Dissolution of a Biopharmaceutics Classification System Class II Free Acid from Immediate Release Tablets Containing a Microenvironmental pH Modulator: Comparison of a Biorelevant Bicarbonate Buffering System with Phosphate Buffers

Abstract

Poor water dissolution of active pharmaceutical ingredients (API) limits the rate of absorption from the gastrointestinal tract. Increasing the pH of a solid form microenvironment can enhance the dissolution of weakly acidic drugs, but data on this phenomenon in a physiologically relevant bicarbonate media are lacking. In this paper, we examined the effect of a microenvironmental pH modulator (Na2HPO4) on the dissolution of a Biopharmaceutics Classification System (BCS) class II free weak acid (ibuprofen) at biorelevant conditions, including an automatic bicarbonate buffering system, as well as in compendial (50 mM) and low-concentration (10 mM) phosphate buffers with no external pH control. The tablets of 200 mg ibuprofen with either Na2HPO4 (phosphate formulation, PF) or NaCl (reference formulation, RF) were manufactured using a compression method. In a pH 2 simulated gastric fluid, only PF produced a transient supersaturation of ibuprofen, dissolving a fourfold higher drug amount than RF. In a bicarbonate-buffered simulated intestinal fluid with a dynamically controlled pH (5.7, 7.2, and 5.8 to 7.7 gradient), PF dissolved more drug within 30 min than RF (p ≤ 0.019). Of note, the use of a 50 mM phosphate buffer pH 7.2 provided opposite results—RF dissolved the API much faster than PF. Moreover, 10 mM phosphate buffers of pH 5.6 and 7.2 could neither maintain a constant pH nor mimic the bicarbonate buffer performance. In conclusion, the use of a bicarbonate-buffered intestinal fluid, instead of phosphate buffers, may be essential in dissolution tests of BCS class II drugs combined with pH modulators. Graphical abstract

A Rational Approach to Predicting Immediate Release Formulation Behavior in Multiple Gastric Motility Patterns: A Combination of a Biorelevant Apparatus, Design of Experiments, and Machine Learning

“…The key features of the apparatus are the ability to simulate pressure events of up to 500 mbar, mimicking the gradients of the dissolution medium flow rate and temperature, the rapid neutralization of the gastric content, and dynamic pH control and adjustment with hydrogen carbonate buffers. These were proven to be crucial for biorelevant dissolution tests [ 35 , 36 , 37 , 38 , 39 ]. PhysioCell consists of three vessels: the StressCell, Overflow Vessel, and Collection Vessel.…”

Integrative Salt Selection and Formulation Optimization: Perspectives of Disproportionation and Microenvironmental pH Modulation

“…37,38 It was recognized through decades of research that the diffusion layer is critical to the dynamics of the dissolution process. 39,40 The Noyes−Whitney equation defines the drug dissolution rate as 33,41 C t…”

“…Among the pH-modulation approaches, adding a pH modifier as an excipient is the most common strategy to achieve pH-independent solubility. There are examples of using enteric polymer or carriers to optimize the release further; ,, however, most of the cases have been the addition of small-molecule acids or bases, particularly organic acids (e.g., citric, succinic, tartaric) − , or alkalizers (e.g., sodium carbonates, magnesium oxide). − ,,, A summary of the physical properties of these frequently used pH modifiers can be found in the literature . The pH modifiers’ effectiveness in controlling microenvironmental pH (pH M ) varies with their acid/base strength (p K a ) and aqueous solubility.…”