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Crystal shape alteration using combined wet-milling and temperature cycling approaches

  • Full or part time
  • Application Deadline
    Applications accepted all year round
  • Funded PhD Project (European/UK Students Only)
    Funded PhD Project (European/UK Students Only)

Project Description

Crystallization is the most frequently used separation process in the manufacturing of active pharmaceutical ingredients (API), where it provides purification and form control and enables isolation of the API as solid particles that can be further processed into a formulated drug product. Alongside yield and purity, of paramount importance is the forward processability of the API, a phenomenon dominated by the particle size and shape distribution (PSSD) of the fine powder; for instance, poor powder processability can manifest in solid dosage form manufacture (for example tableting), or an increase in the ability of the material to retain solvent during filtration. Poor powder flowability is often associated with particle size and shape distributions that are too wide (containing fine particles, as well as larger particles) and contain undesirable needle-like (or platelet-like) particle shapes.

The propensity of crystals to grow in different shapes is linked to their well-ordered, anisotropic internal structure, which is terminated by the crystals’ facets. Depending on the surface chemistry of these facets, they grow with different kinetics, which in turn leads to anisotropic shapes. The processing conditions experienced by crystals in a vessel (supersaturation, temperature, hydrodynamics, etc.) affect crystal growth kinetics as well, so they can also influence the crystals’ shape. This introduces some scope to tune particle size and shape through robust design of crystallization processes, e.g., temperature or anti-solvent addition profile, stirring rate, etc. However, due to the inherent tendency of many pharmaceutical molecules to form crystals with extreme morphologies (e.g. needles, laths, plates), these approaches are often found to be rather limited with respect to their ability to generate particles with a compact shape and a desirable size distribution (and thus good flowability). Furthermore, regulatory and purity concerns may result in an inability to modify the crystallisation solvent composition. This creates the need to develop further means to manipulate and optimize the shape and size of crystalline particles and to devise efficient process design methodologies that implement these means.

In this project the traditional crystallisation process design strategy will be combined with wet milling and temperature cycling approaches. Molecules for which the crystal structure and growth kinetics alone would lead to extreme needle morphologies during crystallisation, wet milling provides an attractive alternative to alter the particles’ aspect ratio (since needles are more likely to break somewhere along their thin axis, rather than along their length). Employing intermittent wet milling steps during a crystallisation process, rather than a dry milling step afterwards, also has the inherent advantage of being a “softer” means for breaking particles than a post-crystallisation dry milling step, so that possible amorphisation of the API crystals can be avoided. However, while such milling steps make particles more compact, they lead to a wider distribution of particle sizes as the particles break stochastically. To counteract this effect, temperature cycles can be employed. In these cycles the temperature is first reduced to induce crystallisation and growth of particles (with or without concomitant milling) and later raised to partially re-dissolve the crystals. Any fine particles formed during the crystallisation and milling process will be completely dissolved, while larger, more compact particles remain.

This project aims at developing fundamental insight into the operation of such combined crystallisation-wet milling-temperature cycling processes and to ultimately deliver robust process design methodologies for these processes that deliver particle size and shape distributions with desirable characteristics.

The project is funded by two leading pharmaceutical companies and EPSRC (iCASE award). Strong collaborative work is foreseen in the project.

Applicants should have or expect to achieve at least a 2.1 honours degree in Chemical Engineering, Chemistry, or a closely related subject.

Funding Notes

The project is funded by two leading pharmaceutical companies and EPSRC (iCASE award). Strong collaborative work is foreseen in the project.
This position is funded for UK/EU students only (tuition fees and stipend)

Related Subjects

How good is research at University of Manchester in Aeronautical, Mechanical, Chemical and Manufacturing Engineering?
Chemical Engineering

FTE Category A staff submitted: 33.90

Research output data provided by the Research Excellence Framework (REF)

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