I. Fundamental differences in diffusion cell structures in USP <1724>: Model A and Model B

In the United States Pharmacopeia (USP) <1724> specification, vertical diffusion cells (VDCs) have different geometric flow path structures. The industry-standard designs and the advanced architecture adopted by Logan exhibit drastically different performance characteristics in terms of fluid dynamics and exhaust.

Traditional upright side-tube type (USP Model B architecture): This architecture uses a top or side tube for vertical downward needle insertion for sampling. The sampling pipeline is essentially a dead zone, where tiny bubbles easily become trapped. Sampling requires manual tilting and tapping of the diffusion cell, and bubbles are easily trapped at bends and cannot be expelled. If an automated needle is used for deep sampling, it is extremely difficult to achieve a completely consistent depth each time, and when the medium is replenished from above, splashing is likely to occur, directly injecting outside air into the recipient chamber. This causes bubbles to adhere to the skin on the top of the recipient chamber or the back of the release membrane, resulting in an effective diffusion area obscuration rate that is often as high as 10% to 30%.

Logan's bottom-inlet and low-level flow path design (USP Model A evolution architecture): Logan abandons the traditional long neck dead zone that easily accumulates air, placing the sampling and refill paths at the bottom of the receiver chamber and in the low-level pipeline. Magnetic stirring directly drives the flow throughout the bottom area, completely eliminating fluid stagnation dead zones. The system utilizes the slight positive pressure and natural buoyancy of the fluid rising from the bottom to automatically guide microbubbles upwards for discharge. In fully automated operation, the closed pipeline is directly connected to the bottom, and push-pull injections are smoothly replaced from the bottom layer without disturbing the top contact interface. Fluid dynamics continuously scour the bottom of the membrane, preventing microbubbles from adhering and achieving a truly zero-bubble state.

II. In-depth analysis of the physical mechanism: Why does the traditional Model B "side tube and top sampling" method easily generate bubbles?

Traditional Model B or older Franz Cell cells are prone to accumulating air bubbles due to the following three physical structural defects:

First, stagnant water and natural precipitation of dissolved gases: When the acceptor medium is in a constant temperature environment of 32°C or 37°C, the solubility of dissolved air in the liquid will decrease due to the increase in temperature, and microbubbles will gradually precipitate. Traditional side tubes lack direct convection stirring, and the precipitated microbubbles will float upward along the side wall, getting stuck in the dead corner arch of the acceptor chamber where they come into contact with the skin.

Second, manual sampling introduces artificial air disturbance: Traditional sampling requires inserting a long needle into the side arm to extract liquid. When replenishing with fresh medium, the liquid is injected or dripped from above, which easily traps outside air to form bubbles and directly impacts the inside of the recipient chamber.

Third, capillary backlash during replacement of the entire tank of media: When conducting intravenous bioequivalence (IVPT) tests for topical preparations, regulations require "full sampling and full replenishment." If the liquid is evacuated from above and then refilled, the liquid level rises from the bottom and re-contacts the back of dry or semi-dry skin. Due to surface tension and microcapillary phenomena, a large number of microbubbles will inevitably form on the skin's texture, causing severe masking.

III. Core Advantages and Bubble-Free Mechanism of Logan Diffusion Cell Bottom Sampling

Logan completely solves the above problems through fluid dynamics optimization design, and its core technology mechanism includes four major features:

First, the natural flow separation of buoyancy and microfluidics: In physical principles, the density of bubbles is much less than that of liquid media, and the natural buoyancy of bubbles is always upward. Logan's acceptor medium recharge line is introduced from the bottom of the acceptor chamber. When fresh medium enters, it rises steadily from the bottom, pushing out the existing liquid. The thrust generated by the bottom liquid inlet is completely consistent with the direction of bubble buoyancy. Tiny bubbles are pushed along the flow lines to the top of the side arm and naturally discharged, never lingering in the core working area of the acceptor chamber or below the membrane.

Second, the omnidirectional dynamic cleaning effect of the magnetic stirrer: A high-precision Teflon or PVDF stirrer is positioned at the center of the bottom of the receiving chamber. The bottom inlet and outlet flow paths work in conjunction with the rotating flow field of the stirrer to form a stable, rising annular microvortex. At standard stirring speed, a uniform shear flow continuously and gently brushes the skin or releases the bottom surface of the membrane, disrupting interfacial tension and eliminating the conditions for microbubbles to adhere and grow.

Third, the closed-loop bidirectional syringe pump features a stable bottom replacement: When paired with the Logan DSC-800 automated workstation and the SYP high-precision bidirectional syringe pump, the system directly performs desiccation and isothermal injection via the bottom connecting pipe. The entire sampling and replenishment path is a completely closed system. The fresh replenishment medium is smoothly pushed in from the bottom in a pulseless manner, completely eliminating the drawbacks of traditional top-drip injection that introduces air into the diffusion cell.

Fourth, patented adaptive venting tilt mechanism: Both the Logan dry thermal diffusion system and the flow cell system are equipped with an adaptive micro-tilt mechanism. During the initial filling of the medium, the diffusion cell can be tilted to the side at a specific angle, and the airflow generated by the liquid inlet at the bottom will escape smoothly along the guide pipe. After filling is completed, it returns to the upright position, achieving a perfect full liquid and bubble-free state, without the need for operators to use a vibrator to tap or shake it.

IV. Significant Value in Methodology and Regulation

First, it eliminates falsely low uptake rates and abnormal deviations: In in vitro release testing (IVRT), even a single bubble with a diameter of one millimeter can reduce the effective diffusion surface area by 5% to 10%, causing the release curve to deviate significantly from the Higuchi equation and resulting in the correlation coefficient squared value failing to meet the standard. Logan's bottom sampling design ensures that the effective area of all diffusion cells is completely consistent, allowing the intra-batch relative standard deviation (RSD) to be stably controlled within an extremely low range.

Second, ensuring the authenticity of IVPT test data and the reliability of BE exemption: In in vitro penetration testing (IVPT), human ex vivo skin samples are extremely scarce and expensive. If bubble blockage causes a sudden drop in the flux of a specific diffusion cell, the entire experiment becomes invalid and will fail to meet the stringent statistical reliability requirements of the US FDA or other national regulatory authorities. A bubble-free bottom structure is the hardware foundation for ensuring data integrity.

Third, it enables 24/7 automated "full sampling and full replenishment": The fluid's self-venting and stable replacement characteristics prevent the diffusion cell from generating bubbles again, even under harsh conditions of frequent evacuation and filling, enabling stable operation of high-throughput sampling without human intervention for 24 to 48 hours.

V. Core Summary

Traditional Model B side-arm sampling goes against the laws of physics and fights against bubbles, while Logan's bottom-sampling architecture follows natural buoyancy and microfluidics, pushing away bubbles from bottom to top. Without bubbles blocking the diffusion area, the true drug release rate can be represented, producing high-quality data that fully complies with international pharmacopoeia and review standards.

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• Official website : www.dissolution.com.tw

• Product Section : USP1724 Transdermal Absorption

• Technical consultation hotline : 04-2241-1607