Celine Valeria Liew

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.

In-line quantification of micronized drug and excipients in tablets by near infrared (NIR) spectroscopy: Real time monitoring of tabletting process.

The objectives of this study were to assess the utility of near infrared (NIR) spectroscopy for simultaneous in-line quantification of the contents of drug and excipients in tablets and to monitor the tabletting process in real time. Direct compression tablet formulations comprising micronized chlorpheniramine maleate, lactose, microcrystalline cellulose and magnesium stearate were used. A custom built NIR setup was used for in-line spectral acquisition (980-1900nm with 1nm resolution) during the tabletting process. Calibration models using dynamic spectral acquisition were prepared and validated using design of experiment approach. During tabletting, stratified sampling of tablets was also carried out to compare the NIR prediction results and subsequent UV analysis results for drug content. The results obtained with calibration and validation statistics confirmed the accuracy of models used to predict contents of tablet components. Stratified sampling results for drug content did not exhibit any significant statistical variation. However, in-line quantification enabled the content analysis of individual tablets in the production batch and detection of content uniformity problems towards the end of the tabletting process. Furthermore, it provided the assurance of in-process content uniformity monitoring of the individual excipients during the tabletting process.

Modifying matrix micro-environmental pH to achieve sustained drug release from highly laminating alginate matrices.

Lamination of alginate matrix tablet at acidic pH can compromise its function as a sustained release carrier. This phenomenon is associated with the conversion of sodium alginate to alginic acid. An innovative approach for controlling the release of a highly water-soluble drug from such matrices is presented in this paper. Inclusion of pH-modifiers was employed to raise the micro-environmental pH within matrices undergoing dissolution at gastric pH. The changes in micro-environmental pH of hydrating alginate matrices were visualized with the aid of a pH-indicator and subsequently quantified using image analysis. Transient elevation in micro-environmental pH impeded alginate protonation and minimized or prevented matrix lamination, contributing to preservation of drug diffusion barrier. Significant reduction in the rate of drug release at pH 1.2 was achieved in the presence of such additives. The action of pH-modifiers was synergistically enhanced in the presence of a carbon dioxide barrier formed by effervescing sodium bicarbonate, reducing drug release in the acidic medium from 60 to 20%. Further insight into the influence of lamination on drug release from alginate compacts was given.

Review of Disintegrants and the Disintegration Phenomena

Disintegrant is one of the most important components in a typical tablet dosage form. It is responsible for ensuring the break-up of the tablet matrix upon ingestion. Disintegrants act by different mechanisms, and a number of factors may affect their performance. It is important for formulators to understand how disintegrants function so as to be able to judiciously use disintegrants to develop optimized formulations. If the formulator is required to implement the quality by design paradigm while developing a tablet formulation, it would be important to determine the impact of component ranges and process variations on tablet performance and of particular importance, tablet disintegration. Thus, a better understanding of the mechanisms of disintegrants and the tablet disintegration processes can be critical to product design success. This review aims to provide an overview of tablet disintegrants and the disintegration processes with particular focus on the factors affecting the functionalities of disintegrants. An updated compendium of different techniques employed to evaluate disintegrant action and measure disintegration time is also provided. The objective of this review is to assemble the knowledge about disintegrants and the measurement of tablet disintegratability so that the information provided could be of help to tablet formulation development.

The Role of Moisture and Gap Air Pressure in the Formation of Spherical Granules by Rotary Processing

Spheroids are usually produced by a multi-step extrusion-spheronization process. The single-step production of spheroids may be carried out in a rotoprocessor. The use of feed materials in powder form requires an adaptation of the spheronizer machinery. This study investigates the formation and growth of spheroids and the changes in the spheroid moisture content in a single-step agglomeration-spheronization method. There was a rapid increase in size and formfactor values when spheroids started to form and grow from the powder mix. Although there was a continual and considerable loss of moisture with time, this did not have an appreciable effect on spheroid size and shape after the spheroid formation stage as the spheroid structure had already been determined. Spheroid size increased with higher liquid spray rates. The use of higher gap air pressures resulted in a greater rate of moisture loss and the production of smaller spheroids.

Understanding Disintegrant Action by Visualization

The aim of this study was to utilize high-speed video imaging for understanding the disintegrability of compacts and disintegrant action upon wetting. High-speed video imaging was used to visualize the disintegration of compacts and effect of wetting on free disintegrant particles. Acquired images were processed using MATLAB, and changes in the compact area and instantaneous motion of compacted particles on contact with water were analyzed. The capillary action of compacts was also determined for various disintegrants. Finally, the breakdown behavior of compacts prepared with selected disintegrants was analyzed at different compression forces to evaluate recovery of compaction strain. Water-insoluble inert diluent, dicalcium phosphate, was used as a comparator. The results from this visualization study provided an in-depth understanding of the disintegrant behavior of free and compacted disintegrant particles upon wetting. The mechanisms of swelling, capillary action, disruption of particle-particle bonds and strain recovery were successfully monitored by video imaging. The disintegration of compacts containing crospovidone appeared to be less influenced by swelling or wicking action. The influence of compression force on the disintegration of selected disintegrants confirmed that strain recovery is the dominant mechanism for the disintegrant action of crospovidone.

Mechanistic Study on Hydration and Drug Release Behavior of Sodium Alginate Compacts

ABSTRACT The influence of sodium alginate viscosity on the dynamics of matrix hydration, solvent front movement, swelling, erosion, and drug release from alginate matrix tablets were examined. The solvent front showed preferential penetration from the radial direction even though matrix swelling showed axial predominance. This study proposed alternative views for the anisotropic behavior of hydrating alginate compacts, namely, formation of gel barrier with different permeability characteristics, tension at the gel-core interface and preferential radial erosion, in addition to an in-depth examination on the contribution of stress relaxation of hydrated polymer as well as core expansion. Alginate matrices demonstrated pH-dependent hydration, swelling and erosion behavior, resulting in pH-dependent drug release mechanisms. Dissolution profiles for alginate matrices of different viscosities were similar in acid but differed upon increase of pH. This was due to the influence of alginate viscosity grade on liquid uptake, erosion and pronounced swelling at near neutral pH.

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.

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.

Development of a visiometric process analyzer for real-time monitoring of bottom spray fluid-bed coating

Particle recirculation within the partition column is a major source of process variability in the bottom spray fluid-bed coating process. However, its locality and complex nature make it hidden from the operator. The aim of this study was to take snapshots of the process by employing a visiometric process analyzer based on high-speed imaging and ensemble correlation particle image velocimetry (PIV) to quantify particle recirculation. High-speed images of particles within the partition column of a bottom spray fluid-bed coater were captured and studied by morphological image processing and ensemble correlation PIV. Particle displacement probability density function (PDF) obtained from ensemble correlation PIV was consistent with validation experiments using an image tracking method. Particle displacement PDF was further resolved into particle velocity magnitude and particle velocity orientation histograms, which gave information about particle recirculation probability, thus quantifying the main source of process variability. Deeper insights into particle coating process were obtained and better control of coat uniformity can thus be achieved with use of the proposed visiometric process analyzer. The concept of visiometric process analyzers was proposed and their potential applications in pharmaceutical processes were further discussed.