1. Dissolution of drugs in the presence of additives under
conditions of changing pH to simulate GI transit
Jon Mole, Karl Box, John Comer, Tom Gravestock, Elizabeth Frake
Purpose
At the 2008 AAPS Annual Meeting, we described the GI Dissolution Assay for assessing dissolution, supersaturation and precipitation of a pharmaceutical substance
during passage through the gastro-intestinal (GI) tract. In the current study, this assay method was used to investigate the dissolution of drugs in the presence of additives
and simulated GI fluids.
Methods
A solid drug is introduced into a stirred chamber containing hydrochloric acid at pH2 or below to represent conditions in the stomach. A fibre-optic probe connected to a
UV spectrometer monitors the concentration of sample released into solution. The pH is varied with time to represent passage of the compound from the stomach to the
intestine. The incorporation of additives or simulated GI fluids can be used to mimic drug-formulations or in-vivo conditions. UV spectra record the concentration in
solution at the new pH. The concentration of the sample in solution can thus be monitored under conditions more relevant to the normal modes of delivery of
pharmaceutical substances.
Results GI Dissolution Assays are run on Sirius GLpKa/D-PAS or SiriusT3 instruments. UV absorption data is
converted to an absolute sample weight using previously determined (pH-dependent) molar extinction
EQUATION [1]:
[ X ]t = S (1 − e−kd (t −to ) )
The dissolution of a number of pharmaceutical substances (acids, bases, ampholytes and coefficients. Dissolution rates are calculated from a fit of equation [1] to the experimental data, where
[X]t is the weight (g) of drug X in solution at experiment time t (min); S is the extrapolated solubility (g) of Pellet press
neutrals) has been investigated in the presence of simulated intestinal fluids and additives drug X; kd is the rate constant for dissolution (min-1); and t0 (min) is a term allowing for a temporal offset.
The dissolution rate (g/min) is reported as the product, kdS, i.e. the dissolution rate at t0, when the
(mannitol, cavasol and PVP) under static and dynamic pH control. The results are compared concentration of X in solution is zero. Tablet die and accessories
to those obtained under aqueous conditions. The dissolution of several acidic compounds Sirius vial with tablet disc holder; the
three legs allow buffer, FaSSIF or
(carprofen, tolmetin, warfarin) in simulated gastric fluid is also compared. FeSSIF powder, or additives to be
introduced without wetting the
tablet surface. Upon automated
Conclusion addition of water or KCl solution, the
tablet is wetted with solution at the
A method is described for studying concentration-time profiles of drugs at different pH and in required start pH, and UV data
Tablet disc holder
collection starts immediately. The hydraulic press is used with the tablet die to press a pellet of pure drug directly into the tablet
the presence of additives and simulated GI fluids. Such experiments could be used to assess disc, which is then pushed into the tablet disc holder and held in place with an “O” ring seal.
compounds’ availability for oral absorption.
Dissolution in presence of simulated GI fluids
The GI Dissolution Assay was used to study several compounds at four pH values for 30 minutes at each pH to simulate pH in the GI tract. Experiments were done at room
temperature (25-28°C) in 15 mL of dissolution medium using tablet weights in the range 6 – 24 mg. They were run in aqueous 0.15M KCl
Table 1. As expected, dissolution rates for chloramphenicol
do not change significantly in a given medium as a
function of pH.
Dissolution rates of bases and acids are influenced by their
pKa values. Thus clopidogrel (base, pKa 4.74) precipitates
at higher pH under all conditions, whereas maprotiline pH 1.9 pH 3.8 pH 5.3 pH 7.2
(base, pKa 10.33) dissolves in ionized form at similar rates
at all pH values.
Conversely, dissolution rates of tolmetin (acid, pKa 3.5) and
carprofen (acid, pKa 4.25) increase significantly above their
pKa, although rates for warfarin (acid, pKa 4.94) remain
slow until the solution reaches pH 7.2.
FaSSIF and FeSSIF increase the dissolution rates of Dissolution of carvedilol (base, pKa = 7.97) is slower in
clopidogrel (until it precipitates at higher pH), and FeSSIF FaSSIF and FeSSIF relative to 0.15M aqueous KCl at low
strongly promotes the dissolution of dipyridamole, keeping pH, suggesting that it forms salts with the negatively
it in solution at pH 7.2. However, in some cases, charged bile acid portion of the simulated fluids, which
dissolution is slower in the presence of FaSSIF and FeSSIF , inhibits further dissolution. This example shows that
presumably because of salt formation (e.g. carvedilol, the bioavailability of a low solubility drug could be
right). over-predicted by in-vitro data obtained under
aqueous conditions.
Dissolution in presence of solubility-enhancing additives
Additives are often used during formulation to enhance the solubility of drugs. The GI Dissolution Assay provides a quick way to assess the effects of additives over a
biologically significant pH range using minimal quantities of sample. In these experiments, a weighed amount of additive is placed into the vial before the addition of water
wets the pellet at the start of the assay.
Dissolution of clopidogrel (base, pKa Dissolution of dipyridamole (base,
4.74). Clopidogrel is a NON-CHASER, pKas 0.8, 6.2). Dipyridamole dissolves
and does not form supersaturated rapidly at pH 1.9 under all conditions,
solutions. As shown above, it dissolves pH 1.9 pH 3.8
pH 5.3
and remains in solution at pH 3.8, as
pH 7.2
rapidly in ionized form at pH 1.9 in the indicated by the unchanging
presence of all four additives. It concentration vs. time. It remains in
remains completely dissolved at pH solution above its pKa in the presence
pH 1.9 pH 3.8 pH 5.3 pH 7.2 3.8 and above in the presence of of Triton X-100 and Tween 80.
Triton X-100 and Tween 80. However, However, it precipitates at higher pH in
as indicated by the unchanging aqueous solution and in the presence
concentration vs. time, it rapidly of other additives. Precipitation is slow
precipitates and quickly reaches its because dipyridamole is a CHASER,
equilibrium solubility in the presence and forms supersaturated solutions,
of DGME and mannitol. which take time to precipitate.
Triton X-100 is a non-ionic surfactant. Tween 80, a trademark of ICI Americas, Inc., is a nonionic surfactant and emulsifier. DGME is diethylene glycol monoethyl ether.
CAVASOL® W7 HP is a beta-cyclodextrin derivative, from Wacker Chemie AG. Pluronics is a trade name of BASF Corp for nonionic triblock copolymers, also known as
Poloxamers. PVP (polyvinyl-pyrrolidone) aids the solubility of drugs by inhibiting recrystallization. Mannitol is an alcohol derived from sugar. NON-CHASERS are drugs that
do not form supersaturated solutions. CHASERS are drugs that readily form supersaturated solutions
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