PREFORMULATION
Definition:
Preformulation may be described as a phase of the research and
development process where the preformulation scientist characterizes the
physical, chemical and mechanical properties of a new drug substance, in order
to develop stable, safe and effective dosage form.
Objectives:
The preformulation investigations confirm that there are no
significant barriers to the compound’s development as a marketed drug. The
formulation scientist uses these informations to develop dosage forms.
Preformulation is a multidisciplinary development of a drug
candidate. See TABLE-1
Principal areas of
preformulation
1.
Bulk characterization
(i)
Crystallinity and polymorphism
(ii)
Hygroscopicity
(iii)
Fine particle characterization
(iv)
Powder flow
2.
Solubility analysis
(i)
Ionization constant – pKa
(ii)
pH solubility profile
(iii)
Common ion effect – KSP.
(iv)
Thermal effects
(v)
Solubilization
(vi)
Partition coefficient
(vii)
Dissolution
3.
Stability Analysis
(i)
Stability in toxicology
formulation
(ii)
Solution stability
– pH stability profile
(iii)
Solid state stability
–
Bulk stability
–
Compatibility
1.
Bulk characterization
When a drug molecule is discovered all the solid-forms are hardly
identified. So during bulk characterization the following characteristics are
studied.
(i) Crystallinity and polymorphism
Chemical Compounds
 |
Habit Internal
Structure |
Crystalline Amorphous
Single Entity Molecular
Adduct
POLYMORPHS
 |
Non-stoichiometric Stoichiometric
Inclusion
compounds solvates
/ hydrates
Channel Layer Cage
(Clathrate)
TABLE –1
  Medicinal Chemistry
And Pharmacology
|
Preformulation
Research
|
Formulation
Development
|
Process Research
And Development
|
Analytical Research
And Development
|
Toxicology and
Drug Metabolism
|
|
·
Flowability of powder and
chemical stability depends on the habit and internal structure of a drug.
Habit is the description of the outer appearance of a crystal. A single
internal-structure for a compound can have several different habits, depending
on the environment for growing crystals. Different habits of crystals are given
below.
Internal Structure
Crystalline state
In this state of matter atoms or molecules are arranged in highly
ordered form and is associated with three-dimensional periodicity.
[N.B. Atoms or molecules tend to organize themselves into their most
favorable thermodynamic state, which under certain conditions results in their
appearance as crystals.
N.B. The repeating
three-dimensional patterns are called crystal lattices. The crystal
lattice can be analyzed from its X-ray diffraction pattern.]
Amorphous forms
In this forms the solids do not have any fixed internal structure.
They have atoms or molecules randomly placed as in a liquid.
e.g. Amorphous Novobiocin
[N.B. Amorphous
forms are prepared by rapid precipitation, lyophillization or rapid cooling of
molten liquids e.g. glass]
Difference between
crystalline and amorphous form
Crystalline forms
|
Amorphous forms
|
(i)
Crystalline forms have fixed
internal structure
(ii)
Crystalline forms are more
stable than its amorphous forms.
(iii)
Crystalline forms are more
stable than its amorphous forms.
(iv)
Crystalline form has lesser
solubility than its amorphous form.
(v)
Crystalline form has lesser
tendency to change its form during storage.
|
(i)
Amorphous forms do not have
any fixed internal structure
(ii)
Amorphous form has higher
thermodynamic energy than its crystalline form.
(iii)
Amorphous forms are less
stable than its crystalline forms.
(iv)
Amorphous forms have greater
solubility than its crystalline forms.
(v)
Amorphous tend to revert to
more stable forms during storage.
|
Polymorphs
When a substance exists in more than one crystalline form, the
various forms are called Polymorphs and the phenomenon as polymorphism .
e.g . Chloramphenicol palmitate has
three polymorphs A, B and C .
[N.B. various polymorphs can be prepared by crystallizing the drug from
different drugs under diverse conditions . Depending on their relative
stability, one of the several polymorphic forms will be physically more stable
than the others. Such a stable polymorph represents the lowest energy state,
has highest melting point and least solubility. The representing polymorphs are
called metastable forms which represents higher energy state, the metastable
forms have a thermodynamic tendency to convert to the stable form . A
metastable form cannot be called unstable because if it is kept dry, it will
remain stable for years.]
Molecular Adducts
During the process of crystallization, some compounds have a
tendency to trap the solvent molecules.
1.
Non-Stoichiometric inclusion
compounds (or adducts)
In these crystals solvent molecules are entrapped within the crystal
lattice and the number of solvent molecules are not included in stoichiometric
number. Depending on the shape they are of three types :-
(1) Channel
When the crystal contains continuous channels in which the solvent
molecule can be included. e.g . Urea forms channel.
(2) Layers:- Here solvent molecules are entrapped in between layers
of crystals.
(3) Clathrates(Cage):-
Solvent molecules are entrapped within the cavity of the crystal from all
sides.
2.
Stoichiometric inclusion
compounds (or stoichiometric adducts)
This molecular complex has incorporated the crystallizing solvent
molecules into specific sites within the crystal lattice and has stoichiometric
number of solvent molecules complexed.
When the incorporated solvent is water, the complex is called
hydrates and when the solvent is other than water, the complex is called
solvates. Depending on the ratio of water molecules within a complex the following
nomenclature is followed.
(i)
Anhydrous : 1 mole compound + 0 mole water
(ii)
Hemihydrate: 1 mole compound + ½ mole water
(iii)
Monohydrate: 1 mole compound + 1 mole water
(iv)
Dihydrate : 1 mole compound + 2 moles water
Properties of solvates /
hydrates
(i)
Generally, the anhydrous form
of a drug has greater aqueous solubility than its hydrates. This is because the
hydrates are already in equilibrium with water and therefore have less demand
for water. e.g. anhydrous forms of theophyline and ampicillin have higher aqueous
solubility than the hydrates.
(ii)
Non aqueous solvates have
greater aqueous solubility than the non-solvates. E.g. chloroform solvates of
griseofulvin are more water soluble than their nonsolvate forms.
ANALYTICAL METHODS FOR CHARACTERIZATION OF SOLID FORMS
Methods of studying solid forms are listed as below:
Method
|
Material required per sample
|
Microscopy
Hot stage microscopy
Differential Scanning Calorimetry (DSC)
Differential Thermal Analysis (DTA)
Thermogravimetric Analysis
Infrared Spectroscopy
X-ray Powder Diffraction
Scanning Electron Microscopy
Dissolution / Solubility Analysis
|
1 mg
1 mg
2 – 5 mg
2 – 5 mg
10 mg
2 – 20 mg
500 mg
2 mg
mg to gm
|
Microscopy
In this type of
microscope light passes through cross-polarizing filters.
Amorphous substances (e.g. super-cooled glass and non-crystalline organic compounds or
substances with cubic crystal lattices e.g. NaCl ) have single refractive
index. Through this type of microscope the amorphous substances do not transmit
light, and they appear black. They are called isotropic substances.
Hot-stage microscopy
In this case, the
polarizing microscope is fitted with a hot stage to investigate polymorphism,
melting points, transition temperatures and rates of transition at controlled
rates.
It facilitates in explaining the thermal behavior of a substance
from the DSC and TGA curves.
[N.B. A problem often encountered during thermal microscopy is that
organic molecules can degrade during the melting process, and recrystallization
of the melt may not occur, because of the presence of contaminant degradation
products. ]
Thermal Analysis
Differential Thermal
Analysis
In DTA instrument a
record is produced where temperature difference (DT) (between the sample and reference
material) is plotted against temperature (T) when two specimens are subjected
to an identically controlled temperature regime.
The reference material is alumina, keiselguhr.
Differential Scanning
Calorimetry
In DSC method the
difference in energy inputs (DH) into a
sample and reference material is measured as a function of temperature as the
specimens are subjected to a identically controlled temperature programme.
Samples that may be studied
by DSC or DTA are:
Powders, fibres, single crystals, polymer films, semi-solids or
liquids.
Applications of DTA / DSC
in preformulation studies
1.
To determine the purity of a
sample
2.
To determine the number of
polymorphs and to determine the ratio of each polymorph.
3.
To determine the heat of
solvation
4.
To determine the thermal
degradation of a drug or excipients.
5.
To determine the
glass-transition temperature (tg) of a polymer.
Thermogravimetric Analysis
(TGA)
|
TGA measures the changes in sample weight as
a function of time (isothermal changes) or temperature.
Application of TGA in
preformulation study
1.
Desolvation and decomposition
processes are monitored.
2.
Comparing TGA and DSC data
recorded under identical conditions can greatly help in the explanation of the
thermal process.
TGA and DSC analysis of an acetate salt of an organic amine that has
two crystalline forms, anhydrous and dihydrate are shown above. Anhydrous /
dihydrate (10:1) mixture was prepared by dry blending. Heating rate was 50C/min.
From DSC curve, it
is evident that the dihydrate form loses two molecules of water via an
endothermic transition between 700C and 900C. The second
endotherm at 1550C corresponds to melting process.
From TA curve, it
is evident that at 70 – 900C weight-loss was due to the loss two
molecules of water and the weight loss at 1550C was due to
vaporization of acetic acid and decomposition.
X-RAY POWDER DIFFRACTION
When a X-ray beam falls on a powder the beam is diffracted. This
diffraction in found only in case of crystalline powder. Amorphous forms do not
show X-ray diffraction.
Uses:
(i)
Each
diffraction pattern is characteristic of a specific crystalline lattice for a
given compound. So in a mixture different crystalline forms can be analyzed
using normalized intensities at specific angles.
Each
diffraction pattern is characteristic of a specific crystalline lattice for a
given compound. So in a mixture different crystalline forms can be analyzed
using normalized intensities at specific angles.
(ii)
Identification of crystalline
materials by using their diffraction pattern as a ‘finger print’. First, the
powder diffraction photograph or diffractometer trace are taken and matched
with a standard photograph. All the lines and peaks must match in position and
relative intensity.
HYGROSCOPICITY
Definition: Many pharmaceutical materials
have a tendency to adsorb atmospheric moisture (especially water-soluble salt
forms). They are called hygroscopic materials and this phenomenon is known as
hygroscopicity.
Equilibrium moisture content depends upon:
(i)
the atmospheric humidity
(ii)
temperature
(iii)
surface area
(iv)
exposure time
(v)
mechanism of moisture uptake.
Deliquescent materials:
They absorb sufficient amount of moisture and dissolve completely in
it. (e.g. anhydrous calcium chloride).
Tests of hygroscopicity
Procedure
Bulk drug samples are placed in open containers with thin powder bed
to assure maximum atmospheric exposure. These samples are then exposed to a
range of controlled relative humidity (RH) environments prepared with saturated
aqueous salt solutions.
The amount of moisture adsorbed can be determined by the following
methods:
(i)
Gravimetry
(ii)
Thermogravimetric analysis
(TGA)
(iii)
Karl-Fischer titration
(KF-titration)
(iv)
Gas chromatography (GC)
Time of monitoring depends on the purpose:
(i)
For the purpose of ‘handling’ data points from 0 to 24 hours
are taken
(ii)
For the purpose of ‘storage’ data points from 0 to 12 weeks
are taken.
Significance of
hygroscopicity test
(a)
To decide special handling procedure
(with respect to time).
(b)
To decide
(i) the storage condition i.e. at low humidity environment.
(ii) special packaging – e.g.
with desiccant.
(c) Moisture level in a powder
sample may affect the flowability and compactibility which, are important
factors during tableting and capsule filling.
(d) After adsorption of moisture, if
hydrates are formed then solubility of that powder may change affecting the
dissolution characteristics of the material.
(e) Moisture may degrade some
materials. So humidity of a material must be controlled.
FINE PARTICLE CHARACTERIZATION
Parameters those are measured:
(i)
particle size and
size-distribution
(ii)
shape of the particle
(iii)
surface morphology of the
particles
Instrumental methods of particle size characterization
(i) Light microscope
First a standard graticule (BS 3625) is standardized with a stage
micrometer. Then snall number of particles are spread over a glass slide
and placed on the stage of the microscope. Particles are focussed and the
particle diameters are measured. Several hundred particles are measured and
reported as a histogram.
Disadvantage: The procedure is time consuming.
(ii) Stream counting
devices
Examples: (a) Coulter counter – electrical sensing zone method
(b)
HIAC – counter – optical sensing
zone
(c) Malvern particle & droplet
sizer – Laser diffraction method.
Procedure:
Samples prepared
for analysis are dispersed in a conducting medium (e.g. saline) with the help
of ultrasound and a few drops of surfactant (to disperse the particles
uniformly). A known volume (0.5 to 2 ml) of this suspension is then drawn into
a tube through a small aperture (0.4 to 800 mm diameter) across which a voltage is applied.
As each particle passes through the hole, it is counted and sized
according to the resistance generated by displacing that particle’s volume of
conducting medium.
Size distribution is reported as histogram.
(iii) Sieve analysis
A powder sample is passed
through a standard sieve set. The particle size is plotted against % weight
retained on each sieve.
Use: This method is used generally for large samples.
Instrumental method for
determination of specific surface area
Brunauer, Emmett and Teller
(BET) nitrogen adsorption method:
A layer of nitrogen
molecules is adsorbed to the sample surface at –1960C. Once the
surface is saturated, the sample is heated to room temperature, the nitrogen
gas is desorbed, and its volume is measured and converted to the number of
adsorbed molecules via the gas law. Since each N2 molecule occupies
an ara of 16 A2, one may readily compute the surface area per gram
of each pre-weighed sample.
Instrumental method for
characterization of surface morphology
The scanning electron microscope creates the magnified images by
using electrons instead of light waves. The images are black and white.
Procedure
·
Biological materials are dried
in a special way that prevents them from shrinking.
·
Since SEM illuminates them with
electrons, they are made conductive by coating with a very thin layer of gold
by a machine called sputter-coater.
·
The sample is placed inside the
microscope’s vacuum column through an airtight door.
·
After the air is pumped out of
the column, an electron gun emits a beam of high-energy electrons. This beam
travels downward through a series of magnetic lenses designed to focus the
electrons to a very fine spot.
·
Near the bottom, a set of scanning
coils moves the focussed beam back and forth across the specimen, row by row.
·
As the electron beam hits each
spot on the sample, secondary electrons are knocked loose from its surface. A
detector counts these electrons and sends the signals to an amplifier.
·
The final image is built up
from the number of electrons emitted from each spot on the sample.
BULK DENSITY
Apparent Bulk Density
(g/cm3)
Bulk drug powder is sieved through 40 mesh screen. Weight is taken
and poured into a graduated cylinder via a large funnel. The volume is called bulk volume.
Tapped density (g/cm3)
Bulk powder is sieved through 40 mesh screen. Weight is taken and
poured into a graduated cylinder. The cylinder is tapped 1000 times on a
mechanical tapper apparatus. The volume reached a minimum – called tapped volume.
True density (g/cm3)
Solvents of varying densities are selected in which the powder
sample is insoluble. Small quantity of surfactant may be mixed with the solvent
mixture to enhance wetting and pore penetration. After vigorous agitation, the
samples are centrifuged briefly and then left to stand undisturbed until
floatation or settling has reached equilibrium.
The samples that remains suspended (i.e. neither suspended not
floated) is taken. So the true density of the powder are equal. So the true
density of the powder is the density of that solvent. The density of that
solvent is determined accurately with a pycnometer.
Source of variation of bulk
density
Method of crystallization, milling, formulation.
Methods of correction
By milling,
slugging or formulation.
Significance
(i) Bulk density
Bulk density is
required during the selection of capsule size for a high dose drug.
In
case of low dose drug mixing with excipients is a problem if the bulk densities
of the drug and excipients have large difference.
(ii) Tapped density
Knowing
the dose and tapped density of the formulation, the capsule size can be
determined.
(iii) True density
From bulk density and true density of powder, the void volume or
porosity can be measured.
Powder flow properties
Powder flow properties depends on
(i)
particle size
(ii)
density
(iii)
shape
(iv)
electrostatic charge and
adsorbed moisture
that may arise from processing or formulation.
A free-flowing powder may become cohesive during development. This
problem may be solved by any of the following ways.
(i)
by granulation
(ii)
by densification via slugging
(iii)
by filling special auger feed
equipment (in case of powder)
(iv)
by changing the formulation.
Procedure
For free flowing powder
A simple flow rate apparatus consisting of a grounded metal tube
from which drug flows through an orifice onto an electronic balance, which is
connected to a strip chart recorder. Several flow rate (g/sec) determinations
at various orifice sizes (1/8 to ½ inch) should be carried out.
The grater the standard deviation between multiple flow rate
measurements, the greater will be the weight variation of the product (tablets
or capsules).
Compressibility :-
rt =
tapped bulk density
r0 =
Initial bulk density
Solubility Analysis
Determination of equilibrium solubility of a drug
The drug is dispersed in a solvent. The suspension is agitated at a
constant temperature. Samples of the suspension are withdrawn as a function of
time, clarified by centrifugation, and assayed to establish a plateau
concentration.
Solvents taken
(i)
0.9% NaCl at room temperature
(ii)
0.01 M HCl at RT
(iii)
0.1 M HCl at RT
(iv)
0.1 M NaOH at RT
(v)
At pH 7.4 buffer at 370C
Drug concentration is
determined by the following analytical methods
(i)
HPLC
(ii)
UV –Spectroscopy
(iii)
Fluorescence Spectroscopy
(iv)
Gas Chromatography
Solubility depends on
(i)
pH
(ii)
Temperature
(iii)
Ionic strength
(iv)
Buffer concentration
Significance
(i)
A drug for oral administrative
should be examined for solubility in an isotonic saline solution and acidic pH.
This solubility data may provide the dissolution profile invivo.
(ii)
Solubility in various mediums
is useful in developing suspension or solution toxicologic and pharmacologic
studies.
(iii)
Solubility studies identify
those drugs with a potential for bioavailability problems. E.g. Drug having
limited solubility (7 %) in the fluids of GIT often exhibit poor or erratic
absorption unless dosage forms are tailored for the drug.
pKa
Determination
When a weakly acidic or basic drug partially ionizes in GI fluid,
generally, the unionized molecules are absorbed quickly.
Handerson-Hasselbach
equation provides an estimate of the ionized and unionized drug concentration
at a particular pH.
For acidic drug : e.g.
For basic compounds e.g.
Drug
|
Stomach
PH 1.5
|
Plasma
PH = 7.4
|
Duodenum
PH = 5.0
|
||
Weak acid
e.g. Ibuprofen
pKa = 4.4
|
|||||
Weak base
e.g. Nitrazepam
pKa = 3.2
|
Method of determination of pKa of a drug
(i) Detection of
spectral shifts by UV or visible spectroscopy at various pH.
Advantage:
Dilute aqueous solutions can be analyzed by this method.
(ii)
Potentiometric titration
Advantage:
Maximum sensitivity for compounds
with pKa in the range of 3 to 10.
Disadvantage: This method is unsuccessful
for candidates where precipitation of the unionized forms occurs during
titration. To prevent precipitation a co-solvent e.g. methanol or
dimethylsulfoxide (DMSO) can be incorporated.
(iii) Variation of
solubility at various pH.
Effect of temperature on stability
Heat of solution, DHS represents the heat released or absorbed when a mole
of solute is dissolved in a large quantity of solvent.
Significance
·
Most commonly, the solubility
process is endothermic, e.g. non-electrolytes, unionized forms of weak acids
and bases Þ DH is positive Þ
Solubility increases if temperature increases.
·
Solutes that are ionized when
dissolved releases heat
Þ the
process is exothermic Þ DHS is negative Þ Solubility increases at lower temperature.
Determination of DHS.
The working
equation 
where, S = molar
solubility of the drug at T0K
where, S = molar
solubility of the drug at T0K
and
R = gas constant
S is
detemined at 50C, 250C, 370C and 500C.
DHS = – Slope x R
Solubilization
For drug candidates with poor water solubility, preformulation
studies should include limited experiments to identify the possible mechanisms
for solubilization.
Means of
increasing the solubility are:
(i) Addition of a
cosolvent to the aqueous system e.g. ethanol, propylene glycol and glycerin.
MOA: These co-solvents disrupt the hydrophobic interactions of water at
the non-polar solute / water interfaces.
(ii) Solubilization
in micellar solutions such as 0.01 M Tween 20 solution.
(iii)
Solubilization by forming molecular complexes e.g. benzoic acid forms complex
with caffeine.
Partition coefficient
Partition
coefficient is defined, as the ratio of un-ionized drug concentrations between
the organic and aqueous phases, at equilibrium.
Generally,
octanol and chloroform are taken as the oil phase.
Significance
Drug molecules
having higher KO/W will cross the lipid cell membrane.
Dissolution
The dissolution
rate of a drug substance in which surface area is constant during
disintegration is described by the modified Noyes-Whitney equation.
where, D = diffusion coefficient of the drug in the
dissolution medium
h = thickness of the diffusion layer
at the solid/liquid interface
A = surface area of drug exposed to
dissolution medium.
V = volume of the medium
CS = Concentration of saturated solution of
the solute in the dissolution medium at the experimental temperature.
C = Concentration of drug in
solution at time t.
When A = constant
and CS >> C the equation can be rearranged to
where, 
where, W = weight (mg) of drug dissolved at time t
k = intrinsic dissolution rate constant
Determination of k
·
Pure drug powder is punched in
a die and punch apparatus to give a uniform cylindrical shape. The tablet is
covered with wax in all sides. One circular face is exposed to the dissolution
medium. Thus, as dissolution proceeds, the area, A, remains constant.
·
Time to time dissolution medium
is taken out and fresh medium added to the chamber.
·
With
two types of assembly, the experiments can be carried out.
With
two types of assembly, the experiments can be carried out.
Stability analysis
Preformulation
stability studies are the first quantitative assessment of chemical stability
of a new drug. This may involve
1.
Stability study in toxicology
formulation
2.
Stability study in solution
state
3.
Stability study in solid state.
Stability study in toxicology formulation
A new drug is administered
to animals through oral route either by
(i) mixing the drug in the feed
(ii) in the form of solution
(iii) in the form of suspension in aqueous vehicle
·
Feed may contain water,
vitamin, minerals (metal ions), enzymes and different functional groups that
may severely reduce the stability of the new drug. So stability study is should
be carried out in the feed and at laboratory temperature.
·
For solution and suspension,
the chemical stability at different temperature and pH should be checked.
·
For suspension-state the drug
suspension is occasionally shaken to check dispersibility.
Solution stability
Objective: Identification of conditions necessary to form a stable solution.
Stability of a new drug may depend on:
(i) pH (ii)
ionic strength (iii)
co-solvent
(iv) light (v)
temperature (vi)
oxygen.
pH stability study
(i) Experiiments
to confirm decay at the extremes of pH and temperature. Three stability studies
are carried out at the following conditions
(a)
0.1N HCl solution at 900C
(b)
Solution in water at 900C
(c)
0.1 N NaOH solution at 900C
These experiments
are intentionally done to confirm the assay specificity and for maximum rates
of degradation.
(ii) Now aqueous buffers are used to
produce solutions with wide range of pH values but with constant levels of drug
concentration, co-solvent and ionic strength.
All the rate constants (k) at a single temperature are
then plotted as a function of pH.
(ii) Ionic
strength
Since most
pharmaceutical solutions are intended for parenteral routes of administration,
the pH-stability studies should be carried out at a constant ionic strength
that is compatible with body fluids. The ionic strength (m) of an isotonic 0.9%w/v sodium chloride solution is 0.15.
Ionic strength for any buffer solution can be
calculated by
where, mi
= molar concentration of the ion
Zi =
valency of that ion
For computing, m all the ionic species of the buffer solution and drugs are also
taken into calculation.
(iii) Co-solvents
Some drugs are not sufficiently soluble to give concentrations of
analytical sensitivity. In those cases co-solvents may be used. However,
presence of co-solvents will influence the rate constant. Hence, k values at
different co-solvent concentrations are determined and plotted against % of
co-solvent. Finally, the line is extrapolated to 0% co-solvent to produce the
actual k value (i.e. in pure solvent).
(iv) Light
Drug
solutions are kept in
(a)
clear glass ampoules
(b)
amber color glass container
(c)
yellow-green color glass
container
(d)
container stored in card-board
package or wrapped in aluminium foil – this one acts as the control.
Now the stability
studies are carried out in the above containers.
(v) Temperature
The rate constant
(k) of degradation reaction of a drug varies with temperature according to
Arrhenius equation.
or , 
where, k = rate constant
A = frequency factor
Ea = energy of activation
R = gas constant
T = absolute temperature
Procedure
Buffer solutions
were prepared and kept at different temperatures. Rate constants are determined
at each temperature and the ln k value is plotted against (1/T)).
Inference
·
The relationship is linear Þ a constant decay mechanism over the temperature range
has
occurred.
·
A broken or non-linear
relationship Þ a change in the rate-limiting step of the reaction or change
in decay
mechanism.
Uses
Shelf life of the drug may be calculated.
e.g. Time Concentration of drug remaining
0
100 %
t10% 90%
Therefore, ln
C = ln C0 – k1t
Ln C/C0 = – k1t
or, 
or, 
or,
where, t10%
= time for 10% decay to occur if the reaction follows 1st order
kinetics
Conclusion
If the drug is
sufficiently stable, liquid formulation development may be started at once.
If the drug is
unstable, further investigations may be necessary.
Solid state stability
Objectives
Identification of
stable storage conditions for drug in the solid state and identification of
compatible excipients for a formulation.
Characteristics
Solid state reactions
are much slower, so the rate of appearance of decay product is measured (not
the amount of drug remaining unchanged).
·
To determine the mechanism of
degradation thin layer chromatography (TLC), fluorescence or UV / Visible
spectroscopy may be required.
·
To study polymorphic changes
DSC or IR-spectroscopy is required.
·
In case of surface
discoloration due to oxidation or reaction with excipients, surface reflectance
equipment may be used.
A sample scheme for determining the bulk stability profile of a new
drug:
Storage condition 4
weeks 8 weeks 12 weeks
50C – Refrigerator
220C – Room Temperature
370C – Ambient humidity
370C /
75% RH (Relative Humidity)
Light box
Clear box
Amber glass
Yellow-Green glass
No exposure (Control :-
Card-board box or wrapped with aluminium foil)
500C – Ambient Humidity
– O2 Head Space
– N2 Head Space
700C – Ambient Humidity
900C – Ambient Humidity
Procedure
1.
Weighed samples are placed in
open screw-capped vials are exposed to a variety of temperatures, humidities an
dlight intnesities. After the desired time samples are taken out and measured
by HPLC (5 – 10 mg), DSC (10 to 50mg), IR (2 to 20mg).
2.
To test for surface oxidation
samples are stored in large (25ml) vials for injection capped with Teflon-lined
rubber stopper. The stoppers are penetrated with needles and the headspace is
flooded with the desired gas. The resulting needle holes are sealed with wax to
prevent degassing.
3.
After fixed time those samples
are removed and analyzed.
Drug-excipient stability profile
Hypothetical
dosage forms are prepared with various excipients and are exposed to various
conditions to study the interactions of drug and excipients.
FOR PHARMACEUTICS THEORY
FOR PHARMACEUTICS THEORY
