Anthony C. Moffat

The use of near infra-red spectroscopy to detect changes in the form of amorphous and crystalline lactose

Abstract The suitability of near infra-red spectroscopy (NIR) to follow changes in both the amorphous and crystalline state of lactose at room temperature was investigated. Amorphous lactose samples were stored in sealed glass jars with saturated salt solutions to control the relative humidity. NIR spectra were recorded after various periods of storage and the data related to calorimetric and thermo-gravimetric assessments of the physical form of the material. Differentiation between crystalline and amorphous states of lactose was found possible by studying the shape and magnitude of regions of the near infra-red spectrum corresponding to combination and first overtone stretching frequencies of water. It was possible to follow changes in the amorphous, the onset of crystallisation and the solid state transition from β - to α -lactose. NIR with benefits of being non-invasive, non-destructive and operating at room temperature, has been shown to be a valuable tool with which to assess changes in the physical form of lactose.

Meeting the International Conference on Harmonisation's Guidelines on Validation of Analytical Procedures: Quantification as exemplified by a near-infrared reflectance assay of paracetamol in intact tablets

This Perspective explains how the International Conference on Harmonisations Guidelines on Validation of Analytical Procedures for quantitative methods can be met by near-infrared (NIR) assays of intact pharmaceutical products. Each of the validation characteristics (accuracy, precision, specificity, detection limit, quantification limit, linearity, range, robustness and system suitability testing) is defined, examined for their relevance to quantitative methods and examples given on how they may be used to demonstrate that near-infrared assays are fit for purpose. Methods for preparing samples for calibration are given in detail. The intention is to provide information so that a pharmaceutical manufacturer could validate a method suitable for an application for a variation of a marketing authorisation for an existing product and use a NIR assay instead of the previous method. The perspective is illustrated in detail using a NIR reflectance assay of paracetamol in intact tablets. This proven assay gives results comparable to the British Pharmacopeia ultraviolet assay for paracetamol, the standard errors of calibration and prediction for the NIR method being 0.48% w/w and 0.71% w/w respectively. The method is also precise, the standard deviation and coefficient of variation for six NIR assays on the same day being 0.14% w/w and 0.16% w/w respectively, while measurements over six consecutive days gave 0.31% w/w and 0.36% w/w respectively.

Correlation of partition coefficients in n‐heptane‐aqueous systems with buccal absorption data for a series of amines and acids

Partition coefficients in n‐heptane‐0·1n sodium hydroxide or 0·1n hydrochloric acid have been determined for a series of amines and acids; linear relations between chain‐lengths and the logs of their partition coefficients were found. The plot of alkyl chain‐length against buccal absorption of some amphetamines and fenfluramines, when they were 1% unionized, was linear. There was also a linear relation between the logs of the partition coefficients and buccal absorption of the amines and acids when these were 1 and 10% unionized. Those amines and acids having similar partition coefficients, when equally unionized, were absorbed to the same extent in the buccal test over the pH range 4 to 9. During the test the pH at the surface of the buccal membrane was shown to be the same as that of the solution in the mouth. n‐Heptane is considered to be equivalent in solvent properties to the buccal lipid membrane for the compounds used in the present test.

The application of multiple linear regression to the measurement of the median particle size of drugs and pharmaceutical excipients by near-infrared spectroscopy

A number of powdered drugs and pharmaceutical excipients were used to demonstrate the ability of near-infrared spectroscopy to measure median particle size (d50). Sieved fractions and bulk samples of aspirin, anhydrous caffeine, paracetamol, lactose monohydrate and microcrystalline cellulose were particle sized by forward angle laser light scattering (FALLS) and scanned by fibre-optic probe FT-NIR spectroscopy. Two-wavenumber multiple linear regression (MLR) calibrations were produced using: NIR reflectance; absorbance and Kubelka-Munk function data with each of median particle size, reciprocal median particle size and the logarithm of median particle size. Best calibrations were obtained using reflectance data versus the logarithm of median particle size (NIR predicted lnd50 versus ln(FALLS d50) for microcrystalline cellulose and lactose monohydrate sieve fraction calibrations: r = 0.99 in each case). Working calibrations for lactose monohydrate (median particle size range: 19.2-183 microns) and microcrystalline cellulose (median particle size range: 24-406 microns) were set-up using combinations of machine sieve-fractions and bulk samples. This approach was found to produce more robust calibrations than just the use of sieved fractions. The method has been compared with single wavenumber quadratic least squares regression using reflectance and mean-corrected reflectance data with median particle size. Correlation between NIR predicted and FALLS values was significantly better using the MLR method.

Water sorption and near IR spectroscopy to study the differences between microcrystalline cellulose and silicified microcrystalline cellulose before and after wet granulation

Silicified microcrystalline cellulose (SMCC) has been shown to have advantages over conventional microcrystalline cellulose (MCC). These advantages are (i) improved tablet strength compared to that achieved with MCC, (ii) the retention of compressibility after wet granulation, whereas MCC produces weaker tablets after wet granulation, and (iii) superior flow properties than MCC. In this study gravimetric and calorimetric vapour sorption data and near IR spectroscopy have been used to study MCC and SMCC before and after wet granulation. It was found that MCC, SMCC and wet granulated SMCC had essentially identical physical structures (except for a size increase due to granulation). Wet granulated MCC had a different enthalpy of water sorption at low RH, and its near IR spectrum was different from the other samples in the region which relates to C-H bonding. It can be concluded that MCC and SMCC are of very similar structures, thus these analytical techniques cannot provide an explanation for the improvements in compressibility. However the change in compressibility in MCC after wet granulation may relate to the observed differences in internal bonding in this sample.

Application of transmission near-infrared spectroscopy to uniformity of content testing of intact steroid tablets

Transmission near-infrared (NIR) spectroscopy was used for the rapid and non-destructive determination of the content of a hormone steroid in single intact tablets. Tablets produced for clinical trial purposes containing 5, 10, 15, 20 and 30 mg (2.94, 5.88, 8.82, 11.76 and 17.64% m/m, respectively) were used to develop calibration models without the need to specially prepare any out of specification tablets. Reference values for the individual tablets used in the NIR calibration models and test set were measured by reversed-phase high performance liquid chromatography (HPLC). Partial least squares regression using standard normal variate transformed second-derivative spectra over the range 800 to 1040 nm gave the optimum calibration model with a standard error of calibration of 0.52 mg per tablet. Measurements of an independent test set gave comparable results (standard error of prediction 0.31 mg per tablet). Measurement errors for a single tablet (RSD < 2.5% for a given active level) were sufficiently small to allow the procedure to be applied to pharmacopoeial uniformity of content testing of batches of these tablets and permitted the non-destructive testing of 30 tablets in under 20 min as compared to 6 h by HPLC.

Measurement of the cumulative particle size distribution of microcrystalline cellulose using near infrared reflectance spectroscopy

The cumulative particle size distribution of microcrystalline cellulose, a widely used pharmaceutical excipient, was determined using near infrared (NIR) reflectance spectroscopy. Forward angle laser light scattering measurements were used to provide reference particle size values corresponding to different quantiles and then used to calibrate the NIR data. Two different chemometric methods, three wavelength multiple linear regression and principal components regression (three components), were compared. For each method, calibration equations were produced at each of eleven quantiles (5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95%). NIR predicted cumulative frequency particle-size distributions were calculated for each of the calibration samples (n = 34) and for an independent test set (n = 23). The NIR procedure was able to predict those obtained via forward angle laser light scattering.

Non-invasive determination of ethanol, propylene glycol and water in a multi-component pharmaceutical oral liquid by direct measurement through amber plastic bottles using Fourier transform near-infrared spectroscopy.

Fourier transform near-infrared (FT-NIR) spectroscopy was used to quantify rapidly the ethanol (34-49% v/v), propylene glycol (20-35% v/v) and water (11-20% m/m) contents within a multi-component pharmaceutical oral liquid by measurement directly through the amber plastic bottle packaging. Spectra were collected in the range 7302-12,000 cm-1 and calibration models set-up using partial least-squares regression (PLSR) and multiple linear regression. Reference values for the three components were measured using capillary gas chromatography (ethanol and propylene glycol) and Karl Fischer (water) assay procedures. The calibration and test sets consisted of production as well as laboratory batches that were made to extend the concentration ranges beyond the natural production variation. The PLSR models developed gave standard errors of prediction (SEP) of 1.1% v/v for ethanol, 0.9% v/v for propylene glycol and 0.3% m/m for water. For each component the calibration model was validated in terms of: linearity, repeatability, intermediate precision and robustness. All the methods produced statistically favourable outcomes. Ten production batches independent of the calibration and test sets were also challenged against the PLSR models, giving SEP values of 1.3% v/v (ethanol), 1.0% v/v (propylene glycol) and 0.2% m/m (water). NIR transmission spectroscopy allowed all three liquid constituents to be non-invasively measured in under 1 min.

Kinetics of buccal absorption of some carboxylic acids and the correlation of the rate constants and n‐heptane:aqueous phase partition coefficients

A simple model for the buccal absorption of some carboxylic acids is proposed. This model has been used, in conjunction with an analogue computer, to determine the rate constants of buccal absorption of ten acids from solutions of pH 4·0 using a single subject. These rate constants gave a positive correlation with the logarithms of previously determined n‐neptane:0·1 N hydrochloric acid partition coefficients (correlation coefficient 0·89).

The influence of substitution in phenylacetic acids on their performance in the buccal absorption test

In the buccal test there is a linear relation between percentage absorption and alkyl chain length for a series of p‐n‐alkyl phenylacetic acids. Branching and cyclizing the alkyl chain reduces the percentage absorption. With the p‐halogeno‐acids, absorption increases as the atomic weight of the halogen atom increases; a chlorine atom is approximately equivalent to a methyl group in its effect on absorption. An oxygen atom between an alkyl group and ring is equivalent to reducing the chain length by one methylene group. The absorptions of α‐methyl‐substituted acids are greater than those of the unsubstituted acids.