From form to function: Crystallization of active pharmaceutical ingredients

Abstract

Since the introduction of aspirin in 1899, and more particularly since the advent of antibiotic ‘‘wonder drugs’’ in the 1940s, society has come to rely on the widespread availability of therapeutic drugs at reasonable prices. It was a tremendous challenge to bring penicillin to market and could not have been done without the simultaneous development of both product and process under the inspired leadership of Howard Florey over a 10 year period starting in the early 1930s, as revealed in the riveting story told by Eric Lax. 1 In the interim, much has changed in drug development, but the timelines remain long, and the obstacles to success remain high. For drugs delivered to patients in crystalline form, the physical properties of the active pharmaceutical ingredient (API) including crystal form, size and shape have the potential to impact bioperformance, particularly for low-solubility compounds, where the rate-limiting-step in drug uptake may be the dissolution of the API in the gut. These physical properties of the API are often controlled in the final API crystallization step. Because most small molecule drugs (.90%) are delivered in crystalline form, and currently about 90% of new API’s being pursued are classified as having low solubility in water, a well-controlled crystallization of the API is often a vitally important operation in pharmaceutical manufacturing. Moreover, it is a difficult operation because of uncertainty in the crystal forms that will appear, and because of the many challenges associated with scaling-up crystallizations from laboratory to manufacturing scale. Although great emphasis is placed on the therapeutic and chemical discovery aspects of new APIs, it must be emphasized that the successful entities will eventually need to be manufactured. Pisano 2 has made a detailed study of the strategic value of process development and concludes that the benefits of a superior manufacturing process can include early product launch and consistent, higher product quality. Most companies seek to minimize manufacturing costs and maximize process portability by applying the simplest manufacturing process capable of producing their drug product with desired attributes. Because only 10% of the compounds in development survive the efficacy and safety hurdles in the clinic and become marketed drugs, there is also great value in minimizing R&D costs (including clinical trials), which are estimated to be about $1 billion per launch, with a remaining life protected on-patent of typically only 6–10 years. In this perspective, we describe the state-of-the-art in API crystal product and process design, highlight barriers that currently prevent the production of better, cheaper crystalline products, and give our best estimate of where the field is going and should go during the next decade.