Chapter 20 Polymer

20 PHARMACEUTICAL POLYMERS
At the conclusion of this chapter 5 Explain the glass transition temperature and factors
CHAPTER OBJECTIVES the student should be able to: affecting the Tg .
1 Know the basic concepts of polymers, definitions, and 6 Understand how polymer molecular weight affects its
descriptive terms. properties.
2 Understand the principles of polymer synthesis. 7 Know what types of polymers are generally used in the
3 Distinguish the basic principles of homogeneous and dis- pharmaceutical area.
persion polymerizations. 8 Explain why polymers are used in drug delivery appli-
4 Understand the thermal, physical, and mechanical prop- cations.
erties of polymers in general.
INTRODUCTION and those based on phenoxy, epoxy, acrylic, and ketone resins
were used as cheap substitutes for many parts in the auto and
Synthetic and natural-based polymers have found their way electronic industries. Other synthetic polymers were invented
into the pharmaceutical and biomedical industries and their later including polyethylene (1933), poly (vinyl chloride)
applications are growing at a fast pace. Understanding the (1933), polystyrene (1933), polyamide (1935), Teflon (1938),
role of polymers as ingredients in drug products is impor- and synthetic rubbers (1942). Polyethylene was used to make
tant for a pharmacist or pharmaceutical scientist who deals radar equipment for airplanes. The British air force used
with drug products on a routine basis. Having a basic under- polyethylene to insulate electrical parts of the radars in their
standing of polymers will give you the opportunity to not airplanes. Synthetic rubber, which could be made in approx-
only familiarize yourself with the function of drug products imately 1 hr as compared to 7 years for natural rubbers, was
but also possibly develop new formulations or better delivery used to make tires and other military supplies. Teflon was
systems. This chapter will provide the basis for understand- used in atomic bombs to separate the hot isotopes of ura-
ing pharmaceutical polymers. The basic concepts of polymer nium. Nylon was used to make parachutes, replacing silk,
chemistry, polymer properties, types of polymers, polymers which had to be imported from Japan.
in pharmaceutical and biomedical industries, and reviews of The plastics revolution advanced technologies in the
some polymeric products in novel drug delivery systems and 20th century and opened new fields of application in the phar-
technologies will be covered. maceutical and biomedical sectors. In recent years, polymers
have been used to develop devices for controlling drug deliv-
ery or for replacing failing natural organs. In oral delivery,
polymers are used as coatings, binders, taste maskers, pro-
HISTORY OF POLYMERS tective agents, drug carriers, and release controlling agents.
Targeted delivery to the lower part of the gastrointestinal tract
Polymers have a wide-ranging impact on modern society. (e.g., in the colon) was made possible by using polymers that
Polymers are more commonly referred to as “plastics” since protect drugs during their passage through the harsh environ-
people are more familiar with plastic products that they ment of the stomach. Transdermal patches use polymers as
encounter around the house than any other type of poly- backings, adhesives, or drug carriers in matrix or membrane
meric product. Plastics have the ability to be molded, cast, products (these are described later in the book). Controlled
extruded, drawn, thermoformed, or laminated into a final delivery of proteins and peptides has been made possible
product such as plastic parts, films, and filaments. The first using biodegradable polymers. In many drug products you
semisynthetic polymer ever made was guncotton (cellulose may find at least one polymer that enhances product per-
nitrate) by Christian F. Schönbein in 1845. The manufactur- formance. The key difference between early polymers and
ing process for this polymer was changed over the years due pharmaceutical polymers is biocompatibility.
to its poor solubility, processability, and explosivity resulting
in a variety of polymers such as Parkesine, celluloid (plas-
ticized cellulose nitrate), cellulose acetate (cellulose treated
with acetic acid), and hydrolyzed cellulose acetate soluble POLYMERS IN GENERAL 1−5
in acetone. In 1872, Bakelite, a strong and durable synthetic
polymer based on phenol and formaldehyde, was invented. The word “polymer” means “many parts.” A polymer is a
Polycondensation-based polymeric products such as Bakelite large molecule made up of many small repeating units. In the
492
CHAPTER 20: PHARMACEUTICAL POLYMERS 493
Monomer Oligomer (30–100 mers) the physical and mechanical properties of the polymer can be
Dimer tailor-made. This can be achieved by changing the structure
Trimer
of the monomer building blocks or by blending them with
other polymers. Blending is a process intended to achieve
superior properties that are unattainable from a single poly-
mer. For example, polystyrene is not resistant against impact,
so a polystyrene cup can be easily smashed into pieces if com-
pressed between your fingers. However, polystyrene blended
with polybutadiene is an impact resistant product. Alterna-
Polymer (over 200 mers)
tively, monomers of styrene and butadiene can be copolymer-
ized to make a new copolymer of styrene–butadiene.
Degree of Polymerization (DP) = Number of monomers in a chain
Fig. 20–1. Polymer anatomy. POLYMER SYNTHESIS

early days of polymer synthesis, little was known about the To make polymers, monomers have to interact with each
chemical structures of polymers. Herman Staudinger, who other. Let us consider a simple scenario in which just one
received the Nobel Prize in Chemistry in 1953, coined the monomer type is going to be polymerized. The structure of
term “macromolecule” in 1922 and used it in reference to the monomer molecule will tell us how we should polymer-
polymers. The difference between the two is that polymers ize it. A monomer may be unsaturated; in other words it may
are made of repeating units, whereas the term macromolecule contain a double bond of σ (sigma) and π (pi) between a
refers to any large molecule, not necessarily just those made pair of electrons. The π bond generally requires low energy
of repeating units. So, polymers are considered to be a subset to break; therefore, polymerization starts at this site by the
of macromolecules. addition of a free radical on the monomer. On the other hand,
A monomer is a small molecule that combines with other if a monomer does not contain a double bond but possesses
molecules of the same or different types to form a polymer. functional groups such as hydroxyl, carboxyl, or amines, they
Since drawing a complete structure of a polymer is almost can interact via condensation. These two types of polymer-
impossible, the structure of a polymer is displayed by show- ization processes are described in the next two sections.
ing the repeating unit (the monomer residue) and an “n”
number that shows how many monomers are participating in Addition Polymerization
the reaction. From the structural prospective, monomers are Free-radical polymerization is also known as chain or
generally classified as olefinic (containing double bond) and addition polymerization. As the name implies, a radical-
functional (containing reactive functional groups) for which generating ingredient induces an initiator triggering polymer-
different polymerization methods are utilized. If two, three, ization. The initiator is an unstable molecule that is cleaved
four, or five monomers are attached to each other, the product into two radical-carrying species under the action of heat,
is known as a dimer, trimer, tetramer, or pentamer, respec- light, chemical, or high-energy irradiation. Each initiating
tively. An oligomer contains from 30 to 100 monomeric units. radical has the ability to attack the double bond of a monomer.
Products containing more than 200 monomers are simply In this way, the radical is transferred to the monomer and
called a polymer (Fig. 20–1). From a thermodynamic per- a monomer radical is produced. This step in polymeriza-
spective, polymers cannot exist in the gaseous state because tion is called initiation. The monomer radical is also able to
of their high molecular weight. They exist only as liquids or attack another monomer and then another monomer, and so
high solid materials. on and so forth. This step is called propagation by which
a macroradical is formed. Macroradicals prepared in this
EXAMPLE 20–1
way can undergo another reaction with another macrorad-
Molecular Weight
ical or with another inert compound (e.g., an impurity in the
A polyethylene with molecular weight of 100,000 g/mol is made reaction) which terminates the macroradical. Figure 20–2
of almost 3570 monomer units ( CH2 CH2 ) with the molecular
weight of 28 g/mol.
shows the free-radical polymerization of styrene, a monomer,
to polystyrene. Monomers such as acrylic acid, acrylamide,
acrylic salts (such as sodium acrylate), and acrylic esters
Since polymers originate from oil, they are generally (methyl acrylate) contain double bonds and they can be poly-
cheap materials. Unlike other materials such as metals or merized via addition reactions.
ceramics, polymers are large molecular weight materials and
their molecular weight can be adjusted for a given applica-
tion. For example, silicone polymers are supplied as vacuum
Condensation Polymerization
grease (low molecular weight) and as durable implants (very In condensation polymerization, also called step polymer-
high molecular weight). By changing the molecular weight, ization, two or more monomers carrying different reactive
494 MARTIN’S PHYSICAL PHARMACY AND PHARMACEUTICAL SCIENCES
Styrene
monomer
Styrene
Initiator radical
radical
R* C= C R C C*
Condensation polymerization Addition polymerization

R C C* C= C R C C C C* Fig. 20–4. Condensation versus addition polymerizations.
at the beginning of the reaction. On the other hand, conden-

sation polymerization is a stepwise reaction in which smaller
*
C C species are initially formed first and then combined to make
n
* higher-molecular-weight species. This reaction tends to be
slow generally lasting for several hours. Figure 20–4 shows
Macroradical growth and combination Polystyrene
the concept.
Fig. 20–2. Addition or free-radical polymerization of styrene.
functional groups interact with each other as shown in POLYMERIZATION METHODS

Figure 20–3. For example, a monomer containing a reac-
tive hydrogen from the amine residue can react with another Now, the question is how can polymers be made from
monomer containing a reactive hydroxyl group (a residue of monomers? Reactions may be carried out in homogeneous
carboxyl group) to generate a new functional group (amide) or heterogeneous systems. The former includes bulk and
and water as a side product. If a monomer containing the solution polymerizations, whereas the latter includes any
reactive hydrogen reacts with a monomer containing reactive dispersed system such as suspensions, emulsions, and their
chlorine, the side product will be hydrochloric acid. Since reverse phase counterparts; in other words, inverse suspen-
each monomer is bifunctional (in other words, it contains sions and inverse emulsions.
two reactive hydrogens or two reactive chlorines), the reac-
tion product can grow by reacting with another monomer
generating a macromonomer. Nylon is prepared via conden- Homogeneous Polymerization
sation polymerization of a diamine and diacid chloride. The Bulk polymerization occurs when no other materials except
diamine and diacid chloride are dissolved in water and tetra- the monomer and initiator are used. If the monomer is
chloroethylene, respectively. Since the two solutions do not water-soluble, a linear water-soluble polymer is theoreti-
mix with each other, they form two immiscible separate lay- cally prepared. With oil-soluble monomers, the polymer will
ers, with tetrachloroethylene at the bottom. At the interface be linear and soluble in oil. Surprisingly, sometimes when
of the two solutions, the two monomers interact and form an olefinic water-soluble monomer is polymerized in bulk,
the polymer. The polymers can then be gently removed from a water-swellable polymer is prepared. This is due to exces-
the interface as fiber. There are no radicals involved in this sive exothermic heat resulting in hydrogen abstraction from
polymerization reaction. the polymer backbone, which promotes cross-linking reac-
Free-radical polymerization is an addition reaction that tions at the defective site. The cross-linked polymer obtained
is characterized by fast growth of macroradicals. There is a without using any chemical cross-linker is called a popcorn
high chance that high–molecular-weight chains are formed polymer and the reaction is called “popcorn polymerization.”
Crospovidone, a superdisintegrant in solid dose formulations,
is a cross-linked polymer of vinyl pyrrolidone which is pro-
NH 2 – R – NH 2 - R – NHCO – R’ – NHCO - duced by popcorn polymerization.
HOOC – R’ - COOH Polyamide In certain circumstances when the monomer is very tem-
perature sensitive, a popcorn polymer can be obtained even
HO – R – OH - NHCOO – R – NHCOO – R’ -
without using an initiator. The monomer acrylic acid is glacial
O = C = N – R’ – N = C = O Polyurethane
with a melting point around 13◦ C. If the monomer was stored
HO – R – OH - R – COO –R’ – COO - at freezing temperature, the polymerization stabilizer will be
HOOC – R’- COOH Polyester unevenly distributed between the liquid and thawing phases.
This results in poor protection of the monomer and sudden
Fig. 20–3. Examples of condensation polymerization. polymerization that generates tremendous amounts of heat.
To solve the problems associated with exothermic heat particle sizes around 0.2 to 0.8 mm below the critical micelle
in bulk polymerization, polymerization can alternatively be concentration. Above the critical micelle concentration, 10
conducted in solution. Depending on the monomer solubility, to 100 μm particles are formed. Nanosize particles can be
water or organic solvents can be used as diluents or solvents. made if a sufficient amount of surfactant is used. Nanoemul-
Again, a water-soluble or an oil-soluble polymer is obtained if sion or inverse nanoemulsion systems are rarely used in the
monomers are water-soluble or oil-soluble, respectively. The pharmaceutical industry because of the amount of surfactant
solvent or diluent molecules reside in between the monomer required to stabilize the system. Surfactants represent unde-
molecules and they reduce the amount of interaction between sirable impurities that affect drug stability and formulation
the two neighboring monomers. In this way, less amounts acceptability. Water-insoluble polymers based on acrylic or
of heat are generated in a given period of time and a less methacrylic esters are prepared via suspension or emulsion
exothermic but controllable reaction is conducted. Polymers polymerization. Eudragit L30D is a copolymer of methacrylic
prepared accordingly are generally soluble in their corre- acid and ethyl acrylate which is manufactured using an emul-
sponding solvents, but they are swellable if a cross-linker sion technique. Eudragit NE30D is also a copolymer of ethyl
is used during their polymerization. The cross-linker can be acrylate and methyl methacrylate which can be manufactured
water-soluble or oil-soluble. Swellability of a polymer can in an emulsion system. On the other hand, water-soluble poly-
be modified by the simultaneous use of water-soluble and mers based on acrylic or methacrylic salts as well as acry-
oil-soluble cross-linkers. lamide can be prepared using inverse suspension or inverse
emulsion systems. Emulsion systems that use water as a con-
tinuous phase are known as latex. Table 20–1 summarizes
Dispersion Polymerization important polymerization methods that are potentially used
Dispersion polymerization occurs in suspensions, emulsions, to prepare pharmaceutical polymers.
inverse suspensions, and inverse emulsions. In dispersion
polymerization, two incompatible phases of water and oil are
dispersed into each other. One phase is known as the minor COPOLYMERS AND POLYMER BLENDS
(dispersed) phase and the other as the major (continuous)
phase. The active material (monomer) can be water-soluble or If one polymer system cannot address the needs of a partic-
oil-soluble. To conduct polymerization in a dispersed system, ular application, its properties need to be modified. For this
the monomer (in the dispersed phase) is dispersed into the reason, polymer systems can be physically blended or chemi-
continuous phase using a surface-active agent. The surfactant cally reacted. With the former, a two-phase system generally
is chosen on the basis of the nature of the continuous phase. exists, whereas with the latter a monophase system exists.
Generally, a successful dispersion polymerization requires This can clearly be seen in a differential scanning calorime-
that the surfactant be soluble in the continuous phase. There- ter by monitoring the glass transition temperature (Tg ) of
fore, if the continuous phase is water, the surfactant should the individual polymers. With polymer blends, two Tg values
have more hydrophilic groups. On the other hand, if the are observed while one single Tg is detected for copolymers.
continuous phase is oil, a more hydrophobic (lipophilic) sur- Thermal analysis is discussed in detail in Chapter 2.
factant would be selected. Generally, two basic factors con- Copolymerization refers to a polymerization reaction in
trol the nature of the dispersion system. These are surfactant which more than one type of monomer is involved. Generally,
concentration and the surface tension of the system (nature copolymerization includes two types of monomers. If one
of the dispersed phase) as shown in Figure 20–5. Dispersed monomer is involved, the process is called polymerization
systems were discussed in earlier chapters. The surfactant and the product is a homopolymer. For example, polyethy-
concentration determines the size of the polymer particles. lene is a homopolymer since it is made of just one type of
The system will be a suspension or inverse suspension with monomer. Depending on their structure, monomers display
different reactivities during the polymerization reaction. If
the reactivities of two monomers are similar, there will be no
Dispersion Stability preference for which monomer is added next, so the poly-
mer that is formed is called a random copolymer. When
Macrodispersions Microdispersions Nanodispersions one monomer is preferentially added to another monomer,
the monomers are added to each other alternatively and the
O/W Suspension Emulsion Microemulsion Nanoemulsion
polymer product is called an alternate copolymer. Some-
times, monomers preferentially add onto themselves and a
W/O Inverse Inverse Inverse Inverse
Suspension Emulsion Microemulsion Nanoemulsion block copolymer is formed. This happens when one monomer
has a very high reactivity toward itself. Once more reactive
Surfactant Concentration monomers have participated in the reaction, the macroradical
of the first monomer will attack the second monomer with
CMC
the lower activity, and the second monomer will then grow as
Fig. 20–5. Dispersion systems. a block. Pluronic surfactants (EO-PO-EO terpolymers) are
TABLE 20–1
POLYMERIZATION METHODS
Inverse Inverse Pseudo
Bulk Solution Suspension Suspension Emulsion Emulsion latex
Monomer WS or OS WS or OS OS WS OS WS
Initiator WS or OS WS or OS Generally OS Generally WS Generally OS Generally WS
Cross-linker∗ WS or OS WS or OS Generally OS Generally WS Generally OS Generally WS
Water If WS monomer CP DP CP DP CP
is used
Organic If OS monomer DP CP DP CP DP
solvent is used
Surfactant WS; Csurf OS; Csurf WS; Csurf OS; Csurf WS
<CMC; high <CMC; low >CMC; high >CMC; low
HLB HLB HLB HLB
Polymer OS†
∗
Cross-linker is added if a swellable polymer is desired.
†
Polymer is soluble in organic solvents, but the latex itself is water dispersible.
Key: WS = water-soluble; OS = organic-soluble; DP = dispersed phase; CP = continuous phase; CMC = critical micelle concentration; HLB = hydrophilic
lipophilic balance; Csurf = surfactant concentration.
composed of block units of ethylene oxide and propylene applications. These polymers are made of acrylic esters (methyl
oxides attached to each other. The major difference between methacrylate, ethyl acrylate). Their solubility, swellability, and pH
graft copolymer and the other copolymer types is the nature dependent properties have been modified by incorporating anionic
and cationic monomers such as methacrylic acid and dimethy-
of their building blocks. Other copolymer types are made of laminoethyl acrylate.
two or more monomer types, while a monomer and a polymer
are generally used to make graft copolymers. For example,
From a commercial standpoint, polymer properties can be
the physical chemical properties of carboxymethyl cellulose
simply changed by mixing or blending one or two polymer
(CMC) can be changed by grafting various monomers such as
systems. Polymer blends are simply made by physical blend-
acrylic acid, acrylamide, and acrylonitrile onto the cellulose
ing of two different polymers in molten or in solution state.
backbone. Although not very common, a terpolymer will be
The blend is either solidified at lower temperature if prepared
obtained when three monomers participate in the polymer-
by melting or recovered at higher temperature if prepared in
ization reaction. Different types of copolymer products are
solution. Some thermoplastic polymers are not resistant to
shown in Figure 20–6.
sudden stresses. Once impacted, the craze (microcrack) and
EXAMPLE 20–2 macrocracks will grow very quickly within their structure
Pharmaceutical Polymers and the polymer will simply and suddenly break apart. These
polymers have rigid structures with high Tg values. Adding
In pharmaceutical solid oral dosage forms, the Eudragit polymers
are used for sustained release, drug protection, and taste-masking a low Tg polymer (in other words, a flexible polymer) such
as rubber particles improves the impact resistance of these
polymers by preventing the cracks from growing.
Homopolymer
Random copolymer INTERPENETRATING POLYMER NETWORKS

Alternate copolymer Interpenetrating polymer networks (IPNs) are also composed
of two or more polymer systems but they are not a simple
Block copolymer
physical blend. Semi-IPNs or semi-interpenetrating polymer
networks are prepared by dissolving a polymer into a solution
of another monomer. An initiator as well as a cross-linker is
Graft copolymer
added into the solution and the monomer is polymerized and
cross-linked in the presence of the dissolved polymer. The
result will be a structure in which one cross-linked polymer
interpenetrates into a non–cross-linked polymer system. With
fully interpenetrated structures, two different monomers and
their corresponding cross-linkers are polymerized and cross-
Fig. 20–6. Polymers made of two or more monomer units. linked simultaneously. This results in a doubly cross-linked
polymer system that interpenetrates into one another. Alter- Linear Cross-linked
natively, conducting the cross-linking reaction on a semi-
interpenetrated product can form a full-IPN structure. The
non–cross-linked phase of the semi-IPN product will be fur-
ther cross-linked with a chemical cross-linker or via physical
complexation.6,7
EXAMPLE 20–3
IPN Polymer Structure
Elastic superporous hydrogels have been developed for oral gas-
tric retention of the drugs with a narrow absorption window. These
hydrogels are prepared using a two-step process. First, a semi-IPN
structure is prepared by polymerizing and cross-linking a synthetic
monomer (such as acrylamide) in the presence of a water-soluble
polymer (e.g., alginate). Although the cross-linked acrylamide poly-
mer is not soluble in water, the alginate component is. In the second
step, the prepared semi-IPN is further treated with cations (such as Glass transition temperature
calcium) to provide insolubility to the alginate component via ion- Viscosity
Processability Swellability
complexation. This results in a full IPN structure with a balanced
swelling and mechanical properties. Solubility Rigidity
Thermal stability
Fig. 20–7. Polymer topology and properties.

TOPOLOGY AND ISOMERISM
stereoisomerism (Fig. 20–8c). Gutta Percha natural rub-
The topology of a polymer describes whether the polymer ber (trans-polyisoprene) and its synthetic counterpart (cis-
structure is linear, branched, or cross-linked. Topology can polyisoprene) are similar in structure but their trans and cis
affect polymer properties in its solid or solution states. With nature results in a medium-crystal and amorphous behavior,
a linear polymer, the polymer chains are not chemically respectively. This important feature can be accounted for in
attached to each other, instead weaker intermolecular forces terms of the position of a methyl group. The cis and trans
hold the polymer chains together. A linear polymer can show isomers of a same polymer display different Tg and Tm val-
dual behavior. Chains in a linear polymer can freely move, ues, for example, polyisoprene (Tg of −70◦ C versus −50◦ C;
which offers the polymer a low melting temperature. On the Tm of 39◦ C versus 80◦ C), polybutadiene (Tg of −102◦ C ver-
other hand, linear chains have a higher chance of approach- sus −50◦ C; Tm of 12◦ C versus 142◦ C).1 With sequence iso-
ing each other in their solid state, which increases their crys- merism, monomers with pendant groups can attach to each
tallinity and melting temperature. The same holds true for other in head-to-tail, head-to-head, or tail-to-tail conforma-
branched polymers in which short or long side groups are tion. Stereoisomerism applies to polymers with chiral cen-
attached to the backbone of the polymer. Branched poly- ters, which results in three different configurations—isotactic
mer chains move with difficulty because of the steric hin- (pendant groups located on one side), syndiotactic (pendant
drance induced by the side groups but they presumably pos- groups located alternatively on both sides), and atactic (pen-
sess weaker intermolecular forces, which apparently help dant groups located randomly on both sides) configurations.
them move freely. With cross-linked polymers, the chains
EXAMPLE 20–4
are chemically linked and will be restricted from moving
to a sensible extent depending on the level of cross-linking. Stereoisomerism
Very highly cross-linked polymers are very rigid structures The isotactic and atactic polypropylenes display glass transition
that degrade at high temperatures before their chains start to temperatures of 100◦ C and −20◦ C, respectively. While the isotactic
one is used for special packaging purposes, the atactic one is com-
move. monly used as a cheap excipient in general adhesive formulations.
In solution, a branched polymer might display a better
solvent permeability compared to its linear counterpart due
to its side groups. Gum Arabic is a highly branched poly-
mer with very high solubility in water. If a linear polymer is THERMOPLASTIC AND THERMOSET POLYMERS
cross-linked, its solubility will be sacrificed at the expense of
swellability. Therefore, a cross-linked polymer can swell in Polymers with a linear or branched structure generally behave
a solvent to an extent that is inversely related to the amount as thermoplastics. Thermoplastic polymers can undergo mel-
of cross-linker. Figure 20–7 summarizes and correlates poly- ting, which is potentially useful in processes such as com-
mer topology to its solution and melt properties. pression molding, injection molding, and thermoforming.
Isomerism can be classified as structural isomerism In other words, a polymer that is originally a solid can flow
(Fig. 20–8a), sequence isomerism (Fig. 20–8b), and upon application of heat. The process of thermomelting and
solidification can be repeated indefinitely with thermoplas-

CH2 CH2 CH2 H tic polymers. Examples include polystyrene, polyethylene,
C=C C=C and poly (vinyl chloride). On the other hand, thermosetting
CH3 H CH3 CH2
polymers are cross-linked polymers, which are formed upon
combined application of a cross-linker and heat or combined
application of heat and reaction of internal functional
groups. In some cross-linking reactions such as in curing
Natural Rubber Gutta Percha
(mostly cis) (mostly trans)
rubbers, the reaction is assisted by simultaneous application
Tg ⫺70ºC Tg ⫺50ºC of heat and pressure. Therefore, these polymers assume a
Tm 39ºC Tm 80ºC different status than thermoplastic polymers as their flow
(a) Amorphous Medium crystalline behavior is temperature independent. Once a thermoset
polymer is formed, it does not soften upon heating and
Head decomposes with further application of heat. Since there is
Tail
no reversible melting and solidifying in thermoset polymers,
this feature is very useful when a thermoresistant polymer
C
C is desirable. Processing of polymers is generally favored
C C by increasing temperature. A more processable polymer is
C C one that requires a lower temperature to move its chains.
A cross-linked polymer loses its processability as chain
Head to Head movement is hindered with the addition of cross-linker. On
C C
C C the other hand, linear and branched polymers gain more
freedom to move as temperature increases.
Tail to Head For a polymer in its solution state, solubility in a solvent
C C is also an entropy-favored process. In other words, a linear
C C or branched polymer generally dissolves in an appropriate
(b) Tail to Tail solvent. Addition of cross-links to their structure will hinder
chain movement and reduce their solubility in that solvent.
This is why cross-linked polymers swell when they are placed
C Isotactic in a compatible solvent.
C C C
C C
C C
Syndiotactic
POLYMER PROPERTIES
C
C C C C
C C C Crystalline and Amorphous Polymers
Atactic
Polymers display different thermal, physical, and mechani-
C
C C C
cal properties depending on their structure, molecular weight,
C C
C C linearity, intra- and intermolecular interactions. If the struc-
(c) ture is linear, polymer chains can pack together in regular
arrays. For example, polypropylene chains fit together in a
Fig. 20–8. (a) Structural isomerism; (b) sequence isomerism; and way that intermolecular attractions stabilize the chains into
(c) stereoisomerism.
a regular lattice or crystalline state. With increased tempera-
ture, the crystal cells (crystallites) start to melt and the whole
K E Y C O N C E P T CROSS-LINKING
A ladder is composed of two long legs and multiple short pieces (ladder legs connector). Cross-linked polymers are also intended
that are used to connect them. When a ladder is used, you for applications where a certain amount of load is applied. Exam-
do not want its legs to move or even worse, to separate from ples of this are tires (made of cross-linked rubbers) and hydrogels
each other. A ladder with more connection points on the two (made of cross-linked hydrophilic polymers) that are expected
legs is more secure and more stable than a ladder with less. to function and to survive under the service load of mechanical
One cannot climb on a ladder without a connector. In polymer and swelling pressure, respectively. When you drive your car,
terms, cross-linked polymers are long linear chains (ladder legs) the last thing you want is to have your tire melt away.
that are cross-linked using a functional or an olefin cross-linker
polymer mass suddenly melts at a certain temperature. Above or an amorphous polymer is preferred when the release of
the melting temperature, polymer molecules are in continu- a drug or an active material is intended. Crystallinity in a
ous motion and the molecules can slip past one another. given polymer depends on its topology and isomerism (linear
In many cases, the structure of a polymer is so irregular versus branched; isotactic versus atactic), polymer molec-
that crystal formation is thermodynamically infeasible. Such ular weight, intermolecular forces, pendant groups (bulky
polymers form glass instead of crystal domains. A glass is a versus small groups), rate of cooling, and stretching mode
solid material existing in a noncrystalline (i.e., amorphous) (uniaxial versus biaxial). Another unique property of a crys-
state. Amorphous structure is formed due to either rapid cool- talline polymer or a polymer-containing crystalline domains
ing of a polymer melt in which crystallization is prevented is anisotropy. A crystal cell displays different properties along
by quenching or due to the lack of structural regularity in the longitudinal and transverse directions. This causes the poly-
polymer structure. Rotation around single bonds of the polymer to behave like an anisotropic material.
mer chains becomes very difficult at low temperatures dur-
ing rapid cooling; therefore, the polymer molecules forcedly
adopt a disordered state and form an amorphous structure.
Thermal Transitions
Amorphous or glassy polymers do not generally display a Thermal transitions in polymers can occur in different orders.
sharp melting point; instead, they soften over a wide temper- In other words, the volume of a polymer can change with tem-
ature range.8 perature as a first- or second-order transition. When a crystal
melts, the polymer volume increases significantly as the solid
EXAMPLE 20–5 turns to a liquid. The melting temperature (Tm ) represents a
Crystalline and Amorphous first-order thermal transition in polymers. On the other hand,
Polystyrene and poly (vinyl acetate) are amorphous with melting the volume of an amorphous polymer gradually changes over
range of 35◦ C to 85◦ C and 70◦ C to 115◦ C, respectively. On the other a wide temperature range or so-called glass transition tem-
hand, poly (butylene terephthalate) and poly (ethylene terephtha- perature. This behavior represents a second-order thermal
late) are very crystalline with sharp melting range of 220 and 250◦ C
to 260◦ C, respectively.
transition in polymers. As shown in Figure 20–9, Tm and Tg
of a given polymer can be detected by differential scanning
calorimetry (DSC) as an endothermic peak and a baseline
Polymer strength and stiffness increases with crystallinity shift, respectively. These two thermal transitions reflect the
as a result of increased intermolecular interactions. With an structural movement of the crystalline and amorphous regions
increase in crystallinity, the optical properties of a poly- of a polymer chain.
mer are changed from transparent (amorphous) to opaque
(semicrystalline). This is due to differences in the refractive
indices of the amorphous and crystalline domains, which lead
Glass Transition Temperature
to different levels of light scattering. From a pharmaceutical Tg is an expression of molecular motion, which is depen-
prospective, good barrier properties are needed when poly- dent on many factors. Therefore, the Tg is not an absolute
mers are used as a packaging material or as a coating. Crys- property of a material and is influenced by the factors affect-
tallinity increases the barrier properties of the polymer. Small ing the movement of polymer chains. At temperatures well
molecules like drugs or solvents usually cannot penetrate or below the Tg , amorphous polymers are hard, stiff, and glassy
diffuse through crystalline domains. Therefore, crystalline although they may not necessarily be brittle. On the other
polymers display better barrier properties and durability in hand, at temperatures well above the Tg , polymers are rub-
the presence of attacking molecules. Diffusion and solubility bery and might flow. The Tg values for linear organic poly-
are two important terms that are related to the level of crys- mers range from about −100◦ C to above 300◦ C. Even though
tallinity in a polymer. On the other hand, a less crystalline some organic polymers are expected to have Tg values above
K E Y C O N C E P T ANISOTROPY
Take a roll of toilet paper from your bathroom and try to tear it chains are aligned in the direction of the force. When you try to
apart from two directions perpendicular to each other. What will tear the tissue in this direction, there is no barrier to the force
you observe? and the material does not resist. On the other hand, tearing the
If you tear it along the roll direction (its length), it will easily tissue requires cutting the chains in the perpendicular direc-
tear apart and the tear line will be smooth and even. On the other tion that implies resistance from the material. This is anisotropy,
hand, tearing in the other direction would be very difficult and which means material properties are different in different direc-
the tear line will appear as a random irregular corrugated line. tions. Pharmaceutical tablets are generally compressed in one
Why is this? direction, which might affect drug release or tablet properties
Toilet paper is manufactured using a process that applies a throughout.
force along the roll direction. Because of the applied force, the
space in between the polymer chain ends, also called the free
Crystalline
volume. As the free volume increases, polymer segments gain
more freedom to move and this affects the temperature at
which the movement occurs. For example, low- and high-
density polyethylenes are different in terms of the size of the
Amorphous free volume inside their structures. At a given weight, a low-
density polymer occupies more volume as compared with its
high-density counterpart. This means the polymer chain in
Specific
volume general and the chain segments in particular can move with
more ease resulting in a lower Tg value.
Tg and the length of the polymer chain: Long polymer
chains provide smaller free volume than their shorter counter-
Second order First order parts. Since more free volume corresponds to lower Tg values,
polymers containing short chains or having lower molecular
weight possess lower Tg values.
Tg and polymer chain side group: A side group may be
Enthalpy
bulky or polar. Because of its steric hindrance, higher tem-
perature is needed to induce segmental motion in poly-
mers containing bulky groups. For example, polystyrene
Tg Tm and polypropylene are only different in terms of their side
groups, phenyl versus methyl, respectively. The larger size
Fig. 20–9. Thermal transitions in polymers. of the phenyl group results in the much higher Tg value of
polystyrene, 100◦ C as opposed to −20◦ C for polypropylene.
300◦ C, they decompose at temperatures below their transition On the other hand, polar side groups provide stronger inter-
temperatures. From a pharmaceutical standpoint, Tg is an molecular interactions that significantly affect the segmental
important factor for solid dosage forms. For example, a chew- motion of the polymer chains. Poly (vinyl chloride) is similar
able dosage form needs to be soft and flexible at mouth tem- to polyethylene except hydrogen is replaced by one chlorine
perature of about 37◦ C. This means the polymer used as a atom. Since chlorine is more polar than hydrogen, the PVC
chewable matrix should be softened at this temperature. Phar- polymer displays a much higher Tg of 100◦ C compared to
maceutically acceptable polymers with their Tg values close −120◦ C for polyethylene.
to the service temperature of 37◦ C would be the best can- Tg and polymer chain flexibility: Flexible polymer
didates. Nicotine gum (Nicorette) gum is used as an aid in chains display higher entropy (desire to move) than rigid
smoking cessation. It works by providing low levels of nico- chains. Flexible and rigid chains behave similar to liquid and
tine, which lessens the physical signs of withdrawal symp- solid, respectively. Groups such as phenyl, amide, sulfone,
toms. The nicotine is released into the mouth as the patient and carbonyl either inside the backbone or as a side group
chews the gum. After placing a piece of the Nicorette gum hanging on the backbone affect the overall polymer flexi-
into the mouth the patient should chew it slowly several times. bility. For example, poly (ethylene adipate) and poly (ethy-
The patient should stop chewing it once he or she notices a lene terephthalate) are structurally very similar except for the
tingling sensation or a peppery taste in the mouth. At this phenylene residue in phthalate versus the butylene residue in
point the nicotine is being released and the patient should adipate. This results in almost a 100◦ C difference in Tg values
“park” the gum in the buccal area (in other words, between of the two polymers (−70◦ C versus 69◦ C, respectively).
the cheek and the gum) and leave it there until the taste or Tg and polymer chain branching: Linear polymer chains
tingling sensation is almost gone. The patient can resume possess smaller free volume as opposed to their branched
chewing a few more times and then stop once the taste comes counterparts. Therefore, higher Tg values are expected for lin-
back. The patient should repeat this for about 30 min or until ear polymers. On the other hand, branches in branched poly-
the taste or tingling sensation does not return. The reason that mers impose hindrance or restriction to segmental motion,
the patient “parks” the gum is because the release of nico- for which higher Tg values are expected. Therefore, branch-
tine should be slow and constant chewing will release the ing has no obvious effect on the Tg unless the whole structure
nicotine too quickly resulting in nausea, hiccups, or stomach of the polymer is known.
problems. The patient should also avoid drinking or eating at Tg and polymer chain cross-linking: Compared to cross-
this time. You have most likely experienced how gum behaves linked chains, linear chains have a higher entropy and the
differently when you drink cold water or hot tea. This is all desire to move; hence, they display low Tg values. Adding
reflected in glass–rubber transition of the chewable matrix. cross-links to linear polymer chains limits chain movement
As mentioned before, the Tg of a polymer is dependent on resulting in less entropy at a given temperature and hence a
many factors and the most important ones are discussed here. higher Tg value. For very highly cross-linked polymers, Tg
Segmental motion in polymers is facilitated by the empty values are expected to be very high to the extent that the
polymer starts to decompose before it shows any segmental narrow molecular weight distribution is very much desired
motion. for a polymer that is intended to be mechanically strong. On
Tg and processing rate: In order to prepare polymer prod- the other hand, a polymeric adhesive may have wide distri-
ucts, the polymer needs to be processed at different temper- bution of molecular sizes. In general, a given polymer cannot
atures or pressures that can significantly affect the molecular be identified as a molecule with a specific molecular weight.
motion in polymers. Therefore, the rate of processes such as Since chains are different, the molecular weight of all chains
heating, cooling, loading, and so on and so forth might be should be considered and must be averaged to have a more
considered when evaluating the Tg value of a given polymer. realistic figure for molecular weight of a given polymer. There
Kinetically speaking, if the rate of the process is high (fast are different ways that molecular weights of a polymer can
cooling, fast loading), the polymer chains cannot move to be expressed; by the number of the chains, by the weight
the extent that they are expected to. They virtually behave of the chains (the chain size), or by viscosity. However, the
like rigid chains with lower tendency to move, which results two most common ways are number (Mn ) and weight (Mw )
in reading high Tg values. For instance, when a differential average calculations. If all polymer chains are similar in size,
scanning calorimeter is used to measure the Tg of a polymer, then the number and weight average values will be equiva-
different Tg values may be observed if the same polymer is lent. If chains are of different sizes, then weight average is
heated up at different heating rates. This implies that the heat- distancing itself from the number average value. The term
ing rate has to be very realistic and should be consistent with polydispersity (PD) indicates how far the weight average can
the conditions in which the polymer is expected to serve. distance itself from the number average. A PD value closer
Tg and plasticizers: Plasticizer molecules can increase the to 1 means the polymer system is close to monodispersed
entropy and mobility of the polymer chains. This is translated and all of the polymer chains are almost similar in size. The
to lower Tg values for plasticized polymers compared with farther the value from 1 indicates that the polymer system is
their nonplasticized counterparts. polydispersed and chains are different in size. Figure 20–10
shows the concept.
Consider that you have received two different batches of
Plasticized Polymers a same polymer as shown in Table 20–2. The first batch con-
A plasticizer is added to a polymer formulation to enhance tains 2 chains of 50,000 g/mol and 10 chains of 20,000 g/mol
its flexibility and to help its processing. It facilitates relative in size. The second batch contains 2 chains of 100,000 g/mol
movement of polymer chains against each other. The addi- and 10 chains of 10,000 g/mol in size. Calculations show
tion of a plasticizer to a polymer results in a reduction in both batches have the same number averages of 25,000 g/mol.
the glass transition temperature of the mixture. Since plas- Should you, as a pharmaceutical scientist, claim that the two
ticizers increase molecular motion, drug molecules can dif- batches are similar and you can use them interchangeably
fuse through the plasticized polymer matrix at a higher rate within your formulation? You continue with the calculation
depending on the plasticizer concentration. to find out the weight average values for the two batches.
Surprisingly, two very different numbers, 30,000 g/mol and
EXAMPLE 20–6 70,000 g/mol, are found for the batch 1 and the batch 2,
Plasticized Polymers
Fluoxetine (Prozac Weekly) (fluoxetine hydrochloride) capsules con- Monodispersed
tain hydroxypropyl methylcellulose and hydroxypropyl cellulose Polydispersity ⫽ 1
acetate succinate plasticized with sodium lauryl sulfate and tri- Mw ⫽ Mn
ethyl citrate. Omeprazole magnesium (Prilosec), a delayed release
oral suspension, contains hydroxypropyl cellulose, hydroxypropyl
methylcellulose, and methacrylic acid copolymer plasticized with
glyceryl monostearate, triethyl citrate, and polysorbate. Triacetin
can be found in ranitidine HCl (Zantac) 150-tablet formula-
tions, which contains hydroxypropyl methylcellulose as its polymer
matrix. Dibutyl sebacate is found in methylphenidate HCl (Meta-
date) CD which contains polymers such as povidone, hydroxypropyl
methylcellulose, and ethyl cellulose.
Polydispersed
Polydispersity ⬎⬎1
Molecular Weight Mw ⬎⬎ Mn
Addition of a monomer to a growing macroradical during

polymer synthesis occurs by a diffusion or a random walk pro-
cess. Monomers may or may not be added equally to the grow-
ing macroradicals. As a result, a polymer batch may contain
polymer chains with different lengths (molecular weights)
and hence different molecular weight distributions. A very Fig. 20–10. Molecular weight distribution in polymer systems.
K E Y C O N C E P T NUMBER AND WEIGHT AVERAGES

A research institute is planning to hire a good scientist who can tute has found a tool to discriminate between the achievements
publish a tangible number of high-quality manuscripts per year. of the two scientists. These new numbers show that the scien-
The institute receives two resumes in which both scientists have tist 2 is more capable in publishing high-quality manuscripts. A
claimed 20 publications a year. The applicants were then asked similar discussion is valid for different polymer chains (journals)
to submit more details about the journals in which they have with different molecular weights (impact factors). With number
published. Now, the institute knows not only the total number of average, all chains are considered similar and the effect of their
publications but also the type and the number of journals they size is simply overlooked.
have published in. Journals were then categorized on the basis of
their impact factor (IF) as very high, high, medium, and low. If the
Journal IF Scientist 1 Scientist 2 N1 W1 N2 W2
total number of publications is divided by the number of journals,
both scientists score the same with an average of five publica- Very high IF 20 2 8
tions per journal per year. The number will change if the impact High IF 10 4 6 5 1.6 5 3.4
Medium IF 4 6 4
factors of the journals are also considered in the calculation. So,
Low IF 1 8 2
the new calculation shows average numbers of 1.6 as opposed Total 35 20 20
to 3.4 for the scientists 1 and 2, respectively. It looks like the insti-
respectively. This shows that the two batches are beyond a a given polymer. On the other hand, the weight average relies
doubt different. Another important piece of data that can help on the size of the molecules. Techniques such as light scatter-
you with your decision is PD which is the ratio of weight to ing are also reliant on the size of the molecules. Large- and
number averages. Polydispersity of 2.8 versus 1.2 indicates small-sized molecules scatter light in a very different way.
that the batch 2 contains very different chains. If both polymer Therefore, it is reasonable to use a light-scattering technique
batches are soluble in water, they will definitely show differ- to calculate the average Mw of a polymer.
ent solubility behavior in the presence of water. The shorter
chains are dissolved faster in water than longer chains. Drug
release from these batches will certainly be different as they
Mechanical Properties
assume different PD values. Depending on their structure, molecular weight, and inter-
Different techniques are used to calculate different aver- molecular forces, polymers resist differently when they are
ages. Since the number average relies on the number of poly- stressed. They can resist against stretching (tensile strength),
mer chains, technique to measure this should also rely on the compression (compressive strength), bending (flexural
number of species such as number of particles, and so on and strength), sudden stress (impact strength), and dynamic load-
so forth. It is well-known that colligative properties such as ing (fatigue). With increasing molecular weight and hence
osmotic pressure and freezing point depression are depen- the level of intermolecular forces, polymers display superior
dent on the number of particles in the solution. Colligative properties under an applied stress. As far as structure is con-
properties were introduced earlier in the book. These tech- cerned, a flexible polymer can perform better under stretch-
niques are very appropriate for calculating the average Mn of ing whereas a rigid polymer is better under compression.
TABLE 20–2
AVERAGE MOLECULAR WEIGHTS AND POLYDISPERSITY
Number of Chains Batch 1 Batch 2
2 50,000 g/mol 100,000 g/mol
10 20,000 g/mol 10,000 g/mol
Batch 1 Batch 2
Mn Mw PD Mn Mw PD
25,000 g/mol 30,000 g/mol 1.2 25,000 g/mol 70,000 g/mol 2.8

Mi N i (M1 N1 ) + (M2 N2 ) + (M3 N3 ) + (M4 N4 ) + · · ·
Mn = =
Ni N1 + N2 + N3 + N4 + · · ·
2
Mi N i (M1 2 N1 ) + (M2 2 N2 ) + (M3 2 N3 ) + (M4 2 N4 ) + · · ·
Mw = =
Mi N i (M1 N1 ) + (M2 N2 ) + (M3 N3 ) + (M4 N4 ) + · · ·
K E Y C O N C E P T MOLECULAR WEIGHT DISTRIBUTION

If you are planning to hire individuals for a cheerleading team, you for the forward. In polymer terms, chain size distribution per
may impose very strict requirements. For example they should all se is not a bad or a good thing. Depending on the application,
be 6-feet tall with a body mass index of 20. In the same sense, a the polymer needs to have a sharp or wide size distribution. A
soccer team might need a goalkeeper as well as a defense and polymer for an engineering application like the ones they use in
forward, for each of which you may have different requirements. aircrafts or spacecrafts may need to have a narrow size distri-
For example, height is very important for the goalkeeper position, bution, whereas for a general-purpose application you may use
whereas speed and accuracy is the most important requirement a polymer with a wider size distribution.
A polymer is loaded and its deformation is monitored to (fiber, tough plastic, or rubber), certain amounts of energy
measure its strength. Figure 20–11 shows the stress–strain are needed to break the polymer apart (in other words, tough-
behavior of different materials. For elastic materials such ness) and the area under the stress/strain curve measures it.
as metals and ceramics, the stress and strain (deformation) The larger the area is, the tougher the polymer.
correlation is linear up to the failure point. Generally, these
materials show high stress and very low elongation (defor-
mation, strain) at their breaking point. Polymeric materials Viscoelastic Properties
such as fibers and highly cross-linked polymers display elas- Mechanical properties of a given polymer are generally mea-
tic behavior, in other words, a linear stress/strain correlation sured at a fixed rate of loading, certain temperature or relative
up to their breaking point. With an increase in intermolecu- humidity, and so on and so forth. Polymers are neither a pure
lar forces within a fibrous product or cross-link density of a elastic nor a pure fluid material. They have the ability to store
cross-linked polymer, the slope of the stress/strain line will energy (display elastic behavior) and to dissipate it (display
become steeper. The sharper the slope, the higher the mod- viscous behavior). For this reason, most polymers are vis-
ulus. Modulus and stiffness are two terms that can be used coelastic materials. For example, poly (vinyl chloride) has
interchangeably to demonstrate the strength of a polymer. a glass transition temperature of about 100◦ C. This means,
Some polymeric materials do not display a sharp or abrupt it behaves like a solid at temperatures below its Tg and like
breaking point. Instead, they yield at certain stresses and con- a fluid at temperatures above its Tg . Since a typical PVC
tinue to deform under lower stresses before they finally break product is generally used at room temperature, its Tg is sup-
apart. Tough plastics show this typical behavior. Rubbers or posed to be well above the temperature of the environment in
elastomers on the other hand display completely different which it is expected to serve. In other words, a PVC product
behavior, which depends on the level of cross-linking or cur- behaves like a solid or glass at any temperature (including
ing. Generally, under very small stresses, they deform to a its service temperature) below its Tg . Now, assume that your
large extent to more than 10 to 15 times their original lengths. PVC product is expected to serve under a certain load (ther-
You may recall a rubber band when you stretch it from both mal, mechanical, etc.) and at certain temperature below its
ends. Highly cross-linked rubbers show very low deformation Tg , but for various periods of time. Such a loaded polymer,
at their breaking point. In fact, cross-linking is the process which originally behaves as a solid, or elastic may change
by which properties of a rubber can be enhanced to a very its behavior upon a long-term loading. Over time, the poly-
tough plastic or even a fiber. Regardless of the polymer type mer intermolecular forces will essentially become weaker
and hence, the polymer becomes softer. This can be seen in
Stress to break the glass windows used in the old churches as they show
(strength) High modulus different thicknesses from top to the bottom.
There are generally two methods to evaluate the viscoelas-
ticity in polymers; the creep test and the stress relaxation
Stress ␴
Low modulus test. With the former, the polymer is first loaded with a
certain weight and its deformation is then monitored over
the time. With the latter, the polymer is first deformed to a
certain extent, and then its stress relaxation (internal stress)
(Stiffness, modulus) Energy to break
(toughness) is monitored with the time.
␣
Strain ␧ Molecular Weight and Polymer Properties

Elongation at break
Mechanical properties of a given polymer generally increase
Fig. 20–11. Mechanical properties of polymers. with an increase in molecular weight. Polymer melts and
K E Y C O N C E P T ENTANGLEMENT
Let us say that there are two laundry machines with the total of this, the washer should be loaded with a smaller number of
capacity of each 20 lb and you separate your clothes into two large articles of clothing as it makes it easier to wash and dry
small (shorts) and large (pants) groups, each weighing 20 lb. Once them. In polymer terms, large molecular-weight polymers (large
the laundry step is completed, the clothes are to be transferred clothes) have a better affinity to tie into each other as opposed
into a dryer. An important observation to make is that more time to their smaller molecular-weight counterparts (small clothes).
will be spent to separate the large clothes from each other, which This is called entanglement. This occurs after a certain molecu-
is not the case with the small clothes. This happens because lar weight and affects the polymer properties in both the solution
large clothes have a tendency to tie into each other. Because and solid states.
polymer solutions are handled with more difficulty as their is basically made of an air-impermeable rubber called butyl.
molecular weight increases. This is due to a phenomenon Silicone is a very inert rubber with almost no affinity to any
called entanglement, which affects the flow of the polymer material. Therefore, silicone rubber is an excellent candidate
chains. As molecular weight increases, polymer chains are for very durable parts such as implants in biomedical applica-
more likely entangled into each other at certain molecular tions. Rubbers in general are not very strong in their raw form
weights. This results in poor polymer flow either in solid but they have a potential to be cross-linked and cured. None
state (as a melt) or in solution state (as a solution). For many of the rubbers used in tires can serve this application without
applications, there is a working range of molecular weights undergoing a curing process. Rubber is loaded with certain
that a given polymer in solid or solution state can successfully chemicals (curing agents) and is cured or cross-linked at high
be processed. pressure and temperature. Generally speaking, the glass tran-
sition temperatures of the rubbery polymers (elastomers) are
below the room temperature.
VARIETY OF POLYMERS
Plastics
Depending on their applications, polymers may be classi-
fied as rubbers, plastics, fibers, adhesives, and coatings. Each Plastics on the other hand possess completely different prop-
application requires a polymer to possess certain properties. erties. Their glass transition temperature is generally above
the room temperature as opposed to elastomers as shown in
Figure 20–12. Plastic parts are manufactured by techniques
Rubbers such as injection molding, extrusion, and thermoforming that
Rubbers are mostly used in tire manufacturing. A tire is a require the plastic to be in its molten state. Plastics that are
dynamic service environment that experiences friction with used in general applications such as packaging are generally
the ground surface; has to carry a heavy load of car weight cheap and are structurally weak. Polymers such as polyethy-
and its passengers; and is exposed to ultraviolet radiation, lene, polypropylene, and polystyrene have only carbon in
ozone, oxygen (inside and outside of the tire), weathering their backbone. The other groups of plastics which are used
conditions (wind, rain), and fatigue (dynamic loading and in engineering applications are required to be impact resis-
unloading). From a processing prospective, a tire is a com- tant, weather resistant, solvent resistant, and so on and so
posite of a few rubbers, metal, fiber, particulate fillers, and forth. These are generally heterogeneous plastics, which have
more. This requires rubber components of a tire to have elements other than carbon such as N, Si, and O in their back-
excellent cohesive (strength) and adhesive (adhesion) proper- bone. Polyesters, polyamides, and polyacetals are engineer-
ties. Rubbers have unique elongation properties, they can be ing plastics with very high intermolecular forces and hence
stretched without failure, and they can be loaded with static high melting point.
and dynamic loads under very severe conditions. Just imag-
ine for a moment, landing of a fully loaded cargo plane or a
commercial aircraft. Different rubbers offer different proper-
Fibers
ties. Those with double bonds (e.g., isoprene, butadiene) offer Polymers for fibrous products are required to have a crys-
resiliency but are very susceptible to oxidation and ozonation. talline structure with a very sharp melting point. For this
Those without double bonds (e.g., ethylene–propylene rub- application, polymers need to be meltable and spinnable.
ber) are very durable against weathering conditions. Some are Polypropylene fibers are used for plastic baskets, they are
very resistant to oil (e.g., chloroprene and nitrile) and some weak, and do not possess any specific properties. On the
have excellent impermeability (e.g., isobutylene–isoprene other hand, Kevlar fibers are used for bulletproof jack-
rubber). Tube-in tires are still used in which the tube part ets. This application requires the fiber to have very strong
Glass Glass
Mechanical property
Rubber Rubber
RT Tg Tg RT
Temperature
Plastics Elastomers Fig. 20–12. Plastics and elastomers.
intermolecular forces. In manufacturing fibers, both general Coating and adhesive applications rely on similar con-
and engineering plastics are used. Examples of fiber-forming cepts. A successful adhesive or coating process requires that
materials are cellulose acetate, rayon, polypropylene, nylon, the matrix onto which the adhesive is applied to be fully cov-
polyester, polyamide, and polyacrylonitrile. ered by the polymer material, which is generally applied in an
emulsion form. Coatings are used for protection purposes. A
Adhesives and Coatings successful adhesive application requires careful understand-
ing of the properties of the adhesive and adherents since an
The required properties of polymers for adhesive and coating adhesive is generally trapped in between two or more materi-
applications are tackiness and adhesiveness. This means that als. For coating applications, the coating polymer is generally
adhesive forces (interaction with a second material) should be exposed to a second environment such as air, oxygen, water,
in balance with cohesive forces (interaction with itself ). Both stomach fluid, intestinal fluid, solvents, and so on and so forth.
forces increase with the molecular weight of the polymer as This requires a thorough understanding of the coated matrix,
molecular interactions increase between the same or different coating material, as well as the service environment in which
molecules due to increased surface area. Structurally speak- the material is expected to serve. Examples of coating mate-
ing, the cohesive forces within a polymer can be modulated rials are poly (vinyl acetate), acrylate esters, ethyl cellulose,
by changing its molecular weight, crystallinity, or addition and so on and so forth.
of a second material such as plasticizers or oils. The adhe-
sive intended for a nonpolar adherent should be nonpolar
as well. On the other hand, very polar adhesive materials POLYMERS AS RHEOLOGY MODIFIERS
such as epoxy and cyanoacrylate are suggested for very polar
adherents including metals. Generally speaking, the rule of Polymer chains are in a coiled conformation at rest, and they
thumb “like dissolves like” is simply applied to polymers for assume extended conformation once they are loaded. In appli-
adhesive and coating applications. Like plastics, adhesives cations where increased viscosity of the solution is desirable,
can be categorized as general and engineering (structural). the goal is to increase the chain end-to-end distance under a
The difference is the level of intermolecular forces within the given load. In dissolution of a polymer and polymer swelling,
adhesive structure. Structural adhesives are generally used for the load originates from the interaction of a polymer and a
engineering application such as in air and aerospace indus- solvent as well as concentration gradient of ions inside the
tries where high quality, durability, and strength are the basic polymer structure and the solution. Apparently longer end-to-
requirements. To ensure that these requirements are met, end distances are potentially obtained if the polymer chains
the adhesive undergoes special treatment such as curing. are longer and have more interaction with the solvent. In case
Cyanoacrylate-based adhesives or silicone adhesives are gen- of water as a solvent, the more hydrophilic polymer will be
erally cured by absorbing moisture from the air. Epoxy adhe- better. On the other hand, a more lipophilic polymer would be
sives are generally supplied as two components and cured in more desirable when the dissolution or swelling medium is
the presence of a third component (primary, secondary, and organic. Figure 20–13 shows how different polymer chains
tertiary amines). Polyester adhesives are cured using perox- and solutions display different rheological behavior, which is
ides and catalyzed by amines. The curing process increases characterized by the volume occupied by the polymer chains.
the cohesive forces at the expense of adhesive forces. Since an Because of their hydrophilicity and high molecular weight,
adhesive should possess a balance of cohesive and adhesive gums are the candidate of choice for increasing the viscosity
properties, the curing process should also be optimized. of the aqueous solutions or dispersions.
K E Y C O N C E P T POLYMER STRUCTURE AND SOLUTION VISCOSITY

Your cotton-based clothes get wetter on a rainy day as com- functional groups make more and closer contacts with water,
pared to plastics. So, if you go for a daylong trip on a rainy day, which causes molecules of water to move slower, which means
you might want to wear a poncho which is 100% plastic in order they generate more viscosity.
to repel the water. In polymer terms, polymers with water-loving
HYDROGELS state and has the tendency to obtain more freedom as it goes
into solution. If a polymer structure is nonionic, the major
The concept of an end-to-end distance is also applied in driving force of swelling will be polymer–solvent interac-
swellable polymers. As mentioned earlier, the driving force tions. As the ion content of a hydrogel increases, two very
for the dissolution and swelling processes are similar. Cer- strong osmotic and electrostatic forces are generated within
tain materials, when placed in excess water, are able to swell the hydrogel structure. The presence of ions inside the gel and
rapidly and retain large volumes of water in their structures. the absence of the same ions in the solvent trigger a diffusion
Such aqueous gel networks are called hydrogels. These are process (osmosis) by which water enters the polymer struc-
usually made of a hydrophilic polymer that is cross-linked ture until the concentration of the ion inside the gel and the
either by chemical bonds or by other cohesion forces such as solvent becomes equivalent. In fact, the polymer diffuses into
ionic interaction, hydrogen bonding, or hydrophobic interac- water to balance its ion content with the surrounding solu-
tions. Hydrogels behave like an elastic solid in a sense that tion. Polymer chains carrying ions are charged either nega-
they can return to their original conformation even after a tively (anionic) or positively (cationic). In either case, similar
long-term loading. charges on the polymer backbone will repel each other upon
A hydrogel swells for the same reason as its linear polymer ionization in an aqueous medium. This creates more spaces
dissolves in water to form a polymer solution or hydrosol. inside the hydrogel and more water can be absorbed into its
From a general physicochemical standpoint, a hydrosol is structure. Since swelling in many applications is a desirable
simply an aqueous solution of a polymer. Many polymers property (e.g., in superabsorbent baby diapers or superdisin-
can undergo reversible transformation between hydrogel and tegrants in pharmaceutical solid dosage forms), the infinite
hydrosol. When a hydrogel is made by introducing gas (air, dilution of the polymer needs to be restricted. Linking poly-
nitrogen, or carbon dioxide) during its formation, it is called mer chains to each other can do this, generating elastic forces
a porous hydrogel. and causing less entropy.
A hydrogel swells in water or in any aqueous medium EXAMPLE 20–7
because of positive forces (polymer–solvent interaction,
Superdisintegrants
osmotic, electrostatic) and negative forces (elastic) acting
In pharmaceutical solid dosage forms, a superdisintegrant is gen-
upon the polymer chains as shown in Figure 20–14. Disso- erally used to help the dosage form with a proper disintegration.
lution of a polymer in a solvent is an entropy-driven process The concept behind this is the osmotic pressure that is generated
that happens spontaneously. A dry hydrogel is in its solid by either hydrophilicity (as in vinyl pyrrolidone) or ionic (as in
In water
Less In alcohol or
hydrophilic salt solutions
Fig. 20–13. Polymers as rheology

Low Mw High Mw More hydrophilic modifier.
Coiled conformation
Extended conformation
Chain–water
interaction
Electrostatic
repulsive
forces
Osmotic
forces
Fig. 20–14. Swelling forces in

hydrogels.
carboxymethyl cellulose) nature of the structure. Sodium starch drilled orifice on top of the tablet. Since 1983, this technology has
glycolate (Explotab, Primojel, Vivastar P), cross-linked poly (vinyl been used in a number of prescription and over-the-counter prod-
pyrrolidone) (Crospovidone), and cross-linked sodium salt of car- ucts marketed in the United States, including nifedipine (Procardia
boxymethyl cellulose (Ac-Di-Sol, Croscarmelose) are widely used as XL), glipizide (Glucotrol XL), methylphenidate, oxybutynin, and
a tablet and capsule disintegrant in oral dosage forms. pseudoephedrine (Sudafed 24 Hour). Duros technology is utilized
in implants that deliver drugs over a very long period. Leupro-
lide implant (Viadur) osmotic implant is based on Alza’s Duros
pump technology which delivers leuprolide acetate over a year long
EXAMPLE 20–8 period.
Osmotic Tablet and Pump
Alza’s Oros and Duros technologies are based on an osmosis con-
cept. Oros provides 24 hr controlled drug release that is indepen- Depending on the nature of cross-linking, a hydrogel is
dent of many factors such as diet status. Tablets using Oros tech- classified as chemical or physical.
nology as shown in Figure 20–15 are made of two sections coated
with a semipermeable material. The upper section contains drug
and the lower section contains the osmotic agent either a salt or
a water-soluble/swellable polymer. The membrane allows water or Chemical Gels
the aqueous medium to enter into the osmotic agent compartment.
In the presence of water, osmotic pressure pushes the bottom com- Chemical gels are those that are covalently cross-linked.
partment upward which in turn forces the drug through a laser- Therefore, chemical gels will not dissolve in water or other
organic solvent unless the covalent cross-links are broken
apart. At least two different approaches can be used to
Tablet coating form chemical gels, either by adding an unsaturated olefinic
Laser-drilled orifice
Semipermeable monomer carrying more than one double bond (e.g., N,N -
membrane methylene bisacrylamide, ethylene glycol dimethacrylate) or
Drug compartment
by reacting the functional groups on the polymer backbone.
The first approach is used to make water swellable gels or
hydrogels. In general, cross-linking through double bond is
energetically favored as less energy is required to break a dou-
ble bond than to react the functional groups. Cross-linked
polymers of acrylic acid, sodium acrylate, and acrylamide
have found extensive application in hygiene and agricultural
Osmotic compartment
industries as water absorbent polymers. These can absorb
Fig. 20–15. An osmotic tablet based on Oros technology. urine in diapers or can retain the water in the soil.
As far as the swelling is concerned, temperature has often sive hydrogels are ideal for making sensors and modulated
a positive effect on the swelling process. Most chemical gels drug delivery systems.
especially those made of hydrophilic chains can swell more
in warmer solutions. These gels are so-called thermoswelling
chemical gels. On the other hand, some hydrogels made of POLYMERS FOR PHARMACEUTICAL
relatively hydrophobic monomers shrink upon increase in
temperature, and they are known as thermoshrinking chem- APPLICATIONS
ical gels. The thermoshrinking hydrogels undergo thermally
reversible swelling and deswelling. The temperature at which In a traditional pharmaceutics area, such as tablet manufactur-
this sharp transition occurs is corresponded to a lower critical ing, polymers are used as tablet binders to bind the excipients
solution temperature of the non–cross-linked polymer. of the tablet. Modern or advanced pharmaceutical dosage
forms utilize polymers for drug protection, taste masking,
controlled release of a given drug, targeted delivery, increase
Physical Gels drug bioavailability, and so on and so forth.
Hydrogen bonding, hydrophobic interaction, and complex- Apart from solid dosage forms, polymers have found
ation are three major tools in preparing a physical gel. A application in liquid dosage forms as rheology modifiers.
hydrogen bond is formed when two electronegative atoms, They are used to control the viscosity of an aqueous solu-
such as nitrogen and oxygen interact with the same hydrogen, tion or to stabilize suspensions or even for the granulation
N–H· · ·O. The hydrogen is covalently attached to one atom, step in preparation of solid dosage forms. Major application
the donor, but interacts electrostatically with the other, the of polymers in current pharmaceutical field is for controlled
acceptor. This type of interaction occurs extensively in poly drug release, which will be discussed in detail in the fol-
(vinyl alcohol), for example. Although its structure suggests lowing sections. In the biomedical area, polymers are gen-
an easy dissolution in water, a poly (vinyl alcohol) at molec- erally used as implants and are expected to perform long-
ular weight more than 100,000 g/mol is water insoluble. In term service. This requires that the polymers have unique
order to dissolve the polymer, the hydrogen bonds need to be properties that are not offered by polymers intended for gen-
broken and that requires the solution to be heated up to 80◦ C eral applications. Table 20–3 provides a list of polymers
to 90◦ C. with their applications in pharmaceutical and biomedical
Hydrophobic interactions are considered to be the major industries.
driving force for the folding of thermoresponsive hydrogels In general, the desirable polymer properties in pharma-
and globular proteins. The existence of hydrophobic groups ceutical applications are film forming (coating), thickening
will change the hydrophilic lipophilic balance (HLB) of the (rheology modifier), gelling (controlled release), adhesion
polymer that in turn affects its solubility in water. The more (binding), pH-dependent solubility (controlled release), sol-
hydrophobic groups within the hydrogel structure, the more ubility in organic solvents (taste masking), and barrier prop-
temperature dependent the swelling will be. As the number erties (protection and packaging).
of hydrophobic group increases, the solubility–insolubility From the solubility standpoint, pharmaceutical polymers
transition or swelling–deswelling transition shifts to a lower can be classified as water-soluble and water-insoluble (oil-
temperature. Polymers, such as methylcellulose, hydrox- soluble or organic soluble). The cellulose ethers with methyl
ypropyl methylcellulose, or certain PEO/PPO/PEO triblock and hydroxypropyl substitutions are water-soluble, whereas
copolymers, dissolve only in cold water and form a vis- ethyl cellulose and a group of cellulose esters such as cellu-
cous solution. Once the solution temperature increases up lose acetate butyrate or phthalate are organic soluble. Hydro-
to a certain point, these solutions become thicker by forming colloid gums are also used when solubility in water is desir-
a gel. able. The synthetic water-soluble polymers have also found
Complexation may happen between two oppositely extensive applications in pharmaceutical industries, among
charged groups of different polymer structures or via metal them polyethylene glycol, polyethylene glycol vinyl alco-
ions. In water, alginic acid with negatively charged groups hol polymers, polyethylene oxide, polyvinyl pyrrolidone, and
and chitosan with positively charged groups can form a com- polyacrylate or polymethacrylate esters containing anionic
plex. The solubility of the complex is generally dependent on and cationic functionalities are well-established.
the pH of the dissolution medium and the pKa of the polymers.
On the other hand, alginic acid carrying negatively charged
carboxyl groups can form insoluble complexes with divalent
Cellulose-Based Polymers
and trivalent ions such as calcium, aluminum, and iron. These Although cellulose itself is insoluble in water, its water-
complexes are also reversible and pH dependent. Hydrogels soluble derivatives have found extensive applications in
either chemical or physical are also known as smart, intelli- pharmaceutical dosage forms. The structure of cellu-
gent, or responsive as they react to the environmental changes lose is shown in Figure 20–16. Methyl cellulose, CMC,
such as pH, temperature, salt concentration, salt type, solvent and hydroxypropyl methylcellulose are the most common
composition, or pressure. The unique properties of respon- cellulose-based polymers with methyl, carboxymethyl, and
TABLE 20–3
POLYMERS IN PHARMACEUTICAL AND BIOMEDICAL APPLICATIONS
Water-Soluble Synthetic Polymers
Poly (acrylic acid) Cosmetic, pharmaceuticals, immobilization of cationic drugs, base for Carbopol polymers
Poly (ethylene oxide) Coagulant, flocculent, very high molecular-weight up to a few millions, swelling agent
Poly (ethylene glycol) Mw <10,000; liquid (Mw <1000) and wax (Mw >1000), plasticizer, base for suppositories
Poly (vinyl pyrrolidone) Used to make betadine (iodine complex of PVP) with less toxicity than iodine, plasma
replacement, tablet granulation
Poly (vinyl alcohol) Water-soluble packaging, tablet binder, tablet coating
Polyacrylamide Gel electrophoresis to separate proteins based on their molecular weights, coagulant,
absorbent
Poly (isopropyl acrylamide) and poly Thermogelling acrylamide derivatives, its balance of hydrogen bonding, and hydrophobic
(cyclopropyl methacrylamide) association changes with temperature
Cellulose-Based Polymers
Ethyl cellulose Insoluble but dispersible in water, aqueous coating system for sustained release applications
Carboxymethyl cellulose Superdisintegrant, emulsion stabilizer
Hydroxyethyl and hydroxypropyl Soluble in water and in alcohol, tablet coating
celluloses
Hydroxypropyl methyl cellulose Binder for tablet matrix and tablet coating, gelatin alternative as capsule material
Cellulose acetate phthalate Enteric coating
Hydrocolloids
Alginic acid Oral and topical pharmaceutical products; thickening and suspending agent in a variety of
pastes, creams, and gels, as well as a stabilizing agent for oil-in-water emulsions; binder
and disintegrant
Carrageenan Modified release, viscosifier
Chitosan Cosmetics and controlled drug delivery applications, mucoadhesive dosage forms, rapid
release dosage forms
Hyaluronic acid Reduction of scar tissue, cosmetics
Pectinic acid Drug delivery
Water-Insoluble Biodegradable Polymers
(Lactide-co-glycolide) polymers Microparticle–nanoparticle for protein delivery
Starch-Based Polymers
Starch Glidant, a diluent in tablets and capsules, a disintegrant in tablets and capsules, a tablet binder
Sodium starch glycolate Superdisintegrant for tablets and capsules in oral delivery
Plastics and Rubbers
Polyurethane Transdermal patch backing (soft, comfortable, moderate moisture transmission), blood
pump, artificial heart, and vascular grafts, foam in biomedical and industrial products
Silicones Pacifier, therapeutic devices, implants, medical grade adhesive for transdermal delivery
Polycarbonate Case for biomedical and pharmaceutical products
Polychloroprene Septum for injection, plungers for syringes, and valve components
Polyisobutylene Pressure sensitive adhesives for transdermal delivery
Polycyanoacrylate Biodegradable tissue adhesives in surgery, a drug carrier in nano- and microparticles
Poly (vinyl acetate) Binder for chewing gum
Polystyrene Petri dishes and containers for cell culture
Polypropylene Tight packaging, heat shrinkable films, containers
Poly (vinyl chloride) Blood bag, hoses, and tubing
Polyethylene Transdermal patch backing for drug in adhesive design, wrap, packaging, containers
Poly (methyl methacrylate) Hard contact lenses
Poly (hydroxyethyl methacrylate) Soft contact lenses
Acrylic acid and butyl acrylate copolymer High Tg pressure–sensitive adhesive for transdermal patches
2-Ethylhexyl acrylate and butyl acrylate Low Tg pressure–sensitive adhesive for transdermal patches
copolymer
Vinyl acetate and methyl acrylate High cohesive strength pressure–sensitive adhesive for transdermal patches
copolymer
Ethylene vinyl acetate and polyethylene Transdermal patch backing (occlusive, heat sealable, translucent)
terephthalate
Ethylene vinyl acetate and polyethylene Transdermal patch backing (heat sealable, occlusive, translucent)
Polyethylene and polyethylene Transdermal patch backing (when ethylene vinyl acetate copolymer is incompatible with the
terephthalate drug)
CH2OR CH2OR
O O
RO OR O OR O
R
OR OR n
Fig. 20–16. Cellulose structure.
hydroxypropyl/methyl substitution, respectively. Table 20–4 Hydrocolloids

shows how functional group substitution results in different
cellulose-based polymers with different properties. Various hydrocolloids or polysaccharide gums are originated
Methocel polymers including pure methylcellulose and from a variety of sources as summarized in Table 20–5.
hydroxypropyl-substituted methylcellulose display thermo- Most gums are hydrophilic and contain very long poly-
gelling property in water. As the temperature of the solution meric chains as well as different functional groups. These
increases, the hydrophobic groups of these polymers start features are very attractive in many pharmaceutical processes
to aggregate, as a result the polymer solution will assume such as coating, stabilization, thickening, binding, solubiliza-
a cloudy appearance. The cloud point temperature for the tion, and disintegration. Gums behave differently in water and
pure methyl cellulose (with no hydroxypropyl substitution) aqueous solutions. Almost all display thickening property,
is about 50◦ C. As more methyl groups are substituted with whereas some show gelling property. Although thickening
hydroxypropyl groups, which have better solubility in water, is a desirable property for solution, suspension, and emul-
the cloud point temperature shifts to higher temperature sion dosage forms, gelling property is utilized in drug encap-
(60◦ C–85◦ C for the Methocel E, F, and K). Generally speak- sulation for controlled delivery applications. Gums such as
ing, cloud point temperature is critically dependent on the guar gum can provide excellent thickening property, whereas
methyl substitution. On the other hand, aqueous viscosity of gums including alginate and chitosan can offer a gelling prop-
the Methocel polymers is more dependent on the polymer erty in the presence of ions. Similar to synthetic polymers,
molecular weight than its methyl/hydroxypropyl content. gums can be blended to provide superior properties through
TABLE 20–4
CELLULOSE-BASED POLYMERS
R Polymer Characteristics
H Cellulose Water-insoluble due to excessive hydrogen bonding
H and CH3 Methyl cellulose (MC) Soluble in cold water only; commercially available as Methocel A (Dow
Chemical); swells and disperses slowly in cold water to form a colloidal
dispersion; practically insoluble in ethanol, saturated salt solutions, and hot
water; soluble in glacial acetic acid, displays thermogelling property
H and CH2 CH3 Ethyl cellulose (EC) Water-insoluble; aqueous coating system for sustained release applications;
impermeable barrier; plasticized EC composed of dibutyl sebacate and oleic
acid; Ethocel is commercially available from Dow; Ethyl cellulose latex,
Aquacoat, is also available from FMC Corp
H and CH2 COOH Carboxymethyl cellulose Water-soluble; variable degree of substitution; cross-linked CMC is
(CMC) water-swellable and known as croscarmellose sodium in National Formulary
(NF); FMC Corp. supplies cross-linked CMC (Ac-Di-Sol; Accelerated
Dissolution) as tablet superdisintegrant
H and CH2 CH2 OH Hydroxyethyl cellulose Soluble in water and in alcohol
(HEC)
H and Hydroxypropyl cellulose Water-soluble at low temperature; film-coating application
CH2 CHOHCH3 (HPC)
H and CH3 and Hydroxypropyl Soluble in water below 60◦ C and in organic solvents; Dow Chemical supplies
CH2 CHOHCH3 methylcellulose (HPMC) HPMC as Methocel (such as E, F, K) for tablet coating; HPMC coating
replaced sugar coating with the advantage of much shorter coating time;
possess thermogelling property; is also used as capsule material to substitute
the animal-based gelatin
TABLE 20–5
HYDROCOLLOIDS FROM DIFFERENT SOURCES
Seaweed Plant
Plant Exudates Seed Gum Extract Microbial Extract Animal-Based
Gum arabic Guar Agar Xanthan Pectin Chitosan
Karaya Locust bean Carrageenan Gellan Konjac Gelatin
Tragacanth Psyllium Alginate Curdlan
Ghatti
synergy, which cannot be achieved by individual gum alone. product rich in G block offers stronger gel in the presence
On the negative side, gums are obtained from natural sources of ions, in particular, calcium. Excipient suppliers provide
with different assay and qualities. Therefore, as opposed to different grades of alginate with broad range of G/M ratios.
synthetic polymers, the batch-to-batch consistency and qual- Apparently, the mechanical property of the alginate gel is
ity would be a major challenge for pharmaceutical suppliers. determined by the G/M contents of the product, the type of
Besides, gums are a good platform for bacteria growth, which ion (monovalent, divalent, trivalent), the concentration of ion
limits their shelf life and requires sterilization. in the solution, as well as the duration of the gelling pro-
Polysaccharides and their derivatives can be used as a cess. For the encapsulation purposes, all these factors have
rate controller in sustained release formulations due to their to be considered in designing a tailor-made delivery system.
gelling property.9 Gums can easily be derivatized to change Alginic acid and its derivatives have found applications as
their solution properties. For instance, chitosan is only sol- a stabilizing agent, binding agent, drug carrier, and so on
uble in acidic water, but its carboxymethyl derivative is and so forth. The antibiotic griseofulvin, which is supplied
soluble at a wider pH range. Gums offer a wide range of as oral suspension, contains sodium alginate stabilized with
molecular weights that also affect their dissolution proper- methylparaben. Alginic acid and ammonium calcium algi-
ties. They are biodegradable and their chemical composition nate can be found in metaxalone tablets. Alginate microbeads
varies greatly.10 The physicochemical properties of polysac- can be used to entrap drugs, macromolecules, and biological
charide solutions and gels have recently been reviewed for cells. For this application, parameters such as calcium salt,
pharmaceutical and food applications.11 Polysaccharides are other hardening agents, and different drying methods have
claimed to effectively treat local colon disorders if they been studied.15 Islets of Langerhans embedded into alginate
are used in colon-targeting delivery systems, which utilize encapsulates can be transplanted without the risk of protein
the colonic microflora.12 Inulin, amylase, guar gum, and contamination and immune system suppression.16
pectin are specifically degraded by the colonic microflora Carrageenan is a sulfated linear polysaccharide of galac-
and used as polymer drug conjugates and coating. It has tose and anhydrogalactose. It carries a half-ester sulfate group
been shown that drug release in the colon can be maxi- with the ability to react with proteins. If carrageenan is used
mized if the hydrophobicity of the gums is modified chem- in a solution containing proteins, the solution becomes gel or
ically or physically using other conventional hydrophobic viscous due to a complex formation between carrageenan and
polymers.13 In cancer therapy, polysaccharides are used as charged amino acids of the protein. Therefore, a formulation
immune-modulators. A few fungal polysaccharides, either scientist should be aware of any incompatibility issues which
alone or in combination with chemotherapy and/or radio- might jeopardize the stability of the drug solution, suspen-
therapy, have been used clinically in the treatment of various sion, or emulsion. Depending on the concentration and loca-
cancers.9 It was suggested that iron stabilized into a polysac- tion of the sulfated ester groups, carrageenan can be found
charide structure can be used to treat anemia. The product in three different grades of kappa, iota, and lambda. Kappa
can also be used in resonance imaging as well as in separa- carrageenan can form a strong and brittle gel, especially in
tion of cells and proteins utilizing magnetic fields due to its the presence of potassium ions or if blended with locust bean
magnetic properties.14 gum. If a drug formulation requires a softer and more elastic
Alginic acid is a linear polysaccharide that mainly consists gel, iota carrageenan can be used. Both kappa and iota car-
of two building blocks of mannuronic (M) and guluronic (G) rageenan can be used for controlled delivery application as
acid residues. Alginic acid and its salts are anionic poly- they display gelling properties under certain circumstances. If
mers that can offer gelling properties. Since they contain car- a drug formulation needs to be thickened and does not contain
boxyl group, they can easily undergo a complexation reac- proteins of any source, a lambda carrageenan can be utilized.
tion in the presence of ions. Depending on its source, the Donepezil hydrochloride orally disintegrating tablets and cef-
mannuronic and guluronic contents of the alginate product podoxime proxetil oral suspension contain carrageenan. Car-
can be different. Between the two building blocks, the G rageenan is shown to increase the permeation of sodium flu-
blocks are responsible for the gelling property; as such, a orescein through porcine skin as it changes the rheological
properties of the drug solution.17 In capillary electrophore- 65% soluble solids and low pH (<3.5) to form a gel, whereas
sis, a sulfated polysaccharide such as carrageenan can be used low methoxyl pectins require calcium and may form a gel
to separate the enantiomers of weakly basic pharmaceutical at a much lower solid content, that is, 20%. Gelation and
compounds. Different enantiomers of racemic compounds association of pectin chains in the presence of pH-reducing
such as propranolol and pindolol have been separated using additives has also been reported.30 While pectin is generally
carrageenan.18,19 known as a suspending and thickening agent, it is also claimed
Chitosan is obtained from chitin, the second most abun- to reduce blood cholesterol levels and to treat gastrointestinal
dant natural polymer after cellulose, which can be found disorders.31 Pectin can be found in amlexanox oral paste.
in shrimp, crab, and lobster shells. Chitosan is a cationic Xanthan gum is found in a number of drug formula-
polymer and has been investigated as an excipient in tions including cefdinir oral suspension and nitazoxanide
controlled delivery formulations and mucoadhesive dosage tablets. It is a highly branched glucomannan polysaccha-
forms because of its gelling and adhesive properties. The bit- ride with excellent stability under acidic conditions. Xan-
ter taste of natural extracts such as caffeine has been masked than is generally used in solution and suspension products
using chitosan. Chitosan can potentially be used as a drug for its thickening property. Because of its very rigid struc-
carrier, a tablet excipient, delivery platform for parenteral for- ture, its aqueous solution is significantly stable over a wide
mulations, disintegrant, and tablet coating.20,21 From toxicity pH range. Similar to locust bean gum, xanthan gum is also
and safety standpoint, lower–molecular-weight chitosan (as nongelling but forms a gel once it is mixed with the locust
an oligosaccharide) has been shown to be safer with negligi- bean gum. Concentrated xanthan gum solutions resist flow
ble cytotoxicity on Caco-2 cells.22 During the encapsulation due to excessive hydrogen bonding in the helix structure, but
process using synthetic polymers, the protein is generally they display shear-thinning rheology under the influence of
exposed to the conditions which might cause their denatura- shear flow. This feature of xanthan gum solutions is crit-
tion or deactivation. Therefore, a biocompatible alternative ical in food, pharmaceutical, and cosmetic manufacturing
such as chitosan is desirable for such applications.23 Because processes.32 Oxymorphone hydrochloride extended-release
of its cationic nature, chitosan can make complexes with tablets contain TIMERx, which consists of xanthan gum, and
negatively charged polymers such as hyaluronic acid (HA) locust bean gum for controlled delivery.33 Rectal delivery of
to make a highly viscoelastic polyelectrolyte complex. The morphine can be controlled using cyclodextrins as an absorp-
complex has the potential to be used as cell scaffold and as a tion enhancer and xanthan as a swelling hydrogel. This com-
drug carrier for gene delivery.24 Gels based on chitosan and bination produces a sustained plasma level of morphine and
ovalbumin protein have been suggested for pharmaceutical increases its rectal bioavailability.34
and cosmetic use.25 In veterinary area, chitosan can be used in HA consists of N-acetyl-d-glucosamine and beta-
the delivery of chemotherapeutics such as antibiotics, antipar- glucoronic acid and has been used as fluid supplement in
asitics, anesthetics, painkillers, and growth promotants.26 As arthritis, in eye surgery, and to facilitate healing of surgical
an absorption enhancer, a protonated chitosan is able to wounds. Solaraze gel for the topical treatment of actinic ker-
increase paracellular permeability of peptide drugs across atoses is composed of 3% sodium diclofenac in 2.5% HA
mucosal epithelia. While trimethyl derivative of chitosan is gel.35 Sodium hyaluronate and its derivatives have been eval-
believed to enhance the permeation of neutral and cationic uated in vitro and in vivo for optimized delivery of a variety of
peptide analogs, the carboxymethyl derivative of chitosan active molecules such as antibiotic gentamicin and cytokine
offers gelling properties in an aqueous environment or with interferon.36 Hyaluronan is biocompatible and nonimmuno-
anionic macromolecules at neutral pHs.27 Chitosan can also genic and has been suggested as a drug carrier for ophthalmic,
be mixed with nonionic surfactants such as sorbitan esters nasal, pulmonary, parenteral, and dermal routes.37 Sodium
to make emulsion like solutions or creams.28 To prepare hyaluronate topical (Seprafilm), which is used to reduce scar
chitosan beads or microspheres, the chitosan matrix needs tissue as a result of abdominal or pelvic surgery, is a biore-
to be treated with an anionic compound like pentasodium sorbable membrane containing sodium hyaluronate.
tripolyphosphate. A sustained release dosage form of salbuta- Gum arabic or gum acacia is best known for its emulsi-
mol sulfate bead can be prepared using chitosan in phosphate fying property and its solution viscosity at very high solid
buffer.29 concentration. Locust bean gum consists of mannose and
Pectin is a ripening product of green fruits such as lemon galactose sugar units at a ratio of 4:1. Like almost all gum
and orange skin. Protopectin is an insoluble pectin precursor solutions, an aqueous solution of this gum displays shear-
present in such fruits, which is converted to pectinic acid and thinning rheology. It shows synergistic effect with xanthan
subsequently to pectin. The main component of pectin is d- and kappa carrageenan. Gellan gum has been used in phar-
galacturonic acid, which is in part esterified via methylation. maceutical dosage forms as a swelling agent,38 as a tablet
Depending on its methoxyl content, pectin is classified as binder,39 and as a rheology modifier.40 Drug delivery behav-
high methoxyl (HM, 50% or more esterification) and low ior of scleroglucan hydrogels has been examined using theo-
methoxyl (LM, less than 50% esterification). Pectins can form phylline as a model drug.41 As an alternative tablet binder
a gel in an aqueous solution if certain conditions are existed. to starch and polyvinyl pyrrolidone, seed galactomannan
For instance, high methoxyl pectins require a minimum of of Leucaena, a natural polysaccharide comparable to guar
gum, has been evaluated for poorly compressible drugs such Synthetic Polymers
as paracetamol.42 Schizophyllan, which is secreted by fun-
gus, has been evaluated as an immunostimulant (to sup- Synthetic polymers based on acrylic or methacrylic acids
press tumor growth), antitumor, antihepatitis, anti-HIV, and have found extensive applications in the drug delivery area to
antiviral agent.43,44 Sustained release formulations based on protect the drug or to release the drug in a controlled manner.
guaran,45 in situ gel-forming ability of xyloglucan,46 and These are classified as cationic, anionic, and neutral (non-
borax–guar gum complexes for colon specific drug delivery ionic) polymers. Despite the different solubility and swella-
have also been studied.47 bility across the GI tract, the drug release from these matrices
One of the most recent applications of gums is in film occurs through a diffusion process.
forming. Recent concepts and products such as breath films, Cationic polymers: One of the most widely used cationic
cough strips, flu, and sore throat strips have all been real- polymers for protective coating applications has dimethyl
ized on the basis of film-forming ability of gums. Generally aminoethyl methacrylate for a functional group. As far as its
speaking, as opposed to branched gums, linear gums have purity is concerned, the polymer contains less than 3000 ppm
more sites available for intermolecular hydrogen bonding; of residual monomers including butyl methacrylate (<1000
as a result, they offer better film-forming properties. Indi- ppm), methyl methacrylate (<1000 ppm), and dimethyl
vidual and blended gum products based on agar, alginate, aminoethyl methacrylate (<1000 ppm). These are used as
κ-carrageenan, methyl cellulose, pectin, CMC, and guar can pH-dependent drug delivery platforms to protect sensitive
potentially be used in film dosage forms. drugs, to mask unpleasant tastes and odor, to protect the active
ingredient from moisture, and also to improve drug storage
stability. Eudragit E 100 is, for instance, supplied as a gran-
ule and is used in taste-masking applications where a low pH
POLYMERS IN DRUG DELIVERY solubility (<5) is desirable.
Anionic polymers: Anionic polymers have methacrylic
Introduction acid as a functional group and are generally used for drug
Pharmaceutical polymers are widely used to achieve taste delivery past the stomach into the duodenum, jejunum, ileum,
masking; controlled release (e.g., extended, pulsatile, and or colon. As discussed in Chapter 10, since the pH of the
targeted), enhanced stability, and improved bioavailability. fasted stomach is below pH 3 in nearly every healthy person
Monolithic delivery devices are systems in which a drug is and below pH 2 in most people, the stomach represents a
dispersed within a polymer matrix and released by diffusion. harsh environment for many drugs. Since the methacrylic
The rate of the drug release from a matrix product depends group dissociates at the higher pH of the small intestine and
on the initial drug concentration and relaxation of the poly- colon, anionic polymers such as Eudragit L 100-55 (with
mer chains, which overall displays a sustained release char- dissolution at pH 5.5) and Eudragit S 100 (with dissolution
acteristic. Extended release alprazolam tablet is an exam- at pH >7.0) are highly desirable. Aqueous dispersions of
ple of monolithic products, in which extended or sustained these polymers (Eudragit L 30 D-55) are generally available
delivery is provided by swelling and erosion of the polymer for direct use in enteric coating applications. Kollicoat MAE
matrix. Alternatively, a drug can be released from a drug 30 DP (Fig. 20–17), a combination of methacrylic acid and
core through a porous or nonporous membrane. While drug ethyl acrylate (1:1) monomers, is supplied as a 30% aqueous
release through a nonporous membrane is essentially driven dispersion. The polymer is used as a film-former in enteric
by diffusion, porous membrane generates an extra path for coating of solid dosage forms.
the drug release, that is, through pores. The status of drug Neutral polymers: Acrylate or methacrylate polymers with
release from membrane systems can generally be modified or without aminoethyl functionality are generally insoluble
via membrane thickness, use of plasticizers, pore structure or have pH-independent swelling property. These are neutral
(size, size distribution, and morphology), and filler tortuos- acrylic polymers which are used for sustained release applica-
ity (filler orientation). Membrane systems have found appli- tions where insolubility of the polymeric drug carrier is very
cations in drug stability, enteric release, taste masking, and much desirable. Neutral polymers with added functionality
sustained release. Enteric-coated products are the ones that are supplied as powder (e.g., Eudragit RS PO), granule (e.g.,
pass the stomach environment safely and release the drug Eudragit RS 100), and aqueous dispersions (e.g., Eudragit
at a higher pH environment of the intestine. These have to
be coated with a pH-operative coating such as an anionic
polymer. Examples of enteric-coated products are duloxetine, CH3 H
mesalazine, naproxen, omeprazole, and amino salicylic acid.
CH2 C CH2 C
Drugs such as lutein and lycopene are more stable in mem- n m
brane dosage forms. Reservoir systems have been utilized to COOH COOC2H5
taste mask acetaminophen and caffeine. Potassium chloride
Methacrylic acid Ethyl acrylate
and diltiazem are also offered sustained release property if
formulated in a membrane system. Fig. 20–17. A copolymer for an enteric tablet-coating application.
RS 30 D). Neutral polymers with no added functionality are resins are produced on the basis of methacrylic acid (contain-
supplied as aqueous dispersions (Eudragit NE30D, NM30D, ing COOH) monomer cross-linked with DVB. The counter-
and NE40D). ion of the acidic carboxyl group is hydrogen (as in Polacrilex
resin, Amberlite IRP64) or potassium (as in Polacrilin potas-
sium, Amberlite IRP88). To make an ion-exchange resin
Biodegradable Polymers with stronger acidity, the water-insoluble styrene is used as
Alternatively the drug can be released from a dosage form a monomer, which is sulfonated to become water compati-
as a result of polymer erosion. Erosion occurs because of ble. Similarly, DVB is used to cross-link the polymer and the
biodegradation or swelling and might happen within the bulk counter-ion of the sulfate group (SO3 ) is generally sodium.
of the polymer or may be limited to the polymer surface at a The commercial product of sodium polystyrene sulfonate
time. Porous and nonporous platforms can provide bulk and (Amberlite IRP69) is used to treat hyperkalemia. Cation
surface erosion, respectively. Polymers with ester and amide exchangers are anionic polymers which contain carboxyl
functional groups are susceptible to a hydrolytic degrada- or sulfate groups with hydrogen, potassium, and sodium
tion in strong acidic and basic environment. When a polymer as counter-ions. On the other hand, cationic ion-exchange
starts to erode from its surface, the drug imbedded within resins with the ability to exchange anions carry quaternary
the polymer matrix will be released at a rate depending on ammonium groups, −N+ (R)3 with chlorine as a counter-ion.
the erosion rate of the polymer. If erosion happens in bulk, Cholestyramine resin (Duolite AP143) is cationic styrene
a much faster release is expected as an enormous number of DVB polymer which is an anion exchanger and used to reduce
hydrolysable sites are simultaneously cleaved up in water. cholesterol or to sequestrate the bile acid. Because of their
Biodegradable polymers are classified as natural-based unique properties, the ion-exchange resins are generally used
and synthetic. Polysaccharides and protein-based poly- for taste masking, drug stabilization, tablet disintegration, and
mers are obtained from the natural sources. Polyesters or sustained release applications.
copolyesters of lactic acid and glycolic acid, polycaprolac- Cationic or anionic drugs can be complexed into the struc-
tone, polyanhydrides, and polyethylene glycol are the most ture of an ion-exchange resin due to its ionic structure. The
common synthetic biodegradable polymers, which are used stability of the complex inside the mouth masks the taste of
for variety of pharmaceutical applications. the drug since the drug will not be free to interact with taste
buds. The drug will be released in the gastric medium once the
EXAMPLE 20–9 complex becomes unstable. Certain drugs have a poor shelf
Injectable Implant life due to their instability against moisture, light, heat, and
Injectable implants have been developed on the basis of biodegrad- so on and so forth. Shelf stability and bioavailability of these
able polymers. Leuprolide (Eligard), a delivery system for prostate drugs increase when formulated with ion-exchange resins.
cancer, is supplied as an injectable suspension that utilizes the Atrigel The DVB–cross-linked potassium methacrylate copolymer
technology for delivering the hormone leuprolide acetate. The deliv-
possesses a very high swelling capacity in water. Although
ery system consists of a biodegradable (lactide-co-glycolide) copoly-
mer dissolved in a biocompatible solvent. The polymer gradually this polymer generally swells fast and to a high degree, its
loses its organic solubility once it is injected subcutaneously. Doxy- swelling properties are significantly affected by pH, the pres-
cycline (Atridox), a bioabsorbable delivery system for the treatment ence of salts, and the ionic strength of the aqueous solution.
of periodontal disease, also uses Atrigel technology to deliver an Nevertheless, the swelling pressure generated by this polymer
antibiotic, doxycycline hyclate.
is sufficient to disintegrate tablet dosage forms in an aqueous
medium. These polymers can also provide a sustained or a
Alternatively, a drug may be released as a result of matrix zero-order release due to their high swelling capacity.
swelling. The matrix is made of nonbiodegradable but erodi-
ble polymers, which control the drug delivery due to its
swelling. A polymer in its swollen form is mechanically weak CHAPTER SUMMARY
and can be eroded at different rates depending on the swelling
feature of the matrix.48 A fast swelling hydrogel may undergo Polymers have been used as a main tool to control the drug
faster erosion and provide faster drug release compared with a release rate from the formulations. They are also increasingly
slow swelling hydrogel. The release kinetics from a swellable used as taste-masking agent, stabilizer, and protective agent
matrix is generally zero-order. in oral drug delivery. Polymers can bind the particles of a
solid dosage form and also change the flow properties of a
liquid dosage form. Extensive applications of polymers in
Ion-Exchange Resins drug delivery have been realized because polymers offer
These are polymeric materials with two characteristics; they unique properties which so far have not been attained by any
swell in an aqueous medium and they contain complexable other materials. Polymers are macromolecules having very
and ionizable groups. Ion-exchange resins are generally made large chains, contain a variety of functional groups, can be
of methacrylic acid, sulfonated styrene, and divinyl benzene blended with other low- and high–molecular-weight materi-
(DVB). The acidic resins can be weak or strong. Weak acid als, and can be tailored for any applications. Understanding
the basic concepts of polymers provides a foundation for fur- 19. G. M. Beck and S. H. Neau, Chirality, 12(8), 614–620, 2000.
ther understanding of drug products and designing of better 20. O. Felt, P. Buri, and R. Gurny, Drug Dev. Ind. Pharm. 24(11), 979–993,
1998.
delivery systems. 21. A. K. Singla and M. Chawla, J. Pharm. Pharmacol. 53(8), 1047–1067,
This chapter provides basic concepts behind the behavior 2001.
of polymers in the solid and solution states. Chapter begins 22. S. Y. Chae, M. K. Jang, and J. W. Nah, J. Control. Release, 102(2),
with a general introduction on polymers and continues with 383–394, 2005.
23. M. George and T. E. Abraham, J. Control. Release, 114(1), 1–14, 2006.
different types of polymer structure and polymerization meth- 24. J. Wu, et al., J. Biomed. Mater. Res. A 80(4), 800–812, 2007.
ods to make them. The major polymer concepts and proper- 25. S. Y. Yu, et al., Langmuir, 22(6), 2754–2759, 2006.
ties, such as synthesis, topology, crystallinity, thermal transi- 26. S. Senel and S. J. McClure, Adv. Drug Deliv. Rev. 56(10), 1467–1480,
tions, molecular weight (averages and distribution), swelling, 2004.
27. M. Thanou, J. C. Verhoef, and H. E. Junginger, Adv. Drug Deliv. Rev.
entanglement, rheology, and mechanical properties, are dis- 52(2), 117–126, 2001.
cussed in detail. The chapter continues with a variety of 28. J. Grant, J. Cho, and C. Allen, Langmuir, 22(9), 4327–4335, 2006.
polymer products including rubbers, plastics, fibers, adhe- 29. E. A. El Fattah, et al., Drug Dev. Ind. Pharm. 24(6), 541–547, 1998.
30. P. S. Holst, et al., Polym Bull. 56(2–3), 239–246, 2006.
sives, and coatings, and also highlights important properties
31. B. R. Thakur, R. K. Singh, and A. K. Handa, Crit. Rev. Food Sci. Nutr.
of each group. The chapter concludes with major applications 37(1), 47–73, 1997.
of polymers in pharmaceutical industry, such as ion-exchange 32. K. W. Song, Y. S. Kim, and G. S. Chang, Fibers Polym. 7(2), 129–138,
resins. Many examples, pictures, and concept boxes have 2006.
33. M. J. Tobyn, et al., Int. J. Pharm. 128(1–2), 113–122, 1996.
been added to better appreciate these topics. This chapter can 34. K. Uekama, et al., J. Pharm. Sci. 84(1), 15–20, 1995.
serve as a valuable source of information for those with little 35. M. B. Brown and S. A. Jones, J. Eur. Acad. Dermatol. Venereol. 19(3),
or no background in polymers, researchers in the polymer, 308–318, 2005.
pharmaceutics and biomedical areas, as well as pharmacy 36. N. E. Larsen and E. A. Balazs, Adv. Drug Deliv. Rev. 7(2), 279–293,
1991.
students. 37. Y. H. Liao, et al., Drug Deliv. 12(6), 327–342, 2005.
38. P. J. Antony and N. M. Sanghavi, Drug Dev. Ind. Pharm. 23(4), 413–415,
Practice problems for this chapter can be found at 1997.
thePoint.lww.com/Sinko6e. 39. P. J. Antony and N. M. Sanghavi, Drug Dev. Ind. Pharm. 23(4), 417–418,
1997.
40. P. B. Deasy and K. J. Quigley, Int. J. Pharm. 73(2), 117–123, 1991.
References 41. M. E. Daraio, N. Francois, and D. L. Bernik, Drug Deliv. 10(2), 79–85,
2003.
1. F. Rodriguez, Principles of Polymer Systems, Taylor & Francis, Philadel- 42. U. P. Deodhar, A. R. Paradkar, and A. P. Purohit, Drug Dev. Ind. Pharm.
phia, PA, 1996. 24(6), 577–582, 1998.
2. G. Odian, Principles of Polymerization, 3rd Ed., Wiley, New York, 1991. 43. T. Fuchs, W. Richtering, and W. Burchard, Macromol. Symp. 99, 227–
3. P. J. Flory, Principles of Polymer Chemistry, Cornell University, Ithaca, 238, 1995.
New York, 1953. 44. J. Munzberg, U. Rau, and F. Wagner, Carbohydr. Polym. 27(4), 271–276,
4. F. W. Billmeyer, Textbook of Polymer Science, 3rd Ed., Wiley, New 1995.
York, 1984. 45. B. P. Nagori and N. K. Mathur, Ind. J. Chem. Technol. 3(5), 279–281,
5. L. H. Sperling, Introduction to Physical Polymer Science, Wiley, New 1996.
York, 1992. 46. N. Kawasaki, et al., Int. J. Pharm. 181(2), 227–234, 1999.
6. H. Omidian, et al., Hydrogels having enhanced elasticity and mechanical 47. A. Rubinstein and I. Glikokabir, Stp. Pharma. Sci. 5(1), 41–46, 1995.
strength properties. US patent 6,960,617. 2005. 48. H. Omidian and K. Park, J. Drug Deliv. Sci. Technol. 18(2), 83–93,
7. H. Omidian, J. G. Rocca, and K. Park, Macromol. Biosci. 6(9), 703–710, 2008.
2006.
8. D. Braun, Simple Methods for Identification of Plastics, 2nd Ed., Hanser Recommended Readings
Publishers, Munchen, Wien, 1986.
9. S. C. Jong, J. M. Birmingham, and S. H. Pai, Eos-Rivista Di Immunolo- A. T. Florence and D. Attwood, Physicochemical Principles of Pharmacy,
gia Ed Immunofarmacologia, 11(3), 115–122, 1991. 4th Ed., Pharmaceutical Press, London, 2006, Chapter 8, pp. 273–322.
10. L. Hovgaard and H. Brondsted, Crit. Rev. Ther. Drug Carrier Syst. 13(3– D. Jones, Rapra Rev. Rep. 174, 124, 2004.
4), 185–223, 1996. M. Saltzman, Tissue Engineering: Engineering Principles for the Design of
11. K. Nishinari and R. Takahashi, Curr. Opin. Colloid Interface Sci. 8(4–5), Replacement Organs and Tissues, Appendix A: Introduction to Polymers,
396–400, 2003. Oxford University Press, Inc., New York, 2004, pp. 453–480.
12. A. W. Basit, Drugs, 65(14), 1991–2007, 2005. A. M. Stephen, Food Polysaccharides and Their Applications, Marcel
13. T. F. Vandamme, et al., Carbohydr. Polym. 48(3), 219–231, 2002. Dekker, Inc., New York, 1995.
14. K. I. Shingel and R. H. Marchessault, in Robert H. Marchessault, Fran-
cois Ravenelle, Xiao Xia Zhu (Eds.), Polysaccharides for Drug Delivery
and Pharmaceutical Applications, ACS Symposium Series 934, Amer- CHAPTER LEGACY
ican Chemical Society, 2006, pp. 271–287. Fifth Edition: published as Chapter 21 (Biomaterials). Updated by
15. L. W. Chan, H. Y. Lee, and P. W. S. Heng, Int. J. Pharm. 242(1–2), Bozena Michniak-Kohn.
259–262, 2002. Sixth Edition: published as Chapter 20 (Pharmaceutical Polymers).
16. J. Dusseault, et al., J. Biomed. Mater. Res. A 76(2), 243–251, 2006.
Rewritten de novo by Hossein Omidian, Kinam Park, and Patrick
17. C. Valenta and K. Schultz, J. Control. Release, 95(2), 257–265, 2004.
Sinko.
18. G. M. Beck and S. H. Neau, Chirality, 8(7), 503–510, 1996.

Chapter 20 Polymer

Uploaded by

Copyright:

Available Formats

Chapter 20 Polymer

Uploaded by

Document Information

Original Description:

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Chapter 20 Polymer

Uploaded by

Copyright:

Available Formats

What are some of the basic concepts of polymers discussed in the chapter?

How have polymers impacted modern society?

20 PHARMACEUTICAL POLYMERS

Fig. 20–1. Polymer anatomy. POLYMER SYNTHESIS

Condensation polymerization Addition polymerization

at the beginning of the reaction. On the other hand, conden-

functional groups interact with each other as shown in POLYMERIZATION METHODS

Random copolymer INTERPENETRATING POLYMER NETWORKS

Fig. 20–7. Polymer topology and properties.

solidification can be repeated indefinitely with thermoplas-

Addition of a monomer to a growing macroradical during

K E Y C O N C E P T NUMBER AND WEIGHT AVERAGES

K E Y C O N C E P T MOLECULAR WEIGHT DISTRIBUTION

Strain ␧ Molecular Weight and Polymer Properties

K E Y C O N C E P T POLYMER STRUCTURE AND SOLUTION VISCOSITY

Fig. 20–13. Polymers as rheology

Fig. 20–14. Swelling forces in

hydroxypropyl/methyl substitution, respectively. Table 20–4 Hydrocolloids

You might also like