December 1, 2008 (Vol. 28, No. 21)

Solid-State Chemistry Is One Component in Addressing the Critical Path Problem

The decline in new molecular entity and biologics licensing application approvals by the FDA over the last decade has left drug developers searching for ways of improving their R&D productivity and broadening their development pipelines. Each drug failure represents a significant loss in time and resources spent on candidate development.

Failures in industrialization—the process of developing a laboratory concept into a prototype for IND studies and then a manufacturable product—are a key element in the approval’s decline. There are several challenges in the process of industrializing a candidate molecule, not the least of which is addressing solubility and stability. A molecule’s solid state—the forms it can take when in its solid phase—can have a significant impact on both of these characteristics, and by extension, its bioavailability, toxicity, and efficacy.

High-throughput screens of large chemical libraries, a popular method of identifying candidate molecules, preferentially identify compounds with high molecular weight and poor solubility. Thus, drug developers may end up with dozens of compounds on their laboratory shelves that have promising activity but which are insufficiently soluble and, therefore, insufficiently bioavailable. It is estimated that only 40 percent of the average company’s candidate portfolio has the solubility and bioavailability required to be effective in vivo.

Solubility and stability concerns are exacerbated in part by a failure of the industry to embrace advanced techniques of solid-state chemistry and molecular concepts in product design. Solid-state chemistry, as a discipline, focuses on the synthesis, structure, and properties of solid materials. The information gained through solid-state chemical analyses of candidate molecules can give great insight into their developability and potential for success by allowing researchers and managers to balance each candidate’s physical and chemical characteristics with its pharmacological benefit.

At the same time, investigating alternative solid forms of failed or poorly soluble compounds can provide opportunities to enhance those compounds’ bioavailability and give each a new chance at clinical success.

Different solid forms of the same molecule can vary in solubility by as much as a factor of 106. Knowing this, application of the principles and techniques of solid-state chemistry presents drug developers with a pair of opportunities when launching a development program.

A molecule’s chemistry, in particular its solubility and bioavailability, is greatly dependent on its solid state.

Informing Product Design

First, if the level of bioavailability and stability required to reach a desired target is known, solid-state chemistry can provide a scientific rationale for designing a dosage form of a candidate molecule that can achieve those characteristics. Second, if a candidate has already been identified, knowledge of its solid-state chemistry can provide insight into the apparent solubility and stability of its different solid states (e.g., crystal, solvate, salt, cocrystal, liquid or plastic crystal, amorphous form), which allows researchers to predict how it will behave before attempting first-in-man or proof-of-concept testing, and can provide insight into the robustness of its associated preclinical toxicology data.

Apart from these biochemical considerations, a full understanding of a given molecule’s various solid forms also provides a basis for securing strong intellectual property protection for that molecule. Patents based on polymorph screening (analyses that identify all possible solid forms of a molecule) are second only to patents on molecules themselves in strength and ease of enforcement.

Solid-state chemistry also provides opportunities for taking active measures to revive failed but therapeutically important compounds by unlocking new solubility and stability characteristics. In a sense, because the solubility of the different forms can vary so much, each solid form of a candidate constitutes a unique molecular or supramolecular system for delivering the candidate to its biological target.

Enhancing Bioavailability

For instance, there is a great deal of interest in the use of co-crystal (crystalline structures containing at least two different molecules) or liquid crystal (solid forms with a level of order intermediate between liquid and crystal) forms of candidate molecules. These forms can achieve both high solubility and bioavailability. Amorphous forms (noncrystalline forms that lack long-range order) have also garnered recent attention.

To assess the feasibility of resynthesis as a means of enhancing bioavailability, Aptuit recently conducted a pilot project using the antifungal agent itraconazole. This molecule, while stable, has poor solubility and no clinical effect in its crystalline form. Applying solid-state chemistry techniques in an attempt to improve itraconazole’s bioavailability, Aptuit redesigned the drug’s dosage form in two steps: resynthesis as an amorphous dispersion, followed by an amorphous screen to identify polymers that would maintain the drug in an amorphous state (amorphous forms tend to recrystallize over time, significantly reducing bioavailability).

At the end of the project, Aptuit produced an amorphous dispersion of itraconazole with the polymer HPMC-P that in dogs showed greatly improved bioavailability when compared with the drug’s crystal form. This project, which mimicked precisely the steps needed to develop a candidate molecule from selection to IND submission, was completed in 26 weeks.

Prototype Development

The application of advanced technologies and techniques for solid-state chemistry (which allow for the true design of a safe and efficacious dosage form), combined with efficient techniques for loading almost any powder into a capsule, gives drug developers a new capacity for developing prototype pharmaceutical products for use in proof-of-concept and preclinical studies, including those supporting a regulatory filing.

Considered to be evolutionary steps in a candidate’s industrial design, prototypes provide developers with the confidence that the foundational elements of a product and its processes are valid, can be advanced to the next step of industrialization, and can be efficiently scaled-up for commercial manufacture. The integration of solid-state chemistry as a fundamental element of the prototyping process can help ensure that the proper form of a candidate is selected or formulated so as to effectively and safely address patients’ needs.

Stephen R. Byrn, Ph.D. ([email protected]), chairs the scientific advisory board of Aptuit. Web:

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