00:03and i think uh we're just on time so i'm
00:06trying to share the screen it's a it's a
00:10it's a still learning curve for me and
00:13to to be able to speak to the screen and
00:15i can see that there are more and more
00:16participants coming in
00:18uh it's actually the first uh one of the
00:24web seminars organized by by
00:27research group and the first
00:31introduction introduction to
00:34will be presented by um two excellent
00:37denis ponceley and james oxley one from
00:40france and one from usa
00:42and i will be hosting from uk so it's
00:45a variety where we are
00:49it took us a little bit to understand uh
00:53how to organize the meetings so remotely
00:56but i'm really happy to to to um to
01:01um opening uh with everyone
01:04um i think i'll start uh by that this is
01:07actually just one of many
01:09um seminars that will come organized by
01:12the bank observation research group and
01:15some um here if you want to be part
01:18of uh and register you can see um
01:22on the right side of the screen
01:25where you can register if you want to
01:27participate in any of them
01:30of the seminars that are on the screen
01:33and i'll just say a little bit about the
01:35buy encapsulation research group
01:38it has been around for more than 30
01:41it has housed a number of workshops and
01:44training schools and it's an amazing
01:46environment to actually
01:48meet fellow academic students i remember
01:54it's now more than 10 years ago
01:57after my phd i went and did my
02:00presentation initially
02:02as a part of my encapsulation research
02:05it went on that you start maybe working
02:08um you know collaborating with your phd
02:10uh colleagues and friends and then you
02:12start to build networks and uh one of
02:15amazing thing that kind of uh came out
02:18is current uh encapsulation for health
02:28scheme that kind of combines
02:35smes and also universities and research
02:39facilities and it's an amazing platform
02:44and grant to actually collaborate
02:47and south america so that's something
02:50this by encapsulation race research
02:53um a part of at the at the moment and
02:55i'm sure there will be number of these
02:58in the future so uh what we're gonna be
03:01trying uh we will be uh covering with
03:04particular first webinar is actually the
03:08on micro encapsulation so we will have
03:13the first one will be by denise
03:15poncelais and the second one
03:17uh by james oxley about the
03:20encapsulation um and where you can
03:23different types of encapsulations and
03:27uh by a presentation from james on the
03:30applications itself and uh also uh
03:34costs and markets uh or of that the
03:37seminar will be recorded
03:39um so so if you if if you want to uh
03:43knowledge on you can go and on the
03:46website that you can see on the bottom
03:48and register for any other upcoming uh
03:52webinars so i'll start initially by
03:57introducing denis ponceley i'm sure
04:00he doesn't need that much introduction
04:04but you can see from uh amazing
04:06biography that's on the slide
04:08at the moment is that he starts it uh
04:11in a field of encapsulation
04:15i would say more than 30 years ago and
04:19an amazing part of the bioencapsulation
04:22research group and has been professor
04:25and also has been a founder of
04:28number of smes relating also to
04:33the encapsulation so what i'll do now i
04:37sharing this particular screen and i
04:41make sure that i uh start the the
04:49welcome to this first part for the
04:52micro encapsulation introduction i will
04:55in this first part define
04:57the encapsulation and the objective and
04:59then i will go to the method and
05:04before to start i'd like to convince you
05:07importance of the encapsulation you know
05:11that you are forming by 10 to 12 human
05:14and even 10 to 14 bacterial cells
05:18but what is a cells it's just an
05:21encapsulation of the biochemistry which
05:24provide immobilization and structuration
05:28if you look at the membrane which is
05:30probably the best encapsulation membrane
05:33it will provide in fact protection and
05:36mass transfer in and out of the cells
05:40if you look like a hypozone you will see
05:44needed without hypotenuse membrane you
05:49which is the condition for the cell to
05:53and then you have the functionalization
05:55and you already have
05:56the five reason why to make an
06:00but the most important is that in the
06:03the bacteria the bacterial cells or the
06:07encapsulation help to fight against some
06:10when you stop to fight against entropy
06:16microencapsulation in fact is simply
06:20active in the micro particle in front of
06:24you can have the pure capsule which is a
06:27with a shell or it could be a
06:30solid with a coating on the other side
06:34you can have beads which is solid or an
06:37angel gel and then you
06:38can have many intermediate form with
06:41multi core or matricial form and so on
06:46the capsule could be spheric but also
06:50sometimes the size go from
06:54let's say one nanometer with the
06:56cyclotic swing when you can have
06:58one molecule coming in the middle of the
07:01up to millimeter like in the molecular
07:08i would like to come back a little bit
07:10to the different reasons why to make
07:13and using five examples we work on
07:17cheese ripening and you have to
07:21the enzyme to accelerate the ripening
07:25but you have to introduce it and
07:27release it when the cheese is formed and
07:30you have to encapsulate and avoid that
07:32you will be untrained
07:35with the liquid you have
07:38the possibility to make a protection and
07:40i give you one example we have work on
07:43is was to form pellets using a high
07:46temperature extrusion and normally you
07:50the cells will die and we succeed to
07:54up to 70 percent of probiotic
07:58surviving during this process by making
08:02if you immobilize and protect
08:05you have at some stage most probably to
08:09and i give you one example of a
08:10commercial product which contained two
08:14the first one is on the packaging and
08:16will break when you touch the packaging
08:19releasing some red foods smell
08:22and when you open the box and take a tea
08:27smell nothing but if you put it in warm
08:30you have again a release but by the
08:34and then in this case you have again the
08:38encapsulation is often to make
08:41structuration and for example for the
08:43aquaculture you cannot spray
08:45protein vitamin antibiotics
08:48like this you have to transform it
08:51in this form which is looking like the
08:56fish and this is a kind of encapsulation
09:00and you can create new function using
09:03the encapsulation i give you the example
09:07on top of it you have some capsule
09:10which will contain some glue and when
09:13you will break the capsule and you fix
09:17in the car for example
09:21the encapsulation process is generally
09:25five four step the first one is the
09:28incorporation of the active in the
09:30capsule core because
09:31generally you make the the capsule
09:34around the active you don't feel the
09:37after they've been done you have a step
09:40of dispersion which will mainly define
09:44then you have the encapsulation itself
09:46which is a solidification
09:48either of the full particle or only the
09:51membrane around the particle and then
09:54you have a step which is
09:56quite important which is the scale up
10:00that many people forgot to use
10:05let's go for the first step if you have
10:09which could be a solution or a melt if
10:12have if you have a high-temperature
10:16melting point if the active
10:20is soluble in this liquid you have a
10:25you can make an emulsion if the active
10:28not soluble but still liquid and a
10:31suspension if you have in fact
10:33the active which is particle not soluble
10:36in the core if you go to the solid core
10:41which is genuine powder
10:43you can make an absorption of the active
10:47you can make layer of your active on the
10:50or you can agglomerate and then trap
10:53the active inside the border but in fact
10:57the active itself could be poured
11:03i found most of the classification in
11:05the letter that you're not really clear
11:08and often you will see that some
11:12one classification and on the other
11:14author i will place in another
11:18ideally say could you get all the
11:20technology for micro encapsulation not
11:23then you have one type of equipment then
11:26the best classification is based
11:28on the your specific equipment and
11:31looking which technique which
11:33kind of encapsulation you can do with it
11:36best classification is probably based on
11:42before we need to start with going step
11:45by step through the different
11:47classification i have to explain you the
11:50difference between spraying a drain
11:53if you take a nozzle and you have a low
11:56you will have four missions of drop
11:59one by one you know with a low
12:03if you increase the flow you will form a
12:05jet and you can break the jet
12:08by in a smaller droplet
12:11with a low dispersion and if you put too
12:15high flow what will happen is that you
12:18you will form probably smaller particles
12:22but with a high dispersion these two
12:25are generally considered as the dripping
12:30then let's start with the spraying is
12:33in a big tank and we use
12:36a two fluid nozzle or heart that is
12:38nozzle to form infect the spray
12:41and we get small size left side
12:43dispersion but you can produce a large
12:48the solidification or encapsulation is
12:51really done through a physical process
12:53the first one is spray drying when you
12:56a solution and you inject warm air which
13:01provoke the evaporation in a few seconds
13:04infect collected the ants solid particle
13:08the second option is to take a melt
13:11and then inject cool air and again
13:15in a certain time you will in fact
13:18the small particles solidify
13:22for the dripping let's explain you you
13:25drop by drop and if you want to reduce
13:29you can apply an electro potential which
13:32allow to get smaller one or you can make
13:37to reduce the size if you include
13:40increase the flow you will have a jet
13:44cut by a small vibration or using a tool
13:48in fact the jet in small droplet
13:53you can replace in fact the gravity
13:56main factor here by the centrifuge
14:00and as you apply your centrifuge force
14:03you will have either rotating nozzle or
14:08allowing to form dropper drop or some
14:11jet which will be cut a sim in a similar
14:17now as we have formed a droplet we have
14:21it and we can play on the physics and in
14:24this case we can for example take a melt
14:27and inject the droplet in cool air
14:31you can play on the physical chemistry
14:35one of the most important example is
14:38using alginate which is
14:39negatively charged and dropped in a
14:44and then you will have a cross-linking
14:47alginate chain to form in fact the
14:51hydrogel you can replace in fact
14:54the calcium by polycartium or you can
14:56use other kind of polyanion than the
15:00and in this case you will have an
15:01interaction at the interface
15:03and form in fact a membrane when here
15:05you have formed probably
15:07beats technology which is developing for
15:12is to not only inject
15:15one liquid but coextro two liquid
15:18and this allows you to have a
15:21large range of different material for
15:25and for the shell let's switch to the
15:30usual technology to make an emulsion is
15:34with a turbine or using a static mixer
15:37if you want to go to larger scale
15:40what is developing for now is using the
15:42microfluidic then you
15:43inject liquid in this capillary and you
15:49and one extrapolation of this
15:53is to use a membrane when you have many
15:55canal and then you form
15:57a lot of droplet in direction
16:01but you can also change the surface
16:04tension by using some surfactant until
16:07the interfacial tension
16:08becomes mainly near to zero and then you
16:11a nano emulsion which form very small
16:15and thick droplet as you have formed a
16:19you have to solidify and encapsulation
16:22using emulsion is probably the most
16:24and i will give you only three examples
16:26of how to make infect capsule from an
16:30but it exists many on other one
16:33for the physics you can have a solvent
16:35evaporation you take a polymer
16:37solvent and you disperse in water and
16:40then you remove the solvent
16:42and you get solid particles of the
16:46for the physical chemistry you can take
16:49disperse in a polymer solution and then
16:52probably change the ph
16:53and then you provide the precipitation
16:57around in fact the oil droplet
17:00for the physics for the chemistry you
17:03in fact have one monomer in the
17:07one monomer in the continuous phase they
17:09will react in the interface
17:12forming a membrane around each droplet
17:16let's switch now if we start from a
17:20one solution is to make a coating in air
17:23and for this you will pass the particle
17:26in front of the spray and as you pass
17:28a lot of time the particle around the
17:30spray you will cover
17:32completely infect the particle
17:35if you go too fast you will have an
17:38you know and then it's not a full
17:41encapsulation but it's one process which
17:44usually consider also a little bit
17:46like encapsulation but you can switch
17:48from one to another one
17:49you can coat and then agglomerate and
17:51then code the glomerate and so on and so
17:55now to make it you have to move the
18:00if you're a small particle you have you
18:02will use what we call a fluid bet
18:04you will have air passing through a tank
18:08making the particle in suspension or in
18:12and they will pass in front of the
18:15as many times as you want if the
18:20you will have to pass too much air and
18:22in this case it's probably
18:24more interesting to at least help you by
18:28mechanical system and for example using
18:32you will move the particle and again
18:35you spray on the particle
18:39with this process you have formed some
18:41kind of liquid layer
18:42around the particle and you have to
18:45solidifying and you can make it by
18:48you know injecting for example in the
18:51fridge but some warm air
18:54if you have a melt and you spray the
18:57you will use a cooling hair to solidify
19:01the thing and we have work on one
19:03process consisting in fact
19:05to spray a fine powder and a bender
19:09and then glue in fact this small
19:11particle around the bigger one
19:14and even some time if so coalescence
19:18next approach when you have particle and
19:21i will take the example of the arginine
19:23beach which is negatively charged
19:25you know you can see spans in a
19:29solution like the cathode and the
19:31keratosis and will in fact
19:32fix on the particle and forming a kind
19:36coating this process is generally used
19:39in medical domain and they don't like to
19:42have positively charged particles
19:44this is why often they resuspense
19:47the particle in an alginate solution
19:51to make a sergent coating and then get
19:58the last approach is the extrusion
20:02if you for example take starch an inject
20:05screw and have a high temperature
20:08and probably high pressure you will in
20:12exit after introducing the active some
20:17the pellets is still re-transformed to
20:19more spherical particles by
20:21what they call spheronization which
20:25turn the particle in the reactor at
20:30you see it's already a lot of technology
20:34just gave you a few examples but you can
20:38many type of polymer and i just put here
20:43the polymer which is food grade but you
20:45can also have many polymer which is not
20:48food crate for many other applications
20:51on top of it you may modify
20:55in fact the capsule by using some filler
20:57some surfactant or even some additive
21:00which will for example will explode when
21:04or you know any anything you think then
21:07technology of encapsulation is not
21:09simple in principle but
21:11selecting the bright one is not so easy
21:16the last step is the scale up and down
21:20is generally not really taking in
21:22consideration when people develop the
21:25encapsulation but if you don't think
21:28about it at the beginning
21:29you will have trouble at some stage i
21:32take the example for the scale up the
21:35only multiplying the size
21:38it's also that the process is still
21:46acceptable or technically acceptable
21:49and i give you example of the spray
21:52many articles used in fake alginate or
21:57for making the capsule and in this case
22:00you have to evaporate a large quantity
22:03because the concentration of polymer is
22:06and as you have a large quantity of
22:10water to evaporate you have a
22:12high cost per active you know and this
22:15is only for the evaporation you have
22:17equipment you have to have demand power
22:22if you increase by for example using the
22:25maltread extreme you see you decrease
22:28completely the price of the capsule
22:32cleaning is something that we do and i
22:34remember when i started to work on
22:38the we was washing the capsule
22:41with a large volume of water containing
22:45and i'm sure that if i will compute
22:49what is the cost of this liquid
22:52it's higher than the cost for making the
22:55then when you will go to the industrial
22:59you have to reduce the volume and
23:00probably find some tricks
23:02like making a multi-step cleaning
23:05in the way that the cleaning not will
23:10the higher cost in the production
23:13drying is also a big problem often
23:1699 percent of the capsule sale on the
23:20is dry and very often the capsule
23:23are producing with water and people
23:26that the drying is an important step
23:30let's assume we want for example to dry
23:33they look like caviar then they stick
23:37how you can dry something like this
23:40and one solution one this is big
23:44is probably to use a drum you know and
23:48will move inside and they will be
23:51pushed away from the wall by the air
23:54and they step by step they will dry in
23:58than if you simply have a trail and then
24:02pass airform in top of it
24:07the design of the process of
24:08encapsulation is probably relatively
24:13but you have also to think that you have
24:16whole the system i will take the example
24:20you have to select the probiotic not all
24:23the probiotic will be
24:24enhanced by the encapsulation
24:28you have to find a system of production
24:32link to the state of the
24:35cells at the end you know you have to
24:38formulate and probably adding some
24:41in the formulation will help to support
24:44the encapsulation especially the drying
24:47after this you have a storage and then
24:50you have to make the capsule which will
24:52help for keeping the surviving during
24:56but the capsule has to be redraped
24:58probably when you will be in the
25:00and probably not during the gastric
25:03you have to release and you have
25:05probably to promote the absorption
25:07of the probiotic in the intestine
25:11and these bring a lot of questions and
25:14jamie welcome back to this
25:15with the whole of the question you can
25:18probably think about it
25:20before to leave you i would like to tell
25:23probably the most funny application of
25:27it's called the camacho draw the draw is
25:30a sheet that you put on your bed
25:32with some capsule on it and when you
25:35on the bed you will break the capsule
25:38and release some aphrodisiac
25:41i really thank you for your attention
25:44you have enjoyed my presentation so that
25:46was the first presentation
25:48um by denis poncelle so following on
25:52uh following on from the from the
25:55denise presentation on
25:58encapsulation and different methods
26:02how you can actually encapsulate
26:05different types of materials
26:07we follow on on the presentation by
26:10oxley and i will give quick introduction
26:15to james before the the presentation
26:19james uh uh have been doing uh
26:22and you can see from the from the
26:25is now on the on the on the slide that
26:28he has been in within the encapsulation
26:33uh almost more than 20 years now and
26:36uh has been quite involved in number of
26:39um societies including also controlled
26:43release society as well as by
26:47group his presentation will be focused
26:50on the economical factors and if you're
26:54deciding to go for a specific type of
26:57of microencapsulation how you can
27:00within the within the process itself
27:04hi my name is james oxley i'm a staff
27:06scientist at the southwest research
27:09i've been here about 16 years doing
27:10nothing but micro nano encapsulation and
27:12have collected quite a bit of knowledge
27:14and experience with regard to the
27:15variety of applications
27:17where microencapsulation is applied
27:19working on probably 500 different
27:20projects in this time so
27:22hopefully i can pass along some of that
27:24knowledge in this presentation spend the
27:25next 20 to 30 minutes talking about
27:27the different applications where you'll
27:29find micro encapsulation
27:30a little bit of information on some of
27:32the costs regarding encapsulation and
27:35some thoughts on on how you might start
27:36to design your capsule
27:39so you've already heard from denis a
27:40little bit about what microencapsulation
27:43give you a little bit of my perspective
27:45i put it into three different categories
27:47the first is art and so these are the
27:50technicians that have been in the lab
27:52these are the experienced scientists who
27:53have been working with
27:54microencapsulation for a while
27:56and can look at reactions can look at
27:59emulsions and things like that and
28:01understand what changes need to be made
28:02without digging into
28:04some of the science behind it of course
28:06it's our job to take this and convert
28:08that into the scientific portion and
28:10that's of course what denis focused on
28:12what i'm focusing on
28:14but it is important to be aware that
28:15some of this encapsulation space does
28:18have a little bit of art to it
28:19and there is a third category and that's
28:21the industrial proprietary those are the
28:22trade secrets and those are the recipes
28:25corporations and companies have that
28:27they apply to microencapsulation now
28:30unfortunately we can't get into those
28:32protected information and so forth we
28:34have some insight into what they may be
28:37for the most part of course we'll be
28:38focusing on the the science portion of
28:42so micro capsules can be found in a
28:44variety of spaces both inside and
28:45outside the home and workspace
28:47here i've shown quite a few different
28:49examples of where you might find
28:50microcapsules from vaccines
28:53pharmaceuticals maybe whiteners and
28:56fragrances from deodorants were
28:58controlled released there
29:00different hair care products or
29:01cosmetics or perhaps some laundry
29:04also fragrances there that might be
29:06encapsulated for shelf life or shelf
29:08and of course beverages and functional
29:10foods nutrients and so forth that
29:12may be added to provide better
29:14nutritional value from those beverages
29:17and then when you go outside there's
29:18plenty of additional applications
29:20from antimicrobials that might be used
29:22in paints and coatings
29:23phase change materials that are now
29:25being used in building materials for
29:29better control temperature and become
29:31more energy efficient of course
29:32fertilizers and pesticides have long
29:35encapsulated active ingredients to help
29:38slow the release preventing them from
29:40washing away and allowing application
29:42less frequently so rather than having to
29:45or pesticide once a week you can now
29:49months at a time adhesives
29:52if you're not familiar many nuts and
29:54bolts are held together by a glue that
29:56is activated when the nuts and bolts are
29:59and even petroleum products in the
30:00fracking industry specifically
30:02is a place where they use encapsulated
30:04breakers during fracking so of course a
30:08good place to look for
30:10potential applications of
30:11microencapsulation is the patent
30:14i urge you all to go to a website like
30:16lens.org there's plenty of other patent
30:17search websites but lens is quite nice
30:19in terms of breaking this down to some
30:21nice statistical information some nice
30:24so here i've listed out some of the top
30:26hits for micro encapsulation
30:28as well as some of the common companies
30:30so you may recognize them by their logos
30:32or their company names from canon to
30:34pfizer bear so they span a lot in terms
30:37of pharmaceuticals down to agricultural
30:39paints and coatings other commercial
30:41applications from companies like 3m
30:43or e-ink if you've ever used an amazon
30:45kindle and you can see many of these
30:47thousands of patents related to
30:51helping show you how diverse and how
30:53widespread its use is
30:56so if we're going to micro encapsulate
30:58it's of course important to understand
31:00why and this helps open the door to
31:01the potential applications that might be
31:03used of course the first
31:05is converting a liquid to a solid and so
31:08this was some of the first encapsulation
31:11over 100 years ago spray drying eggs and
31:14milk to make milk powder and egg powder
31:16in the early 1900s for converting flavor
31:18oils into solids and powders
31:20of course it's still widely used today
31:22and spray drying is the most common
31:23application in spaces like flavors and
31:27second application or separate reason
31:29might be to separate reactive components
31:30and so this was the emergence of
31:32carbonless copy paper for example where
31:34you encapsulate the leukodye keep it
31:36separated from an acidic activator
31:38until you press down on the paper to
31:40break the capsule releasing that dye
31:42where it comes into contact with that
31:45or a third example might be protecting
31:47from the outside environment
31:49so if you've ever tried to work with
31:51omega-3s or fish oil for example you
31:53know they're highly sensitive to
31:54oxidation and so you want to encapsulate
31:57to slow down that oxidation or prevent
31:59that oxidation so you can use them in a
32:00variety of products and avoid any
32:04side effects of that use and related to
32:07that masking o voter there's some things
32:10inherently will have an odor where it'll
32:11be thiols amines for example
32:14and so you can encapsulate those to mask
32:16that odor or in the case of
32:17pharmaceuticals maybe masking tastes so
32:21oral formulations taste better or if you
32:24different nutraceuticals or functional
32:26foods you might want to incorporate
32:27vitamins and nutrients that might
32:29otherwise taste bad unless they're
32:32another application or reason to
32:33encapsulate is for controlling release
32:36here we're entrapping an active
32:38ingredient and controlling its release
32:40whether it be immediate whether it be a
32:42zero order there's different ways or
32:44mechanisms to release an ingredient
32:46but one of the main reasons for
32:47encapsulation is to again control that
32:49release whether before the carbon-less
32:51copy paper so you're controlling release
32:54or for flavors and fragrances converting
32:57them to a free-flowing solid you want
32:59that to release as soon as it hits the
33:00mouth so you get that impact of that
33:05second to last we have just altering
33:06properties so you can incorporate an
33:10into say a microsphere to prevent
33:13and have it remain in an amorphous state
33:15and this is very important in the
33:17nutraceutical or pharmaceutical space
33:19you may have different crystal forms or
33:21an amorphous form that is more
33:24and has better efficacy when it's
33:27and then the final applications is
33:30targeting a lot of this is used in the
33:32pharmaceutical space so that your drugs
33:34and medications can target certain parts
33:36of the body but we're now seeing this
33:38into other areas as well including
33:39nutraceuticals food and agriculture
33:42so that your pesticides for example
33:45plants certain pests to maximize their
33:48efficiency and minimize the
33:49amount of material that's needed for
33:51encapsulation and for use in the final
33:54of course the common question is well i
33:56know why i want to encapsulate now but
33:58what can i encapsulate the general
34:00categories of course solids liquids and
34:02gases you can encapsulate all three
34:05there's always a but however this comes
34:07into the the limitations and the
34:09exceptions related to
34:10either the material you're trying to
34:12encapsulate the application you're
34:14or the exceptions that might be uh
34:16present in in what you're trying to do
34:18and i've here included just count three
34:20common examples related to
34:22solids in the case of maybe a
34:24pharmaceutical ingredient for an oral
34:27a liquid in the case of omega-3s using
34:31phase change materials or liquid crystal
34:32materials used in labeling applications
34:35the label on this this beer changes
34:38as it goes from colder to warmer to
34:41indicate the temperature
34:42of the beverage and then gas so
34:45two applications here one is in the
34:47confectionary space pop rocks it's an
34:48encapsulated carbon dioxide
34:50or an encapsulated fluorinated gas used
34:53in ultrasonic contrast agents
34:55so there's there's several ways or
34:57several applications for solids and
34:59liquids and gases but again feasibility
35:01a lot will depend on what you're trying
35:05so we don't have a lot of time but i'll
35:07quickly go through some applications
35:09pharmaceuticals and nutraceuticals the
35:12technology and the formulations kind of
35:13flows down from pharma down into
35:15nutraceuticals and foods
35:16get a little bit into flavors and
35:17fragrances of course cosmetics consumer
35:20products which use a lot of fragrances
35:23paints and coatings agriculture and then
35:25finish out with some industrial
35:29so starting with pharmaceuticals this is
35:31where a lot of the funding research is
35:32and so if you go into the academic
35:34literature for example this is probably
35:35where you'll find most of the research
35:37related to microencapsulation a variety
35:39of ways to use microencapsulation this
35:41is why it took off in the 1980s as a
35:43common technology for controlled release
35:45and these different formulations
35:47of course one being oral you want to
35:48maximize compliance of the patient
35:50so that they are willing to take the
35:52medication if any of you were
35:54when you were a kid and had bad
35:56medication like myself you know that
35:58you want it to taste good a bad medicine
36:01is not a good experience and you want to
36:02make sure again patients are willing to
36:05so taste masking oral delivery of course
36:07sustaining release so when you do take a
36:10it's longer lasting so that's the case
36:12of say ambien which is a sleep
36:13medication you don't want it to wear off
36:16you also don't want to overdose within
36:18the first hour so you want to maintain
36:19that therapeutic level throughout
36:21enteric release specifically to get a
36:24medication past the gastric
36:26or past the acidic environment of the
36:27stomach and into the intestinal system
36:29so that you do not have any acidic
36:32drug for example increasing viability
36:34bioavailability i mentioned previously
36:37or just reducing size and this is
36:38related to bioavailability but you can
36:40encapsulation to help control and reduce
36:42the size often down into the nano size
36:44so that it's a microparticle but once it
36:46gets into the digestive tract breaks
36:48apart into nanoparticles
36:50targeting i mentioned and then of course
36:51just stabilization making sure these
36:53drugs are shelf stable so you don't have
36:55to have a cold chain for example
36:57and can have these at room temperature
36:58and this also helps with
37:00distribution of drugs and
37:01pharmaceuticals to third world countries
37:04electrification and refrigeration is
37:07related to pharmaceuticals we get to
37:09nutraceuticals so these are
37:10over-the-counter either pills or
37:13juices or liquid formulations that
37:16consumers will purchase to help
37:18supplement their diet with different
37:20vitamins and nutrients to perhaps
37:22prevent a deficiency or
37:24address a deficiency and again taste
37:26masking is quite important here because
37:27you want to maximize patient compliance
37:30also increasing bioavailability so you
37:32can reduce the dosage because you don't
37:34most of it just passing through the body
37:35you'd like for it to be absorbed and
37:37again enteric release is quite important
37:39here as many vitamins and nutrients can
37:41be degraded in the stomach and so you
37:42want these to get into the intestine
37:45maximum efficacy and controlling release
37:47and stabilization so some of the same
37:49themes that we saw with
37:50pharmaceuticals and also you'll see some
37:52common names associated
37:54often with pharmaceutical excipients and
37:57apply well to nutraceuticals
38:01moving a step further down we go to
38:05several examples here shown in the
38:06pictures from again the omega-3 peanut
38:10leavening agents used in a microwavable
38:13frozen pizzas and so that would be a
38:15controlled release application to
38:18the enhance the shelf life of that
38:20leavening agent then release it while
38:22you're cooking it i mentioned pop rocks
38:24again also the omega-3 example so you're
38:28stabilizing that on the shelf you don't
38:30want your orange juice to taste like
38:32so a lot of the same reasons to to
38:35encapsulate taste maxing and controlled
38:37you may also have just some processing
38:38gates something that's not used in the
38:41encapsulation helps facilitate the
38:43manufacturing of that product
38:45so those are often hidden behind the
38:47scenes and not always listed on a label
38:50one of the more complex areas of
38:52microencapsulation are flavors and
38:54fragrances so these can be combinations
38:55of dozens if not hundreds of different
38:57organic molecules with varying
38:59solubilities volatilities reactivities
39:02and so they become a little bit more
39:03challenging to encapsulate and
39:05incorporate into a product to either
39:07release early to help stabilize that
39:11in many cases you're trying to get a
39:13burst release or a triggered release so
39:15that's shown here in this uh liquid ice
39:18product from hershey's these were
39:21roughly five millimeter sized beads with
39:23a mint oil inside and so when you crush
39:25down on them you release
39:26burst release that mint oil or the
39:28stride shift gum where it changed flavor
39:30is halfway to chewing the gum so there's
39:33or sustain release throughout this
39:35product or scratch and sniff so that's a
39:39in most cases you're just converting a
39:40liquid to a solid so you're taking these
39:42liquid formulations converting from the
39:44and then a secondary objective might be
39:46having that burst or trigger release
39:49a lot of times you're trying to enhance
39:50shelf life you want to make sure that
39:53has that same burst of fragrance or that
39:56flavor fragrance profile by the time it
39:58gets to the consumer
40:00and so this is a very very common
40:02application of microencapsulation
40:05related to fragrances is cosmetics
40:07oftentimes you'll have
40:09control release fragrances used in
40:10cosmetics in addition to other
40:12cosmeceutical ingredients or
40:14ingredients that are beneficial to the
40:15skin to either control release so they
40:18efficacy increasing that bioavailability
40:21so they are available to
40:22diffuse or penetrate through the skin
40:24stabilizing those products so they're
40:26shelf stable so that
40:27by the time you do purchase this
40:28cosmetic ingredient that active
40:30ingredient is still active
40:31in some cases just marketing being able
40:33to have something on the label that says
40:34controlled release or liposomes
40:36another common technology used in
40:40or controlling appearance most consumers
40:43would like a cosmetic product that
40:45also looks good so that the cream looks
40:47good you're more likely to put on a nice
40:49cream indicating purity versus maybe a
40:52cream that that might not look as
40:56or just controlling odor because again
40:58you don't want to apply a cream or some
40:59type of cosmetic that smells bad
41:02so you can control or mask odor in
41:04combination with releasing an ice
41:06help control that odor plenty of
41:10consumer products as well a very wide
41:12variety of consumer products out there
41:15to toothpaste deodorant
41:18bath soap or as i mentioned e-ink and
41:20kindles and displays
41:21uh control release is used for a variety
41:23of reasons in this space whether it be
41:25again to control release of a
41:27material so this is a razor blade with a
41:29little bit of a healing agent to help
41:31the nicks and scratches while you're
41:32shaving to no release at all so in the
41:35case of the e-ink or the amazon kindle
41:37you do not want that ink to come out you
41:38want it to remain there for the life of
41:40the product so we're controlling release
41:42preventing it all together and this
41:44enables new products so again the e-ink
41:47wouldn't be around without
41:49stabilizing ingredients or again just
41:51converting a liquid to a solid something
41:54the phase changement or the excuse me
41:57the fragrances used in soaps or these
41:59deodorants next category of applications
42:02are paints and coatings and so here we
42:04have a few different ways to use
42:05microencapsulation whether it be just to
42:07add some multi-functionality in terms of
42:10corrosion resistance or perhaps
42:14impact indications so that's related to
42:16carbon-less copy paper
42:18but here you might have a higher impact
42:19such as a hammer or something hitting
42:22and self-healing came about i'd say
42:24about 20 years ago as a common
42:26potential common application and
42:27including encapsulated healing agents so
42:31or cut the surface you release a healing
42:33agent to fill that crack
42:35and help seal off the surface from
42:37underneath to prevent any further
42:40antimicrobial inclusion is very common
42:42so that you have a nice controlled
42:43release of antimicrobials throughout the
42:46or phase change materials as previously
42:48mentioned whether for
42:49energy conservation or for inclusion of
42:52perhaps color change
42:55the second to last category is
42:56agriculture so this came about in the
42:5850s and 60s for leveraging the
43:01encapsulation technology and controlled
43:03release technology used in carbonless
43:04copy paper but applying it to pesticides
43:07for example that's grown now not only to
43:08pesticides but fertilizers herbicides
43:11as well as animal feed so you can cross
43:16food nutrient fortification used in
43:18human foods now for also veterinary
43:20as well as animal feed applications for
43:24requirements of feed animals again we're
43:27controlling release we're converting
43:28liquids to solids that's quite common
43:31improving handling or safety so if you
43:33imagine on a larger scale
43:35farmers are having to handle tons of
43:36this material and so you need to enhance
43:39so that they minimize their exposure and
43:41stay below any occupational exposure
43:44stabilizing the ingredients whether it
43:46be a suspension stability or
43:48shelf life stability and of course
43:49bioavailability towards the animal or
43:53pest or the herb in question for that
43:55target so several applications for
43:57for pesticides and probably one of the
43:59larger markets for encapsulation
44:03so the final application space are is
44:05industrial applications this is a very
44:07diverse space where you have
44:08applications ranging from the
44:10energy industry petroleum construction
44:14catalysts chemical processing packaging
44:17i think military applications as well a
44:19few examples here this is
44:21a technology now owned by microtech but
44:24originally developed by basf
44:25encapsulating phase change materials for
44:27use in building materials like concrete
44:29companies like baker hughes have
44:30encapsulated agents used in the fracking
44:33industry for extracting petroleum from
44:37encapsulated phase change materials used
44:39in solar thermal energy applications so
44:41melting points here core materials up to
44:43800 to 1000 degrees celsius so some very
44:47temperatures and environments often
44:49required of encapsulation in these cases
44:51requiring very specialized
44:52microencapsulation solutions and
44:54challenging problems for
44:56scientists to solve so after 16 years in
44:59the industry i've seen a lot of overlap
45:01and similarities between these different
45:04applications that i've discussed from
45:06pharmaceuticals paint and
45:08nutraceuticals down to paints and
45:09coatings and industrial applications and
45:11there's several global challenges that
45:13have come to the surface that i think
45:14are applicable to all potential uses of
45:18the three main i don't want to call them
45:20enemies but most difficult things to
45:22protect against are water
45:23oxygen and heat there's some barriers
45:25that work good against water and oxygen
45:27for example but nothing is 100 effective
45:29you're always going to have
45:30some diffusion of water oxygen through a
45:34it's just a matter of how much can you
45:35slow it down relative to your
45:37size of your capsule thickness of the
45:38shell and so forth it's also general
45:41trend to go smaller in capsule size
45:43reducing the size down to nanometers now
45:46but as you do that i caution that you
45:48start to increase your surface area
45:50decrease the thickness of your shell
45:52and your protection starts to decrease
45:53so there's advantages from
45:55size in terms of how it might look in a
45:57suspension or dispersion or uniformity
45:59but you start to lose that protection so
46:01protection is always best on a larger
46:05plenty of ideas out there in the
46:06encapsulation space especially once you
46:09to search through the academic and
46:10patent literature those ideas can
46:12transcend applications but
46:14the cost time and research really is
46:15needed to make sure you
46:17apply the right regulations to the
46:19materials and the equipment and the
46:22like to spend the next few minutes
46:24talking about the cost of encapsulation
46:25i just gave you a variety of examples
46:27and applications where
46:29of course the margins for those products
46:30very significantly so the amount
46:32that you can spend on an encapsulation
46:34process or formulation will also vary
46:37so it's not uncommon to have this
46:38question of how much will it cost either
46:40for a few grams to test a
46:42batch of capsules maybe for kilos for a
46:44pilot scale or getting into the ton
46:46quantity for a big batch to actually
46:48support production of a final product
46:51so i generally divide encapsulation
46:53costs into six categories that i'd like
46:56including materials your core your shell
46:59the design of the capsule the size the
47:00payload how it's going to release
47:02the process you might use for making the
47:04capsule uh what you're going to do with
47:06the materials afterwards shipping and
47:08and of course the regulatory aspects
47:11related to the industry that you're
47:12using these capsules for
47:14and then finally the costs that are
47:15often ignored so these are the uh
47:17the gna and overhead costs
47:20so for the first category the materials
47:22it supplies both your core and your
47:24shell now presumably the core material
47:26is something you're already familiar
47:27it's something you might be already
47:28manufacturing or keep in stock so you
47:31but there may be some additional cost
47:34with regard to pre-processing either
47:37through making an emulsion
47:38or perhaps reducing particle size or
47:40increasing particle size
47:42you'll also have to account for the
47:43shell materials that you need to buy as
47:44well as any processing aids ph
47:46modifications surfactants antimicrobials
47:50and so forth so this can start to add
47:51costs as well once you put these
47:54and also consider is this a solid or
47:56liquid material do you have to melt it
47:58do you have to dissolve it
47:59that will be time and energy that on a
48:01larger scale is significantly more
48:02difficult than on a small scale in a lab
48:04in a beaker how long can you keep your
48:07materials on hand before you have to buy
48:10considering lots of materials and how
48:11those will change over time
48:13of course how are you going to handle
48:14them in terms of safety handling
48:16something on a small scale
48:17laboratory is much simpler than say
48:19handling tons of this material in a
48:21production environment so you have to be
48:23aware of occupational exposure hazards
48:26and of course where are you getting the
48:27material from and is that a consistent
48:28source and do you have backups for those
48:31and now we get into the design of the
48:33capsule so i have a few trends here and
48:36these arrows can flip depending on the
48:37application but this is sort of a
48:40uh trend to look at so as your size of
48:43down the cost typically will go up you
48:47a lot more energy to break down droplet
48:50perhaps prepare smaller atomized
48:52droplets longer coating times and a
48:56so depending on the process and in most
48:57cases again as your size goes down your
49:01loading that really depends on what
49:03you're considering as your metric for
49:06in some cases the lower percent loading
49:09the lower the cost of the capsule
49:10because now you can replace it with a
49:11cheaper shell or matrix material
49:14but definitely as as the complexity of
49:16the capsule decreases the cost will
49:18decrease now you can use something like
49:19spray drying to make a microsphere
49:22perhaps a more complex morphology of a
49:23microsphere with a shell around it in
49:25which case you might need two processes
49:27or perhaps even three depending on what
49:29you have to do to your core material
49:31before you encapsulate it of course the
49:33release will influence
49:35in most cases your design as well as
49:37your formulation and then how will that
49:39final product be used do you need it dry
49:41performing a liquid-based encapsulation
49:44process or emulsion-based
49:45that will most likely be a aqueous
49:48suspension and do you want to remove
49:50or leave it in and ship it around with
49:52the rest of the product
49:54so now we get to the third piece of the
49:55pie this is the process this is how
49:57you're going to make the capsule so you
49:59pay for the materials figure out what
50:01the design of your capsule is
50:02and that will help dictate the process
50:04that you're going to use
50:06so one thing to consider is is the
50:07process available whether it be lab
50:08scale pilot scale or
50:10large scale their party tolling
50:12manufacturers is the equipment available
50:14if the process is available is it within
50:16your industry do you need pharma gmp
50:18do you need food do you need
50:20agricultural pesticides
50:21that will start to narrow your list of
50:23potential options in terms of
50:24availability of the process
50:26is it going to be a batch or continuous
50:28generally a continuous process on a
50:30large scale will be less expensive
50:32with regards to the cost the capsule
50:34while batch wise will be
50:36a bit more expensive how are you going
50:39dry these materials what utilities and
50:42manpower so now we start to get in
50:43is the process something you're hosting
50:45at your facility so you have to power it
50:47you have to have the people to work it
50:49operate it you'll have to collect the
50:52depending on your organization you'll
50:54probably have some quality control that
50:55you would have to adhere to
50:56you'll certainly have some waste that
50:58will need to be collected
51:00and disposed of and that can be a
51:02significant cost depending on what
51:04and of course the economy is scale the
51:06more you make generally the less
51:07expensive per kilo this is going to be
51:11part of the encapsulation chain that's
51:12not always considered as storage and
51:14transportation of your materials
51:16so depending on what you're trying to
51:17encapsulate you'll have to think about
51:20both your raw materials
51:21intermediates and then your finished
51:23products of the capsules not to mention
51:25the finished product of your actual
51:28end-use consumer application that you're
51:31building towards so your materials you
51:33have to think about bringing them in do
51:36storage do they require that climate
51:38again how much do you keep on hand
51:39what size facility do you need to do
51:41that and what regulations will you need
51:44then when you're shipping and so forth
51:46what sort of packaging will you need
51:47does this need to be already
51:48individually packaged bulk packaging
51:50if you think about core shell capsules
51:52which might have some
51:53some rupture strength to them are you
51:56packing this in a large super sac where
51:58capsules on the bottom might have a lot
51:59of mechanical pressure on them and you
52:01might break a few along the way
52:02especially if it's going down a bumpy
52:04road or a bumpy uh transportation
52:07so you'll have to think about how you're
52:08packaging them is again dryer suspended
52:11and are you shipping water halfway
52:13across the world you need to remove it
52:15and add it back in later
52:16and of course import export costs and
52:19again thinking about your your storage
52:21but also shipping does it need to be
52:23climate controlled and cold chain
52:25because transportation sometimes if it's
52:27not climate controlled you can get up to
52:2855 even 60 degrees celsius which can be
52:30detrimental to some products
52:33now we get into the regulations and
52:35perhaps what industry are in this will
52:36be highly dependent on what you're
52:38making so again if you're in the
52:40pharmaceutical space you'll most likely
52:44good manufacturing practices or gmp that
52:46can add considerable cost
52:48or if you're working with pesticides
52:50perhaps environmental regulations you'll
52:52have to adhere to but generally the more
52:53regulation you have the more costly the
52:55capsules will be to to handle
52:57transport and store so make sure you're
53:00also using approved materials that can
53:02drive up the cost considerably for a raw
53:05you're going to have to qualify and keep
53:06equipment maintained and have the proper
53:08operating procedures in place
53:10and then where those materials going so
53:12you may have to do an environmental
53:13study with regards to the materials that
53:14you're using so for example we're
53:16potentially coming up upon a ban of
53:18microplastics in the european union
53:21and along with that it may include some
53:22micro capsules and so you'll have to
53:24switching over formulations or
53:26demonstrating or proving that the
53:27capsule formulation you have is
53:31and finally we have the i'll call the
53:32hidden cost so that's the
53:34iceberg here so you see the tip of the
53:35iceberg but the hidden costs are those
53:37that are underneath everything
53:39behind the scenes your g a or general
53:41administrative costs
53:42we mentioned quality control but even
53:44beyond observing processes you might
53:46have some additional quality control
53:49disposing of that waste maintaining the
53:52maintenance contracts any support staff
53:56facilities costs insurance and so forth
53:59so these these are small
54:01little costs in some cases that add up
54:04uh behind the scenes that can add
54:06further to the cost of your micro
54:08capsule so now you have materials
54:09design process shipping storage
54:12regulations and then finally your
54:13overhead costs all of these combined
54:16is what will give you the potential cost
54:19of making micro capsules
54:22so i want to present just a few quick
54:23scenarios with regards to
54:25making capsules so i'll caution that
54:27these are just for educational purposes
54:29these won't necessarily be the actual
54:31cost of what you pay
54:32and of course credit goes to a few that
54:34have provided this information
54:35for us to to be able to share here
54:38one is from the coding place a fluid vet
54:40coding contract manufacturer up in
54:42wisconsin in the united states uh this
54:44is an example of fluid bed coating with
54:46regards to the size of the micro capsule
54:48and what you're trying to coat so fluid
54:49bit coating is is quite difficult to
54:51operate the smaller you go in size so
54:53here we're on the low end of 150 microns
54:55150 to 500 micron starting material and
54:58then a millimeter size starting material
55:00and with the same batch size putting on
55:03the same amount of coating you can see
55:06cost it's considerably higher almost an
55:08order of magnitude higher to make
55:10capsules and particles that are order
55:12magnitude smaller that's because we have
55:14a much larger surface area so in the
55:15case of the one millimeter beads
55:17lower surface area quicker coating time
55:20in the case of the smaller capsule
55:21significantly higher surface area and so
55:24you need a lot more time because the
55:25spray rate of the fluid bed coater is
55:27fixed you can't simply increase the
55:29spray rate because the particle size is
55:30smaller so our time increases
55:32quite a bit second example this is uh
55:35some information that came from our
55:36institute i'm looking at co-extrusion so
55:40two fluids out of a concentric nozzle to
55:42make a core shell droplet where the
55:43outside of that droplet hardens to form
55:46something like a vibratory nozzle uh
55:48depending on how we collect the capsules
55:50and the type of shell material for going
55:53the per kilo cost is on the lower end
55:55because that powder bed actually adds to
55:58and sticks to the capsule and becomes
56:00part of the capsule so we have less flow
56:02rate needed to make the same final
56:03kilo cost i'm congealing so a wax or fat
56:07it's kind of in the middle and then
56:09finally chemical crosslinking or ionic
56:11crosslinking this might be alginate for
56:13example so we're collecting into a
56:14calcium chloride bath
56:16and there's considerable expense here
56:17because water is is adding a lot to the
56:19cost of processing so this is quite a
56:21bit higher so three times the cost to do
56:23a alginate bead versus something maybe a
56:27captured in a powdered bed in the final
56:30example we have a coast servation this
56:33ron versic at rt dodge again they're
56:35their contract manufacturer as well
56:37primarily focusing on some
56:38emulsion-based capsules like
56:39coastervation or in-situ polymerization
56:42and here we have three examples we have
56:45coastervation looking at either dried
56:48capsules or slurry so you can see if we
56:49dry the capsules we're on the order of
56:52nine dollars per per kilo we keep them
56:55as a slurry much lower
56:56we didn't take the time or need the time
56:58to dry down this this batch of capsules
57:01but if we make a smaller batch five
57:03kilos the cost per kilo is
57:05significantly higher and really the only
57:07difference is the size of the vessel
57:09it's still the same amount of time
57:11which is where a lot of the costs come
57:12from for somebody to make a five kilo
57:15the same amount of people in time to
57:17make a 550 kilo batch in this scenario
57:19so batch size or economy of scale has a
57:21big impact especially
57:23on the lab to production scale
57:28and finally just a few closing thoughts
57:30on how to design a capsule so
57:33denis talked about the different types
57:36i've presented several examples a little
57:37bit of information on cost but you have
57:40different parameters how do you start to
57:41think about making a micro capsule
57:44one approach and what i consider be the
57:47is what's called shotgun where you have
57:49a lot of different inputs that you're
57:51trying to squeeze through the funnel of
57:53designing a capsule so you have your
57:55chosen you have your payload chosen you
57:57know what morphology you want you know
57:59what materials you want and you know
58:00what process you want
58:01so you try and squeeze all of these
58:05your micro capsule but in many cases one
58:07or more of these might fail due to
58:10of morphology or the materials or the
58:12process whatever it may be and so you're
58:13often in search of a holy grail in this
58:16and most likely what you end up as
58:18failure so it's more important to take a
58:21strategic approach with regards to the
58:23design of the capsule
58:25so you want to pick a starting point you
58:27say absolutely have to have this size or
58:29this payload or a set process that you
58:31have to work with start with that
58:33and then work your way around and you
58:35notice i have a web in the middle
58:36because as you change one it will
58:38influence the other components of
58:39designing that capsule
58:41so you need to be flexible with regards
58:44moving some of these around to help
58:46achieve the objective and you need to
58:47balance those expectations so you can
58:49start again with size
58:50you could start with payload it has to
58:52be 80 payload so that might limit you to
58:54core shell morphology
58:55or you have to start with a matrix
58:58start on this side so pick your starting
59:01point and then start to fill in the gaps
59:02based on the limitations
59:04that are currently hindering parts of
59:07the other parts of this web that you're
59:10achieve so to finish out here's quite a
59:13more information where you can go and
59:16more applications more cost information
59:18on microencapsulation there are plenty
59:20of scientific articles journals patents
59:23multiple conferences once we're all able
59:25to uh to meet each other one in person
59:27um either through the bioencapsulation
59:29research group control relief society
59:31some good search engines are scopus
59:33even google scholar i've been using lens
59:36quite a bit lens.org
59:37and it's a global contribution so
59:40not just the us but plenty in europe
59:42china japan india and so forth so
59:45microencapsulation not only is used in
59:48applications but also used around the
59:52so with that i appreciate your attention
59:54uh and i'm sure we'll wrap up here and
59:57any further questions and if you want
59:58any further information about these
01:00:00slides that you didn't hear about or
01:00:01didn't answer during the webinar and
01:00:03you're watching a webcast later or
01:00:06feel free to uh send me an email so
01:00:08those were the two presentations by
01:00:11both james oxley and damie sponsor lame
01:00:15uh with that i think we we are coming to
01:00:18end of the of the the webinar today if
01:00:21you have not registered feel free to go
01:00:23register on the buy encapsulation
01:00:26um this particular webinar will be
01:00:29um available as a recording afterwards i
01:00:33i think danny mentioned something about
01:00:3548 hours but feel free to
01:00:38to give a little bit maybe a few more
01:00:41on top of that and i would really like
01:00:43to thank both to james and denim
01:00:45uh on the presentations today and uh if
01:00:49free to um any questions and answer
01:00:52options to to to ask um additionally
01:00:56or maybe you want to contact james and
01:00:57denise separately by emails
01:00:59within the presentations they were also
01:01:01their emails thanks everyone for the
01:01:04and uh hope to to meet you again at the
![#Uwu #Uwuvoice #Itshannahowo Hannah UwU || Hannah UwU voice ❤ [Compilation]](/_next/image?url=https%3A%2F%2Fi.ytimg.com%2Fvi%2F2V2xm_LDYPA%2Fhqdefault.jpg&w=3840&q=75)
