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Videos:

Hello everyone, welcome to another lecture for Drug Delivery- Engineering and Principles. We have been talking about now nano and microparticles and we defined some of the things and we were talking about the synthesis methods.
(Refer Slide Time: 00:43)

So, let us get started; so, just a quick recap of what we learned in the last class itself. So, as I said we talked about particles, both micro and nano. So, the definitions as to what are micro, what are nano, what are the size limits and things like that. And, then we talked about that these particles have advantages over, let’s say, an implant system where
these can be used for delivery to intracellular regions.
So, you can have a cell- usually if a drug is hydrophilic or charged the drug is not able to go through, if let us say the drug is charged and is hydrophilic. However, once you package it into a particle and encapsulate this drug inside, these cells have endocytosis
mechanisms through which they can take up these particles with drug and that is how you can deliver things intracellularly as well. Then we talked about proton sponge effect.
So, what was proton in sponge effect?

So, again zooming into this if we have let us say a vesicle containing particles, these vesicles will have to burst for the particles to come out into the intracellular environment . Because, we do not really want to deliver most of the drugs to these
endosomes and lysosomes which are very sort of toxic to these drugs. So, for that to happen we use something called a proton sponge effect and in this you make your
polymer with lots of tertiary and secondary amines. And so, they keep on absorbing H
plus ions that are being pumped into these endosomes and does not let the pH to drop.
And, because of that the cell keeps on pumping more and more H plus and other ions
into these vesicles causing an osmotic pressure and the water to start moving in because
of this is osmotic pressure and ultimately the vesicle then bursts. Then, talked about few
of the particle synthesis methods, both chemical and physical, one last thing that we were
talking about before we left in the last class the solvent evaporation, single emulsion
method. And, what we do in this is you have, let us say, your polymer being dissolved in
let us say some oil phase and which contains your polymer plus drug.
And, then what you essentially do is you add that to an aqueous phase and give some
energy that results in emulsion main form which is essentially is the separation of this oil
from the aqueous phase. And, you let the oil slowly evaporate out maybe its volatile and
that causes the precipitation of these polymers will be present in the oil phase to form
particles encapsulating the drug. So, we are going to continue further today in a particle
synthesis methods.

(Refer Slide Time: 03:59)

So, we talked about it briefly in the last class too, but emulsion formation is when the
key steps which leads to the synthesis of these particles. So, what is emulsion? Emulsion
is nothing, but if you apply some mechanical energy to disrupt the interface between two
phases it causes the droplets to form. So, let us say, if I have this beaker and if I put both
the oil and the water phase. So, what will happen they will phase separate out, they do
not really want to interact with each other. So, you will have water or aqueous phase
separating from the oil phase again depending on which one is lighter. So, typically oil is
lighter than water, so it will float above water.
However, what happens if now I come and give some energy to it? So, what will happen
because of this energy and like forcing this oil and water to mix, but the oil and water
does not really want to mix. So, what will eventually happen is instead of mixing, there
will be a single phase, depending on which one is the higher amount. If water is in excess
or oil in excess and the other phase, the oil or the water will tend to form these droplets.
And, these droplets are being formed because of this energy we are sort of breaking this
interface again and again.
So, the more energy will give the smaller these droplets will be and these droplets will
then tend to form. So, this process is nothing, but it is an emulsion. But, let us say I stop
this process, what will happen is because these droplets are continuously moving around
and they do not really want to interact with the water interface, let us say this is oil and

this is water. So, these do not really want to interact, they want to minimize the contact
with the water. So, what will they will do is they will start to coalesce, so they will mix
and essentially go back to the initial separation. But, this is something that we do not
want because ultimately all of these individual particles that we had initially is what is
going to give us the particles.
So, to prevent that we add these surfactants or sometimes they are also called as
stabilizers to these mixtures. And so, it stabilizes- if I now zoom into one of these
droplets. So, this surfactant and what a surfactant is nothing, but an amphiphilic
molecule which has parts which are both hydrophilic and hydrophobic. So, what will
happen if let us say this is oil, this is water. So, what the surfactant will do is the
hydrophilic part will try to interact with water and the hydrophobic part will try to
interact with the oil. So, it will form this barrier between the oil and the water.
And so, what this does is it sort of stabilizes this droplet because now technically
speaking the oil is not in direct contact with water and neither is the water in contact with
oil. So, in that way these droplets are much more stable and they do not tend to mix with
another droplet. So, this will not happen once the stabilizer is present.
(Refer Slide Time: 07:57)

And, once we have that, the emulsion size and the stability will directly affect the size
and internal architecture of the particle form. So, bigger is these droplets that we have,
the bigger is the particle, if this is higher then now eventually the particle will also be

bigger. And, that is because whatever polymer is there will essentially collapse and they
will be more polymer in the bigger droplet. So, that is how you will determine the sizes
of your particle.
So, if I want bigger particles what I will do is this mechanical energy supplied will
decrease. Because, if it is decrease then you get bigger sized droplets and those will
eventually result in bigger sized particles. And, if I want smaller and smaller particles I
will continue to increase this mechanical energy till I achieve that size range that I am
desiring.
(Refer Slide Time: 08:53)

So, what can be the sources of these mechanical energy? So, there can be several of
them; so, it could be just simply shaking - you this hold the beaker in your hand and just
keep on rotating it, you can give it a lot more energy, you can put a magnetic stirrer bead
in that. So, this is very commonly seen. So, you have a magnetic heat plate, it has some
kind of a magnetic rotation that is happening and you keep a magnetic bead here. So, this
magnetic bead will also rotate giving energy in the system.
So, these are some somewhat some low energy based things that we talked about, then
you can have high speed homogenizers. Homogenizers that can then have a propeller in
them and these things can spin it anywhere between 1000 rpm to 20,000, 30,000 rpm.
And, that can give a lot more energy to get smaller sizes or you can give something like
an ultrasonicator which will then send out these very strong magnetical forces that will

result in very small droplets. So, all of these methods you can then use to sort of vary the
size range that you are looking for. So, we talked about the single emulsion already.
(Refer Slide Time: 10:13)

We are going to now take this forward and talk about double emulsion. So, the problem
of the single emulsion is that you can only get a hydrophobic drugs in there, because let
us say if this was this is my particle that is form of a single emulsion. This particle is
completely covered with polymer. And then this polymer let us say in case of PLGA, this
polymer is fairly hydrophobic which essentially means that the drug that is going to stay
in here has to be hydrophobic.
If it is a hydrophilic drug then it will not tend to stay in, but it will never actually go in
the oil phase, it will always be remaining in the water phase which is outside and you
will never get that drug encapsulated. So, this double emulsion is sort of a modification
to the single emulsion process which allows you to encapsulate both hydrophilic and
hydrophobic drugs and let us talk about how we actually do that.

(Refer Slide Time: 11:13)

So, to do that what we have is we have aqueous drug solution which is typically water or
you can have water in oil. So, in this case you have this is an oil phase, you have aqueous
drug that you add a little bit of it let us say this was some 10 ml, then you added let us
say 1 ml to that and then you homogenize it. So, what will happen you will get a very
similar thing that happened in the previous case so, you will get an emulsion. Single
emulsion in this case and the single emulsion is the other way round. So, in the previous
case we had oil in water, in this case now we have since oil is in excess and water is in
limitation.
So, let us say this was 10 ml and this was 1 ml. So, what you will have is you will have
predominantly small-small water droplets in the oil phase which is the PLGA phase. And
so, that is single emulsion there which is called water in oil, then what you do is; so, this
is essentially just a zoomed an image. So, you have drug in the aqueous water core, you
have this the polymer in the organic phase, this could be DCM, this could be chloroform.
And so, that is how you stabilize the first sort of your emulsion process and then you
take this whole first emulsion and let us say you dump it in 50 ml water phase. So now,
what is happening and now we have now increased the water content in the whole
mixture and now if you give energy to this. So, now you are basically taking that whole
thing and giving it energy. So, what will happen is these initial droplets have already
stabilized.

So, what will happen now is these will result in a double emulsion. So, earlier we were
talking about we have water in oil. Now, we have water in oil in water; now this water is
in excess, but this water is stabilized within this oil. So, you will get something like this
where you have this is an aqueous. So, in this case we have used polyvinyl alcohol which
is a stabilizer or say a factor. You have an inner aqueous phase which is the same as this
guy and then you have these blue oil phase has been pinched off into smaller smaller
droplets.
So, essentially you have this is oil, this is water and this is water as well. So now, what
you will get is you will get a hollow particle, so instead of getting a solid particle in the
single emulsion case now you are getting a hollow particle. So, then all you have to do is
let this oil phase to evaporate. So, DCM or chloroform both have very with a very
volatile and they will evaporate fairly quickly. And then you will get microspheres which
you can then use centrifugation by pelleting and then lyophilize them to dry them off and
that is how they will typically look.
So, if you notice here there is a sort of a shell, so this is in an SEM image one of the
particle or two of the particles have broken down. So, what you can see is that there is a
shell and then inside its just hollow. So, this is the inner water phase this was what was
the oil phase and then of course, the outside is all water which of course, pelleted here.
So, that is how you will get a hollow particle and why is that advantageous because, now
since this is initially water phase you can have hydrophilic drugs getting encapsulated.
So, here is sort of how this is going to look, so that you will have a PLGA shell which is
surrounding a hydrophilic drug. The PLGA shell can still be used to encapsulate
hydrophobic drugs because, any drug that I have which is here can also be hydrophobic.
So, that way you can have both hydrophobic drug as well as hydrophilic drug being
present in the same particle and so just some more terminologies. So, the internal
aqueous phase is what you had added initially.

(Refer Slide Time: 16:17)

So, whatever was here - this is called internal aqueous space, whatever is here it is called
the oil phase (there is only one oil phase in this case). And, whatever was in the final
larger water volume is called the external aqueous space or the continuous phase.
(Refer Slide Time: 16:41)

So, let us talk about some of the key concepts from this double emulsion process. So,
again as I said it is generally used if you want to encapsulate with water soluble drugs.
So, if you are looking for drugs that are only going to be hydrophobic then the single
emulsion is the best way to go about it its simpler as well as you get a lot more area or

volume in which you can encapsulate drug. But, if you want a water soluble drug then
you want to create some sort of a cavity where the water phase can reside and that is
where your drugs get will get encapsulated. So, these produces micro and nano capsules.
So, this is some sort of a reservoir system or hollow particles that we are talking about.
So, unlike your single emulsion where the particles will be completely uniform inside,
this is going to be more of a capsule sort of scenario, where this is a small shell
surrounding your empty cavity. So, as I said, this emulsion could be called as water in oil
in water. So, typically you will find this written as w / o / w and again this is not really
limited to this emulsification could also be water in oil in oil . I mean it does not have to
be the external phase has to be water, it is just that you just have to ensure that they are
between the two oil phases the polymer is only soluble in one of the oil phase.
So, that way you can also make sure although this is not really used in any of the
biological sort of scenarios because, the particles that you want has to be able to survive
in water, has to be able to go and be stable in water. So, typically the external phase is
also usually water, but you technically can have a two immiscible oils being used here as
well.
(Refer Slide Time: 18:31)

So, one example to that is in the first emulsion could be re-emulsified in hexanes or
pentanes and the PLGA is insoluble in all of these. So, if you essentially what we are
talking about here is you will have water, you will have a shell of oil after the first

emulsion, after the second emulsion and let us say this oil is DCM. Now, if I know that
the DCM and hexane are immiscible that is they are not going to mix; then what I can do
is I can add this to a solution of hexane which will not solubilized my PLGA and which
is not going to mix with DCM.
So, this can technically still result in a emulsion as well as particles, the only problem is
these particles will tend to agglomerate in water because these are stable in hexanes. But
once you put them in water they may not want to interact with water whereas, when we
had PVA in the water, the PVA had quoted these particles and had kind of stabilized
these particles, but this may not happen in case of hexane.
(Refer Slide Time: 19:49)

And, then the second method is often used to prevent diffusion on the drug out of the
external aqueous phase. So, so this is going to result in a more pronounced in single
emulsion process. So, the drug has to be insoluble or less soluble in the oil 2 also
because, initially when we are talking about these emulsion process this is still liquid.
This is still liquid oil 1 and then oil 2 and then water, the drug. So, then let us say the
drug is soluble and oil 2 then the drug will tend to slowly diffuse out into the oil 2 and
the drug is insoluble or it will not really tend to go there. And so, this will still you have
to make sure also that whatever drug you are encapsulating is insoluble in oil 2.

(Refer Slide Time: 20:51)

So, a little bit more about the solvent evaporation process. So, again as I said this is what
you get you have these hollow particles that you will get with a polymeric shell
surrounding it. And then external is of course, in biological applications will be water
and then you can use various kinds of techniques. So, this is an SEM image you can use
other techniques, you can determine the particle size by dynamic light scattering, using
coulter counter or other similar instruments. And, you can get some sort of an idea as to
what is the size; in this case since this scale bar is about 20 microns. We can say that the
average size here might be about 5 microns, but you can then again vary that by
changing the energy that you are providing to the system.

(Refer Slide Time: 21:41)

So, what are the different parameters that are going to affect these particles? So, of
course, the first thing is the what polymer you are using and what is the molecular
weight. So, that is going to have a profound effect on first of all whether it is hydrophilic,
hydrophobic and then also what is the thickness of the shell, how stable it is, how fast it
degrades all of that will depend on the polymer you are using. Then of course, the
polymer concentration in the oil phase. So, the more concentration you have the more
closely we will pack. So, all of that will determine what sort of particles you get the type
of drug.
So, that is of course, very important because that will determine what method to use. So,
you can whether its hydrophilic, hydrophobic whether its liquid or some suspension,
depending on that. So, if its hydrophobic you only will go with single emulsion this is of
course, in case of PLGA if its hydrophilic then you will have to go with double
emulsion. So, all of these are important criteria that you have to consider and then of
course, what organic solvent you are using and what is the polymer solubility that will
determine how much polymer concentration you can get in that particular solvent. So, all
of these are important parameters.

(Refer Slide Time: 23:03)

What about the type of amount and surfactants? So, of course, you would want to add
some surfactant to make sure that these particles are stable and are not very poly
dispersed. So, and then how much the amount of its the most surfactants will find in
literature is also toxic. So, if you add too much of that and you are not able to wash it off
then new particles may not be compatible with your biological assess. So, all of that
needs to be sort of optimized and you need to use surfactants which is a fairly
biocompatible as well as their amount is also limited. So, amount should be enough so,
that these particles are stable, but not too much that they become toxic.
Then what is the ratio of your internal aqueous phase to organic solvent? So, that will
determine what is the size of your particles as well, how much energy you need to give;
again energy by far is the most important criteria in terms of determining the size. So, if
you have very high amount of energy being given it you will have a decreased amount of
particle size as a result.
Whereas, if your energy is lower then you will get a bigger sized particle and that is very
easy to see, if you do not give any energy you get a huge block of PLGA; I mean if I do
not give any energy and I have these water and oil phase separate out and if I let it
evaporate. Then eventually what I will end up with? Eventually, I will end up with a
block of the polymer.

So, this is going to be a huge block, this we are talking about centimeters and the more
energy will give the smaller this will become, so it is easy to remember. And then at
what rate we are evaporating it out, what temperature we are evaporating out, so when
we say evaporation this is we are talking about the oil phase itself.
So, the oil phase will have different evaporation rate at different temperatures and
pressure. So, depending on all that you will have a different amount of precipitation of
your polymer happening. So, that will also affect the particle size. So, again you know
how much volume is there, what is the temperature at the time of evaporation.
(Refer Slide Time: 25:17)

So, a little bit more on the solvent extraction or the removal method. So, most solvents
that are used to dissolve the polymer have some solubility in water. So, I actually how
does it happen, how does these things able to evaporate through the water? So, that can
only happen if they have certain solubility in the water. And so, what do you mean by
that? So for that to happen the emulsion has to get into very large amount of a aqueous
solution with or without surfactant and the value should be large enough. So, that the
organic solvent is actually soluble in the water phase. So now, what I am saying is
initially if you look at the system after the emulsion has been done, what we are saying is
let us say for a single emulsion this is your oil droplet.
And then of course, there is some shaking going on so, it is been continuously moving
around, but to be very the evaporation can only happen from the surface. So, but the

surface is here is water. So, for this oil to evaporate there has to be some oil present on
the surface and so, for that to happen what happens is the oil will have some solubility in
water. So, let us say the solubility is very low, let us say it is only about 0.0001
milligram per ml of water. And, then as more and more oil is going to evaporate more
and more oil is going to come out from here and dissolve in water and this process is
going to continue.
So, if you want to evaporate everything, you want to make sure you have a very high
surface area at this interface; so, that more and more oil is getting evaporated. So, that is
what we mean by the solubility of the oil in water- it is low, but then it is there hence
highly volatile, so it is going to continue to facilitate that process. So, again the solvent is
rapidly extracted out of the polymer phase into the external continuous phase. So, this is
the external continuous phase. So, because it has had the solubility and the solubility
decreases or the amount decreases as its evaporating. So, to compensate for that more
and more oil comes and gets dissolved in the external aqueous phase.
(Refer Slide Time: 27:33)

And so, what this does is eventually let us say you had; so, if I focus now only on the on
the particle. So, this is oil, so slowly and slowly; so, let us say this is a certain volume V
ml of oil in here. So, what is happening slowly and slowly this V is now decreasing it is
becoming V by 2, it is becoming V by 4 and further so and so forth. But, the amount of
polymer that is there in this amount is actually constant that cannot evaporate.

So, that is now condensing more and more; more and more chains are coming closer
together and eventually it starts to form this thick particle. So, the thickness of the shell
will be determined on what? Will be essentially determined on the polymer itself. So,
how much polymer, what is the molecular weight all of this will determine the thickness
of the shell. The internal particle structure porosity etc. can be altered.
So, if I if I do it very slowly, I will get a very very hard particle, but if I let us say
evaporate this oil phase very very quickly these polymer chains may not have time to
move around and sort of make a very condensed structure. So, in that case what will
happen is instead of getting a very condensed structure you may have lots of polymer in
one phase, lots of polymer another phase and then very little polymer in this. So, you
may get like these pores and sort of these holes into these polymer structure.
(Refer Slide Time: 29:15)

And then finally, one of the disadvantages of this system as it requires very very large
volumes. So, the reason for that is if you want to evaporate out and especially at a
reasonable time frame, you need to make sure that it has a lot of surface area through
which the oil is evaporating. So, just to give you an example DCM has a solubility of
about 1.5 and percent weight by weight. So, to extract 10 ml of DCM rapidly by this
process the volume of external phase will come out to be greater than 660 ml and that is
extremely large volume.

So now, you are talking about very high volume that you need to now precipitate or sort
of centrifuge to collect the particles and you need very large reactors and all that. So, that
sort of poses quite a lot of limitations on to what you can do ok. So, we will stop right
here for this lecture and we will continue the rest in the next class.
Thank you.