Process analytical technology (PAT): effects of instrumental and compositional variables on terahertz spectral data quality to characterize pharmaceutical materials and tablets

The aim of this study was to use terahertz spectroscopy to characterize pharmaceutical materials and tablets, and to understand the effects of measuring conditions and compositional variability on the data quality. Tests were performed on five formulation components (theophylline, lactose, starch, Avicel, magnesium stearate) and a series of tablets composed of various concentrations of theophylline and excipients. Transmission spectra of polyethylene (PE) disks derived from each of the samples were analyzed. Three factors (component loading, component chemistry, and disk drying time) were screened as critical factors associated with the magnitude and location of THz absorbance peaks. Applying the standard sample spectra divided by PE reference spectra ratio method revealed that, to a large extent, PE was responsible for the disk drying time dependence. Direct spectral feature analysis along with mass-transfer analysis of the disk drying process revealed THz absorption peak maxima of lactose (255 cm(-1)) and water (54 and 210 cm(-1)) which is also supported by literature values for the peak maxima assignment for water. Particle scattering due to specimen and PE was found to be also partially responsible for the observed spectral intensities. The importance of THz spectroscopy was demonstrated for characterization of pharmaceutical materials and tablet.     

A process analytical technology approach based on near infrared spectroscopy: tablet hardness, content uniformity, and dissolution test measurements of intact tablets

Near infrared spectroscopy (NIRS) is a nondestructive analytical technique that enables simultaneous measurements of chemical composition (viz. the content in active pharmaceutical ingredient, API) and various physical properties (viz. tablet hardness and dissolution profile) in pharmaceutical tablets. In this work, partial least squares (PLS) calibration models and discriminant partial least squares (DPLS) classification models were constructed by using calibration sets consisting of laboratory samples alone. The laboratory samples were mixtures of the API and excipients that were pressed into tablets. API content, tablet hardness, and dissolution measurements of intact tablets were made by using three different calibration models that are fast--results can be obtained within a few seconds--, simple and robust--they involve minimal analyst intervention--, and clean--they use no toxic reagent and produce no toxic waste. Based on the results, the proposed NIR method is an effective alternative to current reference methods for the intended purpose. The advantages provided by NIR spectroscopy in this context confirm its potential for inclusion in process analytical technologies in the pharmaceutical industry.     

Measurement of Active Content in Escitalopram Tablets by a Near-Infrared Transmission Spectroscopy Model that Encompasses Batch Variability

Near-infrared transmission (NIT) spectroscopy, with high-performance liquid chromatography as reference method, was used to study the variation of the active pharmaceutical ingredient (API), escitalopram, in five tablet batches (4%–12%, w/w) manufactured by direct compression. This study investigates the influence of sample orientation, powder segregation, and compression force on the NIT spectra. For this purpose, tablet samples were taken at six different production time points, at three different compression forces, and presented to the spectrometer in four different orientations and in three spectroscopic replicates. A total set of 2160 NIT spectra was recorded. The variances between the spectra at each level of API content were thoroughly investigated by partial least squares regression using theory of sampling. The results show that a minimum of 18 tablets from each level of API content is required to establish a robust NIT calibration. The identified number of spectra is required for covering small differences in the spatial heterogeneity of the API as well as minor variations in optical properties, due to variations in the tablet compression force. NIT spectroscopy is demonstrated to be a powerful technique not only for measuring the API content in escitalopram tablets but also for routine content uniformity analysis.     

Quantification and spatial distribution of salicylic acid in film tablets using FT-Raman mapping with multivariate curve resolution

In this study, we proposed a rapid and sensitive method for quantification and spatial distribution of salicylic acid in film tablets using FT-Raman spectroscopy with multivariate curve resolution (MCR). For this purpose, the constituents of film tablets were identified by using FT-Raman spectroscopy, and then eight different concentrations of salicylic acid tablets were visualized by Raman mapping. MCR was applied to mapping data to expose the active pharmaceutical ingredients in the presence of other excipients by monitoring distribution maps and combination of FT-Raman mapping with MCR enabled the determination of lower salicylic acid concentrations. In addition, the distribution of major excipient, lactose, was examined in the tablet form. A calibration curve was obtained by plotting the intensity of the Raman signal at 1635 cm⁻¹ versus the concentration of salicylic acid and the correlation was found to be linear within the range of 0.5%–3.9% with a correlation coefficient of 0.99. The limit of detection for the technique was determined 0.35%. The ability of the technique to quantify salicylic acid in tablet test samples was also investigated.     

An efficient method-development strategy for quantitative chemical imaging using terahertz pulse spectroscopy

The purpose of our research was to investigate efficient procedures for generating multivariate prediction vectors for quantitative chemical analysis of solid dosage forms using terahertz pulse imaging (TPI) reflection spectroscopy. A set of calibration development and validation tablet samples was created following a ternary mixture of anhydrous theophylline, lactose monohydrate, and microcrystalline cellulose (MCC). Spectral images of one side of each tablet were acquired over the range of 8 cm⁻¹ to 60 cm⁻¹. Calibration models were generated by partial least-squares (PLS) type II regression of the TPI spectra and by generating a pure-component projection (PCP) basis set using net analyte signal (NAS) processing. Following generation of the calibration vectors, the performance of both methods at predicting the concentration of theophylline, lactose, and MCC was compared using the validation spectra and by generating chemical images from samples with known composition patterns. Sensitivity was observed for the PLS calibration over the range of all constituents for both the calibration and the validation datasets; however, some of the calibration statistics indicate that PLS overfits the spectra. Multicomponent prediction images verified the spatial and composition fidelity of the system. The NAS-PCP calibration procedure yielded accurate linear predictions of theophylline and lactose, whereas the results for MCC prediction were poor. The poor sensitivity for MCC is assumed to be related to the relative lack of phonon absorption bands, which concurs with the characterization of MCC as being semi-crystalline. The results of this study demonstrate the use of TPI reflection spectroscopy and efficient NAS-PCP for the quantitative analysis of crystalline pharmaceutical materials.     

Process analytical technology: chemometric analysis of Raman and near infra-red spectroscopic data for predicting physical properties of extended release matrix tablets

The purpose of this work was to develop a correlation between pharmaceutical properties such as hardness, porosity, and content with prediction models employed using Raman and near infra-red (NIR) spectroscopic methods. Metoprolol tartrate tablets were prepared by direct compression and wet granulation methods. NIR spectroscopy and chemical imaging, and Raman spectra were collected, and hardness, porosity, and dissolution were measured. The NIR PLS model showed a validated correlation coefficient of >0.90 for the predicted versus measured porosity, hardness, and amount of drug with raw and second derivative NIR spectra. Raman spectra correlated porosity of the tablets using raw data for directly compressed tablets and wet granulated tablets (r(2) > 0.90). A very close root-mean square error of calibration (RMSEC) and root-mean square error of prediction (RMSEP) values were found in all the cases indicating validity of the calibration models. Raman spectroscopy was used for the first time to predict physical quality attribute such as porosity successfully. Chemical imaging utilizing NIR detector also demonstrated to show physical changes due to compression differences. In conclusion, sensor technologies can be potentially used to predict physical parameters of the matrix tablets.     

Raman spectroscopy of coated pharmaceutical tablets and physical models for multivariate calibration to tablet coating thickness

Raman spectra of a set of coated pharmaceutical tablets were analyzed for the purpose of calibrating the spectra to tablet coating thickness. Acetaminophen tablets were coated with a hydroxypropylmethylcellulose/polyethylene glycol film coating whose thickness was varied from 0 to 6% weight gain. Coatings were also prepared with two concentrations of TiO2 at several film thicknesses. The resulting spectral data set was analyzed using several different multivariate calibration procedures. The procedures examined in this study included spectral correction followed by target factor analysis, spectral correction with baseline subtraction followed by principal component regression, and first derivative computation followed by principal component regression. The results demonstrate that target factor analysis is a viable method for calibration of Raman spectra to tablet coating thickness. Calibration based on derivative spectra resulted in linear correlation that was equal to that of the results of target factor analysis for coatings without TiO2. However, target factor analysis was found to be superior to other methods when TiO2 was present in the tablet coatings. The effect of sample fluorescence on each of these chemometric methods was also examined. It was found that when photobleaching of fluorescent impurities due to exposure to the Raman excitation source was controlled, the tablet coating thickness could be calibrated to the intensity of the fluorescence signal. The results also demonstrate that for the samples examined here, calibration by target factor analysis is insensitive to variation in fluorescent intensity when the tablet coating emission spectrum is included in the matrix of target vectors.     

Predicting the physical properties of tablets from ATR-FTIR spectra using partial least squares regression

Context: The formulation of a new tablet is a time-consuming activity involving the preparation and testing of many different formulations with the aim of identifying one with the desired properties. In complex formulations it may not be clear which excipient is responsible for eliciting a particular property.

Objective: To investigate partial least squares (PLS) regression analysis of ATR-FTIR spectra of tablets as a predictive and investigative tool in the formulation of novel tablet formulations.

Materials: Magnesium stearate, lactose, acetylsalicylic acid and Ac-Di-Sol.

Results and discussion: ATR-FTIR spectra of a simple aspirin tablet formulation with varying amounts of the lubricant magnesium stearate were obtained. PLS models were built using the spectral data as the multivariate variable and various physical properties of the tablets as the univariate variables. PLS models that allowed good predications to be made for samples not included in the training set were obtained for tablet hardness and disintegration time. It was clear from PLS model regression coefficients that magnesium stearate was responsible for the variation in the tablets’ physical properties.

Conclusion: PLS regression in combination with ATR-FTIR spectroscopy has been shown to be a useful approach for the prediction of the physical properties of tablets.     

Characterization of different laser irradiation methods for quantitative Raman tablet assessment

Quantitative Raman spectroscopy of conventional wet granulated pharmaceutical immediate release tablets and subsequent data evaluation was investigated. Different aspects of quantitative assessment of active pharmaceutical ingredient (API) in intact tablets with special focus on sub-sampling issues were addressed. Four different geometric laser irradiance patterns were examined to study the effect of sub-sampling within the tablets. The Raman data was evaluated using both univariate and multivariate techniques. UV absorbance spectroscopy was used as a reference method. The best result in terms of prediction error was attained by irradiating a large area of the tablets. Using multivariate calibration with multiplicative signal correction (MSC) the prediction error was 1.7%. In addition, the effect of tablet density on the Raman assessment was investigated. It was found that quantitative Raman assessment of chemical content can be made insensitive to variations in tablet density corresponding to a manufacturing compression interval of 5-20 kN provided that adequate data treatment is used. A short discussion about sample heating in the context of different irradiation patterns is included with reference to previous work. In conclusion, the present study provides a platform for developing an implementation strategy for quantitative Raman spectroscopy for both laboratory analysis and process analytical technology (PAT) applications.     

Determination of the crushing strength of intact tablets using Raman spectroscopy

In the present study, the Raman spectroscopy technique was used as a non-invasive, rapid analytical method for measuring the crushing strength of tablets. The compressed tablets were individually detected, using Raman spectroscopy, and the respective crushing strength values were measured, using a tablet hardness tester as a reference method. The tablets were compressed from a granule mass containing theophylline anhydrate as an active substance. For measuring the crushing strength of the tablets, Raman spectra were recorded from the tablets. Partial least squares (PLS) regression models were constructed to obtain information from the spectra. The correlation between measured and predicted crushing strength values for the tablets was shown to be very favorable. With Raman spectroscopy, shifting of the baseline was observed as the crushing strengths of tablets (and the smoothness of the tablet surface) were increased. Consequently, correlation between the crushing strength data on the present tablets and Raman spectra was observed. Multiple scanning electron (SEM) and non-contact laser profilometry (LP) micrographs from the surfaces of the tablets were taken to describe the surfaces and applied as supportive information for the proposed spectroscopy approach. In conclusion, Raman spectroscopy is a promising alternative for established off-line/at-line tablet-testing methods for some tablet formulations.     

Application of near-infrared spectroscopy for nondestructive analysis of Avicel powders and tablets

The purpose of this study was to use near-infrared spectroscopy (NIRS) as a nondestructive technique to (a) differentiate three Avicel products (microcrystalline cellulose [MCC] PH-101, PH-102, and PH-200) in powdered form and in compressed tablets with and without 0.5% w/w magnesium stearate as a lubricant; (b) determine the magnesium stearate concentrations in the tablets; and (c) measure hardness of tablets compressed at several compression forces. Diffuse reflectance NIR spectra from Avicel powders and tablets (compression forces ranging from 0.2 to 1.2 tons) were collected and distance scores calculated from the second-derivative spectra were used to distinguish the different Avicel products. A multiple linear regression model was generated to determine magnesium stearate concentrations (from 0.25 to 2% w/w), and partial least squares (PLS) models were generated to predict hardness of tablets. The NIRS technique could distinguish between the three different Avicel products, irrespective of lubricant concentration, in both the powdered form and in the compressed tablets because of the differences in the particle size of the Avicel products. The percent error for predicting the lubricant concentration of tablets ranged from 0.2 to 10% w/w. The maximum percent error of prediction of hardness of tablets compressed at the various compression forces was 8.8% for MCC PH-101, 5.3% for MCC PH-102, and 4.6% for MCC PH-200. The NIRS nondestructive technique can be used to predict the Avicel type in both powdered and tablet forms as well as to predict the lubricant concentration and hardness.     

Hardness and Density Distributions of Pharmaceutical Tablets Measured by Terahertz Pulsed Imaging

We present terahertz pulsed imaging (TPI) as a novel tool to quantify the hardness and surface density distribution of pharmaceutical tablets. Good agreement between the surface refractive index (SRI) measured by TPI and the crushing force measured from diametral compression tests was found using a set of tablets that were compacted at various compression forces. We also found a strong correlation between TPI results and tablet bulk density, and how these relate to tablet hardness. Numerical simulations of tablet surface density distribution by finite element analysis exhibit excellent agreement with the TPI measured SRI maps. These results show that TPI has an advantage over traditional diametral compression and is more suitable for nondestructive hardness and density distribution monitoring and control of pharmaceutical manufacturing processes. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:2179–2186, 2013     

Nondestructive Analysis of Structure and Components of Tablet Coated with Film by the Usage of Terahertz Time-Domain Reflection Spectroscopy

Nondestructive analysis of tablet is of great importance from the aspect of productivity and safety. In terahertz (THz) region, however, the analysis of core of coated tablet has not been progressed. In this study, we have measured a flat-surface push–pull osmotic pump tablet, having no orifice, having bilayer core and a coating film layer. The bilayer core was made from the drug layer and the push layer, and acetaminophen was contained in the drug layer as a model drug. To study its structure and components, we have obtained reflection spectra from the drug layer side and the push layer side measurements using THz time-domain reflection spectroscopy (THz-TDRS). From these results, detection of the peak of acetaminophen in the spectrum from the drug layer side measurements was confirmed. We have made ridges approximated toward the peak using a general method of linear regression analysis in both spectra. Two-sample t-test was applied to their gradients, and significant difference between the drug layer and the push layer was shown. These results suggested that THz-TDRS is applicable to the analysis of structure and component of a coated tablet.     

Application of Raman microscopy and band-target entropy minimization to identify minor components in model pharmaceutical tablets

The aim of the current study is to establish a useful analytical technique to detect and identify minor components of pharmaceutical drug tablets using Raman microscopy and advanced multivariate data analysis method, namely band-target entropy minimization (BTEM). Model pharmaceutical tablets comprising four components with varying proportions were prepared with a custom press tooling after blending. One of the components, magnesium stearate, was made as a minor component, with weight percentages of 2%, 1%, 0.5%, and 0.2% in four model tablets. Raman point-by-point mapping was performed on an area of 200 microm x 200 microm using a near infrared laser source and a 50x objective lens with a step size of 5 microm in both the x and y directions. Advanced multivariate analysis, BTEM, was then performed on the Raman mapping data to recover all observable pure component spectra. BTEM was successfully applied to recover the pure component spectrum of magnesium stearate, which was present as a minor component (as low as 0.2 wt%) in the prepared tablet. The success of BTEM in identifying minor chemical species offers a new analytical technology for detecting impurities or any other minor components in pharmaceutical tablets.     

Investigation of triacetin effect on indomethacin release from poly(methyl methacrylate) microspheres: evaluation of interactions using FT-IR and NMR spectroscopies

The influx of medicines from different sources into healthcare systems of developing countries presents a challenge to monitor their origin and quality. The absence of a repository of reference samples or spectra prevents the analysis of tablets by direct comparison. A set of paracetamol tablets purchased in Malaysian pharmacies were compared to a similar set of sample purchased in the UK using near-infrared spectroscopy (NIRS). Additional samples of products containing ibuprofen or paracetamol in combination with other actives were added to the study as negative controls. NIR spectra of the samples were acquired and compared by using multivariate modeling and classification algorithms (PCA/SIMCA) and stored in a spectral database. All analysed paracetamol samples contained the purported active ingredient with only 1 out of 20 batches excluded from the 95% confidence interval, while the negative controls were clearly classified as outliers of the set. Although the substandard products were not detected in the purchased sample set, our results indicated variability in the quality of the Malaysian tablets. A database of spectra was created and search methods were evaluated for correct identification of tablets. The approach presented here can be further developed as a method for identifying substandard pharmaceutical products.     

Quality by design, part I: application of NIR spectroscopy to monitor tablet manufacturing process

To monitor tableting production using near infrared (NIR) spectroscopy, chemometric models were developed to analyze peak compression force, crushing strength and content uniformity. To measure tablet content uniformity, orbifloxacin tablets with drug content ranging from 60 to 90 mg were made and analyzed using ultraviolet (UV) and NIR spectroscopy. To assess the compression force and crushing strength, several batches of tablets were made on a Stokes B2 rotary tablet press and compression force was varied from 360 to 3500 lb. Principal component analysis (PCA) was used to identify tablets with regular and capped tablets breakage patterns. Comparison of statistical parameters showed that partial least squares (PLS) models gave better fit than the multiple linear regression (MLR) models. The best fit PLS models had a standard error of calibration (SEC) and a standard error of prediction (SEP) for content uniformity of 1.13 and 1.36 mg; for compression force of 69.86 and 59.48 lb and for crushing strength 0.55 kP and 0.57 kP, respectively. NIR spectroscopy in combination with multivariate modeling is a rapid and nondestructive technique that could reliably predict content uniformity, compression force and crushing strength for orbifloxacin tablets.     

Nondestructive tablet hardness testing by near-infrared spectroscopy: a new and robust spectral best-fit algorithm

A new algorithm using common statistics was proposed for nondestructive near-infrared (near-IR) spectroscopic tablet hardness testing over a range of tablet potencies. The spectral features that allow near-IR tablet hardness testing were evaluated. Cimetidine tablets of 1-20% potency and 1-7 kp hardness were used for the development and testing of a new spectral best-fit algorithm for tablet hardness prediction. Actual tablet hardness values determined via a destructive diametral crushing test were used for construction of calibration models using principal component analysis/principal component regression (PCA/PCR) or the new algorithm. Both methods allowed the prediction of tablet hardness over the range of potencies studied. The spectral best-fit method compared favorably to the multivariate PCA/PCR method, but was easier to develop. The new approach offers advantages over wavelength-based regression models because the calculation of a spectral slope averages out the influence of individual spectral absorbance bands. The ability to generalize the hardness calibration over a range of potencies confirms the robust nature of the method.     

Near-Infrared Spectroscopy as a Nondestructive Alternative to Conventional Tablet Hardness Testing

Purpose. Near-infrared reflectance Spectroscopy (NIRS) was used to evaluate and quantify the effect of compression force on the NIR spectra of tablets. Methods. Flat, white tablets with no orientation (scoring, etc.) were manufactured on a Stokes Rotary Tablet Press. NIRS was used to predict tablet hardness on the following four formulations and one placebo matrix: hydrochlorothiazide (HCTZ) 15% and 20% in a placebo matrix (microcrystalline cellulose and magnesium stearate), and chlorpheniramine maleate (CTM) 2% and 6% in a placebo matrix. Five or six levels of tablet hardness from 2 to 12 kg were used for each formulation. Laboratory hardness data was compared to NIR reflectance data using a NIRSystems Rapid Content Analyzer^®. Multiple linear regression and partial least squares regression techniques were used to determine the relationship between tablet hardness and NIRS spectra. Results. An increase in tablet hardness produced an upward shift (increase in absorbance) in the NIRS spectra. A series of equations was developed by calibrating tablet hardness data against NIR reflectance response for each formulation. The results of NIRS hardness prediction were at least as precise as the laboratory hardness test (SE = 0.32). Conclusions. A NIRS method is presented which has the potential as an alternative to conventional hardness testing of tablets.     

Content uniformity in granules for aceclofenac controlled release (CR) tablets determined using near-infrared spectroscopy and wide area illumination (WAI) raman spectroscopy

Non-destructive and rapid determination methods were developed for aceclofenac controlled release (CR) tablets. The tablet is composed of two layers, rapid release and controlled release (CR) layers. The pharmaceutical manufacturing process for CR granules is very critical for dissolution control of CR tablets. During processing, a rapid and nondestructive method to test content uniformity of aceclofenac granules is required. Chemometrics using near-infrared (NIR) and Raman spectroscopy have found significant uses in quantitative analysis of pharmaceutical products in complex matrixes. Most of the pharmaceutical products can be measured directly with little or no sample preparation using these spectroscopic methods. This study showed NIR and wide area illumination Raman spectroscopy with partial least squares (PLS) was very effective for the content uniformity of granules while high performance liquid chromatography (HPLC), a conventional method, was time-consuming and ineffective for real time control. This study showed that on-line control of content uniformity control of aceclofenac CR tablets can be achieved using NIR and Raman spectroscopy.     

Quantitative measurements of localized density variations in cylindrical tablets using X-ray microtomography.

Direct compaction is a complex process that results in a density distribution inside the tablets which is often heterogeneous. Therefore, the density variations may affect the compact properties. A quantitative analysis of this phenomenon is still lacking. Recently, X-ray microtomography has been successfully used in pharmaceutical development to study qualitatively the impact of tablet shape and break-line in the density of pharmaceutical tablets. In this study, we evaluate the density profile in microcrystalline cellulose (Vivapur 12) compacts obtained at different mean porosity (ranging from 7.7% to 33.5%) using X-ray tomography technique. First, the validity of the Beer-Lambert law is studied. Then, density calibration is performed and density maps of cylindrical tablets are obtained and visualized using a process with colour-scale calibration plot which is explained. As expected, important heterogeneity in density is observed and quantified. The higher densities in peripheral region were particularly investigated and appraised in regard to the lower densities observed in the middle of the tablet. The results also underlined that in the case of pharmaceutical tablets, it is important to differentiate the mechanical properties representative of the total volume tablet and the mechanical properties that only characterize the tablet surface like the Brinell hardness measurements.