10/11/ ENGINEERING RESEARCH CENTER FOR S TRUCTURED O RGANIC P ARTICULATE S YSTEMS RUTGERS UNIVERSITY PURDUE UNIVERSITY NEW JERSEY INSTITUTE OF TECHNOLOGY UNIVERSITY OF PUERTO RICO AT MAYAGÜEZ Vibrational Spectroscopy for Pharmaceutical Analysis Part X. Diffuse Reflectance and Transmittance NIR Rodolfo J. Romañach, Ph.D.

2 High Reflectance Low Reflectance Shorter pathlength Smaller particle sizes Larger pathlength Larger particle sizes High scattering Low Scattering Prepared by Martha Barajas Meneses, MS 2006.

3 Scattering  When a molecule is exposed to the oscillating electromagnetic field of a light wave, it is polarized at the frequency of the incident light. The oscillating electric charges in the molecule cause the radiation of light in other directions. Scattering (Alberty, Farrington, Daniels, Physical Chemistry, Fifth Edition).  The changes in direction are a result of reflection, refraction, and random diffraction at the surfaces of various particles. The combination of these effects is called light scattering. (M.C. Pasikatan, et. al., J. Near Infrared Spectroscopy, 2001, 9, 153 – 164).

4 Scattering  The radiation that comes back to the entry surface is called diffuse reflectance.  Light propagates by scattering.  As light propagates, both scattering and absorption occur, and the intensity of the radiation is reduced.

5 Diffuse Reflectance (DRIFTS) - Reflectance is termed diffuse where the angle of reflected light is independent of the incident angle Spectra Affected by:  Particle size of sample.  Packing density of sample, and pressure on sample.  Refractive index of sample.  Crystalline form of sample.  Absorption coefficients of sample.  Characteristics of the sample’s surface. J.M. Chalmers and G. Dent, “Industrial Analysis with Vibrational Spectroscopy”, Royal Society of Chemistry, 1997, pages

6 Diffuse Reflectance Source Detector Fiber Optic Probe By Raúl E. Gómez Perez, MS, 2000

7 Near Infrared Spectrometer By Nelson N. Hernandez, MS, 2001

8 Powder & Solids Probe with liquid attachment Powder and Solids Probe – Courtesy Bruker Optics Extra-long immersion depth: 12” Diffuse Reflection Probe Schematic IR Source IR Energy Sample Delivery Fiber Bundle Collection Fiber Bundle Reflected IR Energy Detector

9 Transflection Source Detector mirror Analyte I0I0 I trans Fiber probe for solids with liquid attachment mirror Courtesy Bruker Optics

10 Transflectance using gold plate reflector. M. Blanco, M.A. Romero, “Near infrared transflectance spectroscopy Determination of dexketoprofen in a hydrogel”, Journal of Pharmaceutical and Biomedical Analysis, 30 (2002) 467–472.

11 Diffuse Reflectance Detector Sample Source Integrating Sphere By Raúl E. Gómez Pérez, MS, 2000

12 Lab scale and pilot plant equipment are used for process understanding during development, and are also available at manufacturing site to continue process understanding. CDI Lab Scale NIRS system,

13 30 cubic feet V-blender Courtesy of Mova Pharmaceuticals.

14 Ivelisse Suárez, B.S. Chemistry, Inter American University, San Germán, December 2004, Expected Graduation: May 2007.

15 Lab scale hopper and connecting tube. Mort er Optic Fiber Bulbs Probe Powdered Lactose Focused Radiation spot

16 Multiplicative Effect in Diffuse Reflectance  According to the Kubelka Munck theory light scattering is multiplicative.  This means that if the spectrum is first properly transformed to the KM scale, a difference in scatter between two “equal” samples can be compensated by multiplying the measurement at each wavelength of one of the samples by the same constant. A similar multiplicative effect has been seen in A = log (1/R) spectra. N Naes, Isaksson, Fearn, and Davis, Multivariate Calibration and Classification, page 106, NIR Publications, 2002.

17 Additive Scatter Component  The KM theory assumes that all or a constant part of the reflected light is detected.  However, it is likely that the diffuse reflectance accessory is constructed so that only a fraction (1/c) of the reflected light is detected for a particular sample.  I detected = 1/c x I reflected  A detected = - log (R detected ) = - log (I detected /I 0 ) = log c + log (I 0 /I reflected ) = c’ + A If c’ = log (c) is sample dependent, this will cause an additive baseline difference between the samples, i.e. an additive effect in the absorbance values. Naes, Isaksson, Fearn, and Davis, Multivariate Calibration and Classification, page , NIR Publications, 2002.

18 Lactose Retained by No. 60 Mesh Sieve (>250 μm) SEM obtained in Dr. Miguel Castro’s lab, by Lewis Gomez and Alex Rodriguez Cassiani.

19 Lactose Retained by Sieve No. 120 (> 125 μM) SEM obtained in Dr. Miguel Castro’s lab (UPR-Mayaguez), by Lewis Gomez and Alex Rodriguez Cassiani. –

20 Ibuprofen Crystals Retained by No. 60 Mesh Sieve (>250 μm) SEM obtained in Dr. Miguel Castro’s lab (UPR-Mayaguez), by Lewis Gomez and Alex Rodriguez Cassiani.

21 Particle Size of Pharmaceutical Powders P. Frake, et.al., “Near-infrared mass median particle size determination of lactose monohydrate, evaluating several chemometric approaches”, Analyst, 1998, 123, 2043–2046.

22 M.J. Barajas, A. Rodriguez Cassiani, W. Vargas, C. Conde, J. Ropero, J. Figueroa, and R. J. Romañach, “A Near Infrared Spectroscopic Method for Real Time Monitoring of Pharmaceutical Powders during Voiding”, Applied Spectroscopy, 2007, 61(5), 490 – 496.

23 Transmittance Spectra  Advantage is that the radiation comes into contact with a greater portion of the sample.  Sometimes called diffuse transmittance.  Could be pathlength limited.

24 Diffuse Transmittance Tablet Sample Detector Position IR Beam Prepared by: María A. Santos R.J. Romañach and M.A. Santos, “Content Uniformity Testing with Near Infrared Spectroscopy”, American Pharmaceutical Review, 2003, 6(2), 62 – 67.

25 Determination of Drug Content in Tablets A Tablet is a Sample of a Blend

26 Diffuse Reflectance (DRIFTS) – Reflectance is termed diffuse where the angle of reflected light is independent of the incident angle Spectra Affected by:  Particle size of sample.  Packing density of sample, and pressure on sample.  Refractive index of sample.  Crystalline form of sample.  Absorption coefficients of sample.  Characteristics of the sample’s surface. J.M. Chalmers and G. Dent, “Industrial Analysis with Vibrational Spectroscopy”, Royal Society of Chemistry, 1997, pages

27 Spectroscopy of the Solid State  Spectroscopy - Interaction between radiation and matter.  NIR – offers possibility of study of interaction of solids with radiation since sample preparation is not required.

28 Recommended Reading Naes, Isaksson, Fearn, and Davis, Multivariate Calibration and Classification, Chapter 10 “Scatter Correction of Spectroscopic Data”, NIR Publications, 2002.