Preformulation.pptx

Preformulation Technology
Lecture 1
Presented By-
Md. Hafizur Rahman
General Manager & Head of PDD
The IPI Ltd.
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4/30/2023

Preformulation
 Preformulation is branch of Pharmaceutical science that utilizes
biopharmaceutical principles in the determination of physicochemical
properties of the drug substance.
 Prior to the development of any dosage form new drug , it is essential that
certain fundamental physical & chemical properties of drug powder are
determined .
 This information may dictate many of subsequent event & approaches in
formulation development.
 focus on those physicochemical properties of the new compound that could
affect drug performance and development of dosage form
 Preformulation testing is the first step in the rational development of dosage
forms.
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DEFINITION
It can be defined as an investigation of physico-chemical properties of the
new drug compound that could affect drug performance and development of
an efficacious dosage form”.
Physiochemical properties are those that can be determined from in vitro
experiments.
Preformulation commences when a newly synthesized drug shows a sufficient
pharmacologic promise in animal model to warrant evaluation in man.
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Goals /Objectives of Preformulation
 To establish the necessary physicochemical parameters of new drug substances.
 To determine kinetic rate profile.
 To establish physical characteristics.
 To establish compatibility with common excipients.
 It provides insights into drug products should be processed and store to ensure
their quality
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Why Preformulation is Important ?
It describes the process of optimizing the delivery of drug
thorough determination of physical, chemical properties of new
drug molecule that affect drug performance and development of an
efficacious stable and safe dosage form.
Preformulation studies on a new drug molecule provide useful
information for subsequent formulation of a physicochemically
stable and biopharmaceutically suitable dosage form.
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6
Before embarking on a formal programme of preformulation,
scientist must consider the following :
1. Available physicochemical data (including chemical
structure, different salt available).
2. Anticipated dose.
3. Supply situation and development schedule.
4. Availability of stability – indicating assay.
4/30/2023

Major Area of Preformulation
Research
ORGANOLEPTIC CHARACTERS
BULK CHARACTERS
Crystallinty and polymorphism
Hygroscopicity
Fine particle characterization
Bulk Density &Powder flow properties
SOLUBILITYANALYSIS
ionization constant-PKa
pH solubility profile
Common ion effect-Ksp
Thermal effects











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Solubilization
Partition co-efficient
Dissolution
STABILITYANALYSIS










Stability in toxicology
Solution stability
pH rate profile
Solid state stability
Bulk stability
Compatibility
formulations
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ORGANOLEPTIC CHARACTERS
 Colour, odour,
recorded
taste of the new drug must be
COLOUR ODOUR TASTE
Off-white pungent Acidic
Cream yellow sulphurous Bitter
tan Fruity Bland
shiny Aromatic Intense
Odourless Sweet
T
asteless
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BULK CHARACTERIZATION
Crystallinity
 Crystal habit & internal structure of drug can affect bulk &
physicochemical property of molecule.
 Crystal habit is description of outer appearance of crystal.
 Internal structure is molecular arrangement within the solid.
 Change with internal structure usually alters crystal habit.
Eg. Conversion of sodium salt to its free acid form produce
internal structure & crystal habit.
both Change in
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Different shapes of crystals
 Depending on internal structure compounds is classified as
1. Crystalline
2. Amorphous
 Crystalline compounds are characterized by repetitious spacing of
constituent atom or molecule in three dimensional array.
 In amorphous form atom or molecule are randomly placed.
 Solubility & dissolution rate are greater for amorphous form than
crystalline, as amorphous form has higher thermodynamic energy.
Eg. Amorphous form of Novobiocin is well absorbed whereas
crystalline form results in poor absorption.
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Different Shapes of crystal
cubic tetragonal triclinic orthombic
{
monoclinic trigonal
hexagonal
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Polymorphism
It is the ability of the compound to crystallize as more distinct crystalline
species with different internal lattice. Polymorph has same chemical properties
but their physical properties are different. e.g. melting point, boiling point.
than one
 Different crystalline forms are called polymorphs.
 According to conversion Polymorphs are of 2 types -
1. Enatiotropic
2. Monotropic
 The polymorph which can be changed from one form into another by varying temp or
pressure is called as Enantiotropic polymorph.
Eg. Sulphur.
 One polymorph which is unstable at all temp. & pressure is called
as Monotropic polymorph.
Eg. Glyceryl stearate.
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Polymorphism
 Polymorphs differ from each other with respect to their physical
property such as
• Solubility
Melting point
Density
Hardness
Compression characteristic
•
•
•
•
Eg. 1)Chloromphenicol exist inA,B & C forms, of these B form is
more stable & most preferable.
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According to stability, Polymorphs are of three types:
I. stable
II. Metastable
III. Unstable

ANALYTICALMETHODS FOR THE
CHARACTERIZATION
 Microscopy
 Hot stage microscopy
 Thermal analysis
 X-ray diffraction
OF SOLID FORMS
 Infrared (IR) spectroscopy
 Proton magnetic resonance(PMR)
 Nuclear magnetic resonance (NMR)
 Scanning electron microscopy (SEM)
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Microscopy
 Material with more than one refractive index are anisotropic &
bright with brilliant colors against black polarized background.
appear
 The color intensity depends upon crystal thickness.
 Isotropic material have single refractive index and this substance transmit light with
crossed polarizing filter and appears black.
 Advantage :
do not
By this method, we can study crystal morphology & difference between
polymorphic form.
 Disadvantage :
This require a well trained optical crystallographer, as there are many
possible crystal habit & their appearance at different orientation.
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Hot stage microscopy
 The polarizing microscope fitted with hot stage is useful for
investigating polymorphism, melting point & transition temp.
 Disadvantage :
In this technique,
process.
the molecules can degrade during the melting
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Thermal analysis
Differential scanning calorimetry (DSC) & Differential thermal analysis are (DTA) are
particularly useful in the investigation of polymorphism.

It measures the heat loss or gain resulting from physical or
changes within a sample as a function of temp.
chemical

For characterizing crystal forms , the heat of fusion can be
from the area under DSC- curve for melting endotherms.
obtained

Similarly, heat of transition from one polymorph to another may
calculated.
be

A sharp symmetric melting endotherm can indicate relative purity
molecule.
 Abroad asymmetric curve indicates presence of impurities.
of

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X- ray diffraction
 Working :
When beam of nonhomogenous X-ray is allow to pass through the
crystal, X-ray beam is diffracted & it is recorded by means of
photographic plate.
 Diffraction is due to
grating toward X-ray.
crystal which acts as 3dimensional diffraction
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 Random orientation of crystal lattice in the powder causes the
X-ray to scatter in a reproducible pattern of peak intensities.
 The diffraction pattern is characteristic of a specific
crystalline lattice for a given compound.
 An amorphous form does not produce a pattern
different crystalline forms.
mixture of
 Single – Crystal x-ray provide the most complete information
about the solid state.
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HYGROSCOPICITY
Many drug substances, particularly water –soluble salt forms, have a
tendency to adsorb atmospheric moisture.

Adsorption and moisture content depend upon the atmospheric

humidity, temperature, surface area, exposure and the mechanism of
moisture uptake.
The degree of Hygroscopicity is classified into four classes:

Slightly hygroscopic: increase in weight is ≥ 0.2% w/w and < 2% w/w

Hygroscopic : increase in weight is ≥ 0.2 % w/w and < 15 % w/w

Very hygroscopic : increase in weight is ≥ 15% w/w
Deliquescent : sufficient water is adsorbed to form a solution


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Hygroscopicity is tested
Samples are exposed to the moisture
by:
exposed to controlled relative humidity environments
moisture uptake is monitored at different time
Analytical methods which is used are :
 Gravimetry
points
 Karl Fischer Titration
 Gas chromatography
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With most hygroscopic materials changes in moisture level can influence many
important parameters, such as:
- Chemical stability
- Flowability
- Compactibility

PARTICLE SIZE
Particle size is characterized using these terms :
V
ery coarse, Coarse, Moderately coarse, Fine ,V
ery
fine .


 Particle size can influence variety of important factors :
-
-
-
-
-
Dissolution rate
Suspendability
Uniform distribution
Penetrability
Lack of grittiness
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Methods to Determine ParticleSize
 Sieving (5µ-150µ)
 Microscopy(0.2µ-100µ)
 Sedimentation rate method(1µ-200µ)
 Light
 Laser
energy diffraction(0.5µ-500µ)
holography(1.4µ-100µ)
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POWDER FLOW PROPERTIES
 Powder flow properties can be affected by change in
particle size, shape & density.
 The flow properties depends upon following-
1. Force of friction.
2. Cohesion between one particle to another.
 Fine particle posses poor flow by filling void spaces
between larger particles
of particles.
causing packing & densification
 By using glident we can
e.g. Talc
alter theflow properties.
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Determination of Powder FlowProperties
 By determining Angle of Repose.
 Agreater angle of repose indicate
poor flow.
 It should be less than 30°. & can
be determined by following
equation.
tan θ = h/r.
where, θ = angle of repose.
h=height of pile.
r= radius.
Angle of
Repose
( In degree)
Type of Flow
<25
Excellent
25-30
Good
30-40 Passable
>40
Very poor
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Methods to
Static angle of
determine angle of

repose
Fixed-funnel
method
Fixed-cone method
Kinetic or dynamic



method
Rotating cylinder
method
Tilting box method


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repose

Determination of Powder Flow Properties
 Measurement
compressibility.
of free flowingpowderby
 Also known as Carr's index.
CARR’S INDEX(%) =(TAPPED DENSITY – POURED DENSITY) 100
X
TAPPED DENSITY
 It is simple, fast & popular method of predicting
powder flow characteristics.
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Determination of Powder Flow Properties
Carr’s Index Type of flow
5-15 Excellent
12-16 Good
18-21 Fair To Passable
23-35 Poor
33-38 V
ery Poor
>40 Extremely Poor
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Solubility analysis
 it is important for orally administered drugs or drugs needed to be converted
into solutions.
It includes:
 pKa determinations
 pH solubility profile and common ion effects
 Effect of temperature
 Solubilization
 Partition coefficient
 Dissolution
4/30/2023 30

 Table: Solubility based classificatio n of drug
SOLUBILITY STUDIES
Solution phase equilibrium with solid phase at a stated temperature and
pressure .
1.
Determines amount of drug dissolved , amount of drug
absorption.
Solubility reduction is carried out in certain conditions:
Enhancement of chemical stability.
taste masking products.
Production of sustained release products.
available for
2.
3.



Descriptive term Parts of solvent required for 1 part of
solute
V
ery soluble Less than 1
Freely soluble From 1 to 10
Soluble From 10 to 30
Sparingly soluble From 30 to 100
Slightly soluble From 100 to 1000
V
ery slightly soluble From 1000 to 10,000
Practically insoluble 10,000 and over
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 The equilibrium solubility is based on the phase-solubility technique
proposed by Higuchi-Connors .
Method
Drug dispersed in solvent in a closed container
agitated at a constant temperature using shakers
samples of the slurry are withdrawn as a function of time
clarified by centrifugation and assayed by HPLC, UV
, GC etc
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pKa determination
 pKa is the dissociation constant of a drug
 The un-ionized drug is lipid soluble thus permeates through lipid membrane.
 The ionized substance is lipid insoluble therefore permeation is slow
 Degree of ionization depends on pH
Henderson-Hasselbalch equation
 For basic compounds: [ionized]
pH  pKa 
[un  ionized]
pKa 
[un ionized ]
pH 
 For acidic compounds: [ionized]
( pHpKa)
10
%ionized  ( pHpKa)
1 10
 Determined by uv spectroscopy, potentiometric titration, titrimetric
method
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pKa determinations
 It is important for drugs capable of ionization within a pH range (1-10), since
solubility and then absorption can be changed by pH changes.
As example, for a weakly acidic drug with pka value greater than 3, the unionized
form is present within the acidic contents of the stomach, but the drug is ionized
predominantly in the neutral media of the intestine.
 for basic drugs such as erythromycin, (pka ˜ 8-9), the ionized form is
predominant in both the stomach and intestine.
4/30/2023 34

 pka can be determined using potentiometric pH titration (the drug is
dissolved in water forming either w.a or w.b. which titrated and pH
recorded).
 Conductivity, potentiometry and spectroscopy methods can be used. (all
these at controlled conditions)???
4/30/2023 35

SOLUBILIZATION
“Solubilization is defined as the spontaneous
passage of poorly water soluble solute
moleculesinto an aqueoussolution
which
solution
of a
a
is
soap or detergent in
thermodynamically stable
formed ”.
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 It is the process by which apparent solubility of an otherwise
sparingly soluble substance is increased by
micelles .
the presence of surfactant
 MICELLES: -

to
The mechanism involves the property of surface active agents
form colloidal aggregates known as micelles .
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 When surfactants are added to the liquid at low concentration they
tend to orient at the air-liquid interface .
 On further addition of surfactant the interface becomes completely
occupied and excess molecules are forced into the bulk of liquid.
At very high concentration surfactant molecules in the bulk of liquid
begin to form micelles and this concentration is know as CRITICAL
MICELLE CONCENTRATION (CMC)
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Solubilization
How we can increase the solubility extent in water?
Addition of co-solvent (depending on chemical structure of drug?).
Addition of
surfactant
Complexation
4/30/2023 39

General Method of Increasing the Solubility
 Addition of co-solvent
 pH change method
 Reduction of particle size
 Temperature change method
 Hydotrophy
 Addition of Surfactant
 Dielectrical Constant
 Complexation
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Partition coefficient
•
4/30/2023 41

Partition Coefficient
 A measurement of drug lipophilicity i,e the ability to cross the cell
corganic
caqueous
p 
membrane
o / a
Distribution coefficient
( pH  pKa )
10 )
log D  log P  log (1
 For acids: 10 10 10
pKapH
log D  log P  log (1
10 10 10
10 )
 For bases :
 The octanol-water system is widely accepted to explain these phenomenon.
 Buccal membrane : butanol-pentanol system
 Blood-Brain barrier: chloroform-cyclohexane
 Determined by SHAKE FLASK METHOD
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SHAKE FLASK METHOD
 Drug is shaken between octanol and water.
 Aliquot is taken and analyzed for drug content
 RULE OF FIVE : for drug permeates through passive diffusion
1
. Log P is greater than 5
2
. Molecular weight >500
3. There are more than 5 hydrogen bond donors (number of NH + OH)
4. There are more than 10 hydrogen bond acceptors (number of hydrogen +
oxygen )
5. Molar refractivity should be between 40-130
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DISSOLUTION
Rate Rate
constant of
absorption
K
constant of
dissolution
K d a
Solid drug in the
G.I Fluid
Drug in solution Drug systemic
circulation
in the G.I fluid
 When Kd << Ka ,dissolution is significantly slower and the absorption is
described as dissolution-rate limited.
 The dissolution rate of drug substance in which surface area is constant
during dissolution is described by Noyes-Whitney equation.
dC/dt=dissolution rate
h=diffusion layer thickness
C=solute concentration in bulk solution V=volume of
the dissolution medium D=diffusion coefficient
A=surface area of the dissolving solid Cs=solute
concentration in the diffusion layer
dC
dt
DA
hV
(CS C
  )
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 Constant surface area is obtained by compressing powder into a disc of
known area with a die and punch apparatus.
 Hydrodynamic conditions are maintained with Static-disc dissolution
apparatus and Rotating disc apparatus
 fig : static dissolution apparatus and rotating disc apparatus
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Stability analysis
 Is usually the first quantitative assessment of chemical stability of a
new drug.
 It includes both solution and solid state experiments under conditions
typical for the handling, formulation, storage and administration of a
drug candidate.
 Generally, it includes:
1. Stability in toxicology formulations
2. Solution stability
3. Solid state stability
4/30/2023 47

Stability in toxicology formulations
 A drug is administered to the animal in their feed, or by oral gavage of a
solution or suspension of the drug in an aqueous vehicle.
Water, vitamins, minerals (metal ions), enzymes and a multitude of
functional groups are present in feed, which can severely reduce the shelf-
life of a drug.
 Solution and suspension formulations are checked for ease of
manufacture and then stored in flame-sealed ampoules at various
temperatures.
4/30/2023 48

Solution stability
 It is important for identification of conditions necessary to
form a stable solution including the effects of (pH, ionic
strength, co-solvent, light, temperature and oxygen).
pH for maximum stability is determined using different types
of buffers at constant conditions(?).
4/30/2023 49
Rate
(K)
Acid-base catalysis
(pH rate profile)

 Ionic strength depends on the molar concentrations of ion (with
valency), it must be constant specially for injectable solutions (about
0.15).
Co-solvent can affect solubility and stability (hydrolysis prevention),
solvents effects originated from dielectric constants values?, toxicity
and compatibility. So the selected cosolvent must be selected at
controlled conditions like (temperature not causes evaporation,
sealing/packaging).
 The studies include photodegradation and oxidation depending on
the drug, so if found (must be prevented ? how).
4/30/2023 50

Then, Arrhenius equation ? is used for studying the effect of
temperature on solution at controlled conditions.
The fractions of remaining drugs are assayed using UV, HPLC (the
best?).
After determination of the rate constant at 25°C, the shelf life can be
calculated using the equation: t10% = 0.105/K25
 Depending on the results, we can decide if, the drug can prepared in
soluble, stable and effective form or not.
4/30/2023 51

 Includes identification of the suitable conditions for
storage of solid drugs and drug-excipients compatibility.
Solid state changes may include changes in the bulk
properties.(so must be assayed as before)
The reaction rates are much slower and more difficult to
interpret.(why?)
 Generally, it involve placing of a new drug (certain
weight) in open screw cap vials and then exposed
directly to a variety of temperatures, humidities, and
light intensities for long period of time.
4/30/2023 53

STABILITYANALYSIS
Solution stability
SOLUTION STABILITY
1.
2.
The decomposition of drug occurs through hydrolysis, oxidation,
photolysis.
Hydrolysis (anaesthetics, vitamins etc )


a) Ester hydrolysis
H+ + OH-
R’-COOR +
ester
Amide hydrolysis
RCOOH + ROH
acid alcohol
b)
H+ + OH-
RCONHR’+
amide
RCOOH
acid
+ H2N-R’
amine
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Oxidation
 used to evaluate the stability of pharmaceutical preparations
 Eg : steroids, vitamins, antibiotics, epinephrine
 Autoxidation
Materials + molecular oxygen
homolytic fission
Free radicals are produced.
 Oxygen sensitivity is measured by
adding hydrogen peroxide.
bubbling air through the compound or
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 Photolysis
pharmaceutical compounds
exposure to uv light
absorbs the radiant energy
undergoes degradative reactions
SOLID-STA
TE STABILITY
1o objective: identification of stable storage conditions.

identification of compatible excipients.
 Solid-state stability depends on the temperature , light, humidity,
polymorphic changes, oxidation.
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ug -
Dr Excipient Compatibility
 Compatibility test play a very important role in the preformulation
studies of oral dosage forms
An incompatibility in the dosage form can result in any of the following
changes:
 Changes in organoleptic properties
 Changes in dissolution performance
 Physical form conversion
 An decrease in potency
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METHOD
Drug + Excipients
(1:1)
Powder samples dispersed into glass ampoules
1 ampoule 1 ampoule (sample + water)
stored at a particular temperature (500 C) and analysed
 In emulsions the studies include measuring the critical micelle
concentration of the formulations
 For oral use preparations compatibility of the ingredients (ethanol, glycerine, syrup,
sucrose, buffers and preservatives)
60
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