Author Topic: Valium 5mg titration - dry or liquid micro taper?  (Read 3321 times)

[Buddie]

Re: Valium 5mg titration - dry or liquid micro taper?
« Reply #50 on: May 09, 2022, 08:31:25 pm »
Thank you for your replies, [...].

I admit the scale was a bit of a panic buy, but planning ahead, this is actually a good plan B that I want to have. In case the oral prescription solution goes out of stock again, I can switch to pills and vice-versa. (I don’t feel a difference between the pills and the solution.)

Yesterday was the first time I diluted the solution and it did look clear and homogeneous, even after sitting for nearly 3 hours in the mixing recipient. I did shake it again before removing the excess 1mL. I suppose I can continue that way for some time and see if crystallization happens at some point.

Indeed, the density of the oral prescription solution is not indicated on the leaflet. Weighing .75mL of solution is a good idea, but if it is indeed in the ballpark of 750mg, the scale must be precise enough to measure 10mg / 0.01g (which it hopefully really is) to allow for 0.1mg diazepam decrements.

Edit: pictures of the diluted solution: https://imgur.com/a/afGBCbf

Here, it had been prepared around 20 minutes prior and had since been sitting still. It looks clear / homogeneous. On the second picture, although it is hard to see, there are some small bubbles at the top of the solution floating against the glass.
« Last Edit: May 09, 2022, 10:01:55 pm by [Buddie] »
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[Buddie]

Re: Valium 5mg titration - dry or liquid micro taper?
« Reply #51 on: May 09, 2022, 10:00:49 pm »
[...]: Your diluted liquid looks fine to me. I hope [...]’s comments did not cause you undue concern.  I’m certain he is trying to be helpful, but he is new to the forum and may not be aware that many members have used diluted commercial diazepam solutions to taper.  He also may not have read our Titration: FAQs where we make it clear that making modifications in commercial dosage forms conveys risk.  The approach you and I have been discussing minimizes the known risks (e.g. your diluted liquid may be a suspension not a true solution so ‘best practices’ for using suspensions are suggested; the stability of your diluted liquid over time is unknown so making small batches is suggested).
Suggestions, opinions and/or advice provided by the author of this post should not be regarded as medical advice; nor should it substitute for professional medical care. Consult your doctor before making any changes to your medication. Please read our Community Policy Documents board for further information.

[Buddie]

Re: Valium 5mg titration - dry or liquid micro taper?
« Reply #52 on: May 09, 2022, 10:07:53 pm »
Ah, there was cause for concern, theoretically, but I’m fine now. You are right about the disclaimer, [...], and indeed in practice the diluted solution looks OK.

I am very glad for your help. Chemistry and specifically pharmacology are tricky to navigate for the layperson that I am (although I have a scientific background).
Suggestions, opinions and/or advice provided by the author of this post should not be regarded as medical advice; nor should it substitute for professional medical care. Consult your doctor before making any changes to your medication. Please read our Community Policy Documents board for further information.

[Buddie]

Re: Valium 5mg titration - dry or liquid micro taper?
« Reply #53 on: May 09, 2022, 10:55:10 pm »
To address [...]’s concern, it would seem to me that adding 5-10mL alcohol (say vodka, 40% ethanol by volume) and then the remaining distilled water fixes the issue? Diazepam is much more soluble in ethanol (1g dissolves in 16mL of 95% ethanol). 5-10mL vodka, even if only 40% ethanol, should be plenty enough.

Edit: my calculation gives that 38mL vodka (40% ethanol) dissolves 1 gram diazepam, so 0.04mL dissolves 1mg diazepam. A very tiny amount of 0.3mL vodka should suffice to dissolve 7.5mg.

In fact, the leaflet states that the oral prescription solution contains 40% ethanol by volume, so exactly the computed amount of 0.04mL per 1mg diazepam (8mL ethanol total in the 20mL vial, at 10mg / mL).

So I’m left confused. What’s the matter with diluting with distilled water, since the diazepam is already dissolved in the alcohol contained in the oral prescription solution?

Source: PubChem entry on diazepam https://pubchem.ncbi.nlm.nih.gov/compound/Diazepam#section=Solubility
Quote
One gram of diazepam dissolves in about 350 mL of water, in approximately 15 mL of 95% ethanol, or in approximately 2 mL of chloroform.
Lewis, R.J. Sr.; Hawley's Condensed Chemical Dictionary 15th Edition. John Wiley & Sons, Inc. New York, NY 2007., p. 389
« Last Edit: May 10, 2022, 12:44:55 am by [Buddie] »
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[Buddie]

Re: Valium 5mg titration - dry or liquid micro taper?
« Reply #54 on: May 10, 2022, 01:14:14 am »
If memory serves, your commercial diazepam solution contains three solvents — ethanol, propylene glycol, and water.  In my opinion, you do not need to change the approach we’ve discussed.  However, this is your taper, so it’s your call.  If you wish to continue discussing alternatives with [...] — or any other member — please do so. I am sending all best wishes your way for a successful taper!
« Last Edit: May 10, 2022, 01:33:04 am by [Buddie] »
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[Buddie]

Re: Valium 5mg titration - dry or liquid micro taper?
« Reply #55 on: May 10, 2022, 09:05:15 am »
I am curious to understand the issue, if anything. Lack of knowledge of chemistry and cognitive impairment make it difficult.

I have read the discussion between BB members Aweigh and SG57 about the solubility of diazepam in an alcohol/water mixture on this thread: http://www.benzobuddies.org/forum/index.php?topic=110496.msg1708227#msg1708227

SG57 makes the following assumption. All hinges on it being true or false:
Quote
(…) Jouyban has measured the solubility on water for A, K, V, Librium, and X and they are as follows:

A - .05mg/ml
K - .03mg/ml
V - .04mg/ml
Lib - .11mg/ml
X - .04mg/ml

I'm thinking the benzo dissolves into the alcohol then, as it is diluted with water, the water has just enough solubility to keep it in solution.  After all, 100ml of water will hold 5mg A, 3mg K, 4mg V, 11mg[...], and 4mg X, right?  I'm a mechanical engineer and have just enough familiarity with chemistry to be dangerous, so I am a little unsure of my conclusion.  What do you think?  Also, I think the method can be extended to K.

On the other hand, Aweigh believes that whichever benzo would not remain in solution in an alcohol/water mixture with mostly water but would instead precipitate:
Quote

If you dissolve a benzo in a small amount of alcohol, it will go into solution, although you may not notice it because about 99% of the tablet is insoluble. If you then add a quantity of water to that solution, it will become too dilute to hold the benzo, which will come back out of solution, also known as precipitation. If you look carefully through transmitted light and know what to look for, you can see it happening. I keep my alcohol solutions fairly concentrated (~ 0.2 mg/mL) and only dilute them with water right before consumption. Water accelerates the decomposition of benzos in solution — or dry, for that matter.
Quote
I don't think the benzo stays in solution, the data indicate that it wouldn't. I think it comes out and the reason people are able to make it work is that it precipitates as particles small enough to remain in suspension in the water. I know a very sophisticated and knowledgeable taperer who is coming off of several psych meds and does them all in distilled water. She says she likes that better than milk because she can see what settles out and what remains in suspension.

If I understand correctly, [...] explains that SG57’s assumption is wrong and shares Aweigh’s concern that precipitation is bound to occur (in the form of crystallization). Is that correct, [...]?

In this case, I circle back to asking whether adding more alcohol to the mixture may help keep diazepam in solution. (e.g. for 0.75mL oral prescription solution, 30mL vodka at 40% ethanol + the remaining 44.25mL distilled water).
« Last Edit: May 10, 2022, 11:27:45 am by [Buddie] »
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[Buddie]

Re: Valium 5mg titration - dry or liquid micro taper?
« Reply #56 on: May 10, 2022, 09:41:19 am »
Here is a quick search of the literature available on the solubility of diazepam in various solvents or aqueous mixtures. I do not know how to derive the mg/mL solubility from these articles, but I think either of you may be able to, and see what may be practically feasible based on these data.

https://pubs.acs.org/doi/10.1021/je3009842

https://www.sciencedirect.com/science/article/abs/pii/S0021961417301246?via%3Dihub

Interestingly, Jouyban et al also found that adding sodium lauryl sulfate (an emulsifying agent / food
additive) enhances the solubility of diazepam in an ethanol + water mixture by 7733-fold. They argue that SLS reduces the quantity of organic solvent (ethanol) needed — which is desirable in our case —. https://link.springer.com/article/10.1007/s10953-014-0253-5

Extract from the Results section of the article (ambient temperature 25C):
Quote
The aqueous solubility of DZP (1.50 x 10^-4 mol.L-1) is the minimum value and the solubility in ethanol + water (phi_1 = 0.80) and SDS of 6.4 x 10^-3 mol.L-1 (1.16 mol.L-1) is the maximum observed value among the investigated systems. The enhancement factors for ethanol + SDS, ethanol alone and SDS alone are 7733, 900, and 11, respectively. The enhancement factors of ethanol + PVP and PVP alone (0.01 g.mL-1) are 1,925 and 2, respectively. [28]

SLS has a molar mass of 288.38 g/mol, so 6.4 x 10^-3 mol/L works out to 1.8 to 1.9g/L. For instance, this is about 200mg in 100mL solution, which should be safe for human consumption (according to https://ecommons.cornell.edu/bitstream/handle/1813/56141/sodium-lauryl-sulfate-MRP-NYSIPM.pdf?sequence=1 ). However, I do not know if the solution remains stable.

In practice, one could add small amounts of vodka (e.g. 20mL / 100mL diluted solution) and SLS as per the above, and I believe the diazepam would then likely remain in solution.

(Food or pharma grade SLS is relatively inexpensive, e.g. $81 for 125g https://www.spectrumchemical.com/sodium-lauryl-sulfate-fcc-s1332)

Edit: warning: there are significant concerns with the dermal toxicity and inhalation of SLS. It should be operated with under safe conditions only (e.g. fume hood and appropriate gloves).
« Last Edit: May 10, 2022, 02:46:21 pm by [Buddie] »
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[Buddie]

Re: Valium 5mg titration - dry or liquid micro taper?
« Reply #57 on: May 10, 2022, 12:59:44 pm »
EDIT:

I might have made a mistake. I relied on two PubChem  listings for solubility that are inconsistent with other literature sources. [...] listed one reference, also from PubChem, that suggests wayyyy greater solubility of diazepam in water than the references that I cited. I don't know which is correct now, and the primary literature available for free is scant. This is pretty odd to have wildly conflicting solubility data reported in the literature.
« Last Edit: May 10, 2022, 10:15:07 pm by [Buddie] »
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[Buddie]

Re: Valium 5mg titration - dry or liquid micro taper?
« Reply #58 on: May 10, 2022, 01:30:01 pm »
I am not sure this is correct, [...].

In this study, 3mL of 5mg / mL commercial solution (i.e. 15mg diazepam) was diluted to 50mL with distilled water. The authors found that the solubility of diazepam in this diluted solution was 0.041mg / mL at 25C (or 41mg / L), which equates to 2mg / 50mL. Thus, 13mg diazepam did not dissolve.

To dissolve the entire 15mg diazepam, the volume required for dilution is 15 / 0.041 = 365mL.

As a result, the authors recommend:
Quote
The aqueous solubility data for diazepam corroborate other reported values and are tantamount to recommending against less than a 1:100 volume dilution of diazepam injection when compounding i.v. admixtures.

Meaning that the 3mL solution should be diluted to at least 300mL with distilled water.

They note that their result — the solubility of 41mg / L — corroborate previous reports on the (poor) solubility of diazepam in water, which are likely to be those you found on PubChem (50 to 66mg / L). It is also the exact same value as that determined by Jouyban et al (https://pubs.acs.org/doi/10.1021/je3009842).
« Last Edit: May 10, 2022, 02:03:39 pm by [Buddie] »
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[Buddie]

Re: Valium 5mg titration - dry or liquid micro taper?
« Reply #59 on: May 12, 2022, 08:11:55 am »
Important note: this post addresses making a diluted diazepam oral solution from a more potent oral solution. If you are fine with making a suspension out of the potent solution, you may use water or other liquids to do so. For more information on the differences, please read [...]’s post: http://www.benzobuddies.org/forum/index.php?topic=267260.msg3372213#msg3372213

After many hours of research and helpful discussions with [...], the best solvent in terms of solubility, tolerability, safety, manipulation and cost turns out to be homogenized whole milk, thanks to the lipophilic nature of diazepam.

[...] and I sought a solubility around 10-fold that of the concentration of the diluted solution (0.1 mg/mL), i.e. 1 mg/mL.

The solvents we investigated were: purified water, propylene glycol, ethanol, polyethylene glycol (either 200, 400 or 600), PEG-PG mixtures in various ratios with or without water, dimethyl sulfoxide (DMSO), medium chain triglyceride (MCT) oil (e.g. Kollisolv MCT 70), cow milk (skim and whole) and coconut milk (full and reduced fat).

Except for water and milks, none of these are safe for human consumption or usable at the amounts required for 100-fold dilution.

All the solubilities below are given for an ambient temperature of 25C.

Purified water

The Handbook of Aqueous Solubility Data (2nd ed., 2010) lists solubilities between 31 mg/L and 66 mg/L (at 25C), compiled from 6 references in the literature. [1] As discussed previously, the solubility likely leans towards 40-50 mg/L, considering that solubilities in this range have been replicated by 5 studies cited in the handbook and a further two later references [1, 2, 3]. I am not sure where the solubility of 3 g/L (1g in 333mL) listed on PubChem originates from, but it is rather dubious because of the replicated finding.

More concerning is the fact that even when diazepam is highly diluted with water, it cannot be guaranteed that it does not precipitate. The only positive indication of proper dissolution is the clear aspect of the liquid, which is necessary but not necessarily sufficient. [4]

As a consequence of precipitation in water, diazepam can cause the formation of blood clots when administered intravenously (IV) along with other drugs rather than separately (directly into the vein). [5] The monograph explicitly states that it is “insoluble in water” and instructs in the Dosage and Administration section: “Do not mix or dilute diazepam with other solutions or drugs in syringe or infusion container”. Instead of water, IV bags of diazepam contain 40% propylene glycol and 10% ethanol per volume as solvents. [6]

As of May 2022, the Benzodiazepine Information Coalition’s (BIC) website states the following about West-Ward’s 5mg / 5mL diazepam solution (formerly Roxane Laboratories’ solution) [7]:

Quote
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, the former monograph of the 5mg / 5mL diazepam solution (which is the one that BIC based its recommendation on) 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 on proper use of the solution in the Dosage and Administration section (bolding mine) [8]:

Quote
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 the diazepam solution 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.

Propylene glycol (PG)

Propylene glycol has a solubility of 7.67 mg/mL as a monosolvent and reaches the desired solubility as a 60-40 PG-water mixture (1.57 mg/mL) [2, 3], resulting in a dose of 62.4g per 100mL diluted solution.

Based on a review of the literature, the European Medicines Agency updated in 2017 the information that must be provided in the package leaflets of medications containing PG. They concluded that a PG intake of 500mg/kg/day or above requires medical monitoring (e.g. 35g for a 70kg / 155lb person), “can have the same effects as drinking alcohol and increase the likelihood of side effects” and is associated with the following adverse events [9]:

Quote
Various adverse events, such as hyperosmolality, lactic acidosis; renal dysfunction (acute tubular necrosis), acute renal failure; cardiotoxicity (arrhythmia, hypotension); central nervous system disorders (depression, coma, seizures); respiratory depression, dyspnoea; liver dysfunction; haemolytic reaction (intravascular haemolysis) and haemoglobinuria; or multisystem organ dysfunction, have been reported with high doses or prolonged use of propylene glycol.

Clinically, PG intake can range up to 69g/day when administered IV (amount of PG in an IV bag of lorazepam), which, per the above, can be severely toxic. [9] It is also important to note that this amount is not ingested (orally) at once but delivered over the course of a day through continuous injection.

Overall, the amount of PG required for 100-fold dilution poses a significant health risk, especially with prolonged use, and it should be avoided.

Ethanol

Although ethanol is a common solvent for diazepam, the concentration in the diluted solution should be min. 40% (v/v) for a solubility of 1.90 mg/mL [10]. Unfortunately, for 20 to 100mL diluted solution, this is quite a high intake of alcohol (16-80g ethanol).

It may be considered when ingesting no more than 15mL diluted solution, i.e. 12g ethanol, which is slightly under the CDC’s definition of a standard drink (14g ethanol, i.e. 1.5 fl oz 80-proof / 45mL 40% ethanol by volume beverage, such as vodka). [11]

Note that the CDC recommends that alcohol should not be consumed everyday, and on the days that it is, women and men should consume no more than 1 and 2 standard drink(s), respectively. [11]

Some diazepam oral prescription solutions are formulated with 40% ethanol by volume. Interestingly, in ethanol-water mixtures, there is a sharp increase in solubility between 30% (0.56 mg/mL) and 40% (1.90 mg/mL) [10]. This is the concentration at which diazepam is the most preferentially solubilized by ethanol [12, 13], which may explain this choice.

A rule of thumb that is commonly shared among BB members is to dissolve 1mg diazepam in 2mL vodka (40% ethanol by volume / 80-proof). This is not supported by the evidence: only 0.56 mL/mg is required, as per the above. However, this rule is usually given in the context of liquid tapering by crushing diazepam tablets, rather than diluting a prescription oral solution, and it is not known how excipients in the tablets may affect the solubility of diazepam in ethanol.

Polyethylene glycols (PEG) 200, 400, 600

PEGs 200, 400, 600 achieve maximal solubility out of the solvents listed above, respectively: 7.67, 25, 27.42 mg/mL as monosolvents. To achieve the desired solubility, they can be mixed 60-40 PEG-water: 1.17 mg/mL (PEG 200), 1.57 mg/mL (PEG 400). No data is available for PEG 600-water (only for a ternary mixture with PG). [2, 3]

While PEGs are nontoxic even when ingested in large doses, it has been shown that PEGs with these molecular weights accelerate small intestine transit and thus very likely reduce either or both the rate and extent of absorption of diazepam [14]. Further, they can inhibit CYP3A4, which is a key enzyme for metabolizing diazepam [15].

Although they do not seem to be laxative at a dose of 10g [14], unlike PEG 3350 (Movicol / Miralax, which respectively contain 13 and 17g PEG per sachet), it is not known if they cause gastrointestinal upset acutely at large doses (here, at most 60g).

As for chronic use, rats that underwent PEG 400 gavage for 13 weeks seemed to have developed slight but reversible renal toxicity, had loose faeces and increased water consumption [16]. In rats and monkeys who were administered PEG 200 orally for 13 weeks, only monkeys developed small kidney stones. [17]

Note that for ease of manipulation, only PEG 200 or 400 could have been considered as they are liquid at room temperature, unlike PEG 600 which has a melting point of 20-25C. PEG 400 is also easier to purchase as a private customer (through vaping liquid shops).

The combination of PEGs with PG and water as studied by Jouyban’s group shows that a 20-40-40 PEG 400-PG-water combination attains the desired solubility (1.13mg / mL) [3], but this concentration of PG remain excessive for 100-fold dilution with regards to human consumption.

Dimethyl sulfoxide (DMSO)

DMSO inhibits CYP3A4 and there are health safety concerns with its usage. [18]

Medium chain triglyceride (MCT) oil

MCT oil is sold as a solvent for lipophilic compounds (e.g. BASF’s Kollisolv MCT 70).

The administration of diazepam in soft capsules containing MCT has been studied, and appears to provide more uniform plasma concentrations across repeat doses than tablets. In rodents, it was shown that diazepam is absorbed mostly in the stomach while it is retained in MCT (i.e. still dissolved), rather than in the small intestine. Only a small part of diazepam is released into the aqueous phase produced by digestion, where its solubility is significantly enhanced by lipid digestion products and where it thus remains fully dissolved (both in fasted and non-fasted conditions) [19, 20]. Diazepam should therefore not precipitate when administered orally with MCT.

However, as MCT oil is very caloric (approx. 900kcal / 100mL), and considering that drinking pure oil is difficult, it is practically infeasible to use it as a solvent to dilute an oral prescription solution. Importantly, it should also be noted that the monograph for Valium tablets cautions about delayed and reduced absorption when they are taken with a “moderate fat meal” [21]:

Quote
Pharmacokinetics
Absorption

After oral administration >90% of diazepam is absorbed and the average time to achieve peak plasma concentrations is 1 – 1.5 hours with a range of 0.25 to 2.5 hours. Absorption is delayed and decreased when administered with a moderate fat meal. In the presence of food mean lag times are approximately 45 minutes as compared with 15 minutes when fasting. There is also an increase in the average time to achieve peak concentrations to about 2.5 hours in the presence of food as compared with 1.25 hours when fasting. This results in an average decrease in Cmax of 20% in addition to a 27% decrease in AUC (range 15% to 50%) when administered with food.


While MCT are rapidly digested compared to long chain triglycerides, which a meal would contain, and the absorption rate and extent may differ slightly between diazepam tablets and an oral solution, this likely applies to the latter and goes against using MCT oil as a solvent for dilution.

Cow milk (homogenized, skim and whole)

Diazepam binds at 69% to skim milk (0.75% fat content) and 83% to whole milk (3.5%), specifically and mainly to casein; the former attains a solubility of around 0.2 mg/mL and the latter a better solubility of around 0.37 mg/mL (and up to 0.6 mg/mL at 40C) [22, 23]. Greater solubility in a medium richer in fat is as expected, given the lipophilic nature of diazepam.

It is important for whole milk to be homogenized. Milk is an emulsion (mixture of oil and water) and homogenization reduces the size of milk fat globules, down from about 4 micrometers (um) on average, spanning from 2.5 to 5.7 um on average, to 0.4-0.5 um on average. [24, 25, 26] This prevents the fat globules from separating from the water and disperses them more evenly inside it, which enhances the solubility of diazepam.

Of particular importance is that the milk must be brought up to the same temperature every time it is measured, and the chosen temperature must be between 25C to 40C (diazepam remains stable at high ambient temperatures even after a long time of exposure [27]). A food thermometer suffices to monitor milk temperature. This is necessary to increase the solubility of diazepam (only 0.17 mg/mL at 10C in whole milk) [22] and to stabilize the volume of milk, given that it expands (i.e. its density decreases) as its temperature rises [28, 29, 30, 31, 32].

Indeed, when taken out of the fridge and let to sit, 100mL whole milk expands by about 0.5 to 0.8mL at 25C and up to more than 1mL at 40C. This expansion can reverse one step of the micro taper (decrements of 1mL / 0.1mg diazepam).

If a food thermometer is not available, it is possible to estimate the volume of milk to measure right out of the fridge using only a regular thermometer. If the fridge is at temperature T_f, the volume out of the fridge, denoted V_mf, will then expand to the desired volume V_m at room temperature T (e.g. V_m = 99mL milk for 1mL diazepam). It can be estimated as [[...]]:

V_mf = (V_ds - V_sol) * exp(0.0000889277 * (t_f^2 - t^2) - 0.0000008992 * (t_f^3 - t^3) + 0.00000000447904 * (t_f^4 - t^4))

where:

- t_f = T_f + 5.14
- t = T + 5.14
- V_ds is the total volume of diluted solution (e.g. 100mL for 10mg diazepam)
- V_sol is the volume of oral prescription solution (e.g. 1mL for 10mg diazepam and a 10 mg/mL solution).

Alternatively, if the fridge temperature is between 4 to 4.4C and the room temperature is 18C or above, the following estimation can be used:

V_mf = (V_ds - V_sol) * 0.968 * (1.031 - 0.00038 * (T-18))

For the derivation of the second estimation and more information on the density of full fat milk, please see annex A below.

However, it may be unnecessary to adjust for expansion if the estimation of milk to measure out of the fridge falls within the tolerance of the graduated cylinder around a milliliter graduation. For instance, with a tolerance of +/- 0.25mL, the estimation gives 49.77mL milk to measure out of the fridge for it to expand to 50mL at 25C, which falls within the tolerance of the cylinder at the 50mL graduation (49.75 to 50.25mL). Thus, 50mL milk could instead be measured directly out of the fridge.

Note that besides temperature, the natural variation in the composition of milk affects its density. This is influenced by external factors such as cow breed, feed, seasonality and location / sourcing [30, 34]. To attempt to reduce variance in composition, it is preferable to consistently buy milk sourced from the same location (same farm or region/province/state).

Coconut milk

Although there is no data available on the solubility of diazepam in coconut milk in the literature, it may be a suitable dairy-free alternative given that it is rich in MCT (it could somewhat be regarded as “diluted” MCT oil).

Retail coconut milk typically ranges from 17 to 21% fat content (cf. annex B). Given that the absorption of diazepam is slowed and decreased when taken with a moderate fat meal (cf. MCT oil), it would seem sensible to use light / reduced fat coconut milk with 5-10% fat content (at most approx. 100 kcal for 100mL). Diluting full fat coconut milk with water is not recommended as this would decrease the concentration of the added emulsifying agent, which is required in sufficient quantity (explanation below).

A major difficulty is the large size of fat globules in non-homogenized and homogenized coconut milks without additives (volume-weighted averages: 12.1um and approx. 10um, respectively). [35] These are 2 to approximately 5 fold, and on average 3 to 3.5 fold, larger than in raw and homogenized cow milk. Homogenizing coconut milk slightly reduces the average size of fat globules, but not to a sub-micron level, and has the side effect of causing them to flocculate. [24, 25, 26, 35]

However, when small-molecule surfactants (emulsifying or thickening agents) such as polysorbate (Tween) 20 or sodium dodecyl/laureth sulfate (SDS) are added prior to homogenization, at a concentration of no less than 1% by weight, flocculation does not occur and homogenization becomes as efficient as that of cow milk (sub-micron globules: 0.25-0.44um vs 0.37-0.49 um on average, respectively). [25, 35]

On the other hand, when added to non-homogenized milk, they are minimally effective; when added after homogenization, they can reverse some of the flocculation induced by homogenization (though SDS at concentrations 0.5% and greater by weight actually causes some flocculation) but they do not reduce fat globule size. [35]

Coconut milk must therefore be homogenized with a surfactant added before homogenization to improve the solubility of diazepam. While neither homogenization, or the lack thereof, nor the step at which the surfactant is added are publicly disclosed (e.g. on the nutritional informational label), this study strongly suggests that the presence of a surfactant in retail coconut milk indicates that the latter has been homogenized and that the former was added prior to homogenization (as per the above).

Tetra Pak’s Coconut Handbook states that when fresh coconut milk cannot be directly supplied to a market because of perishability, for instance the US, Europe and Oceania, it is made by recombination. In the recombination process, additives such as emulsifiers and thickeners are added first in a large tank; afterwards, at the end, “[a] homogenization step is usually incorporated in the pasteurizer (…)”. This follows the above order. [36] The lead author of [35] confirmed this (personal communication):

Quote
To my knowledge processed coconut milk products (canned, UHT) are homogenized with emulsifier. Homogenization is conducted after mixing with additives, prior to heat treatments.

Unfortunately, while carboxymethyl cellulose and SDS have been shown to enhance the solubility of diazepam [37, 38], guar and xanthan gums are two other common surfactants in retail coconut milk for which this has not been studied. These gums are large molecules, thus it is not known if the results for SDS and Tween 20 apply to those. It can be assumed that they are unlikely to interfere with diazepam, especially at the small concentrations used in coconut milk.

Some brands of coconut milk containing polysorbate are listed in annex B.

Regarding the thermal expansion of coconut milk, it is probably more pronounced than that of whole cow milk due to its higher fat content. However, only data on its density between 60 to 80C has been published in the literature. [39] It is therefore not possible to provide an estimation of the thermal expansion of coconut milk.

Coconut milk must be brought up to the same temperature every time it is measured (between 25-40C), especially when taken out of the fridge as the fat may solidify at a cold temperature.

Conclusion

In conclusion, at a temperature of 25C, diazepam is about 9 to 10-fold more soluble in homogenized whole milk than in water. Homogenized whole milk enables the dilution of an oral prescription solution in a safe, practical and low cost way, and should be recommended for this purpose instead of water, which is not an appropriate solvent for diazepam.

Light coconut milk (5-10% fat content) may be a suitable dairy-free alternative given its fatty acid composition (mostly MCT), but it must be homogenized, contain an emulsifier (see annex B for relevant brands), and brought up to the same temperature (between 25-40C, measured with a food thermometer) every time it is used.

Caveat: the stability of diazepam in milk is unknown. Preparing and storing batches of diluted solution, rather than preparing a dose per day and consuming it right away, cannot be recommended.

Whether fatty milks other than whole cow milk and coconut milk can be used is unknown (e.g. almond, cashew or hazelnut milks).

Annex A: influence of temperature on the density of whole cow milk

The literature provides the following densities for raw, homogenized and pasteurized whole milk [28, 29, 30, 31, 32, [...]]:

- fridge temp, 4 to 4.4C: 1.033 to 1.036 g/L
- typical room temperature, 20C to 22.7C: 1.029 to 1.031 g/L
- warm day, 28 to 30C: 1.024 to 1.028 g/L
- hot day, 39 to 40C: 1.020 to 1.023 g/L

Pasteurization and homogenization do not affect the density of full fat milk, while sterilization has a small impact that is negligible in our case. [40]

The density of whole cow milk decreases linearly between 18C and 40C [17], so it can be approximated to be 1.028 g / L at 25C on average. Hence, the expansion factor when milk is taken out of the fridge and let to sit is at least 1.033 / 1.028 = 1.0049 at 25C. At 40C, it is at most 1.036 / 1.020 = 1.016.

The volume of milk to measure right out of the fridge, V_mf, expands to the desired volume V_m at room temperature T as per Eq. (1):

V_mf = c_T * (V_m - V_sol) (1)

where, as above, V_ds is the volume of diluted solution, V_sol is the volume of oral prescription solution, T is the reading of the room temperature given by the thermometer. c_T is the coefficient of expansion at temperature T given by:

c_T = d_T / d_Tf (2)

where Tf is the temperature of the fridge, and d_T and d_Tf are the densities of full fat milk at temperatures T and Tf, respectively.

Typically, Tf is constant and in the range of 3 to 4.4C (per the FDA’s recommendation [41]). Assuming that the bottle of milk is stored on the door of the fridge (usually a warmer area, i.e. closer to 4.4C), we chose the lowest of milk densities between 4 to 4.4C given above, and Eq. (2) yields:

c_T = d_T / 1.033 = 0.968 * d_T

Eq. (1) can then be rewritten as:

V_mf = 0.968 * d_T * (V_ds - V_sol) (3)

Assuming that T is between 18C and 40C, the linear regression derived in [13] allows to approximate the milk density at room temperature:

d_T =  1.031 - 0.00038 * (T - 18) (4)

Combining Eqs. (3) and (4) yields:

V_mf = 0.968 * (1.031 - 0.00038 * (T-18)) * (V_ds - V_sol)

which is the desired approximation.

Annex B: brands of coconut milk with polysorbate

Last revised: 22 May 2022

The most common polysorbate used for coconut milk seems to be polysorbate 60, often denoted E435 on the label. Other polysorbates are polysorbate 20 (E432), polysorbate 40 (E434), polysorbate 65 (E436) and polysorbate 80 (E433). Check the label for these name and/or codes.

If you are able to, the easiest way is to go to a local Asian or Thai supermarket. You may also search for “coconut milk + E43x” (x between 2 to 6) or “coconut milk + polysorbate” in your language on a search engine such as Google.

Open Food Facts has a worldwide, crowdsourced list of coconut milks containing E435, but be aware that some entries may be outdated. https://world.openfoodfacts.org/additive/en:e435-polyoxyethylene-sorbitan-monostearate/ingredient/en:coconut-milk

Common additional stabilizers are guar gum (E412) and carboxymethyl cellulose (E466).

International:

- Aroy-D: regular version (19% fat) with polysorbate 80, lite version (5.9% fat) with polysorbate 60
- Flying Goose: regular version (18% fat) with polysorbate 60 and carboxymethyl cellulose, lite version (6% fat) with polysorbate 60, carboxymethyl cellulose and guar gum
- Grace: regular version (16.6% fat) with polysorbate 60 and carboxymethyl cellulose, lite version (7% fat) with polysorbate 60, carboxymethyl cellulose, guar gum and other stabilizers
- Chaokoh: lite version (9% fat) with polysorbate 60, carboxymethyl cellulose, microcrystalline cellulose
- Chef’s Choice: regular non-organic (20% fat) and lite version (7.8% fat) with polysorbate 60

North America:

- Signature Select (Albertsons, USA & Canada?): regular version (17.5% fat) with polysorbate 60 and guar gum, lite version (6% fat) with polysorbate 60, carboxymethyl cellulose and guar gum
- Polar (USA): regular and lite version (17.5% fat) with polysorbate 60, carboxymethyl cellulose and guar gum, lite version (6% fat) with polysorbate 60 and guar gum.
- Roland (USA): regular and lite* versions (resp. 17% and 5.5% fat) with polysorbate 60, carboxymethyl cellulose and guar gum
- Compliments (Canada): regular non-organic and lite versions (latter 6% fat) with polysorbate 60, carboxymethyl cellulose and guar gum

* Lite version in brown-green can; the white can contains only guar gum.

UK:

- Morrisons: regular version (18% fat) with polysorbate 60 and carboxymethyl cellulose, light version (6.4% fat) with polysorbate 60 and guar gum
- Sainsbury’s: regular and light versions (resp. 18.2% and 6.7% fat) with polysorbate 60 and carboxymethyl cellulose
- Kingfisher (Tesco, Ocado): regular and light versions (resp. 21.3% and 8% fat) with polysorbate 60, carboxymethyl cellulose and guar gum.
- Oriental & Pacific (Ocado): reduced fat (6.6% fat) with polysorbate 60, carboxymethyl cellulose and guar gum
- East End (Tesco, Ocado): light version (7.6% fat) with polysorbate 60 and guar gum

Australia:

- Pandaroo (Woolsworth): regular version (12% fat) with polysorbate 60 and carboxymethyl cellulose,  lite version (5.5% fat) with polysorbate 60 and guar gum

Belgium:

- So Thai (Delhaize): light version (6% fat) with polysorbate 60 and carboxymethyl cellulose

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