PRAFORMULASI

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 Pengembangan Bentuk Sediaan

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 SEDIAAN PADAT

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 Pharmaceutic and Formulation
Considerations

Nonmedical agents, referred to as

pharmaceutic ingredients / exipient

Drug substances are seldom administered alone

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 The pharmaceutic ingredients

❖ solubilize,
❖ suspend,
❖ thicken
❖ dilute
❖ emulsify
❖ stabilize
❖ preserve
❖ color
❖ flavor

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 A drug product
✓ stable
✓ efficacious
✓ attractive
✓ easy to administer
✓ safe
✓ manufactured under appropriate
measures of quality control

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 The need for dosage forms

Besides providing the mechanism for the safe and convenient delivery
of accurate dosage, dosage forms are needed for additional reasons:

1. Protection from oxygen and humidity

(coated tablets, sealed ampuls)

2. Protection from gastric acid after oral

administration (enteric-coated tablets)

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 The need for dosage forms

3. To conceal the bitter, salty, or offensive taste or

odor of a drug substance (capsules, coated
tablets, flavored syrups)

4. Liquid preparation
insoluble
unstable
in the desired vehicle

Suspension
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 The need for dosage forms
5. Clear liquid dosage forms Syrups/ solutions

6. To provide rate-controlled drug action

(various controlled-release tablets, capsules
and suspensions)

7. To provide topical drug action from

topical administration sites
(ointments, creams, transdermal
patches, ophthalmic, ear, and nasal
preparations)

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 The need for dosage forms
8. To provide for the insertion of a drug into one
of the body’s orifices (e.g., rectal or vaginal
suppositories)

9. To provide for the placement of drugs directly

into the bloodstream or into body’s tissues (e.g.,
injections)

10. To provide for topical drug action through inhalation

therapy (e.g., inhalants and inhalation aerosols)

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 PRAFORMULASI

Langkah awal pengembangan bahan obat dalam bentuk

sediaan yang rasional, melalui pengumpulan informasi sifat
fisiko-kimia bahan obat baik secara sendiri maupun
kombinasinya dengan eksipien (bahan tambahan)
Tujuan Preformulasi :
Mengumpulkan informasi yang lengkap sehingga dapat
digunakan oleh formulator untuk mengembangkan bentuk
sediaan yang stabil dan aman sebelum diproduksi secara
massal

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 PREFORMULATION

DEFINITION:
Characterization of physical, chemical and mechanical
properties of new drug molecule in order to develop safe,
effective, and stable dosage form

GOAL OF PREFORMULATION:
❖To formulate an elegant, safe, efficacious dosage form with
good bioavailability.
❖To formulate new dosage form of already existing drug.
❖Determination of all the properties of drug and the best
suitable dosage form for the drug molecule.
❖To establish compatibility with common excipients.

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 Preformulation commences when a newly
synthesized drug shows a sufficient
pharmacologic promise in animal model to
warrant evaluation in man.

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 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

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 Preliminary Evaluation

e. Potential hazards
f. Initial bulk lots:
❖ Lot number
❖ Crystallization solvent(s)
❖ Particle size range
❖ Melting point
❖ % volatiles
g. Analytical methods:
❑ HPLC assay
❑ TLC assay
❑ UV/ Visible spectroscopy
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 ORGANOLEPTIC PROPERTIES

COLOR ODOUR TASTE

OFF-WHITE PUNGENT ACIDIC

CREAM- SULFUROUS BITTER

YELLOW
SHINY FRUITY SWEET

AROMATIC TASTELESS

ODOURLESS

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 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.

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 Odour
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. 20
 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

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 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.

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 PARTICLE SIZE

Particle size is characterized using these terms :

i. Very coarse (#8)
ii. Coarse (#20)
iii. Moderately coarse (#40)
iv. Fine (#60)
v. Very fine (#80)

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 PARTICLE SIZE

Particle size can influence variety of important

factors :
❑ Dissolution rate
❑ Suspendability
❑ Uniform distribution
❑ Penetrability
❑ Lack of grittiness

24
 Methods to Determine
Particle Size

❑ Sieving
❑ Microscopy
❑ Sedimentation rate method
❑ Light energy diffraction
❑ Laser holography
❑ Cascade impaction

04/05/2012 KLE College of Pharmacy, Nipani. 25

 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.
26
 Methods to Determine Particle Size

3. Sedimentation method :
❖ Range : 1 - 200 µm
❖ Andreasen pipette is used.
❖ Particle size is calculated by stoke’s law :

18 0 h
d st =
( 1 −  0 ) gt

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 27
 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.

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.

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 DRUG MOLECULE

1. Solubility Determination
2. pKa Determination
3. Partition Coefficient
4. Chemical stability profile
5. Crystal Properties and Polymorphism

6. Particle Size, Shape and Surface Area

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 1. Solubility Determination:

The solubility of drug is an important physicochemical property

because it affects the bioavailability of the drug, the rate of drug
release into the dissolution medium, and consequently, the
therapeutic efficacy of the pharmaceutical product.

The solubility of a molecule in various solvents is determined as a first

step.

Solubility is usually determined in a variety of commonly used

solvents and some oils if the molecule is lipophilic.

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The solubility of a material is usually determined by the equilibrium
solubility method, which employs a saturated solution of the material,
obtained by stirring an excess of material in the solvent for a
prolonged period until equilibrium is achieved
Common solvents used for solubility determination are:

Water
Polyethylene Glycols Isopropyl Alcohol
Propylene Glycol Tweens
Glycerin Polysorbates
Sorbitol Castor Oil
Ethyl Alcohol Peanut Oil
Methanol Sesame Oil
Benzyl Alcohol Buffers at various pHs

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 2. pKa Determination:
Determination of the dissociation constant for a drug capable of
ionization within a pH range of 1 to 10 is important since solubility,
and consequently absorption, can be altered by orders of magnitude
with changing pH.

The Henderson-Hasselbalch equation provides an estimate of the

ionized and un-ionized drug concentration at a particular pH.

For acidic compounds:

pH = pKa + log ([ionized drug]/[un-ionized drug])

For basic compounds:

pH = pKa + log ([un-ionized drug]/[ionized drug])

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 2. pKa Determination:

pKa of a compound is thus a measure of drug un-ionized at a

certain pH

pKa = -log Ka ,
where Ka is the acidity or ionization constant of a weak acid.

For a weak base, Ka = Kw/Kb,

where Kw is the ionic product of water (Kw=[H3O+] x [OH-]) and
Kb is the basicity or ionization constant of the weak

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 3. Partition Coefficient:

Partition coefficient (oil/water) is a measure of a drug's lipophilicity

and an indication of its ability to cross cell membranes.

It is defined as the ratio of un-ionized drug distributed between the

organic and aqueous phases at equilibrium.

Po/w = (C oil/C water) equilibrium

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Water and small, non-charged molecules have no difficulty crossing the
lipid portion of the membrane.
Ions and charged molecules cannot cross easily, nor can large molecules

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 4. Chemical stability profile:
Preformulation stability studies are usually the first quantitative assessment of
chemical stability of a new drug. These studies include both solution and
solid state experiments under conditions typical for the handling, formulation,
storage, and administration of a drug candidate as well as stability in presence
of other excipients.
Factors affecting chemical stability critical in rational dosage form
design include temperature, pH and dosage form diluent.
1. The method of sterilization of parenteral products will be largely
dependent on the temperature stability of the drug.
Drugs having decreased stability at elevated temperatures cannot be
sterilized by autoclaving but must be sterilized by another means, e.g.,
filtration.

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2. The effect of pH on drug stability is important in the development of both
oral and parenteral dosage forms; acid labile drugs intended for oral
administration must be protected from the highly acidic environment of
the stomach.
3. Buffer selection for parenteral dosage forms will be largely based on the
stability characteristics of the drug.

4. 1. Solid State Stability:

The primary objectives of this investigation are identification of stable

storage conditions for drug in the solid state and identification of
compatible excipients for a formulation

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In general, solid state reactions are much slower and more difficult
to interpret than solution state reactions, and it is customary to use
stress conditions in the investigation of stability.

The data obtained under stress conditions are then extrapolated to

make a prediction of stability under appropriate storage conditions.

Stress conditions utilized by the scientists are:

Elevated temperature Studies
Stability under High-Humidity Conditions
Photolytic Stability
Oxidative Stability

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 4.1.1. Elevated Temperature Studies:
The elevated temperatures most commonly used are 40°, 50° and 60° C in
conjunction with ambient humidity
The samples stored at the highest temperature should be examined for
physical and chemical changes at weekly intervals,

If a substantial change is seen, samples stored at lower temperatures are

examined .
If no change is seen after 30 days at 60°C, the stability prognosis is
excellent
The data obtained at elevated temperatures may be extrapolated using the
Arrhenius treatment to determine the degradation rate at a lower
temperature.
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4.1.2. High-Humidity Conditions:

In the presence of moisture, many drug substances hydrolyze,

react with other excipients, or oxidize. These reactions can be
accelerated by exposing the solid drug to different relative-
humidity conditions.
Preformulation data of this nature are useful in determining if the
material should be :
1. protected and stored in a controlled low-humidity
environment,
2. or if the use of an aqueous-based granulation system, in the
case of a solid dosage form, should be avoided.
3. the use of excipients that absorb moisure significantly.

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4.1.3. Photolytic Stability:

Many drug substances fade or darken on exposure to

light. Usually the extent of degradation is small and limited to the
exposed surface area.
This can be controlled by :
1. using amber glass or anopaque container or
2. by incorporating a dye in the product to mask the
discoloration (if the only issue is aesthetics).

Exposure of the drug substance to 400 and 900 footcandles of

illumination for 4- and 2-week periods, respectively, is adequate to
provide some idea of photosensitivity

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4.1.4. Oxidative Stability:

The sensitivity of each new drug entity to atmospheric oxygen

must be evaluated to establish if the final product should be

1. packaged under inert atmospheric conditions and if it

2. should contain an antioxidant.

Sensitivity to oxidation of a solid drug can be ascertained by

investigating its stability in an atmosphere of high oxygen
tension. Usually a 40% oxygen atmosphere allows for a rapid
evaluation. Results should be compared against those obtained
under inert or ambient atmospheres.

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4.2. Solution Phase Stability:

The primary objective of this phase of preformulation research is

identification of conditions necessary to form a stable solution. These
studies should include the effects of pH, ionic strength, cosolvent, light,
temperature and oxygen.
Solution stability investigations usually commence with probing
experiments to confirm decay at the extremes of pH and temperature
(e.g., 0.1N HCl, water, and 0.1N NaOH all at 90°C).

If a drug substance is adjudged to be physically or chemically unstable

when exposed to moisture, a direct compression or nonaqueous-solvent
granulation procedure is to be recommended for the preparation of
tablets. Before using a nonaqueous solvent for this purpose, stability of
the drug in the solvent must be ascertained.
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4.3. Compatibilty Studies:

In the tablet dosage form the drug is in intimate contact with

one or more excipients; the latter could affect the stability of the
drug. Knowledge of drug-excipient interactions is therefore
very useful to the formulator in selecting appropriate
excipients.
A typical tablet contains binders, disintegrants, lubricants, and
fillers. Compatibility screening for a new drug must consider two
or more excipients from each class. The ratio of drug to excipient
used in these tests is very much at the discretion of the
preformulation scientist.
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 COMPATIBILITY TESTS

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 DSC
DIFFERENTIAL SCANNING CALORIMETRY
DSC
is widely used to investigate and predict any physico-
chemical interaction between drug and excipients involving
thermal changes.
METHOD
1. The preformulation screening of drug-excipient
interaction requires (1:1)Drug:excipient ratio, to
maximize the likehood of observing an interaction.
2. Mixture should be examined under N2 to eliminate
oxidative effects at heating rate ( 2, 5 or 100 c / min) on
DSC apparatus.

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 DSC- DIFFERENTIAL SCANNING CALORIMETRY

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 EXAMPLE: DSC IN OFLOXACIN TABLETS

Trace 1 of figure 1-4 shows peak at 278.330C. (melting endothermic

peak of Ofloxacin).
Trace 3 (Physical mixture of Ofloxacin & Lactose) shows absence of
peak at 278.330C and slight pre shift in Lactose peaks.

DSC RESULT → INCOMPATIBLE

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 Trace 5 (Physical mixture of Ofloxacin & Starch) shows
an early onset at 268.370C. But no other changes in
thermogram.

DSC RESULT → COMPATIBLE

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 Trace 7 (Physical mixture of Ofloxacin & PVP) shows no change
in position of endothermic peak for PVP but there is increase in
peak area and size & shape of peak for Ofloxacin is also
decreased.

DSC RESULT → INCOMPATIBLE

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 Trace 9 (Physical mixture of Ofloxacin & Talc) shows
combine features of each component but there are evident
changes in onset.

DSC RESULT → COMPATIBLE

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 5. Particle Size, Shape and Surface Area:

Bulk flow, formulation homogeneity, and surface-area

controlled processes such as dissolution and chemical
reactivity are directly affected by size, shape and surface
morphology of the drug particles.

Various chemical and physical properties of drug substances are

affected by their particle size distribution and shapes. The effect
is not only on the physical properties of solid drugs but also, in
some instances, on their biopharmaceutical behavior.

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 6. Crystal Properties and Polymorphism:
Many drug substances can exist in more than one crystalline
form with different space lattice arrangements. This property is
known as polymorphism. Polymorphs generally have
different melting points, x-ray diffraction patterns, and
solubilities, even though they are chemically identical.

e.g . Chloramphenicol palmitate has three polymorphs A, B

and C .

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 PHARMACEUTICAL FACTORS
AFFECTING DOSAGE FORMS

Pharmaceutical factor mainly include those parameters of drug

which affect the final dosage form manufacturing process like :

1. Flow property
2. Density
3. Compressibility
4. Hygroscopicity
5. Electrostatic charge
6. Rheology
7. Wettability

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 1. FLOW PROPERTY

❑ Flow property is an important factor that determines the

fate of drug molecule.
❑ Sufficient flow is required for uniformity of dosage form.
So it is necessary to judge the flow of material in
preformulation stage of the dosage form.
❑ However extreme increase in flow may improve weight
uniformity but may reduce content uniformity through
increased segregation.

Method of determination :
By Angle of repose
By hopper flow rate
By bulk density
By angle of spatula
By vibrational capillary method
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 1.1 Angle of Repose
❖ Indirect method of quantifying powder
flowability,because of their relationship with
interparticle cohesion.

❖ It is a maximum angle between the surface of a

pile of powder & horizontal plane.

Angle of repose is measured by the equation:

tan Ɵ = h /r

here, h= height of conical heap &

r= radius of horizontal plane of powder

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 RELATION BETWEEN ANGLE OF REPOSE & TYPE
OF FLOW & TYPE OF POWDER

Angle of repose Type of flow Type of powder

<25 Excellent Non cohesive

25-30 Good Non cohesive

Passable
30-40 Cohesive

>40 Very Cohesive

Very poor

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 HAUSNER’S RATIO

This is a simplex index that can be determined on small quantities of

powder.
Hausner ratio Type of Flow
<1.25 Good flow
1.25-1.5 Moderate
>1.5 Poor flow

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 FACTOR AFFECTING FLOW PROPERTY
❖ Particle size and Particle size distribution
❖ Particle shape and Surface roughness
❖ Density and Porosity
❖ Hygroscopicity
❖ Electrostatic charge

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 IMPROVEMENT OF FLOWABILITY
➢ By addition of glidant
➢ By addition of fine or by size reduction
➢ By wet granulation
➢ By removing static charge
➢ By densification with the help of slugging
➢ Using auger feed equipment
➢ By addition of flow activator. Eg. MgO
➢ By use silicon treated powder for Hygroscopic &
moist powder.
e.g. silicon coated talc or Na-bicarbonate
➢ By altering process condition like vibration
assisted hopper or forced feeder
➢ By use of spray drying : Advantose 100 maltose
powder has improved flow property than MCC by
using this process.

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 2. DENSITY

The ratio of mass to volume is known as density.

massa( gram)
Density =  =
volume(mL)

TYPES OF DENSITY :
❖ Bulk density
❖ Tapped density
❖ True density
❖ Granule density :- may affect compressibility, tablet
porosity, disintegration, dissolution

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 Method of Determination

Parameter Method
1. Bulk density Measuring cylinder

2. Tapped Density Mechanical Device

Mercury Displacement

3. True Density Helium densitometer

(Helium Pycnometer)
Mercury Instrution Porosimetry

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Bulk density measurement
It is determined by pouring
presieved (40-mesh) bulk drug
into a graduate cylinder via-a
large funnel and measuring the
volume and weight.
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Tapped density measurement
It is determined by placing a graduated
cylinder containing an known mass of
drug or formulation on a mechanical
tapper apparatus, which is operated for
a fixed numbers of taps(about-
1000)untill the powder bed volume has
reached a minimum.
MF ARIFIN 64
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 IMPORTANCE

1. In case of combination therapy or physical mixture ,if both

drug or drug & excipients have different density then
creates problem of segregation (demixing).
2. Important in decide size & type of processing equipment.
E.g. decide size of capsule formulation, Suppositories.

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 3. COMPRESSIBILITY
Compressibility is the ability of powder to decrease in
volume under pressure.

Relationship between powder flowability and % compressibility

SR. % COMPRESSIBILTY RANGE FLOW DESCRIPTIONS
NO
1 5-15 Excellent (free flowing granules)

2 12-16 Good ( free flowing powder granules)

3 18-21 Fair to passable ( powder granules

4 23-28 Poor ( very fluid powder)

5 28-35 Poor ( fluid cohesive powder)

6 35-38 Very poor ( fluid cohesive powder)

7 >40 Extremely poor ( cohesive powder)

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 The characteristics Of material may be

1. PLASTICITY
Plastic material are capable of permanent deformation, also exhibit a degree of
brittleness (fragmentability)
But plastic material will get bonding after Viscoelastic deformation.

2. FRAGMENTABILITY
If material is fragmentable, neither lubricant mixing time nor dwell time affecting the
tablet strength.

3. ELASTICITY
E.g. paracetamol, acetyl salicylic acid
If material is elastic, it rebound when compression force is released.
Elastic material may lead to capping & lamination
They require wet massing to induce plasticity or plastic tableting material.

4. PUNCH FILMING [STICKING]:

This may lead to chipping of tablet.

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METHOD OF IMPROVEMENT

If plastic material → add fragmentable excipient

e.g.. Lactose .
If Elastic material → By plastic tableting material
Wet granulation ,
Pre compression.
If sticky material → By change in salt form,
By using high excipient ratio,
By wet massing,
By addition of Mg-stearate.

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 4. HYGROSCOPICITY

Hygroscopicity: - It is the tendency of material to absorb

moisture from atmosphere & be dynamic equilibrium
with water in the atmosphere.

Deliquescent: - It is the hygroscopic substance which

absorb moisture from air and they can be liquefied by
partially or wholly forming solution.

Efflorescent: - a substance which loses water to form a

lower hydrate or become anhydrous is term as
efflorescent

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 Hygroscopic & Deliquescent Efflorescent
Ephedrine atropine
Hyoscymine cocaine
Phenobarbital codeine
Pilocarpine scopolamine
Physostigmine caffeine
Glycerinated gelatin & PEG base of suppository are
hygroscopic in nature.
IMPORTANCE:
It affects the flow property.
It affects compression characteristic , granulation & hardness of
final tablet.
It also affects compaction.
Important in aerosol.
Affects chemical stability of hydrolysable drug.

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 METHODS OF IMPROVEMENT
For granulation of hygroscopic material use non-aqueous solvent.
For efflorescent material , use anhydrous salt.
Add finely powdered adsorbents like MgO or Mg carbonate.
Perform the entire tableting operation under controlled humidity
condition.
Store in desiccant, foil, blister, glass bottle.

Starch is hygroscopic ,but on pregelatinization it exhibits

lower propensity for moisture, thus providing excellent
stabilization for moisture sensitive active drugs

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 5. ELECTROSTATIC CHARGE

Electrostatic charges are the consequence of classic

attraction & repulsion effect between the charges
Electrostatic charge is produced:
By separation of positive & negative charge
By mechanical impact
By friction between two surface
By rupturing of particle
By separation of solid & liquid surface
Pharmaceutical processing procedure such as
mixing,micronizing, milling, sieving, rubbing (gosok),
compressing, spray drying & congealing (pembekuan), pan
coating & packaging can induce static charge.

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 IMPORTANCE
In preformulation of suspension .
Affects flow property of powder.
Affects mixing process.
For thermal stability of emulsions.
It may damage tablet machine.
It may affect compression coating

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 6. RHEOLOGY
It describes flow of liquid and/or deformation of solid
under stress.
TYPE OF FLOW:
Newtonian flow
Non Newtonian flow

IMPORTANCE
FLUID
For mixing
For particle size reduction of disperse system
Passing though orifice, pouring, packaging in bottle, passing though hypodermic
needle.
Flow though pipe
Physical stability of disperse system

QUASISOLIDS
Spreading and adherence to skin
Removal from jar
Capacity of solids to mix with liquid
Release of drug from base
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 IMPORTANCE

SOLID
Flow of powder from hopper and into a die cavity in
tableting or in encapsulation
Packagability of powder or granules solids.

PROCESSING
Production capacity of the equipment
Processing efficiency

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 7. WETTABILITY
Wettability of a solid is an important property with
regards to formulation of solid dosage form.

Adsorption at solid surface is involved in wetting &

detergency.

It may influence granulation of solid, penetration of

dissolution fluid into tablet and granules & adhesion
of coating material to tablet.

IMPORTANCE:
Crystal structure can influence the contact angle.
Problems associated with Wettability of powder are poor dissolution rate
& low adhesion of film coating.

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 IMPROVEMENT
Mixing with hydrophilic excipient like Na CMC (water
soluble) and bentonite, Al Mg silicate & colloidal silica
(water insoluble).

Use of wetting agent (HLB value 6-9) which acts by

lowering contact angle. It displaces air & replace it
with liquid phase.

Wetting of powder by non aqueous solvent can be

enhanced by certain lanolin derivative.

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 5. Crystal Properties and Polymorphism:

Many drug substances can exist in more than one crystalline form with
different space lattice arrangements. This property is known as
polymorphism. Polymorphs generally have different melting points, x-
ray diffraction patterns, and solubilities, even though they are
chemically identical.

Differences in the dissolution rates and solubilities of different

polymorphic forms of a given drug are very commonly
observed. When the absorption of a drug is dissolution rate limited, a
more soluble and faster-dissolving form may be utilized to improve the
rate and extent of bioavailability.

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 Different polymorphs also lead to different morphology, tensile strength
and density of powder bed which all contribute to compression
characteristics of materials

Although a drug substance may exist in two or more polymorphic forms,

only one form is thermodynamically stable at a given temperature and
pressure. The other forms would convert to the stable form with time.

In general, the stable polymorph exhibits the highest melting point,

the lowest solubility, and the maximum chemical stability.

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 6. Particle Size, Shape and Surface Area:

Bulk flow, formulation homogeneity, and surface-area controlled

processes such as dissolution and chemical reactivity are directly
affected by size, shape and surface morphology of the drug particles.

Various chemical and physical properties of drug substances are

affected by their particle size distribution and shapes. The effect is not
only on the physical properties of solid drugs but also, in some
instances, on their biopharmaceutical behavior.

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In case of tablets, size and shape influence the flow and the mixing
efficiency of powders and granules. Size can also be a factor in
stability; fine materials are relatively more open to attack from
atmospheric oxygen, the humidity, and interacting excipients than are
coarse materials.

6.1. Particle Size Determination:

Classical methods for measuring particle size

Microscopy
Sieving or screening
Sedimentation
Commonly used instruments

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 6.2. Surface Area Determination:

The determination of the surface areas of powders has been getting

increasing attention in recent years. The techniques employed are
relatively simple and convenient to use, and the data obtained reflect
the particle size. The relationship between the two parameters is an
inverse one, in that a grinding operation that reduces the particle size
leads to an increase in the surface area.
Two commonly available methods for determining surface area are:
Adsorption Method
Air Permeability Method

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