Development and Performance of a Highly Sensitive Model Formulation Based on Torasemide to Enhance Hot-Melt Extrusion Process Understanding and Process Development.

The aim of this work was to investigate the use of torasemide as a highly sensitive indicator substance and to develop a formulation thereof for establishing quantitative relationships between hot-melt extrusion process conditions and critical quality attributes (CQAs). Using solid-state characterization techniques and a 10 mm lab-scale co-rotating twin-screw extruder, we studied torasemide in a Soluplus® (SOL)-polyethylene glycol 1500 (PEG 1500) matrix, and developed and characterized a formulation which was used as a process indicator to study thermal- and hydrolysis-induced degradation, as well as residual crystallinity. We found that torasemide first dissolved into the matrix and then degraded. Based on this mechanism, extrudates with measurable levels of degradation and residual crystallinity were produced, depending strongly on the main barrel and die temperature and residence time applied. In addition, we found that 10% w/w PEG 1500 as plasticizer resulted in the widest operating space with the widest range of measurable residual crystallinity and degradant levels. Torasemide as an indicator substance behaves like a challenging-to-process API, only with higher sensitivity and more pronounced effects, e.g., degradation and residual crystallinity. Application of a model formulation containing torasemide will enhance the understanding of the dynamic environment inside an extruder and elucidate the cumulative thermal and hydrolysis effects of the extrusion process. The use of such a formulation will also facilitate rational process development and scaling by establishing clear links between process conditions and CQAs.

In vitro characterization of ritonavir formulations and correlation to in vivo performance in dogs.

Ritonavir (RTV) is a weakly basic drug with a pH-dependent solubility. In vitro characterization of dissolution and supersaturation behaviors of three PEG-8000 based amorphous solid dispersions (ASD) and a physical blend (PB) with crystalline drug were performed in the biomimetic media (e.g., FaSSGF, FaSSIF, FaSSIF-V2). A two-stage dissolution test and a biphasic dissolution-partition test at the small scale (referred as to biphasic test) were employed with intention to examine the in vitro and in vivo relationship (IVIVR) with retrospective PK data in dog model. The two-stage dissolution test revealed a high degree of supersaturation of RTV from these ASDs accompanied by the occurrence of liquid-liquid phase separation (LLPS) in the biomimetic media. A rapid decrease of apparent RTV concentrations of these ASDs was associated with significant precipitation upon the pH shift of the dissolution medium, revealing the important role of "the gastric stage". In comparison, the biphasic test revealed a lower degree of supersaturation of RTV that is attributed to removal of RTV through partition into octanol, acting as "the absorption compartment". These two dissolution tests provide characterization of the supersaturation state with a complex, dynamic interplay among dissolution, precipitation and partition processes. Results of both in vitro dissolution tests are in good agreement with in vivo results in dogs. In addition, three commercial generic RTV drug products were examined by the biphasic test. Agreement was also obtained between the RTV concentrations in octanol at 3 h from these generic drug products and their corresponding relative bioavailability in dogs.

The BioGIT System: a Valuable In Vitro Tool to Assess the Impact of Dose and Formulation on Early Exposure to Low Solubility Drugs After Oral Administration.

The purpose of this study was to evaluate the usefulness of the in vitro biorelevant gastrointestinal transfer (BioGIT) system in assessing the impact of dose and formulation on early exposure by comparing in vitro data with previously collected human plasma data of low solubility active pharmaceutical ingredients. Eight model active pharmaceutical ingredients were tested; Lu 35-138C (salt of weak base in a HP-beta-CD solution, three doses), fenofibrate (solid dispersion, tablet, two doses), AZD2207 EQ (salt of weak base, capsule, three doses), posaconazole (Noxafil® suspension, two doses), SB705498 (weak base, tablets vs. capsules), cyclosporine A (Sandimmun® vs. Sandimmun® Neoral), nifedipine (Adalat® capsule vs. Macorel® tablet), and itraconazole (Sporanox® capsule vs. Sporanox® solution). AUC0-0.75h values were calculated from the apparent concentration versus time data in the duodenal compartment of the BioGIT system. Differences in AUC0-0.75h values were evaluated versus differences in AUC0-1h and in AUC0-2h values calculated from previously collected plasma data in healthy adults. Ratios of mean AUC0-0.75h, mean AUC0-1h, and mean AUC0-2h values were estimated using the lowest dose or the formulation with the lower AUC0-0.75h value as denominator. The BioGIT system qualitatively identified the impact of dose and of formulation on early exposure in all cases. Log-transformed mean BioGIT AUC0-0.75h ratios correlated significantly with log-transformed mean plasma AUC0-1h ratios. Based on this correlation, BioGIT AUC0-0.75h ratios between 0.3 and 10 directly reflect corresponding plasma AUC0-1h ratios. BioGIT system is a valuable tool for the assessment of the impact of dose and formulation on early exposure to low solubility drugs.

Formation of nano/micro-dispersions with improved dissolution properties upon dispersion of ritonavir melt extrudate in aqueous media.

The objective of the study was to characterise the aqueous dispersions of ritonavir melt extrudates. More specifically to look into the particular system formed when melt extrudate of a poorly soluble drug dissolved in a hydrophilic polymer matrix containing a surfactant is dispersed in an aqueous medium. Melt extrudates with and without ritonavir were studied. The drug containing extrudate was confirmed to be molecular dispersions of drug in a polymer/surfactant matrix. Particulate dispersions were formed in water from both drug and placebo extrudates. The dispersions were investigated with respect to mean particle size and particle size distribution (photon correlation spectroscopy and optical particle counting), surface charge (zeta potential), particle composition (ultracentrifugation), tendency to form aggregates and precipitate (turbidity), in vitro dissolution rate and drug release. It was concluded that dispersion of melt extrudates in aqueous medium give rise to nano/micro-dispersions. The stability of the nano/micro-dispersion is sensitive to anions and may be subjected to association/aggregation/flocculation as time proceeds after preparation of dispersion. Melt extrudate showed improved dissolution rate and drug release properties compared to crystalline raw material. From studies of single components and physical mixtures of the formulation composition it can be concluded that the drug delivery system itself, namely solid dispersion prepared by melt extrusion technology, plays a key role for the formation of the observed particles.