Polymers in Pharmaceuticals
Introduction
“Polymer” word is derived from Greek roots “Poly” meaning many and “Meros” meaning parts. Polymers have very large molecular weights made up of repeating units (or monomers) throughout their chains. Polymers are considered to be a subset of macromolecules. A monomer is a small molecule which combines with other molecules of the same or different types to form a polymer. If two, three, four, or five monomers are attached to each other, the product is known as a dimer, trimer, tetramer, or pentamer, respectively. An oligomer contains from 30 to 100 monomeric units. Products containing more than 200 monomers are simply called as polymer.
From the structural
prospective, monomers are generally classified as functional (containing
reactive functional groups) and olefinic (containing double bond). Polymers can
have different chemical structures, physical properties, mechanical behavior,
thermal characteristics. [1]
The pharmaceutical
applications of polymers range from their use as binders, disintegrant in
tablets, thickner, suspending , emulsifying agents in liquids formulations such
as suspensions and emulsions. Polymers can be used as film/ enteric coatings to
mask the unpleasant taste of a drug, to enhance drug stability and to modify
drug release characteristics. Pharmaceutical polymers are widely used to
achieve taste masking; controlled release (e.g. extended, pulsatile and
targeted) enhanced stability and improved bioavailability. Monolithic delivery
devices are systems in which a drug is dispersed within a polymer matrix and released
by diffusion. The rate of the drug release from a matrix product depends on the
initial drug concentration and relaxation of the polymer chains which overall
displays a sustained release characterristic. [2]
Classification of Polymers :
Polymers can have
different chemical structures, physical properties, mechanical behavior,
thermal characteristics and can be classified in different ways by following
below are,
1.Based on the origin [1]
i) Natural Polymers
Protein-based
:
Albumin, Collagen, gelatin etc.
Polysaccharides
:
Agarose, alginate, carrageenan, chitosan, cyclodextrins, dextran, hyaluronic
acid, polysialic acid etc.
ii)
Synthetic Polymers
Biodegradable
Polyesters : Poly(lactic acid)
(PLA), poly (glycolic acid) (PGA), poly (hydroxyl butyrate) (PHB),poly
(Ɛ-caprolactone) (PCL), poly(β-malic acid) (PMA), poly(dioxanones) (PDA) etc.
Polyanhydrides
:
Poly(sebacic acid) (PSBA), poly(adipic acid) (PAPA), poly(terphthalic acid)
(PTA) and various copolymers etc.
Polyamides
:
Poly(imino carbonates) (PIC),polyamino acids (PAA) etc.
Phosphorus-based
:
Polyphosphates, polyphosphonates, polyphosphazens etc.
Others
:
Poly(cyano acrylates) (PCA), polyurethanes, polyortho esters,
polydihydropyrans,polyacetals etc.
Non-biodegradable
Cellulose
derivatives : Carboxymethyl cellulose (CMC)
,ethylcellulose (EC), cellulose acetate (CA), cellulose acetate propionate
(CAP), hydroxypropyl methylcellulose (HPMC) etc.
Silicones
:
Polydimethylsiloxane (PDS), Colloidal silica etc.
Acrylic
polymers : Polymethacrylates (PMA), poly(methyl methacrylate)
(PMMA), poly hydro(ethyl methacrylate) (PHEM) etc.
Others
:
Polyvinyl pyrrolidone (PVP), ethyl vinyl acetate (EVA), poloxamers, poloxamines
etc.
iii)
Semi-synthetic Polymer: Hydrogenated natural
rubber,Cellulose nitrate,methyl cellulose etc are chemically modified polymers.
2.Based on Backbone [1]
Polymers
with carbon chain backbone : Polyethylene,
polypropylene,polystyrene, poly(vinyl chloride),polytetrafluoroethylene,
polyacrylonitrile, poly(vinyl alchol), poly(vinyl acetate), polyacrylamide,poly(methyl
methacrylate), polyvinylpyrrolidone,etc.
Polymers
with hetero chain backbone : Poly(ethylene
oxide), poly(propylene oxide),cellulose (poly –glucoside,β →1,4), amylase
(poly-glucoside, alpha → 1,4) (component of starch), pectinic acid
(polygalacturonoside), polyethylene glycol terphthalate, polydimethylsiloxane
etc.
3.Based on the presence of carbon (organic and inorganic) [4]
Organic
Polymers: Polymer whose backbone chain is essentially made of
carbon atoms is termed an organic polymer. The atoms attached to the side
valencies of the backbone carbon atoms are, however, usually those of hydrogen
(H), oxygen (O), nitrogen (N), etc. The majority of synthetic polymers is
organic and they are extensively studied.
Inorganic
Polymers: The molecules of inorganic polymers, on the other
hand, generally contain no carbon atom in their chain backbone. E.g: Glass and silicone rubber
4.Based on the types of monomer [3]
On this basis, polymers
can be classified into two classes.
Homoplymer
: A
polymer containing a single type of repeat units is called a homopolymer,e.g.,
polystyrene.
Copolymer : If a polymer is made up of two different
monomers then it is called copolymer, e.g., styrene butadiene (SBS) rubber and
Sty-co-An.
5.Based
on the Polymerization process [5]
Carothers in 1929
classified polymers into two types on the basis of mechanism of polymerization
reaction:
(i)
Addition polymers
(ii)
Condensation polymers
Addition
polymers: Addition polymerization reaction is responsible for
formation of polymer. Double and triple bonds are possessed by these monomer
molecules. E.g: polythene, polypropene, polystyrene, polyvinyl chloride, etc.
Condensation
polymers: Condensation polymerization reaction is responsible
for the formation of polymers. Elimination of small molecule such as water,
alchol, hydrogen chloride etc takes place by this polymerization reaction. It
possesses bi functional or poly functional monomers. The reaction can take
place between two similar or different monomers.Nylon-6, 6 Nylon-6, Terylene,
glyptal etc are the examples of condensation polymers.
But there were some
polymers that didn’t fit into either of the strict categories proposed above.
Therefore, these terms were modified by H.F. Mark on the basis of kinetics of
polymerization (1950) as
(i)
Chain polymerization
(ii)
Step polymerization
Chain
growth polymer: Chain polymers are the products of self
addition reaction of monomer molecules through a chain reaction. No by-product
is formed in this reaction, the molecular weight of the polymer is the exact
multiple of the molecular weight of monomer, e.g., all the vinyl monomers.
Step
growth polymers: A step growth polymers is the product of
a reaction that involves a random reaction of two molecules that may be any combination
of a monomer, oligomer or a long chain molecule. It proceeds by step-wise
fashion. Some of the examples of step growth polymers are nylons, polyurethanes
6.Based
on the Line structure
The monomer units in a
polymer may be present in linear, branched or crosslinked fashion.
Linear
Polymer: A straight chain species i.e., the units are
connected to each other in a chain arrangements. Linear polymers may be
represented by a chain with two ends, e.g., high density polyethylene. [5]
Branched
Polymer: The main chains of polymer molecules have small
branches of the same or different molecules. Branched polymers have side
chains, or branches of significant length which are bonded to the main chain at
branched points, and are characterized in terms of the number and size of the
branches. Polymers with well controlled modes of branching, e.g., comblike
polymers, star polymers, dendrimers, low density polyethylene, graft copolymers
etc. [5]
Cross-linked
Polymer: Those polymers in which two linear chains are joined
together by covalent bonds i.e, the chains are crosslinked. E.g., Bakelite.
Vulcanized rubber Novolac, melamine-formaldehyde. [5,6]
7.
Based on thermal characteristics / thermo response [5,7]
Polymers can be
classified into two categories on the basis of their behavior towards
temperature:
Thermoplastic
polymers: They are those polymers which can be softened on
heating and hardened on cooling, e.g., linear polymers. Since no chemical
change occurs in the structure of the polymer molecule as a result of heating,
therefore these polymers can be recycled many times. Examples of such polymers
are Polyolefins, nylons, linear polyesters and polyether’s, PVC, sealing wax
etc.
Thermosetting
polymers: Conversion of polymers into an infusible mass is
because of chemical changes. Production of giant molecules and cross-linking of
polymer chain molecules and the curing or setting process involves chemical
reaction leading to further growth.They cannot be softened once get solidified
either by heating or by curing agents.Thermosetting polymers cannotbe recycled
as a chemical change occurs in thermoset polymers as a result of heating. For
example, crosslinked epoxy resins, polydicyclopentadiene, polycarbonates,
polyisoprene, etc.
8.
Based on interaction with water [8]
Non‐biodegradable
hydrophobic Polymers: E.g. Polyvinyl chloride
Soluble
Polymers: CP, HEC, HPC, HPMC, PEG, PAA, sodium CMC,
sodium alginate
Insoluble
polymers: Chitosan (soluble in dilute acids), ethyl cellulose,
PC
Hydro gels: Polyvinyl pyrrolidone
9.
Based on stimuli response
Stimuli are commonly
classified in three categories: physical, chemical, or biological [9, 10] .
Physical stimuli (like light, temperature, ultrasound, magnetic, mechanical,
electrical) usually modify chain dynamics, i.e. the energy level of the
polymer/solvent system, while chemical stimuli (like solvent, ionic strength,
electrochemical, pH) modulate molecular interactions, whether between polymer
and solvent molecules, or between polymer chains [11]. Biological
stimuli (like enzymes, receptors) relate to the actual functioning of
molecules: enzymatic reactions, receptor recognition of molecules [12].
Photoresponsive
polymers: PAA [13, 14], PHPMAm [15, 16],
and PNIPAM [17, 18].
pH
responsive polymers: Chitosan [19], albumin [20],
gelatin [21], poly(acrylic acid) (PAAc)/chitosan IPN [22]
, poly(methacrylic acid-g-ethylene glycol) [P(MAA-g-EG)] [23, 24],
poly(ethylene imine) (PEI) [25], poly(N,N-diakylamino
ethylmethacrylates) (PDAAEMA), and poly(lysine) (PL) [26, 27].
Inflammation
responsive polymers: Hyaluronic acid. [3]
Temperature
responsive polymers: : Poly(N-alkyl substituted acrylamides):
e.g. poly(N-isopropylacrylamide) (PNiPAAm) [35, 36], Poly
(N-vinylalkylamides): e.g. poly(N-vinylcaprolactam)
(PNVC) [37], and copolymers such as poly (L-lactic
acid)-poly(ethylene glycol)-poly(L-lactic acid) (PLLA-PEG-PLLA) triblock
copolymers [38], and poly (ethylene oxide)-poly(propylene
oxide)-poly (ethylene oxide) (PEO–PPO–PEO) copolymers. [39]
Electro-Responsive
Polymers: Polythiophene
(PT) or sulphonated-polystyrene (PSS). [24,25]
Redox-Responsive
Polymers: Acid labile moieties inside polyanhydrides [28,
29], poly(lactic/glycolic acid) (PLGA) [30], and poly(b-amino
esters) (PbAEs) [31] induce redox responsiveness.
Enzyme-Responsive Polymers: Pectin, chitosan, amylase/amylopectin, cyclodextrin and dextrin. [32,33,34]
10.
Based on Morphology [6]
Crystalline
Polymers: e.g, syndiotactic polypropylene.
Amorphous
polymers: e.g., atactic polypropylene.
11.
Based on tacticity [5]
With respect to main
chain (back bone) of the polymer, the polymer posses geometric arrangement of
characteristic group of monomer units which is called as tacticity. It
classified into three groups as following:
Isotactic
polymers :A polymer in which substitents group is located on
one side of plane of carbon-carbon chain, i.e., every chiral carbon has the
same co figuration, is called isotactic.. E.g: Isotactic polypropene.
Syndiotactic
polymers: A polymer, in which substituents group is attached
alternatively above and below the plane of carbon-carbon chain, is called
syndiotactic. E.g., syndiotactic polypropylene
Atactic
polymers: A polymer, in which there is no systematic
configuration is called atactic polymers, e.g., atactic polypropylene. It has
proper strength and more elasticity.
12. Based on Charge [8]
Cationic: Aminodextran, chitosan,
(DEAE)- dextran, TMC
Anionic:
Chitosan-EDTA, CP, CMC, pectin, PAA, PC, sodium alginate, sodium CMC, xanthan
gum
Non-ionic:
Hydroxy ethyl starch, HPC, poly (ethylene oxide), PVA
13.
Based on Potential [8]
Covalent
:
PVP, scleroglucan
Hydrogen
bond : Cyanoacrylate
14.
Based on bioadhesive forces [8]
Electrostatic
interaction: Acrylate (hydroxylated methacrylate), poly
(methacrylic acid), CP, PC, PVA, chitosan.
15.
Based on mucoadhesive property
Excellent
mucoadhesion: Carbopol 934, CMC, polycarbophil, trgacanth, sodium alginate, HEC, HPMC.
Fair
mucoadhesion: Gum karaya, guar gum.
Poor
mucoadhesion: PVP, PG, HPC.
16.
Based on Physical properties [7]
Elastomers:
e.g.,
Natural rubbers, synthetic rubber.
Plastic : e.g.,
polyethylene, polystyrene.
Fibres : e.g., saran, vinyon,
orlan.
17. Based on Geometrical isomerism [5]
Polymer having double bonds in their back bones shows cis and trans isomerism.
Cis isomeric polymers: cis-1,3-butadiene
Trans isomeric polymers: trans -1,3-butadiene.
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