5 research outputs found
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
Effect of Particle Properties of Powders on the Generation and Transmission of Raman Scattering
Transmission Raman measurements of a 1 mm thick sulfur-containing
disk were made at different positions as it was moved through 4 mm
of aspirin (150–212 μm) or microcrystalline cellulose
(Avicel) of different size ranges (<38, 53–106, and 150–212
μm). The transmission Raman intensity of the sulfur interlayer
at 218 cm<sup>–1</sup> was lower when the disk was placed at
the top or bottom of the powder bed, compared to positions within
the bed and the difference between the sulfur intensity at the outer
and inner positions increased with Avicel particle size. Also, the
positional intensity difference was smaller for needle-shaped aspirin
than for granular Avicel of the same size. The attenuation coefficients
for the propagation of the exciting laser and transmitted Raman photons
through the individual powders were the same but decreased as the
particle size of Avicel increased; also, the attenuation coefficients
for propagation through 150–212 μm aspirin were almost
half of those through similar sized Avicel particles. The study has
demonstrated that particulate size and type affect transmitted Raman
intensities and, consequently, such factors need to be considered
in the analysis of powders, especially if particle properties vary
between the samples
Quantitative Analysis of Powder Mixtures by Raman Spectrometry: the influence of particle size and its correction
Particle size distribution and compactness have significant
confounding
effects on Raman signals of powder mixtures, which cannot be effectively
modeled or corrected by traditional multivariate linear calibration
methods such as partial least-squares (PLS), and therefore greatly
deteriorate the predictive abilities of Raman calibration models for
powder mixtures. The ability to obtain directly quantitative information
from Raman signals of powder mixtures with varying particle size distribution
and compactness is, therefore, of considerable interest. In this study,
an advanced quantitative Raman calibration model was developed to
explicitly account for the confounding effects of particle size distribution
and compactness on Raman signals of powder mixtures. Under the theoretical
guidance of the proposed Raman calibration model, an advanced dual
calibration strategy was adopted to separate the Raman contributions
caused by the changes in mass fractions of the constituents in powder
mixtures from those induced by the variations in the physical properties
of samples, and hence achieve accurate quantitative determination
for powder mixture samples. The proposed Raman calibration model was
applied to the quantitative analysis of backscatter Raman measurements
of a proof-of-concept model system of powder mixtures consisting of
barium nitrate and potassium chromate. The average relative prediction
error of prediction obtained by the proposed Raman calibration model
was less than one-third of the corresponding value of the best performing
PLS model for mass fractions of barium nitrate in powder mixtures
with variations in particle size distribution, as well as compactness
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