Calibration sampling paradox in near infrared spectroscopy: a case study of multi-component powder blend.

The objective of this study was to illustrate the sampling paradox resulting from the different strategies of spectral acquisition while preparing and implementing the calibration models for prediction of blend components in multi-component cohesive blends. A D-optimal mixture design was used to create 24 blending runs of the formulation consisting of chlorpheniramine maleate, lactose, microcrystalline cellulose and magnesium stearate. Three strategies: (a) laboratory mixing and static spectral acquisition, (b) IBC mixing and static spectral acquisition and (c) IBC mixing and dynamic spectral acquisition were investigated for obtaining the most relevant and representative calibration samples. An optical head comprising a sapphire window mounted on the lid of the IBC was used for static and dynamic NIR spectral acquisition of the powder blends. For laboratory mixed samples, powders were blended for fixed period of 30 min and later on scanned for NIR spectra. For IBC mixed blends, the spectral acquisition was carried out in-line for 2 min and stopped for static spectral acquisition. The same cycle was repeated for the next 28 min. Partial least square (PLS) calibration models for each component were built and ranked according to their calibration statistics. Optimal calibration models were selected from each strategy for each component and used for in-line prediction of blend components of three independent test runs. Although excellent statistics were obtained for the PLS models from the three strategies, significant discrepancies were observed during prediction of the independent blends in real time. Models built using IBC mixed blends and dynamic spectral acquisition resulted in the most accurate predictions for all the blend components, whereas models prepared using static spectral acquisition (laboratory mixed and IBC) showed erroneous prediction results. The prediction performance differences between the models obtained using the different strategies could be explained in the context of relevancy and representative sample collection at the initial stage of calibration model building.

In-line quantification of drug and excipients in cohesive powder blends by near infrared spectroscopy.

This work was aimed at investigating the utility of near infrared (NIR) spectroscopy for simultaneous in-line quantification of drug and excipients in cohesive powder blends in a bin blender. A model formulation containing micronized chlorpheniramine maleate (microCPM), lactose, microcrystalline cellulose (MCC) and magnesium stearate (MgSt) was selected for the blending study. An optical head comprising a sapphire window mounted on the lid of the bin was used to collect in-line NIR spectral data of the powder blends. Validated partial least square (PLS) calibration models were used to quantify each component from the NIR spectra of the blends. Additionally, effects of premixing by sieving and high shear mixing and use of an internal prism fixed within the bin on the mixing performance of each component were studied. The statistical results obtained for PLS calibration models and their validation showed the sensitivity of NIR for accurate quantification of blend components. The blend prepared with high shear premixing and with prism achieved uniformity more rapidly than that with high shear premixing but without prism during blending in a bin blender. Premixing using sieving proved to be inadequate for uniform mixing of the blend components as none of the components except MgSt achieved uniform distribution after the preset blending time when blended in the bin blender. This study demonstrated that by high speed sampling and rapid spectral acquisition, distribution of individual blend components can be assessed with high accuracy during blending. Furthermore, high shear premixing facilitated rapid distribution and uniformity achievement of blend components. This technique may be used to monitor the relative distribution of individual blend components in real time and thus, to assess the performance of a bin blender for mixing of cohesive multi-component powder blends during development and production.

A study on microwave-induced melt granulation in a single pot high shear processor.

Microwave-induced high shear melt granulation was compared with conventional melt granulation performed in the same processor. Admixtures of lactose 200M and anhydrous dicalcium phosphate were granulated with polyethylene glycol 3350. Different heating mechanisms in the two processes necessitated the use of different parameters for process monitoring and control. Mixer power consumption was suitable for monitoring agglomerate growth under microwave-induced heating. Product temperature was a better indicator of agglomeration propensity in conventional melt granulation. These were attributed to the disparities in heat acquisition rates and heating uniformities of the powders as well as variation in baseline mixer power consumption between the two processes.

Microwave-assisted drying of pharmaceutical granules and its impact on drug stability.

The advent of microwave technology has intensified the search for pharmaceuticals amenable to microwave processing. This study investigated the influences of powder load, diluent particle size and amount of granulating liquid employed on the microwave-assisted drying and stability of acetylsalicylic acid (ASA)-loaded granules in a single pot high shear processor. Powder load affected the profiles, rate and extent of drying. Drying was more dependent on the size and structural properties of granules rather than their surface areas as heat was generated volumetrically. Increased granule size brought about by increasing the size of diluent particles and amount of granulating liquid resulted in higher drying rates. Drug stability was negatively correlated to the drying time of granules.

Impact of cross-linker on alginate matrix integrity and drug release.

Sodium alginate, a biopolymer, was employed in the formulation of matrix tablets. They cracked or laminated at acidic pH, compromising their dissolution performance. Improved mechanical strength and reduced barrier permeability of calcium alginate gel provided the rationale for cross-linking the alginate matrix to sustain drug release. Studies had suggested that the incorporation of soluble calcium salts in alginate matrix tablets could sustain drug release at near-neutral pH due to in situ cross-linking. However, results from the present study showed otherwise when gastrointestinal pH conditions were simulated. Significant reduction in drug release rate was only observed when an external calcium source was utilized at low concentration. High calcium ion concentrations caused matrix disintegration. In contrast, matrices pre-coated by calcium alginate could sustain drug release at pH 1.2 followed by pH 6.8 for over 12h. The presence of cross-linked barrier impeded matrix lamination and preserved matrix structure, contributing to at least three-fold reduction in drug release at pH 1.2. Zero order release as well as delayed burst release could be achieved by employing appropriate grade of alginate and cross-linking conditions.

Drying efficiency and particle movement in coating--impact on particle agglomeration and yield.

The purpose of this study was to determine the influences of drying efficiency and particle movement on the degree of agglomeration and yield of pellets coated under different conditions. Thermodynamic conditions were varied using different inlet air temperatures and airflow rates, fluid dynamics were varied using different airflow patterns and air velocities, and two sizes of pellets were coated at different airflow rates and partition gaps. Agglomeration was minimized when all the moisture introduced into the system was removed by the drying air. Excessively dry conditions led to increased loss of yield due to spray-drying effect and attrition. Fluid dynamics were still important even with adequate drying, as the degree of agglomeration was relatively higher in the non-swirling airflow of Wurster coating than in the swirling airflow of precision coating. Increasing air velocities increased pellet velocities, resulting in lower degrees of agglomeration. Hence, agglomeration due to fluid dynamics was attributed to differences in pellet velocities, pellet proximity and pellet trajectories within the partition column. Smaller pellets agglomerated primarily from inadequate drying and not due to inadequate opportunities for particle movement. Larger pellets were more affected by the partition gap due to restriction of their movement through the partition gap. Hence, both thermodynamics and fluid dynamics were found to be important in minimizing agglomeration and ensuring quality coated products.

Feasibility of eliminating premixing for the production of pellets in a rotary processor.

This current study aims to explore the feasibility of eliminating the premixing step for making pellets in a rotary processor. Microcrystalline cellulose (MCC) and lactose were used as starting materials. They could be loaded into the rotary processor separately using three different loading configurations (Methods I, II, and III) or as MCC:lactose blend, which was prepared in the separate mixer prior to loading (Method IV). Physical properties of the pellets prepared in Methods I-III were evaluated and compared against those prepared using a premixed blend (Method IV). The effects of loading configuration on pellet quality can be assessed by comparing the pellets prepared in Methods I, II, and III. Physical characterization of pellets included mean size, size distribution, oversized fraction, and shape. No significant difference in pellet properties could be attributed to the effect of premixing. Pellet properties were not significantly affected by the different loading configurations either. This study demonstrated that homogeneous powder blends are not required for the production of pellets in rotary processing. The tumbling action of the powders at the start of rotary processing is sufficient to ensure adequate powder mixing. However, it may be judicious to cofeed the different powders to achieve some preliminary mixing during loading under extreme processing conditions.

Torque rheological parameters to predict pellet quality in extrusion-spheronization.

This study explored the feasibility of predicting the quality of microcrystalline cellulose (MCC) pellets prepared by extrusion-spheronization using torque rheological characterization. Rheological properties of eleven MCC grades as well as their binary mixtures with lactose (3:7) at various water contents were determined using a mixer torque rheometer (MTR). Derived torque parameters were: maximum torque and cumulative energy of mixing (CEM). CEM values of MCC powders (CEM((MCC))) could be attributed to their physical properties such as crystallinity, V(low P) and V(total) (volumes of mercury intruded in their pores at low pressure and the total intrusion volume), bulk and tapped densities. For both MCC powders and their binary mixtures, strong correlation was observed between their torque parameters and the properties of their pellets formed with 30 and 35% (w/w) water. Since this relationship was valid over a broad water content range, rheological assessment for pre-formulation purposes need not be performed at optimized water contents. These results demonstrated the usefulness of torque rheometry as an effective means of comparing and evaluating MCC grades especially when substitution of equivalent grades is encountered. In so doing, the tedious and expensive pre-production (pre-formulation and optimization) work can be considerably reduced.

Roller compaction of crude plant material: influence of process variables, polyvinylpyrrolidone, and co-milling.

Roller compaction of a milled botanical (Baphicacanthus cusia) with and without a binder, polyvinylpyrrolidone (PVP) was conducted. Effects of co-milling on binder function and flowability of the powder blend was also investigated. Flakes were comminuted, and the size and size distribution, friability, Hausner ratio, and Carr index of the granulations were determined. Crude herb should be reduced to a suitable size for it to be successfully roller compacted. Larger-sized and less friable granules were obtained with decreasing roller speed. Addition of PVP affected the flowability and binding capacity of the herbal powder blend, which influenced size and friability of the granules. Co-milling of PVP with the herbal powder enhanced the flow of the blends and the effectiveness of the binder, which contributed favorably to the roller-compacted product. Roller compaction is a convenient and cost-effective granulating technique suitable for milled botanicals. Co-milling can be used to improve the properties of roller-compacted products.

Wet spheronization by rotary processing--a multistage single-pot process for producing spheroids.

Spheronization is an agglomerative size enlargement process for producing spherical agglomerates that have many technological and therapeutical advantages. Rotary processing is an efficient multistage, single-pot spheroid production method. The rotary processor can be used for spheroid production, drying as well as coating. In the course of spheroid production, centrifugal, fluidizing, and gravitational forces act upon the product from different directions and collectively contribute to the spheroid formation process during rotary processing. The outcome of the process depends on the complex interactions between the equipment, formulation, and process variables.

Influence of teardrop studs on rotating frictional base plate on spheroid quality in rotary spheronization.

The effects of teardrop-shaped studs on the quality of rotary processed spheroids were investigated. The spheroids were produced under similar conditions using three rotating frictional base plates with teardrop studs of different height, volume, cross-sectional area and surface area. Spheroid properties were rated by size, size distribution, shape, friability and density. The amounts of lumps and fines produced, and the adhesion of material on the rotating frictional base plates was also looked into. The dimension of the teardrop studs on the rotating frictional base plate affected spheroid quality. The resultant shear forces and energy input during rotary spheronization differed depending on the different height, volume, cross-sectional area and surface area of studs. With the increase in height, volume, cross-sectional area and surface area of studs on the frictional base plate, the mass median diameter, e(R) and circularity of spheroids increased with corresponding decrease in span, lumps and fines. Although the frictional base plate with shortest studs had little adhesion, it may not supply enough shear force and energy input for the spheronization process, resulting in a less stable process. A balance between energy input and adhesion on the rotating frictional base plate was needed in order to optimize the production of spheroids by rotary processing.

Effect of tabletting compaction pressure on alginate microspheres.

Alginate and alginate-hydroxypropylmethylcellulose (HPMC) microspheres were prepared by the emulsification method. The compaction of microspheres for producing tablet dosage forms raises concerns about possible damage to microsphere walls with subsequent unpredictable dissolution rates. The effect of different compaction pressures on the integrity of the microspheres was investigated. The addition of a diluent, microcrystalline cellulose (MCC), was required to make compacts containing alginate and alginate-HPMC microspheres. Compacts containing alginate-HPMC (7:3) microspheres had the highest crushing strength followed by compacts containing alginate-HPMC (9:1) microspheres and alginate microspheres. However, compact crushing strength did not vary significantly with increased compaction pressures over the range of compaction pressures investigated. Differences in the drug release profiles of the original non-compacted and compacted alginate and alginate-HPMC microspheres were slight and not marked. Although dentation and distortion of the microspheres were observed with increasing compaction pressures, the microspheres generally remained intact, with minimal rupture/fracture.

Role of base plate rotational speed in controlling spheroid size distribution and minimizing oversize particle formation during spheroid production by rotary processing.

The occurrence of material adhesion and formation of oversize particles in the product yield during one-pot spheroid production by rotary processing leads to a less predictable process and a decrease in the usable portion of the total product yield obtained from each production run. The use of variable speeds of the rotating frictional base plate during the spheronization run was investigated for achieving optimal spheroid production. When the base plate speed was increased during liquid addition, the greater centrifugal forces generated improved liquid distribution and the mixing of the moist powder mass, resulting in a decrease in the amount of oversize particles formed. When the base plate was maintained at a high speed throughout the run, the amount of oversize particles and mean spheroid size increased, and a greater "between batch" mean spheroid size variability was also observed. The findings showed that, when higher speeds were used, the residence time must be adjusted accordingly to avoid excessive coalescence and growth while maintaining even liquid distribution. A "low-high-low" speed variation during rotary processing may be used to produce spheroids with a narrow size distribution and with a minimal amount of oversize particles in the total product yield.