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As appeared in Tablets & Capsules January 2015 www.tabletscapsules.com

granulation analysisDensity mapping of roller-compacted ribbonsusing terahertz spectroscopy

Mark Sullivan, David Heaps,Richard McKay, Eiji Kato, andXiao Hua ZhouAdvantest AmericaChuan-Yu Wu, Chun-lei Pei, Jian-yi Zhang, and Serena SchianoUniversity of Surrey

Terahertz (THz) spectroscopy and imaging are non-destructivetools for measuring the chemical and physical attributes ofpharmaceutical raw materials, intermediates, and finishedproducts [1]. Examples include determining the crystallinity andpolymorphism of drug substances, the 3D spatial uniformity oftablet coating thickness, and tablet hardness. Terahertzspectroscopy is also well suited to measure and control the density(solid fraction, porosity) of roller-compacted ribbons. In thisarticle, we describe the principals of terahertz analysis and giveexamples of how it can help with formulation development andscale-up and commercialization of the roller compaction process.

amount of energy for drying, roller compaction canoperate as a continuous process and entails no drying.Figure 1 illustrates the major parts of the equipment: afeeder to introduce the powder blend, rollers to compactthe powder into a ribbon, and a mill to reduce the ribbonto granules. The figure also shows the optical path of aterahertz beam.

he terahertz range (0.1 to 10 THz) lies between themicrowave and infrared regions of the electromagneticspectrum and offers a unique combination of highmaterial transparency and spectroscopic information.Terahertz spectroscopy uses extremely short pulses thatyield a broadband response and provides a direct meansto measure the bulk physical properties of materials,including refractive index, permittivity, and absorptioncoefficient. As a result, we can measure the density ofroller-compacted ribbons—the most critical property ofthe process—quickly, non-destructively, and withoutcontact in the lab and production settings.

The design of the pulsed terahertz spectrometer wasdescribed previously [1], and its operation resembles thatof other types of Fourier transform instruments that collecta background and analyze the intact solid sample usingacquisition times of less than a second. Sampling can bedone for at-line and in-line analyses, as detailed below.

Roller compactionRoller compaction is a dry process that agglomerates

powders into ribbons and mills them into granules for themanufacture of tablets and other solid dosage forms.Unlike traditional wet granulation, which operates inbatch mode and requires a liquid binder and a large

Figure 1Roller compactor

1. Feeder introduces powder2. Counter-rotating rollers compact powder into ribbon3. Mill reduces ribbon to granules4. Optical path of terahertz beam to ribbon

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The ribbon’s density is the most important qualityattribute to control because it determines how well thegranules flow and compact during tabletting. Theparameters that can be adjusted to control the ribbon’sphysical properties are feeding speed, roller speed, rollergap, and roller pressure. In addition, one or both of thesmooth-surface rollers can be replaced with knurled-surface rollers in order to decrease slippage of the powderas it enters the nip zone.

A deep understanding of the roller compaction processis required to ensure consistent product quality andperformance across a range of environments. In fact, oneof the most important challenges of process scale-up andtechnology transfer is identifying the process parametersthat will produce granules with consistent properties.Accurate measurement of ribbon density is critical toachieving that. Furthermore, because terahertz spectro -scopy correlates the properties of raw and in-processmaterials and process parameters to measurable productperformance attributes, it jibes with the goals of Qualityby Design. It can also serve as a Process AnalyticalTechnology tool by offering fast, non-destructive, andreal-time analysis of roller-compacted ribbons to provideprocess understanding and help ensure product quality.

Roller-compacted ribbons are inherently porous andcan be characterized by apparent density, solid fraction,and percentage porosity (Table 1).

There are several ways to measure the envelope volumeof roller-compacted ribbons (Table 2). Direct volume

measurement is the easiest to implement but can be tediouswhen used routinely; it also lacks accuracy when applied totextured ribbons. Volume displacement is a betterapproach for measuring complex shapes and is not subjectto operator variability and bias. Yet it requires cutting theribbon into pieces small enough to fit inside a samplechamber. Another option is laser scanning, in which a lasermicrometer pair is coupled with motion control to traversethe sample and create a two-dimensional (2D) pattern of it.Laser scanning can also be used to profile ribbon thicknessand thus calculate its volume.

The most direct way to determine apparent density isto cut the ribbon into rectangular pieces, measure theirdimensions, and weigh them to calculate envelope vol -ume. Despite its relatively poor precision, this tech niqueis often the primary method for calibrating the rollercompactor. But using volume displacement or laserscanning provides substantially more accurate and precisemeasurements of apparent density.

While this article focuses on applying terahertz tech -nology to roller-compacted ribbons, other tech niques canalso measure density profiles (Table 3). Each has itsadvantages, but the terahertz method stands out as a fast,non-destructive, non-contact technique suitable for spatialmapping and in-line process applications. In addition, mostpharmaceutical materials are highly transparent to terahertzradiation, which can penetrate approximately 10 milli -meters into the material. There fore, terahertz samples theentire ribbon thickness, not just the surface. It is also highlyprecise and sensitive to changes in apparent density.

Theory of terahertz density measurementThe unique characteristics of pulsed terahertz spec -

troscopy make it well suited for measuring the densitiesof solid compacts. The terahertz source (emitter)generates a very narrow, phase-coherent pulse of lightthat reaches a phase-sensitive detector whose fast digit -ization rate makes it possible to measure in the pico -second range. When a terahertz pulse passes through ahomogeneous solid, its speed decreases relative to aterahertz pulse that traverses the same distance throughair. The ratio of the speed of light in air to the speed oflight in a denser material is, in fact, the definition of therefractive index (RI) of that material. The time difference

Table 1Material properties of roller-compacted ribbons

Material property Definition

Apparent density Weight � envelope volume or bulk density (where envelope volume is obtained by direct measurement of the dimensions of the compact)

Solid fraction Apparent density � true density (where true density is the material density in the absence of voids)

Percentage porosity (1 � solid fraction) • 100%

Table 2Techniques for measuring envelope volume

Technique Device Advantages Disadvantages Direct measurement Micrometer caliper Low cost Destructive, manual, subject to operator variability, poor spatial resolution

Volume displacement Pycnometer Accurate for irregular shapes Destructive (sample cut to fit in chamber), (e.g., textured ribbons), not subject poor spatial resolution to operator variability Laser scanning Laser micrometer Fast, non-destructive, suitable Sensor array or traversing sensor for in-line applications required for ribbon profiling

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(�t) between the arrival of the air reference and samplepulses can be obtained from the time-domain terahertzspectrum (Figure 2). The RI, �, is obtained using

�(group frequency) � 1 � �t [c] Equation 1d

where c is the speed of light and d is ribbon thickness.

Of course a roller-compacted ribbon is a porous materialwhose effective RI depends on void volume, providedscattering effects are minor. The terahertz pulse will passmore quickly through a highly porous sample than a tightlycompacted one (Figure 3). Therefore, the effective RI,while not an intrinsic property of the ribbon material, isdirectly proportional to the ribbon’s apparent density andsolid fraction; it is inversely proportional to porosity (Table1). Note that in transmission mode, the ribbon thicknessmust be known in order to calculate the RI.

Alternatively, the RI can be obtained from the fre -quency domain spectrum (Equation 2) following Fouriertransformation of the time-domain spectrum.

�(�) � 1 � [(�)] [c] Equation 2� d

where �(�) is the RI and�(�) is the phase shift at theangular frequency ��.

Measuring the RI in the frequency domain gives youthe flexibility to select the frequency-dependent beamdiameter to obtain optimal spatial resolution in 2Dmapping of the density, which will be discussed andshown in more detail later.

Table 3Techniques for measuring apparent density of roller-compacted ribbons

Technique Advantages Disadvantages Section and weigh Low cost Destructive, poor precision, manual operation, low spatial resolution Terahertz Fast, non-destructive, non-contact, deep penetration Spatial resolution limited by material absorption (transmission), low-energy beam, no effect on sample integrity, suitable for in-line process applications

Micro-indentation [2] Sensitive to material’s elastic properties and hardness Destructive, indirect, surface only, requires observation by skilled operator

Near infrared [3, 4] Fast, non-contact, suitable for in-line process applications Indirect, surface only, sensitive to beam orientation on patterned ribbons X-ray micro-computed tomography [2] High spatial resolution, deep penetration Complex, radiation safety issues, may affect sample integrity

Acoustic wave [5] Fast, sensitive to elastic properties and mass density Direct contact with acoustic couplant required between sample surface and transducers, susceptible to interference from roller compactor’s vibration

Figure 2Terahertz time-domain signals for measuring time-of-flight for

a solid compact vs. an air reference

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Time-of-flight concept: Air vs. high-porosity and low-porosity solids

Air High-porosity solid Low-porosity solid

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The RI can also be obtained from surface reflectanceusing a simple expression derived from the Fresnelequations and assuming a 90-degree angle of incidence(Equation 3).

� � [1�r] Equation 31�r

where r �Intensity of the sample reflection and nair � 1

Intensity of a reference mirror reflection

Studies on surface-density mapping of compacts usingterahertz imaging spectrometers have shown excellentresults [6, 7]. Surface-reflectance RI measurements areindependent of ribbon thickness and therefore have norestriction on ribbon dimensions. However, the reflec -tance mode is generally less accurate than the trans -mission mode when measuring bulk RI. This is becausefactors such as surface roughness, which causes scat tering,can significantly decrease sample reflection intensity buthave little effect on phase. In addition, the surface densitymay not be representative of the bulk sample.

Terahertz sampling modesFigure 4 shows three terahertz sampling modes, each

with a different design geometry, for measuring thedensity of roller-compacted ribbons. For transmission, theemitter-detector pair is placed on opposite sides of theribbon (Figure 4a.) Laser micrometers may be mounted onthe terahertz elements to provide a serial reading of themoving ribbon’s thickness, followed by a terahertz readingat the same location. This combination allows nearly real-time density measurements. For most static samples, suchas those measured for QA/QC, ribbon thickness would berecorded manually and the results entered into software asa sample parameter in the calculation of RI.

Depending on the roller compactor’s design andoperating conditions, material may exit the rollers as arigid, freestanding ribbon or it may adhere as a layer tothe roller surface until a scraper removes it, whichgenerally reduces the ribbon to flakes before they enterthe mill. Rigid ribbons can be analyzed by transmission,but when they flake, density must be measured while theribbons adhere to the roller.

Alternatively, the ribbon can be measured in trans -flectance mode, where the roller serves as a metallicreflector between the angled emitter-detector pair (Figure4b). In that case, because the terahertz waves must passthrough the ribbon twice, its path is twice as long as it isin transmission. While that enhances sensitivity whenmeasuring thin ribbons, it reduces the maximumthickness that can be measured. Because there is nopractical way to measure thickness while a ribbonadheres to the roller, the minimum roller gap—plus afixed percentage increase to account for the ribbon’selastic recovery—can provide a reasonable gauge ofribbon thickness for in-line applications.

The surface-reflectance sampling mode shown inFigure 4c—essentially identical to the transflectancegeometry in the absence of a metallic reflector—isincluded here for completeness. This mode is useful forsurface characterization but is generally not as accurate astransmission or transflectance and is not a bulkmeasurement.

Single-point density measurementsTerahertz spectroscopy measures the RI of a solid

directly, and converting the RI results to density, solidfraction, and percentage porosity requires calibration.The easiest conversion entails preparing powdercompacts at different compaction forces and measuringthem with an analyzer like the one in the photo on thenext page. Apparent density is calculated from the sampleweight and envelope volume, which are easily obtainedby directly measuring the cylindrical compacts. Figure 5ashows the linear correlation between RI and apparentdensity for fresh and relaxed compacts of microcrystallinecellulose (MCC). The plot demonstrates the sensitivityof terahertz spectroscopy when measuring the elasticrecovery of materials after compression. It alsodemonstrates the need to measure envelope volumesimultaneous to terahertz analysis of freshly madecompacts. To convert apparent density to percentage

Figure 4Sampling modes for terahertz measurements

Laser micrometers

Ribbon

a. Transmission b. Transflectance c. Surface reflectance

DetectorDetector

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Figure 5Correlation of refractive index (RI) to apparent density and

to percentage porosity for fresh and relaxed MCC compacts over a range of compaction forces

a. RI vs. apparent density b. RI vs. percentage porosity1.9

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Fresh RelaxedLinear (fresh) Linear (relaxed)

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porosity, use the formula in Table 1, which also requiresknowing the true density of the powders [8]. The plot inFigure 5b shows the correlation of RI to percentageporosity.

Two-dimensional density mappingTwo-dimensional mapping of ribbon density is

accomplished by moving the sample stepwise in a gridpattern and collecting an array of spectra (photo below).The step size should correspond to the desired spatialresolution and the diameter of the terahertz beam. Forexample, the map of the ribbon section in Figure 6a wasconstructed from steps of 10 by 4 millimeters in thewidth dimension and 8 by 2 millimeters in the lengthdimension. In this case, the pixels were color-codedaccording to the RI, which can be converted to apparentdensity, solid fraction, or porosity, as discussed above. Itis generally easier, however, to see RI gradients in acontour map (Figure 6b). This pattern is typical of mostcompacted ribbons: The RI value is highest near thecenter and tapers off at the edges.

Figure 7 shows the RI gradients of two sets of roller-compacted ribbon sections prepared at high and lowcompaction force. While the graphics provide insight intoimportant qualitative spatial differences, plotting the RIdistribution as a histogram (Figure 8) enables you to applyquantitative comparisons and quality metrics. Asexpected, the ribbon sections prepared at high com -paction force show a wider distribution in RI than theribbon sections prepared at low compaction force.However, the latter distribution shows a longer tail at thelowest RI values, which may indicate weaker granules andmore fines.

Figure 9 shows three different 2D spatial RI maps of atextured ribbon section made using knurled rollers. The

Terahertz spectroscopy measurement unit equipped with transmission module.Inset shows placement of sample on transmission stage.

Motorized X-Y stage platform with terahertz transmission optics for mapping thedensity of roller-compacted ribbons

Figure 6Two-dimensional RI mapping of a roller-compacted ribbon

section

a. Raw data b. Contour map of same ribbon section

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Figure 7Two-dimensional RI mapping of roller-compacted ribbons

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b. Four sections of same ribbon, low compaction force

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data were collected using a motorized X-Y stage withstep sizes of 1 millimeter in both the width and lengthdimensions. The resulting maps appear different becauseof how the data were processed. The left plot wasobtained with the highest frequency and, therefore, thesmallest beam diameter. In fact, the beam diameter wassmaller than the step size, so the fine features of theribbon’s texture are apparent, and the map is pixelated. Incontrast, the plot on the right was obtained at the lowestfrequency using a beam diameter larger than the step size,and the ribbon texture is smoothed out on the RI map.

As noted above, RI values obtained by transmission aredirectly dependent on the measurement of ribbonthickness at the point where the beam is located. In thecase of a high-frequency observation where the beamdiameter is similar in size to the pattern of the texturedribbon, it is impossible to measure thickness accurately.The best compromise in that case is to conduct a low-frequency observation using a beam diameter larger than

Figure 8Histograms of RI

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Figure 9Two-dimensional RI maps of a textured roller-compacted ribbon measured using three different beam diameters

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the pattern of the textured ribbon. The more accurateaverage thickness over a wider area will yield lowerspatial resolution, but the RI values will be more accurate.

Understanding the relationships between processparameters and the critical quality attributes (CQAs) ofroller-compacted ribbons is important for small-scaledevelopment, scale-up, and commercial manufacturing.Figure 10 shows the results of an experiment to measurehow roll speed affects bulk density. The 2D maps (figures10a, 10b, and 10c) show that RI decreases as roll speedincreases. In Figure 10d, the overlaid average cross-sectionprojection line plots of RI are averaged over 40millimeters in the machine direction (X) versus the ribbonwidth (Y) for the three roll speeds. In Figure 10e, thisaverage cross-section projection line plot of RI wasconverted to the line plot of apparent density using theequation for correlating between average RI and apparentdensity (Figure 10f) that was established independently onMCC compacts. The plot in Figure 10e shows that theapparent density is highest in the middle of the ribbon’swidth and tapers off toward the edges. Ribbon densitydecreases as roll speed increases, which corresponds to ashorter dwell time in the nip region of the rollers.

Figure 11 shows the results of an experiment to measurehow the size of the roller gap affects apparent density. Asthe average cross-section projection line plots in figures 11cand 11d show, apparent density decreases as the roller gapincreases. The terahertz results (red line) are superimposedon the density data that were obtained by cutting the

ribbon into sections (blue line). This section-and-weighmethod generated fewer points across the ribbon because itwas difficult to cut the ribbon into small pieces. Moreimportant, the standard deviation is high compared to thatof the terahertz results, where the standard deviation is lessthan the height of the marker on the plot.

In-line density measurementTerahertz 2D mapping of roller-compacted ribbons

yields detailed quantitative spatial density and porosityinformation, which enables you to optimize processparameters and ensure different types of equipment providefunctional equivalence. Once the process parameters areset, the objective is to monitor the process over time, andthis can be done with an in-line terahertz analyzer (Figure12). In production, ribbons typically travel at linear speedsof 50 to 150 millimeters per second, which is compatiblewith terahertz sampling intervals of less than 1 second.

Different sampling patterns can be used, and figures12a and 12b illustrate how to use a small spot size tomonitor a single track and traverse the ribbon. Figure 12cshows how a cylindrical lens is used to generate a largeelliptical spot, which provides efficient sampling over alarge area and improves the signal-to-noise ratio. Thisoptical arrangement is preferred for monitoring theapproach of steady-state operation at startup and tomonitor short- and long-term ribbon density variationsduring operation. Ideally, this information would be fedback to the machine to provide real-time process control.

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Figure 12Terahertz sampling patterns for in-line analysis

a. Small spotmonitors single

track

b. Small spottraverses ribbon

c. Cylindrical lens generates large elliptical spot

Figure 11Effect of process parameters on ribbon apparent densitycross section: Variable gap with fixed roller speed (1 rpm)

and 2D RI maps

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ConclusionsTerahertz spectroscopy is a fast, non-destructive, non-

contact technique for measuring density (solid fraction,percentage porosity), which is the most important CQAof roller-compacted ribbons. This information can beused to optimize process parameters during development,facilitate scale-up, and to control the process duringcontinuous manufacturing. T&C

Figure 10Effect of process parameters on ribbon apparent density cross-section: Variable roller speed and fixed gap (0.95 mm) and

2D RI maps

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Width, Y (mm) Width, Y (mm) Apparent density (g/cm3)

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References1. Sullivan, M.J., King, E.; Kato, E.; Heaps, D.;

McKay, R.; Zhou, X.H. Using terahertz spectroscopy tomap tablet cores and coatings. Tablets & Capsules, 2013.11(7): pp. 10-16.

2. Miguélez-Morán, A.M., Wu, C.Y., Dong, H., andSeville, J.P.K. Characterisation of density distributions inroller-compacted ribbons using micro-indentation and X-ray micro-computed tomography. Eur J Pharm Biopharm,2009. 72(1): pp. 173-182.

3. Lim, H., Dave, V.S., Kidder, L., Neil Lewis, E.,Fahmy, R., and Hoag, S.W. Assessment of the criticalfactors affecting the porosity of roller compacted ribbonsand the feasibility of using NIR chemical imaging toevaluate the porosity distribution. Int J Pharm, 2011.410(1-2): pp. 1-8.

4. Samanta, A.K., Karande, A.D., Ng, K.Y., and Heng,P.W.S. Application of near-infrared spectroscopy in real-time monitoring of product attributes of ribbed rollercompacted flakes. AAPS PharmSciTech, 2013. 14(1): pp.86-100.

5. Akseli, I., Iyer, S., Lee, H.P., and Cuitiño, A.M. Aquantitative correlation of the effect of densitydistributions in roller-compacted ribbons on themechanical properties of tablets using ultrasonics and X-ray tomography. AAPS PharmSciTech, 2011. 12(3): pp.834-853.

6. May, R.K., Su, K., Han, L., Zhong, S., Elliott, J.A.,Gladden, L.F., Evans, M., Shen, Y., and Zeitler, J.A.Hardness and density distributions of pharmaceuticaltablets measured by terahertz pulsed imaging. J PharmSci, 2013 102(7): pp. 2179-86.

7. Palermo, R., Cogdill, R.P., Short, S.M., Drennen III,J.K., and Taday, P.F. Density mapping and chemicalcomponent calibration development of four-componentcompacts via terahertz pulsed imaging. J PharmaceutBiomed, 2008. 46(1): pp. 36-44.

8. Hancock, B.C., Colvin, J.T., Mullarney, M.P., andZinchuk, A.V. The Relative Densities of PharmaceuticalPowders, Blends, Dry Granulations, and Immediate-Release Tablets. Pharm Tech, 2003(April): pp. 64-80.

Mark Sullivan is a senior R&D scientist; David Heaps andRichard McKay are principal scientists; Eiji Kato is a terahertztechnology expert; and Xiao Hua Zhou is an analyticalscientist at Advantest America, 508 Carnegie Center, Suite 102,Princeton, NJ 08540. Tel. 609 897 7320. E-mail:mark.sullivan@advantest.com. Chuan-Yu Wu is a professorin the Department of Chemical and Process Engineering at theUniversity of Surrey, Guildford, GU2 7XH UK. Chun-leiPei, Jian-yi Zhang, and Serena Schiano are members of Wu’sresearch group.

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