Modeling, Simulation, and Influence of Operational Parameters on

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Modeling, Simulation and Influence of Operational Parameters on Crystal Size and Morphology in Semi batch Antisolvent Crystallization of #-Lactose Monohydrate Nitin Pawar, shailesh agrawal, and Ravi Methekar Cryst. Growth Des., Just Accepted Manuscript • Publication Date (Web): 14 Jun 2018 Downloaded from http://pubs.acs.org on June 14, 2018

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Crystal Growth & Design

Modeling, Simulation and Influence of Operational Parameters on Crystal Size and Morphology in Semi batch Antisolvent Crystallization of α-Lactose Monohydrate Nitin Pawar, Shailesh Agrawal*, Ravi Methekar 1,2,3

Department of Chemical Engineering, Visvesvaraya National Institute of Technology, Nagpur, Maharashtra, India. Email id: [email protected]*

ABSTRACT: This work summarizes the study of semi-batch antisolvent crystallization of α-lactose monohydrate using ethanol as an antisolvent. The main objective of the work is to study the impact of operational parameters such as anti-solvent flow rate, initial concentration of the solute and the application of ultrasound on the crystal size and morphology. Mathematical modeling of semi-batch antisolvent crystallization was formulated comprising of population balance equation (PBE) and material balance. The growth and nucleation kinetic parameters were estimated by fitting the model estimates to the experimental data. It was found that with an increase in anti-solvent addition rate and initial lactose concentration the crystal morphology changed from polyhedral shape (α-lactose monohydrate) to curved needle/rod shape (β-lactose). The application of ultrasound led to the formation of smaller size crystals; however, no change in the morphology was observed. The work shows that there is a potential to engineer the shape, size and the phase of lactose crystals by changing the operational parameters. Keywords: Lactose, Semi-batch, Mathematical Modeling, Morphology, Ultrasonication

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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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Introduction Lactose is an important commodity compound and finds wide use as an excipient and sweetener in the pharmaceutical and food industry 1. It is produced from deproteinated whey by a series of evaporative and cooling crystallization steps and appears in different morphological forms depending on the crystallization conditions. It generally occurs in αand β- forms, with α- hydrated form being the most stable exhibiting polyhedral crystal habit 2,3

whereas, β- form exhibits needle or rod shaped morphology 4. Due to the wide applications

of lactose, it is necessary to have intimate knowledge of properties of crystals like size, shape and surface which have a direct impact on powder flowability, blending and mixing, compaction, caking, bioavailability, and dissolution rate 5. The control of these crystal properties is critical for successful drug development by the pharmaceutical industry 6. The production of the crystals with desired properties can be achieved during the final purification step in the manufacturing of many organic compounds i.e. crystallization. Crystallization is a technique in which solids are produced in their purest form from solutions. It occurs in two steps: nucleation followed by crystal growth 7. The driving force for crystallization is supersaturation

8

and is achieved by cooling the solution, evaporating

the solvent or by using another solvent known as an antisolvent. For lactose, cooling and evaporative crystallization give limited avenues for particle engineering in terms of size and shape 9. Due to the higher solubility of β-lactose compared to α-lactose at a temperature below 93 °C, β-lactose crystallises only above 93 °C 2.

Anti-solvent crystallization of

lactose; based on the operating conditions has been reported to produce a range of crystal size, morphology and phase (α- and β-) composition

1,5,10

. Also, the time required for the

production of lactose crystals is reduced to minutes in case of antisolvent crystallization from hours for cooling crystallization 11,12.


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One of the disadvantages of antisolvent crystallization is the production of agglomerates. This can be overcome by the use of ultrasonication. The exact mechanism of ultrasonication is still contentious. Several authors proposed different theories but all agree on the effect of power ultrasound on crystallization is due to the cavitation phenomenon. The application of ultrasound creates turbulence inside the solution, along with the formation of vapour cavity due to a decrease in the vapour pressure of the solution. This vapour cavity undergoes sequential cycles of compression and rarefaction. The cavity when implodes, creates zones of very high temperature and pressure

13

. Also, during the expansion of vapour cavity

evaporation of solvent occurs which results in the generation of localized high supersaturation 14. Other theory proposed that during expansion stage, cooling at the surface of cavity occurs, thereby generating supersaturation

15

.

Nalajala and Moholkar (2011)

reported pressure shock wave produced during cavity implosion separates solute from the solvent. This leads to the formation of solute clusters, resulting in rapid nucleation

16

.

Another theory similar with the pressure shock wave states that during bubble explosion solute aggregates near the bubble wall due to high pressure present inside the bubble, inducing nucleation

17

. Schembecker et al. (2009) suggested that cavity bubble acts as sites

for heterogeneous nucleation

18

. Studies have also shown that the application of ultrasound

has other positive impact on crystallization like faster nucleation, high growth rates, and narrow size distribution of the crystals 19,20. Some studies on sono-crystallization reported the reduction in size due to attrition and breakage of crystals due to high pressure shock waves created by cavity collapse 21,22.

The literature reported crystallization of lactose includes continuous crystallization

23,24

,

antisolvent crystallization using acetone 25,26, ethanol 5, isopropanol 1 and ultrasound assisted crystallization

27,28

All the previous work on antisolvent crystallization of lactose


10,29,30

,


barring Kougoulos et al. (2010) were conducted in batch mode. The semi-batch mode offers better control and operational flexibility than the batch systems 31. This work investigates the anti-solvent crystallization of lactose in a semi-batch mode at a high range of lactose concentrations and anti-solvent feed rate than that by Kougoulos et al. (2010). The operating parameters varied were the starting lactose concentration, antisolvent feed rate and application of ultrasound. Their impact on the crystal shape, size and solid phase was measured. The values of crystallization kinetic parameters are essential for designing of crystallization system and are not reported in the previous studies on lactose anti-solvent crystallization. A mathematical model was developed and the growth and nucleation kinetic parameters determined by fitting the predicted values to the measured values of particle size and dissolved lactose concentration.

Experimental Procedure and Analytical Methods The experimental set-up is illustrated in Figure 1. It consists of a single jacketed crystallizer of around 450 ml capacity of 8.5 cm diameter and 9 cm height with 3 symmetrically placed baffles (Alka Scientific Instruments Pvt. Ltd., Nagpur). The thermostatic water circulator (Polyscience Ltd Mumbai, model no MX07R-20-A12E) with operating range of -20 °C to 150 °C was used for water circulation through the crystallizer jacket to maintain the required temperature. A magnetic stirrer was provided for uniform mixing. Refractometer (0 to 85 % o

Brix) (Hanna Equipments Pvt Ltd Mumbai, Model no HI96801) was used for determination

of dissolved lactose concentration in the solution. Ultrasonic bath (Life care Pvt Ltd Mumbai, Model No LC/QTN/0276) of 6.5 L capacity (500 W) capable of generating ultrasound frequencies at 20 and 40 kHz was used to study the effect of sonication. Since magnetic stirring was not possible while using the sonication bath, an overhead stirrer (Remi


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Elektrotechnik Ltd. Vasai, Model no RQT-124-A) was used for homogenous mixing of the solution during the sonication trials (Figure 1b).

(a)

(b)

Figure 1. The schematic of experimental set-up (a) Conventional (b) Sono-crystallization

Dissolved lactose measurement. Refractometer (Refractive index) is a popular technique for concentration measurement of sugars. The ‘ oBrix ’ unit represents the strength of the solution in terms of mass of sucrose per 100 gram of the solution. To use it for lactose concentration measurement, a relationship with known lactose concentration vs. oBrix was determined. The trials in this study involve the use of ethanol as an anti-solvent. Since ethanol’s refractive index is higher (1.361) than water (1.333), a sugar solution in presence of alcohol will give a higher reading than the actual solids. Thus, another relationship between oBrix readings at different ethanol concentrations (% v/v) was also determined.



The actual concentration of lactose in presence of ethanol can be measured by subtracting the contribution of ethanol from the total oBrix reading. This was confirmed by analysing the samples taken at different time intervals (containing ethanol, water, crystallized lactose and dissolved lactose) during the trials. The crystals were removed by filtering them through 0.45 µm syringe filter. The filtrate was then analyzed for dissolved lactose concentration by gravimetric method (drying in an oven at 110 oC for 6 hrs) and also by a refractometer (oBrix). The actual lactose concentration from

o

Brix measurement was obtained by

subtracting the contribution of ethanol and then adjusting the oBrix reading for lactose using the standard curve obtained previously. The % v/v concentration of ethanol was calculated by the flow rate of ethanol addition. The lactose measured by refractometer matched very well with that measured by gravimetric analysis. From here, all the dissolved lactose concentration was determined using the refractometer. All the standard curves pertaining to dissolved lactose concentration measurements are provided in the supplementary information file. Experimental Procedure. 100 gm of lactose solution of desired concentration was prepared in a jacketed crystallizer by adding the appropriate amount of lactose and water with constant stirring. Hot water (at a temperature higher than the corresponding saturation temperature) was then circulated through the jacket of the crystallizer. Once a clear solution was obtained, the content of the crystallizer was kept at that temperature for 15 minutes to ensure the complete dissolution 32. The lactose solution in crystallizer was then cooled and maintained at a constant temperature of 40 oC by thermostatic water chiller. To study the effect of sonication, the crystallizer was placed in an ultrasonic bath capable of generating ultrasonication at two frequencies (20 and 40 kHz). Samples were collected at the fixed time interval for determination of total dissolved lactose concentration in the solution using a refractometer after filtering through the 0.45 µm syringe filter. 10 µl of the slurry was taken in a micropipette then loaded into the chamber of 6 ACS Paragon Plus Environment

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Neubauer hemocytometer (Model no T11MFS0001) and covered with a glass cover slip. The hemocytometer was then placed under optical microscope and images were taken at 10X magnification by using a digital camera (5 Megapixel) attached to the microscope at the top. 20-25 images of each sample were taken and approximately 1000 crystals 33,34 (30-40 crystals per image) were counted per sample. The crystal sizes were measured by image analysis using the Fiji-ImageJ software. For the image analysis, first, the scale of the image was converted into µm from the pixel. Then the background and the noises from the image were removed followed by thresholding. The watershed feature was used to separate the agglomerated particles in the image. The volume weighted mean diameter D[4,3] was calculated from the number distribution obtained by image analysis by the following formula ∑

4,3 = ∑

(1)

where i is the size bin, Ni is the number of particles in the size bin and Di is the average size of particles in the size bin i.

SEM analysis. Morphological analysis of lactose samples was performed using Scanning Electron Microscopy (SEM) (JEOL, JSM-6380A) at different magnifications. Carbon tape was used to stick the powder lactose sample onto SEM holder stub and after sputter coating of gold, scanning electron microscope analysis was carried out at 5 kV voltage. PXRD analysis. The powder lactose samples were analyzed by using X-ray diffraction technique (PANalytical – X ‘Pert’ Pro) under Cu Kα radiation (λ =1.54060 Å) operated at 45 kV and 40 mA with θ/θ geometry. The XRD patterns were recorded between 0° and 35° at a continuous scan rate of 10.336 sec-1 with a step size of 0.0170 at standard laboratory conditions.



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Modeling of Antisolvent Crystallization The mathematical model for the anti-solvent crystallization was developed from previous studies 35,36. The model consists of crystal population balance and lactose mass balance. The mutarotation is the phenomenon of the inter-conversion of α- and β- lactose that occurs when lactose is dissolved in water. At equilibrium, the lactose solution contains around 60% βlactose 4. The general population balance model considering nucleation and size independent growth with an assumption of negligible breakage and agglomeration is given by equation (2) 35

.

,

−B+

,

+

=0

(2)

Here, n(L) is the crystal number density, G is the size-independent crystal growth, L is the characteristic length, ms is the total mass of the solution, and B is the nucleation rate. The term dn(L)/dt describes the change in crystal number density with respect to time, whereas the term G(∂n(L)/∂L) describes the change in crystal number density due to the growth in crystal size between L and dL. The expression (n(L)/ms)(dms/dt) takes into account the changes in total solution mass with respect to time as it increases in antisolvent crystallization due to the continuous addition of antisolvent. The above population balance equation (PBE) (equation 2) was solved by the method of moments (MOMs). The MOM convert the PBE into series of ODEs that can be solved together with the mass balance equations with each moment giving a particular information regarding the crystal population; the zeroth (number), the first (length), the second (area) and the third moment (volume). The ith moment is represented as 37 #

= $

! "

(3)

From equation 3, the zero moment derivative is given as 8 ACS Paragon Plus Environment

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%

=B−

%

(4)

&

The first moment derivative '

= G$ −

'

(5)

&

The second moment derivative )

= 2G+ −

)

(6)

&

The third moment derivative

= 3G, −

(7)

&

The fourth moment derivative

= 4G- −

(8)

&

For a semi-batch process as τ = ∞, the second term on the right-hand side in the moment equations becomes zero. The change in solute mass (mc) (crystal content per kg of solution) has been determined as the mass of the crystals formed in the crystallizer due to nucleation and/or growth

m/ = ρ1 k 3 nLL- dL

(9)

where ρc is the density of α-lactose monohydrate crystal (1545 kg/m3) 38, and kv is the shape factor (kv = 0.8) 30. The term nLL- dL represents third moment (m3) and gives the volume of crystal present. Differentiating equation (9) gives 7

= ρ1 k 3

(10)



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By using equation (7), equation (10) can be expressed as 7

= 3ρ1 k 3 8,

(11)

The solute mass balance indicates that the rate of decrease in the concentration of the solute in the liquid is equal to the rate of formation of the solid crystals in the solution. The αlactose monohydrate contains one water molecule. The crystalline lactose term is multiplied by 0.95 (MWαL/MWαLH = 342/360 = 0.95) to account for the water of crystallization present in the solution. The rate of formation of crystals can be determined using the following equation 1

= −0.95 ∗ 3ρ/ Gk 3 ,

(12)

where C is the concentration of the solute in kg//kg of solution. The total mass of solution is determined as the addition of the initially added lactose solution and the mass of antisolvent added during the process.

m= = m=>?@ QBC t

(13)

where ms is the total mass of solution, msol is the initial mass of lactose solution added, Q is the volumetric flow rate of antisolvent, ρs is the density of antisolvent and t is the time. α-Lactose monohydrate solubility. The total lactose concentration (C) is the sum of α- and β- lactose concentrations 39,

C = CF + CG

(14)

The equilibrium mutarotation rate constant (Km) is defined as

K = CG /CF

(15)

Km is represented as (McLeod (2007) 40 10 ACS Paragon Plus Environment

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K = −0.0024T + 1.6353

(16)

where T is the temperature (oC). The Km value of 1.5393 (at 40℃) is used in this study. The αlactose monohydrate concentration can be calculated from the total lactose concentration by +

CF = +@M

(17)

N

The saturation concentration of α-lactose monohydrate concentration can be calculated by

CF= =

OPQR∗ST ∗OQOP

(18)

+@ST

where F is the temperature dependent correction factor, and represented as 41.

F = 0.0187X $.$,-YZ

(19)

The primary nucleation rate (B) of the crystals is given as

B = k [ ΔC[

(20)

where ]^ is the concentration driving force (Cα-Cαs), Cα is the concentration of dissolved αlactose monohydrate in the solution and Cαs is the equilibrium concentration of α-lactose monohydrate in the solution. kb is the nucleation coefficient and b is the order of the nucleation. Growth rate (G) (m/s) is given by the following equation

G = k _ ΔC_

(21)

where kg is the growth coefficient, g is the order of the crystal growth. Equilibrium concentration (Ce) of the lactose in ethanol-water solution at 40 oC was obtained by data fitting from Machado et al. (2000) 42.

Ce = −0.4948x b + 0.9069x - − 0.1292x , − 0.5362x + 0.2527

(22)

where x is the fraction of antisolvent mass in the total mass of liquid and can be expressed as



x=

cde

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(23)

fg @cde

Above equations were solved in MATLAB (R2009) to simulate the antisolvent crystallization of α-lactose monohydrate. The initial concentration C(0) was taken as the concentration of the solution at which the trial was performed. For the moment equations, the initial values (at t = 0), were taken as zero since no seeding was performed. The kinetic parameters for the nucleation and growth models (kg, g, kb, b) were taken as the adjusted parameters and estimated by using the fminsearch subroutine in MATLAB (R2009). The subroutine uses the Nelder-Mead simplex algorithm for minimizing the objective function. The objective function was defined as the combined sum of the square of the errors between the experimental and model predicted for crystal size and residual lactose concentration. The initial guess for the kinetic parameters are taken as kg = 5*10-5 m/s, kb = 1.2*108 number/m3s, g = 1.5, n = 3. These values are similar to the values reported by McLeod (2007) 40.

Results and Discussion Effect of initial concentration. The effect of initial concentration of lactose (0.25, 0.30, 0.37 and 0.45 kg/kg of solution) on the crystal phase, shape and size were studied. The temperature was kept constant at 40 °C and antisolvent addition rate was 0.1 ml/s. The concentration of 0.25 kg per kg is the saturation concentration of lactose at 40 °C.


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Figure 2. Average particle size profile for different starting lactose concentrations. The lines show the simulated profiles. Antisolvent addition rate was 0.1 ml/s.

The evolution of average crystal size with time of 0.25, 0.30 and 0.37 kg/kg of solution is shown in Figure 2. During crystallization both nucleation and growth occurs simultaneously and competes for the available driving force. If nucleation is more dominant phenomenon (having a higher order than growth) then more but smaller crystals will be formed. However, in the present case, the growth rate has a higher order dependency on supersaturation compared to nucleation, thereby leading to a net small increase in crystal size. The dissolved lactose profile is shown in Figure 3.



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Figure 3. Residual lactose concentration profile for different starting lactose concentrations. The lines show the simulated profiles. Antisolvent addition rate was 0.1 ml/s.

The micrographs of the crystals recovered for 0.25, 0.30 and 0.37 kg/kg of solution at 10X magnification at the end of 60 min are shown in Figure 4. All the photographs show polyhedral crystal morphology (tomahawk, triangular, pyramid) that are associated with αlactose crystals 2.

a)

b)

c)


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Figure 4. Micrographs of the samples recovered at time 60 min for initial lactose concentration of a) 0.25 b) 0.30 and c) 0.37 kg/kg of solution. Antisolvent addition rate was 0.1 ml/s.

Figure 5. a) XRD analysis of lactose samples recovered at 60 min for 0.25, 0.30, 0.37 and 0.45 kg/kg of lactose solution. b) XRD patterns measured by MacFhionnghaile et al. (2017). Antisolvent addition rate was 0.1 ml/s.

The powder X-Ray diffraction (PXRD) patterns for the crystals recovered at the 60 minutes (Figure 5) confirms that the crystals formed at 0.25, 0.3, 0.37 kg/kg concentrations were dominantly α-lactose monohydrate. The β-lactose peaks at 13.21, 15.57, 17.62 and 19.58

o

were present. It is also interesting to note that the XRD data for 0.25 kg/kg at 20 minutes (see Figure 9) shows no β-lactose peaks which were present in samples after 60 minutes (Figure 5). This shows that the β-lactose is formed during the later half of the trial. However, the characteristic peak at 10.51 ° is missing 1,5. This could be either due to preferred orientation or non-development of face {110} of β-lactose corresponding for the reflection at 10.51 ° 10. 15 ACS Paragon Plus Environment


The trial at 0.45 kg/kg of solution produced crystals of different morphology and is discussed separately below. For the trial, at 0.45 kg/kg concentration, a distinct change of morphology to curved needle/rod was observed (Figure 6b) at the second sampling instance i.e. after 20 minutes with polyhedral crystals obtained at 10 minutes (Figure 6a). The XRD pattern shows the formation of β-lactose with distinct peaks for α-lactose at 12.52 ° and 16.45 ° also present (Figure 5). The XRD pattern obtained at 0.45 kg/kg concentration matches exactly with that measured by MacFhionnghaile et al. (2017) for a mixture of α-lactose monohydrate and βlactose thus confirming the presence of both α- and β- forms. Kougoulos et al. (2010) suggested that needle/rod shaped crystals contain 40-50 % by wt β-lactose using quantitative phase analysis. In order to understand this transition from polyhedral to needle shape morphology, the interplay between mutarotation kinetics and crystallization rate needs to be analysed.

a)

b)

Figure 6. Micrographs of the crystals recovered at the end of 10 min and 20 min for initial lactose concentration of 0.45 kg/kg of solution. Antisolvent addition rate was 0.1 ml/s.

It is an established fact that the two anomeric forms of lactose; α- and β-lactose exist in equilibrium in an aqueous lactose solution. The α-form, being much less soluble precipitates out first whenever supersaturation is generated. The β-lactose form then converts into α16 ACS Paragon Plus Environment

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lactose to restore the equilibrium, maintaining the concentration of α-lactose (simultaneously decreasing β-lactose concentration) and thus maintaining the driving force for α-lactose crystallization 4. The driving force is defined as the difference between the concentration present in the solution and its equilibrium solubility. The presence of ethanol decreases the equilibrium solubility of both α- and β-lactose as well as their individual rotation rates 43. At lower starting concentrations of α-lactose, the crystallization of α-lactose and the subsequent conversion of β-lactose to α-lactose keeps the β-lactose driving force below that for α-lactose, forming α-lactose crystals. As the lactose concentration increases, the supersaturation driving force increases. At 0.45 kg/kg, the α-lactose driving force was higher than that of β-lactose for the initial 10 minutes, precipitating α-lactose crystals. However, after 10 minutes, the driving force of β-lactose became higher than that of α-lactose due to higher starting β-lactose concentration and slowing of mutarotation rate β- to α-lactose due to ethanol (leading to an increase in β-lactose concentration). The increased β-lactose concentration inhibits α-lactose nucleation and acts as a habit modifier

44

, resulting in the formation of β-lactose (needle

shaped). Kougoulos et al. (2010)

5

studied the semi-batch antisolvent crystallization of lactose and

reported the formation of needle shaped crystals at the starting lactose concentration of 0.166 kg/kg solution for the ethanol addition rate of 0.1 ml/s. The starting concentration was slightly undersaturated at the studied temperature (25 °C). We did not observe needle/rod morphology for a saturated solution at 40 °C (0.25 kg/kg) or in fact, for supersaturated solutions at 0.3 and 0.37 kg/kg. A transition to needle/rod crystals only occurred at 0.45 kg/kg. Secondly, for the batch studies performed by Crisp et al. (2011) 10, the formation of needle/rod morphology was reported at an ethanol concentration of 80 % v/v. In the current study, the formation of rod/needle morphology occurred around 20 minutes during the semibatch trial at a starting lactose concentration of 0.45 kg/kg. At this juncture, the total ethanol 17 ACS Paragon Plus Environment


Page 18 of 35

added was 120 ml corresponding to an ethanol concentration of 45 % v/v which is less than reported by Crisp et al. (2011). The following can probably explain the different observations. For Crisp et al. (2011)

10

lactose concentration of 0.09 kg/kg of solution at ‘room temperature’ was used. Since the exact temperatures were not mentioned, it is difficult to comment on the saturation state of the solution. In absolute terms, the initial concentration is much smaller than that used in this study and hence required much larger antisolvent concentration for the β- phase formation. Kougoulos et al. (2010) used 20 ml as the initial volume of lactose solution as against 100 ml used in the current study. For the same ethanol addition rate, the smaller initial volume for Kougoulos et al. (2010) resulted in a much more rapid increase in ethanol concentration and leading to the formation of needle/rod morphology. The dominance of β-lactose at higher lactose concentration could be attributed to the nucleation inhibition of α-lactose by β-lactose 44

.

Effect of antisolvent flow rate. The effect of antisolvent flow rates (0.1, 0.25 and 0.5 ml/s) was studied at 0.25 kg/kg initial concentration of lactose. Due to the limited capacity of the crystallizer (450 ml), the trials with 0.25 and 0.5 ml/s could be run for 20 and 10 minutes, respectively after which the crystallizer began to overflow.

The results show that

morphological transition occurred after 20 min for 0.25 ml/s and after 10 min for 0.5 ml/s of addition rate reported in Figure 7 and 8. A transition from tomahawk to needle/rod shape crystal was observed with an increase in anti-solvent flow rate. This is inline with the findings of Crisp et al. (2011) and Kougoulos et al. (2010) who reported similar transition when the initial lactose concentrations and antisolvent flow rates were increased, respectively.


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a)

c)

e)

b)

d)

Figure 7. Micrographs of lactose samples recovered for different antisolvent addition rate; 0.1 ml/s a) 10 min. b) 20 min. for 0.25 ml/s c) 10 min. d) 20 min. for 0.5 ml/s at e) 10 min

a )

b)

c)



Page 20 of 35

Figure 8. SEM images of lactose samples recovered at different time with different antisolvent addition rate a) 0.1 ml/s at 20 min b) 0.25 ml/s and at 20 min for c) 0.5 ml/s at 20 min. The initial lactose concentration was 0.25 kg/kg of solution.

The XRD analysis of recovered samples confirmed that at 0.1 ml/s predominantly α-lactose monohydrate was formed, whereas at higher flowrates both α- and β-lactose were present. For 0.25 ml/s addition rate of anti-solvent, the change in the morphology from polyhedral crystals to needle/rod was observed after 20 minutes while at 0.5 ml/s the needle morphology was predominantly visible at 10 minutes. As discussed previously, the faster addition rate generated much higher supersaturation and crystallization rate, making mutarotation the controlling step.

At 0.25 ml/s, this stage would have been achieved after 10 minutes,

producing crystals containing dominantly α-lactose in the initial 10 minutes.

The rate

controlling mutarotation was unable to restore the α-lactose lost to crystallization, leading to an increase in β-lactose concentration and subsequent β-lactose dominated crystallization. This is similar to that observed at 0.45 kg/kg of initial lactose concentration as discussed in the previous section.


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Figure 9. XRD patterns of lactose samples recovered at 20 min for a) 0.1 b) 0.25 and at 10 min for c) 0.5 ml/s of antisolvent addition rate. The initial lactose concentration was 0.25 kg/kg of solution.

Effect of sonication. In this study, application of power ultrasound at 20 and 40 kHz was studied at an antisolvent addition rate of 0.1 ml/s. Investigations showed the trials conducted with ultrasound resulted in the formation of smaller size crystals compared to non sonicated trials. The application of ultrasound results in higher nucleation rates, thereby reducing the crystal size The more number of cavitation bubbles act as heterogenous nucleation sites, leading to higher nucleation rates, thereby marginally reducing the crystal size.. A number of mechanisms by which ultrasound enhances the nucleation rate had been reported in the literature

14-18

. The size decreased marginally at higher ultrasound frequency (Figure 10).

Although less violent, higher number of cavitation event (bubble formation and collapse) occurs at higher frequency 45.



a)

b)

Figure 10. Average particle size profile for different starting lactose concentrations for sonication frequency a) 20 kHz b) 40 kHz. The lines show the simulated profiles. Antisolvent addition rate was 0.1 ml/s.


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To clearly illustrate the effect of ultrasound on crystal size, crystal size with and without sonication at 0.3 kg/kg of initial lactose concentration were plotted on the same figure (Figure 11). It can be seen that the crystal size obtained with sonication were on an average half the size that obtained without sonication.

Figure 11. Average particle size profile for 0.30 kg/kg of lactose solution at (o)Without sonication (*)20 kHz and (x) 40 kHz. The lines show simulated profiles. Antisolvent addition rate is 0.1 ml/s

The dissolved lactose profile for the sonicated trials at 20 and 40 kHz are shown in Figure 12. The application of power ultrasound resulted in more rapid lactose removal (due to higher nucleation rates) than for non-sonicated samples as shown in Figure 13.



a)

b)

Figure 12. Residual lactose concentration profile for different starting lactose concentrations for sonication frequency of a) 20 kHz b) 40 kHz. The lines show the simulated profiles. Antisolvent addition rate was 0.1 ml/s.


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Figure 13. Comparison of residual lactose concentration profile for 0.3 kg/kg of lactose solution at (o) Without sonication (*) 20 kHz (x) 40 kHz trials. Antisolvent addition rate was 0.1 ml/s.

Photographs of lactose crystals recovered at low and high sonication frequency at 10X magnification and at 60 min are shown in Figure 14. It was observed that the ultrasound only reduces the size of the crystal without making any change in the morphology of the crystals. The SEM image shown for 0.25 kg/kg confirms the formation of polyhedral shaped α-lactose crystals. No significant effect of ultrasonication on crystal shape and morphology was also reported by Kougoulos et al. (2010) 5. a)

c)

b)



d)

e)

Page 26 of 35

f)

Figure 14. Micrographs of lactose crystals recovered at time 60 min for a) 0.25 b) 0.30 c) 0.37 kg/kg of solution at 20 kHz and for d) 0.25 e) 0.30 and f) 0.37 kg/kg of solution at 40 kHz. For 0.25 kg/kg the corresponding SEM image is shown in the inset. Antisolvent addition rate was 0.1 ml/s.

Kinetic parameter estimation. Crystal size and dissolved lactose concentration data were used for determining the kinetic rate constants. These kinetic constants have a strong influence on the size of crystals formed and the rate at which dissolved lactose comes out of the solution. The data fitting to estimate the kinetic parameters was carried out for the trial at 0.25 kg/kg initial lactose concentration with the values given in Table 1. The values obtained of the kinetic constants (kg, kb, b, and g) obtained by fitting were then used to estimate the profiles of particle size and lactose concentration for the trials at 0.30 and 0.37 kg/kg of solution. A similar procedure was followed for sonicated trials. The predicted profiles matches well with the measured values at higher concentration (Figure 2, 3, 10 and 12). It needs to be mentioned that the above parameter fitting exercise was only carried out for trials where α-lactose crystals were obtained. The formation of β-lactose occurs when the mutarotation rate will be unable to maintain the equilibrium (crystallization rate faster than the muta-rotation rate). The current model is thus, unable to predict the formation of β-lactose crystallization parameters due to lack of solubility and mutarotation data for lactose in ethanol-water solutions. This will be looked at in our future work.


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Table 1. Estimated values of kinetic parameters for antisolvent crystallization of lactose

kb (number/m3s)

kg (m/s)

b

g

No sonication

7.56*107

2.29*10-6

0.60

1.72

At 20 kHz

8.75*108

2.23*10-6

0.60

1.77

At 40 kHz

2.09*109

2.15*10-6

0.65

1.81

The nucleation rate constant values are approximately 10 times and 25 times higher at the application of 20 and 40 kHz of ultrasonication, respectively compared to non-sonicated trials.

However, the growth rate and the orders remained nearly constant. This is in

agreement with Bari et al. (2017) who estimated the kinetics of sono-crystallization of K2SO4 and reported an order of magnitude increase in nucleation rate compared to non-sonicated trials 21. The growth rate increased slightly (20%) at higher supersaturations with no effect observed at lower supersaturations. Jiang (2012) reported no change in the kinetics and mechanism of growth of α-glutamic acid in presence of ultrasound 46.



Conclusion Semi-batch antisolvent crystallization of lactose has been studied under varying lactose concentrations, anti-solvent feed rates and sonication. The proposed analysis method for dissolved lactose concentration using a refractometer was in good agreement with the reported gravimetric analysis. It was found that at anti-solvent feed rates of 0.1 ml/s, αlactose monohydrate crystals were formed; while at higher flow rates (0.25 and 0.5 ml/s) both α-lactose monohydrate and β-lactose were formed. The transition was apparent with marked change in morphology from polyhedral crystals to needle shaped crystals. Similarly, βlactose was formed only at high initial lactose concentration (0.45 kg/kg of solution). This was attributed to increased β-lactose concentration and subsequent crystallization due to reduced muta-rotation rates in presence of ethanol. Application of power ultrasound led to reduction in crystal size due to order of magnitude higher nucleation rates as estimated by fitting. The fitted parameters suggest that the growth kinetics and mechanisms do not change under sonicated conditions.

Associated Content Supporting Information. The details regarding the methodology developed for the measurement of dissolved lactose concentration using refractometer and the nomenclature for the different symbols used in the manuscript are included in the supporting information file.


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For Table of Contents Use Only

Modeling, Simulation and Influence of Operational Parameters on Crystal Size and Morphology in Semi batch Antisolvent Crystallization of α-Lactose Monohydrate Nitin Pawar, Shailesh Agrawal*, Ravi Methekar

TOC Graphic

Synopsis The work discusses the avenues to engineer the size, phase and morphology of lactose crystals in semi-batch mode by manipulating the operating parameters, namely: antisolvent flow rate, initial lactose solution concentration and application of sonication. The growth and nucleation kinetics for anti-solvent lactose crystallization (with and without sonication) were also predicted by fitting the experimental data to model estimates.


Modeling, Simulation, and Influence of Operational Parameters on

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