Controlled drug delivery systems that are considered
to deliver drugs at predetermined rates for predefined timeframe, have been
utilized to control the limitations of conventional drug formulations. In some
cases drug has to be delivered in response to pH in the body, it would be
invaluable if the medication could be controlled in a way that correctly
matches the physiological needs at appropriate circumstances at the predefined
target sites. The scope of fluids in different sections in the GIT may offer
environmental stimuli that are responsive to drug release ph. Stimuli-responsive
polymers are one of the most important excipients in in DDS and pharmaceutical
formulations. These are designed to produce specific and desired pH
concentration activated response according to body physiological environment
PH sensitive drug delivery systems (PSDDS) supply the
drug at particular time according to the pathophysiological need of the body
and gives enhanced patient compliance and therapeutic efficacy that is the
reason it is gaining significance.
All the PH sensitive polymers consist of pendant
acidic (carboxylic acid and sulfonic acids) and basic (ammonium salts) groups
that either accept or discharge protons in response to changes in environmental
PH. The polymers having substantial number of ionizable groups are called
The charge density of the polymers is dependent on the
PH and ionic concentration of the external solution (in which the polymer is
introduced). Swelling or de-swelling of the polymer can be caused by modifying
the pH of the solution.
sensitive ionization of polyelectrolytes. Poly (acrylic acid) at the top and
poly (N, N-diethylaminoethyl methacrylate) bottom
low pH poly-acidic polymers are un-swollen as the acidic groups will be
protonated and hence unionized.
increasing pH poly-acidic polymers are going to swell
polybasic polymers with diminishing pH ionization of basic group is going to
of acrylic acid are mostly used pH sensitive polymers.
Methodologies for PH Sensitive Drug Delivery
Properties of PH Sensitive Hydrogel and Mechanism
Hydrogels are made up of cross linked polyelectrolytes
that have large differences in swelling properties relying upon the environmental
scale of PH. The pendant acidic or basic groups on polyelectrolytes experience ionization
however it is difficult due to electrostatic effects applied by different
adjacent ionized groups, creating the apparent dissociation constant (ka) completely
different from that of corresponding monoacid or monobase, ionizable groups that
are present on polymer chains leads to swelling of the hydrogels. The swelling
of the polyelectrolyte hydrogels happens due to the electrostatic repulsion that
is among charges present on the polymer chain, the extent of swelling is
affected by means of any condition that lessen electrostatic repulsion such as
pH, ionic strength and counter ions type. The swelling and pH responsiveness of
polyelectrolyte hydrogels can be maintained by usage of neutral comonomers such
as 2-hydroxyethyl methacrylate and methyl methacrylate.
Different hydrophobicity is provided by different
comonomers to the polymer chain, as a result distinct pH sensitive behaviour is
Hydrogels made up of poly methacrylic acid attached
with poly ethylene glycol have special pH sensitive properties. The acidic
protons of carboxylic acid of PMA at low pH interact with ether oxygen of PEG
via hydrogen bonding resulting in condensation of hydrogels. At high PH the
carboxylic groups of PMA become ionized, the resulting complexation ends up in
swelling of the hydrogels.
Applications of pH sensitive hydrogels
Controlled drug delivery
PH Sensitive hydrogels are usually used to expand
controlled release formulations for oral administration. The pH in stomach
(<3) is quite different from impartial pH in the intestine and that difference is sufficient to generate pH sensitive behaviour of polyelectrolyte hydrogels. For poly-cationic hydrogel the swelling is minimum at neutral pH, as a result minimizing the release of drug from hydrogels. This characteristic has been used to stop the release of foul-tasting drugs in the neutral pH environment of the mouth. Poly cationic hydrogels that are in the form of semi-IPN have been used for the drug delivery in stomach. Semi-IPN of cross-linked chitosan and PEO have shown more swelling under acidic conditions (in stomach). This kind of hydrogels would be ideal for localized delivery of antibiotics such as amoxicillin and metronidazole in the stomach for Helicobacter Pylori treatment. Hydrogels that are made up of PPA and PMA can be used to advance formulations that release drug in the neutral pH environment. Hydrogels comprising of poly anion (PPA) crosslinked with azo-aromatic cross-linkers were developed for colon-specific drug delivery. Swelling of such hydrogels in the stomach is minimal so the drug release is also minimized. The degree of swelling increases as hydrogels is passed along the intestinal tract due to increasing pH leading to the ionization of carboxylic groups. The azo-aromatic crosslinks of hydrogels can be degraded only in the colon by azo-reductase generated through the microbial flora of the colon. The degradation kinetics and pattern can be controlled by cross-linking density. Schematic illustration of oral colon-specific drug delivery using biodegradable and pH-sensitive hydrogels. Super porous hydrogels for transport of drug in the alkaline pH have been formulated involving acrylamide and methacrylic acid by free radical polymerization. They are swelled only in the basic pH and have shown very fast swelling kinetics. Super porous hydrogels are formulated as gastro-retentive drug delivery system as they swell only in acidic pH and are exceptionally sensitive. Schematic illustration of on-off release from a squeezing hydrogel device for drug delivery Hydrogels that are responsive to both temperature and pH can be made simply by combining ionisable and hydrophobic functional groups to the corresponding hydrogels. When a small quantity of anionic monomer such as acrylic acid is mixed in a thermos-reversible polymer, the LCST of the hydrogel is dependent on the ionization of pendant carboxyl groups. As the pH of the medium increases above the pka of carboxyl groups of the polyanions, the LCST shifts to higher temperatures due to the increased hydrophilicity and charge repulsion. Terpolymer hydrogels consisting of NIPPAAm, acrylic acid and 2-hydroxyethyl methacrylate were formulated for the pulsatile delivery of streptokinase and heparin as a function of stepwise pH and temperature changes.