Structure, morphology and surface properties of α-lactose monohydrate in relation to its powder properties.

The particulate properties of α-lactose monohydrate (αLMH), an excipient and carrier for pharmaceuticals, is important for the design, formulation and performance of a wide range of drug products. Here an integrated multi-scale workflow provides a detailed molecular and inter-molecular (synthonic) analysis of its crystal morphology, surface chemistry and surface energy. Predicted morphologies are validated in 3D through X-ray diffraction (XCT) contrast tomography.

Predicting the Strength of Cohesive and Adhesive Interparticle Interactions for Dry Powder Inhalation Blends of Terbutaline Sulfate with α-Lactose Monohydrate.

Grid-based systematic search methods are used to investigate molecule-molecule, molecule-surface, and surface-surface contributions to interparticle interactions in order to identify the crystal faces that most strongly affect particle behavior during powder blend formulation and delivery processes. The model system comprises terbutaline sulfate (TBS) as an active pharmaceutical ingredient (API) and α-form lactose monohydrate (LMH). A combination of systematic molecular modeling and X-ray computed tomography (XCT) is used to determine not only the adhesive and cohesive interparticle energies but, also the agglomeration behavior during manufacturing and de-agglomeration behavior during delivery after inhalation.

Microstructural insight into inhalation powder blends through correlative multi-scale X-ray computed tomography.

Dry powder inhalers (DPI) are important for topical drug delivery to the lungs, but characterising the pre-aerosolised powder microstructure is a key initial step in understanding the post-aerosolised blend performance. In this work, we characterise the pre-aerosolised 3D microstructure of an inhalation blend using correlative multi-scale X-ray Computed Tomography (XCT), identifying lactose and drug-rich phases at multiple length scales on the same sample. The drug-rich phase distribution across the sample is shown to be homogeneous on a bulk scale but heterogeneous on a particulate scale, with individual clusters containing different amounts of drug-rich phase, and different parts of a carrier particle coated with different amounts of drug-rich phase.

Nanoformulation-by-design: an experimental and molecular dynamics study for polymer coated drug nanoparticles.

The formulation of drug compounds into nanoparticles has many potential advantages in enhancing bioavailability and improving therapeutic efficacy. However, few drug molecules will assemble into stable, well-defined nanoparticulate structures. Amphiphilic polymer coatings are able to stabilise nanoparticles, imparting defined surface properties for many possible drug delivery applications.

Poly (Glycerol Adipate): From a Functionalized Nanocarrier to a Polymeric-Prodrug Matrix to Create Amorphous Solid Dispersions.

Amorphous solid dispersions are a promising strategy to overcome poor solubility and stability limitations, reducing the crystallinity of the drug through incorporation within a polymer matrix. However, to achieve an effective amorphous solid dispersion, the polymer and drug must be compatible, otherwise the drug can undergo recrystallization. In this work, we investigated the potential of the enzymatically synthesized poly(glycerol-adipate), as a pharmaceutical tool for producing a nanoamorphous formulation.

Poly (glycerol adipate) (PGA), an Enzymatically Synthesized Functionalizable Polyester and Versatile Drug Delivery Carrier: A Literature Update.

The enzymatically synthesized poly (glycerol adipate) (PGA) has demonstrated all the desirable key properties required from a performing biomaterial to be considered a versatile "polymeric-tool" in the broad field of drug delivery. The step-growth polymerization pathway catalyzed by lipase generates a highly functionalizable platform while avoiding tedious steps of protection and deprotection. Synthesis requires only minor purification steps and uses cheap and readily available reagents.

CoCo-MD: A Simple and Effective Method for the Enhanced Sampling of Conformational Space.

CoCo ("complementary coordinates") is a method for ensemble enrichment based on principal component analysis (PCA) that was developed originally for the investigation of NMR data. Here we investigate the potential of the CoCo method, in combination with molecular dynamics simulations (CoCo-MD), to be used more generally for the enhanced sampling of conformational space. Using the alanine penta-peptide as a model system, we find that an iterative workflow, interleaving short multiple-walker MD simulations with long-range jumps through conformational space informed by CoCo analysis, can increase the rate of sampling of conformational space up to 10 times for the same computational effort (total number of MD timesteps).

Synthesis and properties of a biodegradable polymer-drug conjugate: Methotrexate-poly(glycerol adipate).

Polymer-drug conjugates have been actively developed as potential anticancer drug delivery systems. In this study, we report the first polymer-anticancer drug conjugate with poly(glycerol adipate) (PGA) through the successful conjugation of methotrexate (MTX). MTX-PGA conjugates were controllably and simply fabricated by carbodiimide-mediated coupling reaction with various high molar ratios of MTX.