Solid Dosage Forms - Role of Excipients

Why Drugs Are Not Administered as Pure Substances

  • Dose:
    • Aspirin tablet typically has 300 mg API.
    • Patients are unlikely to be able to measure such small amounts accurately.
    • Many drugs require even lower doses (e.g., ethinyl estradiol - 0.035 mg, which is 1/80001/8000 of the aspirin dose).
    • Blending uniformity makes accurate dose manufacturing challenging.
  • Taste:
    • Many drugs are extremely bitter, making them unpalatable.
    • Film-coating can mitigate this issue.
  • Physical Properties:
    • Solubility
    • Partitioning
    • Bioavailability
    • Stability
  • Control Rate of Absorption:
  • Allow Administration via Specific Routes:
  • Handling, Transportation, and Marketing:

Excipients and Formulation Science

  • Excipients and formulation science can control factors such as dose, taste, physical properties, rate of absorption, administration route, handling, transportation and marketing.

Dose Control

  • Why Formulate to Control Dose?
    • Aspirin tablet typically has 300 mg API.
    • Patient unlikely to be able to measure this amount.
    • Many drugs have lower doses (e.g., Ethinyl estradiol - 0.035 mg which is 1/80001/8000 of the dose of aspirin!).
    • Difficult to manufacture - blend uniformity
  • High-dose (low potency) drugs can be problematic to formulate if they have poor flow/compressibility, hindering tablet production.

Taste

  • Taste is subjective and difficult to quantify.
  • Many drugs are extremely bitter.
  • Taste can be mitigated by film-coating.

Effervescent Tablet Formulation

  • Anhydrous Citric Acid: 15%
  • Granular Tartaric Acid: 15%
  • Sodium Bicarbonate: 36%
  • PVP K30: 1%
  • Paracetamol: 16%
  • Sodium Saccharin: 1%
  • PEARLITOL 500 DC Mannitol: 9%
  • Sodium Benzoate: 4%
  • PEG 6000: 3%

Panadol Formulation

  • Paracetamol (Active ingredient)
  • Starch (disintegrant)
  • Povidone (PVP) (diluent/disintegrant)
  • Potassium sorbate (E202) (sweetener)
  • Talc (flow agent)
  • Stearic acid (lubricant)
  • The 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)
  • The film coating contains polydextrose, hypromellose (HPMC), glycerol triacetate and polyethylene glycol

Mode of Action of Sodium Bicarbonate in Panadol ActiFast

  • Sodium bicarbonate increases the rate of tablet disintegration and dissolution.
  • It also increases the rate of gastric emptying (movement of drugs from the stomach into the small intestine).
  • This enables a faster speed of absorption of paracetamol, providing faster onset of relief.
  • Two tablets of Panadol ActiFast are required per dose to have such an effect.
  • If one tablet is taken or if taken with less than 100mL of water, the rate of absorption of paracetamol for Panadol ActiFast is the same as for standard paracetamol tablets.

What is an Excipient?

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

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

Role of Excipients on Dissolution

  • Rates of drug dissolution can be adversely affected by the choice of formulation additives.
  • Tableting lubricants are particularly troublesome.
  • Insoluble magnesium stearate imparts hydrophobicity to a formulation, which inhibits drug dissolution.
  • Need to minimize the % of lubricant in a solid dosage formulation, if possible!

Diluents (Bulking Agents)

  • Inert substances added to the active ingredient to make a reasonable-sized tablet.
  • The principle substance employed as a diluent is lactose (pleasant taste, rapidly dissolves in water, and is not hygroscopic).
  • Dicalcium phosphate is also readily used, particularly in wet granulation (insoluble in water, less hygroscopic).
  • Starches are used as diluents and binding agents (very hygroscopic >14% moisture uptake).
  • A very popular direct compression diluent is microcrystalline cellulose (MCC).

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 (MCC)

  • Produced by partial hydrolysis of cellulose.
  • Outstanding compressibility, 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.
  • Talc and magnesium stearate are most effective as punch lubricants.
  • Stearic acid is more effective as a die lubricant

Magnesium Stearate

  • Most popular lubricant in tableting.
  • 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.

Disadvantages of Mg Stearate

  • Requires additional processing steps.
  • Increased concentration decreases disintegration time, drug dissolution, and weakens the bonding forces (soft tablets).
  • Reduction due to its hydrophobic nature.
  • Incompatible with many drugs (e.g., Aspirin requires talc or stearic acid).

The Role of Glidants (Flow Agents)

  • Flow agents/Glidants are materials added to tablet formulations to improve the flow properties of granules.
  • They act by reducing inter-particulate friction.
  • The most commonly used and effective glidant is fumed silica, a synthetic amorphous colloidal silicon dioxide (Aerosil or Cab-O-Sil).
  • Addition of < 0.1% w/w of colloidal silica can dramatically improve the flowability of granules.

Action of Flow Agents

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

Disintegrants

  • Disintegrants are always added to tablets to promote the breakup 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 deaggregates, promoting rapid release of the drug.
  • Various modes of action

Disintegration and Deaggregation

  • Disintegration involves the breakup of the tablet into granules.
  • Deaggregation involves the breakup of granules into primary drug particles.
  • Increasing surface area of drug exposed to GI fluids.

Mechanisms of Disintegrant Action

  • Swelling
  • Porosity and capillary action – Draws liquid into capillary pathways and ruptures interparticulate bonds.
  • Deformation
  • Gas production
  • An inter-relationship probably occurs in most formulations.
  • Most common disintegrant is starch.
  • Others include polyvinylpyrrolidone (PVP), modified starches, and cellulose materials.

Super Disintegrants

  • Starch is satisfactory in many respects, but faster disintegration times may be required.
  • Modified starch (Sodium starch glycolate) has rapid and extensive swelling with minimal gelling.
  • The chemically treated starch is more effective in lower concentrations (4 – 6%).
  • Reduces issues relating to the compressibility and flowability problems of starch.
  • However, more hygroscopic.

Binding Agents (Adhesives)

  • Bind powders together in the wet granulation process or granules during direct compression.
  • Can be added in 2 ways:
    • As a powder in the formulation
    • As a solution to the mixed powders in wet granulation
  • Liquid additives must be removed prior to compression.
  • Can affect dissolution rate.

Binding Agents

  • Typical binding agents include starch mucilage and gelatin.
  • One of the most important binders is polyvinylpyrrolidone (PVP), which is soluble in water and alcohol and releases the drug rapidly.
  • Typical concentration is 2 – 10% (w/v) in granulating fluids.

Adsorbents

  • Adsorbents are substances capable of holding quantities of fluids in an apparently dry state.
  • Liquid flavorings, fluid extracts, or oils can be mixed with adsorbents, granulated, and compressed into tablets.
  • Fumed silica, microcrystalline cellulose, kaolin, and magnesium carbonate are commonly employed adsorbents.