Are we as PhD students doing enough to facilitate collaborations across PSSRC?
Written by Anne Linnet Skelbæk-Pedersena word from one of our "Best Presentation Award" winners:
Anne Linnet Skelbæk-Pedersen
STAR PhD student
Oral Pilot and Process Development
Novo Nordisk A/S
Influence of the Suspension Composition on the Mechanical Strength of Dried Microspheres
Written by Manuel KreimerSpray drying is widely used in pharmaceutical manufacturing to produce microspheres from solutions or suspensions. The mechanical properties of the microspheres are reflected by the morphology formed in the drying process. In suspension drying, solids dissolved in the carrier liquid may form bridges between the suspended primary particles, producing a microsphere structure which is resistant against mechanical loads. Experiments with individual, acoustically levitated droplets were performed to simulate the drying of suspension droplets in a spray drying process.
Novel stand-alone test tool for scientific qualification of a dosator capsule filling process
Written by Sandra StranzingerOne of the biggest problems in the manufacturing of high-quality low-dose inhalation products, is dose uniformity of filled capsules [1]. Our approach towards a scientific qualification of dosator nozzles for low-fill weight (1–45 mg) capsule filling comprises a decoupling of the filling process in dynamic and static mode tests, whereas the latter was carried out using a novel filling system, i.e. stand-alone static test tool, developed by us.
Modeling Powder Compaction using a Multi-Particle Finite Element Model
Written by Peter Loidolt, Manfred H. Ulz & Johannes Khinast1. Introduction
Cold compaction of powder is important for many industrial processes, e.g., for the production of green bodies before sintering of metallic or ceramic parts in mechanical engineering, pellets for mineral or animal food industry or the production of tablets in the pharmaceutical industry. The final powder compact requires a minimum strength as otherwise it would disintegrate during processing, transportation or storage. Experiments can be used to adjust the process to get the desired compact strength. This is time-consuming, as process parameters change often, e.g., the geometry of the machine tools or the powder properties. Hence, reliable numerical models to predict the properties of compacts with simulations are crucial.
Controlled expansion of supercritical solutions: an alternative method for producing nanoparticles with supercritical carbon dioxide
Written by Jenni PessiControl performance of different roll compactors
Written by Kitti CsordasDoes PLGA microparticle swelling control drug release?
Written by Hanane GasmiBackground
Poly(lactic-co-glycolic acid) (PLGA)-based microparticles offer a great potential as parenteral controlled drug delivery systems [1]. Different types of drug release patterns can be obtained from PLGA microparticles, in particular mono-, bi-, or tri-phasic drug release kinetics. Interestingly, yet the underlying mass transport mechanisms in PLGA microparticles are not fully understood, despite their great practical importance. This can be attributed to the complexity of the involved mass transport mechanisms. The aim of this study was to better understand the mass transport mechanisms controlling drug release from PLGA microparticles. Importantly, new insight was gained based on the experimental monitoring of the swelling kinetics of single microparticles.
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Ensuring thermodynamic stability of amorphous solid dispersions by predicting drug-polymer solubility
Written by Matthias Manne Knopp, Rene Holm and Thomas RadesThe potential of amorphous solid dispersions to improve the solubility, dissolution rate and bioavailability of poorly water soluble drugs is well known. However, the number of formulations that have made it through to the market is limited because of the unstable nature of the amorphous form, which often results in recrystallization of the drug with the subsequent loss of the solubility and dissolution advantages. Thus, ensuring the stability constitutes a major challenge in the development of amorphous solid dispersions.
Downstream processing of a co-amorphous drug-amino acid formulation
Written by Elisabeth LenzFor the first time, an appropriate solid dosage form was developed for a co-amorphous drug-amino acid formulation, demonstrating the high physical stability for the particular system during further processing to tablets and during long-term storage thereof.
Beyond Traditional Disintegration Testing
Written by Samy Yassin and Axel ZeitlerWe have developed a new technique to better understand what happens to the microstructure inside a tablet during rapid disintegration.
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Improved Process Understanding of Tablet Film Coating
Written by Hungyen LinBackground
Terahertz pulsed imaging (TPI) was first introduced in 2007 to non-destructively measure the coating thickness of pharmaceutical tablets. Ever since then, there has been a concerted research effort throughout the PSSRC to further develop and exploit this technique for improving the quality of pharmaceutical coatings and to shed light on the intricacies behind the pharmaceutical tablet coating process.
Effect of Compression on Local and Segmental Mobility of PVPVA: Broadband Dielectric Spectroscopy Study
Written by Zelalem Ayenew Worku, Bram Vanroy,‡ Michael Wübbenhorst, Amrit Paudel and Guy Van den MooterBackground
The mechanism of plastic deformation in amorphous polymers is still obscure due to lack of experimental techniques to probe molecular mobility during active deformation. Lee et al. showed an increase in a segmental mobility by several decades using a specific active deformation protocol (uniaxial tensile creep) by directly measuring the molecular mobility using an optical photobleaching approach [1]. Our previous studies using ATR-FTIR spectroscopy showed that compression of amorphous solid dispersions containing naproxen and PVP or PVP-VA appeared to affect the drug-polymer interactions, the drug-polymer mixing and the physical stability of the system [2, 3]. Deformation can affect the molecular dynamics of amorphous polymers that include local bonds, segmental and whole chain mobility. It potentially leads to conformational changes and also enhances or affects local bond motions of polymers which may be involved in intermolecular interactions with drugs in solid dispersions. The objective of this study is to understand the effect of compression on the local and segmental mobility of PVP-VA to understand the molecular origin of the differences in drug-polymer interactions between the compressed and the uncompressed solid dispersions. The impact of pharmaceutical tabletting on the molecular dynamics of amorphous solid dispersions can be critical in terms of physical stability of the drug during storage.
Methods
High resolution broadband dielectric spectroscopy (ALPHA Analyzer, Novocontrol Technologies) was used to measure the complex dielectric responses (Eqn. \ref{eq:1}, ε' and ε'' are the real and the imaginary part) of the compressed (565 MPa) (comp), the slightly compressed (scomp) and the powder (pow) PVP-VA 64 and powder PVP K25 samples in the frequency range from 10-1 to 106 Hz.
\begin{equation}\varepsilon (\omega)=\varepsilon' (\omega) - i\varepsilon'' (\omega)\label{eq:1} \end{equation}
The “conduction free” dielectric loss was computed from the real part of the dielectric spectra using the Kramers-Kronig relation to suppress the Ohmic conduction interference in the imaginary part of the dielectric response (Eqn. \ref{eq:2}) [4].
\begin{equation}\varepsilon'' (\omega_0)=\frac{\sigma_{dc}}{\varepsilon_\nu\omega_0}+\frac{2}{\pi}\int_0^\inf \varepsilon'(\omega)\frac{\omega_0}{\omega^2-\omega_0^2}\text{d}\omega\label{eq:2} \end{equation}
Generally, the activation energy according to the Arrhenius-law is usually considered a true energetic barrier, however, processes that involve cooperativity might additionally show an entropic “barrier”. The Starkweather analysis allows to separate the activation energy into its enthalpic and entropic part to assess the cooperative nature of the secondary relaxation of PVP-VA (Eqns. \ref{eq:3} and \ref{eq:4}) (for the details of the equations refer to [5]).
\begin{equation}f=\frac{k_B T}{2\pi h}\exp \left( -\frac{\Delta H^{\ddagger}}{RT} \right)\exp\left(\frac{\Delta S^{\ddagger}}{R} \right)\label{eq:3} \end{equation}
\begin{equation}E^{*}_{a}=RT\left( 1+ \ln \frac{k_B}{2\pi h} \ln \frac{T}{f} \right)\label{eq:4} \end{equation}
Results and Discussion
The secondary relaxation of compressed PVP-VA shifts synchronously with the primary relaxation to lower temperature compared to the powder and slightly compressed samples even after annealing in the supercooled liquid state (Fig. 1). The source of the secondary relaxation process is likely originating from the vinyl pyrrolidone moiety of PVP-VA. Thus, compression appeared to enhance the localised motion which likely originates from the conformational transition involving the N-C(H) bond in PVP-VA and also the segmental mobility due to dynamic Tg [6].
The non-zero activation entropy of compressed PVP-VA was higher than the powder sample which indicates the presence of a higher entropic barrier during conformational reorientation for the compressed sample (Table 1). Moreover, it may also indicate a higher cooperative nature of the β relaxation process for the compressed sample as the result of enhanced conformational rotations.
The primary relaxation process starts at a very low temperature for the compressed PVP-VA and an additional wing was also identified with a mean relaxation time smaller than the powder and the slightly compressed PVP-VA (Fig. 2).
http://pssrc.org/research-highlights/graz/content/research-highlights#sigProGalleriaac1dd7175f
Conclusion and Outlook
The molecular dynamics results support the idea that severe compression affects the local and the segmental mobility of PVP-VA. Compression of PVP-VA appeared to lead to a shorter time scale for the secondary (β) relaxation process. Moreover, the primary relaxation process starts at a very low temperature for the compressed PVP-VA and an additional wing was also identified with a mean relaxation time smaller than the powder and the slightly compressed PVP-VA due to the heterogeneity in segmental mobility imparted by compression. The observation can be very useful for drug containing amorphous solid dispersions which are stabilised by specific drug-polymer interactions. The current study on PVP-VA should also be extended to one with binary solid dispersions stabilised by a strong and a weak drug-polymer hydrogen bonding further to probe the effect of compression in the molecular dynamics of both the drug, the polymer and their specific interactions.
References
[1] Lee, H. N.; Paeng, K.; Swallen, S. F.; Ediger, M. Science 2009, 323, 231.
[2] Ayenew, Z.; Paudel, A.; Van den Mooter, G. Eur. J. Pharm. Biopharm. 2012, 81, 207.
[3] Worku, Z. A.; Aarts, J.; Van den Mooter, G. Mol. Pharmaceutics 2014, 11, 1102.
[4] Wübbenhorst, M.; van Turnhout, J. J. Non-Cryst. Solids 2002, 305, 40.
[5] Starkweather Jr, H. W. Polymer 1991, 32, 2443.
[6] Tonelli, A. Polymer 1982, 23, 676.
PSSRC Facilities
The Research group of Prof. Guy Van den Mooter focuses on the study of the physical chemistry of solid (molecular) dispersions prepared by hot melt extrusion, spray drying, bead coating and spray congealing. It is the aim to correlate the physical structure of the drug-polymer dispersions to their pharmaceutical performance and stability profile, and to correlate formulation and processing parameters to the resulting physical structure. Analytical techniques such as thermal analysis (DSC, MTDSC, TGA, hot-stage microscopy, isothermal microcalorimetry, solution calorimetry), X-ray powder diffraction, infrared spectroscopy, solid state NMR, broadband dielectric spectroscopy and in vitro (intrinsic) dissolution testing are being used for this purpose. Other (solid state) analytical techniques that are available are (powder) rheology, He-pycnometry, instrumented compression testing, SEM, TEM, coulter counter and Laser diffraction.
As part of the Center for Drug Delivery and Analysis of KU Leuven, this research group is also involved in formulation development and preformulation studies (a.o. study of polymorphism) for pharmaceutical companies.
Nanocrystals - from fast dissolution and improved solubility to controlled release applications
Written by Leena PeltonenProblems related to low oral bioavailability due to poor solubility of new drug candidates are an increasing challenge in pharmaceutical research and formulation development. One efficient way to improve solubility is the utilization of nanocrystallization techniques: pharmaceutical nanocrystals are solid drug particles covered by a stabilizer layer with approximated size typically between 100 and 500 nm. Nanocrystal studies have been conducted since the beginning of the 1990’s and the first product entered the market after 10 years of intensive research. At first, nanocrystals were utilized purely for improved dissolution, but today also controlled release applications are in use.
Injection Molding as an Hot Melt Extrusion Downstream Process
Written by Simone Schrank, Daniel TrefferIntroduction
Over the last years, hot melt extrusion (HME) has attracted significant interest in the pharmaceutical industry. HME is performed at elevated process temperatures that cause the material to soften or even melt. Thereby, the formation of molecular solid dispersions is possible, given that the formulation and the HME process are carefully designed.