Industrial Pharmacy

Getahun Paulos (B.Pharm;MSc; PhD)

5/19/2020 Preformulation by Getahun P 1

• Industrial pharmacy is a discipline which includes
manufacturing, development, marketing and distribution of
drug products including quality assurance of these activities

• The reasons for the increasing of large scale manufacturing

– Economic — As the scale of manufacturing batches increases so,
proportionally, does the cost of production decreases
– Accuracy — The larger the quantities of materials involved so,
proportionally, is the accuracy of measurements increased
– Greater scope – The increasing complexity of modern therapy
has made it virtually impossible to prepare many medicaments
on a small scale

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 Bulk characteristics
(Solid State Properties)

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 1. Particle size characterization

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 A. Particle size
• Are standardized according to the USP descriptive terms, such as,
very fine, fine, moderately coarse, coarse, and very coarse.

Maximum
Designation Requirements
Diameter
Very Fine ≤ 180 μm (All pass through No. 80 sieve)
Fine ≤ 250 μm (No. 60 & not more than 40% No.100150)
Moderatly Coarse ≤ 425 μm (No. 40 & not more than 40% No.80)
Coarse ≤ 850 μm (No. 20 & not more than 40% No. 60)
Very coarse ≤ 2360 μm (No. 8 & not more than 20% No. 60)

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 Particle size…
The size of a sphere is readily expressed in terms of its diameter.

Equivalent spherical diameter

• Is used to express the size of asymmetric particles
• Equivalent spherical diameter relates the size of the particle to
the diameter of a sphere having the same surface area, volume
or diameter.
– surface diameter, ds, is the diameter of a sphere having the same
surface area as the particle in question.
– Volume diameter, dv, is the diameter of a sphere having the same
volume as the particle
– Projected diameter, dp, is the diameter, dp, is the diameter of a
sphere having the same observed area as the particle when viewed
in its most stable plane.
– Stokes’ diameter, dst, is the diameter of a sphere undergoing
sedimentation at the same rate as the asymmetric particle.
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Particle size…

Influences of Particle size

• Dissolution rate & solubility
• Bioavailability of a drug product e.g. griseofulvin,
phenacetin, tolbutamide, spironolactone
– Sulphadiazine suspension
• 1-3μm absorption more rapid and efficient than 7-21μm
• 40% higher (max. blood levels) occurred 2 hours earlier
– Griesofulvin
• Extent of absorption increased by 2.5 times when surface
area increased by 6 times

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Particle size…

• Suspendability & uniform distribution

• Content uniformity & flow property (e.g Tablets
& capsules
• Stability
– Attack from atmospheric oxygen &humidity (e.g.
aspirin);
• Penetrability
• Grittiness

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Particle size…

Methods to determine particle size

• Sieving (sieve analysis and image analysis)
• Microscopy (light microscope with calibrated
grid)
• Sedimentation rate method (andreason Pippet)
• Coulter counter
• Laser light scattering method (laser diffraction,
PCS)

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Particle size…

Criteria to determine method of analysis/

instrument
• Measuring range required (min & max size)
• Precision required
• Quantity of sample to be analyzed
• Time of analysis
• Media in which sample can be analyzed (dry
or in liquid)
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Particle size…
a. Sieving
• ISO sets in the range of 45-1000µm of aggregate or particles
• Sieve practically can measure 5-125,000µm
• Requires long time for analysis (5-30min)

Advantage
– Simple
– low cost
– little skill for operation
Disadvantage
– Large sample size required
– Blinding of the screens due to mechanical clogging

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 Particle size…
b. Microscopy
• Particles are sized directly and
individually using projected Advantage
area diameter • Shape, photomicrographs ,
aggregate can be detected,
Disadvantage
• Tedious & time consuming (500 – Range of analysis
1000 particles)
– TEM: 0.001-0.1µ
• Require more skill
– SEM: 0.01-1000µ
• Sampling is important (true
– Light microscope: 1-1000µ
representation)
• SEM and TEM give three
dimentional image
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Optical Microscopy
• Particle size measurement in the range of 0.2 µm to about 100 µm.

• In this method, an emulsion or suspension is mounted on a slide

and placed on a mechanical stage.

• The microscope eyepiece is fitted with a micrometer by which the

size of the particles may be estimated.

• The field can be projected onto a screen where the particles are
measured more easily.

• The particles are measured along an arbitrary chosen fixed line,

generally made horizontally across the center of the particle.

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• Popular measurements are the Feret diameter,
the Martin diameter and the Projected area
diameter (Figure--).
– Martin’s diameter (No. 1 in the figure)
• is the length of a line that bisects the particle image
– Feret’s diameter (No. 2 in the figure)
• is the distance between two tangents on opposite sides of
the particle parallel to some fixed direction (y-direction in
the figure).
– The projected area diameter (No.3 in Figure)
• is the diameter of a circle with the same area as that of the
particle observed perpendicular to the surface on which the
particle rests.

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 3 1 2

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• Disadvantage of the microscopic method
– the diameter is obtained from only two
dimensions of the particles, length and breadth.
– No estimation of the depth (thickness) of the
particle is available.
– the number of particles that must be counted
(300 to 500) to obtain a good estimation of the
distribution makes the method somewhat slow
and tedious

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Particle size…

c. Sedimentation
• Range: 1-200microns
• Andreasen pipette is used

Principle:
• Difference in the velocity of fall of particles in
suspension
• V= distance/time = 2r2(ρs-ρl)g/ η
• Limitations: assumes spherical shape
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 The Andreasen apparatus
• consists of 550 ml vessel containing 10 ml pipette sealed
into a ground-glass stopper.
• A 1 or 2% suspension of the particles in a medium
containing a suitable deflocculating agent is introduced
into the vessel and brought to the 550 ml mark.
• The stoppered vessel is shaken to distribute the particles
uniformly throughout the suspension and the apparatus
with the pipette is clamped securely in a constant-
temperature bath.
• At various time intervals, 10 ml samples are drawn and
discharged by means of the two-way stopcock.
• The samples are evaporated and weighed or analyzed by
other appropriate means correcting for the
deflocculating agent added.

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Particle size…

d. Coulter Counter/Stream Scanning

Electrical stream sensing-zone method
• Size range 0.1-1000µm
• Principle: blockage of electrical conductivity;

• Particle suspension passes through a sensing zone where

individual particles/cells are electronically sized, counted as
they pass through an aperture

Advantage:
• Reasonable accuracy;
• Data generated in short time.
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Particle size…
• Fastest and reliable: counts 1000 particle in
one second.
• Multisizer™ 3 COULTER COUNTER® provides
– number, volume, mass and surface area size
distributions in one measurement, with an overall
sizing range of 0.4 μm to 1,200 μm;

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Particle size…

e. Light scattering
Laser Diffraction
• Particles are presented either in liquid or in air suspension.
– 0.01 μm to 2000 μm

• Measures light diffraction from suspended particles

without forming an image of the particles onto a detector
– Based on the interaction of laser light with particles
• Example: Malvern laser diffraction, Sympathec particle sizer

• Fast (analysis time, 10 sec)and inexpensive

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Particle size…

Scatterers
– solid particles (such as metal oxides, mineral
debris, and latex particles) or
– Soft particles (such as vesicles and micelles) in
suspension, or
– Macromolecular chains (such as synthetic
polymers and biomaterials) in solution.

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Particle size…

i. Static light scattering/Fraunhofer diffraction

• For particles that are much larger than the wave
length of light,

• Degree of diffraction is proportional to particle

size
– By measuring the angles & intensity of scattered light
from the particles, a particle size distribution is
obtained.
• Each particle is treated as spherical and
essentially opaque to the impinging laser light
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Particle size…
ii. Dynamic light scattering/Photon-correlation
spectroscopy
• Principle:
– Brownian motion of smaller particles suspended in a fluid
• Uses the scattered light to measure the rate of
diffusion of the particles.

• This motion data is conventionally processed to derive

a size distribution for the sample
• Size is given by “stockes radius” or hydrodynamic
radius”.

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Particle size…
• Brownian Motion • This movement* arises from
the random thermal motion of
the medium’s molecules
• First observed by the English
botanist Robert Brown

Advantages of PCS
• Require only a small sample
• Method of choice for sizing
submicron particles.

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 B. Particle shape
• Spherical smooth, spherical rough, spherical
irregular
• Rounded, angular, elongated irregular
• Acicular, angular, dentritic

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• Particle shape influences:
– Surface area
– Flow property
– Packing
– Compaction properties of the particles

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 C. Surface area
• Specific surface area: the surface area per unit
weight or unit volume of the material.
• Surface area determination
– Adsorption method &
– Fluid permeability methods

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Adsorption method
• Most substances adsorb mono molecular layer of
gas at a given temperature.
• Monolayer adsorption of gas (under certain
conditions: partial pressure of the gas and temp)
– N2 is used at a specific P by mixing it with an inert gas, He
• Degree of adsorption is proportional to SA
– Interaction: van der waals; non specific
• The volume of nitrogen gas adsorbed at
monomolecular per gram of powder is given by
Brunauer Emmett Teller (BET) equation

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• This equation is usually written in the form:

• Where
– p0 is the saturation vapour pressure (monolayer),
– V is the equilibrium volume of gas adsorbed per unit mass (per gram of
powder) of adsorbent,
– Vm is the volume of gas required to cover unit mass of adsorbent with
monolayer,
– P= pressure of the adsorbate (the pressure attained after adsorption has
taken place)
– C is a constant that express the difference b/n the heat of adsorption & heat
of liquefaction of the adsorbate (nitrogen)
• The equation reduces to the Langmuir equation if adsorption is restricted
to monolayer formation.

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 Air permeability method:
• The principle: based on the resistance to the
flow of a fluid, such as air, through a plug of
compacted powder.
– Rate of flow that is permeability of fluid depends
on particle size.
– The greater the surface area per gram of powder,
the greater the resistance to flow.
– Measurement of rate of fluid enables mean
particle size to be calculated.

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 2. Crystallinity and polymorphism

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 Polymorphism
• Polymorphism:
– Ability of a compound to crystallize as more than one
distinct crystalline species
• Formation of different polymorphs
– depends on solvents, temperature, rate of cooling, etc.
– Polymorphic transitions can also occur during milling,
granulating, drying and compressing operations.
• Different polymorphs vary in physical properties
– dissolution, solid state stability, compatibility, solubility,
melting point, density, hardness, compression etc

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• Polymorphs are of 2 types
– Enantiotropic polymorph: A polymorph which can
be reversibly changed from one form into another
by varying the temperature or pressure (stability
of polymorphs vary with temprature and
pressure) e.g. sulfur
– Monotropic polymorph: a polymorph which is
unstable at all temp. & pressure (only one form is
stable at all temp and pressure, other metastable);
eg. Glyceryl stearate

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• Remarkably common, particularly within certain
structural group:
– 63% of barbiturates, 67% steriods and 40%
sulfonamides exhibit polymorphisms.

• During preformulation it is important to identify

the polymorph that is stable at room temp, eg
– Chloramphenicol exist in A,B & C forms, of these B
form is more stable and most preferable.
– Riboflavin has I,II & III forms, the III form shows 20
times more water solubility than form I.

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 Influence of polymorphism on drugs and products

• Influence on solubility, dissolution, & bioavailability

and bioequivalence
• Influence on manufacturing of the drug product
– particle shape, density, flowability, and compactibility
• Influence on stability (different physical and chemical
reactivity properties)

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 3. Hygroscopicity

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 Hygroscopicity
• The tendency of a solid to take up water from the
atmosphere
– Particularly for water soluble salt forms
– Deliquescent: adsorbs sufficient water to dissolve
completely (e.g. anhydrous calcium chloride).

• Greatly influence solid state parameters e.g.

– Chemical stability
– Flowability
– Compactibility

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Effect of moisture on powder compaction
• Optimal moisture increases the compaction
strength by:

– Increasing the tensile strength of the powder bed,

– Recrystallization

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 Moisture uptake
Saturated salt solutions used for different
relative humidity levels

Salt RH (%) @ 20°C

– Magnesium chloride 33
– Potassium carbonate 44
– Sodium nitrite 65
– Sodium chloride 75
– Potassium chloride 85

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 Water uptake profile

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 Water sorption isotherm

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 Deliquescence

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 4. Powder properties

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Derived properties of powders
• The fundamental properties
– Size distribution and
– Surface areas
• Derived properties that are based upon these
fundamental properties
– Porosity,
– Packing arrangements,
– Densities of particles,
– Bulkiness,
– Flow properties and
– Compaction

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A) Porosity
bulk volume, Vb
• Suppose a powder is placed in a graduated cylinder and the
total volume is noted, the volume occupied is known as the
bulk volume, Vb.

• The volume of the spaces, known as the void volume, v, is

given by the equation,
V = Vb - Vp Vp is the true volume of the particles

• The porosity or voids, Є, of the powder is defined as the ratio

of the void volume to the bulk volume of the packing:
Є = Vb - Vp = 1 - Vp
Vb Vb

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B) Packing arrangements
• Powder beds of uniform sized spheres can
assume either one of two ideal packing
arrangements:
– closest or rhombohedral packing, and
– most open, losest, or cubic packing

• The theoretic porosity of a powder consisting of

uniform spheres in closest packing is 26% and
loosest packing is 48%.
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C) Densities of particles
• Density is defined as weight per unit volume.
• For convenience, three types of densities may be defined:
– True density of the material itself, exclusive of the voids and
intraparticle pores larger than molecular or atomic dimensions
in the crystal lattices.
– Granule density as determined by the displacement of mercury,
which doesn’t penetrate at ordinary pressures into pores
smaller than about 10 micrometer.
– Bulk density as determined form the bulk volume and the
weight of a dry powder in a graduated cylinder.

• When a solid is nonporous, true and granular density are

identical.

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 Density
Density
• Absolute density (True density)
• Bulk density (important for drug of low potency, packaging e.g.
capsule)
• Tapped density and Vibratory Packing Density

Methods
• Pycnometry (Specific gravity bottles):
– Hydrostatic weighing (Displacement method)
– Compares the weight of the sample in air to the weight of the sample
immersed in a liquid of known density
• Air pycnometry (air displacement)
• Density gradient column

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• Tape density analyser

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 D) Bulkiness
bulkiness
• Specific bulk volume (the reciprocal of bulk
density) is often called bulkiness or bulk.
• It is an important consideration in the
packaging of powders.

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 E) Flow
Flowability
• Important for powder, capsule and tablet dosage
forms
• A bulk powder is somewhat analogous to a non-
Newtonian liquid
– which exhibits plastic flow and sometimes dilatancy,
the particles being influenced by attractive forces to
varying degrees.
• Accordingly, powders may be free-flowing or
cohesive.
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Factors affecting flow properties of powders
• Physical properties of the powder (size, size range,
density, shape, porosity, interactions between particles,
surface texture)
• Environmental factors (air or moisture content, external
pressure, vibration, which modify the physical distribution
and arrangement of the particles in the powder mass)
• Individual particle changes (due to; attrition,
agglomeration, electrostatic charge and chemical changes)

Experimental investigation should evaluate the flow

properties of the powders at worst-case scenario

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 flow…
Effect of moisture on powder flow
• Two fundamental forces affecting powder
flow:
– Cohesion (mutual attraction and resistance to
separation of contacting powder particles of
identical material)
– Friction (resistance exerted by one particle
against the motion of another particle at the
points of contact)

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 Determination of powder flow properties

Flow rate:
• Several rate flow (g/sec) determinations at each
of variety of orifice sizes (1/8 to ½ inches) should
be made.
• Greater standard deviation leads to greater
weight variation
– The dependence of flow rate (W) on true particle
density (p), gravity (g), orifice diameter(D), is given by
D=A (4W/60g)^1/n
• Where A & n are constants dependent on material and
particle size

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Flow…
• Angle of repose: Angle of repose Type of flow
tan θ = h/r
(in degree)
• where
– θ = angle of repose <20 Excellent
– h =height of the powder
cone/pile 20-30 Good
– r = radius of the powder 30-40 Passable
cone
• It should be less than >40 Very Poor
300

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Flow…

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Flow…

Derived properties Value Type of flow

Carr’s index =
5-15 Excellent
100 (Tapped density– Bulk density)/
Tapped density 12-16 Good
– less than 15% are 18-21 Fairly passable
indicative of free-flowing
powders; 23-35 Poor
– greater than 40% 33-38 Very poor
correspond to very poor
flow >40 Extremely poor

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• Hausner ratio = Tapped density / Bulk density
– less than 1.25 indicate good flow properties
– greater than 1.5 indicate poor flow properties

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