ences vol 71 no 3 pp 252ndash258 2009

[66] J Muzıkova S Havova P Ondrejcek A Komersova and VLochar ldquoA study of tablets with a co-processed dry bindercontaining hypromellose and 120572-lactose monohydraterdquo Journalof Drug Delivery Science and Technology vol 24 no 1 pp 100ndash104 2014

[67] L Yang ldquoDetermination of continuous changes in the gellayer of poly(ethylene oxide) and HPMC tablets undergoinghydration a texture analysis studyrdquo Pharmaceutical Researchvol 15 pp 1902ndash1906 1998

[68] E Maskova K Kubova J Vyslouzil S Pavlokova and DVetchy ldquoInfluence of pH modulation on dynamic behavior ofgel layer and release of weakly basic drug from HPMCWaxmatrices controlled by acidic modifiers evaluated by multivari-ate data analysisrdquo AAPS PharmSciTech vol 18 no 4 pp 1242ndash1253 2017

[69] J L Ford ldquoDesign and evaluation of hydroxypropyl methyl-cellulose matrix tablets for oral controlled release a historicalperspectiverdquo in Hydrophilic Matrix Tablets for Oral ControlledRelease P Timmins S Pygall and C Melia Eds vol 16 ofAAPS Advances in the Pharmaceutical Sciences Series pp 17ndash51Springer New York NY USA 2014

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with neutral groups enable controlled time release of theactive ingredient by pH-independent swelling [9 14] Theyare used in sustained release drug delivery separately or incombination with other poly(meth)acrylates (pH-dependentsoluble or insoluble type of Eudragit) [12 15] or withdifferently structured polymers very often with cellulosederivatives such as hypromellose (HPMC) [16 17]

The hydrophilic polymer selected for the present studywas hypromellose K100M (HPMC K100M) Hydrophilicpolymer matrix systems are widely used for designing oralsustained release delivery systems because of their flexibilityto provide the desirable drug release profile cost effective-ness and broad regulatory acceptance [16] The drug releasefrom HPMC polymer matrix especially the release of highlywater-soluble drugs formulated into HPMCmatrices may becharacterized by an initial burst effect because of the rapiddiffusion of the dissolved drug through the hydrophilic gelnetwork created on thematrix surfaceThe initial high releaserate may lead to drug concentration near or above the toxiclevel in vivo [18]

A combination of water-insoluble polymers with HPMCcould solve this problem as they decrease the penetration ofwater in the matrix leading to a decreased diffusion of thedrug and slower initial release The insoluble polymers thatcould be incorporated into theHPMCmatrices include insol-uble methacrylic acid copolymers (eg Eudragit NE 30D)and ammonio-methacrylate copolymers (eg Eudragit RL100 or PO RS 100 RS 30D) ethylcellulose (eg Ethocel orSurelease) cellulose acetate or polyvinyl acetate [9 19ndash24]To reduce the burst effect an ethanolic solution of EudragitRL 100 and RS 100 was added to a mixture of freely water-soluble drug nicorandilHPMC K4M [25]

As a more effective tool proved to be the application of aninsoluble polymer in a liquid formdirectly on the API (ActivePharmaceutical Ingredient) or APIinsoluble filler mixturecurrently the information on this issue is relatively limitedin the literature and available only for non-HPMC matrixsystems In the study published by Krajacic et al the slightlysoluble diclofenac sodium was successfully granulated withthe aqueous polymer dispersion of Eudragit NE 40D toobtain prolonged drug dissolution profiles from matriceswithout the burst release [26] Similarly Tabasi et al [27]described the granulation of the mixture of slightly solubletheophyllinelactose monohydratemicrocrystalline cellulose(PH 101) with a different concentration of Eudragit NE 30Dto investigate the dissolution behavior of prepared matricesOn the other hand burst effect of freely soluble drug diltiazemhydrochloride was reduced by applying Eudragit NM 30Don the druginsoluble microcrystalline cellulose (PH 101)blend in the ratio 11 during the high-shear granulation [28]Additionally Tsai et al [29] granulated conventional excip-ients such as lactose and dibasic calcium phosphate withthe Eudragit RS 30D Eudragit RL 30D and ethylcellulose(Surelease) Granulated excipients were directly compressedto fabricate sustained release captopril tablets

In our previous recently published studies focused onHPMC K4M matrices with a reduced burst effect we inves-tigated an application of water dispersions of insolubleEudragit polymers on a very soluble model API during

high-shear granulation It was concluded that there is nopossibility of applying them directly in one-step processdue to the creation of a highly sticky mass unsuitable forconsequent processing This problem was solved by theaddition of insoluble filler such as MCC or Neusilin US2to create a drugfiller mixture [30 31] Nevertheless thebehavior of the highly soluble API directly granulated withwater dispersions of insoluble Eudragit polymers has notbeen published yet The main aim of the present study wasto explore a near zero-order release of highly soluble modeldrug directly granulated by water dispersions of EudragitNENM RL and RS respectively fromhypromellose K100Mmatrix tablets Moreover the matrix systems were inves-tigated using gel layer investigation and multivariate dataanalysis The integral part of this study was a presentation ofdifficulties observed during the granulation process

2 Materials and Methods

21 Materials Levetiracetam was kindly donated by Zentivaks Prague Czech Republic HPMC K100M was procuredfrom Colorcon Limited Dartford Great Britain and themicrocrystalline cellulose (MCC) Avicel PH 102 was pur-chased from FMC Biopolymers Rockland United States ofAmerica Eudragit NE NM RL and RS in the form of 30water dispersions were received as a gift sample from EvonikRohmGmbHDarmstadt GermanyMagnesium stearatewasobtained from Peter Greven BadMunstereifel Germany andcolloid silica from Degussa Vicenza Italy All materials wereof European Pharmacopoeia (Ph Eur) quality

22 Methods

221 Preparation and Evaluation of Granules The granulesfrom themodel drug levetiracetam (particle size 14157plusmn 287120583m laser diffraction HELOS Sympatec Germany aqueoussolubility at 20∘C 104 g100 ml [32]) and 30 aqueousdispersion of four different insoluble Eudragit polymerswere prepared in a high-shear mixer (ROTOLAB ZanchettaS Salvatore Montecarlo Italy) The instrument settings wereas follows impeller pause time 0 s impeller working time300 s cycle time 300 s and impeller speed 1200 rpmThe granulation liquid (30 water dispersion of Eudragitpolymers) was manually added for the first 60 seconds thenthe mixture was granulated for 240 s at 1200 rpm The wetmass was passed through a 125 mm mesh sieve and thegranules were dried for 24 hours at 40∘C in a cabinet dryerAfter drying the granules were again passed through the 125mmmesh sieve

The amount of water dispersion used in the granulationprocess was limited by the absorption capacity of the drugwhich allowed an application of only a limited amount of a30 Eudragit water dispersion on the drug in individualsteps of the granulation process Set 25 including samplesNE25 NM25 RL25 and RS25 was prepared by the appli-cation of 139 69 and 70 g of water dispersion in three-stepgranulation Set 5 including samples NE5 NM5 RL5 andRS5 was prepared by the application of 139 69 70 88 100























1198912 = 50 times log[1 + (1119899)

119899sum119894=1

1003816100381610038161003816119877119894 minus 11987911989410038161003816100381610038162]minus05

times 100(1)






















Levetiracetam

13 CPMAS NMR

（3

O

ON

（2

(a)

(b)

(c)

(d)

(e)

150 100 50

ppm

1

23

4

56

7

8

1 23

45

67 8













0102030405060708090

100

0 60 120 180 240 300 360 420 480 540 600 660 720Time [min]


Diss

olve

d am

ount

of d

rug

[]

(a)

0102030405060708090

100

0 60 120 180 240 300 360 420 480 540 600 660 720Time [min]


Diss

olve

d am

ount

of d

rug

[]

(b)










4698RS5 861 plusmn 095 7747 plusmn 489 4405













PC 2

(22

4)

PC 1 (561)

2

1

0

minus1

minus2


RS25 RL5

RL25

NE5

RS5

NM5

NE25

NM25R

(a)

PC 2

(22

4)

PC 1 (561)

06

04

02

00

minus02


dis (300 min)

dis (720 min)


hardness

n (KPM)

R2 (0)

(b)












0

05

1

15

2

25

3

35

4

0 60 120 180 240 300 360Time [min]

R

NE25

NE5

NM25

NM5

Gel

layer

thic

knes

s [m

m]

(a)

032

034

036

038

040

042

044

046

048

30 60 90 120 150 180 210 240 270 300 330 360

Pene

trat

ion

forc

e [N

]

Time [min]R

NE25

NE5

NM25

NM5

(b)

0

05

1

15

2

25

3

35

4

0 60 120 180 240 300 360Time [min]

R

RL25

RL5

RS25

RS5

Gel

layer

thic

knes

s [m

m]

(c)

032

034

036

038

040

042

044

046

048

30 60 90 120 150 180 210 240 270 300 330 360

Pene

trat

ion

forc

e [N

]

Time [min]

R

RL25

RL5

RS25

RS5

(d)


(a) (b) (c)




4 Conclusion


Data Availability




Acknowledgments


References














































































Arthritis










AddictionJournal of







Journal of


Pharmaceutics



Volume 2018



Canadian Journal of






of
























1198912 = 50 times log[1 + (1119899)

119899sum119894=1

1003816100381610038161003816119877119894 minus 11987911989410038161003816100381610038162]minus05

times 100(1)






















Levetiracetam

13 CPMAS NMR

（3

O

ON

（2

(a)

(b)

(c)

(d)

(e)

150 100 50

ppm

1

23

4

56

7

8

1 23

45

67 8













0102030405060708090

100

0 60 120 180 240 300 360 420 480 540 600 660 720Time [min]


Diss

olve

d am

ount

of d

rug

[]

(a)

0102030405060708090

100

0 60 120 180 240 300 360 420 480 540 600 660 720Time [min]


Diss

olve

d am

ount

of d

rug

[]

(b)










4698RS5 861 plusmn 095 7747 plusmn 489 4405













PC 2

(22

4)

PC 1 (561)

2

1

0

minus1

minus2


RS25 RL5

RL25

NE5

RS5

NM5

NE25

NM25R

(a)

PC 2

(22

4)

PC 1 (561)

06

04

02

00

minus02


dis (300 min)

dis (720 min)


hardness

n (KPM)

R2 (0)

(b)












0

05

1

15

2

25

3

35

4

0 60 120 180 240 300 360Time [min]

R

NE25

NE5

NM25

NM5

Gel

layer

thic

knes

s [m

m]

(a)

032

034

036

038

040

042

044

046

048

30 60 90 120 150 180 210 240 270 300 330 360

Pene

trat

ion

forc

e [N

]

Time [min]R

NE25

NE5

NM25

NM5

(b)

0

05

1

15

2

25

3

35

4

0 60 120 180 240 300 360Time [min]

R

RL25

RL5

RS25

RS5

Gel

layer

thic

knes

s [m

m]

(c)

032

034

036

038

040

042

044

046

048

30 60 90 120 150 180 210 240 270 300 330 360

Pene

trat

ion

forc

e [N

]

Time [min]

R

RL25

RL5

RS25

RS5

(d)


(a) (b) (c)




4 Conclusion


Data Availability




Acknowledgments


References














































































Arthritis










AddictionJournal of







Journal of


Pharmaceutics



Volume 2018



Canadian Journal of






of

















Levetiracetam

13 CPMAS NMR

（3

O

ON

（2

(a)

(b)

(c)

(d)

(e)

150 100 50

ppm

1

23

4

56

7

8

1 23

45

67 8













0102030405060708090

100

0 60 120 180 240 300 360 420 480 540 600 660 720Time [min]


Diss

olve

d am

ount

of d

rug

[]

(a)

0102030405060708090

100

0 60 120 180 240 300 360 420 480 540 600 660 720Time [min]


Diss

olve

d am

ount

of d

rug

[]

(b)










4698RS5 861 plusmn 095 7747 plusmn 489 4405













PC 2

(22

4)

PC 1 (561)

2

1

0

minus1

minus2


RS25 RL5

RL25

NE5

RS5

NM5

NE25

NM25R

(a)

PC 2

(22

4)

PC 1 (561)

06

04

02

00

minus02


dis (300 min)

dis (720 min)


hardness

n (KPM)

R2 (0)

(b)












0

05

1

15

2

25

3

35

4

0 60 120 180 240 300 360Time [min]

R

NE25

NE5

NM25

NM5

Gel

layer

thic

knes

s [m

m]

(a)

032

034

036

038

040

042

044

046

048

30 60 90 120 150 180 210 240 270 300 330 360

Pene

trat

ion

forc

e [N

]

Time [min]R

NE25

NE5

NM25

NM5

(b)

0

05

1

15

2

25

3

35

4

0 60 120 180 240 300 360Time [min]

R

RL25

RL5

RS25

RS5

Gel

layer

thic

knes

s [m

m]

(c)

032

034

036

038

040

042

044

046

048

30 60 90 120 150 180 210 240 270 300 330 360

Pene

trat

ion

forc

e [N

]

Time [min]

R

RL25

RL5

RS25

RS5

(d)


(a) (b) (c)




4 Conclusion


Data Availability




Acknowledgments


References














































































Arthritis










AddictionJournal of







Journal of


Pharmaceutics



Volume 2018



Canadian Journal of






of



0102030405060708090

100

0 60 120 180 240 300 360 420 480 540 600 660 720Time [min]


Diss

olve

d am

ount

of d

rug

[]

(a)

0102030405060708090

100

0 60 120 180 240 300 360 420 480 540 600 660 720Time [min]


Diss

olve

d am

ount

of d

rug

[]

(b)










4698RS5 861 plusmn 095 7747 plusmn 489 4405













PC 2

(22

4)

PC 1 (561)

2

1

0

minus1

minus2


RS25 RL5

RL25

NE5

RS5

NM5

NE25

NM25R

(a)

PC 2

(22

4)

PC 1 (561)

06

04

02

00

minus02


dis (300 min)

dis (720 min)


hardness

n (KPM)

R2 (0)

(b)












0

05

1

15

2

25

3

35

4

0 60 120 180 240 300 360Time [min]

R

NE25

NE5

NM25

NM5

Gel

layer

thic

knes

s [m

m]

(a)

032

034

036

038

040

042

044

046

048

30 60 90 120 150 180 210 240 270 300 330 360

Pene

trat

ion

forc

e [N

]

Time [min]R

NE25

NE5

NM25

NM5

(b)

0

05

1

15

2

25

3

35

4

0 60 120 180 240 300 360Time [min]

R

RL25

RL5

RS25

RS5

Gel

layer

thic

knes

s [m

m]

(c)

032

034

036

038

040

042

044

046

048

30 60 90 120 150 180 210 240 270 300 330 360

Pene

trat

ion

forc

e [N

]

Time [min]

R

RL25

RL5

RS25

RS5

(d)


(a) (b) (c)




4 Conclusion


Data Availability




Acknowledgments


References














































































Arthritis










AddictionJournal of







Journal of


Pharmaceutics



Volume 2018



Canadian Journal of






of









PC 2

(22

4)

PC 1 (561)

2

1

0

minus1

minus2


RS25 RL5

RL25

NE5

RS5

NM5

NE25

NM25R

(a)

PC 2

(22

4)

PC 1 (561)

06

04

02

00

minus02


dis (300 min)

dis (720 min)


hardness

n (KPM)

R2 (0)

(b)












0

05

1

15

2

25

3

35

4

0 60 120 180 240 300 360Time [min]

R

NE25

NE5

NM25

NM5

Gel

layer

thic

knes

s [m

m]

(a)

032

034

036

038

040

042

044

046

048

30 60 90 120 150 180 210 240 270 300 330 360

Pene

trat

ion

forc

e [N

]

Time [min]R

NE25

NE5

NM25

NM5

(b)

0

05

1

15

2

25

3

35

4

0 60 120 180 240 300 360Time [min]

R

RL25

RL5

RS25

RS5

Gel

layer

thic

knes

s [m

m]

(c)

032

034

036

038

040

042

044

046

048

30 60 90 120 150 180 210 240 270 300 330 360

Pene

trat

ion

forc

e [N

]

Time [min]

R

RL25

RL5

RS25

RS5

(d)


(a) (b) (c)




4 Conclusion


Data Availability




Acknowledgments


References














































































Arthritis










AddictionJournal of







Journal of


Pharmaceutics



Volume 2018



Canadian Journal of






of









0

05

1

15

2

25

3

35

4

0 60 120 180 240 300 360Time [min]

R

NE25

NE5

NM25

NM5

Gel

layer

thic

knes

s [m

m]

(a)

032

034

036

038

040

042

044

046

048

30 60 90 120 150 180 210 240 270 300 330 360

Pene

trat

ion

forc

e [N

]

Time [min]R

NE25

NE5

NM25

NM5

(b)

0

05

1

15

2

25

3

35

4

0 60 120 180 240 300 360Time [min]

R

RL25

RL5

RS25

RS5

Gel

layer

thic

knes

s [m

m]

(c)

032

034

036

038

040

042

044

046

048

30 60 90 120 150 180 210 240 270 300 330 360

Pene

trat

ion

forc

e [N

]

Time [min]

R

RL25

RL5

RS25

RS5

(d)


(a) (b) (c)




4 Conclusion


Data Availability




Acknowledgments


References














































































Arthritis










AddictionJournal of







Journal of


Pharmaceutics



Volume 2018



Canadian Journal of






of




4 Conclusion


Data Availability




Acknowledgments


References














































































Arthritis










AddictionJournal of







Journal of


Pharmaceutics



Volume 2018



Canadian Journal of






of




























































Arthritis










AddictionJournal of







Journal of


Pharmaceutics



Volume 2018



Canadian Journal of






of


highly soluble drugs directly granulated by water...

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