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Valium 5mg titration - dry or liquid micro taper?


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Thank you for your replies, Nogoldchain.

 

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.

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Ah, there was cause for concern, theoretically, but I’m fine now. You are right about the disclaimer, Libertas, 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).

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To address Nogoldchain’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

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

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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:

(…) 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 Lib, 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:

 

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.

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, Nogoldchain 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, Nogoldchain?

 

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).

 

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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):

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).

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EDIT:

 

I might have made a mistake. I relied on two PubChem  listings for solubility that are inconsistent with other literature sources. Libertas 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.

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I am not sure this is correct, Nogoldchain.

 

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:

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).

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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 Nogoldchain’s post: http://www.benzobuddies.org/forum/index.php?topic=267260.msg3372213#msg3372213

 

After many hours of research and helpful discussions with Nogoldchain, 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.

 

Nogoldchain 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]:

 

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]:

 

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]:

 

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]:

 

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 [33]:

 

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):

 

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, 33]:

 

- 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

 

References

 

[1] Yalkowsky, S. H., He, Y., & Jain, P. (2010). Handbook of aqueous solubility data (2nd edition). CRC Press.

 

[2] Soltanpour, S., Bastami, Z., Sadeghilar, S., Kouhestani, M., Pouya, F., & Jouyban, A. (2013). Solubility of clonazepam and diazepam in polyethylene glycol 200, propylene glycol, N-methyl pyrrolidone, ethanol, and water at (298.2 to 318.2) K and in binary and ternary mixtures of polyethylene glycol 200, propylene glycol, and water at 298.2 K. Journal of Chemical & Engineering Data, 58(2), 307-314. https://doi.org/10.1021/je3009842

 

[3] Bastami, Z., Soltanpour, S., Panahi-Azar, V., & Jouyban, A. (2014). Solubility of clonazepam and diazepam in binary and ternary mixtures of polyethylene glycols 400 or 600, propylene glycol and water at 298.2 K-experimental data and modeling. Journal of the Serbian Chemical Society, 79(4), 445-456. https://doi.org/10.2298/JSC121212079B

 

[4] Onuki, Y., Hasegawa, N., Kida, C. et al. Supersaturated state of diazepam injection following dilution with infusion fluid. J Pharm Health Care Sci 1, 9 (2015). https://doi.org/10.1186/s40780-014-0009-9

 

[5] Jusko, W. J., Gretch, M., & Gassett, R. (1973). Precipitation of diazepam from intravenous preparations. Jama, 225(2), 176-176. https://doi.org/10.1001/jama.1973.03220290054019

 

[6] US National Library of Medicine. (2021). DailyMed - LABEL: DIAZEPAM injection, solution. Accessed online on 17 May 2022. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=83646a0f-eb43-4871-b95e-683c2533d2be

 

[7] Benzodiazepine Information Coalition. (2022). Benzodiazepine Tapering Strategies And Solutions. Accessed online on 17 May 2022. https://web.archive.org/web/20220330080055/https://www.benzoinfo.com/benzodiazepine-tapering-strategies/#manufacturers-oral-solution

 

[8] Roxane Laboratories. Diazepam Intensol Oral Solution and Concentrate monograph. Accessed online on 17 May 2022. https://docs.boehringer-ingelheim.com/Prescribing%20Information/PIs/Roxane/Diazepam/Diazepam%20Oral%20Solution.pdf

 

[9] European Medicines Agency. (2017). Questions and answers on propylene glycol used as an excipient in medicinal products for human use. Accessed online on 17 May 2022. https://www.ema.europa.eu/en/documents/scientific-guideline/questions-answers-propylene-glycol-used-excipient-medicinal-products-human-use_en.pdf

 

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[13] Tinjacá, D. A., Shayanfar, A., Jouyban, A., Martínez, F., & Acree Jr, W. E. (2018). Preferential solvation of some antiepileptic drugs in {cosolvent (1)+ water (2)} mixtures at 298.15 K. Physics and Chemistry of Liquids, 56(5), 646-659. https://doi.org/10.1080/00319104.2017.1376060

 

[14] Basit, A. W., Newton, J. M., Short, M. D., Waddington, W. A., Ell, P. J., & Lacey, L. F. (2001). The effect of polyethylene glycol 400 on gastrointestinal transit: implications for the formulation of poorly-water soluble drugs. Pharmaceutical research, 18(8), 1146–1150. https://doi.org/10.1023/a:1010927026837

 

[15] Cotreau-Bibbo, M. M., von Moltke, L. L., & Greenblatt, D. J. (1996). Influence of polyethylene glycol and acetone on the in vitro biotransformation of tamoxifen and alprazolam by human liver microsomes. Journal of pharmaceutical sciences, 85(11), 1180–1185. https://doi.org/10.1021/js9601849

 

[16] Hermansky, S. J., Neptun, D. A., Loughran, K. A., & Leung, H. W. (1995). Effects of polyethylene glycol 400 (PEG 400) following 13 weeks of gavage treatment in Fischer-344 rats. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association, 33(2), 139–149. https://doi.org/10.1016/0278-6915(94)00119-9

 

[17] Prentice, D. E., & Majeed, S. K. (1978). Oral toxicity of polyethylene glycol (PEG 200) in monkeys and rats. Toxicology Letters, 2(2), 119-122. https://doi.org/10.1016/0378-4274(78)90084-X

 

[18] Nishiya, Y., Nakamura, K., Okudaira, N., Abe, K., Kobayashi, N., & Okazaki, O. (2010). Effects of organic solvents on the time-dependent inhibition of CYP3A4 by diazepam. Xenobiotica; the fate of foreign compounds in biological systems, 40(1), 1–8. https://doi.org/10.3109/00498250903337392

 

[19] Yamahira, Y., Noguchi, T., Noguchi, T., Takenaka, H., & Maeda, T. (1979). Absorption of diazepam from a lipid-containing oral dosage form. Chemical & pharmaceutical bulletin, 27(5), 1190–1198. https://doi.org/10.1248/cpb.27.1190

 

[20] Kaukonen, A. M., Boyd, B. J., Porter, C. J., & Charman, W. N. (2004). Drug solubilization behavior during in vitro digestion of simple triglyceride lipid solution formulations. Pharmaceutical research, 21(2), 245–253. https://doi.org/10.1023/b:pham.0000016282.77887.1f

 

[21] US National Library of Medicine. (2019). DailyMed - Label: VALIUM- diazepam tablet. Accessed online on 21 May 2022. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=554baee5-b171-4452-a50a-41a0946f956c

 

[22] Macheras, P. E., Koupparis, M. A., & Antimisiaris, S. G. (1990). Drug binding and solubility in milk. Pharmaceutical research, 7(5), 537–541. https://doi.org/10.1023/a:1015881103340

 

[23] Stebler, T., & Guentert, T. W. (1990). Binding of drugs in milk: the role of casein in milk protein binding. Pharmaceutical research, 7(6), 633-637. https://doi.org/10.1023/a:1015826413335

 

[24] Thum, C., Roy, N. C., Everett, D. W., & McNabb, W. C. (2021). Variation in milk fat globule size and composition: A source of bioactives for human health. Critical Reviews in Food Science and Nutrition, 1-27. https://doi.org/10.1080/10408398.2021.1944049

 

[25] Lopez, C. (2005). Focus on the supramolecular structure of milk fat in dairy products. Reproduction nutrition development, 45(4), 497-511. https://doi.org/10.1051/rnd:2005034

 

[26] Wiking, L., Stagsted, J., Björck, L., & Nielsen, J. H. (2004). Milk fat globule size is affected by fat production in dairy cows. International Dairy Journal, 14(10), 909-913. https://doi.org/10.1016/j.idairyj.2004.03.005

 

[27] Itin, C., Liani, M., Zur, M. et al. Stability of Diazepam Solution for Injection Following Long-Term Storage in an Ambient Temperature of the Mediterranean Climate. Pharm Res 38, 361–367 (2021). https://doi.org/10.1007/s11095-020-02984-9

 

[28] Rutz, W. D., Whitnah, C. H., & Baetz, G. D. (1955). Some physical properties of milk. I. Density. Journal of Dairy Science, 38(12), 1312-1318. https://doi.org/10.3168/jds.S0022-0302(55)95113-4

 

[29] Whitnah, C. H., Medved, T. M., & Rutz, W. D. (1957). Some physical properties of milk. IV. Maximum density of milk. Journal of Dairy Science, 40(7), 856-861. https://doi.org/10.3168/jds.S0022-0302(57)94563-0

 

[30] Ueda, A. (1999). Relationship among milk density, composition, and temperature (Doctoral dissertation, University of Guelph). https://www.collectionscanada.gc.ca/obj/s4/f2/dsk2/ftp01/MQ43229.pdf

 

[31] Goff, H. D., Hill, A., & Ferrer M. A. (2022). Dairy Science and Technology eBook (University of Guelph). https://books.lib.uoguelph.ca/dairyscienceandtechnologyebook/

 

[32] Parmar, P., Lopez‐Villalobos, N., Tobin, J. T., Murphy, E., Buckley, F., Crowley, S. V., ... & Shalloo, L. (2021). Effect of temperature on raw whole milk density and its potential impact on milk payment in the dairy industry. International Journal of Food Science & Technology, 56(5), 2415-2422. https://doi.org/10.1111/ijfs.14869

 

[33] Guignon, B., Rey-Santos, I., & Sanz, P. D. (2014). Determination, analysis and prediction of the volumetric behavior of milk at high pressure. Food research international, 64, 336-347. https://doi.org/10.1016/j.foodres.2014.06.046

 

[34] Parmar, P., Lopez-Villalobos, N., Tobin, J. T., Murphy, E., McDonagh, A., Crowley, S. V., Kelly, A. L., & Shalloo, L. (2020). The Effect of Compositional Changes Due to Seasonal Variation on Milk Density and the Determination of Season-Based Density Conversion Factors for Use in the Dairy Industry. Foods, 9(8), 1004. https://doi.org/10.3390/foods9081004

 

[35] Tangsuphoom, N., & Coupland, J. N. (2008). Effect of surface-active stabilizers on the microstructure and stability of coconut milk emulsions. Food Hydrocolloids, 22(7), 1233-1242. https://doi.org/10.1016/j.foodhyd.2007.08.002

 

[36] Tetra Pak. Coconut Handbook. Accessed 16 May 2022. https://coconuthandbook.tetrapak.com/

 

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[39] Tansakul, A., & Chaisawang, P. (2006). Thermophysical properties of coconut milk. Journal of Food Engineering, 73(3), 276-280. https://doi.org/10.1016/j.jfoodeng.2005.01.035

 

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potatosaur, 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 potatosaur (a screen name I have misspelled a few times by now)! 

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Thank you, Nogoldchain, 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.

 

 

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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

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

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Thank you for your question, confuseduser. 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 Libertas 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, confuseduser. Please let me know if something remains unclear or if you have other questions.

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Thank you for your question, confuseduser. 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, Potatosaur. 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 Libertas' excellent instructions for diluting it that Libertas posted on the first page of this thread.  .01 ml of the mix that Libertas 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.  Libertas 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.

 

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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 Nogoldchain’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.

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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

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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.

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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.

 

Hello, confuseduser.  Good to see you on the boards!  In hope of preventing confusion on the part of future readers of this thread, might I clarify that the 5mg/5mL oral diazepam solution is NOT an Intensol?  Intensol is a trademark associated with a 25mg/5mL oral diazepam concentrate currently manufactured by West-Ward (NDC 0054-3185-44).

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Hello, confuseduser.  Good to see you on the boards!  In hope of preventing confusion on the part of future readers of this thread, might I clarify that the 5mg/5mL oral diazepam solution is NOT an Intensol?  Intensol is a trademark associated with a 25mg/5mL oral diazepam concentrate currently manufactured by West-Ward (NDC 0054-3185-44).

 

Thanks, Libertas.  You are so on the ball and so right!.  Sadly I have now earned my user name which I started with on the board, and after I had made a number of posts realized that it was a bad choice of a username.  The 5mg per 5 mL solution that I am using is indeed the West Ward.  I have no idea when or why I started using the word Intersol to describe it.  Ouch!

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You’re most welcome, confuseduser.  Drug product nomenclature is confusing as heck.  It took me a ridiculously long time to figure out that Intensol was a trademarked name for ‘concentrate.’ 

 

Fun trivia for the day: West-Ward is a wholly owned subsidiary of Hikma Pharmaceuticals. Hikma manufacturers six Intensols for the US market including three for benzodiazepines (alprazolam, diazepam, lorazepam).

 

Link:

US products | Hikma

https://www.hikma.com/products/us-products/

(Enter ‘Intensol’ in the search box.)

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Libertas, you are the best in terms of knowledge, helpfullness, and on the ballness with spotting things quickly.  Thanks you for all of the work you do here and the help you provide.
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