Grade Lactose Research Articles

Understanding Powder Behavior in Continuous Feeding: Powder Densification and Screw Layering

Background: Precise continuous feeding of active pharmaceutical ingredients (APIs) and excipients is crucial in a continuous powder-to-tablet manufacturing setup, as any inconsistency can affect the final tablet quality. Method: This study investigated the impact of various materials on the performance of a continuous twin-screw loss-in-weight (LIW) feeder. The materials tested included spray-dried lactose, anhydrous lactose, granulated lactose, microcrystalline cellulose (MCC), an MCC–lactose preblend (50%:50% w/w ratio), and a co-processed excipient (lactose–lactitol at a 95%:5% w/w ratio). The feeding performance of these excipients was systematically assessed, focusing on powder densification and screw layering within the LIW feeder. Results: The results demonstrated densification for the spray-dried lactose and preblend. Densification was more pronounced during the initial feeding cycles for spray-dried lactose, but decreased gradually over time. In contrast, the densification remained relatively constant throughout the feeding process for the preblend. Notably, minor screw layering was observed for both spray-dried lactose and anhydrous lactose, with the extent of this issue reducing over time for the spray-dried lactose. Interestingly, granulated lactose grades did not show screw layering, making them preferable for blending with APIs prone to severe screw layering. The LIW feeder control system successfully managed powder densification and minor screw layering, maintaining the mass flow rate at the set point for all investigated materials. Conclusions: These findings inform the selection of optimal excipients, appropriate tooling for LIW feeders, and the enhancement of control strategies to shorten startup times. By addressing these factors, the precision and reliability of continuous feeding processes can be improved.

Evaluating the impact of stirrer design on powder behaviour in capsule filling using dyed lactose as tracer

Ensuring temporal and spatial uniformity in the chamber of a capsule filling machine with vacuum drum is crucial for consistent dosing to in-row capsules. A stirrer must induce axial mixing to maintain a homogeneous powder bed and prevent accumulation in specific regions, primarily caused by the feeding system above the chamber. To achieve satisfactory filling, the performance of different stirrers was analysed using a tracer particle strategy. This contribution introduces a lactose dyeing process, preventing agglomerate formation and yielding minimal differences in powder properties. Four lactose grades, exhibiting diverse particle sizes and flow behaviours, were dyed with methylene blue. A comprehensive analysis of lactose properties, such as particle size, density, and flow behaviour, confirms minimal alterations post-dyeing. Tracers obtained through this process reveal that a spike-type stirrer induces more axial mixing compared to a wire-type stirrer. The dyed lactose tracers effectively contribute to understanding and optimising the capsule filling process.

Lubricant Sensitivity of Direct Compression Grades of Lactose in Continuous and Batch Tableting Process.

Modern pharmaceutical manufacturing based on Quality by Design and digitalisation is revolutionising the pharmaceutical industry. Continuous processes are promoted as they increase efficiency and improve quality control. Compared to batch blending, continuous blending is easier to scale and provides advantages for achieving blend homogeneity. One potential challenge of continuous blending is the risk of over-lubrication. In this study, blending homogeneity and lubricant sensitivity are investigated for both batch and continuous processes. Given their distinct chemical structures and morphologies, anhydrous lactose and granulated lactose are expected to exhibit varying sensitivities to changes in process settings across both technologies. The findings suggest that both lactose grades provide highly stable blends that can be safely utilised in both batch and continuous modes. Optimisation should focus on process variables, such as the quality of loss-in-weight feeders used for dosing low doses of ingredients. The most significant process parameter for lubricant sensitivity was the type of lactose used. Anhydrous lactose produced harder tablets than the more porous granulated lactose but was more sensitive to lubrication at the same settings. The magnesium stearate content and its interaction with the type of lactose are also critical factors, with magnesium stearate having a counterproductive impact on tabletability.

Impact of material properties and process parameters on tablet quality in a continuous direct compression line

The current paper shows how excipient properties impact the process parameters and the final tablet properties in a fully integrated continuous direct compression line. Blend properties of low-dose (1% w/w) and high-dose (40% w/w) paracetamol formulations were evaluated and linked to the blending and tableting performance via multivariate models (Partial Least Squares analysis, PLS). Feeding behavior was analyzed separately, as the amount of active pharmaceutical ingredient (API) that ended into tablets was driven by random fluctuations in the API feeding behavior. The developed PLS models elucidated that formulation behavior was mainly driven by the concentration of the active pharmaceutical ingredient (API), explained by the distinct API properties. Excipient properties also had a substantial impact on formulation behavior. Generally, formulations with microcrystalline cellulose as a filler showed better compactability, lower hold-up mass, lower flowability and higher cohesion than formulations with different lactose grades. The relative performance of a formulation with different fillers differed for 1% w/w and 40% w/w drug loading. Granular and spray dried lactose grades increased in compactability ranking compared to anhydrous lactose when evaluating higher drug loading, due to the difference in morphology. It was shown that besides understanding the impact of excipients on the formulation performance, processability of ingredients is crucial for formulation design.

“Novel mucoadhesive PLGA-PVM/MA micro-nanocomposites loaded with felodipine intended for pulmonary administration by nebulization”

Poly(latic-co-glycolic) acid (PLGA) nanoparticles loaded with felodipine (FEL) were embedded in a mucoadhesive matrix of poly (methyl vinyl ether-co-maleic anhydride) (PVM/MA) to prepare micro-nanoparticulate composites by particle engineering. Composites were characterized for physical and rheological properties and formulated with inhalable grade lactose. In-vitro characterization studies such as drug release kinetics, and mucoadhesive, and aerodynamic properties were performed. The in-vivo efficacy was evaluated by administering the optimized composites by nebulization in hypertensive rats. The obtained FEL-PLGA-PVM/MA composites of 1,069 ± 82 nm showed sustained drug release and mucoadhesive properties. Bulk and tapped densities of composites mixed with lactose were 0.08–0.13 g/mL and 0.18–0.30 g/mL, respectively, with mass median aerodynamic diameters (MMAD) in a range of 1.29–12.0 µm. After pulmonary administration of the composites, a decrease in systolic and diastolic blood pressure was observed within the first 3 h, of −9.0 ± 1.3 % and −13.9 ± 3.3 %, respectively, with a maximal effect at 12 h (sustained during 144 h), in contrast to pure FEL, which showed no significant decrease in blood pressure (1.6 ± 2.7 % and 4.1 ± 4.1 %). Findings suggest that novel mucoadhesive FEL-PLGA-PVM/MA composites are a promising strategy formulation to treat systemic diseases by pulmonary route.

Spherical Agglomerates of Lactose Reduce Segregation in Powder Blends and Improve Uniformity of Tablet Content at High Drug Loads.

We report here on improved uniformity of blends of micronised active pharmaceutical ingredients (APIs) using addition of spherical agglomerates of lactose and enhanced blend flow to improve tablet content uniformity with higher API loads. Micromeritic properties and intra-particle porosity (using nano-computed X-ray tomography) of recently introduced spherical agglomerates of lactose and two standard lactose grades for the direct compression processes were compared. Powder blends of the individual lactose types and different micronised API drug loads were prepared and subjected to specific conditions that can induce API segregation. Tablet content uniformity during direct compression was related to the lactose material attributes. The distinctive micromeritic properties of the lactose types showed that spherical agglomerates of lactose had high intra-particle porosity and increased specific surface area. The stability of binary blends after intense sieving was governed by the intra-particle porosity and surface roughness of the lactose particles, which determined the retention of the model substance. Greater intra-particle porosity, powder specific surface area, and particle size of the spherical agglomerates provided greater adhesion of micronised particles, compared to granulated and spray-dried lactose. Thus the spherical agglomerates provided enhanced final blend flow and uniformity of tablet content at higher drug loads.

Non-dispersive impact technology for powder flow characterization

This study developed a tester where the powder flow was characterized using a low sample mass (2 g) and impact instead of dispersion mechanism to mitigate test space constraint. An impact chamber was established where the test powder bed of seven lactose grades was weight-impacted to produce impact crater and ejecta, and imaged quantitatively to determine crater profiling signature (crater depth), regional topography (ejecta roughness), Otsu threshold (bed continuity) and edge segmentation (bed deformation). The Hausner ratio (HR) and Carr’s index (CI) values of lactose, and their powder dispersion distance and surface area characteristics evaluated by gas-pressurized dispersibility test were examined as reference method. The crater signature profiling and regional topography were correlated to HR, CI, dispersive distance and surface area. A poorer powder flow was characterized by higher values of crater signature profiling, regional topography, HR, CI, and lower dispersive distance and surface area. The crater signature profiling and regional topography values were higher with smaller and rougher lactose particles that were cohesive. The powder impact flow is a viable non-dispersive approach to characterize powder flowability using a small sample mass and test space.

A triple combination 'nano'dry powder inhaler for tuberculosis: in vitro and in vivo pulmonary characterization.

Inhalation route of drug delivery is the most favorable for pulmonary infections wherein direct drug delivery is desired to the lungs. Tuberculosis is one such infection suffering from poor therapeutic efficacy because of low patient compliance due to high drug dosing and lengthy treatment protocols. The current research work was undertaken to develop a dry powder inhaler (DPI) for administration of three first-line antitubercular antibiotics directly to the lungs to improve the treatment rates. Nanoformulations of isoniazid, pyrazinamide, and rifampicin were prepared, spray-dried to obtain a dry powder system, and blended with inhalation grade lactose to develop the DPI. The DPI was evaluated for its flow properties, pulmonary deposition, dissolution profile, and stability. The DPI possessed excellent flow properties with a fine particle fraction of 45% and a mass median aerodynamic diameter of approximately 5µm indicating satisfactory lung deposition. In vitro drug release exhibited a sustained release of the formulations. In vivo studies showed a prolonged deposition in the lung at elevated concentrations compared to oral therapy. Stability studies proved that the formulation remainedstable at accelerated and long-term stability conditions. The DPI could complement the existing oral therapy in enhancing the therapeutic efficacy in patients.

Site-specific delivery of inhalable antiangiogenic liposomal dry powder inhaler technology ameliorates experimental pulmonary hypertension

Pulmonary Hypertension (PH) is the progressive increase in mean pulmonary arterial pressure (≥ 20 mmHg at rest). Current treatment modalities involve the drugs targeting at nitric oxide pathway, prostaglandin receptors, thromboxane receptors, endothelin receptors, and phosphodiesterase inhibitors, which provide the symptomatic relief. Despite these treatments, the mortality amongst the PH patients remains high due to non-reversal of the condition. Hence, there is a need for disease targeting drug therapy along with the reversal of pathomechanism of the PH. In our previous work, we have reported anti-angiogenic Erlotinib liposomal formulation by using QbD approach and its efficacy in zebrafish tail fin regeneration assay. In this study, this liposomal formulation is successfully converted into a dry powder for inhalation (DPI) using inhalable grade lactose. This DPI formulation was then evaluated for its pharmacodynamic efficacy using an in-vivo hypoxia model of PH. Right ventricular pressure measurement via jugular vein catheterization, ventricular hypertrophy, and pulmonary arterial remodeling are the parameters evaluated for the efficacy. The Erlotinib liposomal DPI formulation reduces the ventricular pressure and significantly reversed the pathological mechanism in PH as evidenced by the histological analysis of ventricular hypertrophy and pulmonary arteries.

Spherical agglomerates of lactose as potential carriers for inhalation

We report here on spherical lactose agglomerates as potential carriers for inhalation applications. Micromeritic properties of three spherical lactose agglomerates (SA-A, SA-B, SA-C) and a standard lactose inhalation grade carrier (Lactohale 100; LH100) were evaluated and compared. Ordered mixtures with micronized salbutamol sulfate as the model active pharmaceutical ingredient (API) and lactose carriers at two drug loadings (2 wt%, 5 wt%) were prepared, and in-vitro aerosolization performance was assessed. The spherical crystallization process led to particles with tailored micromeritic properties. These had larger specific surface area and greater fine fraction < 10 µm, compared to LH100, due to their coarse morphology. Their properties were reflected in the flowability parameters, where two types of spherical agglomerates of lactose showed more cohesive behavior compared to the other lactose grades. Blend uniformity showed improved homogeneous distribution of the API at higher drug load. In-vitro aerosolization tests showed that the spherical agglomerates of lactose enhanced the dose of API, compared to LH100. SA-B and SA-C showed significantly higher fine particle fractions at low drug load compared to the others, whereas overall, the largest fine particle fraction was for SA-B at high drug load. The carrier material attributes related to particle size, specific surface area, compressibility, flowability (cohesion, flow function), and air permeability were critical for aerosolization performance.

Performance Evaluation of a High-Precision Low-Dose Powder Feeder

Highly potent active pharmaceutical ingredients (APIs) and low-dose excipients, or excipients with very low density, are notoriously hard to feed with currently available commercial technology. The micro-feeder system presented in this work is capable of feeding low-dose rates of powders with different particle sizes and flow properties. Two different grades of lactose, di-calcium phosphate, croscarmellose sodium, silicon dioxide, a spray-dried intermediate, and an active ingredient were studied to vary material properties to test performance of the system. The current micro-feeder system is a volumetric feeder combined with a weighing balance at the outlet that measures feeder output rates. Feeding results are shown as a so-called “displacement-feed factor” curve for each material. Since the powder mass and volume are known in the micro-feeder system, in this work, we characterized an observed density variation during processing via a “displacement-feed factor” profile for each of the fed powders. This curve can be later used for calibrating the system to ensure an accurate, constant feed rate and in addition predicting feeding performance for that material at any feed rate. There is a relation between powder properties and feeding performance. Powders with finer particles and higher compressibility show densification during their feeding process. However, powders with larger particles and lower compressibility show both “densification” and “powder bed expansion,” which is the manifestation of dilation and elastic recovery of particles during the micro-feeding process. Through the application of the displacement-feed factor, it is possible to provide precise feeding accuracy of low-dose materials.Graphical abstract

3D projection and multivariate image analysis for quantitative visual modelling of mixability and rheological behavior of lactose powder

BackgroundThis study reports the use of multivariate time and image analysis of avalanche videographic data for quantitative visual modelling of mixability. Its usefulness, in mechanistically modelling a powder’s rheological behavior in relation to mixing, was evaluated. MethodsParticle size distribution (PSD) of a pharmaceutical grade lactose powder was modified to reflect commercially encountered variability. The PSD variants were rheologically distinct and had different mixability. Avalanche testing was performed on the modified lactose powders. Avalanche rheological properties (ARP) profiles and videos were collected for numerical and quantitative visual modelling, respectively. In quantitative visual modelling, videos captured were transformed into serial projected images. Important features of the projected images were extracted as eigen-images, to derive the avalanche rheological visual metric (ARVM). Mixability was modelled as a function of ARP or ARVM and the rotation speed. ResultsRelative to the ARP model, the ARVM models were highly interpretable. As a univariate expression of ARP, ARVM also possessed construct validity (r2 greater than 0.99, slope ≥ 0.96). Important rheological features of the lactose powders were holistically visualized within a single eigen-image which enabled the generation of simpler models (5 versus 34 variables for ARP model). The ARVM models predicted mixability of lactose powders with greater accuracy than the ARP model (relative root mean square error of external validation ≤ 3.30% versus 4.96%). ConclusionsQuantitative visual modelling is a viable alternative to purely numerical approaches. Most significantly, the model’s interpretability and concreteness enable manufacturers to readily understand the risk posed by PSD variability on manufacturing processes and swiftly take pre-emptive actions, without being mired in multivariate data complexity. In addition, the use of quantitative visual approach in time series imaging, for studying and monitoring industrial processes, could also be explored.

A shear cell study on oral and inhalation grade lactose powders

Shear cell tests have been conducted on twenty different lactose powders, most of which commercially available for oral or inhalation purposes, spanning a wide range of particle sizes, particle morphologies, production processes. The aims of the investigation were: i) to verify the reliability of the technique in evaluating and classifying the flowability of powders; ii) to understand the connection between the flowability of a powder and the morphological properties of its particles; iii) to find a general mathematical relationship able to predict the yield locus shape given the particle size, shape and consolidation state of a lactose powder. These aspects and their limitations are detailed in the manuscript together with other interesting findings on the stick-slip behavior observed in most of the lactose powders examined.

The effect of rotation speed and particle size distribution variability on mixability: An avalanche rheological and multivariate image analytical approach.

The utility of modulating rotation speed in tumble mixing and its mechanistic interplay with particle size distribution (PSD) variability in excipients remain underexplored. They were investigated in this study. For the present purpose, PSD of a commercial grade lactose was modified to reflect commercially relevant variations; and mixed with microcrystalline cellulose and chlorpheniramine in a double-cone blender, at various rotation speeds. Model of mixing was constructed using avalanche rheological properties and was also rendered as quantifiable visual models using avalanche rheological visual metric (ARVM), to uncover mechanistic relationships. ARVM was derived through multivariate image analysis of avalanche flow. It was observed that increasing rotation speed reduced the number of rotations needed to achieve blend homogeneity by 30-33% for PSD variants with 16-20% fines, while increasing the number of rotations by 134% in PSD variants with less than 15% fines (p≈0.00). ARVM successfully modelled (root mean square error of external validation=2.46%) and revealed the mechanistic interplay. With increased proportion of fines, lactose exhibited quasi-parabolic motion with disaggregation of soft agglomerates and improved mixing. With decreased proportion of fines, lactose flowed as coherent wave-like masses with imperceptible dispersive tendency and increased dilation, which impeded mixing. In conclusion, this study contributes to process understanding and ideas for designing robust mixing operations. It showcases the usefulness of a quantitative visual approach, exemplified by the ARVM, to evaluate material variability and uncover its mechanistic impact on processing.

Influence of modified induction port, modified DUSA assembly and device air-inlet geometry on the aerosolization pattern of a dry powder inhaler

The objective of the present investigation was to study the effect of inhaler air-inlet size, induction port (IP) geometry and modified dose unit sampling apparatus (DUSA) on the aerodynamic behavior of fluticasone propionate (FP) dry powder inhaler (DPI). The physicochemical properties of FP and inhalation grade lactose particles, such as particle size distribution, moisture content and surface morphology were assessed while developed FP DPI was assessed using energy-dispersive X-ray spectrometry. Afterward, the aerodynamic outcome of the FP DPI was evaluated by using Andersen cascade impactor (ACI) equipped with USP modified IP and inhaler devices with different air-inlet size. Likewise, modified DUSA assembly was used to assess the delivered dose uniformity (DDU) of FP DPI. Micronized irregular shaped FP (d90; 3.30) particles and lactose carriers (d90; 130.84) showed particle size suitable for inhalation. Furthermore, formulated FP FPI achieved good content uniformity (>97%). ACI analysis exhibited a remarkable difference in the stage-wise drug deposition pattern. In terms of FPF, Lupihaler® (uniform air-inlet) displayed 1.12-fold superior performance as compared to Lupihaler-T® (t-shaped air-inlet) device. Moreover, modified DUSA assembly exhibited consistent and reproducible delivered dose using both devices. This research work is a first thorough report of FP DPI using a USP-modified IP inhaler with devices signify the opposite ends of air inlet size. Hence, it can be of budding significance for both institutional and industrial research.

Powder dispersibility characterization using gas-pressurized dispersive technology: Interplay effects of powder mass and powder dispersibility tester contact surfaces

This study re-invented gas-pressurized powder dispersibility tester (9 g) to accommodate a lower test sample mass (2 g). Powder contact surfaces with smooth, diffuse and dense asperities were designed as rough surface was foreseen to result in cohesive powder exhibiting poorer dispersibility thereby allowing differentiation from free flowing powder. The powder dispersibility characteristics of seven lactose grades were examined against Hausner ratio (HR) and Carr’s index (CI) as standard reference values. Using smooth-surface variant, the powder dispersive distance and in particularly surface area were correlatable to HR/CI to a greater extent with 2 g than 9 g load. With dense asperities surface, insignificant correlations were found between surface area of powder dispersion with HR/CI as a result of powder shearing against the asperities into less aggregative particles which were not reflective of those in HR/CI tests. Smooth powder contact surface is preferred in characterization of low mass powder dispersibility.

Continuous twin screw granulation: Impact of the starting material properties and various process parameters

The purpose of this study is to confirm the correlation between the formulation factors and the process parameters using multivariate analysis (MVA) during twin screw granulation. Various grades of lactose and MCC were used as starting materials and the characteristics of final granules were investigated by varying the L/S ratio and feed rate. The size distribution, friability, and various flow properties of granules using powder rheometer were evaluated. When the effect of formulation factors and process parameters were investigated, it was confirmed that the characteristics of granules change largely according to L/S ratio. MVA also showed that the influence of formulation factors on characteristics of granules was significant as L/S ratio. The feed rate had few effects on the characteristics of the granules. MVA is a useful tool to confirm the correlations of various factors. The properties of the starting materials are important in the continuous twin screw granulation process.

Near infrared spectroscopy for rapid and in-line detection of particle size distribution variability in lactose during mixing

Particle size distribution (PSD) variability in excipients may cause unacceptable prolongation of mixing time needed to achieve blend homogeneity. Therefore, it is vital to modulate mixing through real-time monitoring of PSD variability. Notwithstanding the criticality of PSD variability, real-time measurement of PSD during mixing is relatively unexplored; and this is the focus of the present study. The model excipient was commercial grade lactose with modified PSD that conformed to the manufacturer’s specifications. It was mixed with microcrystalline cellulose and chlorpheniramine in a double-cone blender. High and low dose blends were prepared and near infrared spectroscopy (NIRS) was used to collect spectral data, during mixing, for chemometric modelling of PSD. Four modelling approaches based on partial least squares regression (PLSR) were applied. The models were highly interpretable and rapidly measured PSD near the beginning of mixing (5th to 6th rotation), with accuracy (relative standard error of prediction <5.0%, r2 ≈ 1.00, slope ≈ 1.00). Therefore, NIR chemometric modelling is a viable strategy to detect variability in PSD of excipients during blending and could enable real-time control of mixing. Most significantly, this strategy is potentially transferable to the monitoring and controlling of batch and continuous processes, where PSD is either a source of process variability or a critical quality attribute.

Tableting performance of various mannitol and lactose grades assessed by compaction simulation and chemometrical analysis

Mannitol and lactose are commonly used fillers in pharmaceutical tablets, available in several commercial grades that are produced using different manufacturing processes. These grades significantly differ in particulate and powder properties that impact tablet manufacturability. Choice of sub-optimum type or grade of excipient in tablet formulation can lead to manufacturing problems and difficulties, which are magnified during a continuous manufacturing process. Previous characterization of tableting performance of these materials was limited in scope and under conditions not always realistic to the commercial production of tablets. This work seeks to comprehensively characterize the compaction properties of 11 mannitol and 5 lactose grades using a compaction simulator at both slow and fast tableting speeds. These include tabletability, compressibility, tablet brittleness, die-wall stress transmission, and strain rate sensitivity. A chemometrical analysis of data, using the partial least square technique, was performed to construct a model to provide accurate prediction of tablet tensile strength for mannitol grades. Such knowledge facilitates the selection of suitable tablet filler to attain high quality tablet products.

Predicting the Angle of Internal Friction from Simple Dynamic Consolidation Using Lactose Grades as Model

Powder flow and packing behavior are among other factors determined by particle friction, which is traditionally measured in shear cells as the angle of internal friction (AIF). Considering that an AIF at a normal stress should be comparable to friction during tapping consolidation, this work aims at whether dynamic consolidation under gravity can be used to estimate an AIF. Powder consolidation by controlled tapping was studied for seven commercially available types of lactose. A porosity factor was determined, and values were compared with the AIF obtained from Jenike shear cell measurements. Plotting porosity factor vs. number of applied taps provided an estimated angle of internal friction (AIFE) that was obtained from the slope of a linear relationship. A significant linear correlation (r = 0.825; p = 0.0223) was evidenced between AIFE and those AIFJ estimated from linearized yield locus measurements of using the Jenike shear cell. The good linear correlation between the angle of internal friction estimated from dynamic powder consolidation and the internal friction obtained by a shear cell is of high practical relevance. The latter shear cell behavior is only occasionally studied in the pharmaceutical industry, whereas dynamic powder tapping is a standard analysis.