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Salt Selection
Salt formation can enhance solubility and dissolution rate of basic and acidic drugs,
therefore improving their bioavailability and absorption. As such, salt selection
should be viewed as a part of the overall strategy in choosing the optimal form
of the drug substance for development.
Strategy: Salt formation is frequently performed on weak acidic and weak
basic drugs because it is a relatively simple chemical manipulation, which may alter
the physicochemical, formulation, biopharmaceutical and therapeutic properties of
the drug substance without modifying the basic chemical structure. Theoretically,
every drug substance has acidic or basic properties that could be a possible nominee
for salt formation. Consideration should include material that is crystalline, non-hydroscopic,
a high single melting temperature and chemically stable in the solid form.
Methods: The determination of the drug substance’s pKa value(s) by calculated
or experimental means is the two universal focal points in pharmaceutically acceptable
counterion selection. The pKa of the acids used should be at least two pH units
below that of the drug substance and the only ones considered in the test. Solubility
studies are generally conducted with the concentration of the acid being 0.1M. An
In-situ salt screen is conducted with calculated amounts of drug substances to know
which counterion will provide higher or lower aqueous solubility. This process is
used as a guide to aid in rank ordering the salts and identifying a counterion that
will provide the highest solubility in water. Organic solvents or water/organic
cosolvents systems are another procedure for isolation of possible salt formation
utilizing different counterions, temperatures and conditions. All characterization
of solid material obtained from the above experiments should be analyzed by means
of XRPD (wet and dry solids), DSC, TGA, Polarized and Hot Stage Microscopy.
Result: Salts are generated to change the solid state and bulk properties
of the drug substance to help ease the processing steps or formulation aspects.
Salts are also a solution to increase the chemical or physical stability when compared
to its parent form. The areas include a change in the solubility, change in the
rate of dissolution which will aid in the bioavailability and also increase the
options for final drug product route of administration. Salts that show evidence
of beneficial properties over the parent compound can also be patented as new chemical
entities to strengthen a new drug application (NDA).
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