Section 2.6: Basic Pharmaceutics & Dosage Form Design

Section 2.6: Basic Pharmaceutics & Dosage Form Design

Introduction to Dosage Form Design

Pharmaceutics is the branch of pharmacy that deals with the process of turning a new chemical entity (NCE) or drug into a medication that can be safely and effectively administered to patients. Drugs are rarely administered as pure chemical substances; they are formulated into dosage forms with the aid of non-medicinal substances called excipients. This section covers solid, liquid, semi-solid, and transdermal dosage forms, and examines the properties and functions of key excipients.

Solid Dosage Forms: Tablets and Capsules

Tablets

Tablets are solid dosage forms prepared by compressing powder mixtures containing the active pharmaceutical ingredient (API) and excipients. There are three primary manufacturing methods:

1. Direct Compression: Compressing the mixed powders without any prior granulation. It is the most cost-effective method but requires excipients with excellent flowability and compressibility (e.g., spray-dried lactose, microcrystalline cellulose).
2. Wet Granulation: Involves mixing powders, adding a liquid binder to form a wet mass, screening the mass into granules, drying them, and compressing. It is suitable for drugs with poor flowability but cannot be used for moisture-sensitive or heat-sensitive drugs.
3. Dry Granulation (Roller Compaction): Powders are compacted into sheets or ribbons under high pressure, which are then milled into granules. This method is preferred for moisture- and heat-sensitive drugs that have poor flow properties.

Capsules

Capsules are solid dosage forms in which the drug substance is enclosed within a gelatin shell.

• Hard Gelatin Capsules: Composed of two parts (body and cap). Used primarily for dry powders, granules, or pellets.
• Soft Gelatin Capsules (Softgels): A single-piece hermetically sealed shell containing liquids, suspensions, or semi-solids. They are useful for poorly water-soluble drugs dissolved in oil (e.g., cyclosporine, Vitamin D).

Liquid Dosage Forms: Solutions, Suspensions, and Emulsions

Solutions

Solutions are homogeneous, single-phase molecular dispersions of one or more solutes dissolved in a solvent. They have rapid absorption (no dissolution step required) but are chemically less stable than solid dosage forms.

Suspensions

Suspensions are heterogeneous biphasic systems consisting of finely divided solid particles (dispersed phase) suspended in a liquid medium (continuous phase). The physical stability of a suspension (sedimentation rate) is described by Stokes' Law:

$$v = \frac{2r^2 (\rho_p - \rho_f) g}{9 \eta}$$

where $v$ is the sedimentation velocity, $r$ is the particle radius, $\rho_p$ is particle density, $\rho_f$ is fluid density, $g$ is acceleration due to gravity, and $\eta$ is fluid viscosity. To formulate a stable suspension, the manufacturer should reduce the particle size ($r$) and increase the viscosity of the vehicle ($\eta$) using suspending agents (e.g., methylcellulose, xanthan gum).

• Flocculated Suspensions: Particles form loose networks (flocs). They sediment rapidly but do not form a hard cake, making them easy to redisperse with gentle shaking.
• Deflocculated Suspensions: Particles sediment very slowly. However, once sedimented, they pack tightly together, forming a hard, irreversible cake that cannot be redispersed.

Emulsions

Emulsions are thermodynamically unstable biphasic systems consisting of at least two immiscible liquids (usually water and oil), stabilized by an emulsifying agent.

• Oil-in-Water (o/w): Oil droplets are dispersed in water. Used for oral administration (masks oily taste) and topical creams (non-greasy, water-washable).
• Water-in-Oil (w/o): Water droplets are dispersed in oil. Used for external emollient creams and ointments (provides occlusive barrier).
• HLB (Hydrophilic-Lipophilic Balance) Scale (1-20):
  • Low HLB surfactants (3-6) are lipophilic and form w/o emulsions (e.g., sorbitan monooleate/Span 80).
  • High HLB surfactants (8-16) are hydrophilic and form o/w emulsions (e.g., polysorbate 80/Tween 80).

Emulsion Instability Stages:

1. Flocculation: Dispersed droplets group together. Reversible.
2. Creaming: Droplets concentrate at the top or bottom due to density differences. Reversible by shaking.
3. Coalescence/Cracking: Droplets fuse together, breaking the film and separating the emulsion into two distinct layers. Irreversible.
4. Phase Inversion: Emulsion flips from o/w to w/o or vice versa. Can occur due to temperature change or adding excess electrolyte.

Semi-Solid and Transdermal Dosage Forms

• Ointments: Semisolid preparations for external application. Hydrocarbon bases (e.g., white petrolatum) are highly occlusive and greasy. Water-removable bases (creams) are o/w emulsions.
• Transdermal Drug Delivery Systems (TDDS): Deliver drugs through the skin into the systemic circulation. They bypass first-pass hepatic metabolism and provide steady-state drug delivery.
  • Reservoir Type: The drug is in a liquid/gel compartment separated from the skin by a rate-controlling polymeric membrane. If the membrane is damaged (or the patch is cut), it causes dose dumping (rapid, uncontrolled systemic release of the entire dose, potentially fatal for drugs like fentanyl).
  • Matrix Type: The drug is uniformly dispersed in a solid polymer matrix. The polymer matrix itself controls the release rate. Cutting these patches is still not recommended but does not lead to immediate dose dumping.

Properties and Functions of Key Excipients

Excipients must be inert and serve specific roles in the formulation:

• Diluents/Fillers: Add bulk to make the tablet size manageable. Examples: Lactose, microcrystalline cellulose (MCC), dicalcium phosphate.
• Binders: Impart cohesive properties to powders, ensuring the tablet remains intact after compression. Examples: Polyvinylpyrrolidone (PVP), starch paste, gelatin.
• Disintegrants: Absorb water, swell, and cause the tablet to break apart in the GI tract. Examples: Croscarmellose sodium, sodium starch glycolate.
• Lubricants: Prevent the tablet formulation from sticking to punches and dies during manufacture. Example: Magnesium Stearate. Clinical Pearl: Magnesium stearate is highly hydrophobic. If mixed too long (over-blended), it coats the drug particles, retarding water penetration and significantly slowing tablet dissolution.
• Glidants: Improve the flow properties of the powder mixture by reducing interparticulate friction. Examples: Colloidal silicon dioxide (Aerosil), talc.