Ultrasound Assisted Crystallization of Paracetamol: Crystal Size

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Ultrasound assisted Crystallization of Paracetamol: Crystal Size Distribution and Polymorph Control Sukhvir Kaur Bhangu, Muthupandian Ashokkumar, and Judy Lee Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.5b01470 • Publication Date (Web): 09 Mar 2016 Downloaded from http://pubs.acs.org on March 11, 2016

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Crystal Growth & Design

Ultrasound assisted Crystallization of Paracetamol: Crystal Size Distribution and Polymorph Control Sukhvir Kaur Bhangu†, Muthupandian Ashokkumar† and Judy Lee ‡, §,* †

School of Chemistry, University of Melbourne, VIC 3010, Australia

‡

Chemical and Biomolecular Engineering, University of Melbourne, VIC 3010, Australia

§

Chemical and Process Engineering, University of Surrey, Guildford, Surrey GU2 7XH,

United Kingdom *Corresponding Author: [email protected]

Abstract Antisolvent crystallization of paracetamol was conducted using ultrasound. The effect of various ultrasonic frequencies and power on the mean crystal size, crystal size distribution, induction time and type of polymorph obtained was studied. Multibubble sonoluminescence intensity was used to correlate the crystallization results with cavitation activity. Results showed that under optimum conditions, ultrasound can significantly (i) reduce the mean crystal size from 170 µm to 13 µm, (ii) lower the induction time from 360 sec to 30 sec and (iii) narrow the size distribution. A close association between cavitation activity and rate of nucleation was observed. In addition, crystallization under sonication led to the formation of not only monoclinic polymorph (form I) but also orthorhombic polymorph (form II) of paracetamol, which is otherwise difficult to obtain in the absence of ultrasound.

Keywords Antisolvent crystallization, paracetamol, ultrasound, polymorph, crystal size

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1. Introduction Crystallization is a widely used technique in solid-liquid separation processes and is regarded as one of the most important unit operations in process industries since many finished chemical products exist in the form of crystalline solids. Antisolvent crystallization is one of the most beneficial crystallization techniques used by pharmaceutical industries for separation and purification. It is an advantageous method where the substance to be crystallized has very high solubility and is heat sensitive or unstable at high temperatures1-3. The major disadvantages of antisolvent crystallization are improper mixing of the antisolvent with the original solvent and problems associated with the solvent recovery process. The improper mixing of the antisolvent can result in highly localized supersaturation and undesired spontaneous nucleation, leading to a broad distribution of crystal sizes 3, 4. In the pharmaceutical industries, the average size, size distribution and morphology of crystals are important as they can directly affect the drug dissolution rate, solubility and the tableting properties, which can in turn affect the bioavailability of the drug 5-9. In addition, most of the active pharmaceutical ingredients (APIs) exhibit polymorphism, which can further affect filtration, tableting, dissolution and bioavailability of the API10-13. Paracetamol (acetaminophen) is one of the most frequently used antipyretic and analgesic drugs, available both as solid dosage forms (tablets, capsules, suppositories) and liquids (solution, suspensions). Significant attention has been paid to the properties of the solid phases. Three crystal polymorphic structures have been described in literature: a monoclinic (form I) 14-16, an orthorhombic (form II) 14-17 and an unstable phase (form III) 8, 18 which can be stabilized under certain conditions. Form I is stable at ambient temperature and pressure but this is characterized by poor technological and biopharmaceutical properties, which include flowability, compactibility, wettability and dissolution rate. Form I also lacks 2 ACS Paragon Plus Environment

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sliding planes resulting in the need for binding agents during the tableting process whereas form II can undergoes plastic deformation and is suitable for direct compression into tablets without binding agents

11, 19

. Due to differences in solubility of polymorphs, form II may be

more active therapeutically than the other polymorphs of the same drug 11. Therefore, much attention is focused on the production of form II due to its advantages over form I. Form II of paracetamol has been obtained by crystallization from melts 6 but is disadvantageous at large scale. Nichols and Frampton 8 focused on laboratory-scale production of form II from ethanol solutions on the laboratory-scale with the help of seeds obtained from melt crystallization process. It was found that the crystallization under normal conditions can only generate form I and also the solvent mediated transformation of form II to form I can occur very rapidly 8. It is suggested that below 5 ˚C the transformation of form II to I can be retarded. Sudha and Srinivasan 18 have reported the use of swift cooling crystallization of paracetamol at different supersaturations to yield form II as well as form III crystals. Increasingly over the past years sonocrystallization, the use of ultrasound in crystallization processes, has become an important method to better control the crystal nucleation process and to overcome some of the drawbacks associated with conventional seeding20.

Sonocrystallization offers benefits such as nucleation at lower levels of

supersaturation; narrower Metastable Zone Width (MZW); more repeatable and predictable crystallization, narrower particle size distribution, shorter induction time, and improved morphology and polymorph selectivity2, 21-27. It has been shown that ultrasound can influence the primary nucleation and crystal growth of roxithromycin, an organic material crystallized by anti-solvent crystallization

28

. It has also been reported that ultrasound can reduce

agglomeration and change the roxithromycin crystal habit from a hexagonal to rhombus shape 28. Similarly, by examining the sonocrystallization kinetics of L-glutamic acid 29, it was



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found that in addition to a reduction in the metastable zone width and induction time, ultrasound also favours the precipitation of β form by improving the surface nucleation. Ultrasound has previously been used for the crystallization of paracetamol to show the effect of different ultrasound frequencies on the MZW and degradation of paracetamol

30

.

Results show that the MZW decreases with ultrasonic frequency and degradation of paracetamol is significantly greater at higher frequencies 9. Also reported is the melt crystallization of paracetamol using sonication as carrier free approach for enhancing the solubility of poorly soluble drugs. Another very recent report shows that antisolvent sonocrystallization of paracetamol yields monoclinic polymorph (form I) of paracetamol with a smaller crystal size which resulted in a significantly improved compaction behaviour

31

whereas Mori et al.32 reported the formation of orthorhombic (form II) crystals. However, none of these reports provided systematic investigation on the effect of various sonication experimental parameters such as frequency and power on the crystal size, crystal size distribution and different polymorphs of paracetamol, which will be important for a better understanding of the influence of ultrasound on the crystallization process of paracetamol, and will be the focus of this study.


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2. Materials and Methods 2.1. Materials Acetaminophen was purchased from Sigma-Aldrich (≥ 99% purity) and ethanol (100%) was purchased from Chem-Supply. High purity water was obtained from a Millipore system with resistivity of 18.2 MΩ/cm. 2.2. Crystallization and Sonication Anti-solvent crystallization was performed under sonication in a glass cell with the ultrasound transducer fixed at the base of the cell. A Langevin type multi-frequency transducer (22, 44, 98 and 139 kHz) and a 300 kHz piezo-electric ceramic plate transducer, both with a diameter of 4.5 cm and from Honda Electric, were used. The transducers were powered by a T&C Power Conversion, Inc. Amplifier (AG series). The actual power dissipated into the solution was calculated from calorimetry measurements and the different calorimetric powers used were 3, 6 and 10 W. 200 g of antisolvent (water) was placed in the glass cell surrounded by a circulating cooling jacket to maintain a constant temperature inside the cell at 5 ± 0.2 ˚C. The temperature was controlled by manipulating the set-point temperature of a cooling water circulator (F250, JULABO GmbH, Germany). Ultrasound was then turned on as 30 g of 30 wt % paracetamol in ethanol solution, prepared at 65 ˚C, was poured into the glass cell. The solution was sonicated for 180 s. To ensure proper mixing of the solution, an overhead stirrer was operated at 800 rpm. A turbidity probe (Mettler Toledo InPro®8000 Series) was used to measure the turbidity of the solution as a function of time to estimate the induction time. Once the solution has been sonicated for 180 s, paracetamol crystals were vacuum filtered using a 0.45 µm filter and then dried in the oven at 60 - 70 ˚C. For comparison, crystallization experiments without sonication were also performed in the



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same cell and under the same conditions as described above. All experiments were conducted three times in order to ensure consistency of results obtained. The cavitation activity for a given sonication frequency and power was quantified by measuring the total intensity of the sonoluminescence emitted by cavitating bubbles. This was achieved by using a photomultiplier tube (PMT; Hamamatsu end-on; responsive between 300 nm – 650 nm) and by placing the setup in a lightproof enclosure to minimise interference from background light. The signals detected by the PMT are displayed on a Tektronix oscilloscope and the amplitude of the equilibrium sonoluminescence intensities recorded in Volts (V). For all measurements, 200 ml of water was sonicated until the steady state sonoluminescence (SL) intensity is reached. A more detailed procedure is described in a previous report41.

2.3. Characterization The size and morphology of the paracetamol crystals were observed in an inverted Olympus IX71 wide field microscope fitted with a 10 x and 40 x objective lens, and a CCD camera (Cool SNAP FX, Photometrics, Tucson, AZ). The mean size and the size distribution of the crystals were determined by measuring approximately 1000 crystals using the software “analysis LS Research v3.1”. For the characterization of the different polymorphs, rhombohedral crystals are associated with form I and needle-like crystals are associated with form II. Form II is very unstable and it can gradually change to the stable form I during the filtration. If the supersaturated solutions became contaminated, then form I recrystallization will be favoured. It was observed that these contaminants provided sites for the thermodynamically stable form


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I to crystallize

33

and any amount of form I that is formed can act as a nuclei (seed) that can

facilitates further transformation

34

. The conversion of the form II back to form I is more

favourable in solution, resulting in a complete conversion within 6 h, even at 0 °C as suggested by Nichols and Frampton 8, so paracetamol crystals should be harvested as rapidly as possible if the form II polymorph is to be retained. In this study, detection of form II using PXRD and FT-IR was difficult due to the large differences in the mass fractions of the two polymorphs which renders the peak corresponding to form II undetectable7. Therefore, to minimise the transformation of form II to form I, optical microscope images were obtained shortly after the crystallization experiment. To quantify the amount of form II polymorph in each sample, the length to width ratio measurements of the crystals were performed using the same software for at least 200 crystals. The different polymorphs were distinguished by their length to width ratio, i.e. ratios greater than 1 corresponds to the elongated and needle like form II crystals and for form I crystals, which has almost similar length and width, will have a ratio close to or equal to one.

3. Results and discussions 3.1. Antisolvent crystallization of paracetamol without ultrasound In order to identify the advantages of sonication, crystallization of paracetamol was first carried out in the absence of ultrasound. Results obtained showed that crystals were quite large with an average size of approximately 170 µm with a very broad distribution ranging from almost 30 µm to more than 450 µm (Figure 1). All crystals had rhombohedral morphology associated with form I of paracetamol. The induction time was found to be



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around 360 seconds. The induction time is defined as the time required for ‘first nucleation event’ to be detected in a solution kept at a constant level of supersaturation.

3.2. Effect of ultrasonic power and frequency on the mean crystal size and size distribution Figure 2 shows the effect of increasing ultrasonic power at frequencies 22, 44, 98 and 139 kHz on the mean crystal size. The crystals obtained under sonication are much smaller compared to that produced in the absence of ultrasound. For all frequencies there is an apparent decrease in the mean crystal size with increasing ultrasonic power until the crystals have reached a minimum threshold size (≈ 13 µm) and further increase in the power is observed to have negligible effect on the crystal size. As the frequency increases, the minimum crystal size is reached at a much lower power.

The crystal size distribution for the data shown in Figure 2 is plotted in Figure 3. In addition to the apparent reduction in the mean crystal size, the particle size distribution also becomes narrower with increasing ultrasonic power, especially for the lower frequencies (22, 44 and 98 kHz). For the highest frequency studied (139 kHz), the minimum crystal size has already been achieved at 3 W, therefore very little change in the mean crystal size and size distribution is observed within the range of powers investigated. As shown by the error bars (Figure 2), little variation in the mean crystal size was observed at higher frequencies and powers compared to lower frequencies and powers. The narrowing of the size distribution as a function of power and frequency is further supported by determining the Full Width at Half Maximum (FWHM), summarised in Table 1.


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If the data in Figure 3 is replotted in terms of varying frequency at a given power (Figure 4), similar effect is observed, that is increasing frequency at a given sonication power provides a narrower size distribution with the effect being more apparent at an ultrasonic power of 3 W. This reduction in the mean particle size with increasing power and frequency can also be observed from optical microscope images shown in Figures 5 and 6. Ultrasound induced reduction in the crystal size and the narrowing of the crystal size distribution has been reported in the literature

2, 9, 28, 35

. It has been suggested that shock

waves generated by the acoustic cavitation increases the nucleation rate and it is the micro-turbulence that dictates the subsequent growth of these nucleated crystal nuclei 35. The effect of the former is found to be more significant than the latter, with the crystal nucleation rate showing an order of magnitude higher with sonication. It has also been suggested that crystal nucleation in sonocrystallization is heterogeneous with the cavitation bubble surfaces acting as crystal nucleation sites

23, 36-40

leading to an increase in the crystal nucleation rate.

Therefore, the decrease in the crystal size and narrowing of the crystal size distribution under the application of ultrasound could be explained by the number of cavitation bubbles formed in the system. If the surfaces of cavitation bubbles are acting as nucleation sites, then one can postulate that the number of crystals being nucleated or the number of crystal nuclei, is proportional to the population of cavitation bubbles. It has been reported that the number of cavitation bubbles formed is a function of acoustic power

41

. Similarly, with an increase in

frequency, the number of antinodes and hence the number of cavitation bubbles generated also increases 42. Therefore, it is possible that the number of crystal nuclei formed would rise with increasing frequency and power. Since the crystal size and size distribution are



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influenced by the population and growth rate of the crystal nuclei 35, a rise in the number of crystal nuclei would reduce the amount of solute present for the growth of each individual crystal. Consequently, crystals obtained will have smaller sizes. With an increase in the number of cavitation bubbles, physical effects such as shear forces, turbulence and shockwaves would also increase. These physical effects would further induce bulk and local fluid mixing, which can enhance the probability of collisions between molecules as well as local supersaturation as shown by conventional agitation effect

35, 43-45

, both of which will

lead to higher crystal nucleation rates and smaller crystal sizes.

3.3. Relationship between cavitation activity and induction time Cavitation activity is proportional to the population of cavitation bubbles and can be quantified by measuring the multibubble sonoluminescence (MBSL) intensity 41,

46

.

Therefore, in order to relate the nucleation rate with cavitation activity, MBSL measurements and crystallization induction time were carried out at different frequencies and powers. From the results (Figures 7a.) it can be observed that for 22, 98 and 139 kHz the induction time initially decreases with increasing sonication power and then plateaus at about 30 seconds compared to an induction time of 360 seconds in the absence of ultrasound. There seems to be a close association between the decrease in the induction time and the observed rise in the MBSL intensity, and both MBSL and induction time appears to reach a constant value after a certain power. In order to compare between different frequencies, the induction time is plotted as a function of the relative MBSL intensity (Figure 7b.) and the plot appear to show a general decrease in the induction time as a function of increasing relative MBSL intensity until the MBSL plateaus (when the relative SL intensity equals to 1). This suggests that as the cavitation activity plateaus, further increase in the power has very little


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effect on the average size and crystal size distribution, which supports the data shown in Figures 2-4. Since the induction time is considered to be inversely proportional to the rate of crystal nucleation

47

, it can be generally concluded that cavitation is responsible for the

increase in the crystal nucleation rate observed during sonication. For 22 kHz, the induction time appears to plateau at a higher power compared to the MBSL intensity. The MBSL intensity for 22 kHz is much lower compared to the other frequencies and this may therefore be the reason why the association between the induction time and MBSL intensity is weaker. 3.4 Effect of ultrasound on the formation of polymorphs As already discussed, optical microscope images of the paracetamol crystals (Figure 5 and 6) show that with increasing ultrasonic power and frequency, the average crystal size decreases. In previous studies dealing with antisolvent sonocrystallization of paracetamol, some studies reported only the formation of the stable form I 30, 31 whereas another study have shown the formation of form II crystals with sonication

32

. In this study, sonication has

resulted in the formation of different types of paracetamol crystals while in the absence of ultrasound only monoclinic form I was observed. This is shown in Figure 8 where a mixture of different polymorphs of paracetamol is observed, i.e. the stable form I polymorph (monoclinic form), the metastable form II polymorph (orthorhombic form) and traces of unstable form III polymorph. The percentage of form II crystals as a function of calorimetric power for different frequencies is plotted in Figure 9. It shows that with an increase in frequency from 22 to 98 kHz, the percentage of the metastable form II rises, whereas with further increase in frequency the percentage of form II drops. Meanwhile, for all frequencies increasing power resulted in a slight increase in the percentage of form II.



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It has been shown in the literature that the supersaturation can affect the different polymorph formation. Higher supersaturation favours the nucleation of comparatively more energetic metastable orthorhombic form II than monoclinic form I, and lower supersaturation region favours the nucleation of less energetic stable monoclinic form I as per Oswald’s rule of stages

8, 48

.

Nucleation rates are proportional to the supersaturation. Therefore, the

enhancement in the nucleation rates created by the application of ultrasound may explain the formation of form II crystals. In order to confirm whether the change in the percentage of different polymorphs under different sonication parameters is caused by the enhancement in the crystal nucleation rate brought about by ultrasound, induction time studies were performed. Figure 10a shows the variation in induction time and percentage of form II as a function of sonication power at different frequencies (22, 44, 98 and 139 kHz). For all frequencies it can be observed that the percentage of form II and induction time is inversely related to one another, that is the amount of form II seems to be increasing with decreasing induction time and with increasing power for all the frequencies. This association between the amount of form II, induction time and sonication power is better illustrated in (Figure 10b). The formation of form II polymorph is kinetically controlled and since higher supersaturation favours the probability of obtaining kinetically controlled polymorphs 18, it is believed that the enhanced crystal nucleation rate, brought about by ultrasound, also favours the formation of kinetically controlled polymorph. The appearance of a maximum in the yield of form II at 98 kHz suggests that there is an optimum condition required to precipitate form II crystals. As mentioned earlier, shear forces generated from cavitation can enhance crystal nucleation and may contribute to the formation of form II crystals. Shear forces are known to increase as a function of ultrasonic power but decreases with increasing frequency as the cavitation bubbles becomes smaller. On 12 ACS Paragon Plus Environment

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the other hand, the population of cavitation bubbles rises with increasing frequency due to higher number of pressure antinodes available for cavitation activity. Therefore, it is speculated that at 98 kHz there is an optimum condition between the population of cavitation bubbles and an appropriate magnitude of shear to promote the intermolecular interaction between molecules at the clustering phase prior to nucleation, resulting in an increase in the nucleation rate and the growth of the metastable form of paracetamol 29, 36, 49, 50. In addition to the supersaturation, temperature, cooling rate, stirring and seeding can also influence polymorph formation by affecting the differential growth rates of the different faces of the crystal nuclei 107- 1010 K/s

24

13, 51, 52

. It has been suggested that rapid cooling in the orders of

can occur in the fluid surrounding the cavitation bubbles during expansion,

leading to a transient decrease in the solubility of a solute. These transient increase in the degree of supersaturation is what has been speculated to have caused crystal nucleation 23, 53. Cogne et al. 54 theoretically demonstrated this cooling of the liquid by simulating the pressure and temperature fields close to a bubble that is undergoing inertial cavitation. It was shown that strong liquid water undercooling is reached locally after the collapse, which can trigger ice nucleation54. Another proposed explanation behind ultrasound enhanced crystallization is the segregation model which promotes the aggregation of solutes at the bubble interfaces that can lead to localised increase in supersaturation near the bubble surface 55-57.

4. Conclusions The present study demonstrates that sonication during antisolvent crystallization of paracetamol can readily reduce the average crystal size, crystal size distribution, and induction time. These trends were observed with increasing sonication power and frequency. The results obtained were closely associated with the extent of cavitation activity which was 13 ACS Paragon Plus Environment


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determined using multibubble sonoluminescence as a probe. Moreover, in contrast to previous studies where only form I was reported, this study has shown that it is possible to produce form II polymorph by increasing frequency (up to 98 kHz) or the acoustic power. This increase in the formation of form II polymorph was attributed to the decrease in the induction time, brought about by acoustic cavitation activity.

Acknowledgement The financial support through the Australian Research Council for the DECRA (Discovery Early Career Research Award, DE120101567) is gratefully acknowledged.


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References (1) Doki, N.; Kubota, N.; Yokota, M.; Kimura, S.; Sasaki, S., J. Chem. Eng. Jpn. 2002, 35, 10991104. (2) Lee, J.; Ashokkumar, M.; Kentish, S. E., Ultrason. Sonochem.2014, 21, 60-68. (3) Nowee, S. M.; Abbas, A.; Romagnoli, J. A., Chem. Eng. Sci. 2008, 63, 5457-5467. (4) Takiyama, H.; Otsuhata, T.; Matsuoka, M., Chem. Eng. Res. Des.1998, 76, 809-814. (5) Beyer, T.; Day, G. M.; Price, S. L., J. Am. Chem. Soc. 2001, 123, 5086-5094. (6) Di Martino, P.; Guyot-Hermann, A.; Conflant, P.; Drache, M.; Guyot, J., Int. J. Pharm. 1996, 128, 1-8. (7) Méndez del Río, J. R.; Rousseau, R. W., Cryst. Growth Des. 2006, 6, 1407-1414. (8) Nichols, G.; Frampton, C. S., J. Pharm. Sci 1998, 87, 684-693. (9) Kumar, B.; Sharma, V.; Pathak, K., Drug Dev. Ind. Pharm. 2013, 39, 687-695. (10) Mangin, D.; Puel, F.; Veesler, S., Org. Process Res. Dev. 2009, 13, 1241-1253. (11) Varshney, H.; Chatterjee, A., Therap. Appl.2012, 6, 8-13. (12) Mishra, M. K.; Sanphui, P.; Ramamurty, U.; Desiraju, G. R., Cryst. Growth Des.2014, 14, 30543061. (13) Liu, J.; Svärd, M.; Rasmuson, Å. C., Cryst. Growth Des. 2014, 14, 5521-5531. (14) Di Martino, P.; Conflant, P.; Drache, M.; Huvenne, J.-P.; Guyot-Hermann, A.-M., J. Therm. Anal. Calorim.1997, 48, 447-458. (15) Haisa, M.; Kashino, S.; Kawai, R.; Maeda, H., Acta Crystallogr., Sect. B: Struct. Crystallogr. Cryst. Chem 1976, 32, 1283-1285. (16) Szelagiewicz, M.; Marcolli, C.; Cianferani, S.; Hard, A.; Vit, A.; Burkhard, A.; Von Raumer, M.; Hofmeier, U. C.; Zilian, A.; Francotte, E., J. Therm. Anal. Calorim. 1999, 57, 23-43. (17) Haisa, M.; Kashino, S.; Maeda, H., Acta Crystallogr., Sect. B: Struct. Crystallogr. Cryst. Chem. 1974, 30, 2510-2512. (18) Sudha, C.; Srinivasan, K., CrystEngComm 2013, 15, 1914-1921. (19) Joiris, E.; Di Martino, P.; Berneron, C.; Guyot-Hermann, A.-M.; Guyot, J.-C., Pharm. Res. 1998, 15, 1122-1130. (20) De Castro, M. L.; Priego-Capote, F., Ultrason. Sonochem.2007, 14, 717-724. (21) Abbas, A.; Srour, M.; Tang, P.; Chiou, H.; Chan, H.-K.; Romagnoli, J. A., Chem. Eng. Sci.2007, 62, 2445-2453. (22) Bund, R.; Pandit, A., Ultrason. Sonochem.2007, 14, 143-152. (23) Hem, S. L., Ultrasonics 1967, 5, 202-207. (24) Ruecroft, G.; Hipkiss, D.; Ly, T.; Maxted, N.; Cains, P. W., Org. Process Res. Dev.2005, 9, 923932. (25) Nii, S.; Takayanagi, S., Ultrason. Sonochem.2014, 21, 1182-1186. 15 ACS Paragon Plus Environment


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(26) Price, G. J.; Mahon, M. F.; Shannon, J.; Cooper, C., Cryst. Growth Des 2010, 11, 39-44. (27) Wagterveld, R. M.; Miedema, H.; Witkamp, G.-J., Cryst. Growth Des 2012, 12, 4403-4410. (28) Park*, M.-W.; Yeo, S.-D., Sep. Purif. Technol. 2010, 45, 1402-1410. (29) Jiang, S., University of Leeds: 2012. (30) Jordens, J.; Gielen, B.; Braeken, L.; Van Gerven, T., Chem. Eng. Process. 2014, 84, 38-44. (31) Bučar, D. K.; Elliott, J. A.; Eddleston, M. D.; Cockcroft, J. K.; Jones, W., Angew. Chem.2015, 127, 251-255. (32) Mori, Y.; Maruyama, M.; Takahashi, Y.; Ikeda, K.; Fukukita, S.; Yoshikawa, H. Y.; Okada, S.; Adachi, H.; Sugiyama, S.; Takano, K., Appl. Phys. Expr. 2015, 8, 065501. (33) Heng, J. Y.; Williams, D. R., Langmuir 2006, 22, 6905-6909. (34) Kachrimanis, K.; Fucke, K.; Noisternig, M.; Siebenhaar, B.; Griesser, U. J., Pharm. Res. 2008, 25, 1440-1449. (35) Nalajala, V. S.; Moholkar, V. S., Ultrason. Sonochem.2011, 18, 345-355. (36) Lyczko, N.; Espitalier, F.; Louisnard, O.; Schwartzentruber, J., Chem. Eng. J.2002, 86, 233-241. (37) Virone, C.; Kramer, H.; Van Rosmalen, G.; Stoop, A.; Bakker, T., J. Cryst. Growth 2006, 294, 915. (38) Inada, T.; Zhang, X.; Yabe, A.; Kozawa, Y., Int. J. Heat Mass Transfer 2001, 44, 4523-4531. (39) Zhang, X.; Inada, T.; Tezuka, A., Ultrason. Sonochem. 2003, 10, 71-76. (40) Ohsaka, K.; Trinh, E. H., Appl. Phys. Lett. 1998, 73, 129-131. (41) Kanthale, P.; Ashokkumar, M.; Grieser, F., Ultrason. Sonochem 2008, 15, 143-150. (42) Ashokkumar, M.; Lee, J.; Iida, Y.; Yasui, K.; Kozuka, T.; Tuziuti, T.; Towata, A., ChemPhysChem 2010, 11, 1680-1684. (43) Guo, Z.; Zhang, M.; Li, H.; Wang, J.; Kougoulos, E., J. Cryst. Growth 2005, 273, 555-563. (44) Phillips, R.; Rohani, S.; Baldyga, J., AIChE journal 1999, 45, 82-92. (45) Liu, J.; Svärd, M.; Rasmuson, Å. C., Cryst. Growth Des. 2015, 15, 4177-4184. (46) Mason, T. J., Ultrason. Sonochem.2003, 10, 175-179. (47) Mullin, J. W., Crystallization. ed.; Butterworth-Heinemann: 2001. (48) Ghosh, M.; Venkatesan, V.; Mandave, S.; Banerjee, S.; Sikder, N.; Sikder, A. K.; Bhattacharya, B., Cryst. Growth Des.2014, 14, 5053-5063. (49) Sander, J. R.; Zeiger, B. W.; Suslick, K. S., Ultrason. Sonochem.2014, 21, 1908-1915. (50) Gracin, S.; Uusi-Penttilä, M.; Rasmuson, Å. C., Cryst. Growth Des. 2005, 5, 1787-1794. (51) Kitamura, M., CrystEngComm 2009, 11, 949-964. (52) Kitamura, M.; Ishizu, T., J. Cryst. Growth 2000, 209, 138-145. (53) Hunt, J.; Jackson, K., J. Appl. Phys. 1966, 37, 254-257. (54) Cogné, C.; Labouret, S.; Peczalski, R.; Louisnard, O.; Baillon, F.; Espitalier, F., Ultrason. Sonochem.2016, 28, 185-191. (55) Dodds, J.; Espitalier, F.; Louisnard, O.; Grossier, R.; David, R.; Hassoun, M.; Baillon, F.; Gatumel, C.; Lyczko, N., Part. Part. Syst. Char. 2007, 24, 18-28. (56) Grossier, R.; Louisnard, O.; Vargas, Y., Ultrason. Sonochem. 2007, 14, 431-437. (57) Louisnard, O.; Gomez, F. J.; Grossier, R., J. Fluid Mech. 2007, 577, 385-415.


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Table 1: FWHM foe the crystal size distribution obtained at different ultrasonic parameters. 22 kHz

44 kHz

98 kHz

139 kHz

3W

40

32

21

13

6W

25

20

17

10

10 W

17

11

10

9



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Figure Captions Figure 1: Crystal size distribution and optical microscope image of the crystals (insert) obtained in the absence of sonication. Figure 2: Mean crystal size as a function of ultrasonic frequency for three different ultrasonic powers. The error bars reflects the deviation from the mean of at least three independent experiments.

Figure 3: Effect of increasing ultrasonic power on crystal size distribution at different frequencies. Figure4: Effect of increasing frequency on crystal size distribution at 3 W, 6 W and 10 W. Figure 5: Optical microscope images of paracetamol crystals formed by antisolvent crystallization under the application of different ultrasonic frequencies at 3 W. Figure 6: Optical microscope images of paracetamol crystals formed by antisolvent crystallization under the application of 44 kHz ultrasound at 3, 6 and 10 W calorimetric powers. Figure 7: (a) SL intensity and induction time as a function of calorimetric power for 22 kHz (top) 98 kHz (middle) and 139 kHz (bottom). The induction time for no sonication was 360 s. (b) Induction time as a function of relative SL intensity at 22, 44, 98 and 139 kHz. The relative SL intensities are normalised against the SL intensity at the plateau shown in (a). The error bars reflects the deviation from the mean of at least three independent experiments. Figure 8: Optical microscope image of crystals obtained under 98 kHz at 10 W showing the different polymorphs of paracetamol (a) monoclinic, (b) orthorhombic and (c) unstable form III. Figure 9: Percentage of orthorhombic form (form II) as function of frequency at different calorimetric powers. The error bars reflects the deviation from the mean of at least three independent experiments. Figure 10: (a) Induction time and percentage of orthorhombic form (form II) of paracetamol as a function of calorimetric power (W) at different ultrasonic frequencies. (b) Percentage of orthorhombic form (form II) as a function of induction time at different powers. The error bars reflects the deviation from the mean of at least three independent experiments.


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Figure 1



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Figure 2


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Figure 3



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Figure 4


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Figure 5



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Figure 6


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Figure 7a (a)



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Figure 7b (b)


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Figure 8



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Figure 9


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Figure 10(a) (a)



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Figure 10(b)

(b)


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For Table of Contents Use Only Ultrasound assisted Crystallization of Paracetamol: Crystal Size Distribution and Polymorph Control Sukhvir Kaur Bhangu, Muthupandian Ashokkumar and Judy Lee

This study demonstrates that sonication during antisolvent crystallization of paracetamol can readily reduce the average crystal size, crystal size distribution, and induction time. In addition, it is possible to produce form II polymorph of paracetamol by increasing frequency (up to 98 kHz) or the acoustic power. This increase in the formation of form II polymorph was attributed to the decrease in the induction time, brought about by acoustic cavitation activity.


Ultrasound Assisted Crystallization of Paracetamol: Crystal Size

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