Takeru Higuchi

Takeru Higuchi, credited as T. Higuchi in his 1963 paper, developed mathematical descriptions of diffusion-controlled drug release from solid matrices. The University of Kansas archive holds that exact paper among his personal papers, establishing the connection between the initial-only byline and the full name.^[ref]

The paper distinguished a uniform matrix serving as the diffusional medium from a granular matrix penetrated by a solvent. It considered planar and spherical geometries, rather than treating all sustained release as a single first-order process.^[ref] The resulting models connect formulation geometry and material properties with a measurable drug release rate.

A simplified planar derivation illustrates the Higuchi equation. Assume a stationary matrix with constant diffusion coefficient $D$, excess undissolved drug, a perfect sink condition in drug release at its exposed face, and a slowly moving depletion boundary at depth $h(t)$. Approximate the dissolved-drug concentration as linear from zero at the exposed face to its solubility $C_s$ at that boundary. If initial total loading per unit volume is $C_0$, the amount released per exposed area isbecause the depleted layer retains a triangular dissolved-drug profile. The outward mass flux is approximately $D{C}_s/h$, so mass conservation givesThus the cumulative released amount is proportional to $\sqrt{t}$ in this model, whereas its derivative decreases as $t^{-1/2}$. The high-loading approximation $C_0\gg C_s$ makes the slowly moving boundary assumption more plausible; the result is not a general solution for an arbitrary dissolving or swelling material.

For an original illustration, let $Q=k_H\sqrt{t}$ with $k_H=2\mathrm{mg}\mathrm{c}{\mathrm{m}}^{-2}{\mathrm{h}}^{-1/2}$. The cumulative release is $2\mathrm{mg}\mathrm{c}{\mathrm{m}}^{-2}$ at one hour and $4\mathrm{mg}\mathrm{c}{\mathrm{m}}^{-2}$ at four hours, but the instantaneous rates per area are respectively $1$ and $0.5\mathrm{mg}\mathrm{c}{\mathrm{m}}^{-2}{\mathrm{h}}^{-1}$. These are chosen model values. They show why sustained release need not be constant-rate release. Finite thickness, depletion of the solid phase, changing solubility or external transport resistance can end this regime. Measuring release tests the model's transport assumptions; a square-root fit alone does not uniquely identify them.