Solubility of 7-Chloro-2-methylamino-5-phenyl-3H-1,4-benzodiazepine-4-oxide, 7-Chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one, and 7-Chloro-5-(2-chlorophenyl)-3-hydroxy-1,3-dihydro-1,4-benzodiazepin-2-one in (Propane-1,2-diol + Water) at a Temperature of 303.2 K Page: 539
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J. Chem. Eng. Data 2010, 55, 539-542
Solubility of 7-Chloro-2-methylamino-5-phenyl-3H-1,4-benzodiazepine-4-oxide,
in (Propane-1,2-diol + Water) at a Temperature of 303.2 K
Abolghasem Jouyban,*'t Javad Shokri,* Mohammad Barzegar-Jalali,* Davoud Hassanzadeh,' William E. Acree, Jr.,"
Taravat Ghafourian,' and Ali Nokhodchi'
Faculty of Pharmacy and Drug Applied Research Center, Biotechnology Research Center, and Research Center for
Pharmaceutical Nanotechnology, Tabriz University (Medical Sciences), Tabriz 51664, Iran, Department of Chemistry, University
of North Texas, Denton, Texas 76203-5070, and Medway School of Pharmacy, Universities of Kent and Greenwich, Kent ME4
4TB, United Kingdom
Experimental solubilities of 7-chloro-2-methylamino-5-phenyl-3H- 1 ,4-benzodiazepine-4-oxide (chlordiaz-
epoxide), 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one (diazepam), and 7-chloro-
5-(2-chlorophenyl)-3-hydroxy-1,3-dihydro-1,4-benzodiazepin-2-one (lorazepam) in (propane-1,2-diol + water)
at T = 303.2 K were reported. The solubility of drugs increased with the addition of propane-1,2-diol and
reached the maximum values in pure propane-l,2-diol. The Jouyban-Acree model was used to fit the
experimental data, and the solubilities were reproduced using a previously trained version of the
Jouyban-Acree model and the solubility data in monosolvents in which the overall mean relative deviations
(OMRDs) of the back-calculated and predicted values with the corresponding experimental data were 4.2
% and 10.7 %. The solubilities of the three drugs were also predicted using a trained version of the log-linear
model of Yalkowsky, and the OMRD was 21.1 %.
Propane-1,2-diol (known as propylene glycol in the pharma-
ceutical industry) is a common and safe cosolvent to be used
in pharmaceutical formulations. Its solubilization power is
reasonably high, and in many drug formulations the concentra-
tion of propane-1,2-diol is lower than 50 %. Propane-1,2-diol
is a stable and low toxic pharmaceutical cosolvent which is used
as a single or in combination with other cosolvents such as
ethanol or polyethylene glycols in oral and parenteral pharma-
ceutical formulations of poorly soluble drugs.1,2
The solubility of drugs in propane-1,2-diol + water mixtures
is essential information in drug discovery and development
studies. The data could be used in recrystallization of drugs
and excipients (particle engineering) and also in formulation
processes. In addition to the solubilization effects of propane-
1,2-diol, it has a stabilization effect against hydrolytic reactions
as well, and it could increase the stability of benzodiazepines
in the aqueous formulations.3
Despite experimental effort for determination of the solubility
of drugs in water + cosolvent mixtures, a number of math-
ematical models have been presented for predicting the solubility
of drugs in these mixtures which are reviewed in a recent work.4
Of the numerous models developed in recent years, the
* To whom correspondence should be addressed. E-mail: ajouyban@
hotmail.com. Fax: +98 411 3363231.
t Faculty of Pharmacy and Drug Applied Research Center, Tabriz University
*Biotechnology Research Center, Tabriz University (Medical Sciences).
Research Center for Pharmaceutical Nanotechnology, Tabriz University
" University of North Texas.
' Medway School of Pharmacy, Universities of Kent and Greenwich.
10.1021/je900451d CCC: $40.75
Jouyban-Acree model is perhaps one of the more versatile
models. The model provides very accurate mathematical
descriptions for how the solute solubility varies with both
temperature and solvent composition. The model is
log Cm, T 1 log CS"+ 2 log C
CiT o 2,T
q1 2 2
where Ch, is the solute solubility in the binary solvent mixtures
at temperature T; q1 and q2 are the volume fractions of the
solvents 1 (propane-l,2-diol) and 2 (water) in the absence of
the solute; C T andT C denote the solubility of the solute in
the neat solvents 1 and 2, respectively; and Ji are the constants
of the model computed by a regression analysis.4 The existence
of these model constants which require a number of solubility
data in water-cosolvent mixtures for the training process is a
limitation for the model when the solubility predictions are the
goal of the computations in early drug discovery studies. This
limitation could be resolved using a trained version of the model
for a given water-cosolvent mixture. The trained version of
the Jouyban-Acree model for prediction of drug solubility in
(propane-l,2-diol + water) at temperature T is5
log t Sat sat 37.030102
logmT C = log Ca+ 02 log a
C-T 1, C2,T T
319.49102(q1 - 2)
Equation 2 is only applicable for solubility prediction of drugs
in (propane-1,2-diol + water), and the effect of the drug's
functional groups on the solubility was ignored. Equation 2
2010 American Chemical Society
Published on Web 07/31/2009
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Jouyban, Abolghasem; Shokri, Javad; Barzegar-Jalali, Mohammad; Hassanzadeh, Davoud; Acree, William E. (William Eugene); Ghafourian, Taravat et al. Solubility of 7-Chloro-2-methylamino-5-phenyl-3H-1,4-benzodiazepine-4-oxide, 7-Chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one, and 7-Chloro-5-(2-chlorophenyl)-3-hydroxy-1,3-dihydro-1,4-benzodiazepin-2-one in (Propane-1,2-diol + Water) at a Temperature of 303.2 K, article, July 31, 2009; [Washington, D.C.]. (digital.library.unt.edu/ark:/67531/metadc172351/m1/1/: accessed September 24, 2017), University of North Texas Libraries, Digital Library, digital.library.unt.edu; crediting UNT College of Arts and Sciences.