In order to carry out capsule size comparison, there should be standard parameters, measuring devices, and scenario-based verification. According to the United States Pharmacopeia (USP) standard, capsule sizes from 000 (capacity 1.37 mL, diameter 9.91 mm, length 26.14 mm) to 5 (capacity 0.13 mL, diameter 4.91 mm, length 11.10 mm) are 8 specifications that can meet over 90% of the demands for oral solid preparations. For Catalent, a pharmaceutical company, for example, it uses a laser micrometer (accuracy ± 0.001mm) in size sampling of gelatin capsules (300 capsules are randomly sampled in each batch) to discover diameter and length variations and verify whether they fall within the USP tolerance limit (diameter ± 0.05mm, length ± 0.15mm). The unqualified rate is kept below 0.1%.
In material fit testing, capsule size comparison requires quantitation of powder characteristics. For example, for the above-said Chinese medicine having a bulk density of 0.6 g/cm³ and an Angle of rest of 35°, the content filled was 220 mg±3% when No. 2 capsule (capacity 0.37 mL) was selected, while the content filled was 300 mg when No. 1 capsule (capacity 0.50 mL) was used, but the capsule closure strength (≥ 0.7N) must be tested in order to meet the standard. When filled with high viscosity powder (Carr Index>25), Vcaps series HPMC capsules from Capsugel in the UK have a 40% reduction in weight deviation (±2% vs ±3.5%) compared to gelatin capsules due to low electrostatic adsorption.
Compatibility with manufacturing equipment is another key consideration. The German Bosch GKF 7200 capsule filling machine offers size 0-5 changeover, 8 minutes mold change time (20 minutes for traditional models), and mold cost of around $1,200-2,500 / set. If the company produces multi-specification products (e.g., pharmaceuticals and health care products mixed line), it needs to estimate the capacity loss: e.g., a plant changes size three times a day (15 minutes each shutdown), the annual capacity loss of 48,000 tablets (assuming 300 days/year), the equivalent revenue loss of 120,000 US dollars (assuming a profit of 0.25 US dollars per pill).
Regulatory requirements directly impact capsule size comparison methods. The EU EMA requires pediatric capsules to be ≤8 mm in diameter (corresponding to No. 3 and smaller sizes), and the FDA limits the length of capsules for sustained-release preparations to ≤20 mm (for No. 00 and smaller). In 2021, Pfizer selected HPMC capsule No. 1 (6.91 mm diameter) for COVID-19 oral drug Paxlovid because of its ability to enhance the drug release curve (Tmax 15% quicker) through the gastric empting time model (average 35 minutes) and to pass the dissolution test (≥85% release in 30 minutes).
Technological innovation increases relative efficiency. 3D scanning equipment, such as Keyence VR-5000, can generate a capsule 3D model in 10 seconds with a measuring accuracy of ± 0.002mm, 80% less than the error of traditional calipers (± 0.01mm). Based on 100,000 groups of historical data, AI algorithms (such as MTS’s iCvision system) can predict the filling failure rate (R²=0.92) of capsules of a specific size. For example, when the powder flow rate (flow rate <10 g/s) is combined with capsule No.5, the blocking probability is 23%, and it is recommended to use capsule No. 4 with the addition of 0.5% silica flow aid.
Cost optimization comes with numerous trade-offs. An Indian pharmaceutical company compared No.00 gelatin capsule with No.0: The first is $0.012 per capsule, but needs double coating (add $0.005); The second one is filled directly at $0.015 per capsule, but reduces coating operation to save 15 percent labor time. Finally, capsule 00 was implemented, and the cost saving per annum was 240,000 US dollars (based on 200 million capsules/year). In addition, capsule size also has an impact on packaging: Capsule 3 holds 90 capsules/bottle (bottle diameter 28 mm), while the same volume of capsule 0 holds only 60 capsules, the packaging cost difference of up to 0.02 USD/bottle.
Environmental concerns cannot be ignored. The HPMC capsule expansion ratio at humidity >60% is 1.2% higher than that of gelatin (0.08mm larger in diameter at 30℃/ 75%RH), and whether the size change affects the sealing performance shall be verified in the stability test (ICH Q1A). Laboratory experiments carried out by Harro Hofliger in Germany showed that after 6 months of accelerated testing (40℃/75% RH), HPMC capsule No. 2 closure strength decreased by 12%, while that of gelatin capsule decreased by 25%, demonstrating that plant capsules also show better dimensional stability under long-term storage conditions.
Briefly, capsule size matching needs to integrate physical property data (pile density ± 0.05g /cm³), machine variables (filling speed ≥90% theoretical value), regulatory standards (dimensional tolerance ± 0.1mm), and economic models (ROI≤18 months). Science-based decision making through tool innovation (e.g., AI prediction) and scenario verification (dissolution curve fit ≥0.95). According to Grand View Research, the global capsule size optimization services market will be valued at $370 million by 2028, with AI-based solutions accounting for more than 40% of this.