Effect of Counterions on Dissolution of Amorphous Solid Dispersions Studied by Surface Area Normalized Dissolution

Abstract

Solubility enhancement has become a common requirement for formulation development to deliver poorly water soluble drugs. Amorphous solid dispersions (ASDs) and salt formation have been two successful strategies, yet there are opportunities for further development. For ASDs, drug–polymer phase separation may occur at high drug loadings during dissolution, limiting the increase of drug loadings in ASD formulations. For salt formation, a salt form with high crystallinity and sufficient solid-state stability is required for solid dosage form development. This work studied the effect of counterions on the dissolution performance of ASDs. Surface area normalized dissolution or intrinsic dissolution methodology was employed to eliminate the effect of particle size and provide a quantitative comparison of the counterion effect on the intrinsic dissolution rate. Using indomethacin (IMC)–poly­(vinylpyrrolidone-co-vinyl acetate) ASD as a model system, the effect of different bases incorporated into the ASD during preparation, the molar ratios between the base and IMC, and the drug loadings in the ASD were systematically studied. Strong bases capable of ionizing IMC significantly enhanced drug dissolution, while a weak base did not. A physical mixture of a strong base and the ASD also enhanced the dissolution rate, but the effect was less pronounced. At different base to IMC molar ratios, dissolution enhancement increased with the base to IMC ratio. At different drug loadings, without a base, the IMC dissolution rate decreased with the increase of drug loading. After incorporating a strong base, it increased with the increase of drug loading. The observations from this study were thought to be related to both the ionization of IMC in ASDs and the increase of microenvironment pH by the incorporated bases. With the significant enhancement of the drug dissolution rate, our work provides a promising approach of overcoming the dissolution limitation of ASD formulations at high drug loadings.

Increasing Drug Loading of Weakly Acidic Telmisartan in Amorphous Solid Dispersions through pH Modification during Hot-Melt Extrusion

“…Upon dissolution, it achieved a 65% drug release that was 25.9× greater than the physical mixture. This substantial drug release result is in line with a recent study showing that the inclusion of NaOH in an ASD of indomethacin (a weakly acidic API) and PVPVA exhibited a high drug release even at 80% w/w drug loading, in contrast to an ASD prepared without a pH modifier . Buffered FaSSiF (pH 6.5) was used to isolate the effect of the ASD from the pH-dependent water solubility of TEL, and the pH of the medium was measured before and after dissolution.…”

“…This substantial drug release result is in line with a recent study showing that the inclusion of NaOH in an ASD of indomethacin (a weakly acidic API) and PVPVA exhibited a high drug release even at 80% w/w drug loading, in contrast to an ASD prepared without a pH modifier. 34 Buffered FaSSiF (pH 6.5) was used to isolate the effect of the ASD from the pH-dependent water solubility of TEL, and the pH of the medium was measured before and after dissolution. The pH of the medium changed by only 0.02 from the initial reading, which indicates that the pH change in the medium was not a major contributor to the solubility of TEL.…”

“…31−33 Recently, Chen et al prepared indomethacin (a weakly acidic API) and PVPVA ASDs via solvent evaporation with 20−80% w/w drug loading, with and without added NaOH. 34 All formulations, with and without NaOH, were amorphous at the drug loadings studied, but the formulations that contained NaOH showed an increased intrinsic dissolution (i.e., the dissolution per unit area exposed to the dissolution medium) as drug loading increased. This was in contrast to the decreasing intrinsic dissolution rate exhibited by the ASDs without NaOH.…”

“…Another challenge for ASDs with high drug loading is that the dissolution rate tends to decrease as drug loading increases, especially above 20–30% w/w. − Recently, Chen et al prepared indomethacin (a weakly acidic API) and PVPVA ASDs via solvent evaporation with 20–80% w/w drug loading, with and without added NaOH . All formulations, with and without NaOH, were amorphous at the drug loadings studied, but the formulations that contained NaOH showed an increased intrinsic dissolution (i.e., the dissolution per unit area exposed to the dissolution medium) as drug loading increased.…”

Effect of Buffer pH and Concentration on the Dissolution Rates of Sodium Indomethacin–Copovidone and Indomethacin–Copovidone Amorphous Solid Dispersions

“…Similarly, Duong et al discovered that the addition of acidic counterions to a weakly basic drug, delamanid, not only improved its dissolution performance from its ASD formulations but also stabilized its ASDs owing to the increase of glass transition temperature ( T g ) . In addition, using the surface area-normalized dissolution methodology, Chen et al successfully quantified the dissolution rate enhancement by adding strong basic counterions to the ASD of a weakly acidic drug, indomethacin (IMC) . The authors also discovered that the addition of a counterion and the formation of an amorphous sodium salt of IMC in the ASD especially facilitated the drug dissolution rate at high drug loadings, providing a promising approach to overcome the challenge of dissolution rate reduction with the increase of drug loading in the ASD .…”