Edwin T. Sugita

Aspects of the epimerization of certain tetracycline derivatives

The epimerization of several tetracycline derivatives was examined at several pH values using varying conditions of temperature and buffer strength. Rate coefficients for the epimerization of tetracycline and demethylchlortetracycline are reported and factors associated with the epimerization of chlortetracycline and oxytetracycline are discussed. Under the conditions used calcium had no effect on the rate of epimerization and copper promoted degradation other than epimerization.

Theophylline controlled-release formulations: in vivo-in vitro correlations.

Four experimental controlled-release oral solid dosage formulations were developed and the in vitro dissolution characteristics of theophylline from these formulations were studied in USP apparatus I. Pharmacokinetic evaluation of these formulations was carried out in eight beagle dogs under fasting conditions. Theophylline in a 5% dextrose injection USP, oral solution, and Slo-Phyllin were used as controls to estimate the in vivo dissolution of these four formulations in the GI tract. The percentage cumulative amounts of drug absorbed and the percentage cumulative amounts of drug released into the GI tract from these four controlled-release formulations were obtained by numerical deconvolution methods. The in vivo and in vitro dissolution data demonstrated good correlation indicating that in vitro dissolution tests can be used to optimize the further design of controlled drug release oral solid dosage formulations for theophylline.

Metal binding tendencies of various antibiotics

A method to determine the presence of metal‐drug complexes in dilute solutions is described. Using this method cycloserine was found to complex with cupric, nickelous, zinc and cobalt ions; streptomycin and novobiocin complexed with cupric ions; erythromycin complexed with cobalt ions, and chloramphenicol exhibited no metal binding tendencies. Various penicillins were found to interact with zinc and cupric ions. Preliminary investigations suggest that cupric ions, rather than simply complexing with penicillin as suggested by previous workers, promote the degradation of penicillin to penicilloic acid. Evidence is presented to confirm the presence of penicilloic acid in reaction mixtures initially containing penicillin G or V and cupric ions, and to establish that the reaction follows second order kinetics and ceases when all available cupric ion has been consumed. Good correlation was noted for these results and previous work which showed the effects of metal ions on the antibacterial properties of penicillin.

Complexation of penicillins and penicilloic acids by cupric ion

A kinetic method was developed to study the interactions between cupric ion and penicillins G and V. Complexation was found to occur with the intact penicillins, followed by rapid hydrolysis of the complex into the corresponding penicilloic acid‐cupric ion complex. The logarithmic stability constants for the interaction between cupric ion and penicillins G and V were found to be 2·61 and 2·24, respectively. In addition, the method of continuous variation was used to determine the logarithmic stability constants for the cupric ion‐penicilloic acid complexes. These were found to be 4·20 and 4·50, for penicilloic V and G acids respectively.

Bead Coating: II. Effect of Spheronization Technique on Drug Release from Coated Spheres

AbstractThe effect of spheronization method on drug release from coated spheres may be evaluated by determining the drug release rate, the critical coating level and the release mechanism. Drug release is faster from pan beads than from marumerizer beads at the same coating level. An equation is proposed which indicates that the critical coating level is inversely proportional to sphere size and sphere density, which in turn results from the different spheronization techniques. From the calculation, the critical coating levels for 14/16 mesh cuts of marumerizer beads and pan beads are 12% and 18%, respectively. Disintegration, pore-control and barrier control are involved in the release mechanisms of drugs from coated pan beads.

Gas chromatographic analysis of theophylline in human serum.

Abstract A method is presented for the analysis of theophylline in human serum. The method is specific with no interference from theophylline metabolites, ephedrine, hydrocortisone, or caffeine and their metabolites. It is sensitive to approximately 1 μg/ml and analyses over the range of 5–11 μg/ml were found to have an average relative error of 7.5%.

The Effect of Controlled Release Tablet Performance and Hydrogel Strength on In Vitro/In Vivo Correlation

The impact of controlled release (CR) formulations having different gel strength values (Γ) on in vivo tablet performance and the in vitro/in vivo correlation of the formulations was investigated. The CR tablets containing either hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), or carbomer were formulated with theophylline and Fast Flo® lactose to produce tablets with a polymer content of 8 and 30% w/w. Γ was measured using a previously reported method. Male beagle dogs were utilized. Results showed that dissolution profiles were similar for all three polymers at the same % w/w level of polymer, irrespective of media (DI H2O, 0.1 N HCl, and pH 6.8 phosphate buffer). Mean Γ values were significantly different (p≤0.05) and were in order of HPMC K100MP>HPC HXF>carbomer 971P (same 30% w/w) with absolute Γ values at 30% w/w in DI H2O of 6600, 4600, and 1600 ergs/cm3, respectively. Drug profiles in plasma for the 30% HPMC K100MP tablets were consistent with in vitro dissolution profiles and Γ values. Plasma profiles for the 30% HPC HXF tablets were similar in vivo as the HPMC tablets. Plasma profiles for the 30% carbomer 971P formulation showed much higher drug concentrations (compared to HPMC and HPC) in vivo in all dogs. This finding is not consistent with the slow drug release found in the dissolution profiles but consistent with its low in vitro Γ values. Assessment of the predictability of a level A in vitro/in vivo correlation was quantified by absolute mean percent prediction error (PE). Formulations having Γ≈6000 ergs/cm3 have acceptable PE <20%, and low standard deviation (σ). Results showed that Γ values of CR hydrogel tablets in vitro will affect the in vivo performance (i.e., absorption kinetics of the drug) of the tablets and were also found to better assess (compared to in vitro dissolution profiles alone) the predictability of in vitro/in vivo correlations (level A and multiple level C).

Five modified numerical deconvolution methods for biopharmaceutics and pharmacokinetics studies.

Four improved finite-difference numerical deconvolution methods and one nonlinear regression numerical deconvolution method are proposed and implemented using IMSL/IDLTM. These five numerical deconvolution methods are evaluated using simulated data generated with and without added noise under six different dosing cases. Comparisons between these methods are made in terms of the superimposability of the calculated cumulative amount of drug released or absorbed-time profiles with the theoretical data. The results indicate that the proposed fixed step number equal step length numerical deconvolution method is simple and accurate and therefore is appropriate for pharmacokinetic and biopharmaceutic studies. When an analytic function is legitimate to represent the drug input rate, the nonlinear regression numerical deconvolution method will yield enhanced numerical accuracy and stability.

A multi-mechanistic drug release approach in a bead dosage form and in vitro/in vivo correlations

An in vitro/in vivo relationship of a combined multi‐mechanistic dosage form has now been established in the literature. In our previous study, we successfully prepared a combination of immediate release, enteric coated, and controlled‐release (CR) beads and mathematically modeled in vitro and in vivo drug release characteristics of the combination based on the release profiles of individual beads. The objective of the present study is to develop in vitro/in vivo correlations (IVIVC) for three individual beads and the combination using theophylline as a model drug and the beagle dog as an animal model. In the study, an IVIVC correlation is estimated by two‐stage procedures: deconvolution followed by comparison of the fraction of drug absorbed to the fraction of drug dissolved. The Wagner–Nelson mass balance method was used to deconvolute plasma drug concentration—time curves. In vitro, a two‐stage medium (0.1 N HCl and pH 6.5 phosphate buffer) was used for the dissolution test; a 2h first stage (acidic) was selected based on the average gastric emptying time in a fasted dog. In vivo, tlag was used for the gastric emptying process for enteric coated beads and the combination, which contains enteric coated beads. A time‐scaling technique was used to consider the rate difference between in vitro dissolution and in vivo absorption in the process of IVIVC. As shown in the results, a point‐to‐point correlation was established for each formulation. The linear regression analysis of the correlation was r2 > 0.99 for all three individual beads and 0.97 for the combined bead dosage form. The results suggest level A IVIVCs indicating an appropriateness for the in vitro and in vivo models used in this study.

Size-exclusion chromatographic determination of dextran sulfate in rat serum.

A sensitive and selective method for the determination of dextran sulfate in rat serum has been developed. The analysis is suitable for quantitation of the drug and for monitoring molecular mass changes occurring during biotransformation. Dextran sulfate is resolved from higher molecular mass serum components by high-performance aqueous size-exclusion chromatography. The method has been validated for the direct injection of serum. Sensitive detection is achieved by post-column reaction of the polyanionic drug with the dye 1,9-dimethylmethylene blue. Components of serum which inhibit complex formation are separated chromatographically from dextran sulfate. Absorbance of the metachromatic complex is monitored at 525 nm.