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Dr Walkiria Schlindwein

Job: Principal Lecturer

Faculty: Health and Life Sciences

School/department: Leicester School of Pharmacy

Research group(s): Pharmaceutical Technologies

Address: 51Âț»­, The Gateway, Leicester, LE1 9BH.

T: +44 (0)116 257 7124

E: wss@dmu.ac.uk

W: /pharmacy

 

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Personal profile

Dr Schlindwein graduated as Chemical Engineer in 1984 from the Federal University of Rio de Janeiro, UFRJ, Brazil. She obtained her M.Sc. in Polymer Science and Technology from the Institute of Macromolecules of the UFRJ, Brazil in 1986, PhD in Chemistry from the Department of Chemistry of the University of Leicester, England, in 1990, and DSc in Chemistry from the UFRJ in 1992. 

Research group affiliations

  • Pharmaceutical Technologies

Publications and outputs


  • dc.title: Optimizing extrusion processes and understanding conformational changes in itraconazole amorphous solid dispersions using in-line UV–Vis spectroscopy and QbD principles dc.contributor.author: Triboandas, Hetvi; Bezerra, M.; Almeida, J.; De Castro, M.; Santos, B.; Schlindwein, W. S. dc.description.abstract: This paper presents a comprehensive investigation of the manufacturing of itraconazole (ITZ) amorphous solid dispersions (ASDs) with KolllidonÂź VA64 (KVA64) using hot-melt extrusion (HME) and in-line process monitoring, employing a Quality by Design (QbD) approach. A sequential Design of Experiments (DoE) strategy was utilized to optimize the manufacturing process, with in-line UV–Vis spectroscopy providing real-time monitoring. The first DoE used a fractional factorial screening design to evaluate critical process parameters (CPPs), revealing that ITZ concentration had the most significant impact on the product quality attributes. The second DoE, employing a central composite design, explored the interactions between feed rate and screw speed, using torque and absorbance at 370 nm as responses to develop a design space. Validation studies confirmed process robustness across multiple days, with stable in-line UV–Vis spectra and consistent product quality using 30 % ITZ, 300 rpm, 150 °C and 7 g/min as the optimized process conditions. Theoretical and experimental analyses indicated that shifts in UV–Vis spectra at different ITZ concentrations were due to conformational changes in ITZ, which were confirmed through density functional theory (DFT) calculations and infrared spectroscopy. This work offers novel insights into the production and monitoring of ITZ-KVA64-ASDs, demonstrating that in-line UV–Vis spectroscopy is a powerful tool for real-time process monitoring and/or control. dc.description: open access article

  • dc.title: Itraconazole Amorphous Solid Dispersion Tablets: Formulation and Compaction Process Optimization Using Quality by Design Principles and Tools dc.contributor.author: Triboandas, Hetvi; Pitt, Kendal; Bezerra, Mariana; Ach-Hubert, Delphine; Schlindwein, W. S. dc.description.abstract: BCS Class II drugs, such as itraconazole (ITZ), exhibit poor solubility (1–4 ng/mL) and so require solubility enhancement. Therefore, ITZ and KollidonÂź VA64 (KOL) amorphous solid dispersions (ASDs) were produced using hot-melt extrusion (HME) to improve ITZ’s poor solubility. A novel strategy for tablet formulations using five inorganic salts was investigated (KCl, NaCl, KBr, KHCO3 and KH2PO4 ). These kosmotopric salts are thought to compete for water hydration near the polymer chain, hence, preventing polymer gelation and, therefore, facilitating disintegration and dissolution. Out of all the formulations, the KCl containing one demonstrated acceptable tensile strength (above 1.7 MPa), whilst providing a quick disintegration time (less than 15 min) and so was selected for further formulation development through a design of the experiment approach. Seven ITZ-KOL-ASD formulations with KCl were compacted using round and oblong punches. Round tablets were found to disintegrate under 20 min, whereas oblong tablets disintegrated within 10 min. The round tablets achieved over 80% ITZ release within 15 min, with six out of seven formulations achieving 100% ITZ release by 30 min. It was found that tablets comprising high levels of AvicelÂź pH 102 (30%) and low levels of KCl (5%) tend to fail the disintegration target due to the strong bonding capacity of AvicelÂź pH 102. The disintegration time and tensile strength responses were modeled to obtain design spaces (DSs) relevant to both round and oblong tablets. Within the DS, several formulations can be chosen, which meet the Quality Target Product Profile (QTPP) requirements for immediate-release round and oblong tablets and allow for flexibility to compact in different tablet shape to accommodate patients’ needs. It was concluded that the use of inorganic salts, such as KCl, is the key to producing tablets of ITZ ASDs with fast disintegration and enhanced dissolution. Overall, ITZ-KOL-ASD tablet formulations, which meet the QTPP, were achieved in this study with the aid of Quality by Design (QbD) principles for formulation and compaction process development and optimization. dc.description: open access article

  • dc.title: Development and Validation of an In‐Line API Quantification Method Using AQbD Principles Based on UV‐Vis Spectroscopy to Monitor and Optimise Continuous Hot Melt Extrusion Process dc.contributor.author: Almeida, Juan; Bezerra, Mariana; Markl, Daniel; Berghaus, Andreas; Borman, Phil; Schlindwein, W. S. dc.description.abstract: A key principle of developing a new medicine is that quality should be built in, with a thorough understanding of the product and the manufacturing process supported by appropriate process controls. Quality by design principles that have been established for the development of drug products/substances can equally be applied to the development of analytical procedures. This paper presents the development and validation of a quantitative method to predict the concentration of piroxicam in KollidonÂź VA 64 during hot melt extrusion using analytical quality by design principles. An analytical target profile was established for the piroxicam content and a novel in‐line analytical procedure was developed using predictive models based on UV‐Vis absorbance spectra collected during hot melt extrusion. Risks that impact the ability of the analytical procedure to measure piroxicam consistently were assessed using failure mode and effect analysis. The critical analytical attributes measured were colour (L* lightness, b* yellow to blue colour parameters—in‐process critical quality attributes) that are linked to the ability to measure the API content and transmittance. The method validation was based on the accuracy profile strategy and ICH Q2(R1) validation criteria. The accuracy profile obtained with two validation sets showed that the 95% ÎČ‐expectation tolerance limits for all piroxicam concentration levels analysed were within the combined trueness and precision acceptance limits set at ±5%. The method robustness was tested by evaluating the effects of screw speed (150–250 rpm) and feed rate (5–9 g/min) on piroxicam content around 15% w/w. In‐line UV‐Vis spectroscopy was shown to be a robust and practical PAT tool for monitoring the piroxicam content, a critical quality attribute in a pharmaceutical HME process. dc.description: open access journal

  • dc.title: Modelling the Effect of Process Parameters on the Wet Extrusion and Spheronisation of High-Loaded Nicotinamide Pellets Using a Quality by Design Approach dc.contributor.author: Theismann, Eva-Maria; Keppler, Julia K; Owen, Martin; Schwarz, Karin; Schlindwein, W. S. dc.description.abstract: The aim of the present study was to develop an alternative process to spray granulation in order to prepare high loaded spherical nicotinamide (NAM) pellets by wet extrusion and spheronisation. Therefore, a quality by design approach was implemented to model the effect of the process parameters of the extrusion-spheronisation process on the roundness, roughness and useable yield of the obtained pellets. The obtained results were compared to spray granulated NAM particles regarding their characteristics and their release profile in vitro after the application of an ileocolon targeted shellac coating. The wet extrusion-spheronisation process was able to form highly loaded NAM pellets (80%) with a spherical shape and a high useable yield of about 90%. However, the water content range was rather narrow between 24.7% and 21.3%. The design of experiments (DoE), showed that the spheronisation conditions speed, time and load had a greater impact on the quality attributes of the pellets than the extrusion conditions screw design, screw speed and solid feed rate (hopper speed). The best results were obtained using a low load (15 g) combined with a high rotation speed (900 m/min) and a low time (3–3.5 min). In comparison to spray granulated NAM pellets, the extruded NAM pellets resulted in a higher roughness and a higher useable yield (63% vs. 92%). Finally, the coating and dissolution test showed that the extruded and spheronised pellets are also suitable for a protective coating with an ileocolonic release profile. Due to its lower specific surface area, the required shellac concentration could be reduced while maintaining the release profile dc.description: Open access article

  • dc.title: Pharmaceutical excipients properties and screw feeder performance in continuous processing lines: a Quality by Design (QbD) approach dc.contributor.author: Santos, B.; Carmo, F.; Schlindwein, W. S.; Muirhead, G.; Rodriguez, C.; Cabral, L.; Westrup, J.; Pitt, K. dc.description.abstract: Screw feeder performance is a critical aspect in continuous manufacturing processes. Pharmaceutical excipients, such as mannitol, microcrystalline cellulose, lactose monohydrate, and anhydrous dibasic calcium phosphate can present problems in ensuring a continuous stable feed rate due to their sub-optimal flow properties. In alignment with Quality by Design (QbD) goals, the aim of this work was to identify and explain critical sources of variability of some powder excipients delivery by screw feeding, in particular to continuous processing lines. Pharmaceutical excipients with a wide range of material properties were selected, and the impact of their flow and density properties on screw feeder performance was investigated. The analysis of the powder conveying by the screws was performed at different hopper fills and different screw speeds. A multivariable model involving bulk density (CBD) and parameters from FT4 dynamic downwards testing (SI) and dynamic upwards testing (SE) explained 95.7% of excipients feed rates (p<.001). The study gathers valuable information about the screw feeder performance and input materials properties that can help process understanding and QbD-based development of solid dosage forms in continuous processing lines. dc.description: The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link.

  • dc.title: In-Line UV-Vis Spectroscopy as a Fast-Working Process Analytical Technology (PAT) during Early Phase Product Development Using Hot Melt Extrusion (HME) dc.contributor.author: Schlindwein, W. S.; Bezerra, M.; Almeida, J.; Berghaus, A; Owen, M.; Muirhead, G. dc.description.abstract: This paper displays the potential of an in-line PAT system for early phase product development during pharmaceutical continuous manufacturing following a Quality by Design (QbD) framework. Hot melt extrusion (HME) is used as continuous manufacturing process and UV– Vis spectroscopy as an in-line monitoring system. A sequential design of experiments (DoE) (screening, optimisation and verification) was used to gain process understanding for the manufacture of piroxicam (PRX)/KollidonÂź VA64 amorphous solid dispersions. The influence of die temperature, screw speed, solid feed rate and PRX concentration on the critical quality attributes (CQAs) absorbance and lightness of color (L*) of the extrudates was investigated using multivariate tools. Statistical analysis results show interaction effects between concentration and temperature on absorbance and L* values. Solid feed rate has a significant effect on absorbance only and screw speed showed least impact on both responses for the screening design. The optimum HME process conditions were confirmed by 4 independent studies to be 20% w/w of PRX, temperature 140 °C, screw speed 200 rpm and feed rate 6 g/min. The in-line UV-Vis system was used to assess the solubility of PRX in KollidonÂź VA64 by measuring absorbance and L* values from 230 to 700 nm. Oversaturation was observed for PRX concentrations higher than 20% w/w. Oversaturation can be readily identified as it causes scattering in the visible range. This is observed by a shift of the baseline in the visible part of the spectrum. Extrudate samples were analyzed for degradation using off-line High-Performance Liquid Chromatography (HPLC) standard methods. Results from off-line experiments using differential scanning calorimetry (DSC), and X-ray diffraction (XRD) are also presented. dc.description: open access article

  • dc.title: Pharmaceutical quality by design: a practical approach. dc.contributor.author: Schlindwein, W. S.; Gibson, Mark

  • dc.title: EPR and XANES studies of anaerobic photolysis of iso-propilpyridinecobaloxime: Elucidation of the reactivity of the Co(II) primary product dc.contributor.author: Rangel, M.; Leite, A.; Silva, A.; De Castro, B.; Schlindwein, W. S.; Murphy, L. dc.description.abstract: Anaerobic photolysis of iso-propilpyridinecobaloxime was monitored by EPR and X-ray Absorption Near Edge spectroscopy (XANES). The spectra of the cobalt(II) photolysis products were analyzed and compared with those obtained for parent cobalt(II) dimethylglyoximato complexes in order to rationalize the involvement of photolysis primary products in further reactions in solution. The results obtained upon photolysis in frozen matrix, confirm that the photolysis primary product is the five coordinate cobalt(II) complex, [Co(DH)2py], and that this species is only observable in frozen solution. As the matrix is relaxed to room temperature the five coordinate species evolves to give rise to a six coordinate cobalt(II) complex, [Co(DH)2py2], that persists at room temperature and that is observable in EPR upon re-cooling to frozen solution. When monitoring the warming up of the irradiated frozen solution we observe an EPR signal which is assigned to a square planar species, [Co(DH)2], providing evidence for the source of pyridine molecules to originate the compound with two bound pyridine molecules. Since the latter signal is lost upon warming we hypothesize that the four coordinate species polymerizes or packs into diamagnetic forms at room temperature. The supposition is corroborated by comparison of the values of the magnetic moments of compounds [Co(DH)2py2], [Co(DH)2py] and [Co(DH)2] as powders and in solution. EPR titration of compound [Co(DH)2] with pyridine substantiates the latter results and shows that the complex with two bound pyridine molecules is the predominant species from a 1:1 M ratio. The XANES profiles of powder and solution samples of compound [Co(DH)2] are meaningfully different and indicative that substantial axial interactions are present in solution while the powder’s profile is closely related with those described for square planar complexes. The presence of two solvent molecules bound to [Co(DH)2] in solution is confirmed by the values of the spin-Hamiltonian parameters obtained for the same sample. The use of XANES spectroscopy was particularly valuable to provide independent evidence that the structure of [Co(DH)2] and [Co(DH)2py] is different in powder and in solution and to monitor the change in oxidation state and geometry during the progression of the photolysis process.

  • dc.title: Using the Box-Behnken experimental design to optimise operating parameters in pulsed spray fluidised bed granulation dc.contributor.author: Liu, H.; Wang, K.; Schlindwein, W. S.; Li, M. dc.description.abstract: In this work, the influence factors of pulsed frequency, binder spray rate and atomisation pressure of a top-spray fluidised bed granulation process were studied using the Box–Behnken experimental design method. Different mathematical models were developed to predict the mean size of granules, yield, relative width of granule distribution, Hausner ratio and final granule moisture content. The study has supported the theory that the granule size can be controlled through the liquid feed pulsing. However, care has to be taken when the pulsed frequency is chosen for controlling the granule size due to the nonlinear quadratic relation in the regression model. The design space of the ranges of operating parameters has been determined based on constraints of the mean size of granules and granule yield. High degree of prediction obtained from validation experiments has shown the reliability and effectiveness of using the Box–Behnken experimental design method to study a fluidised bed granulation process.

  • dc.title: Comparison of in vitro dissolution tests for commercially available aspirin tablets dc.contributor.author: Khan, F.; Li, M.; Schlindwein, W. S.

Key research outputs

  • Quality by Design
  • Dissolution
  • X-ray spectroscopy
  • Cocrystals
  • Granulation

Research interests/expertise

Her current research interests are in the areas of material sciences with particular interest in polymers used in pharmaceutical applications. She collaborates with Dr Mingzhong Li and supervises PhD students in the areas of formulation of poorly soluble drugs and dissolution studies using flow through cells, USP IV and Surface Imaging techniques.

More recently, she was involved with the validation and implementation of two Postgraduate courses, a full time MSc in Pharmaceutical Quality by Design and an online flexible learning MSc in Quality by Design for the Pharmaceutical Industry.  The latter was the result of a unique collaboration between 51Âț»­ and more than 50 industrialists from 22 companies including AstraZeneca, GlaxoSmithKline, Pfizer and Bristol-Myers Squibb.

Areas of teaching

  • Quality by Design Principles and Tools
  • Pharmaceutical Materials Sciences
  • Pharmaceutical Processes and Technologies
  • Product Formulation
  • Pharmaceutical Product Development and Manufacture

Qualifications

  • PhD, MSc, ChemEng

Courses taught

  •  BSc Pharmaceutical and Cosmetic Science,
  •  Full time MSc Pharmaceutical Quality by Design,
  •  Distance learning in MSc Quality by Design for the Pharmaceutical Industry

Membership of professional associations and societies

  • Member of the UK Biomaterials Network
  •  Member of the Academy of Pharmaceutical Sciences
  •  Member of the European Federation of Pharmaceutical Sciences

Conference attendance

APS Materials Science, 13-14 May 2013, EMCC, Nottingham, invited presentation: Introduction to Qbd Concepts.

Consultancy work

Quality by Design Approaches to Pharmaceutical Product & Process Development.

Current research students

  • Miss Ning Qiao, PhD, 2nd supervisor
  • Mr Huolong Liu, PhD, 2nd supervisor
  • Miss Shi Qiu, PhD, 2nd supervisor
  • Mr Yan Lu, PhD, 2nd supervisor
  • Ms Tayseer Kabsoun, MSc, 1st supervisor

Internally funded research project information

  • Quality by Design, ERDF, £100K, 2010-2011
  • Pharmaceutical Quality by Design, HEIF5, £71720 Aug 2011 - Jul 2013, PI
Walkeria Schlindwein