Introduction and Objective Physiologically based pharmacokinetic (PBPK) models are increasingly used to predict food effect (FE) but model parameterization is challenged by in vitro-in vivo (IVIV) disconnect and/or parameter nonidentifiability. To overcome these issues, we propose a simplified PBPK model, in which all solubility-driven processes are lumped into a single parameter, solubility, which is optimized against observed concentration-time data. Methods A set of commercially available biopharmaceutical classification system (BCS) II/IV compounds was selected to measure the solubility in a fasted state simulated intestinal fluid (FaSSIF) medium. The compounds were ranked from the lowest to the highest dose-adjusted FaSSIF solubility (FaSSIF/D) value and subdivided into three areas based on an upper and a lower limit: drugs with FaSSIF/D > upper limit having no FE, drugs with FaSSIF/D < lower limit having FE, and drugs between the limits said to be in the sensitivity range (SR), for which we tested the hypothesis that solubility-limited absorption (SLA) identified by simplified PBPK model can reliably predict positive FE if their exposures are not impacted by gut efflux or gut metabolism. Results We demonstrate, using a subset of drugs within SR for which PBPK models were available, that drugs with SLA exhibited a positive FE, while those with no SLA did not show FE. Conclusions This proposal allows for a reliable binary prediction of FE to enable timely decisions on the need for pilot FE studies as well as the timing of pivotal FE studies.

Microencapsulation of active pharmaceutical ingredients (APIs) for preparation of long acting injectable (LAI) formulations is an auspicious technique to enable preclinical characterization of a broad variety of APIs, ideally independent of their physicochemical and pharmacokinetic (PK) characteristics. During early API discovery, tunable LAI formulations may enable pharmacological proof-of-concept for the given variety of candidates by tailoring the level of plasma exposure over the duration of various timespans. Although numerous reports on small scale preparation methods for LAIs utilizing copolymers of lactic and glycolic acid (PLGA) and polymers of lactic acid (PLA) highlight their potential, application in formulation screening and use in preclinical in vivo studies is yet very limited. Transfer from downscale formulation preparation to in vivo experiments is hampered in early preclinical API screening by the large number of API candidates with simultaneously very limited available amount in the lower sub-gram scale, lack of formulation stability and deficient tunability of sustained release. We hereby present a novel comprehensive platform tool for tailored extended-release formulations, aiming to support a variety of preclinical in vivo experiments with ranging required plasma exposure levels and timespans. A novel small-scale spray drying process was successfully implemented by using an air brush based instrument for preparation of PLGA and PLA based formulations. Using Design of Experiments (DoE), required API amount of 250 mg was demonstrated to suffice for identification of dominant polymer characteristics with largest impact on sustained release capability for an individual API. BI-3231, a hydrophilic and weakly acidic small compound with good water solubility and permeability, but low metabolic stability, was used as an exemplary model for one of the many candidates during API discovery. Furthermore, an in vitro to in vivo correlation (IVIVC) of API release rate was established in mice, which enabled the prediction of in vivo plasma concentration plateaus after single subcutaneous injection, using only in vitro dissolution profiles of screened formulations. By tailoring LAI formulations and their doses for acute and sub-chronic preclinical experiments, we exemplary demonstrate the practical use for BI-3231. Pharmacological proof-of-concept could be enabled whilst circumventing the need of multiple administration as result of extensive hepatic metabolism and simultaneously superseding numerous in vivo experiments for formulation tailoring.

Lung selective inhibition of the endothelial sodium channel (ENaC) is a potential mutation agnostic treatment of Cystic Fibrosis (CF). We describe the discovery and development of BI 1265162, the first ENaC inhibitor devoid of the amiloride structural motif that entered clinical trials. The design of BI 1265162 focused on its suitability for inhalation via the Respimat® Soft Mist™ Inhaler and a long duration of action. A convergent and scalable route for the synthesis of BI 1265162 as dihydrogen phosphate salt is presented, that was applied to support clinical trials. A phase 2 study with BI 1265162 did not provide a clear sign of clinical benefit. Whether ENaC inhibition will be able to hold its promise for CF patients remains an open question.

Dabigatran etexilate mesylate is polymorphic and can exist in different crystalline forms. Two polymorphs have been encountered during the development of this drug substance, namely anhydrous form I and anhydrous form II. Additionally, a hemihydrate was observed, if larger amounts of water were present during crystallization in the salt formation step. Finally, a high temperature form III can be obtained by heating anhydrous form I above 150 degrees C. All three at room-temperature accessible forms were characterized by means of microscopy, X-ray powder diffraction, thermal analysis, IR- and Raman spectroscopy. In addition, solubility parameters (equilibrium solubility and intrinsic dissolution rate, heat of solution) were collected on all three forms. The crystal structure of all three at room-temperature accessible forms could be obtained using electron diffraction. Anhydrous form I has a monoclinic crystal lattice (C2/c), anhydrous form II a triclinic one (P1), and the hemihydrate crystallizes also in a monoclinic space group (P2/c). From the obtained data there is clear evidence that anhydrous form II is thermodynamically more stable than anhydrous form I. Form I and form II are monotropically related to each other indicating that they may coexist over a wide temperature range. The hemihydrate is a completely independent crystalline modification of dabigatran etexilate mesylate. It is another thermodynamically stable form and structurally not related to the two anhydrous forms. The hemihydrate melts at ca. 125 degrees C, there is no conversion to either anhydrous form I or form II upon dehydration. The high temperature form III is enantiotropically related to form I and only stable above the phase transition temperature at ca. 150 degrees C and its melting point at ca. 183 degrees C. The energy difference between anhydrous form I and form II was found to be only 2.5 - 3.0 J/g. Both forms have very similar aqueous solubility characteristics. Although anhydrous form II is the thermodynamically more stable form, anhydrous form I was chosen for development. The selection of form I for development was mainly based on the superior bulk processing properties of anhydrous form I in drug substance synthesis and further drug product processing as well as its slightly better chemically stability in pivotal long term stability studies. Anhydrous form I, although meta stable, is still stable enough that conversion to the more stable form II can occur only to a limited extent during drug substance synthesis and drug product manufacturing. From long term stability data on both bulk drug substance as well as drug product, there is no indication that form I transforms to form II during storage. Even under stress conditions where form I was stored up to 4 weeks at 70 degrees C, no conversion to form II was observed.

We present the first comprehensive study on the prediction of reactivity for propynamides. Covalent inhibitors like propynamides often show improved potency, selectivity, and unique pharmacologic properties compared to their non-covalent counterparts. In order to achieve this, it is essential to tune the reactivity of the warhead. This study shows how three different in silico methods can predict the in vitro properties of propynamides, a covalent warhead class integrated into approved drugs on the market. Whereas the electrophilicity index is only applicable to individual subclasses of substitutions, adduct formation and transition state energies have a good predictability for the in vitro reactivity with glutathione (GSH). In summary, the reported methods are well suited to estimate the reactivity of propynamides. With this knowledge, the fine tuning of the reactivity is possible which leads to a speed up of the design process of covalent drugs.

Azulene is a bicyclic scaffold rarely applied in medicinal chemistry. Here we report physicochemical and in vitro parameters relevant for drug discovery for a series of diversely substituted azulenes. We syn-thesized and characterized several scaffold hopping series of analogously substituted azulenes, indoles and naphthalenes. This enabled a comparison of azulene with the more common scaffolds indole and naphthalene. Our data indicates that undesirably low photostability of azulenes is restricted to certain substitution patterns. Generally, we conclude that azulene is an underused lipophilic bicycle and should be considered as a valuable complement to the collection of medicinal chemistry scaffolds. (c) 2022 The Authors. Published by Elsevier Masson SAS.

Bidirectional permeability measurement with cellular models grown on Transwell inserts is widely used in pharmaceutical research since it not only provides information about the passive permeability of a drug, but also about transport proteins involved in the active transport of drug substances across physiological barriers. With the increasing number of investigative drugs coming from chemical space beyond Lipinski's Rule of 5, it becomes more and more challenging to provide meaningful data with the standard permeability assay. This is exemplified here by the difficulties we encountered with the cyclic depsipeptides emodepside and its close analogs with molecular weight beyond 1000 daltons and cLogP beyond 5. The aim of this study is to identify potential reasons for these challenges and modify the permeability assays accordingly. With the modified assay, intrinsic permeability and in vitro efflux of depsipeptides could be measured reliably. The improved correlation to in vivo bioavailability and tissue distribution data indicated the usefulness of the modified permeability assay for the in vitro screening of compounds beyond the Rule of 5.

Drop on demand inkjet printing was applied to obtain excipient-free particles with a narrow size distribution. The objective of this work was to establish the general applicability of the process on a range of structurally different active pharmaceutical ingredients (APIs). Four APIs; fluticasone, budesonide, tiotropium and olodaterol were utilized. The droplet generation protocols could be established based on the solvent system, chosen with regard to stable printability and solubility of the APIs. Triple actuation pulse was applied to generate droplets of desired dimensions. Drying temperature and dispensing frequency were used to optimize the drying of the droplets. The particle size of the product was dictated by the concentration of the ink and the volume of the droplets. These parameters were used to obtain the particle diameters of 1-6 mu m. Infra-tracheal instillation to rats of fluticasone in suspensions of polydisperse spray dried particles and print dried particles of 3 and 5 mu m was performed. Amounts of residual drug content in the lung and systemic exposures differed depending on the total surface area. The developed methodology can improve the mechanistic understanding of pulmonary drug dissolution and absorption on the wide range of structurally diverse APIs in the preclinical setting.

The identification and optimization of a novel series of centrally efficacious gamma secretase modulators (GSMs) offering an alternative to the privileged aryl imidazole motif is described. Chiral bicyclic tetrahydroindazolyl amine substituted triazolopyridines were identified as structurally distinct novel series of GSMs. Representative compound BI-1408 ((R)-42) was demonstrated to be centrally efficacious in rats at a 30 mg/kg oral dose.

pH-dependent solubility - permeability profiles offer a simple way to predict bioavailability after oral application, if bioavailability is only solubility and permeability driven. Combining both pH-dependent solubility and pH-dependent permeability in one diagram provides a pH-window (= ΔpHsol-perm) from which the conditions for optimal oral bioavailability can be taken. The size of this window is directly proportional to the observed oral bioavailability. A set of 21 compounds, with known absolute human oral bioavailability, was used to establish this correlation. Compounds with ΔpHsol-perm < 2 exhibit poor oral bioavailability (< 25%). An increase of ΔpHsol-perm by one pH-unit increases oral bioavailability typically by approximately 25%. For compounds where ΔpHsol-perm ≥ 3 but still showing poor bioavailability, most probably other pharmacokinetic aspects (e.g. high clearance), are limiting exposure. Interestingly, the location of this pH-window seems to have a negligible influence on the observed oral bioavailability. In scenarios, where the bioavailability is impaired by certain factors, like for example proton pump inhibitor co-medication or food intake, the exact position of this pH-window might be beneficial for understanding the root cause.

The purpose of this study was to investigate the interlaboratory variability in determination of apparent solubility (Sapp) and intrinsic dissolution rate (IDR) using a miniaturized dissolution instrument. Three poorly water-soluble compounds were selected as reference compounds and measured at multiple laboratories using the same experimental protocol. Dissolution was studied in fasted-state simulated intestinal fluid and phosphate buffer (pH 6.5). An additional 6 compounds were used for the development of an IDR measurement guide, which was then validated with 5 compounds. The results clearly showed a need for a standardized protocol including both the experimental assay and the data analysis. Standardization at both these levels decreased the interlaboratory variability. The results also illustrated the difficulties in performing disc IDR on poorly water-soluble drugs because the concentrations reached are typically below the limit of detection. The following guidelines were established: for compounds with Sapp >1 mg/mL, the disc method is recommended. For compounds with Sapp <100 μg/mL, IDR is recommended to be performed using powder dissolution. Compounds in the interval 100 μg/mL to 1 mg/mL can be analyzed with either of these methods.

The aim of this study was to investigate if amorphous solid dispersions of telmisartan, prepared in presence of different polymers, exhibit different structural and thermodynamic characteristics and whether these differences can be correlated to their physical stability (time to crystallisation) and dissolution behaviour. Amorphous samples were prepared by melt quenching. The resulting amorphous materials were characterised using X-ray diffraction, Raman spectroscopy and differential scanning calorimetry. All freshly prepared samples were completely X-ray amorphous (with a halo being the only feature in the diffractograms). The shape of the halos in the diffractograms varied suggesting structural variations in the near order of the molecules between the different amorphous solid dispersions (ASDs). Principal component analysis of the Raman spectra of the various ASD revealed that the samples clustered in the scores plot, again suggesting structural differences due to the presence of different drug–polymer interaction. The ranking of the samples with respect to physical stability and interaction parameter was: ASD of telmisartan:eudragit > ASD of telmisartan:soluplus > ASD of telmisartan:HPMC > ASD of telmisartan:PVP > amorphous telmisartan. The interaction parameter, calculated by using the Flory Huggins theory, showed a good correlation with the experimentally determined stability whereas a weak correlation was found with dissolution behaviour of different ASD. This study showed that correlation of physical stability and dissolution behaviour with calculated interaction parameter is possible for the same amorphous systems prepared by using different polymers. This could aid in selecting the most appropriate polymer for the development of optimised formulations containing amorphous drugs. It can be concluded that ASD prepared by using different polymers have different structural and thermal properties. These differences affect the physical stability and dissolution profiles of the amorphous solids. Thus, choosing the right polymer for preparing ASD is critical for producing materials with desired dissolution profiles and enhanced stability.

Crystalline tiotropium bromide anhydrate, characterized by a unit cell determined monoclinic by structural analysis of X-rays with the parameters a = 10 4336 (2) A, b = 11 3297 (3) A, c = 17 6332 (4) A alpha = 90, beta = 105, 158 (2) oy gamma = 90 ° (cell volume = 2011 89 (8) A 3).