3.1 Solid Dosage Forms & Compounding

3.1 Solid Dosage Forms & Compounding

Solid dosage forms represent the most frequently compounded nonsterile preparations in pharmacy practice. Compounded solid dosage forms include bulk powders, divided powders (chartulae), hard shell capsules, tablet triturates, and molded lozenges (troches). Compounding high-quality solid dosage forms requires mastery of particle size reduction (comminution), powder blending, capsule size selection, fill weight calculations, and rigorous quality control testing.

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Powders & Comminution Techniques

Powders are intimate mixtures of dry, finely divided drugs and excipients. The physical properties of powders—including particle size distribution, bulk density, surface area, and flowability—directly determine dissolution rates, content uniformity, and fill accuracy.

Comminution (Particle Size Reduction)

Comminution is the process of mechanically reducing the particle size of a solid substance. Smaller, uniform particles dissolve more rapidly and blend homogeneously. The three primary methods of comminution are:

1. Trituration: Continuous rubbing or grinding of a solid powder in a mortar with a pestle. Porcelain mortars with rough inner surfaces are preferred for particle size reduction of coarse crystals, whereas glass mortars are used for smooth blending or liquid incorporation.
2. Levigation: Triturating a powder with a small volume of a viscous liquid (the levigating agent) in which the solid is insoluble. Levigation forms a smooth paste and eliminates grittiness before incorporation into semisolids.
3. Pulverization by Intervention: Used for hard crystalline or gummy substances (e.g., camphor, iodine, menthol) that resist mechanical grinding. A volatile solvent (such as ethanol or acetone) is added to dissolve the substance ("intervention"). As the solution is triturated in a mortar, the solvent rapidly evaporates, leaving behind extremely fine, recrystalized powder particles.

Powder Blending Methods

Achieving uniform distribution of the active pharmaceutical ingredient (API) throughout a powder mixture is critical for patient safety, particularly when compounding potent medications.

• Geometric Dilution: The essential technique for mixing a small mass of potent drug with a large mass of diluent (e.g., lactose monohydrate or microcrystalline cellulose). The API is placed in the mortar with an equal volume of diluent and triturated until uniform. A second volume of diluent equal to the total volume currently in the mortar is added and mixed. This step-by-step doubling process continues until all diluent is fully incorporated.
• Spatulation: Blending small quantities of powders on an ointment tile or paper using a flexible spatula. Spatulation produces minimal compression force and is ideal for eutectic mixtures (substances that liquefy when mixed together at room temperature, such as camphor and phenol).
• Tumbling: Rotating powders inside a sealed container (e.g., a V-blender or clear plastic bag). This method avoids particle degradation and loss to mortar walls.
• Sifting: Passing powders through wire mesh sieves. Sifting yields light, fluffy powders but is not suitable for incorporating potent drugs due to potential particle segregation.

Powder Flowability & Angle of Repose

Powder flow properties dictate how smoothly a formulation flows into capsule shells or tablet molds. Flowability is quantified using the Angle of Repose (theta):

tan(theta) = Height of Powder Cone (h) / Radius of Powder Base (r)

• theta < 30 degrees: Excellent flow properties.
• 30 degrees <= theta <= 45 degrees: Good to fair flow properties.
• theta > 50 degrees: Poor flowability; requires addition of a glidant (e.g., 0.25–1.0% silicon dioxide or magnesium stearate).

Effervescent Granules

Effervescent powders or granules release carbon dioxide gas (CO2) upon hydration, masking bitter drug tastes and accelerating dissolution. The standard effervescent vehicle contains a combination of citric acid monohydrate, tartaric acid, and sodium bicarbonate in a precise stoichiometric ratio of 1 : 2 : 3.4 by weight. Citric acid alone produces a sticky powder, while tartaric acid alone yields crumbly granules; combining them ensures proper structural binding during heat-assisted wet granulation.

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Hard Shell Capsules: Materials, Sizes, & Calculations

Capsules are solid dosage forms in which drug substances and excipients are enclosed within a small soluble shell, usually composed of gelatin or hypromellose (hydroxypropyl methylcellulose, HPMC).

Capsule Size Scale & Volumetric Capacities

Human hard capsules are available in eight standard sizes, ranging from size 000 (largest) down to size 5 (smallest).

• Size 000: Volume ~ 1.37 mL (Typical powder fill: 600 – 1400 mg)
• Size 00: Volume ~ 0.95 mL (Typical powder fill: 400 – 900 mg)
• Size 0: Volume ~ 0.68 mL (Typical powder fill: 300 – 600 mg)
• Size 1: Volume ~ 0.50 mL (Typical powder fill: 200 – 400 mg)
• Size 2: Volume ~ 0.37 mL (Typical powder fill: 150 – 300 mg)
• Size 3: Volume ~ 0.30 mL (Typical powder fill: 100 – 200 mg)
• Size 4: Volume ~ 0.21 mL (Typical powder fill: 75 – 150 mg)
• Size 5: Volume ~ 0.13 mL (Typical powder fill: 40 – 90 mg)

Determining Capsule Size & Fill Mass

To compound capsules, the technician must determine the target total weight per capsule. If the API dose is small (e.g., 5 mg), an inert diluent (such as microcrystalline cellulose, lactose, or cornstarch) must be added to fill the capsule body completely.

The Rule of Seven

The Rule of Seven provides a quick empirical estimate for selecting capsule size based on grains of powder per capsule (where 1 grain = 64.8 mg or ~65 mg):

1. Express the target weight of powder per capsule in grains.
2. Subtract the number of grains from 7:

Capsule Size Number = 7 - (Weight of Powder per Capsule in Grains)

Example: If a capsule contains 4 grains (~260 mg) of powder, Capsule Size = 7 - 4 = Size 3.

Volumetric Density Calibration Method

For precise compounding, technicians determine the tapped bulk density (rho_tapped) of the mixed powder formulation in g/mL:

Powder Fill Weight per Capsule (mg) = Capsule Volume (mL) * Powder Bulk Density (g/mL) * 1000

Capsule Compounding Methods

• Hand-Punch Method: The powder mixture is placed on an ointment tile and compressed into a flat, uniform bed with a height equal to approximately one-third to one-half the length of the capsule body. The open body of the capsule is repeatedly punched into the powder bed until filled. The cap is placed on the body, locked, and the filled capsule is weighed on an analytical balance.
• Manual Capsule Filling Machines: Benchtop capsule machines (e.g., 100-cap or 300-cap plates) separate caps from bodies simultaneously, allow uniform powder spreading across all bodies using a scraper/tamper, and lock all capsules in a single operation.

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Tablet Triturates & Molded Lozenges

• Tablet Triturates: Small, cylindrical, molded tablets prepared using a hard rubber or plastic tablet triturate mold. The base consists of lactose and sucrose (typically 4:1 ratio). The powder blend is moistened with a hydroalcoholic diluent (e.g., 50–80% ethanol in water). The ethanol acts as a temporary binder; upon pressing the moist mass into mold cavities and drying, the alcohol evaporates, leaving fragile, rapidly dissolving tablets.
• Molded Lozenges / Troches: Solid oral dosage forms designed to dissolve slowly in the mouth for localized or systemic delivery. Hard candy lozenges utilize sucrose and corn syrup matrices cooked to the hard-crack stage (149–154°C). Soft troches utilize polyethylene glycol (PEG 1450 or PEG 4000) or glycerinated gelatin matrices.

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Quality Control & Weight Variation Testing

Compounded capsules and molded solids undergo the checks defined in the master formulation and facility SOP before release. Weight variation can detect filling inconsistency, but the sample size and acceptance limits must come from an applicable monograph, validated formulation, or SOP; USP <795> does not impose one blanket rule on every compounded capsule.

1. Weigh 10 individual filled capsules individually on a calibrated balance.
2. Calculate the average weight (W_avg) of the 10 capsules.
3. Determine the percentage deviation for each individual capsule:

Percent Deviation = [(W_individual - W_avg) / W_avg] * 100%

• Illustrative facility criterion: If the approved SOP sets ±10% around the target for this formulation, calculate that range and investigate any unit outside it. Do not label ±10%/±15% as a universal USP criterion; USP <905> uses product- and test-specific procedures.

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Worked Numerical Examples

Worked Example 1: Capsule Batch Formulation & Diluent Calculation

Scenario: A pharmacy technician must compound 30 capsules of Baclofen 5 mg per capsule using Size 1 capsules (volume 0.50 mL). The tapped bulk density of lactose monohydrate diluent is 0.60 g/mL. Calculate the required API mass, target total capsule weight, and total diluent mass required (include 10% overage for compounding loss).

Solution Steps:

1. Calculate total capsules to weigh for (with overage):

   • Target count = 30 capsules
   • Count with 10% overage = 30 * 1.10 = 33 capsules

2. Calculate total Baclofen API mass required:

   • API mass = 33 capsules * 5 mg/capsule = 165 mg Baclofen API

3. Calculate total target fill mass per capsule using bulk density:

   • Fill weight per capsule = 0.50 mL * 0.60 g/mL = 0.300 g = 300 mg per capsule

4. Calculate diluent mass per capsule:

   • Diluent per capsule = Total capsule weight - API weight
   • Diluent per capsule = 300 mg - 5 mg = 295 mg Lactose Monohydrate

5. Calculate total batch diluent mass for 33 capsules:

   • Total Diluent mass = 33 * 295 mg = 9,735 mg = 9.735 g Lactose Monohydrate

6. Compounding Procedure: Weigh 165 mg Baclofen and 9.735 g lactose. Perform geometric dilution in a glass mortar. Fill Size 1 capsules to a target weight of 300 mg + empty capsule shell weight.

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Worked Example 2: Weight Variation Quality Control Analysis

Scenario: A facility SOP for this DHEA formulation calls for 10-unit gross-weight sampling with an illustrative ±10% limit. Evaluate the recorded batch against that stated facility criterion.

• Individual Gross Weights (mg): 320, 325, 318, 330, 312, 328, 322, 315, 326, 334.

Solution Steps:

1. Calculate average gross capsule weight (W_avg):

   • Sum = 320 + 325 + 318 + 330 + 312 + 328 + 322 + 315 + 326 + 334 = 3,230 mg
   • W_avg = 3,230 mg / 10 = 323.0 mg

2. Calculate lower and upper acceptance limits (+/- 10% of W_avg):

   • Lower Limit (-10%) = 323.0 mg * 0.90 = 290.7 mg
   • Upper Limit (+10%) = 323.0 mg * 1.10 = 355.3 mg

3. Evaluate individual capsule weights:

   • Lowest gross weight = 312 mg (Percent Deviation = [(312 - 323)/323] * 100% = -3.4%)
   • Highest gross weight = 334 mg (Percent Deviation = [(334 - 323)/323] * 100% = +3.4%)

4. Conclusion: All 10 values fall within the stated 290.7–355.3 mg facility range. The batch passes this illustrative SOP criterion; the calculation is not a universal USP rule.