(M1030-12-82) Investigation of Rational Selection of Small Molecule Acids in pH-Independent Extended-Release Matrix Tablets of Weakly Basic Drugs

Purpose: Extended-release (ER) systems are designed to make the drug available over an extended period after ingestion, thus allowing a reduction in dosing frequency. ER formulations can also provide further advantages including improved therapeutic effect, increased patient compliance, and attenuated adverse effects. Most pharmaceutical compounds are weak bases or acids that exhibit pH-dependent solubility in the pH range of the gastrointestinal tract (GIT), resulting in pH-dependent release in different segments of GIT for matrix and reservoir ER systems. This presents a major challenge in achieving consistent and desired in-vivo performance. To overcome this problem, one commonly reported approach is to incorporate pH-modifying excipients to modulate microenvironment pH of the dosage form. However, most of the study findings are specific to API and/or formulation with limited or no general applicability due to the large number of variables involved and their complex interactions. Therefore, there is a need to decipher the complex relationships among active pharmaceutical ingredient (API), pH-modifiers, ER technology, formulation composition and in vitro test to develop a systematic approach to the design of pH-independent release ER dosage forms. The first part of this project is aimed at rank ordering small molecule acids as the appropriate pH-modifier in ER tablets of three model drugs with varying solubilities and pKas (Table 1&2). In addition, the effectiveness of pH-modifiers in modulating microenvironment pH was evaluated (pH_m) using pH-sensitive indicator dyes.

Methods: API solubilities were determined by adding excess drug in different pH buffers and placing in an incubator shaker at 37ºC for 72 h before injecting on HPLC. Final pH (pH_f) of acids was determined by adding excess amount of acid in pH 6.8 phosphate buffer on a shaker for 24 h at 37ºC. pH probe was used to determine pH_f. Solubility of APIs in saturated acid solutions were completed after 48 h of shaking at 37ºC. Raman spectroscopy, pXRD, and FTIR were used to evaluate new salt forms occurring between API and acid. Composition of control tablets (with no pH modulator) consisted of 5% API, 30% HPMC K1500, 65% Avicel PH102. Composition of tablets containing acid replaced 20% of Avicel with corresponding acid. Tablets were prepared by direct compression using Carver press to make 300 mg tablets with solid fraction of 0.9. In-vitro drug release was performed using USP II paddle method (37 ± 0.5 ºC, 75 rpm) at two pH conditions (900 mL of 50 mM phosphate buffer pH 6.8 or 0.1 N HCl pH 1.1). Samples were analyzed on the HPLC. The pH indicator tablets were prepared by directly incorporating 0.1% w/w of indicator to powder blend or by wet granulation with Avicel. Control and acid tablets were submerged in pH buffers for 2 h before images were taken on the stereo microscope. Using ImageJ software, RGB values of individual tablets were collected and then converted to CIE 1931-XYZ color space to extrapolate the calibration curve. The equation is then used to calculate the pH of the acid tablets according to their corresponding RGB values.

Results: 1) Table 1 displays the physiochemical properties of clopidogrel bisulfate (CLB), thiabendazole (THZ), and lamotrigine (LAG). All three APIs exhibit pH-dependent solubilities to different extents at low and high pH. Table 2 summarizes the acids’ properties, with p-Toluenesulfonic acid (TSA) showing highest solubility but also highest acid capacity (pH_f in pH 6.8 = 0.11), followed by cyclamic acid (CA, pH_f = 0.98), and fumaric acid (FA, pH_f = 2.79). 2) f₂ similarity factor was used to evaluate drug release profiles of formulations at pH 1.1 and 6.8. f₂ value >50 indicate pH-independent dissolution. Results showed only LAG achieved pH-independent release with TSA (f₂= 62) and CA (f₂= 51) (Figure 1). THZ and CLB were unable to reach f₂ > 50 with any pH modifiers, though reduced pH-dependence was observed. This can be attributed to the huge solubility difference of API between pH 1.1 and 6.8. Overall, the rank order of acids in their capability in increasing release at pH 6.8 is TSA >CA >FA. 3) Thymol blue and bromophenol blue were used as pH indicators incorporated into the tablets. Robust calibration curves were generated, and results showed good agreement with pH measurement for future studies (Figure 2). This study further corroborated the acid rank order, with TSA maintaining the lowest gel layer pH (1.78) at pH 6.8 after 2 h.

Conclusion: The initial study findings provide a rank order of acids as pH modifiers in ER systems. The solubilities difference of API at pH 1.1 and 6.8 played a large role in determining whether this approach would be successful to reach pH-independent release. Further studies involving other APIs and acids will be required to provide the underlying relationships between factors related to API, pH-modifiers, and formulation composition. Pending work on the novel method using indicator pH dyes in determining gel layer pH_m is in progress.

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. 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: Physiochemical properties of weakly basic compounds that demonstrate pH-dependent solubility.
Table 2: Physiochemical properties of the organic acids used a pH modifiers to improve the release of weakly basic drugs from matrix tablets.

Figure 1: Drug release profiles of (A) Thiabendazole (THZ), (B) Lamotrigine (LAG), and (C) Clopidogrel Bisulfate (CLB). Dissolution profile similarity factor f2 for (D) THZ, (E) LAG, and (F) CLB.​

Figure 2: Development of pH indicator tablets. Powder bed validation of (A) thymol blue and (B) bromophenol blue in different pH buffer solutions, along with tablet images. Images and predicted pH values of (C) TSA and (D) CA tablets after submerging in pH 1.1 or 6.8 buffer solutions for 2 h using thymol blue as pH indicator. (E) Images and predicted pH values of FA tablets used bromophenol blue as pH indicator. *Calculated pH was outside of the standard curve range.