Development and internal validation of an in vitro-in vivo correlation for a hydrophilic metoprolol tartrate extended release tablet formulation

PURPOSE: To develop and validate internally an in vitro-in vivo correlation (IVIVC) for a hydrophilic matrix extended release metoprolol tablet. METHODS: In vitro dissolution of the metoprolol tablets was examined using the following methods: Apparatus II, pH 1.2 & 6.8 at 50 rpm and Apparatus I, pH 6.8, at 100 and 150 rpm. Seven healthy subjects received three metoprolol formulations (100 mg): slow, moderate, fast releasing and an oral solution (50 mg). Serial blood samples were collected over 48 hours and analyzed by a validated HPLC assay using fluorescence detection. The f2 metric (similarity factor) was used to analyze the dissolution data. Correlation models were developed using pooled fraction dissolved (FRD) and fraction absorbed (FRA) data from various combinations of the formulations. Predicted metoprolol concentrations were obtained by convolution of the in vivo dissolution rates. Prediction errors were estimated for Cmax and AUC to determine the validity of the correlation. RESULTS: Apparatus I operated at 150 rpm, and pH of 6.8 was found to be the most discriminating dissolution method. There was a significant linear relationship between FRD and FRA when using either two or three of the formulations. An average percent prediction error for Cmax and AUC for all formulations of less than 10% was found for all IVIVC models. CONCLUSIONS: The relatively low prediction errors for Cmax and AUC observed strongly suggest that the metoprolol IVIVC models are valid. The average percent prediction error of less than 10% indicates that the correlation is predictive and allows the associated dissolution data to be used as a surrogate for bioavailability studies.     

A mixture experiment approach for controlling the dissolution rate of a sustained-release tablet

Several sustained-release tablet formulations with acceptable pharmacokinetic properties were found to be unstable because of the effects of lactose. Because the pharmacokinetic properties were acceptable, an attempt was made at developing stable formulations that reproduced the in vitro drug release characteristics of the unstable formulations. Through the use of a statistically designed mixture experiment, alternative formulations were generated and tested for dissolution. The dissolution data collected in the mixture experiment were used to develop a statistical regression model for identifying formulations with dissolution rates equal to those of the unstable formulations. The form of the regression model was based on the Higuchi equation. The data analysis indicated that it is possible to generate dissolution profiles that reproduce those of the original formulations by adjusting the ratios of Methocel K4MCR Premium and Methocel K100MCR Premium and by replacing the detrimental lactose with calcium phosphate dibasic anhydrous.     

An evaluation of fit factors and dissolution efficiency for the comparison of in vitro dissolution profiles

Dissolution efficiency (D.E.), the area under a dissolution curve between defined time points, and the fit factors (f1 and f2) have been compared for the characterisation of dissolution profiles, using data from three batches of a product in nine different packs stored under two conditions. The factors f1 and f2 offer ease of calculation and a simple measure of similarity between pairs of dissolution profiles. This is well suited to the qualitative determination of 'similarity' as required by the FDA's SUPAC Guide. However, they do not provide information on individual batches, including their consistency. In contrast, D.E. does provide such information is well-suited to making quantitative comparisons amongst batches. Because D.E. has a simple physical meaning, it is easier to interpret D.E. data then corresponding f1 and f2 results. The confidence limits in D.E. values provide a useful measure of the variability in batch dissolution and allow the statistical significance of difference in D.E. between pairs of batches to be determined. Both of the above measures lead to the same conclusions regarding the similarity in protective power amongst the nine packs under test and to the value of added desiccant in maintaining the dissolution profile of the product when stored under high humidity conditions. It is concluded that D.E. offers a suitable alternative to the single point dissolution measurement for QC of immediate release products.     

Controlled-release delivery system for the alpha-MSH analog melanotan-I using poloxamer 407

The overall objective of these studies was to develop a controlled-release formulation of Melanotan-I (MT-I) containing poloxamer 407 (P407). Various aqueous formulations were evaluated containing MT-I and 25% w/v P407 alone, or with one of the following additives present, i.e., poly(vinylpyrrolidone) 10000 (PVP), methylcellulose (MC), or hydroxypropyl methylcellulose (HPMC). The in-vitro release profiles of MT-I from the P407 formulations and the dissolution of the gel were obtained simultaneously using a membraneless in-vitro model. These data were obtained at 37 degrees C and room temperature (24 degrees C). It was observed that the PVP-containing P407 formulations of MT-I accelerated the dissolution of gel and the release of the peptide compared to the control formulation. The formulations containing MC or HPMC exhibited the slowest dissolution rates and release of MT-I. The same rank order was observed for the dissolution and release profiles of MT-I from the various formulations at both temperatures. The in-vivo release kinetics of selected formulations were analyzed in guinea pigs following intraperitoneal administration. The plasma concentration-time profiles showed an extended release of the peptide formulated with gel compared to the intraperitoneal administration of MT-I in solution. On the basis of the in-vitro and in-vivo results, the P407 formulations of MT-I with MC or HPMC as an additive showed potential for use as a controlled-release delivery system for MT-I.     

A parametric confidence interval for a moment-based scaled criterion for individual bioequivalence

Confidence intervals of proposed individual bioequivalence metrics are difficult to determine in closed form because their stochastic distributions are unknown. In this article, it is shown that, with slightly modified weights, the Relative Individual Risks (RIR) moment-based scaled statistic for individual bioequivalence that was presented by Schall and Williams has an exact noncentral Fisher's F distribution with noncentrality parameter give by a scaled squared difference in formulations means. This can be approximated by a central F with adjusted degrees of freedom from which it follows that an upper (1-alpha) confidence bound for RIR is given by [formula: see text] where [formula: see text] is the least square estimate of RIR; dfER is the degrees of freedom associated with the reference intrasubject variance estimate, v is the subject-by-formulation degrees of freedom adjusted for noncentrality and alpha is the significance level. Individual bioequivalence is concluded if UL does not exceed the regulatory limit. The performance of this confidence interval was investigated by comparing its experimental bioequivalence rate to that of the unweighted metric under known parameter situations through simulations of two formulations in a fully replicated study design. Results showed that the proposed metric is slightly less biased and more precise than the unweighted metric.     

Identification of formulation and manufacturing variables that influence in vitro dissolution and in vivo bioavailability of propranolol hydrochloride tablets

The purpose of this study was to evaluate the effect of formulation and processing changes on the dissolution and bioavailability of propranolol hydrochloride tablets. Directly compressed blends of 6 kg (20,000 units) were prepared by mixing in a 16-qt V blender and tablets were compressed on an instrumented Manesty D3B tablet press. A half-factorial (2(5-1), Resolution V) design was used to study the following variables: filler ratio (lactose/dicalcium phosphate), sodium starch glycolate level, magnesium stearate level, lubricant blend time, and compression force. The levels and ranges of the excipients and processing changes studied represented level 2 or greater changes as indicated by the Scale-up and Post Approval Changes (SUPAC-IR) Guidance. Changes in filler ratio, disintegrant level, and compression force were significant in affecting percent drug released (Q) in 5 min (Q5) and Q10. However, changes in magnesium stearate level and lubricant blend time did not influence Q5 and Q10. Hardness was found to be affected by changes in all of the variables studied. Some interaction effects between the variables studied were also found to be significant. To examine the impact of formulation and processing variables on in vivo absorption, three batches were selected for a bioavailability study based on their dissolution profiles. Thirteen subjects received four propranolol treatments (slow-, medium-, and fast-dissolving formulations and Inderal 80 mg) separated by 1 week washout according to a randomized crossover design. The formulations were found to be bioequivalent with respect to the log Cmax and log AUC0-infinity. The results of this study suggest that (i) bioavailability/bioequivalency studies may not be necessary for propranolol and perhaps other class 1 drugs after level 2 type changes, and (ii) in vitro dissolution tests may be used to show bioequivalence of propranolol formulations with processing or formulation changes within the specified level 2 ranges examined.     

Polymorphism in anhydrous theophylline--implications on the dissolution rate of theophylline tablets

The objects of this investigation were (i) to prepare and characterize a new anhydrous theophylline phase that is metastable under ambient conditions, and (ii) to prepare model tablet formulations containing either this metastable anhydrate (I*) or stable anhydrous theophylline (I), store them under different relative humidity (RH) conditions, and compare their dissolution behavior. I* was prepared by dehydration of theophylline monohydrate (II). Variable temperature X-ray powder diffractometry of II revealed the following series of transitions: II-->I*-->I. The metastable anhydrate, I*, which has not yet been reported in the literature, appears to be related monotropically to I. It was characterized by ambient and variable temperature X-ray powder diffractometry, Karl Fischer titrimetry, and thermoanalytical techniques (differential scanning calorimetry and thermogravimetric analysis). Tablet formulations containing either I* or I were prepared and stored at 33 and 52% RH (room temperature). The solid state of the drug was monitored by X-ray powder diffractometry and the tablets were subjected to the USP dissolution test. In tablets, I* completely converted to I in < or = 10 days when stored at either 33 or 52% RH. Scanning electron microscopy provided direct visual evidence of recrystallization. This recrystallization was accompanied by a decrease in the dissolution rate of the stored formulations that was so pronounced in the formulations stored at 52% RH that they failed the USP dissolution test. The in situ solid-state transition appears to be responsible for the decrease in dissolution rate observed following storage. Stored tablets containing I showed neither a phase transition nor an alteration in their dissolution behavior.     

The effect of aluminum hydroxide dissolution on the bleeding of aluminum lake dyes

The effect of pH on the bleeding of FD&C yellow No. 5 aluminum lake and FD&C red No. 40 aluminum lake was investigated. The pH-bleeding profiles corresponded to the pH-solubility profile of aluminum hydroxide. The similarity of the bleeding profiles of both lake dyes and the pH-solubility profile of aluminum hydroxide indicates that pH related bleeding, other than that occurring by competition with anions, is a result of dissolution of the aluminum hydroxide substrate. This dissolution is related to the properties of the substrate rather than to the structure of adsorbed dye.     

Biomimicry, dental implants and clinical trials

The overall objective of this study was to develop pluronic F127 (PF127)-containing formulations of pilocarpine hydrochloride (PHCL) suitable for controlled-release ocular delivery of PHCL. Various aqueous formulations were evaluated containing 1% w/v PHCL and 25% w/v PF127 alone or with one of the following additives present: poly(ethylene glycol) 4600 (PEG), poly(vinylpyrrolidone) 10,000 (PVP), poly(vinyl alcohol) 10,000 (PVA), methylcellulose 15 cP (MC), and hydroxypropyl methylcellulose 80-120 cP (HPMC). The in vitro dissolution of the PF127 formulations and the pilocarpine release profiles from them were obtained simultaneously at 34 degrees C and room temperature using a membraneless in vitro model. It was observed that the PEG- and PVP-containing PF127 formulations of PHCL dissolved the quickest and released the drug at a significantly faster rate than the control PF127 formulation, which had no additive present. The PF127 formulations of PHCL containing MC or HPMC exhibited the slowest dissolution rates and released the drug the slowest. The same rank order was observed at each temperature for the dissolution and PHCL release profiles of each formulation. On the basis of the in vitro results, the PF127 formulations of PHCL containing MC or HPMC as an additive showed potential for use as controlled-release ocular delivery systems for PHCL.     

Auditory models of formant frequency discrimination for isolated vowels

Thresholds for formant discrimination of female and male vowels are significantly elevated by two stimulus factors, increases in formant frequency and fundamental frequency [Kewley-Port et al., J. Acoust. Soc. Am. 100, 2462-2470 (1996)]. The present analysis systematically examined whether auditory models of vowel sounds, including excitation patterns, specific loudness, and a Gammatone filterbank, could explain the effects of stimulus parameters on formant thresholds. The goal was to determine if an auditory metric could be specified that reduced variability observed in the thresholds to a single-valued function across four sets of female and male vowels. Based on Sommers and Kewley-Port [J. Acoust. Soc. Am. 99, 3770-3781 (1996)], four critical bands around the test formant were selected to calculate a metric derived from excitation patterns. A metric derived from specific loudness difference (delta Sone) was calculated across the entire frequency region. Since analyses of spectra from Gammatone filters gave similar results to those derived from excitation patterns, only the 4-ERB (equivalent rectangular bandwidth) and delta Sone metrics were analyzed in detail. Three criteria were applied to the two auditory metrics to determine if they were single-valued functions relative to formant thresholds for female and male vowels. Both the 4-ERB and delta Sone metrics met the criteria of reduced slope, reduced effect of fundamental frequency, although delta Sone was superior to 4-ERB in reducing overall variability. Results suggest that the auditory system has an inherent nonlinear transformation in which differences in vowel discrimination thresholds are almost constant in the internal representation.     

电感耦合等离子体原子发射光谱法测定Ti80钛合金中铝铌锆钼铁的酸体系溶解条件探讨

为实现Ti80钛合金样品的快速有效溶解,并制得适用于电感耦合等离子体原子发射光谱法(ICP-AES)测定Ti80钛合金中铝、铌、锆、钼、铁含量的样品溶液,对硫酸-硝酸、硝酸-氢氟酸、硫酸-氢氟酸-硝酸及盐酸-氢氟酸-硝酸4种酸体系对应的溶解条件进行了探讨。对4种溶解体系分别进行不同条件试验,根据溶解现象及样品溶解的完全程度初步确定了每种酸体系的溶解条件。硫酸-硝酸溶解体系的溶解条件为:10.0 mL硫酸(1+1),290~310 ℃下加热溶解,溶解完全后逐滴加入硝酸至溶液褪色;硝酸-氢氟酸溶解体系的溶解条件为:预先在样品中加入10.0 mL水,然后相继加入2.0 mL硝酸和2.0 mL氢氟酸,直至样品溶解完全;硫酸-氢氟酸-硝酸溶解体系的溶解条件为:预先在样品中加入10.0 mL硫酸(1+3),然后加入2.0 mL氢氟酸使样品溶解完全,加入2.0 mL硝酸至溶液褪色,再加热至冒烟;盐酸-氢氟酸-硝酸溶解体系的溶解条件为:预先在样品中加入15.0 mL盐酸(1+1),然后加入1.0 mL氢氟酸使样品溶解完全,加入2.0 mL硝酸使溶液褪色。在初步确定的溶解条件下,分别采用4种溶解体系对Ti80钛合金样品进行溶解,制得样品溶液;对样品溶液中铝、铌、锆、钼和铁的稳定性进行了考察并对其含量进行了测定,结果表明4种酸体系对应的溶解条件下制得的样品溶液均适用于电感耦合等离子体原子发射光谱法(ICP-AES)测定Ti80钛合金中铝、铌、锆、钼和铁含量,确定的4种酸体系对应溶解条件合理。     

Experimental evaluation of three single-particle dissolution models

The dissolution of the 60-85-mesh fraction os recording, flow-through dissolution apparatus equipped with a dissolution cell; it was particularly suitable for kinetic analysis of multiparticulate systems. By using a time-scaling approach, experimental data are compared with theoretical calculations to evaluate, quantitatively, which of three single-particle dissolution models best describes the data and how well the multiparticulate kinetics can be explained mathematically. The nonspherical tolbutamide particles are replaced in the calculations by a hypothetical system of spherical particles that appears to be log-normally distributed. This procedure permits the calculation of the intrinsic dissolution profile, considering both size distribution and particle shape effects.     

In vitro-in vivo relationships for oral extended-release drug products

It is of interest to predict the in vivo behavior of an oral extended-release drug product based on its in vitro dissolution profile. In some cases a suitable convolution-based prediction model can be found. We present a methodology for developing statistical models of in vitro-in vivo relationships under the framework of the mixed-effects nonlinear model and discuss methods for assessing the validity and strength of the relationship. These methods are illustrated and contrasted with a level A in vitro-in vivo correlation using data from a study involving four different formulations of an oral extended-release drug product.     

Predictors of supportive coparenting after relationship dissolution among at-risk parents.

Supportive coparenting after relationship dissolution is associated with increased father involvement which can buffer against the negative effects of parental relationship dissolution. Low-income, at-risk families are much more likely to experience relationship dissolutions; hence, supportive coparenting after dissolution is particularly important in these families. We examined whether relationship (commitment and quality) and child (difficult temperament and gender) characteristics predicted initial levels of, and change in, supportive coparenting after relationship dissolution in the Fragile Families and Child Wellbeing Study (N = 1,603). We used structural equation modeling of latent growth curves to examine four time points collected at the focal child's birth and first, third, and fifth birthdays. Ninety-percent of the mothers had nonmarital births, and about three-quarters had a high school diploma or less education. Overall, supportive coparenting decreased over time. Mothers in more committed relationships prior to the dissolution initially had significantly lower supportive coparenting. But over time, mothers who had been in more committed relationships increased in supportive coparenting. Mothers who had been in higher quality relationships prior to dissolution initially reported more supportive coparenting. At each time point, if a mother was romantically involved with a new partner, she reported significantly lower supportive coparenting compared to mothers who were single. With regard to child characteristics, mothers who reported their child as more difficult had significantly lower initial supportive coparenting. Similar results for fathers are discussed. Overall, the relationship characteristics of parents were important predictors of supportive coparenting both initially and over time. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Evaluating Four Storm-Water Performance Metrics with a North Carolina Coastal Plain Storm-Water Wetland

Storm-water best management practices (BMPs) are typically assessed using the performance metric of pollutant concentration removal efficiencies. However, debate exists whether this is the most appropriate metric to use. In this study, a storm-water wetland constructed and monitored in the coastal plain of North Carolina is evaluated for water quality and hydrologic performance using four different metrics: concentration reduction, load reduction, comparison to nearby ambient water quality monitoring stations, and comparison to other wetlands studied in North Carolina. The River Bend storm-water wetland was constructed in spring 2007 and was monitored from June 2007 through May 2008. Twenty-four hydrologic and 11 water quality events were captured and evaluated. The wetland reduced peak flows and runoff volumes by 80 and 54%, respectively. Reductions were significant. Concentrations for the following pollutants increased: total kjeldahl nitrogen (TKN), NH4–N, total nitrogen (TN), and total suspended solids (TSS); inflow and outflow concentrations did not change for total phosphorus (TP), while only NO2–3–N and orthophosphorus (OP) concentrations were lower at the outlet. Using a load reduction metric, results were strikingly different, showing positive load reductions of 35, 41, 42, 36, 47, 61, and 49% for these respective pollutants: TKN, NO2–3–N, NH4–N, TN, TP, OP, and TSS. When comparing the effluent concentrations from the wetland to ambient water quality in the Trent River, all effluent nitrogen species concentration were either similar or lower. TP and TSS concentrations leaving the wetland were higher than ambient water quality data. Finally, by comparing pollutant concentrations among different North Carolina wetlands, it is apparent the River Bend wetland received relatively “clean” water and released water with pollutant concentrations comparable to all other studies examined. Major conclusions from this study include: (1) storm-water wetlands sited in sandier soils (such as those of the North Carolina coastal plain) should be considered a low impact development tool and (2) the selection of performance metric has a pronounced bearing on how a BMP’s performance is perceived. Sole reliance on a concentration reduction metric is discouraged.     

Cyclosporine disposition and metabolite profiles in renal transplant patients receiving a microemulsion formulation

Several lines of evidence suggest that cyclosporine may undergo prehepatic metabolism, the possible contribution of which to the overall biotransformation of the drug is, however, unclear. A recently developed oral formulation of cyclosporine, Sandimmune Neoral, which incorporates the drug in a microemulsion preconcentrate, exhibits a faster rate of absorption and a shorter residence time in the gastrointestinal tract compared to the currently marketed formulation, Sandimmune. If prehepatic metabolism plays an important role, this could, theoretically, have an impact on the metabolite profile from the microemulsion formulation. Therefore, the pharmacokinetics of cyclosporine and its major metabolites were assessed in 13 clinically stable renal transplant patients receiving the commercial and the new formulations at steady state. Whole blood samples were collected over a dosing interval and analyzed by high-performance liquid chromatography (HPLC). Model-fitting of the concentration-time profiles of the parent compound indicated that while the systemic disposition was similar between formulations, absorption-related pharmacokinetic differences were evident. This was manifested in patients at steady state as shorter lag time and faster rate of absorption of the parent compound from the microemulsion formulation. The metabolite-to-parent area under the curve (AUC) ratios for the major metabolites AM1, AM4N, and AM9 were comparable between formulations. Specifically for metabolites AM1 and AM9, which predominated in whole blood and could, therefore, be fully characterized, the area ratios were bioequivalent when comparing the two formulations. Hence, absorption-related differences between the two oral formulations does not affect the systemic metabolite profile during steady-state administration in patients.     

Second phase dissolution

A detailed theoretical study was made of the dissolution of precipitates. The kinetic analyses of the atomic mechanisms included the concurrent effects of diffusion, interface reaction, and curvature, and considered the more complex problems of precipitate arrays and nondepleted matrices. The general formalism thus obtained was used to interpret the results of an experimental investigation of the technologically important problem of the dissolution of “reluctantly soluble” carbides in the Fe-C-V system. It was found that vanadium carbide (and iron carbide as well) were quite easily dissolved while complex alloy sulfides, silicates and oxides (possibly associated with the presence of vanadium) persisted, with little if any dissolution. Previous views of the reasons for poor hardenability were reevaluated in light of these results. Formerly with the Process Research Department, Scientific Research Staff, Ford Motor Co. This paper is based on an invited talk presented at a symposium on Homogenization of Alloys, sponsored by the IMD Heat Treatment Committee, and held on May 11, 1970, at the spring meeting of The Metallurgical Society of AIME, in Las Vegas, Nev.     

Arbitrary metrics redux.

Reducing the arbitrariness of a metric is distinct from the pursuit of validity, rational zero points, data transformations, standardization, and the types of statistical procedures one uses to analyze interval-level versus ordinal-level data. A variety of theoretical, methodological, and statistical tools can assist researchers who wish to make their metrics less arbitrary. These approaches can be combined with perspectives from classic test theory, item response theory, or other scaling models. The importance of considering arbitrary metrics for some applied areas of research is reemphasized. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Release of norfenefrine from sustained-release formulations by an in vitro dissolution model. Simulation of "drug levels" by calculation using pharmacokinetical constants and comparison with in vivo course of action (author's transl)

Drug release and dissolution behaviour of 1-(3'-hydroxyphenyl)-2-amino-ethan-1-ol hydrochloride (norfenefrine-HCl) from a sustained-release norfenefrine preparation (Esbuphon) were tested by an in vitro dissolution model in comparison with other norfenefrine formulations. By using pharmacokinetical constants, relative "drug levels" were calculated and compared with the activity curves from animal experiments. Conformities in time course were shown. Variations are discussed. The application of the model is justified if determination of serum concentration of norfenefrine cannot be done.     

An experimental and theoretical study of cementite dissolution in an Fe-Cr-C alloy

The dissolution of cementite at 910 °C in an Fe-2.06Cr-3.91C (at. pct) alloy is investigated experimentally. The Cr concentration profiles in austenite and cementite are measured by means of the scanning transmission electron microscopy/energy dispersive spectrometry (STEM/EDS) technique at different dissolution times. The measurements show the Cr enrichment in the cementite during the dissolution process. The measurements suggest that the main part of the reaction for this alloy is controlled by Cr diffusion in the cementite or in the austenite matrix. This observation is in agreement with predictions of the local equilibrium hypothesis. The carbide fraction and average particle diameter are evaluated as functions of dissolution time. The Cr enrichment of the cementite results in a supersaturation and a possible decomposition of the cementite. Microstructural evidence for such a decomposition is found by scanning electron microscopy (SEM) and transmission electron microscopy (TEM). A new program package called DICTRA,_[11] which is suitable for the simulation of diffusional reactions in multicomponent alloys, has been applied to the present case. The simulation is compared with the experimental data, and a good agreement between the two is found.