Assessment of Diverse Solid−State Accelerated Autoxidation Methods for Droperidol

The present study aimed to investigate methods for accelerating autoxidation of crystalline drugs in the solid-state that can potentially predict real−time stability. Solid droperidol (DPD) was selected as the model drug. A common free−radical initiator, 2,2′−azobisisobutyronitrile (AIBN), was used to induce autoxidation in solutions. AIBN decomposes at elevated temperatures to yield carbon−centred cyano−isopropyl free radicals that can auto−oxidize neighboring drug molecules. Although the reaction of AIBN is relatively straightforward in solution, it is less so in solids. In this study, we used solid AIBN mixed with DPD powder in the presence and absence of pressurized oxygen headspace. Samples were prepared directly in the form of binary mixtures with DPD and additionally in the form of powder compact/pellet with DPD. The main challenge in carrying out the reaction was related to the preservation of AIBN at elevated temperatures due to the disintegration of the pellet containing the latter. A commercially available free−radical coated silica particle (i.e., 2,2,6,6−tetramethyl−1−piperinyloxy (TEMPO) or (SiliaCAT(TM) TEMPO)) was tested as a potential stressor, but with limited success to induce autoxidation. The most valuable results were obtained when a physical mixture of pre−milled PVP K−60 containing free radicals and DPD was exposed to elevated oxygen−temperature conditions, which yielded significant degradation of DPD. The study highlights the practical challenges for conducting accelerated solid−state stress studies to assess the autoxidation susceptibility of drugs using traditional free−radical initiators and presents a proof of application of milled PVP with free−radical as a potential alternative

Strategies to Calculate Water Binding Free Energies in Protein–Ligand Complexes

Water molecules are commonplace in protein binding pockets, where they can typically form a complex between the protein and a ligand or become displaced upon ligand binding. As a result, it is often of great interest to establish both the binding free energy and location of such molecules. Several approaches to predicting the location and affinity of water molecules to proteins have been proposed and utilized in the literature, although it is often unclear which method should be used under what circumstances. We report here a comparison between three such methodologies, Just Add Water Molecules (JAWS), Grand Canonical Monte Carlo (GCMC), and double-decoupling, in the hope of understanding the advantages and limitations of each method when applied to enclosed binding sites. As a result, we have adapted the JAWS scoring procedure, allowing the binding free energies of strongly bound water molecules to be calculated to a high degree of accuracy, requiring significantly less computational effort than more rigorous approaches. The combination of JAWS and GCMC offers a route to a rapid scheme capable of both locating and scoring water molecules for rational drug design

Interactions between crystal surfaces in solution and agglomeration: A theoretical approach

Agglomeration can have a crucial impact on the yield of crystallisation processes and the product quality. In this thesis molecular scale modelling is used to gain insights into the mechanism of crystal agglomeration and factors that determine its progress. The first study analyses the use of the attachment energy model to predict which surfaces of a crystal would be observed and hence the crystal morphology. It is shown that comparatively simple model potentials suffice to provide reasonably accurate morphology predictions within the limitations of the neglect of solvent. A classical empirical force field for potash alum (KAl(S0₄)₂.12H₂O) is developed. After having established its capability to reproduce experimentally determined properties of the crystal bulk and the solution, different potash alum crystal faces in contact with aqueous solution are modelled via Molecular Dynamics simulations. A range of different methods of modelling polar crystal surfaces, including a novel one, are investigated. The results are used to rationalise experimental results quantifying the agglomerative strength of PA crystallites as a function of super-saturation and the structure of the crystal faces. Common models for the theoretical prediction of crystal agglomeration include an efficiency parameter which is essentially a material property and a functional of the average force between two particles in solution. A set of Molecular Dynamics simulations of potassium chloride nano-crystallites in aqueous KCl solution is performed in order to establish whether it is possible to obtain reproduceable forces using an explicit water model and an extended system geometry to maintain constant chemical potential of the solution in between two crystal surfaces and a bulk phase. Although the results highlight some interesting aspects, and can give qualitative explanations of agglomeration tendencies, quantitative predictions of agglomeration will require further research

Relative Contributions of Solubility and Mobility to the Stability of Amorphous Solid Dispersions of Poorly Soluble Drugs: A Molecular Dynamics Simulation Study

Amorphous solid dispersions are considered a promising formulation strategy for the oral delivery of poorly soluble drugs. The limiting factor for the applicability of this approach is the physical (in)stability of the amorphous phase in solid samples. Minimizing the risk of reduced shelf life for a new drug by establishing a suitable excipient/polymer-type from first principles would be desirable to accelerate formulation development. Here, we perform Molecular Dynamics simulations to determine properties of blends of eight different polymer–small molecule drug combinations for which stability data are available from a consistent set of literature data. We calculate thermodynamic factors (mixing energies) as well as mobilities (diffusion rates and roto-vibrational fluctuations). We find that either of the two factors, mobility and energetics, can determine the relative stability of the amorphous form for a given drug. Which factor is rate limiting depends on physico-chemical properties of the drug and the excipients/polymers. The methods outlined here can be readily employed for an in silico pre-screening of different excipients for a given drug to establish a qualitative ranking of the expected relative stabilities, thereby accelerating and streamlining formulation development

Computer aided drug design in the development of proteolysis targeting chimeras

Proteolysis targeting chimeras represent a class of drug molecules with a number of attractive properties, most notably a potential to work for targets that, so far, have been in-accessible for conventional small molecule inhibitors. Due to their different mechanism of action, and physico-chemical properties, many of the methods that have been designed and applied for computer aided design of traditional small molecule drugs are not applicable for proteolysis targeting chimeras. Here we review recent developments in this field focusing on three aspects: de-novo linker-design, estimation of absorption for beyond-rule-of-5 compounds, and the generation and ranking of ternary complex structures. In spite of this field still being young, we find that a good number of models and algorithms are available, with the potential to assist the design of such compounds in-silico, and accelerate applied pharmaceutical research

Calculated potentials of mean force between pseudo proteins.

<p>A: three PPs with varying net-charge, constant hydrophobicity and dipole moment; B: the two PPs with the largest and smallest hydrophobicities () but identical net-charges and dipole moments; C: six PPs with varying dipole moment, identical net-charge and similar values.</p

Effects of point directed mutagenesis on descriptors.

a<p>PDB ID.</p>b<p>Net-charge of wildtype (WT) in elementary charge units, e.</p>c<p>Net-charge, difference between mutant and WT.</p>d<p>Dipole moment of wildtype in eÅ.</p>e<p>Dipole moment, difference between mutant and WT.</p

Structure Based Descriptors for the Estimation of Colloidal Interactions and Protein Aggregation Propensities

<div><p>The control of protein aggregation is an important requirement in the development of bio-pharmaceutical formulations. Here a simple protein model is proposed that was used in molecular dynamics simulations to obtain a quantitative assessment of the relative contributions of proteins’ net-charges, dipole-moments, and the size of hydrophobic or charged surface patches to their colloidal interactions. The results demonstrate that the strength of these interactions correlate with net-charge and dipole moment. Variation of both these descriptors within ranges typical for globular proteins have a comparable effect. By comparison no clear trends can be observed upon varying the size of hydrophobic or charged patches while keeping the other parameters constant. The results are discussed in the context of experimental literature data on protein aggregation. They provide a clear guide line for the development of improved algorithms for the prediction of aggregation propensities.</p> </div