Available online at www.sciencedirect.com
International Journal of Pharmaceutics 357 (2008) 305–313
Pharmaceutical Nanotechnology
Release kinetics of procaine hydrochloride (PrHy) from
pH-responsive nanogels: Theory and experiments
Jeremy P.K. Tan
a
, Angeline Q.F. Zeng
a
, Chean C. Chang
a
, Kam C. Tam
b,∗
a
School of Mechanical and Aerospace Engineering, Nanyang Technological University, 50 Nanyang Avenue, Singapore 639798, Singapore
b
Department of Chemical Engineering, University of Waterloo, 200 University Avenue West, Waterloo, Ontario, Canada N2L 3G1
Received 30 July 2007; received in revised form 10 January 2008; accepted 29 January 2008
Available online 8 February 2008
Abstract
pH-responsive nanogels consisting of methacrylic acid–ethyl acrylate (MAA–EA) cross-linked with di-allyl phthalate (DAP) were synthesized
via emulsion polymerization. Drug release studies were conducted under different pHs, drug loading and concentration gradient difference. The
drug loading capacity depended on the cross-link density and MAA–EA molar content, where a lower cross-link density and higher MAA–EA molar
content resulted in higher loading capacity. A drug selective electrode was used to directly measure the concentration of procaine hydrochloride
(PrHy) released from MAA–EA nanogels. More than 50 data points were acquired, where the mathematical fitting to the Berens and Hopfenberg
model allowed the parameters describing the contributions of chain relaxation and diffusion process to be determined. The release rate increased
with pH and concentration gradient difference due to a reduction in diffusion barrier and higher concentration gradient driving force, respectively,
but it decreased with drug loading as the nanogel could not relax from the compact structure as evident from the contribution of Fickian diffusion,
φ
F
, and chain relaxation, φ
R
. A balance between chain relaxation and Fickian diffusion process controlled the release of drugs from these pH-
responsive nanogels. Exponential relationships could be established between diffusion coefficient, characteristic relaxation time and various physical
parameters, where the drug release kinetics could be predicted in a quantitative manner.
© 2008 Elsevier B.V. All rights reserved.
Keywords: pH-responsive nanogels; MAA; In vitro release; Drug selective electrode; Berens and Hopfenberg model
1. Introduction
New controlled release systems such as nanogels that are
responsive to pH (Pillay and Fassihi, 1999; Kim and Peppas,
2003; Kurkuri and Aminabhavi, 2004) or ionic strength (Sutani
et al., 2002) are interesting and could be considered for pos-
sible applications as specific drug carriers. They are useful in
pulsed drug delivery, where their structures or intra-molecular
interactions will change in response to external stimuli. Various
types of controlled drug delivery formulations have been consid-
ered, depending on the end-use requirements, the most popular
being nanoparticles followed by microparticles and hydrogels
(Kumar et al., 2002). Various pH-responsive nanogels consist-
ing of methacrylic acid–ethyl acrylate (MAA–EA) cross-linked
with di-allyl phthalate (DAP) (Tan et al., 2004, 2005) have been
synthesized via the emulsion polymerization technique, where
∗
Corresponding author. Tel.: +1 519 888 4567x38339; fax: +1 519 746 4979.
E-mail address: mkctam@uwaterloo.ca (K.C. Tam).
the polymers exist as insoluble lattices at low pH. By increasing
the pH, ionization of acid groups is enhanced, which increases
the solubility and enhances the electrostatic repulsion between
polymeric chains, yielding interesting changes in particle inter-
action potential. An advantage of using pH-responsive nanogels
is that the release profile of drugs can be controlled by manipu-
lating the pH or ionic strength.
Recently, we have reported the benefits of using a drug
selective electrode (DSE) for measuring the drug release from
pH-responsive microgels (Tan and Tam, 2007). Previous stud-
ies on drug release using nanoparticles have focused on using
techniques such as UV-spectroscopy (Govender et al., 1999;
Soppimath et al., 2001; Yang et al., 2004) or high-performance
liquid chromatography (HPLC) (Torres-Lugo and Peppas, 1999;
Foss et al., 2004) to monitor the concentration of drugs. All these
techniques required the use of a dialysis membrane or centrifugal
machine to isolate the nanoparticles from drugs prior to measure-
ments. Such techniques are often fraught with problems, such
as the probable absorption of drugs on the dialysis membrane
(yielding a lower measured drug concentration), and the intro-
0378-5173/$ – see front matter © 2008 Elsevier B.V. All rights reserved.
doi:10.1016/j.ijpharm.2008.01.058