3.2 Semisolid Dosage Forms

3.2 Semisolid Dosage Forms

Semisolid dosage forms encompass topically and mucosally applied preparations, including ointments, creams, gels, pastes, and suppositories. They serve as protective barriers, therapeutic emollients, or vehicles for localized and systemic drug absorption. Understanding base chemistry, rheological properties, levigation mechanics, and mold calibration is essential for extemporaneous semisolid compounding.

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Classification of Ointment Bases

Ointment bases are traditionally organized into four classes: oleaginous, absorption, water-removable, and water-soluble. The teaching table separates anhydrous absorption bases from water-in-oil emulsion absorption bases to make their behavior clear; those are two subtypes of the same absorption class, not a fifth official class.

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Compounding Semisolids: Incorporation & Fusion Methods

Incorporation & Levigation

Incorporation involves mixing insoluble solid powders or liquid ingredients directly into a pre-formed base using an ointment slab (tile) and a flexible stainless steel or hard rubber spatula.

• Levigation: Powdered active ingredients must be levigated with a suitable liquid agent prior to incorporation into the base to eliminate particle grittiness and ensure uniform dispersion.
• Selecting Levigating Agents: The levigating agent must be physically and chemically compatible with the active drug and base:
  • For Oleaginous, Absorption, and W/O bases: Use Mineral Oil or liquid petrolatum.
  • For O/W Creams and Water-Soluble bases: Use Glycerin, Propylene Glycol, or PEG 400.
• Levigation Volume Rule: The volume of levigating agent used should be kept to the absolute minimum necessary (typically equal to 0.5 to 1.0 times the weight of the powder mass) to avoid thinning or liquefying the final semisolid base.

Fusion Method

Fusion is employed when the base contains solid high-melting-point components such as natural waxes, cetyl alcohol, paraffin, or high-molecular-weight PEGs.

1. Melt the ingredients with the highest melting points first in a porcelain dish or beaker over a water bath (e.g., beeswax at ~62–65°C).
2. Add components with lower melting points in decreasing order of melting temperature.
3. Slowly add heat-labile APIs or volatile components after cooling the melt to approximately 40–45°C.
4. Stir the mixture gently and continuously until congealed to prevent phase separation or crystalline precipitation.

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Rheology of Gels & Pastes

Gels (Jellies)

Gels are semisolid systems consisting of dispersions of small or large molecules in an aqueous liquid vehicle rendered jelly-like by the addition of a gelling agent.

• Carbomer Gels (Carbopol): Synthetic high-molecular-weight acrylic acid polymers. Un-neutralized carbomer dispersions are acidic (pH 2.8–3.2) and low viscosity. Adding a neutralizer such as Triethanolamine (TEA) or Sodium Hydroxide (NaOH) neutralizes the carboxyl groups, causing electrostatic repulsion that uncoils polymer chains into a clear, thick, high-viscosity matrix between pH 6.0 and 11.0.
• Cellulose Gels: Methylcellulose, Hydroxypropyl methylcellulose (HPMC), and Sodium carboxymethylcellulose (NaCMC). Methylcellulose dissolves best in cold water after initial hydration in hot water (thermal gelation inversion).
• Poloxamer (Pluronic) Gels: Polyoxyethylene-polyoxypropylene block copolymers (e.g., Pluronic F-127). Display reverse thermal gelation: free-flowing liquids at refrigerated temperatures (2–8°C) that transition into firm clear gels at room/body temperatures (20–37°C).

Pastes

Pastes are stiff semisolid preparations containing a high proportion of finely divided solid powders (typically 20% to 50% w/w) dispersed in an ointment base (e.g., Zinc Oxide Paste USP, containing 25% zinc oxide and 25% starch in white petrolatum). Pastes remain in place where applied, absorb serous secretions, and form an opaque protective barrier.

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Suppositories & Pessaries: Mold Calibration & Density Factors

Suppositories are solid dosage forms designed for insertion into bodily orifices (rectal, vaginal/pessaries, urethral/bougies) where they melt or dissolve to exert local or systemic effects.

Suppository Bases

1. Fatty / Oleaginous Bases:
   • Cocoa Butter (Theobroma Oil): Triglyceride base melting at body temperature (34–35°C). Displays polymorphism: overheating above 35°C during melting converts stable beta crystals into unstable alpha (mp ~22°C) or gamma (mp ~18°C) forms that fail to solidify at room temperature.
   • Synthetic Fatty Bases: Fattibase, Wecobee, Witepsol. Blends of hydrogenated vegetable oils that eliminate polymorphism risks and provide uniform solidification.
2. Water-Soluble / Miscible Bases:
   • Glycerinated Gelatin: Gelatin (20%), Glycerin (70%), Water (10%). Slow-dissolving base preferred for vaginal pessaries.
   • Polyethylene Glycol (PEG) Blends: Blends of PEG 400, 1450, and 8000. Do not melt at body temp but dissolve in mucous secretions. Higher melting point (>37°C) permits storage at room temperature without refrigeration.

Mold Calibration & Density Factor Calculations

Because APIs have different densities than suppository bases, adding a drug displaces a specific volume of base. Suppository molds are calibrated by volume, but components are weighed by mass. Technicians must calculate the Density Factor (DF) of the drug relative to the base.

Density Factor Equation:

DF = B / (A - C + B)

• A = Average weight of blank suppository shell (g)
• B = Weight of active drug per suppository (g)
• C = Average weight of medicated suppository (g)

Total Base Weight Required Equation:

Weight of Base Required = (N * A) - [ (N * B) / DF ]

• N = Number of suppositories to compound (plus overage, typically +10–20%).

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Worked Numerical Examples

Worked Example 1: Suppository Mold Displacement & Base Calculation

Scenario: A technician is asked to compound 12 Indomethacin 50 mg rectal suppositories using Fattibase in a nominal 2.0 g suppository mold. Mold calibration reveals that the average blank suppository weight (A) is 2.00 g. A test batch of medicated suppositories containing 50 mg indomethacin weighs an average (C) of 2.03 g per suppository. Calculate the Density Factor of indomethacin and the total mass of Fattibase needed for 14 suppositories (including overage).

Solution Steps:

1. Identify parameters:

   • A (blank weight) = 2.00 g
   • B (drug dose) = 50 mg = 0.050 g
   • C (medicated weight) = 2.03 g
   • N = 14 suppositories

2. Calculate Density Factor (DF):

   • DF = B / (A - C + B)
   • DF = 0.050 / (2.00 - 2.03 + 0.050)
   • DF = 0.050 / (-0.03 + 0.050) = 0.050 / 0.020 = 2.50 (Indomethacin is 2.5 times denser than Fattibase)

3. Calculate total drug required for 14 suppositories:

   • Total Drug = 14 * 0.050 g = 0.700 g Indomethacin

4. Calculate base displaced by drug:

   • Base Displaced = Total Drug / DF = 0.700 g / 2.50 = 0.280 g base displaced

5. Calculate total Fattibase required:

   • Total Blank Base Mass = 14 * 2.00 g = 28.00 g
   • Net Base Required = 28.00 g - 0.280 g = 27.72 g Fattibase

6. Compounding Summary: Melt 27.72 g Fattibase over a water bath (<45°C), incorporate 0.700 g finely triturated indomethacin, pour into mold cavities, cool, trim, and package.

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Worked Example 2: Topical Ointment Levigation & Incorporation Calculation

Scenario: Compound 60 g of Hydrocortisone 1% and Salicylic Acid 2% Ointment in a White Petrolatum base. Calculate the masses of APIs, levigating agent (mineral oil), and base required.

Solution Steps:

1. Calculate active ingredient masses:

   • Hydrocortisone API = 60 g * 0.01 = 0.60 g
   • Salicylic Acid API = 60 g * 0.02 = 1.20 g
   • Total Powder Mass = 0.60 g + 1.20 g = 1.80 g

2. Calculate mineral oil levigating agent mass (1:1 ratio with powder):

   • Mineral Oil Mass = 1.80 g (approx. 2.0 mL based on density 0.88 g/mL = 1.76 g)
   • Use 1.80 g Mineral Oil

3. Calculate White Petrolatum base required:

   • Base Required = Total Weight - (Powder Mass + Levigating Agent Mass)
   • Base Required = 60.0 g - (1.80 g + 1.80 g) = 60.0 g - 3.60 g = 56.40 g White Petrolatum

4. Compounding Procedure: Levigate hydrocortisone and salicylic acid with 1.80 g mineral oil on an ointment tile until smooth. Geometrically incorporate 56.40 g White Petrolatum. Package in a 2 oz ointment jar.