1. Measuring drug supersaturation in the presence of
additives and simulated GI fluids
Jon Mole, Karl Box, John Comer , Tom Gravestock, Elizabeth Frake
Purpose
To investigate the kinetic and intrinsic solubility of drugs and the amount of supersaturation in the presence of simulated gastrointestinal fluids and other formulation
excipients.
Methods
The CheqSol method was used to measure kinetic and intrinsic solubility of several weakly basic drugs. In this method the solid drug is dissolved in ionized form, and the
solution titrated with KOH until precipitation is detected. Thereafter, small aliquots of KOH or HCl solution are added to maintain the system close to equilibrium, and
solubility results are calculated from rates of pH change vs. concentration. After some of these hour-long experiments, the solutions with suspended solids were set aside
and the concentration of dissolved drug in the supernatant was also measured by UV spectroscopy after typically 1, 4 and 8 days.
Results New SiriusT3 titrates in 1.0mL volumes, with pH control and in-situ UV.
Results are presented for solubility of several basic drugs, including dipyridamole and dicyclomine, under Solubility measured by CheqSol method with approx. 1mg of sample.
aqueous conditions and in the presence of mannitol, PVP, Cavasol, taurocholic acid and fasted- and fed-state
simulated intestinal fluids (FaSSIF and FeSSIF). The data shows that some drugs (e.g. dipyridamole) always UV dip probe
temperature
sensor
dispenser tips
formed supersaturated solutions in aqueous solution or in the presence of additives. Other drugs (e.g.
inert gas
dicyclomine) did not form a supersaturated solution under any conditions studied. A new graph (NSCP) derived argon cap
from the CheqSol data shows how the neutral species concentration changes with time after precipitation, and
can be used to assess the amount of supersaturation still present in the system at a given time. This was verified
by the UV measurements. stirrer pH electrode
Conclusion glass vial 1mL solution
of sample
The methods described in this poster could be used to measure the kinetic and intrinsic solubility of ionizable
drugs, and to assess the amount of supersaturation present in the system.
Kinetic solubility, intrinsic solubility, supersaturation
Kinetic Solubility is the concentration of a compound in solution when an induced precipitate appears. When precipitation is induced by pH change, many drugs become
supersaturated before precipitating.
Equilibrium Solubility is the concentration of compound in a saturated solution when excess solid is present, and solution and solid are at equilibrium. The result is pH-
dependent for ionizable drugs.
Intrinsic solubility (S0) is the equilibrium solubility of the free acid or free base form of an ionizable compound at a pH where it is fully unionized.
Supersaturated solutions contain excess neutral species in solution, which will carry on precipitating until the system reaches equilibrium. If drugs can be maintained in
supersaturated solution (i.e. at higher concentration) in the intestine, it is more likely they will be absorbed.
Solubility of dipyridamole (a base CHASER) in aqueous
First, measure kinetic solubility What happens after precipitation? Result = 3.6 μg/mL
0.15 M KCl by CheqSol method
Imipramine (a base with pKa 9.54) is dissolved in ionized form What happens after precipitation depends on the extent of Precipitates here
at low pH, then titrated with KOH. Precipitate is detected by supersaturation at the time of precipitation.
light scattering. Kinetic solubility is estimated from the NON-CHASERS do not appear to form supersaturated solutions
concentration of unionized species at the pH of precipitation. under any conditions; their solubility is measured by a curve-
Supersaturated here
fitting method. CHASERS readily form supersaturated solutions; Chases equilibrium
here
BH+ B their solubility is measured by the CheqSol method (Chasing
Equilibrium Solubility). Solubility results are obtained by mass Solubility of dicyclomine (a base NON-CHASER) in aqueous
0.15 M KCl by curve-fitting method
balance and charge balance calculations using experimental pH Result = 4.3 μg/mL
Kinetic solubility =
concentration of unionized
and titrant volumes. Both methods may be visualised by Precipitates here
species at pH9
Precipitate detected at pH 9
calculating Bjerrum curves from the pH-mL data. Solution Bjerrum
curve for a base
with one pKa ,
Precipitation Bjerrum curve for a
base with one pKa,
+ 30 minutes to [H+ ]
] H[ 0S nH =
nH = get here [H+ ] + Ka
a K] latot X[
Supersaturation in neutral species concentration profiles (NSCPs)
Neutral species concentration profiles (NSCPs) show concentration of neutral species vs. time, and are derived from the same data used to plot the Bjerrum curves.
NSCP for Imipramine (a base NON-CHASER)
NSCPs for experiments with additives and simulated GI fluids
Concentration of neutral species after precipitation, i.e.
intrinsic solubility
NSCP for Dipyridamole (a base CHASER)
Extent of supersaturation
Duration of supersaturation
NSCPs for metoclopramide (a base CHASER). NSCPs for dipyridamole in the NSCPs for dipyridamole showing
Polyvinylpyrrolidone (PVP) prolongs the presence FaSSIF, FeSSIF, NaTC and increasing extent of supersaturation in
Intrinsic solubility
duration of supersaturation, probably by lecithin. Super- saturation has the presence of increasing weights of
keeping the precipitate in amorphous form. longer duration in the presence of Cavasol®. At the highest weight, the
NaTC alone; lecithin has little sample did not precipitate.
effect.
New technology for assessing solubility and supersaturation
New methods have been described for measuring solubility of ionizable drugs, and for assessing the likely extent and duration of supersaturation. These
methods could be used for testing drugs with additives, in order to choose additives that maximise bioavailability by preserving drugs at higher solubility for
the longest possible time.
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