Poor Powder Flow Research Articles

Assessment of granulation technologies for an API with poor physical properties

Granulation technologies are widely used in solid oral dosage forms to improve the physical properties during manufacture. Wet, dry, and melt granulation techniques were assessed for Compound A, a BCS class II compound. Characterization techniques were used to quantify physical property limitations inherent for Compound A including hygroscopicity, low solubility and bulk density, and poor powder flowability. High shear aqueous wet granulation induced an undesirable water mediated phase transition of the solid form. A formulation and process for dry granulation by roller compaction was developed and scaled to 10 kg batch size. Roll force, and roll gap parameters were assessed. Porosity of compacted ribbons was analyzed by mercury intrusion porosimetry, and particle size distributions of milled ribbons by sieve analysis. A roll force of 15 kN/cm produced granules with higher density and improved flow properties compared to the pre-blend. Fines content (<75 µm) decreased from approximately 90% pre-granulation to 26% post-granulation. Cohesive properties of Compound A limited drug loading (API:excipient ratio) in roller compaction to 0.6:1 or less. Hot melt granulation by extrusion assessed with four polymers. A vast improvement in drug loading of 4:1 was achieved via melt processes using low molecular weight thermo-binders (glyceryl behenate and Polyethylene glycol 4000). Granules produced by melt processing contained less fines compared to wet and dry granulation. Both roller compaction and melt extrusion are viable granulation process alternatives for scale up to overcome the physical property limitations of Compound A.

Profoundly improving flow properties of a cohesive cellulose powder by surface coating with nano‐silica through comilling

Poor flow properties hinder the easy handling of powders during industrial-scale processing. In this work, we show that powder flow can be substantially improved by reducing the cohesion of powders by coating them with nanosized guest particles. We further show that comilling is an efficient process for nanocoating. We have systematically investigated the effects of total number of comilling cycles (10-70 cycles) and silica loading (0-1.0 wt %) on the flow behavior of a highly cohesive and poorly flowing grade of microcrystalline cellulose powder (Avicel PH105). Optimum flow enhancement has been achieved with 1.0 wt % silica loading at 40 comilling cycles. The flow properties of nanocoated Avicel PH105 are comparable to those of Avicel PH102, which exhibits adequate flowability for processing on a high-speed tablet press. Comilling is fast and suitable for continuous processing. It shows potential for addressing industrial powder handling problems caused by poor powder flow properties.

Drug release mechanisms of cast lipid implants

The aim of this work was to better understand which physicochemical processes are involved in the control of drug release from lipid implants prepared by melting and casting. Lipid implants gain steadily in importance as controlled parenteral drug delivery systems: In contrast to PLGA-based devices, no acidic microclimates are created, which can inactivate incorporated drugs. The melting and casting method offers various advantages over the commonly used direct compression technique. For example, powder de-mixing during manufacturing and highly challenging scale-up due to poor powder flowability are avoided. Importantly, broad spectra of drug release patterns can be easily provided by varying the type of lipid. The resulting drug release rates are generally lower than those of implants prepared by direct compression. This is probably due to the differences in the microstructure of the pore network of the systems. Drug or water diffusion plays a dominant role for the control of drug release, potentially combined with limited drug solubility effects, caused by the low amounts of water available within the implants. In the case of pure diffusion control, a mechanistic realistic mathematical theory is proposed, which allows for quantitative predictions of the effects of formulation parameters on the resulting drug release kinetics. Importantly, these theoretical predictions could be successfully confirmed by independent experiments. Thus, the obtained new insight into the underlying drug release mechanisms can significantly facilitate the optimization of this type of advanced drug delivery systems. This is particularly helpful if long release periods are targeted, requiring time-consuming experimental studies.

Improving Powder Flow Properties of a Cohesive Lactose Monohydrate Powder by Intensive Mechanical Dry Coating

The objective of this study was to improve the cohesive lactose powder flowability. A cohesive lactose monohydrate powder was processed in either a tumbling blender or an intensive mechanical processor with either magnesium stearate or fumed silica. No substantial changes in particle size were detected by laser diffraction following either treatment. The untreated lactose sample exhibited very poor powder flow. Only limited improvements in powder flowability were indicated after the tumbling blending, intensive mechanical processing with the fumed silica or without additives. However, the intensive mechanical processing of the lactose sample with magnesium stearate demonstrated exceptionally large increases in both poured and tapped density as well as notable improvements in all powder flowability indicators examined. Our findings support the use of intensive mechanical processing technique as an effective method to coat cohesive pharmaceutical powders with selected additives, modify the surface nature of the particles, reduce the interparticle cohesive forces and hence improve powder flowability. The subtle differences in powder flow behaviour of lactose samples between the untreated and tumbling blended powders with magnesium stearate were only detected by the powder rheometer using its dynamic mode, indicating its potential advantages over traditional powder flow characterisation approaches. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:969–981, 2010

Effect of host particle size on the modification of powder flow behaviours for lactose monohydrate following dry coating

Our previous work demonstrated that the powder flowability of a cohesive lactose sample can be improved substantially using a dry coating technique. Our study reported here aims to investigate the influence of host particle size on the modification of powder flowability following dry coating process. Four commercial lactose monohydrate powders with different particle sizes were coated by an intensive mechanical process or mixed using a conventional tumbling process, both with magnesium stearate. All four untreated lactose samples showed a relatively poor powder flow. After dry coating, poured and tapped densities of all the lactose samples increased, while Carr indices and Hausner ratios decreased substantially. The angle of repose values were reduced to a notable extent only for particles with a median size larger than about 7 μm after dry coating. Both specific energy (SE) and cohesion values of lactose samples, measured by a powder rheometer system, decreased substantially after coating. In contrast, no apparent changes in powder flow were evident for conventionally mixed batches, except that in the dynamic powder rheometry measurement, a relatively small change in SE was observed. This study demonstrated that for the finer particles examined, cohesive forces were more influential in the powder bed after the surface treatment and resulted in a relatively poor flow. However, for the larger powders studied, the cohesive inter-particle forces could be overcome after this dry coating, whereby satisfactory flow could be obtained. This study indicated that the host particle size was a critical factor in influencing the modification of cohesive powder flowability.

Investigations into the use of pregelatinised starch to develop powder-filled hard capsules

The use of pregelatinised starch in tamp filling of hard capsules with powder formulations containing a low-solubility drug (theophylline anhydrous) with very poor powder flow and stickiness to metal surfaces was investigated. Twenty-one mixtures containing the drug, pregelatinised starch, lactose monohydrate and magnesium stearate were produced, with their quantitative composition based on a central composite design. These mixtures were filled into hard capsules using an instrumented tamp-filling machine. Seven different compression settings ranging from “no” to “firm” compression were employed, and the tamping force was recorded on stations 3 and 4. It was found that the use of pregelatinised starch as an excipient in the manufacture of powder-filled hard capsules could be beneficial in terms of reducing the coefficient of fill weight variability. To improve drug dissolution of poorly soluble drugs, larger amounts of this excipient were required, and the maximum capsule fill weight that could be achieved was slightly reduced at the same time.

Novel Method for Assessment of Critical Powder Packing During Powder Forming

AbstractPowder forming of a successful product requires initial selection of powder with appropriate packing characteristics. Packing estimations from particle characteristics are erratic, and estimations from apparent density and tap density measurements are only moderately good because of poor powder flow as a result of inter particulate friction. Use of a wetting fluid in the torque measurement method avoids friction and allows particle rearrangement, but the monitoring of torque or viscosity changes with powder binder mixing requires costly equipment. A simpler method for the assessment of the critical packing volume concentration (CPVC) of a given powder by monitoring temperature during mixing is proposed. The CPVC values of different powders are measured with the new method. The effects of powder characteristics and operational parameters on the CPVC estimation are studied. The packing values arrived at by this method are found to agree with those from the torque measurement method. PM/0703