Protein Crystals and Pharmaceutical Processes: A Fluid-dynamic Approach to Macromolecular Crystal Engineering

The relevance of self-organization, pattern formation and non-equilibrium behaviour in a wide range of problems, related to macromolecular crystal engineering and typical pharmaceutical processes for the production of drugs and medicines, calls for a concerted approach using the tools of statistical physics

Macromolecules at the basis of typical Pharmaceutical processes are extremely complex physical–chemical systems whose properties and behaviour vary as a function of many environmental influences. Many drugs, medicines and protein crystalsare typically produced in the form of “seeds” (small crystals) nucleating in a supersaturated liquid. The perplexing difficulties that arise in the crystallization of these substances stem from the fact that they behave in a very peculiar way, which make techniques and principles valid for inorganic materials not applicable to these cases.

In general, macromolecular crystallization is a matter of searching, as systematically as possible, the ranges of the individual parameters that impact upon crystal formation, finding a set or multiple sets of these factors that yield some kind of crystals, and then optimizing the variable sets to obtain the best possible crystals.

Two directions of research will be considered in the framework of the present PhD project, one dealing with issues of complex behaviour at the microscopic level (“how the crystal grows”) and the other referring to the macroscopic evolution of these systems (how the “pattern” is formed). Different models will be developed and used according to the desired scale length; i.e., according to the level of detail required by the analysis (local or global). If the local evolution of the crystal surface is the subject of the investigation (distribution of the local growth rate along the crystal face, shape instabilities, onset of surface depressions due to diffusive and/or convective effects, etc.; i.e. all those factors dealing with the local history of the shape) the model will be conceived to provide microscopic and morphological details [1,2].

On the contrary, if the size of the crystals is negligible with respect to the size of the reactor (i.e., if they are small and undergo only small dimensional changes with respect to the overall dimensions of the growth reactor), the shape of the crystals will be ignored and the proposed approach rely directly on a simplified algebraic formulation of the nucleation events [3,4].

Crystallization at a macroscopic scale is characterized by the interplay of different phenomena: transport in liquid phase, nucleation and ensuing growth, competition among different crystals, sedimentation and convection, etc. Understanding this interplay requires a global analysis that would consider all the relevant phenomena simultaneously in order to track system evolution.

From a theoretical point of view, training to the student will be provided with regard to 1) the general background (importance of this kind of research and potential practical applications), 2) governing parameters, 3) governing equations 4) Multiscale modeling, 5) Moving Boundary Numerical Methods. From a numerical-simulation standpoint, the student will be trained to use OpenFoam and other numerical codes available at the Department of Mechanical and Aerospace Engineering.

The opportunity is open to Home, EU and International applicants, who meet the required University of Strathclyde eligibility criteria. In particular, the applicant must not have been awarded a previous Doctoral degree.

The applicant will hold, or in the process of obtaining an integrated Master’s degree or equivalent in Mechanical Engineering, Chemical Engineering, Materials Science, Materials Engineering, Aeronautical or Aerospace Engineering, Physics, or another discipline related to the proposed research projects.

Experience with OpenFoam or Ansys Fluent will be appreciated (but is not strictly required)

[1] M. Lappa, (2003) “An ’attachment-kinetics-based’ Volume of Fraction Method for organic crystallization: a fluid-dynamic approach to macromolecular crystal engineering”, Journal of Computational Physics, 191 (1): 97-129.

[2] M. Lappa, (2005), “Discrete layers of interacting growing protein seeds: convective and morphological stages of evolution”, Phys. Rev. E Statistical Nonlinear, and Soft Matter Physics, 71 (3): 031904 (12 pages).

[3] M. Lappa, D. Castagnolo (2003), “Complex dynamics of rhythmic patterns and sedimentation of organic crystals: a new numerical approach”, Num. Heat Transfer Part B - Fundamentals (ISSN: 1040-7790), 43 (4): 373-401.

[4] M. Lappa, C.Piccolo, L. Carotenuto, (2003), “Numerical and experimental analysis of periodic patterns and sedimentation of lysozyme”, J. Cryst. Growth (ISSN: 0022-0248), 254/3-4: 469-486.