The most common and desirable way to deliver active pharmaceutical ingredients (APIs) is in the crystalline form. APIs can be formulated in pure form, as salts, or as multicomponent (solvate, cocrystal) solids and these offer due to stability and processing advantages over other formulations. The choice among these forms depends very much on the specific chemical properties of the drug molecule as well as factors such as solubility. However, there is the pervasive issue of crystal polymorphism to consider: a given composition is not constrained to crystallize in a predictable way and multiple packing motifs of the same unit possess different thermodynamic stabilities that can influence bioavailability. The proposed program will develop more rapid and comprehensive techniques to control the crystallization of bioactive organic molecules while being less material intensive. Thi will enable early stage screening of potential drugs to determine which form has the appropriate solubility and stability to be formulated into a bioavailable dosage. Three interconnected aims are designed to develop and deploy more efficient and robust polymorph discovery methodology.
Aim 1 adapts the polymer-induced heteronucleation (PIHn) approach towards solid form discovery so that it functions in a high throughput manner suitable for polymorph discovery. Two of the key advances proposed are miniaturization of the technology and automation of the solid form screening, which together will make the PIHn method much better suited for the screening of preclinical drug candidates.
Aim 2 addressed the issue of crystal polymorphism outside of the well-studied realm of neutral molecular compounds. Because solvates, salts, and cocrystals are increasingly the solid forms of choice for drugs entering the clinic, there is a pressing need for understanding solid form diversity in such APIs. The methodology proposed in Aim 1 is perfectly suited to polymorph discovery in solvates, salts, and cocrystals because it can generate solid form diversity even under the relatively narrow sets of conditions employed in multicomponent crystal formation. Finally, in Aim 3 a new strategy for identifying targeted inhibitors of crystal forms will be introduced. The approach involves a new paradigm, based on the mechanistic understanding of how PIHn accelerates nucleation, redeployed for creating soluble polymeric nucleation inhibitors.

Public Health Relevance

Due to advantages such as ease of administration and stability, drugs are most commonly delivered in solid form to patients. The choice of the crystalline form of this drug, in other words the way in which the drug molecules are arranged with respect to each other, can considerably influence the rate and the ultimate efficiency by which the drug exerts a therapeutic effect. This proposal concerns methods for finding the most favorable form for a dosage for administration by exhaustively revealing the potential crystalline forms in which a drug molecule can exist.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01GM106180-02
Application #
8737297
Study Section
Gene and Drug Delivery Systems Study Section (GDD)
Program Officer
Okita, Richard T
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Pfund, Laura Y; Matzger, Adam J (2014) Towards exhaustive and automated high-throughput screening for crystalline polymorphs. ACS Comb Sci 16:309-13