Evidence of Crystal Nuclei Breeding in Laboratory Scale Seeded

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Evidence of Crystal Nuclei Breeding in Laboratory Scale Seeded Batch Isothermal Crystallisation Experiments Brian de Souza, Giuseppe Cogoni, Rory Tyrrell, and Patrick J. Frawley Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.6b00407 • Publication Date (Web): 19 Apr 2016 Downloaded from http://pubs.acs.org on April 23, 2016

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Crystal Growth & Design

Evidence of Crystal Nuclei Breeding in Laboratory Scale Seeded Batch Isothermal Crystallisation Experiments

Brian de Souza*, Giuseppe Cogoni, Rory Tyrrell, Patrick J. Frawley

Synthesis and Solid State Pharmaceutical Centre (SSPC), Materials & Surface Science Institute (MSSI), University of Limerick, Ireland.

*Corresponding author: Address: L1-025, Lonsdale Building, Department of Mechanical, Aeronautical and Biomedical Engineering, University of Limerick, Castletroy, Co. Limerick, Ireland. Tel: +353 (0)61 213134. Fax: +353 (0)61 202944. E-mail: [email protected]. URL: http://www.ul.ie/sspc.

ACS Paragon Plus Environment


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ABSTRACT Experimental investigations of the batch seeded crystallisation of paracetamol in 2-propanol were carried at 200, 300 &375 RPM agitation rates, using a large seed size (355-500 µm) and a low level of initial supersaturation (S0=1.2) in a laboratory scale reactor. Such experiments are normally conducted for the indirect measurement of crystal growth, contingent on the assumption of negligible nucleation, agglomeration and breakage. In the present work a copious increase in crystals nuclei was noted shortly following seed addition. The formation of substantial numbers of new nuclei was substantiated through FBRM, laser diffraction and SEM. Secondary nucleation was proposed as the origin of the new crystals and a Secondary Nucleation Threshold (SNT) determined, with relative supersaturation between 1.09-1.11. Below this limit, crystal growth only was apparent. A study was undertaken to investigate the origin of secondary nucleation. Crystal nuclei breeding, as a mechanism of secondary nucleation, has being theorised for many years, however it is only very recently that definitive molecular dynamics simulations have provided mechanistic insight as to its action. The mechanically driven attrition and breakage mechanism of secondary nucleation remains prominent in literature. Stirred vessel experiments were conducted using paracetamol seed crystals suspended in a non-solvent indicated. Despite three hours of continuous agitation, no significant change in particle number or size was detected. Only after a threshold of four hours were significant crystal fatigue and fragmentation evident.

Shadowgraphy

investigations of crystal jet wall impingement revealed the squeeze film as a key protective element in preventing crystal attrition and breakage.

A low temperature (283.15 K)

crystallisation was conducted which indicated a significant temperature dependency, entirely inconsistent with the attrition and breakage mechanism of secondary nucleation. It was shown that through the use of smaller seed crystals (125-250 µm), a high agitation rate and elevated solution temperature that the rate of secondary nucleation could be enhanced thereby


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creating the potential for confounding rapid secondary nucleation with growth. The current work elucidates the potential impact of cluster breeding in laboratory scale crystallisations and furthermore, provides additional experimental support for the crystal breeding mechanism of secondary nucleation.



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1. INTRODUCTION Crystallisation is a multi-functional operation widely employed in the production of pharmaceutical drugs. Crystallisation serves not only as a purification process, through impurity rejection in developing crystals, but also as a transformative process, allowing separation of solid state crystals from solution.

Moreover, crystallisation serves as a

production technique, allowing physical characteristics of the active pharmaceutical ingredient (API) such as crystal size and shape to be tailored. These physical characteristics are well known to have a significant impact on the bioavailability and efficacy of API’s. Furthermore, the physical characteristics of the API can impact on downstream manufacturing operations such as filtration. Control over crystal size may therefore be regarded as a significant research and process development goal. The evolution of the particle size distribution (PSD) is often determined by the competitive balance between the dominating crystal growth and nucleation mechanisms, which is ultimately controlled by the level of supersaturation prevailing during the course of the crystallisation. This is evident whether the supersaturation is created by cooling, anti-solvent addition, evaporation or chemical reactions1. During crystallisation processes, a supersaturated solution nucleates more readily (at a lower level of supersaturation) when crystals of the solute are already present. The term secondary nucleation thus describes nucleation which is dependent on the presence of parent crystals. On the contrary, primary nucleation has no such stipulation of parent crystals but requires higher levels of supersaturation. Both in research and industry, it is common practice to employ crystal seeds to induce crystallisation though secondary nucleation2. This approach confers several advantages over the non-seeded case such as promoting the selective crystallisation of a specific crystalline form. Furthermore, the use of seeded crystallisations can lead to a more consistent particle size3, given the stochastic nature of primary nucleation.


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There have been several reviews on the mechanisms of secondary nucleation in past years4,5. From the literature, it is evident that two distinct ideologies have been advocated in order to rationalise the origin of secondary nuclei: Those that attribute their origin to mechanical micro-attrition in such processes as initial, needle or collision breeding6. This could be the case of a single crystal colliding with another crystal, perhaps a baffle or the impeller. The alternative proposition suggests that the origin of secondary nuclei relates back to the presence of semi-ordered clusters of solute molecules at the solid-liquid interface. Only very recently, have molecular simulations by Anwar et al.7 elucidated in detail this process of crystal breeding. Molecular aggregates are seen to form in solution, which upon coming in contact with the surface of a seed particle undergo nucleation to form crystallites. These crystallites are weakly bound to the crystal and can be readily sheared by the fluid. The parent crystals thus serve in a catalytic fashion, potentially leading to a many-fold increase in the number of new crystals formed. The formulation of nucleation and growth kinetics for population balance modelling has traditionally been achieved though experiments, specifically designed to decouple individual processes such as growth, nucleation, breakage and agglomeration. For instance, primary nucleation kinetics have been determined using induction time measurements in combination with the metastable zone width (MSZW)8,9. Growth kinetics are most commonly obtained on the basis of isothermal seeded batch growth experiments, as conducted by Schöll et al.10 for α L-glutamic acid, and further applied by Mitchell et al.11 for the determination of paracetamol in ethanol growth kinetics. The procedure for experimentally determining growth kinetics from isothermal batch seeded crystallisations involves firstly creating a supersaturated solution, into which seed crystals are added.

The critical assumption made in these

experiments is that nucleation, agglomeration and breakage are negligible and this assumption is generally supported by focused beam reflectance measurement (FBRM) data.



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The combination of experimental desaturation data, population balance modelling and an optimisation function, leads to the ultimate determination of growth rates. The original focus of the present work was to establish crystal growth rates of paracetamol in 2-propanol though the use of seeded batch cooling crystallisation experiments using large seed crystals of size 355-500 µm. During the course of this work, it became apparent that significant rates of particle formation were occurring during the crystallisation, contrary to the findings of previously published studies. Considerable differences in seed size, seed loadings and supersaturation were noted, however, between current and previous studies. Consequently, a heuristic set of experiments was devised and undertaken in order to determine the mechanism of particle formation, and further to investigate why particle formation was not observed in the previous growth measurement studies. This experimental work detailed below, provides additional evidence to support and expand upon the very significant molecular modelling findings of Anwar et al.7 and elucidates the potential impact of cluster breeding in laboratory scale crystallisations.

2. THEORETICAL DESCRIPTION The experiments conducted in this work were principally based upon isothermal seeded batch crystallisations as used for the indirect measurement of crystal growth. For a batch reactor, the generalised population balance equation governing the time-dependent evolution of particle size distribution with growth and nucleation terms only, can be expressed as follows:

∂n( L, t ) ∂ (G L ( L, t ) n( L, t )) + =0 ∂t ∂L


(1)

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where the amount and the size of particles are expressed in terms of number density n(L,t). Crystals are assumed to have a uniform shape, such that their size is defined by a single internal coordinate L which is representative of crystal length. GL(L,t) is the linear size dependent growth rate. In the above equation it is assumed that agglomeration and breakage terms can be neglected. This assumption is commonly made in population modelling studies given the dominance of the nucleation and growth terms. In the case of crystal growth measurement studies, a further simplification is generally made in assuming that the number of particles remains constant, with neither primary nor secondary nucleation. The mass balance equation for the solute, excluding nucleation, can be expressed as:

∞

dc = −3k v ρ c ( ∫ G L ( L, t ) nL2 dL ) dt 0

(2)

where c represents the solute concentration, ρc is the crystal density and kv is the volume shape factor of the solute crystals.

Appropriate specification of seed loading is an important consideration when conducting isothermal seeded batch crystallisations. Maintaining the assumption of constant particle numbers and known supersaturation, one can estimate the product particle size (Lprod), as a ratio to the seed crystal size (Lseed). This relationship is described in equation 3 below.

m seed L3 = 3 seed 3 ∆m L prod − L seed

(3)

where ∆m is the mass of solids formed in the batch process and mseed refers to the mass of the seed.



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In the case of the desupersaturation experimental runs presented in the current work, seed loadings were determined in order to ensure a significant change in the size of the particles through growth, while remaining within the limits of the online and offline sizing tools (0.013500 µm).


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3. MATERIALS AND METHODS The experimental work outlined herein was performed using a single solute for all experiments, namely Paracetamol (Acetaminophen) A7085 Sigma Ultra, ≥ 99 %, as sourced from Sigma-Aldrich without undergoing any further purification. Two polymorphic forms of paracetamol are commonly documented in the literature, monoclinic and orthorhombic12,13. Monoclinic paracetamol is the thermodynamically stable modification at room temperature with respect to the orthorhombic modification14. Whilst earlier studies previously found the transition temperature to be in the region of 87 °C15, more recent studies have solution mediated polymorphic transformation can occur at lower temperatures16. Hence, it was necessary to verify the polymorphic form prior to and post crystallisation. In this work, the pharmacologically active and commercially marketed monoclinic form was considered, as verified by X-ray powder diffraction with consistent characteristic peaks (2Θ): 15.5 ± 0.2, 18.2 ± 0.2, 20.3 ± 0.2, 24.4 ± 0.2 and 26.5 ± 0.2.

Solvent mediated polymorphic

transformation was not observed. Three solvents were used in the present work, all of HPLC grade, all with purities of ≥ 99.9 % and all of which were sourced from Sigma-Aldrich. Solvents were used as received, without further purification.

2-Propanol, also known as isopropanol, was used for the

isothermal batch cooling experiments. Methanol was used as solvent for the crystallisation of paracetamol seeds. Cyclohexane was primarily used as a dispersant for the measurement of particle size.

It was further used in non-solvent experiments which investigated the

mechanism of secondary nucleation, as will be described later in Section 4.3. The solubility of paracetamol in cyclohexane is negligible, with a maximum value of 0.0539 g/kg at 298.15 K17.

Hence, paracetamol crystal seeds of paracetamol could be suspended in cyclohexane

without the risk of any significant dissolution. Solubility data for paracetamol in pure 2propanol and pure methanol were taken from Granberg and Rasmuson18.



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3.1

Batch Crystalliser Setup

A 1 L LabMax® borosilicate glass jacketed reactor with an inner diameter of 100 mm from Mettler-Toledo was employed for all crystallisation experiments conducted during this work. Agitation was provided by a four blade PTFE stirrer of 60 mm diameter, with 45̊ inclined blades. The stirrer was positioned approximately 25mm from the base of the reactor. The mixing time of the reactor was determined using transient Computational Fluid Dynamics (CFD) simulations to be less than ten seconds at 200 RPM, considerably faster than the growth process, across the full range of agitation considered in the present work. The mixing time prediction was additionally validated through conductivity and Planar Laser-Induced Fluorescence (PLIF) experiments. The approximate range of Reynolds number (Re=ρND2/µ, ρ is the fluid density, µ is the dynamic viscosity, N is the impeller rotational speed in rev/s and D is the impeller diameter) considered in the present work was calculated to be between a minimum of 3.3x103 to a maximum of 13.6x103 in the case of 2-propanol and methanol respectively, thus spanning the lower limit of the turbulent regime with considerable regions of transitional flow. FBRM and ATR-FTIR probes, as described in the following section, alongside a temperature probe were positioned in the region of high velocity, close to the impeller and where appropriate, at such an angle as to avoid encrustation of the probe windows. In order to minimise the possibility of breakage, through crystal-wall collisions, no baffles were used in the course of the experiments.

3.2

Online Measurements of Particle Count & Solution Concentration

A Mettler-Toledo Focused Beam Reflectance Measurement (FBRM) D600L probe was used in order to provide online and in-situ measurement of particle chord length and number. The


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probe employs a laser beam rotated with high speed optics at 2 m/s which scans a circular path.

Particles are detected with chord length distribution (CLD) and particle count

determined through analysis of the backscattered light signal. Conversion from CLD to PSD is not a trivial matter, and has been the subject of considerable research focus19,20. Hence, offline measurements of particle size were taken by laser diffraction, in addition to the FBRM online measurements. In the case of the current study, the FBRM was primarily used to provide an online measurement of particle counts. Additionally it was used to provide a qualitative description of particle size evolution through monitoring of particle size metrics such as the 10th, 50th and 90th percentile values (D10, D50, D90, respectively) and the average volume weighted diameter (D4,3). Concentration of paracetamol in solution was measured in-situ using a Mettler-Toledo ReactIR ic10 with a 9.5 mm DiComp AgX immersion probe. The system operates in the mid-IR region, with a usable wavenumber range of 1900-650 cm-1, within which the fundamental vibrations of most organic functional groups can be observed. In this work ATR-FTIR was used to monitor the concentration of paracetamol using a single band in the IR spectra at 1516 – 1520 cm-1, relative to a solvent peak baseline. Calibration of the concentration measurement through IR was performed using a set of solutions with known paracetamol concentrations and applying the Beer-Lambert law. An average relative error of less than 2.0% was obtained over the range of concentration investigated.

Further

information on both FBRM and ATR-FTIR is documented in earlier work11,21.

3.3

Offline Measurement of Particle Size

A Mastersizer 3000 laser diffraction particle size distribution analyser was employed in this work to evaluate the PSDs of the seed sieve fractions and of the final product.

This

instrument is equipped with a Hydro MV which circulates the samples in wet suspension of



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the dispersal medium through the measurement window. The mastersizer is equipped with two independent light sources, a red 4 mw He-NE laser at 632.8 nm and a 10 mW blue LED at 470 nm. This allows for measurement of particle sizes from 0.01-3500 µm. Particles are classified into 100 distinct logarithmically spaced size classes with a manufacturer certified accuracy of better than 0.6% and repeatability better than 0.5% variation. Sufficient sample was added to ensure an obscuration value in the region of 8-10%. The use of excess sample leads to the risk of multiple scattering which is likely to be more prevalent with smaller sized particles.

Too little of the sample can lead to a non-representative measurement.

An

appropriate stir speed was determined in order to ensure suspension of all particles including coarser particles. A refractive index of 1.619 was specified for paracetamol with absorption of 0.1 and density ρ=1.33 g/cm3 as per the CAS datasheet. cyclohexane likewise was taken as 1.426.

The refractive index of

The laser alignment was adjusted, stable

background signal recorded before addition to of the paracetamol crystal sample. Cyclohexane is particularly sensitive to thermal gradients, as it is a volatile solvent. As such ultrasound was not used, with mechanical agitation sufficient to fragment any agglomerates present.

3.4

Preparation and Characterisation of Seed Crystals

Paracetamol seed crystals were prepared through recrystallization of the paracetamol in methanol. The key steps in the recrystallization process included complete dissolution of the as received paracetamol through heating of the reactor as verified through FBRM. The reactor was then cooled beyond the established metastable zone limit, held for an appropriate duration to allow for primary nucleation and finally heated, to a sustained low value of supersaturation (≤ 1.1) allowing for crystal growth. The precipitated crystals were separated from the solution by filtration, using a büchner vacuum filtration rig with 0.2 µm filters. Subsequently, the crystals were wet sieved using


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stainless steel, woven wire cloth sieves with square apertures. Seed crystals were collected in the size ranges 355-500 µm. Crystals sized outside this range were discarded. Finally, the crystals of all fractions were washed and dried in a vacuum oven at 40 ̊C for 12 hours. In order to characterise the seed crystals, SEM (Figure 1) and PSD measurements (Figure 2) were taken. It could be observed that the seed crystals consisted of mostly single crystals with few agglomerates present.

Figure 1: SEM image of 355-500 µm sieve seed fraction paracetamol crystals exhibiting largely single crystals with few agglomerates present.



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Figure 2: Monomodal PSD of 355-500 µm sieve seed fraction paracetamol crystals.

Laser diffraction particle size measurements were repeated on five occasions with statistical analysis of the measurements provided in Table 1.

Table 1: Repeatability of Laser Diffraction measurements using 355-500 µm seed crystals. Distribution Statistic

Mean Value (µm)

Standard Deviation (µm)

Relative Standard Deviation (%)

D10

165

1.52

0.92

D50

330

2.80

0.85

D90

598

5.92

0.99

D[4,3]

357

3.03

0.85


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3.5

Experimental Procedure

Isothermal batch crystallisation experiments were carried out using 355-500 µm paracetamol seeds, suspended in supersaturated 2-propanol. A low value of supersaturation (1.2) was selected in order to reduce the likelihood of nucleation events, remaining well within the established metastable zone width22 (MSZW). It was noted that in previous work of Mitchell et al.11 that supersaturation values of 1.2-1.7 were chosen, while in the earlier work of Schöll et al.10 significantly higher supersaturation values (up to 3.86) were utilised. The baseline agitation rate was set at 300 RPM, in order to ensure appropriate suspension of the particles without introducing air bubbles in the solution. The solvent selected for this work was 2-propanol with a fill volume of 1 L. Using such a large volume of solvent further minimised the risk of air entrapment, and furthermore allowed direct comparison of the reactor hydrodynamics with previously established CFD simulations. The experimental procedure required the creation of a supersaturated solution. This was achieved by adding the appropriate mass ratio of paracetamol and 2-propanol to the crystalliser. The reactor was then heated to a temperature of 328.15 K at which point no particles of paracetamol could be detected. The solution was held at this temperature for 5 minutes to ensure complete dissolution of the solute. The reactor was then slowly cooled, at a rate of 0.1 K/min to the target isothermal hold temperature of 313.15 K. Dry seed crystal of mass 6.8 g and sieved size 355-500 µm were carefully introduced into the solution using a bespoke funnel to ensure rapid dispersion within the high velocity zone. The mass of seed added was determined as per Equation 3 in order to ensure a significant yet measurable change in particle size. The time of seed addition was noted and FBRM and IR measurements taken with reference to the seed addition time. This experiment was allowed to progress for between two and three hours at which point the supersaturation was verified to be substantially consumed (S < 1.03) through ATR-FTIR. At



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the end of the experiment, the slurry was filtered with a 0.2 µm filter, as per the seed crystals, washed and sampled for analysis using laser diffraction. This procedure was repeated in later runs, but with different agitation intensities.


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4. RESULTS AND DISCUSSION 4.1

Extensive Particle Formation

Measurement of crystal growth rates can be achieved by several methods including direct measurement of individual crystals through microscopy, or secondly by indirect measurements, through monitoring of populations of crystals and analysis of mass deposition rates.

Indirect measurement of crystal growth from batch multi particle crystallisers is

advantageous in that the average growth rate obtained is directly suitable for crystalliser design23. FBRM is normally utilised in such growth measurement experiments to validate the assumption of little or no nucleation, through monitoring of counts of small chord length particles which would be associated with nucleation. The copious increase in total particle count, as revealed by FBRM post seed addition in the baseline 300 RPM experiment was therefore most unexpected (Figure 3). Particle density was seen to increase almost linearly post seed addition, for a duration of approximately twenty minutes during which time the solution supersaturation reduced from an initial value of 1.2 to 1.11 approximately. Thereafter, the total FBRM counts recorded remained relatively consistent. Given that the mixing time of the reactor was established to be in the order of seconds, it was clear that the increase in particle count could not be attributed to the dispersion of the seed crystals in the reactor. In parallel to the recorded increase in total counts, a commensurate reduction in mean square particle chord length was noted, dropping from approximately 130 µm to 80 µm.

Additionally, a change in the opacity of solution from clear to milky white was

observed, ostensibly due to the presence of fines significantly smaller than the seed particles.



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Figure 3: Formation of New Nuclei at an agitation rate of 300 RPM. Significant rise in FBRM count post seed addition, with commensurate reduction in mean, square weighted, particle chord length.

Given that the supersaturation selected was well within the MSZW, primary nucleation was excluded as a cause of new particle formation. Similarly, SEM images of the seed crystal showed largely single crystals with few agglomerates (Figure 1). Certainly, there were far too few agglomerates present to account for the extensive increase in particle number observed post seed addition and thus deagglomeration was also discounted as the critical driver of particle formation. The origin of new particles, leading to an increase in counts, therefore could only be rationalised as arising through secondary nucleation, either by means of microattrition and breakage of the seed particles and breakage, or alternatively, secondary nucleation by means


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of crystal nuclei breeding whereby the nuclei would not originate from the crystal surface itself, but from pre-ordered layers adjacent the crystal surface containing clusters of solute growth units.

A combination of both mechanisms to secondary nucleation was also

considered as suggested by Cui and Myerson24. The design of and results arising from experimental investigations aimed at elucidating the secondary nucleation mechanism are discussed later in Section 4.3.

4.2

Influence of Agitation Rate

Agitation rate has long been associated with secondary nucleation. The relationship between agitation rate and secondary nucleation is clearly captured in classical power law equations, which relate the secondary nucleation rate of a suspension of growing crystals B0 to empirically accessible parameters including stirrer rotational rate N, crystal growth rate G and the crystal mass MT. These equations take the form:

B0 = k N G i N h M Tj

(4)

Where the superscripts i,j,h represent empirically determined values.

The original intention of equations of the form set out above was to capture secondary nucleation arising from the three postulated attritional processes of crystal-impeller, crystalwall and crystal-crystal interactions in a single empirical expression. Correlation of the power values with the mechanisms has proven difficult, and the predictive power of the equation has been criticised, particularly during scale-up6. The crystal breeding mechanism of secondary nucleation, likewise to the microattrition ideology, reflects a dependence on agitation rate. As part of this mechanism, seed surfaces



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are seen to induce secondary nucleation of pre-existing clusters. These are weakly bound to the seed surface and can be readily mechanically sheared by agitated fluid. The influence of hydrodynamics on particle formation is therefore hugely significant. In a stirred vessel, hydrodynamic parameters such as shear stress are dominated by the agitation rate. In order to fully capture the full influence of agitation rate on secondary nucleation, it was necessary to determine minimum and maximum agitation rate values. Without baffles, a maximum stir rate of 375 RPM was determined for the crystallisation runs within the labmax reactor.

Beyond this threshold agitation rate, a significant risk of air entrainment was

evident. A minimum agitation rate of 200 RPM was determined in order to mitigate settling of larger particles on the floor of the reactor. Consistent with expectations, a strong correlation between enhanced secondary nucleation and agitation rate was determined from the FBRM data in the form of particle formation. Across all agitation rates investigated, a rapid increase in particle count was observed in the first twenty minutes of the crystallisation post seeding. The peak FBRM total particle counts observed for the 375 RPM run was approximately double that of the baseline case, while reducing the RPM to 200 had the effect of reducing the peak FBRM count by approximately one third. In the case of the 200 RPM crystallisation run, the rotational rate was not sufficient to maintain all particles in uniform suspension, particularly at the level of the FBRM probe. A progressive reduction in particle count was thus observed 20-160 minutes post seeding. Increasing the level of agitation at the end of the experiment initially to 300 RPM allowed for resuspension of crystals, with a uniform dispersion and count consistent with that measured prior to settling. A further increase in agitation rate to 375 RPM showed no significant further increase in particle counts.


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Figure 4: Comparison of FBRM counts for agitation rates of 200, 300 & 375 RPM.

The concept of a secondary nucleation threshold (SNT) beyond which crystal growth occurs unaccompanied by crystal proliferation is well known yet barely mentioned recognised or acknowledged in mainstream crystallisation literature25.

Kraus and Nyvlt26 mention the

concept of a region within which supersaturation is entirely consumed by existing crystals, implying a growth-only region. In agreement with this, the simulations of Anwar et al. reference three distinct supersaturation regimes.

At high supersaturations, spontaneous

nucleation is observed in the solution phase corresponding with primary nucleation. At low supersaturations, growth is observed on the parent crystal with neither primary nor secondary nucleation, while at intermediate levels of supersaturation, the cluster breeding secondary mechanism as previously discussed is observed.



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Supersaturation data corresponding to the isothermal batch crystallisations is presented in Figure 5.

Increasing agitation rate results in a faster desupersaturation which may be

attributed to the increased formation of new nuclei and the subsequent growth thereof. From interpretation of the supersaturation data in combination with FBRM data, the SNT can be determined as a supersaturation ratio of approximately 1.09-1.11, consistent across all agitation rates tested. The stabilisation in particle numbers can thus be explained by the crossing of the SNT.

Figure 5: Effect of agitation rate on desupersaturation of 2-propanol.

At the end of each crystallisation run, a representative sample of the product crystals was analysed through laser diffraction. The product particle size distributions resultant from the agitations rate experiments are compared in Figure 6, with comparison to the seed data.


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Figure 6: Final Product PSDs of 200, 300 & 375 RPM crystallisation experiments with comparison to the Seed PSD.

While the seed crystals were mono-modal with a D4,3 of approximately 357 µm, the product crystals were clearly bimodal, with an increasing number of fines evident at elevated agitation rates as expected. Data presented in Figure 6 are displayed on a volume basis, which places significant weight on larger volume particles relative to smaller particles. The profuse the extent of particle formation is more greatly accentuated on a numbers basis. By number, in the case of the 375 RPM agitation rate, over 76% of the product particles are fines less than 20 µm in size. By comparison, laser diffraction measurements of the seed indicate negligible (0.0%) particles of this size. A reduction in the mean particle size of the second mode (i.e. seed crystals which have grown, as opposed to secondary nuclei) was observed with increasing agitation rate. The



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shift between a volume weighted second mode mean particle size of 600 µm in the case of the 375 RPM run to 504 µm in the case of the 300 RPM run is largely attributable to competition for supersaturation arising from the generation of new fine particles. The data is summarised in Table 1 below on a volume weighted basis.

Table 2: Influence of the agitation rate employed on the apparent growth of seed particles.

4.3

Agitation Rate [RPM]

D4,3 Overall [µm]

Mean Particle Size Coarse Mode [µm]

Relative Change in Coarse Mode Mean Particle size: Lx/L375 [%]

375

410

504

0

300

450

512

+1.5

200

602

600

+19

Seed

357

-

-

Secondary Nucleation Mechanistic Investigations

Having clearly established a many fold increase in particle numbers in indirect batch growth measurement experiments, it was necessary to investigate in further detail the secondary nucleation mechanism. In particular, the question arose as to whether the origin of new particles could be attributed to microattrition and breakage of the seed crystals, alternately to crystal breeding or lastly whether a combination of both mechanisms was responsible for the fine particle formation. Attrition refers to the process by which asperities and fines are removed from the surface of parent particles suspended in solution, such that there is only a gradual change in their size. Breakage (or fragmentation) is the process by which the parent particles are broken down into smaller entities of significant size, resulting in a rapid disappearance of the original particles.


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The issue of attrition and breakage in agitated crystal suspensions has been the subject of much debate in recent years with mechanical collision of crystals with the impeller, crystalliser walls or other crystals, and turbulent fluid mechanical breakup considered as the main causes of fragments and secondary nucleation5,27,28. One approach to examining attrition and breakage is to decouple these processes from others such as growth and dissolution. This can be done by suspending seed crystals, in stirred vessel experiments, in either a non-solvent (like those studies of Nienow and Conti29. or Mazzarotta27) or in a saturated solution (Synowiec et al.28). Correlations are then determined between factors such as energy dissipation, or agitation rate, crystal loading, seed surface size, crystal and impeller hardness with resultant fragment size and number. Similarly to the isothermal batch crystallisation runs, 6.8g of paracetamol seeds (size 355500µm) were suspended in the labmax reactor. Cyclohexane was used as a non-solvent for suspension of the crystals and the maximum agitation rate of 375 RPM selected. FBRM was utilised to monitor particle count, and also to give an indicative measurement of chord length distribution. The experiment was run for over three hours. Results from this study are presented in Figure 7.



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Figure 7: FBRM counts and chord length data showing no significant change over a period of three hours with continuous agitation (375 RPM).

Examination of the FBRM data indicated no significant change in the particle counts or in the mean square size of particles. Considering that the FBRM was sufficiently sensitive to capture a substantial and rapid increase in counts in the earlier isothermal seeding crystallisations, the implication was clear: abrasion and breakage mechanisms were not responsible for the dramatic increase in particle count.

Analysis of the particle size

distributions through laser diffraction showed no discernible change. That microattrition and breakage was not found to be principle mechanism of secondary nucleation under the conditions considered is hardly surprising. Whilst microattrition has been shown as an important mechanism for nuclei generation at high contact force, these observations have mainly come from large single crystal experiments, for instance the crystals employed in the study of Biscans30 were up to 2 mm in size.


In stirred

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crystallizations involving smaller crystal seeds, impact energy can be better accommodated by lattice slip. Ultimately, the accumulation of stress within the crystal ultimately leads to brittle failure and microattrition. This fatigue like effect was observed in earlier studies with the same seed size and agitation rate but doubled seed loading. Extension of the experiment duration to over ten hours led to an exponential increase in particle counts, with significant attrition observed to commence following four hours of continuous agitation at 375 RPM. Large count increases were seen in the smaller size bands due to fragments of the seed. SEM analysis of the crystals following agitation showed a distinct crated appearance (Figure 8).

Figure 8: SEM images of paracetamol crystals showing evidence of significant fatigue and fragmentation following ten hours of continuous agitation at 375 RPM.



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Further to SEM imaging, a particle tracking method known as shadowgraphy was implemented in order to directly investigate the attrition mechanism through particle wall collisions. A particle impact test rig was developed in-house and used to fire paracetamol crystals at a target wall thereby simulating the impact conditions occurring in crystallisers. The imaging equipment employed consisted of a Phantom v1211 high speed camera capable of a maximum image rate of 10 kHz, a Constellation 120 LED lamp with colour temperature of 5600 K and a Questar QM100 long distance microscope with optical resolution of greater than one micron. Particles entered the test-section with a nominal velocity corresponding to the impeller tip speed (1.2m/s) and normal to the wall.

Stokes number, a function of velocity, is a

dimensionless number is commonly used for characterising the behaviour of particles suspended in a fluid flow. It provides a measure of the fidelity of particle to observe changes due to the velocity field of the fluid. Where stokes numbers of greater than one are observed, particles tend to detach from the flow especially where the flow decelerates abruptly thus risking collision of particle with wall. A Stokes number significantly greater than one was calculated for the batch reactor, considering a mean particle diameter of 357 µm and 375 RPM agitation rate.

 ρ d d d2   18µ s stk =  l0

 u 0  

(5)

Despite the high Stokes number of the crystalliser, analysis of the shadow imaging videos (Figure 9) clearly demonstrates few collisions of particles with the wall. This is explained by particle-wall interaction, directly influenced by the boundary layer, with a squeeze film leading to a diversion of most particles away from the wall without incurring any noticeable fragmentation. It was observed that while the vast majority of particles were diverted laterally


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from the wall, some particles typically with larger chord lengths did at times reach the target wall but insufficient residual velocity to cause breakage of their structure upon contact.

Figure 9: Shadowgraphy tracing of crystal particle tracks in Impingement Jet experiments; the squeeze film effect serves to protect the crystal from fragmentation.

As a final investigation of the secondary nucleation mechanism at lab scale, a temperature dependency study was performed. Breakage and attrition processes can be considered as mechanical processes, thus broadly independent of temperature.

Therefore, it was

rationalised that should a temperature-dependence be observed in the secondary nucleation rate, that this then would provide further evidence supportive of the crystal nuclei breeding



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mechanism of secondary nucleation, in keeping with the commonly observed temperature dependence in growth kinetics. An isothermal seeded batch desupersaturation crystallisation of paracetamol in 2-propanol was carried out as before, however the seed addition temperature was reduced to 283.15 K thereby allowing comparison with the 313.15 K desupersaturation experiments carried out earlier. Corresponding to the reduction in temperature, the mass of paracetamol used as solute was reduced to preserve the starting supersaturation (S0=1.2). The agitation rate selected for the investigation was 200 RPM. As before, 6.8g of paracetamol seed (size 355500µm) was added to the supersaturated solution and FBRM used to monitor total particle counts. The FBRM data captured from this set of experiments are shown in Figure 10 below.

Figure 10: Comparison of FBRM data for 283.15 K and 313.15 K desupersaturation experiments with 200 RPM agitation rate.


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In the case of the earlier high temperature (313.15 K) experiment a rapid increase in particle count was noted followed by settling and resuspension. In contrast to this, the formation of secondary nuclei appeared to be delayed in the case of the lower temperature (283.15 K) crystallisation. Immediately after addition of seed, a measurement of approximately 180 particle counts per second was recorded by the FBRM probe, indicative of the particle count without nucleation. Thereafter, secondary nucleation was seen to progress slowly with the number of counts increasing more than four fold over the course of four hours. As with the earlier higher temperature experiment, the agitation rate was briefly increased to 375 RPM at the end of the experiment to ensure a uniform distribution of particles in suspension. Correspondingly, a minor increase in FBRM counts per second from approximately 900 to 1100 was noted. This strong dependency of particle creation on temperature, and delayed rate of particle formation, was determined to be consistent with the mechanism of crystal breeding, and not in keeping with the breakage and microattrition ideology of secondary nucleation. As with the earlier isothermal batch experiments, representative samples of the product crystals were analysed through laser diffraction. The higher temperature crystallisation leads to particles nucleating earlier, this allowing more time to grow and reduced separation between the modes of the newly created fines and the seed particles.

The secondary

nucleated particles compete for supersaturation with the established seed particles, and as such the seeds were observed to grow to a smaller final size.

4.4

Further Investigations: Seed Size

As a further investigation to the current work, the issue of seed size was examined. In the case of Schöll et al.10 three seed classes were utilised for the determination of growth, 64125µm, 125-250 µm and 250-355 µm. In the case of Mitchell et al.11 the seed classes utilised



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were 63-90 µm, 90-125 µm and 125-250 µm. The intent of this investigation was to address the question as to why secondary nucleation was so prevalent in the present work, whereas in previous works, no such observation was made.

A single additional isothermal batch

experiment was conducted as per the agitation rate experiments conducted earlier, but using the smaller 125-250 µm size band. A consistent seed mass was used for both experiments. The obvious implication of using a consistent mass of crystals was that the number of smaller crystals would greatly exceed the number of larger crystals by virtue of the smaller volume and thus mass of each crystal. The maximum agitation rate of 375 RPM was selected to enhance secondary nucleation. FBRM data from both experiments are compared in Figure 11.

Figure 11: A comparison of FBRM counts for seed sizes 125-250 µm and 355-500 µm.

The addition of seed crystals of size 125-250 µm to the isothermal supersaturated solution leads to what could be adjudged as a step change in particle numbers with a higher number of


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counts, as expected that the corresponding experiment with the 355-500 µm seed size. While it is not obvious from the FBRM data, SEM images of the product crystal indicates the presence of significant secondary nuclei, as shown in Figure 12.

Figure 12: Secondary nucleation results in a many fold increase in nuclei, as revealed through SEM analysis of the 125-250 µm product.

The rapid rate of crystal breeding in the case of the small seed size is hardly surprising, given that the surface area of the smaller seeds is significantly larger thereby amplifying the crystal breeding process. Furthermore, the rapid rate of secondary nucleation in the case of the small seed size makes it much more difficult, through FBRM, to discern between the new nuclei and dispersion of seed crystals. In the case of the 355-500 µm seeds, the increase in FBRM particle counts due to secondary nucleation is much more gradual, and the phenomena of crystal breeding thus more apparent.



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5. CONCLUSIONS Isothermal seeded batch desupersaturation experiments are used for the indirect measurement of crystal growth, commonly invoking the assumption of consistent particle number over the duration of the experiment. In the current work, batch seeded crystallisations of paracetamol in 2-propanol were conducted at low levels of initial supersaturation (S0=1.2) and using a large size of seed crystal (355-500 µm). From the resultant data it was apparent that copious nuclei were being formed shortly after seed addition.

The cause of this increase in fine

particles was determined to be secondary nucleation. Both crystal breeding, as well as agitation and breakage, ideologies of secondary nucleation incorporate a mechanistic dependency on the rate of agitation. A trend towards enhanced particle formation with increasing agitation rate was observed as expected. At the highest agitation rate, 76% of product crystals by number were observed to be newly nucleated particles. Evaluation of the secondary nucleation data indicated a secondary nucleation threshold for this system of between 1.09 and 1.11, across all agitation rates examined. Below this level of supersaturation, a growth only zone was observed. In order to investigate the mechanism of secondary nucleation both microattrition and breakage and temperature dependency studies were conducted.

In the case of the

microattrition and breakage experiment, no significant change in FBRM crystal count or size was noted despite many hours of agitation of seed particles suspended in a non-solvent. A fatigue type mechanism was observed thereafter, with an exponential rise in particle count. Analysis of jet impingement experiments revealed the protective nature of the squeeze film, despite large fluid flow Stokes numbers, in shielding crystals from damaging impacts consistent with attrition.


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Agitation and breakage are mechanistic processes, therefore the strong temperature dependency of the secondary nucleation process provided additional evidence to support the conclusion that the secondary nucleation nuclei observed in the isothermal batch seed crystallisation experiments were resultant from an alternative mechanism, namely cluster nuclei breeding. An important conclusion of this the current work is that the impact of secondary nucleated crystals should be carefully considered in seeded batch desupersaturation growth measurement experiments.

The assumption of consistent particle numbers introduces a

significant risk of confounding secondary nucleation with growth. The use of smaller seeds in combination with high rates of agitation and high solution temperature may inadvertently promote rapid and confounding secondary nucleation. Growth measurements may thus be dominated by the growth of secondary nucleated particles rather than by the actual growth of the seed particles. Despite crystal nuclei breeding being theorised for many years, it is only very recently that definitive molecular dynamics evidence has provided mechanistic insight as to its action. Furthering knowledge of factors governing secondary nucleation such as temperature and seed size, as is done in this paper, is central to the future development of new kinetic models for secondary nucleation, thus allowing for better control of both batch and continuous crystallisation processes. Models based on the crystal breeding mechanism are likely to offer superior predictive quality in scale-up.



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FUNDING: This research has been conducted within the Synthesis and Solid state Pharmaceutical Centre (SSPC) with financial support provided by Science Foundation Ireland (SFI) through grant 07/SRC/B1158.


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For Table of Contents Use Only

Evidence of Crystal Nuclei Breeding in Laboratory Scale Seeded Batch Isothermal Crystallisation Experiments

Brian de Souza*, Giuseppe Cogoni, Rory Tyrrell, Patrick J. Frawley

Synopsis: Through the use of bulk crystallisation experiments, the competing contemporary mechanistic thoughts of secondary nucleation are examined. Some compelling experimental evidence is gathered which both supports and illustrates the dramatic impact of cluster breeding in terms of new particle formation.


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Evidence of Crystal Nuclei Breeding in Laboratory Scale Seeded

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