L51 Solid Dosage Forms- role of excipients

• Reasons not to administer a pure drug

  • Dose
  • Taste
  • Physical properties: Solubility, Partitioning, Bioavailability, Stability
  • To control rate of absorption
  • To allow administration via specific routes
  • Handling, transportation and marketing
• All of these factors can be controlled with the use of excipients and formulation science
• Dose Control


  Why formulate to control dose?
• Dose


  • Aspirin tablet typically has 300mg API
  • Ethinyl estradiol - 0.035mg (1/8000 of the dose of aspirin)
• Difficult to manufacture - blend uniformly for low dose drugs
• Dose


  High dose (low potency) drugs can be a problem to formulate if they have poor flow/compressibility
• Taste


  Very subjective and difficult to quantify. Many drugs are extremely bitter. Can be mitigated by film-coating.
• Panadol formulation


  • Paracetamol (API)
  • Starch (disintegrant)
  • Povidone (PVP) (diluent/disintegrant)
  • Potassium sorbate (E202) (sweetener)
  • Talc (flow agent)
  • Stearic acid (lubricant)
  • Film coating contains hydroxypropyl methylcellulose (HPMC) and triacetin
• Panadol Actifast Formulation


  • Paracetamol (Active ingredient)
  • Sodium bicarbonate (super-disintegrant)
  • Soluble starch (disintegrant)
  • Povidone (PVP) (diluent/disintegrant)
  • Potassium sorbate (E 202) (Sweetener)
  • Microcrystalline cellulose (filler)
  • Magnesium stearate (lubricant)
  • Carnauba wax (coating)
  • Titanium dioxide (E 171) (Whitening agent)
  • Film coating contains polydextrose, hypromellose (HPMC), glycerol triacetate and polyethylene glycol
• Sodium bicarbonate


  Can increase the rate of tablet disintegration and dissolution as well as the rate of gastric emptying. Enables a faster speed of absorption of paracetamol to provide faster onset of relief.
• If one tablet or if taken with less than 100mL water, the rate of absorption of paracetamol for Panadol ActiFast is the same as for standard paracetamol tablets.
• Excipient


  All the other components of a formulation other than the active drug
• Excipients


  • Each component requires an appropriate evaluation for safety
  • An excipient should be chemically and physiologically inert
• People may have moral or religious problems with excipients e.g. gelatin
• Uses for excipients


  • Aid processing of the system during manufacture
  • Protect, support or enhance stability, bioavailability or acceptability
  • Assist in product identification
  • Enhance any other attribute of the overall safety and effectiveness of the drug product during storage and use
• Common Pharmaceutical Excipients


  • Lactose, Micro Crystalline Cellulose – Diluent, compressive
  • Sodium Bicarbonate – Effervescent excipient
  • Magnesium Stearate – Lubricant
  • Colloidal Silicon Dioxide
• Dissolution


  Rates of drug dissolution can be adversely affected by choice of formulation additives
• Tableting lubricants are particularly troublesome. Insoluble magnesium stearate imparts hydrophobicity to a formulation which inhibits drug dissolution.
• Need to minimise the % of lubricant in a solid dosage formulation. If possible!
• Diluents (bulking agents)


  Inert substances which are added to the active ingredient to make a reasonable sized tablet
• Tablet Diluents


  • Dicalcium Phosphate- inexpensive, insoluble in water
  • α-Lactose monohydrate- inexpensive, relatively inert, compressibility related to crystalline/amorphous form
  • Mannitol- Freely soluble, chewable tablets
  • Microcrystalline cellulose- excellent compression properties, has some disintegration properties
  • Sodium chloride- freely soluble, used for solution tablets
  • Sucrose- sweet taste but hygroscopic
  • Starch- very hygroscopic, good disintegration properties
• Microcrystalline Cellulose


  • Outstanding compressibility and high tablet strength from low compression forces
  • Has some lubricant & disintegrating properties
  • Sensitive to lubricant – lubricant hinders strong bonds forming between layers (weakens tablet)
  • Moisture sensitive (5% moisture uptake)
• MCC- Various Grades


  • Particle Size (90 µm, 200 µm, 15 µm)
  • Low moisture grade (1.5%) – reduced compression
  • Higher bulk density – aids in blending
  • Low bulk density – increase tablet strength
• Lubricants


  • Necessary to prevent adherence of the formulation to punches and dies
  • They also ensure smooth ejection of the tablet from the die
  • Some act as anti-adherents and flow aids
• Lubricants


  • Talc
  • Magnesium stearate
  • Stearic acid
• Magnesium Stearate


  • Most popular lubricant in tabletting
  • Incorporated with dry granules prior to compression
  • A thin layer of magnesium stearate around the granules is as effective a lubricant as a thick layer (concentration up to 1% w/w)
  • Self-lubricating properties
• Increased concentration of magnesium stearate decreases disintegration time, drug dissolution and weakens the bonding forces (soft tablets), reduction due to its hydrophobic nature.
• Magnesium stearate is incompatible with many drugs (e.g. Aspirin requires talc or stearic acid)
• Flow agents/Glidants


  • Materials which are added to tablet formulations in order to improve the flow properties of granules
  • They act by reducing inter-particle friction
• Flow agents


  • Fumed silica, a synthetic amorphous colloidal silicon dioxide (Aerosil or Cab-O-Sil)
• Action of flow agents

  The reduction in contact area between granules reduces the interparticle cohesion/adhesion, which determines flowability
• Disintegrants


  • Promote break up of tablets in vivo
  • First stage in the dissolution process of a drug
  • Important primarily in the dissolution of insoluble drugs, particularly those with a high dose
  • Its role is to rapidly disintegrate a tablet to increase the surface area of the formed disaggregates, promoting rapid release of drug
• Mechanisms of disintegrant action


  • Swelling
  • Porosity and capillary action
  • Deformation
  • Gas production
• Most common disintegrant is starch. Others include polyvinylpyrrolidone (PVP), modified starches and cellulose materials.
• Super disintegrants


  • Modified starch (Sodium starch glycolate) has rapid and extensive swelling with minimal gelling
  • More effective in lower concentrations (4 – 6%)
  • Reduces issues relating to the compressibility and flowability problems of starch
  • However, it is more hygroscopic
• Binding agents (adhesives)


  • Bind powders together in the wet granulation process or granules during direct compression
  • Can affect dissolution rate
• Binding agents


  • Starch mucilage
  • Gelatin
  • Polyvinylpyrrolidone (PVP)
• Adsorbents


  • Substances which are capable of holding quantities of fluids in an apparently dry state
  • Liquid flavourings, fluid extracts or oils can be mixed with adsorbents and granulated and compressed into tablets
• Adsorbents


  • Fumed silica
  • Microcrystalline cellulose
  • Kaolin
  • Magnesium carbonate