Capillary Drop Penetration Method to Characterize the Liquid Wetting of Powders.

We present a method to characterize the wettability of powders, based on the penetration dynamics of a sessile drop deposited on a slightly compressed powder bed. First, we show that a direct comparison of the wetting properties of different liquids is possible without having to solve the three-dimensional liquid penetration problem, by considering the appropriate dimensionless variables. We show that the contact area between the sessile drop and the powder bed remains constant during most of the penetration process and demonstrate that as a result, the evolution of the dimensionless penetration volume is given by a universal function of the dimensionless time, with no dimensionless parameters. Then, using a reference liquid that completely wets the powder, it is possible to obtain an effective contact angle for a test liquid of interest, independent of other properties of the powder bed, such as permeability and a characteristic pore size. We apply the proposed method to estimate the contact angle of water with different powder blends, by using silicone oil as the reference liquid. Finally, to highlight the potential of the proposed method to characterize pharmaceutical powders, we consider a blend of lactose, acetaminophen, and a small amount of lubricant (magnesium stearate). The proposed method adequately captures a significant decrease in hydrophilicity that results from exposing the blend to excessive mixing, a well-known effect in the pharmaceutical industry.

Statistical comparison of dissolution profiles.

Statistical methods to assess similarity of dissolution profiles are introduced. Sixteen groups of dissolution profiles from a full factorial design were used to demonstrate implementation details. Variables in the design include drug strength, tablet stability time, and dissolution testing condition. The 16 groups were considered similar when compared using the similarity factor f2 (f2 > 50). However, multivariate ANOVA (MANOVA) repeated measures suggested statistical differences. A modified principal component analysis (PCA) was used to describe the dissolution curves in terms of level and shape. The advantage of the modified PCA approach is that the calculated shape principal components will not be confounded by level effect. Effect size test using omega-squared was also used for dissolution comparisons. Effects indicated by omega-squared are independent of sample size and are a necessary supplement to p value reported from the MANOVA table. Methods to compare multiple groups show that product strength and dissolution testing condition had significant effects on both level and shape. For pairwise analysis, a post-hoc analysis using Tukey's method categorized three similar groups, and was consistent with level-shape analysis. All these methods provide valuable information that is missed using f2 method alone to compare average profiles. The improved statistical analysis approach introduced here enables one to better ascertain both statistical significance and clinical relevance, supporting more objective regulatory decisions.

Statistical data treatment for residence time distribution studies in pharmaceutical manufacturing.

Residence time distribution (RTD) method has been widely used in the pharmaceutical manufacturing for understanding powder dynamics within unit operations and continuous integrated manufacturing lines. The dynamics thus captured is then used to develop predictive models for unit operations and important RTD-based applications ensuring product quality assurance. Despite thorough efforts in tracer selection, data acquisition, and calibration model development to obtain tracer concentration profiles for RTD studies, there can exist significant noise in these profiles. This noise can make it challenging to identify the underlying signal and get a representative RTD of the system under study. Such concerns have previously indicated the importance of noise handling for RTD measurements in literature. However, the literature does not provide sufficient information on noise handling or data treatment strategies for RTD studies. To this end, we investigate the impact of varying levels of noise using different tracers on measurement of RTD profile and its applications. We quantify the impact of different denoising methods (time and frequency averaging methods). Through this investigation, we see that Savitsky Golay filtering turns out to a good method for denoising RTD profiles despite varying noise levels. The investigation is performed such that the key features of the RTD profile (which are important for RTD based applications) are preserved. Subsequently, we also investigate the impact of denoising on RTD-based applications such as out-of-specification (OOS) analysis and RTD modeling. The results show that the degree of noise levels considered in this work do not significantly impact the RTD-based applications.

Effects of powder flow properties on capsule filling weight uniformity.

Filling capsules with the right amount of powder ingredients is an important quality parameter. The purpose of this study was to develop effective laboratory methods for characterizing flow properties of pharmaceutical powder blends and correlating such properties to weight variability in filled capsules. The methods used for powder flow characterization were bulk and tapped density, gravitational displacement rheometer (GDR) flow index, Freeman Technology V.4 (FT4) powder rheometer compressibility, FT4 basic flow energy (BFE), and cohesion parameters [cohesion, (C) and flow factor (ffc)] measured in a shear cell also using the FT4. Capsules were filled using an MG2-G140 continuous nozzle dosator capsule-filling machine. Powder flow properties were the most predominant factors affecting the weight and weight variability in the filled capsules. Results showed that the weight variability decreased with increasing bulk and tapped density, ffc and BFE, while the weight variability increased with increasing compressibility, cohesion and GDR flow index. Powder flow properties of the final blends were significantly correlated to the final capsule weight and weight variability of the filled capsules.

Method to study the effect of blend flowability on the homogeneity of acetaminophen.

CONTEXT: Excipient selection is key to product development because it affects their processability and physical properties, which ultimately affect the quality attributes of the pharmaceutical product. OBJECTIVE: To study how the flowability of lubricated formulations affects acetaminophen (APAP) homogeneity. MATERIALS AND METHODS: The formulations studied here contain one of two types of cellulose (Avicel 102 or Ceollus KG-802), one of three grades of Mallinckrodt APAP (fine, semi-fine, or micronized), lactose (Fast-Flo) and magnesium stearate. These components are mixed in a 300-liter bin blender. Blend flowability is assessed with the Gravitational Displacement Rheometer. APAP homogeneity is assessed with off-line NIR. RESULTS: Excluding blends dominated by segregation, there is a trend between APAP homogeneity and blend flow index. Blend flowability is affected by the type of microcrystalline cellulose and by the APAP grade. CONCLUSION: The preliminary results suggest that the methodology used in this paper is adequate to study of the effect of blend flow index on APAP homogeneity.

Optimal quantification of residence time distribution profiles from a quality assurance perspective.

Residence time distribution (RTD) has been widely applied across various fields of chemical engineering, including pharmaceutical manufacturing, for applications such as material traceability, quality assurance, system health monitoring, and fault detection. Determination of a representative RTD, in principle, requires an accurate process analytical technology (PAT) procedure capturing the entire range of tracer concentrations from zero to maximum. Such a wide concentration range creates at least two problems: i) decreased accuracy of the model across the entire range of concentrations, relating to limit of quantification, and ii) ambiguity associated with the detection of the tracer for low concentration levels, relating to limit of detection (LOD). These problems affect not only the RTD profile itself, but also RTD-based applications, which can potentially lead to erroneous conclusions. This article seeks to minimize the impact of these problems by understanding the relative importance of different features of RTD on the detection of out-of-specification (OOS) products. In this work, the RTD obtained experimentally was truncated at different levels, to investigate the impact of the truncation of RTD on funnel plots for OOS detection. The main finding is that the tail of the RTD can be truncated with no loss of accuracy in the determination of exclusion intervals. This enables the manufacturing scientist to focus entirely on the peak region, maximizing the accuracy of chemometric models.

Improvement of tablet coating uniformity using a quality by design approach.

A combination of analytical and statistical methods is used to improve a tablet coating process guided by quality by design (QbD) principles. A solid dosage form product was found to intermittently exhibit bad taste. A suspected cause was the variability in coating thickness which could lead to the subject tasting the active ingredient in some tablets. A number of samples were analyzed using a laser-induced breakdown spectroscopy (LIBS)-based analytical method, and it was found that the main variability component was the tablet-to-tablet variability within a lot. Hence, it was inferred that the coating process (performed in a perforated rotating pan) required optimization. A set of designed experiments along with response surface modeling and kriging method were used to arrive at an optimal set of operating conditions. Effects of the amount of coating imparted, spray rate, pan rotation speed, and spray temperature were characterized. The results were quantified in terms of the relative standard deviation of tablet-averaged LIBS score and a coating variability index which was the ratio of the standard deviation of the tablet-averaged LIBS score and the weight gain of the tablets. The data-driven models developed based on the designed experiments predicted that the minimum value of this index would be obtained for a 6% weight gain for a pan operating at the highest speed at the maximum fill level while using the lowest spraying rate and temperature from the chosen parametric space. This systematic application of the QbD-based method resulted in an enhanced process understanding and reducing the coating variability by more than half.

SEM/EDX and Raman chemical imaging of pharmaceutical tablets: A comparison of tablet surface preparation and analysis methods.

A better understanding of a pharmaceutical tablet's microstructure has the potential to unlock the black box between material attributes, process parameters and the critical quality attributes. Microstructure determination requires measuring the spatial-, particle size-distributions (absolute and relative) of the ingredients, and the void space, which is the overt goal of chemical Imaging (CI). Reliable quantitative results can be obtained by imaging multiple layers per tablet, with each layer having a minimal surface roughness. This study utilized scanning electron microscopy/energy dispersive X-ray spectroscopy (SEM/EDX) and Raman chemical imaging (RCI) to provide a comparative discussion of results obtained when determining the microstructure of commercial zinc sulfate tablets, using three methods of tablet surface preparation: scoring & hand-fracturing, microtoming, and grating. A description of the working principles of the measurement and surface preparation methods is followed by a comparison of microstructure (particle size distribution and homogeneity of distribution) using chemical images. A comparison of the general advantages and disadvantages of SEM/EDX and RCI and the common errors in analyzing microstructure are also discussed. The results indicate that in addition to selecting the correct tablet surface preparation method, chemical imaging method, and the subsequent microstructural analyses method, correct problem formulation is also critical.

Prediction of entire tablet formulations from pure powder components' spectra via a two-step non-linear optimization methodology.

Process analytical technology in the pharmaceutical industry requires the monitoring of critical quality attributes (CQA) through calibrated models. However, the development, implementation, and maintenance of these quantitative models are both resource and time-intensive. This study proposes the implementation of a non-linear iterative optimization technology (IOT) to study the magnitude of analytical errors when the calibration tablet used to extract the λ vector deviates physically and chemically from the test samples. IOT is based on mathematical optimization of excess spectral absorbance. It requires minimum calibration effort and allows simultaneous prediction of the entire formulation instead of only the active pharmaceutical ingredient (API), with just one standard and pure component spectral data. Unlike Partial Least Squares (PLS), which requires the development of standards to incorporate variations in the process, this non-destructive methodology minimizes significant calibration effort by developing a mathematical model that uses only one standard and spectral information of pure powders present in the tablet. The method described in this study allows a fast re-calculation to include factors such as change of spectroscopic instruments, variations in raw materials, environmental conditions, and methods of tablet preparation. The robustness of the proposed approach for variation in compaction (physical changes) and variation in composition (chemical changes) was evaluated for correlated and uncorrelated formulations. For uncorrelated formulation a PLS model was also constructed to compare the robustness of the proposed methodology. The RMSEP of API in target formulation predicted using non-linear IOT method was varied from 0.17 to 1.50 depends on compaction of tablet chosen to compute λ vector. On the other hand, the RMSEP of API in target formulation predicted using PLS-based model was varied from 0.13 to 0.57 depending on compaction of tablet. The additional accuracy achieved in PLS based model required significant calibration effort of preparing 84 tablets compared to just one in proposed non-linear IOT method.

Characterization and propagation of RTD uncertainty for continuous powder blending processes.

Residence time distribution (RTD) is a probability density function that describes the time materials spend inside a system. It is a promising tool for mixing behavior characterization, material traceability, and real-time quality control in pharmaceutical manufacturing. However, RTD measurements are accompanied with some degree of uncertainties because of process fluctuation and variation, measurement error, and experimental variation among different replicates. Due to the strict quality control requirements of drug manufacturing, it is essential to consider RTD uncertainty and characterize its effects on RTD-based predictions and applications. Towards this end, two approaches were developed in this work, namely model-based and data-based approaches. The model-based approach characterizes the RTD uncertainty via RTD model parameters and uses Monte Carlo sampling to propagate and analyze the effects on downstream processes. To avoid bias and possible reduction of uncertainty during model fitting, the data-based approach characterizes RTD uncertainty using the raw experimental data and utilizes interval arithmetic for uncertainty propagation. A constrained optimization approach was also proposed to overcome the drawback of interval arithmetic in the data-based approach. Results depict probability intervals around the upstream disturbance tracking profile and the funnel plot, facilitating better decision-making for quality control under uncertainty.

NIR Spectroscopy as an Online PAT Tool for a Narrow Therapeutic Index Drug: Toward a Platform Approach Across Lab and Pilot Scales for Development of a Powder Blending Monitoring Method and Endpoint Determination.

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.

Residence time distribution as a traceability method for lot changes in a pharmaceutical continuous manufacturing system.

Residence time distribution (RTD) models were developed to track raw material lots and investigate batch transitions in a continuous manufacturing system. Two raw materials with similar physical properties (granular metformin and lactose) were identified via Principal Component Analysis (PCA) from a library of bulk material properties and used to simulate the switching of lots during production. In-line near-infrared (NIR) spectra were collected with the powder flowing through a chute in a continuous manufacturing system to monitor metformin and lactose concentration in step-change experiments with Partial Least Squares (PLS) models. RTD provided an understanding of raw material propagation through the continuous manufacturing system. Transition times between raw material changes were identified using the results of two multivariate approaches PLS and PCA. The methodology was implemented to discriminate the transition zone in a raw material change, contributing to design control strategies for acceptance and diverting mechanisms.

Binder-free twin-screw melt granulation: An effective approach to manufacture high-dose API formulations.

This study investigates the use of twin-screw binder-free melt granulation (BFMG) in the development of high-dose solid dose formulations for low melting point thermally stable drugs. Both ibuprofen and guaifenesin are examined. By granulating pure API powder, it is shown that BFMG can successfully be used to produce granules that contain 100% API. A design of experiments (DoE) response surface methodology was used to establish the design space for the end-product. The effects of the most relevant process variables (barrel operating temperature, powder feed rate, screw speed and screw configuration) on granule properties (outlet temperature, size distribution, morphology, flowability, compressibility, porosity) and tablet attributes (tensile strength and in-vitro dissolution) were thoroughly studied. Barrel temperature (alone or in interactions with the other variables) represented the most significant variable for both drugs since it governs the formation of granules by partial melting and subsequent agglomeration of the fed powder. Interestingly, the shear action originated by screw speed and screw configuration resulted in various significant responses depending on the drug substance, indicating that it can also be affected by the nature of the processed molecule. Flow properties were improved (i.e., lower Hausner ratio) for both drugs after formation of granules. Tabletability was also tested by preparing 600 mg tablets for all samples. Surprisingly, the resulting granules were highly compactible, requiring only 1% lubricant to form strong tablets containing 96% API and 3% disintegrant. The results also showed that tablets become harder as the granule size increased, especially for guaifenesin. As expected, in-vitro dissolution results indicated that tablets and capsules showed slightly slower dissolution rates than the granules.

Performance assessment of linear iterative optimization technology (IOT) for Raman chemical mapping of pharmaceutical tablets.

Raman chemical mapping is an inherently slow analysis tool. Accurate and robust multivariate analysis algorithms, which require least amount of time and effort in method development are desirable. Calibration-free regression and resolution approaches such as classical least squares (CLS) and multivariate curve resolution using alternating least squares (MCR-ALS), respectively, help in reducing the resources required for method development. However, conventional CLS does not consider appropriate constraints, which may result in negative and/or greater than 100 % Raman concentration scores, while MCR-ALS may not always be as accurate as regression-based algorithms. Linear iterative optimization technology (IOT) is another calibration-free algorithm, which with appropriate constraints has previously shown promise in online and offline pharmaceutical mixture composition determination. This paper aims to evaluate the performance of the linear IOT algorithm for Raman chemical mapping of the active pharmaceutical ingredient (API), diluent, and lubricant in pharmaceutical tablets. Two pre-processing strategies were applied to the raw Raman mapping spectra. The results were compared with CLS (current reference method) and MCR-ALS. Special emphasis was given to mapping at low Raman exposure times to enable feasible total acquisition times (< 5 h). The quality of IOT/CLS/MCR-ALS estimated Raman concentration predictions were assessed by calculating a correlation factor between the spectrum corresponding to the maximum predicted concentration (or resolved spectra) of a component for IOT/CLS (or MCR-ALS) and the pure powder component spectrum. The Raman chemical maps were visualized, and the average Raman concentrations scores were compared. The results demonstrated the utility of IOT in Raman chemical mapping of pharmaceutical tablets. The diluent (lactose) and API (semi-fine APAP) used in this study were reliably estimated by IOT at relatively short Raman exposure times. On the other hand, as expected, the lubricant (magnesium stearate) could not be detected in any of the cases investigated here, irrespective of the algorithm used. Overall, for the API and diluent used in this formulation as well as the chemical mapping conditions, linear IOT seemed to better estimate the pure spectrum intensities and the average Raman scores (closer to CLS) in comparison to MCR-ALS. Moreover, application of appropriate constraints in linear IOT avoided the presence of negative and/or greater than 100 % Raman concentration scores, as observed in CLS-based Raman chemical maps.

Using residence time distribution in pharmaceutical solid dose manufacturing - A critical review.

While continuous manufacturing (CM) of pharmaceutical solid-based drug products has been shown to be advantageous for improving the product quality and process efficiency in alignment with FDA's support of the quality-by-design paradigm (Lee, 2015; Ierapetritou et al., 2016; Plumb, 2005; Schaber, 2011), it is critical to enable full utilization of CM technology for robust production and commercialization (Schaber, 2011; Byrn, 2015). To do so, an important prerequisite is to obtain a detailed understanding of overall process characteristics to develop cost-effective and accurate predictive models for unit operations and process flowsheets. These models are utilized to predict product quality and maintain desired manufacturing efficiency (Ierapetritou et al., 2016). Residence time distribution (RTD) has been a widely used tool to characterize the extent of mixing in pharmaceutical unit operations (Vanhoorne, 2020; Rogers and Ierapetritou, 2015; Tezyk et al., 2015) and manufacturing lines and develop computationally cheap predictive models. These models developed using RTD have been demonstrated to be crucial for various flowsheet applications (Kruisz, 2017; Martinetz, 2018; Tian, 2021). Though extensively used in the literature (Gao et al., 2012), the implementation, execution, evaluation, and assessment of RTD studies has not been standardized by regulatory agencies and can thus lead to ambiguity regarding their accurate implementation. To address this issue and subsequently prevent unforeseen errors in RTD implementation, the presented article aims to aid in developing standardized guidelines through a detailed review and critical discussion of RTD studies in the pharmaceutical manufacturing literature. The review article is divided into two main sections - 1) determination of RTD including different steps for RTD evaluation including experimental approach, data acquisition and pre-treatment, RTD modeling, and RTD metrics and, 2) applications of RTD for solid dose manufacturing. Critical considerations, pertaining to the limitations of RTDs for solid dose manufacturing, are also examined along with a perspective discussion of future avenues of improvement.

Dissolution Study on Grape Polyphenol Hard Gelatin Capsule Dietary Supplements.

Methods for a dissolution study by ultra-high performance liquid chromatography/triple quadrupole mass spectrometry (UHPLC-QqQ/MS) analysis of grape polyphenol dietary supplements, namely, grape seed extract (GSE) and resveratrol (RSV) capsules, were developed following the guidance of United States Pharmacopeia (USP) <2040>. Two dissolution media, 0.1 N hydrochloric acid (pH 1.2) and 0.05 M acetate buffer (pH 4.6), were evaluated with dissolution apparatus (USP 1), 100 rpm rotation speed, and 900 ml dissolution medium volume. Dissolution profiling was performed over 120 min. Major phenolic compounds of gallic acid, catechin, epicatechin, and procyanidin B2 were quantitated to obtain the dissolution profile of GSE capsules, and trans-RSV was used for RSV capsules. Results indicated that the released trans-RSV for RSV capsules in both of the dissolution media meets the USP standards, and that for the GSE capsules, all the four marker compounds passed the dissolution test in the HCl medium but did not reach a 75% release within 60 min in the acetate buffer. These promising results suggest that the general USP dissolution protocols are adequate for the successful release of RSV capsules in HCl medium and acetate buffer and GSE capsules (in HCl medium), but may be inadequate for GSE capsules in acetate buffer. These results showed that under a low pH of 1.2 (simulated stomach environment), bioactive compounds were released on time from the GSE capsules and met the USP guidelines; however, under a higher pH of 4.6 (simulated duodenum environment), the same biomarkers failed, suggesting the need to further improve the dissolution of GSE over a wider range of pH environments to enhance bioavailability and efficacy.

Sampling optimization for blend monitoring of a low dose formulation in a tablet press feed frame using spatially resolved near-infrared spectroscopy.

In-line measurements of low dose blends in the feed frame of a tablet press were performed for API concentration levels as low as 0.10% w/w. The proposed methodology utilizes the advanced sampling capabilities of a Spatially Resolved Near-Infrared (SR-NIR) probe to develop Partial Least-Squares calibration models. The fast acquisition speed of multipoint spectra allowed the evaluation of different numbers of co-adds and feed frame paddle speeds to establish the optimum conditions of data collection to predict low potency blends. The interaction of the feed frame paddles with the SR-NIR probe was captured with high resolution and allowed the implementation of a spectral data selection criterion to remove the effect of the paddles from the calibration and testing process. The method demonstrated accuracy and robustness when predicting drug concentrations across different feed frame paddle speeds.

Characterization of NIR interfaces for the feeding and in-line monitoring of a continuous granulation process.

This work describes the characterization of three NIR interfaces intended to monitor a continuous granulation process. Two interfaces (i.e. a barrel interface and a rotating paddle interface) were evaluated to monitor the API concentration at the entrance of the granulator, and a third interface (i.e. an outlet interface), was evaluated to examine the quality of the resulting outlet granules. The barrel interface provided an assessment of the API concentration during the feeding process by scanning the material conveyed by the screws of the loss-in-weight feeder. The rotating paddle interface analyzed discrete amounts of powder upon exiting the feeder via the accumulation of material on the paddles. Partial Least Squares (PLS) calibration models were developed using the same powder blends for the two inlet interfaces and using the outlet granules for the outlet interface. Five independent batches were used to evaluate the prediction performance of each inlet calibration model. The outlet interface produced the lowest error of prediction due to the homogeneity of the granules. The barrel interface produced lower errors of prediction than the rotating paddle interface. However, powder density affected only the barrel interface, producing deviations in the predicted values. Therefore, powder density is a factor that should be considered in the calibration sample design for spectroscopic measurements when using this type of interface. A variographic analysis demonstrated that the continuous 1-dimensional motion in the barrel and outlet interfaces produced representative measurements of each batch during calibration and test experiments, generating a low minimum practical error (MPE).

Method transfer of a near-infrared spectroscopic method for blend uniformity in a poorly flowing and hygroscopic blend.

The challenges in transferring and executing a near-infrared (NIR) spectroscopic method for croscarmellose (disintegrant) in binary blends for a continuous manufacturing (CM) process are presented. This work demonstrates the development of a NIR calibration model and its use to determine the blending parameters needed for binary blends at a development plant and later used to predict CM process blends. The calibration models were developed with laboratory scale powder blends ranging from 4.32%-64.77 (%w/w) of croscarmellose and evaluated using independent test blends. The selected model was then transferred to the continuous manufacturing development site to determine the croscarmellose concentration for spectra collected in real-time. A total of 18 development plant runs were monitored using an in-line NIR spectrometer, however, these spectra showed high baseline variations. The baseline variations were caused by the poor flow of the material within the system. An inconsistent bias which varied from 2.51 to 14.95 (%w/w) was observed in the predictions of croscarmellose. High baseline spectra were eliminated and the bias was significantly reduced by 42-51%. Experiments at lower flow rate speeds did not show significant changes in baseline and bias values showed more consistency. The calibration model was then transferred to two NIR spectrometers installed at-line at the commercial site, where powder samples were collected at the beginning middle and end of each CM plant run. The NIR calibration model predicted disintegrant concentration from the powder samples. Results showed the bias values for the NIR (1) varied from 0.74 to 2.21 (%w/w) and NIR (2) from 0.28 to 3.39 (%w/w). Average concentration values for both equipments were very close to the reference concentration values of 43.18 and 50.98 (%w/w). The study showed the model was able to identify flow issues, identified as baseline shifts, that could be used to alert to problems in the powder bed that may warrant diversion from a production line. These powder flow problems such as air gaps and inconsistent powder bed height affected the NIR spectra collected at the development plant and provided results with high bias. A lower bias was obtained in samples collected at line after blending.

Practical methods for improving flow properties of active pharmaceutical ingredients.

OBJECTIVE: The essential aim of this article is to develop effective methods for improving the flow properties of active pharmaceutical ingredients (APIs) without requiring particle size or shape modification. METHODS: The 'formulation' approach used here focuses on enhancing flow properties of three chemically different drug powders (micronized acetaminophen, levalbuterol tartrate, and didesmethylsibutramine tartrate) by using small amounts of lubricants, glidants, and other additives, both individually and in combination. Additives are intimately mixed using a laboratory-scale V-blender with an intensifier bar. Flow index, dilation, and electrical impedance were measured for a total of 24 blends. RESULTS: The flow behavior of all three APIs improved with the addition of these additives. Relative effectiveness of different additive combinations displayed remarkable consistency for all three APIs. Simultaneous presence of SiO2, MgSt, and talc led to substantial decreases in cohesiveness, causing major improvements in flowability of powder. All three properties showed a very tight correlation. CONCLUSIONS: Drug powders with improved flow were found to exhibit low dilation and low impedance values. A common linear correlation between flow index and impedance and also between dilation and impedance was observed for all three APIs, indicating that electric properties play a substantial role in the cohesivity of all three APIs, and suggesting the presence of a common mechanism for the emergence (and mitigation) of cohesive phenomena.