Continuous Crystallization of Paracetamol (Acetaminophen) Form II: Selective Access to a Metastable Solid Form

Abstract

The first continuous crystallization of a metastable polymorphic form of an active pharmaceutical ingredient is reported. Paracetamol form II, which displays enhanced solubility and compressibility in comparison to the stable form I, has been successfully crystallized in two continuous platforms: a continuous oscillatory baffled crystallizer and a mixed suspension mixed product removal (MSMPR) system, in the presence of the structurally similar molecule metacetamol as a template molecule. Samples from both crystallizers display high polymorphic purity and high solid phase purity, with the samples from the MSMPR in particular showing no evidence of the presence of a residual template molecule. The crystallization was found to be rapidly transferrable between the two continuous platforms. Samples produced display good stability with respect to the known form II to form I transition, reflecting the polymorphic selectivity achieved.

All-electron, real-space perturbation theory for homogeneous electric fields: theory, implementation, and application within DFT

“…It is interesting to note that experimental spectra may sometimes differ slightly from one another as well. These differences are noticeable in the relative intensities of peaks or appearance/disappearance of low-intensity peaks [71][72][73][74]. These differences reflect the difficulty to control the experimental setup for a wide range of frequencies and to synthesize a pure sample especially in the case of those polymorphic crystals, which undergo phase transitions under specific thermodynamic conditions.…”

“…These differences reflect the difficulty to control the experimental setup for a wide range of frequencies and to synthesize a pure sample especially in the case of those polymorphic crystals, which undergo phase transitions under specific thermodynamic conditions. In particular, as explained in [72], the crystallization of paracetamol in form II is often not perfect, as some traces of metacetamol may remain present, leading to partially mixed Raman spectra.…”

In situ non-invasive Raman spectroscopic characterisation of succinic acid polymorphism during segmented flow crystallisation

“…PCM II was prepared by crystallisation in the continuous oscillatory baffle crystalliser (COBC) as previously published in the group. 17 α-SA was prepared by melting of β-SA at 190°C and confirmed by powder X-ray diffraction (PXRD), see Fig. S3.…”

“…Due to the complications of integrating Raman into crystallisation environments, previously published examples of exploring crystallisation processes through Raman spectroscopy have either used microscopy in static environments [14][15][16] or immersion probes in batch, 6,[17][18][19] mixed suspension mixed product removal (MSMPR) 5 and hot melt extrusion (HME) 20 environments.…”

The Role of Residence Time Distribution in the Continuous Steady-State Mixed Suspension Mixed Product Removal Crystallization of Glycine

“…Continuous crystallization of small molecule active pharmaceutical ingredients (APIs) is currently an area of strong interest in pharmaceutical manufacturing due its potential for delivering consistent particle attributes, 1 -3 reducing manufacturing costs through process intensification, 4,5 shortening process development times, 6,7 and providing flexibility in supply. 8 The most common continuous crystallization technologies are the conventional tubular plug flow crystallizer (PFC), 9 -12 the tubular continuous oscillatory baffled crystallizer (COBC), 13,14 and the stirred tank MSMPR crystallizer.…”