Online - 2455-3891

Vol 10, Issue 6, 2017 Print - 0974-2441

Review Article

POLYMER GRAFTING AND APPLICATIONS IN PHARMACEUTICAL DRUG DELIVERY

SYSTEMS - A BRIEF REVIEW

MAHESH S SAKHARE*, HRISHIKESH H RAJPUT

Department of Pharmaceutics, Government College of Pharmacy, Aurangabad, Maharashtra, India. Email: [email protected]
Received: 21 February 2017, Revised and Accepted: 24 March 2017

ABSTRACT

Selection of proper polymer system is a critical step involved in the formulation of dosage form. Type of polymer/s incorporated in pharmaceutical
formulation majorly decides the stability of formulation and drug itself, mechanism, and rate of drug release. Pharmaceutical and biological therapeutics
are suffered from disadvantages such as short half-lives, poor bioavailability, and physical and chemical instability. Delivery of drugs to target site at a
specific concentration for a specific time can be successfully achieved by the use of suitable polymer/s. Thus, it is not necessary that available polymer
till the date should have all ideal properties with respect to above. This makes a demand of tailored polymers with desired features and introduces
concept of grafting for making new polymers to be used in dosage forms. Grafting can be achieved by various techniques described herein and can
be analyzed by various modern analytical techniques including infrared, NMR, X-ray diffractometer, and differential scanning calorimeter. These
grafted polymers offer many applications in terms of site drug/biological carrying capacity, tailored physicochemical properties based dosage form
modifications and with desired features, and also to deliver therapeutics at specific sites. Considering these advantages, a number of applications of
grafted polymers developed and many patents were filed in this area till the date. This review highlights the basic concept of grafting and its various
techniques and their significant pharmaceutical applications.

Keywords: Polymer grafting, Pharmaceutical formulation, Drug delivery, Grafting techniques, Analytical techniques, Patents.

© 2017 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license (http://creativecommons.
org/licenses/by/4. 0/) DOI: http://dx.doi.org/10.22159/ajpcr.2017.v10i6.18072

INTRODUCTION To overcome disadvantages of natural gums and synthetic polymers,

gums can be tailored or modified in desired compound through different
Pharmaceutical and biological therapeutics are suffered from ways not only to overcome their drawbacks but also to modulate the
disadvantages such as short half-lives, poor bioavailability, and physical site of drug release and it’s kinetic and also to makes them superior
and chemical instability. Physical instability mainly includes alteration to their counterparts. Tailor-made specifications intended for desired
of highly ordered protein structure, leading to undesirable processes applications. Reactive functional groups in the chemical structure of
such as denaturation, aggregation, and precipitation. Chemical polymers, including thio, hydroxyl, amino, and carboxylic acid groups,
reactions such as oxidation, deamidation, hydrolysis, and racemization indicate the possible sites for chemical modification or means of
contribute to the chemical instability of drugs [1]. grafting. In the polymeric age, it is essential to modify the properties of
a polymer according to tailor-made specifications designed for target
Furthermore, delivery of drugs to target site at a specific concentration
applications. There are quite a few ways to modify polymer properties
for a specific time can be successfully achieved by the use of suitable
such as blending, grafting, and curing [4].
polymer/s. The major benefits for which polymer with desired property
incorporated in drug delivery systems include ease of preparation, GRAFTING
maintenance of desired therapeutic concentration with a single dose,
prolonged release of incorporated drug, and improved stability. The main purposes of a surface modification are improving the
wettability, biocompatibility, mechanical properties, etc., of a surface
Therefore, selection of proper polymer system is a critical step involved polymer.
in formulation of drug into dosage form. Type of polymer/s incorporated
in formulation majorly decides the stability of formulation and drug Two major types of grafting may be considered:
itself, mechanism, and rate of drug release. i. Grafting with a single monomer and
ii. Grafting with a mixture of two (or more) monomers.
Polymers are macromolecules composed of monomers linked
covalently. The term polymer was first introduced by Jöns Jacob Furthermore, grafting copolymers can be obtained mainly by two
Berzelius d [2]. In the past few years, polymers obtained from plant mechanisms known as grafting from and grafting to. The several
source, microbial source, marine source, and synthetic sources have process-related parameters such as the type and concentration of
suggested marvelous awareness owing to their varied pharmaceutical initiator, monomer concentration, reaction temperature, and time
applications such as binder, diluents, disintegrates in tablets, protective influences grafting parameters such as grafting percentage and
colloids in suspension, gelling agent in gels, thickeners in oral liquids, grafting efficiency. The properties of the resulting graft copolymers are
and bases in suppositories [3]. However, it is not necessary the polymers widely controlled by the characteristics of the side chains including
we had till the date from variety of sources should possess all the molecular structure, length, and number [5]. Following are the different
desired properties, formulation scientist seeking particular properties techniques of grafting:
in polymers might be absent in the polymers present. This introduced 1. Chemical grafting
a significant role of polymer grafting in formulation development cycle. a. Free radical grafting
With modification of chemical functional groups of polymer, wide range b. Ionic grafting.
of favorable properties can be imparted to polymer and unfavorable 2. Grafting through living polymerization
one can be diminished. 3. Photochemical grafting
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4. Enzymatic grafting attention in literature was on styrenic monomers [10].

5. Plasma radiation technique b. Reversible addition-fragmentation chain transfer (RAFT) is achieved
6. Radiation grafting. by performing a free radical polymerization in the presence of dithio
compounds, which act as efficient RAFT agents [11].
Chemical grafting c. Atom transfer radical addition (ATRP) - dormant chains are capped by
In the chemical grafting, the role of initiator is very important as it halogen atoms, which are reversibly transferred to metal complexes
determines the path of the grafting process. It is further classified as in the lower oxidation state. This generates the transient growing
free radical grafting and ionization grafting. radicals and complexes in the higher oxidation state. The key
a. Free radical grafting reaction of ATRP is the activation–deactivation dynamic equilibrium
Free radicals are produced from the initiators and transferred to process [11].
the substrate to react with monomer to form the graft copolymers.
Initiator systems used in free radical initiated grafting are as Sonmez et al. reported acrylamide grafting by ATRP; the initiation
follows [5]: appears to take place through radical formation in a redox reaction of
• FAS: Ferrous ammonium sulfate N-chlorosulfonamide groups with CuBr [12].
• CAN: Ceric ammonium nitrate
• PDC: Potassium diperiodatocuprate (III) Each of these methods relies on the establishment of a rapid dynamic
• PPS: Potassium persulfate equilibrium between a low concentration of active propagating chains
• TCPB: Thiocarbonationpotassium bromate and a predominant amount of dormant chains that are unable to
• APS: Ammonium persulfate. propagate or terminate and is more tolerant toward functional groups
Xie et al. prepared hydroxypropyl chitosan-grafted MAA using APS and impurities [13].
initiator, obtaining a derivative that also presented a good solubility
in water [6]. Photochemical grafting
b. Ionic grafting To initiate the grafting process, photochemical radiations are used;
Grafting can be triggered in ionic conditions proceeding mainly these radiations cause dissociation of a chromophore into reactive free
through ionic mode. Grafting can proceed through an anionic radicals using. The grafting process by a photochemical technique can
mechanism where alkoxide of alkali metals used as initiators (such proceed in two ways: With or without a sensitizer.
as sodium methoxide) or by cationic mechanism where alkaline
metal salts are used such as alkyl aluminum (R3Al) [4]. The mechanism without sensitizer involves the generation of free
radicals on the backbone, which react with the monomer free radical
Anionic grafting: Hossein Hosseinzadeh modified a polysaccharide, to form the grafted copolymer. On the other hand, in the mechanism
sodium hyaluronate, through graft copolymerization of acrylic acid. This “with sensitizer,” the sensitizer forms free radicals, which can undergo
graft copolymerization was initiated using anionic initiator ammonium diffusion so that they abstract hydrogen atoms from the base polymer,
persulfate. Increase in the molecular mass of sodium hyaluronate, after producing the radical sites required for grafting.
extraction of homopolymer, was considered as the end point of grafting,
and also the basis for the determination of the grafting parameters. In Liu and Xu photochemically grafted a hydrophilic polymer, poly (N-vinyl-
this study, effect of concentration of acrylic acid, sodium hyaluronate, 2-pyrrolidone), onto the surface of polypropylene microfiltration
and ammonium persulfate as well as grafting temperature on grafting membrane (PPMM) using ultraviolet and γ-radiations. Grafting resulted
process was evaluated [7]. in an enhanced hydrophilicity for the modified membrane. Evaluation
of the biocompatibility of poly(N-vinyl-2-pyrrolidone)-modified PPMM
Cationic grafting: Yoshikawa et al. grafted chitosan with cationic living had shown positive result in their research [14].
polymers such as poly(isobutyl vinyl ether) and poly(2-methyl-2-
oxazoline). In this study, analysis of the effect of molecular weight of Enzyamatic grafting
living polymer cation on the mole number of grafted polymer was done. It is based on the principle that an enzyme can be used to initiates the
With the grafting process, viscosity of the resulting polymer was found chemical/electrochemical grafting reaction [15]. Application of enzyme
to increase with the increasing percentage of grafting. This grafted can offer a green approach in grafting techniques by eliminating the
polymer was also found to be soluble in water [8]. use of reactive reagents with respect to safety, efficacy, and economy.
Furthermore, enzymes specificity may offer the potential for precisely
Grafting through living polymerization tailoring macromolecular properties to desired ones.
Szwarc et al. define the living polymerization as “living polymer” is “that
retains their ability to propagate for a long time and grow to a desired Chen et al. studied tyrosinase initiated the grafting of peptides onto the
maximum size while their degree of termination or chain transfer is still amine-containing polysaccharide chitosan [15].
negligible.” [9]
Plasma radiation-induced grafting
Controlled free radical polymerizations combine features of Slow discharge plasma radiations offer about the same grafting
conventional free-radical and ionic polymerizations. In case of a living probabilities as with ionizing radiation. The main events in plasma
polymerization, it provides living polymers with regulated molecular radiation-induced grafting are electron-induced excitation, ionization,
weights and low polydispersities [4]. and dissociation. Thus, the high-energy accelerated electrons from the
plasma used to induce cleavage of the chemical bonds in the polymeric
A conventional radical polymerization suffers from disadvantage structure, which subsequently form macromolecule radicals and
that it does not possess control over the molecular weight, molecular initiates graft copolymerization [16].
weight distribution, and architecture of the polymer, making its
macroscopic properties very difficult to be tailored. While living Acrylic acid grafted polyethylene tetrapthalate used successfully
ionic polymerizations can provide a methodology for preparation of to reduce antithrombogenic property of polymer polyethylene
copolymers with well-defined structures, such as controlled molecular terephthalate, and heparin immobilized over grafted polymer was
weights and narrow molecular weight distribution, defined copolymer found to be blood compatible [17].
compositions, branching, and end-group functionalities.
a. Stable free radical polymerization (SFRP) - reversible homolytic Radiation grafting
cleavage of a dormant chain end to form a stable free radical as well High energy radiation exposure over the polymeric backbone to form
as an active radical site was applied to the polymerization. SFRP active sites (free radicals) serving as the site of grafting for propagation
mainly applied for styrenics, acrylates, and acrylamides, still major to form side-chain grafts. These radicals easily react with appropriate

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functional monomers to form covalent bonds and, as a consequence, hydrogel using “grafting to” technique, using Р-Benzoquinone as the
growth of macromolecular chains, and all of this without the use of coupling agent later by click grafting of chitosan chains through NH2
chemical initiators [18,19]. groups [24].

Singh and Roy studied radiation grafting of chitosan with N,N-dimethy To achieve tailored physicochemical properties by grafting of
laminoethylmethacrylate. Radiation parameters such as radiation dose polymers
rate and total dose/time were found to affect the rate of grafting and Although chitosan is an effective flocculating agent only in acidic media,
homopolymerization. In this study, it was found that a desired level the derivatives having side chain carboxyl groups showed zwitterionic
of grafting was achieved by appropriate selection of these radiation characteristics with high flocculation abilities in both acidic and basic
parameters in grafting conditions [20]. media [5].
a. Free radical grafting
The irradiation of macromolecules can cause homolytic fission and Hydrogels based on poly(N-isopropylacrylamide) (PNIPAAm)-grafted
thus forms free radicals on the polymer. In the radiation technique, chitosan were developed by Cai et al., by applying irradiation. The
the presence of an initiator is not essential. The medium is important swelling behavior of these chitosan-g-PNIPAAm hydrogels increased
in this case, e.g. if irradiation is carried out in air, peroxides may with the increase in the amount of the grafted branches, i.e. grafting
be formed on the polymer. The lifetime of the free radical depends percentage [25].
on the nature of the backbone polymer. Grafting proceeds in three
different ways: (a) Pre-irradiation, (b) peroxidation, and (c) mutual Many applications of acrylic acid grafts of chitosan as possible means of
irradiation technique [18]. creating hydrophilic and mucoadhesive polymers have been reported
b. Radiation grafting can also proceed through an ionic mode recently. Such as CS - poly(acrylic acid) (PAA) graft proved to be a
With the ions formed through high-energy irradiation, ionic grafting promising vehicle for the administration of hydrophilic drugs, proteins,
may be of two different types: Cationic or anionic. The polymer and peptides in the work of Hu et al., where they used silk peptide as a
is irradiated to form the polymeric ion and then reacted with the model drug [26].
monomer to form the grafted copolymer. The potential advantage
of the ionic grafting is high reaction rate [4]. Modified psyllium exhibiting altered pH-sensitivity, swellability,
biodegradability, and ultimately drug release mechanism produced
ANALYTICAL TECHNIQUES UTILIZED IN CHARACTERIZATION OF by chemical grafting of psyllium with N-hydroxymethylacrylamide,
GRAFTED POLYMERS mixtures of acrylamide and 2-acrylamido-2-methylpropane sulfonic
acid, and succinic acid treatment [27].
Following are analytical techniques used to characterize and evaluate
grafted polymeric materials: Fourier transmission infrared (FTIR), Thermostable system generated by Vihola et al. through stabilization of
NMR, X-ray diffractometer (XRD), differential scanning calorimeter, thermally responsive particles by grafting of thermosensitive polymers
ELEMENTAL ANALYSIS, and MW ANALYSIS explained in following poly (N-vinylcaprolactam) (PVCL) with poly (ethylene oxide) to produce
Table 1 [21]. PVCL-graft-C11EO42. These new polymeric materials provide hydrogel
particles with more thermostable system can be used for controlling
PHARMACEUTICAL UTILITIES OF GRAFTED POLYMERS drug release [28].
To alter drug of biological carrying capacity
Dailey et al. improved biomolecules carrying capacity of PLGA was To achieve desired dosage form characteristics
by its grafting with PVA polymer. The PVA backbone can be modified Pistel et al. grafted poly (lactic-co-glycolic acid), PLGA, onto water-
conveniently to create negatively or positively charged surface soluble poly (vinyl alcohol) (PVAL) backbones. Biodegradable
properties using sulfobutyl or amine functional groups tethering. This polyesters generated had considerable potential for parenteral
grafting process increased hydrophilicity which in turn enhanced drug delivery systems with lower burst effects and controlled
biomolecule carrying capacity, especially sensitive biomolecules such release profiles based on the structure and molecular weight of the
as proteins, peptides, and DNA [22]. copolymer [29].

Jung et al. developed the application of grafted polymer sulfobutylated Kulkarni and Sa developed pH-sensitive controlled drug delivery
poly(vinyl alcohol)-graft-poly(lactide-co-glycolide) with association of systems of ketoprofen using pH-sensitive interpenetrating polymer
tetanus toxoid in combination with cholera toxin enabled the use of network (IPN) beads of PAAm-g-XG and NaCMC. The grafting of acryl
tetanus toxoid as oral and nasal vaccination [23]. amide on the backbone of Xanthan Gum (XG) and IPN of PAAm-g-XG–
NaCMC was used for this purpose [30].
Omer et al. prepared and characterized pH sensitive polyelectrolyte
complex hydrogel microcapsules for the oral delivery of proteins. In Patil S A et al. developed transdermal films using modified XG, which
this research, the Omer et al. prepared chitosan (CS) grafted alginate obtained by grafting acrylamide onto XG. Successful controlled release
of atenolol was obtained by these modified XG films [31].

Table 1: Analytical technique and property being characterized Conteras-garcia et al. grafted N,N-dimethylacryl amide and
N-Isopropylacryl amide on polypropylene film these functionalized
Analytical Characterization PP films have desirable bioproperties along with sustained release of
technique norfloxacin [18].
FTIR Specific functional groups added to blend as a
result of grafting Siraj et al. blended PVAL and with a natural polymer, methylcellulose
13C‑solid state Hydrocarbon backbone characterization (MC) and incorporated with 6-thioguanine. As a result of this blending,
NMR Interpenetrating polymer network microsphere so generated which
XRD Polymorphism of polymers effectively controlled release of drug in the in vivo study [32].
DSC Purity and melting point of polymers
Elemental analysis Elemental composition such as C, H, N content To achieve site specific delivery by grafting of polymers
MW analysis Gain in molecular weight after grafting Kumbar et al. prepared microspheres of polyacrylamide-grafted-
characterized chitosan crosslinked with glutaraldehyde to encapsulate indomethacin,
FTIR: Fourier transmission infrared, DSC: Differential scanning calorimeter, for treatment of arthritis. The initial release of indomethacin from these
XRD: X‑ray diffractometer microspheres occurs by polymer chain relaxation process, while at

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