This document summarizes various physicochemical characterization techniques used to analyze solid oral dosage forms, including microscopy, X-ray powder diffraction, thermal analysis, FTIR microspectroscopy, NMR imaging and spectroscopy, mass spectrometry, and Raman spectroscopy. Specific examples are provided to illustrate how each technique can provide insight into the drug substance distribution, solid state properties, and release characteristics. Near infrared analysis is also discussed for applications in qualitative analysis like raw material identification and blend homogeneity assessment and quantitative analysis for assaying finished drug products.

1. Prepared by :- PATEL PARTH
M.Pharm
(QA-Sem II)
S.J. Thakkar Pharmacy College, Rajkot
Guided by :- Mrs. Jagruti P. Vaghela
(Assistant Professor) &
Mrs. Parula B. Patel
(Associate Professor)
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2. I. INTRODUCTION :-
 Solid oral dosage forms are designed to deliver the drug through physiological
mechanisms that preside throughout the gastrointestinal tract.
 Solid oral dosage forms provide a highly reproducible and convenient form of
drug delivery
 To design an effective delivery system, it is important to know the physical state
of the API in the dosage form; therefore, this chapter will focus to a large extent
on the solid-state aspects of the solid oral dosage forms.
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3. II. Physicochemical characterization techniques :-
 Physicochemical characterization techniques are beginning to play a major role
in the drug development process because they help us to understand the
mechanism of drug delivery.
 An assessment of the internal structure of the dosage form and the micro
homogeneity and morphology of the API in the dosage form can be made with
the techniques that are discussed in this chapter.
 These techniques include,
A. Microscopy
B. X-ray powder diffraction
C. Thermal analysis
D. FTIR micro spectroscopy
E. NMR imaging
F. Mass spectroscopy
G. Raman spectroscopy
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4. A. Microscopy :-
 Light microscopy, PLM, SEM, and transmission microscopy are nondestructive
techniques that can provide insight into the composition and homogeneity of the
API throughout the dosage form.
 PLM and energy-dispersive X-ray spectroscopy (used in conjunction with SEM)
are utilized to determine how an API is distributed within a granulation.
 Energy-dispersive X-ray spectroscopy, an elemental analysis technique, used to
map chlorine content and reveal the distribution of the API in the granulation.
 These experiments demonstrate that the API exists as the hydrochloride salt in
the granulation and retains its original particle size distribution; therefore, the
high temperatures and drying conditions used in the manufacturing process do
not appear to have negatively affected the drug substance.
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5. FIGURE 1 FIGURE 2
Polarized light micrograph of a granulation. Chlorine mapping of a granulation containing a
Crystals of the API (see arrow) are visible hydrochloride salt API.
within the matrix of the granulation.
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6. B. X-Ray Powder Diffraction :-
 The molecules in a crystalline compound are ordered in a three-dimensional
array called a lattice.
 When a collimated beam of X-rays is incident upon this lattice, X-rays are
diffracted.
 Every crystal form of a compound produces its own characteristic X-ray
diffraction pattern.
 This technique is useful for distinguishing between solid-state forms of a bulk
drug substance and for characterizing changes in the solid state (e.g.,
distinguishing between polymorphs, hydrates, and solvates and characterizing
phase transitions between them).
 The technique is also useful for characterizing changes in the drug substance in
a solid state as it exists in a matrix of a formulation—for example, a change
from a crystalline to an amorphous form or hydration, dehydration, etc.
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7. • To confirm that polymorphic form of the API does not change during the
manufacturing process, an experiment was done utilizing X-ray powder
diffraction patterns of crushed tablets, crushed placebo tablets and three lots
of API were acquired.
FIGURE 3
• X-ray powder diffraction patterns of crushed tablets (pattern 1), crushed placebo tablets
(pattern 2), and three lots of the API (patterns 3–5).
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8.  As seen in the diffraction patterns, the crystal structure of the API remained
unchanged during processing. This study revealed no obvious evidence of
polymorphic changes of the API due to the manufacturing process.
C. Thermal analysis :-
 Simultaneous thermo gravimetric and differential thermal analysis (TG/DTA) is
a useful technique for the solid-state characterization of pharmaceutical
materials.
 Such characterization includes the determinations of loss on drying, phase
transition temperatures, thermal stability, and whether or not water is bound or
unbound. The TG/DTA data are derived from the response of the sample to a
heating program.
 TG/DTA was utilized to monitor changes in the crystal morphology and physical
changes of a hydrated API in a granulation blend and in tablets compressed
from the blend.
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9. D. FT-IR Micro spectroscopy :-
 FTIR micro spectroscopy, equipped with an automated stage, is a nondestructive
technique that can be utilized to analyze small samples and to chemically map
locations by identifying components within the sample.
 When unidentified crystalline particles were found growing on tablets during a
stability study, FTIR micro spectroscopy with a spectral resolution of about 5 μm
was used to chemically analyze and identify the minute particles.
E. NMR Spectroscopy :-
I. NMR Imaging :-
 To understand the release of an API from controlled-release tablets containing
HPMC, NMR imaging techniques were used to measure the relaxation times and
self-diffusion coefficients (SDCs) of water across the gel layer.
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10.  In this study, the SDC values were found to increase with increasing distance
from the gel region to the core of the tablet.
 The SDC gradients (the change in SDC value over distance) were found to vary
among HPMC tablets with different levels of polymer substitution.
 This type of in vitro NMR imaging experiment can provide important information
to guide formulation optimization and aid in the design of drug products that
deliver the desired in vivo release characteristics.
FIGURE 4
Self-diffusion coefficients
of water across the gel layer
of an HPMC tablet
after 3 hours hydration.
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11.  In another study, NMR imaging with a modified flow-through dissolution
apparatus was used to assess the swelling of HPMC tablets.
 The series of images reproduced to show the physical changes in HPMC tablets
over time under static conditions.
 Determining the swelling behavior of the HPMC with this type of imaging may
increase the understanding of the release of the API from the dosage form.
 This approach was successfully applied to the study of matrix-controlled-
release tablets as well as osmotic-release tablets.
 NMR imaging techniques provide information about the nature of the physical
processes involved in the disintegration and dissolution of the drug product.
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12. FIGURE 5
NMR images of HPMC tablets within a flow-through dissolution apparatus under static
conditions at swelling times of 1, 5, 13, and 19 hours (a–d, respectively). The black center
regions show where the tablet is dry, and the bright regions around the tablet show
where the gel is swollen.
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13. II. Solid-State NMR :-
 Solid-state NMR studies have been used to study the characteristics of an API in
melt-extruded pellets.
 The purpose of the study was to determine whether the high temperatures at
which the melt extrusion process was conducted caused physical changes in the
drug substance, such as the formation of a different polymorph or a change in
salt form.
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14. F. Mass Spectrometry :-
 Recently, time-of-flight MS combined with secondary-ion monitoring (TOF-SIMS)
has been reported to be a useful tool for characterizing and imaging the
distribution of the components within a solid dosage form.
 A pellet consisting of a ∼100-μm-wide silica core, a ∼100-μm-wide metoprolol
drug layer, and a ∼50-μm-wide outer coating of ethyl cellulose was cross
sectioned and bombarded with a 15-keV Ga+ ion source, and the mass spectra
obtained from the regions of interest provided information about the
distribution of the various components.
 The resulting image for the metoprolol molecular species reveals the absence of
drug in the inner and outer layers of the pellet
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15. FIGURE 6
 This technique :-
 could be extremely important for assessing the controlled release properties of
a solid oral dosage form.
 The homogeneity and quality of the manufacturing process could be determined.
 applied to the analysis of the surface of beads, tablets, and granulations,
allowing the chemical composition of more than one layer to be evaluated.
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16. F. Raman spectroscopy :-
 Laser source Raman spectroscopy is used to analyze solid dispersion to
evaluate the physical properties and determine the distribution of ibuprofen in
extrudates of polyvinyl pyrrolidone.
 As shown in figure, a shift in the raman spectra occurs when the crystalline
form of ibuprofen is compared to a solution or a PVP extrudate containing
ibuprofen.
 The lack of any raman shifts during a stability study indicates that ibuprofen in
the melt extrudate is stable and that there were no crystallization processes
that could affect the dissolution and bioavailability.
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17. FIGURE 7
Raman spectra of three ibuprofen formulations. Ibuprofen formulations: solution
(dimer 3), solid line; extrudate (PVP), dashed line; crystalline powder, dotted line. The
ibuprofen extrudate and solution are shifted compared to the crystalline form of ibuprofen.
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18. III. NEAR INFRARED ANALYSIS :-
 There is intense interest in using NIR techniques in several major areas of
pharmaceutical operations: clinical supply identification, incoming raw material
identification, assay and content uniformity testing of finished products.
 The following sections describe qualitative and quantitative examples of
validated NIR methods currently in use.
a) Qualitative NIR Analysis :-
1. Verification of the Identity of Packaged Clinical Supplies :-
 An NIR spectroscopic method to identify pharmaceutically active and inactive
(placebo) clinical dosage forms is recently developed.
 NIR analysis is particularly suited to the verification of the identity of packaged
clinical supplies because of its nondestructive nature, speed, and low cost.
 The method was developed to create and validate a one-time-use library of the
spectra of clinical dosage forms prepared for double-blind clinical trials.
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19. FIGURE 8
NIR spectra of known active and placebo (inactive) products packaged into
blister cards.
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20. 2. Raw Material Identification :-
 Use of the technique for raw material identification is done for preparing the
library which is composed of spectra from dozens of lots that are averaged into
a single spectrum for each raw material.
 The spectrum of an unknown material is matched against all possible similar
compounds.
 The unknown is either accepted or rejected based upon how close (within
accepted variations) its spectrum matches that of a known compound.
3. Blend Homogeneity :-
 NIR spectra obtained after different mixing intervals were used to assess the
extent to which four components were blended in a V-blender at ―high,‖ ―middle‖
and ―low‖ positions on the blender at the 1, 5, 15 & 20 minute intervals.
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21.  This experiment shows the feasibility of using NIR to determine the blend
homogeneity of both API and excipients simultaneously in real time, thus
ensuring optimal content uniformity during compression or capsule filling.
 Spectra of four component blend after 1 minute and 20 minutes of mixing are
illustrated in figures.
FIGURE 9
NIR spectra at high, middle, and low positions of a V-blender after 1 minute of mixing.
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22. FIGURE 18
NIR spectra at high, middle, and low positions of a V-blender after 20 minutes of
mixing.
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23. b) Quantitative NIR Analysis :-
 Once an NIR method is validated, the scanning of the tablets and calculation of
the results require less than 1 minute.
 Thus, it becomes practical to assay hundreds of finished units from a batch
throughout a production run instead of selecting a few samples on a small,
randomized sampling protocol.
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24.  References :-
 SEPARATION SCIENCE AND TECHNOLOGY A reference series edited by Satinder
Ahuja volume-III Handbook of modern pharmaceautical analysis by Satinder
Ahuja and Stephen Scypinski, published by Academic press pg no. 235 to 252.
 www.opticsinfobase.org Article – drug characterization using Raman
spectroscopy
 www.horiba.com Article – Particle size and shape analysis of API
 Handbook of Thermal analysis and calorimetry volume-5 , recent advances,
techniques and applications, Editors-Michael E. Brown, Patrick Kent Gallagher
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