Flux-Based Formulation Development—A Proof of Concept Study

Abstract

The work aimed to develop the Absorption Driven Drug Formulation (ADDF) concept, which is a new approach in formulation development to ensure that the drug product meets the expected absorption rate. The concept is built on the solubility-permeability interplay and the rate of supersaturation as the driving force of absorption. This paper presents the first case study using the ADDF concept where not only dissolution and solubility but also permeation of the drug is considered in every step of the formulation development. For that reason, parallel artificial membrane permeability assay (PAMPA) was used for excipient selection, small volume dissolution-permeation apparatus was used for testing amorphous solid dispersions (ASDs), and large volume dissolution-permeation tests were carried out to characterize the final dosage forms. The API-excipient interaction studies on PAMPA indicated differences when different fillers or surfactants were studied. These differences were then confirmed with small volume dissolution-permeation assays where the addition of Tween 80 to the ASDs decreased the flux dramatically. Also, the early indication of sorbitol’s advantage over mannitol by PAMPA has been confirmed in the investigation of the final dosage forms by large-scale dissolution-permeation tests. This difference between the fillers was observed in vivo as well. The presented case study demonstrated that the ADDF concept opens a new perspective in generic formulation development using fast and cost-effective flux-based screening methods in order to meet the bioequivalence criteria.

Understanding the pH Dependence of Supersaturation State—A Case Study of Telmisartan

“…The kinetic solubility measurements of TEL were determined using µDISS™ profiler (Pion Inc., Billerica, MA, USA). The method was described earlier by Kadar et al [13].…”

“…X-ray powder diffraction (XRD) measurements were performed by X'pert Pro MPD X-ray diffractometer (PANalytical B.v., Armelo, The Netherlands) [1,13].…”

“…Although the number of publications on developing formulations to achieve a supersaturated state during dissolution is rapidly increasing [1][2][3], supersaturation as a solution phenomenon is still challenging to understand, and therefore many recent publications focus on this topic [4][5][6][7][8]. While most studies focus on finding the upper limit of supersaturation called amorphous or kinetic solubility with state-of-theart analytical techniques [9][10][11][12][13], only a little information is available about the molecular interactions or structural and physicochemical properties that may enable a drug in solution to reach supersaturation. The fact that the pH of the gastrointestinal environment is 2 of 14 dynamically changing from acidic to neutral, adds to the complexity of supersaturation phenomenon, since pH dependence in species associations needs to be also considered.…”

The Effect of Surfactants and pH Modifying Agents on the Dissolution and Permeation of Pimobendan

“…Recently, a new approach, called flux-based formulation development has been published: this concept uses not only dissolution and solubility but also simultaneous dissolution-permeation assays in each step of the formulation development from the selection of excipients to the testing of final dosage forms. By using this concept the interplay between solubility and permeability can be monitored constantly during formulation development [26].…”