A counter ion that fulfils all needs
The solubility of an active drug substance is
critical to a successful dosage delivery. Dr Steffen
Denzinger, Merck Millipore’s head of technical
marketing pharma raw materials, reveals how meglumine
can improve the solubility of an anionic drug.
During the formulation of pharmaceutical drugs,
many properties must be optimised to create an
active pharmaceutical ingredient that will be
delivered in the right amount, at the right time,
at the right place in the body in order to achieve
the desired effect. In addition to classical properties
such as dissolution and disintegration for solid
dosage forms, or stabilisation for liquid dosage
forms that can be supported by excipients, the
solubility of the active drug substance is critical
to success.
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The structural formula
of meglumine. Under physiological conditions,
the amine is partly protonated, resulting
in a weak cationic counter ion.
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For liquid dosage forms, aqueous solubility under
the right buffer conditions plays an important
role for the successful storage of a pharmaceutical
drug. Even more important is solubility under
physiological conditions within the body, a property
that is independent from the chosen dosage forms.
Enhancing solubility
Interestingly, the solubility of new drug substances
has been
decreasing. Fortunately, additives can help change
the solubility
of active drug substances. One option for enhancing
solubility
is complexation of the drug substance. This can
be achieved by,
for example, cyclodextrines forming stable aggregates;
however,
kinetics of the release from these complexation
agents has to
be studied in order to ensure the pharmacokinetics
of the active
drug substance remain adequate.
Another option involves the chemical transformation
of a
drug molecule by changing the protein kinase A
(pKa) of the
drug through the formation of an applicable salt.
In most
instances, the salts resulting from the synthetic
routes of
chemical entities are the sodium, calcium or potassium
salts
in the case of anionic moieties, which are numerous
among
known drug substances. All the counter ions are
derived from
strong bases with pKa values above 12. Nevertheless,
a large
number of active ingredients are derived from
rather weak
acids. Therefore, the solubility of such actives
can be
enhanced significantly by exchanging these counter
ions with
weaker organic counter ions with pKa values of
8-9.
Meglumine as a counter ion
Selecting the right counter ion for a drug
substance is an important factor for enhancing
the
solubility of a drug. A counter ion frequently
used
to enhance the solubility of active ingredients
is
N-Methyl-D-glucamin, known as meglumine,
which is an amino sugar derived from sorbitol
with
a pKa of 8.03. Meglumine is used to replace sodium
because it has a comparable osmotic activity and
is
impermeable towards cell membranes.
Examples of current products with
meglumine as a counter ion are meglumine
antimonate (for human use) and flunixin
meglumine (for animal use). Meglumine is
also widely used in the manufacturing of contrast
media in
combination with iodine containing compounds.
As the counter ion closely interacts with the
drug
substance, the quality and supply chain security
of the
manufacturing process for these substances should
be considered carefully. For human use, the quality
standard both in purity and the manufacturing
process
should be equal to the standard of the API itself.
As
such, manufacturing with a tight quality control
under
an ICH Q7/A standard provides the most security
and
peace of mind.
Unfortunately, organic counter ions such as meglumine,
tromethamine or piperazine are frequently derived
from
technical sources due in part to a lack of suppliers
who can
offer grades manufactured under cGMP.
Improving bioavailability
Merck Millipore provides meglumine that fulfils
the
stringent requirements of drug manufacturers.
Its
meglumine is an API grade that is accompanied
by full
documentation including DMF and CEP.
Counter ions of this quality open new possibilities
for
drug manufacturers. Therefore, Merck Millipore
will dedicate
itself to offer more such materials as it strives
to help drug
manufacturers to enhance the bioavailability of
drugs.
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