This seminar discusses techniques for characterizing solid oral dosage forms. It describes several analytical techniques used to characterize the physical and chemical properties of drugs and excipients in oral dosage forms, including microscopy, thermal analysis, spectroscopy, and dissolution testing. The techniques provide information on drug distribution, polymorphic forms, interactions, and release properties which can guide formulation optimization and quality control. Recent applications of these characterization methods in published case studies are also summarized.

1. A
Seminar
On
Prepared by :-
PATEL PARTH
M.Pharm QA( Sem : II)
Enrollment no:112070804010
APMC COLLEGE OF PHARMACY 1
HIMMATNAGAR

2. 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.
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3. The techniques include :
Light microscopy,
Polarized light microscopy (PLM),
Scanning electron microscopy (SEM),
Transmission microscopy,
Fourier transform infrared (FTIR)
Micro spectroscopy,
Nuclear magnetic resonance (NMR) imaging,
Near-infrared (NIR) analysis, and
Raman spectroscopy.
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4. 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 here.
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5. These techniques include,
 Microscopy
 X-ray powder diffraction
 Thermal analysis
 FTIR micro spectroscopy
 NMR imaging
 Mass spectroscopy
 Raman spectroscopy
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6. 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 6
process do not appear to have negatively affected the drug substance.

7. FIGURE 1 FIGURE 2
Polarized light micrograph of Chlorine mapping of a
a granulation. Crystals of the granulation containing a
API (see arrow) are visible hydrochloride salt API.
within the matrix of the
granulation. 7

8. 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 useful for characterizing changes in the drug substance in a 8
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.

9. 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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10. 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.
Thermal analysis :-
 Simultaneous thermo gravimetric and differential thermal analysis
(TGA/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.
 TGA/DTA combines the measurement of a change in mass of a sample as a
function of temperature (TGA) with the temperature difference of a sample
10
compared with an inert reference material as a function of temperature
(DTA).

11. The TGA/DTA data are derived from the response of the sample to a
heating program. In DTA the sample temperature remains constant
throughout an endothermic transition, whereas the sample
temperature increases during an exothermic transition.
A TGA curve is simultaneously acquired, yielding the corresponding
mass change curve. These dual pieces of information make
interpretations more straightforward than interpretation with either
technique alone.
TGA/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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12. 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.
NMR Spectroscopy :-
 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 12
gel layer.

13. 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. 13

14. 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. 14

15. 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.
15

16. 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.
16

17. 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.
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. 17

18. NEAR INFRAREDANALYSIS :-
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.
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19. Qualitative NIR Analysis :-
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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20. FIGURE 6
NIR spectra of known active and placebo (inactive) products packaged into
blister cards.
20

21. 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.
Blend Homogeneity :-
 The homogeneity of pharmaceutical raw materials during blending was
followed by visual matching, spectral matching, or principal component
21
analysis of the spectra after discrete time intervals.

22. NIR spectra obtained after different mixing intervals were used to assess
the extent to which four components were blended in a V-blender.
NIR reflectance spectra were collected with the use of a fiber-optic probe at
―high,‖ ―middle,‖ and ―low‖ positions on the blender at 1, 5, 10, 15, and
20-minute intervals. Spectra of the four-component blend after 1 minute
and 20 minutes of mixing are illustrated in Figures 13 and 14 respectively.
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 figure.
22

23. FIGURE 7
NIR spectra at high, middle, and low positions of a V-blender after
1 minute of mixing.
23

24. FIGURE 8
NIR spectra at high, middle, and low positions of a V-blender after 20 minutes of
mixing.
24

25. At each interval, the relative standard deviation (RSD) of the NIR
results at a wavelength specific to the active component was
calculated.
In addition, parallel HPLC analysis of the blend was performed. To
show that the NIR method is comparable to results obtained by
analysis by HPLC, the RSDs of the NIR results and the RSDs
obtained from the HPLC assay results were plotted versus minutes
mixed.
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. 25

26. Recent scenario :-
X-ray diffraction method and thermal analytical method, both
technique were used by Macaroni E., et al. for structural
characterization of two benfluorex hydrochloride polymorphs.
Raman spectroscopic technique was used by Henson M.J., et al. to
analyze the low concentration (0.5 % w/w) of API. The domain sizes
and spatial distribution of API and major excipient are obtained.
Thermal analysis was performed by Pfeiffer S., et al. for the process
of characterization and identification of different crystalline forms
and its thermodynamic relationship.
New perspectives of 19F MAS NMR was used by Jiri B., et al. in the
characterization of amorphous forms of atorvastatins in dosage 26
formulations.

27. FT-Raman spectroscopic technique was used by Skorda D., et al. for
identification and quantitative determination of atorvastatin calcium
polymorph in tablet. FT-Raman spectroscopic method was used by Sylwester
M., et al. for quantitative determination of captopril and prednisolone in
tablets.
FT-IR technique was performed by Andrewchan K.L., et al. for spectroscopic
imaging of a solid dispersion of nifedipine in PEG which is valuable in
optimization in manufacturing of formulations.
Near infrared technique was used by Hua Ma, et al. for characterization of
powder blends. NIR technique was used by Weiyong Li, et al. as qualitative
method for monitoring of nucleation and granule growth in fluid bed wet
granulation. NIR technique was used by Weiyong Li, et al. for determination
of polymorph conversion of an API in wet granulation using NIR calibration 27
models generated fron the premix blends.

28. Different types of solid oral dosage form:-
Capsules
• Hard Gelatine Capsules
• Soft Gelatine Capsules
• Modified-release Capsules
• Enteric Capsules
Tests
• Content of active ingredients.
• Determine the amount of active ingredient(s) by the method
described in the Assay and calculate the amount of active
28
ingredient(s) per tablet.

29. The result lies within the range for the content of active ingredient(s)
stated in the monograph. This range is based on the requirement that
20 tablets, or such other number as maybe indicated in the
monograph, are used in the Assay.
Where 20 tablets cannot be obtained, a smaller number, which must
not be less than 5, may be used, but to allow for sampling errors the
tolerances are widened in accordance with Table 1.
The requirements of Table 1 apply when the stated limits are between
90 and 110 per cent. For limits other than 90 to 110 percent,
proportionately smaller or larger allowances should be made.
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30. Table 1
Weight of active ingredients in Subtract from each lower limit Add to the upper
tablet for samples limit for
of samples of
15 10 5 15 10 5
0.12 g or less 0.2 0.7 1.6 0.3 0.8 1.8
More than 0.12 g but less than 0.2 0.5 1.2 0.3 0.6 1.5
0.3 g
0.3 g or more 0.1 0.2 0.8 0.2 0.4 1.0
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31. Uniformity of content
This test is applicable to tablets that contain 10 mg or less than 10 mg or
less than 10 per cent w/w of active ingredient. For tablets containing
more than
one active ingredient carry out the test for each active ingredient that
corresponds to the aforementioned conditions.
The test is also applicable to coated tablets other than filmcoatedtablets,
irrespective of their content of active substance(s).
The test for Uniformity of content should be carried out only after the
content of active ingredient(s) in a pooled sample of the tablets has been
shown to be within accepted limits of the stated content.
The test for Uniformity of content is not applicable to tablets containing 31
multivitamins and trace elements.

32. Tablets
Film-coated tablets.
Dispersible Tablets
Effervescent Tablets
Modified-release Tablets
Enteric-coated Tablets
Prolonged- release Tablets
Soluble Tablets
Tablets for Use in the Mouth
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33. Test
Uncoated Tablets
 Disintegration
Use water as the liquid. Add a disc to each tube. Operate the apparatus for
15 minutes, unless otherwise stated in the individual monograph.
Examine the state of the tablets.
If the tablets fail to comply because of adherence to the discs, repeat the
test on a further 6 tablets omitting the discs. The tablets comply with the
test if all 6tablets have disintegrated.
The test does not apply to chewable tablets.
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34. Coated Tablets
 Disintegration
 For coated tablets other than film coated tablets.
Use water as the liquid. Add a disc to each tube. Operate the apparatus for
60 minutes, unless otherwise stated in the individual monograph.
Examine the state of the tablets.
If any of the tablets has not disintegrated, repeat the test on a further6
tablets, replacing water with 0.1 M hydrochloric acid. The tablets comply
with the test if all 6 tablets have disintegrated in the acid medium.
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35.  For film-coated tablets.
Carry out the test described above but operate the apparatus for 30
minutes, unless otherwise stated in the individual monograph.
If coated tablets fail to comply because of adherence to the discs, repeat
the test on a further 6 tablets omitting the discs . The tablets comply with
the test if all 6 tablets have disintegrated.
The test does not apply to chewable tablets.
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36. Dispersible Tablets
 Disintegration
Determine at 24º to 26º and operate the apparatus for 3 minutes.
 Uniformity of dispersion.
Place 2 tablets in 100 ml of water and stir gently until completely
dispersed. A smooth dispersion is obtained which passes through a sieve
screen with a nominal mesh aperture of 710 mm (sieve number 22).
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37. Effervescent Tablets
 Disintegration
Place one tablet in a 250-ml beaker containing water at 20º to 30º;
numerous gas bubbles are evolved.
When the evolution of gas around the tablet or its fragments has ceased
the tablet shall have disintegrated, being either dissolved or dispersed in
the water so that no agglomerates of particles remain.
Repeat the operation on a further 5 tablets. The tablets comply with the
test if each of the 6 tablets disintegrates in the manner prescribed within
5minutes, unless otherwise stated in the individual monograph.
37

38. Enteric-coated Tablets
 Disintegration
If the tablet has a soluble external coating, immerse the basket in water at
room temperature for 5 minutes.
Suspend the assembly in the beaker containing 0.1 M hydrochloric acid and
operate without the discs for 120minutes, unless otherwise stated in the
individual monograph.
Remove the assembly from the liquid. No tablet shows signs of cracks that
would allow the escape of the contents of disintegration, apart from
fragments of coating.
Replace the liquid in the beaker with mixed phosphate buffer pH 6.8, add a
disc to each tube and operate the apparatus for a further 60minutes. Remove
38
the assembly from the liquid. The tablets pass the test if all six have
disintegrated.

39. Soluble Tablets
 Disintegration
 Soluble tablets disintegrate within 3 minutes. The test is carried out using
water at 15º to 25º.
39

40. References :-
Ahuja S , Scypinski S , Separation and science
technology A reference series vol-3 Handbook of modern
pharmaceutical analysis, academic press, p.235-252
pharmacopeal dosage forms:Tablets,edited by Herbert A.
Liberman,Leon Lachman and Joseph.B.Schwartz , 2nd
edition,Vol-2,Page No.318 to 337
Indian pharmacopeia – 2007, Volume – 2, page no.633 –
634 and 662-665 .
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