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An online near-infrared (NIR) spectroscopy platform system for real-time powder blending monitoring and blend endpoint determination was tested for a phenytoin sodium formulation. The study utilized robust experimental design and multiple sensors to investigate multivariate data acquisition, model development, and model scale-up from lab to manufacturing. The impact of the selection of various blend endpoint algorithms on predicted blend endpoint (i.e., mixing time) was explored. Spectral data collected at two process scales using two NIR spectrometers was incorporated in a single (global) calibration model. Unique endpoints were obtained with different algorithms based on standard deviation, average, and distributions of concentration prediction for major components of the formulation. Control over phenytoin sodium's distribution was considered critical due to its narrow therapeutic index nature. It was found that algorithms sensitive to deviation from target concentration offered the simplest interpretation and consistent trends. In contrast, algorithms sensitive to global homogeneity of active and excipients yielded the longest mixing time to achieve blending endpoint. However, they were potentially more sensitive to subtle uniformity variations. Qualitative algorithms using principal component analysis (PCA) of spectral data yielded the prediction of shortest mixing time for blending endpoint. The hybrid approach of combining NIR data from different scales presents several advantages. It enables simplifying the chemometrics model building process and reduces the cost of model building compared to the approach of using data solely from commercial scale. Success of such a hybrid approach depends on the spectroscopic variability captured at different scales and their relative contributions in the final NIR model.

Continuous manufacturing (CM) is an emerging technology in the pharmaceutical manufacturing sector, and the understanding of the impact on product quality is currently evolving. As the final purification and isolation step, crystallization has a significant impact on the final physicochemical properties of drug substance and is considered a critical process step in achieving the continuous manufacturing of drug substances. Although many publications previously focused on various innovative techniques to continuously make crystals with desired properties, engineering difficulties such as system design, automation, and integration with process analytical technology (PAT) tools have not been thoroughly discussed. Here, we focus on how to develop a continuous crystallization system, from the perspective of process engineering, and the related risk considerations on product quality. Specifically, we designed and built an automated two-stage mixed suspension mixed product removal (MSMPR) crystallization platfor...

The roles of surface oxide film and metal-film interfacial defects in corrosion initiation on aluminum were investigated. In the first part, a mathematical model was developed for oxide thickness and faradaic current, assuming high-field conduction and a uniform oxide layer thickness, and incorporating as input the measured potential. Electrochemical current and potential transients were measured for various aluminum foils during anodic oxidation of aluminum. The ratio of the experimental faradaic current density to the predicted one using high field model, p, was calculated. The measured faradaic current is about 104 times smaller than that predicted by this model initially, but the two converge after the initial period of time when p approaches 1. This discrepancy may be caused by several reasons. Our nonuniform oxide thickness hypothesis was supported by: (1) similar p~x characteristics for the same film obtained from different polarization experiments, where x is the solid-state barrier layer thickness of the oxide film; (2) the model's capability of predicting film structure change due to pretreatment such as NaOH dissolution, H2SO4 immersion, and electropolishing; (3) the capacity of predicting long-time current decays using high field model; (4) the lower anodic current of the foils subjected a short anodic pulse previously. In the second part, the effect of H3PO4 immersion on pit nucleation on aluminum during anodic etching in hot HC1 solution was investigated. It was found that the phosphoric acid immersion dramatically enhances the susceptibility of aluminum foil to anodic pitting corrosion, and the trend of the pit number density with the immersion time corresponds to decrease of surface oxide film thickness. AFM observation of the topography of foils which were experienced phosphoric acid treatment followed by oxide stripping in chromicphosphoric acid solution revealed presence of cavities. PAS measurements show the existence of interfacial voids of nm dimensions, whose metallic surface is oxide-free. These defects can be introduced by electropolishing and H3PO4 immersion. The strong similarity between the surface cavities and the pits in terms of size, shape, and distribution suggests that interfacial voids may sever as pitting initiation sites. A phenomenological mechanism for pitting precursor site was proposed.

Compared to small molecule process analytical technology (PAT) applications, biotechnology product PAT applications have certain unique challenges and opportunities. Understanding process dynamics of bioreactor cell culture process is essential to establish an appropriate process control strategy for biotechnology product PAT applications. Inline spectroscopic techniques for real time monitoring of bioreactor cell culture process have the distinct potential to develop PAT approaches in manufacturing biotechnology drug products. However, the use of inline Fourier transform infrared (FTIR) spectroscopic techniques for bioreactor cell culture process monitoring has not been reported. In this work, real time inline FTIR Spectroscopy was applied to a lab scale bioreactor mAb IgG3 cell culture fluid biomolecular dynamic model. The technical feasibility of using FTIR Spectroscopy for real time tracking and monitoring four key cell culture metabolites (including glucose, glutamine, lactate, and ammonia) and protein yield at increasing levels of complexity (simple binary system, fully formulated media, actual bioreactor cell culture process) was evaluated via a stepwise approach. The FTIR fingerprints of the key metabolites were identified. The multivariate partial least squares (PLS) calibration models were established to correlate the process FTIR spectra with the concentrations of key metabolites and protein yield of in-process samples, either individually for each metabolite and protein or globally for all four metabolites simultaneously. Applying the 2nd derivative pre-processing algorithm to the FTIR spectra helps to reduce the number of PLS latent variables needed significantly and thus simplify the interpretation of the PLS models. The validated PLS models show promise in predicting the concentration profiles of glucose, glutamine, lactate, and ammonia and protein yield over the course of the bioreactor cell culture process. Therefore, this work demonstrated the technical feasibility of real time monitoring of the bioreactor cell culture process via FTIR spectroscopy. Its implications for enabling cell culture PAT were discussed.

This study demonstrates the feasibility of predicting polymeric film coating and dissolution of theophylline (active pharmateutical ingredients, API) tablets based on integration of multivariate data analysis of near-infrared (NIR) spectra and first-principal modeling. Tablets of various API strengths were manufactured and were spray-coated in a fluid bed using a mixture of ethyl cellulose and hydroxypropyl methylcellulose. Tablets were subjected in NIR spectroscopy and in vitro USP dissolution testing. The characteristic peaks of coating materials were identified via Norris Gap second derivative preprocessing of the NIR spectra of coated tablets. Principal component analysis revealed a linear relationship between PC1 score and tablet coating level. Principal component regression and partial least squares calibration models were developed to correlate the NIR spectra with the dissolution data within the time window of 10–120 min. A linear relationship between tablet initial dissolution rate and tablet coa...

This multiauthor review article aims to bring readers up to date with some of the current trends in the field of process analytical technology (PAT) by summarizing each aspect of the subject (sensor development, PAT based process monitoring and control methods) and presenting applications both in industrial laboratories and in manufacture e.g. at GSK, AstraZeneca and Roche. Furthermore, the paper discusses the PAT paradigm from the regulatory science perspective. Given the multidisciplinary nature of PAT, such an endeavour would be almost impossible for a single author, so the concept of a multiauthor review was born. Each section of the multiauthor review has been written by a single expert or group of experts with the aim to report on its own research results. This paper also serves as a comprehensive source of information on PAT topics for the novice reader.

The objective of the current work was to investigate the effect of liquid to solid ratio (L/S), impeller speed and the wet massing time on the critical quality attributes of granules in a high shear wet granulation process for a two component (API and excipient) system. The parameters were evaluated for their effect on granule properties using a design of experiment based approach. Granules were characterized for their particle size distribution, content uniformity, morphology and porosity. The liquid to solid (L/S) ratio was found to have a dominant effect on the median particle size and exhibited a clear trend. The system was found to be extremely well mixed for all conditions thus implying robust composition uniformity within and between batches, independent of process parameters. The release kinetics of granules within the batch were found to be identical, independent of particle size. The granules were found to be fairly spherical as observed through a scanning electron microscope with no distinct agglomeration. The images indicate granulation by layering and consolidation. All three process parameters were found to have an effect on granule porosity, with the wet massing time having the most pronounced effect. A judicious selection of the afore mentioned process parameters will enable a balance between granule growth and porosity to be achieved without compromising on the mixing efficiency of the process thereby allowing one to build quality into the final product.

Accurate assessment of tablet content uniformity is critical for narrow therapeutic index drugs such as phenytoin sodium. This work presents a near-infrared (NIR)-based analytical method for rapid prediction of content uniformity based on a large number of phenytoin sodium formulation tablets. Calibration tablets were generated through an integrated experimental design by varying formulation and process parameters, and scale of manufacturing. A partial least squares model for individual tablet content was developed based on tablet NIR spectra. The tablet content was obtained from a modified United States Pharmacopeia phenytoin sodium high-performance liquid chromatography assay method. The partial least squares model with 4 latent variables explained 92% of the composition variability and yielded a root mean square error of prediction of 0.48% w/w. The resultant NIR model successfully assayed the composition of tablets manufactured at the pilot scale. For one such batch, bootstrapping was applied to calculate the confidence intervals on the mean, acceptance value, and relative SD for different sample sizes, n = 10, 30, and 100. As the bootstrap sample size increased, the confidence interval on the mean, acceptance value, and relative SD became narrower and symmetric. Such a ‘large N’ NIR-based process analytical technology method can increase reliability of quality assessments in solid dosage manufacturing.

The manufacturing of pharmaceuticals suffers from the problem of drug development in general. Many drug manufacturing processes are characterized by inefficiency, waste, and a slow adoption of modern process control technologies. To implement this evolving science and risk-based regulatory science framework in the pharmaceutical sector, collaborative efforts among the regulated industry, the academia, and the regulatory agencies are needed such that best medical products are available to the public. The Quality-by-Design (QbD) principles and scientific case studies discussed below would provide some examples on how robust process and consistent quality may be achieved by applying Quality QbD principles to capsule formulation and process development. First, the general QbD principles applied to capsule formulation and process development will be introduced. Then, several scientific case studies that illustrate how QbD principles are applied to capsule-filling process control and product quality will be provided. Finally, the current challenges and future outlook on capsule fill QbD will be discussed.

In this work, a model pharmaceutical powder blending system consisting of ibuprofen (drug), MCC, and lactose anhydrous was monitored in real-time via inline near-infrared (NIR) spectroscopy for dua...

In this review, a brief overview of the current regulatory science framework pertinent to pharmaceutical crystallization and process characterization is made first. The FDA’s scientific research on pharmaceutical crystallization process understanding and product characterization is then illustrated via several aspects: (1) Combined real-time PAT monitoring and process chemometrics for mapping the state of a pharmaceutical crystallization process; (2) Combined real-time PAT process monitoring and first-principle modeling for elucidating the nucleation mechanisms of a dynamic pharmaceutical crystallization process; (3) Combined real-time PAT process monitoring, Design of Experiments (DOE), and General Linear Modeling (GLM) to establish a hybrid approach for process characterization and process design space development; and (4) Integrated PAT approach for nucleation induction time measurement. Finally, some of the current challenges and future outlook on pharmaceutical crystallization process and product cha...

This work is concerned with the theoretical development of a semi-mechanistic aggregation kernel in a population balance model (PBM) which takes into account the effect of droplet spreading on a particle surface that aids in the coalescence of particles. Empirical aggregation kernels are more commonly used in simulations however they do not reflect the true physics of the system. The proposed kernel is computationally less expensive, yet it takes into account the various key operating parameters that affect the process. The kernel has been validated qualitatively and the lumped and distributed properties show good agreement with the expected behavior of the process. The various empirical parameters present in the granulation model have been identified and expressed as a function of the measurable operating quantities, thus providing a better knowledge regarding the effect of the process parameters on the final product with the help of a more fundamental, first principle based model. A detailed sensitivity analysis (involving viscosity, impeller speed, contact angle and liquid spray rate) has also been conducted in order to study the influence of the process parameters on the final granule properties. This knowledge provides a theoretical basis for the high-shear wet granulation process design space development. The model has also been able to successfully capture the steady and induction behavior of the process under the expected operating conditions.

This paper focuses on the predictive model development for a pharmaceutically relevant model granulation process. A population balance modeling (PBM) framework has been employed for modeling purposes which is then utilized to obtain accurate predictions of the process. The model is aligned to adequately describe the high-shear mode of granulation operation in a batch process. The model is calibrated using the particle swarm algorithm (PSA) in the form of a multiobjective optimization problem. The multiobjective optimization problem was implemented based on the e-constraint method which involves the handling of multiple cost functions in the form of constraints with the minimization of one primary objective function from the entire set of cost functions. The resultant solutions obtained from the model are Pareto optimal. The effects of the impeller speed, liquid-to-solid ratio, and wet massing time on the particle size distributions were characterized, and predicted size distributions were in agreement with experimental results. The predictive model framework lends itself to the quality by design (QbD) initiative undertaken by the US Food and Drug Administration (US FDA).

A comprehensive, real-time PAT process monitoring scheme of using near-infrared (NIR) spectroscopy, focused beam reflectance measurement (FBRM), and particle vision microscopy (PVM) was established for process characterization and process understanding of a model dynamic multicomponent pharmaceutical antisolvent crystallization system. The NIR spectra were subjected to principal component analysis (PCA) to construct the process trajectory; and the final products were characterized by X-ray powder diffraction (XRPD), raman spectrometry, and microscopy. Regardless of the PAT technique (i.e., the NIR–PCA method, the FBRM method, and the PVM method) used, this study shows that the nucleation induction time (tind) increases with temperature. In addition, correlations were observed with R2 of 0.70–0.98 between PVM method and FBRM method and of 0.58–0.84 between NIR–PCA method and FBRM method. Accounting for the dynamic nature of the experiments and changes in the liquid volume (V) as a function of time, a simpl...

As an emerging technology, THz spectroscopy has gained increasing attention in the pharmaceutical area during the last decade. This attention is due to the fact that (1) it provides a promising alternative approach for in-depth understanding of both intermolecular interaction among pharmaceutical molecules and pharmaceutical product quality attributes; (2) it provides a promising alternative approach for enhanced process understanding of certain pharmaceutical manufacturing processes; and (3) the FDA pharmaceutical quality initiatives, most noticeably, the Process Analytical Technology (PAT) initiative. In this work, the current status and progress made so far on using THz spectroscopy for pharmaceutical development and pharmaceutical PAT applications are reviewed. In the spirit of demonstrating the utility of first principles modeling approach for addressing model validation challenge and reducing unnecessary model validation “burden” for facilitating THz pharmaceutical PAT applications, two scientific case studies based on published THz spectroscopy measurement results are created and discussed. Furthermore, other technical challenges and opportunities associated with adapting THz spectroscopy as a pharmaceutical PAT tool are highlighted.

The objective of this study was to demonstrate the feasibility of using an integrated process analytical technology (PAT) approach to determine nucleation and growth mechanisms of a dynamic naproxen (drug)-Eudragit L100 (polymer) coprecipitation process. The influence of several thermodynamically important formulation and process variables (drug/polymer ratio, alcohol, and water usages) on coprecipitation process characteristics was investigated via real-time in situ focused beam reflectance measurement (FBRM) monitoring and near real-time particle vision microscopy measurement. The final products were characterized by near-infrared (NIR) spectroscopy and NIR chemical imaging microscopy. The coprecipitation nucleation induction time (t(ind) ) was measured by both FBRM trend statistics and process trajectory method, respectively. Furthermore, nucleation kinetics was evaluated based on t(ind) measurement and corresponding supersaturation ratio (S) estimated. It was found that plots of ln(t(ind) ) versus (ln(2) S)(-1) consist of two linear segments and are consistent with classical primary nucleation mechanisms. Apparently, the coprecipitation process is governed by heterogeneous primary nucleation mechanism at low S (14 ≤ S ≤ 503) and by homogeneous primary nucleation mechanism at high S (1216 ≤ S ≤ 3649). Off-line characterizations collectively supported this statement. Therefore, it demonstrated that integration real-time PAT process monitoring with first-principles modeling and off-line product characterization could enhance understanding to coprecipitation process dynamics and nucleation/growth mechanisms, which is impossible via off-line techniques alone.

In this work, an integrated PAT approach was developed for monitoring a pharmaceutical (naproxen) and a polymer (eudragit) coprecipitation process: real-time in-line near-infrared (NIR) absorbance monitoring, real-time on-line turbidity monitoring, and in situ crystal size monitoring. The data and information obtained through these three monitoring techniques confirmed the observation of the onsets of three distinct stages: incubation, nucleation, and crystal growth. The process trajectory constructed based on results of applying principal component analysis (PCA) to either process NIR spectra data or process turbidity profile, clearly demonstrated that various distinguishable process events, including incubation, nucleation, and crystal growth, could be accurately tracked and differentiated. These findings were further supported by process knowledge and information, such as process design, process sequence, thermodynamic and mass-transfer analysis. Therefore, this work provides a case study that illustrated a rational approach to develop a science-based and knowledge-based process monitoring strategy, which is essential for establishing both a suitable process control strategy and an operational process space for a pharmaceutical unit operation.

The objective of this study was to develop an integrated process monitoring approach for evaluating powder blending process kinetics and determining blending process end-point. A mixture design was created to include 26 powder formulations consisting of ibuprofen as the model drug and three excipients (HPMC, MCC, and Eudragit L100-55). The mixer was stopped at various time points to enable near-infrared spectroscopy scan of the powder mixture for obtaining the time course of the blending process. The evaluation of the blending process kinetics and process end-point was studied through three quantitative approaches: (1) Spectra linear superposition method; (2) Characteristic peak method; (3) Moving block standard deviation method. It was found that the powder blending experienced an initial rapid process to reach a quasi- end point within the first few minutes. Afterwards, a demixing occurred. Then, a real blending end-point was reached as characterized by an inflection point. ANOVA shows that the compositions of ibuprofen and MCC are the most statistically significant variables that impact the time required to reach the blending end-point. This highlighted the critical importance of developing quantitative chemometric approaches to extract critical process information and generate essential process knowledge to enable real-time release of the blending process. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:2784–2798, 2009

The goal of this study was to assess the utility of near infrared (NIR) spectroscopy for the determination of content uniformity, tablet crushing strength (tablet hardness), and dissolution rate in sulfamethazine veterinary bolus dosage forms. A formulation containing sulfamethazine, corn starch, and magnesium stearate was employed. The formulations were wet granulated with a 10% (wt/vol) starch paste in a high shear granulator and dried at 60 degrees C in a convection tray dryer. The tablets were compressed on a Stokes B2 rotary tablet press running at 30 rpm. Each sample was scanned in reflectance mode in the wavelengths of the NIR region. Principal component analysis (PCA) of the NIR tablet spectra and the neat raw materials indicated that the scores of the first 2 principal components were highly correlated with the chemical and physical attributes. Based on the PCA model, the significant wavelengths for sulfamethazine are 1514, (1660-1694), 2000, 2050, 2150, 2175, 2225, and 2275 nm; for corn starch are 1974, 2100, and 2325 nm; and for magnesium stearate are 2325 and 2375 nm. In addition, the loadings show large negative peaks around the water band regions ( approximately 1420 and 1940 nm), indicating that the partial least squares (PLS) models could be affected by product water content. A simple linear regression model was able to predict content uniformity with a correlation coefficient of 0.986 at 1656 nm; the use of a PLS regression model, with 3 factors, had an r (2) of 0.9496 and a standard error of calibration of 0.0316. The PLS validation set had an r (2) of 0.9662 and a standard error of 0.0354. PLS calibration models, based on tablet absorbance data, could successfully predict tablet crushing strength and dissolution in spite of varying active pharmaceutical ingredient (API) levels. Prediction plots based on these PLS models yielded correlation coefficients of 0.84 and 0.92 on independent validation sets for crushing strength and Q(120) (percentage dissolved in 120 minutes), respectively.

Crystallization of active pharmaceutical ingredient (API) or pharmaceutical drug substances is a crucial unit operation. In this paper challenges and scientific progress over the last two decades in the areas of pharmaceutical crystallization thermodynamics, kinetics, polymorphism, process modeling, and process control were attempted. Effective utilization of such scientific knowledge for optimized control of API crystallization process was discussed. A conceptual PAT framework for API crystallization process control was proposed. Three case studies from the literatures were discussed as hypothetical examples to illustrate the application of PAT framework to pharmaceutical crystallization process.

Crystallizations of pharmaceutical active ingredients, particularly those that posses multiple polymorphic forms, are among the most critical and least understood pharmaceutical manufacturing processes. Many process and product failures can be traced to a poor understanding and control of crystallization processes. The Food and Drug Administration's process analytical technology (PAT) initiative is a collaborative effort with industry to introduce new and efficient manufacturing technologies into the pharmaceutical industry. PAT's are systems for design, analysis, and control of manufacturing processes. They aim to assure high quality through timely measurements of critical quality and performance attributes of raw materials, in-process materials, and final products. Implementation of PAT involves scientifically based process design and optimization, appropriate sensor technologies, statistical and information tools (chemometrics), and feedback process control strategies working together to produce quality products. This review introduces the concept of PAT and discusses its application to crystallization processes through review of several case studies. A variety of in situ analytical methods combined with chemometric tools for analysis of multivariate process information provide a basis for future improvements in modeling, simulation, and control of crystallization processes.

Electrochemical current and potential transients were measured during anodic oxidation of aluminum, on time scales of 0.1–100 ms after anodizing began. Aluminum foil samples were prepared by surface treatments yielding oxide films of thickness 5 nm or smaller. A mathematical model was developed for the transients based on steady-state and transient conduction phenomena established for much thicker anodic films. Model calculations and experimental transients were in quantitative agreement, indicating that the electrochemical behavior of the nanometer-thick films during their growth is strongly similar to that of anodic films. No electrochemical processes other than uniform oxide growth were detected, as might have been associated with defects constituting easy conduction paths. The rate of oxide growth was shown to be controlled by oxygen ion transfer at the film–solution interface.

We appreciate the opportunity to respond to the comments by D.D. Macdonald. Before proceeding, there are regrettably several unresolved typographical errors in the equations found in the published version of the paper. We take this occasion to point out some of the more important ones: in Eq. (8) (numbering as in original paper), the term Rs should be iRs; in Eq. (10), ia should be ic0; in Table 1, Ia0, Ic0 and IL0 should be ia0, ic0 and iL0; in Eq. (11), the factor F should appear in the numerator in the argument of each exponential function. In the following discussion, Macdonald’s objections are considered in turn. Equation numbers from his comment will be used, unless otherwise stated.

The aim of this work was to develop an integrated process analytical technology (PAT) approach for a dynamic pharmaceutical co-precipitation process characterization and design space development. A dynamic co-precipitation process by gradually introducing water to the ternary system of naproxen–Eudragit L100–alcohol was monitored at real-time in situ via Lasentec FBRM and PVM. 3D map of count-time-chord length revealed three distinguishable process stages: incubation, transition, and steady-state. The effects of high risk process variables (slurry temperature, stirring rate, and water addition rate) on both derived co-precipitation process rates and final chord-length-distribution were evaluated systematically using a 3 3 full factorial design. Critical process variables were identified via ANOVA for both transition and steady state. General linear models (GLM) were then used for parameter estimation for each critical variable. Clear trends about effects of each critical variable during transition and steady state were found by GLM and were interpreted using fundamental process principles and Nyvlt's transfer model. Neural network models were able to link process variables with response variables at transition and steady state with R 2 of 0.88–0.98. PVM images evidenced nucleation and crystal growth. Contour plots illustrated design space via critical process variables’ ranges. It demonstrated the utility of integrated PAT approach for QbD development.

The objective of this study was to develop an integrated multivariate approach to quantify the constituent concentrations of both drug and excipients of powder blends. A mixture design was created to include 26 powder formulations consisting of ibuprofen as the model drug and three excipients(HPMC, MCC, and Eudragit L100-55). The mixer was stopped at various time points to enable near infrared(NIR) scan of the powder mixture and sampling for UV assay. Partial least square (PLS), principal component regression (PCR), and multiple linear regression (MLR) models were established to link the formulation concentrations with the Savitzky-Golay 1st derivative NIR spectral data at various characteristic wavelengths of each component. PLS models based on the NIR data and UV data were calibrated and validated. They predicted the main components' concentrations well in the powder blends, although prediction errors were larger for minor components. As expected from the complete random-mixture (CRM) model, the measurement uncertainties were higher for minor components in the powder formulations. The prediction performance differences between the NIR model and UV model were explained in the context of scale of scrutiny and model applicability. The importance of understanding excipient variability in powder blending and its implication for blending homogeneity assessment is highlighted.

This paper examines how one may assess spectral changes with instrument configuration (or composition), in combination with the spectral changes in the measurement that are caused by experimental effects, and subsequently select an appropriate measurement modality for tablet content uniformity determination with near-infrared (NIR) spectroscopy. Two NIR spectrometers furnished with three configurations in the sample measurement interface were evaluated. One spectrometer, Bruker MPA (multiple purpose analyzer), was equipped with two measurement modalities, diffuse transmission (DT) and diffuse reflection based on integrating sphere optics (DR/IS). The other spectrometer, Bruker StepOne, was equipped only with diffuse reflection mode based on a fiber-optic probe (DR/FO). The data were collected with each of the configurations for the tablets associated with two dosage strengths differing significantly in diameter and thickness. Spectral diagnosis was performed in terms of sensitivity and selectivity. The signal-to-noise ratio computed for the data collected with the DT and DR/IS spectrometers was approximately an order of magnitude greater than that computed for the DR/FO spectrometer. The net-analyte-signal-based selectivity analysis of NIR spectra associated with the sample tablet and the placebo tablet indicated that both transmission and reflection mode provided similar selectivity when the optimal spectral range was chosen. A partial least squares (PLS) calibration model was developed for each data set. The overall standard error of calibration for each DT and DR/IS measurement was approximately 0.3% in weight for each strength, significantly better than the value of 1.0% in weight produced by the DR/FO measurement. This result was consistent with the sensitivity analysis based on spectral noise characterization. The poor analytical performance of the DR/FO spectrometer was attributed to the small illumination spot size of the reflection probe and thus the sensitivity of the measurements to the tablet engraving. The PLS analysis and spectral diagnostics both showed that transmission and reflection modes based on the Bruker MPA provided similar measurement accuracy for each strength. However, the robustness study clearly revealed that the transmission mode would be more robust than the reflection mode when there is considerable variability in the chemical composition and physical properties of tablets.

Quantification analysis with near-infrared (NIR) spectroscopy typically requires utilizing chemometric techniques, such as partial least squares (PLS) method, to achieve the desired selectivity. This article points out a major limitation of these statistical-based calibration methods. The limitation is that the techniques suffer from the potential for chance correlation. In this article, the impact of chance correlation on the robustness of PLS model was illustrated via a pharmaceutical application with NIR to the content uniformity determination of tablets. The procedure involves evaluating the PLS models generated with two sets of calibration tablets incorporated with distinct degree of concentration correlation between the active pharmaceutical ingredient (API) and excipients. The selectivity and robustness of the two models were examined by using a series of data sets associated with placebo tablets and tablets incorporated with variations from excipient content, hardness and particle size. The result clearly revealed that the strong correlation observed in the PLS model created by the correlated design was not solely based on the API information, and there was an intrinsic difference in the variances described by the two calibration models. Diagnostic tools that enable the characterization of the chemical selectivity of the calibration model were also proposed for pharmaceutical quantitative analysis.

The objective of this study was to examine the effects of testing parameters and formulation variables on the segregation tendency of pharmaceutical powders measured by the ASTM D 6940-04 segregation tester using design of experiments (DOE) approaches. The test blends consisted of 4% aspirin (ASP) and 96% microcrystalline cellulose (MCC) with and without magnesium stearate (MgS). The segregation tendency of a blend was determined by measuring the last/first (L/F) ratio, the ratio of aspirin concentrations between the first and last samples discharged from the tester. A 2(2) factorial design was used to determine the effects of measurement parameters [amount of material loaded (W), number of segregation cycles] with number of replicates 6. ANOVA showed that W was a critical parameter for segregation testing. The L/F value deviated further from 1 (greater segregation tendency) with increasing W. A 2(3) full factorial design was used to assess the effects of formulation variables: grade of ASP (unmilled, milled), grade of MCC, and amount of lubricant, MgS. MLR and ANOVA showed that the grade of ASP was the main effect contributing to segregation tendency. Principal Component Regression Analysis established a correlation between L/F and the physical properties of the blend related to ASP and MCC, the ASP/MCC particle size ratio (PSR) and powder cohesion. The physical properties of the blend related to density and flow were not influenced by the grade of ASP and were not related to the segregation tendency of the blend. The direct relationship between L/F and PSR was determined by univariate analysis. Segregation tendency increased as the ASP to MCC particle size increased. This study highlighted critical test parameters for segregation testing and identified critical physical properties of the blends that influence segregation tendency.

Terahertz (THz) spectroscopy and chemometric analysis of resultant absorption spectra in the 30–500 cm−1 range has been applied to perform quantitative determination of both active ingredient and excipient concentrations of tablets. Tests were performed on a series of tablets composed of various concentrations and processes of theophylline formulated with lactose, magnesium stearate, starch or Avicel, and as a function of tablet hardness. Transmission spectra of polyethylene pellets derived from each of the samples were analyzed using three approaches. Spectral superposition method was used as an indirect measure to examine whether and when the interaction among various pharmaceutical components and the tableting history could be considered insignificant for quantification purpose. Spectral characteristic peak method was able to correlate peak maxima with correction for tablets having the same hardness. Multivariate analysis (PCR and PLS 1) was capable of correlating THz spectra with tablet concentrations. The predicted concentrations of independent samples using multivariate models agreed well with nominal concentrations. The best correlations were obtained using multivariate analysis. With these studies, the advantage of using multivariate approach was demonstrated for process analytical technology (PAT) application. Further, the feasibility of integrating THz spectroscopy and chemometrics for the purpose of quantifying pharmaceutical tablet concentrations was demonstrated. © 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:970–984, 2008

The mechanism was investigated by which pit initiation on aluminum foils during anodic etching is affected by the use of phosphoric acid as a pretreatment. Positron annihilation measurements, coupled with atomic force microscope images of foils with chemically stripped oxide layers, show evidence that the pretreatment introduces nanometer-scale voids in the metal, at or near the metal-oxide film interface. The location and morphology of voids compares favorably with those of pits, suggesting that voids act as pit initiation sites. The number of void sites was estimated to be 10 7 cm -2 , the same magnitude as the maximum number of pits formed by anodic etching. Capacitance measurements further indicate that the treatment decreases the surface oxide thickness to about 2 nm. Formation of large numbers of pits during etching is promoted by either reduced oxide thicknesses or more positive etching potentials. It is suggested that the rate of initiation of pits at interfacial voids is determined by the electric field in the overlying surface oxide.

High-purity aluminum foils were examined using positron annihilation spectroscopy (PAS) after dissolution for various times in 1 M NaOH at room temperature. Measurements of the S and W shape parameters of the annihilation photopeak at 511 keV show the presence of voids of at least nanometer dimension located at the metal-oxide film interface. The large S parameter suggests that the metallic surface of the void is free of oxide. Voids are found in as-received foils and are also produced by dissolution in NaOH, evidently by a solid-state interfacial process. Atomic force microscopy (AFM) images of NaOH-dissolved foils, after stripping the surface oxide film in chromic-phosphoric acid bath, reveal cavities on the order of 100 nm size The average cavity depth is in quantitative agreement with the PAS-derived thickness of the interfacial void-containing layer, and the dissolution time dependence of the defect layer S parameter closely parallels that of the fractional coverage of the foil surface by cavities; thus, the cavities are believed to he interfacial voids created along with those detected by PAS. The cavity distribution on the surface closely resembles that of corrosion pits formed by anodic etching in 1 M HCl, thereby suggesting that the interfacial voids revealed by AFM serve as sites for pit initiation.

Aluminum foils with two different surface topographic textures were anodically oxidized at constant current in a phosphoric acid bath. In situ atomic force microscopy (AFM) was used to follow the initial development of surface topography on a 1 μm scale, during the early stages of porous oxide film formation. Microscopic convex features such as ridges on both foils begin to increase in height and width when the anodic film thickness exceeds the initial feature height. Equations of a mathematical model are presented incorporating established interfacial reactions and oxide conduction behavior. The model indicates that the film-solution interface recedes into the metal during anodizing, since the current efficiency for oxide formation is smaller than the oxygen ion transport number in the film. Ridge surfaces increase in height due to the higher local conduction resistance to the film-solution interface, while film deposits rapidly at ridges because of the low local resistance to the metal-film interface. In agreement with the AFM results, enhanced oxide growth at ridges should start when the potential field in the film becomes two-dimensional, as a result of the film growing to a thickness larger than the ridge height.