Capsule technology

• Capsules


  Solid preparations with hard or soft shells of various shapes and capacities, usually containing a single dose of active substance(s)
• Hard capsules


  Hard gelatin capsules, two-piece capsules
• Soft capsules


  Soft gelatin capsules, softgels, one-piece capsules
• Most hard and soft capsules are orally delivered
• Some hard capsules are for inhalation
• Some soft capsules are intended for rectal or vaginal insertion
• Hard capsules are more common than soft ones
• Capsule cap


  Shorter piece of a hard capsule
• Capsule body

  Longer piece of a hard capsule
• Capsule shoulder


  Where the cap goes over the body to contain contents
• Gelatin


  • Derived from collagen (a natural protein found in animal skins, bones, & connective tissues)
  • Type A gelatin from acid treatment of porcine skin
  • Type B gelatin from alkaline treatment of bovine bones
  • Types A & B have different isoelectric points, thus different solubility as a function of pH
• Why gelatin


  • Edible, non-toxic, economical, readily available
  • Soluble in physiological fluids at body temperature
  • Good film-former, produces strong flexible film
  • Solutions of high concentration (e.g. 40% w/v) are mobile at 50°C
  • Undergoes gelation at temperatures only a few degrees above ambient
• Gelatin capsule shells


  • Contains 13-16% w/v moisture
  • Moisture strongly bonded to gelatin molecule so won't support bacterial growth
  • Properties affected by relative humidity (low RH: brittle, high RH: absorb moisture, soften, shape distortion)
  • Moisture acts as a plasticiser, increases elasticity and pliability
  • 5% Polyethylene glycol (PEG) 4000 can be added as an additional plasticiser
• Some patients may not prefer gelatin capsules due to religious or ethical reasons
• There were safety concerns in the 1980s-90s of bovine spongiform encephalopathy (BSE; commonly called mad cow disease) related to gelatin from bovine sources

  
• Gelatin substitutes


  • Hydroxypropyl methylcellulose (HPMC)
  • Chitosan
  • Modified starch
• Raw materials of capsule shells

  • Polymer (e.g. gelatin, HPMC)
  • Water
  • Colourants
  • Process aids (wetting agent, preservatives)
• Colourants


  • Dyes (water soluble) & Pigments (water insoluble)
  • Dyes are mostly synthetic (azo dyes & non-azo dyes)
  • Pigments (e.g. titanium dioxide, iron oxides) are preferred over dyes
• Wetting agent


  • Ensures metal moulds are uniformly covered with gelatin solution during capsule shell manufacture
  • Not more than 0.15% w/w sodium lauryl sulfate
• Capsule shell manufacture


  1. Prepare concentrated gelatin solution (35-40% w/v) in hot water (60-70°C)

  2. Apply vacuum to remove entrapped air bubbles

  3. Add colourant solutions/suspensions

  4. Measure & adjust viscosity

  5. Transfer liquid mixture to a heated holding hopper on manufacturing machine

  6. Dip mould pins into gelatin mixture to form caps and bodies

  7. Dry the formed films, remove from pins, cut to length, join caps and bodies

  8. Sort, check, and print capsules if needed

  9. Pack capsules in moisture-proof packaging
• Bloom test


  • Measures gel rigidity
  • Gelatin used in hard capsule manufacture has higher Bloom strength (200-250 g) than that for soft capsules (150 g)
• Capsule shell sizes

  • Size 5 (0.13 mL)
  • Size 4 (0.20 mL)
  • Size 3 (0.28 mL)
  • Size 2 (0.37 mL)
  • Size 1 (0.50 mL)
  • Size 0 (0.69 mL)
  • Size 00 (0.95 mL)
  • Size 000 (1.36 mL)
• Hard capsules


  Capsules made of gelatin
• Soft capsules


  Capsules made of a soft, pliable material like gelatin or cellulose derivatives
• Advantages of capsules


  • Accurate dosing
  • Good bioavailability
  • Ease of filling & production
  • Good stability
  • Elegant appearance
• Disadvantages of capsules


  • Capsule shell can interact with formulation
  • Capsule shell can have high moisture content
  • Volume of unit dose must be smaller than the capsule size
• Hard capsule manufacture


  1. Develop & prepare the formulation

  2. Select the capsule size

  3. Fill the capsule shells

  4. Capsule sealing (optional)

  5. Clean & polish the filled capsules
• Formulation types for hard capsules


  • Dry solids (powders, granules, pellets, capsules, tablets)
  • Semi-solids (thermosoftening mixtures, thixotropic mixtures, pastes)
  • Liquids (non-aqueous liquids e.g. oils)
• Important considerations for hard capsule formulation


  • Cannot interact with gelatin
  • Cannot contain high moisture level
  • Volume of unit dose must be smaller than the capsule size
• Formulation types for hard capsules


  • Powder or granules
  • Pellets
  • Paste
  • Capsule
  • Tablet
• Powder properties for hard capsule filling


  • Good flow
  • Non-adhesive
  • Cohesive
• Excipients used in hard capsule formulations


  • Fillers or diluents
  • Glidants
  • Lubricants
  • Disintegrants
  • Surfactants or wetting agents
• Disintegration of hard capsule shell

  Shell starts to dissolve at 37°C -> Shell splits -> Contents 'empty out' before shell completely dissolves
• Factors affecting drug release from hard capsules


  • Physicochemical properties of the drug
  • Nature and type of excipients
  • Filling process
• Effect of particle size on drug release

  Small particle size should dissolve faster due to large surface area-to-volume ratio
• Effect of solubility on drug release


  Poorly water-soluble drugs should be formulated with highly soluble excipients to increase the hydrophilicity of powder mass
• Effect of lubricants on drug release


  Lubricants (e.g. magnesium stearate) may have adverse effect on release due to their hydrophobic nature
• Bench scale filling of hard capsules


  Filling small quantities (50-1000 capsules) for formulation development, hospital pharmacies, special prescriptions, or clinical trials
• Industrial scale filling of hard capsules

  Semi- to fully automatic, Output: 5000 to 150,000 per hour, Common filling systems: Auger, Dosing tube/dosators, Dosing disc & tamping
• Capsule sealing


  Banding (Kapseals, Qualicaps) or thermal bonding at 40-45°C to create tamper-evident capsules