Orally
dosed drugs must dissolve in the gastrointestinal (GI) tract
before being absorbed through the epithelial cell membrane. In vivo drug dissolution depends on the GI tract’s
physiological conditions such as pH, residence time, luminal buffers,
intestinal motility, and transit and drug properties under fed and
fasting conditions (Paixão, P. et al. Mol. Pharm.
2018 and Bermejo, et al. M. Mol. Pharm.
2018). The dissolution of an ionizable
drug may benefit from manipulating in vivo variables
such as the environmental pH using pH-modifying agents incorporated
into the dosage form. A successful example is the use of such agents
for dissolution enhancement of BCS class IIb (high-permeability, low-solubility,
and weak base) drugs under high gastric pH due to the disease conditions
or by co-administration of acid-reducing agents (i.e., proton pump inhibitors, H2-antagonists, and antacids). This study
provides a rational approach for selecting pH modifiers to improve
monobasic and dibasic drug compounds’ dissolution rate and
extent under high-gastric pH dissolution conditions, since the oral
absorption of BCS class II drugs can be limited by either the solubility
or the dissolution rate depending on the initial dose number. Betaine
chloride, fumaric acid, and tartaric acid are examples of promising
pH modifiers that can be included in oral dosage forms to enhance
the rate and extent of monobasic and dibasic drug formulations. However,
selection of a suitable pH modifier is dependent on the drug properties
(e.g., solubility and pK
a) and its interplay with the pH modifier pK
a or pK
as. As an example of this
complex interaction, for basic drugs with high pK
a and intrinsic solubility values and large doses, a polyprotic
pH modifier can be expected to outperform a monoacid pH modifier.
We have developed a hierarchical mass transport model to predict drug
dissolution of formulations under varying pH conditions including
high gastric pH. This model considers the effect of physical and chemical
properties of the drug and pH modifiers such as pK
a, solubility, and particle size distribution. This model
also considers the impact of physiological conditions such as stomach
emptying rate, stomach acid and buffer secretion, residence time in
the GI tract, and aqueous luminal volume on drug dissolution. The
predictions from this model are directly applicable to in
vitro multi-compartment dissolution vessels and are validated
by in vitro experiments in the gastrointestinal simulator.
This model’s predictions can serve as a potential data source
to predict plasma concentrations for formulations containing pH modifiers
administered under the high-gastric pH conditions. This analysis provides
an improved formulation design procedure using pH modifiers by minimizing
the experimental iterations under both in vitro and in vivo conditions.