Ali N. Saleemi

Automated direct nucleation control for in situ dynamic fines removal in batch cooling crystallization

Secondary nucleation (e.g. due to attrition) and accidental seeding (e.g. from crust on the wall of vessels) are undesired events that often take place during industrial crystallization processes. The crystal size distribution is greatly affected by these events. The typically used open loop control strategies fail to respond to these dynamic changes resulting in undesired end product properties. Variations in seed quality during seeded operations (e.g. initial breeding) can also result in undesired product quality. The automated direct nucleation control (ADNC) approach presented in this paper automatically detects any changes in the system and removes fines in situ. The approach is tested for external seed additions and accidental seeding scenarios. The results show that the ADNC approach is able to detect any changes in the metastable zone width and drive the system accordingly to dissolve unwanted fines providing an automatic in situ fines removal mechanism.

Enhancing crystalline properties of a cardiovascular active pharmaceutical ingredient using a process analytical technology based crystallization feedback control strategy

Pharmaceutical regulatory bodies require minimal presence of solvent in an active pharmaceutical ingredient (API) after crystallization. From a processing point of view bigger crystals with minimal agglomeration and uniform size distribution are preferred to avoid solvent inclusion and for improved downstream processing. The current work addresses these issues encountered during the production of the potential anti-arrhythmic cardiovascular drug, AZD7009. This paper demonstrates that by applying the automated direct nucleation control (ADNC) approach problems with agglomeration and solvent inclusion were resolved. This model free approach automatically induces temperature cycles in the system, with the number of cycles, temperature range and adaptive heating and cooling rates determined to maintain the number of particles in the system, as measured by a focused beam reflectance measurement (FBRM) probe, within a constant range during the crystallization. The ADNC approach was able to produce larger and more uniform crystals and also removed the residual solvent trapped between the crystals compared to the typical crystallization operation using linear cooling profile. The results illustrate the application of process analytical technologies, such as FBRM and ATR-UV-vis spectroscopy, for the design of optimal crystallization operating conditions for the production of pharmaceuticals, and demonstrate that the ADNC approach can be used for rapid crystallization development for APIs exhibiting problems with agglomeration and solvent inclusion.

Effects of a structurally related substance on the crystallization of paracetamol

Paracetamol (PCM) was crystallized from an isopropanol (IPA) solution containing various small amounts of metacetamol as an additive. The effect on the nucleation kinetics was studied by measuring the induction time to nucleation and the metastable zone width using focused beam reflectance measurements (FBRM) and attenuated total reflectance (ATR-UV/Vis) spectroscopy. Both the induction time and the metastable zone width were expressed as functions of the additive concentration. Small amounts of metacetamol (1–4 mol-%) were found to cause significant inhibition to the nucleation by extending both the induction time and the metastable zone width. A progressive change in the morphology of the paracetamol crystals from tabular to columnar habit was observed with increasing metacetamol concentration. The solvent also had a significant effect on the size of the paracetamol crystals as smaller crystals were obtained in IPA than in aqueous solution. The dissolution rate of paracetamol was improved by the incorporation of metacetamol with 4 mol-% having the most effect. A supersaturation control (SSC) approach was implemented for the PCM-IPA system with and without metacetamol in an attempt to control and obtain larger metacetamol-doped paracetamol crystals.

Towards multi-component crystallisation in a continuous-flow environment

As a valuable tool in materials development, crystal engineering and more specifically cocrystallisation have facilitated the production of new materials which retain their original function but with enhanced physical properties. As an example, the important function may be the bioavailability of an active pharmaceutical ingredient (API), while the target physical property might be improved solubility or optimised morphology [1]. It is possible to tune these desired physical or physicochemical properties through systematic alteration of crystallisation conditions and the co-formers used. It has also been shown that such techniques present a route to crystal form (polymorphism) control in single component systems through crystallisation in a multicomponent environment. In addition to new materials discovery for property optimisation, multi-component crystallisation also offers a means of modifying and improving processes for the bulk production of desired materials. To date, much of the work in this area has focused around the use of batch or static crystallisation methods. As part of a collaborative effort in Continuous Manufacturing and Crystallisation, (CMAC, an EPSRC Centre for Innovative Manufacturing), our research is focused on translating both new and previously identified multi-component systems into a continuous flow crystallisation environment. The continuous flow environment in this investigation is predominantly achieved using a continuous oscillatory baffled crystalliser (COBC) [2]. This brings about the challenge of producing multi-component systems via cooling crystallisation instead of using tried and tested small scale evaporative crystallisation techniques. The move to continuous crystallisation aims to address scale up issues previously encountered when using the more common stirred tank batch reactor; increase productivity via higher throughput and promote increased manufacturing flexibility and product quality [3]. The work to be presented explores crystallisation of new multi-component molecular complexes with enhanced properties, as well as optimising the nonevaporative crystallisation conditions for production of established multi-component molecular materials, including complexes of barbituric acid and urea [4], which were previously obtained via evaporative crystallisation. We will describe how these complexes can successfully be obtained by cooling crystallisation, detail attempts to ascertain the crystallisation conditions required to isolate a specific complex via cooling crystallisation and give an account of progress towards the overarching aim of transferring these systems into the continuous crystallisation environment.