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Drug Development and Industrial Pharmacy

ISSN: 0363-9045 (Print) 1520-5762 (Online) Journal homepage: http://www.tandfonline.com/loi/iddi20

To prepare and characterize microcrystallinecellulose granules using water and isopropylalcohol as granulating agents and determine itsend-point by thermal and rheological tools

Smruti P. Chaudhari & Rutesh H. Dave

To cite this article: Smruti P. Chaudhari & Rutesh H. Dave (2015) To prepare and characterizemicrocrystalline cellulose granules using water and isopropyl alcohol as granulating agents anddetermine its end-point by thermal and rheological tools, Drug Development and IndustrialPharmacy, 41:5, 744-752, DOI: 10.3109/03639045.2014.900080

To link to this article: http://dx.doi.org/10.3109/03639045.2014.900080

Published online: 24 Mar 2014.

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Drug Dev Ind Pharm, 2015; 41(5): 744–752! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/03639045.2014.900080

RESEARCH ARTICLE

To prepare and characterize microcrystalline cellulose granules usingwater and isopropyl alcohol as granulating agents and determine itsend-point by thermal and rheological tools

Smruti P. Chaudhari and Rutesh H. Dave

Division of Pharmaceutical Sciences, Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, Brooklyn, NY, USA

Abstract

Microcrystalline cellulose (MCC-102) is one of the most commonly used excipient in thepharmaceutical industry. For this research purpose, authors have developed a differenttechnique to determine the end point for MCC-102 using water and isopropyl alcohol 70% (IPA)as granulating agent. Wet and dry granules obtained were characterized for their flowproperties using the powder rheometer and thermal analysis. Powder rheometer was used tomeasure basic flowability energy (BFE), specific energy (SE), percentage compressibility,permeability and aeration. Thermal analysis includes effusivity and differential scanningcalorimetry (DSC) measurements. BFE and SE results showed water granules requires highenergy as compared to IPA granules. Permeability and compressibility results suggest IPA formsmore porous granules and have better compressibility as compared to water granules.Hardness data reveals interesting phenomena in which as the amount of water increases,hardness decreases and vice-versa for IPA. Optimal granules were obtained in the range of45–55% w/w. DSC data supported the formation of optimal granules. Empirical measurementslike angle of repose did not reveal any significant differences between powder flow amongvarious granules. In this paper, with the help of thermal effusivity and powder rheology wewere able to differentiate between various powder flows and determine the optimal range forgranule formation.

Keywords

Effusivity, end point determination,granulation, microcrystalline cellulose,powder rheometer

History

Received 2 December 2013Revised 24 February 2014Accepted 26 February 2014Published online 26 March 2014

Introduction

Oral drug delivery systems (ODDS) are the most convenientdosage forms available in the market. Despite many years ofresearch, content uniformity and weight variation still remain as amajor issue in ODDS. These issues can be attributed to poor flowof powder from hopper to the die or segregation of the powders inthe hopper, which creates the need to understand powderbehavior.

There are several ways to address these issues and the mostcommon is to redesign the hopper using a recommended hopperangle, the use of force feeders or addition of flowing agents. Wetgranulation is also one of the most commonly used techniques.There are two types of granulations: wet granulation and drygranulation. Dry granulation is preferred due to its cost effect-iveness and ease of manufacturing. However, the granules formedusing the dry granulation process are more dense and irregularthan the original powder, since the material is densified under

pressure and milled to obtain granules1. Conversely, granulesformed by wet granulation are voluminous and show bettercompressibility and compactibility as compared to granulesformed by dry granulation2. The wet granulation process hasthree most important steps: solvent selection, optimization of themixing time and determination of end point. In this paper, wehave used a wet granulation process for granulation and charac-terization of microcrystalline cellulose -102 (MCC-102) usingwater and isopropyl alcohol 70% (IPA) using powder rheometer.

MCC-102 is the most commonly used filler in the tabletingindustry. The tablet compact formed using MCC-102, whenexposed to humid conditions tends to swell and soften but regainsits original properties on the removal of excess moisture; however,it has been reported that even after water removal, there is stillchange in enthalpy of water sorption which again is responsiblefor change in the internal bonding within the cellulose structureupon wet granulation and drying3. MCC-102 also shows fastdisintegration in high-polarity solvents, since hydrogen bonding islargely responsible for holding individual crystallites of MCC intablet compacts4. It has also been reported that water wetgranulated MCC-102 shows the loss of binding ability duringtableting, swelling and disintegration, due to irreversible hydro-gen bonding and densification during drying5. Change inhydrogen bonding can also be expected after wet granulationusing water as solvent of choice6. However, X-ray diffraction,

Address for correspondence: Rutesh H. Dave, Division of PharmaceuticalSciences, Arnold & Marie Schwartz College of Pharmacy andHealth Sciences, Long Island University, Brooklyn, NY 11201, USA.Tel: +718-488-1660. Fax: +718-780-4586. E-mail: rutesh.dave@liu.edu

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magnetic angle spinning nuclear magnetic resonance, degree ofcrystallinity and oxygen combustion calorimetry, fail to provideevidence for significant change in hydrogen bonding7. Highporosity pellets were formed when water–ethanol or water–isopropyl alcohol was used as compared to water alone7.Granulating fluid influences mechanical and structural propertiesof pellets by governing contraction driving and contractioncounteracting forces during drying8. Porosity of MCC pelletsdepends on the drying method, hence drying methods like freezedrying which allows minimal capillary flow gives pellets ofhighest porosity as compared to conventional drying methodswhen using water as a granulating fluid9.

Mixing time is one critical step involved in wet granulation.Optimum mixing time is required to attain equilibrium granulesize. Excessive mixing changes the packaging arrangement ofgranules due to dissolving of excess material during drying,causing granules to become non-porous and dense10. In thisresearch, we have utilized thermal effusivity measurementtechnique to optimize mixing time. It can also be used as theindicator of mixing time efficiency as it depends on the heatcapacity, thermal conductivity and density of the material11–13.

Another critical step in wet granulation is end-point determin-ation. It is of utmost importance since over-granulated powdersoften result in larger granules with lower tablet ability. Largegranules have lower intragranular bonding which causes granulesto become hard and resistant to grinding14. It has also been shown,that flowability is improved as we lower the particle size.However, if the particle size is reduced below a certain limit theopposite effect can be observed due to dominant interparticulateforces such as vander Waals’ forces and electrostatic forces.Optimum particle size range is required for good flowability.MCC shows segregation issues with broad particle size distribu-tion which in turn result in weight variation and contentuniformity issues15.

Over recent years a few methods have developed for end-pointdetermination. The most commonly used is to measure powerconsumption in high shear granulator. A linear correlation wasfound between mean granule size and power consumption. Thisapproach is limited to impellar design, impellar speed, liquidaddition rate and type of binder16. Some scientists havedetermined end-point based on a mathematical model, wherethe amount of water needed for each excipient was determinedwith the help of a refractive near-infrared moisture sensorwhich measures the moisture at the surface of the powder.Summation of water need to all excipients gives the waterneeded for tablet formulation17. Near infra-red spectroscopy18,19,acoustic emission20, and the application of artificial neuralnetworks21 are some methods used to characterize powder flowand determination of end points. However, these methods lackreproducibility.

Granule flowability can be measured with the help of arheometer. Previously, it has reported that powder flow propertiescan be characterized by powder rheometer22. Researchers haveused mixer torque rheometer to determine the relationshipbetween dried granules and wet mass consistency. It is provedthat wet mass with good consistency produces granules with goodflow property23. The addition of water to MCC changes thermalproperties of MCC like glass transition temperature (Tg) whichsuggests that isopropyl alcohol does not have any significantchange in Tg24.

In this study, we have used a powder rheometer to determinepowder flowability of wet mass as well as dried granules formedby using water and isopropyl alcohol as granulating agents. Weused effusivity measurements and thermal analysis to support ourdata. This information will provide a unique way to identify theend point of wet granulation and give importance to various

energies involved in powders and finally comparison using twodifferent granulating agents.

Materials and methods

Material

Microcrystalline Cellulose (MCC, Avicel� 102) was generouslydonated by FMC Biopolymer, Newark, DE (Lot# P209821062),deionized water was obtained using Barnstead Nanopure systembelow 13 mV-cm (Thermoscientific system, Waltham, MA) andiso-propyl alcohol was obtained from VWR, Westchester, PA (lotno. 110308B).

Preparation of granules (wet and dried)

Wet granules were prepared using a Cuisinart mixer (EastWindsor, NJ). Seven hundred grams of MCC-102 were granulatedusing purified water and IPA. Granulating liquid was addedwithin 30 s while mixing at 15 rpm. Granulating liquids wereadded to make the final concentration of water/IPA mixture 35,45, 50, 55 and 60% w/w. After the addition of granulating liquid,it was further mixed for an additional 3 min at 70 rpm.Approximately 250 g of wet mass were collected and subjectedto a powder rheological and thermal analysis. The remaining wetmass was passed through sieve #12 and dried in an oven at 60 �Cuntil constant loss on drying (LOD) of 3% was obtained. Driedsamples were further passed through sieve #30 and subjected topowder rheological measurements.

Powder rheological measurements

Powder rheological measurements were carried out using an FT-4rheometer (Freeman Technology, Worcestershire, UK). Thesecharacterizations include measurement of basic flowability energy(BFE), specific energy (SE), compressibility, permeability andaeration ratio (AR). The rheometer was initially calibrated forforce, torque and height measurements. All tests are performedusing 48 mm diameter helical blade in a 50 mm vessel. Allsamples were initially subjected to conditioning by moving theblade slowly in upward and downward while rotating clockwise.

Basic flowability energy measurements

This test was performed using a 50 mm� 160 ml split vesselassembly, fitted with a base and rested on an FT-4 platform usinga 48 mm blade. BFE is the energy required by the blade to movedown the blade through the powder bed at 100 mm tip speed and�5� helix angle. Powder is forced to flow on the face of the blade.Wet mass and dried granules were subjected to BFE measure-ments. Two kinds of forces act on the blade, rotational force andthe axial force.

BFE is calculated using Equation (1):

Energy consumed : dE ¼ T=ðR tan�Þ þ Fð ÞdH ð1Þ

where R¼ blade radius; L¼ vertical distance moved during onecomplete revolution; �¼ helical path angle; F¼ axial force on theblade, in Newtons (N); T¼ torque acting on blade (Nm).

Specific energy measurement

Specific energy is the energy required by the blade to move fromthe bottom to the top of the vessel. This test was performed usinga 50� 160 ml assembly fitted with a solid base and rested onthe platform and a 48 mm diameter helical blade was used forenergy measurements. Energy is calculated as work done inupward traverse movement of the blade from the bottom of thepowder blade.

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Pressure drop measurements

This test was performed on wet and dried powders using50� 85 ml assembly fitted with an aerated base and a ventedpiston was used to compress the powder. Powders werecompressed at 1, 2, 4, 6, 8, 10, 12 and 15 kp, respectively, anda constant air velocity of 2 mm/s was maintained throughout theexperiment. Data generated using this experiment did not showsignificant change in permeability readings at different compres-sion pressure and henceforth, 15 kp was selected as the compres-sion pressure for wet mass and dried powders. Pressure drop (PD)can be measured using the following equation:

k ¼ q�L=DP ð2Þ

where k¼ permeability (cm2); �¼ air viscosity (Pa s)(1.74� 10�5 Pa s); q¼ air flow rate (cm/s); L¼ length of thepowder bed (cm); DP¼ pressure drop across the powder bed(mbar).

Aeration ratio measurements

Aeration ratio (AR) measurements were carried out using a48 mm blade and 50 mm� 260 ml vessel fitted with an aerationbase. Variable amount of air is introduced from bottom of thevessel, starting from 2 mm/s, followed by increase in incrementsof 2 mm/s till it reaches 10 mm/s. AR is calculated using Equation(3), where N¼ 10 mm/s.

Aeration ratio ¼ Energy Airvelocity 0ð ÞEnergy Airvelocity nð Þ ð3Þ

This test is performed only on the dried granules.

Compressibility

Compressibility is expressed as the percentage change in volumeafter compression. This test is carried out in a 50� 85 ml vesselfitted with a solid base and compressed using a vented piston.In this test, powder is compressed at 15 kp. Change in volume isnoted at each compression pressure.

% Compressibility ¼ Percentage change in volume

after compression %ð Þð4Þ

Tablet compression

Prepared granules were compressed into a 500 mg tablet using anEnerpac single compression machine (GlobePharma, NewBrunswick, NJ) at 1500 psi, 2000 psi and 2500 psi. Round flatfaced punches (13 mm diameter) were used to compress tablets.Hardness was measured using a Schleuniger tablet tester 6D(Schleuniger Pharmatron Inc, Manchester, NH).

Sieve analysis

Sieve analysis was carried out using a sieve shaker Octagon 200(Endecotts, UK). 100 g of powder were passed through sievesstacked in ascending # 12, 14, 18, 20, 30 and 60. Sieves werefitted on a collecting pan at the bottom. Sieves were subjected tovibration for 5 min. Sieves were weighed before and after the testand the mass retained on the sieve was calculated by thedifference in the initial and final sieve weight.

Angle of repose

A plastic funnel was fixed from a horizontal surface (glass plate)and powder was placed in the plastic funnel and allowed to flowunder gravity. The height of the pile was kept 1.5 cm and radius

was measured. The angle of repose (AOR) was calculated byEquation (5):

tan � ¼ h

rð5Þ

where, h¼ height of the pile of the powder; r¼ radius of the pileof the powder; y¼ angle of repose.

Thermal measurements

Differential scanning calorimetry (DSC) and thermal effusivitywere used to perform thermal analysis.

Differential scanning calorimetry

The wet granules obtained were weighed approximately 5–15 mgand placed in hermetically sealed aluminum pans, and measure-ments were performed using Q100 (TA Instruments, New Castle,DE) instrument with nitrogen (50 ml/min) as purge gas.Samples were heated from 40 to 200 �C at a constant heatingrate of 10 �C/min. DSC was calibrated using indium beforestarting the experiments.

Thermal effusivity measurements

Wet and dried granules were subjected to effusivity measurementsusing a TC Probe (Mathis Instruments, New Brunswick, Canada).The TC Probe sensor was inverted and placed in contact with thegranules. This instrument detects the heat flow and effusivity iscalculated using Equation (6):

" ¼ffiffiffiffiffiffiffiffiffiffiffiffiK�Cp

pð6Þ

where, "¼ effusivity; K¼ thermal conductivity (W/m K); �¼density (kg/m2); Cp¼ heat capacity (J/kg K).

Effusivity was used to optimize mixing time. For thisexperiment, 700 g of MCC-102 were granulated with 45% w/wof water and IPA, respectively. Samples were mixed at 70 rpmafter the addition of granulating fluid for 30 s, and samples weretaken at 1, 2, 3, 7 and 10 min after mixing and effusivity wasmeasured at each time point.

Effusivity was also used to determine end-point determinationfor lab scale (7 g) and feasibility experiments (700 g). For labscale, 20, 30, 35, 40, 45, 50, 55, 60 and 70% w/w of granulatingagent was used. However, in case of feasibility studies, 35, 45, 50,55 and 60% w/w of granulating agent was used. A detailedexplanation is given in ‘‘Results and discussion’’ section. Afteraddition and mixing of the granulating agent, 2–3 g of sampleswere collected and subjected to effusivity measurements.

Results and discussion

Rheological measurements

Conditioning of the powders

In a powder rheometer, the packing of the powder is of utmostimportance. Powder, which is filled gently, will behave differentlyfrom powder, which is consolidated, due to air entrapped in it.Therefore, the conditioning of powders is carried out beforeperforming any tests, to remove compaction due to the loading ofa cell and to remove residual compaction from previous tests onthe powder25. In a conditioning cycle, the blade moves indownward direction followed by a move upwards in clockwisedirection, as shown in Figure 1. Typically a conditioning cycledoes not induce any compaction on powder; hence, a positivehelix angel is created in the downward movement of the blade,which creates a slicing action to remove stress and excess air. Thisresults in a low stress packaging state. On other hand, a negative

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helix angle is created during upward movement of the blade,which gently lifts the powder and drops it over the blade to resultin particles falling from the blade and creating a properly packedpowder bed26.

Characterization of BFE and SE related to wet and dried granules

Basic flowability energy depends on several physical properties ofpowders such as particle size distribution, shape, texture, stiffness,cohesivity, density, electrostatic charge, moisture content, elasti-city, porosity, friability and surface additives. The interaction ofthese powder properties will influence BFE measurements. BFEis the measure of energy required to produce flow during adownward traverse anticlockwise motion of the blade into thepowder to generate a high stress environment similar to those infeeders. Compacting motion is generated due to the anticlockwisedownward direction of the blade. Since the powder is forced toflow due to blade movement, many factors like attrition agglom-eration, segregation and de-aeration plays a pivotal role.

In our case, as the granulating fluid is added in incrementalpercentages, BFE increases. This phenomenon is due to decreasein air pockets in-between wet granules as seen in Figure 2(a). Theenergy required by the blade is increased due to high inter-particlefriction and high contact stresses throughout the flow zone. In awet mass the blade will require high energy, due to the cohesivenature of the wet mass. As seen from Figure 2(a), there iscontinuous rise in BFE until 55% of granulating fluid is added,

after which a sudden drop is observed in BFE. MCC-102 formshighly cohesive mass after 55% of water addition, large amount ofair is entrapped in agglomerate. At this point, inter-particulateforces are high as compared to gravitational force acting on theparticle. When particles are forced to flow at the blade face, airpockets inside the agglomerate can accommodate the particle,which results in low BFE values due to localized stresstransmission zone. In the case of IPA, MCC-102 forms slurryafter 55% of IPA addition, which results in the low BFE value.

Dried granules BFE which are obtained after the addition ofincreasing granulating fluid are shown in Figure 2(b). Initiallyafter the addition of 35% granulating fluid, the BFE decreases ascompared to MCC-102 alone, followed by rise in BFE values. Inthe case of IPA granules, they require less energy as compared towater granules which implies the IPA granules are better flowing.This phenomenon is due to hydrogen bonding in water gran-ules3,27, which tends to hold the granules tightly. It can also bedue to the strength of hydrogen bond being stronger in water ascompared to alcohol7.

SE measures the powder flow in unconfined low stressenvironments. It correlates with powder flow when being fedgravimetrically. This process is analogous to die filling process.It measures the flow of powders under gravity; hence, cohesionforces between particles play an important role. Particle size,texture, shear force and shape can also be the contribution factors.

Generally, the higher the SE values, higher the cohesion. Asthe amount of water increases, MCC-102 forms a cohesive masswhich results in higher SE values as shown in Figure 3(a). SEincreases as the amount of IPA increases until 55% addition ofliquid. After this point, a sudden drop is observed in SE at 60%addition of IPA due to the formation of slurry. It also reduces theenergy required by the blade, resulting in low SE values. Driedgranules formed after the addition of water (45%) show decreasein SE values, above which, increases in SE values are observed asseen in Figure 3(b). It suggests that cohesive forces are increasedas the amount of water increases. However, dried IPA granulesshows decrease in SE until they reach equilibrium at 45%;after 45%, IPA granules show minimal change in SE as seen inFigure 3(b). It should be noted that MCC-102 is a good flowingpowder by itself, however, the addition of water and IPA changesthe properties of the granules as expected. In the case of water, asmentioned above, SE values increase as the percentage of wateraddition increases and the opposite phenomena is observed incase of IPA. This is due to the bonds formed in water are strongeras compared to the ones which are formed using IPA.

Figure 2. BFE as a function of increasing granulating fluid.

Figure 1. Conditioning mode of blade.

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Pressure drop

Pressure drop (PD) is the measure of permeability of the powders.Permeability is influenced by many physical properties likeparticle size distribution, cohesivity, particle stiffness, shape,surface texture and bulk density. This test is helpful inunderstanding the effect of permeability on many processenvironments like pneumatic transfers, storage in and out of thehoppers, vacuum transfer, vial filling or dry dose inhalation.Permeability increases as the PD decreases (Equation (2)).

The PD of the 35, 45, 50, 55 and 60% w/w of granulating fluidwas measured as 2.56, 1.68, 0.90, 0.499 and 1.19 mbar,respectively. It is evident, the PD decreases until 55%, beyondthat the PD starts to increase (Figure 4a). IPA shows decrease inPD until 50%, and after that it starts to increase. In this test, thepowder bed is compressed using vented piston and the air issupplied from below at 2 mm/s and the difference in pressuregives us the PD. The compact mass formed by IPA does not allowair to permeate through it resulting in large pressure differenceafter 45% and the PD increase. Dried granules prepared fromboth water and IPA showed a decrease in PD as granulatingfluid increased as seen in Figure 4(b). PD for the IPA granulesis less as compared to dried water granules; permeability of theIPA granules is more than water granules. This result is inagreement with the previous study carried on water/ethanolmixtures27.

Aeration ratio

The aeration test measures how easily powders get fluidized frombulk powders. Some powder easily gets aerated, while somerequires sufficient amount of air to get fluidized. There are twokinds of forces acting on the particle in the powder: cohesionforces between the particles and forces acting due to gravity onthe particles. For a good flowing powder, restraining forces actingon neighboring particles are sufficiently less as compared togravitational forces. Hence, AR is affected most by the cohesionforces acting between the particles although some other physicalproperties of the powders, like particle shape, texture and density,can also play an important role.

Air supplied from the bottom in this test will reduce the energyrequired by the blade to produce flow. Hence, the energy requiredto produce powder flow will keep on decreasing as air velocityincreases. AR is calculated using Equation (3). Granules withgood flowability will easily get fluidized and energy required athighest air velocity (10 mm/s) will be lower, resulting in higherAR values, compared to granules with poor flow. As granulatingfluid increases, dried water granules and IPA granules show adecrease in AR (Figure 5). However, the IPA shows higher AR ascompared to the water. IPA granules formed are easily fluidized ascompared to granules formed using water, suggesting that water-formed granules have more cohesive forces than IPA-formedgranules.

Figure 3. SE as a function of increasing granulating fluid.

Figure 4. Pressure drop as a function of increasing granulating fluid.

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Compressibility

Compressibility measures percentage change in volume aftercompression. Here compression pressure of 15 kp was applied tothe powder bed. It measures the volume change of the powder bedfrom initial state to final state, and % compressibility is calculatedfrom Equation (4). As the amount of water increases, the %compressibility of the granules increases until 45% of wateraddition, followed by a decrease in % compressibility until 55%,seen in Figure 9. This is due to formation of cohesive mass after55% addition of water. As we form cohesive wet mass there ismore air entrapped in it resulting in these phenomena. Granulesformed after the addition of IPA shows increase in % compress-ibility values till 45% followed by plateau till 55% (Figure 6a).After the addition of 55% IPA, it shows a decrease in compress-ibility values due to slurry formation. In the case of dried granulesobtained by water, granulation shows continuous decreases incompressibility seen in Figure 6(b). However, dried granulesformed by using IPA shows initial decrease at 35%, after which itremains fairly constant. Water forms hard and strong granules,which are difficult to compress and are resistant to grinding. Thismay be the cause of the decrease in compressibility values.

Hardness measurement

In order to verify compressibility and compactibility, properties ofthe granules hardness measurements were performed. Tabletswere compressed at 1500, 2000 and 2500 psi and data is shown inFigure 7. It is seen that water forms granules with good shape but

they tend to be hard. As a result, more compaction energy isutilized in breaking primary granule structure28. In comparison totablets obtained using IPA as a granulating agent, hardnessincreases as the percentage of IPA increases. This shows thatwater granules are hard and are resistant to grinding and hence itshows very less compressibility properties.

Water has previously been shown to have irreversible hydrogenbonding4. Scientists have also hypothesized that these differencein strength are due to conversion of some of the intramolecularhydrogen bonded amorphous fibrils at the surface of the MCCparticles to intermolecular hydrogen bonded fibrils with otherMCC particles5. It has also been shown that the change in strengthcan also be due to internal hydrogen bonding as well asC-bonding4.

Sieve analysis

Sieve analysis was performed and results are shown in Figure 8,both IPA and water formed granules shows even distribution ofthe particles at 55% of the granulating fluid. Even distribution isalso seen at 50% of granulating fluid but with more number offines. This suggests that 50–55% of granulating fluid is adequatefor the granulation.

Angle of repose

Powder is considered to be of excellent flowability if AOR lies in25�–30� whereas if AOR lies in 31�–35� powder is considered tobe good flowable. Similarly if AOR is 36�–40� it is fairly

Figure 6. Compressibility as a function of increasing granulating fluid.

Figure 5. Aeration as a function of increasing granulating fluid. Figure 7. Tablet hardness as a function of increasing granulating fluid.

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flowable and 41�–45� it is passable and above 46� powders isconsidered to be of poor flowability29. AOR of water and IPAgranules are shown in Table 1. All granules lie in an excellentflowability range so AOR is not a suitable method to concludewhich one is better as compared to other.

Thermal analysis

Thermal Analysis was performed on wet granules obtained byusing water and IPA as granulating agents. Figure 9 shows theoverlay of thermograms of water and IPA granules, respectively.The thermograms of the MCC-102 using IPA shows two peaksdue to the presence of water in IPA and presence of moisture inMCC 102. Delta H values were calculated with increasing amountof granulating fluid. Delta H represents the total enthalpy change

in the system. This is obtained by integrating the area under thecurve in the DSC. It is shown that MCC-102 absorbs granulatingfluid as the amount increases. Delta H values were calculated andit has been seen that it increases with increasing amount ofgranulating fluid.

Mixing time and end-point determination using thermal effusivity

Mixing time was optimized using effusivity measurements;Figure 10(a) shows the effusivity measurements as a function ofthe mixing time. After 3 min of mixing the effusivity readingsdoes not show any significant changes suggesting that nosignificant changes are observed if mixing time is increased,hence all the samples were mixed for 3 min at 70 rpm after 30 s ofgranulating fluid addition.

Figure 8. Mass retained on sieves.

Figure 9. Overlay of thermograms.

Table 1. Angle of repose as a function of increasing granulating fluid.

Water added IPA (70%) added

% w/w granulating fluid Angle of repose Standard deviation Angle of repose Standard deviation

0 26.37 0.95 26.37 0.9535 26.95 1.31 23.27 0.9945 30.29 1.95 28.03 1.0450 27.26 1.61 27.78 0.7755 29.48 2.67 28.32 0.96

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Thermal effusivity measurements were used to determine theend-point of wet granulation. Effusivity is directly proportional tothe heat capacity, thermal conductivity and density. Here we usedwater and IPA as granulating agents. Water has highest effusivity(�1600 Ws1/2/m2K). As the amount of water increases, it willshow rise in effusivity values as seen from Figure 10(b). It isobserved that after the addition of 55% w/w of granulating fluidthere is sudden jump in the effusivity values. This suggests thatinitially MCC-102 absorbs the solvent and after certain point(55%) it starts to show on the surface of MCC-102 resulting inover-granulation. Figure 10(b) shows the effusivity as the functionof addition of water and IPA on lab and feasibility scale batchesand depicts the regions for under, optimum and over-granulation.

Conclusion

Rheological measurements like BFE, SE, aeration and compres-sibility results show IPA forms granules with good flowability andcompressibility. Water forms hard and strong granules and itscompressibility reduces as the water increases. Effusivity datashows that for proper granule formation, 50 to 55% of thegranulating fluid is required and the data is in agreement with theDSC. Effusivity gives highly reproducible results. Traditionallyused empirical approaches like angle of repose could notdifferentiate the flowability of the powders.

Declaration of interest

The authors report no declaration of interest.

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Figure 10. Effusivity as a function of time and increasing granulating fluid.

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25. Trivedi MR, Dave RH. To study physical compatibility betweendibasic calcium phosphate and cohesive actives using powderrheometer and thermal methods. Drug Develop Indust Pharmacy.

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