Novel Physics-Based Ensemble Modeling Approach That Utilizes 3D Molecular Conformation and Packing to Access Aqueous Thermodynamic Solubility: A Case Study of Orally Available Bromodomain and Extraterminal Domain Inhibitor Lead Optimization Series.

Drug design with patient centricity for ease of administration and pill burden requires robust understanding of the impact of chemical modifications on relevant physicochemical properties early in lead optimization. To this end, we have developed a physics-based ensemble approach to predict aqueous thermodynamic crystalline solubility, with a 2D chemical structure as the input. Predictions for the bromodomain and extraterminal domain (BET) inhibitor series show very close match (0.5 log unit) with measured thermodynamic solubility for cases with low crystal anisotropy and good match (1 log unit) for high anisotropy structures. The importance of thermodynamic solubility is clearly demonstrated by up to a 4 log unit drop in solubility compared to kinetic (amorphous) solubility in some cases and implications thereof, for instance on human dose. We have also demonstrated that incorporating predicted crystal structures in thermodynamic solubility prediction is necessary to differentiate (up to 4 log unit) between solubility of molecules within the series. Finally, our physics-based ensemble approach provides valuable structural insights into the origins of 3-D conformational landscapes, crystal polymorphism, and anisotropy that can be leveraged for both drug design and development.

Direct Visualization of Drug-Polymer Phase Separation in Ritonavir-Copovidone Amorphous Solid Dispersions Using in situ Synchrotron X-ray Fluorescence Imaging of Thin Films.

Amorphous solid dispersions (ASDs) are new formulations currently being used in pharmaceutical industry. The ASDs, in which amorphous drug and polymeric excipients are intimately mixed at the molecular level, exhibit dramatically enhanced solubility and dissolution characteristics relative to their crystalline drug counterparts. In the process of achieving an ever-increasing drug loading (DL), it is noticed, however, that the drug release profile deteriorates significantly beyond a certain DL. As an example, a ritonavir-copovidone ASD achieves continuous and full drug release when DL ≤ 25 wt %. The release drops at 30 wt % and when DL ≥ 35 wt % there is virtually no drug release, behaving like a pure amorphous drug. In this Communication, the phase miscibility of ASD thin films has been investigated by in situ synchrotron X-ray fluorescence (XRF) imaging to elucidate the mechanism for the unique change in the extent of drug release as a function of DL. It is found that the drug release profile correlates well with the amorphous-amorphous phase separation (AAPS) onset. At a lower drug loading (up to 20 wt %), it takes more than 12 h for AAPS to happen while in sharp contrast, it only needs less than 10 min for DL ≥ 32.5 wt %. During AAPS, amorphous drug accumulates on the surface of the film, which prevents further dissolution from the interior of the ASD. The current study provides a mechanistic understanding of the confounding drug release profile of ASDs as a function of DL and opens the door for studying drug-excipient (e.g., polymer, surfactant) interactions via XRF imaging in the future.

Mechanistic Physiologically Based Pharmacokinetic Modeling of the Dissolution and Food Effect of a Biopharmaceutics Classification System IV Compound-The Venetoclax Story.

Venetoclax, a selective B-cell lymphoma-2 inhibitor, is a biopharmaceutics classification system class IV compound. The aim of this study was to develop a physiologically based pharmacokinetic (PBPK) model to mechanistically describe absorption and disposition of an amorphous solid dispersion formulation of venetoclax in humans. A mechanistic PBPK model was developed incorporating measured amorphous solubility, dissolution, metabolism, and plasma protein binding. A middle-out approach was used to define permeability. Model predictions of oral venetoclax pharmacokinetics were verified against clinical studies of fed and fasted healthy volunteers, and clinical drug interaction studies with strong CYP3A inhibitor (ketoconazole) and inducer (rifampicin). Model verification demonstrated accurate prediction of the observed food effect following a low-fat diet. Ratios of predicted versus observed Cmax and area under the curve of venetoclax were within 0.8- to 1.25-fold of observed ratios for strong CYP3A inhibitor and inducer interactions, indicating that the venetoclax elimination pathway was correctly specified. The verified venetoclax PBPK model is one of the first examples mechanistically capturing absorption, food effect, and exposure of an amorphous solid dispersion formulated compound. This model allows evaluation of untested drug-drug interactions, especially those primarily occurring in the intestine, and paves the way for future modeling of biopharmaceutics classification system IV compounds.

JRgui: A Python Program of Joback and Reid Method.

Using the modern object-oriented programing language Python (e.g., tkinter and pandas modules) and a chemoinformatics open-source library (RDKit), the classic Joback and Reid group contribution method was revisited and written into a graphical user interface program, JRgui. The underlying algorithm behind the program is explained, herein, with the users being able to operate the program in either a manual or automatic mode. In the manual mode, the users are required to determine the type and occurrence of functional groups in the compound of interest and manually enter into the program. In the automatic mode, both of these parameters can be detected automatically via user input of the compound simplified molecular input line entry specification (SMILES) string. An additional advantage of the automatic mode is that a large number of molecules can be processed simultaneously by parsing their individual SMILES strings into a text file, which is read by the program. The resulting predicted physical properties along with approximately 200 molecular descriptors are saved in a spreadsheet file for subsequent analysis. The program is available for free at https://github.com/curieshicy/JRgui for Windows, Linux, and macOS 64-bit operating systems. It is hoped that the current work may facilitate the creation of other user-friendly programs in the chemoinformatics community using Python.

The solubility-permeability interplay: mechanistic modeling and predictive application of the impact of micellar solubilization on intestinal permeation.

Surfactants are routinely employed to increase the apparent aqueous solubility of poorly soluble drugs. Yet the impact of micellar solubilization on the intestinal membrane permeability of a lipophilic drug is often overlooked and poorly understood. In this work, the interplay between the apparent solubility increase and intestinal membrane permeability decrease that exists when surfactants are used as drug solubility enhancers is described. A quasi-equilibrium mechanistic mass transport analysis was developed and employed to describe the effect of micellar solubilization by sodium taurocholate (STC) and sodium lauryl sulfate (SLS) on the intestinal membrane permeability of the lipophilic drug progesterone. The model considers the effects of micellar solubilization on both the membrane permeability (P(m)) and the unstirred water layer (UWL) permeability (P(aq)), to predict the overall effective permeability (P(eff)) dependence on surfactant concentration (C(S)). The analysis reveals that (1) the effective UWL thickness (h(aq)) quickly decreases with increasing C(S) above the critical micelle concentration (CMC), such that P(aq) markedly increases with increasing C(S); (2) the free fraction of drug available for membrane permeation decreases with increasing C(S) above CMC, such that P(m) decreases with increasing C(S); and (3) P(aq) increases and P(m) decreases with increasing C(S) above CMC, consequently the UWL is effectively shorted out and the overall P(eff) tends toward membrane control with increasing C(S). The model enabled excellent quantitative prediction of the progesterone P(eff) as a function of C(S) in the rat jejunal perfusion model. This work demonstrates that a trade-off exists between micellar apparent solubility increase and permeability decrease that must be taken into account to strike the optimal solubility-permeability balance. The model presented in this work offers the formulation scientist a simple method for a priori prediction of this interplay, in order to maximize the overall oral absorption.

Co-crystals of caffeine and hydroxy-2-naphthoic acids: unusual formation of the carboxylic acid dimer in the presence of a heterosynthon.

A group of caffeine-containing co-crystals of hydroxy-2-naphthoic acids were synthesized and analyzed via single-crystal X-ray diffraction and IR analysis. The imidazole-carboxylic acid synthon was observed in co-crystals involving 1-hydroxy-2-naphthoic and 3-hydroxy-2-naphthoic acid. In the case of 6-hydroxy-2-naphthoic acid, the co-crystal exhibits a hydrogen-bonded carboxylic acid dimer in the presence of a hydroxyl-caffeine heterosynthon.

Efficient co-crystal screening using solution-mediated phase transformation.

We have extended the established physical stability treatment for hydrates/solvates to co-crystals with solid co-crystal formers. Based on the proposed treatment, a suspension/slurry screening technique is developed and tested in sixteen pharmaceutical co-crystal systems with success. The theoretical treatment and the practical screening technique should benefit the researchers in the field of co-crystallization in improving the screening efficiency.

A "hidden" co-crystal of caffeine and adipic acid.

Co-crystal formation between caffeine and adipic acid has been explored over the years without success; utilizing the newly developed co-crystal screening method, we have finally discovered this "hidden" caffeine and adipic acid co-crystal.