(W1230-01-01) Understanding the Role of Acidic pH Modifiers in Achieving pH-Independent Release from Extended-Release Matrix Tablets of Weakly Basic Drugs

Purpose: Extended-release (ER) systems are designed to make the drug available for absorption over an extended period after ingestion, thus reducing the dosing frequency. ER formulations may provide additional advantages including improved therapeutic effect, increased patient compliance, and attenuated adverse effects. Most pharmaceutical compounds are weak bases with pH-dependent solubility. Thereby, drug release from ER systems can vary with pH in different segments of gastrointestinal tract. This presents a major challenge in achieving consistent and desired in-vivo performance. To overcome this, one commonly reported approach is to incorporate pH-modifiers to modulate microenvironment pH (pH_m) of the dosage form. Presently, most published works are specific to API and/or formulation with limited general applicability due to the large number of variables involved. Therefore, there is a need to decipher the complex relationships among active pharmaceutical ingredients (APIs), pH-modifiers, and formulation composition to develop a systematic approach to the design of pH-independent ER systems. The objectives of this study are (1) to evaluate the effects of different acidic pH-modifiers on pH-dependency of drug release for weakly basic APIs with different solubility and pKa, and related mechanisms, and (2) to develop a novel colorimetric method for comparing effectiveness of pH-modifiers through measuring pH_m of tablets during dissolution.

Methods: API solubilities were determined by adding excess drug in pH buffers (pH 1.1 and 6.8), followed by incubator shaking for 72 h. pH of saturated acid solutions was measured with pH probe after adding excess amount of acid in pH 6.8 buffer and. Composition of control tablets consisted of 5% API, 30% HPMC K1500, and 65% Avicel PH102. Formulations with pH-modifier were designed by replacing 20% of Avicel with an acid. Tablets were prepared by direct compression with solid fraction of 0.9. In-vitro drug release was performed using USP II paddle method (37ºC, 75 rpm) at two pH conditions (50 mM phosphate buffer pH 6.8 or 0.1 N HCl pH 1.1). Similarity factor f₂ was calculated for each formulation between two pHs. For mechanistic studies, solubility of APIs in saturated acid solutions were completed after 48 h of shaking. Raman spectroscopy and pXRD were used to evaluate residual solid-state forms. Polymer (HPMC) dissolution was determined using phenol-sulfuric acid assay. For colorimetric method, pH indicators were wet granulated with Avicel before tableting. Standard tablets were submerged in pH buffers before images were taken. RGB values of tablets were converted to CIE 1931-XYZ color space to extrapolate the calibration curve using machine learning. The equation was used to calculate pH_m of the acid tablets during dissolution, where images were captured from a flow cell setup.

Results: Effects of pH-modifiers: Table 1 displays the physiochemical properties of five weakly basic compounds that exhibit pH-dependent solubilities to different extents at low and high pH. Table 2 summarizes the acid properties. p-Toluenesulfonic acid (TSA) shows highest solubility and highest acid capacity (pH_f in pH 6.8 = -0.29), followed by cyclamic acid (CA, pH_f = 0.98), and fumaric acid (FA, pH_f = 2.79). Table 3 summarizes the effect of drug release by using f₂ similarity factors to compare drug release profiles of formulations at pH 1.1 and 6.8. f₂ value >50 indicates pH-independent dissolution. There was a rank order of TSA >CA >FA for THZ and LMT. But with CVD, VEH, and VEB, most acids achieved pH-independent release. Mechanisms of pH-independent release: Fig.1A&B showed evidence of in-situ salt formation which decreased drug release at pH 1.1. Fig.1C showed congruent HPMC and THZ drug release for TSA and FA formulations, whereas Fig.1D demonstrated VEB drug release is faster than HPMC release in both formulations. Colorimetric detection of pH_m: Fig.2A summarizes the pH-indicator calibration curve for tablets using machine learning. Fig.2B-D are examples of image analysis of acid containing tablets at 1h timepoint. Fig.2E-G are pH vs tablet distance graphs of these tablets at selected timepoints. TSA led to the lowest pH_m, but also had the highest release rate from the matrix tablet. FA was at the other extreme among the three acids.

Conclusion: Observations from the dissolution studies indicate that smaller the pH-solubility difference of the drug, the less challenging it is to achieve pH-independent release. With APIs pKa < 7, pH-modifiers with higher solubility is more likely to achieve pH-independent release (rank order: TSA >CA >FA). For APIs pKa >7, impact of solubility of acid diminished as evidenced by similar results of all acids. Mechanistic studies demonstrated in-situ salt formation plays an important role in achieving pH-independent release by decreasing dissolution rate at pH 1.1. At pH 6.8, for low pKa API (THZ), acids increase drug release through increasing polymer erosion. For high pKa API (VEB), acids increase drug release primarily by acting as a solubility enhancer to accelerate drug diffusion (Fig.1E). Finally, a novel colorimetric method was developed to evaluate pH_m during dissolution that provides additional information on the effectiveness of pH-modifiers.

Acknowledgements: AbbVie contributed to the design; participated in collection, analysis, and interpretation of data; and in writing, reviewing, and approval of the final version. AbbVie sponsored and funded the study. X.W., T.L., H.Z., H.P., Y.Q., and D.L are either current or former employees of AbbVie and may own AbbVie stock.


Table 1: List of selected basic model compounds. Final pH (pHf) was measured using a pH probe.
Table 2: Physiochemical properties of the selected pH-modifiers.
Table 3: Similarity factor f2 between pH 1.1 and 6.8 dissolution profiles.


Figure 1: Mechanistic studies to explain pH-independent release. (A) Solubility of THZ in saturated acid solutions and in-situ salt conversion at pH 1.1. (B) pH-solubility profile of THZ and salt solubility using TSA, CA, and FA pH modifiers. Comparison between HPMC erosion profile and drug release at pH 6.8 for (C) THZ and (D) VEB. (E) Table summary of mechanisms explaining pH-modifier strategy in achieving pH-independent extended release.


Figure 2: Colorimetric detection of pHm. (A) Schematic summarizes the establishment of pH-indicator tablet calibration curve using machine learning and flow cell setup to image tablet dissolution. Examples of image analysis of acid tablets at 1h timepoint for (B) TSA, (C) CA, and (D) FA. Summary of tablet pHm of (E) TSA, (F) CA, and (G) FA at four selected timepoints (1, 8, 16, and 24 h).