Application of PAT Probes in Aluminum Phosphate Adjuvant Manufacturing.

PURPOSE: This study is focused on monitoring process parameters and quality attributes of aluminum phosphate (AlPO4) using multiple in-line probes incorporated into an industrial-scale adjuvant suspension manufacturing unit. METHODS: The manufacturing of aluminum adjuvant suspension was monitored at manufacturing scale using conductivity, turbidity, infrared, and particle sizing and count probes to follow the continuous evolution of particle formation and size distribution, and the reaction kinetics during the synthesis of AlPO4. RESULTS: The data showed that AlPO4 forms large particles at the early stages of mixing, followed by a decrease in size and then stabilization towards the later stages of mixing and pH adjustment. The results provided a complementary view of process events and assisted in optimizing several parameters, e.g., flow rate of reactants AlCl3 and Na3PO4 solutions, mixing rate, pH, and conductivity of AlPO4, as well as adjuvant quality attribute such as particle size, thus streamlining and shortening the process development stage. CONCLUSION: The results of this study showed the usefulness of the in-line probes to automate continuous assessment of AlPO4 batch-to-batch consistency during in-house adjuvant production at the industrial scale.

Polymer type effect on PLGA-based microparticles preparation by solvent evaporation method with single emulsion system using focussed beam reflectance measurement.

AIM: This study aimed to investigate the effect of polymer type on solidification rate of PLGA polymeric microparticles and particle size/distribution of the emulsion droplets/hardened PLGA polymeric microparticles during solvent evaporation process using FBRM (Focussed Beam Reflectance Measurement). METHODS: PLGA polymeric microparticles were prepared by an O/W solvent evaporation method using various PLGA polymers, including PLGA Resomer® RG503H, RG502H and RG752H. The particle size mean, chord length distribution (CLD), and chord count of the emulsion droplets/hardened microparticles were monitored by FBRM. The morphology of polymeric microparticles were characterised by optical microscopy and scanning electron microscopy (SEM). RESULTS: The transformation of the emulsion droplets into solid microparticles occurred within the first 30 (± 1.04), 34 (± 1.15) and 37 (± 0.82) min and square weighted mean chord lengths are 64.08 (± 3.18), 52.36 (± 5.27) and 42.18 (± 4.61) µm when PLGA Resomer® RG503H, RG502H and RG752H were used respectively. Larger square weighted mean chord length of PLGA polymeric microparticles gave lower chord counts. PLGA RG752H microparticles gave smallest square weighted mean chord length and the chord counts was the highest. The CLDs measured by FBRM showed that a larger particle size mean gave longer CLD and a lower peak of particle number. SEM data revealed that the morphology of microparticles was influenced by type and physical properties of polymer. CONCLUSIONS: FBRM can be employed for online monitoring of the shift in the microparticle CLD and detect transformation of the emulsion droplets into solid microparticles during the solvent evaporation process. The microparticle CLD and transformation process were strongly influenced by polymer type.

Elucidating spray-dried dispersion dissolution mechanisms with focused beam reflectance measurement: contribution of polymer chemistry and particle properties to performance.

Amorphous spray-dried dispersions (SDDs) are a key enabling technology for oral solid dosage formulations, used to improve dissolution behaviour and clinical exposure of poorly soluble active pharmaceutical ingredients (APIs). Appropriate assessment of amorphous dissolution mechanisms is an ongoing challenge. Here we outline the novel application using focused beam reflectance measurement (FBRM) to analyse particle populations orthogonal to USP 2 dissolution. The relative impact of polymer substitution and particle attributes on 25% BMS-708163/HPMC-AS SDD dissolution was assessed. Dissolution mechanisms for SDDs were categorized into erosion versus disintegration. Beyond an initial mixing period, FBRM particle counts diminish slowly and particles are detectable until the point where API dissolution is complete. There is correlation between FBRM particle count decay rate, representing loss of SDD particles in the dissolution media, and UV dissolution rate, measuring dissolved API. For the SDD formulation examined, the degree of succinoyl substitution for HPMC-AS, SDD particle size and surface area all had an impact on dissolution. These data indicate the SDD displayed an erosion mechanism and that FBRM is capturing a rate-limiting step. From this screening tool, the mechanistic understanding and measured impact of polymer chemistry and particle properties can inform a risk-assessment and control strategy for this compound.

Online monitoring lignocellulosic particles by focus beam reflectance measurement for efficient bioprocessing.

Lignocellulose presents a promising alternative to fossil fuels. Monitoring the mass and size changes of lignocellulosic particles without disrupting the process can assist in adjusting pretreatment and enzymatic hydrolysis, where conventional sieving methods fall short. A method utilizing focused beam reflectance measurement (FBRM) was developed to establish mathematical correlations between FBRM chord information (chord length and count) and particle characteristics (weight and size) quantified through sieving. Results indicate particle size exhibits a linear correlation with the square weighted median chord length (Lsqr) with R2 at 0.93. Further, real-time bulk particle mass can be predicted using Lsqr and chord count (R2 0.98). These correlations are applicable in range 53 µm to 358.5 µm. Real-time monitoring of enzymatic hydrolysis of corn stalks has demonstrated the practical applicability of FBRM. This study introduces a novel approach for online characterization of lignocellulosic particles, thereby enhancing lignocellulosic biorefineries.

Preparation of a Lignin-Based Cationic Flocculant and Its Application in Kaolin Suspension Treatment.

The preparation of an environmentally friendly and efficient flocculant for solid-liquid separation in industrial wastewater is highly important. In this study, a novel cationic flocculant (AL-g-PAMA) was synthesized by a thermal initiation method using alkali lignin (AL) as the main chain and acrylamide (AM) and methacrylamido propyl trimethyl ammonium chloride (MAPTAC) as the grafted side chains. The structure, thermal stability, and surface morphology of the copolymers were investigated by various characterization methods. The results indicated the successful synthesis of AL-g-PAMA. AL-g-PAMA was applied to improve solid-liquid separation in kaolin suspensions. The results showed that AL-g-PAMA had excellent flocculation-sedimentation and dewatering efficiency. When the dosage of AL-g-PAMA #5 was 600.0 g/t(s), the thickness of the compressed layer was 2.2 cm, the floc settling velocity was 24.1 cm/min, and the transmittance of the supernatant was 84.0%. The moisture content of the filter cake decreased from 55.0% to 43.4% after treatment with AL-g-PAMA #5. The results of zeta potential and focused beam reflectance measurement (FBRM) analysis indicated that bridging and electroneutralization were the main flocculation mechanisms. Therefore, this study extends the potential for using lignin as a bioflocculant and provides a feasible approach to efficiently purify high-turbidity wastewater.

The Synergistic Effects of Al3+ and Chitosan on the Solid-Liquid Separation of Coal Wastewater and Their Mechanism of Action.

It is important to identify an environmentally friendly and efficient flocculant that can replace polyacrylamide for the solid-liquid separation of coal wastewater. In this study, to explore whether chitosan can be used as an environmentally friendly and efficient flocculant for the solid-liquid separation of coal wastewater, AlCl3-chitosan was used to conduct flocculation-sedimentation and dewatering tests under different chitosan dosages and shear-strength conditions for the prepared coal wastewater. Focused beam reflectance was measured to dynamically monitor the number of refractory fine particles, and the settled flocs were photographed and analyzed with microscopy to explore the effect of AlCl3-chitosan on the flocculation settlement effect and floc characteristics. The synergistic mechanisms of AlCl3 and chitosan were investigated using quartz crystal dissipative microbalance and zeta potential measurement. The results showed that the addition of chitosan can significantly improve the flocculation-sedimentation and dewatering effects of coal wastewater. A reasonable dosage under a certain shear strength is conducive to the reduction of fine slime particles, which results in a compact floc structure, increases the floc size, and improves the settling effect. The synergistic effect of AlCl3-chitosan improved the electric neutralization and adsorption bridging abilities of the chitosan, and the mixed solution of AlCl3 and chitosan had stronger adsorption on the carbon surface. This study provides a new approach to the selection of flocculants for coal wastewater treatment.

PAT solutions to monitor adsorption of Tetanus Toxoid with aluminum adjuvants.

The focus of this study was to examine the small-scale adsorption process of Tetanus Toxoid (TT) as a model protein antigen to aluminum phosphate (AlPO4) and aluminum oxyhydroxide (AlOOH) adjuvants with real-time monitoring by in-line ReactIR™, ParticleTrack™ based on Focused Beam Reflectance Measurement (FBRM) and EasyViewer™ probes. The adsorption process of AlPO4 and AlOOH with TT using was monitored in the small-scale reactors. Conformational changes in TT were monitored using in-line infrared probe ReactIR, whereas particle formation associated with protein adsorption were measured by particle size, count, and imaging tools, such as ParticleTrack with FBRM and EasyViewer probes. ParticleTrack distribution results and kinetic measurements were also supported by observations made using EasyViewer. In addition to EasyMax, BioBLU reactor was also used for the adsorption experiments. ReactIR with ATR-Fiber probe was effectively able to monitor adsorption progress of TT to AlOOH and to AlPO4. ReactIR, EasyViewer, and ParticleTrack provided detailed mechanistic and kinetic information for reaction of TT with AlPO4 and AlOOH. These in-situ measurements revealed a possible multi-step process for TT to AlPO4 which may be an indication of antigen adsorption.

Data on the application of the focused beam reflectance measurement (FBRM): A process parameters dataset for the ethyl cellulose (EC) microparticles preparation by the solvent evaporation method.

The data article refers to the paper "Effect of solvent type on preparation of ethyl cellulose microparticles by solvent evaporation method with double emulsion system using focused beam reflectance measurement" [1]. Data presented here include the effect of solvent type, method of emulsification (an oil-in-water (O/W) or a water-in-oil-in-water (W/O/W)), external aqueous phase volume, stirring speed and ethyl cellulose concentration on the preparation of ethyl cellulose microparticles. Data also refer to the effect of above mentioned factors on the solidification rate, hardening time, particle size, particle size mean, chord length distribution (CLD) and chord count of microparticles. Additionally, data exhibit process parameters when emulsion droplets transformed into solid microparticles during fabrication. The transformation of the emulsion droplets into solid microparticles occured within the first 10, 10.5, 12 and 60 minutes (O/W), and the first 12, 11.5, 10 and 90 minutes (W/O/W) when dichloromethane/methanol (1:1), dichloromethane, ethyl acetate and chloroform were used respectively. Either in O/W and W/O/W emulsion system, Chloroform gave smallest square weighted mean chord length. In contrast, its chord counts was not to be the highest.

Effect of Pre-Shear on Agglomeration and Rheological Parameters of Cement Paste.

Cementitious pastes are multiphase suspensions that are rheologically characterized by viscosity and yield stress. They tend to flocculate during rest due to attractive interparticle forces, and desagglomerate when shear is induced. The shear history, e.g., mixing energy and time, determines the apparent state of flocculation and accordingly the particle size distribution of the cement in the suspension, which itself affects suspension's plastic viscosity and yield stress. Thus, it is crucial to understand the effect of the mixing procedure of cementitious suspensions before starting rheological measurements. However, the measurement of the in-situ particle agglomeration status is difficult, due to rapidly changing particle network structuration. The focused beam reflectance measurement (FBRM) technique offers an opportunity for the in-situ investigation of the chord length distribution. This enables to detect the state of flocculation of the particles during shear. Cementitious pastes differing in their solid fraction and superplasticizer content were analyzed after various pre-shear histories, i.e., mixing times. Yield stress and viscosity were measured in a parallel-plate-rheometer and related to in-situ measurements of the chord length distribution with the FBRM-probe to characterize the agglomeration status. With increasing mixing time agglomerates were increasingly broken up in dependence of pre-shear: After 300 s of pre-shear the agglomerate sizes decreased by 10 µm to 15 µm compared to a 30 s pre-shear. At the same time dynamic yield stress and viscosity decreased up to 30% until a state of equilibrium was almost reached. The investigations show a correlation between mean chord length and the corresponding rheological parameters affected by the duration of pre-shear.

Effect of Different Shear Rates on Particle Microstructure of Cementitious Materials in a Wide Gap Vane-in-cup Rheometer.

Rheological properties of cementitious suspensions are affected not only by their mixture composition but also by process-related factors such as shear history. To enable a model-based description, investigations were carried out on the effect of shear history (shear rate variation over time) on the cement paste agglomeration state. Therefore, a Focused Beam Reflectance Measurement (FBRM) system and a wide gap rheometer were coupled to study the relation between shear history and in-situ chord length distribution simultaneously, indicating particle agglomeration. Hence, the effect of average shear rates (resulting from the applied shear profile), as well as shear rate distribution within the gap (local shear rates) on the particle agglomeration state have been investigated. The rheological properties of cement paste were evaluated with the Reiner-Riwlin approach. Furthermore, the agglomeration state of the particles was compared for different average shear rates and local shear rates at various positions of the FBRM probe. The results show that the median chord length increases in all positions when the average shear rate is decreased, indicating increasing particle agglomeration. Moreover, due to variable local shear rates at different FBRM probe positions, different agglomeration states are observed, resulting from two factors, shear rate dependent particle agglomeration and shear-induced particle migration.

Application of percolation threshold to disintegration and dissolution of ibuprofen tablets with different microcrystalline cellulose grades.

The study presented was conducted to determine whether a percolation threshold value, previously determined for ibuprofen/microcrystalline cellulose (MCC) blends using percolation theory and compression data (Queiroz et al., 2019), could translate to tablet disintegration and dissolution data. The influence of MCC grade (air stream dried versus spray dried) on tablet disintegration and dissolution was also investigated. Complementary to conventional disintegration and dissolution testing, Raman imaging determined drug distribution within tablets, and in-line particle video microscopy (PVM) and focused-beam reflectance measurement (FBRM) monitored tablet disintegration. Tablets were prepared containing 0-30% w/w ibuprofen. Raman imaging confirmed the percolation threshold by quantifying the number and equivalent circular diameters of ibuprofen domains on tablet surfaces. Across the percolation threshold, a step change in dissolution behaviour occurred, and tablets containing air stream dried MCC showed slower disintegration rates compared to tablets containing spray dried MCC. Dissolution measurements confirmed experimentally a percolation threshold in agreement with that determined using percolation theory and compression data. An increase in drug domains, due to cluster formation, and less efficient tablet disintegration contributed to slower ibuprofen dissolution above the percolation threshold. Slower dissolution was measured for tablets containing air stream dried compared to spray dried MCC.

Understanding the Efficiency of Aluminum Coagulants Used in Dissolved Air Flotation (DAF).

This paper reports on the efficiency of five aluminum coagulants for the treatment of a paper mill wastewater by dissolved air flotation (DAF). The coagulants studied were: alum, a polyaluminum chloride coagulant of high aluminum content and intermediate basicity (PAC-MB), another with intermediate aluminum content and high basicity (PAC-HB), a polyaluminum nitrate sulfate of intermediate aluminum content and basicity (PANS) and one hybrid coagulant formed by the combination of PANS and a mixture of polyamines (PANS-PA). The influence of Al speciation on contaminants removal and the main flocculation mechanisms involved have been analyzed. High removal of suspended solids together with significant removal of dissolved and colloidal material (COD and silica) were obtained, which is required for extended reuse of this process water. PAC-HB was the best product for removing suspended solids (85%) and soluble silica (50%) with a rather limited COD removal (5%), while PANS-PA obtained high turbidity (90%) and silica removal (45%) together with a significant soluble COD removal (15%). Monomeric Al (Ala, Alm) was more efficient in removing suspended solids and soluble COD than polymeric or colloidal Al (Alc, Alu), but the latter was more efficient in removing soluble silica. Results demonstrated that the main flocculation mechanism varies with the aluminum dosage, being predominantly charge neutralization at low dosages and sweep flocculation at high dosages. The floc strength factor however, was very high and similar for all the coagulants and dosages tested (85-90%), as it was mainly determined by the behavior of the pre-flocculated suspended solids present in wastewater. The reflocculation factor varied from 45 to 75% at the lowest dosages to almost zero at the highest dosages, confirming the transition from charge neutralization to sweep flocculation. The flocs formed by PANS-PA had lower strength than the others and it decreased with the dosage while its reflocculation factor was almost zero, even at low dosages. Due to the polyamines present in this coagulant, its flocculation mechanism is through both charge neutralization and patch formation, especially at low dosages, and sweep flocculation and interparticle bridge formation at high dosages.

Monitoring microsphere coating processes using PAT tools in a bench scale fluid bed.

Among the factors that influence adherence to medication within the pediatric population, taste/irritation has been identified as a critical barrier to patient compliance. With the goal of improving compliance, microspheres (matrix systems within which the drug is dispersed) can be coated with a reverse enteric polymer that will prevent the release of the drug in the oral cavity while maintaining an immediate release once the drug product reaches the stomach, thereby achieving a taste neutral profile. In this work, the in-line performance of three process analytical technology (PAT) tools is evaluated in order to monitor the microsphere coating process. These tools are Raman spectroscopy, near-infrared spectroscopy and focused beam reflectance measurements, together with process data and raw material attributes. The ability of these different sources of information to predict the coating's barrier performance is evaluated by using a combined-data-approach: multiblock partial least squares (MBPLS). Results show that Raman spectroscopy has a superior predictive performance and that it has the potential to monitor the coating process of the microspheres as well as to detect process discrepancies (such as spray rate changes), demonstrating its usefulness for the monitoring of fluid bed coating processes. It was also demonstrated that Raman can be used to clearly differentiate batches with significantly difference in-vitro dissolution performance. This monitoring is considered critical to ensure consistent coating performance for this thin film barrier membrane that is essential to patient compliance.

Filtration and dewatering of the mixture of quartz and kaolinite in different proportions.

Fine minerals, such as silicate and clay minerals are difficult to filtrate and dewater in mineral processing industry. In this study, quartz and kaolinite particles were mixed in different proportions to investigate the filtration and dewatering behavior difference. Combined with the calculation of DLVO theory, the particles size of quartz flocs, kaolinite flocs and the flocs of quartz and kaolinite mixture under pH of 7 and 11 were analyzed by focused beam reflectance measurement (FBRM). In addition, the structure of quartz/kaolinite flocs and the filter cake porosity were analyzed by 3D-high solution X-ray microanalyser (3D-XRM). The mixture of 80% quartz and 20% kaolinite had the maximum filtration velocity. The DLVO theoretical analyses show that the interaction between the aluminum-oxygen surface of kaolinite and silicon-oxygen surface of kaolinite/quartz particles is an attractive force at pH of 7, but repulsion force at pH of 11. The FBRM tests found that quartz and kaolinite tended to form relative larger agglomerates at pH of 7 when compared to a pH of 11. The results of 3D-XRM showed the kaolinite flocs were surrounded by amounts of quartz particles at pH of 7, which formed many quartz-kaolinite agglomerates, and therefore the porosity of the cake was increased for the water to easily pass through, which finally sped up the filtration process. However, quartz and kaolinite were evenly dispersed and had no obvious aggregates phenomenon at pH of 11, and the filtration velocity was slow because the kaolinite filled in the gap between quartz particles, which reduced the porosity of filter cake.

Insights on role of polymers in precipitation of celecoxib from supersaturated solutions as assessed by focused beam reflectance measurement (FBRM).

Supersaturating drug delivery systems (SDDS) have dominated the commercial and academic spheres owing to their potential in overcoming the solubility issue of poorly soluble drugs. Precipitation inhibitors are used as excipients in such formulations which has necessitated the development of supersaturation assays that evaluate their precipitation-inhibition efficacy. Such assays are able to give relative estimates of polymer efficacy ceteris paribus within a given set-up. However, the estimates of different laboratories cannot be compared with each other owing to high variability in procedure. Microarray plate method allows comprehensive replicates and decent statistics that make the method an edge over the other exploratory assays. In the current study, the precipitation-inhibition performance of three polymers on the precipitation of a model BCS class II drug was evaluated using the microarray plate method. Quantitative estimations were made through application of Poisson equation for nucleation rates and area under curve. Insights of the precipitation process at particle level were obtained through focused beam reflectance measurement (FBRM) technique coupled with end-process PVM imaging. Through real-time particle size analysis, FBRM technique demonstrated the potential for discerning the role of polymer as nucleation-inhibitor or crystal growth inhibitor. The events observed in the scaled-up FBRM analysis could be correlated with the events observed visually and spectrophotometrically. Powder X-ray diffraction and scanning electron microscopy were performed to capture the influence of polymers on the precipitates formed. This study was able to demonstrate the applicability of microarray plate method for quantitative estimations of precipitation kinetics that can be utilized for excipient screening for poorly soluble drugs having intra-luminal precipitation as a problem. FBRM analysis is highly valuable to gain mechanistic insights and put to rest the prevalent conjecture-based role attribution for polymers.

PAT-based batch statistical process control of a manufacturing process for a pharmaceutical ointment.

In this study, a process analytical technology (PAT)-based batch statistical process control (BSPC) model was developed for the laboratory-scale manufacturing process of a commercially available pharmaceutical ointment. The multivariate BSPC model was developed based on the in-line measured viscosity (viscometer), product temperature (viscometer), particle size distribution (PSD) (focused beam reflectance measurement (FBRM)) and active pharmaceutical ingredient (API) concentration (Raman spectroscopy) of four reference batches using a partial least squares (PLS) approach. From this in-line collected data, the characteristic trajectory of the batch process under normal operating conditions was acquired. To assess the capability of the process analyzers and BSPC model to detect deviations from the expected batch trajectory, two test batches with induced process and formulation disturbances were monitored in-line. The elevated process temperature in test batch 1 resulted in a deviating viscosity, product temperature and number of small particles (<100 µm). After correcting the process temperature, the viscosity and product temperature were within the control interval, while the particle size was smaller compared to the reference batches. For test batch 2, API was added at three different time points, whereas the same amount of API was added in one step during manufacturing of the reference batches. The induced disturbance was reflected in the in-line measured viscosity, PSD and API concentration. The combination of process analyzers and multivariate batch modelling enabled early fault detection and real-time process adjustments, thereby preventing batch loss or reprocessing. In addition, the feasibility of the investigated process analyzers to measure certain quality attributes in-line during manufacturing of an ointment was demonstrated.

Aluminum Phosphate Vaccine Adjuvant: Analysis of Composition and Size Using Off-Line and In-Line Tools.

PURPOSE: Aluminum-based adjuvants including aluminum phosphate (AlPO4) are commonly used in many human vaccines to enhance immune response. The interaction between the antigen and adjuvant, including the physical adsorption of antigen, may play a role in vaccine immunogenicity and is a useful marker of vaccine product quality and consistency. Thus, it is important to study the physicochemical properties of AlPO4, such as particle size and chemical composition. Control of the vaccine adjuvant throughout the manufacturing process, including raw materials and the intermediate and final product stages, can be effectively achieved through monitoring of such key product attributes to help ensure product quality. METHODS: This study focuses on the compositional analysis of AlPO4 adjuvant at the intermediate and final manufacturing stages using the off-line methods Fourier-Transform Infrared (FTIR) and Raman spectroscopy, X-ray Photoelectron Spectroscopy (XPS), and the in-line method Attenuated Total Reflectance (ATR). Particle size distribution of AlPO4 was measured off-line using Laser diffraction (LD) and in-line using Focused Beam Reflectance Measurement (FBRM®). RESULTS: There was no observable difference in size distribution between the intermediate and final stage AlPO4 by off-line and in-line analysis, in both small- or large-scale production samples. Consistent peak shifts were observed in off-line and in-line infrared (IR) spectroscopy as well as off-line XPS for both small- and large-scale AlPO4 manufacturing runs. Additionally, IR spectroscopy and FBRM® for size distribution were used as in-line process analytical technology (PAT) to monitor reaction progress in real-time during small-scale AlPO4 manufacturing from raw materials. The small-scale adsorption process of a model protein antigen (Tetanus toxoid) to AlPO4 adjuvant was also monitored by in-line ReactIR probe. CONCLUSION: This study demonstrated that in-line PAT can be used to monitor particle size and chemical composition for the various stages of adjuvant manufacturing from raw materials through intermediate to final adjuvant product stage. Similar approaches can be utilized to help assess lot-to-lot consistency during adjuvant manufacturing and vaccine product development. Moreover, the use of in-line PAT is highly conductive to advanced manufacturing strategies such as real-time product release testing and automated processes of the future.

Effect of polyglycerol esters additive on palm oil crystallization using focused beam reflectance measurement and differential scanning calorimetry.

The effect of 0.1-0.7% (w/w) of polyglycerol esters (PGEmix-8) on palm oil crystallization was studied using focused beam reflectance measurement (FBRM) to analyze the in-line changes of crystal size distribution during the crystallization. FBRM results show that 0.1-0.5% (w/w) of PGEmix-8 did not significantly affect nucleation but slightly retarded crystal growth. The use of 0.7% (w/w) additive showed greater heterogeneous nucleation compared to those with lower dosages of additive. Crystal growth was also greatly reduced when using 0.7% (w/w) dosage. The morphological study indicated that the palm oil crystals were smaller and more even in size than when more additive was added. Isothermal crystallization studies using differential scanning calorimetry (DSC) showed increased inhibitory effects on palm oil crystal growth with increasing concentration of PGEmix-8. These results imply that PGEmix-8 is a nucleation enhancing and crystal growth retarding additive in palm oil crystallization at 0.7% (w/w) dosage.

Application of In-line Focused Beam Reflectance Measurement to Brivanib Alaninate Wet Granulation Process to Enable Scale-up and Attribute-based Monitoring and Control Strategies.

Application of in-line real-time process monitoring using a process analytical technology for granule size distribution can enable quality-by-design development of a drug product and enable attribute-based monitoring and control strategies. In this study, an in-line laser focused beam reflectance measurement (FBRM) C35 probe was used to investigate the effect of formulation and process parameters on the granule growth profile over time during the high shear wet granulation of a high drug load formulation of brivanib alaninate. The probe quantitatively captured changes in the granule chord length distribution (CLD) with the progress of granulation and delineated the impact of water concentration used during granulation. The results correlated well with offline particle size distribution measured by nested sieve analyses. An end point indication algorithm was developed that was able to successfully track the process time needed to reach the target CLD. Testing of the brivanib alaninate granulation through 25-fold scale-up of the batch process indicated that the FBRM CLD profile can provide a scale-independent granule attribute-based process fingerprint. These studies highlight the ability of FBRM to quantitate a granule attribute of interest during wet granulation that can be used as an attribute-based scale-up and process monitoring and control parameter.

Effect of polyelectrolyte morphology and adsorption on the mechanism of nanocellulose flocculation.

The effect of polyelectrolyte morphology, charge density, molecular weight and concentration on the adsorption and flocculation of Microfibrillated Cellulose (MFC) were investigated. Linear Cationic Polyacrylamide (CPAM) and Branched Polyethylenimine (PEI) of varying charge density and molecular weight were added at different dosages to MFC suspensions. The flocculation mechanisms were quantified by measuring gel point by sedimentation, and floc size, strength and reflocculation ability through Focussed Beam Reflectance Measurements. Polymer adsorption was quantified through zeta potential and adsorption measurements using polyelectrolyte titration. The flocculation mechanism of MFC is shown to be dependent on polyelectrolyte morphology. The high molecular weight branched polymer, HPEI formed rigid bridges between the MFC fibres. HPEI had low coverage and negative zeta potential at the optimum flocculation dosage, forming flocs of high strength. After breaking of flocs, total reflocculation was achieved because the high rigidity of polymer did not allow reconformation or flattening of the polyelectrolyte adsorbed on MFC surface. The lower molecular weight branched polymer, LPEI (2kDa) showed rapid total deflocculation, complete reflocculation and had maximum flocculation occurring at the point of zero charge. These characteristics correspond to a charge neutralisation mechanism. However, if the flocculation mechanism was purely charge neutralisation mechanism, the minimum gel point would be at the point of zero charge. Since this is not the case, this difference was attributed to the high polydispersity of the commercial LPEI used, allowing some bridges to be formed by the largest molecules, changing the minimum gel point. With the linear 80% charged 4MDa CPAM, bridging mechanism dominates since maximum flocculation occurred at the minimum gel point, negative zeta potential and low coverage required for maximum flocculation. Reflocculation was not possible as the long linear polymer reconformed on the MFC surface under a flat conformation. Flocculation with the linear 50% charged 13MDa CPAM happened by bridging with the minimum gel point and maximum flocculation corresponding to roughly half polyelectrolyte surface coverage on cellulose.