Influence of Process Parameters on the Heterogeneous Nucleation of

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The influence of process parameters on the heterogeneous nucleation of active pharmaceutical ingredients onto excipients Raquel Arribas Bueno, Clare M. Crowley, Benjamin Kieran Hodnett, Sarah P. Hudson, and Peter John Davern Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.6b00425 • Publication Date (Web): 09 Mar 2017 Downloaded from http://pubs.acs.org on March 10, 2017

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Organic Process Research & Development

The influence of process parameters on the heterogeneous nucleation of active pharmaceutical ingredients onto excipients Raquel Arribas Bueno, Clare M. Crowley, Benjamin K. Hodnett, Sarah Hudson and Peter Davern*

Synthesis and Solid State Pharmaceutical Centre, Department of Chemical Sciences, Bernal Institute, University of Limerick, Limerick, Ireland

ACS Paragon Plus Environment

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Graphic – for Table of Contents only:

Acetaminophen on α/β-Lactose α/β

10 µm


2

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ABSTRACT

It is known that chemical and physical compatibility between a heterosurface and the crystallizing molecule promotes heterogeneous nucleation. In this work acetaminophen (AAP), α/β-Lactose (α/β-Lac) and methanol (MeOH) were selected as the model API, excipient and solvent, respectively. The excipient – suspended in a supersaturated solution of AAP in MeOH – was used as a heterogeneous surface (‘seed’), and parameters influencing the heterogeneous nucleation of the AAP, such as (a) AAP solution/excipient contact time, (b) AAP supersaturation, and (c) AAP to excipient loading, were varied to demonstrate how the nucleation rate and the degree of crystallization can be manipulated to control the particle size and the balance between nucleation and growth. In this regard, the crystallizations were performed at a supersaturation which was shown not to promote nucleation of AAP up to 2 hours in the absence of α/β-Lac. Thereafter, during the heterogeneous crystallizations of AAP in the presence of α/β-Lac, AAP particles nucleated on the α/β-Lac surface and then grew uniformly, producing small AAP particles ( 99.9 %), acetaminophen (AAP) (paracetamol, ≥ 98 %) and α/β-Lactose (α/β-Lac) (≤ 20% α-anomer; ≥ 99% total lactose) were supplied by Sigma-Aldrich and used ‘as received’. The PXRD diffractogram of the ‘as received’ AAP confirmed it to be the monoclinic Form I polymorph (CCDC HXACN01), while the corresponding diffractogram of the ‘as received’ α/β-Lac matched that of the pure β-Lactose (CCDC BLACTO) and from the relative peak intensities was determined to be > 80 wt-% β-Lactose. 2. Methods


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2.1. Solubility of AAP and α/β-Lac in MeOH The solubility of AAP and α/β-Lac was measured in MeOH between 5 and 35 °C; each solubility measurement was performed in triplicate. Excess solids were added to approximately 20 mL of MeOH, placed in a temperature-controlled water bath (± 0.1 °C) at the required saturation temperature (Tsat) and agitated with a magnetic stirrer at 500 rpm for 24 hours. Agitation was then stopped and the suspensions allowed to settle for more than 1 hour. The concentrations of the dissolved AAP or α/β-Lac were then determined using the dry mass method, i.e., three aliquots of the clear supernatant were transferred to pre-weighed vials fitted with pre-weighted plastic screw lids and PTFE seals using pre-heated (Tsat + 5°C) syringes and 0.2 µm Nylon filters and the total mass recorded. The lids were then removed, the solvent evaporated at room temperature in a ventilated laboratory hood, and the vials then transferred to an oven at 40 °C until a constant weight was achieved; the visual appearance of the samples was monitored during drying. The amount of AAP or α/β-Lac present in the supernatant, expressed in terms of concentration as g solute/kg MeOH, was then calculated 33. 2.2. Determination of the metastable zone width (MSZW) of AAP in MeOH All MSZW experiments were conducted in triplicate at three different Tsat (20, 25 and 30 °C) in a HEL PolyBLOCK system at a constant agitation rate of 200 rpm using a PTFE-coated magnetic stirrer. Saturated AAP-MeOH solutions were prepared in accordance with the solubility data: 200 mL of MeOH and the appropriate amount of AAP were placed in the crystallizer of the HEL PolyBLOCK and heated to 10 °C above the saturation temperature (Tsat) for 1 hour to ensure complete dissolution. Three heating/cooling cycles per batch and at least three batches were examined per condition. Each crystallizer in the HEL had an internal reactor


8

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temperature probe and a turbidity probe enabling the crystallization and dissolution to be monitored. 2.3. Determination of the induction time for AAP in MeOH in the absence of α/β-Lac Stock solutions of AAP in MeOH, saturated at 25 °C, were placed in a water bath at Tsat + 5 °C (30 ± 0.1 °C) and agitated at 400 rpm with a PTFE-coated magnetic stirrer for ≥ 12 hours. 20 mL aliquots of the saturated solution were then transferred to 25 mL vials (n=20), sealed with PTFE-lined lids, using pre-heated syringes and filters (PTFE, 0.2 µm).

The vials were

equilibrated at Tsat + 5 °C (30 ± 0.1 °C, 200 rpm, ≥ 12 hours) prior to quench-cooling to the desired crystallization temperatures (Tcry).

Agitation was maintained via a PTFE-coated

magnetic stirrer at 200 rpm throughout the isothermal treatment. The induction time of each vial (defined as the time when the first crystals of AAP are observed to crystallize in the first vial) was measured using a webcam (Microsoft life cam, wide angle f/2.2, HD Lens 720 p HD, 30 FPS, Autofocus widescreen). The induction time was measured at Tcry of 5, 10, 15 and 20 °C

corresponding to supersaturations (S) of 1.56, 1.39, 1.25 and 1.12 respectively (S = ∗ , where c = the initial concentration of AAP in MeOH in g AAP/kg MeOH, and c* = the equilibrium concentration of AAP in MeOH at Tcry in g AAP/kg MeOH). All measurements were performed in triplicate. 2.4. Crystallization of AAP from MeOH in the presence of α/β-Lac 20 mL aliquots of the saturated AAP-MeOH solutions were prepared at a Tsat of 25 °C as described in Section 2.3. Following equilibration at Tsat + 5 °C the vials were transferred to a water bath at Tcry and held for 15 minutes prior to addition of α/β-Lac. Following the addition of α/β-Lac the suspensions were agitated at 700 rpm, with a PTFE-coated magnetic stirrer, and held


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isothermally at Tcry. All crystallizations were performed in triplicate. The following parameters deemed capable of influencing the crystallization of AAP in the presence of α/β-Lac were examined: (a) the contact time between the AAP-MeOH solution and the α/β-Lac, (b) the supersaturation of the AAP-MeOH solution, and (c) the amount of AAP available to crystallize from the AAP-MeOH solution in the presence of the α/β-Lac, where all supersaturation is consumed via either heterogeneous or homogeneous nucleation, i.e. the maximum attainable AAP loading (% w/w) which is defined as follows in Equation 1: % ⁄ =

– ∗ ×

– ∗ ×

!"#$%

!"#$% & '()*)#

× 100

Equation 1

where: c

= initial concentration of AAP prior to addition to the excipient (g AAP / kg MeOH)

c*

= equilibrium concentration of AAP at Tcry obtained from solubility data presented in the Results section (g AAP / kg MeOH)

mmethanol

= mass of MeOH (kg)

mexcipient

= mass of excipient (g)

2.5. Treatment of the slurries generated following the crystallization of AAP from MeOH in the presence of α/β-Lac Following the required contact time between the AAP-MeOH solution and the suspended particles of α/β-Lac, agitation of the resultant slurry was stopped and the solid fraction was


10

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allowed to settle. The supernatant and solid fraction were separated by vacuum filtration (Büchner funnel + 2.5 µm cellulose filter paper), and the solid fraction was dried in an oven at 50 °C and atmospheric pressure to a constant weight (> 24 hours). 2.6. Characterisation of the supernatant and the isolated solid fractions 2.6.1 Quantification of the amount of AAP in the supernatant The concentration of AAP in the supernatant, expressed as g AAP/kg MeOH, was determined as described in Section 2.1. From this, the percentage desupersaturation was calculated using Equation 2: % -. /- / = 100 × 0

1 23*4#" 1 ∗

"#

5

Equation 2

where: csupernatant = concentration of AAP remaining in the supernatant (g AAP/kg MeOH) c

= initial concentration of AAP (g AAP / kg MeOH)

c*

= equilibrium concentration of AAP at Tcry (g AAP / kg MeOH)

Additionally, as required, the actual AAP loading (% w/w) was determined according to Equation 3: 6 % ⁄ = %/ ×

% 89:;?;=>?@AB CDD

Equation 3

2.6.2 Analysis of the solid fractions i. PXRD PXRD diffractograms were recorded on a Phillips PANanalytical X'Pert MPD PRO diffractometer using a Cu radiation source (λ=1.541 nm) at 40 mA and 40 kV. Scans


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were performed in the range 5 – 40° 2θ at a scan rate of 0.005° 2θ/min. ii. SEM The habit of the isolated particles was examined by SEM (JCM-5700 and JSM6510LV (JEOL)).

Samples were gold-coated (SI50B, Edwards) and the surface

appearance of the ‘as received’ α/β-Lac, MeOH-washed α/β-Lac and isolated particles compared.

The mean size of the AAP particles crystallized in the presence of the

suspended α/β-Lac were measured from the micrographs using image analysis (Adobe Measurement Tool) with at least 20 AAP particles measured per sample. iii. In situ SEM-Raman Spectroscopy Micro-Raman measurements were performed on an InVIA Reflex spectrometer (Renishaw) coupled to an optical microscope (DM2500, Leica) and an SEM (JSM6510LV, JEOL), the latter being referred to as the SEM-SCA (SEM-Structure & Chemical Analyser). Instrument calibration was performed using the Si (100) peak (520.5 ± 1 cm−1). Spectra were acquired using the 785 nm laser, variable laser power (0.1 – 10 mW), acquisition times (10 – 500 s) and accumulations (1 – 20) over the spectral range of interest. Spectra collection and processing were performed with the WIRE™ 4.1 software (Renishaw). RESULTS 1.

Influence of temperature on the solubility of AAP and α/β-Lac in MeOH, and determination of the MSZW for the crystallization of AAP from MeOH Figure 2 shows (i) the experimentally determined and literature solubility values for AAP in

MeOH over the range 5 to 35 °C, (ii) the experimentally determined solubility curve for α/β-Lac


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in MeOH over the range 5 to 35 °C, (iii) the corresponding MSZ limit determined at a cooling rate of 1 °C/min over the range 20 to 30 °C, and (iv) selected data points from the induction time measurements for the crystallization of four different AAP-MeOH solutions at Tcry values that spanned the MSZW giving four different supersaturations.

450 400

Solubility (g AAP/kg MeOH)

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


350 300 250 MSZ limit (cooling rate = 1 °C/min) S = 1.56; induction time = 7 min S = 1.39; induction time = 33 min S = 1.25; induction time = 128 min S = 1.12; induction time = 292 min AAP solubility curve (experimental) AAP solubility curve (literature) lactose solubility (experimental)

200 150 100 50 0 -5

0

5

10

15

T (°C)

Figure 2: Experimental and literature solubility values

20 33

25

30

35

40

for AAP in MeOH from 5 to 35 °C,

experimental solubility values for α/β-Lac in MeOH from 5 to 35 °C, and the MSZ limit of AAP in MeOH at a cooling rate of 1 °C/min over the range 20 to 30 °C. Selected saturation data points for AAP in MeOH and their corresponding induction times are also shown: number of vials = 20, volume of each vial = 20 mL. The experimentally determined solubility of AAP compared favorably with that previously reported by Granberg and Rasmuson 33. The ratio for the solubility of AAP in MeOH to that of α/β-Lac at 15 °C was 629. Thus, the solubility of α/β-Lac in MeOH was deemed negligible


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compared with that of AAP in the context of the crystallization experiments performed in this study. The MSZW for saturated solutions of AAP in MeOH within the range 20 – 30 °C was ca. 19°C. At Tsat =25 °C, this corresponded to a maximum attainable supersaturation of 1.56, above which AAP crystallizes spontaneously.

2.

Determination of the induction times for the nucleation of AAP from MeOH solutions in the absence of α/β-Lac at different levels of supersaturation Figure 3 presents the data obtained during the determination of the induction time for the

nucleation of AAP from MeOH solutions in the absence of α/β-Lac at different supersaturations. No crystallization of AAP (via homogeneous nucleation) was observed in any vial up to 2 hours at a supersaturation of 1.25 (corresponding to a Tcry of 15 °C), and the first vial to show signs of crystallization was only observed after 128 minutes. At higher supersaturations, however, homogeneous nucleation occurred much sooner; for example, the first vial to show signs of crystallization at S = 1.39 (Tcry=10 °C) was observed after 33 minutes, and after just 7 minutes at S=1.56 (Tcry=5 °C). The data clearly indicate that higher supersaturations promote shorter induction times.


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100 90 80

% vials crystallized

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


70 60

S = 1.56

50

S = 1.39

40

S = 1.25 S = 1.12

30 20 10 0 0

50

100

150

200

250

300

Induction time (min)

350

400

450

500

Figure 3: Induction times for the nucleation of AAP from MeOH solutions in the absence of excipients at Tsat = 25 °C and S = 1.12 (▲), 1.25 (), 1.39 () and 1.56 (); number of vials = 20.

3.

Influence of contact time on the crystallization of AAP from MeOH solutions in the presence of α/β-Lac From a consideration of the solubility curve and MSZ limit for AAP in MeOH, and in

addition to the induction time measurements for the crystallization of AAP from supersaturated MeOH solutions, it was decided to use S = 1.25 (corresponding to a Tcry=15 °C) to examine the influence of the contact time with the excipient on the crystallization of AAP. These conditions were selected with the aim of reducing the likelihood of homogeneous AAP nucleation (and


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subsequent crystal growth) from the supersaturated MeOH solutions in favor of promoting the selective proliferation of AAP crystal particles via heterogeneous nucleation onto the suspended α/β-Lac particles. A limitation of working at this low supersaturation is that only 17.5 % of the AAP present in solution can be recovered. However, greater process efficiency should be achievable by recycling the mother liquors for use in the next crystallization. Figure 4 presents the desupersaturation profile of supersaturated AAP-MeOH solutions (S=1.25 at Tcry=15 °C) in the presence of α/β-Lac. In these experiments, the quantity of α/β-Lac added to the supersaturated AAP-MeOH solutions was such that the maximum attainable AAP loading was 26 % w/w. The desupersaturation profile indicates that nucleation of AAP occurred within the first 30 minutes of contact with α/β-Lac and that close to full desupersaturation was achieved after 3 hours. For the purposes of comparison, the crystallization was also performed in the absence of excipient (S = 1.25 at Tcry=15°C) but using 1 % w/w of AAP as ‘seed’ instead. Here, the initial nucleation rate was considerably faster, with ca. 60% desupersaturation being achieved after 15 minutes compared with ca. 20% in the presence of the excipient after 30 minutes.


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% desupersaturation

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Mean AAP particle size (µ µm)

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0

0 0

0.5

1

1.5

2

2.5

3

Time (hours)

Figure 4: Desupersaturation of AAP-MeOH supersaturated solutions in the presence of suspended α/β-Lac particles at different contact times from 0 to 3 hours (S = 1.25, Tcry = 15 °C, maximum attainable AAP loading = 26 % w/w): influence of the contact time (hours) on the % desupersaturation (■) and the mean AAP particle size (◊). PXRD diffractograms of the solid fractions isolated at each time interval (Figure 5) displayed diffraction peaks at 14°, 15.8° and 18.2° 2θ indicating the presence of the stable monoclinic polymorph of AAP, Form I. These peaks correspond to the (0 0 1), (2 0 1F) and (2 1 1F) planes of AAP Form I respectively, and the relative increase in their intensities with time shows good general correlation with the observed desupersaturation profile in Figure 4.


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3h

2h

1 h 30 min

1h

30 min 0h (1 1 1)

(1 1 0) (ii) 'as-received' α/β-Lac α/β

(0 0 1) (2 0 1F) (2 1 1F) (i) recrystallized AAP 10

15

Degrees (2θ) θ)

20

Figure 5: Comparison of the PXRD diffractograms of (i) AAP recrystallized from MeOH, (ii) ‘as received’ α/β-Lac, and the isolated solid fractions obtained at various time intervals following the addition of α/β-Lac to a supersaturated AAP-MeOH solution (S = 1.25, Tcry = 15 °C). The isolated solid fractions were analyzed by SEM microscopy and in-situ SEM-Raman (Figure 6, 7, 8 and 10). The habit and particle size of the isolated solid fractions were compared with those obtained for (a) the ‘as received’ α/β-Lac particles, (b) the MeOH-washed α/β-Lac particles, and (c) the recrystallized AAP (Figure 6). SEM micrographs of the ‘as received’ α/βLac revealed crystal agglomerates of 10 – 150 µm in the longest dimension. Analysis of


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individual α/β-Lac particles showed that the agglomerates had numerous smaller crystals attached to their surface which varied in habit from elongated-columnar to plate-like; the particles also contained numerous voids giving rise to the extensive surface roughness typically seen for roller-dried lactose 35. Washing the ‘as received’ α/β-Lac with MeOH did not appear to alter the habit of the particles; however it did result in an increase in the population of smaller α/β-Lac crystals (Figure 6 (a) and (b)). SEM micrographs of the solid fractions isolated after different intervals during the crystallization of AAP from MeOH in the presence of α/β-Lac revealed the presence of particles of a different habit on the surface of the α/β-Lac particles (Figure 7). The micrographs further indicated that (i) these particles were predominantly found on the surface of the α/β-Lac particles rather than existing independently even at longer contact times, and (ii) longer contact times between the α/β-Lac and the AAP-MeOH solutions coincided with the observation of some larger particles on the surface of the α/β-Lac. This latter observation was supported by particle size measurements from the corresponding micrographs (Figure 9). The particles were found to be more defined and more readily discernible on the micrographs of those solid fractions produced following contact times of longer than 30 minutes (Figure 8).


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(a)

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(b)

(c)

20 µm

5 µm

10 µm

Figure 6: (a) and (b): SEM micrographs of isolated α/β-Lac washed in MeOH, and (c) SEM micrograph of recrystallized AAP.

AAP

AAP AAP 10 µm

(a) 30 min

10 µm

(b) 1 h

10 µm

(c) 2 h 30 min

Figure 7: SEM micrographs of α/β-Lac particles after contact times with the AAP-MeOH solution of (a) 30 min, (b) 1 h, and (c) 2h 30 min. S = 1.25, Tcry = 15 °C. Actual AAP loadings: 7.5 % w/w at 30 min, 17.2 % w/w at 1 h, and 23.8% w/w at 2h 30 min. PSD – number of particles measured per SEM micrograph = 20.

20 µm

5 µm

5 µm

Figure 8: SEM micrographs of α/β-Lac particles following contact with a supersaturated AAPMeOH solution for 1.5 h. S = 1.25, Tcry = 15 °C; actual AAP loading = 19.6% w/w.


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2.5 h

Number of particles

14 12 10 8 6 4 2 0 0

10

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30

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50

0

10

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30

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50

0

10

20

30

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50

1h

Number of particles

14 12 10 8 6 4 2 0 14

30 min

Number of particles

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


12 10 8 6 4 2 0

Particle size (µm)

Figure 9: Particle size distribution (based on measurements taken from the corresponding SEM micrographs) of the AAP particles observed on the surface of α/β-Lac after contact times of 30 minutes, 1 hour and 2.5 hours between α/β-Lac and the AAP-MeOH solution at S = 1.25 and Tcry = 15 °C. Analysis via SEM-Raman (Figure 10) confirmed these particles to be crystals of AAP (monoclinic Form I). Figure 10 (a) shows illustrative SEM micrographs of an AAP–α/β-Lac agglomerate isolated after a contact time of 2.5 hours between the supersaturated AAP-MeOH solution and the α/β-Lac, and indicates the region from where the Raman spectra were captured. The Raman spectra and high resolution SEM micrographs of five discrete spots within this region are presented in Figure 10 (b). The spectra collected from all five spots confirm the presence of AAP as indicated by the peaks centered at 798 and 858 cm-1 Raman shift. The relative intensity of the AAP peaks compared with that of the α/β-Lac peak at 878 cm-1 indicates


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that the concentrations of AAP at spots 1, 2 and 5 are higher than at spots 3 and 4. Analysis of the micrographs of these regions shows numerous AAP particles in the range 1 – 5 µm.

(a)

1 2 4 3 5

(b)

Spot 1 Spot 4 α/β-Lac ‘as received’ AAP

Spot 2

Spot 1

Spot 2

Spot 5

Spot 3

Spot 4

Spot 3 Spot 5

Raman shift (cm-1)


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Figure 10: (a) SEM micrographs of an isolated α/β-Lac particle obtained following the crystallization of AAP (contact time = 2.5 hours, Tcry = 15 °C, S = 1.25, actual AAP loading = 23.9 % w/w) indicating the position of spots 1 – 5 on the particle surface; (b) SEM micrographs and the corresponding Raman spectra at spots 1 – 5; scale bar = 2 µm; region from where each spectrum was collected is indicated with a box in the centre of the corresponding micrograph.

4.

Influence of supersaturation on the crystallization of AAP from MeOH solutions in the presence of α/β-Lac Figure 11 shows the % desupersaturation and the mean AAP crystal particle size for the

crystallization of AAP from MeOH in the presence of α/β-Lac at six discrete AAP supersaturations in the range 1.12 – 1.64 and with an API/excipient contact time of 2 hours. This contact time was considered suitable as it gave % desupersaturations of > 80% with good precision during the earlier ‘contact time’ experiments. The different saturation levels were achieved by performing the crystallizations at the appropriate Tcry; for example, Tcry=20 °C gave S = 1.12, Tcry=15 °C gave S=1.25, Tcry= 10 °C gave S = 1.39, and Tcry=5 °C gave S = 1.56. As before, in each case the amount of added α/β-Lac was adjusted accordingly to keep the maximum attainable AAP loading constant at 26% w/w. A direct consequence of this was the need to add ever-increasing amounts of α/β-Lac to those AAP-MeOH solutions with larger supersaturations, making the resultant suspensions increasingly difficult to agitate effectively. The plot shows a % desupersaturation in excess of 65 % after 2 hours for all supersaturations examined. As the supersaturation increased from 1.12 to 1.47, the % desupersaturation increased from 67 % to a maximum of 89 %. Thereafter it decreased to 68 % as S approached 1.64.


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% Desupersaturation

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0

Mean AAP particle size (µ µm)


0 1

1.1

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S

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1.6

1.7

Figure 11: Desupersaturation of AAP-MeOH solutions and AAP mean particle sizes produced during crystallizations in the presence of suspended α/β-Lac particles at a constant maximum attainable AAP loading of 26 % w/w and a contact time of 2 hours: influence of the supersaturation (S) on (a) the % desupersaturation (■), and (b) the mean AAP particle size (◊).


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From the experience gained during the earlier ‘contact time’ experiments, it was possible to recognize AAP particles on the α/β-Lac surfaces via visual inspection of the SEM micrographs for the relevant isolated solid fractions. On this basis, no pronounced difference was found in the range of AAP crystal particle sizes produced across the series of supersaturations, as shown in Figures 12 and 13. Furthermore, AAP particles which had crystallized independently of the α/βLac were only observed at S > 1.39. S = 1.12

(a)

(b)

AAP

S = 1.47

S = 1.55

AAP

AAP

20 µm

5 µm

(c)

10 µm

Figure 12: SEM micrographs of α/β-Lac particles following contact with supersaturated AAPMeOH solutions at (a) S = 1.12, (b) S = 1.47 and (c) S = 1.55 (contact time = 2 hours, maximum attainable AAP loading = 26% w/w).


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Number of particles

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S = 1.55

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S = 1.12

30 20 10 0 0

10

20

30

40

Particle size (µm)

Figure 13: Particle size distribution (based on measurements taken from the corresponding SEM micrographs) of the AAP particles observed on the surface of α/β-Lac after a contact time of 2 hours between α/β-Lac and AAP-MeOH solutions at S = 1.12, 1.47 and 1.55.

5.

Influence of the maximum attainable AAP loading (% w/w) on the crystallization of AAP from MeOH solutions in the presence of α/β-Lac When studying the influence of the maximum attainable AAP loading on the crystallization

of AAP from MeOH in the presence of α/β-Lac, a supersaturation of 1.25 and a contact time of 2 hours were chosen because (i) the supersaturation of 1.25 (for Tcry=15°C) sat approximately midway along the MSZW (Figure 2), and (ii) no homogeneous nucleation of AAP had been observed up to 2 hours at S=1.25 during the earlier induction time measurements. Therefore, a


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series of experiments was carried out (S=1.25, Tcry = 15 °C, contact time = 2 hours) whereby the % desupersaturation was monitored in circumstances where the maximum attainable AAP loading was varied by adjusting the amount of α/β-Lac added to the supersaturated AAP-MeOH solution. As such, increasing the amount of α/β-Lac added to supersaturated MeOH solutions containing fixed amounts of AAP (at S=1.25) meant decreasing the maximum attainable AAP loading of the resultant solid fractions, and vice versa. The amount of α/β-Lac added was varied such that the maximum attainable AAP loading of the solid fractions at full desupersaturation ranged from ca. 8 to 84 % w/w. In this context, the amount of α/β-Lac added to the 20 mL aliquots of supersaturated AAP-MeOH solutions varied from 0.2 g to 12 g (giving maximum attainable AAP loadings of between ca. 84 and 8% w/w respectively), although agitation of the resultant suspensions became increasingly difficult as more α/β-Lac needed to be added. Figure 14 plots the % desupersaturation and the mean AAP crystal size obtained after a contact time of 2 hours as a function of the maximum attainable AAP loading. For all maximum attainable AAP loadings examined, the presence of suspended α/β-Lac particles increased the % desupersaturation after 2 hours of contact time compared to that observed for homogeneous nucleation in the absence of the excipient, with maximum attainable AAP loadings between ca. 23 and 68 % w/w affording % desupersaturations in the range ca. 87 – 95%. Particle sizes of ca. 5 – 15 µm were obtained in a range of AAP loadings from ca. 23 to 68 % w/w. However, larger AAP particle sizes were observed above 68 % w/w.


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α/β-Lac (wt %) α/β 90

80

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0 0

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maximum attainable AAP loading (% w/w) Figure 14: Desupersaturation of AAP-MeOH solutions in the presence of suspended α/β-Lac particles at S = 1.25, Tcry = 15 °C and a contact time = 2 hours: influence of the maximum attainable AAP loading (% w/w) on the % desupersaturation (■), and the mean AAP particle size (◊). Again, SEM micrographs of the resultant solid fractions were visually examined to establish the presence and size of any AAP crystals formed, and also their relative proximity to the α/βLac particles. As illustrated in Figures 15 and 16, this examination indicated that (i) the mean AAP crystal size increased gradually as the maximum attainable AAP loading increased, and (ii) AAP crystals were more likely to exist independently for maximum attainable AAP loadings greater than 51 % w/w.


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30 % w/w

23 % w/w AAP

AAP

20 µm

20 µm

51 % w/w AAP

78 % w/w AAP

50 µm

20 µm

Figure 15: SEM micrographs of the solid fractions obtained following a contact time of 2 hours between suspended α/β-Lac particles and supersaturated AAP-MeOH solutions (S = 1.25, Tcry = 15 °C) designed to produce maximum attainable AAP loadings of 23, 30, 51 and 78 % w/w.


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Number of particles Number of particles

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78 %

10 8 6 4 2 0 0

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10 15 20 25 30 35 40 45 50 55 60

8

51 %

6 4 2 0 0

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10 15 20 25 30 35 40 45 50 55 60

30 %

6 4 2 0 0

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10 15 20 25 30 35 40 45 50 55 60

23 % 2

0 0

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Particle size (µm)

Figure 16: Particle size distributions (based on measurements taken from the corresponding SEM micrographs) of the AAP particles observed on the surface of α/β-Lac after a contact time of 2 hours between suspended α/β-Lac particles and supersaturated AAP-MeOH solutions (S = 1.25, Tcry = 15 °C) designed to produce maximum attainable AAP loadings of 23, 30, 51 and 78 % w/w.


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DISCUSSION In practical terms, this study sought to examine the influence of varying the following three parameters on the crystallization of a model API, namely AAP, from supersaturated MeOH solutions in the presence of a model excipient which was predominately insoluble, namely α/βLac: (i) the API/excipient contact time, (ii) the API supersaturation, and (iii) the maximum attainable API loading (% w/w).

(i) the influence of API/excipient contact time The API/excipient contact time had a pronounced influence on the crystallization of AAP from a supersaturated MeOH solution in the presence of α/β-Lac in terms of the extent of desupersaturation produced (Figure 4). As such, ca. 20% desupersaturation occurred within the first 30 minutes (at S=1.25, Tcry=15 °C) when α/β-Lac was present. Thereafter, the % desupersaturation rose to ca. 80% after 2 hours. In contrast, during the induction time measurements performed under the same conditions of S and Tcry but in the absence of α/β-Lac, crystallization of AAP was not observed for up to 2 hours (Figure 3). Clearly, the presence of the suspended excipient, with its available heterosurfaces, facilitates the more rapid onset of AAP nucleation by reducing the associated free energy barrier. Almost 100% desupersaturation was achieved by 3 hours of API/excipient contact, though the rate of desupersaturation was seen to decrease considerably over time as ever-less supersaturation remained to ‘drive’ the


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crystallization to completion (i.e. to equilibrium saturation). PXRD diffractograms of the isolated solid fractions (Figure 5) confirmed the presence of AAP Form I, while the prominence of the (2 0 1F) peak suggests some element of preferred orientation. From an assessment of the corresponding SEM micrographs for these isolated solids fractions, the very small AAP crystal particles (ca. 2 – 3 µm) initially observed on the surface of the excipient were seen to give way to more well-defined AAP particles of quite a consistent size (ca. 10 µm) at contact times of 1 hour and longer. Additionally, very few ‘independent’ AAP crystal particles were observed on the micrographs, even at longer contact times. These observations suggest a desupersaturation / crystallization process dominated by the heterogeneous nucleation of AAP onto the excipient surfaces in the early stages. Over time, the process evolved to one where growth of the formed nuclei became more prominent and mostly occurred on the surfaces of the AAP particles already attached to the excipient. That these AAP particles did not continue to grow appreciably as the contact time lengthened suggests that an ample stock of AAP nuclei was available to consume the remaining supersaturation in a uniform manner. The effect of the excipient on the desupersaturation and on the maximum attainable API loading (% w/w) will be discussed below in the context of crystallization experiments which were conducted for 2 hours. At this time point, the degree of desupersaturation is > 80 % and the influence of the process parameters on the efficiency of the process to recover the API available to crystallize can be studied. At 2 hours, all of the nucleation and some growth will have occurred (Figures 4 and 9). Thus the API particles should be close to their final size and can be characterized at this time. (ii) the influence of the API supersaturation


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Desupersaturations levels of ca. 66 – 89% were observed across the range of AAP supersaturations examined (1.12 – 1.64) during the crystallization of AAP after 2 hours from supersaturated MeOH solutions in the presence of suspended α/β-Lac particles. The desupersaturation profile (Figure 11) initially rises to a maximum of ca. 89% corresponding at supersaturations in the range 1.4 – 1.5. Beyond this, the observed fall-off in desupersaturations to 67.6% at S=1.64 is likely due to the comparatively larger quantities of α/β-Lac particles (> 0.2 g/mL of MeOH) necessarily added to the supersaturated MeOH solutions at these higher supersaturations in order to maintain the constant maximum attainable AAP loading of 26 % w/w. The resultant poorer mixing of these thicker suspensions likely caused some sedimentation of the α/β-Lac particles, thus reducing their wettability and hindering the desired heterogeneous nucleation/growth of AAP despite the stronger ‘driving force’ provided by the higher supersaturations. Indeed, this driving force appears to have had a limited influence on the range of AAP particle sizes obtained. While acknowledging that this may be due in part to the observed poorer mixing at higher values of S, the range remained quite consistent regardless of the supersaturation used, with small particles (< 15 µm) predominating at all supersaturation levels examined (Figure 13). This suggests that the available surface area of α/β-Lac (as defined by the constant maximum attainable AAP loading of 26% w/w at each supersaturation) was sufficient to facilitate an initial surge of heterogeneous nucleation of AAP which thereafter transitioned to crystal growth in a broadly uniform manner during the remainder of the 2 hours. Similar to the earlier ‘contact time’ experiments, very few ‘independent’ AAP crystal particles were seen on the SEM micrographs of the isolated solid fractions for the series of supersaturations examined. This again supports the view that heterogeneous nucleation predominates.


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(iii) the influence of varying the maximum attainable API loading (% w/w) As shown in Figure 14, it is possible to define three general zones in relation to the variation of % desupersaturation as a function of the prevailing maximum attainable AAP loadings (% w/w) for the crystallization of AAP from supersaturated MeOH solutions (S = 1.25, Tcry = 15 °C) and constant API/excipient contact time (2 hours). Zone 1 sees a rise in the extent of desupersaturation from ca. 60 to 90% as the maximum attainable AAP loadings increases from 8 %w/w to 15% w/w and onwards to 23% w/w. In this context, the lower % desupersaturations seen at lower maximum attainable AAP loadings are likely the consequence of poor mixing within the thick suspensions caused by the larger amounts of α/β-Lac necessarily added to generate these lower maximum attainable AAP loadings. As before, the resultant sedimentation of α/β-Lac particles has likely reduced their ability to better contact the supersaturated AAPMeOH solution, thus adversely impacting the desupersaturation process. An examination of the SEM micrographs (Figure 15) of the isolated solid fractions revealed that the Zone 1 crystallization conditions generated small AAP crystals (typically < 5 µm) that resided predominantly on the excipient surface. As such, despite the issues of poor mixing and sedimentation, it would appear that sufficient nucleation sites existed on those available excipient surfaces to consume much of AAP’s supersaturation via a mechanism where heterogeneous nucleation took precedence over crystal growth. Zone 2, which extends from a maximum attainable AAP loading of ca. 23% to ca. 68% w/w, is characterized by satisfactory mixing of the API-excipient suspensions – an attribute which likely facilitated the observed average desupersaturation of almost 91% after 2 hours. Though AAP crystal particle sizes typically remained small within this zone (6 – 12 µm), a gradual shift towards slightly larger AAP particle sizes as the maximum loading increased was observed


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within Zone 2 (Figure 14). This suggests the emergence of crystal growth as a viable contender to heterogeneous nucleation as the dominant contributor to desupersaturation for AAP at higher maximum attainable AAP loadings. Within Zone 3, where maximum attainable AAP loadings are greater than 68% w/w, the above trend towards larger AAP crystals becomes more pronounced (Figure 15) and the related particle size distributions broaden (Figure 16). To some extent, this may be due to the relative paucity of excipient surfaces at these high maximum attainable AAP loadings, leading to a reduced number of available nucleation sites, thus encouraging more crystal growth. Zone 3 also sees a decline in the extent of desupersaturation with increasing maximum attainable AAP loadings, with desupersaturations dropping to the low/mid-70% range as loadings increase past ca. 80% w/w. Extending the API/excipient contact times beyond 2 hours might reasonably be assumed to raise these levels of desupersaturation up to those obtained in Zone 2. On this point, the coincidence of enhanced crystal growth at desupersaturations that are lower than those in Zone 2 suggests that the rate of crystallization via crystal growth in Zone 3 may be greater than the corresponding rate in Zone 2 where heterogeneous nucleation likely plays a more prominent role. Taken together, and while readily acknowledging the occasional challenges encountered with physical agitation of some crystallization slurries, the above study illustrates that a degree of control may be exercised over the particle size of AAP crystals produced via heterogeneous nucleation onto the surface of suspended particles of α/β-Lac. In particular, the crystallization process showed good robustness over quite a broad intermediate range of maximum attainable AAP loadings in terms of the desupersaturations obtained and AAP crystal particle sizes produced.


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CONCLUSIONS Heterogeneous nucleation of AAP onto α/β-Lac produces small AAP particles (< 15 µm) in a robust manner such that the PSD can be maintained constant over a range of contact times, supersaturations, and AAP loadings. By varying the API supersaturation, the maximum attainable API loading and the API/excipient contact time for supersaturated solutions and suspended excipients particles, it has been shown that there are optimal ranges for supersaturation and maximum attainable API loading capable of producing consistently small API particles at high levels of desupersaturation. This highlights the importance of optimizing process parameters for heterogeneous nucleation in the presence of solid excipient carrier particles.


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AUTHOR INFORMATION Corresponding Author * e-mail: [email protected], tel.: +353 61 213185 Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. ACKNOWLEDGMENT This publication has emanated from research conducted with the financial support of the Synthesis and Solid State Pharmaceutical Centre, funded by Science Foundation Ireland (SFI) under Grant Numbers 12/RC/2275, as well as support from the Bernal Institute and the Department of Chemical Sciences, both at the University of Limerick.

ABBREVIATIONS AAP, Acetaminophen; α/β-Lac, α/β-Lactose; API, Active Pharmaceutical Ingredient; MeOH, Methanol; MSZ, metastable zone; MSZW, metastable zone width; PSD, particle size distribution; PTFE, polytetrafluoroethylene; PXRD, Powder X-Ray Diffraction; S, Supersaturation; SAMs, self-assembled monolayers; SEM, Scanning Electron Microscopy; SEM-SCA, SEM-Structure & Chemical Analyser.


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Influence of Process Parameters on the Heterogeneous Nucleation of

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