Solubility of amlodipine besylate

Question

In European Pharmacopoeia, the drug amlodipine besylate is characterised as slightly soluble in water and freely soluble in methanol (additionally, sparingly soluble in anhydrous ethanol and slightly soluble in 2-propanol). Why is this? Both water and methanol are polar protic solvents.

Answer 1

According to OP, the monograph in the European Pharmacopoeia says:

the drug amlodipine besylate is characterized as slightly soluble in water and freely soluble in methanol (additionally, sparingly soluble in anhydrous ethanol and slightly soluble in 2-propanol).

Theory and application of solubility Parameters are at least beyond my scope. Yet, above excerpts doesn't make any sense. If amlodipine besylate (AMB) is slightly soluble in water and freely soluble in methanol, to my common knowledge in organic chemistry, it should be at least moderately (not sparingly) soluble in absolute ethanol based on increasing organic nature from methanol to ethanol (see my answer in this question to understand one of parameters in solubility theory). Thus, I'd say OP might have misunderstood the facts given in European Pharmacopoeia. I haven't seen this monograph, but I assume it might be talking about different salts of amlodipine (e.g., amlodipine acetate).

I have tried to find some reliable data in literature, but it wasn't as successful as I expected. Yet again, different publications give different values for solubility. For example, Ref.1 gives Experimental Mole Fraction Solubility $(X_{m,T}^{Exp})$ of AMB at $\pu{30 ^\circ C}$ as $2.56 \times 10^{-5}$ and $6.20 \times 10^{-7}$ in absolute ethanol and water, respectively. According to this results, AMB dissolves highly in absolute ethanol compared to that in water (definitely not slightly in water to sparingly in absolute ethanol). Note that, in Ref.2, even though it is from the same research group, $(X_{m,T}^{Exp})$ of AMB in water at $\pu{30 ^\circ C}$ as $6.30 \times 10^{-5}$ $(\pu{0.0051 M})$.

When the counter ion is changed from besylate to acetate, the solubility has changed dramatically (Ref.3):

$(X_{m,T}^{Exp})$ of amlodipine acetate at $\pu{30 ^\circ C}$: $4.370 \times 10^{-3}$ (in methanol); $6.951 \times 10^{-3}$ (in ethanol); and $7.737 \times 10^{-3}$ (in 2-propanol).

As I expected, the solubility has increased with the increasing organic nature of the protic solvent.

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References:

1. Faroukh Sardari and Abolghasem Jouyban, "Solubility of 3-Ethyl-5-methyl-(4RS)-2-((2-aminoethoxy)methyl)-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate Monobenzenesulfonate (Amlodipine Besylate) in Ethanol + Water and Propane-1,2-diol + Water Mixtures at Various Temperatures," J. Chem. Eng. Data 2012, 57(10), 2848–2854 (DOI: https://doi.org/10.1021/je3005672).
2. Elmira Behboudi, Jafar Soleymani, Fleming Martinez, and Abolghasem Jouyban, "Solubility of amlodipine besylate in binary mixtures of polyethylene glycol 400 + water at various temperatures: Measurement and modelling," Journal of Molecular Liquids 2022, 347, 118394 (10 pages) (DOI: https://doi.org/10.1016/j.molliq.2021.118394).
3. Chao Cheng, Yang Cong, Cunbin Du, Jian wang, Ganbing Yao, and Hongkun Zhao, "Solubility determination and thermodynamic models for dehydroepiandrosterone acetate in mixed solvents of (ethyl acetate + methanol), (ethyl acetate + ethanol) and (ethyl acetate + isopropanol)," The Journal of Chemical Thermodynamics 2016, 101, 372-379 (DOI: https://doi.org/10.1016/j.jct.2016.06.014).