Spectroscopic Techniques for Nondestructive Quality Inspection of Pharmaceutical Products: A Review

  • Kandpal, Lalit Mohan ;
  • Park, Eunsoo ;
  • Tewari, Jagdish ;
  • Cho, Byoung-Kwan
  • Received : 2015.10.22
  • Accepted : 2015.11.16
  • Published : 2015.12.01


Spectroscopy is an emerging technology for the quality assessment of pharmaceutical samples, from tablet manufacturing to final quality assurance. The traditional methods for the quality management of pharmaceutical tablets are time consuming and destructive, while spectroscopic techniques allow rapid analysis in a non-destructive manner. The advantage of spectroscopy is that it collects both spatial and spectral information (called hyperspectral imaging), which is useful for the chemical imaging of pharmaceutical samples. These chemical images provide both qualitative and quantitative information on tablet samples. In the pharmaceutics, spectroscopic techniques are used for a variety of applications, such as analysis of the homogeneity of powder samples as well as determination of particle size, product composition, and the concentration, uniformity, and distribution of the active pharmaceutical ingredient in solid tablets. This review paper presents an introduction to the applications of various spectroscopic techniques such as hyperspectroscopy and vibrational spectroscopies (Raman spectroscopy, FT-NIR, and IR spectroscopy) for the quality and safety assessment of pharmaceutical solid dosage forms. In addition, various chemometric techniques that are highly essential for analyzing the spectroscopic data of pharmaceutical samples are also reviewed.


Applications;Chemometrics;Hyperspectroscopy;Pharmaceutical;Vibrational spectroscopy


  1. Aldridge, P. K., C. L. Evans, H. W. Ward and S. T. Colgan. 1996. Near-IR detection of polymorphism and process-related substances. Analytica Chemica Acta 68:997-1002.
  2. Alvarenga, L., D. Ferreira, D. Altekruse, J. C. Menezes and D. Lochmann. 2008. Tablet identification using near-infrared spectroscopy (NIRS) for pharmaceutical quality control. Journal of Pharmaceutical and Biomedical Analysis 48:62-69.
  3. Amigo, J. M., J. Cruz, M. Bautista, J. Maspoch, J. Coello and M. Blanco. 2008. Study of pharmaceutical samples by NIR chemical-image and multivariate analysis. Trends in Analytical Chemistry 27:696-713.
  4. Amigo, J. M., C. Ravn, N. B. Gallagher and R. Bro. 2009. A comparison of a common to partial least squares-discriminant analysis and classical least squares in hyperspectral imaging. International Journal of Pharmaceutics 373:179-182.
  5. Amin, A. A. and G. O. Kokwaro. 2009. Antimalarial Drug Quality in Africa. Europe PMC Finders Author Manuscripts 35(5):429-440.
  6. Bai, S. J., M. Rani, R. Suryanarayanan, J. F. Carpenter, R. Nayar and M. C. Manning. 2004. Quantification of glycine crystallinity by near-infrared (NIR) spectroscopy. Journal of Pharmaceutical Sciences 93(10):2439-2447.
  7. Blanco, M. and M. Alcala. 2006. Content uniformity and tablet hardness testing of intact pharmaceutical tablets by near infrared spectroscopy. Analytica Chemica Acta 557:353-359.
  8. Blanco, M., M. Alcala, J. M. Gonzalez and H. Torras. 2006. Determination of dissolution profiles in intact pharmaceutical tablets by NIR spectroscopy. PAT 3:25-28.
  9. Blanco, M. and A. Villar. 2000. Polymorphic analysis of a pharmaceutical preparation by NIR spectroscopy, The Analyst 125:2311-2314.
  10. Blanco, M. and A. Villar. 2003. Development and validation of a method for the polymorphic analysis of pharmaceutical preparations using near infrared spectroscopy. Journal of Pharmaceutical Sciences 92:823-830.
  11. Buckton, G., E. Yonemochi, J. Hammond and A. Moffat. 1998. The use of near infra-red spectroscopy to detect changes in the form of amorphous and crystalline lactose. International Journal of Pharamceutics 168:231-241.
  12. Cairos, C., J. M. Amigo, R. Watt, J. Coello and S. Maspoch. 2009. Implementation of enhanced correlation maps in near infrared chemical images: Application in pharmaceutical research. Talanta 79:657-664.
  13. Clark, D. and S. Sasic. 2006. Chemical images: Technical approaches and issues. International society for Analytical Cytology 69:815-824.
  14. Corredor, C. C., D. Bu and D. Both. 2011. Comparison of near infrared and microwave resonance for at-line moisture determination in powders and tablets. Analytica Chimica Acta 696:84-93.
  15. Cruz, J., M. Bautista, J. M. Amigo and M. Blanco. 2009. NIR-chemical imaging study of acetylsalicylic acid in commercial tablets. Talanta 80(2):473-478.
  16. Cruz, J. and M. Blanco. 2011. Content uniformity studies in tablets by NIR-CI. Journal of Pharmaceutical and Biomedical Analysis 56:408-412.
  17. Das, R. S. and Y. K. Agrawal. 2011. Raman Spectroscopy: Recent advancements, techniques and applications. Vibrational spectroscopy 57:163-176.
  18. Deisingh, A. K. 2005. Pharmaceutical counterfeiting. Analyst 130:271-279.
  19. Donoso, M. and E. S. Ghaly. 2004. Prediction of drug dissolution form tablets using near-infrared diffuse reflectance spectroscopy as a nondestructive method. Pharm. Dev. Technol 9:247-263.
  20. Doub, W. H., W. P. Adams, J. A. Spencer, L. F. Buhse, M. P. Nelson and P. J. Treado. 2007. Raman chemical imaging for ingredient-specific particle size characterization of aqueous suspension nasal spray formulations: A progress report. Pharmaceutical Research 24(5):934-945.
  21. Dowell, F. E., E. B. Maghirang, F. M. Fernandez, P. N. Newton and M. D. Green. 2008. Detecting counterfeit antimalarial tablets by near-infrared spectroscopy. Journal of Pharmaceutical and Biomedical Analysis 48:1011-1014.
  22. Fathima, N., T. Mamatha, H. K. Qureshi, N. Anitha and J. V. Rao. 2011. Drug-excipient interaction and its importance in dosage form development. Journal of Applied Pharmaceutical Science 01(06):66-71.
  23. Fernandes, R. S., F. S. L. Costa, P. Valderrama, P. H. M. Marco and K. M. G. Lima. 2012. Non-destructive detection of adulterated tablets of glibenclamide using NIR and solid-phase fluorescence spectroscopy and chemometric methods. Journal of Pharmaceutical and Biomedical Analysis 66:85-90.
  24. Firkala, T., E. Talas, J. Mihaly, T. Imre and S. Kristyan. 2013. Specific behavior of the p-aminothiophenol-Silver sol system Ultra-violet-visible (UV-Visible) and Surface Enhanced Raman (SERS) sepctra. Journal of Colloid and Interface Science 410:59-66.
  25. Freitas, M. P., A. Sabadin, L. M. Silva, F. M. Giannotti, D. A. Couto, E. Tonhi, S. Medeiros, G. L. Coco, V. F. T. Russo and J. A. Martins. 2005. Prediction of drug dissolution profiles from tablets using NIR diffuse reflectance spectroscopy: A rapid and nondestructive method. Journal of Pharmaceutical and Biomedical analysis 39:17-21.
  26. Gendre, C., M. Boiret, M. Genty, P. Chaminade and J. M. Pean. 2011. Real time predictions of drug release and end point detection of a coating operation by in-line near infrared measurements. International Journal of Pharmaceutics 421:237-243.
  27. Gendrin, C. and Y. Roggo. 2008. Pharmaceutical applications of vibrational chemical imaging and chemometrics: A review, Journal of Pharmaceutical and Biomedical Analysis 48:533-553.
  28. Gombas, A., I. Antal, P. Szabo-Revesz, S. Marton and I. Eros. 2003. Quantitative determination of crystallinity of alphalactose monohydrate by near infrared spectroscopy (NIRS). International Journal of Pharmaceutics 256:25-32.
  29. Grohganz, H., M. Fonteyne, E. Skibsted, F. Thomas, B. Palmqvist and J. Rantanen. 2009. Role of excipients in the quantification of water in lyophilised mixtures using NIR spectrosocpoy. Journal of Pharmaceutical and Biomedical Analysis 49:901-907.
  30. Grohganz, H., D. Gildemyn, E. Skibsted, J. M. Flink and J. Rantanen. 2010. Towards a robust water content determination of freeze-dried samples by near-infrared spectroscopy. Analytica Chimica Acta 676:34-40.
  31. Hagrasy, A. S., S. Y. Chang, D. Desai and S. Kiang. 2006. Raman spectroscopy for the determination of coating uniformity of tablets: assessment of product quality and coating pan mixing efficiency during scale-up. Journal of Pharmaceutical Innovation 48:533-533.
  32. Heigl, N., A. Hodzic, M. Liusa, W. Tritthart, F. Reiter, S. D. Fraser, P. Laggner and J. G. Khinast. 2012. Potential of Raman spectroscopy for evaluating crushing strength of tablets. J Pharm Innov 7:76-86.
  33. Jones, A. W. 2011. Early drug discovery and the rise of pharmaceutical chemistry. Drug Testing and Analysis 3:337-344.
  34. Kuriyama, A. and Y. Ozaki. 2014. Assessment of active pharmaceutical ingredient particle size in tablets by Raman chemical imaging validated using polystyrene microsphere size standards. AAPS PharmSciTech 15(2):375-387.
  35. Lee, M., C. Park, A. Kim, B. Kwon, K. Bang, Y. Cho, M. Jeong and G. Choi. 2009. Dynamic calibration for the in-line NIR monitoring of film thickness of pharmaceutical tablets processed in a fluid-bed coater. Journal of Pharmaceutical Sciences 99(1):325-335.
  36. Lewis, E. N., L. H. Kidder and E. Lee. 2005. NIR chemical imaging as a process analytical tool. Innovation in pharmaceutical technology, 1st ed:187-225.
  37. Li, T., A. D. Donner, C. Y. Choi, G. P. Frunzi and K. R. Morris. 2003. A statistical support for using spectroscopic methods to validate the content uniformity of solid dosage forms. Journal of Pharmaceutical Sciences 92:1526-1530.
  38. Li, W., A. Woldu, R. Kelly, J. McCool, R. Bruce, H. Rasmussen, J. Cunningham and D. Winstead. 2008. Measurement of drug agglomerates in powder blending simulation samples by near infrared chemical imaging. International Journal of Pharmaceutics 350:369-373.
  39. Lyon, R. C., D. S. Lester, E. N. Lewis, E. Lee, L. X. Yu, E. H. Jefferson and A. S. Hussan. 2002. Near-infrared spectral imaging for quality assurance of pharmaceutical products: Analysis of tablets to assess powder blend homogeneity. AAPS PharmSciTech 3:1-15.
  40. Ma, H. and C. A. Anderson. 2007. Characterization of pharmaceutical powder blends by NIR chemical imaging. Journal of Pharmaceutical Sciences 97(8):3305-3320.
  41. Mainali, D., J. Li, P. Yehl and N. Chetwyn. 2014. Development of a comprehensive near infrared spectroscopy calibration model for rapid measurements of moisture content in multiple pharmaceutical products. Journal of Pharmaceutical and Biomedical Analysis 95:169-175.
  42. May, R. K., K. Su, L. Han, S. Zhong, J. A. Elliott, L. F. Gladden, M. Evans, Y. Shen and A. Zeitler. 2013. Hardness and density distributions of pharmaceutical tablets measured by Terahertz pulsed imaging. Journal of Pharmaceutical Sciences 102:2179-2186.
  43. Moes, J., M. M. Ruijken, E. Gout, H. W. Frijlink and M. I. Ugwoke. 2008. Application of process analytical technology in tablet process development using NIR spectroscopy: Blend uniformity, content uniformity and coating thickness measurements. International Journal of Pharmaceutics 375:108-118.
  44. Morisseau, K. H. and C. T. Rhodes. 1997. Near-infrared spectroscopy as a nondestructive alternative to conventional tablet hardness testing. Pharmaceutical Research 14:0724-8741.
  45. Muzzio, C. R., N. G. Dini and L. D. Simionato. 2011. Determinaiton of moisture content in lyophilized mannitol through intact glass vials using NIR-spectrometers. BJPS, 47(2):1984-8250
  46. Neves, A. C. O., G. M. Soares, C. Morais, F. S. Costa, D. L. Porto and K. M. G. Lima. 2012. Dissolution testing of isoniazid, rifampicin, pyrazinamide and ethambutol tablets using near-infrared spectroscopy (NIRS) and multivariate calibration. Journal of Pharmaceutical and Biomedical Analysis 57:115-119.
  47. Nissankararao, S., V. Kallam and R. Bhimavarapu. 2013. Dissolution method development and validation: A review. IJPRD 5:106-112.
  48. Otsuka, M., F. Kato, Y. Matsuda and Y. Ozaki. 2003. Comparative determination of polymorphs of indomethacin in powders and tablets by chemometrical near-infrared spectroscopy and x-ray powder diffractometry. AAPS PharmSciTech 4(2):58-69.
  49. Otsuka, M., T. Mouri and Y. Matsuda. 2003. Chemometric evaluation of pharmaceutical properties of antipyrine granules by near-infrared spectroscopy. AAPS Pharma SciTech 4(3):142-148.
  50. Otsuka, M., H. Tanabe, K. Osaki, K. Otsuka and Y. Ozaki. 2007. Chemoinformetrical evaluation of dissolution property of indomethacin tablets by near-infrared spectroscopy. J. Pharm, Sci 96:788-801.
  51. Otsuka, M. and Yamane, I. 2005. Prediction of tablet hardness based on near infrared spectra of raw mixed powders by chemometrics. Journal of Pharmaceutical Sciences 95:424-68-8658.
  52. Ozaki, Y. 2012. Near-infrared spectroscopy-its versatility in analytical chemistry. Analytical Sciences 28(6):545-63.
  53. Palou, A., J. Cruz, M. Blanco, J. Tomas, J. Rios and M. Alcala. 2012. Determination of drug, excipients and coating distribution in pharmaceutical tablets using NIR-CI. Journal of Pharmaceutical Analysis 2:90-97.
  54. Park, T., D. Ko, Y. J. Kim and Y. Kim. 2009. Polymorphic characterization of pharmaceutical solids, donepezil hydrochloride, by 13C CP/MAS solid-state nuclear magnetic resonance spectroscopy. Bull. Koran Chem. Soc. 30(9):2007-2010.
  55. Pawar, H. A. and S. R. Kamat. 2014. Chemometrics and its application in pharmaceutical field. J Phys Chem Biophys 4:2161-0398.
  56. Puchert, T., D. Lochmann, J. C. Menezes and G. Reich. 2010. Near-infrared chemical imaging (NIR-CI) for counterfeit drug identification-A four-stage concept with a novel approach of data processing (Linear image signature). Journal of Pharmaceutical and Biomedical Analysis 51:138-145.
  57. Ravn, C., E. Skibsted and R. Bro. 2008. Near-infrared chemical (NIR-CI) on pharmaceutical solid dosage forms-comparing common calibration approaches. Journal of Pharmaceutical and Biomedical Analysis 48:554-561.
  58. Rodionova, O. Y., L. P. Houmoller, A. L. Pomerantsev, P. Geladi, J. Burger, V. L. Dorofeyev and A. P. Arzamastsev. 2005. NIR spectrometry for counterfeit drug detection. A feasibility study. Analytica Chimica Acta 549:151-158.
  59. Roggo, Y., A. Edmond, P. Chalus and M. Ulmschneider. 2005. Infrared hyperspectral imaging of qualitative analysis of pharmaceutical solid forms. Analytica Chimica Acta 535:79-87.
  60. Romer, M., J. Heinamaki, C. Strachan, C. Sandler and J. Yliruusi. 2008. Prediction of tablet film-coating thickness using a rotating plate coating system and NIR spectroscopy. AAPS PharmSciTech 9(4):1047-1053.
  61. Sasic, S. 2008. Chemical imaging of pharmaceutical granules by Raman global illumination and near-infrared mapping platforms. Analytica Chimica Acta 6:73-79.
  62. Seyer, J. J., P. E. Luner and M. S. Kemper. 2000. Application of diffuse reflectance near-infrared spectroscopy for determination of crystallinity. Journal of Pharmaceutical Sciences 89(10):1305-1316.<1305::AID-JPS8>3.0.CO;2-Q
  63. Shah, R. B., M. A. Tawakkul and M. R. Khan, 2006. Process analytical technology: Chemometric analysis of Raman and near infra-red spectroscopic data for predicting physical properties of extended release matrix tablets. Journal of Pharmaceutical Sciences 96:1356-1365.
  64. Singh, I., P. Juneja, B. Kaur and P. Kumar. 2013. Pharmaceutical applications of Chemometric techniques. ISRN Analytical Chemistry 2013(2013):13.
  65. Sovany, T., K. Nikowitz, G. Regdon, J. P. Kasa and J. K. Pintye-Hodi. 2009. Raman spectroscopic investigation of film thickness. Polymer Testing 28:770-772.
  66. Tabasi, S. H., R. M. Fahmy, D. Bensley, C. O'Brien and S. W. Hoag. 2008. Quality by design. Part III. Study of curing process of sustained release polymer products using NIR spectroscopy. J. Pharm. Sci 97:4067-4086.
  67. Tabasi, S. H., V. Moolchandani, R. Fahmy and W. H. Stephen. 2009. Sustained release forms dissolution behavior prediction: A study of matrix using NIR spectroscopy. International Journal of Pharmaceutics 382:1-6.
  68. Tanabe, H., K. Otsuka and M. Otsuka. 2007. Theoretical analysis of tablet hardness predication using chemoinformetric near-infrared spectroscopy. Analytical Sciences 23(7):857-862.
  69. Thiruvengadam, E. and G. Vellaisamy. 2014. Polymorphism in pharmaceutical ingredients: A review. World Journal of Pharmacy and Pharmaceutical Sciences 3:621-633.
  70. Uppaluri, S. G ., S . K. Bompelliwar, P . R. Johnson, M. R. Gupta, A. Al-Achi, W. C. Stagner and R. V. Haware. 2014. Evaluation of the moisture prediction capability of near-infrared and attenuated total reflectance fourier transform infrared spectroscopy using superdisintegrants as model compounds. Journal of Pharmaceutical Sciences 103:4012-4020.
  71. Vajna, B., A. Farkas, H. Pataki, Z. Zsigmond, T. Igricz and G. Marosi. 2012. Testing the performance of pure spectrum resolution form Raman hyperspectral images of differently manufactured pharmaceutical tablets. Analytica Chimica Acta 712:45-55.
  72. Veij, M. D., A. Deneckere, P. Vandenabeele, D. D. Kaste and L. Moens. 2008. Detection of counterfeit Viagra$^{(R)}$ with Raman spectroscopy. Journal of Pharmaceutical and Biomedical Analysis 46:303-309.
  73. Virtanen, S., O. Antikainen and J. Yliruusi. 2008. Determination of the crushing strength of intact tablets using Raman spectroscopy. International Journal of Pharmaceutics 360:40-46.
  74. Wang, I., M. Lee, D. Seo, H. Lee, Y. Choi, W. Kim, C. Kim, Y. Jeong and G. Choi. 2011. Polymorph transformation in paracetamol monitored by in-line NIR spectroscopy during a cooling crystallization process. AAPS Pharm SciTech 12(2):764-770.
  75. World Health Organization (WHO). 2007. Quality assurance of pharmaceuticals: Compendium of guidelines and related materials: Good manufacturing practices and inspection. 2nd edition: Vol. 2.
  76. Zhang, X., Y. Feng and C. Hu. 2008. Feasibility and extension of universal quantitative models for moisture content determination in beta-lactam powder injections by near-infrared spectroscopy. Analytica Chimica Acta 630:131-140.
  77. Aldridge, P. K., C. L. Evans, H. W. Ward and S. T. Colgan. 1996. Near-IR detection of polymorphism and processrelated substances. Anal. Chem. 68:997-1002.
  78. Alvarenga, L., D. Ferreira, D. Altekruse, J. C. Menezes and D. Lochmann. 2008. Tablet identification using near-infrared spectroscopy (NIRS) for pharmaceutical quality control. Journal of Pharmaceutical and Biomedical Analysis 48:62-69.

Cited by

  1. Raman spectral imaging technique for API detection in pharmaceutical microtablets vol.260, 2018,
  2. Raman Hyperspectral Imaging for Detection of Watermelon Seeds Infected with Acidovorax citrulli vol.17, pp.10, 2017,
  3. Color evolution during a coating process of pharmaceutical tablet cores by random spraying pp.03612317, 2018,
  4. Particles Size Estimation of Polydopamine Based Polymeric Nanoparticles Using Near-Infrared Spectroscopy Combined with Linear Regression Method vol.09, pp.05, 2018,


Supported by : Ministry of Agriculture, Food and Rural Affairs (MAFRA)