Robert G. Buice

Biological and Medical Applications of Near-Infrared Spectrometry

Near-infrared spectrometry is being applied in the solution of problems in many areas of biomedical and pharmaceutical research, including cardiovascular radiology, brain imaging, formulation, quality/process control, and even clinical trials. The technique can also play a role in the biotechnology industry in the nondestructive analysis of small quantities of expensive materials. This report first defines near-IR spectrometry and imaging and then describes its application to atherosclerosis and stroke research. New developments in near-IR optics and instrumentation that make effective biomedical near-IR spectrometry possible are related, and, finally, new computational research results in parallel supercomputing for near-IR imaging are described. Together, instrumentation, optics, and computing combine to poise biomedical near-IR spectrometry for great advances as it enters the next century.

Acoustic-resonance spectrometry as a process analytical technology for the quantification of active pharmaceutical ingredient in semi-solids

The purpose of this study was to demonstrate acoustic resonance spectrometry (ARS) as an alternative process analytical technology to near infrared (NIR) spectroscopy for the quantification of active pharmaceutical ingradient (API) in semi-solids such as creams, gels, ointments, and lotions. The ARS used for this research was an inexpensive instrument constructed from readily available parts. Acoustic-resonance spectra were collected with a frequency spectrum from 0 to 22.05 KHz. NIR data were collected from 1100 to 2500 nm. Using 1-point net analyte signal (NAS) calibration, NIR for the API (colloidal oatmeal [CO]) gave anr2 prediction accuracy of 0.971, and a standard error of performance (SEP) of 0.517%CO. ARS for the API resulted in anr2 of 0.983 and SEP of 0.317%CO. NAS calibration is compared with principal component regression. This research demonstrates that ARS can sometimes outperform NIR spectrometry and can be an effective analytical method for the quantification of API in semi-solids. ARS requires no sample preparation, provides larger penetration depths into lotions than optical techniques, and measures API concentrations faster and more accurately. These results suggest that ARS is a useful process analytical technology (PAT).

Detection of Formaldehyde-Induced Crosslinking in Soft Elastic Gelatin Capsules Using Near-Infrared Spectrophotometry

The purpose of this research was to monitor the migration of formaldehyde from a polyethylene glycol (PEG) fill into the gelatin shell of a soft elastic gelatin capsule (SEGC) using near-infrared (NIR) spectrophotometry. SEGCs were filled with five solutions of aqueous formaldehyde in PEG (0, 0.05, 0.10, 0.20, and 0.40 v/v%), stored at ambient conditions for 48 hr, emptied, and scanned in NIR spectrophotometer. Principal component regression (PCR) was employed to analyze the spectra of the empty capsules. Good correlation was established (r2 = 0.988) when actual concentrations of formaldehyde in the PEG fill of the capsules were regressed against the principal component (PC) values from NIR spectra of the emptied and washed capsules. The loadings of the first PC describe a baseline shift in the spectra that arises from a change in water concentration. Lower PC loadings reveal the presence of signals at 1780 and 2200 nm that are not due to water absorbance, confirming the hypothesis that chemical bonds are formed during the formaldehyde-induced crosslinking of the gelatin in SEGCs. Gelatin crosslinking, initiated by formaldehyde migration from the PEG fill into the shell of an SEGC, was detected by NIR spectrophotometry. When NIR was coupled to principal component analysis, a linear relationship was found between the NIR spectra of empty SEGCs and the amount of crosslinking induced by concentrations of formaldehyde in the original fill material.

Bioequivalence of a Highly Variable Drug: An Experience with Nadolol

AbstractPurpose. To assess the bioequivalence of nadolol 40mg and 160mg tablets (Zenith-Goldline Pharmaceuticals) using Corgard® 40mg and 160mg tablets (Bristol-Meyers Squibb) as reference products, to estimate the effect of food in the gastrointestinal tract on nadolol bioavailability, and to evaluate the effectiveness of standard pharmacokinetic metrics AUCt, AUC∞, and Cmax in bioequivalence determinations. Methods. Four bioequivalence studies were conducted as described in the FDA Guidance. Four additional studies of varying designs were conducted to establish bioequivalence of the 40mg tablet in terms of Cmax. Results. Fasted and food-effect studies of the 160mg tablet clearly established bioequivalence and revealed an unexpected reduction in nadolol bioavailability from test and reference products in the presence of food. The food-effect study of the 40mg tablet (80mg dose) revealed a similar reduction in bioavailability from each product. Fasted studies of the 40mg tablet (80mg dose) established bioequivalence in terms of AUCt and AUC∞. However, Cmax criteria proved extremely difficult to meet in the initial 40mg fasted study because of the large variability, leading to additional studies and ultimately requiring an unreasonable number of subjects. Conclusions. Final results clearly established bioequivalence of both strengths and characterized an unexpected food effect which did not appear to be formulation-related. However, the Cmax of nadolol is only slightly sensitive to absorption rate and the relatively large variability of Cmax reduces its effectiveness as a bioequivalence metric. Findings suggest that bioequivalence criteria for highly variable drugs should be reconsidered.

Optimization of Acoustic-Resonance Spectrometry for Analysis of Intact Tablets and Prediction of Dissolution Rate

Acoustic-resonance spectrometry (ARS) provides a means of identifying and quantifying materials. A new ARS instrument incorporates a three-transducer design that increases sensitivity through interferometry and uses polyvinylidene fluoride piezoelectric films instead of ceramic transducers to give high output voltages, broader bandwidth, and lower cost. The operating parameters of the ARS are optimized with a widely applicable technique named Universal Numerical Optimization (UNO). The UNO technique allows refinement of instrumental parameters on the basis of distances in hyperspace between sample sets. The new ARS is able to identify different intact tablets and predict the percent dissolution of intact carbamazepine tablets at one hour in a standard apparatus to within 4.6% at a fraction of the cost of traditional or even near-IR methods.

Determination of Cholesterol Using a Novel Magnetohydrodynamic Acoustic-Resonance Near-IR (MARNIR) Spectrometer

Near-IR spectrometric determination of minor constituents of biological systems is complicated by the fact that near-IR spectra of these materials vary in different chemical and physical environments. In such cases, wavelength selection methods and full-spectral techniques such as partial least-squares and principal component regression (which weight each wavelength in calibration) produce excess error because they must attempt to model both variations in major constituents and variations in the analyte. A magnetohydrodynamic acoustic-resonance near-IR (MARNIR) spectrometer can determine major constituents of biological materials noninvasively and nondestructively, leaving the near-IR spectrum of the analyte to be used quantitatively with less prediction error.

Bioequivalence of two orally administered nicardipine products.

The relative bioavailabilities of orally administered nicardipine (Zenith Laboratories) and nicardipine (Cardene Syntex Laboratories) were compared following a single 30 mg dose under fasted conditions using a two-way crossover study with 34 healthy adult male subjects. In a separate study the effect of food on the relative bioavailabilities of these products was assessed following an identical dose by comparing the Zenith product under fasted conditions, the Zenith product under fed conditions, and the Syntex product under fed conditions using a three-way crossover study with 17 healthy adult male subjects. In the fasted study, 90% confidence intervals surrounding ratios (Zenith/Syntex) of least-squares means derived from 1n-transformed data were 0.84-1.02 for AUCt, 0.85-1.04 for AUCinfinity, and 0.86-1.05 for Cmax, clearly demonstrating bioequivalence of the two products. In the food-effect study ratios of least-squares means (Zenith under fed conditions/Zenith under fasted conditions) were 0.62 for AUCt, 0.65 for AUCinfinity, and 0.40 for Cmax, with tmax delayed from 0.906 +/- 0.337 h (Zenith under fasted conditions) to 2.33 +/- 0.717 h (Zenith under fed conditions) and 2.84 +/- 0.834 h (Syntex under fed conditions). Findings indicate that the presence of food in the gastrointestinal tract reduces the bioavailability of orally administered nicardipine. However, ratios under fed conditions (Zenith/Syntex) were very close to unity for each metric, suggesting that the observed food effect is independent of the product formulation. Findings further suggested that food effects on conventional pharmacokinetic metrics might be attributed to alteration of extent, rather than rate, of gastrointestinal absorption. Finally, these results question the applicability of the peak plasma concentration (Cmax) as an index of absorption rate in nicardipine studies.