Solubility of Benzodiazepines in Polyethylene Glycol 200 + Water Mixtures at 303.2 K Page: 519
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J. Chem. Eng. Data 2010, 55, 519-522
Solubility of Benzodiazepines in Polyethylene Glycol 200 + Water Mixtures at
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 chlordiazepoxide, diazepam, and lorazepam in polyethylene glycol 200 (PEG
200) + water mixtures at 303.2 K were reported. The solubility of each drug increased exponentially with
the addition of PEG 200 and reached the maximum value in neat PEG 200. The Jouyban-Acree model was
used to mathematically describe the experimental data, and the solubilities were predicted using a previously
trained version of the Jouyban-Acree model for PEG + water mixtures and the solubility data in
monosolvents. The overall mean relative deviations of the models were 3.7 % and 18.3 %, respectively, for
the fitted model and the trained version.
Polyethylene glycols (PEGs) are water-soluble polymers with
a general formula of HO-(CH2CH20),-H and have been used
in many pharmaceutical formulations including oral, parenteral,
topical, ophthalmic, and rectal preparations.1'2 Generally, they
are regarded as nontoxic and nonirritant materials. PEGs are
also utilized in the industry to precipitate/crystallize proteins,
and stable formulation of protein powders has been developed
employing PEG-induced precipitation.3 PEGs are used in
pharmaceutical formulations by acting as a cosolvent (lower
molecular weight PEGs) to increase the aqueous solubility of
poorly water-soluble drugs in liquid pharmaceutical formulations
and/or as dissolution rate enhancers (higher molecular weight
PEGs) in solid dispersions.4 PEGs are stable and low toxic
pharmaceutical excipients which are used in many commercially
available oral and parenteral pharmaceutical formulations of
poorly soluble drugs.5'6 In addition to the solubilization power
of polyethylene glycol 200 (PEG 200), it possesses stabilization
ability on the enzymes and facilitates the biotransformation of
low aqueous soluble substrates in aqueous solutions.7
The solubility of drugs in PEG 200 + water mixtures is essential
information in drug development studies. The composition of PEG
200 in pharmaceutical preparations should be kept as low as
possible (usually a volume fraction less than 50 %), and the often
used method to optimize the solvent composition of the mixtures
for dissolving a desired amount of a drug in a given volume of the
solution is the trial-and-error approach which is both time-
consuming and expensive. Moreover, in the early stages of drug
discovery processes, the scarcity of the drug and/or drug candidate
* 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/je900330p CCC: $40.75
is another limiting factor. To address this issue, numerous
mathematical models have been presented for predicting the
solubility of drugs in water-cosolvent mixtures. These models and
their advantages and limitations were recently reviewed.8
Of the models developed in recent years, the 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
Sat Sat Sat
log xm,T =P log x,T + T2 log x2,T
where xSmt is the solute (mole fraction) solubility in the binary
solvent mixtures at temperature T; Ql and Q2 are the volume
fractions of the solvents 1 (PEG 200) and 2 (water) in the absence
of the solute; xf, and x2, denote the mole fraction solubility of
the solute in solvents 1 and 2, respectively; and Ji are the constants
of the model computed by a regression analysis.8 Knowledge of
these model constants, which requires 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 overcome 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 PEG 400 + water
mixtures at temperature (T) is9
Sat Sat sat 394.82____ 2_
log Xm, = (1) log Xl,T + P2 log X2,T T/K
355.28-912((1 -P2) 388.8991-2(P1 2- 2)2
which was trained using 80 data sets of Rytting et al.10 and
produced reasonable prediction error (r40 %).9 It should be
noted that we considered that the addition of the solvent 1
2010 American Chemical Society
Published on Web 06/15/2009
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Jouyban, Abolghasem; Shokri, Javad; Barzegar-Jalali, Mohammad; Hassanzadeh, Davoud; Acree, William E. (William Eugene); Ghafourian, Taravat et al. Solubility of Benzodiazepines in Polyethylene Glycol 200 + Water Mixtures at 303.2 K, article, June 15, 2009; [Washington, D.C.]. (digital.library.unt.edu/ark:/67531/metadc172356/m1/1/: accessed December 15, 2017), University of North Texas Libraries, Digital Library, digital.library.unt.edu; crediting UNT College of Arts and Sciences.