Nora Anne Urbanetz

Spray Drying of Mannitol as a Drug Carrier—The Impact of Process Parameters on Product Properties

Powders intended for the use in dry powder inhalers have to fulfill specific product properties, which must be closely controlled in order to ensure reproducible and efficient dosing. Spray drying is an ideal technique for the preparation of such powders for several reasons. The aim of this work was to investigate the influence of spray-drying process parameters on relevant product properties, namely, surface topography, size, breaking strength, and polymorphism of mannitol carrier particles intended for the use in dry powder inhalers. In order to address this question, a full-factorial design with four factors at two levels was used. The four factors were feed concentration (10 and 20% [w/w]), gas heater temperature (170 and 190°C), feed rate (10 and 20 L/h), and atomizer rotation speed (6,300 and 8,100 rpm). The liquid spray was carefully analyzed to better understand the dependence of the particle size of the final product on the former droplet size. High gas heater temperatures and low feed rates, corresponding to high outlet temperatures of the dryer (96–98°C), led to smoother particles with surfaces consisting of smaller crystals compared to those achieved at low outlet temperatures (74–75°C), due to lower gas heater temperatures and higher feed rates. A high solution concentration of the feed also resulted in the formation of comparably rougher surfaces than a low feed concentration. Spray-dried particles showed a volume-weighted mean particle size of 71.4–90.0 µm and narrow particle size distributions. The mean particle size was influenced by the atomizer rotation speed and feed concentration. Higher rotation speeds and lower feed concentrations resulted in smaller particles. Breaking strength of the dried particles was significantly influenced by gas heater temperature and feed rate. High gas heater temperatures increased the breaking strength, whereas high feed rates decreased it. No influence of the process parameters on the polymorphism was observed. All products were crystalline, consisting of at least 96.9% of mannitol crystal modification I.

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. The RMSEPs (root-mean-squared errors of prediction) obtained by PLS for the modifications (mods.) I(o), II and III were 0.44%, 0.34% and 0.36% respectively. The estimated limits of detection are approximately 0.5% (mod. I(o)) and <1% (mods. II and III). The ANNs model yielded slightly higher RMSEP values of 0.51%, 0.39% and 0.41%. In contrast to related previous studies, calibration was performed with carefully prepared ternary mixtures of all polymorphs, which is one of the reasons for the high precision and accuracy of the presented multivariate models.

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. This leads to an increase in coating efficiency of the process. The impact of various liquid additives and their properties like spreading behavior, viscosity and plasticizing activity were investigated with respect to their influence on the coating efficiency of the process. Ethylcellulose and hydroxypropyl methylcellulose acetate succinate were used as coating polymers. Spreading behavior of the liquid additive on the polymer was the most influencing parameter and could be successfully predicted with contact angle measurements on polymer films. Calculations of works of adhesion and spreading coefficients also revealed to be promising predictive techniques for choosing suitable additives to improve process efficiency. Isopropyl myristate showed the best spreading behavior resulting in the highest coating efficiency. Based on these results, a formulation for ethylcellulose containing isopropyl myristate was developed and film formation was examined using dissolution testing and imaging techniques to evaluate the optimum curing conditions.

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. Glass beads were chosen as model carriers because various prospects of physical surface modification may be applied without affecting other factors also impacting interparticle interactions like particle size and shape. To generate rough surfaces glass beads were processed mechanically by friction and impaction in a ball mill with different grinding materials that were smaller and harder with respect to the glass beads. By varying the grinding time (4 h, 8 h) and by using different grinding media (tungsten carbide, quartz) surfaces with different shades of roughness were generated. Depending on the hardness of the grinding material and the grinding time the surface roughness was more or less pronounced. Surface roughness parameters and specific surface area were determined via several complementary techniques in order to get an enhanced understanding of the impact of the modifying procedure on the surface properties of the glass beads.

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

Abstract 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. The total solubility parameter of about 24 MPa0.5 was confirmed by various procedures and compared with values of plasticizers. Twenty common pharmaceutical plasticizers were evaluated in terms of their suitability for supporting film formation of HPMCAS under dry coating conditions. Therefore, glass transition temperatures of mixtures of polymer and plasticizers were inspected and film formation of potential ones was further investigated in dry coating of pellets. Contact angles of plasticizers on HPMCAS were determined in order to give a hint of achievable coating efficiencies in dry coating, but none was found to spread on HPMCAS. A few common substances, e.g. dimethyl phthalate, glycerol monocaprylate, and polyethylene glycol 400, enabled plasticization of HPMCAS; however, only triethyl citrate and triacetin were found to be suitable for use in dry coating. Addition of acetylated monoglycerides to triacetin increased coating efficiency, which was likewise previously demonstrated for triethyl citrate.

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

Abstract 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. The drug detachment from the modified glass beads is also more reproducible than from untreated glass beads indicated by lower standard deviations for the FPFs of the modified glass beads. Moreover, the FPF of the modified glass beads correlates with their surface characteristics. The higher the surface roughness and the higher the specific surface area of the glass beads the higher is the FPF. Thus, surface-modified glass beads make an ideal carrier for tailoring the performance of DPIs in the therapy of asthma and chronically obstructive pulmonary diseases.

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. It was shown that the crystallization speed of salbutamol sulphate and base is a non-linear function of both temperature and relative humidity. The higher the relative humidity the higher is the crystallization speed. At 60% relative humidity salbutamol base as well as salbutamol sulphate were found to be amorphous even after 12 h, however samples changed optically. At 70% and 90% RH recrystallization of salbutamol base is completed after 3 h and 30 min and recrystallization of salbutamol sulphate after 4h and 1h, respectively. Higher temperature (35 °C) also leads to increased crystallization speeds at all tested values of relative humidity.

Evaluation and prediction of powder flowability in pharmaceutical tableting

Abstract 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. Using this system, flowability of different materials is measured at varying die speeds. A new curve fit to assess die fill ratio vs die speed is suggested improving predictability, and a novel flowability metric, “Die Fill Index” (DFI), is derived. The DFI is appropriate to describe flowability for most of the tested materials, and sensitivity of a material with respect to tableting speed. A correlation is generated predicting DFI from particle size. Additionally, it is shown that model die filling is the preferable method to assess flowability for tableting compared to ring shear tester.

Nano- and Microstructured model carrier surfaces to alter dry powder inhaler performance

The present study investigates the effect of different carrier surface modifications on the aerosolisation performance and on the effective carrier payload of interactive blends for inhalation. Two different active pharmaceutical ingredients (APIs) were used: Formoterol fumarate dihydrate (FF) and budesonide (BUD). Blends were prepared with glass beads as model carriers which have been subjected to mechanical surface modifications in order to introduce surface roughness via treatment with hydrofluoric acid (HF) and/or milling with tungsten carbide (TC). As far as effective carrier payload, in this study expressed as true surface coverage (TSC), is concerned, surface modification had varying effects on blends containing BUD or FF. Aerodynamic characterisation in vitro showed a significant decrease in respirable fraction for glass beads treated with HF (40.2-50.1%), due to the presence of clefts and cavities, where drug particles were sheltered during inhalation. In contrast, grinding with TC leads to surface roughness on a nano scale, ultimately increasing aerodynamic performance up to 20.0-38.1%. These findings are true for both APIs, regardless of their chemical properties.

Dry powder inhaler performance of spray dried mannitol with tailored surface morphologies as carrier and salbutamol sulphate

Nowadays, dry powder inhalation as applied in the therapy of pulmonary diseases is known as a very effective route of drug delivery to the lungs. Here, the system of coarse carrier and fine drug particles attached to the carrier surface has successfully been applied to overcome the cohesiveness of small drug particles. Particle properties of both carrier and drug are known to affect drug dispersion as has widely been discussed for lactose monohydrate and various drugs. This study utilises particle-engineered mannitol as an alternative carrier to discover the effect of mannitol carrier particle properties like particle shape, surface roughness, flowability or particle size on aerodynamic performance during inhalation. Spray drying as a technique to accurately control those properties was chosen for the generation of carrier sizes between 50 and 80 μm and different morphologies and therefore various carrier flowabilities. A set of these carriers has then been blended with different spray dried and jet-milled qualities of salbutamol sulphate as model drug to examine the influence of carrier particle properties on aerodynamic behaviour and at the same time to cover the effect of drug particle properties on particle-particle interactions. This experimental setup allowed a general view on how drug and carrier properties affect the Fine Particle Fraction (FPF) as indicator for inhalation performance and gave the first study to distinguish between mannitol carrier particle shape and surface roughness. Further it was possible to relate carrier particle size and shape to drug accumulation and detachment mechanisms during inhalation as size and shape had the main influence on drug detachment. The addition of jet-milled mannitol fines provided an initial insight into the improving effect of ternary powder blends as has been intensively studied for lactose monohydrate but not for mannitol yet.