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Hello everyone, welcome to another lecture for Drug Delivery Principles and
Engineering. Just a quick recap on what we have done so far. So, previously we had
learned about what is drug delivery, how are the drugs distributed in the body, so (Refer
Time: 00:43) pharmacokinetics.
Now, this was followed by little bit of discussion on prodrugs as well as some polymers.
So, we are going to just quickly recap on what we did in the last class in particular. So,
we talked about prodrugs, nearly 10 percent of all the drugs in the market are prodrugs.
(Refer Slide Time: 01:06)

We also talked about controlled release and long circulation advantages. So, why would
you want the drugs to be prolonged and release in the body. So, essentially instead of
having a traditional drug delivery system where you have to give high dose, so that it
reaches toxicity and then comes down we want more to be stable in this therapeutic
window. And then finally, we talked about a little bit about what polymers are and what
are the different types in all and we are going to continue our discussion on polymers
today.

(Refer Slide Time: 01:36)

So, first of all how are polymers synthesized? So, simply speaking its essentially
individual monomer molecules come together and are covalently linked by various
chemical reactions to produce variety of polymer molecules. So, this is a very simple
definition there. So, essentially bringing in monomers and combining them chemically to
get different polymers.
Their various classifications in way in which the polymers are synthesized. A traditional
classification that has been known in the literature is Carothers classification and it is
subdivided into two different types of polymerization one is addition another is
condensation. In addition polymerization you essentially have each repeat unit has the
same number of atoms as the monomers.
So, essentially they add without releasing any other molecule that is not the part of the
polymer, how when condensation polymerizations you have less number of atoms in the
polymer, then the individual monomers because typically the reactions involve release of
water or acid or something else as a reaction product. This is again as I said Carother is a
very traditional classification and on the modern classification is based on how the
reaction occurs.
So, in this way it is again subdivided into two different classification when is step
polymerization and another is chain polymerization. So, we are going to talk about both
of them as we go along in these slides.

(Refer Slide Time: 03:06)

So, talking about step polymerization in this in this process the polymer chains are
essentially build up in a stepwise fashion and this could be the random union of
individual monomer molecules. So, essentially if we look at reaction here, so you have a
dimer being formed by combining of two monomers. A trimer is form again by
combining of a dimer to a monomer, but then from there on forward there are several
ways that this can happen. So, a tetramer can form either by combining to dimers or by
combining a trimer with a monomer and similarly the possibilities increased further as
you go along.
So, it is essentially just a random union of monomer molecules which are combining,
you can get a linear polymerization this could include both the poly condensation or the
addition polymerization or this could be non linear in which there might be instead of
combining linearly they might be combining in many multiple places essentially creating
a network of polymerization.

(Refer Slide Time: 04:08)

So, what is the effect of functional group? Number on this, so let us consider this
chemical reaction. So, we have an acid reacting with an alcohol to give an ester group
and also releasing water so; obviously, since there is a release of water this is a
condensation reaction. The important to note is that acetic acid and ethyl alcohol which
are being used here as monomers they both have one functional group each.
So, let us say that this reaction has happened there is a really no functional group left in
the product that is formed, given that there is no functional group in this product the
resulting molecule cannot go further reaction. So, no polymerization will further happen.
So, essentially all you have done is a simple reaction making a small molecule which is
essentially not a polymer.
So, what does this tell us? This tells us that for the polymerizations to happen we need at
least 2 functional groups one each of the monomer. So, an example here is the
terephthalic acid with ethylene alcohol, so in this case you have groups which contain
both the acid has two different acids two different COOH group and then the ethyl
alcohol again has two different OH group.
So, in this way whatever the product is formed even though you have used 2 of the
functional groups one each on the monomers there are still 2 more functional groups
available on the resulting product for it to further continue to react. So, quick thing here

is what will happen if you have more than two functional groups in your monomer any
guesses then you may have. So, I will give you a moment to think about that.
So, as most of you might have guessed it already, if you have more than 2 functional
groups it can essentially reach to branch. So, you can have a situation in which you have
a group here; a group here if there is only two then essentially it can only grow linearly,
but; however, if there is another group on the monomer which is here it cannot only grow
linearly it will also grow in branches leading to a complex network essentially leading a
lot of branches in the polymer.
(Refer Slide Time: 06:36)

So, some more examples of linear step polymerization, so now we have been only
talking about linear ,this also is examples of poly condensation. So, it means that it will
result in an elimination of small molecules. So, here is one example which we have
already used in the in the previous slide which is di acids reacting with di alcohols they
are typically rarely used they do not have very good reactivity; however, they are used
and essentially you will have released a water molecule as well as forming of the
polymer.
Another reaction is dichloride with di alcohols this is more energetically favorable
because the chloride is a good reactive group and so you will essentially get a very
efficient reaction in this in such cases, but in this case as it is a poly condensation
reaction you will have a small HCL molecule being released.

And then alternatively, polyesters can also be made from single monomers. So, it does
not have to be two different monomers you can have a single monomer containing both
the hydroxyl as well as the carboxyl group and then they can react within the same
monomers to form a polymer.
(Refer Slide Time: 07:56)

Again some more examples here, so this time we are talking about synthesis of
polyamides and do you know where the polyamides are seen in our body? Yes if you if
you are familiar with proteins all proteins are essentially nothing, but polyamides and
what it is a reaction of carboxyl groups with an amine group. So, it could be something
we had two carboxyls and one monomer are present and two amines on another
monomer represent and they will react to form this amide bond which is a CONH bond.
So, essentially this is an amide bond and this will be this will be the reaction that will
happen.
Another example here is synthesis of polyanhydrides, so this is reaction of two different
acids with each other. So, this could be that you have a monomer R 1 containing to
different acids and this will essentially react with itself to form this anhydride group
which is again represented as this group and this essentially is an anhydride group and
you can have a polymerization happening like this as well.

And then again there are lots of variation another example here is synthesis of polyethers
and that is essentially reaction of alcohol with themselves. So, you can have two alcohol
that continually react to form a polymer as well.
(Refer Slide Time: 09:39)

So some concepts here, let us talk about the chain polymerization now. So, in this the
polymer chain grows by reaction of a monomer with a reactive end group, so there is
some order to it rather than being random as it was the case in the previous example in
the step polymerization. In chain polymerization there is some order to it and I will
explain how this order works. So you may have a initiator molecule which is highly
reactive , that initiates the growth of these polymer chains.
So, an initiator molecule represented by I here will react with the monomer to form an
IO, this IO will then propagate further to continue to react and the way the chain will
grow is only in this uniform direction rather than any random combination of different
reactants at that at the particular time. Typically, such reactions unlike step
polymerization there is no release of by product and so the monomer is consumed slowly
throughout the course of this reaction.
So, typical monomers those that contain double bond are very commonly used for chain
polymerization also polymers that monomers that have rings in them can be used for
chain polymerization with the ring opens up and results in polymerization to occur and
we will discuss some examples as we go along.

(Refer Slide Time: 11:04)

So, chain polymerization some general process. So, generally there are three distinct
kinetic steps we already talked about initiation where you have that initiator molecule
reacting with a monomer, so this is an initiate the this generally results in generation of
some free radicals, but anions, cations some other kind of complexes which are
essentially the active center these are the reactive sites that are going to go find another
monomer and react with it.
So, this is the initial phase and this is; obviously, started, so if you want to start a chain
polymerization you will have to add a certain concentration of initiator to it, so that these
initiation reactions can occur. The next is followed by a propagation, so once the
initiation of the polymerization has already happened, propagation is nothing, but these
active centers reacting with the monomers and continuing to grow.
So, to again give you an example the initiator in the initiation in this case is you have an
initiator containing a free radical which then reacts with let us say here C double bond C
react resulting in a product which is combining that initiator with the with the molecule
as well as another reactor site at the end of it.
So, this reactor side then can go within react with another double bond to result in a
larger molecule and this will continue to propagate as time goes on. Here is the ring
opening polymerization reaction, so you have another initiator B here which is an anion
and it will go and react with this ring structure to give rise to a larger anion which will

again then find another ring structure and this reaction will continue till the reactants are
all consumed. So, just as I discussed this propagation will happen as we go along.
(Refer Slide Time: 13:02)

So, what about terminations and when does it typically stop? So, it can stop when all the
reactants are consumed or they can be several the things it can happen, so this is
combination. So, it can happen that a one reactive site can instead of reacting to the
monomer can react with another reactive site and that will result in the loss of the
reactive sites on two different molecules and if enough combinations like this happen all
the reactive sites will be consumed.
And another as sometimes this proportion where instead of actually having reacting one
of the active site takes up the electron from the another active site and does not really
combine with the growing polymer, but still results in depletion of the reactive sites
resulting in loss of the polymerization. So, this is called disproportionation.
So, typically both reactions take place depends on what polymers you are using different
polymers will result in different kinds of reactions. So, for example, in polystyrene
mainly the termination happens through the combination in PMMA another polymer
widely used , its typically disproportionation dominates at the temperature above 60
degree Celsius.

(Refer Slide Time: 14:16)

And then we have something called a living polymerization, so this is essentially if the
chain polymerization continue to go on and you still have reactive sites present, but it
runs out of the monomers, then you will still have free radicals the active centers that are
available for the polymerization to occur and this is something that we can then use to
modify our polymers through different ways.
So, one thing we can do is that the in this case since the chain ends are reactive we can
then put in another type of monomer which will then continue the reaction. So, instead of
having just a single type of monomer throughout the reaction we can have two different
types of monomer arranged in an order.
So, essentially we can synthesize block copolymers because what will happen is you will
have a molecule being generated here which is I let us say reacting with monomer 1;
monomer 1 continue and then let us say the monomer one finishes at this point, then if
you add a monomer 2 to this reaction mixture with the active site already present what
will happen is this will then continue to react with monomer 2. And essentially result in a
block copolymer because you have a block of M 1 here and a block of M 2 here.
So, that is how you can continue to do this typically you can continue to do this up to try
block copolymers. So, you can have another one monomer here M 3 continuing to grow
as the reaction is continuing, typically by the time you have finished with three of these
different types of monomers there is enough combination and disproportionation

termination that has happened that not many active sites are remaining. So, you do not
get more than try block copolymers by this method.
(Refer Slide Time: 16:24)

So, just a couple of examples on ring opening polymerization. So, you can have a
polymerization that starts from a cyclic monomer and normally the ring is opened by
some kind of acid or basis and then the polymerization proceeds by chain growth
reaction as we just discussed. Very commonly used with cationic and anionic initiators.
So, some examples are polyesters, polyethylene oxide, polypropylene oxide,
polycaprolactone and PDMS all of them pretty much are very widely used for biological
applications. And we will talk about most of these as we go along some of these terms
you are going to become very familiar with in this course and remember all we are
discussing all these polymers because we essentially want to build up some of the basic
concepts of what different polymers are there that we can use for drug delivery
applications and what are the properties. And once we have some basic knowledge of
that , it will help us later in this course to then identify how can we modify them for
different applications and requirements.
So, here is a very common reaction I mean this is a PLGA polymer which is very widely
used in drug delivery applications and the synthesis of this is through a ring opening
polymerization where it you have a lactide and a glycolide group that reacts in presence
of an catalyst to give rise to a long polymer of PLGA.

(Refer Slide Time: 17:56)

So the comparison between the step and the chain polymerization each has its own
properties advantage and disadvantages. So, typically for step polymerization the growth
occurs throughout in a non uniform manner, so you can have monomers reacting with
oligomers forming polymers and all those kinds of things whereas, in chain reaction it is
it is much more directional where you will have an active site only reacting with the
monomers.
Degree of polymerization typically get with the chain reaction is low and what I mean by
that is its difficult to get long polymers through step reaction. But with the chain reaction
the degree of polymerization can be very high because you can add very less amount of
initiator and the reaction will continue to go on till all the monomer is being consumed
has been consumed.
The monomer again is very rapidly consumed just because the reaction is happening at
all monomer sites at once, in case of chain reaction in the monomer consumption is
much slower, but the molecular weight increases quite quickly as the chain grows.One
advantage of the step reaction was is where there is no need for initiator it is a single
reaction mechanism, typically most of these initiators we talked about can be toxic
because they are fairly reactive.
However, in chain reaction you need an initiator to begin the reaction and so
subsequently for drug delivery applications when you talk about using these kinds of

polymers you have to worry about, if there is initiator contamination, nonreactive
initiator represent there and things like that. No termination step is required, usually the
termination occurs through the combination and the disproportionation we talked about,
as the functional groups react you have less and less monomer and then the
polymerization rate decreases.
However, in this case initially there is increase in the polymerization rate because the
initiator is creating more and more reactive sites and then it reaches a relative constant
rate till the monomer starts to deplete significantly.
(Refer Slide Time: 20:05)

So, we are going to talk about some basic properties of the polymers. So, the molecular
weight is essentially the molar mass is the single most important parameter that
characterizes a polymer or a macro molecule.We are going to talk about this throughout
this course. Poly dispersity essentially, it tells you what is the size distribution of the
polymer molecules.
So, lf I say polymer molecule is 100 kilo Dalton that means, that the average size of
these polymer chains is 100 kilo Daltons, but it does not mean that all of them will be
100 kilo Dalton there will be some polymer chains which will be 110 they will be some
which will be 90. So, this spread from 100 in this case essentially did it defines what
polydispersity index is.

The crystallinity and amorphousness this affects a wide range of mechanical and optical
properties or how crystalline or how amorphous the polymer is and again all of this will
be discussed in greater details as we go along. The melting temperature which is again
related to crystallinity we are going to discuss glass transition temperature if this related
to amorphousness we are going to discuss in the next class.
And then of course, the degradability how fast it degrades is very important because that
is going to essentially determine how fast the drug is releasing from this polymer or how
fast different properties are changing. And of course, for certain applications,
mechanical and electrical properties also become important let us say if you are going to
use it in bone you want it to be mechanically stable, if you are going to use it for neuron
applications you want it to be electrically conductive, so some of those properties also
become very important.
(Refer Slide Time: 21:53)

So, just quickly on the molecular weight, so the molar mass of the polymer is essentially
mass of one mole of the polymer as it is for any other molecule. So, essentially; that
means, what is the mass of an Avogadro number of molecules of the polymer this is
usually expressed in grams per mole or Daltons. So, molecular weight of 100,000
Daltons means the molar mass, essentially one mole has about 100,000 gram of this
polymer.

So, for a homo polymer the mass is essentially nothing, but the x times the mass of the
monomer where x is the total number of repeat units and then the polymerization process
inherently creates polymer molecules from different lengths as I just said you will not get
all at the single molecular mass they will all have a distribution. So, typically we always
measure the average molecular mass which is essentially nothing, but the average degree
of polymerization for these polymers ok.
So, for this course will stop here, we will talk more about the molecular weight in
subsequent classes and discuss more about the properties of the polymer in the next
couple of classes.
Thank you.