A comparative study of freeze-drying heat transfer in polymeric vials and glass vials.

Implementation of polymeric vials for freeze-dried drug products has been practically non-existent because of unique moisture barrier and thermodynamic technical challenges. Hybrid vials, which combine the benefits of polymer and glass, have been shown to address the challenges of ordinary polymeric vials. Tackling thermodynamic challenges starts with a clear understanding of the heat transfer mechanism. To this end, multi-physics simulations and experimentation were used to compare the heat transfer between hybrid cyclic olefin polymer (COP) vials and borosilicate glass vials during freeze-drying. Parametric models were developed for hybrid COP and glass vials to systematically study the effect of five design parameters based on the arrangement of the vials on a tray inside a lyophilization chamber. Heat transfer in glass vials were dominated by heat conduction with the surrounding vapor, while hybrid COP vials were governed by conduction with the bottom shelf. Furthermore, hybrid COP vials exhibited more consistent heat flow rate and total heat transfer coefficient compared to glass vials, suggesting higher product quality as a result. The distance between adjacent vials and the drug product height were the most important parameters affecting heat transfer irrespective of vial type. Results indicated that hybrid COP vials can be filled to higher fill volumes with higher heat transfer and without the risk of breakage. Results of this study can help design innovative primary packaging systems for freeze drying or optimizing heat transfer for existing glass or hybrid COP vial systems regarding product consistency and drying time.

Recommended Best Practices in Freeze Dryer Equipment Performance Qualification: 2022.

Best practices for performing freeze dryer equipment qualification are recommended, focusing on identifying methods to quantify shelf thermal uniformity (also known as "shelf surface uniformity"), equipment capability, and performance metrics of the freeze dryer essential to the pharmaceutical Quality by Design paradigm. Specific guidelines for performing shelf temperature mapping, freeze dryer equipment limit testing (the capability curve), and condenser performance metrics have been provided. Concerning shelf temperature mapping and equipment capability measurements, the importance of paying attention to the test setup and the use of appropriate testing tools are stressed. In all the guidelines provided, much attention has been paid to identifying the balance between obtaining useful process knowledge, logistical challenges associated with testing in the production environment vs that at laboratory scale, and the frequency of the testing necessary to obtain such useful information. Furthermore, merits and demerits of thermal conditions maintained on the cooled surfaces of the freeze dryer condenser have been discussed identifying the specific influence of the condenser surface temperature on the process conditions using experimental data to support the guidelines. Finally, guidelines for systematic leak rate testing criteria for a freeze dryer are presented. These specific procedural recommendations are based on calculations, measurements, and experience to provide useful process and equipment knowledge.

Recommended Best Practices for Process Monitoring Instrumentation in Pharmaceutical Freeze Drying-2017.

Recommended best practices in monitoring of product status during pharmaceutical freeze drying are presented, focusing on methods that apply to both laboratory and production scale. With respect to product temperature measurement, sources of uncertainty associated with any type of measurement probe are discussed, as well as important differences between the two most common types of temperature-measuring instruments-thermocouples and resistance temperature detectors (RTD). Two types of pressure transducers are discussed-thermal conductivity-type gauges and capacitance manometers, with the Pirani gauge being the thermal conductivity-type gauge of choice. It is recommended that both types of pressure gauge be used on both the product chamber and the condenser for freeze dryers with an external condenser, and the reasoning for this recommendation is discussed. Developing technology for process monitoring worthy of further investigation is also briefly reviewed, including wireless product temperature monitoring, tunable diode laser absorption spectroscopy at manufacturing scale, heat flux measurement, and mass spectrometry as process monitoring tools.

Magnifying lens for 800 MeV proton radiography.

This article describes the design and performance of a magnifying magnetic-lens system designed, built, and commissioned at the Los Alamos National Laboratory (LANL) for 800 MeV flash proton radiography. The technique of flash proton radiography has been developed at LANL to study material properties under dynamic loading conditions through the analysis of time sequences of proton radiographs. The requirements of this growing experimental program have resulted in the need for improvements in spatial radiographic resolution. To meet these needs, a new magnetic lens system, consisting of four permanent magnet quadrupoles, has been developed. This new lens system was designed to reduce the second order chromatic aberrations, the dominant source of image blur in 800 MeV proton radiography, as well as magnifying the image to reduce the blur contribution from the detector and camera systems. The recently commissioned lens system performed as designed, providing nearly a factor of three improvement in radiographic resolution.

Measurement of angular distributions of Drell-Yan dimuons in p+p interactions at 800 GeV/c.

We report a measurement of the angular distributions of Drell-Yan dimuons produced using an 800 GeV/c proton beam on a hydrogen target. The polar and azimuthal angular distribution parameters have been extracted over the kinematic range 4.5

Direct observation of the phenomenology of a solid thermal explosion using time-resolved proton radiography.

We present a new phenomenology for burn propagation inside a thermal explosion based on dynamic radiography. Radiographic images were obtained of an aluminum cased solid cylindrical sample of a plastic bonded formulation of octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine. The phenomenology observed is ignition followed by cracking in the solid accompanied by the propagation of a radially symmetric front of increasing proton transmission. This is followed by a further increase in transmission through the sample, ending after approximately 100 micros. We show that these processes are consistent with the propagation of a convective burn front followed by consumption of the remaining solid by conductive particle burning.

Measurement of Upsilon production for p + p and p + d interactions at 800 GeV/c.

We report a high statistics measurement of Upsilon production with an 800 GeV/c proton beam on hydrogen and deuterium targets. The dominance of the gluon-gluon fusion process for Upsilon production at this energy implies that the cross section ratio, sigma(p+d-->Upsilon)/2sigma(p+p-->Upsilon), is sensitive to the gluon content in the neutron relative to that in the proton. Over the kinematic region 0

Measurement of angular distributions of Drell-Yan dimuons in p+d interactions at 800 GeV/c.

We report a measurement of the angular distributions of Drell-Yan dimuons produced using an 800 GeV/c proton beam on a deuterium target. The muon angular distributions in the dilepton rest frame have been measured over the kinematic range 4.5

Optimization of metabolic stability as a goal of modern drug design.

Metabolism and other pharmacokinetic (PK) studies have always played a critical role in helping to optimize the bioavailability and duration of action of new drugs thereby increasing their success rate. With the advent of automated combinatorial synthesis, high-throughput pharmacological testing, and the ability to create extensive databases in the past decade, drug discovery has undergone an amazing evolution. With the increased throughput of drug discovery, metabolism and other PK studies have evolved to keep pace. Often called "early ADME" studies, these studies are characterized by parallel processing and higher throughput than before. This article focuses on a particular class of early ADME (absorption, distribution mechanism, and excretion) studies known as "metabolic stability" studies. The theoretical basis for metabolic stability and its relationship to the concept of metabolic intrinsic clearance is briefly presented. Some key relationships between structure and metabolism are summarized. Several case studies from recent medicinal chemistry literature are reviewed to exemplify how metabolic stability studies influenced drug design and led to improvements in bioavailability and half-life. Finally, future trends in drug metabolism and analytical chemistry and how they may influence metabolic stability studies are reviewed.

Evaluation of the BBMEC model for screening the CNS permeability of drugs.

Combinatorial synthesis and high-throughput pharmacology screening have greatly increased compound throughput in modern drug-discovery programs. For CNS drugs, it is also important to determine permeability to the blood--brain barrier. Yet, given the increased pace of discovery, it difficult to conduct this screen in a timely fashion. In this presentation, we describe several improvements to an existing CNS permeability screen, the bovine brain microvessel endothelial cell (BBMEC) model. By implementation of these incremental process improvements, we have achieved a robust, facile screen for determination of CNS permeability of multiple compounds.

Observation of polarization in bottomonium production at square root of s = 38.8 GeV.

We present a measurement of the polarization observed for bottomonium states produced in p-Cu collisions at square root of s = 38.8 GeV. The angular distribution of the decay dimuons of the Upsilon(1S) state shows no polarization at small values of the fractional longitudinal momentum x(F) and transverse momentum p(T) but significant positive transverse production polarization for either p(T)>1.8 GeV/c or for x(F)>0.35. The Upsilon(2S+3S) (unresolved) states show a large transverse production polarization at all values of x(F) and p(T) measured. These observations challenge NRQCD calculations of the polarization expected in the hadronic production of bottomonium states.

Early ADME in support of drug discovery: the role of metabolic stability studies.

The area of Drug Discovery has undergone an amazing evolution in the past decade. This evolution is typified by the development of automated combinatorial synthesis and high throughput pharmacological testing. This, in turn, has lead to the ability to create and mine extensive databases and then model this new information. The overall result is a substantial increase in the rate of target identification, generation of new leads, and finally, optimization of those leads into clinical candidates. ADME studies have always played a critical role in helping to optimize the pharmacokinetic (PK) properties of new drugs thereby increasing their success rate. As a consequence of the increased throughput of drug discovery, ADME studies have evolved to keep pace. These so-called "early ADME" studies, are characterized by parallel processing and higher throughput than before. A primary concern of medicinal chemists is to design molecules that will have not only the desired activity, but also suitable potency and duration of action, which is influenced by pharmacokinetic properties such as bioavailability and half-life. This article focuses on a particular subset of eADME studies known as "metabolic stability", which can be an important contributor for a good pharmacokinetic profile. Metabolic stability studies represent the adaptation of more complex metabolism rate studies to a minimized system suitable for parallel processing of large numbers of compounds. The theoretical basis for metabolic stability lies in its relationship to the concept of metabolic intrinsic clearance. Typical metabolic stability protocols are discussed with respect to their relation to drug design. How metabolic stability studies have evolved to keep pace with advances in drug discovery is also discussed. Several case studies of the role of metabolic stability in drug design over the past few years are summarized to exemplify the utility of this kind of study. Finally, future trends in drug metabolism and analytical chemistry and how they may influence metabolic stability studies are reviewed.

Experimental models for evaluating enzyme induction potential of new drug candidates in animals and humans and a strategy for their use.

Experimental models that have application for evaluating enzyme induction potential have been described in order of increasing complexity. The main focus was on models that have had wide application thus far. However, many new models are currently being developed that may have future applications in evaluating enzyme induction potential. A strategy to evaluate the enzyme induction potential of drug candidates was outlined. This scheme uses a combination of new and established techniques to evaluate data in a stepwise manner that is appropriate to the drug's current stage of development.

Mass balance of 14C-bismuth sucrose octasulfate in Sprague-Dawley rats: evidence for dissociation of bismuth from sucrose octasulfate.

The mass balance of 14C bismuth sucrose octasulfate (BISOS) was investigated in eight male Sprague-Dawley rats after single oral doses of 1.0 g kg-1. Bismuth and radioactivity were monitored in blood, urine, and feces for up to 144 h post-dose, while kidneys, brain, liver, and lungs were assayed for bismuth at 144 h post-dose. In a separate experiment, bismuth was monitored in bile of bile-duct-cannulated animals for 48 h post-dose. Fecal excretion of bismuth averaged 95.8 +/- 5.30% bismuth dose, while 99.2 +/- 3.63% of the radiolabel was excreted in feces. Urinary excretion of bismuth averaged 0.051 +/- 0.028% bismuth dose, and 1.83 +/- 1.08% radioactive dose. Biliary excretion of bismuth averaged 0.0003 +/- 0.0006% bismuth dose, and 0.026 +/- 0.030% radiolabeled dose. An average 0.005 +/- 0.002% of the bismuth dose was present in kidney, liver, and lung. Bismuth levels in brain were below quantifiable limits. Though BISOS contains 57.3% by weight of bismuth, peak blood concentrations of bismuth were three orders of magnitude lower than for BISOS equivalents (Cmax for BISOS averaged 110 +/- 55.4 micrograms eq mL-1, while for bismuth it was 26.1 +/- 10.3 ng mL-1). This data indicates that bismuth dissociates from sucrose octasulfate, probably during the absorption phase, and exhibits differential pharmacokinetic characteristics from sucrose octasulfate. The low biliary and urinary excretion of both bismuth and BISOS equivalents is indicative of low systemic absorption. Greater than 96% recovery in feces, bile, and urine indicates that mass balance was achieved following oral administration.

Pharmacological evaluation of selected, orally active, peptidyl inhibitors of human neutrophil elastase.

Human neutrophil elastase (HNE) is a serine proteinase capable of degrading a number of connective tissue macromolecules and has been implicated in the destructive processes associated with several chronic inflammatory diseases. A large series of peptidyl electrophilic ketones have been shown to be potent inhibitors of HNE in vitro and in vivo. We report the pharmacology and pharmacokinetics of selected inhibitors from this series. MDL 101, 146, MDL 102, 111, MDL 102,823 and MDL 100,948A are -Val-Pro-Val-pentafluoroethylketones with various amino-terminal protecting groups. Although their Ki values varied considerably, (25-170 nM), these compounds demonstrated similar ED50 values after oral administration in the HNE-induced hemorrhage model in hamsters and rats. The duration of action of MDL 102,111 was shorter than that of the other analogs in the HNE-induced pulmonary hemorrhage model in both species. The duration of action of all of the compounds was longer in the rat than in the hamster. Isolated sections of rat jejunum were used to determine the in situ absorption of these compounds. MDL 102,111 showed the greatest extent of absorption, with MDL 102,823, MDL 100,948A and MDL 101,146 following in descending rank order. The comparative metabolic stability of these analogs was measured over a 2-hr incubation period using rat liver homogenates. MDL 101,146 was the most stable, followed by MDL 102,823, MDL 102,111 and MDL 100,948A. MDL 101,146 was more stable in a liver homogenate from rats compared with a liver homogenate from hamsters.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of hepatic microsomal enzyme inducers on the pharmacokinetics of ouabain after portal and systemic administration to rats.

The microsomal enzyme inducers 3-methylcholanthrene, phenobarbitone and pregnenolone-16alpha-carbonitrile (PCN) are known to affect other aspects of hepato-biliary disposition in addition to metabolism. This study was designed to determine if presystemic elimination of the non-metabolized xenobiotic ouabain could be altered by these inducers. Male Sprague-Dawley rats were pretreated with inducers or saline for four days. A day later, ouabain (0.5 mg kg-1) was administered into either the ileocolic vein (portal administration) or the femoral vein (systemic administration). Blood and bile samples were collected for up to 90 min after ouabain administration. Biliary excretion rate and cumulative biliary excretion of ouabain were increased by pretreatment with PCN (75 mg kg-1 day-1) relative to controls. Phenobarbitone pretreatment (75 mg kg-1 day-1) also increased these parameters, but to a lesser extent than PCN. In contrast, 3-methylcholanthrene pretreatment (20 mg kg-1 day-1) had no effect on biliary excretion. Plasma concentrations of ouabain were much lower after PCN pretreatment relative to controls, whereas neither phenobarbitone nor 3-methylcholanthrene had any effect. Similarly, clearance (both biliary and total) and volume of distribution were increased by PCN, but not by phenobarbitone or 3-methylcholanthrene pretreatment. Interestingly, the magnitude of biliary and plasma effects induced by PCN appeared to be comparable whether ouabain was administered portally or systemically. Pretreatment of rats with PCN, but not phenobarbitone or 3-methylcholanthrene was shown to increase total clearance of ouabain, mainly via an increase in biliary clearance. Furthermore, because the enhanced clearance occurs after systemic as well as after portal administration of ouabain, a significant change in hepatic presystemic elimination was not detected.

Pharmacodynamic effects of cotinine in abstinent cigarette smokers.

The nicotine metabolite cotinine was administered to abstinent cigarette smokers to determine whether it has pharmacologic activity as assessed by various physiologic and subjective measurements. By means of a randomized, double-blind, placebo-controlled counterbalanced-order design, subjects received cotinine base (30 mg) intravenously after 48 hours of abstinence from cigarette smoking. Serum cotinine concentrations increased to levels commonly achieved during daily cigarette smoking, whereas no change in serum nicotine concentration was observed. Cotinine compared with placebo produced subjective differences in self-reported ratings of restlessness, anxiety and tension, insomnia, sedation, and pleasantness. Cotinine had minimal effects on cardiovascular measurements. These findings indicate that cotinine is behaviorally active in the setting of cigarette abstinence at blood concentrations similar to those commonly achieved through daily cigarette smoking.

Determination of ML-1035 enantiomers in plasma by chiral high-performance liquid chromatography.

ML-1035, is a gastroprokinetic agent structurally related to metoclopramide. Because ML-1035 contains an asymmetric chiral sulphoxide moiety, a chiral HPLC method has been developed to separate and quantitate its R- and S-enantiomers in plasma. The ML-1035 enantiomers present in plasma are extracted with dichloroethane under alkaline conditions, the extract evaporated to dryness and reconstituted in the mobile phase. Samples are chromatographed on a Chiralcel OD HPLC column with hexane-absolute ethanol (1% TEA) (1:1, v/v) as the mobile phase. The enantiomers of the unchanged drug are determined by fluorescence measurement (ex: 310 nm, em: 350 nm). The method provides a linear response for both enantiomers over a concentration range of 25 (limit of determination) to 2500 ng ml-1 with correlation coefficients of 0.9987 or greater. The inter-assay precision is 9.5% or less and the accuracy ranges from 93.9 to 103.4% of the theoretical value. The method is used to determine the plasma concentrations of the R- and S-enantiomers following oral and intravenous administration of R- or S-enantiomers to dogs. The method is also adapted to measure enantiomer levels from in vitro reaction mixtures so that the possibility of metabolic inversion may be assessed. The data suggest that no significant level of inversion between the enantiomers occurred either in vivo or in vitro.

Perturbation of red blood cell flow in small tubes by white blood cells.

The flow of blood in the microcirculation is facilitated by the dynamic reduction in viscosity (Fahraeus-Lindquist effect) resulting from the axial flow of deforming erythrocytes (RBCs) and from the decrease in the ratio of cell to vessel diameter. RBC velocity exceeds that of average fluid velocity; however the slower moving white blood cells (WBC) perturb flow velocity and the ratio of cell to vessel diameter by obstructing red cell flow through formation of "trains" of red cells collecting behind the white cell. This effect of white cells was studied quantitatively in a model in vitro tubes less than 10 microns in diameter with the demonstration that flow resistance increases linearly with white cell numbers up to 1,000 WBC/mm3 at tube hematocrit of 17.7%. The increase in resistance exceeds the flow resistance of WBC and appears to relate directly to train formation. A mechanical model of train formation developed to predict WBC influence in flow resistance over the range of WBC studied reasonably fits observed WBC effects.