Midazolam solubility

[aced126]

Why is midazolam soluble in water? Why is, say, diazepam not?

Midazolam has 3 nitrogens where hydrogen bonds could form? Diazepam has 2 nitrogen and also a ketone group. So would one not expect similar solubilities? Diazepam is only soluble in solvents like propylene glycol, but midazolam is soluble in water, and is appropriate for IV usage.

Also just realised that the extra nitrogen in midazolam has its lone pair electrons delocalised around the ring structure, making it less able to form a hydrogen bond. Why is this compound soluble in water?

 

[adder]

Unlike other benzodiazepines midazolam is sold as its hydrochloride salt, that's what makes it soluble in water. Basically all benzodiazepines could be made into salts in the same way though. Midazolam itself isn't really more soluble in neutral solutions than other benzodiazepines.

As you can see, midazolam can exist in two forms depending on the pH of the solution, this is an equilibrium. Under pH=4 it will mostly exist as the open-ring form which is much more soluble. This is nothing unusual, you'll notice that the closed-ring form is actually a cyclic imine and imines can be hydrolyzed in aqueous solutions to amines and ketones, as this is an equilibrium, the key here is the right pH. When you take the drug, it will turn back into its closed-ring form in your blood due to slightly alkaline pH.

On the other hand loprazolam or flurazepam are much more soluble at neutral pH than most triazolobenzodiazepines due to the presence of multiple hydrogen bond acceptors.

Check this thread for solubility values of some common benzodiazepines.

 

[aced126]

Unlike other benzodiazepines midazolam is sold as its hydrochloride salt, that's what makes it soluble in water. Basically all benzodiazepines could be made into salts in the same way though. Midazolam itself isn't really more soluble in neutral solutions than other benzodiazepines.

As you can see, midazolam can exist in two forms depending on the pH of the solution, this is an equilibrium. Under pH=4 it will mostly exist as the open-ring form which is much more soluble. This is nothing unusual, you'll notice that the closed-ring form is actually a cyclic imine and imines can be hydrolyzed in aqueous solutions to amines and ketones, as this is an equilibrium, the key here is the right pH. When you take the drug, it will turn back into its closed-ring form in your blood due to slightly alkaline pH.

On the other hand loprazolam or flurazepam are much more soluble at neutral pH than most triazolobenzodiazepines due to the presence of multiple hydrogen bond acceptors.

Check this thread for solubility values of some common benzodiazepines.

Isnt it not a good idea to iv acidic solution?

 

[sekio]

It depends how acidic. Most solutions of street drugs are acidic but not to the point where they cause irritation or damage.