Absorbing the arrow of electromagnetic radiation.

We argue that the asymmetry between diverging and converging electromagnetic waves is just one of many asymmetries in observed phenomena that can be explained by a past hypothesis and statistical postulate (together assigning probabilities to different states of matter and field in the early universe). The arrow of electromagnetic radiation is thus absorbed into a broader account of temporal asymmetries in nature. We give an accessible introduction to the problem of explaining the arrow of radiation and compare our preferred strategy for explaining the arrow to three alternatives: (i) modifying the laws of electromagnetism by adding a radiation condition requiring that electromagnetic fields always be attributable to past sources, (ii) removing electromagnetic fields and having particles interact directly with one another through retarded action-at-a-distance, (iii) adopting the Wheeler-Feynman approach and having particles interact directly through half-retarded half-advanced action-at-a-distance. In addition to the asymmetry between diverging and converging waves, we also consider the related asymmetry of radiation reaction.

A Multicompany Assessment of Submicron Particle Levels by NTA and RMM in a Wide Range of Late-Phase Clinical and Commercial Biotechnology-Derived Protein Products.

One of the major product quality challenges for injectable biologics is controlling the amount of protein aggregates and particles present in the final drug product. This article focuses on particles in the submicron range (<2 µm). A cross-industry collaboration was undertaken to address some of the analytical gaps in measuring submicron particles (SMPs), developing best practices, and surveying the concentration of these particles present in 52 unique clinical and commercial protein therapeutics covering 62 dosage forms. Measured particle concentrations spanned a range of 4 orders of magnitude for nanoparticle tracking analysis and 3 orders of magnitude for resonant mass measurement. The particle concentrations determined by the 2 techniques differed significantly for both control and actual product. In addition, results suggest that these techniques exhibit higher variability compared to well-established subvisible particle characterization techniques (e.g., flow-imaging or light obscuration). Therefore, in their current states, nanoparticle tracking analysis and resonant mass measurement-based techniques can be used during product and process characterization, contributing information on the nature and propensity for formation of submicron particles and what is normal for the product, but may not be suitable for release or quality control testing. Evaluating the level of SMPs to which humans have been routinely exposed during the administration of several commercial and late-phase clinical products adds critical knowledge to our understanding of SMP levels that may be considered acceptable from a safety point of view. This article also discusses dependence of submicron particle size and concentration on the dosage form attributes such as physical state, primary packaging, dose strength, etc. To the best of our knowledge, this is the largest study ever conducted to characterize SMPs in late-phase and commercial products.

Effect of Moisture Sorption on Free Volume and Relaxation of Spray Dried Dispersions: Relation to Drug Recrystallization.

The effect of vapor sorption on the free volume of drug-polymer spray-dried dispersions (SDDs) was investigated, along with the crystallization propensity of drug molecules in SDDs after exposure to humidity. Subsequently, the correlation of free volume change and relaxation time with drug recrystallization was examined. Four polymers, including polyvinylpyrrolidone, polyvinylpyrrolidone vinyl acetate copolymer, hydroxypropyl cellulose, and hydroxypropyl methylcellulose acetate succinate, and 2 drugs (indomethacin and ketoconazole) were selected for preparing SDDs. Free volume data of the exposed SDDs were obtained with positron annihilation lifetime spectroscopy, while the relaxation time was measured using a TA rheometer. Additionally, the crystallization propensity of active pharmaceutical ingredients (APIs) in the exposed SDDs was assessed using both polarized light microscopy and powder X-ray diffraction, followed by relating API crystallization inclination with expansion of holes and relaxation time. Finally, Cohen and Turnbull molecular transport model, along with its extensions by Vrentas and Duda, was qualitatively utilized for interpreting the recrystallization propensity of API molecules. In conclusion, API recrystallization is closely related to free volume change upon moisture sorption and relaxation time, but system dependent; overall, drug-hydroxypropyl methylcellulose acetate succinate SDDs appear physically stable against recrystallization due to less increase in free volume.

Separation, Characterization and Discriminant Analysis of Subvisible Particles in Biologics Formulations.

BACKGROUND: The presence of subvisible particles (SVPs) in parenteral formulations of biologics is a major challenge in the development of therapeutic protein formulations. Distinction between proteinaceous and non-proteinaceous SVPs is vital in monitoring formulation stability. METHODS: The current compendial method based on light obscuration (LO) has limitations in the analysis of translucent/low refractive index particles. A number of attempts have been made to develop an unambiguous method to characterize SVPs, albeit with limited success. RESULTS: Herein, we describe a robust method that characterizes and distinguishes both potentially proteinaceous and non-proteinaceous SVPs in protein formulations using Microflow imaging (MFI) in conjunction with the MVAS software (MFI View Analysis Suite), developed by ProteinSimple. The method utilizes two Intensity parameters and a morphological filter that successfully distinguishes proteinaceous SVPs from non-proteinaceous SVPs and mixed aggregates. CONCLUSION: The MFI generated raw data of a protein sample is processed through Lumetics LINK software that applies an in-house developed filter to separate proteinaceous from the rest of the particulates.

How Quantum Mechanics can consistently describe the use of itself.

We discuss the no-go theorem of Frauchiger and Renner based on an "extended Wigner's friend" thought experiment which is supposed to show that any single-world interpretation of quantum mechanics leads to inconsistent predictions if it is applicable on all scales. We show that no such inconsistency occurs if one considers a complete description of the physical situation. We then discuss implications of the thought experiment that have not been clearly addressed in the original paper, including a tension between relativity and nonlocal effects predicted by quantum mechanics. Our discussion applies in particular to Bohmian mechanics.

Real-time observation of protein aggregates in pharmaceutical formulations using liquid cell electron microscopy.

Understanding the properties of protein-based therapeutics is a common goal of biologists and physicians. Technical barriers in the direct observation of small proteins or therapeutic agents can limit our knowledge of how they function in solution and in the body. Electron microscopy (EM) imaging performed in a liquid environment permits us to peer into the active world of cells and molecules at the nanoscale. Here, we employ liquid cell EM to directly visualize a protein-based therapeutic in its native conformation and aggregate state in a time-resolved manner. In combination with quantitative analyses, information from this work contributes new molecular insights toward understanding the behaviours of immunotherapies in a solution state that mimics the human body.

Resolution and Sensitivity of Inline Focused Beam Reflectance Measurement During Wet Granulation in Pharmaceutically Relevant Particle Size Ranges.

Real-time process monitoring using a process analytical technology for granule size distribution can enable quality-by-design in drug product manufacturing. In this study, the resolution and sensitivity of chord length distribution (CLD) measured inline inside a high shear granulator using focused beam reflectance measurement (FBRM) C35 probe was investigated using different particle size grades of microcrystalline cellulose (MCC). In addition, the impact of water and impeller tip speed on the measurement accuracy as well as correlation with offline particle sizing techniques (FBRM, laser diffraction [Malvern Mastersizer®], microscopy [Sympatec QicPic®], and nested sieve analysis) was studied. Inline FBRM resolved size differences between different MCC grades, and the data correlated well with offline analyses. Impeller tip speed changed the number density of inline CLD measurements while addition of water reduced the CLD of dry MCC, likely due to deagglomeration of primary particles. In summary, inline FBRM CLD measurement in high shear granulator provides adequate resolution and reproducible measurements in the pharmaceutically relevant size range both in the presence and in the absence of water. Therefore, inline FBRM can be a valuable tool for the monitoring of high shear wet granulation.

The effect of polymeric excipients on the physical properties and performance of amorphous dispersions: Part I, free volume and glass transition.

PURPOSE: To investigate the structural effect of polymeric excipients on the behavior of free volume of drug-polymer dispersions in relation to glass transition. METHODS: Two drugs (indomethacin and ketoconazole) were selected to prepare amorphous dispersions with PVP, PVPVA, HPC, and HPMCAS through spray drying. The physical attributes of the dispersions were characterized using SEM and PXRD. The free volume (hole-size) of the dispersions along with drugs and polymers was measured using positron annihilation lifetime spectroscopy (PALS). Their glass transition temperatures (Tgs) were determined using DSC and DMA. FTIR spectra were recorded to identify hydrogen bonding in the dispersions. RESULTS: The chain structural difference-flexible (PVP and PVPVA) vs. inflexible (HPC and HPMCAS)-significantly impacts the free volume and Tgs of the dispersions as well as their deviation from ideality. Relative to Tg, free volume seems to be a better measure of hydrogen bonding interaction for the dispersions of PVP, HPC, and HPMCAS. The free volume of polymers and their dispersions in general appears to be related to their conformations in solution. CONCLUSIONS: Both the backbone chain rigidity of polymers as well as drug-polymer interaction can impact the free volume and glass transition behaviors of the dispersions.

The effect of the physical state of binders on high-shear wet granulation and granule properties: a mechanistic approach to understand the high-shear wet granulation process. part IV. the impact of rheological state and tip-speeds.

The purpose of this study is to provide a mechanistic understanding concerning the effect of tip-speed on a granulation at various binder rheological states; the in situ rheological state of a binder was controlled by exposing a granulation blend to 96% relative humidity. This approach allowed us to investigate the impact of tip-speed on granule consolidation coupled with the in situ binder state, which was not possible using a conventional granulation approach. Experimentally, the rheological state of binders was characterized using a rheometer. Granule size and granule porosity were measured by Qicpic instrument and Mercury Intrusion Porosimetry, respectively. For the granulations containing binders at viscous state (PVP K17 and PVP K29/32), the granule size increased significantly with mixing time and the growth rate increased with tip-speed until 5.8 m/s; when binders were at viscoelastic state, tip-speed had no impact on granulation. Furthermore, the granule porosity was higher for granulation with binders at viscoelastic state (HPC and PVP K90), whereas it was lower for granulation with binders at viscous state. In addition, the impeller tip-speed had minimal impact on the porosity of the final granules. Finally, Ennis' model was used for interpreting results, providing mechanistic insights on granulation.

Effect of physical states of binders on high-shear wet granulation and granule properties: a mechanistic approach toward understanding high-shear wet granulation process, part 3: effect of binder rheological properties.

Ternary blends consisting of efavirenz (a model drug compound), lactose monohydrate, and a polymeric binder were investigated to verify the "physical state theory" in which granulation occurs only when binders undergo transition from glassy state to rubbery solution state. Furthermore, it was found that the rheological properties of the binders can significantly affect the granulation process. The blends with binders of viscous flow [polyvinylpyrrolidone (PVP) K17, PVP K25, and PVP K29/32 after exposure to 96% RH] showed an increase in particle size with both binder concentration and mixing time. On the contrary, binders with viscoelastic properties, such as hydroxypropylcellulose (HPC) EXF and PVP K90, did not flow well and thereby, the blends with HPC and PVP K90 did not show much effect of binder concentration and mixing time on their granule size. Moreover, the friability of granules made with HPC EXF and PVP K90 is low, indicating that the strength of the granules largely depends on the viscosity of the binders, as the binders of higher viscosity tend to produce stronger granules. Finally, the viscoelastic state of the polymeric binders upon absorbing water was analyzed using the glass-rubber transition model, which shows five regions with different viscoelastic properties.

The effect of the physical states of binders on high-shear wet granulation and granule properties: a mechanistic approach toward understanding high-shear wet granulation process. Part II. Granulation and granule properties.

The objective is to provide mechanistic understanding of a preferred wet granulation process that a binder is added in a dry state. Blends of CaCO(3) and binders were prepared and used as model systems, and they were exposed to either 96% RH (rubbery/solution state) or 60% RH (glassy state) at room temperature to control the physical state of the binders, followed by high-shear granulation and particle size measurement. The blends of PVP K12, PVP K29/32, and HPC showed a significant increase in particle size after exposure to 96% RH. An increase of aspect ratio was also observed for the blend of HPC. In contrast, the blends being exposed to 60% RH did not exhibit any increase in particle size or aspect ratio. Regarding the effect of binder molecular weight on the mechanical strength of granules, granules of PVP K29/32 had higher strength than granules of PVP K12. This can be explained using polymer entanglement theory, in which the degree of polymerization (DP) of (N ∼ 440-540) of PVP K29/32 is above the critical value (N(c) ∼ 300-600) for entanglement; while DP of PVP K12 (N ∼ 20-30) is below it. Finally, a water sorption-phase transition-diffusion induced granule growth model for granulation has been suggested.

The effect of the physical states of binders on high-shear wet granulation and granule properties: a mechanistic approach towards understanding high-shear wet granulation process. Part I. Physical characterization of binders.

In this study, the objective is to investigate the effect of the physical state of a binder on wet granulation and granule properties using a binary model system (CaCO(3)-binder), which is essential for understanding the mechanism of wet granulation when binder is added in a dry state. Part I focus on studying the phase behavior or the physical state change of four binders: PVP K12, K29/32, HPC, and HPMC, after exposure to either moisture or liquid water. Their interaction with water was studied by measuring the water sorption of binders and the binary blends of CaCO(3)-binder. Changes in the physical states of the binders at room temperature as a function of water content was monitored via dialysis experiments, and characterized by determining the glass transition temperatures (T(g)) of the binders with water. The results suggest that the PVP binders can absorb more water than the cellulosic binders which is same for binder alone and in the binary blends. PVP K12 undergoes a phase transition from the glassy state to the rubbery/solution state at much lower water content than PVP K29/32 (10% vs. 20%) at room temperature. The phase transition for HPC occurs with 10-15% water based on rheological measurements.

Form conversion of anhydrous lactose during wet granulation and its effect on compactibility.

The purpose of this study was (a) to evaluate the factors affecting the form conversion of anhydrous lactose to the monohydrate form during wet granulation using water as the granulating agent and (b) study the effect of lactose form conversion on its compaction properties. A two-level full factorial design with two center points was used to evaluate the factors affecting form conversion. The three variables evaluated were percentage of microcrystalline cellulose (low 0 and high 20), water to intragranular solids ratio (low 0.10 and high 0.18) and drying conditions (tray drying and fluid bed drying). The presence of microcrystalline cellulose in the formulation did not provide any benefit in reducing the percent lactose conversion. But, the conversion was significantly reduced by decreasing the amount of water added to the granulation and/or by decreasing the drying time, using a fluid bed dryer compared to a tray dryer. In the second part of the study, complete conversion of the anhydrous lactose to monohydrate was achieved by storing the anhydrous form under 25 degrees C/97% RH for 4 weeks. Physical characterization (compactibility, surface area and surface morphology) was performed on the form converted material and compared to the as received anhydrous lactose. The physical characterization results indicated that even though anhydrous lactose undergoes complete form conversion to monohydrate form under high humidity and/or during wet granulation, it retains its inherent higher as received material compactibility and the BET surface area and porosity of the form converted material are higher than that of the as received anhydrous lactose.