Mechanistic insight into the evaporative crystallization of two polymorphs of nitrofurantoin monohydrate

ARTICLE IN PRESS Journal of Crystal Growth 311 (2009) 2580–2589

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Mechanistic insight into the evaporative crystallization of two polymorphs of nitrofurantoin monohydrate F. Tian a, H. Qu b,1, M. Louhi-Kultanen b, J. Rantanen a, a b

Department of Pharmaceutics and Analytical Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Denmark Department of Chemical Technology, Lappeenranta University of Technology, Lappeenranta, Finland

a r t i c l e in f o

a b s t r a c t

Article history: Received 11 December 2008 Received in revised form 2 February 2009 Accepted 4 February 2009 Communicated by Y. Furukawa Available online 10 February 2009

This study was conducted to gain a deeper understanding of the crystallization behavior of both known nitrofurantoin (NF) monohydrates (monohydrates I and II). NF monohydrate crystals were obtained by evaporative crystallization from a series of acetone–water mixtures. The water activity of each solution together with the solubility of NF was used for calculation of the NF supersaturation profiles during evaporative crystallization. The crystallization process for each solution was monitored in situ by optical and Raman microscopy. It was found that the fraction of the metastable monohydrate I in the final product increased with decreasing water fraction, suggesting that the nucleation rate of monohydrate I increases with decreasing water activity. In addition, the morphology of both monohydrate forms was affected by the water fraction in the solvent. The in situ images and Raman spectra taken during the evaporative crystallization from water–acetone mixture (0.67 mole fraction of water) demonstrated that the crystallization of the stable monohydrate II was encountered first, and the nucleation of the metastable monohydrate I happened afterwards at a reduced supersaturation level. This indicates that the crystal packing of the NF monohydrate from acetone–water solutions was affected by both supersaturation and water activity. & 2009 Elsevier B.V. All rights reserved.

PACS: 81.10.Dn 81.10.Aj 87.15.nt Keywords: A1. Crystallization A1. Water activity A1. Supersaturation A1. Nucleation A1. Polymorph A1. Optical microscopy

1. Introduction The equilibrium between anhydrate and monohydrate forms is of great importance within pharmaceuticals [1–7]. Some hydrate systems are complicated in nature. For instance, nedocromil sodium has heptahemihydrate, trihydrate and monohydrate [8] and amoxicillin can exist as monohydrate, dihydrate and trihydrate [9]. Also, there are several hydrates which themselves exhibit polymorphism, for example fluprednisolone monohydrate [10], succinyl sulfathiazole monohydrate [11], nedocromil sodium monohydrate [12] and nitrofurantoin (NF) monohydrate [13]. This aspect of hydrates has rarely been investigated. The present study is therefore focused on the latter area where two polymorphs of NF monohydrate were chosen as model compounds. These two monohydrates have the same chemical composition and same molar ratio of water in the crystalline lattice, differing only in the crystal packing arrangements. The term polymorphism of two Corresponding author. Tel.: +45 35 33 65 85; fax: +45 35 33 60 30.

E-mail address: [email protected] (J. Rantanen). Current address: Institute of Chemical Engineering, Biotechnology and Environmental Technology, University of Southern Denmark, Denmark. 1

0022-0248/$ - see front matter & 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.jcrysgro.2009.02.004

hydrates, rather than pseudopolymorph, was used in this paper, because numerous definitions have been offered for this phenomenon [14–19]. The preparation methods and single crystal identification of NF metastable and stable monohydrates, designated monohydrates I and II, have been reported by Pienaar et al. [13]. Caira et al. consequently characterized the metastable NF monohydrate (monohydrate I) using several commonly employed solid state characterization techniques including XRPD, DSC and Mid-IR [20]. In a recent study, NF monohydrate I was also observed as an impurity during the crystallization of monohydrate II [21]. Furthermore, Otsuka and Matsuda found that monohydrate II converted to monohydrate I via grinding at 50% and 75% RH [22]. However, the crystallization mechanism of this polymorphic hydrate system and the formation of metastable NF monohydrate I have not been reported until now, which are both obvious challenges. For anhydrate/hydrate systems, water activity has been found to be a crucial factor, which not only determines the relative thermodynamic stability of the anhydrate/hydrate phases [23], but also significantly affects the overall crystallization phenomenon of the hydrate [24]. The dependence of the relative stability of anhydrate/hydrate on water activity in the surrounding

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medium has been studied in the literature for several pharmaceutical compounds, including theophylline [25], ampicillin [26] and carbamazepine [24,27]. Because the crystallization of a hydrate requires the incorporation of water molecules into the crystal lattice, the water activity in the solvent is very likely to play an important role in the crystallization kinetics of various hydrate systems. However, the influence of water activity on the overall crystallization phenomenon of polymorphic hydrate systems remains unknown so far. Recently, process analytical tools have been encouraged to be applied in situ to gain an improved understanding of systems and processes so that the risk of failure can be minimized [28,29]. Spectroscopic techniques have demonstrated a high potential in polymorph identification and quantification, and also in process monitoring and control [30–39]. Traditional microscopy provides direct and fast identification of morphology, and when combined with Raman spectroscopy the physical information in terms of the internal structure of crystals can be obtained at the same time. This analysis could also be performed during the processing of pharmaceuticals. Raman microscopy was employed in this study for rapid polymorph identification. In this study, we investigated the crystallization of a polymorphic hydrate system of nitrofurantoin monohydrates I and II. Evaporative crystallization of NF was performed, optical and Raman microscopy was used for monitoring the overall crystallization phenomenon.

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2.2. Solubility measurement The solubility of NF in six acetone–water solutions containing 0.07, 0.14, 0.18, 0.33, 0.56 and 0.71 mole fractions of water were measured gravimetrically, where NF powder (purchased from Unikem A/S, Copenhagen, Denmark) was used as the starting material. The suspensions were kept at a predetermined temperature with sufficient mixing for 24 h to attain solid–liquid equilibrium. After that about 20 ml of clear solution was taken from each solution through a syringe filter of 0.2 mm pore size. Raman spectroscopy was used to identify the form of the filtered solid. The solution samples were evaporated in an oven at 125 1C until the resulting dry solid reached a constant weight. The solubility measurements were carried out in duplicate. The details of the experimental setup have been reported in an earlier publication [40]. 2.3. Crystal structure visualization Crystal structures of nitrofurantoin monohydrates I and II were obtained from Cambridge Structural Database (CSD refcode HAXBUD01 [13] and HAXBUD [13], respectively) and visualized using the software Mercury 1.4.2 (Cambridge Crystallographic Data Centre, UK). 2.4. Light microscopy

2. Materials and methods 2.1. Sample preparation Stable NF monohydrate II was crystallized according to the method reported by Pienaar et al. in 1993, where it was also reported that NF anhydrate can exist as two polymorphs, metastable a-polymorph and stable b-polymorph [13]. NF powder (obtained from Unikem A/S, Copenhagen, Denmark) was identified as b-polymorph and used as purchased. One gram of NF powder (b-polymorph) was dissolved in a 200 cm3 acetone–water solution (volume ratio 1:1) at 55 1C, and then cooled to room temperature. Metastable NF monohydrate I was prepared by a method slightly modified from that published by Pienaar et al. in 1993 [13]. Firstly, polyethylene glycol aqueous solution (1% w/v) was prepared by dissolving polyethylene glycol (500 mg) in distilled water (50 ml) at room temperature. 75 mg NF powder (used as purchased from Unikem A/S, Copenhagen, Denmark) was then dissolved in a mixture of acetone (20 ml) and polyethylene glycol solution (1% w/v, 10 ml) at 55 1C. The solution vessel was then covered and placed undisturbed at room temperature to allow slow evaporation. Solid state characterization of the resulting crystals was carried out, including XRPD, DSC, IR and Raman. The results were in good agreement with the earlier publication [20]. For the crystallization process monitoring study, 0.075 g NF powder (used as purchased from Unikem A/S, Copenhagen, Denmark) was dissolved separately in 30 cm3 of six acetone– water mixtures containing 0.80, 0.67, 0.44, 0.26, 0.21 and 0.11 mole fractions of water at 55 1C. These solutions will be referred to as S1, S2, y, S6 for each mixture, respectively, throughout the rest of the paper. The solution vessels were then tightly sealed and left undisturbed at room temperature. Each clear solution (approximately 3 ml) was then placed on a microscopic slide to allow solvent evaporation, where the crystallization process was then recorded with optical and Raman microscopy.

The morphology of crystals produced during the crystallization process was observed using a Zeiss Axiolab microscope (Carl Zeiss, Inc., Beograd, Austria), and recorded every 20 s by a DeltaPix digital camera (Infinity X with 1.3 Mega Pixels CMOS, Maalov, Denmark). DeltaPix software 1.6 (Maalov, Denmark) was used for data acquisition. 2.5. Raman microscopy A Renishaw Ramascope System 1000 with a NIR diode laser (l=785 nm) was employed in this study. A thin layer of each liquid solution sample (approximately 3 ml) was placed separately on a microscopy slide and viewed under an optical Raman microscope through a 20  objective. The Raman laser beam with a spot area of approximately 12  89 mm was immediately focused on the liquid surface using the same objective after sampling, and spectra were then recorded continuously. A Rencam charge coupled device (CCD) silicon detector was used to acquire Raman shifts. The exposure time for data collection was set to 1 s and 2 accumulations per sample with a laser power of 50 mW. Wire V.2.0 software was used for instrument control and data acquisition. 2.6. Principal component analysis (PCA) PCA modeling was performed with SIMCA-P+ (Version 11.0.0.0). Cross-validation was used to determine the optimum number of principal components (PCs). All the spectral data were processed using multiplicative scattering correction and then used in the final PCA models. In PCA, the dimensionality of the multidimensional data is reduced by transforming the original variables into new axes, which will be laid along the directions of maximum variance of the data, with the constraint that the axes are orthogonal. The orthogonal features are called principal components. Mathematically, the spectral matrix is composed into a set of eigenvectors and scores and is then regressed against constituent

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concentrations. All the parameters in PCA for the new variables are linearly combined. The first principal component in PCA, PC1, always describes the largest variance with normalized coefficients applied to the variables used in the linear combinations, the second principal component, PC2, always has the largest remaining variance etc. A detailed description of PCA has been provided in several books and tutorials [41–43].

A

3. Results and discussion 3.1. Structural differences between NF monohydrates I and II Fig. 1 illustrates the chemical structure of NF anhydrate (top), as well as crystal structures of NF monohydrates I and II characterized by hydrogen bonding (A and B, respectively).

B

C 1615

1345

Intensity (a.u.)

NF monohydrate II

NF monohydrate I

1650

1600

1550

1500

1450

1400

1350

1300

1250

1200

1150

1100

-1 Wavenmuber (cm )

Fig. 1. Chemical structure of NF anhydrate (top); crystal structure and H–bonds in NF monohydrate I (A) and monohydrate II (B); Raman spectra of monohydrates I and II (C).

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NF monohydrate I is formed through hydrogen bond bonding between the N11 of NF molecule and the O atom (water). The H atoms of a water molecule are also hydrogen bonded with the O14 (carbonyl group) from two different NF molecules. These hydrogen bonding connections are indicated by the green dotted lines in Fig. 1. In NF monohydrate II, the monohydrate is also formed by the hydrogen bonding of N11yO–H (water), where one H atom of a water molecule is linked to O15 (second NF monohydrate). Therefore, each water molecule in monohydrate II is hydrogen bonded with two nitrofurantoin molecules. Furthermore, as suggested by Pienaar et al. [13], there also exists a series of other hydrogen bonds in NF monohydrate II. The distances O (water)yO (NO2), O (water)yO5, O (water)yO14 and O (water)y N8 are all in the range 2.961(4)–3.211(4) A˚, indicating weak and possibly bifurcate hydrogen bonds. Intermolecular contact C7–H7yO15 also showed a geometry meeting the criteria for a hydrogen bond. Therefore, NF monohydrate II has a more complex hydrogen bonding scheme than monohydrate I. It can be speculated that this complex hydrogen bonding scheme of monohydrate II might contribute to its higher stability, and thus leads to a more favorable crystallization of monohydrate II than monohydrate I. Furthermore, this structural difference enabled the differentiation between these two polymorphic monohydrates using Raman microscopy (Fig. 1C). The Raman spectrum of pure monohydrate I is reported for the first time. As shown in Fig. 1C, most bands in the spectral range 1650–1100 cm1 are different in either position or pattern between the two monohydrates. One of the most prominent differences was observed at around 1615 cm1. This band is associated with stretching of the CQN linkage between the nitrofurantoin and hydantoin moieties. Also, the band at 1345 cm1 for monohydrate II shifted to 1352 cm1 in monohydrate I. This band is originated from in-phase NO2 stretch, and is affected by different intermolecular distances between the O atoms in the NO2 group and H atoms in the furan and hydantoin moieties of neighboring molecules [44].

3.2. Crystallization of NF monohydrates I and II from acetone–water solutions 3.2.1. Solubility of NF anhydrate and monohydrate II The solubility of NF in various acetone–water mixtures are shown in Fig. 2. The final solid in equilibrium with the solution

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after 24 h was either starting anhydrate (b-polymorph) or monohydrate II. This indicated that the thermodynamically stable form is either b-polymorph or the monohydrate II, depending on the water activity in the solvent and the temperature. As shown in Fig. 2, the open symbols represent the solubility of NF monohydrate II, and the solid symbols represent the solubility of anhydrate NF. The solubility of NF exhibited a maximum value at a particular acetone–water composition, which was temperature dependent.

3.2.2. Effect of water activity on the morphology and polymorph of NF hydrate yielded by evaporative crystallization Solvent selection has been commonly accepted as the first strategy in the polymorphic screening process. The different combination of solvents, however, also provides a range of water activity for the crystallization. In an earlier report, the solvent combination used for preparing pure monohydrate I was water and acetone (volume ratio 1:2) [13]. The water activity in this water–acetone mixture was calculated to be 0.801, using the equations from Eduljee et al. (1958) [45]. To gain a deeper understanding of the water activity effect on the crystallization, five other solvent systems with different water activity values were also selected. These were named S1 to S6 (red triangles in Fig. 3) corresponding to the sequence of decreasing water activity as stated earlier. The morphologies of the crystallized products under each water activity condition are presented in Fig. 4 (right). The crystallization products appeared to be a mixture of two morphologically different crystals under all conditions. Moreover, the relative ratio of these two types of crystals seems to vary with different solvent compositions. The crystals obtained from S1 with the highest water activity were mostly of fan-like needle clusters, where only closer scrutiny revealed a very small number of plate-like crystals. With increasing acetone ratios, S2 exhibited a clear increase in the number of plate-like crystals. Also, the needle clusters appeared to be of a smaller size than those from S1. The morphology of needles from S3 remained similar, though the density of needle clusters seemed to be decreased. However, the morphology of the other crystals began to show clear changes from S3, where plate-like crystals disappeared but some very small crystals with unclear shape appeared. From S4 to S6, the needles were still discernable, but their proportion and size started to reduce with decreasing water activity. In contrast, the

1.50 S1 S2

0.8

1.00

water activity

Solubility (g/100g solvent)

1.0

1.25

0.75 0.50

S3 S4 S5

0.6 S6

0.4

40 °C 30 °C

0.25

20 °C

0.00

0.2

0.0

0.2

0.4

0.6

0.8

Water mole fraction in solvent Fig. 2. Solubility of NF anhydrate (b-polymorph) and NF monohydrate II in different acetone–water mixtures (the open symbols represent the solubility of NF monohydrate II, and the solid symbols represent the solubility of anhydrate NF).

0.0

0.2

0.4

0.6

0.8

1.0

Water mole fraction Fig. 3. Relation between water activity and water mole fraction in acetone+water mixtures (Eduljee et al., 1958) (the solutions selected for the water activity study were labeled S1–S6).

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A

S1

Intensity (a.u.)

NF hydrate II (reference)

50 µm S2 NF hydrate I (reference)

1600

1500

1400

1300

1200

Wavenumber (cm-1)

B

50 µm NF hydrate II (reference)

Intensity (a.u.)

S3

50 µm NF hydrate I (reference) S4

1600

1500

1400

1300

1200

Wavenumber (cm-1)

C 50 µm NF hydrate II (reference)

Intensity (a.u.)

S5

50 µm NF hydrate I (reference) S6

1600

1500

1400

1300

1200

Wavenumber (cm-1)

50 µm Fig. 4. Morphology of NF crystals yielded from each solvent system (S1–S6; right), and the corresponding physical state identified by Raman microscopy (left).

proportion of the other crystals with unclear morphology showed a tendency to increase with decreasing water activity. One possible explanation for the other crystals growing from S3 to

S6 as reduced particle size and unclear morphology could be that acetone evaporated too rapidly in these solutions, since there was a very low percentage of water in these solutions. As a

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consequence of this, these crystals would not have had sufficient time to grow, hence their small size and indiscernible external morphology. Raman microscopy was used here for identifying the chemical and physical composition of these crystallized products. Several areas with crystals having differing morphology were measured for each solvent system. For a better comparison, only the representative spectra from each area are plotted together with the Raman spectra from pure monohydrate I and II powder samples in Fig. 4 (left). In S1 and S2, Raman spectra showed that the needle-like crystals were monohydrate II, and the plate-like crystals were the metastable monohydrate I (Fig. 4A). The morphology of these monohydrate crystals agrees well with the earlier report [20]. All the needle-like crystals from S3 to S6 demonstrated a similar Raman scattering to that of pure monohydrate II, despite there being some difference in Raman intensity. It is certain that the needle-like crystals were all of monohydrate II. The intensity difference is due to the relatively low sample density of the recrystallized monohydrate II from the suspension as compared to its pure powder sample. Although the morphology of the other crystal is indiscernible from S3 to S6, its Raman spectrum showed a high degree of similarity to that of monohydrate I, suggesting that they are monohydrate I (Fig. 4B and C). Therefore, it has been verified that the crystallization products from all six solutions were a mixture of monohydrates I and II.

The driving force of crystallization from a solution is supersaturation, which can be defined as the concentration of the solute in excess solubility of the solute at a certain temperature and solvent. There are four main methods for generating supersaturation in a solution: changing the temperature, when the solubility of the compound varies at different temperatures (in most cases cooling of the solution), evaporation of solvent, changing the solvent composition and chemical reaction. Usually, the supersaturation level and the rate and mode of supersaturation generation strongly influence the nucleation and growth kinetics of the crystals. As a consequence, the properties of the crystals, such as their size, morphology and polymorphic state, are significantly affected by the supersaturation profile during crystallization. The evaporative crystallization of NF from acetone–water mixtures is different from the evaporative crystallization from a pure solvent. The water and acetone fraction in the solvent changed during evaporation, due to the different volatility of water and acetone. As the water fraction in the solvent increased during evaporation, the generation of NF supersaturation is due to the decreasing of the total solvent and the change in the solvent composition. The evaporation process of acetone and water in the mixtures can be described by the following equations: Ntot;iþ1 ¼ Nwater;iþ1 þ Nacetone;iþ1 ¼ Ntot;i  DNi xwater;i ¼

3.2.3. Insight into the evaporative crystallization through the generation of a supersaturation profile A deeper insight into the evaporative crystallization can be gained by following the generation of a supersaturation profile.

Water mole fraction in vapor phase (%)

1.0 3

2

y = 0 .6089x − 0.7989x + 0. 431x + 0. 0069

0.8

0.6

0.4

0.2

0.0 0.0

0.2

0.4

0.6

0.8

1.0

Water mole fraction in liquid phase (%) Fig. 5. Liquid–vapor equilibrium of acetone–water binary mixture computed with the (n) UNIFAC method and (J) equations from Eduljee et al., 1958 (the equation shown in the figure is the fitted equation of data series (n) at water mole fraction below 0.8 (R2=0.9969)).

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Nwater;i N tot;i

(1) (2)

Nwater;iþ1 ¼ Nwater;i  DNwater;i ¼ N water;i  DNi ywater;i

(3)

ywater;i ¼ f ðxwater;i Þ

(4)

where N is the number of moles of solvent, and x and y are the molar fraction of water in liquid and vapor phase, respectively. DN stands for the number of moles of solvent evaporated. i=1, yy, n, i=1 refers to the initial condition of the evaporation, and i=n refers to the condition under which the water mole fraction in liquid phase xwater,n and in vapor phase ywater,n approached 1. The vapor phase composition ywater,i is a function of liquid phase composition xwater,i, as shown in Fig. 5. All evaporative crystallizations were assumed to start from the solution containing 3 ml of solvent and 0.0075 g NF. The initial values of Nwater,i and Nacetone,i at i=1 for different solvent systems are shown in Table 1. By assuming the value of DN to be 1% of Ntot,1, the change in water mole fraction in the solvents during evaporation at room temperature can be obtained from Eqs. (1)–(4). The composition profile of 3 ml acetone–water mixtures, with the composition shown in Table 1, is also plotted for a clear presentation (Fig. 6A). It can be seen from this that the water mole fraction in the solvent increased during the evaporation. The concentration profiles of NF during evaporation of the solvents in different solvent mixtures are shown in Fig. 6B. The solubility curve of NF as a function of water mole fraction in the solvent is also shown in the figure. It can be seen from Fig. 6B

Table 1 The initial composition of the solvent, and the initial concentration of NF for different evaporative crystallization systems. Solvent system

Nwater

Nacetone

Water mole fraction in solvent

NF mole fraction NNF/(NNF+Nwater+Nacetone)

S1 S2 S3 S4 S5 S6

0.08317 0.05544 0.02714 0.01303 0.01015 0.00484

0.02043 0.02724 0.03419 0.03766 0.03837 0.03967

0.80 0.67 0.44 0.26 0.21 0.11

0.000304 0.000381 0.000513 0.000621 0.000649 0.000707

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Starting clear solution

S2 0.6 8 min

0

S3

0.4

S4 S5

0.2

600000

S6 0.0 0.12

0.10

0.0

80.0

570000 60.0

40.0

20.00

5 min Hydrate II

Total mole of solvent

0 0.006 NF mole fraction in solution

100000 2 %]

Hydrate I

S1

PC3 [0.99

0.8

-200000

-400000 PC2 [9.33 %]

S6 S5

0.005

540000

PC1 [89.3 %]

Water mole fraction in the solvent

1.0

-600000

0.004 S4

1 min

0.003 0.002

NF solubility

2 min S3

0.001

S2 S1

4 min

0.000 0.2

0.4 0.6 0.8 Water mole fraction in solvent

1.0

1.2

Fig. 6. (A) Water mole fraction change during evaporation for the 3 ml pure solvents with the initial compositions shown in Table 1; (B) demonstration of the generating path of NF supersaturation for evaporative crystallizations starting from different solution systems (the initial concentration of NF and the initial composition of each solvent system are shown in Table 1).

that the solvent system S1 started from supersaturated solution, for which the dissolution of NF was achieved by heating the solution to a higher temperature during the solution preparation. The solvent system S2 started from a saturated solution. The solvent systems S3–S6 all started from undersaturated solutions. For a crystallization process, a generation profile of the supersaturation is crucial in determining the nucleation and crystal growth kinetics and therefore the properties of the final crystalline product. As an example, the generation of supersaturation in cooling crystallization can be realized by different cooling strategies, which may result in crystals with different properties in terms of polymorphism, crystal shape and crystal size distribution. In both cooling crystallization and conventional evaporative crystallization, the generation of supersaturation is solely due to the change in one of these two parameters, temperature or the amount of solvent. However, the evaporative crystallization of NF from acetone–water solutions is very different from both cooling crystallization and conventional evaporative crystallization. Firstly, the generation of supersaturation is caused by a combination of change in solvent composition and evaporation of solvent. Since acetone evaporates faster than water, the water fraction in the solvent increases as the evaporating process proceeds. This leads to a decreasing NF solubility, and therefore an increasing supersaturation. As an example, for the curve marked as S3 in Fig. 6B, the NF

NF hydrate II (reference) Intensity (a.u.)

0.0

6 min

7 min

8 min

NF hydrate I (reference)

1600

1500

1400

1300

1200

-1

Wavenumber (cm ) Fig. 7. (A) Crystallization kinetics of NF from solvent system S2 (0.67 mole fraction of water in acetone–water mixture) monitored by Raman combined with PCA (arrows indicate the direction of the crystallization trend, and the time points for the last sample in each direction were indicated. The number next to each principal component describes the percentage of total variation accounted by the corresponding principal component); (B) Raman spectra obtained during the crystallization process of NF in solvent system S2 (0.67 mole fraction of water in acetone–water mixture) (the time point at which each spectrum was recorded is indicated).

concentration changes slowly, but the supersaturation of NF, defined as S=c/c* (c refers to the NF concentration and c* refers to the solubility of NF in the corresponding solvent composition),

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Start

4 min

7 min

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2 min

6 min

8 min

Fig. 8. Crystallization process of NF from solvent system S2 (0.67 mole fraction of water in acetone–water mixture) observed under light microscopy (the time point when each picture was taken is indicated). Crystals having plate-like morphology at 6 and 7 min are encircled to clarify their initial appearance.

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increases significantly, and the generation of supersaturation is mainly due to the change of the water mole fraction in solvent. In contrast, the NF concentration changes significantly with solvent evaporation for the curve marked as S6, and the generation of NF supersaturation is primarily caused by the evaporation of the solvent. Furthermore, the increase in the supersaturation S=c/c* in the solvent S6 takes place at a slower rate than that in the solvent S3. In addition, Fig. 6B also shows that both NF concentration and water fraction in the solvent change with evaporation. In other words, the water activity changed during the evaporation. With decreasing water fraction in the solvent from S1 to S6, the crystallization was performed at lower water fraction regions. Each evaporative crystallization system followed a unique supersaturation-water activity profile, which consequently yielded different fractions of NF monohydrates I and II in the final crystal products. This observation suggests that the crystallization kinetics of NF monohydrate I and II are determined by both NF supersaturation and water activity in the solution.

3.2.4. Crystallization kinetics of NF monitored by Raman combined with PCA The overall crystallization phenomenon of NF from solution containing 0.67 mole faction of water monitored by Raman and analyzed by PCA is presented below (Fig. 7A). Interestingly, the crystallization kinetics consistently showed two trends which crossed at one point but had two different directions. To aid the understanding of these kinetic data, microscopy pictures providing direct visual observation are presented in Fig. 8, where the Raman spectra obtained at each corresponding time point during crystallization are also shown (Fig. 7B). As shown in Fig. 8, needle-like monohydrate crystallized immediately following solvent evaporation, which also grew very markedly during the initial 4 min. During this period, almost no plate-like crystals could be observed. At about 6–7 min, several plate-like crystals began to be discernible. This crystallization phenomenon was also reflected in the Raman spectra recorded inline during crystallization (Fig. 7B). From 0 to 4 min, all Raman spectra were similar to that of needle-like monohydrate, but at about 6 min, signal from monohydrate I (Fig. 7B) started appearing in the spectra. The spectrum was thus a mixed scattered signal from both monohydrates I and II from the 6 min on, from when the signal of monohydrate I also continuously increased. These spectral data thus confirm the microscopy observations. The results of the present work have pointed out a direction for the future work of finding the appropriate crystallization parameters to produce the metastable NF monohydrate I. Also, to further elucidate the crystallization mechanism of two polymorphs of NF monohydrate, different crystallization strategies, including cooling crystallization at constant solvent composition with and without seeds, are currently being tried out.

4. Conclusions The current study has investigated a hydrate system consisting of two polymorphic monohydrates. Though this type of hydrate system is not common, such a system could potentially be encountered with any compound. Raman microscopy has demonstrated a potential for monitoring and controlling crystallization processes. This could be envisaged to be applied more widely as a process analytical technology (PAT) tool in the pharmaceutical industry as well as other fields of the chemical industry.

The evaporative crystallization of NF monohydrates from acetone–water solutions performed in this study revealed the crucial effects of both supersaturation level and water activity on the crystallization kinetics of NF monohydrates I and II. With decreasing water fraction, the fraction of the metastable monohydrate I increased in the final product, suggesting an increase in the nucleation rate of monohydrate I with decreasing water activity. The in situ images and Raman spectra taken during the evaporative crystallization from water–acetone mixture (0.67 mole fraction of water) showed that the crystallization of the stable monohydrate II was encountered first, and that the nucleation of the metastable monohydrate I happened afterwards at a reduced supersaturation level. These results indicated that the form of the NF monohydrate crystallized out from acetone– water solutions depends on both supersaturation and water activity in the solution.

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