Arch Pharm Res Vol 33, No 12, 2003-2009, 2010
DOI 10.1007/s12272-010-1216-z
2003
pH-Independent Sustained Release Matrix Tablet Containing
Doxazosin Mesylate: Effect of Citric Acid
Kwang-Ho Cha*, Thanh-Huyen Tran*, Min-Soo Kim, Jeong-Soo Kim, Hee Jun Park, Junsung Park,
Wonkyung Cho, and Sung-Joo Hwang
Center for Nanotechnology-based New Drug Dosage Form, College of Pharmacy, Chungnam National University, Dae-
jeon 305-764, Korea
(Received May 31, 2010/Revised August 12, 2010/Accepted September 18, 2010)
The aim of this study was to develop a pH-independent sustained release matrix tablets of
doxazosin mesylate. The matrix tablets were prepared by direct compression technique using
polyethylene oxide, sodium alginate and citric acid as a pH modifier. Formulations were eval-
uated for an
in vitro
drug release study, erosion study, and the microenvironmental pH was
studied using the pH indicator methyl red. For formulations without citric acid, the extent
and rate of drug release in simulated gastric fluid were much higher than those in simulated
intestinal fluid. By adding the citric acid, the drug release rate in simulated intestinal fluid
was increased, and microenvironmental pH values within the tablets were maintained at low
pH during drug release. Furthermore, drug release from the matrix tablet containing 20% w/
w citric acid was comparable to that from a commercial product, Cardura
®
XL, and a pH-
independent release could be achieved. Therefore, the incorporation of citric acid as a pH
modifier to Polyethylen oxide-sodium alginate matrix tablets effectively produced pH-
independent doxazocin mesylate release profiles.
Key words:
Citric acid, Doxazosin mesylate, pH-Independent, Polyethylen oxide
INTRODUCTION
Doxazosin mesylate (DOX) is a quinazoline com-
pound, 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(1,
4-benzodioxan-2-ylcarbonyl) piperazine methanesul-
fonate. It is a potent candidate in relieving symptoms
of urinary obstruction in benign prostatic hyperplasia
and for the treatment of hypertension. Since it is the
salt of a weakly basic drug, its solubility is expected to
be pH-dependent. Therefore, formulations of this type
of drug for oral administration can result in decreas-
ing release rates with increasing pH in the gastro-
intestinal tract (Espinoza et al., 2000). In order to main-
tain the constant drug release rate over a period of 16-
24 h, the commercial product Cardura
®
XL (Pfizer)
was developed using an oral controlled osmotic pump
system (Chung et al., 1999). However, this system has
implications for high overall costs and time of
production, when compared to those of a conventional
matrix dosage form (Jain et al., 2005).
Recently, the trends in solving the solubility problem
of weakly basic drugs have focused on using organic
acids within the formulations (Martínez González and
Villafuerte Robles, 2003; Nie et al., 2004; Kranz et al.,
2005a, 2005b). Organic acids maintain low pH values
within tablets during drug release in intestinal pH
range and, thus, improve the solubility of drugs. The
increments of solubility have been obtained for the
weakly basic drugs, pelanserin hydrochloride, 4-amino-
pyridine or vinpocetine from hydroxypropylmethylcel-
lulose (HPMC) matrix tablets by adding citric acid into
the formulations. However, the effect of organic acids
on the release of weakly basic drugs from a polyethyl-
ene oxide (PEO) matrix or from the blend of PEO and
an anionic polymer (sodium alginate) has not yet been
*These authors equally contributed in this study as first author.
Correspondence to: Sung-Joo Hwang, Center for Nanotechnol-
ogy-based New Drug Dosage Form, College of Pharmacy, Chun-
gnam National University, Daejeon 305-764, Korea
Tel: 82-42-821-5922, Fax: 82-42-823-6566
E-mail: sjhwang@cnu.ac.kr
Selected by Editors