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Reactions and Separations

Apply Solubility
Theory for Process
Improvements
For solid compounds that dissolve in solvents
Michael J. Gentilcore
Tyco Healthcare but do not ionize, the thermodynamics of
solubility can provide valuable predictions
and insights.

ANY CHEMICAL PROCESSES DEPEND on The activity of a solid in solution is described by

M the solubility of solids in liquid solvents to de-


fine key process steps. Some common examples
include crystallization to isolate a product at good yields,
the following thermodynamic relationship (3):

d ln ans HnF
= (3)
recrystallization to remove impurities, reaction where a dT RT 2
solid reactant must be dissolved in order to participate in
a chemical conversion, and filtration where a dissolved This relationship is similar to the Clausius-Clapey-
product solution is filtered from a solid catalyst. Solubili- ron equation for vapor pressure of a pure liquid:
ty is often a major determinant of the economic effec-
d ln p 0 H V
tiveness of a particular process step. = ( 4)
Typically, solubility data are provided as experimental dT RT 2
data summarized in tabular or graphical form, and they
are often extremely limited in scope. Solubility theory Substituting Eq. 1 into Eq. 3 and integrating, assum-
can easily be applied to many compounds that do not ing that the heat of fusion is constant from the melting
ionize or dissociate to provide and predict solubility over point temperature (Tm) to any other temperature (T), the
a wide range of conditions. This article reviews the ba- equation for the solubility of solids in solution is (3):
sics of solubility theory and discusses how to apply solu-
bility theory to process improvement. HnF 1 1
ln n x n = (5)
R T Tm
Solubility theory of non-electrolytes
The activity of a component in a solution is a multi-
ple of its mole fraction (3): Equation 5 is applicable to compounds that do not
ionize or dissociate in solution and where the solid phase
an = nxn (1) is pure. It cannot be used for electrolytes like salts, or-
ganic acids and amines. Derivations are available for
The multiple is called the activity coefficient. This cases where the heat of fusion is not assumed to be con-
is the same activity coefficient used to correct Raoults stant (3). Systems where the solid phase is not pure are
law for predicting partial pressure above a solution: those where the solvent has a true solubility in the solid
phase as opposed to where the solvent is simply en-
pn = nxn pn0 (2) trapped or otherwise unremoved as free solvent that con-
taminates the solids. For extreme pressure changes (more

38 CEP March 2004 www.cepmagazine.org


the scope of this article. Many of these methods require
Nomenclature computer subroutines to fit experimental data, and there-
fore are somewhat cumbersome when used for solubility
a = activity of a component in solution, dimensionless problems. Thus, this article will present only the van Laar
A = van Laar correlation parameter, cal/gmol correlation for simple two-component systems, which con-
B = van Laar correlation parameter, cal/gmol sists of the following two equations (1):
H = molal enthalpy, kcal/gmol
2
MW = molecular weight, g/gmol
A x1
p = partial pressure of component above solution, mmHg RT ln 1 = A1 + ( 9)
p0 = vapor pressure of pure liquid, mmHg B x2
R = universal gas constant = 1.987 cal/gmol/K 2
B x2
S = molal entropy, cal/gmol/K RT ln 2 = B1 + (10)
T = temperature, K A x1
V = molal volume, cm3/gmol
x = mole fraction of a component in solution, dimensionless By a few mathematical transforms, the van Laar corre-
X, Y = simplifying terms for van Laar correlation lation is especially useful in correlating solubility data
Greek Letters using linear regression. Equation 9 can be rearranged to:
= activity coefficient, dimensionless
1 A x1 1
= density, g/cm3
= + (11)
Subscripts RT ln 1 B x2 A
m = melting point
n = nth component Defining the following two mathematical transforms:
1 = first component
x1
2 = second component X= (12)
Superscripts x2
F = fusion, i.e., melting 1
L = liquid Y= (13)
S = solid
RT ln 1
V = vaporization
0 = standard state, pure liquid gives the equation:

A 1
than 100 atm), the change in solubility and melting points
Y= X+ (14)
B A
with pressure cannot be ignored. Derivations are available
for the change in solubility with pressure (3). Equation 14 is in the form of y = mx + b. A plot of trans-
The entropy of fusion is given by the equation (2): formed experimental data (Y vs. X) will be linear with inter-
cept 1/A0.5 and slope (A0.5)/B. If only a single solubility data
HF = TmSF (6) point exists, the van Laar equation can be reduced to a one-
parameter form by assuming the following relationship (1):
Substituting Eq. 6 into Eq. 5 give the following equiva-
A V1L
lent equation for solubility (1): = (15)
B V2L
S Eq.
F
Tmm6 into
1 Eq. 5 gives the following equiv-
F
ln Substituting
nn x nn =
nn
(7)
alent equation R for solubility
T (1): For the solid component, the molal volume of the pure
liquid melt is the proper volume to estimate i.e., not the
Finally, for ideal solutions, the activity coefficient is set specific gravity of the solid or the bulk density of the
to unity to give the ideal solubility equation (2): solid. The one-parameter simplification works best for
non-polar solvents and solutes (1). It is not reliable for
SnF Tm
ln x n = 1 (8) polar components.
R T
Examples
Activity coefficient correlations The following examples illustrate the general use of
Numerous methods to calculate an activity coefficient these equations.
are available (e.g., the Margules, Wilson, NRTL, UNI- Example 1 ideal solubility estimate. What is the ideal
QUAC and UNIFAC methods), but these are beyond the solubility at 25C of a compound that melts at 58C with a

CEP March 2004 www.cepmagazine.org 39


Reactions and Separations

heat of fusion of 8.1 kcal/gmol? Solution: Tm = 273 + 58 = using the goal seek feature in a spreadsheet or writing a
331 K and SF = (8.1/331)(1,000) = 24.5 cal/gmol/K. Solve user-defined function. Notice how the solubility has dra-
Eq. 8 for x: x = exp{(24.5/1.987)[331/(25 + 273) 1]} = matically increased for this compound (from 0.05 mole
0.255 mole fraction. Comment: The ideal solubility is inde- fraction at 25C to 0.33 mole fraction at 40C) as it ap-
pendent of the solvent. The solvents molecular weight will proached its melting point of 58C.
change the solubility on a weight-percent basis, but not the
mole fraction. Physical properties
Example 2 activity coefficient estimate. For the com- Only two physical properties are required to employ
pound in the first example, the observed solubility at 25C solubility theory, heat of fusion and melting point. Thermal
is 0.05 mole fraction. What is the activity coefficient? So- analysis systems that perform differential scanning
lution: a = 0.255 and x = 0.05. Solve Eq. 1 for : = calorimetry (DSC) and thermogravimetric analysis (TGA)
0.255/0.05 = 5.1. Comment: Activity coefficients are de- easily measure these properties if they are not otherwise
pendent on real data. The solvent was not stated in this ex- available in standard references.
ample, but the calculated activity coefficient is unique to DSC/TGA testing is quite common in research and pro-
that solvent in combination with the solid compound. cess development as part of the initial safety testing
Example 3 one-parameter van Laar correlation. For screening of new compounds. Typically, the focus of these
the compound in the previous examples, the solvent is tests is to assess thermal stability risks for compounds by
CCl4 (MW = 154 g/gmol, = 1.58 g/cm3). The solid is quantifying decomposition temperatures, mass changes on
nonpolar (MW = 218 g/gmol). The density of the liquid decomposition, heat of the decomposition reactions, and
from the solid upon melting is 0.90 g/cm3. What are the decomposition reaction kinetics.
van Laar parameters for the solvent and for the solid? With the predominant focus on collecting safety data, heat
Solution: Assign component 1 to be the solid and compo- of fusion and melting points may be observed but not report-
nent 2 to be the solvent. V1 = 218/0.90 = 242.2 cm3/gmol ed. If they are reported, their value in predicting solubility
and V2 = 154/1.58 = 97.5 cm3/gmol. Per Eq. 15, A/B = and guiding process development is often overlooked.
242.2/97.5 = 2.484. RTln1= (1.987)(25 + 273)[ln 5.1] = Some good advice ask specifically for these proper-
964.7 cal/gmol. x1 = 0.05 and x2 = 1 0.05 = 0.95. Solve ties when DSC/TGA work is performed.
Eq. 9 for A: A = (964.7)(1 + 2.484[0.05/0.95])2 = 1,233.4.
B = A/(A/B) = 1,233.4/2.484 = 496.5. Thus, A = 1,233.4 Application of theory
cal/gmol and B = 496.5 cal/gmol. Comment: The same pa- As can be seen in the examples, a very minimal amount
rameters are used for both the solid and the solvent. In this of data (the melting point, the heat of fusion and a single
example, Eq. 9 is used for the solid and Eq. 10 for the sol- solubility data point) can quickly be used to predict the en-
vent. The assignment of component 1 and 2 is arbitrary. If tire solubility curve. When available, additional data points
more than one data point is available, obtain the van Laar showing temperature dependence will increase confidence
parameters by plotting 1/(RTln1)0.5 vs. x1/x2. in the estimated solubility curve.
Example 4 partial pressure estimate. At 25C, the A solubility curve could be used to estimate yield losses
vapor pressure of CCl4 is 114 mmHg. What is the vapor for material balance for a process with a crystallization/fil-
pressure of a CCl4 solution at 25C (298 K) saturated with tration step. The ratio of the solubility of an impurity to
the solid in the previous examples? Solution: First, find 2 the solubility of a product could be used to define the best
using Eq. 10: 2 = exp {[496.5/(1.987 298)][1 + crystallization temperatures and solvent amounts. A solu-
(496.5/1,233.4)(0.95/0.05)]2} = 1.011. Then, Eq. 2 gives p2 bility curve could also be used to define minimum purge
= (1.011)(0.95)(114) = 109.5 mm Hg. Comment: Note that amounts of impurities required in a recycle process.
solubility data have been used to estimate a vapor-liquid When optimizing solvent charges and crystallization
equilibrium quantity. Activity coefficients from solubility temperatures for a process, fresh solvents should not be ar-
data can be used to estimate any property based on solution bitrarily added to a process to prevent slurry concentra-
theory such as boiling points or osmotic pressures (3). tions from becoming too thick. The amounts of solvents
Example 5 solubility estimate. What is the solubility added to a process should be based on what is needed to
of the compound in the previous examples at 40C (313 K) control impurities based on solubility. Process mother
in CCl4? Solution: The following trial-and-error procedure liquors can be recycled as diluents (rather than fresh sol-
is used: guess x1, calculate 1 by Eq. 9, calculate x11 and vents) to control the slurry concentration.
compare it to the value of x11 calculated from Eq. 7. If x1 Solubility theory could be used to evaluate operating con-
= 0.33, then x2 = 1 0.33 = 0.67, and 1 = ditions for process improvement potential that are not easily
exp{[1,233.4/(1.987 313)][1 + (2.484)(0.33/0.67)]2} = explored by a bench chemist (e.g., at elevated pressures and
1.49; x11 = (0.33)(1.49) = 0.49; by Eq. 7, x11 = temperatures), prior to committing to an expensive research
exp{[24.5/1.987][331/313 1]} = 0.49. Comment: Com- program. Higher solubility at elevated temperatures might be
mon ways to deal with trial-and-error calculations include taken advantage of for several reasons, including:

40 CEP March 2004 www.cepmagazine.org


higher payloads for a reaction where the product is kept Process improvement example:
in solution and filtered away from other solids such as het- Eliminating reaction solvent
erogeneous catalyst, solid absorbents, or byproduct salts A process dissolves a solid S in a solvent and then re-
faster reaction kinetics, especially for reactions where acts it with a liquid L to create a product P according
the solids are predominantly out of solution to the following stoichiometry: S + 8L P. P has a melt-
reduced energy costs, solvent costs and waste disposal ing point of 180C and a heat of fusion of 4 cal/gmol. L
costs, which can be achieved by processing with reduced has a normal boiling point of 110C. What is the best-case
amounts of solvent present; this is especially true if the sol- usage of L if the reaction is conducted only in L at atmo-
vent must be subsequently evaporated or distilled, or a reac- spheric reflux conditions and the reaction must finish as a
tion byproduct must be stripped to complete the reaction uniform solution of P in L? For simplicity, ignore any
elimination of reaction solvent by conducting the re- boiling point elevations.
action of a solid with no solvent in a small excess of a liq- Answer: The ideal solubility mole fraction of P at
uid reactant. 110C is 0.445. The amount of L needed over stoichio-
Solubility may also be used to estimate vapor/liquid metric requirements is (1 0.445)/0.445 = 1.25 moles
equilibrium or other properties predicted from solution L/mole of P. The best-case usage is then 8 + 1.25 = 9.25
theory such as osmotic pressure. moles of L per mole of P, or 15% over theory. This usage
could be compared to that of the current process, the raw
Process improvement example: material cost for the usage of original process solvent,
Crystallization temperature and the operating costs for any solvent recovery steps for
A process crystallizes a product from a solvent. The the original solvent.
final crystallization temperature is less than 10C to mini-
mize the yield loss from solubility. The process is run very Final thoughts
dilute to keep an impurity from co-crystallizing. The phys- Process simulation software has made extensive in-
ical property information for the system is presented in vestment in solution theory, especially for non-elec-
Table 1. Do you agree the cold temperatures and extra sol- trolytes, for prediction of vapor/liquid equilibrium. An
vent are the proper approach? activity coefficient prediction based on structure (UNI-
Answer: The solubility of the impurity will increase FAC) is a common feature in such software. However,
faster with temperature than the solubility of the product, the extension of activity coefficient to the solubility of
as illustrated by the ideal solubilities shown in Table 2. non-electrolytes has often been overlooked in process
Increasing the crystallization temperature from 10C simulation software. CEP

to 25C and cutting the amount of solvent in the pro-


cess by one-half to two-thirds is the directionally cor-
rect approach to improving the process. The combined MICHAEL J. GENTILCORE is an engineering consultant at Tyco
Healthcare Mallinckrodt (675 McDonnell Blvd., Hazelwood, MO
change of warmer crystallization temperatures and half 63042; Phone: (314) 654-4031; Fax: (314) 654-7174; E-mail:
the solvent will result in no increased product losses mike.gentilcore@tycohealthcare.com). He has over 25 years of chemical
and an improved ability to keep impurities in solution. engineering experience in design, research and development, and
Estimating activity coefficients could further refine manufacturing, and he holds several patents. He received a BS in
chemical engineering from Clarkson Univ. and an MS in engineering
these estimates. management from the Univ. of MissouriRolla. He is a member of AIChE
and a licensed P.E. in Missouri.
Table 1. Physical property data for
crystallization temperature example.

Product Impurity Literature Cited


Melting Point, C 150 165 1. Reid, R. C., et al., The Properties of Gases and Liquids, 4th
Heat of Fusion, cal/gmol-C 8 13 ed., McGraw-Hill, New York, NY (1987).
2. Castellan, G. W., Physical Chemistry, 2nd ed., Addison-
Wesley Publishing Co., Reading, MA (1971).
3. Hildebrand, J. H., and R. L. Scott, The Solubility of Non-
Table 2. Ideal solubilities for electrolytes, 3rd ed., Reinhold Publishing Co., New York, NY
crystallization temperature example.
(1950).

Product Impurity Website of Interest


10C 0.0091 0.00028 www.chemstations.net/documents/examples.htm Readers
who use CHEMCAD may find the information at the Predictive
20C 0.0185 0.00090
Crystallizer link on this site useful.
Increase in solubility 2.0 times 3.2 times3

CEP March 2004 www.cepmagazine.org 41