Publications

In this study, a quality-by-design (QbD) approach was used to optimize the development of paracetamol (PMOL) sustained-release formulations manufactured by hot-melt extrusion (HME). For the purpose of the study, in-line near-infrared (NIR) spectroscopy as a process analytical technology (PAT) was explored while a design of experiment (DoE) was implemented to assess the effect of the process critical parameters and to identify the critical quality attributes (CQA) of the extrusion processing. Blends of paracetamol, ethyl cellulose (EC) and Compritol® 888 ATO (C888) were processed using a twin screw extruder to investigate the effect of screw speed, feed rate and drug loading on the dissolution rates and particle size distribution. The principal component analysis (PCA) of the NIR collected signal revealed the optimum extrusion processing parameters. Furthermore, the integration of the DoE experiments demonstrated that drug loading has a significant effect on the only quality attribute, which was the PMOL dissolution rate. This QbD approach was employed as a paradigm for the development of pharmaceutical formulations via HME processing.

The purpose of this work was to develop stable xylitol particles with modified physical properties, improved compactibility and enhanced pharmaceutical performance without altering polymorphic form of xylitol. Xylitol was crystallized using antisolvent crystallization technique in the presence of various hydrophilic polymer additives, i.e., polyethylene glycol (PEG), polyvinylpyrrolidone (PVP) and polyvinyl alcohol (PVA) at a range of concentrations. The crystallization process did not influence the stable polymorphic form or true density of xylitol. However, botryoidal-shaped crystallized xylitols demonstrated different particle morphologies and lower powder bulk and tap densities in comparison to subangular-shaped commercial xylitol. Xylitol crystallized without additive and xylitol crystallized in the presence of PVP or PVA demonstrated significant improvement in hardness of directly compressed tablets; however, such improvement was observed to lesser extent for xylitol crystallized in the presence of PEG. Crystallized xylitols produced enhanced dissolution profiles for indomethacin in comparison to original xylitol. The influence of additive concentration on tablet hardness was dependent on the type of additive, whereas an increased concentration of all additives provided an improvement in the dissolution behavior of indomethacin. Antisolvent crystallization using judiciously selected type and concentration of additive can be a potential approach to prepare xylitol powders with promising physicomechanical and pharmaceutical properties.

The purpose of the study was to investigate and identify the interactions within solid dispersions of cationic drugs and anionic polymers processed by hot-melt extrusion (HME) technique. Propranolol HCl (PRP) and diphenhydramine HCl (DPD) were used as model cationic active substances while pH sensitive anionic methacrylic acid based methyl methacrylate copolymers Eudragit L100 (L100) and ethyl acrylate copolymer Eudragit L100-55 (Acryl EZE) (L100-55) were used as polymeric carriers. The extrudates were further characterised using various physicochemical characterisation techniques to determine the morphology, the drug state within the polymer matrices and the type of drug-polymer interactions. Molecular modelling predicted the existence of two possible H-bonding types while the X-ray photon spectroscopy (XPS) advanced surface analysis of the extrudates revealed intermolecular ionic interactions between the API amino functional groups and the polymer carboxylic groups through the formation of hydrogen bonding. The magnitude of the intermolecular interactions varied according to the drug-polymer miscibility.

The ability of anionic polymer sodium carboxymethylcellulose to influence the release of four model cationic drugs (chlorpheniramine maleate, venlafaxine hydrochloride, propranolol hydrochloride and verapamil hydrochloride) from extended release (ER) hydrophilic matrices based on non-ionic polymer polyethylene oxide was investigated by X-ray photoelectron spectroscopy (XPS), isothermal titration calorimetry (ITC) and differential scanning calorimetry (DSC). For all studied APIs, a combination of polyethylene oxide with sodium carboxymethylcellulose produced slower drug release compared to the matrices of single polymers. This behaviour was mainly attributed to the interaction of ester/carboxylic acid functionalities to yield H-bonding between the anionic polymer groups and the additionally protonated N-atoms of the active substances. X-ray photoelectron and isothermal titration calorimetry studies confirmed drug-polymer interaction and polymer-polymer interaction (i.e. the PEO binding with negatively charged NaCMC), whilst differential scanning calorimetry indicated the existence of both crystalline and molecularly dispersed active forms in the created complexes. The drug release mechanisms were fitted to various models suggesting diffusion control for the majority of the formulations. The Korsmeyer-Peppas model was found to be the most suitable for description of release profiles of all formulations. The present study showed that XPS and ITC in combination with DSC can be valuable tool to investigate the presence and nature (mechanism) of synergistic interactions between polymers and drugs in extended release matrix tablets.

Mesoporous silica nanoparticles (MSNs) are a versatile drug delivery system that can be used for loading of different guest molecules such as peptides, proteins, anticancer agents, and genetic material. MSNs are considered promising drug carriers due to their tuneable particle size, pore structure, and surface functionalization. Thus, MSNs provide opportunities for their effective application in a wide variety of fields. In the current review, we discuss both conventional and advanced MSNs synthesis methods, including their applications for drug delivery, gatekeepers, and biosensors. In addition, the research progress in biocompatibility, cytotoxicity, and internalization mechanisms is reported.

The aim of this study was to investigate the efficiency of hydrophilic polymers to enhance the dissolution rate of poorly water-soluble active pharmaceutical ingredients (APIs) processed by hot-melt extrusion (HME). Indomethacin (INM) and famotidine (FMT) were selected as model active substances while polyvinyl caprolactam graft copolymer, soluplus (SOL) and vinylpyrrolidone-vinyl acetate copolymer grades, Kollidon VA64 (VA64) and Plasdone S630 (S630) were used as hydrophilic polymeric carriers. For the purpose of the study, drug-polymer binary blends at various ratios were processed by a Randcastle single screw extruder. The physicochemical properties and the morphology of the extrudates were evaluated through X-ray diffraction (XRD), differential scanning calorimetry (DSC) and scanning electron microscopy (SEM). Increased drug loadings of up to 40% were achieved in the extruded formulations for both drugs. INM and FMT exhibited strong plasticization effects with increasing concentrations and were found to be molecularly dispersed within the polymer blends. The in vitro dissolution studies showed increased INM/FMT release rates for all formulations compared to that of pure APIs alone.

The aim of this work was to develop sustained release solid lipid matrices of diclofenac sodium (Df-Na) processed by hot melt extrusion (HME) and subsequent compression into tablets. Different extrusion processing approaches such as "cold", "hot" and pre-mixed formulations were used to develop the Compritol(®) 888 ATO lipid matrices by altering the extrusion temperatures, drug loading and formulation composition. The extrudates were characterized via a range of techniques such as differential scanning calorimetry (DSC), hot stage microscopy (HSM) and X-ray powder diffraction (XRPD) to identify the drug state within the lipid matrix. Df-Na was found to be either in crystalline or amorphous state depending on the processing conditions. Energy dispersive X-ray (EDX) microanalysis demonstrated excellent drug distribution of Df-Na on the surface of the compressed tablets. The lipid matrices developed by HME provided sustained release of pre-mixed formulations for 12h mainly controlled by diffusion.

Over the last three decades industrial adaptability has allowed hot-melt extrusion (HME) to gain wide acceptance and has already established its place in the broad spectrum of manufacturing operations and pharmaceutical research developments. HME has already been demonstrated as a robust, novel technique to make solid dispersions in order to provide time controlled, modified, extended, and targeted drug delivery resulting in improved bioavailability as well as taste masking of bitter active pharmaceutical ingredients (APIs). This paper reviews the innumerable benefits of HME, based on a holistic perspective of the equipment, processing technologies to the materials, novel formulation design and developments, and its varied applications in oral drug delivery systems.

The purpose of this study was the in vitro and in vivo evaluation of the masking efficiency of hot melt extruded paracetamol (PMOL) formulations. Extruded granules containing high PMOL loadings in Eudragit EPO (EPO) or Kollidon VA64 (VA64) were prepared by hot-melt extrusion (HME). The taste masking effect of the processed formulation was evaluated in vivo by a panel of six healthy human volunteers. In addition, in vitro evaluation was carried out by an Astree e-tongue equipped with seven sensors. Taste sensing technology demonstrated taste improvement for both polymers by correlating the data obtained for the placebo polymers and the pure APIs alone. The best masking effect was observed for VA64 at 30% PMOL loading. The e-tongue results were in good agreement with the in vivo evaluation. In vitro dissolution of the extruded granules showed rapid PMOL releases.

In the current study Ibuprofen was embedded in a methacrylate copolymer (Eudragit® EPO) matrix to produce solid dispersions by hot-melt extrusion (HME) processing. The obtained granules were incorporated in orally disintegrating tablets (ODTs). The tablets were developed by varying the ratio of superdisintegrants such as sodium croscarmellose and crosslinked polyvinylpyrrolidone grades while a direct compression process was used to compress the ODTs under various compaction forces to optimize tablet robustness. The properties of the compressed tablets which included porosity, hardness, friability and dissolution profiles were further evaluated and compared with Nurofen® Meltlet ODTs. The taste and sensory evaluation in human volunteers demonstrated excellence in masking the bitter active and improved tablet palatability.