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Controlling the product crystal size distribution by strategic application of ultrasonication Kiran A. Ramisetty, and Åke C. Rasmuson Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.7b01619 • Publication Date (Web): 20 Feb 2018 Downloaded from http://pubs.acs.org on February 20, 2018

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Crystal Growth & Design

1

Controlling the product crystal size distribution by strategic application of ultrasonication

2

Kiran A. Ramisetty, Åke C. Rasmuson*

3

Department of Chemical and Environmental Science, Synthesis and Solid State Pharmaceutical

4

Centre (SSPC), Bernal Institute, University of Limerick, Limerick, Ireland.

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*Email: [email protected]

6

ABSTRACT:

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In this work, different strategies of ultrasonication (continuous, single-pulse and multiple-pulse)

8

are compared for control of the product crystal size distribution of three model API compounds:

9

piracetam, paracetamol, and ibuprofen. Experiments have been performed in 0.5L and 3L scale

10

continuously recorded by FTIR and FBRM. Irrespective of the sonication operating mode,

11

sonication in general produced smaller sized crystals with a more narrow size distribution than a

12

normal cooling crystallization process. A multiple pulse sonication mode, in particular, was

13

capable of delivering more narrow size distributions. Sonication power per unit mass of solution

14

does not appear to be a relevant scaling-up parameter.

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Crystal Growth & Design 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

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1. INTRODUCTION

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In the manufacturing of Active Pharmaceutical Ingredients (API), crystallization is

28

of vital importance and is often the critical process technology to ensure the product purity,

29

and to deliver the required crystal size, shape, surface area and bulk density; of importance

30

for downstream processing and end-use. Traditionally, often the solid product from the

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API manufacturing is exposed to a milling step, which adds another unit operation to the

32

manufacturing is energy consuming and may lead to undesirable or even unacceptable

33

alternations of essential product characteristics like changes in crystal structure or

34

dehydration. A desirable alternative would be directly in the crystallization step to produce

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the right size distribution that meets the requirements of the drug formulation. Thus,

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processes that can deliver a narrow size distribution around a particular mean size below

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100 µm is of significant interest.

38

Careful monitoring of the solution concentration using an in situ ATR-FTIR probe

39

is becoming popular and gaining a considerable attention as it allows to precisely control

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crystallization kinetics and thus the final product quality.1,2,3 During the API

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manufacturing process, size and shape engineered crystals are usually obtained either in

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batch or continuous mode via concentration feedback control strategy, anti-solvent

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addition, optimal cooling with or without the addition of seed crystals, etc.4 Under this

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context, feedback control strategy of direct nucleation control (DNC) seems to be a

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promising technique to control final crystal size.5,6 The DNC approach relies on a protocol

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to directly control the apparent onset of nucleation or in situ fines removal by switching

47

between heating and cooling cycles or solvent or anti-solvent addition to the nucleated

48

supersaturation solution until a desired number of FBRM counts is reached. Additionally,

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DNC provides a model-free approach to design and does not require concentration

50

measurement, or information on nucleation or growth kinetics to design an operating

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curve. Despite the advantages of these controlling strategies, they usually produce larger

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crystals with narrow crystal size distribution (CSD) depending on the method applied and

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thus require the additional step of milling (to reduce the crystal size) to meet size

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requirements for pharmaceutical processing in various dosage forms. It is worth to mention

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here, that dry milling is unsuitable for potent compounds for reasons like human exposure, 2 ACS Paragon Plus Environment

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undesirable polymorphic changes, and product loss. Although the wet milling can mitigate

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some of these issues, the high shear force and breakage due to attrition usually produce

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bimodal CSD.

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Technologies such as spray drying, supercritical anti-solvent, sono-crystallization,

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sono-milling can surpass the limitations discussed above and provide an elegant way to

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produce

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sonocrystallization pose some advantages over the other techniques. Recent advances in

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the design of ultrasonic probes that can operate either in-situ or transfer ultrasound

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externally (or indirect sonication) via a metal column or the steel wall of the crystallizer

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which is attached to an ultrasonicator probe, makes this technique versatile and easy to

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scale-up at least at the pilot plant scale level. Current technologies and methods allow the

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design of a sonicated crystallizer that handles large batch volume (required by industries)

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that are comparable to any conventional crystallizers.7 Though indirect sonication is

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expensive, it enjoys the advantage of no metal scavenging, a much-needed design property

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for API crystallization as it avoids the incorporation of impurities in the final product. In

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sonocrystallization, nucleation occurs within the supersaturated solution, induced by

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transient cavitation when an ultrasound of sufficient amplitude is applied.8 The

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mechanisms involved in sonocrystallization have been discussed elsewhere.9,10

smaller

sized

crystals

with

targeted

CSD

directly.

Amongst

these,

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Generally, nucleation can be enhanced by increasing the supersaturation, addition

75

of appropriate anti-solvents or by adjusting the cooling rate. Alternatively, nucleation can

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be created/enhanced by introducing an external field such as ultrasound. Conceptually,

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ultrasonication increases the nucleation rate as it effectively creates cavitation, which

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enhances the creation of a large number of the nucleus via heterogeneous primary

79

nucleation. Earlier studies confirm introducing ultrasound to a conventional crystallizer

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will drastically modify the nucleation and the growth kinetics.11 Sonocrystallization is

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considered a proven technique to produce smaller crystals; however, the strategies required

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to produce uniform-sized crystals are not clear. As discussed above, product size and CSD

83

can be controlled simultaneously by identifying the right control strategy for

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sonocrystallization.



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The purpose of this work is to propose and test different ultrasonication strategies

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to precisely control the product CSD concerning mean size and distribution width. The

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strategies directly rely on ‘when and how’ the ultrasound is applied while operating the

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batch cooling crystallizer. To execute this approach, we systematically modified the mode

89

of ultrasonication and determined the product size distribution, and use various PAT

90

technologies to trace the behaviour of the process.

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piracetam, paracetamol, and ibuprofen were used in this work, and the objectives were to

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produce a narrow size distribution in the lower size range (20 – 50 µm), potentially

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allowing for downstream milling to be circumvented.

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2. MATERIALS AND METHODS

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2.1. Materials. Piracetam (Oxo Industries) recrystallized before use; Isopropanol (99.5%),

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Acetaminophen (98.0-102.0%), Ibuprofen, and Acetonitrile (99.8%), purchased from

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Sigma Aldrich and used as obtained

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2.2 Equipment

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Figure.1 shows the schematic representation of the experimental setup and image analysis

100

procedures used to determine the CSD. The experiments were performed in 2 different

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glass-jacketed reactors from Lenz Laborglas (GmbH & Co.KG) with working volumes of

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0.5L (CR1) and 3L (CR2). To prevent vortexing and mixing dead zones, and to ensure

103

complete mixing, two beavertail (Cowie) baffles with a baffle clearance of 0.5 cm placed

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inside the crystallizers. A 45 degree pitched blade impeller with 4 blades placed

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diametrically at the center of CR1 and CR2, respectively, with a clearance of 16.5mm for

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CR1 and 26mm for CR2 from the bottom of the reactor. Precision controlled overhead

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stirrer (IKA Eurostar 100) used to adjust the impeller speed. All the experiments performed

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at 500 rpm in CR1 and 464 rpm in CR2. The agitation speed was chosen carefully to

109

ensure and maintain the same agitation power per unit mass (ɛ = 0.211W/kg). The

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temperature of the solution mixture measured with the help of a PT 100 thermocouple,

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controlled by LAUDA E300 circulator and Wintherm Software. An ultrasonic processor

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(Qsonica Q500) with a maximum power of 500W and with operating a fixed frequency of


Three model API compounds,

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20 kHz used (VWR International Ltd) to study the effect of ultrasound on the process of

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crystallisation.

115 116

Specifications Volume Dimensions Impeller Diameter Agitation speed Power per unit mass (ε) Number of Baffles Impeller Clearance from bottom of the reactor 117

Crystallizer-1 (CR1) 0.5(L) Diameter = 100 mm, Height = 110 mm 40mm 500rpm ɛ = 0.211W/kg 2 + (3 in-situ Probes)

Crystallizer-2 (CR2) 3(L) Diameter = 150 mm, Height = 230 mm 60mm 464rpm ɛ = 0.211W/kg 2 + (3 in-situ Probes)

16.5mm

26mm

Table 1, Crystallizer specifications Most of the experiments were performed with

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2.3. Experimental Methodology.

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Piracetam; the procedures of these experiments are described in detail here. Some

120

experiments were performed with Acetaminophen and Ibuprofen and the conditions are

121

described in conjunction with presenting the corresponding results in chapter 3.5. A

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solution saturated at 40 oC of Form III Piracetam in isopropanol with a concentration of

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32g/L was prepared and heated to 45 oC, and maintained for 30 min at 500-rpm agitation to

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ensure complete dissolution.12 The solution was then cooled down to 40 oC, maintained for

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30min and then cooled down to 0 oC at specified cooling rates. Three different ultrasonic

126

power levels: 25, 43 and 60 W were used, and the power delivered to the liquid per unit

127

volume (W/kg) was determined by the calorimetric method.

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129 130

Figure 1. Schematic representation of experimental setup and CSD analysis

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This work mainly focuses on the influence of sonication on the final crystal size

132

distribution. The ultrasound is applied in a cooling crystallizer in different modes: (i) CU –

133

continuous ultrasonication, (ii) SPU - single-pulse ultrasonication and (iii) MPU – multi-

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pulse ultrasonication. In CU, ultrasound was applied throughout the crystallization time. In

135

SPU the ultronication is turned on after 2500 s of cooling at 0.5 ℃/min when the solution

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is close to the metastable limit (MSZW as determined in the absence of sonication in CC

137

experiments). The influence of the time of ultrasonication on the crystal size distribution

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was studied for three different US times: 2, 7 and 12 min at a constant sonication power of

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60 W/kg. The influence of the US power on the CSD was studied at a constant US time of

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2 minutes and with three different US power, 60, 103 and 144 W/kg. In MPU, ultrasound

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was applied to the crystallizer at certain and specific time intervals (2min on and 5min off

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per cycle), beginning from ∆Tmax to the end of the crystallization experiment (see section

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3.3 for more details).

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Introducing ultrasound into industrial crystallizers can create undesirable noise in

145

addition to other technical difficulties such as crystal contamination by metal scavenging,

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attrition of the crystals affecting product quality and thermal fluctuations in the suspension

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etc..13,14,15. Ultrasonication transfer energy to the solution leading to a rise in temperature

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that tends to upset the intended cooling profile. This effect was observed in the 6 ACS Paragon Plus Environment

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introductory CU sonocrystallization experiments. The heat generated by sonication in CU

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mode created a temperature upset at least by +5oC from the actual set temperature profile at

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a cooling rate of 1oC/min. In the sonocrystallization experiments performed with 0.1

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o

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of 0.5 oC/min was chosen as it provided a balance between sonication time and solution

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temperature control (the temperature difference between the linear profile and the solution

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temperature is < 0.3 oC). Additionally, in order to bypass the temperature upset created by

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sonication, an equilibration time was provided at the beginning of each sonication

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experiment (not shown), which allows the temperature to reach the set point or the

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saturation temperature. At some stage and only for demonstration purpose, experimental

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results obtained for different cooling rates and US power are briefly discussed. Only for

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demonstration purpose, experimental results obtained for different cooling rates and US

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power are briefly discussed.

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2.4. Analytical Technique. The concentration of Piracetam was monitored online with the

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Attenuated Total Reflectance Fourier Transform Infrared in-situ probe (ATR-FTIR, model

164

iC 10, DiComp probe with AgX halide fibre). The spectra with a resolution of 4 cm-1 were

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collected in the spectral region of 600 - 1890 cm-1 and analysed using iC IR software v.4.3.

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FTIR spectra showed a characteristic peak for Piracetam at 1684 cm-1 and for isopropanol

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950 cm-1 (see Figure 2).16 The dissolved solute concentration was obtained using a relation

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that correlates the ratio of peak area of piracetam to the peak area of the isopropanol. This

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relation was obtained by dissolving 20 g of Piracetam in 500 ml of isopropanol at 0oC. This

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solution was then heated up to 40oC at a very low heating rate of 0.1oC/min. It is assumed

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that, this low heating rate provides the sufficient time for the piracetam to completely reach

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the saturation at the studied temperature range. The ratio of the peak area of piracetam to

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the peak area of isopropanol, PAp/PAipa recorded during this experiment was then plotted

174

against the solubility to obtain a relation that correlates the dissolved concentration as a

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function of PAp/PAipa (see the polynomial expression in Figure.2 (B)). This relation was

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later used in the cooling crystallization experiments in order to determine the concentration

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from the PAp/PAipa (See in Figure.2 (C)). Additionally, IR absorbance (A.U) is sensitive to

178

temperature and in general, they linearly increase with a decrease in temperature. Thus,

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during the cooling crystallization experiments, after converting the PAp/PAipa to

C/min the sonication time became prohibitedly long. Thus, an intermideate cooling rate



180

concentration, a correction was applied to the concentration in order to subtract the

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temperature effect (see in Figure.2 (D)). This was done by subtracting the concentration by

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a value m*T. Where T is the temperature and m is the slope that measures the change in

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concentration with respect to temperature.

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Figure 2. A) ATR- FTIR spectra (600-1900cm-1) for isopropanol and a saturated solution of

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Piracetam in isopropanol. B) The correlation between solubility v’s peak area ratio. C)

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Calculated solubility from peak area ratio. D) Temperature correction on concentration

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profile in typical experiment.

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Focused Beam Reflectance Measurement (FBRM, model S400A) manufactured by

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Metler-Toledo was used to monitor the chord length distribution (CLD) and change in

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count rate with the measurement time of 10 s using the software iCFBRM. The nucleation

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or cloud point was determined with the help of FBRM and ATR-FTIR. The FBRM and

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ATR-FTIR probes were placed at a certain distance (60mm) from the ultrasonic probe. In

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Figure 3, the initial rise in FBRM counts when the ultrasonication starts is due to the

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cavitation bubbles generated. However, this contribution to the number counts is negligible

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compared to the following crystal nucleation contribution. For an accurate measurement of

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the CSD, optical microscopy was (Olympus IX53) used. Crystals suspended in antisolvent 8 ACS Paragon Plus Environment

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or saturated solution in a glass cuvette (Starna Scientific) were dispersed in an ultrasonic

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bath for 3 s and then placed under a microscope. The glass cuvette image was divided into

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regular frames based on the magnification of the microscopic lens to avoid repeated

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measurement of the same crystals. Image analysis software called ImageJ was then used to

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analyze the images to determine the crystal size distribution (CSD). The Ferret diameter

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was used as the characteristic linear dimension of the crystal. The ImageJ macro program

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was used to analyze a number of images by which more than 20,000 crystals from each

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experiment were analyzed. MS-Excel and Minitab software were used to analyze the CSD

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and is in this paper presented as number based percentage distribution.

Point of nucleation Cavity bubbles shown in FBRM counts

207 208

Figure 3. Observed cavity bubble size smaller than crystal size in FBRM count rate.

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To calibrate the FBRM count rate in separate experiments, the solution was seeded

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by a well-defined number of crystals of known size.17 Different size range of seed crystals

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were carefully isolated by sieving using 125, 250, 300, 355 and 500 µm mesh sieve plates

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using dry sieving followed by wet sieving. The volumetric shape factor (0.93) was

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determined by counting and weighing the seed crystals, which was the same for all seed 9 ACS Paragon Plus Environment


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crystals regardless of their size. Using this shape factor (f) and the crystal density (ρc) the

215

number of crystals (N) added per unit volume of solution (V) is known from the equation. =

(

)

216

For example, for 250-300µm sieved crystals of mass 1.5 g and 3 g, respectively, the

217

corresponding number concentration becomes 7.58 × 107 and 1.52 × 108 (#/m3). In Figure

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4, the relation between the actual number concentration and the FBRM count rate at the

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CR1 conditions is shown. A power law model is fitted to the data and the exponent

220

becomes very close to unity. This correlation is used to convert the count rate during the

221

experiments to the actual number of concentrations. This correlation is only applicable to

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CR1 conditions. 1.E+10 Actual Number of Crystals/m3

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y = 567274x0.984 R² = 0.9858

1.E+9

1.E+8

1.E+7 10

100

223

Counts/s

1000

10000

224

Figure 4. Calibration of FBRM counts with an actual number of crystals per unit volume

225

for CR1.

226

The crystal structure of the product has been examined by PXRD. In all experiments only

227

the stable Form III with nice hexagonal block shape crystals is found.

228

3. RESULTS AND DISCUSSION.


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Figure 5 shows the product crystal size distribution and the temperature as a function of the

230

time profile during the cooling crystallization of piracetam at three different modes of

231

ultrasonication. For comparison purposes, we also show the results obtained from

232

conventional crystallization (CC-no ultrasound) experiments. All experiments started at 40

233

o

234

few experiments where the cooling rate is 0.1 or 1 oC/min. For the cases of SPU and MPU,

235

the arrows in Figure 5 show the time at which ultrasound is introduced to the system and

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how the temperature of the solution increases due to the ultrasonication (on-cycle), and

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rapidly decreases during the off-cycle. The rapid cooling is the result of the temperature

238

control system trying to bring the solution temperature back to the linear cooling profile.

239

The crystal size distribution shown in Figure 5 points to a major conclusion that switching

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sonication mode can produce crystals with different size and size distribution. Below the

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manuscript is structured to detail how the crystal size distribution is influenced by the

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mode of the sonication, and how the outcome compares to a normal cooling process, and to

243

explain why certain experimental conditions produce more narrow crystals size

244

distributions, for instance SPU, and MPU can produce smaller crystals with a a more

245

narrow size distribution compared to the CU mode.

246 247

Figure 5. The temperature profiles at various conditions of ultrasound modes, 1. CC, 2.

C and the solution was cooled to 0 oC with a constant cooling rate of 0.5 oC/min, besides a



248

CU, 3. SPU, 4. MPU and their corresponding final CSD. (Arrow marks show the point

249

where the ultrasound applied for SPU and MPU)

250

3.1 Continuous Ultrasonication (CU):

251

Figure 6 shows the concentration vs temperature curve obtained from CU experiments

252

performed with different ultrasonication power at a constant cooling rate of 0.5 oC/min.

253

The results obtained from the conventional cooling crystallization experiments performed

254

at different cooling rates are shown for comparison. Quite clearly, the depletion in

255

concentration begins at an earlier temperature and the concentration rapidly decreases

256

towards the solubility line in the sonicated experiments. Theoretically this difference in

257

saturation temperature and the temperature at which nucleation occurs is defined as the

258

metastable zone width (MSZW). The MSZW obtained from Figure 6 is plotted against

259

product crystal mean size for different operating conditions in Figure 7. Figure 7 shows

260

that, ultrasonication significantly decreases the MSZW. With conventional cooling

261

crystallization performed at a cooling rate of 0.1, 0.5 and 1oC/min, the MSZW was 14.5,

262

19.4 and 23.4 oC, respectively (Table 4). This is as expected, much higher compared to the

263

MSZW of 8.1, 7.2 and 5.1 oC observed in the sonicated experiments performed with a

264

cooling rate of 0.5 oC/min and ultrasound power of 60, 103 and 144 kg/m3, respectively.

265

The decrease in MZW, reflects that nucleation in a supersaturated solution is stimulated by

266

the sonication, and increasingly so with increasing sonication power.18,19 The MSZW can

267

be altered by changing the ultrasonication power; MSZW of the sonicated crystallization

268

performed at 0.5 oC/min is significantly lower than that of a conventional cooling

269

crystallization even when performed at a higher (1 oC/min) or lower cooling rate (0.1

270

o

271

conditions (no ultrasound) with a very low cooling rate still produced a higher MSZW,

272

compared to the CU experiments. Increase in the creation of collapsing cavitational events

273

with increase in power of ultrasound would be the possible reason for an earlier nucleation

274

at increasing power of ultrasonication. Even with the low US frequency of 20kHz it is

275

possible to reduce the energy barrier for the nucleation with a high US power.

C/min). As evidenced from Figure 6, the cooling crystallization performed at silent


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276 277

Figure 6. Concentration vs temperature in the case of CC and CU experiments.

CC

CU

278 279

Figure 7: MSZW and its corresponding mean crystal size at CU and CC

280

experiments: From table 1, exp no 1-6 in CC-mode and exp no 7-15 in CU-mode are

281

included in this graph for comprehensive relation between mean size and MSZW.



282 283

Figure 8. CSD for CC and CU experiments at various conditions and microscopic image of

284

crystals (A: 0.5oC/min for CC, B: 0.5oC/min, for CU 60W/kg, (scale bar is 500µm))

285

Figure 8 shows the influence of the cooling rate in a CC process and of the sonication

286

power in a CU process on the final crystal size distribution. The crystal size and the

287

distribution width (D90-D10/D50) (CSDW) obtained using the microscopic image analysis

288

techniques are given in Table 4. Increasing the cooling rate and sonication power decrease

289

the mean size and the CSDW, but with sonication, the product crystals are much smaller

290

and the distribution is much more narrow. The reported hypothesis is that solvent

291

evaporation at the hotspots created by cavity implosion, produces a massive number of

292

nucleation sites which results in a reducing MSZW and product crystal size20,21. It has

293

been reported that the cavitation bubbles act similarly to seed crystals or gas bubbles22.

294

Since the nucleation time distribution basically controls the product crystal size

295

distribution, an increase in nucleation rate due to ultrasonication leads to smaller product

296

crystals when using ultrasound.23 CU experiments performed at a constant cooling rate

297

show a moderate decrease in crystal size and a fairly significant decrease in CSDW with

298

increasing US power from 60W/kg to 144W/kg: for CSDW from 1.72 to 1.45 at 0.1 14 ACS Paragon Plus Environment

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299

o

C/min, from 1.65 to 1.32 at 0.5 oC/min, and from 1.55 to 1.35 at 1 oC/min. CU

300

experiments performed at constant US power showed a decrease in mean crystal size and

301

CSDW at an increasing cooling rate, but the influence of cooling rate appears to decrease

302

as the sonication power increases. In CC experiments, the mean crystal size decreases from

303

133 to 70 µm as the cooling rate increases from 0.1 to 1oC/min, and the CSDW becomes

304

higher (>2) for the highest cooling rate (1oC/min). Continuous ultrasonication at 144 W/kg

305

and a cooling rate of 1 oC/min) produced the smallest sized crystals (~25 um) and a CSDW

306

of 1.35.

307

The reduced mean size is a consequence of ultrasonication generating a higher

308

number of crystals to share the total product mass as is illustrated in Figure 9. In the CC

309

process, a higher cooling rate leads to an increased number of crystals, and ultrasonication

310

substantially increases the number. The graphs reveal that the number generation includes

311

two different regions: a very fast primary nucleation and a following slower secondary

312

nucleation, in accordance with previous reports.24,25 From straight-line approximations of

313

the slopes, we have estimated the corresponding nucleation rates and they are collected in

314

Table 2. Obviously, the primary nucleation rates are much higher in the CU process as

315

compared to the CC process even though the supersaturation is much lower (Figure 6).

316

Also, the secondary nucleation rates are clearly higher for the CU process. For instance, the

317

CC experiments performed with a cooling rate of 0.5 oC/min exhibited a low nucleation

318

rate, lower by several orders of magnitude when compared to CU experiments. Irrespective

319

of the cooling rate, the number of crystals involved or the nucleation rate in CC

320

experiments is always remarkably lower than the experiments performed with CU.

321

Ultrasound continuously generates a vast number of cavition bubbles that burst and collide

322

within the solution which promotes the formation of crystal nuclei.These nucleation results

323

are more detailed in the Supplementary Information, in relation to Figure S1, clearly

324

showing the effect of supersaturation on the nucleation rate and how it is influenced by the

325

sonication. The nucleation rate increases with increasing sonication power. These

326

observations commensurate with the results shown in Figure 8; the higher the nucleation

327

rate the lower is the crystal size. In spite of a much lower D50 value, the CSDW observed

328

in CU crystallization is lower, i.e., the distribution width relative to the mean size is 15 ACS Paragon Plus Environment


329

narrower. The Table 2 also reveals that the nucleation rates – primary and secondary –

330

increase with increasing sonication power. As shown in Table 4 the metastable zone width

331

becomes narrower, i.e. ultrasonication does induce primary nucleation at lower

332

supersaturation than the normal MSZW limit. 1.E+10 9.E+09 Number of Crystals(#)/m3

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

Page 16 of 37

1 °C/min, CC

8.E+09 0.5 °C/min, CC

7.E+09

0.1 °C/min, CC

6.E+09 5.E+09

60W/kg, 0.5 °C/min, CU

4.E+09

103W/kg, 0.5 °C/min, CU

3.E+09

144W/kg, 0.5 °C/min, CU

2.E+09 1.E+09 0.E+00 0

5000

10000

15000

20000

25000

Time, s

333 334

Figure 9. Comparison of nucleation rates in CC and CU conditions at varying cooling rates

335

and power of ultrasound. The slope of the trend lines showing empirical nucleation rates. Bprim(#/m3/s) 0.1 oc/min 0.5 oc/min 1 oc/min 60W/kg, 0.5oc/min 103W/kg, 0.5oc/min 144W/kg, 0.5oc/min

336

CC CC CC CU CU CU

5.67E+05 1.01E+06 2.36E+06 6.72E+06 8.11E+06 8.66E+06

Bsec (#/m3/s) 1.10E+04 1.70E+05 4.53E+05 3.88E+05 6.37E+05 9.14E+05

Table 2: Nucleation rates in CU and CC experiments calculated from the slopes of

337

the lines presented in Figure 9.

338

3.2 Single Pulse Ultrasonication (SPU):

339

SPU experiments were performed at different power of ultrasound and different

340

sonation time at a constant cooling rate of 0.5 oC/min. The effect of time of ultrasonication 16 ACS Paragon Plus Environment

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341

on the crystal size distribution was studied for three different US times: 2, 7 and 12 min at

342

a constant sonication power of 60 W/Kg. The influence of the US power on the CSD was

343

studied using three different US power, 60, 103 and 144 W/Kg, at a constant US time of 2

344

minutes. Figure 10 shows the crystal size distribution as a function of US time and power

345

in SPU experiments. The higher the US power, the lower the mean size and the CSDW

346

(Table 4). As mentioned earlier, when ultrasound is applied at the maximum

347

supersaturation (MSZW), there is a rapid supersaturation consumption as a consequence of

348

crystal growth of the nuclei formed. Throughtout the rest of the process, the concentration

349

in the solution remains close to the solubility because of the big crystal surface area

350

available. Increase in the power of ultrasound reduced the final mean crystal size and

351

narrowed the crystal size distribution. The width of the distribution is 1.44, 1.24 and 1.19

352

at ultrasonic powers of 60, 103 and 144W/Kg. The influence of the sonication time is not

353

entirely clear, but overall does not appear to be strong. US time of 7 min produced the

354

smallest crystals (the mean sizes produced are 53, 36, and 44 µm for 2, 7 and 12 min of

355

sonication), while the distribution width increases with sonication time ( 1.44, 1.50, and

356

2.12, respectively), as shown Figure 10.

357



358

Figure 10. The comparison of CSD for all SPU experiments at the varying condition

359 360

of US time and power.

9.E+9

Number of crystals(#)/m3

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

Page 18 of 37

8.E+9

B

a)

7.E+9

C

D

B C

6.E+9 5.E+9

B

D C

4.E+9 3.E+9

2min SPU 144W/kg 2min SPU 103W/kg 2min SPU 60W/kg

2.E+9 1.E+9 0.E+0 2000

A

2500

3000

361

3500 Time, s


4000

4500

D

Page 19 of 37 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


362 363

Figure 11a) Effect of ultrasonic power and b) time on the nucleation rate in an SPU

364

experiment at a supersaturation ratio of 2.8. The lines indicating the time of sonication

365

from point A (∆Tmax).

366

Bprim(#/m3/s) 1.93E+07 1.43E+07 1.05E+07 1.04E+07 0.98E+07

144W/kg, 2min 103W/kg, 2min 60W/kg, 2min 60W/kg, 7min 60W/kg, 12min 367 368

Table 3: Empirical nucleation rates calculated from the slopes of the lines presented in Figure 11.

369

Figure 11 shows the influence of US power and time on the crystal number

370

generation with time of crystallization. The crystal number here refers to the number of

371

particles (of size > 1 µm) in the suspension as obtained from the FBRM counts.

372

Irrespective of the operating conditions, a rapid and linearly increasing crystal number is

373

followed by a smaller or more pronounced decrease. The initial rapid rise in the crystal 19 ACS Paragon Plus Environment


374

number characterizes the primary nucleation (point A to B in Figure 11), whereas the latter

375

is attributed to a partial dissolution. Secondary processes like secondary nucleation and

376

crystal aggregation (all these features are shown in Figure.S2) will influence the rest of the

377

curve. From the early straight-line part of the number, increase with time the nucleation

378

rates have been determined and are given in Table 3. Obviously, the nucleation rate clearly

379

increases with increasing sonication power, but the influence of the sonication time in SPU

380

is very low. We also note that the nucleation rates in general are higher than those of the

381

CU process given in Table 2. The likely reason for this is that a higher supersaturation has

382

been built up in the SPU experiments before the nucleation commence.

383

At lower US power of 60 W/kg and 103 W/kg the process ends with an increase in

384

the number of crystals (point C to Point D in Figure 11a), while at 144 W/kg the number

385

decreases during the second half of the process. The lower the US power, the lower the

386

primary nucleation rate is and thus the lower is the number of crystals generated in the

387

system during the early period. A lower number generated early may lead to a higher

388

supersaturation later on depending on the cooling rate, thus leading to a stronger secondary

389

nucleation during the second half of the process. When the US power is higher, an exact

390

opposite trend can be realized. At high US power, the primary nucleation rate is high and

391

the number of crystals generated becomes high. With increasing US power the number of

392

cavitational collapses in the solution increases.26 The solution contains a higher number of

393

crystals and surface area leading to lower supersaturation during the second half of the

394

experiment, and thus lower secondary nucleation rate. This means crystal size is inversely

395

proportional to the US power as shown in Figure .10 and also in Table 1 The decrease in

396

the number of particles can be correlated with the frequently encountered phenomenon in

397

this particular system: crystal aggregation that occurs in the absence of sonication27. A

398

similar behaviour of decrease in the number of crystals is observed in experiments

399

performed by longer US time (Figure. 11b). This explains why both the mean size of the

400

final crystals and the CSDW obtained with low US power are higher than the

401

corresponding values for 144 W/kg.

402

As shown in Figure 11a), the nucleation continues beyond the sonication time (2

403

min) for additional 5 minutes and the primary nucleation basically end at the same time 20 ACS Paragon Plus Environment

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404

regardless of the sonication power. As shown in figure 11b) for the experiments with

405

different sonication time, not only the nucleation rate is about the same but also the time

406

period of nucleation. At 2 minutes sonication, the nucleation continues for another 5 min,

407

at 7 minutes sonication it ends at about the same time as the sonication ends and at 12

408

minutes sonication the nucleation ends 5 minutes before the sonication ends. This suggests

409

a mechanism where the effect of the sonication is primarily to initiate the nucleation

410

process, and the ones this initiation has occurred nucleation continues probably up to the

411

point where the supersaturation has decreased sufficiently for this type of nucleation to

412

terminate.28,29 This resembles the behaviour of an avalanche and is actually a description

413

introduced by Mersmann perhaps 30 years ago30. A reasonably short sonication pulse

414

initiates the nucleation, which then proceed and spread out through the solution without the

415

need for further sonication.

416

3.3 Multiple Pulse Ultrasonication (MPU):

417

In Figure 5, it shows one example of the final crystal size distribution and how the

418

temperature varies with the ultrasonication in an MPU experiment. The first sonication

419

pulse is applied at the normal metastable zone limit of 19 oC at the concentration used (first

420

arrow in Figure 5), and the sonication instantly leads to an increased solution temperature

421

by approximately 5 oC (during the US on-cycle period). During the following US off-cycle

422

period, the solution temperature is forced back towards the predetermined linear cooling

423

profile (see Figure 5). It takes approximately 5 minutes for the solution temperature to

424

reach the set linear cooling profile, and based on this observation, the MPU cycle times

425

were fixed to 7 minutes: 2 minutes for the on - cycle period and 5 minutes for the off-cycle

426

period. Thus, at the end of the US off-cycle period, the next US pulse was introduced, and

427

this was repeated in total five times in a row while cooling the solution from 19 oC to 0 oC

428

at a cooling rate of 0.5 oC/min.



2.5

2 (D90 -D10)/D50

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

Page 22 of 37

1.5

1 CC SPU

0.5

CU MPU

0 0

429 430

20

40

60

80

100

120

140

Crystal Size, µ m

Figure 12. Plot of CDSW vs crystal size for all experiments in Table 4

431

Figure 12 summarizes the characteristics of the product from MPU process experiments in

432

comparison to those of other processing modes and includes experiments in a larger scale.

433

Obviously, the MPU mode is capable of producing small crystals width a narrow size

434

distribution. The crystals obtained from SPU and CU could produce equally small crystals,

435

but the CSDW tends to be higher. This illustrates that by changing the mode of

436

ultrasonication, it is possible to alter the product size distribution to meet specific needs of

437

small crystals with a narrow distribution

438

In Figure 13, the evolution of the process during an MPU experiment is illustrated.

439

Because of the first ultrasonication pulse at the metastable limit, nucleation occurs, and the

440

concentration instantly decreases because of crystal growth. The supersaturation dropped

441

from 31 g/L of solution (S = 2.8; point A) to 20 g/L (S = 1.18; point B) in Figure 13a. In

442

addition, the temperature increases from 20℃ to 25.6 oC, partly due to the release of

443

enthalpy of crystallization (as evidenced from the increase in the number of particles – see

444

Figure 13 b) but primarily because of the ultrasonication as is evidenced from the

445

temperature profile shown in Figure 5. A larger generation of crystals is confirmed by the

446

FBRM counts shown in Figure 13b. During the first US off-cycle period (point B to C) the

447

solution temperature is forced to approach the previously set linear cooling profile (as 22 ACS Paragon Plus Environment

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448

discussed earlier in section 3.1 and 3.2), and there is a slight decrease in the number of

449

particles. The rise in the number of particles and increase in temperature during the US on-

450

cycle period and the drop in the number of particles and decrease in temperature during the

451

US off-cycle period, is repeated for every US pulse, but is most pronounced during the first

452

cycle. During the US on-cycle period, the rise in temperature favours the dissolution of the

453

smaller crystals and any generated secondary nuclei. Deora et.al reported that in

454

dissolution studies, ultrasound leads to faster dissolution of crystals than by thermal

455

treatment because of the heat generation near collapsing cavitational events.26 However, If

456

the supersaturation is sufficiently high, sonication obviously trigger nucleation to occur, in

457

spite of the simultaneous increase in temperature. In MPU mode, nucleation primarily

458

occurs during the first pulse where the supersaturation is very high. This high

459

supersaturation is however rapidly consumed by crystal growth. During the second and

460

third pulse the supersaturation is low and primary nucleation tends to be much weaker or

461

non-existent, while some dissolution of fine crystals will occur due to the temperature

462

increase. This is evidenced from Figure.13b, exposing the increase and decrease in FBRM

463

count during the US on-cycle and off-cycle period, respectively. Despite the fluctuation in

464

FBRM counts, overall (see the linear trendline in Figure 13 b) there is an increase in the

465

number of larger sized particles with respect to time. This effect is more pronounced or at

466

least clearly visible with medium sized crystals (5-10 and 10-20µm) than with the smaller

467

ones (1-3 and 3-5 µm). On the other hand, larger crystals (20-30 and 30-40µm) are the

468

least affected by sonication.31 Instead, their number tends to increase slightly due to the

469

earlier discussed Ostwald ripening effect. This is also supported by the decrease in the

470

CLD (Chord Length Distribution) width (C90-C10) with each US on-cycle period (see the

471

annotation symbol

472

the annotation symbol in figure 13b) due to dissolution of fines and growing of larger

473

crystals at the expense of smaller ones, respectively.

474

According to figure 13a), the solution temperature does not increase enough for it to

475

become undersaturated. We have investigated whether a substantial temperature increase

476

can be recorded locally close to the US probe where the sonication field strength should be

477

the highest. However, we only find about 0.5℃ higher temperature here as compared to the

in figure 13b) followed by an increase during the off-cycle period (see



478

average temperature, and the main reason for this is probably that there is a significant

479

flow of liquid passing by the probe. This confirms the observations stated by Gielena

480

et.al.32 Accordingly, this reduction in the number of very small crystals is either due to

481

normal Oswald ripening perhaps reinforced by a particularly low stability of the fresh

482

crystals nucleated in the sonication field, or due to dissolution because of the very extreme

483

conditions close to the collapsing sonication cavities.

484

40 35

Concentration, g/L

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

Page 24 of 37

A

30 25

B

20 15

C

10

F

E

Solubility(g/L)

D

2min, MPU, 144W/Kg

5 0 0 485

10

20 30 Temperature, oC

486


40

50

Page 25 of 37 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


487 488

489 490

Figure .13a) Desupersaturation of MPU experiment b) Change in FBRM count rate with

491

the time of the experiment c) corresponding CLD at specified moments ( )

492

The above-made arguments were further confirmed by measuring the mean crystal size and

493

the CLD (Chord Length Distribution) of the crystals obtained at the end of each US on25 ACS Paragon Plus Environment


Page 26 of 37

494

cycle periods ( ). The CSDW decreases with each sonication pulse, whereas the mean size

495

of the crystals tends to increase. This behaviour is typical of a system where the growth of

496

the larger crystal occurs at the expense of smaller crystals, and as such show similarities

497

with the ADNC or DNC (Direct Nucleation Control) techniques.33

498

3.4 Effect of volume of reactor

499

For the scaling-up investigation, Single Pulse Ultrasonication (SPU) and Multiple Pulse

500

Ultrasonication (MPU) experiments were carried out also in 3L scale (CR2) using the same

501

cooling rate (0.5 ℃/min). The same sonication probe (20 kHz) was used as in the 0.5 L

502

experiments and thus, US power/mass is much lower (144 W/kg for CR1 and 24W/kg for

503

CR2). For comparison purpose, also conventional cooling crystallizations

504

performed in the larger volume. Figure 14 shows a comparison of the concentration versus

505

temperature in CR1 and CR2 operated in SPU mode and in the CC mode. Obviously, the

506

principal influence of the SPU in the larger scale is quite similar as in the small scale. The

507

ultrasonication leads to an earlier onset of nucleation and an increase in temperature of the

508

solution. However, the increase in temperature in CR2 is less than in CR1 since the

509

sonication power per unit mass is 6 times lower.

510

As shown in Table 4, in the absence of sonication (CC mode), the product size distribution

511

is essentially independent of crystallization volume – the mean size and the CSDW value

512

are essentially unchanged. Using SPU the mean size from CR2 at 24 W/kg operates lower

513

than that from CR1 at higher specific US power (60W/kg), while the CSDW is essentially

514

unchanged. In addition, a trend of decreasing mean size with increasing US time is found

515

in CR2, but there is no tendency of the CSDW to increase. As stated above for the CR1

516

experiments, primary nucleation continue beyond the SPU sonication being turned off. The

517

fact that the size distribution from CR2 is relatively similar to that from CR1 at only 40 %

518

of the specific power input suggests that a significant part of the primary nucleation is not

519

only taking place after that the sonication has been turned off but is also spreading in space

520

from an initial burst directly generated by the sonication (because otherwise, the product

521

size from CR2 should be larger than that from CR1). This further supports an analogy with

522

the behaviour of an avalanche. 26 ACS Paragon Plus Environment

(CC) were

Page 27 of 37

40 35 Concentration, g/L

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


30 25 20 15

Solubility in g/L 0.5 °C/min,2min SPU, CR1 0.5 °C/min,2min SPU, CR2 0.5 °C/min, CC, CR1 0.5 °C/min, CC, CR2

10 5 0 0

10

523

20 30 Temperature, oC

40

50

524

Figure 14. Comparison of desupersaturation in CR1 and CR2 crystallizers for ultrasonic

525

and non-ultrasonic one pulse mode.

526

Unfortunately, the number of actual crystals present in CR2 cannot be calculated using the

527

empirical correlation shown in Figure 4, since this is only valid for the flow conditions in

528

the small crystallizer.

529

Multipulse sonication (MPU) was also applied in the same way as in CR1, i.e. 2 min of

530

sonication followed by 5 min without ultrasound. As was the case in the 0.5 L crystallizer

531

(please see section 3.1 and 3.2), the MPU mode produced a narrower CSD distribution than

532

the SPU mode, and in the CR2 crystallizer the low mean size is maintained but not further

533

reduced from that obtained by SPU, Figure 15. The rise in temperature observed during the

534

2 min of ultrasonication is again less than that in CR1. The solution concentration stayed

535

close to the solubility curve already after two successive pulses of ultrasound. Ultrasound

536

applied after the first two pulses introduced Ostwald ripening effect as observed earlier in

537

CR1 (Figure 13b).



538 539

Figure 15. Comparison of crystal size distribution of SPU and MPU mode of ultrasound in

540

CR2.

541

3.5 Effect of sonication on Paracetamol/water and Ibuprofen/Isopropanol systems.

542

MPU crystallization experiments were performed with two other model compounds;

543

paracetamol and ibuprofen with a solution concentration corresponding to the saturation

544

temperature of 50 and 20 oC, respectively. For paracetamol, 17 g of paracetamol was

545

dissolved in 500mL (CR1) of water at 50 oC (solubility of paracetamol: 34 g/L at 50 oC).34

546

The solution was heated up to 55 oC (and maintained at this temperature for 10 min) to

547

dissolve the crystals completely and then cooled and maintained at the saturation

548

temperature of 50 oC. The solution was then allowed to cool at a constant cooling rate of

549

0.5 oC /min until it reached the final temperature of 5 oC. The first pulse of US was applied

550

precisely at the metastable zone limit at 41.35 oC (equal to ∆Tmax = 8.65 oC determined

551

experimentally in this work in the absence of the US) for 2 minutes and then followed by a

552

5-minute off-time. The experiment then involves nine additional equal US pulses.

553

The experiments with Ibuprofen was performed by dissolving 63 g of Ibuprofen in 500ml

554

(CR1) of acetonitrile at 20 oC.35 The solution was heated up to 25 oC and maintained at

555

this temperature for 10 min. The solution was then allowed to cool at a cooling rate of 0.5

556

o

C/min until it reached 0 oC. Five sonication pulses were introduced, the first pulse of US 28 ACS Paragon Plus Environment

Page 28 of 37

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557

was applied precisely at the metastable limit, i.e. 15 oC (equal to ∆Tmax = 5 oC ) and

558

throughout the experiment the US on-time period was 2 min followed by a US off-time

559

period of 5 min. For comparison, experiments were also performed in the absence of US

560

(CC experiments) for both compounds.

561

Figure 16 shows the microscopic images and the crystal size distribution of the final

562

crystals obtained from MPU experiments, and the results are compared with the CC mode

563

experiments in Table 4. Clearly, the MPU mode produced much smaller crystals and more

564

narrow distributions than the CC mode. For paracetamol the mean size decreases from 158

565

µm (CC) to 45 µm (MPU), and the CSDW from 1.5 (CC) to 1.12 MPU). For ibuprofen the

566

mean size decreased from 83 µm (CC) to 21 µm (MPU), and the CSDW from 1.45 (CC) to

567

1.14 (MPU). As opposed to previous work (Bhangu et al)23, only the stable polymorph of

568

paracetamol was obtained in the present study.

569 570 571 572



a)

b)

573 574

Figure 16.a) Crystal size distribution comparison of Paracetamol and Ibuprofen b)

575

microscopic image of final crystals of paracetamol and Ibuprofen from MPU mode.

576

From the results of the present work, it appears as if the principal influence of sonication

577

on the product crystal size distribution is the same for different systems.A single-pulse

578

(SPU) and a multiple pulse sonication mode (MPU) obviously can produce small crystals

579

with a narrow size distribution and this finding seems to hold true for all the three different

580

systems studied in this work. The detailed sonication scheme needs to be further

581

researched. It also appears to be quite clear that scaling-up to obtain an equal product

582

crystal size do not require equal US power/unit volume.

583

Conclusions

584

In this work it is shown that ultrasonication can be used during batch cooling

585

crystallization to control the product size distribution into low mean sizes and narrow

586

distributions. There appears to be no benefit from the size distribution point of view in

587

continuously exposing the solution to sonication, but short sonication pulses strategically

588

used will be more efficient, reducing energy consumption and increasing sonication probe

589

life time. In single pulse sonication mode, sonication power is an important factor in 30 ACS Paragon Plus Environment

Page 30 of 37

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590

influencing the product properties but sonication time much less so. Multiple pulse

591

sonication appears to more consistently produce small crystals with a narrow particle size

592

distribution, but more work is needed to detail the optimum sonication strategy. The

593

nucleation generated by the sonication appears to follow an avalanche mechanism. The

594

sonication initiates the nucleation, which then progress by itself in time and space. As a

595

consequence scaling-up of a sonicated process will not require the same sonication power

596

per unit volume to reach the same product size distribution.

597

Supporting Information: The supporting information available for free of charge on the

598

ACS publication site at DOI:

599

Empirical Nucleation rate at measured corresponding supersaturation ratio curves for CC

600

and CUexperiments, FBRM count data and corresponding CLD at pinned locations in the

601

process of crystallization at SPU conditions.

602

Funding: This work has been supported by the Science Foundation Ireland (Grants SFI

603

SSPC2 12/RC/2275)

604

REFERENCES

605 606

(1)

Duffy, D.; Barrett, M.; Glennon, B. Novel, Calibration-Free Strategies for Supersaturation

607

Control in Antisolvent Crystallization Processes. Cryst. Growth Des. 2013, 13, 3321–

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3332.

609

(2)

Aamir, E.; Nagy, Z. K.; Rielly, C. D. Optimal Seed Recipe Design for Crystal Size

610

Distribution Control for Batch Cooling Crystallisation Processes. Chem. Eng. Sci. 2010,

611

65, 3602–3614.

612

(3)

Yu, Z. Q.; Chow, P. S.; Tan, R. B. H. Application of Attenuated Total Reflectance-Fourier

613

Transform Infrared (ATR-FTIR) Technique in the Monitoring and Control of Anti-

614

Solvent Crystallization. Ind. Eng. Chem. Res. 2006, 45, 438–444.

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(4)

Bakar, M. R. A.; Nagy, Z. K.; Rielly, C. D. Seeded Batch Cooling Crystallization with Temperature Cycling for the Control of Size Uniformity and Polymorphic Purity of 31 ACS Paragon Plus Environment


Sulfathiazole Crystals. Org. Process Res. Dev. 2009, 13, 1343–1356.

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(5)

Abu Bakar, M. R.; Nagy, Z. K.; Saleemi, A. N.; Rielly, C. D.; Bakar, M. R. A.; Nagy, Z.

619

K.; Saleemi, A. N.; Rielly, C. D.; Abu Bakar, M. R.; Nagy, Z. K.; et al. The Impact of

620

Direct Nucleation Control on Crystal Size Distribution in Pharmaceutical Crystallization

621

Processes. Cryst. Growth Des. 2009, 9, 1378–1384.

622

(6)

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Controlling the product crystal size distribution by strategic application of ultrasonication

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Author List:

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Kiran A. Ramisetty, Åke C. Rasmuson

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TOC graphic, and synopsis. 2.5

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Crystal Size, µ m

Changing the ultrasonication mode can tailor the crystal size and its distribution width.

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Controlling the product crystal size distribution by ... - ACS Publications

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