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Direct Analysis of Pharmaceutical Tablet Formulations Using Matrix-Assisted Laser Desorptionionisation Mass Spectrometry Imaging

Direct Analysis of Pharmaceutical Tablet Formulations Using Matrix-Assisted Laser Desorptionionisation Mass Spectrometry Imaging

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Direct analysis of pharmaceutical tablet formulationsusing matrix-assisted laser desorption/ionisation massspectrometry imaging
Caroline J. Earnshaw
1
, Vikki A. Carolan
1
, Don S. Richards
2
and Malcolm R. Clench
1
*
1
Biomedical Research Centre, Sheffield Hallam University, Howard Street, Sheffield S1 1WB, UK
2
Pfizer Global R&D, Ramsgate Road, Sandwich CT13 9NJ, UK
Received 6 January 2010; Revised 24 February 2010; Accepted 24 February 2010
Matrix-Assisted Laser Desorption/Ionisation Mass Spectrometry Imaging (MALDI MSI) has beenused to directly analyse a range of tablets in order to assess the homogeneity of the active drugcompound throughout the excipients contained within the tablets studied. The information gainedfrom the imaging experiments can be used to improve and gain a greater understanding of themanufacturing process; such knowledge will enable improvements in finished product quality tomake safer and more efficacious tablet formulations. Commercially available and prescription tabletformulations have been analysed, including aspirin, paracetamol, sildenafil citrate (Viagra
1
) and abatch of tablets in development (tablet X: placebo; 1mg; 3mg and 6mg).MALDI MSI provides semi-quantitative information that is related to ion abundance, therefore Principal Component Analysis(PCA), a multivariate analysis technique, has been used to differentiate between tablets containingdifferent amounts of active drug ingredient. Aspects of sample preparation have also been inves-tigatedwithregardtotabletshapeandtexture.TheresultsobtainedindicatethatMALDIMSIcanbeused effectively to analyse the spatial distribution of the active pharmaceutical component (API) inpharmaceutical tablet formulations. Copyright
#
2010 John Wiley & Sons, Ltd.
Tablets are compacted pharmaceutical dosage forms thatcontain active drug compounds and excipients such as bulking agents, lubricants and disintegrants. There are manydifferent tablet formulations and pharmaceutical manufac-turing techniques that can be used to produce them. Themanufacturing process can vary depending on the chemicalproperties of the active pharmaceutical ingredient (API). It isof extreme importance to the pharmaceutical industry toevaluate the outcomes of the drug formulation process, andin particular for solid dosage formulations,
viz
. tablets, tostudy the distribution of constituents within them. Examin-ingthefinishedpharmaceuticalproduct,forexampletablets,is one way to achieve this and it is vital for slow releaseformulations where the distribution of the active drugingredient throughout the excipients can affect how effectivethe tablet is post-administration.The introduction of the process analytical technology(PAT) initiative by the US Food and Drugs Administration(FDA) has made pharmaceutical companies aware of theincreasing need to improve manufacturing efficiency andfinishedproductquality.
1
Imagingtechniques haveformedpart of this initiative and they have already been used toinvestigate tablet formulations. Techniques used includemagnetic resonance imaging (MRI),
2
Raman and nearinfrared (NIR) chemical imaging.
3–5
Raman spectroscopyin particular has had an important role in the analysis of solid pharmaceutical products owing to the minimalsample preparation required. APIs tend to give a goodRamanresponseandthereislessspectraloverlapinRamanspectra than is observed with NIR. It is possible to useRaman spectroscopy to map APIs in pharmaceutical tabletformulations and this has been successfully demonstrated by Sˇasˇic´.
6
Due to the complexity of the data and the lack of imaging software, this can, however, be a difficult process.These imaging techniques can help to identify compo-sitional or structural defects in tablets that may have animpact on their mechanical stability and drug-releasingproperties. Imaging techniques can also assist in pharma-ceutical safety strategies, for example in the investigationof cases of counterfeit pharmaceutical products. Nyadong
et al
. have demonstrated the use of imaging desorptionelectrospray ionisation to investigate counterfeit antima-larial drugs.
7
A range of mass spectrometry techniques has also beenutilised in the study of pharmaceutical formulations.Secondary ion mass spectrometry (SIMS) is a surfaceionisation technique where secondary ions are generated by focusing a pulsed primary ion beam on the samplesurface. The secondary ions that are generated are usuallyanalysed using a time-of-flight (TOF) mass spectrometer.Prestidge
et al
. have demonstrated the use of TOF SIMS forthe characterisation of solid-state pharmaceutical products.
8
SIMS can be used with imaging software to study thedistribution of the analyte of interest within a sample.
RAPID COMMUNICATIONS IN MASS SPECTROMETRY
Rapid Commun. Mass Spectrom.
2010;
24
: 1665–1672Published online in Wiley InterScience (www.interscience.wiley.com) DOI: 10.1002/rcm.4525
*
Correspondence to
: M. R. Clench, Biomedical Research Centre,Sheffield Hallam University, Howard Street, Sheffield S1 1WB,UK.E-mail: m.r.clench@shu.ac.uk
Copyright
#
2010 John Wiley & Sons, Ltd.
 
Another mass spectrometry technique that has been usedfor the analysis of pharmaceutical drug formulations isdesorption electrospray ionisation mass spectrometry (DESIMS).InDESIMSchargeddropletscreatedbyanelectrospraysource are concentrated onto a solid sample, resulting insurface interaction creating secondary ions that can bedetected using MS. DESI MS has been used to studypharmaceutical drug formulations
9,10
and for the screeningof illicit Ecstasy tablets.
11
Whilst DESI requires no samplepreparation, is relatively fast and is a soft ionisationtechnique, the spatial resolution available for imagingexperiments is only of the order of 0.25mm
12
and selectiveextraction based on the desorption solvent used wouldappear to be a significant issue in DESI experiments.Matrix-assistedlaser desorption/ionisation(MALDI) MS, asoft ionisation technique, utilises a chemical matrix coatedonto the sample of interest to act as an energy transferintermediatebetweenthelaserandthesample.
13,14
Theroleof the matrix is primarily to absorb at the laser wavelength andtransfer energy to the analyte in order to promote efficientionisation. The most commonly used lasers in MALDI MSexperiments are UV lasers nitrogen (
l
¼
337nm) andNd:YAG (
l
¼
355nm and
l
¼
266nm) and, since the majorityof MALDI MS experiments that have been published to datehave been conducted in positive ion mode, the most commonmatrices employed in suchstudiesarestrongly UV-absorbingorganicacids.Themostcommonlyusedorganicacidmatricesinclude
a
-cyano-4-hydroxycinnamic acid (
a
-CHCA), dihy-droxybenzoic acid (DHB) and sinapinic acid (3, 5-dimethoxy-4-hydroxycinnamic acid).Matrix-assisted laser desorption/ionisation mass spec-trometry imaging (MALDI MSI)
14,15
is a relatively newtechnique that offers all of the benefits of conventional massspectrometry such as rapid analysis time, specificity andsensitivity. It can be used for the analysis of a range of samples. Data is obtained by recording mass spectra as asample is moved by set increments under a stationary laser.By plotting the spatial dimensions of the x and y axes againstthe abundance/intensity of selected ion/ions, images can begenerated. Mass spectrometry permits the parallel detectionof multiple analytes thus providing a wealth of informationabout the sample of interest and this is why MALDI MSI has been used in a wide range of biomedical applications.MALDI MS has been applied previously to the analysis of ‘‘street’’ tablets containing prohibited substances.
16
Thetablets were ground into a fine powder and dissolved inmethanol in order to permit conventional MALDIanalysis to be performed using a combination of 
a
-CHCA andcetyltrimethylammonium bromide (CTAB) in a water/acetonitrile solution (50:50 v/v) as matrix.The work presented herein demonstrates the use of MALDI MSI to study whole tablets for the first time. Theaim of this work was to map the distribution of the activedrug throughout all the excipients contained within tablets.MALDI MSI has been used to directly image the distributionof the active drug throughout the tablet, and also to providesome quantitative information in relation to the manufac-tured dose of the tablet.The following tablets were obtained for MALDI MSIanalysis: an unknown tablet formulation, tablet X (placebo,1mg, 3mg and 6mg dosage forms); sildenafil citrate (Viagra25mg); paracetamol (500mg); aspirin (75mg); Anadin Extra(a mixture of aspirin (300mg), paracetamol (200mg) andcaffeine (45mg) and Solpadeine (a mixture of paracetamol(500mg) and caffeine (65mg)).Principal component analysis (PCA) is a form of multi-variate analysis that can be used to simplify multidimen-sional datasets. In previous published work, PCA has beenincorporated into the interpretation of MALDI MSI data todiscriminate between different regions in mammalian tissuesections
17–19
andtoevaluatedatafromtheanalysisofporcineskin that had been treated with hydrocortisone.
20
PCA iscommonly used to reduce the dimensionality of multivariatedata sets while retaining most of the original informationcontent. Discriminant analysis (DA) is often used to define aclassification from an observation of pre-defined groups.PCA-DA is a two-stage supervised statistical techniquewhere the number of variables in the data set is first reduced by the use of PCA before a second discriminant analysisis performed. PCA-DA takes into account user-suppliedinformation about external variables (group information)when reducing the dimensionality of the datasets in the firststage. Therefore, it is better suited than PCA for clusteringanalysis.
21
Here we have demonstrated how PCA-DA can beusedtodifferentiatebetweentheactivedrugcomponent andtheexcipients containedwithinthetabletandalsohowPCA-DA can be used to provide semi-quantitative information.
EXPERIMENTAL(i) Materials
a
-Cyano-4-hydroxycinnamic acid (
a
-CHCA), ethanol andtrifluoroacetic acid (TFA) were purchased from SigmaAldrich (Poole, UK). The following tablets were purchasedcommercially: paracetamol 500mg (Wallis Laboratory Ltd.,Luton, UK), aspirin 75mg (M & A Pharmachem Ltd., Bolton,UK), Anadin Extra (Wyeth Consumer Healthcare, SouthTaplow, UK), and Solpadeine (GlaxoSmithKline Ltd.,Dungarvan,Ireland). Sildenafil citrate (Viagra)25mg dosageform and tablet X in placebo, 1mg, 3mg and 6mg dosageformsweresuppliedbyPfizer(Sandwich,UK).Thechemical
Figure 1.
Photograph of tabletX showing the curved surfaceof the tablet and the position at which the horizontal sectionwas obtained using a commercially available tablet cutter.
Copyright
#
2010 John Wiley & Sons, Ltd.
Rapid Commun. Mass Spectrom.
2010;
24
: 1665–1672DOI: 10.1002/rcm
1666 C. J. Earnshaw
et al.
 
Copyright
#
2010 John Wiley & Sons, Ltd.
Rapid Commun. Mass Spectrom.
2010;
24
: 1665–1672DOI: 10.1002/rcm
Direct analysis of tablet formulations using MALDI-MSI 1667

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