Scale-up analysis of geometrically dissimilar single-use bioreactors.

Cell culture scale-up is a challenging task due to the simultaneous change of multiple hydrodynamic process characteristics and their different dependencies on the bioreactor size as well as variation in the requirements of individual cell lines. Conventionally, the volumetric power input is the most common parameter to select the impeller speed for scale-up, however, it is well reported that this approach fails when there are huge differences in bioreactor scales. In this study, different scale-up criteria are evaluated.

Impact of post-freeze annealing on shrinkage of sucrose and trehalose lyophilisates.

Freeze-drying of pharmaceuticals produces lyophilisates with properties that depend on both the formulation and the process. Characterisation of the lyophilisate in terms of appearance is necessary not only to produce a visually appealing product, but also to gain insight into the freeze-drying process. The present study investigates the impact of post-freeze annealing on the volume of lyophilisates.

Quantitative Analysis of Glassy State Relaxation and Ostwald Ripening during Annealing Using Freeze-Drying Microscopy.

Supercooling during the freezing of pharmaceutical solutions often leads to suboptimal freeze-drying results, such as long primary drying times or a collapse in the cake structure. Thermal treatment of the frozen solution, known as annealing, can improve those issues by influencing properties such as the pore size and collapse temperature of the lyophilisate. In this study we aimed to show that annealing causes a rearrangement of water molecules between ice crystals, as well as between the freeze-concentrated amorphous matrix and the crystalline ice phase in a frozen binary aqueous solution.

Numerical and Experimental Investigation of the Hydrodynamics in the Single-Use Bioreactor Mobius CellReady 3 L.

Two-way Euler-Lagrange simulations are performed to characterize the hydrodynamics in the single-use bioreactor Mobius CellReady 3 L. The hydrodynamics in stirred tank bioreactors are frequently modeled with the Euler-Euler approach, which cannot capture the trajectories of single bubbles. The present study employs the two-way coupled Euler-Lagrange approach, which accounts for the individual bubble trajectories through Langrangian equations and considers their impact on the Eulerian liquid phase equations.

CFD-Based and Experimental Hydrodynamic Characterization of the Single-Use Bioreactor Xcellerex XDR-10.

Understanding the hydrodynamic conditions in bioreactors is of utmost importance for the selection of operating conditions during cell culture process development. In the present study, the two-phase flow in the lab-scale single-use bioreactor XcellerexTM XDR-10 is characterized for working volumes from 4.5 L to 10 L, impeller speeds from 40 rpm to 360 rpm, and sparging with two different microporous spargers at rates from 0.

Influence of particle size and blender size on blending performance of bi-component granular mixing: A DEM and experimental study.

The effect of particle size enlargement and blender geometry down-scaling on the blend uniformity (BU) was evaluated by Discrete Element Method (DEM) to predict the blending performance of a binary granular mixture. Three 10 kg blending experiments differentiated by the physical properties specifically particle size were performed as reference for DEM simulations. The segregation behavior observed during the diffusion blending was common for all blends, while the sample BU, i.

Selection of a round convex tablet shape that mitigates the risk of chipping and capping based on systematic evaluation by utilizing multivariate analysis.

Selecting a tablet shape that minimizes the risk of chipping and capping during manufacture is important in pharmaceutical industry. Here, the selection was performed based on systematic evaluation for the first time. Abrasion and stress relaxation time were utilized as indices of the occurrences of chipping and capping, respectively.

Evaluation and prediction of powder flowability in pharmaceutical tableting.

The focus of this study is to establish a characterization method determining the powder flowability in context of tableting. At first, flowability of different materials is measured using the ring shear tester, and its prediction from particle size is established. Next, the model die-filling system is presented which is a modified version of previous studies.

High efficiency dry coating of non-subcoated pellets for sustained drug release formulations using amino methacrylate copolymers.

Dry coating utilizing a fluidized bed was evaluated in order to produce films with sustained drug release using amino methacrylate copolymers as film former. In contrast to other dry coating procedures using amino methacrylate copolymers, the described method enables an appropriate polymer adhesion by the selection of a plasticizer additive mixture in combination with the use of a three-way nozzle for simultaneous application. Well spreading fatty acid esters were found to increase the coating efficiency from 73% to approximately 86%, when they were used in conjunction with the plasticizer.

Setting the process parameters for the coating process in order to assure tablet appearance based on multivariate analysis of prior data.

Designing efficient, robust process parameters in drug product manufacturing is important to assure a drug's critical quality attributes. In this research, an efficient, novel procedure for a coating process parameter setting was developed, which establishes a prediction model for setting suitable input process parameters by utilizing prior manufacturing knowledge for partial least squares regression (PLSR). In the proposed procedure, target values or ranges of the output parameters are first determined, including tablet moisture content, spray mist condition, and mechanical stress on tablets.

Solubility parameters of hypromellose acetate succinate and plasticization in dry coating procedures.

Solubility parameters of HPMCAS have not yet been investigated intensively. On this account, total and three-dimensional solubility parameters of HPMCAS were determined by using different experimental as well as computational methods. In addition, solubility properties of HPMCAS in a huge number of solvents were tested and a Teas plot for HPMCAS was created.

Crystallization speed of salbutamol as a function of relative humidity and temperature.

Spray dried salbutamol sulphate and salbutamol base particles are amorphous as a result of spray drying. As there is always the risk of recrystallization of amorphous material, the aim of this work is the evaluation of the temperature and humidity dependent recrystallization of spray dried salbutamol sulphate and base. Therefore in-situ Powder X-ray Diffraction (PXRD) studies of the crystallization process at various temperature (25 and 35 °C) and humidity (60%, 70%, 80%, 90% relative humidity) conditions were performed.

Influence of surface characteristics of modified glass beads as model carriers in dry powder inhalers (DPIs) on the aerosolization performance.

The aim of this work is to investigate the effect of surface characteristics (surface roughness and specific surface area) of surface-modified glass beads as model carriers in dry powder inhalers (DPIs) on the aerosolization, and thus, the in vitro respirable fraction often referred to as fine particle fraction (FPF). By processing glass beads in a ball mill with different grinding materials (quartz and tungsten carbide) and varying grinding time (4 h and 8 h), and by plasma etching for 1 min, glass beads with different shades of surface roughness and increased surface area were prepared. Compared with untreated glass beads, the surface-modified rough glass beads show increased FPFs.

Preparation and characterization of physically modified glass beads used as model carriers in dry powder inhalers.

The aim of this work is the physical modification and characterization of the surface topography of glass beads used as model carriers in dry powder inhalers (DPIs). By surface modification the contact area between drug and carrier and thereby interparticle forces may be modified. Thus the performance of DPIs that relies on interparticle interactions may be improved.

Evaluating the process parameters of the dry coating process using a 2(5-1) factorial design.

Context: A recent development of coating technology is dry coating, where polymer powder and liquid plasticizer are layered on the cores without using organic solvents or water. Several studies evaluating the process were introduced in literature, however, little information about the critical process parameters (CPPs) is given.

Aim: Aim of the study was the investigation and optimization of CPPs with respect to one of the critical quality attributes (CQAs), the coating efficiency of the dry coating process in a rotary fluid bed.

Perfusion calorimetry in the characterization of solvates forming isomorphic desolvates.

In this study, the potential of perfusion calorimetry in the characterization of solvates forming isomorphic desolvates was investigated. Perfusion calorimetry was used to expose different hydrates forming isomorphic desolvates (emodepside hydrates II-IV, erythromycin A dihydrate and spirapril hydrochloride monohydrate) to stepwise increasing relative vapour pressures (RVP) of water and methanol, respectively, while measuring thermal activity. Furthermore, the suitability of perfusion calorimetry to distinguish the transformation of a desolvate into an isomorphic solvate from the adsorption of solvent molecules to crystal surfaces as well as from solvate formation that is accompanied by structural rearrangement was investigated.

Impact of excipients on coating efficiency in dry powder coating.

Dry powder coating is a technique to coat substrates without the use of organic solvent or water. The polymer powder is directly applied to the cores to be coated. Liquid additives are often used to lower the glass transition temperature of the polymer and to enhance the adhesion of the powder to the cores.

Stability of dry coated solid dosage forms.

The dry coating process was evaluated in terms of storage stability investigating drug release and agglomeration tendency of the different coated oral dosage forms; hydroxypropyl methylcellulose acetate succinate (HPMCAS) was used with triethylcitrate (TEC) as plasticizer and acetylated monoglyceride (Myvacet) as wetting agent. Talc or colloidal silicon dioxide (Aerosil) was used as anti-tacking agents. In contrast to coating formulations consisting of HPMCAS and Myvacet all formulations containing TEC showed enteric resistance and no agglomeration tendency after preparation.

Simultaneous quantitative analysis of ternary mixtures of D-mannitol polymorphs by FT-Raman spectroscopy and multivariate calibration models.

D-mannitol is known to exist in five solid-state forms, a hemihydrate, an amorphous form and three polymorphic forms (I(o), II and III), which tend to crystallize concomitantly. Therefore, a fast and simple method for the simultaneous quantification of these polymorphs in powder mixtures was developed on the basis of FT-Raman spectroscopic data, partial least-squares (PLS) regression and artificial neural networks (ANNs). A combination of the first derivative and orthogonal signal correction (OSC) was found to be the optimal data pretreatment that significantly increased the predictive performance of the models.

Influence of carrier surface fines on dry powder inhalation formulations.

Background: The performance of carrier-based dry powder inhalation formulations strongly depends on particle interactions between the drug and the carrier. Among other factors like particle size and shape, surface properties of the interacting partners play a decisive role. This study aims at investigating the effect of carrier surface characteristics on the in vitro deposition of ordered mixtures containing salbutamol sulfate as a drug and lactose and mannitol as model carrier compounds.

The role of capillary force promoters in dry coating procedures--evaluation of acetylated monoglyceride, isopropyl myristate and palmitate.

Previous studies described several dry powder coating procedures. Most of these techniques used polymer powders and plasticizers for attaining film formation. Thermo analytical methods showed that some of the used plasticizers did not reduce the glass transition temperature of the polymer markedly and consequently did not act as a plasticizer in a typical way.

Parameters influencing polymer particle layering of the dry coating process.

The dry coating process is an emerging coating technology using neither organic solvents nor water. In contrast to liquid-borne coatings, coating material application and film formation are divided into two phases, the coating phase where the powdery coating material is applied together with the liquid plasticizer, and the curing phase. In this study the coating phase was characterized with respect to the forces acting between the polymer particles during material application.

Quantifying the degree of disorder in micronized salbutamol sulfate using moisture sorption analysis.

Salbutamol sulfate is often micronized for use in dry powder inhalers. Therefore, it is of high interest to quantify the amorphous amount. It was investigated whether moisture sorption is able to measure the amorphous content of salbutamol sulfate.

Characterization of the film formation of the dry coating process.

As the film formation of the dry coating process differs completely from conventional coating methods it is of certain interest to define a parameter like the minimum film formation temperature (MFT) used for aqueous dispersion based processes in order to describe an efficient film formation. Film formation occurs mainly during the curing step following the coating phase. Therefore, the film formation of the dry coating process was analyzed with regard to the two process parameters influencing film formation, namely curing temperature and time.