Project: Combined pharmaceutical compound PREdiction (computational crystal structures) and MAke (Experimental Polymorph Synthesis).

CONFIDENTIAL _x000D__x000D_In pharmaceutical development, a lot of effort is put into understanding the crystalline solid phase of Active Pharmaceutical Ingredients (API). The pharmaceutical industry is frequently confronted with polymorphism: the ability of a molecule to exist as two or more crystalline phases that have different arrangements / conformations of the molecules in the crystal lattices. At room temperature there is only one most stable polymorph; all other polymorphs are metastable, and may convert to the most stable form. Properties that can differ among solid forms include color, melting point, sprectral properties, solubility, crystal shape, water sorption and desorption properties, particle size, hardness, drying characteristics, flow and filterability, compressibility, and density. In a drug substance, these variations can lead to differences in dissolution rate, oral absorption, bioavailability, toxicology results, and clinical trial results, hence both safety and efficacy are impacted._x000D__x000D_The presence of multiple polymorphs of the active pharmaceutical ingredient is particularly challenging with solid, oral dosage drug products. To make solid oral dosage forms with crystalline API, pharmaceutical companies prefer to use the most stable polymorph, to prevent the conversion to a less soluble polymorph, which can affect the efficacy of a drug product._x000D__x000D_Innovation in computational crystal structure prediction_x000D_In an ongoing effort over the past 20+ years, the academic community has pursued the prediction of crystal polymorphs starting from the molecular structure. Ideally, one would wish to search through the complete range of crystal structures and evaluate their energies accurately as a function of temperature and pressure, in order to obtain the global minimum energies of optimal crystal structures. In crystal structure prediction, first millions of trial crystal structures are generated, followed by optimization of the generated structures, and ranking according to their lattice energy. The crystal structure with the lowest lattice energy is expected to correspond to the most stable polymorph that can be found experimentally._x000D__x000D_The unique GRACE algorithms of AMS can predict crystal structures, and rank them in terms of stability, effectively predicting which polymorph is the most stable form in two steps. First, millions of structures are optimized using a tailor-made force field, and then a few hundred promising candidates are further optimized using time-consuming dispersion-corrected density functional theory (d-DFT) calculations. Currently GRACE covers around 5-10% of all pharmaceutical molecules. These include small, neutral APIs, but still exclude more complex APIs, salts and hydrates. In order to cover all kinds of pharmaceutical polymorph screening abilities, in this project the technology for computational crystal structure prediction will be pushed forward by:_x000D_- Radically improving the current predictive algorithms towards more complex molecules, pharmaceutical salts and crystalline hydrates._x000D_- Development of predictive algorithms for tailor-made additives that will promote the formation of specific polymorphs, providing the basis for the AVT experimental routes to polymorph screening._x000D_- Automation of the predictions, leading to less on-hands time required._x000D__x000D_Innovation in high-throughput polymorph screening_x000D_AVT has developed its proprietary high-throughput crystallization screening platform since 2000. Using rational design of experiments, the AVT approach to experimental polymorph screening has been used on more than 300 APIs from pharmaceutical companies from the EU, Asia and the US.Currently, new crystalline forms of a pharmaceutical ingredient are screened without any a priori knowledge of the crystal structures that can be potentially found, and without any a posteriori knowledge of crystal structures that have not been found. The problem is that the outcome of the experimental screen is uncertain: you don’t know what to look for, and you don’t know if what you have found is all that is out there._x000D__x000D_When the most stable crystal structure of pharmaceutical molecules can actually be predicted, the experimental screening protocols will be significantly improved, because the predicted crystal structures of the different polymorphs are known before the experimental screen starts. First of all, the predicted crystal structures allow powder X-ray diffraction pattern matching with powder patterns obtained from crystallized samples. This will greatly simplify the often complicated process of assigning polymorphic forms to samples, where often samples with mixtures of polymorphs are obtained. Secondly, knowing the bulk structure of the polymorphs allows for choosing solvents and experimental conditions that favor the formation of specific polymorphs. Furthermore, if polymorphs turn out to be difficult to make, tailor-made additives can be used to favor their formation over other polymorphs.

Acronym PREMA (Reference Number: 4805)
Duration 02/03/2009 - 01/07/2011
Project Topic Two R&D performing SME’s will combine research on advanced computational crystal structure prediction and high throughput experimental crystallization screening for the pharmaceutical industry. Paracetamol and three other pharmaceutical molecules will generate valuable IP and proof-of-concept.
Network Eurostars
Call Eurostars Cut-Off 2

Project partner

Number Name Role Country
2 Avant-garde Materials Simulation Deutschland GmbH Partner Germany
2 Avantium Technologies BV Coordinator Netherlands