2. CONTENTS
• Introduction
• Organoleptic properties
• Purity
• Particle size, shape and surface area
• Solubilisation, Surfactants and its importance
• Preformulation stability studies
• A consideration of physico-chemical characteristics of
new drug molecules with respect to different dosage
forms
2
3. 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.
• This first learning phase is called as preformulation.
3
4. INTRODUCTION
DEFINITION:-
Investigation of physico-chemical properties of
the new drug compound that could affect drug
performance and development of an efficacious
dosage form”.
Preformulation commences when a newly
synthesized drug shows a sufficient
pharmacologic promise in animal model to
warrant evaluation in man.
4
5. Introduction
• The preformulation is the first step in the rational
development of a dosage form of a drug substance
alone and when combined with excipients.
• Objective :
To generate useful information to the
formulator to design an optimum drug delivery
system.
5
6. Introduction
• 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.
6
7. GOALS 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.
7
8. Preliminary Evaluation
a) Compound identity.
b) Formula and molecular weight.
c) Structure.
d) Therapeutic indications:
- Probable human dose.
- Desired dosage form(s)
- Bioavailability model
- Competitive products
8
Contd…
10. Outline of principal areas of
preformulation research
Principal areas
Physico-chemical
properties
Bulk
characterisation
Stability analysis
Solubility analysis
Organoleptic
properties
Particle size
and shape
Purity
Surface
area
Crystallinity and
polimorphism
Hygroscopicity
Particle size
characterization
Bulk density
Powder flow
properties
Ionization constant pka
PH solubility profile
Common ion
effect ksp
Thermal
effects
solubilization
Partition co-efficient
Dissolution
Solution stability
Solid state
stability
Bulk
stability
Compatibilty
12. COLOR
• Color is generally a function of a drug’s inherent
chemical structure relating to a certain level of
unsaturation.
• Color intensity relates to the extent of conjugated
unsaturation as well as the presence of chromophores.
• Some compound may appear to have color although
structurally saturated.
12
13. ODOR
• The substance may exhibit an inherent odor
characteristic of major functional groups present.
• Odor greatly affects the flavor of a preparation or
food stuff.
Taste:-
• If taste is considered as unpalatable, consideration is
to be given to the use of a less soluble chemical form
of the drug.
• The odour and taste may be suppressed by using
appropriate flavors and excipients or by coating the
final product.
13
14. PURITY
• Designed to estimate the levels of all known &
significant impurities & contaminates in the drug
substance under evaluation.
• Study performed in an analytical research &
development group.
• It is another parameter which allows for comparison
with subsequent batches.
• Occasionally, an impurity can affect stability.
e.g.
- Metal contamination
- Appearance
14
15. PURITY
• The techniques used for characterizing the purity of a
drug are the same as those used for other purpose in a
preformulation study.
• Thin layer chromatography is a wide ranging
applicability & is an excellent tool for characterizing
the purity.
• HPLC, paper chromatography & gas chromatography
are also useful.
• More quantitative information can be obtained by
using quantitative differential scanning colorimetry.
15
16. PARTICLE SIZE
• Particle size can influence variety of
important factors :
- Dissolution rate
- Suspendability
- Uniform distribution
- Penetrability
- Lack of grittiness
16
18. Methods to Determine Particle Size
1. Sieving method :
• Range : 50 – 150 µm
• Simple, inexpensive
• If powder is not dry, the apertures get clogged.
2. Microscopy :
• Range : 0.2 – 100 µm
• Particle size can be determined by the use of
calibrated grid background.
• Most direct method.
• Slow & tedious method.
18
19. Methods to Determine Particle Size
3. Sedimentation method :
• Range : 1 - 200 µm
• Andreasen pipette is used.
• Particle size is calculated by stoke’s law :
dst =
Where,
h = distance of fall in time, t
no = viscosity of the medium
ρs = density of the particles
ρ0 = density of the dispersion medium
g = acceleration due to gravity
19
18 η0 h
(ρs -ρ0) gt
20. Methods to Determine Particle Size
4. Light energy diffraction :
• Range : 0.5 – 500 µm
• Particle size is determined by the reduction in light
reaching the sensor as the particle, dispersed in a liquid
or gas, passes through the sensing zone.
• Quick & fast.
5. Laser holography :
• Range : 1.4 – 100 µm
• A pulsed laser is fired through an aerosolized particle
spray & photographed in three dimensional with
holographic camera, allowing the particles to be
individually imaged & sized.
20
21. Methods to Determine Particle Size
6. Cascade impaction :
• The principle that a particle driven by an
airstream will hit a surface in its path,
provide that its inertia is sufficient to
overcome the drug force that tends to keep in
it in airstream.
21
22. 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 causing packing & densification of particles..
By using glident we can alter the flow properties.
e.g. Starch, Talc.
22
23. Determination Of Powder Flow Properties
By determining Angle Of
Repose.
A greater 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
23
24. Determination Of Powder Flow Properties
Measurement of free flowing powder by
compressibility.
Also known as Carr's index.
CARR’S INDEX(%) =(TAPPED DENSITY – POURED DENSITY) X 100
TAPPED DENSITY
It is simple, fast & popular method of predicting powder
flow characteristics.
24
26. 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 Very Poor
>40 Extremely Poor
26
28. PARTICLE SHAPE
• Particle shape will influence the surface area, flow of
particles, packing & compaction properties of the
particles.
• A sphere has minimum surface area per unit volume.
• Therefore, these properties can be compared for
spheres & asymmetric particles, in order to decide the
shape.
• The following expression can be obtained:
Property Sphere particle
surface area πds
2
αs x dp
2
volume (1/6)πds
3
αv x dp
3
28
Cont…
29. PARTICLE SHAPE
• Therefore,
surface area = πds
2
= αs x dp
2
Volume = (1/6)πds
3
= αv x dp
3
• Solving for αs & αv by equating the appropriate properties provides:
αs =
πds
2
& αv =
πds
3
• When particle shape is spherical, the ds = dp
• Thus, αs = π = 3.124 & αv = π/6 = 0.524
• Therefore, Shape factor = αs = 3.124 = 6
αv 0.524
29
Cont…
dp2 6 dp3
30. SURFACE AREA
• Particle size & surface area are inversely
related to each other.
• Smaller the drug particle, greater the surface
area.
Specific surface is defined as the surface area
per unit weight (Sw) or unit volume (Sv) of
the material.
30
31. SURFACE AREA
Estimation of Sv :
Sv = Surface area of the particles
Volume of particles
= n αs d2
n αv d3
= αs
αv d
• According to shape factor,
αs =
αv
• So, Sv = 6 / d.
31
6
32. SURFACE AREA
Estimation of Sw:
Sw = Surface area = Surface area
Weight density x volume
= Sv
ρ
= 6
ρ . d
32
33. Methods for determining
surface area
1. Adsorption method :
• Particles with a large specific surface are good adsorbents
for the adsorption of gases & of solutes from solution.
• The volume of nitrogen gas, Vm, in cm3
that 1 g of the
powder can adsorb when the monolayer is complete is
more accurately given by using the BET equation, however,
which can be written as:
P = 1 + (b-1) . P
V(P0 – P) Vmb Vmb P0
33
Cont….
34. Methods for determining
surface area
• Where,
V = Volume of gas in cm3
adsorbed per gram of powder
at pressure P.
P = Pressure of the adsorbate, in mmHg.
Po= Saturation vapor pressure (monolayer)
Vm= Amount of vapor adsorbed per unit mass adsorbent,
when the surface is covered with monomolecular
layer
b = Constant that express the difference between the
heat of adsorption & heat of liquefaction of the
adsorbate (nitrogen).
34
Cont….
36. HOW EVER SIZE REDUCTION
IS NOT REQUIRED IN FOLLOWING CASES
• WHEN DRUG IS UNSTABLE.
• DEGRADE IN SOLUTION FORM.
• PRODUCE UNDESIRABLE EFFECTS.
• WHEN SUSTAINED EFFECT IS DESIRED.
36
37. “ Solubilization is defined as the spontaneous
passage of poorly water soluble solute
molecules into an aqueous solution of a soap
or detergent in which a thermodynamically
stable solution is formed ”.
37
38. It is the process by which apparent solubility of
an otherwise sparingly soluble substance is increased
by the presence of surfactant micelles .
MICELLES: -
The mechanism involves the property of surface
active agents to form colloidal aggregates known as
micelles .
38
39. 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}
39
40. Solubilization is thought to occur by virtue of the
solute dissolving in or being adsorbed onto the
micelle.
Thus the ability of surfactant solution to
dissolved or solubilize water insoluble materials
starts at the CMC and increase with increase in the
concentration of micelles.
Solubilization of any material in any solvent
depends on proper selection of solubilising agents.
40
41. The process of solubilization involves the breaking
of inter-ionic or intermolecular bonds in the solute,
the separation of the molecules of the solvent to
provide space in the solvent for the solute,
interaction between the solvent and the solute
molecule or ion.
Step 1: Holes opens in the solvent
41
42. Step2: Molecules of the solid breaks away from the
bulk
Step 3: The free solid molecule is intergraded into
the hole in the solvent
42
43. The amount of substance that passes into
solution in order to establish equilibrium at
constant temperature and pressure to
produce a saturated solution.
43
44. If solubility is <1mg/ml indicates need for salt
formation to improve solubility.
If solubility is <1mg/ml in pH= 1 to 7,
preformulation study should be initiated.
Solubility should ideally be measured at two
temperatures: 4°C and 37°C.
4°C to ensure Physical stability.
37°C to support Biopharmaceutical evaluation.
44
45. Description Parts of solvent required for
one part of solute
Very soluble < 1
Freely soluble 1 - 10
Soluble 10 - 30
Sparingly soluble 30 - 100
Slightly soluble 100 - 1000
Very slightly soluble 1000 - 10,000
Insoluble > 10,000
45
46. Preformulation solubility studies focus on drug
solvent system that could occur during the delivery of
drug candidate.
For e.g. A drug for oral administration should be
examined for solubility in media having isotonic
chloride ion concentration and acidic pH.
46
47. Analytic method that are particularly useful
for solubility measurement include HPLC, UV
spectroscopy, Fluorescence spectroscopy and
Gas chromatography.
Reverse phase HPLC offer accurate and
efficient mean of collecting solubility data of
drug.
47
48. Ionization constant (pKa)
Can be calculated by Henderson Hasselbach
equation-
For acidic drugs….pH= pKa+ log [ionized drug]
[unionized drug]
For basic drugs….pH= pKa+ log[unionized drug]
[ionized drug]
48
49. pH Solubility Profile
The solubility of acidic or basic drug will show
difference in solubility with changes in pH.
pH solubility profile of a drug can be established
by running the equilibrium solubility experiment
within pH range of 3-4.
49
50. Partition Coefficient
It is the ratio of unionized drug distributed
between organic and aqueous phase at equilibrium.
P o/w = ( C oil / C water )equilibrium
50
51. Effect Of Temperature
The heat of solution Hs, represents the heat
released or absorbed when a mole of solute is
dissolved in large quantity of solvent.
Endothermic reaction
Exothermic reaction
51
52. Determination of solubility
The following points should be considered
The solvent & solute must be pure.
A saturated solution must be obtained before any
solution is removed for analysis.
The method of separating a sample of saturated
solution from undissolved solute must be
satisfactory.
The method of analyzing solution must be reliable
Temperature must be adequately controlled .
52
53. Solubility Determination Method
Solubility is normally depends on temperature,
so temperature is recorded in each solubility
measurement.
Plot of solubility against temperature is
commonly used for solubility determination.
Two methods are available for determination
are as follow.
I.Analytical method
II.Synthetic method
53
54. Analytical method
Temperature of equilibrium is fixed and
concentration of the solute in the saturated solution
is determined at equilibrium by a suitable
analytical procedure.
In other words a saturated solution in the
presence of an excess of the undissolved solute is
prepared at an accurately known temperature.
This situation can be achieved by suitable contact
b/w solute and solvent.
54
55. In this method a weighed amount of solute is
placed in the vessel.
While agitating the system at constant
temperature known amount of solvent is added
gradually until the solubility limit is reached.
At equilibrium, temperature and content of the
system is recorded.
This method is carried out at micro scale level by
examining the small amount of the system under
hot stage microscope.
55
Synthetic method
56. Addition of co-solvent
pH change method
Reduction of particle size
Temperature change method
Hydotrophy
Addition of Surfactant
Dielectrical Constant
Complexation
56
General Method of Increasing
the Solubility
57. • Weak Electrolyte :- Phenobarbitone
• Non polar :- Nitro Cellulose
These are poorly soluble in given solvent.
For such poorly soluble materials, to enhance
their solubility, the water miscible solvents are used
in which the drug has good solubility.
This process of improving solubility is known as
co-solvency and the solvent used is known as co-
solvents.
57
Addition Of Co-Solvent
58. e.g. Phenobarbitone is insoluble in water. A clear
solution is obtained by dissolving in mixture of
Alcohol, Glycerin, Propylene glycol.
e.g. Of Cosolvents:-
PG, glycerin, sorbitol, PEG, Glyceryl formal,
glycofurol, ethyl carbamate, ethyl lactate and
dimethyl acetamide.
58
Addition Of Co-Solvent
59. pH change Method
Weak base:- Alkaloids, Local Anaesthesia
Weak acid:- Sulphonamides, Barbiturates
In aqueous medium they dissociate poorly and
undissociated portion is insoluble.
e.g. Benzoic acid, Phenobarbitone
So, solubility of the undissociated portion is
improved by pH control.
For weak acidic drug:- increase pH, solubility is
increase.
For weak base drug:- decrease pH, increase
solubility.
59
60. Reduction in Particle size improve solubility of
drug.
Basically reduction in particle size increase contact
surface area of the particle, there by ultimately it
increase rate of solubility of drug.
Reduction Of Particle size
60
61. In endothermic reaction by increasing
temperature solubility is increase.
In exothermic reaction by increasing temperature
solubility is decrease.
e.g. Methyl Cellulose when mixed with water and
temperature is raised, it becomes insoluble. To
dissolve it cold water is added.
61
Temperature Change Method
62. The term Hydotrophy has been used to designate the
increase in solubility in water of various substances
due to the presences of large amount of additives.
e.g. Solubilization of Benzoic acid with Sodium
benzoate.
62
Hydotrophy
63. Surfactants are molecules with well defined polar
and non-polar region that allow them to aggregate in
solution to form micelles. Non polar drugs can
partition into micelles and be solubilized.
e.g. Surfactant based solution of Taxol, that is
solubilized in 50% solution of Cremophor.
63
Addition of Surfactant
64. Dielectrical Constant is the effect that substances
has, when it acts as a solvent on the case with which it
separates oppositely charged atoms.
e.g. DEC of Water- 80
Kerosene- 2
Glycerine- 48
Benzene- 2.2
64
Dielectrical Constant
65. Complexation
For the Complexation occur both drug and ligand
molecule should be able to donate or accept
electrons.
The solubility of compound is the sum of solubility
of the compound and its complex.
e.g. HgI2 (Mercuric Iodide) is sparingly soluble in
water. Its solubility in water is increased by forming
complex with KI.
HgI2 +2KI K2HgI4 (water soluble)
65
66. Applications of solubilization
Drugs with limited aqueous solubility can be
solubilized. These include oil-soluble vitamins,
steroid hormones and antimicrobial agents etc.
Solubilization of orally administered drugs results
in an improved appearance and improves
unpleasant taste.
Both oil-soluble and water-soluble compounds can
be combined in a single phase system as in case of
multivitamin preparations.
66
67. Solubilization may lead to enhanced absorption
and increased biological activity.
Improves the intestinal absorption of vitamin A.
Drug absorption from ointment bases and
suppositories also increased.
Liquid preparations with small quantity of
preservative can be prepared by solubilization.
67
Applications of solubilization
68. Aqueous concentrates of volatile oils can be
prepared by solubilization.
Example: soaps used for solubilising phenolic
compounds for use as disinfectants- Lysol,
Roxenol etc.
Barbiturates, anticoagulant, alkloidal drugs are
dissolved with polysorbate by solubilization.
68
Applications of solubilization
69. HLB SCALE
Most antifoaming agents
W/O Emulsifying agents
Wetting and Spreading agents
O/W Emulsifying agents
Detergents and Solubilizing agents
0
3
6
9
12
15
18
69
![Pre-Formulation [Autosaved] [Autosaved] [Autosaved].ppt](https://image.slidesharecdn.com/pre-formulationautosavedautosavedautosaved-250726203822-bdd9538f/85/Pre-Formulation-Autosaved-Autosaved-Autosaved-ppt-1-320.jpg)
![ Ionization constant (pKa)
Can be calculated by Henderson Hasselbach
equation-
For acidic drugs….pH= pKa+ log [ionized drug]
[unionized drug]
For basic drugs….pH= pKa+ log[unionized drug]
[ionized drug]
48](https://image.slidesharecdn.com/pre-formulationautosavedautosavedautosaved-250726203822-bdd9538f/85/Pre-Formulation-Autosaved-Autosaved-Autosaved-ppt-48-320.jpg)
