Dissolution assay development for in vitro-in vivo correlations. Theory and case studies.
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Chemistry, Pharmaceutical↗
Biomedical subjects
J W Skoug
Publications and source records attributed to J W Skoug.
Swelling of hydroxypropyl methylcellulose matrix tablets. 2. Mechanistic study of the influence of formulation variables on matrix performance and drug release.
We characterized the effect of hydroxypropyl methylcellulose (HPMC)/lactose ratio and HPMC viscosity grade (molecular weight) on solute release and swelling of matrix tablets. We used a semiquantitative optical imaging method to monitor the swelling of matrices with HPMC content from 20% to 80% (w/w) and four viscosity grades. Several aspects of the swelling process common to all formulations were revealed: (i) swelling is anisotropic with a preferential expansion in the axial direction, (ii) swelling is isotropic with respect to the gel layer thickness and composition in both axial and radial directions, (iii) the gel layer develops in three stages, and (iv) water penetration is Fickian in nature and essentially constant for all formulations. We monitored simultaneously drug, lactose, and HPMC release. Lactose and drug release rates were superimposed, indicating a similar diffusional release mechanism and no interaction with HPMC. The strong dependence of HPMC release on viscosity grade is explained on the basis of the concept of polymer disentanglement concentration. We analyzed drug release rates using a model for a reservoir-type release system that incorporates swelling kinetics. HPMC/lactose ratio modulates drug release rate by altering drug diffusivity, a function of gel composition. In contrast, HPMC viscosity grade impacts matrix dissolution and gel layer thickness development below a critical molecular weight. For slowly dissolving matrices containing high viscosity grade (> 4000 cps) HPMC, similar drug release rates are observed mainly due to the same drug diffusivity as a result of the identical gel composition and thickness. For fast dissolving matrices (< or = 100 cps) swelling inhomogeneity is proposed as being responsible for a higher apparent drug diffusivity and release rate.
Antidepressive Agents↗
Gradient high performance liquid chromatographic assay for degradation products of adinazolam mesylate in a sustained release tablet formulation.
A gradient high performance liquid chromatographic method was developed to determine degradation products of adinazolam mesylate in a sustained release tablet formulation. Sample preparations were chromatographed on a YMC-Basic column using a formate buffer/acetonitrile gradient with absorbance detection at 254 nm. Adinazolam mesylate was found to degrade at high relative humidity and temperature to form a major product, the 6-aminoquinoline analog, plus numerous other compounds. Five of these compounds were identified and their structures indicate that the solid-state degradation of adinazolam, in the presence of sufficient moisture, involves not only a hydrolytic mechanism, but also an oxidative mechanism. Potential process impurities were resolved from the drug and degradation products. Recovery was near 100% over the 0.5 to 10% range for the major degradate (6-aminoquinoline) and over the 0.5 to 1% range for the other analytes. The method was applied to tablet samples stressed at high relative humidity and temperature. The relative standard deviation of the assay for the 6-aminoquinoline was less than 2% and less than 13% for the minor components. Calculated mass balances (sum of adinazolam plus degradation products in the degraded tablet divided by the same sum in the undegraded tablet) were less than 100% and were dependent on the extent of degradation in the tablet. The average mass balance result obtained for samples that were an average of 9.5% degraded was 95.0 +/- 1.5%. It is possible that the decrease in mass balance with increase in percent degradation may be explained by the formation of many components at trace levels due to degradation by various permutations of hydrolytic and oxidative reaction pathways.
Antidepressive Agents↗
Diffusion in HPMC gels. II. Prediction of drug release rates from hydrophilic matrix extended-release dosage forms.
PURPOSE: A mathematical model is described for the prediction of the relative change in drug release rate as a function of formulation composition for HPMC-based extended-release (ER) tablets of adinazolam mesylate and alprazolam. METHODS: The model is based on the equation derived by Higuchi for the diffusional release of soluble drugs from polymeric matrices and on our recent measurements of the concentration dependency of adinazolam diffusivity in dilute HPMC gels and solutions. The assumptions made in applying the model include (i) that diffusion is the sole mechanism of drug release (i.e. swelling kinetics are ignored), and (ii) that the surface area-to-volume ratio and concentrations of adinazolam, lactose and HPMC in the gel layer are proportional to that of the dry tablet. RESULTS: Reasonable correlations were obtained between the experimental drug release rate ratios and the predicted drug release rate ratios for ER adinazolam mesylate (R2 = 0.82) and low-dose (0.5 mg) ER alprazolam tablets (R2 = 0.87). The predictive power for a 6-fold higher dose of ER alprazolam tablets was not as good (R2 = 0.52). CONCLUSIONS: These results are consistent with previous knowledge of the release mechanisms of these formulations. ER adinazolam mesylate and ER alprazolam 0.5 mg exhibit primarily a diffusion controlled release mechanism, while ER alprazolam 3 mg deviates from pure diffusional release. The limitations of the model are discussed and point to the need for continued study of the swelling kinetics of matrix ER systems.
Benzodiazepines↗
In vitro and in vivo evaluation of whole and half tablets of sustained-release adinazolam mesylate.
The mechanism of release from sustained-release adinazolam mesylate tablets was assessed by the Higuchi equation and by analysis of drug release profiles through 60% released using the Peppas equation. Computed values of the diffusional exponent, n, ranged from 0.59 to 0.66. Values of n in this range are consistent with a mixed mechanism of release, with diffusion of drug through the hydrated polymer matrix and relaxation of this matrix being the principal processes controlling release. The rate of in vitro drug release was increased for half tablets relative to whole tablets and is attributed to an increase in the surface to volume ratio of half tablets of about 16%. This increase in surface-to-volume ratio of half tablets was reflected by an increase in the constant, k, from the Peppas equation of 20-23% and by an increase in the slope of Higuchi plots of 12-18% for four lots of tablets. In vivo/in vitro relationships from two bioavailability studies were thoroughly evaluated. Using either a linear or a quadratic relationship, an in vivo/in vitro correlation exists for sustained-release adinazolam mesylate tablets.
Adolescent↗
Effects of reaction variables on nephelometric and turbidimetric responses for the immunochemical reaction of immunoglobulin G.
Here we report a kinetic study of the immunoprecipitin reaction involving immunoglobulins G, A, and M. We used stopped-flow mixing adapted for simultaneous monitoring of nephelometric and turbidimetric signals for some studies and centrifugal mixing for others. The variables having the most significant effects on the kinetic responses in the regions of excess antibody and excess antigen are polyethylene glycol concentration, ionic strength, and the ratio of antigen to antibody. We document effects of these variables on maximum velocities and signal changes over a fixed-time interval for both monitoring modes and on the maximum signal change for nephelometry. We use response-surface methodology to help identify interactive effects among these variables (polyethylene glycol, NaCl, and antibody concentrations) and to select the best combination to use to quantify antigen in all regions of the immunoprecipitin curve. We also observe that turbidimetric responses are more reproducible and much simpler than are nephelometric responses. Implications of these results for quantification of the immunoglobulins are discussed.
Antigens↗
Kinetic turbidimetric method for the immunochemical quantification of immunoglobulins, including samples with excess antigen.
Here we describe a kinetic approach for quantification of the immunoglobulins (IgG, IgA, IgM) in all regions of the immunoprecipitin curve. We use centrifugal mixing and report results for maximum-velocity, two-point, and multipoint curve-fitting methods as well as the use of rate coefficients obtained from the curve-fitting process to differentiate among regions of excess antibody, equivalence, and excess antigen. We show that it is possible to quantify each immunoglobulin over a concentration range from a large excess of antibody to moderate excesses of antigen with a single set of measurements made on a single dilution of each sample. Results for standard additions of the immunoglobulins to pooled sera have relative standard deviations (coefficients of variation) in the range of 1% to 3%, with analytical recoveries in the range of 95% to 106%. Correlations among determined and reported values in individual sera are quite good, with slopes ranging from 0.86 to 1.03 and no intercepts differing from zero by more than two standard deviation units. Concentrations quantified in 14 pathological sera by the proposed method correlated well with concentrations quantified by a fluorescence immunoassay method.
Antigens↗
Kinetic study of the Jaffé reaction for quantifying creatinine in serum: 1. Alkalinity controlled with NaOH.
We studied the kinetic behavior of the reaction of alkaline picrate and creatinine and evaluated a nonlinear curve-fitting method for quantifying creatinine in serum. Using a 3 X 3 factorial experimental design, we evaluated interactive effects among temperature and concentrations of creatinine, picrate, and NaOH. We found no evidence of interference by glucose or unconjugated bilirubin; the effects of the acetoacetate reaction, which is fast, are easily compensated by the curve-fitting method. The reaction with human serum albumin is very complex, but its effects are compensated by the curve-fitting method and by preparing standards containing 50 g of albumin per liter. Calibration plots are linear under a wide variety of conditions for both aqueous standards and standard additions of creatinine to pooled serum. Reproducibility studies with standards containing creatinine at 2, 10, and 20 mg/L yielded relative standard deviations (RSD) of 8.2, 2.5, and 1.3%, corresponding to absolute variations of 0.16, 0.25, and 0.26 mg/L. The average SD for 17 sera containing creatinine at 15-50 mg/L was 0.7 mg/L. The averages of ratios (as percent) of determined vs expected concentrations in 17 sera with added creatinine (7.27 mg/L) were 97.8% for aqueous standards, 99.9% for standards with added albumin.
Acetoacetates↗
Evaluation of multipoint kinetic methods for immunoassays: kinetic quantitation of immunoglobulin G.
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Humans↗
Direct ultraviolet method for enzymatic determination of uric acid, with equilibrium and kinetic data-processing options.
We developed and evaluated a direct ultraviolet method for the enzymatic determination of uric acid in serum, plasma, or urine, without deproteinization of sera and plasma. Equilibrium and nonlinear curve-fitting kinetic options are evaluated and compared, and results of the proposed method are compared with those of a candidate Reference Method. All data-processing options yield a linear relation for absorbance and concentration of uric acid between 0.1 and 2 mmol/L; with the equilibrium option, results are linear to 5 mmol/L. For 100 plasma samples, results correlate well between the proposed method (y) and a reference method (x): y = 0.99x - 0.002 mmol/L. Between-run imprecision is about 2.3%, and interference by hemolyzed, icteric, or lipemic specimens or specimens containing high concentrations of xanthine or paraproteins is minimal. The kinetic option with a data-processing range of 100 s or longer yields results that correlate well with the equilibrium method: y = 1.006x + 0.002 mmol/L (n = 118). For 20 urine samples processed by the proposed (y) and a reference (x) methods, y = 1.04x + 0.038 mmol/L.
Buffers↗
A nonlinear regression-kinetic method for quantification of serum triglycerides.
We report a new kinetic approach to the quantification of triglycerides (triacylglycerols) in human sera. The new approach combines a commercially available enzyme-reagent system with a multiple-linear-regression data-processing method. Values of absorbance collected at 3-s intervals between 20 and 305 s are fitted to a pseudo-first-order model to compute the total change in absorbance expected if the reaction were to proceed to equilibrium. The computed absorbance change varies linearly with triglyceride concentration between 3 and 20 mumol/L (after 250-fold dilution of sample). The pooled relative standard deviation was 7.2% for 23 serum samples with triglyceride concentrations between 3 and 20 mumol/L. Comparison of kinetic (y) and equilibrium (x) absorbance changes for the 23 sera gave a least-squares equation of y = 0.994x + 0.00066, confirming good agreement between the methods. The temperature coefficient is less than 0.2% per degree Celsius.
Humans↗