Paul K. Aldridge

Determination of End-points for Polymorph Conversions of Crystalline Organic Compounds Using On-line Near-infrared Spectroscopy

Trovafloxacin mesylate exists in two anhydrous polymorphic forms, I and II. The fundamental band vibration spectra information does not readily differentiate between the two forms, although the crystal lattice of each form has a distinct X-ray powder diffraction pattern. Subtle spectral differences between the two polymorphs can be detected in the NIR spectral region and the interconversion of the two forms can be monitored in hot solvent crystal slurries using NIR spectroscopy and an on-line fibre optic probe. A generally applicable method has been developed to monitor the conversion of form I into form II as a crystal slurry. The free energy profile in principal component space has been modelled as the process proceeds to give a computer graphic of the change which readily shows when the conversion is complete.

IDENTIFICATION OF TABLET FORMULATIONS INSIDE BLISTER PACKAGES BY NEAR-INFRARED SPECTROSCOPY

Near-infrared spectroscopy was evaluated as a method for nondestructively discriminating tablets containing an active drug from two placebo tablet formulations inside blister-packaged clinical supplies without removing the tablets from the blind study tablet cards. A custom sampling device was constructed to allow the spectra of individual tablets to be collected. Spectra of 165 tables were acquired over the wavelength range of 400 to 2500 nm. These tablets were of two different sizes and three formulations. The second derivatives of the spectra were calculated and randomly divided into two groups, each containing approximately half the samples. A factor-based library/model was constructed with the use of the second-derivative spectra from one of the groups over the wavelength range from 1600 to 2500 nm. The model was then validated by predicting the identity of the tablets in the remaining group. The identity and formulation of all the tablets were correctly predicted. This model was then used to confirm the identity of thousands of clinical trial samples. Apart from being nondestructive, the NIR method is less labor and time intensive than the previously used TLC assay.

Appearance of Discontinuities in Spectra Transformed by the Piecewise Direct Instrument Standardization Procedure

Several years ago, we noted that spectra transformed by the piecewise direct standardization (PDS) method may contain discontinuities. Having noticed that the problem was a recurring one, we studied it and recently diagnosed its source. Our investigations suggest that this problem also occurs in applications of window factor analysis, evolving factor analysis, and any other procedure that uses piecewise principal component models. In this work, we report the source of the problem and illustrate it with one example. A procedure is presented for eliminating the problem that is effective in PDS pattern recognition applications. Further work is needed to develop modified algorithms suitable for calibration applications.

On-Line Determination of Reaction Completion in a Closed-Loop Hydrogenator Using NIR Spectroscopy

An on-line near-infrared (NIR) spectroscopic method has been developed to determine in situ the endpoint of a bulk pharmaceutical hydrogenation reaction in a loop hydrogenator. This hydrogenation employs a 5% palladium-on-carbon catalyst with tetrahydrofuran (THF) as the reaction solvent. The traditional test for monitoring the endpoint of the hydrogenation is a gas chromatographic procedure that requires an estimated 60 min from the time a sample is taken to the point where the analysis results become available. The use of NIR spectroscopy in an on-line mode of operation allows spectra to be collected every 2 min and thereby significantly improves response time and result availability. The need for obtaining results in “real time” stems from the creation of undesired side products if the reaction is allowed to continue past the optimal endpoint. If the reaction is not stopped before these side products reach a level of approximately 0.8% (wt/wt), the batch requires additional purification at considerable time and cost. A partial least-squares model was constructed, validated, and successfully used to determine the endpoint of subsequent batches.

Effective mass sampled by NIR fiber-optic reflectance probes in blending processes

Abstract Recent efforts have demonstrated the in situ use of NIR spectroscopy to determine the homogeneity and potency of powder blends. This work has raised questions regarding the effective mass of a powder blend interrogated by a fiber-optic probe. The effective mass determined from experiments described herein is wavelength dependent and ranges from 0.154 to 0.858 g with a maximum standard deviation of about 0.16 g. Although the precision of this estimate is low, it is sufficiently accurate to demonstrate the usefulness of in situ NIR monitoring of blending operations in the pharmaceutical industry. The method was established by using the relationship between sample mass and spectral variance. Mixtures of lactose (50% w/w), microcrystalline cellulose (40% w/w), and sodium benzoate (10% w/w) were manually blended and sampled at selected intervals. The spectral variance at relevant wavelengths was determined as a function of blend homogeneity and sample mass using a standard micro-sample cup. The spectral variance obtained from micro-cup measurements was used to calibrate the effective mass sampled by a fiber-optic reflectance probe. The estimated mass was greatest at wavelengths where the minor constituent contributed most to the overall spectral variance. Typical pharmaceutical tablets have weights in the range of 0.1–1.0 g. According to FDA regulations, the maximum allowed sample mass for determining the homogeneity of these preparations is 0.3–3.0 g. For many formulations, the effective mass sampled by the fiber-optic probe easily falls below this range.

End-point determination on-line and reaction co-ordinate modelling of homogeneous and heterogeneous reactions in principal component space using periodic near-infrared monitoring

Advancement of organic homogeneous and heterogeneous reactions to their steady state end-points has been determined directly using near-infrared spectroscopy and fibre optic probes. The reaction times can be obtained without specifically measuring decay of individual starting materials or formation of products. The technique is passive and can be generally applied to most organic reactions in the laboratory or chemical plant. This report uses the formation of zopolrestat ethyl ester and its saponification to zopolrestat sodium salt, as typical examples of a heterogeneous and a homogeneous reaction matrix, respectively. Data has been collected directly from full size chemical reactors. The steady state is detected when the change in the spectra does not change significantly with time. The end-point can be confirmed computationally shortly after the data has been collected using open ended models. These can be constructed directly from the spectral data using commercially available software. The end-point can be confirmed with multivariate calibration methods using dendrograms derived from hierarchical cluster analysis or scores plots obtained from principal component analysis. The reaction co-ordinate can be modelled in principal component space using the locus of the spectral scores plot.