Discrete element modeling for continuous powder feeding operation: Calibration and system analysis.

Research emphases on extensive experimental studies and modeling efforts have been on the rise for the development of accurate predictive models of pharmaceutical unit operations and 'digital-twin' framework for continuous manufacturing lines. These exhaustive studies have been conducted at different process conditions to acquire comprehensive knowledge of effects of process parameters on the overall process dynamics. However, there still lacks a detailed understanding of material property effects of pharmaceutical powders on process operation. To address this issue, a discrete element modeling (DEM) approach combined with material calibration is applied for simulation of feeder unit to obtain particle-level insight into effects of material properties on feeder performance with focus on particle flow and powder mixing within the feeder unit. Bulk calibration is implemented to accurately represent powder material properties within the DEM framework. Different refill situations are simulated using DEM to observe powder mixing, measured at the outlet. Feeder DEM simulations are further applied to understand correlations of material properties on feeder operation. These studies provide a detailed physical insight and particle-scale information into the powder mechanics during powder feeding operation.

[Optimum Volume of Water Needed for the Paste State of Pediatric Powders: Considerations Based on Yield Values and Applications to Generic Medicine].

To clarify the volume of water required to paste pediatric powders, we herein established a standard for the powder paste state by measuring yield values when water was added to powders. The powders used in the present study were selected from 8 types including original and generic drugs. Tipepidine hibenzate is prescribed in the pediatric field in combination with ambroxol hydrochloride and l-carbocysteine. The volumes of water needed to achieve the paste state of ambroxol hydrochloride between the original and generic drugs were similar. However, the volumes of water needed for l-carbocysteine markedly differed between the original and generic drugs due to differences in their additives. The spreadability of the mixture when water was added to the powders was evaluated using a spread meter. Among the powders tested in the present study, the yield value to achieve a paste state with the addition of water was approximately 1000 dyne/cm2. The optimum volume of water estimated from this yield value using the linear proportional relationship for the amount of powder may be applied to the mixture of each pediatric power for dosage/body weight.

Optimizing the Quality of Food Powder Products: The Challenges of Moisture-Mediated Phase Transformations.

Water is ubiquitous in the environment and is present to varying degrees even within dry powder products and most ingredients. Water migration between the environment and a solid, or between different components of a product, may lead to detrimental physical and chemical changes. In efforts to optimize the quality of dry products, as well as the efficiency of production practices, it is crucial to understand the cause-effect relationships of water interactions with different solids. Therefore, this review addresses the basis of moisture migration in dry products, and the modes of water vapor interactions with crystalline and amorphous solids (e.g., adsorption, capillary condensation, deliquescence, crystal hydrate formation, absorption into amorphous solids) and related moisture-induced phase and state changes, and provides examples of how these moisture-induced changes affect the quality of the dry products.

Non-destructive Raman spectroscopy as a tool for measuring ASTA color values and Sudan I content in paprika powder.

The aim of this study was developing a non-destructive method for the determination of color in paprika powder as well as for detecting possible adulteration with Sudan I. Non-destructive Raman spectroscopy was applied directly to paprika powder employing a laser excitation of 785 nm for the first time. The fluorescence background was estimated, by fitting a polynomial to each spectrum, and then subtracted. After preprocessing the spectra, some peaks were clearly identified as characteristic from pigments present in paprika. The preprocessed Raman spectra were correlated with the ASTA color values of paprika by partial least squares regression (PLSR). Twenty-five paprika samples were adulterated with Sudan I at different levels and the PLSR model was also obtained. The coefficients of determination (R2) were 0.945 and 0.982 for ASTA and Sudan I concentration, respectively, and the root mean square errors of prediction (RMSEP) were 8.8 ASTA values and 0.91 mg/g, respectively. Finally, different approaches were applied to discriminate between adulterated and non-adulterated samples. Best results were obtained for partial least squares - discriminant analysis (PLS-DA), allowing a good discrimination when the adulteration with Sudan I was higher than 0.5%.

A Science and Risk-Based Pragmatic Methodology for Blend and Content Uniformity Assessment.

This paper describes a pragmatic approach that can be applied in assessing powder blend and unit dosage uniformity of solid dose products at Process Design, Process Performance Qualification, and Continued/Ongoing Process Verification stages of the Process Validation lifecycle. The statistically based sampling, testing, and assessment plan was developed due to the withdrawal of the FDA draft guidance for industry "Powder Blends and Finished Dosage Units-Stratified In-Process Dosage Unit Sampling and Assessment." This paper compares the proposed Grouped Area Variance Estimate (GAVE) method with an alternate approach outlining the practicality and statistical rationalization using traditional sampling and analytical methods. The approach is designed to fit solid dose processes assuring high statistical confidence in both powder blend uniformity and dosage unit uniformity during all three stages of the lifecycle complying with ASTM standards as recommended by the US FDA.

Chemical Composition and Antioxidant Properties of Powders Obtained from Different Plum Juice Formulations.

Among popular crops, plum (Prunus domestica L.) has received special attention due to its health-promoting properties. The seasonality of this fruit makes it impossible to consume it throughout the year, so new products in a powder form may offer an alternative to fresh consumption and may be used as high-quality natural food ingredients. A 100% plum (cultivar "Valor") juice was mixed with three different concentrations of maltodextrin or subjected to sugars removal by amberlite-XAD column, and dried using the freeze, spray, and vacuum (40, 60, and 80 °C) drying techniques. The identification and quantification of phenolic acids, flavonols, and anthocyanins in plum powders was performed by LC-MS QTof and UPLC-PDA, respectively. l-ascorbic acid, hydroxymethylfurfural, and antioxidant capacity were measured by the Trolox equivalent antioxidant capacity (TEAC) ABTS and ferric reducing antioxidant potential (FRAP) methods in order to compare the influence of the drying methods on product quality. The results indicated that the profile of polyphenolic compounds in the plum juice powders significantly differed from the whole plum powders. The drying of a sugar free plum extract resulted in higher content of polyphenolic compounds, l-ascorbic acid and antioxidant capacity, but lower content of hydroxymethylfurfural, regardless of drying method applied. Thus, the formulation of plum juice before drying and the drying method should be carefully selected in order to obtain high-quality powders.

[Physical fingerprint for quality control of traditional Chinese medicine extract powders].

The physical properties of both raw materials and excipients are closely correlated with the quality of traditional Chinese medicine preparations in oral solid dosage forms. In this paper, based on the concept of the chemical fingerprint for quality control of traditional Chinese medicine products, the method of physical fingerprint for quality evaluation of traditional Chinese medicine extract powders was proposed. This novel physical fingerprint was built by the radar map, and consisted of five primary indexes (i.e. stackablity, homogeneity, flowability, compressibility and stability) and 12 secondary indexes (i.e. bulk density, tap density, particle size<50 µm percentage, relative homogeneity index, hausner ratio, angle of repose, powder flow time, inter-particle porosity, Carr index, cohesion index, loss on drying, hygroscopicity). Panax notoginseng saponins (PNS) extract was taken for an example. This paper introduced the application of physical fingerprint in the evaluation of source-to-source and batch-to-batch quality consistence of PNS extract powders. Moreover, the physical fingerprint of PNS was built by calculating the index of parameters, the index of parametric profile and the index of good compressibility, in order to successfully predict the compressibility of the PNS extract powder and relevant formulations containing PNS extract powder and conventional pharmaceutical excipients. The results demonstrated that the proposed method could not only provide new insights into the development and process control of traditional Chinese medicine solid dosage forms.

Real time monitoring of powder blend bulk density for coupled feed-forward/feed-back control of a continuous direct compaction tablet manufacturing process.

The pharmaceutical industry is strictly regulated, where precise and accurate control of the end product quality is necessary to ensure the effectiveness of the drug products. For such control, the process and raw materials variability ideally need to be fed-forward in real time into an automatic control system so that a proactive action can be taken before it can affect the end product quality. Variations in raw material properties (e.g., particle size), feeder hopper level, amount of lubrication, milling and blending action, applied shear in different processing stages can affect the blend density significantly and thereby tablet weight, hardness and dissolution. Therefore, real time monitoring of powder bulk density variability and its incorporation into the automatic control system so that its effect can be mitigated proactively and efficiently is highly desired. However, real time monitoring of powder bulk density is still a challenging task because of different level of complexities. In this work, powder bulk density which has a significant effect on the critical quality attributes (CQA's) has been monitored in real time in a pilot-plant facility, using a NIR sensor. The sensitivity of the powder bulk density on critical process parameters (CPP's) and CQA's has been analyzed and thereby feed-forward controller has been designed. The measured signal can be used for feed-forward control so that the corrective actions on the density variations can be taken before they can influence the product quality. The coupled feed-forward/feed-back control system demonstrates improved control performance and improvements in the final product quality in the presence of process and raw material variations.

Formulation Design of Dry Powders for Inhalation.

Drugs for inhalation are no longer exclusively highly crystalline small molecules. They may also be amorphous small molecules, peptides, antibodies, and myriad types of engineered proteins. The evolution of respiratory therapeutics has created a need for flexible formulation technologies to engineer respirable particles. These technologies have enabled medicinal chemists to focus on molecular design without concern regarding compatibility of physicochemical properties with traditional, blend-based technologies. Therapeutics with diverse physicochemical properties can now be formulated as stable and respirable dry powders. Particle engineering technologies have also driven the deployment of new excipients, giving formulators greater control over particle and powder properties. This plays a key role in enabling efficient delivery of drugs to the lungs. Engineered powder and device combinations enable aerosols that largely bypass the mouth and throat, minimizing the inherent variability among patients that arises from differences in oropharyngeal and airway anatomies and in breathing profiles. This review explores how advances among molecules, particles, and powders have transformed inhaled drug product development. Ultimately, this scientific progress will benefit patients, enabling new classes of therapeutics to be formulated as dry powder aerosols with improved efficacy, reduced variability and side effects, and improved patient adherence.

Preparation of High-Grade Powders from Tomato Paste Using a Vacuum Foam Drying Method.

We present a rapid and gentle drying method for the production of high-grade tomato powders from double concentrated tomato paste, comparing results with powders obtained by foam mat air drying and freeze dried powders. The principle of this method consists of drying tomato paste in foamed state at low temperatures in vacuum. The formulations were dried at temperatures of 50, 60, and 70 °C and vacuum of 200 mbar. Foam stability was affected by low serum viscosity and the presence of solid particles in tomato paste. Consequently, serum viscosity was increased by maltodextrin addition, yielding optimum stability at tomato paste:maltodextrin ratio of 2.4:1 (w/w) in dry matter. Material foamability was improved by addition of 0.5% (w/w, fresh weight) egg white. Because of solid particles in tomato paste, foam air filling had to be limited to critical air volume fraction of Φ = 0.7. The paste was first pre-foamed to Φ = 0.2 and subsequently expanded in vacuo. After drying to a moisture content of 5.6% to 7.5% wet base (w.b.), the materials obtained were in glassy state. Qualities of the resulting powders were compared with those produced by freeze and air drying. Total color changes were the least after vacuum drying, whereas air drying resulted in noticeable color changes. Vacuum foam drying at 50 °C led to insignificant carotenoid losses, being equivalent to the time-consuming freeze drying method. In contrast, air drying caused lycopene and ß-carotene losses of 18% to 33% and 14% to 19% respectively. Thus, vacuum foam drying enables production of high-grade tomato powders being qualitatively similar to powders obtained by freeze drying.

Validation of a stability-indicating RP-LC method for the determination of tigecycline in lyophilized powder.

A reversed-phase liquid chromatography (RP-LC) method was validated for the determination of tigecycline in lyophilized powder. The LC method was conducted on a Luna C18 column (250 × 4.6 mm i.d.), maintained at room temperature. The mobile phase consisted of buffer containing sodium phosphate monobasic (0.015M) and oxalic acid (0.015M) (pH 7.0)-acetonitrile (75:25, v/v), run at a flow rate of 1.0 mL/min and using ultraviolet detection at 280 nm. The chromatographic separation was obtained with a retention time of 8.6 min, and was linear in the range of 40-100 µg/mL (r(2) = 0.9997). The specificity and stability-indicating capability of the method was proven through forced degradation studies, which also showed no interference of the excipients. The accuracy was 99.01% with a bias lower than 1.81%. The limits of detection and quantitation were 1.67 and 5.05 µg/mL, respectively. Moreover, method validation demonstrated satisfactory results for precision and robustness. The proposed method was applied for the analysis of the lyophilized powder formulation, contributing to improve the quality control and to assure the therapeutic efficacy.

Blend uniformity analysis of pharmaceutical products by Broadband Acoustic Resonance Dissolution Spectroscopy (BARDS).

Blend uniformity analysis (BUA) is a routine and highly regulated aspect of pharmaceutical production. In most instances, it involves quantitative determination of individual components of a blend in order to ascertain the mixture ratio. This approach often entails the use of costly and sophisticated instrumentation and complex statistical methods. In this study, a new and simple qualitative blend confirmatory test is introduced based on a well known acoustic phenomenon. Several over the counter (OTC) product powder blends are analysed and it is shown that each product has a unique and highly reproducible acoustic signature. The acoustic frequency responses generated during the dissolution of the product are measured and recorded in real time. It is shown that intra-batch and inter-batch variation for each product is either insignificant or non-existent when measured in triplicate. This study demonstrates that Broadband Acoustic Resonance Dissolution Spectroscopy or BARDS can be used successfully to determine inter-batch variability, stability and uniformity of powder blends. This is just one application of a wide range of BARDS applications which are more cost effective and time efficient than current methods.

[Evaluation methods for quality volatility about yiqi fumai freeze-dried powder used for injection based on bio-thermodynamics exosyndrome].

Yiqi Fumai freeze-dried powder for injection was used as a model drug to establish an evaluation method mainly based on bio-thermodynamics profile detection. Fischer function was used to analyze the chemical and biological data In general, chemical chromatogram can distinguish the expired sample and thermal spectrum of biological activity can distinguish special samples exactly. Thus, we established the evaluation method regarding the quality volatility of Yiqi Fumai freeze-dried powder for injection. The method can be used as a useful supplement in quality control as, and it could provide some technical information for quality control of other varieties of traditional Chinese medicine for injection.

Does electrostatic charge affect powder aerosolisation?

To study if electrostatic charge initially present in mannitol powder plays a role in the generation of aerosols, mannitol was unipolarly charged to varying magnitudes by tumbling the powder inside containers of different materials. The resulting charge in the powder was consistent with predictions from the triboelectric charging theories, based on the work function values from literature and electron transfer tendencies from measurement of contact angle. The latter generated a parameter, gamma(-)/gamma+, which is a measure of the electron-donating capacity relative to the electron-accepting tendency of material. Lowering the work function value or increasing the gamma(-)/gamma+ ratio of the container material resulted in mannitol being more negatively charged, and vice versa. After charging, the powder was dispersed from an Aerolizer(R), at 30 and 60 L/min, to study the aerosol performance. Irrespective of the charge level, the powder showed similar fine particle fraction, emitted dose and device retention at a given flow rate, indicating that charge induced by different containers during tumbling does not play a significant role in mannitol powder aerosolisation.

Evaluation of supercritical fluid engineered budesonide powder for respiratory delivery using nebulisers.

OBJECTIVES: Currently, suspensions prepared from micronised drug substances are the only delivery system marketed for nebulisation of steroids, and reported inconsistent or low bioavailability arising from their use provides a rationale for researching alternative formulations. Supercritical fluid processing of drug substances to obtain respirable-sized particles has been used over the last decade to formulate dry powder inhalers. We aimed thus to process budesonide powder to improve its deposition characteristics. METHODS: In an attempt to overcome the limitations of nebuliser suspensions when prepared from micronised drug particles, budesonide powder was processed using a supercritical fluid based process and suspended using Tween 80 as a surfactant to provide an aqueous nebuliser formulation. The in-vitro characteristics of the emitted dose on nebulisation for the prepared suspension were then compared to a commercially available suspension formulation of budesonide using a jet and a vibrating mesh nebuliser. KEY FINDINGS: The results showed a significant improvement of the in-vitro deposition properties of the suspension containing supercritical fluid engineered budesonide particles. CONCLUSIONS: The results indicated the benefit of such materials compared with traditionally micronised drug powders.

Quality-by-design (QbD): an integrated multivariate approach for the component quantification in powder blends.

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.

Development of a high drug load tablet formulation based on assessment of powder manufacturability: moving towards quality by design.

The development of a robust tablet formulation for a high dose active pharmaceutical ingredient (API) by the trial-and-error approach is challenging. To meet the growing needs of bringing drugs to market faster and with reduced costs, more targeted and efficient development practices are in demand. Here we show detailed understanding of mechanical properties of API and excipients are essential in achieving efficient development of a high API loading formulation. The loading of the experimental drug, AMG458, was 50 wt% plus accompanying 1:1 molar ratio organic acid of approximately 19%. We assessed manufacturability of powders based on their flow and compaction properties using a shear cell and a compaction simulator, respectively. We selected granulation process on the basis of poor flow properties of API and its blends with common direct compaction excipients. During the course of formulation development, we could quickly identify manufacturability deficiencies in the lead formulation. With detailed knowledge of the mechanical properties of excipients and formulated powders, we improved the lead formulation by overcoming manufacturability deficiencies using predictive and material sparing (<10 g) approaches. Larger batches were subsequently manufactured to confirm predictions.

Development and optimization of solid dispersion containing pellets of itraconazole prepared by high shear pelletization.

This study investigated the solid dispersion containing pellets of itraconazole for enhanced drug dissolution rate. The influence of process parameters used during high shear pelletization on the pellet properties including pellet size and dissolution rate was also studied. Solid dispersions of itraconazole were prepared with Eudragit E100, a hydrophilic polymer, by a simple fusion method followed by powdered and characterized by differential scanning calorimetry and X-ray powder diffraction. Solid dispersions containing pellets were consequently prepared using a lab-scale high shear mixer. In order to improve the product quality, a central composite design was applied to optimize the critical process variables, such as impeller speed and kneading time, and the results were modeled statistically. Itraconazole was presented as an amorphous state in the solid dispersion prepared at a drug to polymer ratio of 1:2. Both studied parameters had great effect on the responses. Powdered solid dispersion and pellets prepared using the optimal parameter settings showed approximately 30- and 70-fold increases in dissolution rate over the pure drug, respectively. Solid dispersion prepared by simple fusion method could be an option for itraconazole solubility enhancement. Pelletization process in high shear mixer can be optimized effectively by central composite design.