Jouko Peltonen

Inkjet printing of drug substances and use of porous substrates‐towards individualized dosing

Medicines are most often oral solid dosage forms made into tablets or capsules, and there is little room for individualized doses. The drug substance and additives are processed through multiple production phases, including complex powder handling steps. In drug manufacturing, the control of the solid-state properties of active pharmaceutical ingredient (API) is essential and it offers opportunities for enhancement of drug delivery systems. In this context, inkjet printing technologies have emerged over the last decades in pharmaceutical and biological applications and offer solutions for controlling material and product characteristics with high precision. Here we report the concept of conventional inkjet printing technology to produce printable pharmaceutical dosage forms on porous substrates. Data are shown to demonstrate inkjet printing of APIs into paper substrates, and how the model drug substances (paracetamol, theophylline, and caffeine) are penetrating the porous substrates used. The method enables controlling not only the deposition but also the crystallization of the drug substances. We anticipate that the inkjet printing approach has immense potential in making sophisticated drug delivery systems by use of porous substrates in the future. For example, it may offer new perspectives for solving problems around poorly soluble drugs and dosing low-dose medicines accurately. Furthermore, with the advent of genetic mapping of humans, controlled inkjet dosing can bring solutions to fabricate on-demand individualized medicines for patients.

Tailoring controlled-release oral dosage forms by combining inkjet and flexographic printing techniques.

We combined conventional inkjet printing technology with flexographic printing to fabricate drug delivery systems with accurate doses and tailored drug release. Riboflavin sodium phosphate (RSP) and propranolol hydrochloride (PH) were used as water-soluble model drugs. Three different paper substrates: A (uncoated woodfree paper), B (triple-coated inkjet paper) and C (double-coated sheet fed offset paper) were used as porous model carriers for drug delivery. Active pharmaceutical ingredient (API) containing solutions were printed onto 1 cm × 1 cm substrate areas using an inkjet printer. The printed APIs were coated with water insoluble polymeric films of different thickness using flexographic printing. All substrates were characterized with respect to wettability, surface roughness, air permeability, and cell toxicity. In addition, content uniformity and release profiles of the produced solid dosage forms before and after coating were studied. The substrates were nontoxic for the human cell line assayed. Substrate B was smoothest and least porous. The properties of substrates B and C were similar, whereas those of substrate A differed significantly from those of B, C. The release kinetics of both printed APIs was slowest from substrate B before and after coating with the water insoluble polymer film, following by substrate C, whereas substrate A showed the fastest release. The release rate decreased with increasing polymer coating film thickness. The printed solid dosage forms showed excellent content uniformity. So, combining the two printing technologies allowed fabricating controlled-release oral dosage forms that are challenging to produce using a single technique. The approach opens up new perspectives in the manufacture of flexible doses and tailored drug-delivery systems.

Inkjet-printed gold electrodes on paper: characterization and functionalization.

Gold nanoparticles were synthesized and inkjet-printed on a paper substrate and IR-sintered to produce conductive electrodes. The electrodes were further functionalised by using self-assembled octadecanethiol monolayers (SAMs). The effect of sintering, print quality, and SAM formation were examined by topographical, chemical and electrical methods. With optimised printing parameters, a volume resistivity of ~1.6 × 10(-7) Ω m was attained by a single print layer.

Printing technologies in fabrication of drug delivery systems.

Introduction: There has been increased activity in the field recently regarding the development and research on various printing techniques in fabrication of dosage forms and drug delivery systems. These technologies may offer benefits and flexibility in manufacturing, potentially paving the way for personalized dosing and tailor-made dosage forms. Areas covered: In this review, the most recent observations and advancements in fabrication of drug delivery systems by utilizing printing technologies are summarized. A general overview of 2D printing techniques is presented including a review of the most recent literature where printing techniques are used in fabrication of drug delivery systems. The future perspectives and possible impacts on formulation strategies, flexible dosing and personalized medication of using printing techniques for fabrication of drug delivery systems are discussed. Expert opinion: It is evident that there is an urgent need to meet the challenges of rapidly growing trend of personalization of medicines through development of flexible drug-manufacturing approaches. In this context, various printing technologies, such as inkjet and flexography, can play an important role. Challenges on different levels exist and include: i) technological development of printers and production lines; ii) printable formulations and carrier substrates; iii) quality control and characterization; and iv) regulatory perspectives.

Microbe repelling coated stainless steel analysed by field emission scanning electron microscopy and physicochemical methods

Coating of stainless steel with diamond-like carbon or certain fluoropolymers reduced or almost eliminated adhesion and biofilm growth of Staphylococcus epidermidis, Deinococcus geothermalis, Meiothermus silvanus and Pseudoxanthomonas taiwanensis. These species are known to be pertinent biofilm formers on medical implants or in the wet-end of paper machines. Field emission scanning electron microscopic analysis showed that Staph. epidermidis, D. geothermalis and M. silvanus grew on stainless steel using thread-like organelles for adhesion and biofilm formation. The adhesion threads were fewer in number on fluoropolymer-coated steel than on plain steel and absent when the same strains were grown in liquid culture. Psx. taiwanensis adhered to the same surfaces by a mechanism involving cell ghosts on which the biofilm of live cells grew. Hydrophilic (diamond-like carbon) or hydrophobic (fluoropolymer) coatings reduced the adherence of the four test bacteria on different steels. Selected topographic parameters, including root-mean-square roughness (Sq), skewness (Ssk) and surface kurtosis (Sku), were analysed by atomic force microscopy. The surfaces that best repelled microbial adhesion of the tested bacteria had higher skewness values than those only slightly repelling. Water contact angle, measured (θm) or roughness corrected (θy), affected the tendency for biofilm growth in a different manner for the four test bacteria.

Automating a 96-well microtitre plate model for Staphylococcus aureus biofilms : an approach to screening of natural antimicrobial compounds

The purpose of this study was to establish and automate an assay to be used for screening novel antimicrobial agents against biofilm-forming Staphylococcus aureus bacteria. The selected assay was based on crystal violet staining, which is a well used method for staining bacterial biofilms. The method was first optimised manually, antibiotic susceptibility was established and biofilm formation in plates was confirmed using atomic force microscopy. Automation of the assay was done using a Thermo Scientific Multidrop((R)) Combi dispenser and Biomek((R)) 3000 liquid handling workstation. A detailed comparison of the performance between the manual and the automated method was made in terms of screening window coefficient as well as other statistical parameters and repeatability measurements, such as plate-to-plate and day-to-day variability. Automated screening of an in-house library of natural products gave the same positive hits as previously reported, therefore the developed assay can be regarded as a reliable screening tool.

Behavior of printable formulations of loperamide and caffeine on different substrates—Effect of print density in inkjet printing

The primary goal of the current work was to study the applicability of precision inkjet printing in fabrication of personalized doses of active pharmaceutical ingredients (APIs). Loperamide hydrochloride (LOP) and caffeine (CAF) were used as model compounds. Different doses of the drugs in a single dosage unit were produced, using a drop-on-demand inkjet printer by varying printing parameters such as the distance between jetted droplets (drop spacing) and the physical dimensions of the printed dosage forms. The behavior of the formulated printable inks for both APIs was investigated on the model substrates, using different analytical tools. The obtained results showed that printed LOP did not recrystallize on any substrates studied, whereas at least partial recrystallization of printed CAF was observed on all carrier surfaces. Flexible doses of both APIs were easily obtained by adjusting the drop spacing of the depositing inks, and the results were relevant with regards to the theoretical content. Adapting the dose by varying physical dimensions of single dosage units was less successful than the approach in which drop spacing was altered. In conclusion, controlled printing technology, by means of adjusting the distance between jetted droplets, offers a means to fabricate dosage forms with individualized doses.

Cellulose nanocrystals prepared via formic acid hydrolysis followed by TEMPO-mediated oxidation

Cellulose nanocrystals (CNCs) as a renewable and biodegradable nanomaterial have wide application value. In this work, CNCs were extracted from bleached chemical pulp using two stages of isolation (i.e. formic acid (FA) hydrolysis and 2,2,6,6-tetramethyl-piperidine-1-oxyl (TEMPO) mediated oxidation) under mild conditions. In the first stage, FA was used to remove hemicellulose, swell cellulose fibers, and release CNCs. The FA could be readily recovered and reused. In the second stage, the CNCs isolated by FA were further modified by TEMPO-mediated oxidation to increase the surface charge of CNCs. It was found that the modified CNCs with more ordered crystal structure and higher surface charge had better redispersibility and higher viscosity in aqueous phase. Therefore, the modified CNCs could be more effective when used as rheology modifier in the fields of water based coating, paint, food etc.

A Step Toward Development of Printable Dosage Forms for Poorly Soluble Drugs

The purpose of this study was to formulate printable dosage forms for a poorly soluble drug (piroxicam; PRX) and to gain understanding of critical parameters to be considered during development of such dosage forms. Liquid formulations of PRX were printed on edible paper using piezoelectric inkjet printing (PIJ) and impression printing (flexography). The printed dosage forms were characterized using scanning electron microscopy with energy dispersive X-ray spectroscopy (SEM-EDX) and the amount of drug was determined using high-performance liquid chromatography. Solutions of PRX in polyethylene glycol 400 (PEG-400):ethanol (40:60) and in PEG-400 were found to be optimal formulations for PIJ and flexography, respectively. SEM-EDX analysis revealed no visible solid particles on the printed dosage forms indicating the drug most likely remained in solution after printing. More accurate drug deposition was obtained by PIJ as compared with flexography. More than 90% drug release was achieved within 5 min regardless of printing method used. The solubility of drug in solvents/cosolvents, rheological properties of formulations, properties of substrate, feasibility and accuracy of the printing methods, and detection limit of analytical techniques for characterization of printed dosage forms are some of the concerns that need to be addressed for development of printable dosage forms of poorly soluble drugs.

Identification and surface structure of crystalline cellulose studied by atomic force microscopy

A combination of molecular modelling and atomic force microscopy (AFM) techniques was used to study the surface structure of crystalline cellulose. Two‐dimensional Fourier analysis of the AFM raw data gave crystal parameters as well as a highly filtered inverse‐transformed image. Molecular modelling was used to generate Connolly surfaces based on electron diffraction data for crystalline cellulose. The modelled surfaces were used to interpret the experimental AFM images. Monoclinic () crystal faces were identified. The method used enables the structural analysis of cellulose surfaces at the molecular level, where all biological processes involving cellulose take place.