Continuous Crystallization of Paracetamol (Acetaminophen) Form II

Subscriber access provided by MacEwan University Libraries

Article

Continuous crystallization of paracetamol (acetaminophen) form II: selective access to a metastable solid form Lauren R. Agnew, Thomas McGlone, Helen Patricia Wheatcroft, Amy Robertson, Anna R. Parsons, and Chick C. Wilson Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.6b01831 • Publication Date (Web): 04 Apr 2017 Downloaded from http://pubs.acs.org on April 5, 2017

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

Crystal Growth & Design is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 29

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Crystal Growth & Design

Continuous

crystallization

of

paracetamol

(acetaminophen) form II; selective access to a metastable solid form Lauren

R.

Agnew1,2,

Thomas

McGlone3,

Helen

P.

Wheatcroft4,

Amy

Robertson4,

Anna R. Parsons4 and Chick C. Wilson*1,2 1

EPSRC Centre for Innovative Manufacturing in Continuous Manufacturing and Crystallisation,

University of Bath, Bath, BA2 7AY, U.K 2

Department of Chemistry, University of Bath, Bath, BA2 7AY, U.K

3

EPSRC Centre for Innovative Manufacturing in Continuous Manufacturing and Crystallisation,

c/o Strathclyde Institute of Pharmacy and Biomedical Sciences, Technology and Innovation Centre, 99 George Street, Glasgow, G1 1RD, U.K

4

PT&D, AstraZeneca Macclesfield, Silk Road Business Park, Charter Way, Hurdsfield Industrial

Estate, Macclesfield, SK10 2NA, U.K

ABSTRACT The first continuous crystallization of a metastable polymorphic form of an API 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

ACS Paragon Plus Environment

1


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 2 of 29

continuous oscillatory baffled crystallizer (COBC) 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 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.

Introduction Polymorphism is the ability of a molecule to exist in more than one distinct packing arrangement in the solid state, with different polymorphs often displaying markedly different physicochemical properties; this can give substantial improvements in physical properties such as solubility and melting point, of importance for Active Pharmaceutical Ingredients (APIs) and other solid molecular materials. The case of the anti-HIV drug Ritonavir1 provides a prime example to why knowledge of polymorphism and the ability to control the polymorphic form is of upmost importance in all stages of drug development. Obtaining control of the stable polymorphic form is well reported in literature2-4, however crystallisation of metastable polymorphs of APIs is largely unreported and where it has been reported, the stability of the resulting samples is usually poor; for example the use of polymer additives to obtain paracetamol form II gave samples stable for only five hours5 and spray drying of acedapsone gave samples stable for only six hours.6 Furthermore, access to such elusive forms has focussed on small volume discovery environments (mg quantities).7-9 Metastable polymorphic forms often have the above-mentioned benefit of increased solubility and in some cases bioavailability10-12, making these metastable forms a


2

Page 3 of 29

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


desirable target if a large-scale production method can be identified. Here we present a recently developed concept to target metastable polymorphic forms termed templating; a template is defined in this work as a molecule included in the crystallisation process that forces the adoption of a particular polymorphic form of an active pharmaceutical ingredient (API) without itself being present in the final crystal structure. Second components within a crystallization process such as additives and impurities have previously been used to control the morphology of crystals13-14 but little work has been done on their targeted use to control metastable polymorphic forms of APIs.15 Traditionally, crystallization of active pharmaceutical ingredients (APIs) has been undertaken in large, stirred tank batch reactors which can result in poor heat and mass transfer upon scale-up from the laboratory to industrial scales. As such, there has been a large amount of industry and academic interest in moving these processes into a continuous environment.16-19 Continuous crystallization can offer the advantages of more rapid heat and greater mass transfer as well as reduced downtime between batches, less batch-to-batch variation and greater control over particle attributes such as particle size distribution and polymorphic form.16,

20-21

Due to the

design of many continuous crystallizers, they also make the scale-up from laboratory to manufacturing scale easier. There are a number of types of continuous crystallizers currently operational, however the focus of this work has been on oscillatory baffled flow crystallizers (OBCs) and mixed suspension, mixed product removal systems (MSMPRs). Continuous oscillatory baffled crystallizers (COBCs) are plug flow tubular crystallizers that consist of a series of jacketed straight sections and bends, contained within which are a series of periodically spaced baffles.22-23 They combine flow with oscillation to generate eddies between the baffles; the formation of eddies results in mixing within the system. Flow within COBCs is


3


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 4 of 29

governed by three main equations which give dimensionless constants used to describe flow conditions: the oscillatory Reynolds number (Reo), the net flow Reynolds number (Ren) and the Strouhal number (St). 𝑅𝑒𝑜 =

2𝜋𝑓𝜌𝑑𝜒𝑜 𝜇

𝑅𝑒𝑛 =

𝜌𝑢𝑑

𝑆𝑡 =

𝑑

𝜇

4𝜋𝜒𝑜

(1)

(2)

(3)

Where f = frequency of oscillation (Hz), ρ = density (kgm-3), d = tubing internal diameter (m), χo = center to peak amplitude (m), µ = viscosity (kg m-1 s-1), u = mean velocity (ms-1). General guidelines and limits exist for these quantities in order to direct operation under plug flow including: Reo ≥ 100, St ≤ 0.5 and Ren ≥ 50.22 The COBC has the added benefit of being able to routinely increase the residence time within the crystallizer, through the addition of more sections, without altering the mixing conditions significantly, hence making scale-up easier. Continuous crystallization has been demonstrated in the COBC of β-L-glutamic acid24, a cocrystal of α-lipoic acid and nicotinamide25, lactose26 and a proprietary compound in production16, however the continuous crystallization of a metastable polymorphic form has yet to be reported. MSMPRs are similar to a cascade of stirred tank reactors (CSTRs), however they allow periods of stirring within the vessels (increasing the residence time within the crystallizer) rather than the continuous input and removal of solution/slurries. They can be operated as a single stage or as multiple stages and can be considered easier to implement into an industrial setting as existing batch equipment can be modified, however they do present many of the problems experienced in


4

Page 5 of 29

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


batch crystallisers. Transfer between vessels can be made through peristaltic pumps, which can result in damage to particles, or as demonstrated more recently, through vacuum transfer.27 The use of MSMPRs for the continuous crystallization of a variety of compounds has been demonstrated including paracetamol form I28-29, albuterol sulfate30, cyclosporine27 and preferential crystallization of the enantiomers of threonine.31 The continuous crystallisation of metastable α-glutamic acid has been reported in an MSMPR32, the only other reported example of the continuous crystallisation of a metastable organic solid; the continuous crystallisation of inorganic solids has been reported widely in literature. 33-36 Paracetamol (PCM) is a widely used analgesic and antipyretic which has been studied extensively in the solid state.37-40 There has been extensive work on the monitoring and production of PCM-I in batch crystallizers41-43, with a few studies conducted on the production of PCM-I through continuous crystallization techniques.28-29,

44-45

Previous routes to the

production of PCM-II include reaction coupling,46 rapid cooling,47 enforcing Ostwald’s rule of stages,48 use of polymer additives5 and heterogeneous nucleation.49 We recently reported a multicomponent templating route to the previously elusive, metastable form II (PCM-II)50 in a small scale batch crystallization environment; this form displays enhanced solubility and compressibility and so is a desirable target for industrial production. Inline process analytical technologies (PAT), namely focussed beam reflectance measurements (FBRM) and infra-red (IR) have been used to monitor the solution mediated phase transition that occurs on cooling a saturated solution of PCM.41-42 However, monitoring of the large scale production of PCM-II with PAT is as yet unreported. Herein we report the scale up and initial continuous crystallization experiments for metastable paracetamol form II using the structurally-similar metacetamol as a template molecule. This is the first reported example of the continuous


5


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 6 of 29

crystallization of a metastable polymorphic form, producing dried samples stable for periods of months with high purity. EXPERIMENTAL Paracetamol (4’-hydroxyacetanilide; PCM) was purchased from Sigma Aldrich Chemie Gmbh

(Steinheim,

Germany).

Metacetamol

(3’-hydroxyacetanilide;

MCM)

was

purchased from TCI Ltd. All were used without further purification. Laboratory grade solvents purchased from Sigma Aldrich were used for all crystallizations.

Batch Crystallisation experiments Scaled-up batch experiments were conducted using the Mettler Toledo OptiMax (Figure 1). Crystallisations were monitored with Raman PhAT and FBRM probes. For all experiments, a Mettler Toledo FBRM probe (G400 series) was used with iC FBRM V4.3 incorporated in the iControl V5.2 software. Each measurement was collected with a 2 s scan speed and a 15 s sampling interval. A Kaiser RXN2 Raman spectrometer with PhAT probe was used to monitor the polymorphic form produced throughout the process non-invasively. The PhAT probe had the laser beam optically expanded to give a 3 mm spot size, with a focal length of 12.5 mm. The beam was directed at the process through the top of the vessel. The laser wavelength of 785 nm was produced by an Invictus diode laser operated at 350 mW at the source, with a CCD detector cooled to −40 °C by a Peltier cooling system. In advance of any measurements a verification (which measures relative peak intensity and peak position against known peaks from a cyclohexane standard) using the external sample compartment accessory for the instrument was performed. Raman spectra were recorded using iC Raman V4.1 software, also incorporated in the


6

Page 7 of 29

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


iControl software. Each Raman spectrum was recorded with two scans and a 30 s integration time resulting in one spectrum every 2 minutes. Conditions for the scaled-up batch experiments were informed by small scale experiments (100 ml scale) and a Design of Experiments study was conducted in order to determine the optimal conditions for the production of PCM-II at the 100 ml scale. As a result, a PCM concentration of 300 mg/g of solvent coupled with 25 wt. % metacetamol was used throughout all crystallizations; crystallisations were cooled from 70 °C to 20 °C through a stepped cooling profile. 50

Figure 1. The Mettler Toledo OptiMax with inline process monitoring using a Raman PhAT probe and an FBRM probe Continuous Crystallization experiments in a COBC Continuous crystallization experiments were performed in a 15 mm internal diameter continuous oscillatory baffled crystallizer (COBC) mounted in a vertical geometry (Figure 2). The set-up consisted of eight jacketed straight sections and three non-jacketed bends; the temperature of the jackets was controlled through four Grant R3 TX150 heater/chiller systems filled with water. Three thermocouples were used to monitor the temperature of the reaction mixture throughout the crystallisation. Flow through the system was controlled by a Watson Marlow peristaltic


7


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 8 of 29

pump and the oscillation through a bellows set up (note: due to pressure build up the bellows were operated only partially full). Throughout all experiments, a frequency of oscillation of 2 Hz and a center to peak amplitude of 12.5 mm was employed†, resulting in a flow rate through the system of 50 ml/min. Solids were collected through a tube connected to an outlet piece and separated immediately from solution through Büchner funnel filtration. Solids were collected for each residence time (RT) (throughout this paper we have defined residence time for these experiments as the theoretical time period the reaction mass spends in the crystalliser under continuous flow) ; filter papers were changed every ca .20 mins.

Figure 2. The COBC set-up (left) with a schematic (right) – thermocouples are represented by T Continuous Crystallization experiments in a MSMPR Continuous crystallisation experiments in a MSMPR system were carried out at the AstraZeneca site in Macclesfield; a two-stage MSMPR working in recycle mode was used throughout all

†

Although these conditions are not conducive to plug flow(Ren = 46, Reo = 1538, St = 0.095), they were needed to overcome the partially filled bellows and to ensure complete suspension of particles


8

Page 9 of 29

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


experiments. The set-up consisted of a 500 ml jacketed feed/dissolver vessel and two 140 ml jacketed vessels (Figure 3). To avoid crystal breakage on transfer between vessels, a vacuum transfer system was used to transfer solids from MSMPR 1 to MSMPR 2 and from MSMPR 2 back to the feed/dissolver vessel. A Masterflex peristaltic pump, equipped with Masterflex tubing was used to transfer the clear solution from the feed vessel to MSMPR 1.

Figure 3. Schematic of the MSMPR set-up used (schematic provided by Iyke Onyemelukwe). A dip tube was positioned in MSMPR 1 and MSMPR 2 to allow transfer of a calibrated volume between these two vessels and MSMPR 2 and the feed vessel, respectively. Temperature control was provided by three JULABO heater/chiller units. The transfer tube from MSMPR 2 to the feed vessel was fitted with a three-way valve to allow sampling with an inline filtration unit. Solid characterization. The polymorphic form of all solids was fully characterized through powder X-ray diffraction (PXRD) analysis and differential scanning calorimetry (DSC). For batch cooling crystallization experiments PXRD patterns were collected on a Bruker AXS D8Advance transmission diffractometer equipped with θ/θ geometry, primary monochromatic


9


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 10 of 29

radiation (Cu Kα1, λ = 1.54056 Å), a Vantec 1-D position sensitive detector (PSD), and an automated multi-position x-y sample stage. Samples were oscillated ±0.5 mm in the x-y plane at a speed of 0.3 mms-1 throughout data collection to maximize particle sampling and minimize preferred orientation effects. For COBC experiments, PXRD patterns were collected in flat plate mode on a Bruker D8 Advance equipped with monochromated Cu-Kα radiation (λ=1.54056 Å) in reflection geometry at 298 K. DSC studies were carried out using a Thermal Advantage Q20 DSC from TA Instruments, equipped with Thermal Advantage Cooling System 90 and operated with a dry nitrogen purge gas at a flow rate of 18 cm3 min-1. The samples were placed in sealed Tzero aluminium pans and a heating rate of 5 °C min-1 was used. Data were collected using the software Advantage for Qseries (Ver. 5.40 software © 2001-2011 TA Instruments-Waters LLC). For MSMPR experiments, PXRD patterns and DSC traces were collected at AstraZeneca. The samples were mounted on silicon wafer mounts and analyzed using a Bruker D4 X-ray diffractometer (Cu-K radiation,  = 1.5418 Å) equipped with a LYNXEYE detector.

Each

sample was exposed for 0.32 seconds per 0.02° 2θ increment (continuous scan mode) over the range 2° to 40° in theta-theta mode. The X-ray generator was operated at 40kV and 40mA. DSC studies were carried out using a Thermal Advantage Q2000 from TA Instruments. Up to 3 mg of material was contained in an aluminum pan, fitted with a lid, and heated over the temperature range 25 °C to 200 °C at a constant heating rate of 10 °C min-1. Data were collected using the software Advantage for Qseries (Ver. 5.40 software © 2001-2011 TA Instruments-Waters LLC). Imaging was performed on a Hitachi TM-1000 scanning electron microscope (SEM) operating with an accelerating voltage of 15kV. Samples were mounted on an aluminium stub with carbon tab and gold coated in a Quorum Q150R sputterer to a target thickness of 10 nm.


10

Page 11 of 29

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Results and Discussion Solubility of paracetamol form II. Owing to the fast transformation time from form II to form I in a 60:40 H2O:IPA solvent system, solubility in the solvent system was unable to be measured through turbidimetric or gravimetric methods. As such, the solubility was calculated through use of ratios51, using knowledge of the two solubilities in a pure water solvent50 alongside solubility of the stable form I in the chosen solvent system. The resulting solubility curves are shown in Figure 4.

Figure 4. Solubility curves of PCM-I and PCM-II in 60:40 (v/v) H2O:IPA


11


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 12 of 29

Batch Crystallization Experiments.

Figure 5. Offline reference spectra for PCM-I, PCM-II and MCM To highlight the differences in Raman spectra between the two polymorphic forms of paracetamol, offline Raman spectra were collected for both polymorphic forms of PCM and for metacetamol (MCM) (Figure 5). The two PCM spectra are very closely related, with Table 1 highlighting the differences in each spectral region. The assignment of these Raman bands, combined with analysis of the crystal structures of the PCM polymorphs, shows that the bands where differences between the polymorphs are observed relate to Raman modes that would be different between the polymorphic forms; either through differences in hydrogen bonding, torsion angles or packing interactions. For example, the C-C-N-C torsion angle in paracetamol form I is ~22 ° and in form II is ~17 °; this difference could be responsible for the slight shift in peaks in the Raman spectra. The previous analysis by Szelagiewicz et al

52

did not account for

the differences in spectra above 1260 cm-1; in this region, the main difference is the splitting of


12

Page 13 of 29

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


the peak at 1624 cm-1 in PCM-II; in PCM-I this splitting doesn’t exist, with the peak only displaying a slight shoulder. This peak corresponds to the carbonyl stretch and the difference can be attributed to the slight difference in hydrogen bond lengths, and hence strengths, in the polymorphs. Despite its structural similarity to paracetamol, the Raman spectra for metacetamol shows easily discernable differences, with the peak at 1007 cm-1, corresponding to the aromatic ring, being the strongest. Table 1. Characteristic Raman bands differentiating paracetamol form I and form II (adapted from Szelagiewicz et al. 52 ). Raman shift (cm-1) Form II (cm-1) Form I (cm-1) Functional group 1200-1260 1242 and 1218-1219 1254-1258 and 1233-1238 Amide 855-865 860 857-859 C-C ring stretch 790-810 797-798 795-798 C-N-C ring stretch 450-470 451-452 460-466 O-H vibration 200-220 200-201 207-215 C-C stretch (chain)

Determination of these polymorph specific bands allowed for a peak in the Raman spectrum corresponding to PCM-II (1624 cm-1) and one corresponding to PCM-I (1236 cm-1) to be tracked throughout the crystallisation, to allow rapid elucidation of the polymorphic form being produced. At the point of nucleation in the system (characterized by the sharp increase in total FBRM counts in Figure 6), the peak characteristic of PCM-II increases and that of PCM-I drops off and remains level for the remainder of the crystallization. The peak for form I does not drop to a zero value as the probe still detects paracetamol dissolved in solution, with the signal for PCM-I and dissolved PCM being indistinguishable. The total FBRM counts remain roughly constant towards the end of the experiment, indicating steady state has been achieved.


13


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 14 of 29

Figure 6. Trend output from 800 ml crystallisations in the Optimax showing the temperature profile employed (blue), total FBRM counts (green), PCM-I Raman at 1236 cm-1 (orange) and PCM-II Raman at 1624 cm-1 (pink). Figure 7 shows the change in the spectra produced from the inline Raman probe over the course of the crystallisation. The dominant production of PCM-II at the end of the crystallisation (300 mins) is confirmed by the splitting of the peak at 1624 cm-1, circled in red in Figure 7. Figure 8 also highlights the regions of difference specified in Table 1, again confirming the presence of PCM-II in all cases. However, the presence of extra peaks, circled blue in Figure 7, indicate the presence of another crystalline phase in the solid. Additional PXRD analysis53 shows this to be metacetamol hydrate (Supplementary information Figure S1); this could not be shown by Raman data as phase pure samples of MCM.H2O were unable to be obtained. The intense


14

Page 15 of 29

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


peak at 1800 cm-1 can be attributed to light effects due to the pink colour the solution adopts when metacetamol is dissolved.

Figure 7. Raman spectra collected throughout the course of the crystallisation from the inline PhAT probe (0 mins – suspension, 20 mins – after dissolution of all solid, 300 mins – suspension of final product at end of crystallisation)


15


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 16 of 29

Figure 8. Comparison of the final OptiMax product (at 300 mins) with the two polymorphs of paracetamol (inset – each of the spectral regions where differences between the two polymorphic forms are visible). Continuous crystallization in the COBC. Initial continuous crystallization experiments were carried out using a compact set-up with a total length of 358 cm (4 straight sections) (details of these experiments can be found in SI Table S1). This yielded the first successful continuous crystallisation of PCM-II. However, in order to ensure crystallization within the system, the final straight section had to be set at a temperature of 13 °C, resulting in crystallisation of metacetamol hydrate (MCM.H2O) together with PCM-II in the final solid product. Although this is present at low concentrations, it is important to produce phase pure PCM-II samples. The COBC was therefore increased to a total length of 638 cm (8 straight sections) to give a longer residence time within the system; theoretically, having a longer period of time at a higher temperature should allow for crystallisation of PCM-II in the absence of any metacetamol hydrate impurity. The experimental conditions investigated are shown in Table 2; varying temperature regimes and


16

Page 17 of 29

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


two different metacetamol concentrations were used to attempt to eliminate metacetamol hydrate from the solid product (a concentration of PCM of 300 mg/g with a feed temperature of 55 °C was used throughout all experiments). Table 2. Temperature regimes and experimental outcome for COBC runs

Product

Supersat -uration ratio (S)‡

15

PCM-II +MCM.H2O

1.90

15

20

PCM-II +MCM.H2O

1.63

20

20

20

PCM-II +MCM.H2O

1.63

20

20

20

PCM-II +MCM.H2O

1.63

-

1.49

Exp.

Wt. % MCM

T1

T2

T3

T4

T5

T6

T7

T8

(°C)

(°C)

(°C)

(°C)

(°C)

(°C)

(°C)

(°C)

1

25

30

30

20

20

15

15

15

2

25

30

30

20

20

15

15

3

25

30

30

20

20

20

4

18

30

30

20

20

20

5

18

30

30

25

25

25

25

25

25

No crystallizatio n

6

18

30

30

23

23

23

23

23

23

PCM-II +MCM.H2O

Although this 638 cm set-up improves the phase purity of the initial product, all experimental conditions investigated within the COBC have yielded PCM-II with small (i.e. low levels detectable through PXRD), though sometimes trace (requires DSC or NMR to observe), quantities of MCM.H2O impurity within the final solid product. When using 25 wt.% of

‡

At point of crystallisation relative to PCM-II


17


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 18 of 29

metacetamol, the most promising experimental conditions were seen in Experiment 3. Here, the hydrate impurity was present in very low quantities, not detectable by PXRD, however use of DSC confirmed its presence in the solid product (Figure 9).

Figure 9. PXRD analysis showing presence of PCM-II (left), with DSC analysis showing the presence of metacetamol hydrate (right) As all experiments containing 25 wt. % metacetamol produced PCM-II with a low quantity of the MCM.H2O present in the solid product, the concentration of metacetamol in the feed was decreased to 18 wt. % for further experiments (Table 2). Batch experiments showed that the presence of metacetamol significantly widens the metastable zone width,50 hence reduction in metacetamol concentration should allow for crystallisation at higher temperatures and hence elimination of the metacetamol hydrate impurity. However, all experiments with 18 wt. % metacetamol to date have again resulted in crystallisation of the hydrate alongside PCM-II in the solid product samples. Reduction in the wt. % of metacetamol increases the yield of solid in the crystallisation; in experiment 4 this resulted in eventual blockage of the unjacketed bends of the COBC from the high solid loadings (Figure 10). Significant encrustation was also observed in experiments that used still lower proportions of metacetamol. Encrustation can be detrimental to


18

Page 19 of 29

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


a crystallization causing unwanted seeding, disruption of particle size distributions and eventual blockage of the crystallizer.

Figure 10. High solid loadings in experiment 4, resulting in eventual blockage of the system and significant encrustation. These experiments have demonstrated the possibility to obtain PCM-II in continuous crystallization environment in the COBC at metacetamol concentrations not accessible through large scale batch crystallization experiments, where the addition of more than 25 wt. % metacetamol was required to template the production of PCM-II. This is likely due to the more efficient mixing experienced in the COBC through the generation of eddies in the baffles. Current work is looking at increasing the residence time within the crystalliser further and implementing a small seeding port. Initial results have shown that use of a 970 cm (12 straight) set up leads to the production of phase pure PCM-II within the COBC, eliminating the residual trace MCM.H2O from product samples. This lengthening enables crystallisation at a temperature of 25 °C; at this temperature metacetamol hydrate does not crystallise.


19


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 20 of 29

Overall solid yields, relative to zero concentration, from continuous crystallization experiments have been around 30 % and the optimization of this yield is ongoing. However, increasing the yield, whilst continuing to isolate PCM-II in the absence of metacetamol hydrate, is a fine balance. Continuous crystallisation in the MSMPR As the COBC in the configuration described above has to date produced 100 % polymorphic selectivity for PCM-II but not in a phase pure form, with metacetamol hydrate present in low quantities in the solid product, use of the MSMPR continuous crystallisation platform outlined above was investigated. It was anticipated that this would better mimic the stepped cooling profile employed in the smaller scale batch crystallisations that produced pure PCM-II with no metacetamol hydrate impurity present.50 Table 3 highlights the experimental conditions investigated using this platform (a concentration of PCM of 300 mg/g with a feed temperature of 55 °C was used throughout all experiments).


20

Page 21 of 29

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Table 3. Experimental conditions and output from MSMPR experiments T-

Wt% MCM

RT(mins)§

1

25

45

2

25

3 4

Exp.

FEED

TMSMPR1 TMSMPR2

Product

Supersaturation ratio (S)**

(°C)

(°C)

60

25

20

PCM-II +PCM-I + MCM.H2O

1.63

45

60

30

25

PCM-II

1.03

25

45

60

30

25

PCM-II

1.03

25

30

60

30

25

PCM-II

1.03

(°C)

Initial crystallisations were carried out with the conditions highlighted as Experiment 1 in Table 2. This resulted in crystallisation of mainly PCM-II, however some PCM-I was present in the samples as confirmed through PXRD analysis (Figure 10). DSC analysis also confirms the presence of metacetamol hydrate in the isolated solid for residence times 2 and 3 (Figure 11).

§

This is the residence time within each MSMPR vessel – the total residence time within the crystallizer is double this value **

At point of nucleation, relative to PCM-II


21


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 22 of 29

Figure 11. PXRD patterns showing the presence of PCM-I (circled peaks-left) and DSC showing small amounts of metacetamol hydrate (right). Analysis of SEM images shows the growth of needle-like crystals on the surface of block-like crystals (Figure 12). A sample of pure PCM-II (produced in the presence of metacetamol from later MSMPR experiments) shows a similar block like habit to that observed in these images. It is suggested that the needle crystals on the surface can be attributed to the presence of PCM-I; in contrast, SEM images from batch crystallization experiments show metacetamol hydrate to adopt a block morphology on the surface of PCM-II crystals (SI Figure S4). Interestingly, previous work has always suggested form I adopts a hexagonal block like morphology with form II adopting a needle like morphology.41, 54 This morphology change could help give mechanistic information into how the template molecule is acting in the crystallizations. Further, a block-like morphology is likely to have more desirable flow properties than needles and perform better in downstream processing steps such as filtration and charging in the drug product process, so if this morphology effect can be confirmed it offers an additional advantage to the templating additive method adopted here.


22

Page 23 of 29

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Figure 12. SEM images showing rhombic PCM form II (left) crystals with needle-like crystals, possibly of PCM-I, growing on the surface (right). The presence of PCM-I cannot be seen in later residence times in the PXRD patterns (SI Figure S2), however needle crystals can still be observed in the SEM images. Stability analysis on these samples has been performed; it is well known that the presence of any PCM-I in PCMII samples will seed the conversion to the thermodynamically stable PCM-I in the solid state.50 These studies show partial conversion back to the thermodynamically stable form over a two month period, suggesting the presence of trace PCM-I in the solid product. The large solid loading from Experiment 1 also resulted in some settling of solids in the vacuum transfer lines. For the period of time for which this experiment was operated (4 hours) this did not result in blockage, however over time this may have become detrimental to the crystallisation. In Experiment 2, the temperature of the

MSMPR 2 was increased to that of MSMPR 1 in

Experiment 1 (the analyzed solid from this tank alone contained no PCM-I detectable by PXRD), while MSMPR 1 was now set at 30 °C; the aim was to prevent the formation of PCM-I and metacetamol hydrate. PXRD and DSC analysis confirm the presence of pure PCM-II in the absence of PCM-I or metacetamol hydrate (Figure 13); this is the first continuous crystallization experiment to produce fully polymorph-selective and phase pure PCM-II solid samples.


23


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 24 of 29

Figure 13. PXRD and DSC analysis confirming the presence of PCM-II in the absence of any metacetamol hydrate. Experiment 3 was used to check the reproducibility of Experiment 2, with increased operating time. This experiment was successfully operated for 5 residence times (ca. 5 hours) without any blockages to vacuum transfer lines; the desired selective polymorphic form outcome and absence of metacetamol hydrate were the same as found in Experiment 2. Experiment 4 utilized the same cooling profile as that for 2 and 3, but investigated a reduction in residence time to 30 minutes in each crystalliser. As with experiments 2 and 3, PCM-II was produced in the absence of PCM-I or metacetamol hydrate (SI Figure S3). Conclusions In conclusion, paracetamol form II has been produced with polymorph selectivity in large scale batch crystallizations and two different continuous crystallization platforms; this is the first reported example of a metastable API polymorph being produced in a continuous crystallization environment. By using the MSMPR platform, full phase purity was also achieved for the PCM-II solid product. Previous work accessing these metastable polymorphic forms, which often display enhanced physicochemical properties, has been limited to small-scale discovery environments (mg scale). The work presented here has shown that the manufacture of these polymorphs on


24

Page 25 of 29

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


much larger scales (100s of grams) is now expected to be achievable. Furthermore, the process was found to be rapidly transferable between the two continuous crystallization platforms examined within this work. Within an industrial environment there is a drive for product physical purity (in addition to chemical), and with the method developed here we have shown the possibility to access paracetamol form II in high purity in terms of both a single polymorphic form and absence of any templating molecule in the final solid product. Future challenges in this area are to further scale up such processes and to define control strategies for manufacture of metastable forms using continuous crystallization. ASSOCIATED CONTENT Supporting Information. PXRD and DSC patterns can be found in the supporting information. This material is available free of charge via the Internet at http://pubs.acs.org. AUTHOR INFORMATION Corresponding Author *[email protected] ACKNOWLEDGMENT This work was supported by the EPSRC CMAC grants EP/I033459/1 and EP/K503289/1. The authors would like to acknowledge access to the CMAC National Facility, housed within the University of Strathclyde’s Technology and Innovation Centre, and funded with a UKRPIF (UK Research Partnership Investment Fund) capital award, SFC ref. H13054, from the Higher Education Funding Council for England (HEFCE). The crystallisation department at AstraZeneca, Macclesfield provided access to the MSMPR rig. The authors thank I.


25


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 26 of 29

Onyemelukwe (Loughborough University) for the production of the diagram shown in Figure 3. LRA would like to thank R. Lunt and P.-B. Flandrin for assistance with the COBC experiments.

ABBREVIATIONS PCM – paracetamol, MCM – metacetamol, MCM.H2O – metacetamol hydrate, COBC – continuous oscillatory baffled crystalliser, MSMPR – mixed suspension mixed product removal REFERENCES 1. Bauer, J.; Spanton, S.; Henry, R.; Quick, J.; Dziki, W.; Porter, W.; Morris, J.Pharmaceutical Research 2001, 18 (6), 859-866. 2. Lai, T.-T. C.; Cornevin, J.; Ferguson, S.; Li, N.; Trout, B. L.; Myerson, A. S.Cryst. Growth Des, 2015, 15 (7), 3374-3382. 3. Gracin, S.; Rasmuson, A. C.Cryst. Growth Des, 2004, 4 (5), 1013-1023. 4. Chen, C.; Cook, O.; Nicholson, C. E.; Cooper, S. J.Cryst. Growth Des, 2011, 11 (6), 2228-2237. 5. Sudha, C.; Nandhini, R.; Srinivasan, K.Cryst. Growth Des, 2014, 14 (2), 705-715. 6. Bolla, G.; Mittapalli, S.; Nangia, A.Cryst. Growth Des, 2014, 14 (10), 5260-5274. 7. Lancaster, R. W.; Karamertzanis, P. G.; Hulme, A. T.; Tocher, D. A.; Lewis, T. C.; Price, S. L.Journal of Pharmaceutical Sciences 2007, 96 (12), 3419-3431. 8. Li, J. J.; Bourne, S. A.; Caira, M. R.Chem. Commun 2011, 47 (5), 1530-1532. 9. Karanam, M.; Dev, S.; Choudhury, A. R.Cryst. Growth Des, 2012, 12 (1), 240-252. 10. Shah, J. C.; Chen, J. R.; Chow, D.Drug Development and Industrial Pharmacy 1999, 25 (1), 63-67. 11. Liu, J.; Svaerd, M.; Hippen, P.; Rasmuson, A. C.Journal of Pharmaceutical Sciences 2015, 104 (7), 2183-2189. 12. Zhang, J.; Wu, Y.; Liu, A.; Li, W.; Han, Y.Rsc Advances 2014, 4 (41), 21599-21607. 13. Klapwijk, A. R.; Simone, E.; Nagy, Z. K.; Wilson, C. C.Cryst. Growth Des, 2016. 14. Kuvadia, Z. B.; Doherty, M. F.Cryst. Growth Des, 2013, 13 (4), 1412-1428. 15. Yang, X.; Sarma, B.; Myerson, A. S.Cryst. Growth Des, 2012, 12 (11), 5521-5528. 16. Lawton, S.; Steele, G.; Sharing, P.; Ni, X.-W.; Zhao, L.; Laird, I.Organic Process Research & Development 2009, 13, 1357-1363. 17. Quon, J. L.; Zhang, H.; Alvarez, A.; Evans, J.; Myerson, A. S.; Trout, B. L.Cryst. Growth Des, 2012, 12 (6), 3036-3044. 18. Baxendale, I. R.; Braatz, R. D.; Hodnett, B. K.; Jensen, K. F.; Johnson, M. D.; Sharratt, P.; Sherlock, J.-P.; Florence, A. J.Journal of Pharmaceutical Sciences 2015, 104 (3), 781-791. 19. Chen, J.; Sara, B.; Evans, J. M. B.; Myerson, A. S.American Chemical Society 2011, 11 (11), 887 -895. 20. Swichtenberg, B. Moving Beyond the Batch Pharmaceutical Manufacturing [Online], 2008, p. 24-26.


26

Page 27 of 29

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


21. Pellek, A.; Van Arnum, P. Continuous Processing: Moving with or against the Manufacturing Flow Pharmaceutical Technology [Online], 2008, p. 52-58. 22. McGlone, T.; Briggs, N.; Clark, C.; Brown, C.; Sefcik, J.; Florence, A.Organic Process Research & Development 2015, 19 (19), 1186-1202. 23. Ni, X.; Mackley, M. R.; Harvey, A. P.; Stonestreet, P.; Baird, M. H. I.; Rama Rao, N. V.Chemical Engineering Research and Design 2003, 81 (3), 373-383. 24. Briggs, N. E. B.; Schacht, U.; Raval, V.; McGlone, T.; Sefcik, J.; Florence, A. J.Organic Process Research & Development 2015, 19 (12), 1903-1911. 25. Zhao, L.; Raval, V.; Briggs, N. E. B.; Bhardwaj, R. M.; McGlone, T.; Oswald, I. D. H.; Florence, A. J.2014, 16, 5769-5780. 26. Siddique, H.; Brown, C. J.; Houson, I.; Florence, A. J.Organic Process Research & Development 2015, 19 (12), 1871-1881. 27. Li, J.; Trout, B. L.; Myerson, A. S.Organic Process Research & Development 2016, 20 (2), 510-516. 28. Powell, K.; Saleemi, A.; Ali, N.; Rielly, C. D.; Nagy, Z. K.Organic Process Research & Development 2016. 29. Powell, K. A.; Saleemi, A. N.; Rielly, C. D.; Nagy, Z. K.Chemical Engineering and Processing 2015, 97, 195-212. 30. Tahara, K.; O'Mahony, M.; Myerson, A. S.Cryst. Growth Des, 2015, 15 (10), 5149-5156. 31. Galan, K.; Eicke, M. J.; Elsner, M. P.; Lorenz, H.; Seidel-Morgenstern, A.Cryst. Growth Des, 2015, 15 (4), 1808-1818. 32. Lai, T. T. C.; Ferguson, S.; Palmer, L.; Trout, B. L.; Myerson, A. S.Organic Process Research & Development 2014, 18 (11), 1382-1390. 33. Hostomsky, J.Collection of Czechoslovak Chemical Communications 1987, 52 (5), 11861197. 34. Nebel, H.; Epple, M.Zeitschrift Fur Anorganische Und Allgemeine Chemie 2008, 634 (8), 1439-1443. 35. Hostomsky, J.; Jones, A. G.Journal of Physics D-Applied Physics 1991, 24 (2), 165-170. 36. Tai, C. Y.; Chen, P. C.Aiche Journal 1995, 41 (1), 68-77. 37. Nichols, G.; Frampton, C. S.Journal of Pharmaceutical Sciences 1998, 87 (6), 684-693. 38. Perrin, M.-A.; Neumann, M. A.; Elmaleh, H.; Zaske, L.Chem. Commun 2009, (22), 3181-3183. 39. Zhang, G. G.; Law, D.; Schmitt, E. A.; Qiu, Y.Advanced drug delivery reviews 2004, 56 (3), 371-390. 40. Joiris, E.; Di Martino, P.; Berneron, C.; Guyot-Hermann, A. M.; Guyot, J. C.Pharm Res 1998, 15 (7), 1122-30. 41. Barthe, S. C.; Grover, M. A.; Rosseau, R. W.Cryst. Growth Des, 2008, 8, 3316-3322. 42. Wang, I. C.; Lee, M. J.; Seo, D. Y.; Lee, H. E.; Choi, Y.; Kim, W. S.; Kim, C. S.; Jeong, M. Y.; Choi, G. J.Aaps Pharmscitech 2011, 12 (2), 764-770. 43. Fujiwara, M.; Chow, P. S.; Ma, D. L.; Braatz, R. D.Cryst. Growth Des, 2002, 2 (5), 363370. 44. Hou, G. Y.; Power, G.; Barrett, M.; Glennon, B.; Morris, G.; Zhao, Y.Cryst. Growth Des, 2014, 14 (4), 1782-1793. 45. Power, G.; Hou, G. Y.; Kamaraju, V. K.; Morris, G.; Zhao, Y.; Glennon, B.Chemical Engineering Science 2015, 133, 125-139.


27


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 28 of 29

46. Lee, H. L.; Lin, H. Y.; Lee, T.Organic Process Research & Development 2014, 18 (4), 539-545. 47. Sudha, C.; Srinivasan, K.CrystEngComm 2013, 15 (10), 1914-1921. 48. Burley, J. C.; Duer, M. J.; Stein, R. S.; Vrcelj, R. M.European Journal of Pharmaceutical Sciences 2007, 31, 271-276. 49. Chadwick, K.; Myerson, A.; Trout, B.CrystEngComm 2011, 13 (22), 6625-6627. 50. Agnew, L. R.; Cruickshank, D. L.; McGlone, T.; Wilson, C. C.Chemical communications (Cambridge, England) 2016, 52 (46), 7368-71. 51. Pudipeddi, M.; Serajuddin, A. T. M.Journal of Pharmaceutical Sciences 2005, 94 (5), 929-939. 52. Szelagiewicz, M.; Marcolli, C.; Cianferani, S.; Hard, A. P.; Vit, A.; Burkhard, A.; von Raumer, M.; Hofmeier, U. C.; Zilian, A.; Francotte, E.; Schenker, R.Journal of Thermal Analysis and Calorimetry 1999, 57 (1), 23-43. 53. Pulham, C., Metacetamol hydrate. Agnew, L. R., Ed. 2015. 54. Thompson, C.; Davies, M. C.; Roberts, C. J.; Tendler, S. J. B.; Wilkinson, M. J.International Journal of Pharmaceutics 2004, 280 (1-2), 137-150.


28

Page 29 of 29

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


TABLE OF CONTENTS ENTRY

RAPID TRANSFER

2 CONTINUOUS CRYSTALLIZATION PLATFORMS

Batch - 120g PCM-II

The crystallization of metastable paracetamol form II, using metacetamol as a template molecule, has been demonstrated in a scaled-up batch environment and two different continuous crystallization platforms: a 2- stage MSMPR and a COBC. Crucially, the transfer of the production of this metastable form between the different environments has been shown to be facile.


29

Continuous Crystallization of Paracetamol (Acetaminophen) Form II

Recommend Documents