Toward Mechanistic Design of Surrogate Buffers for Dissolution Testing of pH-Dependent Drug Delivery Systems

Abstract

The in vivo dissolution of enteric-coated (EC) products is often overestimated by compendial in vitro dissolution experiments. It is of great interest to mimic the in vivo conditions as closely as possible in vitro in order to predict the in vivo behavior of EC dosage forms. The reason behind this is the overly high buffering capacity of the common compendial buffers compared to the intestinal bicarbonate buffer. However, a bicarbonate-based buffer is technically difficult to handle due to the need for continuous sparging of the media with CO2 to maintain the desired buffer pH. Therefore, bicarbonate buffers are not commonly used in routine practice and a non-volatile alternative is of interest. A mathematical mass transport modelling approach was previously found to enable accurate calculation of surrogate buffer molarities for small molecule compounds; however, the additional complexity of polymeric materials makes this difficult to achieve for an enteric coat. In this work, an approach was developed allowing relatively rapid screening of potential surrogate buffers for enteric coating. It was found that the effective buffering pKa of bicarbonate at the surface of a dissolving enteric polymer tended to be around 5.5, becoming higher when the dissolving enteric polymer formed a gel of greater firmness/viscosity and vice versa. Using succinate (pKa 5.2 under physiological ionic strength) and/or citrate (pKa 5.7 under physiological ionic strength) at conjugate base molarities corresponding to bicarbonate molarities in the intestinal segments of interest as an initial “guess” can minimize the number of experimental iterations necessary to design an appropriate surrogate.

In Vitro Methodologies for Evaluating Colon-Targeted Pharmaceutical Products and Industry Perspectives for Their Applications

“…This sets bicarbonate apart from the other buffers, the action of which typically involves solely proton transfer reactions. This is because the effective pKa governing the buffering action at the interface between the dissolution medium and the dosage form/API will be a function of the diffusion rates of CO 2 and H 2 CO 3 , which will in turn depend on the hydrodynamics and viscosity [96,101,102].…”

“…Since the high buffer capacity compendial media poorly reflect this, they often tend to greatly overestimate the release rates from pH-dependent drug-delivery systems contributing to occasional in vivo product failure, particularly in cases where pH is not high enough or transit time is too fast [102]. Accordingly, at least during formulation development of pH-dependent drug delivery systems, it is important to use either physiological bicarbonate buffer or properly designed surrogates [96,102].…”

“…One set of bicarbonate-free media is the FaSSIF-related series, including fasted state simulated media resembling gastric fluid (FaSSGF), various versions of fasted state simulated intestinal fluid (FaSSIF-V1, -V2 and V3), ileal simulated intestinal fluid (SIF ileum ) and ascending colon fluid (FaSSCoF) [92,94,98,121]. Those media are characterized by the presence of bile surfactants and buffer capacities lower than those of the compendial buffers, although they still tend to be too high compared to intestinal fluids (Table 2) [96]. The requirement for bile salt inclusion in the buffer may depend on the active ingredient properties.…”

“…This method accurately predicted the pharmacokinetic parameters of these products obtained by deconvolution of healthy subjects' plasma profiles [87]. Although useful, this approach strongly depends on the test product because the bicarbonate pKa eff will vary according to the viscosity of the gel layer formed after the disentanglement of the coating material [96]. Recently, a more mechanistic approach for selecting a surrogate media was proposed and the in vitro dissolution of several products with diverse types of coating in different buffer species under bio-relevant conditions (molarities, temperature and ionic strength) was presented.…”

“…Based on these findings, the authors recommended a decision tree for selecting the most appropriate surrogate buffer. This involves an early assessment of the dissolution in bicarbonate and succinate, followed by only a few fine-tuning experiments depending on differences between dissolution in the surrogate media and in bicarbonate buffer (used as reference) [96].…”