Valium 5mg titration - dry or liquid micro taper?

[[Buddie]]

[...], impressive work!

I am fully convinced after reading quite a few of the same papers regarding diazepam solubility in water that it is very, very low. The range I originally cited of 50 - 66 mg / liter is completely reasonable, with some papers showing a little lower, others showing at the top end or a little bit higher, but very consistent. Especially convincing are the more recent studies where they tended to employ more sophisticated analytical tools (especially HPLC).

With this now confirmed, I stand by my full original post. Thanks again for compiling your last post [...] (a screen name I have misspelled a few times by now)! 

[[Buddie]]

Thank you, [...], for your kind words and your input. I agree with your conclusion regarding the poor solubility of diazepam in water.

I have proof-read my previous reply and added further information on whole milk. In particular, to measure it correctly, I have proposed an approximation based on the literature to measure it right out of the fridge instead of waiting for it to settle at room temperature.

For those who are interested, I have prepared a spreadsheet to help with micro tapering via dilution of an oral prescription solution with full fat milk. To make your own copy, click on “Share and export” then “Make a copy”. You will then be able to edit your copy.

Please read the entire section on milk, the conclusion and the caveat in my previous reply before using the spreadsheet.

https://docs.google.com/spreadsheets/d/1LR8pt77N9BCGHJ_rRw5G48aXkN0vaukF9NF_qamxvp8/edit

Please fill in the spreadsheet with the following information:

- the concentration of your oral prescription solution (e.g. 5 mg / mL)
- the amount of diazepam you want to obtain for your taper
- if you are measuring the milk right out of the fridge instead of letting it settle at room temperature first, either:
   - your room temperature in Celsius degrees as measured with a thermometer. Your room temperature must be at or above 18C.
   - it is strongly suggested that the milk be brought up to between 25 to 40C with a gentle warming method (possibly a cup warmer). In this case, instead of indicating your room temperature, indicate the temperature that you plan to attain — between 25C and 30C to attain sufficient solubility of diazepam in the milk —. Use a food thermometer to monitor milk temperature as it warms up.

[[Buddie]]

I have updated my post (reply #59) to reflect the research I’ve done on coconut milk. As with animal milks, it must be homogenized down to sub-micrometer fat globule size, which requires that it contains a surfactant added before the homogenization process.

More information has been added on the homogenization of full fat cow milk.

Direct link to the post: http://www.benzobuddies.org/forum/index.php?topic=267260.msg3372864#msg3372864

[[Buddie]]

Post updated with more information on the solubility of diazepam in purified water, and the safety of ethanol and PG as solvents.

[[Buddie]]

[...], your post #59 was an amazing post which you obviously put a lot of time and effort into researching and writing.  I do have a question about this part:

As of May 2022, the Benzodiazepine Information Coalition’s website states the following about Roxane Laboratories’ 5mg / 5mL diazepam Intensol solution [7]:

For an even more dilute solution and smaller dose reductions, the manufacturer’s diazepam solution can also be safely combined with water.

As with the IV injection monograph, that of diazepam Intensol reads that diazepam is “insoluble in water”. Diluting it creates a suspension, the safety of which with regards to tapering is unknown. Further, the paragraph “Proper use of an Intensol(TM)” in the Dosage and Administration section (bolding mine) [8]:

An Intensol is a concentrated oral solution as compared to standard oral liquid medications. It is recommended that an Intensol be mixed with liquid or semi-solid food such as water, juices, soda or soda-like beverages, applesauce and puddings.

The instructions only mean to say that diazepam Intensol can be consumed with liquid (presumably to mask its taste), but not that it can be diluted with water. A suspension made from mixing the solution with a liquid is not problematic in this case, as diazepam is accurately dosed from the oral solution vial prior to mixing. However, it is unclear whether diluting the solution with water and then dosing from the resulting suspension is accurate.

I may have read your post incorrectly, but are you saying that the Roxane Laboratories’ 5mg / 5mL diazepam Intensol** solution cannot be mixed with water and consumed?  Myself and many other people on the board have done this successfully.

1 ML of the 5mg / 5mL diazepam Intensol** solution is equal to 1 mg of valium/diazepam.  When you mix 1 mL of that solution with 9 mL of water, you have a mix where 1 mL is equal to 1/10 mg of valium/diazepam.  I can easily use a syringe to measure this out to 1/10 of a ml or 1/100 of a mg of valium or .01 mg of valium.  This allowed me to smoothly reduce by very small amounts.   It became more useful as I got to lower daily doses.  Typically I made larger daily cuts  like .04 MG.  But I slowed it down as I got to lower doses since the cuts represented a greater percentage of the total dose.  Of course I used holds when necessary, including some very long holds do to life and outside circumstances.

**I mistakenly and incorrectly used the word Intensol to describe the wrong brand of solution.  It is not the solution that I am using or writing about.  My apologies.

[[Buddie]]

Thank you for your question, [...]. I realize I may not have expressed myself clearly, so I will try to explain my point again.

Once the diazepam oral prescription solution is mixed with food or a liquid it does not dissolve in, like water, it creates a suspension. It is unknown how accurate dosing from this suspension is (i.e. removing some of the liquid for the purpose of tapering) — it may or may not be correct —. In your example (10-fold dilution of the 5mg / 5mL diazepam solution), when you removed 0.1mL with a syringe, you could have been removing 0.005, 0.01, 0.02mg diazepam, or less, or more. We can’t be certain of the exact amount. This is what I tried to convey in the part of my post you quoted.

The reason behind this is that in a suspension, the particles of diazepam can precipitate, especially in water. We do not know if they are each of equal size, nor whether they are spread evenly in the liquid or food. As a result, when you remove some of the liquid with a syringe, the actual amount of diazepam removed depends on the amount and sizes of diazepam particles in the part of the suspension that you draw from with the syringe. You could be removing a “big blob” of diazepam, or the amount you want, or close to nothing. (Of course, shaking the suspension vigorously prior to dosing helps with distributing the particles more evenly, but, to my knowledge, it cannot undo precipitates if they have already formed.)

Importantly, in addition to the uncertainty of dosing from a suspension, dosing accuracy would also have been significantly affected by the accuracy of your 1mL syringe, considering that you removed amounts below 0.5mL. You may be interested in reading the article that [...] referred me to (see the paragraph “syringe accuracy”): https://connect.ashp.org/blogs/dennis-tribble/2019/03/05/the-illusion-of-accuracy

On the other hand, if you first dose the diazepam oral prescription solution with the calibrated dropper or a syringe, then mix it with food or a liquid and consume all of it, the problem of removing an accurate amount of diazepam from the suspension does not apply.

Indeed, many BB members have successfully tapered with diazepam suspensions. Diazepam is particularly forgiving thanks to its long half-life, so small daily variations in dosage caused by tapering accuracy issues may not result in increased symptoms. This may not be the case with other shorter-lived benzodiazepines, though. It is up to every member to decide whether the risks associated with tapering with a suspension instead of a solution are acceptable, and this requires providing them with accurate information on those risks. The sole goal here was to inform interested members on how to preserve a solution when diluting their oral prescription solution, based on the evidence in the literature (see the note at the beginning of the post), as this should improve dosing accuracy when tapering.

I hope this answers your question, [...]. Please let me know if something remains unclear or if you have other questions.

[[Buddie]]

Thank you for your question, [...]. I realize I may not have expressed myself clearly, so I will try to explain my point again.

Once the diazepam Intensol solution (concentrate or not) is mixed with food or a liquid it does not dissolve in, like water, it creates a suspension. It is unknown how accurate dosing from this suspension is (i.e. removing some of the liquid for the purpose of tapering) — it may or may not be correct —. In your example (10-fold dilution of the 5mg / 5mL diazepam Intensol solution), when you removed 0.1mL with a syringe, you could have been removing 0.005, 0.01, 0.02mg diazepam, or less, or more. We can’t be certain of the exact amount. This is what I tried to convey in the part of my post you quoted.

Thanks, [...]. You are fine with the way you expressed yourself.  These are technical subjects and are often difficult to understand.

I think we are talking about two different things here: your experience/situation and my experience/situation.  I reread this thread over carefully.  I knew that you were using a 1mL = 10mg diazepam solution, which is different than the 5 mg per 5 mL solution that I use.  I would consider following [...]' excellent instructions for diluting it that [...] posted on the first page of this thread.   .01 ml of the mix that [...] described may not be perfectly equal to .001 mg, but it should be close enough to be usable and will allow you to make much smaller cuts than .1 mg which should lead to a more comfortable taper.

Even with pills, there are small variances in the amount of medicine contained in each individual pill.  So you are not getting the exact same perfect measurement with each pill.

I found that using the mix of of one part 5mg / 5mL diazepam Intensol*** solution with nine parts water was easier than splitting 2 mg diazepam pills in quarters as I had previously been doing.  The diluted solution I use allows me to make smaller cuts than the method that I had been previously using, and to do so more easily.  This resulted in a much more comfortable taper for me.

I previously wrote: "1 ML of the 5mg / 5mL diazepam Intensol*** solution is equal to 1 mg of valium/diazepam.  When you mix 1 mL of that solution with 9 mL of water, you have a mix where 1 mL is equal to 1/10 mg of valium/diazepam.  I can easily use a syringe to measure this out to 1/10 of a ml or 1/100 of a mg of valium or .01 mg of valium." 

I should have specified that  .1 mL of this mix might not be a perfect .001 mg  of diazepam/valium, but it is close enough to allow me to more easily make smaller cuts than I was able to do by splitting 2 mg diazepam pills.  Likewise, when I am using a 10 ml syringe that has graduations of .1 mL to measure my dose, I might be off by .1 ml by eyesight.  But myself and many other people have found it to work well, and worked worked better for us than trying to cut pills into small amounts when we got to lower daily doses of our taper.

Before using the diluted liquid diazepam, I was using 2 mg diazepam pills to taper.  I found that when I cut them in quarters to try to approximate .5 mg of diazepam, I had problems because as I got lower the .5 mg of diazepam represented a larger percentage cut in my total dosage.  I was fine cutting them in half to allow me to make cuts from 20 mg per day down to 10 mg a day.  When I got to 10 mg a day I started cutting the pill in quarters to allow me to cut by .5 mg.  As I got lower, the .5 mg cuts represented a larger percentage of my total dose. It became an issue when I got down to about 7.5 mg, and got really bad when I got down to 7 mg and below.

In using the 5 mg/5 mL liquid diazepam, here is how I mix it and dosed it.  It might be applicable to your situation, but you would have to  adapt the numbers to the proper ratio of your 1mL = 10mg diazepam solution.  [...] posted perfect examples of this.  I am using the numbers that are in this example for illustrative purposes.  I use a 10 ml syringe and a 160 ml jar.  I use the 10 ml syringe to draw 10 ml of the 5 mg/ 5 mL liquid diazepam and squirt it into the jar.  Then I use the same syringe to draw 10 ml of filtered water into the jar.  I do this 9 times with the water in the syringe so that I have a jar with 10 ml of the liquid valium and 90 mL of water.  I seal the jar and shake it after mixing, and give it a few shakes before daily use.  For my daily dosage, I use the 10 ml syringe to draw the dosage and squirt it into my mouth.

I will typically make a 4 - 5 day supply of this at a time. 

**I mistakenly and incorrectly used the word Intensol to describe the wrong brand of solution.  It is not the solution that I am using or writing about.  My apologies.

[[Buddie]]

Regardless of how concentrated the solution is, what eventually matters is the amount of diazepam that is held in water once the solution is diluted.

Solubilities at 25C reported for diazepam range from 40–50 mg/L; this means that 1mg diazepam should be diluted at the very least in 25mL water. When the 5mg / 5mL diazepam solution is diluted 10-fold — which is what you do — 1mg diazepam (1mL solution) is held in only 9mL water. The 1mL solution does contain PEG and PG, per the manufacturer’s monograph, but not in quantities sufficient to dissolve 1mg diazepam in this amount of water (see the part on PEG-PG-water mixtures in my post #59). Precipitation likely happened unbeknownst to you, resulting in inaccurate dosing when you removed some of the suspension for tapering.

I invite you to read once more [...]’s post where he mentions the importance of having a sufficient “sink factor” to prevent precipitation. A 25-fold dilution of the 5mg / 5mL diazepam solution provides a 1x sink factor, as it just allows attaining the solubility of 40 mg/L (at 25C), whereas a 250-fold dilution would provide a satisfying 10x sink factor but is impractical for tapering. The sink factor is not merely a theoretical consideration but a serious practical issue for pharmaceutical laboratories in the development of liquid formulations, as demonstrated by their choices of solvents and their quantities. http://www.benzobuddies.org/forum/index.php?topic=267260.msg3372213#msg3372213

This part of your post is erroneous in that you made a diluted suspension, not a diluted solution:

I found that using the mix of of one part 5mg / 5mL diazepam Intensol solution with nine parts water was easier than splitting 2 mg diazepam pills in quarters as I had previously been doing.  The diluted solution I use allows me to make smaller cuts than the method that I had been previously using, and to do so more easily.  This resulted in a much more comfortable taper for me.

As I have explained in my reply to your previous post and am reiterating here, this is the crux of the matter.

Indeed, small variations in dosage may not matter for diazepam (long half-life), and, as you point out, pills vary in their actual vs stated amount of diazepam. We do not know the extent of this variation, although given that pill batches are subject to strict quality control, as imposed by pharmaceutical regulations to manufacturers, it may be lower than the extent of the tapering accuracy error when diluting 10-fold the 5mg / 5mL diazepam solution. Further, it should be reminded that syringe accuracy contributes to this error too (although this is true whether the solution is diluted or not, and micro tapering with pills is affected by the accuracy of the scale used).

Once again, the decision of making a suspension vs. a solution when diluting an oral prescription solution comes down to every member. Per your replies, you have made yours and I am glad that it has been working well for you. Other members may wish to do otherwise.

[[Buddie]]

Post updated with a better (experimentally verified & peer-reviewed) estimation of the expansion of whole milk out of the fridge. I have modified the spreadsheet accordingly. (This model yields very similar results to the previous one.)

Edit (22 May):
- expanded the section on MCT oil with two relevant studies, which also apply to coconut milk, and the label information about decreased and slowed absorption of diazepam when having it with a moderate fat meal
- edited the section on coconut milk and the conclusion to recommend light coconut milk instead of full fat (per the information on the label)
- added annex B, a list of brands of coconut milk with polysorbate
- added all missing links to references

[[Buddie]]

Once again, the decision of making a suspension vs. a solution when diluting an oral prescription solution comes down to every member. Per your replies, you have made yours and I am glad that it has been working well for you. Other members may wish to do otherwise.

That is correct.  Everyone is free to choose their own method that they think best suits them.  Myself and many other people who have been on the board have used the 5mg / 5mL diazepam Intensol*** solution mixed 1 part solution to 9 parts water to successfully taper.


**I mistakenly and incorrectly used the word Intensol to describe the wrong brand of solution.  It is not the solution that I am using or writing about.  My apologies.