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

Abstract

The incorporation of counterions into amorphous solid dispersions (ASDs) has been proven to be effective for improving the dissolution rates of ionizable drugs in ASDs. In this work, the effect of dissolution buffer pH and concentration on the dissolution rate of indomethacin–copovidone 40:60 (IMC–PVPVA, w/w) ASD with or without incorporated sodium hydroxide (NaOH) was studied by surface area-normalized dissolution to provide further mechanistic understanding of this phenomenon. Buffer pH from 4.7 to 7.2 and concentration from 20 to 100 mM at pH 5.5 were investigated. As the buffer pH decreased, the IMC dissolution rate from both ASDs decreased. Compared to IMC–PVPVA ASD, the dissolution rate decrease from IMCNa–PVPVA ASD was more resistant to the decrease of buffer pH. In contrast, while buffer concentration had a negligible impact on the IMC dissolution rate from IMC–PVPVA ASD, the increase of buffer concentration significantly reduced the IMC dissolution rate from IMCNa–PVPVA ASD. Surrogate evaluation of microenvironment pH modification by the dissolution of IMCNa–PVPVA ASD demonstrated the successful elevation of buffer microenvironment pH and the suppression of such pH elevation by the increase of buffer concentration. These results are consistent with the hypothesis that the dissolution rate enhancement by the incorporation of counterions originates from the enhanced drug solubility by ionization and the modification of diffusion layer pH in favor of drug dissolution. At the studied drug loading (∼40%), relatively congruent release between IMC and PVPVA was observed when IMC was ionized in ASD or in solution, highlighting the importance of studying the ionization effect on the congruent release of ASDs, especially when drug ionization is expected in vivo. Overall, this work further supports the application of incorporating counterions into ASDs for improving the dissolution rates of ionizable drugs when enabling formulation development is needed.

Generality of Enhancing the Dissolution Rates of Free Acid Amorphous Solid Dispersions by the Incorporation of Sodium Hydroxide

“…Both rotary evaporation and spray drying rely on the evaporation of solvents to produce ASDs. Rotary evaporation is a commonly used technology for ASD preparation at the research scale and is widely employed for preparing ASDs in the reported dissolution studies. ,,, On the other hand, a wider range of sample preparation scales, from research to commercial production, can be achieved by spray drying. These two preparation methods were compared specifically to understand whether proof-of-concept studies that were often conducted by rotary evaporation in the research stage could translate to the ASD formulations prepared by spray drying during the later development stage.…”

“…Further biopharmaceutical performance evaluation is needed to test whether the observed general enhancement of the dissolution rate by the incorporation of NaOH to free acid ASDs could translate to higher in vivo exposures. From the dissolution perspective, it has been reported that a decrease in the buffer pH to the p K a of the drug amplified the dissolution rate enhancement by the incorporation of NaOH into the IMC-PVPVA ASD . Whether such a trend continues at an even lower buffer pH (e.g., below the p H max of an acidic drug or in the fasted-state simulated gastric fluid) remains unknown and warrants further investigation.…”

“…As the carrier for ASD formulation, the hydrophilic polymer PVPVA was found to be superior to the enteric polymer HPMCAS for the dissolution rate enhancement of free acid ASDs when NaOH was incorporated. Together with the successful maintenance of congruent release by the incorporation of NaOH into PVPVA-based free acid ASDs reported previously, , PVPVA or a similar hydrophilic neutral polymer is recommended as the polymer carrier for the development of free acid ASD formulations containing counterions. Finally, to fully implement this strategy for drug development, in vivo pharmacokinetic or simulated in vivo biopharmaceutical studies should be performed on diverse ASD systems (different drugs and different polymers) incorporated with counterions to further understand whether the enhanced dissolution rate achieved by this approach could successfully translate to higher bioavailability.…”

“…Their results showed that at a relatively lower pH and buffer concentration, the dissolution rate enhancement by the incorporated NaOH was more pronounced. From these studies, the authors also discovered that the incorporation of NaOH successfully maintained a congruent release between IMC and PVPVA at drug loadings as high as approximately 80%, , demonstrating a promising approach to maintain congruent release for ASDs of high drug loadings. Despite the various reported examples, a systematic investigation of different drugs, different preparation methods, and different polymer carriers to understand the generality of enhancing ASD dissolution rates by the incorporation of counterions has not been performed.…”

“…In this work, building on previous studies, we tested the generality of enhancing the dissolution rates of free acid amorphous solid dispersions by the incorporation of NaOH. Similar to our previous studies, , a surface-area-normalized dissolution methodology was employed to quantify the dissolution rate enhancement. NaOH was selected as the counterion because it is a strong base that can ionize most acidic functional groups in drug molecules and sodium is the most common cation in the salts of acidic drugs (>75%) .…”