Evolution of the microstructure and the drug release upon annealing the drug loaded lipid-surfactant microspheres.

The present study investigates the drug release-governing microstructural properties of melt spray congealed microspheres encapsulating the drug crystals in the matrix of glyceryl behenate and poloxamer (pore former). The solid-state, morphology, and micromeritics of the microspheres were characterized, before and after annealing, using calorimetry, X-ray scattering, porosimetry, scanning electron microscopy, and, NMR diffusometry. The in vitro drug release from and water uptake by the microspheres were obtained. The extent and the rate of drug release from the microspheres increased with a high poloxamer content and at higher annealing temperature and RH. All the drug release profiles were describable using the Higuchi release kinetics pointing towards the diffusion controlled release, both before and after annealing. The annealing process led to the polymorphic conversion of lipid and the increase in the pore size, predominantly at a higher temperature and humidity and for a high poloxamer content. The poloxamer domain increased from an initial 300 nm, up to 2000 nm upon annealing. The water diffusion rate inside the annealed microsphere was twice as fast as for unannealed counterparts. The findings relate the overall phase and pore structure change of the microsphere to the increased drug release induced by annealing. This work serves as a basis for the rational understanding of the modification of the in vitro performance by annealing, a widely used post-process for solid lipid products.

Computational Fluid Dynamics-Discrete Element Method Modeling of an Industrial-Scale Wurster Coater.

Large-scale fluid bed coating operations using Wurster coaters are common in the pharmaceutical industry. Experimental measurements of the coating thickness are usually analyzed for just few particles. To better predict the coating uniformity of the entire batch, computational techniques can be applied for process understanding of the key process parameters that influence the quality attributes. Recent advances in computational hardware, such as graphics processing unit, have enabled simulations of large industrial-scale systems. In this work, we perform coupled computational fluid dynamics-discrete element method simulations of a large-scale coater that model the actual particle sizes. The influence of process parameters, inlet air flow rate, atomizing air flow rate, bead size distribution, and Wurster gap height is studied. The focus of this study is to characterize the flow inside the coater; eventually, this information will be used to predict the coating uniformity of the beads. We report the residence time distribution of the beads inside the Wurster column, that is, the active coating zone, which serves as a proxy for the amount of coating received by the beads per pass. The residence time provides qualitative and quantitative measurements of the particle-coating uniformity. We find that inlet air flow rate has the largest impact on the flow behavior and, hence, the coating uniformity.

Detailed modeling and process design of an advanced continuous powder mixer.

A vertical in-line continuous powder mixing device (CMT - Continuous Mixing Technology) has been modelled with the discrete element method (DEM) utilizing a calibrated cohesive contact model. The vertical design of the mixing device allows independent control of mean residence time (MRT) and shear rate. The hold-up mass and outlet flow are controlled by an exit valve, located at the bottom of the in-line mixer. A virtual design of experiments (DoE) of DEM simulations has been performed and parameters such as particle velocities, powder bed shape, residence time distribution (RTD), travel distance, and mixing quality are evaluated for the complete operating space. The RTD of the DEM model has been validated with tracer experiments. The resulting RTD has been fitted with an analytical form (generalized cascade of n continuous stirred tank reactors) and utilized to study the downstream response of the continuous mixing device to upstream fluctuations in the inlet material stream. The results indicate a high mixing quality and good filtering properties across the operating space. However, the combination of low hold-up mass and high impeller speeds leads to a reduced filtering capability and wider exit valve openings, indicating a less desirable operating point.

Process modeling in the pharmaceutical industry using the discrete element method.

The discrete element method (DEM) is widely used to model a range of processes across many industries. This paper reviews current DEM models for several common pharmaceutical processes including material transport and storage, blending, granulation, milling, compression, and film coating. The studies described in this review yielded interesting results that provided insight into the effects of various material properties and operating conditions on pharmaceutical processes. Additionally, some basic elements common to most DEM models are overviewed. A discussion of some common model extensions such as nonspherical particle shapes, noncontact forces, and interstitial fluids is also presented. While these more complex systems have been the focus of many recent studies, considerable work must still be completed to gain a better understanding of how they can affect the processing behavior of bulk solids.

Improving the content uniformity of a low-dose tablet formulation through roller compaction optimization.

In this investigation, the potency distribution of a low-dose drug in a granulation was optimized through a two-part study using statistically designed experiments. The purpose of this investigation was to minimize the segregation potential by improving content uniformity across the granule particle size distribution, thereby improving content uniformity in the tablet. Initial operating parameters on the Gerteis 3-W-Polygran 250/100/3 Roller Compactor resulted in a U-shaped potency function (potency vs. granule particle size) with superpotent fines and large granules. The roller compaction optimization study was carried out in two parts. Study I used a full factorial design with roll force (RF) and average gap width (GW) as independent variables and Study II used a D-optimal response surface design with four factors: RF, GW, granulating sieve size (SS), and granulator speed (GS). The planned response variables for Study I were bypass weight % and potency of bypass. Response variables for Study II included mean granulation potency with % relative standard deviation (% RSD), granulation particle size, sieve cut potency % RSD, tablet potency with % RSD, compression force at 7 kP crushing strength, and friability of 7-kP tablets. A constraint on GW was determined in Study I by statistical analysis. Bypass and observations of ribbon splitting were minimized when GW was less than 2.6 mm. In Study II, granulation potency, granulation uniformity, and sieve cut uniformity were optimized when the SS was 0.8 mm. Higher RF during dry granulation produced better sieve cut uniformity and tablets with improved uniformity throughout the run, as measured by stratified tablet samples taken during compression and assayed for potency. The recommended optimum roller compaction and milling operating parameters that simultaneously met all constraints were RF = 9 kN, GW = 2.3 mm, SS = 0.8 mm, and GS = 50 rpm. These parameters became the operating parameter set points during a model confirmation trial. The results from the confirmation trial proved that the new roller compaction and milling conditions reduced the potential for segregation by minimizing the granulation potency variability as a function of particle size as expressed by sieve cut potency % RSD, and thus improved content uniformity of stratified tablet samples.