SOLUBILITY AND STABILITY OF PROROXAN
AT VARIOUS PH VALUES
S. P. Krechetov,
G. O. Nifontova,
O. V. Dolotova,
and M. S. Veselov
Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 52, No. 3, pp. 41 – 45, March, 2018.
Original article submitted April 26, 2017.
The solubility and stability of the nonselective a-adrenoblocker 1-(2,3-dihydro-1,4-benzdioxin-6-yl)-3-(3-
phenyl-1-pyrrolidinyl)-1-propanone hydrochloride (proroxan) at various pH values were investigated. It was
established that proroxan solubility was reduced for 3 < pH < 5.5, which corresponded to the protonated spe-
cies; was uncharacteristic for salts of organic bases; and increased its destruction. It was suggested that this pe-
culiarity of proroxan behavior in aqueous solutions could reflect complexation between its protonated and
unprotonated molecules. The results indicated that proroxan preparations using dosage forms and delivery
systems that provide its maximum absorption in the stomach must be developed.
Keywords: proroxan, solubility, stability, pH.
Use of pharmaceutical substances (PSs) with clinically
proven efficacy in modified-release dosage forms is a current
thrust in new drug design . Use of PSs in such drugs pre-
supposes the availability of detailed information on their
physicochemical properties, in particular, in aqueous systems
of various compositions and acidities .
nyl-1-pyrrolidinyl)-1-propanone hydrochloride] is a nonse-
lective a-adrenoblocker with peripheral and central action
 and is used to treat and prevent hypertonic crises  and
other types of sympathetic-adrenal pathology [5, 6]. Distinc-
tive features of proroxan are the rapid onset of its biological
effect and its short duration . The pharmacokinetics of
proroxan are characterized by rapid attainment of the maxi-
mum concentration in blood and prolonged elimination from
the body . The reported pharmacodynamics and pharma-
cokinetics of proroxan can be explained by common features
of the water solubility of organic bases . However, de-
tailed experimental data on the solubility and stability of this
PS at different pH values are required to develop modi-
fied-release drugs based on it.
PS proroxan was obtained from Chemical Line Co. Ltd.
(RF); 3-phenylpyrrolidine (3-PP) and H
(USA), sodium 1-heptylsulfonate, Alfa Aesar (USA);
high-purity MeCN, Cryochrom (RF); HCl, KCl, KH
NaCl, and chemically pure NaOH, Chemical Line (RF).
O (18 MW·cm) was used for chromatography;
O (PM.2.2.0020.15) obtained via reverse osmo-
sis, for solutions.
Proroxan and 3-PP in solutions were determined quanti-
tatively on a Shimadzu LC-30 high-performance liquid
chromatograph (Japan) with an SPD-M20A diode-array
UV-detector. Ion-pair chromatographic analysis used a Wa-
ters X-Bridge C18 column (150 ´ 4.6 mm; 3.5 mm) (USA).
Gradient elution used a mobile phase produced by mixing
sodium 1-heptylsulfonate solution (0.005 M) acidified with
to pH 3.0 (component A) and MeCN (component B)
at 0 – 2 min (5% B); 2 – 7.5 min (linearly to 40% B);
7.5 – 9 min (linearly to 95% B); and 9.0 – 14 min (95% B).
The mobile-phase flow rate was 1.8 mL/min at 29°C; in-
jected sample volume, 20 mL, detection, at wavelength
Solubility of proroxan was determined by the shake-flask
method  in hermetically sealed 5 mL round-bottomed
glass tubes. The effect of pH on proroxan solubility was
Pharmaceutical Chemistry Journal, Vol. 52, No. 3, June, 2018 (Russian Original Vol. 52, No. 3, March, 2018)
0091-150X/18/5203-0236 © 2018 Springer Science+Business Media, LLC
Department of Biological and Medical Physics, Moscow Institute of Phys
ics and Technology (State University), Dolgoprudnyi, Moscow Region,