Nondestructive analysis of tablet coating thicknesses using terahertz pulsed imaging

Nondestructive Analysis of Tablet Coating ThicknessesUsing Terahertz Pulsed Imaging

ANTHONY J. FITZGERALD, BRYAN E. COLE, PHILIP F. TADAY

Platinum Building, St. John’s Innovation Park, Cambridge, CB4 4WS, UK

Received 27 May 2004; revised 26 August 2004; accepted 30 August 2004

Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.20225

ABSTRACT: An understanding of the finished structure of complex pharmaceuticalcoating is becoming desirable, because tablet coatings are now one of the preferred routesto control the release of active pharmaceutical ingredients. There are few nondestructivetechniques capable of examining the coatings of compressed tablets; for example laserinduced breakdown spectroscopy has been used but this is a destructive method.Terahertz pulsed imaging offers a potential technique to examine coatings quickly andnondestructively. In the study reportedherein, itwas possible to distinguish between twobrands of across-the-counter ibuprofen tablets. The terahertz maps obtained werecomparedwith obtained photographs of cut-through sections; therewas good agreement.The technique is fast: a waveform can be obtained in<20ms allowing the technique to beconsidered as a candidate for on-line or at-line analysis in a process analyticalenvironment. The lateral resolution of the technique is limited by diffraction of theterahertz focus to about 150 mm at 3 THz, whereas the axial resolution is limited by theterahertz pulse duration, which is <200 fs, to about 30 mm. � 2004 Wiley-Liss, Inc. and the

American Pharmacists Association J Pharm Sci 94:177–183, 2005

Keywords: coating; physical characterization; infrared spectroscopy

INTRODUCTION

Recently, there has been a strong drive in thepharmaceutical industry toward process analyti-cal technology (PAT) for comprehensive qualityassurance monitoring. This move opens the wayfor new tools providing useful analysis of tabletformulations. The objective of PAT is to enable thepharmaceutical industry to efficiently monitorquality at each stage of themanufacturing processby integrating analysis systems into the proce-dure. As well as gaining a better understanding ofeach procedure, it should also ensure greaterconsistency across batches and minimize produc-tion downtime. One of the areas highlighted for

specific investigation by the United States Foodand Drug Administration and the pharmaceuticalindustry is dissolution and bioavailability.1

Coatings perform a wide variety of functions.The most important is to regulate the controlledrelease of active ingredients in the body. Aswell ascontributing to the bioavailability of a particulardrug or combination of drugs during certain timesand locations within the body, coatings can protectthe stomach from being exposed to high concentra-tions of active ingredients, improve tablet visualappeal, and extend shelf life by protecting theingredients from degradation by moisture andoxygen.

In relation to tablet coating, the PAT initiativeis intended to improve consistency and predict-ability of tablet action by improving quality anduniformity of pharmaceutical production whichincludes the tablet coatings. Coating issues canarise from problems with the coating materials orflaws in the coating pan or spray process. If acoating is nonuniform or has surface defects, then

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 94, NO. 1, JANUARY 2005 177

Correspondence to: Philip F. Taday (Telephone: þ44-0-1223-435380; Fax: þ44-0-1223-435382;E-mail: [email protected])

Journal of Pharmaceutical Sciences, Vol. 94, 177–183 (2005)� 2004 Wiley-Liss, Inc. and the American Pharmacists Association

the desireddose delivery andbioavailability canbecompromised. From this standpoint, it is impor-tant to characterize tablet coatinguniformity, bothwithin a single tablet and across an entire batch todevelop an understanding of the functional analy-sis of the final product.

Although several analytical and imaging tech-niques are being used to understand the criticalprocesses involved in tablet coating, none are idealto fully characterize the layers. Some of the tech-niques that provide useful information includeatomic force microscopy,2 confocal laser micro-scopy, X-ray photoelectron spectroscopy, electronparamagnetic resonance, Fourier transform infra-red spectroscopy, laser-induced breakdown spec-troscopy,3 and scanning thermal microscopy.However, all of these methods are either destruc-tive to the tablet or cannot be readily implementedfor rapid on-line measurement.

In contrast, terahertz pulsed imaging (TPI) is anondestructivepharmaceutical analysis tool usingextremely low power, ultrashort pulses of electro-magnetic radiation at lower frequencies thantraditional infrared techniques. Terahertz pulsedspectroscopy has already proven useful in distin-guishing between different polymorph forms of adrug.4–6 TPI is an extension of this wherebyterahertz pulses are used to image objects ofinterest. Terahertz technology relies on the factthat when an ultrashort pulse is focused onto asuitable semiconductor, an ultrashort pulse ofcoherent terahertz radiation is emitted. Theradiation is detected using a solid-state roomtemperature receiver.7 Because of the opticalgating technology used, it can achieve a very highsignal-to-noise ratio (>105), as it is a coherenttechnique, with both electric-field amplitude andphase information being measured at the sametime, the spectral absorption coefficients, a(o) andthe refractive indices, n(o) of the material underinvestigation can be extracted. Because the ter-ahertz radiation is emitted from a diffraction-limited point source, it is easy to manipulate, andthis has led to the development of terahertzimaging. We8,9 have used TPI to investigate basalcell carcinomas and have shown that there is asignificant difference between the tumor andhealthy tissue in this spectral region. The contrastmechanism is believed to be a change in the watercontent of the cancerous tissue when comparedwith normal tissue. Water has very strong absorp-tion features10 in the terahertz region, which maymake it an excellent molecular marker for dis-eased tissues. Crawley et al.11 used the technique

to explore decay in teeth. Interferometric techni-ques have been used to improve the depth resolu-tion to about 2% of the coherence length of theterahertz pulse.12 In a proof-of-principle experi-ment, Johnson et al.12 achieved a depth resolutionof<10 mm in a planar sample. TPI can also be usedas a spectroscopic mapping technique as hasrecently been demonstrated in transmission byWatanabe et al.13

Many pharmaceutical tablet coating materialsare semitransparent to terahertz photons and,as the macroscopic structure within the coating ismuch less than the wavelength of the radiation,scattering is not significant. Terahertz pulsesincident on a tablet surface penetrate throughthe different coating layers. At each interface orchange in refractive index, a portion of theterahertz pulse is reflected back to the detector.The amplitude of reflected terahertz radiation isrecorded as a function of time. The techniqueoperates much the same way as ultrasound orradar is used to accurately locate embedded ordistant objects. Similar to these techniques, thesample itself is unaffected by the measurement.Coating thickness uniformity is established sim-ply from the transit time of the pulse to eachinterface. With knowledge of the refractive indexof the coatingmaterial, the actual thickness can bedetermined to a depth resolution of about 30 mmdepending on the terahertz pulse duration. Thelateral spot size of the terahertz pulse, and there-fore lateral resolution, is frequency dependent andcan be as small as 150 mm at 3 THz.

TPI has many advantages over the few existingtechniques for investigating coatings. It is acompletely nondestructive investigative tool thathas similar depth resolution and higher lateralresolution to the destructive laser-induced break-down spectroscopy.3 In addition, because it isnondestructive, tablets can be reexamined at latertimes to monitor coating stability or used forfurther functional studies with prior knowledgeof the coating uniformity. Any number of locationsin the tablet can be probed by TPI, and themeasurement can be extended to produce athree-dimensional map of the tablet, showingtablet uniformity as a function of depth below thesurface.

In this report, we demonstrate the potential ofTPI for the analysis of tablet coating thickness byillustrating the techniquewithmeasurements onareadily available leading-brand ibuprofen tabletand compare the coating on this tablet to that ofanother manufacturer.

178 FITZGERALD, COLE, AND TADAY

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 94, NO. 1, JANUARY 2005

EXPERIMENTAL

Materials

All materials were obtained across the counter.Two different manufacturers of ibuprofen tabletswere investigated. Sample A is the UK brand-leader ‘‘NUROFEN’’ and is produced by CrookesHealthcare Ltd. Sample B is produced by TheWallis Laboratory Ltd., UK. All tablets wereobtained across the counter, used without anyfurther processing. However, for the opticalimages, the tablets were shattered and inspectedunder a light microscope.

Measurements

A schematic diagram of the experimental set-upfor a TPI system is shown in Figure 1. Terahertzpulses are generated when ultrashort laser pulsesare focused onto a gallium arsenide (GaAs)photoconductive switch. A large DC bias voltageis applied across the electrodes of the switch.When no laser radiation is present, there are nophoto-generated carriers present, and thus theresistance is high and no current is able to flow,that is, the switch is open. However, when anultrashort laser pulse is present, photocarriersare generated in the semiconductor. A transientcurrent is then able to flow across the now closedswitch, which acts as a radiating dipole antenna,

giving rise to a short burst of terahertz radiation.The electric field E(t) of the terahertz pulse isproportional to the rate of change of current withrespect to time (i.e., dJ(t)/dt, where J(t) is thetransient current). A hemispherical silicon lens7

couples the radiation out of the GaAs substrateinto free-space. Parabolic mirrors are then used tofocus the terahertz radiation to a diffraction-limited spot on the sample. It is then possible toraster scan either the sample or the terahertzoptics to build up a terahertz map of the sample.Detection of the terahertz radiation is achievedusing an optically gated semiconductor antenna.This device is similar to the emitter, except thatno DC bias voltage is applied across the terminals;instead an ammeter is placed at the electrodes.Again, the femtosecond near-infrared laser pulsesgenerate photocarriers in the GaAs substrate.However, in this case, the electric field from theterahertz pulses themselves provide a drivingvoltage and induces a transient current in acircuit when both the terahertz and optical pulsesare present at the same time, and this is detectedby using an ammeter. The measured current isdirectly proportional to the terahertz electricfield, and by varying the time delay betweenterahertz and optical pulses to produce a repre-sentation of the terahertz field. Figure 2 shows anexample terahertz impulse function for a singlereflection. Impulse functions were obtained fromthe raw terahertz waveform by deconvolving thesystem response as described by Cole et al.14

The deconvolution was performed by dividing, inthe frequency domain, the raw terahertz wave-form reflected from the tablet by a referencewaveform recorded from a air–mirror interface. Anumerical bandpass filter was applied to removehigh- and low-frequency noise. The terahertz

Figure 1. Schematic diagram of the apparatus usedto study the coating structure of pharmaceutical pro-ducts. NIR, near infrared pulses.

Figure 2. A typical terahertz pulse obtained from theTPI instrument.

NONDESTRUCTIVE ANALYSIS OF TABLET COATING 179


pulse duration of <200 fs produces an axialresolution of 30 mm: depending on the refractiveindex of the material under investigation achiev-able. Figure 3 shows a schematic diagram of theregion around the tablet. The pulse is reflectedfirst off the front surface and then from anysubsurface structure within the tablet resultingin multiple pulses returning to the detector.

The technique can operate in one of two modes.One mode allows for a rapid (<20 ms) single-pointmeasurement of the tablet coating thickness; thesecond, slower mode, for multipoint measurementto produce statistics or false-color maps of theuniformity of different layers within a pharma-ceutical product.

Some signal preprocessing is required to isolatefeatures in the back reflected terahertz pulse thatare due to the coating structure rather thaninstrumental effects. To remove any features dueto instrument effects, the reflected waveformsfrom the tablet surfaces are deconvoluted from areflection signal taken from a dielectric surface.9

This also removes any features due towater vapor.

Figure 4. Photograph of cut-through of Sample A, taken through a microscope, of theleading brand shows a number of coating layers; the outermost sucrose coating is 55 mmthick, whereas the darkest central layer extends 350 mm into the tablet. Within this darklayer is a lighter band that is variable but approximately 35 mm thick. The inner-mostlayer is about 100 mm, giving a total thickness of 450 mm.

Figure 3. Schematic diagram of the experimentalarrangement to examine coatings, in this case for twointerfaces. A reflected terahertz signal occurs wheneverthere is a change in boundary conditions.



RESULTS AND DISCUSSION

Microscope photographs of the coatings for bothtablets are shown in Figures 4 and 5. Terahertzpulses were directed onto the tablet and pene-trated through each of the layers. The signalreflected by the coating interfaces was measuredas a function of time shown in Figure 6; this is anexample of the rapid single-point measurement.Coating depth can be derived from the timedomain measurement by calibrating for therefractive indices of the coating materials. WithTPI, it is possible to analyze any region on thetablet, and in the example shown in this article,the terahertz beam was raster scanned across asquare section of the tablet 1� 1 mm at 50-mmsteps.

The terahertz time-domain data can be ana-lyzed and displayed in several formats to char-acterize coating uniformity. In the simplestformat, a typical trace from a single point in thetablet is plotted. The uniformity of each layer canbe determined from the time at which the reflectedpulses are observed. Figure 6 compares exampletime domain data for sample A and sample B. Inagreementwiththemicroscopephotographs, these

Figure 6. Example TPI time domain waveforms atpoint locations on ibuprofen tablets. The bottom trace ingray is for the Sample B, whereas the black offset toptrace is for Sample A. Pulses arise from interfaces in thecoatings as indicated by the schematic illustrations ofthe tablet layers.

Figure 5. The coating of Sample B shows very little structure and is about 320 mmthick.



waveforms clearly show that the brand tablet hasseveral coating layers, and the overall thickness isgreater than the tablet supplied by the othermanufacturer. After conversion of the time-axis todistance using a refractive index of 1.8,15 the totalthicknesses of the coatings are determined as433� 6 microns for sample A and 314� 4 micronsfor sample B; these values agree well with thoseobtained from the optical images, summarized inTable 1.

The uniformity and consistency of the ibuprofentablet coating is better conveyed by an image of the

depth profile, analogous to the typical B-scanultrasound format. B-scan TPI images of the twocoatings are exhibited in Figure 7. These imagesclearly show the difference in structure andthickness of the two coatings. Furthermore, thevariations in layer thickness for sampleAobservedin the microscope image are now apparent, inparticular the light central band within thedarkest layer. This effect would be missed by atechnique that made measurements at selectedsingle-point locations. The analysis can be taken astep further and the tablet coatings mapped inthree dimensions, using surfaces to indicate thepositions of the layers.

CONCLUSIONS

It has previously been shown that terahertzpulsed spectroscopy4,6 can discriminate betweendifferent polymorph forms in finished pharma-ceutical products. In this report, we show that

Table 1. Comparison between the TabletThicknesses Obtained by the Two Techniques of OpticalMicroscope and Terahertz Pulsed Imaging (TPI)

Technique Sample A (microns) Sample B (microns)

Optical 450 320TPI 433� 6 314� 4

Figure 7. Depth profile of ibuprofen tablets displayed using the same format asB-scanultrasound for the leading brand (top) and the other manufactured brand (bottom).The interfaces are clearly shown and demonstrate that the leading brand coating is farmore complex than the other manufactured brand. The B-scan format highlights thevariability of theband in the inner core of the leadingbrandcoating that is apparent in themicroscope photograph.



terahertz radiation can also be used to extractinformation on the internal coating configurationof a tablet. The technique is unprecedented inthat it is nondestructive, noninvasive, and com-pletely safe, and provides information on factorsthat influence bioavailability. TPI can probe anyposition on a tablet in under 20 ms, making itsuitable for rapid online assessment and, with theuse of a computer-controlled robot arm, it can copewith the myriad of tablet geometries. Becauseimage profiles can be obtained, an extra dimen-sion of data is available because the variation ofinternal coating layers can be clearly observed,something that would not be readily apparentfrom separate, isolated point measurements.

With these advantages, the emerging technol-ogy of TPI is ideally suited to fulfill a significantneed in the analysis of drug delivery mechanisms.

REFERENCES

1. http://www.americanpharmaceuticalreview.com/current_issue/3_APR_Fall_2003/Warmuth_article.htm. Warmuth. Accessed December 15, 2003.

2. www.aaps.org/publications/newsmagazine/2003/mar03/28.pdf. Accessed December 15, 2003.

3. Mowery MD, Sing R, Kirsch J, Razaghi A, BechardS, Reed RA. 2002. Rapid at-line analysis of coatingthickness and uniformity on tablets using laserinduced breakdown spectroscopy. J Pharm BiomedAnal 28:935–943.

4. Taday PF, Bradley IV, Arnone DD, PepperM. 2003.Using terahertz pulse spectroscopy to study thecrystalline structure of a drug: A case study of thepolymorphs of ranitidine hydrochloride. J PharmSci 92(4):831–838.

5. Taday PF. 2004. Applications of terahertz spectro-scopy to pharmaceutical sciences. Philos Trans RSoc London A 362:351–364.

6. Strachan CJ, Rades T, Newnham DA, Gordon KC,Pepper M, Taday PF. 2004. Using terahertz pulsedspectroscopy to study crystallinity of pharmaceu-tical materials. Chem Phys Lett 390:20–24.

7. Fattinger C, Grischkowsky D. 1989. Terahertzbeams. Appl Phys Lett 54:490–492.

8. Wallace VP, Taday PF, Fitzgerald AJ, WoodwardRM, Cluff J, Arnone DD. 2004. Terahertz pulsedimaging and spectroscopy for biomedical and phar-maceutical applications. Faraday Discuss 126:255–263.

9. Woodward RM, Wallace VP, Pye RJ, Cole BE,Arnone DD, Linfield EH, Pepper M. 2003. Tera-hertz pulse imaging of ex vivo basal cell carcinoma.J Invest Dermatol 120(1):72–78.

10. Ronne C, Keiding SR. 2002. Low frequency spectro-scopy of liquid water using THz-time domainspectroscopy. J Mol Liq 101(1–3):199–218.

11. Crawley D, Longbottom C, Wallace VP, Cole B,Arnone D, Pepper M. 2003. Three-dimensionalterahertz pulse imaging of dental tissue. J BiomedOpt 8(2):303–307.

12. Johnson JL, Dorney TD, Mittleman DM. 2001.Interferometric imaging with terahertz pulses.IEEE J Sel Top Quantum Electron 7(4):592–599.

13. Watanabe Y, Kawase K, Ikari T, Ito H, Ishikawa Y,Minamide H. 2004. Component analysis of chemi-cal mixtures using terahertz spectroscopic imaging.Opt Commun 234(1–6):125–129.

14. Cole BE, Woodward RM, Crawley D, Wallace VP,Arnone DD, Pepper M. 2001. Terahertz imagingand spectroscopy of human skin, in-vivo. Proc SPIE4276:1–10.

15. Walther M, Fischer BM, Jepsen PU. 2003. Non-covalent intermolecular forces in polycrystallineand amorphous saccharides in the far infrared.Chem Phys 288:261–268.



Documents

Nondestructive analysis of tablet coating thicknesses using terahertz pulsed imaging