I. Basic Information and Research Background of the Literature

• Thesis Title : Investigation of Dissolution Performance of Hard Gelatin Capsule Products Using Various Sinkers

• Published in : Dissolution Technologies , August 2020, pp. 21–32

• DOI : 10.14227/DT270320P21

• Corresponding author : Jennifer Dressman

• Research institutions :

1. Institute of Pharmaceutical Technology, Goethe University, Frankfurt am Main, Germany

2. Fraunhofer Institute for Molecular Biology and Applied Ecology, TMP, Frankfurt am Main, Germany

• Research background and core questions :

• When testing capsule formulations in the USP device 2 (Paddle method), two major flow field interferences are often encountered: floating and coning .

• The ICH M9 guideline (BCS-based Bio-exemption Guidelines) recommends using Sinker to overcome the coning problem, but there is a lack of direct data support in internationally published literature.

• This study aims to validate three key questions :

  • A. Are all sinkers effective in preventing dosage form flotation?

  • B. Does using sinkers necessarily increase the dissolution rate?

  • C. Does the Sinker chip consistently reduce coning?

II. Test Materials, Equipment and Analytical Methods

2.1 Test capsule prescription specifications (excerpted from Supplementary Table S1)

2.2 Testing the geometric shape and material specifications of Sinker (excerpted from Supplementary Table S2)

2.3 Dissolution test and HPLC analysis conditions (Table 1)

• Dissolution instrument : ERWEKA DT 80 dissolution instrument, USP device 2 (Paddle method).

• Test speeds : 50 rpm, 75 rpm, 100 rpm.

• Medium temperature : 37.0 ± 0.5°C.

• Sampling time points : 5, 10, 15, 20, 30, 45 min (samples were filtered through a 0.45 µm PTFE membrane, diluted with a mobile phase of 1:10, and then analyzed by HPLC; all test groups had n = 5).

• Acceptance criteria : All products are subject to the same USP standard Q = 75% at 45 min .

III. In-depth analysis of experimental data and phenomena

3.1 Ketoprofen (weak acid, high solubility, no coning phenomenon)

Ketoprofen capsules (low gas content, apparent density 0.566 g/mL) exhibit extremely high solubility in a medium at pH 7.41, with no coning observed at 50–100 rpm. Without a sinker, they float briefly for approximately 30 seconds before sinking.

• Dissolution test data (Excerpt from Table 2, mean % ± SD, n = 5) :

  • 50 rpm :

    • 15 min : Without Sinker 88.85 ± 6.37% > CLIPS 87.40 ± 14.06% > CAPWAST 81.22 ± 4.87% > CAPLOTH 79.06 ± 10.90% > JP 78.33 ± 13.17%

    • 45 min : All met the target (Without Sinker 103.86%, CLIPS 98.88%, CAPWAST 96.63%, JP 96.54%, CAPLOTH 94.69%).

  • 75 rpm :

    • 10 min : CLIPS (99.37 ± 1.81%) was significantly higher than without Sinker (83.33 ± 10.81%, p = 0.004) . CAPLOTH (83.51%), JP (82.57%), CAPWAST (76.63%).

    • At 15 min : CLIPS reached 103.13%, while the remaining Sinker group ranged from 88.45% to 95.39%.

  • At 100 rpm for 15 min, all groups showed a dissolution rate of 96%–101%, with no significant difference between Sinker and non-Sinker groups.

• Phenomenon Mechanism Analysis :

1. Fastest dissolution at 50 rpm without Sinker : Capsules roll freely in the cup without restraint, effectively reducing the thickness of drug particles and the liquid diffusion layer on the capsule surface, resulting in the highest convection renewal rate.

2. "Artifactual Increase" of CLIPS at 75 rpm : CLIPS weighs only 0.90 g and has a low density. In a flow field of 75 rpm, CLIPS rotates and swings violently with the capsule, acting as an "extra micro-stirring element" and forcibly accelerating the diffusion of particles.

3.2 Fluconazole (highly soluble in acids, forms strong, sticky plugs)

Fluconazole capsules (density 0.661 g/mL) floated for about 5 minutes without a sinker or with CLIPS. Plug formation of varying degrees of capsule contents was observed in all groups at all rotation speeds.

• Dissolution test data (Table 3 excerpt, mean % ± SD, n = 5) :

  • 50 rpm : All groups failed at 45 min (Q < 75%) !

    • Dissolution rates at 45 min: CAPLOTH (65.96 ± 4.56%) > CAPWAST (60.03 ± 10.92%) > Without Sinker (58.11 ± 5.82%) > JP (56.87 ± 6.05%) > CLIPS (56.25 ± 9.98%).

  • 75 rpm :

    • Dissolution rates at 45 min: CAPLOTH (84.33 ± 9.71%), CLIPS (81.07 ± 5.39%), and Without Sinker (79.75 ± 10.81%) met the standards ; while JP (73.01 ± 9.28%) and CAPWAST (73.08 ± 9.90%) were deemed unqualified .

    • The similarity factor f2 for the non-Sinker group between 50 rpm and 75 rpm was 39 (significant difference).

  • 100 rpm :

    • Without Sinker (90.99%), CAPLOTH (83.88%), CLIPS (82.73%), and CAPWAST (76.93%) all passed, but JP Sinker (73.69 ± 3.96%) still did not meet the 75% requirement .

• Phenomenon Mechanism Analysis :

1. The fatal flaw of JP Sinker's metal mesh clogging : The mesh openings of JP Sinker are extremely small, making it difficult for fluid shear to penetrate. When softened gelatin dissolves, it adheres to and clogs the metal mesh pores , causing the capsule shell to collapse inward and become trapped inside the mesh, forming a dense plug that cannot be completely released even under strong hydrodynamic force at 100 rpm.

2. CAPLOTH performs best : CAPLOTH has ample internal space, the capsule is not subjected to radial compression, and the gelatin does not easily encapsulate the drug powder when it melts, resulting in the smallest volume of the powder plug and the fastest drug release.

3. CLIPS floating failure : Because the density of CLIPS plastic is less than that of water (0.92 g/mL), although the capsules are packed tightly, the trace amount of air inside the capsules causes the CLIPS, along with the capsules, to float on the liquid surface for up to 5 minutes, thus losing its settling function.

4. The double-edged sword effect of CAPWAST : the fine helical segments cut through the capsule shell (promoting dissolution), but the longitudinal support columns have a large contact area with the long axis of the capsule, causing the gelatin to collapse inward and encapsulate the drug (inhibiting dissolution).

3.3 Acetaminophen (highly water-soluble, high gas content, typical severe coning)

Acetaminophen capsules (500 mg, 00E capsules, density only 0.549 g/mL, containing a large amount of air) floated on the surface of the liquid for up to 10 minutes at all speeds without Sinker, and showed a severe coning at the center of the bottom of the cup at 50 rpm.

• Dissolution test data (Excerpt from Table 4, mean % ± SD, n = 5) :

  • 50 rpm :

    • 45 min dissolution rate : CLIPS (83.74 ± 3.52%) was the only one that met the standard; Without Sinker reached 79.02 ± 5.73%, which met the standard; All other metals failed the Sinker test : JP (69.87 ± 5.12%), CAPLOTH (65.41 ± 5.62%), CAPWAST (55.09 ± 3.23%).

    • 15-minute release: Without Sinker (57.96%) was 10%–23% higher than CAPWAST (34.65%), CAPLOTH (45.13%), and JP (46.61%)!

  • 75 rpm :

    • Dissolution rates at 45 min: CLIPS (98.09%), Without Sinker (91.69%), CAPLOTH (87.17%), and JP (81.48%) all met the standards; CAPWAST barely passed with a dissolution rate of 76.67 ± 4.03% .

    • Release at 15 min: CLIPS (94.54%) was significantly higher than that without Sinker (81.41%, p = 0.0007).

  • 100 rpm :

    • The cone completely dispersed, reaching 94.8%–100.8% in 45 min. The f² of the dissolution curves without Sinker at 50 rpm and 75 rpm was 34.

• Phenomenon Mechanism Analysis :

1. Refuting the argument of ICH M9 Sinker : Acetaminophen is extremely soluble in water, but at 50 rpm, the dissolution results using three stainless steel metal sinkers (CAPLOTH, CAPWAST, JP) were significantly lower than those of the "no sinker group" .

2. Hydrodynamic Dead Zone Trap : The metal Sinker (density ~8.0 g/mL) forcibly compresses the capsules in a region with near-zero flow rate directly below the stirrer. The gelatin melts and collapses at the contact surface, causing the powder to directly deposit in the center of the bottom of the cup, forming a dense cone mound, resulting in falsely low dissolution data.

3. False interference of CLIPS : Because of its light weight, the CLIPS Sinker rotates and swings at the bottom of the cup with the water flow, mechanically breaking up the sediment cone, resulting in an abnormally high dissolution rate (artificial illusion).

3.4 Empirical Testing of Core Issues and Guideline Controversies

• The scientific blind spot of ICH M9 recommendations : The ICH M9 guidelines recommend the introduction of a sinker when coning occurs. However, data has shown that heavy metal sinkers are precisely the culprit that exacerbates coning false defects, and sinkers fail to reduce the standard deviation (SD) of the data, and sometimes even increase variability.

• The correct scientific approach to eliminating cones and dead zones :

1. Increase stirring speed : Increasing the speed to 75 rpm or 100 rpm can effectively break the hydrodynamic dead zone at the bottom of the paddle, allowing the accumulation cone to disperse naturally and eliminating flow field illusions.

2. Peak Vessels are used : The central convex cone at the bottom completely eliminates dead zones geometrically, forcing undispersed powder into a high-convective flow field, which is an excellent physical solution to replace increasing the rotational speed.

IV. Qinwei Technology Perspective

In the practice of developing dissolution tests and methods for oral capsule solids (OSD), we often find that many researchers habitually add sinkers arbitrarily when faced with capsule floating or coning, which often leads to a sudden increase in the variation of the dissolution curve (%RSD > 20%) or pseudo-dissolution failure (Pseudo-OOS) .

The core root cause of this phenomenon often lies in the mutual interference between the "sinker geometry and the microscopic hydrodynamic flow field at the bottom of the dissolution vessel" . According to authoritative empirical research by the University of Frankfurt and Fraunhofer IME ( Dissolution Technologies , Aug 2020), the ICH M9 guideline recommending "using sinkers to solve cone compaction" has significant scientific blind spots - heavy metal sinkers often forcibly compress the capsules into a dead zone with near-zero flow rate directly below the agitator, causing the gelatin to melt and collapse, tightly binding the powder into a dense plug, and the dissolution rate actually lags far behind that of the group without sinkers.

To address the flow field bottlenecks and pseudo-interferences in the evaluation of capsule-based dissolution, the following scientific decisions should be made regarding procurement and consumable implementation:

• Core, stand-alone mainstay: The entire series of "open, loose spiral Sinker" (CAPLOTH form)

Empirical data shows that it performs the most stably. The open spiral geometry only contacts both ends of the capsule, ensuring unobstructed internal flow and maximizing the effective dissolution surface area of the dosage form, fundamentally preventing gelatin from collapsing inward to encapsulate the drug powder. Prosense should list it as the first recommended stock standard for capsules in sizes 00 to 4.

• Additional niche specification: Oversized Sinker for soft capsules.

When heated and absorbing water, soft capsules expand radially by 10%–20%. Using standard-sized sinkers can easily lead to pinching effect, causing the oil phase of the contents to adhere to the metal wires, resulting in a 3%–5% loss in recovery rate. It is recommended that the Prosense project introduce a width specification with an increased inner diameter and length of 2–3 mm to maintain expansion freedom and data reproducibility.

• Establish a negative procurement list: completely eliminate plastic clamps and gelatin mesh cages.

1. Completely eliminate polypropylene plastic Sinker (such as CLIPS, density 0.92 g/mL) : its buoyancy cannot suppress the floating of gas-filled capsules, and it is prone to artificial pseudo-acceleration by self-rotation and swaying in a flow field of 75 rpm.

2. Strict warning regarding Japanese Pharmacopoeia-style metal mesh baskets (JP Basket) : When gelatin dissolves, it can directly clog the tiny mesh openings, causing serious false OOS. It is only permitted for testing non-disintegrating pellets (Pellets). Gelatin hard capsules are completely prohibited.

• Exquisite materials and strict geometric tolerance control

All metal Sinker components are made of AISI 316L medical-grade stainless steel, mirror-polished by electrolytic polishing (Ra < 0.4 µm) to completely eliminate API adsorption risk (adsorption recovery rate meets 98.0%–102.0%); single-piece weight tolerance is strictly controlled within ±0.1 g, and geometric dimensional tolerance is controlled within ±0.5 mm.

• Systematic solution for Coning: Bundled promotion with the "Peak Vessel"

The cone effect should be resolved through fluid dynamics (such as appropriately increasing the engine speed to 75–100 rpm, or adopting a Peak Vessel with an inverted cone-shaped flow guide at the bottom), rather than blindly adding a Sinker. Prosense can provide pharmaceutical clients with the most professional compliance technical consultation by combining Sinker with Peak Vessel solutions.

V. References and Documents

1. US FDA — Size, Shape, and Other Physical Attributes of Generic Tablets and Capsules (Guidance for Industry).

2. ICH M9 — Biopharmaceutics Classification System-Based Biowaivers (Step 4, 2020).

3. USP <711> Dissolution — The United States Pharmacopeia and National Formulary ; Rockville, MD.

4. EP <2.9.3> Dissolution Test for Solid Dosage Forms — European Pharmacopoeia .

5. JP 18 <6.10> Dissolution Test — Japanese Pharmacopoeia .

6. Mansuroglu, B.; Dressman, J. (2020). Investigation of Dissolution Performance of Hard Gelatin Capsule Products Using Various Sinkers. Dissolution Technologies , 27(3), 21–32. DOI: 10.14227/DT270320P21.

7. Gray, V.; Kelly, G.; Xia, M.; et al. (2009). The Science of USP 1 and 2 Dissolution: Present Challenges and Future Relevance. Pharmaceutical Research , 26(6), 1289–1302.

8. Higuchi, M.; Yoshihashi, Y.; Terada, K.; Sugano, K. (2014). Minimum Rotation Speed to Prevent Coning Phenomena in Compendium Paddle Dissolution Apparatus. European Journal of Pharmaceutical Sciences , 65, 74–78.

9. Baxter, J.; Kukura, J.; Muzzio, F. (2005). Hydrodynamics-Induced Variability in the USP Apparatus II Dissolution Test. International Journal of Pharmaceutics , 292(1–2), 17–28.

10. Mirza, T.; Joshi, Y.; Liu, Q.; Vivilecchia, R. (2005). Evaluation of Dissolution Hydrodynamics in the USP, Peak and Flat-Bottom Vessels Using Different Solubility Drugs. Dissolution Technologies , 12(1), 11–16.