Prediction of tablet weight variability in continuous manufacturing.

This paper provides a method for prediction of weight variability of tablets made in rotary tablet presses as a function of material attributes and processing parameters. The goal was to be able to predict whether or not a formulation is suitable for direct compaction continuous manufacturing using the tablet weight variability as a criterion. The work focused on identifying the significant factors affecting the weight variability in tablets, within the design space studied. A wide range of blends with different powder properties were prepared. It was shown that among powder properties, cohesion, bulk density, and particle size were the most significant and sufficient material attributes to explain tablet weight variability. A response surface model was built and validated with three different blends. The model is not formulation dependent and can be expanded to include other blend properties or processing parameters effects.

Modeling of Semicontinuous Fluid Bed Drying of Pharmaceutical Granules With Respect to Granule Size.

In the transition of the pharmaceutical industry from batchwise to continuous drug product manufacturing, the drying process has proven challenging to control and understand. In a semicontinuous fluid bed dryer, part of the ConsiGma™ wet granulation line, the aforementioned production methods converge. Previous research has shown that the evolution of moisture content of the material in this system shows strong variation in function of the granule size, making the accurate prediction of this pharmaceutical critical quality attribute a complex case. In this work, the evolution of moisture content of the material in the system is modeled by a bottom-up approach. A single granule drying kinetics model is used to predict the moisture content evolution of a batch of material of a heterogeneous particle size, where it is the first time that the single granule drying mechanism is validated for different granule sizes. The batch approach was validated when the continuous material inflow rate and filling time of the dryer cell are constant. The original single granule drying kinetics model has been extended to capture the granules' equilibrium moisture content. Finally, the influence of drying air temperature is captured well with a droplet energy balance for the granules.

Model development and prediction of particle size distribution, density and friability of a comilling operation in a continuous pharmaceutical manufacturing process.

The comilling process plays an important role in solid oral dosage manufacturing. In this process, the granulated products are comminuted to the required size distribution through collisions created from a rotating impeller. In addition to predicting particle size distribution, there is a need to predict other critical quality attributes (CQAs) such as bulk density and tapped density, as these impact tablet compaction behavior. A comprehensive modeling approach to predict the CQAs is needed to aid continuous process modeling in order to simulate interaction with the tablet press operation. In the current work, a full factorial experiment design is implemented to understand the influence of granule strength, impeller speed and residual moisture content on the CQAs. A population balance modeling approach is applied to predict milled particle size distribution and a partial least squares modeling approach is used to predict bulk and tapped density of the milled granule product. Good agreement between predicted and experimental CQAs is achieved. An R2 value of 0.9787 and 0.7633 is obtained when fitting the mean particle diameters of the milled product and the time required to mill the granulated material respectively.

Oral bioavailability enhancement of flubendazole by developing nanofibrous solid dosage forms.

The bioavailability of the anthelminthic flubendazole was remarkably enhanced in comparison with the pure crystalline drug by developing completely amorphous electrospun nanofibres with a matrix consisting of hydroxypropyl-ß-cyclodextrin and polyvinylpyrrolidone. The thus produced formulations can potentially be active against macrofilariae parasites causing tropical diseases, for example, river blindness and elephantiasis, which affect altogether more than a hundred million people worldwide. The bioavailability enhancement was based on the considerably improved dissolution. The release of a dose of 40 mg could be achieved within 15 min. Accordingly, administration of the nanofibrous system ensured an increased plasma concentration profile in rats in contrast to the practically non-absorbable crystalline flubendazole. Furthermore, easy-to-grind fibers could be developed, which enabled compression of easily administrable immediate release tablets.

Lubricant-Induced Crystallization of Itraconazole From Tablets Made of Electrospun Amorphous Solid Dispersion.

Investigation of downstream processing of nanofibrous amorphous solid dispersions to generate tablet formulation is in a quite early phase. Development of high speed electrospinning opened up the possibility to study tableting of electrospun solid dispersions (containing polyvinylpyrrolidone-vinyl acetate and itraconazole [ITR] in this case). This work was conducted to investigate the influence of excipients on dissolution properties and the feasibility of scaled-up rotary press tableting. The dissolution rates from tablets proved to be mainly composition dependent. Magnesium stearate acted as a nucleation promoting agent (providing an active hydrophobic environment for crystallization of ITR) hindering the total dissolution of ITR. This crystallization process proved to be temperature dependent as well. However, the extent of dissolution of more than 95% was realizable when a less hydrophobic lubricant, sodium stearyl fumarate (soluble in the medium), was applied. Magnesium stearate induced crystallization even if it was put in the dissolution medium next to proper tablets. After optimization of the composition, scaled-up tableting on a rotary press was carried out. Appropriate dissolution of ITR from tablets was maintained for 3 months at 25°C/60% relative humidity. HPLC measurements confirmed that ITR was chemically stable both in the course of downstream processing and storage.

Melt-blown and electrospun drug-loaded polymer fiber mats for dissolution enhancement: a comparative study.

Melt blowing (MB) was investigated to prepare a fast dissolving fibrous drug-loaded solid dispersion and compared with solvent-based electrospinning (SES) and melt electrospinning (MES). As a conventional solvent-free technique coupled with melt extrusion and using a high-speed gas stream, MB can provide high-quality micro- and nanofibers at industrial throughput levels. Carvedilol, a weak-base model drug with poor water solubility, was processed using a common composition optimized for the fiber spinning and blowing methods based on a hydrophilic vinylpyrrolidone-vinyl acetate copolymer (PVPVA64) and PEG 3000 plasticizer. Scanning electron microscopy combined with fiber diameter analysis showed diameter distributions characteristic to each prepared fibrous fabrics (the mean value increased toward SES

High speed electrospinning for scaled-up production of amorphous solid dispersion of itraconazole.

High speed electrospinning (HSES), compatible with pharmaceutical industry, was used to demonstrate the viability of the preparation of drug-loaded polymer nanofibers with radically higher productivity than the known single-needle electrospinning (SNES) setup. Poorly water-soluble itraconazole (ITRA) was formulated with PVPVA64 matrix polymer using four different solvent-based methods such as HSES, SNES, spray drying (SD) and film casting (FC). The formulations were assessed in terms of improvement in the dissolution rate of ITRA (using a "tapped basket" dissolution configuration) and analysed by SEM, DSC and XRPD. Despite the significantly increased productivity of HSES, the obtained morphology was very similar to the SNES nanofibrous material. ITRA transformed into an amorphous form, according to the DSC and XRPD results, in most cases except the FC samples. The limited dissolution of crystalline ITRA could be highly improved: fast dissolution occurred (>90% within 10min) in the cases of both (the scaled-up and the single-needle) types of electrospun fibers, while the improvement in the dissolution rate of the spray-dried microspheres was significantly lower. Production of amorphous solid dispersions (ASDs) with the HSES system proved to be flexibly scalable and easy to integrate into a continuous pharmaceutical manufacturing line, which opens new routes for the development of industrially relevant nanopharmaceuticals.

Visualization and understanding of the granulation liquid mixing and distribution during continuous twin screw granulation using NIR chemical imaging.

Over the last decade, there has been increased interest in the application of twin screw granulation as a continuous wet granulation technique for pharmaceutical drug formulations. However, the mixing of granulation liquid and powder material during the short residence time inside the screw chamber and the atypical particle size distribution (PSD) of granules produced by twin screw granulation is not yet fully understood. Therefore, this study aims at visualizing the granulation liquid mixing and distribution during continuous twin screw granulation using NIR chemical imaging. In first instance, the residence time of material inside the barrel was investigated as function of screw speed and moisture content followed by the visualization of the granulation liquid distribution as function of different formulation and process parameters (liquid feed rate, liquid addition method, screw configuration, moisture content and barrel filling degree). The link between moisture uniformity and granule size distributions was also studied. For residence time analysis, increased screw speed and lower moisture content resulted to a shorter mean residence time and narrower residence time distribution. Besides, the distribution of granulation liquid was more homogenous at higher moisture content and with more kneading zones on the granulator screws. After optimization of the screw configuration, a two-level full factorial experimental design was performed to evaluate the influence of moisture content, screw speed and powder feed rate on the mixing efficiency of the powder and liquid phase. From these results, it was concluded that only increasing the moisture content significantly improved the granulation liquid distribution. This study demonstrates that NIR chemical imaging is a fast and adequate measurement tool for allowing process visualization and hence for providing better process understanding of a continuous twin screw granulation system.

Influence of the punch diameter and curvature on the yield pressure of MCC-compacts during Heckel analysis.

The volume reduction behaviour of powders has been quantified by means of the 'in-die' yield pressure (YP) using Heckel analysis. However, because different YPs are reported for the same material, the experimental conditions influencing this material-constant were investigated. Silicified microcrystalline cellulose was compressed into flat-faced and convex tablets using a compaction simulator instrumented with load and displacement transducers. During compression, upper and lower punch force and displacement data were recorded and corrected for punch deformation. A symmetrical triangle wave compression profile was used and the instantaneous punch velocity was kept constant (5mm/s). Individual tablet height and weight were used for Heckel analysis. The influence of the 'effective compression pressure' (P(EFF)) (ranging from 10 to 350 MPa), punch diameter (PD) (4, 9.5 and 12 mm) and filling depth (FD) (4.5, 7.5 and 10.5mm) on YP was statistically evaluated using Response Surface Modelling software. A quadratic surface response equation, describing the relationship between P(EFF), PD, FD and YP, was proposed for concave (Adj R(2): 0.8424; S.D.: 14.60 MPa) and flat-faced (Adj R(2): 0.8409; S.D.: 4.49 MPa) punches. YP and tensile strength were mainly determined by P(EFF), irrespective of punch curvature. FD and PD had only a minor influence on the YP, although more pronounced for the concave punches. The method used resulted in reproducible P(EFF) and tensile strength values and the flat-faced tablets showed less weight variation. Flat-faced punches are preferred over punches with a concave surface when investigating the volume reduction behaviour of a powder by means of Heckel analysis and the experimental parameters should be reported.