The Analytical Methods for Characterization of Solid Forms some of the Methods like DSC PXRD and TGA

1. Pre-formulation Studies
By
Vishesh Rodrigues
1st Year M.Pharm
Pharmaceutics

2. Definition
“Pre-formulation testing is the first step in
the rational development of dosage forms.
It can be defined as an investigation of
physical and chemical property of a drug
substance alone and when combined with
excipients”

3. Analytical Methods for Characterization
of Solid Forms
Microscopy
Differential Scanning Calorimetry (DSC)
Powdered X-Ray Diffraction (PXRD)
Thermo gravimetric Analysis (TGA)

4. Microscopy
Microscopy is the technical field of
using microscopes to view samples and objects that
can not be seen with the unaided eye (objects that
are not within the resolution range of the normal
eye). There are three well-known branches of
microscopy: optical, electron, and scanning probe
microscopy

5. Optical Microscopy
• The optical microscope, often referred to as the
"light microscope", is a type of microscope which
uses visible light and a system of lenses to magnify
images of small samples. Optical microscopes are the
oldest design of microscope and were possibly
invented in their present compound form in the 17th
century. Basic optical microscopes can be very
simple, although there are many complex designs
which aim to improve resolution and
sample contrast.

6. Electron Microscope
• An electron microscope is a microscope that uses
accelerated electrons as a source of illumination.
Because the wavelength of an electron can be up to
100,000 times shorter than that of visible
light photons, the electron microscope has a
higher resolving power than alight microscope and
can reveal the structure of smaller objects.

7. Scanning Electron Microscopy
• Scanning electron microscope (SEM) is a type
of electron microscope that produces images of a
sample by scanning it with a focused beam
of electrons. The electrons interact with atoms in the
sample, producing various signals that can be
detected and that contain information about the
sample's surface topography and composition.

8. SEM Equipment

9. Procedure
• In a typical SEM, an electron beam
is thermionically emitted from an electron
gun fitted with a tungsten filament cathode.
• The beam passes through pairs of scanning
coils or pairs of deflector plates in the electron
column, typically in the final lens, which
deflect the beam in the x and y axes so that it
scans in araster fashion over a rectangular
area of the sample surface.

10. • When the primary electron beam interacts
with the sample, the electrons lose energy by
repeated random scattering .
• The energy exchange between the electron
beam and the sample results in the reflection
of high-energy electrons by elastic scattering,
emission of secondary electrons by inelastic
scattering and the emission
of electromagnetic radiation, each of which
can be detected by specialized detectors.

11. Example
Capsule Containing Amoxicillan Drug at
6,000x Magnification.

13. Differential Scanning Calorimetry (DSC)
• The technique was developed by E.S. Watson and M.J.
O'Neill in 1960, and introduced commercially at the
Pittsburgh Conference on Analytical Chemistry and
Applied Spectroscopy in 1963.
• This technique is used to study what happens to
samples upon heating.
• It is used to study thermal transitions of a sample (the
changes that take place on heating).

14. Principle
• The sample and reference are maintained at the
same temperature, even during a thermal event in
the sample.
• The energy required to maintain zero temperature
difference between the sample and the reference is
measured.
• During a thermal event in the sample, the system will
transfer heat to or fro from the sample pan to
maintain the same temperature in reference and
sample pans.

15. Diagram representing DSC equipment

16. • Depending on the type of change within the
sample, the thermal event may be endothermic or
exothermic
• Endothermic – consume energy
• Exothermic – release energy to the surrounding

17. Procedure
• There are two pans, In sample pan, sample is
added, while the other, reference pan is left empty.
• Each pan sits on top of heaters which are
controlled by a computer
• The computer turns on heaters, and let them heat
the two pans at a specific rate, usually 10oC/min
• The computer makes absolutely sure that the heating
rate stays exactly the same throughout the experiment.

18. • The reason is that the two pans are different. One
has sample in it, and one doesn't. The sample
means there is extra material in the sample pan.
Having extra material means that it will take more
heat to keep the temperature of the sample pan
increasing at the same rate as the reference pan.
• So the heater underneath the sample pan has to
work harder than the heater underneath the
reference pan. It has to put out more heat. How
much more heat it has to put out is what measured
in DSC experiment.

19. • Specifically, a plot is drawn as the temperature
increases. The temperature is taken on x-axis
whist the difference in heat output of the two
heaters at a given temperature on y-axis

20. Differential Scanning Calorimetry
Curve
• The result of a DSC experiment is a curve of heat flux versus
temperature or versus time. There are two different
conventions: exothermic reactions in the sample shown with
a positive or negative peak, depending on the kind of
technology used in the experiment.
• This curve can be used to calculate enthalpies of transitions,
which is done by integrating the peak corresponding to a
given transition. The enthalpy of transition can be expressed
using equation: ΔH = KA
• Where ΔH is the enthalpy of transition,
• K is the calorimetric constant,
• A is the area under the peak

21. Application Of Differential Scanning
Calorimetry
• Glass transitions
• Melting and boiling points
• Crystallizations time and temperature
• Percent crystallinity
• Heats of fusion and reactions
• Specific heat capacity
• Oxidative/thermal stability
• Reaction kinetics
• Purity

22. • Example

23. Powdered X-Ray Diffraction
• X-ray powder diffraction (XRD) is a rapid analytical
technique primarily used for phase identification of a
crystalline material and can provide information on
unit cell dimensions.
• In other methods a single crystal is required whose
size is much larger than microscopic dimensions.
However, in the powder method as little as 1 mg of
the material is sufficient for the study.
• The analyzed material is finely ground, homogenized,
and average bulk composition is determined.

24. Principle
• X-ray diffraction is based on constructive
interference of monochromatic X-rays and a
crystalline sample.
• These X-rays are generated by a cathode ray tube,
filtered to produce monochromatic radiation,
collimated to concentrate, and directed toward
the sample.
• For every set of crystal planes , one or more
crystals will be in the correct orientation to give
the correct Bragg angle to satisfy Bragg's
equation.

25. • The powdered sample generates the concentric cones
of diffracted X-rays because of the random orientation
of crystallites in the sample.
• The powder diffracts the x-rays in accordance with
Bragg’s law to produce cones of diffracted beams.
These cones intersect a strip of photographic film
located in the cylindrical camera to produce a
characteristic set of arcs on the film.
• When the film is removed from the camera, flattened
and processed, it shows the diffraction lines and the
holes for the incident and transmitted beams.
• The x-ray pattern of a pure crystalline substance can
be considered as a “fingerprint” with each crystalline
material having, within limits, a unique diffraction
pattern.

26. Procedure and Equipment

27. • The experimental arrangement of powder crystal
method is shown in figure above its main feature are
outlined as below:
• A is a source of X-rays which can be made
monochromatic by a filter
• The X-ray beam to falls on the powdered specimen P
through the slits S1 and S2. The function of these slits
is to get a narrow pencil of X-rays.
• Fine powder, P, struck on a hair by means of gum is
suspended vertically in the axis of a cylindrical camera.
This enables sharp lines to be obtained on the
photographic film which is surrounding the powder
crystal in the form of a circular arc.

28. • The X-rays after falling on the powder passes out
of the camera through a cut in the film so as to
minimize the fogging produced by the scattering
of the direct beam.
• As the sample and detector are rotated, the
intensity of the reflected X-rays is recorded.
• When the geometry of the incident X-rays
impinging the sample satisfies the Bragg
Equation, constructive interference occurs and a
peak in intensity occurs.
• A detector records and processes this X-ray signal
and converts the signal to a count rate which is
then output to a device such as a printer or
computer monitor.

29. Advantages
• Powerful and rapid (< 20 min) technique for
identification of an unknown mineral.
• In most cases, it provides a clear structural
determination.
• XRD units are widely available.
• Data interpretation is relatively straight
forward .

30. Disadvantages
• Homogeneous and single phase material is
best for identification of an unknown.
• Requires tenths of a gram of material which
must be ground into a powder.
• For mixed materials, detection limit is ~ 2%
of sample.
• For unit cell determinations, indexing of
patterns for non-isometric crystal systems is
complicated .

31. Example
• Figure : An experimental PXRD pattern of an
inclusion compound containing a steroidal drug.

32. Thermal Gravimetric Analysis (TGA)
• Thermogravimetric analysis or thermal
gravimetric analysis (TGA) is a method of thermal
analysis in which changes in physical and
chemical properties of materials are measured as
a function of increasing temperature (with
constant heating rate), or as a function of time
(with constant temperature and/or constant mass
loss).1 TGA can provide information about
physical phenomena, such as second-order phase
transitions,
including vaporization, sublimation, absorption, a
dsorption, and desorption.
1-Coats, A. W.; Redfern, J. P. (1963). "Thermogravimetric Analysis: A Review". Analyst 88: 906–924

33. • Likewise, TGA can provide information about
chemical phenomena
including chemisorptions, desolvation (especia
lly dehydration), decomposition, and solid-gas
reactions (e.g., oxidation or reduction)
• TGA is commonly used to determine selected
characteristics of materials that exhibit either
mass loss or gain due to decomposition,
oxidation, or loss of volatiles (such as
moisture).

34. Principle
• Thermogravimetry is a technique that
measures the variation of mass of a sample
when the latter is subjected to a temperature
program in a controlled atmosphere. This
variation of mass can be a loss (vapour
emission) or a gain (fixing of gases)

35. Procedure
• The TGA instrument continuously weighs a sample as it
is heated to temperatures of up to 2000 °C for coupling
with FTIR and Mass spectrometry gas analysis.
• As the temperature increases, various components of
the sample are decomposed and the weight
percentage of each resulting mass change can be
measured. Results are plotted with temperature on the
X-axis and mass loss on the Y-axis.
• The data can be adjusted using curve smoothing and
first derivatives are often also plotted to determine
points of inflection for more in-depth interpretations .

36. • TGA instruments can be temperature calibrated with
melting point standards or Curie point of ferromagnetic
materials such as Fe or Ni. A ferromagnetic material is
placed in the sample pan which is placed in a magnetic
field.
• The standard is heated and at the Curie point the
material becomes paramagnetic which nullifies the
apparent weight change effect of the magnetic field.

37. Application
• Purity and thermal stability.
• Solid state reaction.
• Decomposition of organic and inorganic compound.
• Determining composition of material.
• Corrosion of metals in various atmosphere.
• Roasting and calcination of minerals.
• Evaluation of gravimetric precipitates.
• Oxidative and Reductive stability.

38. Refrences
•
• http://serc.carleton.edu/research_education/geo
chemsheets/techniques/XRD.html
• http://pubs.usgs.gov/info/diffraction/html/
• Instrumental methods of chemical analysis by
G.R.Chatwal & Sham.K.Anand … Page No. 2.324-
2.326
• Instrumental methods of chemical analysis by B.
K Sharma… Page No.S-494-536
• Practical Pharmaceutical Chemistry Beckett and
Stenlake… Page No. 78-81

39. • Encyclopedia of Pharmaceutical Technology by
James Swarbrick 3rd Edition Volume I
• Martin’s Physical Pharmacy and
Pharmaceutical Sciences By Patrick J Sinko 6th
Edition
• Text book of Remington’s Pharmaceutical
sciences Vol. I &II by Paul Beringer,
AraDerMarderosian and other members of
the editorial board 21st Edition