18 views

Uploaded by AgnesHuberta

mengenai kristalisasi

- Laporan Aspirin
- Kinetics of Seeded Batch Cooling Crstallisation
- 21712_13.pdf
- Sterilisasi
- UTOMO
- 385-389 (2)
- Lecture 1
- Crystal Growth
- chem 5 lab
- Neoprene - Dry Grades Selection Guide (1)
- SOLUBILITY ENHANCEMENT TECHNIQUES: REVIEW
- Chem Book
- Beta
- 10.1063@1.4971885
- STA
- Information Booklet
- is.5055.1996.pdf
- Advances in Polymer Technology
- Adikaari 2007 Excimer Laser Crystallization
- Organic Synthesis

You are on page 1of 9

1

1*

1

School of Chemical Engineering, The University of Queensland, Brisbane, Qld. 4072, Australia.

2

School of Chemical Engineering, Purdue University, West Lafayette IN 47907-2100, USA.

3

Chemical Research & Development, Pfizer Worldwide Research and Development, Sandwich, Kent CT13 9NJ,

United Kingdom..

*E-mail: uqewhit1@uq.edu.au

Abstract. To design a crystallizer for producing an active

pharmaceutical ingredient (API) of the desired crystal size,

it is necessary to know the solubility, the nucleation

metastable zone widths (MSZW), the crystal growth rates

and the nucleation rates. These data have been measured

(and presented in previous conferences) for the popular

anti-inflammatory drug ibuprofen crystallized from

absolute ethanol and water-ethanol mixtures. Using this

data, methods will be outlined to design industrial

crystallizers to recover ibuprofen crystals. From ethanol,

as the solubility increases greatly with temperature,

cooling crystallizers can be used industrially. Both seeded

batch and continuous (MSMPR) designs are considered

2010, 2011). The present paper uses this data and outlines the

procedures for carrying out typical design calculations.

II.

IBUPROFEN

acid] (Figure 1) is a widely used anti-inflammatory drug. In

Figure 1 the asterisk (*) indicates the atom where the

arrangement of the CH3 and COOH entities give the R and S

isomers Ibuprofen is insoluble in water but soluble in many

organics (Gracin & Rasmuson, 2002; Garzon & Martinez,

2004). It is purified by crystallization. Its crystallization from

ethanol and aqueous ethanol is considered here.

crystallizer.

III.

INTRODUCTION

recover or to purify a soluble pharmaceutical. There is an

enormous variety of possible industrial crystallizer

configurations, e.g. tanks or troughs, operated in batch or

continuous mode, run at constant or varying temperatures,

with or without seeding. If the following crystallization data

is available for the range of operating conditions, designs can

be undertaken for all types of crystallizers,

1.

2.

3.

4.

5.

Nucleation metastable region

Growth rate kinetics

Nucleation rate kinetics

Agglomeration and/or breakage

applicable)

kinetics

(if

(Lerdkanchanaporn and Dollimore, 1997).

2.5

2.0

I.

1.5

1.0

0.5

0.0

ibuprofen, crystallizing from absolute ethanol and waterethanol mixtures. Most of the data has been presented at

previous Chemeca conferences (Rashid et al., 2008, 2009,

10

20

30

40

Temperature,oC

50

The crystallization data are summarised here. For design

calculations it is convenient to have results in equation form,

so correlating equations are also given.

wide enough to allow acceptable growth rates without

secondary nucleation.

Table 1: Secondary nucleation metastable zone width for ibuprofen in aqueous

ethanol

Temperature, C

1. Phases and Solubility (Rashid et al., 2008)

Form I ibuprofen, as used in this study, exists as two

enantiomers (R and S). The industrial material is a racemate

and this was used here. A rare Form II ibuprofen has recently

been reported (Dudgnon et al., 2008, Arlin et al., 2009).

Figure 2 shows the solubility in I/E mass units of Form I

ibuprofen (I) in ethanol (E). They are in broad agreement

(Rashid, 2011; Rashid et al., 2008) with previous studies. The

data was correlated by I*/E = 0.497 + 0.001026 * T2, with T =

temperature in oC. This correlation is considered to fit the true

solubility within 1% in the range 10 oC to 40 oC.

Figure 3 shows the solubility of racemic ibuprofen in aqueous

ethanol at 10, 25 and 40oC. No correlation was derived for

this data so any required values will be interpolated from the

figure. At 25 and 40oC, the solubility first rises (salting in)

then falls (salting out) finally to negligible levels. Thus water

(W) overall is an anti-solvent.

XW

10

25

40

0

0.2

0.4

0.5

0.071

0.220

-0.358

0.052

0.008

0.0014

--

0.057

0.021

---

0.6

--

0.0003

--

Ibuprofen crystals from aqueous ethanol show growth rate

dispersion (GRD) (different size crystals have different growth

rates). Figure 4 shows the log Normal distribution of growth

rates for crystals grown from un-sieved ibuprofen nuclei. The

distribution has a coefficient of variation (CVG) of 0.50 (

0.03 %).

The nucleation threshold data are expressed as the 1 hour

secondary nucleation metastable zone widths (secondary

nucleation will only begin in solutions with the indicated

supersaturation held for at least 1 h). Table 1 shows the values

for solutions with different water contents (XW = W/(E+W)

by wt.) at different temperatures. These values are expected to

be accurate within 20 %.

2.5

40o C

rate and Gm is the mean growth rate of the crystals.

[0.339, 2.048]

2.0

Locus of

two liquid

layers 40 oC

Construction

line for tie lines

1.5

25oC

1.0

10o C

0.5

[0.642, 0.080]

0.0

0.0

0.2

0.4

0.6

0.8

1.0

Figure 5: Growth rate constants for ibuprofen from aqueous ethanol at 10, 25

and 40oC.

kG * s, where kG is the growth rate constant. The dependence

of kG on growth conditions is shown in Figure 5. The overall

correlation fitting the data is G = 5.3 * exp(0.024 * T) *

exp[(7.2 0.21 * T) * XW]* s, where G is the growth rate in

m/min, T is the temperature in oC, XW is the fractional water

content of the solvent and s is the supersaturation measured as

I/E (by wt.). This correlation fits 95% of the experimental

data within 80%.

4. Nucleation rate (Rashid et al., 2011)

Nucleation rate data is only needed if crystallizer operation is

at supersaturations above the nucleation metastable threshold.

Above this limit the secondary nucleation rate B (#/min/kg

slurry) has been taken as first order with supersaturation s, i.e.

B = kB * s, where kB is the nucleation rate constant.

Figure 6 shows the dependence of the secondary nucleation

rate constants on water content and temperature. The chosen

fitting correlation is nucleation rate B = 1.73 108 ( 65%)

*exp[- XW/0.12 ( 90%)] * s. The errors shown are 95%

uncertainties on the parameters. This relation fitted 95% of

the experimental results within a factor of 3.

No evidence of agglomeration or breakage was seen in all the

crystallization trials, under the agitation conditions used, so

these mechanisms are not involved.

10, 25 and 40oC.

Crystallization is usually carried out to purify a material from

any impurities in the solution, so impurities must be

considered in discussion of the crystallization process. Even if

a material is being re-crystallised just to improve its crystal

size or shape, there are usually still impurities present, but at

much lower levels. For the following it will be assumed that

the particular impurities (undefined) do not affect the

crystallization equilibrium and kinetics, i.e. do not change the

solubility, growth or nucleation relations. In practice the

major impurity and other impurities would be known and the

experiments data would have been obtained with the

impurities present. The primary concern is at what conditions

the impurity will come out of solution (co-crystallize) and thus

contaminate the crystal product.

In designing a crystallizer, the first decision is the choice of

the means of generating the supersaturation for the

crystallization, e.g. changing temperature, evaporating solvent,

adding an anti-solvent. All three are relevant for the

crystallization of ibuprofen from ethanol.

For ibuprofen crystallization from water free ethanol solutions

the change of solubility with temperature is very large (Figure

2). For negligible effect of any impurity on the solubility I*/E,

cooling a saturated solution from say 35 oC to 25 oC could

crystallize 0.62 kg of ibuprofen per kg of ethanol in the

solvent.

This would correspond to a crystal content

(crystal/total slurry) of 22% w/w which is moderately high.

However there would still be a large amount of ibuprofen in

the mother liquor (1.14 kg of ibuprofen per kg of ethanol in

the liquor at 25 oC). The second method, evaporation of

ethanol (under vacuum) at say 50oC could remove 3.06 kg of

ibuprofen per kg of ethanol evaporated. Evaporation could be

continued until the impurity started to co-crystallize. In the

third method an anti-solvent (e.g. water) could be added. For

water addition at say 25oC to increases the water content of the

solvent XW from 0 to 60%, 1.08 kg of ibuprofen could be

recovered per kg of ethanol in solution. The limiting water

addition again would be constrained by the co-crystallization

of the impurity or too high a crystal content.

To illustrate the design methods, two examples will be

considered, (i) a non-nucleating well mixed batch crystallizer

and (ii) a well mixed continuous (MSMPR) crystallizer. For

the sample calculations, the feed solution will be considered to

contain 1% w/w of impurity Z and at 25oC, it will be assumed

Z will co-crystallise at the 5% level, both as Z/E ratios.

A well mixed seeded batch crystallization operating without

nucleation (operating below the nucleation threshold) will be

considered. It will be assumed the seeds selected are SPG

(size proportional growth, i.e. growth rate proportional to

size). If GRD occurs and non-SPG seeds were used,

calculations can still be done but a further characterisation of

the seeds to give a bivariate distribution in terms of size and

relative growth rate (White et al., 1998) would be required.

Mass of crystal

For theoretical and design purposes the basic size distribution

is that given on a number basis. The size distribution density

function f(L) is defined by f(L) dL as the fraction of the total

number of crystals considered with sizes between L dL/2 to

L + dL/2. The size distribution has a mean size L10 (the

number mean), a coefficient of variation CV (= standard

deviation / mean i.e. / L10) and a skewness Sk (= third

3).

moment about mean / standard deviation3 i.e. m3/

The mass of a crystal of size L is V C L3, where C is the

crystal density and V is the volumetric shape factor. If size is

taken as the volume equivalent size (as is often the case in

crystallization) then by definition V = /6 for all crystals and

is constant.

Consider a collection of N crystals having a size distribution

f(L) then the mass of those crystals with sizes between L

dL/2 to L + dL/2 is N V C L3 f(L) dL. Summing over all

crystals (sizes L from 0 to ), the total mass M = N V C

L3 f(L) dL if all crystals have the same V and C. The

integral is the definition of the third moment about the origin,

i.e. 3 = L3 f(L) dL, so M = N V C 3. The third moment

about the origin can be expressed in terms of moments about

the mean, mi as 3 = L103 + 3 m2 L10 + m3, i.e. 3 = L103 (1 + 3

CV2 + Sk CV3). So the mass of N crystals may be evaluated

by,

M = N V C L103 (1 + 3 CV2 + Sk CV3)

where L10, CV and Sk are properties of the crystal size

distribution (on a number basis) and are measured in a simple

size analysis. If it is convenient to use some other central

reference size measure Lr rather than L10 then the equation

becomes,

M = N V C Lr3 (L10/Lr)3 (1 + 3 CV2 + Sk CV3) = N V C F Lr3

be written as

M = N V C L303 = F L303

(1)

where L30 is the volume number mean of the distribution (L30

= L103 + 3 m2 L10 + m3) and F = N V C. For non-nucleating

growth, F will be unchanged.

The ratio of the mass of product to the mass of seed M/Ms = N

V C F Lr3 / Ns Vs Cs Fs Lrs3. If the crystals have the same

shape (or if volume equivalent size is used) V = Vs. Also the

density is unchanged so C = Cs. If there is no nucleation (or

agglomeration or breakage) then N = Ns. If the seeds are

selected as SPG (size proportional growth) then from above F

= Fs. Hence M/Ms = (Lr/Lrs)3. This relation is illustrated in

Figure 7.

The more seed that is used for a given solute deposition, the

smaller the crystal size. So this relation gives the reference

size change with growth and thus the size distribution. This

calculation applies irrespective of the growth kinetics.

Mass balance

During the course of a batch crystallization, a material balance

can be undertaken at any time to link the mass of crystal

deposited to concentration changes in the solution. There are

many ways the mass change due to the concentration drop can

be written. For example and for this analysis, the mass of

crystal corresponding to the change in concentration will be

written as E (Ci C) where E is the amount of the selected

solvent species in solution, C is the concentration of interest

and Ci the initial concentration. Care is required in the choice

of units for E. Here E is the mass of a tie substance whose

amount is unchanged during the crystallization. If the crystals

contain solvent (e.g. water of crystallization) then the tie

substance can be taken as the free solvent, the mass of

solvent minus the total mass of solvent if all solute

crystallized.

(1)

SPG (size proportional growth) seeds where the growth rate is

proportional to crystal size, the size distribution on a log size

scale retains the same shape and all ratios associated with the

size distribution remain constant as the crystals grow, so with

no nucleation (operating below the SNT), F is unchanged

during growth.

the solute to the tie substance. For this study, concentrations

are expressed as the mass ratio of ibuprofen to ethanol (I/E),

so E would then be the mass of ethanol in the crystallizer.

1.0

0.9

0.8

0.7

where M is the mass of crystal and Ms the initial mass of seed

used. Further M Ms = E [(Ci C*) (C C*)] = E (si s)

where C* is the solubility and s the absolute supersaturation.

Thus,

0.6

0.5

0.4

-X*), dimensionless concn

= (X-X*)/(X

(

t

0.3

0.2

0.1

0.0

3

Batch time

The growth kinetics are necessary to calculate the batch time.

For consistency, the growth rate G should be expressed as the

rate of change of the reference size (G = dLr/dt) and the

supersaturation should be in the same units as used in the

material balance above. The kinetics are usually expressed as

a power law on supersaturation G = kG sn, where n is the order

of the dependence and the growth rate constant kG depends on

operating conditions (temperature, impurity, stirring speed,

etc.).

This equation and the material balance give two equations

with two unknowns (Lr and s) and may be solved. The

equations are,

dLr/dt = kG sn

(3)

(Ms / Lrs3) (Lr3 - Lrs3) = E (si s)

(2)

al., 2006). For example, Figure 8 illustrates the analytical

results for first order kinetics.

A numerical solution is

necessary for non-integer orders.

For the terms in Figure 8, at the end of the batch (at

equilibrium, time ) the crystal size is Lr, the product

mass M and the concentration (here designated as X) is the

solubility X*. Xt is the total amount of solute (including

crystals) in the crystallizer. The dimensionless time is 1 =

(kG/ Lr) M/ E) * t. C1 is an integration constant. For a

particular application, C1 should be taken so that time is zero

for the particular seed size used. For example if = Lrs/Lr is

0.30, C1 should be taken as 0.60.

Sample calculation

Consider ibuprofen SPG seed with the lognormal growth rate

distribution shown in Figure 4 (CVG = 0.50) growing from

ethanol in a batch crystallizer at 25oC.

1 + C 1 , Dimensionless time

crystal mass and solution concentration for non-nucleating batch crystallizers

seeded with SPG crystals first order kinetics (White et al., 2006).

to the growth distribution, i.e. lognormal having a volume

median size of say 20 m. It is desired to grow the crystals to

have a volume median size of 100 m in a non-nucleating

crystallizer (initial supersaturation below the secondary

nucleation threshold relative supersaturation of 0.052 i.e. an

absolute supersaturation of 0.055 kg of I per kg of E). Since

SPG the product distribution will also be lognormal. The size

ratio of the product to the seed L/Ls = 5. Thus the mass of

seed / mass of product = 1/125. Suppose the feed is a solution

saturated at 35oC, then the equilibrium yield is 0.616 kg

ibuprofen per kg ethanol in the crystallizer.

The operation of the crystallizer would have to be controlled

to maintain the operating supersaturation below the secondary

nucleation threshold. This could be done by (a) controlled

addition of the solution at 35oC added to an initial footing

containing the seeds or (b) by having a temperature

programmed cooling crystallizer. Both will be considered.

(a) Controlled solution addition

The crystallizer at 25oC is to produce say 500 kg of crystal.

So the mass of seed needed is 500 / 125 = 4.0 kg. The

crystallizer starts with a saturated footing containing say 100

kg of ethanol (214 kg of solution) at 25 oC. First sufficient

feed (saturated solution at 35 oC) is added very rapidly to

obtain the operating supersaturation at s = 0.040 kg of I per kg

of E (~ 70% of the MSZW to allow a safety zone from the

nucleation threshold). This amount is 19.1 [=

100*0.040/(0.616-0.040)*2.754] kg of feed, since every kg of

feed supplies 0.616 0.040 kg of I / kg E above the operating

supersaturation. The seed is then added and feeding

commenced to maintain the supersaturation constant at s =

0.040. At the end, the feed is stopped and the solution

retained for a time to de-supersaturate the solution to near

equilibrium (solubility).

Table 2 Material balance for controlled feed addition crystallizer (mass in kg).

Initial

Final

Total

Total

Footing

213.8

113.8

100

---

500

500

Crystal

Seed

4.00

4.00

---

905.2

1030.1

1935.3

Solution

Feed

2217.5

1412.3

805.2

Total

2435.3

1530.1

905.2

905.2

1530.1

2435.3

Total

the final equilibrium conditions. Thus 2218 kg of feed will be

used to give a total crystallizer mass of 2435 kg. The feed

would be stopped with 36.2 kg of I remaining in solution (at s

= 0.040), i.e. the product mass = 463.8 kg and the product

volume equivalent size = 97.5 m. The feeding time of the

batch will be (97.5-20)/0.39 = 201 min. The size will increase

linearly during this time (Figure 9) and the masses of product

and feed will rise rapidly. The supersaturation (the units here

are g I/ kg E) is also shown on Figure 9. The Z impurity

concentration will rise from the initial 1% to 1.26% which is

well below the assumed 5% co-crystallization concentration,

so there are no problems with impurities.

After the feed addition is stopped after 201 min, the solution

de-supersaturates as a batch. This stage will take about 30

min. The conditions during this part of the batch as shown in

Figure 9 can be calculated by solving equations 2 and 3 or else

by using the analytical solutions for a batch with first order

growth kinetics (Figure 8).

b. Controlled cooling

In this case the 4.0 kg of seed is added initially to the total

amount of saturated solution (2218 kg) at 35 oC and the batch

is cooled to lower temperatures to maintain the supersaturation

at s = 0.040. No footing is required. The behavior of the

crystallizer can be predicted again by solving equations 2 and

3 numerically, but first by altering the temperature to keep the

supersaturation at 0.040 kg I / kg E. Once the temperature

reaches 25 oC the solution is allowed to de-supersaturate to

near equilibrium, but now allowing s to fall. The variation of

size, supersaturation and mass of crystal against time are

shown in Figure 10.

As is usual with cooled batches, the temperature (purple line)

falls slowly at first then more rapidly at the end (the reverse of

natural cooling). The batch time before the final desupersaturation stage (173 min) is less than for the controlled

feed addition case because now most of the growth is at

temperatures > 25 oC and thus higher than before. The final

crystal content is 22% kg crystal per kg slurry or 19 % v/v,

which may be approaching the slurry circulation limit for

irregularly shaped crystals.

The vertical dotted line shows the end of feed addition.

Figure 10. Conditions during batch experiment with controlled temperature.

The most common industrial type of crystallizer is the selfnucleating continuous well mixed vessel (the MSMPR

Mixed Suspension Mixed Product Removal crystallizer). A

good review is given in Randolph and Larson (1988). For

size independent growth (SIG) systems, the theory is very

simple the product has an exponential size distribution on

a number basis and a third order Gamma distribution on a

mass basis. For size dependent growth (SDG) which

includes growth rate dispersion (GRD), the analysis is more

complex. The product size distribution has to be obtained

by numerical integration.

Assumptions

The assumptions for the MSMPR crystallizer modelling are,

Steady

state

operation

(constant

temperature, feed, flow rate, etc.)

Well mixed contents

Representative overflow (the product is

identical to the contents)

No seeding (particle generation by

nucleation only)

Nuclei initially are of negligible size

(compared to product)

No agglomeration or breakage (only

nucleation and growth)

and for size independent growth (SIG),

There is no SDG (size dependent growth).

At any time the growth rate is the same for

all crystals,

alternatively for size dependent growth (SDG),

Nuclei have a distribution of growth rates

G given by f(z) where z = G/Gm, where

Gm is the mean growth rate of the nuclei.

The methods for SDG material will build on that for SIG,

so this will be summarised first. For SIG (size independent

growth) materials, the calculations are relatively simple

(Randolph and Larson, 1988).

The number size

distribution is exponential i.e. f(x) = exp(-x), where x =

L/Gm and Gm is the SIG growth rate (change in volume

equivalent size with time), is the mean residence time in

the crystallizer and Gm the number mean size . The

distribution by mass then is third order Gamma. The total

number of crystals in the crystallizer is N = B where B is

the secondary nucleation rate (number per unit time per unit

volume of contents) so the mass of crystal per unit contents

volume MT = 6 V C N (Gm)3. Now B and Gm are

a selected material balance (MT = si s) linking the mass of

crystal to the drop in solution supersaturation (si s) will

allow s to be evaluated and hence Gm and thus the number

and mass distributions and the crystal content.

Example of Design

Consider an MSMPR crystallizer operating at 25 oC, fed

with a solution of ibuprofen in water-free ethanol saturated

at 35 oC. From the solubility relation the ibuprofen

concentration in the feed ci = 1.754 kg I / kg E and at

equilibrium at 25 oC, c* = 1.138. So the maximum yield

will be 0.616 kg of crystal per kg of ethanol in solution.

This corresponds to a crystal content again of 22% w/w.

Assuming SIG behaviour, we can write si - s = kG3 kB C

4 s (3a+b) F1 10-18, where si is the inlet supersaturation as

(I/E) w/w, s is the exit supersaturation, G = kG*sa with a =

1 and kG = 10.6 m/min/unit (I/E), B = kB*sb with b = 1

and kB = 1.73 * 108 #/min/(kg slurry)/(unit of (I/E)), C is

the crystal density, F1 = 0.363 kg E/kg init. solution is a

conversion factor to allow for nucleation being based on

slurry and supersaturation on ethanol,

10-18 is the

conversion from m to m and is the mean residence time

of crystals in the vessel. This equation may be solved for s,

from which the recovery (above the solubility), the mean

size and the growth rate may be evaluated. The mean size

does not change much with residence time and is predicted

to have a value as volume median size L[v, 0.5] of ~ 270

m corresponding to a number mean size L10 of 73 m.

The recovery and steady growth rates are shown as a

function of chosen mean residence times in Figure 11.

Figure 11 suggests it may be economic to operate the

MSMPR crystallizer at about 3 h mean residence time. This

would be decided after an economic analysis of the value of

the extra recovery against the extra capital cost.

Figure 11. Recovery and growth rate for MSMPR crystallizer without

GRD.

Figure 12. Size distribution by mass of product from MSMPR. The dotted

vertical line is the volume (mass) median size of the distribution

for mean residence times 2 h or greater. The spread given

by the coefficient of variation on a volume basis CVV is

0.50.

Theory for SDG material

Now the nuclei have a distribution of growth rates G given

by the distribution f(z), where f(z) dz is the fraction of the

nuclei having dimensionless growth rates z = (G/Gm)

between z - dz/2 and z + dz/2, and Gm is the mean of the

distribution of growth rates.

Figure 13 shows the

distribution of growth rates for nuclei having a log Normal

distribution of growth rates with a CVG (coefficient of

variation = standard deviation/mean) of 0.50. Now each

growth range fraction f(z) dz will give an exponential size

distribution with L (i.e. each behaves like a simple SIG

MSMPR) which is given by f(z) dz e-L/zGm where is the

mean residence time in the crystallizer. So adding all these

growth fractions the product size distribution is given by,

- L

(4)

crystallizers.

collapses to the usual MSMPR exponential size distribution

f(L) = e-x, as above. With SDG the product number size

distribution may be found by numerical integration. Figure

14 (red curve) shows the distribution of crystal sizes f(L)

plotted against crystal size L from a continuous well mixed

crystallizer. This was obtained by numerically integrating

the above equation.

For SIG, Figure 14 the log (f[L]) (number density) vs. size

would be a straight line (the blue line, the simple MSMPR

solution). The typical concave upward curvature of the

number distribution for SDG (the red curve in Figure 14) is

the result of size dependent growth. Note that the SDG

curve lies below the simple result at low sizes and above at

lower.

Sample calculation

Considering the above MSMPR case (Figure 12) the

corresponding mass (volume) distribution (satisfying the

material balance) can be calculated. The two curves are

shown in Figure 15. The SDG has a wider spread of sizes

CVV = 0.73 compared with the SIG case with CVV = 0.50.

The impurity concentration is again 1.26%.

VII.

OTHER CASES

other cases, e.g. aqueous ethanol solutions, evaporation of

solvent, salting out with water, fed batch, plug flow or

classifying crystallizers. The information found in this

study provides sufficient information for the majority of

cases to be modelled.

distribution.

IX. REFERENCES

self seeding crystallizer.

VIII.

NOMENCLATURE

a,b

order of growth and nucleation rates

B

nucleation rate, #/min/kg slurry

C

ibuprofen concentration, kg I/kg E

CV

coefficient of variation = std. dev./mean

E

ethanol and mass of ethanol

f(L)

number size distribution density function, m-1

F, F, F1 factors

G

growth rate, m/min

I

ibuprofen

nucleation rate constant, #/min/kg sl./(I/E)

kB

kG

growth rate constant, m/min/(I/E)

L

crystal size (vol. equiv.), m

mi

ith moment about mean

M

mass of crystals, kg

suspension density, kg crystals/cryst. vol.

MT

N

number of crystals

s

supersaturation = (I/E)

Sk

skewness, m3/3

T

temperature, oC

XW

water content = W/(E+W)

W

water

z

dimensionless growth rate

Z

impurity

V

i

C

ith moment about zero size

crystal density, g/cc

standard deviation

growth

G

mean

m

r

reference

s

seed

volume

V

*

equilibrium

Structure determination of a new polymorph of racemic ibuprofen

from lab XRPD data. The 8th Pharmaceutical Powder X-ray

Diffraction symposium, Glasgow, Scotland.

Dudgnon E., Danede, F., Descamps, M. & Correia, T. N. (2008), Evidence

for a new crystalline phase of racemic ibuprofen. Pharmaceutical

Research, 25, 2853-2858..

Garzon, L.C. & Martnez, F., (2004) Temperature dependence of solubility

for ibuprofen in some organic and aqueous solvents, J. Solution

Chemistry, 33(11), 1279 1395.

Gracin, S. and Rasmuson, A. C. (2002) Solubility of phenylacetic acid, phydroxyphenylacetic

acid,

p-aminophenylacetic

acid,

phydroxybenzoic acid, and ibuprofen in pure solvents. J. Chem. Eng.

Data, 47, 1379-1383.

Lerdkanchanaporn S. and Dollimore, D. (1997), A thermal analysis study

of ibuprofen. Journal of Thermal Analysis, 49(2), 879-886.

Randolph, A.D. and Larson, M.L. (1988), Theory of Particulate Processes,

2nd ed., Academic Press New York.

Rashid,A.M. (2011), Crystallization Engineering of Ibuprofen for

Pharmaceutical Formulation, PhD thesis, Chemical Engineering, The

University of Queensland,.

Rashid, A., White, E.T,, Howes, T., Litster, J.D. and Marziano, I. (2008),

Racemic ibuprofen solubility in ethanol and aqueous ethanolic

mixtures, Proc. Chemeca 2008, Newcastle, CDROM IBSN85825-8235, Instn Engrs. Australia, Paper 313 (9 p), 1393-1401.

Rashid, A., White, E.T., Howes, T., Litster, J.D. and Marziano, I. (2009),

Metastable zone width for racemic ibuprofen in ethanol and aqueous

ethanol mixtures. Proc. Chemeca 2009, Perth, CDROM IBSN 9780858259-2255, Instn Engrs. Australia, Paper 118 (9 p).

Rashid, A., White, E.T., Howes, T,. Litster, J.D. and Marziano, I. (2010),

Growth rates of ibuprofen crystals grown from ethanol. Proc Chemeca

2010, Adelaide, Flash drive, IBSN: 978-0858259713, Paper 377 (7 p).

Rashid, A., White, E.T., Howes, T., Liu, L.X., Litster, J.D. and Marziano, I.

(2011), Nucleation kinetics for ibuprofen crystals grown from

aqueous ethanol, Proc Chemeca 2011, Sydney, Flash drive, IBSN:

978-0858259225, Paper 107 (9 p).

White, E.T., Iswanto, N. and. Hardin M.T. (2006), Isothermal batch

crystallization with CH seeds and integer order kinetics, Paper

presented at World Congress on Particle Technology 5. Florida US,

Apr, 6 pages.

White, E.T., Mackintosh, D.L., Butler, B.K., Zhang, H. and Johns, M.R.,

(1998), Modelling growth rate dispersion in sugar crystallization, Proc.

Aust. Soc. Sugar Cane Technol., 20, 524-531.

- Laporan AspirinUploaded byAnonymous ldgGa5LY
- Kinetics of Seeded Batch Cooling CrstallisationUploaded byChanakya Ranga
- 21712_13.pdfUploaded byGaettan Katamba
- SterilisasiUploaded byCristian Gonzales
- UTOMOUploaded byzeolium
- 385-389 (2)Uploaded byingcardona
- Lecture 1Uploaded byAnonymous ETPqS5NG9
- Crystal GrowthUploaded bySakthi Vel
- chem 5 labUploaded byMUHAMMAD AKRAM
- Neoprene - Dry Grades Selection Guide (1)Uploaded byFernando Sanez
- SOLUBILITY ENHANCEMENT TECHNIQUES: REVIEWUploaded byIjupbs Ijupbs
- Chem BookUploaded bySairam Gudiseva
- BetaUploaded byEmj Rocero
- 10.1063@1.4971885Uploaded byAtras
- STAUploaded byAnna Colun
- Information BookletUploaded bynowhinesonchemistry
- is.5055.1996.pdfUploaded byak
- Advances in Polymer TechnologyUploaded byLuis Fernando Guayllas Poma
- Adikaari 2007 Excimer Laser CrystallizationUploaded bycvdamme
- Organic SynthesisUploaded byShafiqueDeshong
- IFR - 1Uploaded byJai Shane Cañete Raman
- achap10Uploaded byMuhammad Sajid
- Fine Tuning of the Sizes of FePt Nano ParticlesUploaded byapi-3709636
- Daftar pustakaUploaded byBilly Danibrodus Sendra
- Phase Change Materials and Their Application to Nonvolatile MemoriesUploaded byTahsin Morshed
- Chapter 13 WsUploaded byranbus
- chapter_12.pptxUploaded byJosé Brites
- Geometric Method Presentation Final 1.Pptx LatestUploaded byDanner Perkins
- iochemical evaluation of antioxidant activity and polysaccharides fractions in seaweedsUploaded byGJESM
- Design and Characterization of Nanocrystals of Lovastatin for Solubility Dissolution EnhancementUploaded byg20kp

- XFEMUploaded byQiang Fang
- Power ElectronicsUploaded bymesahoo
- Tutorial for the Heated Pipe With STARUploaded byAnonymous 8te2h1
- 3310-lr1 james cherryUploaded byapi-301117398
- Trigonometry WorksheetUploaded bytutorciecle123
- Sample Chapter 17Uploaded byFatimah Shellya Shahab
- GATE Material Thermodynamics EnggUploaded byZoher Painter
- SOBM Calculation SheetUploaded byChintan Gohel
- 354021318 xUploaded byosegeno654321
- Dental WaxesUploaded bydrgayen6042
- Lighting Voltage Supprestion in GisUploaded byajay_kairi
- Electromiagnetictheory-lahanasUploaded byRohit Bhardwaj
- Temelj - Spread FootingUploaded byGordana Sejfulovski
- Improving Dichromated Gelatin SensitivityUploaded byArash Rohani
- Oral Rehydration SaltsUploaded byKadek Adit Wiryadana
- Sean A. Hayward- Black holes and traversible wormholes: a synthesisUploaded byRtpom
- ExtrusionUploaded byAakash Singh
- Vibration Characteristics of Rolling Tires 2008Uploaded bySIMULIACorp
- Ridgely-Nevitt C.resistance of a High.1967.TRANSUploaded byTi Annel
- Practical ListUploaded byRana Rashid Abdul Aleem
- plasma and dc bias.pdfUploaded byMaureen Kae Atractivo Subala
- PhysicsUploaded byKeshov Chabra
- particles of matter have space between themUploaded byDeepak Raj
- AstroCel® IUploaded bymohdzamry
- X-ray Fundamentals Part 3 V1.7 Theory TrainingUploaded byKo Phyo Wai
- Tutorial Chemical Energetics Part I SolutionsUploaded byDarren Lim
- MATH12 Spherical Trigonometry by JohnsonUploaded byPaolo Gochingco
- TYPES OF WAVESUploaded byAnup Devkota
- CHE136-1 Week 1 SphericityUploaded byRalph Carlo Evidente
- Kinetic Molecular Theory PptUploaded byAbhishek Saxena