2. INTRODUCTION
• The normal route of administration for most
pharmaceutically active agents is through
the use of solid dosage forms, and these
units are ordinarily produced by the
formulation and processing of powdered
solids.
• The priority of regulatory bodies has always
focused on concerns of safety and efficacy,
which led to emphasis on aspects of
chemical purity.
3. • This situation has changed drastically over
the past decade, with an ever-increasing
degree of attention being given to the
physical properties of the solids that
compromise a dosage form.
• solid-state reactions can affect the stability of
a drug entity, so physical aspects of a
formulation can not be ignored.
4. • sufficient physical information is necessary for
formulator to overcome problems.
• For a well-understood system, it is
theoretically possible to design an automated
or semi automated manufacturing scheme for
which the processing variables are
appropriately controlled and the possibility of
batch failure is, hence, minimized.
• It is presently recognized that to avoid
problems during drug development, the
physical characterization of bulk drugs,
excipients, and blends of them should become
part of the normal process.
5. • Study of polymorphs and solvatomorphs is very
important.
• The nature of the crystal structure adopted by a
given compound upon crystallization exerts a
profound effect on the solid-state properties of that
system, and that these variations can translate into
significant differences in properties is of
pharmaceutical importance.
• It is now accepted that an evaluation of the
polymorphism available to a drug substance must
be thoroughly investigated early during the stages
of development.
6. • The results of these studies must be included in
the chemistry, manufacturing, and control section
of a new drug application, and such information is
required to demonstrate control over the
manufacturing process.
• Therefore a systematic approach to the physical
characterization of pharmaceutical solids has
been outlined and serves as a useful device for
the classification of the many methods of physical
characterization.
7. • Based on this system, physical
properties are classified as being
associated with
• The molecular level (those associated with
individual molecules),
• The particulate level (those pertaining to
individual solid particles),
• The bulk level (those associated with an
assembly of particulate species).
8. • I. PROPERTIES ASSOCIATED WITH THE
MOLECULAR LEVEL
• A. Ultraviolet/Visible Diffuse Reflectance Spectroscopy
• B. Vibrational Spectroscopy
• C. Nuclear Magnetic Resonance Spectrometry
• II. PROPERTIES ASSOCIATED WITH THE
PARTICULATE LEVEL
• A. Microscopy
• B. X-Ray Diffraction
• C. Thermal Methods of Analysis
• III. PROPERTIES ASSOCIATED WITH THE
BULK LEVEL
• A. Particle Size Distribution
• B. Micromeritics
• C. Powder Characterization.
9. PROPERTIES ASSOCIATED
WITH THE MOLECULAR LEVEL
• A. Ultraviolet/Visible Diffuse
Reflectance Spectroscopy
• B. Vibrational Spectroscopy
• C. Nuclear Magnetic Resonance
Spectrometry
10. A. Ultraviolet/Visible Diffuse
Reflectance Spectroscopy
• Most solids are too opaque to permit the conventional
use of ultraviolet/visible (UV/VIS) electronic
spectroscopy.
• As a result, such work must be performed using diffuse
reflection techniques.
• Ultraviolet/Visible Diffuse Reflectance Spectroscopy is
applied to
• -- study the reaction pathways of various solid-state
reactions.
• --The fields of colour measurement and colour matching,
areas that can be of considerable importance when
applied to the coloring agents used in formulations.
11. • It is very useful tool for the study of
interactions among various formulation
components, and the technique has been
successfully used in the characterization of
many solid-state reactions.
• Investigations conducted under appropriately
designed stress conditions have been useful in
the study of drug-excipient interactions, drug
degradation pathways, and alterations in
bioavailability .
12. • EX: diffuse reflectance spectroscopy is used to
study the adsorption of spiropyrans onto
pharmaceutically relevant solids.
• The particular adsorbents studied were
interesting in that the spectral characteristics of
the binary system depended strongly on the
amount of material bound.
• At low concentrations, the pyran sorbent
exhibited its main absorption band around 550
nm.
• As adsorption increased, the 550-nm band was
still observed, but a much more intense
absorption band at 470 nm became prominent.
13. • This secondary effect was attributed to the
presence of pyran–pyran interactions, which
became more important as the concentration
of sorbent increased.
14. B. Vibrational Spectroscopy
• Mid-infrared electromagnetic radiation is 400–
4000 cm−1 utilized for analysis based on
fundamental vibrational modes of a chemical
compound.
• Fourier-transform infrared spectroscopy (FTIR)
is now the method of choice.
• Vibrational transitions also can be observed
using Raman spectroscopy.
• Overtones and combination bands of vibrational
modes are observed in the near-infrared region
of the spectrum (4000–13,350 cm−1).
15. • This all techniques are utilized for the physical
characterization of pharmaceutical solids.
• When the structural characteristics of a solid affects
the pattern of vibrational motion for a given
molecule, these alterations can be used as a
means to study the solid-state chemistry of the
system.
• FTIR spectra often are used to evaluate :
--the type of polymorphism that exists in a drug
substance and
--can be very useful to study the water contained
within hydrate species.
16. • Solid-state IR absorption spectra often are
obtained on powdered solids through the
combined use of FTIR and diffuse reflectance
detection, and interpreted through conventional
group frequency compilations.
• For example, glisentide has been obtained in a
number of polymorphic and solvatomorphic
forms, with the anhydrous forms I and II
exhibiting large differences in infrared spectra.
• The IR spectra of forms I and II are shown in
Figure 1.
17. FIGURE 1 Infrared absorption spectra of glisentide:
upper trace, form I; lower trace, form II.
18. • It can be noted that two bands assigned to
the urea carbonyl group are found at 1635
and 1545 cm−1 in form I and at 1620 and
1545 cm−1 in form II. In addition, the
shoulder that is present in both forms is more
intense in the spectrum of form II.
• The S O stretching band is observed at 1157
cm−1 in the spectrum of form I, but for form II
it shifts to 1165 cm−1.
• The aromatic carbonyl group at 1720 cm−1 is
present in both spectra, but is broadened in
the case of form II.
19. • Another technique of vibrational
spectroscopy that is ideally suited for
characterization of solids is Raman
spectroscopy. In this methodology, the
sample is irradiated with monochromatic
laser radiation, and the inelastic scattering
of the source energy is used to obtain a
vibrational spectrum of the analyte.
20. • The Raman spectrum generally resembles the
spectrum obtained using the FTIR method.
• Differences in peak intensity are often observed.
(Owing to the fundamentally different selection
rules associated with the phenomenon)
• In general, symmetric vibrations and non- polar
groups yield the most intense Raman scattering
bands. whereas antisymmetric vibrations and
polar groups yield the most intense infrared
absorption bands.
21. EX.
• Raman spectroscopy was used to study
the effect of pressure and temperature on
the phase composition of fluoranil crystals.
• Figure 2 shows the Raman spectra
obtained at a series of increasing
pressures, where the changes in band
frequency indicate the existence of
pressure-induced phase transitions.
22. FIGURE 2 Raman spectra obtained at 300 K for crystalline
fluoranil at pressures of (a) 1 atm,
(b) 0.5 GPa, (c) 1.4 GPa, and (d) 2.4 GPa.
23. • It was deduced from sharp discontinuities
in the Raman spectra that a phase
transition took place at a temperature of
around 180 K if the pressure was 1 atm.
• This transition shifted to 300 K if the
pressure was increased to 0.8 GPa.
24. • Near-IR spectra consist of overtone transitions of
fundamental vibrational modes and are not,
therefore, generally useful for identity purposes
without the use of multicomponent analysis.
• But it is utilized in solid state analysis of the
compounds that contain unique hydrogen atoms.
• For example, studies of water in solids can be
easily performed through systematic
characterization of the characteristic OH band,
usually observed around 5170 cm−1.
• The determination of hydrate species in an
anhydrous matrix can be performed easily using
near-IR analysis.
25. • The near-IR technique has been used very
successfully for moisture determination,
whole tablet assay, and blending validation.
• It is possible to use the overtone and
combination bands of water to develop near-
IR methods that have accuracy equivalent to
that obtained using Karl–Fischer titration.
26. C. Nuclear Magnetic Resonance
Spectrometry
• The ultimate molecular level characterization of
a pharmaceutical material is performed on the
level of individual chemical environments of
each atom in the compound, and this
information is best obtained by NMR
spectroscopy.
• Advances in instrumentation and computer
pulse sequences currently allow these studies to
27. • Solid-state NMR spectra is used to deduce
nature of polymorphic variations,
especially when polymorphism is
conformational in nature.
e.g. during development of Fosinopril
sodium, a crystal structure was solved for
most stable phase, but no such structure
could be obtained for its metastable
phase.
28. • NMR data suggest that additional
conformational between the two
polymorphs were associated with cis-trans
isomerization along the peptide bond,
which intern results in the presence of non
equivalent molecules existing in the unit
cell.
29. Why solid NMR spectrum is so different
from liquid NMR?
• There are 3 major factors:
1) dipolar broadening :
The presence of a group of spins around a
given spin may result in a number of
interactions. The most important interaction
between the spin and its surrounding spins is
the dipolar interaction. It could be
homonuclear or heteronuclear dipolar
coupling. It is the dominant broadening factor
in organic solids.
30. For the case of two spins, I and S , the
approximate dipolar Hamiltonian can be
written as:
Hd = ½ ϒHϒCh2 (1-3cos2θ)(3IzSz-I×S)
rHC
in liquid, all possible values of θ exist due to
reorientational motion. The average value of
cos2 θ is 1/3, 1[1] and the dipolar coupling
averages to zero. In a crystal powder or
amorphous solid, all orientations occur, cos2
θ does not average to zero, there is a non
31. • -zero dipolar coupling, produce a broad line.
This broadening may be of the order of 20
kHz.
2) Chemical Shift Anisotropy (CSA)
• This broadening factor arises from
asymmetry in the electron density
surrounding a given nucleus. In liquids an
average chemical shift is observed due to
averaging over all orientations on a timescale
short in comparison with the NMR
measurement time.
32. • In solid, a complex line shape result from a
sum of all possible chemical shifts.
• The chemical shift anisotropy is again related
to the term (3cos2θ-1). This term could be zero
when the angle q is equal to 54044’. It is called
magic angle.
• In practical circumstances, high resolution solid
state NMR spectra can be obtained using a
combination of dipolar decoupling and magic
angle spinning (MAS).
33. • The dipolar decoupling is similar to that
observed in liquid NMR. When acquiring a
13C spectrum, proton decoupling is needed
to decouple the proton attached to the
carbon, since all other protons dipolar
coupling are averaged by molecule self
orientation.
• In the solid ,high power decoupling is
necessary because of abundance of NMR
active nuclei nearby, and could not average
the interaction to zero.
34. • This is one of the reasons to use MgO to
dilute the organic solids sample to avoid
homonuclear dipolar coupling. The effect
of , MAS is to remove chemical shift
anisotropy and dipolar coupling . However
, in order to suppress dipolar couplings,
the spinning speed should fast than the
strength of coupling in Hz.
35. 3) Spin-spin Relaxation and Spin
Lattice Relaxation
• The solids ,spin – spin relaxation time T2 is
very short due to restricted motion. Under
ideal conditions, the residual line width
following decoupling and MAS will be
determined by the magnitude of T2. the
inherent line width is therefore much broad
than that found in liquid state NMR, in tens
of Hz is normal .
36. • In solid, spin lattice relaxation is very inefficient
and T1 is very long, in tens of seconds, due to
the restricted motion. A long pulse delay is
required to re-establish thermal equilibrium.
This could be over come by using cross
polarization technique.
• To observe rare spins 13Cin solids, there are
no significant homonuclear couplings since they
are far away from each other in the sample .on
the other hand, the hetronuclear coupling
between the rare spins(13C) and abundant
spins(1H) are dominant.
37. • By using abundant spins to enhance the
rare spin signals under appropriate
condition is known as polarization transfer
or cross-polarization.
• In liquids, the polarization transfer was
originally achieved by experiment INEPT. In
solids , the polarization transfer could be
achieved by spin lock under Hartmann-
Hahn condition.
38. Properties Associated With Particulate
Level:-
• Particulate properties are defined as those
material characteristics that effectively can
be determined by the analysis of a
relatively small ensemble of particles.
I. Microscopy
i. X-Ray diffraction
ii. Thermal mode of analysis
39. i. Microscopy :-
Estimation of the particle size distribution in a
powdered sample is obtained by microscopy
method . The relative crystallinity of the
material readily determined by this method .
The micromeritic and bulk powder property of
the material is highly influenced by the
evaluation of the morphology of
pharmaceutical solids.
There are mainly two types of microscopy ;
1) Optical microscopy
2) Electron microscopy
40. Magnificent limit for Optical Microscopy for
routine work is 600x,whereas electron
microscopy can be performed at
extraordinarily high magnification levels up to
90,000X on most units and the images
contain three-dimensional information.
41. B)X-Ray Diffraction
• The fundamental structural information on
crystalline substances obtained by the
technique of X-ray diffraction.
• Bragg explained the diffraction of x-rays by
crystals using a model where the atoms of a
crystal are regularly arranged in space and
where they can be regarded as lying in
parallel sheets separated by a definite and
defined distance.
42. • Application
1) Determination of crystal structures
2) Evaluation of polymorphism
3) Solvate Structures
4) Evaluation of degrees of crystallinity
43. (c) Thermal Methods of Analysis
• This analytical method is used to
characterize compound purity,
polymorphism, salvation, degradation
and excipient compatibility
• By the thermal analytical method
endothermic processes (melting, boiling,
sublimation, vaporization, desolvation,
solid-solid phase transitions and chemical
degradation) as well as exothermic
44. • Processes (crystallization and oxidative
decomposition) can be evaluated.
• These are the techniques used to
determine a property of the analyte as a
function of an externally applied
temperature. The property of analyte is
evaluated on a continuous basis as a
function of temperature.
• The major advantage of this method is it is
extremely useful during the conduct of
preformulation studies, because carefully
45. • planned studies can be used to indicate
the existence of possible drug-excipient
interactions in a prototype formulation.
46. Differential Thermal Analysis(DTA)
• This technique of thermal analysis is
having an excellent qualitative advantage
that is useful to deduce the temperature
ranges associated with a variety of thermal
events, as well as to assign the
endothermic or exothermic nature of these
reactions.
• DTA represents an improvement to the
melting point determination in that the
47. • Different temperature between the sample
and a reference is monitored as a function
of temperature.
• However, differences in temperature
between the sample and reference are
manifested when changes occur that
require a finite heat of reaction.
• When the heat capacities of the two that is
sample and reference roughly equivalent
the temperature of the sample and the
reference will be same due to the no
theremal transitions take place
48. • If for the transition is positive (endothermic
reaction) the temperature of the sample
will lag behind that of the reference
(because more heat will be absorbed by
the sample than by the reference) and this
event will be recorded in the thermogram
as a negative-going peak.
• If the H is negative (exothermic reaction) ,
the temperature of the sample will exceed
that of the reference (because the sample
itself will be a source of additional heat )
and the event will be recorded in
thermogram as a positive going peak.
49. Differential scanning Calorimetry (DSC)
• An improvement to DTA analysis is
Differential scanning Calorimeter (DSC)
and has become one of the most widely
used methods of thermal analysis.
• DSC method involves the measurement of
the heat flow required to maintain the
equality in temperature between the
sample and the reference when they kept
at same temperature.
50. • By placing separate heating elements in
the sample and the reference cell, the
equality can be achieved. The rate of
heating by these elements is controlled
and measured.
• This method of measurement is termed
power-compensation DSC, and it yields
positive-going peaks for endothermic
transitions and negative going peaks for
exothermic transitions.
51. Lactos monohydrate (Fig:b)
• The thermal transitions can be seen in the DSC
curves. The curve for anhydrous lactose (fig. a)
shows an endothermic melting peak at about 235 C
• The lactose monohydrate (fig. b) dehydrates around
150 C ; the resulting anthydrous lactose melts at
about 220 C
• The small exothermic peak at 180 C can be
attributed to the recystallisation of some of the
anhydrous lactose into mixed crystal the thermal
effects after the melting peak of lactose are the
result of melting of the mixed crystal and of
decomposition of the liquefied lactose.
52. Thermogravimetry (TG)
• The thermally induced weight loss of a
material is measured as a function of the
applied temperature” is the main principle
behind the thermogravimety (TG) of
thermoanalytical technique.
• The quantitative determination of the total
volatile contents of a solid is the major use
of TG analysis. The magnitude of each
step can be separately evaluated, when a
solid decompose by means of several
discrete, sequential reactions.
53. • It is most commonly used to study desolvation
Processes and compound decomposition
because this method is restricted to studies that
involve either a mass gain or loss (usually loss).
• The stability of similar compounds can be
compare by TG analysis of compound
decomposition. The higher the decomposition
temperature of given compound, the more
negative is the G vaiue and therefore the
greater is the stability.
54. For E.g Degradation pattern of
CuSO4. 5H2O
• CuSO4. 5H2O -- CuSO4. H2O (90 to150
C)
• CuSO4. H2O --- CuSO4 (200 to 274 C)
• CuSO4 ------CuS +SO2 ½ O2 (700 to 900
C)
• 2CuO -- Cu2O + ½ O2 (1000 to 1100 C)
55. PROPERTIES ASSOCIATE WITH BULK
LEVEL
• Bulk properties are those characteristics of
a solid that can be measured only for large
ensemble particles.
• In latter stages of drug development the
physical characteristic compatibility of drug
with other formulation ingredients is in
important.
• Excipients show physical effects like
enhancing powder compaction promoting
dissolution, modifying drug release rate and
improve powder flowabillty
56. • This evaluation requires program for
physical characterization of excipients
especially w.r.t properties related to their
use and functionaliy.
57. Particle size Distribution
• Particle size distribution of API and
excipients exerts profound effect on mixing
and possible segregation and hence affect
bioavailability and powder flowability.
• In absence of electrostatic effects, it is
easy to produce homogenously mixed
powders if the individual components to be
mixed are of equivalent particle size.
58. • All pharmaceutical dosage forms must be
uniform and good content uniformity is
possible only when particle size of API is
carefully controlled.
• Variety of methods are available for this
determination
• Optical microscopy (usually combined with
image analysis )
• Sieve analysis
• Laser light scattering of suspended
particles
• Electrical zone sensing
59. • When proper sampling techniques are
use, most absolute method used is
Microscopy which becomes most efficient
when combined with some form of image
analysis
• In automated method, microscope
parameters are adjusted to optimize
contrast between background and
particles to be sized video image of
powder is transmitted to a computer
system which counts the number of pixels
that make up a particle.
60. • The size of each pixel is easily converted
to um and data are analyzed as desired-
Average particle size, Full weight
distribution or Shape information, etc.
61. Advantages of optical Microscopy :-
• Provides direct and absolute information
on the particles under study.
• Sieve analysis is simplest and widely used
method.
• Here the particles are allowed to distribute
among a series of sieves (typically wire
mesh) and the amount of material retained
on each sieve is determined.
62. • FINES– Smaller particles that passes
through sieve
• COARSE particles– Larger particles that
remains on sieve
• MEDIUM fractions – when multiple sieves
are used the intermediate sized particles
that passes through one or more sieve
but retained on subsequent sieve.
• Facilitation method like vibration
ultrasound or air suspension are used to
assist the passage of particles through
various
63. • A proper size detemination required use of
5-6 sieves whose sizes are selected to
obtain approx. equal amount of powder on
each sieves and past the smallest sieve.
• % material retained on each sieve.
Cumulative% of sample retained and %
sample passing each sieve are obtained.
• Electrical zone sensing (is based on the
coulter principle ) use measurement of
electrical pulses caused by passage of
particles through a sensing zone to get
size information.
64. Micromeritics :-
• For powders, micromeritics is related to
the nature of the surfaces that make up
the solid.
• Of all the properties that could be
measured
Surface area
Porosity and
Density are most revelant pharmaceutical
parameters.
65. • SURFACE AREA – Provides information on
the available void spaces on surface of a
powdered solid and Dissolution rate is also
partially determined.
• Most reproducible measurements of the
surface area of solids are obtained by
adsorbing a monolayer of inert gas onto the
solid surface at reduced temperature and
subsequently desorbing this gas at room
temperature. The sorption isotherms are them
interpreted using equations of BET method.
66. • Unit- square meters of surface per gram of
material
• POROSITY – mercury intrusion porosimetry
is the most widely used method to detemine
pore size distribution of a porous Materials
and void size of tablets and compacts. This
method is based on capillary rise
phenomena where excess pressure is
required to force a nonwetting liquid into a
narrow volume.
67. • Mercury with contact angle of approx. 140
with glass is commonly used as an intrusion
fluid it is forced into the pores of a sample
using as an intrusion fluid. It is forced into the
pores of a sample using an externally applied
pressure where the smallest pores require
highest pressure to effect filling.
• DENSITY- is ratio of mass to volume 3 types
of density which differ in their determination
of volume occupied by the powder are
normally differentiated.
68. • Bulk density is obtained by measuring the
volume of known mass of powder sample
(that has been passed through a mesh
screen ) into a suitable volume measuring
apparatus like graduated cylinder. The
bulk density is then obtained by dividing
the mass of solid by the unsettled
apparent volume.
• Tapped density is obtained by measuring
the volume of solid after subjecting the
system to a number of controlled shocks.
Into a smaller volume. So tapped density
is always higher than bulk density.
69. • True density is an intrinsic property of the
analyte and is determined by composition
of the unit cell. It is average mass per unit
volume, exclusive of all voids that are not
a fundamental part of the molecular
packing arrangement.
• It is measured by Helium pycnometry,
where the volume occupied by a know
mass of powder is determined by
measuring the volume of gas disolaced by
the powder.
70. Powder Characterization
• Flowability of powder is important
parameter for formulators because the
materials need to be moved from place to
place.
• E.g. For tablets compressed at high speed
the efficiency of machine is suitable only it
powder feed delievered at high rate.
• Many pharmaceutical compounds with
cohesive nature have undersirable flow
properties.
71. • One of the alms of granulation is to reduce
this cohesiveness to produce uniform
blend with more suitable physical
properties.
• Powder flowability is evaluated using
• Angle of repose (angle formed when a
cone of powder is poured onto a flat
surface)
• Angle of spatula ( angle formed when
material is raised on a flat surface out of a
bulk pile)
72. • Compressibility (obtained from
measurement of the bulk and tapped
densities)
• Cohesion (attractive forces that exist on
particle surfaces )
73. IMPURITIES AND DEGRADATION
PROFILE
• What is Impurities ???
– Impurities in pharmaceuticals are the unwanted
chemicals that remain with API or develop during
formulation or upon aging.
– The presence of these unwanted chemicals even
in small amounts may influence the efficiency
and safety of the products.
73
74. Source of Impurities in Formulation
Impurities associated with Impurities created during formulation &
API aging or related to formulation forms
Organic Inorganic Residual Process Environmental Dosage Form Functional
Impurities Impuritie Solvents Related Related factor related Group
s related
74
75. Impurities Associated with API
Organic Impurities
(Process / Degradation Product)
Starting By products Reagents, Degradation
Material Ligands, Catalyst Product
e.g.
e.g. 4- Diacetylated Mandelic acid in e.g. Hydroxy
aminophenol Paracetamol as Esomeprazole acid in
in by product in Mag. Simvastatin,
Paracetamol, manufacturing Impurity D in
Loratadine in of Paracetamol Amlodipine
Desloratadine Besylate
75
76. DEGRADATION
• Solid state drug degradation occurs in a
solution phase (in solvent layers
associated with the solid phase ) source of
solvent for such decomposition reaction
may be :-
• A) A melt from the drug it self or an
ingredient in the formulation with low
melting point
• B) Residual moisture or solvent from wet
granulation.
77. • C) Moisture adsorbed onto excipients such
as starch, lactose, or microcrystalline
cellulose.
• D) Adsorbed atmospheric moisture or
• E) Solvate or hydrate that losses its
“bound” Solvent with time or temperature
fluctuation.
78. Chemical decomposition of drugs in
solid state can be divided into 4
categories :-
(1) solvolysis /Hydrolysis :-
• It is most important reaction for solid state
drug degrade on occuring mainly in
compounds containing acy group
involving decomposition of drug by
reaction with solvent like Hydrolysis (with
water as solvent) or other like
decarboxylation, etc.
79. • Solvent acts as nucleophile attacking the
electropositive center in drug molecules.
E.g. NSAIDs, Barbiturates Vitamins, etc.
80. Protection against Hydrolysis
• Hydrolysis occurs in presence of moisture
H+ or OH so protection steps from this
reaction mainly involves their elimination
from the drug system like-
• (a) Buffer :- it stabilizes the drug. Ph of
solution is adjusted to give maximum drug
stability and therapeutic activity.
• (b) Complexation :- Hydrolysis of
Benzocaine in aq solution is inhibited by
addition of caffeine which forms a complex
with it
81. • (c ) suppression of solubility :- as drug
solubility decreases. The conc of drug in
solution phase also decreases so rate of
hydrolysis is reduced.
• (d) Removal of water :- as water is
responsible for hydrolysis its contacts
with the drug is avoided in the preparation
by
• Storing drug in dry form E.g. streptomycin
dry powder injection.
• Using water immiscible vehicle for drug
dispersion E.g. Aspirin in silicone fluid.
82. Oxidation
• It involves interaction of a chemical with
oxygen mostly in a solvent although there
are examples where oxygen may be able
to oxidize drug in absence of a solvent.
• Oxidation means removal of electrons,
electropositive atom or radical or addition
of oxygen or removal of hydrogen
• 2 main types are :-
83. • Proceed slowly under influence of
atmospherice oxygen
• Reversible loss of electrons without
addition of Oxygen E.g. Adrenaline
Riboflavin
• In Pharmaceutical dosage forms, oxidation
is usually AUTOOXIDATION (mediated by
reaction with atmospheric oxygen under
ambient condition ) E.g. Autooxidation of
unsaturated fatty acids in fats and oils.
84. • E.g. Promethazine, Vitamin A Riboflavin
Morphine, etc.
• System can be protected against oxidation
by following ways :-
• (a) Antioxidants : - they or prevent the
oxidation process. E.g. Tocopehrol,
Butylated Hydroxyl Anisole (BHA) ,
Butylated Hydroxyl Toluene (BHT), propyl
gallate, etc,
• (b) Adjustment of Ph :- Potential (E) is
influenced by PH of system . Decrease in
Ph caused rise in E and hence increases
resistance to oxidation.
85. • (c ) Micellar Solubilization :- Surfactans
such as polysorbate enhances the rate of
oxidation ascorbic acid at low conc but
protects above its critical micelle conc
(CMC) by entrapping the drug in spherical
micelle.
86. Photolysis
• Photolysis of drugs like phenothiazine and
vitamin A need Presence of solvent but
sometimes such solvent-dependant
reaction may not be needed.
• Light may cause substantial degradation
of drug molecule by absorbing energy of
particular wavelenght.
• Photochemical reaction – Molecules
absorbing light takes part in photolysis and
photosensitization –absorbing molecules
don’t participate in photolysis.
87. • Photons of shorter wavelength have more
energy so uv visible light can cause
phctolysis.
• E.g. Photodegradation of sodium
Nitroprusside in aq solution
• Photo toxicity caused by drug is common
Problem the Primary reaction for initiating
this toxicity is generation of singlent-state
excited oxygen.
• Prevention-store in dark or enclose it in an
opaque wrapper or in light resistance
containers which donot transmit more than
15 % of incident radiation between 290-
88. Pyrolysis
• It is thermally induced bond rupture
occuring in absence of solvent. It is
normally not an important mechanism
except when the drug is exposed in
processing to a very high temp.
• E.g. P-aminosalicylic acid degradation at
70-80 c range in the absence of molsture
show a significant pyrolysis.
89. REFERENCES
• 1) Ahuj Satinder, scypinki stephen.
Handbook of modem Pharmaceutical
analysis 3rd ed. Academic press
• 2) Zornoza A, de No. C., Goni M.M.
Martinez Oharriz M.C., and Velaz I lnt J.
pharm. 186. 199. 1999.
• 3)
http:/www.emory.edu/NMR/Hall/solid/index
.htm
• 4) http:/www.bionmr-
c1.unl.edu/921/Lectures/chapter11-solid-
