In
Stahl and Wermuth’s book, Pharmaceutical Salts: Properties, Selection and
Use there is a further piece of advice beyond what Kilomentor has already
written about concerning salt selection. Unlike the other advice it is provided
by implication only and needs to be simply stated.
On
pg. 181 of the book, the selection of an appropriate pharmaceutical salt for
the candidate drug called RPR200765 is presented. The following details of that problem are
provided. RPR200765 was a candidate drug substance to be used to treat
rheumatoid arthritis. The drug would have had to be taken regularly for the
rest of a patients’ lives. It is a
crystalline, weak base with a substituted pyridine ring system, a pKa of 5.3
and log P of 2.5. The anticipated
pharmaceutically effective dose was expected to fall between 100-125 mg. One can calculate that the molecular weight
of RPR200765 by itself was 488.48. The actual API material is identified in Bioorganic
& Medicinal Chemistry Letters (200), 11(5) 693-696.
Four
potential salts were identified in the example: mesylate, camphorsulfonate,
hydrochloride and hydrobromide. What was
particularly instructive is the comment concerning the camphorsulfonate. The
authors wrote that the only disadvantage of the camphorsulfonate when compared
to the mesylate (the first choice) was the increased molecular weight due to
the larger counter ion. It was considered that this could create problems with
experimental capsule or tablet later in development.
Camphorsulfonic
acid has a molecular weight of 232. The molecular weight of the
monocamphorsulfonate salt of RPR200765 would have been 720.48. Giving a dose of
100-125 mg on the free base basis (0.256 mmoles), as camphorsulfonate salt,
would amount to giving a dose 184 mg of this pharmaceutical salt. Delivering a dose of 184 mg of API, it is
said, was anticipated to be problematic.
From this it is possible to generalize that the practical limit to the
weight of API that can be confidently handled is about 184 milligrams in the
highest strength. This seriously
restricts the choices of pharmaceutical salts for medicines particularly where
the neutral active has a low molecular weight because this means there will be
more moles in the dose and so more moles of salt former.
To
take a current example, the highest prescribed dose of the cancer drug imatinib
is 400 mg as free base. The molecular weight of the free base is 493. If we
imagine the salt with an acid of molecular weight 232(camphorsulfonate) the
weight of active API would be 588 mg. This is already more than 3 times what
this teaching advises one can be comfortable with for achieving a successful
formulation. It is obvious that the acid used to form the pharmaceutical salt
for imatinib is going to have to have a low molecular weight. Pharmaceutically acceptable acids with
molecular weight below 100 are only: acetic, carbonic, formic, glycolic,
hydrobromic, hydrochloric, isobutyric, lactic, methanesulfonic, nitric, oxalic,
phosphoric, sulphuric and thiocyanic. Of
these the only ones without other concerns are hydrochloric, methanesulfonic,
phosphoric and sulphuric. Suddenly salt
selection becomes a lot easier! In the case of imatinib, the methanesulfonate
was chosen as the drug substance!
Put
as the converse it means that besides camphorsulfonic acid also galactaric,
glucoheptanoic, lactobionic, 2-naphthalene sulfonic, 1,5-naphthalenesulfonic,
oleic, palmitic, pamoic, sebacic, stearic and tannic acids need not be
initially considered for salt formation with candidate bases. Five of these are
from the group of 30 called Class 1 acids, the most preferred acids based on
safety considerations.
Similarly
benethamine, benzathine and hydrabamine are distinctly less preferred for salt
formation with acid candidates based on their molecular weights.
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