Enabling precision manufacturing of active pharmaceutical ingredients: workflow for seeded cooling continuous crystallisations

Continuous manufacturing is widely used for the production of commodity products. Currently, it is attracting increasing interest from the pharmaceutical industry and regulatory agencies as a means to provide a consistent supply of medicines. Crystallisation is a key operation in the isolation of the majority of pharmaceuticals and has been demonstrated in a continuous manner on a number of compounds using a range of processing technologies and scales. Whilst basic design principles for crystallisations and continuous processes are known, applying these in the context of rapid pharmaceutical process development with the associated constraints of speed to market and limited material availability is challenging. A systematic approach for continuous crystallisation process design is required to avoid the risk that decisions made on one aspect of the process conspire to make a later development step or steps, either for crystallisation or another unit operation, more difficult. In response to this industry challenge, an innovative system-wide approach to decision making has been developed to support rapid, systematic, and efficient continuous seeded cooling crystallisation process design. For continuous crystallisation, the goal is to develop and operate a robust, consistent process with tight control of particle attributes. Here, an innovative system-based workflow is presented that addresses this challenge. The aim, methodology, key decisions and output at each at stage are defined and a case study is presented demonstrating the successful application of the workflow for the rapid design of processes to produce kilo quantities of product with distinct, specified attributes suited to the pharmaceutical development environment. This work concludes with a vision for future applications of workflows in continuous manufacturing development to achieve rapid performance based design of pharmaceuticals

250 nm Glycine-Rich Nanodroplets Are Formed on Dissolution of Glycine Crystals But Are Too Small To Provide Productive Nucleation Sites

Recent theoretical and experimental studies have proposed a two-step mechanism for crystal formation in which crystal nucleation is preceded by formation of disordered molecular assemblies. Here, we investigated whether similar intermediates might also form as crystals dissolve, effectively the reverse process. A model system of glycine in water was studied, and the resultant solutions were characterized using small-angle X-ray scattering, dynamic light scattering, and nanoparticle tracking analysis. Invariably, dissolution of glycine crystals into water was observed to produce scattering nanospecies with liquid-like properties and a mean diameter of about 250 nm, at near saturation concentration. The nanospecies persisted indefinitely in solution in the presence of excess glycine crystals and were identified as glycine-rich nanodroplets with an equilibrium population of about 10⁹ per mL. The time to appearance of glycine crystals from quiescent supersaturated solution (<i>S</i> = 1.1) containing either a low population of nanodroplets (nanofiltered) or a high population of nanodroplets (unfiltered) was indistinguishable with typically only a single crystal forming after about 30 h. However, a very significant acceleration of crystal formation was observed whenever a gently tumbling stirrer-bar was introduced into the vial; thousands of microcrystals appeared after an incubation period of only 3–5 h. The possibility of this being caused by factors such as secondary nucleation, bubbles, or glass splinters or scratches was eliminated via control experiments. Further investigation of the glycine solution, just prior to appearance of microcrystals, revealed an additional subpopulation of extremely large glycine-rich nanodroplets (diameter >750 nm), not observed in quiescent solutions. It is proposed that productive nucleation of glycine crystals occurs exclusively within these larger glycine-rich nanodroplets because a critical mass of glycine is required to form nascent crystals large enough to survive exposure to bulk more dilute solution. We hypothesize that nucleation occurs frequently but nonproductively within subcritical mass nanodroplets and infrequently but productively within very rare critical mass solute-rich nanodroplets. Such a model provides a new compelling way of bridging classical mechanisms of crystal nucleation with the more recently proposed two-step processes

Tuning Interfacial Concentration Enhancement through Dispersion Interactions to Facilitate Heterogeneous Nucleation

Classical molecular dynamics simulations were used to investigate how dispersion (van der Waals) interactions between non-polar, hydrophobic surfaces and aqueous glycine solutions affect the solution composition, molecular orientation, and dynamics at the interface. Simulations revealed that dispersion interactions lead to a major increase in the concentration of glycine at the interface in comparison with the bulk solution, resulting from a competition between solute and solvent molecules to be or not to be near the interface. This can then lead to kinetic and/or structural effects facilitating heterogeneous nucleation of glycine at non-polar surfaces, in agreement with recent observations for tridecane, graphene, and polytetrafluoroethylene. A novel parameterization process was developed to map a model surface with tunable dispersion interactions to heptane, tridecane, and graphite materials. The model surface was capable of reproducing the solution structure observed in fully atomistic simulations with excellent agreement and also provided good agreement for dynamic properties, at a significantly reduced computational cost. This approach can be used as an effective tool for screening materials for heterogeneous nucleation enhancement or suppression, based on non-specific dispersion interactions based on bulk material molecular properties, rather than interfacial functional groups, templating or confinement effects

Equilibrium Speciation in Moderately Concentrated Formaldehyde–Methanol–Water Solutions Investigated Using ¹³C and ¹H Nuclear Magnetic Resonance Spectroscopy

We used ¹³C and ¹H NMR spectroscopy to examine the equilibrium speciation in formaldehyde–methanol–water solutions at moderate formaldehyde concentrations such as those used in the synthesis of formaldehyde-based organic gels. Concentrations of small methylene glycol oligomers and their methoxylated forms found in these solutions were quantitatively determined over a range of formaldehyde concentrations and methanol–water ratios, and at temperatures between 10 and 55 °C. Using the measured concentrations, equilibrium constants for methylene glycol dimer and trimer formation as well as methoxylation of these oligomers were calculated. Based on this, we developed a quantitative equilibrium model for calculation of formaldehyde-related species concentrations over a range compositions relevant for formaldehyde based sol–gel processes allowing for more rational design of formaldehyde polymerization systems

Gelation Mechanism of Resorcinol-Formaldehyde Gels Investigated by Dynamic Light Scattering

Xerogels and porous materials for specific applications such as catalyst supports, CO₂ capture, pollutant adsorption, and selective membrane design require fine control of pore structure, which in turn requires improved understanding of the chemistry and physics of growth, aggregation, and gelation processes governing nanostructure formation in these materials. We used time-resolved dynamic light scattering to study the formation of resorcinol-formaldehyde gels through a sol–gel process in the presence of Group I metal carbonates. We showed that an underlying nanoscale phase transition (independent of carbonate concentration or metal type) controls the size of primary clusters during the preaggregation phase; while the amount of carbonate determines the number concentration of clusters and, hence, the size to which clusters grow before filling space to form the gel. This novel physical insight, based on a close relationship between cluster size at the onset of gelation and average pore size in the final xerogel results in a well-defined master curve, directly linking final gel properties to process conditions, facilitating the rational design of porous gels with properties specifically tuned for particular applications. Interestingly, although results for lithium, sodium, and potassium carbonate fall on the same master curve, cesium carbonate gels have significantly larger average pore size and cluster size at gelation, providing an extended range of tunable pore size for further adsorption applications

Digital design of end-to-end manufacturing process for mefenamic acid using mechanistic modelling

Conference abstract

Digital process design to define and deliver pharmaceutical particle attributes

A digital-first approach to produce quality particles of an active pharmaceutical ingredient across crystallisation, washing and drying is presented, minimising material requirements and experimental burden during development. To demonstrate current predictive modelling capabilities, the production of two particle sizes (D90 = 42 and 120 µm) via crystallisation was targeted to deliver a predicted, measurable difference in in vitro dissolution performance. A parameterised population balance model considering primary nucleation, secondary nucleation, and crystal growth was used to select the modes of production for the different particle size batches. Solubility prediction aided solvent selection steps which also considered manufacturability and safety selection criteria. A wet milling model was parameterised and used to successfully produce a 90 g product batch with a particle size D90 of 49.3 µm, which was then used as the seeds for cooling crystallisation. A rigorous approach to minimising physical phenomena observed experimentally was implemented, successfully predicted the required conditions to produce material satisfying the particle size design objective of D90 of 120 µm in a seeded cooling crystallisation using a 5-stage MSMPR cascade. Product material was isolated using the filtration and washing processes designed, producing 71.2 g of agglomerated product with a primary particle D90 of 128 µm. Based on experimental observations, the population balance model was reparametrised to increase accuracy by inclusion of an agglomeration terms for the continuous cooling crystallisation. The dissolution performance for the two crystallised products is also demonstrated, and after 45 minutes 104.0 mg of the D90 of 49.3 µm material had dissolved, compared with 90.5 mg of the agglomerated material with D90 of 128 µm. Overall, 1513 g of the model compound was used to develop and demonstrate two laboratory scale manufacturing processes with specific particle size targets. This work highlights the challenges associated with a digitalfirst approach and limitations in current first-principles models are discussed that include dealing ab initio with encrustation, fouling or factors that affect dissolution other than particle size. </p