Pharmaceutical Dosage Forms Overview

Why Pharmaceutical Dosage Forms?

• Safe and convenient delivery of accurate dosing
• Project drug substance from atmospheric oxygen or humidity
• Protect drug substance from gastric acid after oral administration
• Conceal bitter, salty or offensive taste or odor of a drug substance
• Provide liquid preparations of an insoluble or unstable drug
• Provide rate-controlled drug action
• Provide site-specific drug delivery

 Advantages of Solid Dosage Forms

• Convenient to carry, readily identified and easily taken
• Longer shelf life before expiring
• Efficiently produced
• Easier to package, distribute, ship, and store
• The dosing is more accurate, comparing to liquid formulation
• Possibility of controlled drug delivery

Disadvantages of Solid Dosage Forms

• Certain patients population may have difficulty swallowing large tablets or capsules
• Solid dosage forms are not appropriate for patients who are unconscious or intubated
• Solid dosage forms take longer to break down, dissolve, absorb, and distribute in the body
• Therefore, solid dosage form may not fit for emergency intervention
• Some drugs (esp. biologics) are not suitable in a solid dosage form

Influential Factors in Dosage Form Design

• Molecular Size and Volume
• Drug solubility and pH
• Partition Coefficient
• Polymorphisms
• Stability
• pKa/Dissociation Constant
• Particle size and dissolution rate
• Membrane permeability

Capsules

• Solid dosage forms in which the drug is enclosed within either a hard or a soft soluble container or ‘shell’
• Filled capsules are generally swallowed whole, sometimes caregivers may open the capsule and mix the drug with food/drink

Hard Gelatin Capsules (HGC)

• Elegant
• Easy to use, convenient
• Smooth, slippery, easily swallowed
• Tasteless
• Economical
• Better bioavailability
• Diverse formulations i.e., beads, granules, microtablets, semisolids

Properties of Gelatin

• Molecular weight ~20-200 kDa
• Usually mixtures of Type A and B are used
• Bone gelatin contributes firmness but is hazy
• Pork skin gelatin contributes plasticity and clarity
• Two main physicochemical properties:
  • Bloom strength: empirical measure of gel strength, measured in Bloom gelometer, weight in grams required to depress a standard plunger into the surface of 6.67% w/w gel, desirable bloom strengths: 150-280 g
  • Viscosity

Industrial Manufacture

• Sealing and banding: prevents separation, tamperproof (not safety proof)
• Self-locking caps: Snap-Fit, Coni-snap, coni-snap supra (Capsugel), Loxit (Pharmaphil)

Soft Gelatin Capsules (SGC)

• A one-piece, hermetically-sealed formulation containing medication in a liquid or semi-liquid state that has been formed, filled, and sealed in one operation.

Advantages of SGCs

• Elegant
• Easy to use, portable, convenient
• Smooth, slippery, easily swallowed
• Taste masking
• Requires the drug to be liquid, or at least dissolved, solubilized, or suspended in a liquid vehicle (e.g., clofibrate®, reduces serum triglycerides; is ethyl ester prodrug of clofibric acid, replaced by fenofibrate) or drugs in a liquid vehicle (e.g., digoxin, Lanoxicaps®).
• Metered liquid fill very accurate
• Homogeneous – content uniformity of ± 3% reported
• Local effect: mesalamine

Buccal & Sublingual Tablets

• Bypass the first pass metabolism

Buccal Tablets

• Intended to dissolve in buccal cavity (or gums)
• Usually designed to dissolve slowly
• Prolonged effects – contains bioadhesive to adhere to inside of mouth
• Duration of effect: 15-45 mins to 6-8 hours
• Fentanyl citrate (Actiq) intrabuccal/transmucosal lozenge
• Ideal for drugs that can be destroyed or poorly absorbed in GI
• Local effects – mouth ulcers (directly on affected area)
• Lozenges (troches)

Sublingual Tablets

• Placed under the tongue
• Allow to dissolved
• Rapid effect
• Avoids first pass effect
• Examples: glyceryl trinitrate (rapid effect), testosterone (poor GI availability – no longer in US)

 Controlled Release Dosages

• Control rate of drug delivery (release)
• Control onset, duration, and intensity of effect
• Control site of absorption
• Reduce total dose required
• Improve bioavailability
• Improve safety (particularly of drugs with low TI)
• Improve efficacy of drugs with short plasma half-lives
• Improve compliance

Terminology

• Controlled delivery
• Sustained delivery
• Prolonged delivery
• Delayed delivery
• Pulsed delivery, repeat action
• Localized delivery
• Site-specific delivery, targeted delivery

IDEAL DRUG FOR OCR FORMULATION

• A low molecular weight, freely water-soluble drug that is well and/or predictably absorbed and metabolized after oral administration, with a low plasma half-life (< 8 h) and high therapeutic index (> 10).

Formulation Strategies for CR formulations

• PHYSICAL (most common). Controlled dissolution, diffusion, disintegration (erosion), pH effects, osmosis, density.
• CHEMICAL - prodrugs.
• BIOLOGICAL e.g., antibodies
• MECHANICAL e.g., pumps
• PHARMACOLOGICAL.e.g.Probenecid-penicillin

PHYSICAL STRATEGIES

• Diffusion control
• Dissolution control
• Erosion (disintegration)
• Osmotic control
• pH dependent
• Ion-exchange
• Density control (low and high)
• Partition control (NOT for solid oral formulations)

Diffusion-based formulation

• Diffusion through semi-permeable membrane (film coating). Reservoir system
• Diffusion through nondisintegrating matrix (tablet but also semi-solid ointment or viscous liquid)

Diffusion Controlled Delivery

• Diffusion is the mass transfer of drug molecules by random motion from a region of high concentration to lower concentration. 𝑀
• The diffusional flux is proportional to the concentration gradient, dC/dx. 𝑑𝐶

Diffusion Controlled Delivery

• Diffusion through insoluble, non-disintegrating matrix
• If matrix disintegrates, drug release rate depends on rate of disintegration, dissolution, or both.
• Matrix

OROS

• Drug reservoir- conventional tablet
• coating - semipermeable
• Principle of operation: water flows into tablet due to osmotic pressure, at a rate controlled by permeability of membrane. Water dissolves drug, increases hydrostatic pressure inside tablet. Drug in solution forced to leave via orifice.