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Background/Objectives: Minzasolmin is a weakly basic drug developed as a potential therapy in Parkinson’s. Amongst the strategies that have been developed to enhance API solubility, pH modification is an effective and patient-centric approach that improves solubility by creating a microenvironmental pH around the drug. The objective of this study was to evaluate different formulation approaches to develop an immediate-release tablet or capsule containing fumaric acid as a pH modifier. Methods: Ten formulations were developed, varying the degree of contact between the API and pH modifier. These formulations were then assessed in three biorelevant dissolution conditions to estimate their robustness towards variations in gastric pH. Results: In highly buffered conditions, only the over-encapsulated tablet showed a clear improvement in the dissolution profile, with up to 5.1 times the percentage dissolved compared to the capsule without acid and up to 1.4 times compared to the target granule-in-capsule with acid. In low-buffered conditions, though, all prototypes with acid showed an improvement in the percentage dissolved, between 54 and 79 times compared to that of the capsule without acid, regardless of the degree of contact between the organic acid and the API. This was associated with a decrease in pH to 5 in the gastric compartment. Conclusions: These results suggested that the acidic microenvironment, estimated via the bulk pH, and hence the dissolution rate may not require such a high degree of contact between the API and the pH modifier. Based on in vitro results, the over-encapsulated tablet as well as prototypes with a lower degree of contact between the acid and PI will be evaluated in vivo in a future study to evaluate the bio-relevance of the approach.

Background/Objectives: Minzasolmin is a weakly basic drug developed as a potential therapy in Parkinson’s. Amongst the strategies that have been developed to enhance API solubility, pH modification is an effective and patient-centric one that improves solubility by creating a microenvironmental pH around the drug. The objective of this study was to evaluate different formulation approaches to develop an immediate-release tablet or capsule containing fumaric acid as pH-modifier. Methods: Ten formulations were developed varying the degree of contact between the API and pH-modifier. These formulations were then tested in three Biorelevant dissolution conditions to estimate their robustness towards variations in gastric pH. Results: In vitro data showed the best dissolution rate with the over-encapsulated tablet prototype, even in highly buffered achlorhydric conditions and was therefore the most robust formulation toward elevated gastric pH. However, in low buffered achlorhydric conditions the monolayer tablet with acid exhibited similar dissolution rate and prototypes with less close contact between the API and the organic acid also demonstrated improved dissolution rates. Conclusions: These results suggested that the acidic microenvironment may not require such a high degree of contact between the API and the pH-modifier. Selected prototypes will be evaluated in vivo in a future study to evaluate the bio-relevance of the approach.

The relatively high cost and low availability of chiral organocatalysts, in addition to the high catalytic loading required (typically 1–30 mol%), pose a general challenge to the industrial development of economical asymmetric organocatalytic processes. This challenge can be addressed by recycling the organocatalysts. In this work, the potential of a class of organocatalysts, based on the cinchona alkaloid quinidine, was evaluated for the enantioselective synthesis step of an active pharmaceutical ingredient (API). Enlarging the organocatalysts through polyalkylation made the organocatalysts easier to recycle with organic solvent nanofiltration (OSN) membranes. Each organocatalyst candidate's molecular size, molecular charge and ability to form hydrogen bonds were all important factors which determined the membrane retention of the catalyst. The consideration of these three factors enabled the eventual identification of a catalyst, of MW = 1044 Da, that was almost completely retained by the membrane, making it well-suited for recycling via OSN. In addition, a marked improvement in catalytic performance was observed for the enlarged catalyst compared to the non-enlarged catalyst, with high enantioselectivities of >92% ee obtained for all catalysed asymmetric Michael additions. Finally, a 2-stage membrane process was implemented to improve the productivity of the catalyst recycling process, resulting in a 96% reduction of solvent required for the recycling process.