UNIT OPERATION / PRODUCTION PROCESS


In-Process Quality Control for Powders

Particle Sizes

Particle size distribution is mainly estimated by analytical sieving or by application of other methods, and the powders are standardized according to the USP descriptive terms. The purpose of particle size analysis is to obtain quantitative data on drug and other components used in pharmaceutical formulations on the size, distribution and shape. Their main application is to extract drug compounds from botanical or zoological sources like animal pancreas which can be prepared into powder to extract insulin.

DEFINITION OF POWDERS OF VERGETABLE AND ANIMAL DRUGS

USP Descriptive Terms

Maximum Diameter

Fineness

Very Course (No. 8)

≤ 180 µm (≤ 0.180 mm)

Not more than (nmt) 20% through a no. 60 sieve

Course (No. 20)

≤ 250 µm (≤ 0.250 mm)

Nmt 20% through a no. 80 sieve

Moderately course (No. 40)

≤ 425 µm (≤ 0.425 mm)

Nmt 40% through a no. 80 sieve

Fine (No. 60)

≤ 850 µm (≤ 0.850 mm)

Nmt 40% through a no. 100 sieve

Very Fine (No. 80)

≤ 2360 µm (≤ 2.36 mm)

No limit to greater fineness

 

Designation

Maximum Diameter

Requirements

Very Fine

≤ 180 µm (≤ 0.180 mm)

passes through a No. 80 sieve

Fine

≤ 250 µm (≤ 0.250 mm)

passes through a No. 60 sieve

Moderately Coarse

≤ 425 µm (≤ 0.425 mm)

passes through a No. 40 sieve

Coarse

≤ 850 µm (≤ 0.850 mm)

passes through a No. 20 sieve

Very Coarse

≤ 2360 µm (≤ 2.36 mm)

passes through a No. 8 sieve

 

Designation

Maximum Diameter

Requirements

Very Fine

≤ 125 µm (≤ 0.125 mm)

passes through a No. 120 sieve

Fine

≤ 180 µm (≤ 0.180 mm)

passes through a No. 80 sieve

Moderately Coarse

≤ 425 µm (≤ 0.425 mm)

passes through a No. 40 sieve

Coarse

≤ 850 µm (≤ 0.850 mm)

passes through a No. 20 sieve

 

Particle Size Analysis

  1. Sieving – is the simplest process and the most commonly used method for determining particle size distribution of powders. Sieves are made with a wire cloth woven from brass, bronze, or other suitable wires, and are used for pharmaceutical testing and measurement, and for the reduction of particle size of powders. A powder mass is placed on top of a sifter (mechanical shaker) and then the horizontal sieve motion loosens the packing of particles allowing sub sieve particles to pass through.
  2. Microscopy – this uses light within the visible spectrum and a system of lenses in order to magnify small samples. Powders are measured using a calibrated grid background, then microscopic images of particles can be forwarded to a computer and the size and the size and distribution can be analyzed by an image analyzer. The resolution limit by light microscopy is 0.2 µm, thus electron microscopy can be highly useful for particles smaller than this size.
  3. Sedimentation Rate – gravitational sedimentation measures the settling rate of particles in liquid medium and relates this rate to the particle mass which is determined by density and particle size, by the use of Stoke’s law, which is:

where dx/dt is the rate of settling in cm/s, d is the diameter of the particle in cm, ps is the density of the particles (g/cm3), g is the added acceleration due to gravity (981 cm/s2), and no is the viscosity of the medium in poise (g/(cm·s)).

  1. Coulter Counter – determines the sizing and counting of particles based on measurable changes in electrical impedance produced by nonconductive particles suspended in an electrolyte. A small opening (aperture) between electrodes is the sensing zone through which suspended particles pass.
  2. Light Scattering – particle size can be determined by measuring the random changes in the intensity of light scattered from a solution or in the dry powder state.
  3. Gas Adsorption – surface area of powdered materials can be measured by the adsorption of solute from a solution or gas, which results in the specific area (area/unit mass). Usually, an inert gas, such as nitrogen, is adsorbed as a monolayer and the total volume of gas adsorbed is used to calculate the specific surface area, which in turn provides information on the particle size.
  4. Laser Diffraction – when a beam of light (laser) is scattered by a group of particles, the angle of light scattering is inversely proportional to particle size (i.e. the smaller the particle size, the larger the angle of light scattering).
  5. Cascade impaction – a particle driven by an airstream will heat a surface in its path, provided that its inertia is sufficient to overcome the drag force that tends to keep it in the airstream.
Surface Area
  • As the particle size decreases, the surface are per unit volume (or mass) increases, and vice versa.
  • This criteria is not generally used for drug substances.
  • Mostly used methods are gas adsorption method and air permeability method.
  • In gas adsorption, gas is adsorbed as monolayer on particles. This is in term calculated and converted to surface area.
  • In air permeability, the rate of air permeates a bed of powder is used to calculate surface area of powder sample.
Density
  • Density may influence compressibility, tablet porosity and dissolution
  • Dense hard granules may require higher load to produce cohesive compact to reduce free granules seen on the surface of tablets.
  • Dense granules have less friability but can cause a problem in releasing the drug.

    • Bulk Density

    • If more compressible bed of particles – less flowable powder or granules.
    • If less dense or compressible – more flowable powder or granules

    Pb = M/Vb

    • Pb – bulk density of granules
    • M – mass of granules in gram.
    • Vb – volume of granules in measuring cylinder in mL

    • True or tapped Density

    Pb = M/Vb

    • Pb – bulk density of granules
    • M – mass of granules in gram.
    • Vb – volume of granules in measuring cylinder after tapping in mL

    • Granular Density

    • This is determined by using pycnometer.
    • Intrusion fluid is used but not limited to mercury and any solvent of low surface tension, e.g.: benzene.
    • The accuracy of this method depends upon the ability of intrusion fluid to penetrate the pores of granules.
    • Liquids should not mask dissolved granules, and must have the property to penetrate pores.
    • Density is then determined from volume of intrusion fluid displaced in pycnometer by given mass of granulation.
    • It is calculated by using the equation:

      Granular Density (D) = M/Vp-Vi

      • Where, Vp – total volume of pycnometer

                     Vi – volume of intrusion fluid (mL), containing mass (M) in grams of granules required to fill pycnometer.

    • Granular Strength and Friability

    This affects the following:

    • Changes in particle size distribution of granulations.
    • Compressibility into cohesive tablets.

    Granule strength and friability are measured by:

    • Compressive strength/hardness
    • Using friability measurements/apparatus

    • Flow Properties

    It is an ability of the granule to flow from hopper to die cavity for tablet uniformity.

    Flow property of material results from many forces:

    1. Frictional force
    2. Surface tension force
    3. Mechanical force caused by interlocking of irregular shape particles
    4. Electrostatic force
    5. Cohesive/ Van der Waals forces

    Forces can also affect granule property such as particle size and shape, particle size distribution, surface texture, roughness and surface area.

    1. If particle size of powder is ≤ 150 micrometers, the magnitude of frictional and van der waals force predominate.
    2. When particle size increases mechanical and physical properties become more important with packing properties.
    3. Flow properties of granules are determined by measuring 3 parameters:

      • Angle of repose

    Number

    Angle of repose

    Type of flow

    1

    < 25

    Excellent

    2

    25-30

    Good

    3

    30-40

    Passable

    4

    >40

    Poor


      • • Percentage compressibility index
        • It is directly related to the relative flow rate cohesiveness and particle size. It is simple, fast and popular method of presiding powder flow characters.
        • It can be obtained from bulk density measurements

    % compressibility index = tapped density – bulk density/tapped density *100

    or

    l = (l – V/Vo) *100

    where l is the % compressibility index

              V is the volume occupied by powder/granules after tapping

              Vo is the volume of powder/granules before tapping

    Number

    % Compressibility Index

    Type of Flow

    1

    5-15

    Excellent

    2

    12-16

    Very Good

    3

    18-21

    Good

    4

    23-25

    Passable

    5

    33-38

    Poor

    6

    >40

    Very Poor


    • Hausner’s ratio

    • It is related to interparticulate friction and as such could be used to predict powder flow characteristics.
    • It showed that powder with low particulate friction such as coarse sphere had ratio of approximately 1.2, but for cohesiveness, there were less free flowing powders such as flakes and acquired a Hausner’s ratio greater than 1.6.
      • Hausner’s ratio = Tapped density/Bulk Density
Moisture Content
  • The amount of moisture present in the granule is called moisture content.
  • Generally granules contain 2% moisture. It is required for the binding of the powder or granules during compression in die cavity.
  • Percentage of moisture is calculated by using moisture balance or IR balance.
  • IR balance consists of a balance enclosed in a casing where the IR bulb is attached and thus produce heat inside the chamber.
  • A small sample is taken from the oven to measure its moisture content and then placed in the moisture balance.
  • Initial reading should be noted down after initiating the IR bulb. The moisture is removed from the granules via heating in the initiation of the IR bulb, and once the process is done, the final reading should also be noted.

% moisture content = initial weight – final weight/initial weight * 100

Percentage Fines
  • Percentage fines is defined as the amount of powder remained in the granule.
  • It is necessary for tablet compression since 100% granules hardness is difficult to maintain because they have a large free space in the die cavity.
  • Percentage fines can be calculated by using sieve method.
  • Percentage fine should not be more than 15%.