Analysis of the impact of material properties on tabletability by principal component analysis and partial least squares regression.

Principal component analysis (PCA) and partial least squares regression (PLS) were combined in this study to identify key material descriptors determining tabletability in direct compression and roller compaction. An extensive material library including 119 material descriptors and tablet tensile strengths of 44 powders and roller compacted materials with varying drug loads was generated to systematically elucidate the impact of different material descriptors, raw API and filler properties as well as process route on tabletability. A PCA model was created which highlighted correlations between different powder descriptors and respective characterization methods and, thus, can enable reduction of analyses to save resources to a certain extent.

ASDs of PROTACs: Spray-dried solid dispersions as enabling formulations.

Proteolysis targeting chimeras (PROTACs) are a promising class of pharmaceutical agents with a unique mode of action. PROTACs enable the targeting of a broad variety of structures including transcription factors and other "undruggable" targets. The poor solubility and slow dissolution of PROTACs currently limit the extensive use of their potential.

Elucidating the Impact of Material Properties on Tablet Manufacturability for Binary Paracetamol Blends.

Purpose: Although the mechanical properties of paracetamol and MCC are extensively described in literature, there still is a need for a better understanding of the material properties impacting them. Thus, this study systematically analyzed material properties of paracetamol-MCC blends to elucidate their influence on the mechanical tablet properties in roller compaction and direct compression with special focus on surface properties.

Methods: Multiple material characteristics of binary mixtures of paracetamol and MCC with varying drug loads were analyzed, with particular emphasis on specific surface area and surface energy.

Understanding the Multidimensional Effects of Polymorphism, Particle Size and Processing for D-Mannitol Powders.

The relevance of the polymorphic form, particle size, and processing of mannitol for the mechanical properties of solid oral dosage forms was examined. Thus, particle and powder properties of spray granulated β D-mannitol, β D-mannitol, and δ D-mannitol were assessed in this study with regards to their manufacturability. D-mannitol is a commonly used excipient in pharmaceutical formulations, especially in oral solid dosage forms, and can be crystallized as three polymorphic forms, of which β is the thermodynamically most stable form and δ is a kinetically stabilized polymorph.

Brittle polymers in Fused Deposition Modeling: An improved feeding approach to enable the printing of highly drug loaded filament.

Brittleness is often described as a restricting material property for the processability of filaments via Fused Deposition Modeling. Especially filaments produced from approved pharmaceutical polymers often tend to fracture between feeding gears, the commonly employed feeding mechanism. In order to enhance their mechanical properties, usually extensive formulation development is performed.

Impact of amorphization and GI physiology on supersaturation and precipitation of poorly soluble weakly basic drugs using a small-scale in vitro transfer model.

Formulation of amorphous solid dispersions (ASD) is one possibility to improve poor aqueous drug solubility by creating supersaturation. In case of weakly basic drugs like ketoconazole (KTZ), supersaturation can also be generated during the gastrointestinal (GI) transfer from the stomach to the intestine due to pH-dependent solubility. In both cases, the supersaturation during dissolution can be stabilized by polymeric precipitation inhibitors.

Miniaturized Measurement of Drug-Polymer Interactions via Viscosity Increase for Polymer Selection in Amorphous Solid Dispersions.

Drug-polymer interactions have a substantial impact on stability and performance of amorphous solid dispersions (ASD) but are difficult to analyze. Whereas there are many screening methods described for polymer selection based for example on glass forming ability, drug-polymer miscibility, supersaturation, or inhibition of recrystallization, the distinct detection of physico-chemical interactions mostly lacks miniaturized techniques. This work presents an interaction screening assessing the relative viscosity increase between highly concentrated polymer solutions with and without the model drug ketoconazole (KTZ).

Acid-induced degradation of widely used NIR dye DiR causes hypsochromic shift in fluorescence properties.

DiR (1,1'-dioctadecyl-3,3,3',3'-tetramethylindotricarbocyanine iodide) is one of the most widely used near-infrared dyes for in-vivo imaging due to its favorable optical properties. So far, chemical stability has been taken for granted by most investigators. However, in a recently published imaging study, we found that DiR can exert a hypsochromic shift in fluorescence in-vivo, potentially induced by low pH.

How changes in molecular weight and PDI of a polymer in amorphous solid dispersions impact dissolution performance.

Polymers functionally contribute to supersaturation and precipitation inhibition of the active pharmaceutical ingredient (API) in amorphous solid dispersions (ASD). Therefore, it is necessary to monitor physicochemical changes of the polymeric carrier caused by the manufacturing process. This is especially important when the material is exposed to heat and shear stress as in case of hot-melt extrusion (HME).

Melt-based screening method with improved predictability regarding polymer selection for amorphous solid dispersions.

The predictability of preformulation screening tools for polymer selection in amorphous solid dispersions (ASD) regarding supersaturation and precipitation was systematically examined. The API-polymer combinations were scaled up by means of hot-melt extrusion and spray-drying to verify the predictions. As there were discrepancies between a solvent-based screening and performance of ASD, a new screening tool with improved predictability at minimal investments of time and material is presented.

Dual dye in-vivo imaging of differentially charged PLGA carriers reveals antigen-depot effect, leading to improved immune responses in preclinical models.

The present in-vivo study investigated the behavior and performance of differently charged poly(lactic‑co‑glycolic) acid microparticles (PLGA MP) as vaccination platform. For this purpose, particles loaded with ovalbumin (OVA) as model antigen were subcutaneously (s.c.

Combining R-DOTAP and a particulate antigen delivery platform to trigger dendritic cell activation: Formulation development and in-vitro interaction studies.

The utilization of the cationic lipid R-DOTAP as immune cell stimulant (e.g. its stimulating effects on immature dendritic cells) and correspondingly as possible adjuvant for vaccination is well known.

Investigation of the stabilizer elimination during the washing step of charged PLGA microparticles utilizing a novel HPLC-UV-ELSD method.

Quantification of stabilizer content in microparticles and other products is of great importance for formulation development, drug product quality control as well as for reproducible manufacturing. A fast and sensitive HPLC method with evaporative light scattering detection (ELSD) capable of detecting docusate sodium (DOSS), poly (lactic-co-glycolic acid) (PLGA; Resomer RG 503 H) and R-1,2-dioleoyloxy-3-trimethylammonium-propane (DOTAP) in a single run was successfully developed. In contrast to previously described methods, hydrolysis of PLGA as pretreatment is not necessary, thereby enabling accurate quantification of stabilizer next to the intact matrix polymer.

Development of a new method to assess nanocrystal dissolution based on light scattering.

Purpose: Nanocrystals exhibit enhanced dissolution rates and can effectively increase the bioavailability of poorly water soluble drug substances. However, methods for in vitro characterization of dissolution are unavailable. The objective of this study was to develop an in situ noninvasive analytical method to measure dissolution of crystalline nanosuspensions based on light scattering.

Structural properties of so-called NSAID-phospholipid-complexes.

So-called NSAID-phospholipid-complexes have been recently reported in literature to reduce local gastrointestinal toxicity. The present work was dedicated to the structural characterization of so-called drug-phospholipid-complexes on the example of diclofenac sodium, ibuprofen and piroxicam complexes with dipalmitoylphosphatidylcholine (DPPC) at different stages of preparation. The applied techniques include (1)H/2D ROESY NMR for the structural characterization in organic solvents, FT-IR and X-ray diffraction for the structural characterization in the solid state and PCS, (31)P NMR, as well as MAS (1)H/2D NOESY NMR for the structural characterization in aqueous media following hydration.

The physicochemical parameters of marker compounds and vehicles for use in in vitro percutaneous absorption studies.

In order to prepare for a validation study to compare percutaneous absorption through reconstructed human epidermis with ex vivo skin absorption through human and animal skin, nine test compounds, covering a wide range of physicochemical properties were selected, namely: benzoic acid; caffeine; clotrimazole; digoxin; flufenamic acid; ivermectin; mannitol; nicotine; and testosterone. The donor and receptor media for the test substances, the addition of a solubiliser for the lipophilic compounds, as well as the stability and solubility of the test substances in the vehicles, were systematically analysed. Hydrophilic molecules, being freely soluble in water, were applied in buffered saline solutions.

Structural investigations on lipid nanoparticles containing high amounts of lecithin.

Solid lipid nanoparticles (SLN), an alternative colloidal drug delivery system to polymer nanoparticles, emulsions and liposomes, possess inherent low incorporation rates resulting from the crystalline structure of the solid lipid. To increase the drug loading capacity of SLN, matrix modification by incorporation of the amphiphilic lipid lecithin within the lipid matrices has been proposed as a promising alternative. The objective of this work is to investigate the effects of the lecithin on the microstructure of matrix modified SLN.