3.3 Liquid Dosage Forms

3.3 Liquid Dosage Forms

Compounded liquid dosage forms are classified into monophasic systems (solutions, syrups, elixirs, spirits, tinctures) and biphasic systems (suspensions and emulsions). Monophasic systems contain molecularly dissolved active ingredients in a single homogeneous phase. Biphasic systems consist of two immiscible phases (solid-in-liquid or liquid-in-liquid) requiring physical stabilization.

---

Monophasic Liquids: Solvents, Kinetics, & Formulations

Solvents Used in Nonsterile Compounding

• Purified Water USP: Obtained by distillation, ion exchange, or reverse osmosis. Contains no added substances. Used as the primary solvent for oral and topical aqueous preparations. (Note: Nonsterile Purified Water USP must never be used for parenteral/ophthalmic compounding).
• Alcohol USP: Contains 94.9% to 96.0% v/v C2H5OH (ethanol) at 15.56°C. Excellent solvent for lipophilic organic molecules, resins, and volatile oils.
• Diluted Alcohol NF: Prepared by mixing equal volumes of Purified Water USP and Alcohol USP. Due to volumetric contraction upon mixing, the final concentration is approximately 49% v/v ethanol.
• Glycerin USP (Glycerol): Clear, viscous, sweet liquid miscible with water and alcohol. It acts as a co-solvent and humectant. Any preservative effect depends on the complete formulation and validated concentration; do not assume a universal threshold.
• Propylene Glycol USP: Clear, viscous solvent miscible with water and alcohol; frequently replaces glycerin.
• Fixed Vegetable Oils: Corn oil, sesame oil, peanut oil, olive oil. Used as vehicles for lipophilic drugs or oral/topical oil solutions.

Dissolution Kinetics: Noyes-Whitney Equation

The rate at which a solid solute dissolves in a liquid solvent is described by the Noyes-Whitney Equation:

Dissolution Rate (dC/dt) = (D * A / h) * (C_s - C)

• D = Diffusion coefficient of solute
• A = Surface area of solid particles
• h = Thickness of stagnant diffusion layer surrounding particles
• C_s = Saturation solubility of solute in solvent
• C = Solute concentration in bulk solvent at time t

Practical Compounding Implications: Technicians accelerate dissolution by reducing particle size (increasing surface area A via trituration) and vigorously stirring/agitating the solution (decreasing diffusion layer thickness h).

Formulations: Syrups, Elixirs, Spirits, & Tinctures

---

Biphasic Liquids: Suspensions & Stokes' Law

A pharmaceutical suspension is a coarse dispersion of finely divided insoluble solid drug particles (0.5 to 50 micrometers) distributed throughout a liquid vehicle.

Flocculated vs. Deflocculated Suspensions

• Deflocculated Suspensions: Solid particles exist as individual species. Particles settle slowly, but once settled, they form a dense, tightly packed cake at the bottom of the bottle due to secondary energy minimum attraction. This caking is irreversible and cannot be resuspended by shaking.
• Flocculated Suspensions: Solid particles form loose, fluffy aggregates (flocs) held by weak van der Waals forces. Flocs settle rapidly, leaving a clear supernatant liquid, but are easily resuspended with minimal shaking. Flocculating agents include electrolytes (e.g., monobasic potassium phosphate) and ionic surfactants.

Stokes' Law of Sedimentation

The rate of particle settling in a coarse suspension is governed by Stokes' Law:

v = [ d^2 * (rho_p - rho_m) * g ] / (18 * eta)

• v = Sedimentation velocity (cm/s)
• d = Particle diameter (cm)
• rho_p = Density of solid particle (g/cm³)
• rho_m = Density of liquid medium (g/cm³)
• g = Gravitational acceleration (980 cm/s²)
• eta = Dynamic viscosity of liquid medium (poise or Pa.s)

Strategies to Minimize Sedimentation Rate (v):

1. Reduce particle diameter (d): Micronizing solid powder via trituration dramatically decreases velocity because v is proportional to d^2.
2. Increase vehicle viscosity (eta): Adding hydrocolloid suspending agents (e.g., Xanthan gum, Methylcellulose, Sodium CMC, Ora-Plus) increases viscosity, slowing settling.
3. Match densities (rho_p ~ rho_m): Increasing vehicle density with syrup or sorbitol reduces density difference.

Wetting Agents

Hydrophobic drug powders (e.g., sulfur, hydrocortisone) entrap air and float on aqueous vehicles. Technicians must incorporate a wetting agent (e.g., Glycerin, Propylene Glycol, or Polysorbate 80) to displace air, lower the contact angle, and allow uniform vehicle penetration before adding suspending agents.

---

Biphasic Liquids: Emulsions & The HLB System

An emulsion is a thermodynamically unstable biphasic system consisting of two immiscible liquid phases (Oil and Water) stabilized by an emulsifying agent.

The Hydrophilic-Lipophilic Balance (HLB) System

Surfactants are assigned an HLB value ranging from 1 to 20 based on their molecular affinity for water or oil:

• HLB 3 to 6: Lipophilic surfactants (e.g., Sorbitan monooleate / Span 80) -> Form Water-in-Oil (W/O) emulsions.
• HLB 8 to 18: Hydrophilic surfactants (e.g., Polysorbate 80 / Tween 80, Acacia) -> Form Oil-in-Water (O/W) emulsions.

Primary Emulsion Preparation Methods

To form a stable O/W primary emulsion using fixed oil, water, and acacia gum, technicians use specific stoichiometric ratios:

Fixed Oil Ratio: 4 parts Oil : 2 parts Water : 1 part Acacia (4:2:1)

(For Volatile Oils, use a 2:2:1 or 3:2:1 ratio).

1. Continental (Dry Gum) Method (4:2:1):
   • Triturate 4 parts Oil with 1 part Acacia powder in a dry porcelain mortar until smooth.
   • Add 2 parts Water all at once.
   • Triturate rapidly and continuously in one direction until a crackling sound is heard and a thick, creamy white primary emulsion forms.
   • Add remaining aqueous vehicle and liquid ingredients in small portions with trituration to final volume.
2. English (Wet Gum) Method (4:2:1):
   • Triturate 1 part Acacia with 2 parts Water in a mortar to form a mucilage.
   • Add 4 parts Oil slowly in small increments while triturating continuously.
3. Forbes (Bottle) Method:
   • Used for volatile or low-viscosity oils. Oil and acacia are shaken in a capped bottle, followed by water addition.

Physical Instability of Emulsions

• Flocculation: Droplets aggregate into clusters without losing individual identity; reversible by shaking.
• Creaming: Migration of droplets upward (if oil in O/W) or downward under gravity; reversible by shaking.
• Coalescence & Breaking (Cracking): Droplets fuse together into larger droplets until complete phase separation occurs. Irreversible; cracked emulsions must be discarded.

---

Worked Numerical Examples

Worked Example 1: Continental Method (4:2:1) Primary Emulsion Formulation

Scenario: A pharmacy technician receives an order to compound 120 mL of Sesame Oil Emulsion USP (50% v/v sesame oil) using the Continental (Dry Gum) method. Calculate the required volumes of Sesame Oil, Purified Water for the primary emulsion, mass of Acacia gum powder, and final volume adjustment.

Solution Steps:

1. Determine total Sesame Oil required:

   • Total Emulsion Volume = 120 mL
   • Sesame Oil Volume = 120 mL * 0.50 = 60 mL Sesame Oil

2. Apply Continental 4:2:1 Ratio (Oil : Water : Gum):

   • Oil parts = 4 parts = 60 mL
   • 1 part = 60 mL / 4 = 15 mL equivalent mass
   • Water parts = 2 parts = 2 * 15 mL = 30 mL Purified Water (for primary emulsion)
   • Acacia parts = 1 part = 1 * 15 g = 15 g Acacia Powder

3. Formulation Breakdown:

   • Sesame Oil = 60 mL
   • Acacia Powder = 15 g
   • Purified Water (Primary) = 30 mL
   • Purified Water = q.s. ad 120 mL after the primary emulsion forms. Do not calculate this by simple subtraction: acacia contributes mass and dispersed volume, and mixed volumes are not necessarily additive.

4. Compounding Execution: In a clean, dry mortar, combine 60 mL sesame oil and 15 g acacia. Add the 30 mL primary water at once and triturate vigorously until the primary emulsion forms. Transfer and add purified water in portions, rinsing the mortar, then q.s. the final preparation to 120 mL in suitable volumetric equipment. Package as directed by the master formulation.

---

Worked Example 2: Stokes' Law Sedimentation Velocity Calculations

Scenario: A suspension formulation has insoluble drug particles of diameter d1 = 40 micrometers (0.004 cm) settling at a velocity of v1 = 0.08 cm/min in an un-thickened vehicle. Calculate the new sedimentation velocity (v2) if the technician triturates the drug to reduce particle diameter to d2 = 20 micrometers (0.002 cm) and adds Xanthan gum to double the vehicle viscosity (eta2 = 2 * eta1).

Solution Steps:

1. Recall Stokes' Law proportionality:

   • v is directly proportional to d^2 and inversely proportional to eta:
   • v2 / v1 = (d2 / d1)^2 * (eta1 / eta2)

2. Calculate ratio of particle diameters squared:

   • (d2 / d1)^2 = (20 / 40)^2 = (0.5)^2 = 0.25

3. Calculate ratio of viscosities:

   • eta1 / eta2 = eta1 / (2 * eta1) = 0.50

4. Calculate new sedimentation velocity (v2):

   • v2 / v1 = 0.25 * 0.50 = 0.125
   • v2 = 0.08 cm/min * 0.125 = 0.010 cm/min

5. Conclusion: Combining particle reduction (trituration) and viscosity doubling reduces particle settling rate by 87.5% (from 0.08 cm/min down to 0.010 cm/min).