Varying Release Rates Research Articles

Conventional vs Mechanistic IVIVC: A Comparative Study in Establishing Dissolution Safe Space for Extended Release Formulations.

The use of in vitro-in vivo correlation (IVIVC) for extended release oral dosage forms is an important technique that can avoid potential clinical studies. IVIVC has been a topic of discussion over the past two decades since the inception of USFDA guidance. It has been routinely used for biowaivers, establishment of dissolution safe space and clinically relevant dissolution specifications, for supporting site transfers, scale-up and post approval changes. Although conventional or mathematical IVIVC is routinely used, other approach such as mechanistic IVIVC can be of attractive choice as it integrates all the physiological aspects. In the present study, we have performed comparative evaluation of mechanistic and conventional IVIVC for establishment of dissolution safe space using divalproex sodium and tofacitinib extended release formulations as case examples. Conventional IVIVC was established using Phoenix and mechanistic IVIVC was set up using Gastroplus physiologically based biopharmaceutics model (PBBM). Virtual dissolution profiles with varying release rates were constructed around target dissolution profile using Weibull function. After internal and external validation, the virtual dissolution profiles were integrated into mechanistic and conventional IVIVC and safe space was established by absolute error and T/R ratio's methods. The results suggest that mechanistic IVIVC yielded wider safe space as compared to conventional IVIVC. The results suggest that a mechanistic approach of establishing IVIVC may be a flexible approach as it integrates physiological aspects. These findings suggest that mechanistic IVIVC has wider potential as compared to conventional IVIVC to gain wider dissolution safe space and thus can avoid potential clinical studies.

Recent Innovation in Manufacturing Bi-layer Tablet Technologies: An Emerging Trends Overview

Bi-layer tablet technologies is an upgraded advantageous technology that overcomes the disadvantages of the single - layer tablet. The development of pre-determined active ingredient sustained release and the inclusion of incompatible active pharmaceutical ingredients into a single unit dosage form have both been made possible through the availability of bi layer tablets to the pharmaceutical industry. One of the key design strategies for combining incompatible drugs with various indications and the same drug with a varying release rate is provided by bi layer tablets. A bi-layer tablet is appropriate for the combination of sequential release of two drugs as well as Sustained release of a tablet, wherein the first layer is for Immediate release as a loading dosage and the second layer is a maintenance dose. The best choice for drugs with low bioavailability and brief plasma half-lives is to formulate them as bi layer tablets for sustained release. Bi-layer tablets may be the best alternative to prevent physical separation from developing chemical incompatibilities across APIs and to allow for the development of many different profiles for drug release. Bi-layer tablets are currently being developed by several pharmaceutical companies for a variety of purposes, including patent extension, therapeutic use, and marketing, to name a few. As a result, the use of bi-layer tablet for analgesic, anti-inflammatory, and antihypertensive drugs is significantly different. To develop an innovative bi-layer tablet, a comprehensive mechanistic understanding must be developed through the use of dependable, analytical methods for risk management.

Phenological observations and trapping tactics for the granulate ambrosia beetle Xylosandrus crassiusculus (Coleoptera: Curculionidae, Scolytinae) in New Zealand

Abstract The granulate ambrosia beetle (GAB) Xylosandrus crassiusculus, was first formally detected in New Zealand in 2019. Since then, GAB has subsequently been found infesting numerous tree species in the Auckland region. Flight intercept traps baited with ethanol lures were deployed from October 2019 to May 2021 at three sites in the Auckland region to ascertain the phenology of GAB in New Zealand. Two distinct peak flight periods were identified in early and late summer, while a smaller and inconsistent third peak was detected in early autumn. Logistical analysis of GAB captures in the ethanol‐lured traps and degree‐day (DD) accumulation indicated that 90% of flight activity is completed by 800 DD. To assess monitoring tactics, flight intercept traps were baited with three different ethanol lures with varying release rates or ethanol‐soaked or non‐soaked wood bolts from three species of trees. A lure releasing 2 g ethanol per day was most effective at capturing GAB. Ethanol‐soaked bolts were less effective than the lures. Xylosandrus crassiusculus represents a significant risk for shrubs and trees native to New Zealand, as well as commercial horticultural and forestry trees. We recommend using ethanol‐lured panel traps for monitoring purposes.

Calibrated liposomal release of the anti-mitotic agent BI-2536 increases the targeting of mitotic tumor cells

Cancer drugs which are specifically targeted at mitosis have generally under-delivered as a class. One likely reason is that only a small percentage of cancer cells in a tumor are actually dividing at any moment. If this is the case, then prolonged bioavailability in the tumor should significantly increase the efficacy of antimitotic agents. Here, we show that if the Plk1 inhibitor BI 2536 is co-encapsulated in a liposome with a pair of anions, its release rate is dependent on both the identity and stoichiometry of the anions. We created a library of liposomes with varying release rates using this approach and found that liposomal drug release rates correlated inversely with in vitro cancer cell killing. Xenografted mice treated with a single dose of slow-releasing liposomal BI 2536 experienced tumor volume decreases lasting 12 days and complete responses in 20% of mice. Treatment with two doses a week apart increased the response rate to 75%. This approach, which we termed Paired Anion Calibrated Release (PACeR), has the potential to revive the clinical utility of antimitotic cancer drugs which have failed clinical trials.

Inter-comparison geochemical modelling approaches and implications for environmental risk assessments: A Witwatersrand gold tailings source term characterisation study

Acid mine drainage (AMD) has long been recognised as a major environmental concern from mines associated with especially Fe-sulphide minerals with the ore and/or gangue. The generation of AMD and its associated geochemical risks, e.g. leaching of toxic metal(loid)s into the environment, is a major concern from such mines, as is the case in the Witwatersrand gold mines. Geochemical modelling, incorporating thermodynamic equilibrium and kinetic in modelling geochemical processes in the mineral waste, forms an important part of this process. However, a concern regarding the geochemical modelling is on the meaning of the results, especially when these models are used to make long-term projections, as complex scientific models cannot be validated. This study shows that inter-model comparison using existing data from specifically gold tailings pore water is a viable method to build confidence in geochemical models used for risk assessments. It also demonstrates for trace elements, specifically As, Co, Ni, Pb and Zn, that sources can be identified and the release rates estimated. The process of model confidence building is the most important in identifying problems with the conceptual model as well as determining which sources are important for specific trace elements. The Pb concentration in uraninite exceeds that of pyrite by 2 orders of magnitude; however, pyrite contains sufficient concentrations of Pb so that its’ more rapid dissolution rate renders it the more important source of Pb in the tailings pore water. The varying release rates for the trace metal(loid)s can also be used to estimate their mode of occurrence within source mineral structures. Quantification of the concentration of trace elements in specific host mineral phases should be a requirement of any environmental geochemical risk assessment and can be done using standard mineralogical analytical tools.

Quantitative risk analysis of gas explosions in tunnels

Transportation of flammable liquefied gas in tunnels presents a significant risk of an accidental loss of containment leading to an explosion with major consequences. Possible scenarios include a BLEVE, a non-reactive gas expansion explosion and a reactive gas explosion. Quantification of the risk and consequences associated with such events is central in the design of tunnels and routing of dangerous goods. TNO previously developed a Quantitative Risk Analysis (QRA) method, which combines a probability assessment with state-of-the-art explosion effect and consequence models. The current article extends this model to combine the dispersion of a flammable cloud with its probability of ignition and the resulting physical effects such as overpressure. The model assumes an increasing probability of ignition with both the number and the duration of vehicles present within the flammable cloud. Various case studies are considered to illustrate the effect of different ignition probability parameters. These cases deal with instantaneous and continuous LPG releases with varying release rates including the effect of ventilation. They clearly show the capability to quantify the ignition probabilities and gas explosion load. The combination of the gas dispersion, gas explosion and ignition probability models are needed to derive design loads for tunnels, to perform tunnel risk assessments, and to develop safety measures. These models form the backbone for quantitative risk assessments.

A CFD based explosion risk analysis methodology using time varying release rates in dispersion simulations

A full probabilistic Explosion Risk Analysis (ERA) is commonly used to establish overpressure exceedance curves for offshore facilities. This involves modelling a large number of gas dispersion and explosion scenarios. Capturing the time dependant build up and decay of a flammable gas cloud size along with its shape and location are important parameters that can govern the results of an ERA. Dispersion simulations using Computational Fluid Dynamics (CFD) are generally carried out in detailed ERA studies to obtain these pieces of information. However, these dispersion simulations are typically modelled with constant release rates leading to steady state results. The basic assumption used here is that the flammable gas cloud build up rate from these constant release rate dispersion simulations would mimic the actual transient cloud build up rate from a time varying release rate. This assumption does not correctly capture the physical phenomena of transient gas releases and their subsequent dispersion and may lead to very conservative results. This in turn results in potential over design of facilities with implications on time, materials and cost of a project.In the current work, an ERA methodology is proposed that uses time varying release rates as an input in the CFD dispersion simulations to obtain the fully transient flammable gas cloud build-up and decay, while ensuring the total time required to perform the ERA study is also reduced. It was found that the proposed ERA methodology leads to improved accuracy in dispersion results, steeper overpressure exceedance curves and a significant reduction in the Design Accidental Load (DAL) values whilst still maintaining some conservatism and also reducing the total time required to perform an ERA study.

Controlled Release of Salicylic Acid from Biodegradable Cross-Linked Polyesters.

The purpose of this work was to develop a family of cross-linked poly(xylitol adipate salicylate)s with a wide range of tunable release properties for delivering pharmacologically active salicylic acid. The synthesis parameters and release conditions were varied to modulate polyester properties and to understand the mechanism of release. Varying release rates were obtained upon longer curing (35% in the noncured polymer to 10% in the cured polymer in 7 days). Differential salicylic acid loading led to the synthesis of polymers with variable cross-linking and the release could be tuned (100% release for the lowest loading to 30% in the highest loading). Controlled release was monitored by changing various factors, and the release profiles were dependent on the stoichiometric composition, pH, curing time, and presence of enzyme. The polymer released a combination of salicylic acid and disalicylic acid, and the released products were found to be nontoxic. Minimal hemolysis and platelet activation indicated good blood compatibility. These polymers qualify as "bioactive" and "resorbable" and can, therefore, find applications as immunomodulatory resorbable biomaterials with tunable release properties.

The real-time estimation of hazardous gas dispersion by the integration of gas detectors, neural network and gas dispersion models

Release of hazardous materials in chemical industries is a major threat to surrounding areas. Current gas dispersion models like PHAST and FLACS, use release velocity, release elevation, meteorological parameters, and other related information as model input. In general, such information is not always available during an on-going accident. In this paper, we develop a fast prediction approach which could bypass the input parameters that are difficult to obtain and predict the released gas concentration at certain off-site location using parameters that could be obtained easily. The new approach is an integration of gas detectors, artificial neural network (ANN) and one of the aforementioned gas dispersion models. PHAST is applied to simulate numbers of release scenarios and the results containing the spatial and temporal distributions of released gas concentration are prepared as input and target data samples for training the neural network. The approach was applied to a case study involving a hypothetical chlorine release with varying release rates and atmospheric conditions. The results of the approach that are concentration and dispersion time profiles in the environmental sensitive locations were validated against PHAST. The validation shows highly correlations with PHAST and convincingly demonstrates the effectiveness of the proposed approach.

CFD modeling and consequence analysis of an accidental hydrogen release in a large scale facility

In this study, the consequences of an accidental release of hydrogen within large scale, (>15,000 m3), facilities were modeled. To model the hydrogen release, an LES Navier–Stokes CFD solver, called fireFoam, was used to calculate the dispersion and mixing of hydrogen within a large scale facility. The performance of the CFD modeling technique was evaluated through a validation study using experimental results from a 1/6 scale hydrogen release from the literature and a grid sensitivity study. Using the model, a parametric study was performed varying release rates and enclosure sizes and examining the concentrations that develop. The hydrogen dispersion results were then used to calculate the corresponding pressure loads from hydrogen-air deflagrations in the facility.

Influence of precursor solvent properties on matrix crystallinity and drug release rates from nanoparticle aerosol lipid matrices

The crystallinity of drug-loaded lipid nanoparticles is believed to affect drug release rates; however, effective control over lipid crystallinity has not been achieved by current lipid nanoparticle preparation methods. The present study investigates control over the crystallinity of drug-loaded nanoparticle aerosol lipid matrices (NALM) through differences in evaporation rates of precursor solution drops and the subsequent control over drug release rates from these matrices. Gefitinib-loaded NALM were synthesized in an aerosol reactor using precursor solutions of gefitinib and stearic acid at a ratio of 1:4 w/w in organic solvents with high (dichloromethane) and low (ethyl acetate and chloroform) vapor pressures. Mean mobility diameter measured using a scanning mobility particle sizer was in the range of 123–132nm with a unimodal distribution and a geometric standard deviation of 1.6–1.9. A layered particle structure was observed using transmission electron microscopy, which suggests partial drug enrichment in the surface layer. Higher drug loading (20% w/w) and uniform entrapment efficiencies (∼100%) were achieved. The initial drug to lipid ratio (1:4 w/w) of the precursor solution was preserved in the synthesized lipid matrices. The crystallinity of the gefitinib-loaded lipid matrix was measured using X-ray diffraction and differential scanning calorimetry. In vitro drug release from gefitinib-loaded NALM in phosphate buffered saline (pH 7.2) over 10 days showed an initial fast release period followed by a prolonged sustained release period with varying release rates. Gefitinib-loaded NALM synthesized at higher evaporation rates exhibited lower degrees of crystallinity and faster drug releases. These results suggest the determinant role of lipid crystallinity manipulated by differing evaporation rates during aerosol synthesis on drug releases from nanometer-sized lipid matrices.

Extended Release Dosage Form of Glipizide: Development and Validation of a Level A in Vitro-in Vivo Correlation

Defining a quantitative and reliable relationship between in vitro drug release and in vivo absorption is highly desired for rational development, optimization, and evaluation of controlled-release dosage forms and manufacturing process. During the development of once daily extended-release (ER) tablet of glipizide, a predictive in vitro drug release method was designed and statistically evaluated using three formulations with varying release rates. In order to establish internally and externally validated level A in vitro-in vivo correlation (IVIVC), a total of three different ER formulations of glipizide were used to evaluate a linear IVIVC model based on the in vitro test method. For internal validation, a single-dose four-way cross over study (n=6) was performed using fast-, moderate-, and slow-releasing ER formulations and an immediate-release (IR) of glipizide as reference. In vitro release rate data were obtained for each formulation using the United States Pharmacopeia (USP) apparatus II, paddle stirrer at 50 and 100 rev. min(-1) in 0.1 M hydrochloric acid (HCl) and pH 6.8 phosphate buffer. The f(2) metric (similarity factor) was used to analyze the dissolution data. The formulations were compared using area under the plasma concentration-time curve, AUC(0-infinity), time to reach peak plasma concentration, T(max), and peak plasma concentration, C(max), while correlation was determined between in vitro release and in vivo absorption. A linear correlation model was developed using percent absorbed data versus percent dissolved from the three formulations. Predicted glipizide concentrations were obtained by convolution of the in vivo absorption rates. Prediction errors were estimated for C(max) and AUC(0-infinity) to determine the validity of the correlation. Apparatus II, pH 6.8 at 100 rev. min(-1) was found to be the most discriminating dissolution method. Linear regression analysis of the mean percentage of dose absorbed versus the mean percentage of in vitro release resulted in a significant correlation (r(2)>or=0.9) for the three formulations.

Once-a-Day Extended-Release Dosage form of Divalproex Sodium III: Development and Validation of a Level A in Vitro–in Vivo Correlation (IVIVC)

Defining a quantitative and reliable relationship between in vitro drug release and in vivo absorption is highly desired for rational development, optimization, and evaluation of controlled-release dosage forms and manufacturing process. During the development of a once-daily extended-release (ER) tablet of divalproex sodium, a predictive in vitro drug release method was designed and statistically evaluated using three formulations with varying release rates. In order to establish an internally and externally validated Level A IVIVC, a total of five different ER formulations of divalproex sodium were used to evaluate a linear IVIVC model based on the in vitro test method. For internal validation, a single-dose four-way crossover study (N = 16) was performed using fast-, medium-, and slow-releasing ER formulations and a 12-h IV infusion of valproic acid as reference. To validate the IVIVC externally, a second three-way crossover study (N = 36) was performed using slightly-fast-, medium-, and slightly-slow-releasing ER formulations. The in vivo absorption-time profile was inferred by deconvolution of the observed plasma concentration-time profiles against the unit disposition function (UDF). A linear IVIVC model was established in which the in vivo absorption was expressed as a function of in vitro drug release. Plasma profiles of ER formulations were estimated via convolution of in vitro release profiles with the UDF. Successful internal and external validations of the model were demonstrated by individual and average absolute percent prediction errors of </=9% for both C(max) and AUC(infinity). In conclusion, a Level A IVIVC describing the entire time-course of plasma concentrations was developed and validated, both internally and externally, for ER formulations of divalproex sodium.

Once‐a‐Day Controlled‐Release Dosage Form of Divalproex Sodium II: Development of a Predictive In Vitro Drug Release Method

During formulation design of a once‐daily controlled release matrix system of divalproex sodium, the in vitro dissolution test (USP II, 100rpm, pH 6.8 buffer) was found to result in release rates that were slower than in vivo absorption. The test method also did not sufficiently discriminate formulations with different in vivo absorption rates. To develop an in vitro method that is directly correlated with in vivo absorption, statistically designed studies were carried out to investigate the effects of various in vitro testing variables on drug release using USP dissolution apparatuses. The variables studied included agitation intensity, apparatus, pH, surfactant and ionic strength of the dissolution medium. Experimental data were analyzed using ANOVA. In vitro/in vivo correlation was tested based on the hypothesis that the same linear regression equation holds for three formulations with different release rates. A mixed effects model was used in which the dependence among observations from the same subject was taken into account. Factorial studies indicated that higher pH, addition of sodium lauryl sulphate (SLS) to the dissolution medium, and higher agitation intensity increased the release rate from the matrix tablet. Use of SLS not only lead to increased release rates that are more comparable to in vivo absorption rates, but also improved differentiation among formulations with varying release rates. Furthermore, drug release was also affected by interactions among the variables studied. Statistical analysis indicated that a combination of higher SLS concentration and lower pH provided enhanced differentiation between release profiles of the fast and slow releasing formulations. Based on the above findings, a new set of testing conditions was identified and demonstrated to be predictive of in vivo drug absorption for various controlled release formulations of divalproex sodium. The new method uses USP Apparatus II operating at 100rpm in 500mL of 0.1N HCl for 45min followed by 900mL of 0.05M phosphate buffer containing 75mM SLS, pH 5.5, 37 ± 0.5°C. In conclusion, adjusting dissolution testing conditions to match the behavior of the formulations in vitro with that in vivo is a useful approach in identifying a predictive method in development of in vitro–in vivo correlation. © 2003 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 92:2317–2325, 2003

Field response of Ips paraconfusus, Dendroctonus brevicomis, and their predators to 2-methyl-3-buten-2-ol, a novel alcohol emitted by ponderosa pine.

Methylbutenol (MBO) is a major component of the aggregation pheromone of the European spruce beetle Ips typographus and also has been found to be emitted in large amounts by several species of pine native to western North America. This study investigates the influence this signal may have on the behavior of North American bark beetles and examines whether MBO functions as a defensive compound for emitting pines. The response of two North American bark beetles (Ips paraconfusus and Dendroctonus brevicomis) and their predaceous beetles (Trogositidae and Cleridae) to MBO, pheromone, and monoterpenes in varying release rates was investigated in the field using Lindgren funnel traps. MBO exhibited no repellent properties when tested alone, nor did MBO appear to have any effect on the aggregation response of these bark beetles and their predators to their pheromones. These results provide no support for a defensive function of MBO.

Influence of input rate on the stereospecific and nonstereospecific first pass metabolism and pharmacokinetics of metoprolol extended release formulations.

The purpose of this study was to examine the influence of input rate on the stereoselective and nonstereoselective pharmacokinetics of metoprolol, alpha-hydroxymetoprolol, and its acid metabolite. Extended release formulations (100 mg) of metoprolol with varying release rates (e.g., slow (S), moderate (M), and fast (F)) and an oral solution (OS, 50 mg) were administered to normal, healthy extensive metabolizers. Serial blood samples were collected over 48 h, plasma was obtained, and subsequently analyzed by a validated HPLC method with fluorescence detection. The mean T(max) of metoprolol after the S, M, F (4.43, 4.00, 3.14 h, respectively) was found to be different ( P < 0.05) as compared to the OS (2.07 h). The ratio of alpha-hydroxymetoprolol/metoprolol was higher for the OS (1.26) vs. the S, M, and F (1.02, 0.96, 0.99). The S/R enantiomer ratios of the concentration for metoprolol, ACMB, and alpha-hydroxmetoprolol were calculated at each time point and showed a significant difference ( P < 0.05) in the absorption phase (1-4 h) vs. terminal phase (8-16 h) for fast input (solution and fast extended release formulations). Based on these results, it would appear that input rate influences the pharmacokinetics of metoprolol, its metabolites, and their enantiomers.

Formulation Development of Sustained-Release Hydrophilic Matrix Tablets of Zileuton

ABSTRACTThe purpose of this paper was to develop a hydrophilic matrix system for extended oral delivery of zileuton, and study the effects of certain formulation, processing, and dissolution variables on in vitro drug release. Tablet formulations with 60–70% drug and varying release rates were prepared by wet granulation using low and medium viscosity grades of hydroxypropylmethocellulose. In vitro drug release was evaluated using USP apparatus I. The in vitro drug release from all formulations followed zero-order kinetics and was independent of compression force. In general, the release rate decreased with increasing drug load and higher polymer concentration or viscosity. High-shear granulation also resulted in lower release rate. Accelerated release was observed with increased agitation as well as in the dissolution media with higher surfactant concentration and/or ionic strength. No stereoselective release from the matrix system was observed. The hydrophilic matrix system effectively controlled the in vitro release of zileuton. Matrix tablets with desired release rates can be prepared by adjusting various formulation and processing parameters. The matrix system also has the advantage of simple processing and relatively low cost.

Simple transient release rate models for releases of pressurised liquid petroleum gas from pipelines

Large scale experimental data have been used to compare and derive simple mathematical models to describe the time varying release rate of pressurised liquid petroleum gas (LPG) from a ruptured pipeline. The models studied consisted of a single box, a single-node slip-flow and an empirical model. The empirical model is based on data obtained using 100 metre long pipelines of internal diameters of 50 mm and 150 mm, from an experiment carried out jointly by BP Research and Shell Research Ltd. The empirical model was developed to describe the observed characteristics of the mass history of commercial liquid propane inside the pipe, namely the mass reduced approximately exponentially with time. While the single box model did not compare well with observed data, the single-node slip-flow model was found to produce exponentially time varying release rates.

A method for trapping hylobius abietis (L.) with a standardized bait and its potential for forecasting seedling damage

A method for trapping walking Hylobius abietis (L.) (Coleoptera: Curculionidae) was developed and evaluated. Synergism between α‐pinene and ethanol in attracting H. abietis was confirmed. The effects of varying release rates of these substances and of adding other host terpenes were studied. A simple bait was developed containing α‐pinene and ethanol released from separate vials. The correlation between trap catch and seedling damage was estimated during May, June, and August on 1‐, 2‐, and 3‐year‐old clear‐cuttings. In May and June, population levels were relatively high on all clear‐cuttings and no significant correlations were found. The August experiment showed a strong positive correlation between catch and damage. The percentage damaged seedlings per captured weevil was considerably higher in August than in May or June. Possibilities for developing a system for forecasting seedling damage using this trapping method are discussed.