Understanding the Roles of Excipients in Moisture Management in Solid Dosage Forms.

Excipients are ubiquitous in pharmaceutical products, and often, they can also play a critical role in maintaining product quality. For a product containing a moisture-sensitive drug, moisture can be deleterious to the product stability during storage. Therefore, using excipients that interact with moisture in situ can potentially alleviate product stability issues. In this study, the interactive behavior of starch with moisture was augmented by coprocessing maize starch with sodium chloride (NaCl) or magnesium nitrate hexahydrate [Mg(NO3)2·6H2O] at different concentrations (5 and 10%, w/w). The effect of the formulation on drug stability was assessed through the degradation of acetylsalicylic acid, which was used as the model drug. The results showed that coprocessing of the starch with either NaCl or Mg(NO3)2·6H2O impacted the number of water molecule binding sites on the starch and how the sorbed moisture was distributed. The coprocessed excipients also resulted in lower drug degradation and lesser changes in tablet tensile strength during post-compaction storage. However, corresponding tablet formulations containing physical mixtures of starch and salts did not yield promising outcomes. This study demonstrated the advantageous concomitant use of common excipients by coprocessing to synergistically mitigate the adverse effects of moisture and promote product stability when formulating a moisture-sensitive drug. In addition, the findings could help to improve the understanding of moisture-excipient interactions and allow for the judicious choice of excipients when designing formulations containing moisture-sensitive drugs.

Evaluation of tablet punch configuration on mitigating capping by a quality by design approach.

Capping is a common problem in the manufacture of some types of tablets and unless resolved, the tableting process cannot proceed. Hence, all factors that can help to lessen the likelihood of capping without unnecessarily reduce turret speed and/or compaction force would be tenable. This study investigated the influence of tablet punch configuration on mitigation of tablet capping. Tablets were prepared from high-dose paracetamol-potato starch granules in a rotary tablet press with flat face plain (FFP), flat face bevel edge (FFBE) and flat face radius edge (FFRE) punch configurations. The directly compressible (DC) fillers tested were microcrystalline cellulose (MCC), pre-gelatinised starch (PGS) and lactose. Design of experiments (DoE), a tool of quality by design (QbD) paradigm, was used and the interaction of input variables (compression force, tablet punch configuration and DC filler) affecting the response factors (tablet hardness and capping rating) were evaluated. FFP punches were able to mitigate capping best. FFRE punches showed more potential than FFBE punches at alleviating capping in a particular compression force range, without the limitations of the FFP punches that produce cylindrical tablets that were more friable. Incorporation of PGS in the tablet formulation was observed to be more efficient at mitigating capping than the other DC fillers when FFBE and FFRE punches were used. Overall, this study serves as a model for prospective product development based on the QbD framework and the optimal use of compaction tools.

Influence of the Punch Head Design on the Physical Quality of Tablets Produced in a Rotary Press.

This study aims to investigate the influence of tablet punch head design on compaction and the resultant tablet mechanical properties. Tablets were prepared using flat-face punches with different head flat and head radius configurations, on a rotary tablet press with compression rolls of different diameters. The results showed that tablets produced using punches with head flats consistently displayed higher tensile strengths and lower capping tendencies. Exclusion of the head flat in the punch head geometry caused the compacts to undergo a state of continual deformation during the compaction cycle, possibly with increasing elasticity without the opportunity for more prolonged stress relaxation. Extension of head flat diameter produced small increments in dwell time and this could bring about significant improvements to the tablet mechanical quality. Changes to the punch head radius were found only to affect the compression profiles marginally, but this only produced insignificant differences in the tablet mechanical properties. A smaller compression roll allowed greater plastic flow during the dwell phase, but this was insufficient to effectively counteract the adverse effects due to increased strain rate during the consolidation phase, leading to deterioration of tablet mechanical quality.

A prediction model for monitoring ribbed roller compacted ribbons.

The application of near infrared (NIR) spectroscopy for real-time monitoring of the critical quality attributes of ribbed roller compacted ribbons was studied. Three NIR probes (QR 200, QR 400, and QR 600) of lens diameters, 200, 400, and 600 µm, respectively were used at various fixed distances from the ribbon surface to determine the calibration model with optimum predictive ability for monitoring the roller compaction process. The ribbon attributes studied were micronized chlorpheniramine maleate concentration, roll force, roll speed, ribbon density, and tensile strength. The custom-made belt conveying system was used to simulate the ribbon manufacturing process for NIR spectra capture. Simulation results obtained were then compared with the experimental results. The outcome of this study indicated that QR 400 was the best NIR probe for modeling, followed by QR 200 and QR 600. Of the five spectra measuring distance settings (d = 0.3, 0.6, 0.9, 1.2, and 1.5 mm), there was good correlation between simulation and experimental findings indicating that the calibration models for bigger probe sizes were better if the measuring distance was smaller.

Assessment of disintegration of rapidly disintegrating tablets by a visiometric liquid jet-mediated disintegration apparatus.

The aim of this study was to develop a responsive disintegration test apparatus that is particularly suitable for rapidly disintegrating tablets (RDTs). The designed RDT disintegration apparatus consisted of disintegration compartment, stereomicroscope and high speed video camera. Computational fluid dynamics (CFD) was used to simulate 3 different designs of the compartment and to predict velocity and pressure patterns inside the compartment. The CFD preprocessor established the compartment models and the CFD solver determined the numerical solutions of the governing equations that described disintegration medium flow. Simulation was validated by good agreement between CFD and experimental results. Based on the results, the most suitable disintegration compartment was selected. Six types of commercial RDTs were used and disintegration times of these tablets were determined using the designed RDT disintegration apparatus and the USP disintegration apparatus. The results obtained using the designed apparatus correlated well to those obtained by the USP apparatus. Thus, the applied CFD approach had the potential to predict the fluid hydrodynamics for the design of optimal disintegration apparatus. The designed visiometric liquid jet-mediated disintegration apparatus for RDT provided efficient and precise determination of very short disintegration times of rapidly disintegrating dosage forms.

Insights into the functionality of pelletization aid in pelletization by extrusion-spheronization.

This study investigated the particle sizes of pelletization aids from the different wet processing steps of extrusion-spheronization, and their influence on rheological and pellet properties. Three commercial microcrystalline cellulose (MCC) grades, three commercial cross-linked polyvinyl pyrrolidone (X-PVP) grades and two agglomerated X-PVP grades (prepared using roller compaction from two commercial fine particle size X-PVP grades) were used as pelletization aid. The pelletization aids were analyzed for their dry state particle size, individual particle size (sonicated powder dispersion in water) and in-process particle sizes (dispersions of processed materials from the different processing steps). No remarkable particle size changes were observed with the commercial X-PVP grades under the different conditions. The two fine X-PVP grades, but not the coarse grade, produced good quality pellets. MCC and agglomerated X-PVP grades exhibited spectacularly lower individual and in-process particle sizes, and produced good quality pellets although some of them had dry state particle sizes comparable to that of the commercial coarse X-PVP grade. In-process particle sizes of pelletization aids correlated strongly with the rheological and pellet properties of the pelletization aid:lactose (1:3) binary mixtures. These results demonstrated that small in-process particle size of pelletization aid is a critical requirement for successful pelletization by extrusion-spheronization.

Spray granulation for drug formulation.

INTRODUCTION: Granulation is a key unit process in the production of pharmaceutical solid dosage forms and involves the agglomeration of fine particles with the aid of a binding agent. Fluidized bed granulation, a classic example of spray granulation, is a technique of particle agglomeration brought about by the spray addition of the binding liquid onto a stationary bed of powder particles that is transformed to a fluid-like state by the passage of air through it. AREAS COVERED: The basic working principles, equipment set-up, advantages and challenges of fluidized bed granulation are introduced in this review. This is followed by an overview of the formulation and process-related variables affecting granulation performance. Technological advances, particularly in the application of process analytical tools, in the field of fluidized bed granulation research are also discussed. EXPERT OPINION: Fluidized bed granulation is a popular technique for pharmaceutical production, as it is a highly economical and efficient one-pot process. The research and development of process analytical technologies (PAT) has allowed greater process understanding and control to be achieved, even for the lesser known fluidized bed techniques, such as bottom spray and fluidized hot melt granulation. In view of its consistent mixing, as well as continuous and concurrent wetting and drying occurring throughout processing, fluidized bed granulation shows great potential for continuous production although more research is required to fully implement, validate and integrate the PAT tools in a production line.

Evaluation of the physicochemical properties and compaction behavior of melt granules produced in microwave-induced and conventional melt granulation in a single pot high shear processor.

Recently, microwave-induced melt granulation was shown to be a promising alternative to conventional melt granulation with improved process monitoring capabilities. This study aimed to compare the physicochemical and compaction properties of granules produced from microwave-induced and conventional melt granulation. Powder admixtures comprising equivalent proportions by weight of lactose 200 M and anhydrous dicalcium phosphate were granulated with polyethylene glycol 3350 under the influence of microwave-induced and conventional heating in a 10-L single pot high shear processor. The properties of the granules and compacts produced from the two processes were compared. Relative to conventional melt granulation, the rates at which the irradiated powders heated up in microwave-induced melt granulation were lower. Agglomerate growth proceeded at a slower rate, and this necessitated longer massing durations for growth induction. These factors prompted greater evaporative moisture losses from the melt granules. Additionally, nonuniform heating of the powders under the influence of microwaves led to increased inter-batch variations in the binder contents of resultant melt granules and a reliance of content homogeneity on massing duration. Agglomerate growth proceeded more rapidly under the influence of conventional heating due to the enhanced heating capabilities of the powders. Melt granules produced using the conventional method possessed higher moisture contents and improved content homogeneity. The compaction behavior of melt granules were affected by their mean sizes, porosities, flow properties, binder, and moisture contents. The last two factors were responsible for the disparities in compaction behavior of melt granules produced from microwave-induced and conventional melt granulation.

Dielectric properties of pharmaceutical materials relevant to microwave processing: effects of field frequency, material density, and moisture content.

The rising popularity of microwaves for drying, material processing and quality sensing has fuelled the need for knowledge concerning dielectric properties of common pharmaceutical materials. This article represents one of the few reports on the density and moisture content dependence of the dielectric properties of primary pharmaceutical materials and their relevance to microwave-assisted processing. Dielectric constants (epsilon') and losses (epsilon'') of 13 pharmaceutical materials were measured over a frequency range of 1 MHz-1 GHz at 23 +/- 1 degrees C using a parallel-electrode measurement system. Effects of field frequency, material density and moisture content on dielectric properties were studied. Material dielectric properties varied considerably with frequency. At microwave frequencies, linear relationships were established between cube-root functions of the dielectric parameters [symbols: see text] and density which enabled dielectric properties of materials at various densities to be estimated by regression. Moisture content was the main factor that contributed to the disparities in dielectric properties and heating capabilities of the materials in a laboratory microwave oven. The effectiveness of a single frequency density-independent dielectric function for moisture sensing applications was explored and found to be suitable within low ranges of moisture contents for a model material.

Layered growth with bottom-spray granulation for spray deposition of drug.

The gap in scientific knowledge on bottom-spray fluidized bed granulation has emphasized the need for more studies in this area. This paper comparatively studied the applicability of a modified bottom-spray process and the conventional top-spray process for the spray deposition of a micronized drug during granulation. The differences in circulation pattern, mode of growth and resultant granule properties between the two processes were highlighted. The more ordered and consistent circulation pattern of particles in a bottom-spray fluidized bed was observed to give rise to layered granule growth. This resulted in better drug content uniformity among the granule batches and within a granule batch. The processes' sensitivities to wetting and feed material characteristics were also compared and found to differ markedly. Less robustness to differing process conditions was observed for the top-spray process. The resultant bottom-spray granules formed were observed to be less porous, more spherical and had good flow properties. The bottom-spray technique can thus be potentially applied for the spray deposition of drug during granulation and was observed to be a good alternative to the conventional technique for preparing granules.

Air-dictated bottom spray process: impact of fluid dynamics on granule growth and morphology.

BACKGROUND: Growing interest in the use of the less-explored bottom spray technique for fluidized bed granulation provided impetus for this study. AIM: The impact of fluid dynamics (air accelerator insert diameter; partition gap) and wetting (binder spray rate) on granule properties were investigated. METHOD: In this 3(3) full factorial study, the results were fitted to a quadratic model using response surface methodology. The air velocity at the spray granulation zone for the investigated conditions was measured using a pitot tube. RESULTS: Air accelerator insert diameter correlated to measured air velocity at the spray granulation zone and was found to not only dictate growth but also influence granule morphology. The partition gap was found to play important roles in regulating particle movement into the spray granulation zone and optimizing process yields, whereas binder spray rate significantly affected granule morphology but not granule size. CONCLUSIONS: Unlike conventional fluidized bed granulation, ease of modulation of fluid dynamics and insensitivity of the bottom spray process to wetting allow flexible control of granule size, shape, and flow. Its good drying ability also indicated potential use in granulating moisture-sensitive materials.

Importance of small pores in microcrystalline cellulose for controlling water distribution during extrusion-spheronization.

The purpose of this research was to investigate the effects of particle size on the wet massing behavior of microcrystalline cellulose (MCC). In this study, a series of six fractionated MCC grades were customized and specially classified to yield different particle size varieties of the standard grade, Comprecel M101. All seven MCC grades were extensively characterized for the physical properties and wet massing behavior using mixer torque rheometry. Effects of MCC physical properties on the maximum torque (Torque(max)) were determined using partial least squares (PLS) analysis. Most physical properties varied systematically with particle size and morphological changes. Marked differences were observed in the small pore volumes (V (highP)) and BET surface areas of the MCC grades. Variables that exerted dominant influences on Torque(max) were identified. In particular, the significance of V (highP) in governing wet mass consistency was established. The role of V (highP) has not been reported in any study because this small but significant variation is likely to be obliterated or compensated by variation in other physical properties from MCC grades from different suppliers. The findings demonstrated the role of small pores in governing the wet mass consistency of MCC and provide a better understanding of MCC's superior performance as a spheronization aid by the ability to fulfill the function as a molecular sponge to facilitate pellet formation during wet granulation processes.

Chick chorioallantoic membrane as an in situ biological membrane for pharmaceutical formulation development: a review.

The use of animals in research has always been a debatable issue. Over the past few decades, efforts have been made to reduce, replace, and refine experiments for ethical use of experimental animals. The use of chick chorioallantoic membrane (CAM) was one of the proposed alternatives to the Draize rabbit ocular irritation test with several advantages including simplicity, rapidity, sensitivity, ease of performance, and cost-effectiveness. The recent use of CAM in the development of pharmaceuticals and testing models to mimic human tissue, including drug transport across CAM, will be discussed in this review.

Study of coat quality of tablets coated by an on-line Supercell coater.

The aim of this study was to investigate the nature of Supercell coating, an on-line tablet coater that employed a unique pattern of airflow. Tablets coated at different spray rates (4, 6, 8, 10, and 12 mL/min) were analyzed to investigate the influence of different wetting conditions on the quality of coats formed. Scanning electron micrographs showed that tablet coats formed at a spray rate of 4 mL/min consisted of spray-dried droplets that did not coalesce. At a spray rate of 6 mL/min, surface roughness was found to be lower than at the other spray rates, and the coat appeared smoothest, whereby droplets seemed fused together. At higher spray rates, the droplets appeared as branching arms and scale-like structures. This was attributed to the spread of spray droplets by the processing air and mass transfer of wet coating materials between tablets. Further tests showed that coats formed at higher spray rates had higher drug yield, drug uniformity, color uniformity, and density. However, the variability in coat thickness was increased due to the mass transfer of coats and dissolution of tablet core surfaces by the coating material. Since coats of different characteristics can be formed in Supercell coating, the choice of wetting conditions would depend on the type of coat required and the coating materials used.

Elucidation of spheroid formation with and without the extrusion step.

Spheroid formation mechanisms were investigated using extrusion-spheronization (ES) and rotary processing (RP). Using ES (cross-hatch), ES (teardrop), and RP (teardrop), spheroids with similar mass median diameter (MMD) and span were produced using equivalent formulation and spheronization conditions. During spheronization, the teardrop-studded rotating frictional surface, with increased peripheral tip speed and duration, produced spheroids of equivalent MMD and span to those produced by the cross-hatch rotating frictional plate surface. The roundness of these spheroids was also similar. RP required less water to produce spheroids of MMD similar to that of spheroids produced by ES. However, these RP spheroids were less spherical. Image analysis of 625 spheroids per batch indicated that the size distribution of RP spheroids had significantly greater SD, positive skewness, and kurtosis. Morphological examination of time-sampled spheroids produced by ES indicated that spheroid formation occurred predominantly by attrition and layering, while RP spheroids were formed by nucleation, agglomeration, layering, and coalescence. RP produced spheroids with higher crushing strength than that of ES-produced spheroids. The amount of moisture lost during spheronization for spheroids produced by ES had minimal influence on their eventual size. Differences in process and formulation parameters, in addition to size distribution and observed morphological changes, enabled a greater understanding of spheroid formation and methods to optimize spheroid production.

New indices to characterize powder flow based on their avalanching behavior.

Use of powder avalanches in the study of flow properties of pharmaceutical excipients has yet to be popularized even though it is rather simple to use and yields comparatively reliable results. Commonly employed flow assessment methods include compressibility studies and shear cell and repose angle measurements. Though widely accepted, these methods are not without limitations and inadequacies. More often than not, experimental and environmental conditions lead to a considerable amount of variability in the results obtained. The primary objective of this current work is to propose two new indices, avalanche flow index (AFI) and cohesive interaction index (CoI) based on the avalanche flow behaviors of powders. Not only were these two indices able to describe the ease of powder flow but they also provided a simpler means of quantifying the extent of cohesive interactions within the powder mass without elaborate mathematical functions.

Functionality of cross-linked polyvinylpyrrolidone as a spheronization aid: a promising alternative to microcrystalline cellulose.

PURPOSE: This work seeks to explore and demonstrate the functionality of cross-linked polyvinylpyrrolidone (crospovidone) as a spheronization aid and a promising alternative to microcrystalline cellulose (MCC). METHODS: Pellets were prepared with various grades of crospovidone using both small- and large-scale extrusion-spheronization. A Box-Behnken experimental design was employed to elucidate the effects of operating variables on the quality of the pellets. Size and shape analyses of these pellets were conducted and compared to those prepared using MCC. RESULTS: Crospovidone was believed to behave like a liquid repository in its interaction with water during extrusion-spheronization, although its binding ability was weaker than that of MCC. Spherical pellets of narrow size distribution could be made from the finer crospovidone grades with different lactose grades. However, crospovidone-based formulations required higher water levels than weight-equivalent MCC-based formulations. Crospovidone pellets were of equivalent quality to those prepared with MCC, especially in the shape, size, and yield. CONCLUSIONS: Crospovidone can be successfully employed as a spheronization aid to produce good pellets without the need of a binder, unlike most of the previously proposed materials. This study exemplified the enormous potential of crospovidone to serve as a competent alternative to MCC in the production of pellets by extrusion-spheronization.

A novel preformulation tool to group microcrystalline celluloses using artificial neural network and data clustering.

PURPOSE: To group microcrystalline celluloses (MCCs) using a combination of artificial neural network (ANN) and data clustering. METHODS: Radial basis function (RBF) network was used to model the torque measurements of the various MCCs. Output from the RBF network was used to group the MCCs using a data clustering technique known as discrete incremental clustering (DIC). Rheological or torque profiles of various MCCs at different combinations of mixing time and water:MCC ratios were obtained using mixer torque rheometry (MTR). Correlation analysis was performed on the derived torque parameter Torque(max) and physical properties of the MCCs. RESULTS: Depending on the leniency of the predefined threshold parameters, the 11 MCCs can be assigned into 2 or 3 groups. Grouping results were also able to identify bulk and tapped densities as major factors governing water-MCC interaction. MCCs differed in their water retentive capacities whereby the denser Avicel PH 301 and PH 302 were more sensitive to the added water. CONCLUSIONS: An objective grouping of MCCs can be achieved with a combination of ANN and DIC. This aids in the preliminary assessment of new or unknown MCCs. Key properties that control the performance of MCCs in their interactions with water can be discovered.