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.
(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
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.
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,
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.