INTRODUCTION
Zinc pyrithione (ZPT) is a widely used drug active to treat topical
fungal conditions. It is also used cosmetically to exploit its breadth of antimicrobial activity. It has a history of safe and effective use for more than 50 years. Such a long history may obscure an appreciation of its development history, the breadth of beneficial activities realized over the years as well as the complex pharmaceutics discovered to be relevant in topical delivery of the material in its most active form. The intent of this review is to recount the history of this rationally developed drug, understand the unique physico-chemical properties that lead to the complex pharmaceutics and overview the range of activities and resultant benefits that can result from topical use on skin.
The History of Development of Zinc Pyrithione
The development of ZPT originated in a targeted discovery program at ER Squibb & Sons to model the natural antibiotic aspergillic acid (Figure 1A). Aspergillic acid was isolated in the 1940’s from Aspergillus strains as one of the materials responsible
for the observed antimicrobial activity of the organism. A synthetic program was initiated to focus on the core chemical elements of a cyclic hydroxamic acid functional group in a pyrazine
nucleus. The objective was to develop synthetic analogs with antifungal activity for agricultural applications.
As part of this synthetic program, sodium pyrithione was originally synthesized 1 and shown to exhibit significant antimicrobial
activities. Both the sodium (Figure 1B) and zinc salt (Figure 1C) forms of this material were commercialized by the Mathieson-Olin Chemical Co. While the material never found use in the agricultural field, the zinc salt was discovered as very effective for controlling growth of the scalp fungus Malassezia (called Pityrosporum at the time) that causes dandruff.2
Physico-Chemical Properties of ZPT
Synthesis
ZPT is prepared industrially3 (Figure 2) from sodium pyrithione. The latter is synthesized by oxidation of 2-chloropyridine followed by mercaptization. The sodium salt is then precipitated with zinc sulfate,
which after washing leads to the commercial material, which is normally utilized as an aqueous dispersion. The conditions of the precipitation can be manipulated to alter the morphology and size of the precipitating ZPT particle. ZPT can also be milled after precipitation to alter particle size. These factors contribute to the complex pharmaceutics of this material (see below).
Physical Properties of ZPT
ZPT is a white crystalline material in the dry state with a density
of 1.8 g/cm.3 Solubility in water and most common solvents
