Dosages form Development Pre formulation Studies Bulk Characterization Part 2

Main ideas / concepts covered

• Why bulk particle properties matter for solid dosage form manufacturing and processing:

  • Particle properties influence surface area, flowability, packing, void spaces, airiness of the powder bed, and whether the powder flows properly.
  • These properties must be understood for each starting material so they can be used as-is or modified to meet dosage-form requirements.

• Micrometric (particle) properties discussed:

  • Particle size & distribution
  • Volume
  • Density
  • Porosity
  • Hygroscopicity
  • Overall takeaway conclusions

• Micrometrics definition and property categories

  • Micrometrics = science/technology of properties of small particles.

  • Properties split into:

    • Fundamental properties (inherently due to particle characteristics):

      • Particle size, size distribution, range (min–max), and number of particles
      • Surface area dependence on size: smaller particles → larger surface area (important for solubilization/absorption).
      • Particle shape: regularity vs irregularity (oblong/circular/globular/flaky/needle-like).
        • Example: globular particles flow more easily; irregular particles can interlock and form clumps/aggregates → poor flow.

    • Derived properties (computed/related to fundamental properties):

      • Density (depends on particle/volume characteristics)
      • Porosity / arrangement (depends on how particles pack; arrangement changes with size distribution)
      • Packing leads to different bulk behavior (bulkiness, void spaces, etc.)

• Bulk vs single-particle behavior

  • Bulk behavior concerns kilograms/tons of material, where size range, arrangement, and surface properties vary—affecting processing performance.
  • A small number of particles may behave similarly, but bulk systems behave differently.

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Methodology / instructions and calculation details

A) Particle size and size distribution

• How particle size is defined (equivalent diameters)

  • Diameter of a sphere that has the same:
    • weight (weight-based diameter), or
    • volume (volume-based diameter), or
    • surface area (surface-area-based diameter)
  • Also includes hydrodynamic/aerodynamic base diameter where similar behavior applies (same drag coefficient or sedimentation velocity).

• Monodisperse vs polydisperse

  • Monodisperse: particles fall within a specific narrow size range.
  • Polydisperse: multiple size ranges exist; distribution broadens (higher dispersity).
  • Example ranges mentioned (illustrative):
    • 10–20 µm
    • 100–200 µm
    • 0.1–0.5 µm (100–500 nm)

• Normal/Gaussian size frequency distribution

  • Plot frequency vs size range.
  • For Gaussian behavior: the distribution should be approximately symmetric around the midpoint/average.

• Techniques to determine particle size

  • Microscopy

    • Light microscopy for larger/cruder particles.
    • Electron microscopy for micro/nano range:
      • Transmission electron microscope (TEM) or scanning electron microscope (SEM).

  • Sieving (screening)

    • Use a series of sieves from coarsest → finest.
    • Measure weight retained on each sieve.
    • Correlate retained mass with corresponding particle size.

  • Sedimentation (Stokes’ law)

    • Use a fluid with known viscosity.
    • Measure rate of fall/sedimentation under gravity.
    • Use:
      • gravitational constant G
      • difference between particle density and medium density
    • Compute particle diameter from sedimentation rate.

  • Electrical resistance / orifice method (counter technique)

    • In a suspension (especially dilute), particles pass through an orifice.
    • Electrodes on both sides measure change in electrical resistance.
    • Resistance change corresponds to particle volume passing the aperture.

  • Surface adsorption method

    • Adsorb powder surface with air or liquid forming a monomolecular layer.
    • Use adsorbed volume to estimate mean particle size.

  • Dynamic Light Scattering (DLS)

    • Illuminate particles and analyze:
      • larger particles tend to diffract
      • smaller particles scatter light more effectively
    • Requires dilute suspensions to avoid multiple small particles appearing as one larger particle (reducing error).

  • Cascade impaction / cascade impactor

    • For respirable particles.
    • Fluidize powder and pass through cascades.
    • Larger/heavier particles settle first; size cuts determine where particles are retained.
    • Used to determine aerodynamic diameter.

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B) Linking size to dissolution/solubility

• Concept

  • Smaller particle size → larger surface area → higher dissolution rate → expected higher solubility/bioavailability.

• Noyes–Whitney equation (principle as stated)

  • Dissolution rate depends on surface area.
  • Mentions dependence on:
    • solubility at a specific time
    • saturation solubility
    • thickness of the dissolution layer

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C) Porosity, density, and volume definitions

• Void spaces in bulk powder (3 types)

  1. Open interparticulate voids: between particles, exposed to external environment.
  2. Closed intraparticulate voids: inside particles, not exposed to environment.
  3. Interparticle void spaces: between individual particles.

• Three types of volume

  1. Bulk volume: total volume occupied by mass, including intraparticulate + interparticulate voids.
  2. True volume: volume of solids only; excludes void spaces larger than molecular dimensions (excludes intra- and inter-particulate voids).
  3. Granular volume: cumulative particle volume including intra-particulate voids (closed + open), excluding inter-particulate void spaces.

• Porosity calculation (as described)

  • Void volume = bulk volume − true volume
  • Porosity = (void volume / bulk volume)
  • % porosity = (void volume / bulk volume) × 100

• Density implications

  • Since density = mass / volume and volume varies with void content:
    • true density, granular density, and bulk density differ based on which volume definition is used.

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D) Packing, compressibility, flow ratios, and flow classification

• Bulkiness and packing

  • Packing depends on particle size and arrangement in the dosage form.
  • Bulk behavior differs with size distribution and packing.

• Percent compressibility / Carr’s index

  • % compressibility = (tap density − bulk density) / tap density × 100
  • Known as the Carr index (classification tool).

• Flow pattern classification using Carr’s index (ranges)

  • 5–15: excellent flow
  • 12–16: good flow
  • 18–21: fairly passable (usable; may have challenges)
  • 23–28: poor flow
  • 28–35: poor fluid; cohesive powder (sticky/strong interparticle bonding)
  • 35–38: very poor flow; still cohesive
  • >40: extremely poor and cohesive

• Hausner ratio

  • Hausner ratio = tapped density / bulk density
  • Interpretation:
    • < 1.25: good flow
    • 1.25–1.5: moderate flow
    • > 1.5: poor flow

• How to improve poor flow (process/additives strategies)

  • Modify parent material properties via:
    • additives/excipients (e.g., glidants, lubricants)
    • changing particle size
    • changing processing parameters
  • Example approaches:
    • For coarser particles: spray drying to obtain smoother morphology for better flow.
    • Use size-reduction changes (e.g., milling → spray drying) to obtain more favorable shapes (example: “globular particles”).
  • Goal: move material into an appropriate flow/compressibility range, supporting formulation development and scale-up.

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E) Angle of repose (flow characterization)

• Definition

  • Angle of repose: θ
  • Relation: tan(θ) = h/r (where h = heap height, r = heap radius)

• Three methods described

  1. Funnel method (static)

     • Fixed funnel height over graph paper.
     • Allow a fixed mass (e.g., 5 g or 10 g) to flow.
     • Particles form a triangular heap.
     • Measure heap diameter and height.
     • Compute θ from geometry.

  2. Rotating cylinder method (kinetic/dynamic)

     • Hollow cylinder half-filled with material.
     • One side sealed with a transparent plate.
     • Wall lined with sandpaper to prevent slipping.
     • Rotate cylinder; powder forms a stabilized angle relative to horizontal.
     • Measure θ.

  3. Tilted box method

     • Rectangular box lined with sandpaper filled with powder.
     • Tilt until powder begins to slide.
     • The maximum angle with the powder plane = θ.

• Angle of repose interpretation (ranges)

  • < 25: excellent
  • 25–30: good
  • 30–40: non-cohesive (implied acceptable/less cohesive behavior)
  • > 40: very poor flow; highly cohesive

• Qualitative factors affecting θ

  • Material roughness/smoothness, monodisperse vs polydisperse distribution, fines, cohesiveness/adhesiveness, and particle morphology.

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F) Hygroscopicity and moisture behavior

• Definitions

  • Hygroscopicity: tendency to absorb moisture from atmosphere until equilibrium.
  • Deliquescent: absorbs additional moisture and may liquefy/form a solution/completely solubilize.
  • Efflorescent: loses moisture to atmosphere and becomes dry.

• Classification basis (as stated)

  • Based on % weight increase at 25°C and 80% RH.
  • European Pharmacopoeia technical guide categories:
    • Slightly hygroscopic: >0.2% to <2% increase
    • Hygroscopic: >0.2% to <15% increase
    • Very hygroscopic (highly absorbing): >15% increase
    • Deliquescent: absorbs moisture leading to solution/liquefaction

• Implications for formulation choice

  • Moisture behavior affects suitability for solid processing.
  • If hygroscopic:
    • can be problematic to process as a dry solid (risk degradation)
    • may prefer liquid formulation to keep moisture present and prevent further absorption
  • Alternatively, use excipients that minimize moisture absorption.

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Overall takeaway / summary of lessons

• Particle size and distribution strongly influence surface area and packing/flow behavior.
• Flow and compressibility relate to:
  • porosity/void structure
  • bulk density vs tapped density
  • Carr index and Hausner ratio
  • angle of repose
• Shape and cohesiveness determine whether particles flow smoothly or form clumps/aggregates.
• Moisture interactions (hygroscopicity/deliquescence/efflorescence) are crucial for selecting compatible materials and preventing instability/degradation.
• Final objective: develop a bioavailable and stable dosage form by aligning particle characteristics and moisture behavior with manufacturing needs.

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Speakers / sources featured

• Speaker: Not explicitly identified by name (lecturer; begins with “Namaskar and welcome”).
• Named source / framework:
  • Noyes–Whitney equation (dissolution principle)
  • Stokes’ law (sedimentation sizing)
  • European Pharmacopoeia Technical Guide (hygroscopicity classification)
• Mentioned instruments/techniques: light microscopy, electron microscopy (TEM/SEM), sieving, sedimentation, electrical resistance particle counting (Coulter-like method), surface adsorption method, dynamic light scattering, cascade impactor.