1084 replies to this topic

[niner]

Besides resveratrol being hydrophobic it also tends to stack on top of each other making it even harder to solubilze.

You know, Hedge, I was going to say that the situation notox described sounded like a liquid crystal. At the time, I decided that was kinda unlikely, but now that you bring up the stacking idea, it makes more sense. I wonder if people have seen these shimmery effects with other planar aromatic systems?

[notox]

 RsvMix1.jpg   174.68KB   47 downloads  RsvMix2.jpg   110.16KB   41 downloads

Besides resveratrol being hydrophobic it also tends to stack on top of each other making it even harder to solubilze.

You know, Hedge, I was going to say that the situation notox described sounded like a liquid crystal. At the time, I decided that was kinda unlikely, but now that you bring up the stacking idea, it makes more sense. I wonder if people have seen these shimmery effects with other planar aromatic systems?

Just to give you a glimpse of the effect I've tried to catch it with a photo.
Unfortunately the amazing dynamic of the structure building and decay cannot be reproduced with a photo
and even the shiny/metallic look lacks a bit. But here it is:

Edited by notox, 03 July 2008 - 05:41 PM.

[Hedgehog]

Besides resveratrol being hydrophobic it also tends to stack on top of each other making it even harder to solubilze.

You know, Hedge, I was going to say that the situation notox described sounded like a liquid crystal. At the time, I decided that was kinda unlikely, but now that you bring up the stacking idea, it makes more sense. I wonder if people have seen these shimmery effects with other planar aromatic systems?

Your probably correct. I can't think of anything else. I usually add mine to a mixture that is already colored so I haven't noticed anything like this.

This is why HPMC will work because it is long molecule and can take apart the stacking issues. EtOH (Ethanol) works but it is still a very polar molecule. As you add more non-polar things such as oils or fats resveratrol will increasingly be solubilized. The catch is if you add to much HPMC, oils or fats you will actually decrease the rate of absorbtion of the molecule of intrest. Thus us the min amount possible to get resveratrol into your mixture of choice. I think Edward had a good idea in trying to use medium fatty acid chains. These are metabolized very fast and might make for a good formulation. Ed did you ever try this?

[Hedgehog]

Besides resveratrol being hydrophobic it also tends to stack on top of each other making it even harder to solubilze.

You know, Hedge, I was going to say that the situation notox described sounded like a liquid crystal. At the time, I decided that was kinda unlikely, but now that you bring up the stacking idea, it makes more sense. I wonder if people have seen these shimmery effects with other planar aromatic systems?

Just to give you a glimpse of the effect I've tried to catch it with a photo.

What is the concentration in the photos? Is that in water or EtOH?

[notox]

Besides resveratrol being hydrophobic it also tends to stack on top of each other making it even harder to solubilze.

You know, Hedge, I was going to say that the situation notox described sounded like a liquid crystal. At the time, I decided that was kinda unlikely, but now that you bring up the stacking idea, it makes more sense. I wonder if people have seen these shimmery effects with other planar aromatic systems?

Just to give you a glimpse of the effect I've tried to catch it with a photo.

What is the concentration in the photos? Is that in water or EtOH?

I pre-mixed (water + letcithin) = WL and (56%etho+RSV)= ER.

Then I mixed the WL into the ER under stirring at 1500 rpm.

If I put the WL into the ER in one shot the effect is hardly detectable but if I mix it very slowly
the effect becomes very pronounced.

[Hedgehog]

I wonder if this would work for getting resveratrol into solution?

http://www.benefiber...enefiberPowders

[niner]

I pre-mixed (water + letcithin) = WL and (56%etho+RSV)= ER.

Then I mixed the WL into the ER under stirring at 1500 rpm.

If I put the WL into the ER in one shot the effect is hardly detectable but if I mix it very slowly
the effect becomes very pronounced.

The wavelength of visible light is around 400 to 700 nm. A single resveratrol molecule is a little over one nanometer. This suggests that you're seeing some pretty large (multi-molecule) structures. As you slowly add the water, resveratrol is gradually coming out of solution and forming crystals. Initially, those crystals are going to be well under the wavelength of light; maybe there are very small crystals that are stacking via the aromatic stacking interactions that hedgehog mentioned, and that's forming structures big enough to diffract light. Because those are weak interactions, they may be transient in the stirred solution, so maybe something like that is at the root of the shimmery weirdness. But I'm just guessing. Is there a condensed matter physicist in the house?

[notox]

I pre-mixed (water + letcithin) = WL and (56%etho+RSV)= ER.

Then I mixed the WL into the ER under stirring at 1500 rpm.

If I put the WL into the ER in one shot the effect is hardly detectable but if I mix it very slowly
the effect becomes very pronounced.

The wavelength of visible light is around 400 to 700 nm. A single resveratrol molecule is a little over one nanometer. This suggests that you're seeing some pretty large (multi-molecule) structures. As you slowly add the water, resveratrol is gradually coming out of solution and forming crystals. Initially, those crystals are going to be well under the wavelength of light; maybe there are very small crystals that are stacking via the aromatic stacking interactions that hedgehog mentioned, and that's forming structures big enough to diffract light. Because those are weak interactions, they may be transient in the stirred solution, so maybe something like that is at the root of the shimmery weirdness. But I'm just guessing. Is there a condensed matter physicist in the house?

Then it would be probably better to mix it the fast way to keep crystals as small as possible for better
absorption. Cooling down the Lecithin premix could further minimize crystal building...

What do you think ?

[jans]

It takes a little while to master the mixing. In London, UK I use 79,9% vodka to delute 500mg TransRes 2-3min. Then I add watter and the solution stays stable. first bite the tasteless lechitin capsule so the liquid comes out and drink the solution. Gets me going in the morning. the transRes did not like the Lecitine mixing one bit, but this way it seems to work. Is there anything I can improve?

[notox]

How to make a perfect colloidal suspension from HPMC (fast!) ?

Hello, I received some HPMC a few days ago, and I wonder what would be
the best way to dissolve HPMC.

Even using a magnetic stirrer at full speed it takes me 1.5-2h to create a
perfect colloidal suspension from HPMC using cold water and about
30mg HPMC (Methocel E4M prem.).

After adding 1000 mg 99% RSV Powder it takes a further 1h full speed
stirring to create a milky suspension that contains no clusters or
eye visible particles.

I know some people here in the forum already use HPMC for their RSV formulation
but I never read about a problem using it.

FYI: In another experiment with the HPMC I dissolved 1000mg RSV into etho.,
adding the RSV + etho. mix to the HPMC + water mix resulted in white
clouds separating form the suspension immediately after mixing. When stirring
with a tablespoon the the clouds are forming chewing gum like strings that spin
around the tablespoon and are completely indigestible -> nanonizing RSV with
etho. doesn't work for me when using HPMC (in contrast to lecithin). Any suggestions
how to avoid this effect.

Edited by notox, 16 July 2008 - 05:51 AM.

[maxwatt]

How to make a perfect colloidal suspension from HPMC (fast!) ?
...

If I recall from one of Sinclair's (et al. papers, they used 3% HPMC with micronized resveratrol. Sounds to me like you are using way to much HPMC. The also added DOS (a detergent) to prevent gelling which is only needed to provide stability for storage.

If I have time, I'll try to find the reference later today.

[notox]

How to make a perfect colloidal suspension from HPMC (fast!) ?
...

If I recall from one of Sinclair's (et al. papers, they used 3% HPMC with micronized resveratrol. Sounds to me like you are using way to much HPMC. The also added DOS (a detergent) to prevent gelling which is only needed to provide stability for storage.

If I have time, I'll try to find the reference later today.

I used 1000mg RSV + 30mg HPMC = 3% HPMC/RSV ratio, with 50ml water to dissolve HPMC,
seems not to much for me...

Edited by notox, 16 July 2008 - 12:08 PM.

[malbecman]

I use a pretty similar ratio altho' my water amount is higher, more like 300-400 mls.......

I used 1000mg RSV + 30mg HPMC = 3% HPMC/RSV ratio, with 50ml water to dissolve HPMC,
seems not to much for me...

[malbecman]

I should add that the best way I've found to do this is to sprinkle the HPMC on top of the water first and let it sit for ~10 minutes. It will slowly dissolve on its on this way, spreading across the surfae and not gel or ball-up this way. If I try to stir it in right away, I tend to get gelling of HPMC.
I then gently stir it in and then add my resveratrol.....


Here is a pic of today's "delicious" drink I just made (and no comments from the peanut gallery on the cleanliness of my coffee cup please.....) ;-)

I use a pretty similar ratio altho' my water amount is higher, more like 300-400 mls.......

I used 1000mg RSV + 30mg HPMC = 3% HPMC/RSV ratio, with 50ml water to dissolve HPMC,
seems not to much for me...

Attached Files

•  ResvMalbec.jpg   35.82KB   12 downloads

Edited by malbecman, 16 July 2008 - 06:10 PM.

[Anthony_Loera]

nice Imac..

[niner]

How to make a perfect colloidal suspension from HPMC (fast!) ?
...

If I recall from one of Sinclair's (et al. papers, they used 3% HPMC with micronized resveratrol. Sounds to me like you are using way to much HPMC. The also added DOS (a detergent) to prevent gelling which is only needed to provide stability for storage.

If I have time, I'll try to find the reference later today.

That sounds like a reference to the concentration of HPMC in the water, in which case 30mg is not enough, rather than too much. A 3% solution would be roughly 3 grams of HPMC in 100ml water. That's way more HPMC than people are talking about here.

[hmm]

That sounds like a reference to the concentration of HPMC in the water, in which case 30mg is not enough, rather than too much. A 3% solution would be roughly 3 grams of HPMC in 100ml water. That's way more HPMC than people are talking about here.

Wow that would really change things around for me, I think. If I am micronizing RSV in 12.5 ml vodka, then instead of making any kind of hpmc/water solution to add on to it, it seems like I would just want to stir about 3/8 of a gram of hpmc into the vodka/RSV mixture...

Edited by hmm, 17 July 2008 - 04:22 PM.

[notox]

How to make a perfect colloidal suspension from HPMC (fast!) ?
...

If I recall from one of Sinclair's (et al. papers, they used 3% HPMC with micronized resveratrol. Sounds to me like you are using way to much HPMC. The also added DOS (a detergent) to prevent gelling which is only needed to provide stability for storage.

If I have time, I'll try to find the reference later today.

That sounds like a reference to the concentration of HPMC in the water, in which case 30mg is not enough, rather than too much. A 3% solution would be roughly 3 grams of HPMC in 100ml water. That's way more HPMC than people are talking about here.

Finally I found a (perfect ?) way:

1. Stirring 30mg + 50cl water HPMC for ~10 min
2. Next day it is perfectly clear (now I prepare HPMC for the next day)

-> HPMC done !

3. Boiling 20cl 56% etho in microwave can dissolve 1000mg RSV while hot -> reduces alcohol used!
4. Stirring 1000mg RSV until dissolved completely
5. Adding 30ml of very cold water in one shot while stirring at 1500 rpm

-> RSV+etho done

Shocking the hot RSV solution with cold water results in extremly fine particles
regardless if the starting powder was micronized or not

6. Adding the (HPMC +Water) to the (etho. + RSV)
7. Finally stirring for a minute

-> HPMC(30 mg) + RSV(1000mg) + (~10ml etho) + (~90ml Water) are done!

[malbecman]

nice Imac..

Yes, I love my new 24" iMac, plenty of screen space so I don't have to squint at my spreadsheets anymore.


On to a more relevant topic for this thread. I found this blurb about the ideal way to dissolve HPMC:

"Therefore, the recommended method to prepare HPMC aqueous solutions is to first thoroughly disperse and hydrate the powder in a portion of hot water (about one third of the total volume) heated above 90°C with vigorous stirring to prevent lumping. Complete solubilization is then accomplished by adding the remaining portion as cold water (two thirds of the total volume) to lower the temperature of the dispersion. As the temperature is lowered, HPMC becomes water soluble, resulting in increased viscosity ("hot/cold" techniques)."

from: Williams RO, Sykora MA, Mahaguna V. Method to Recover a Lipophilic Drug From Hydroxypropyl Methylcellulose Matrix Tablets. AAPS PharmSciTech. 2001; 2(2): article 8.

A little too involved for me but would be worth a try perhaps...

edit:
Also found this on a Chem/HPMC supplier website. I've tried #3 with my reseveratrol, it does not seem to work quite so well, perhaps as my resveratrol is much more quantity than the HPMC

HPMC will agglomerate when directly added to water and then dissolve. In this way
it dissolves very slow and hard. Suggested methods as followers:
1) In hot water: add water in container to 1/3 or 2/3 of its content, heated
to over 80°C, because HPMC doesn't dissolve in hot water, it uniformly
disperses in hot water; add cool water or ice to the residual content, stir
and cool down the mixture
2) Powder combination: mix HPMC with identical volume of other powder,
disperses them sufficiently then add water to the mixture result HPMC
dissolves without agglomeration
3) Organic solvent wet: dispersed or wet with organic solvents, such as
ethanol, glycol or oil, then add water can cause HPMC completely dissolves

Edited by malbecman, 17 July 2008 - 05:40 PM.

[hmm]

W seem to be all over the map with figuring the amount of HPMC to use. The original idea was 30 mg HPMC to 90 ml water. Niner pointed out that 3 % of 100 ml water would be 3 grams of HPMC. A recipe just above is mentioning equal measures of HPMC and another powder (RSV).
A couple hours ago I tried mixing 3/8 of a gram of HPMC with 12.5 ml vodka with .3 gram RSV. I ended up with a few clumps of what I supposed to be mainly conglomerated HPMC floating around in the RSV-whitened vodka.

Then I did away with the vodka and placed 1/4 teaspoon RSV with 1/4 teaspoon RSV with 12.5 ml water. Stirring this together caused a thick (and nicely consistent) paste that seemed so close to gelling that I stired in another 1/4 teaspoon of HPMC to see if it might cause an RSV jello-type mixture. It didn't go jello, but maybe if I placed it in the fridge for a few minutes it would have done so. This mixture really looked like the kind of stuff that could be loaded into a gel-cap. However, in the back of my mind is the warning that too much HPMC will actually prevent RSV from getting into your cells.

Which then leads to the question: exactly what amount of HPMC is too much?

[hmm]

OK, went back and tried 12.5 ml water with 1/4 teaspoon RSV and 1/4 teaspoon HPMC and then another 1/4 teaspoon HPMC again. The mixture again appeared smooth and attractive, but (as before) it was opaque white and when I paid attention to its texture in my mouth I realized it did have some lumps.
Ideally the lumps might have been HPMC lumps, but not knowing what kind of lumps I was dealing with led me to go back to dissolving the RSV in vodka first. Next step was to just keep adding HPMC until everything gelled into a single ball. This struck me as possibly being the equivalent of a pill with small RSV particles dispersed and suspended in it. It took about 5/8 of a teaspoon of HPMC to create the ball with 12.5 ml vodka and 1/4 teaspoon RSV.
I believe that a larger portion of RSV could have been dissolved in the vodka and it would then have taken less HPMC to suck the liquid up into a gel. I guess I need to just start eating these gel-clumps and seeing if they alleviate my achilles heel pain as effectively...In the mean time could anyone explain how/why the large proportion of HPMC might prevent bioavailability of the RSV?

[notox]

OK, went back and tried 12.5 ml water with 1/4 teaspoon RSV and 1/4 teaspoon HPMC and then another 1/4 teaspoon HPMC again. The mixture again appeared smooth and attractive, but (as before) it was opaque white and when I paid attention to its texture in my mouth I realized it did have some lumps.
Ideally the lumps might have been HPMC lumps, but not knowing what kind of lumps I was dealing with led me to go back to dissolving the RSV in vodka first. Next step was to just keep adding HPMC until everything gelled into a single ball. This struck me as possibly being the equivalent of a pill with small RSV particles dispersed and suspended in it. It took about 5/8 of a teaspoon of HPMC to create the ball with 12.5 ml vodka and 1/4 teaspoon RSV.
I believe that a larger portion of RSV could have been dissolved in the vodka and it would then have taken less HPMC to suck the liquid up into a gel. I guess I need to just start eating these gel-clumps and seeing if they alleviate my achilles heel pain as effectively...In the mean time could anyone explain how/why the large proportion of HPMC might prevent bioavailability of the RSV?

In my experiments with HPMC I've seen the single ball gelling when the ETHO concentration was high.
I recommed to heat the vodka first then you can dissolve more than the double amout of RSV more
quickly.

Adding cold water (ideally around 0 deg. celsius) in one shot brings the RSV out of solution and
results in extremly fine particles. In my opinion the temperature shock avoids large crystal building
and furthermore the resulting mix is cold enough that you can add a HPMC solution without gelling.

My premixed HPMC solution was clear without lumps and after mixing it with the diluted ETHO+RSV
there are no detectable lumps or visible particles. After waiting 1h there was no settling down of any
particles or phase separation.

Actually I've used a 56% peppermint liquor insted of vodka, which makes the final mix very fresh
and tasty.

The shiny/metallic effect (using lecithin in place of HPMC) I described above occures but to a lower degree
with this mixture.

[hmm]

Thanks notox. I left the clump in its glass in the fridge overnight and peeled it out of the glass and ate it this morning. When I chewed it a little bit I could taste some of the vodka squirting out of the gum-like clump. Then I swallowed it quickly, thinking that I wouldn't chew a pill and I didn't want to disturb whatever stability might have been obtained up to that point.
What is it that leads you to believe that that gum-like state is undesirable for ingesting the RSV? Have the RSV particles been clumped back together at that point?

Edited by hmm, 18 July 2008 - 02:58 PM.

[maxwatt]

Thanks notox. I left the clump in its glass in the fridge overnight and peeled it out of the glass and ate it this morning. When I chewed it a little bit I could taste some of the vodka squirting out of the gum-like clump. Then I swallowed it quickly, thinking that I wouldn't chew a pill and I didn't want to disturb whatever stability might have been obtained up to that point.
What is it that leads you to believe that that gum-like state is undesirable for ingesting the RSV?

I think you probably are using too much HPMC; the "clump" may pass through your gut undigested, carrying the resveratrol with it. Or if it makes it into the bloodstream, the kidneys could excrete it together with the resveratrol. Sirtris used a ratio of HPMC to resveratrol of 3%; still haven't dug up the paper, sorry.

[hmm]

I think you probably are using too much HPMC; the "clump" may pass through your gut undigested, carrying the resveratrol with it. Or if it makes it into the bloodstream, the kidneys could excrete it together with the resveratrol. Sirtris used a ratio of HPMC to resveratrol of 3%; still haven't dug up the paper, sorry.

Thanks maxwatt. So it is clear that the 3% is RSV-to-HPMC. After that ratio is reached, then does it much matter as far as how much water/alcohol/whatever else is added in? (Perhaps the paper will help clarify?)

[hmm]

Since my original system involved mixing (my best guess at) 30 mg HPMC into about 90 ml water, and only adding that mixture to the RSV-alcohol afterward, it wasn't intuitive to me that the important ratio was between the RSV and the HPMC. It still isn't intuitive to me that, for instance, it would be just as effective to place 30 mg HPMC into a quart of water, as long as it was eventually going to be mixed in with 1 gram of RSV. My speculation is that something in the paper led you (maxwatt) to arrive at the conclusion that using 90 ml of water would be optimal...

Edited by hmm, 18 July 2008 - 03:26 PM.

[hmm]

OK, I think I've found something I am comfortable with:
1) Stir 1 gram RSV into 2/3 tablespoon booze in a small shallow bowl as thoroughly as possible
2) Sprinkle 30 mg HPMC (distributing it as evenly as possible) into the mixture and stir that in
3) Microwave bowl/mixture for 15 to 30 seconds to activate the HPMC gelling mechaninsm
4) Place bowl in fridge over night to gel

The end result is not very big -- I think it could fit into a large gelcap. A spoon easily gets almost all of the gelled product out of the bowl, and so far I am using my finger to scrape up a small percentage of remnants.
The possible problem I see is with the microwave heat degrading the HPMC, but this could perhaps be mitigated by using the least amount of heat necessary to activate the HPMC gelling mechanism, and microwaving for the minimum amount of time. (It is listed that a fahrenheit range of 143 to 154 degrees is required to make my F50 HPMC gel to a semi-firm state.) I notice on the Willpowder site there is a methycellulose SGA 150 product (cousin of HPMC?) that will gel to a very firm mass upon reaching a temperature between 100 and 110 degrees. But I don't know if the SGA 150 would duplicate all the great things that HPMC does with RSV...

Edited by hmm, 21 July 2008 - 05:13 AM.

[niner]

I guess I need to just start eating these gel-clumps and seeing if they alleviate my achilles heel pain as effectively...In the mean time could anyone explain how/why the large proportion of HPMC might prevent bioavailability of the RSV?

The problem isn't so much the amount of HPMC but the fact that it has formed a gel. These HPMC gels are used in the pharmaceutical world specifically to make slow-release formulations. The gel holds together in your body and the drug slowly diffuses out of it. This is not what you want for a resveratrol formulation. The 3% HPMC solution that maxwatt mentioned is not the ratio of HPMC to resveratrol, it's the ratio of HPMC to water. It means that 100 grams of solution contains 3 grams of HPMC.

I don't have any HPMC on hand, I recently used up the last of my resveratrol, and in a moment of not having anything better to drink, consumed the last of my Everclear while barbecuing. Since I'm in total reagent crisis, I'll ask the public spirited of you to try this experiment:

First create a 3% HPMC solution using the method malbecman posted. Boil 40 ml water, let it cool to slightly below boiling, and disperse 3 grams HPMC in it with stirring. To this dispersion add 60 ml ice cold water, with stirring. This should form a clear solution without a gel, lumps, or strings. If you don't get that, you might need to play around with the ratio of hot to cold water, or maybe include some crushed ice in the cold water.

Once you get the clear HPMC solution, dissolve some resveratrol in ethanol. You'll get the best results if you obtain a true solution which will be crystal clear with a slight yellowish tint. If you don't have highly concentrated ethanol, you'll need to use more of it. When you have the resveratrol dissolved, pour it into the HPMC solution, with stirring. You should get a milky white suspension that stays suspended. That's the stuff; you just made SRT501, minus the DOSS and plus alcohol. Drink up!

From what notox posted above, it sounds like this is about what he did, and it sounds like it worked. Notox, how much HPMC did you use? I worry that 30mg will not be enough to keep the particles from agglomerating, particularly in the stomach and intestines, but maybe it's ok. Did you get a clear resveratrol solution? How much water did you use? How much resveratrol?

It may be that Sirtris uses more HPMC than notox did so that they can really load up the solution with resveratrol without the patients having to drink large quantities of liquid. The fact that notox saw no precipitation in an hour's time is pretty impressive. That says that HPMC works WAY better than PEG (Miralax). One thing I'd like to know is can we make up a large quantity of HPMC solution and store it in the refrigerator for a reasonable amount of time without gel formation? Maxwatt mentioned somewhere that the DOSS in SRT501 is only there to prevent gelling.

If anyone tries this, let us know how it turns out.

[maxwatt]

I have come to the conclusion that using milk or milk products, such as yogurt or sour cream, is as effective as HPMC and a lot more convenient. My arthritic joints say so.

I am also getting better results taking it mid-afternoon rather than morning or night.

For those who missed the milk discussion earlier in this thread, milk proteins weakly bind to resveratrol (hopefully obviating the molecular clumping problem) and release it easily enough to get it to the body's cells. It is not like green tea (EGCG) where milk reduces availability of the catechins. Milk protein may also sequester resveratrol from glucoronidation and sulfonation to some extent. Micronization isn't necessary with this method, nor is everclear or other ETOH product. Lactose intolerant? Whey protein isolate also works.

Niner: you are clearly suffering withdrawal symptoms. Maybe a 12-step program? Or more resveratrol.

Edited by maxwatt, 21 July 2008 - 01:12 PM.

[missminni]

I have come to the conclusion that using milk or milk products, such as yogurt or sour cream, is as effective as HPMC and a lot more convenient. My arthritic joints say so.

I am also getting better results taking it mid-afternoon rather than morning or night.

For those who missed the milk discussion earlier in this thread, milk proteins weakly bind to resveratrol (hopefully obviating the molecular clumping problem) and release it easily enough to get it to the body's cells. It is not like green tea (EGCG) where milk reduces availability of the catechins. Milk protein may also sequester resveratrol from glucoronidation and sulfonation to some extent. Micronization isn't necessary with this method, nor is everclear or other ETOH product. Lactose intolerant? Whey protein isolate also works.

Niner: you are clearly suffering withdrawal symptoms. Maybe a 12-step program? Or more resveratrol.

As you know, I've been using milk all along and it dissolves the res completely and I have had
excellent results. For Minni I dissolve it in very oily tomato sauce sardines....she won't drink milk....I've tasted it and it tastes great
and as I've reported, she is doing phenomenally well.