Niklas Sandler

Pharmaceutical co-crystals–an opportunity for drug product enhancement

By maximizing our understanding of materials and the relative importance of interactions on all levels (i.e., molecular, particle, powder, product), we can improve the manufacture of drug dosage forms and thus meet target specifications for mechanical durability, stability and biopharmaceutical performance. Pharmaceutical co-crystals are the latest material being explored in order to enhance drug properties using this bottom-up approach. In this review we provide a general introduction to pharmaceutical co-crystals. We also address common aspects of co-crystal formation, discuss screening strategies and outline methodologies for co-crystal functionality. Pharmaceutical co-crystals that have a distinct solid phase possess a unique set of properties, thus co-crystal formation can act as an advantageous alternative to other solid-state modification techniques. More research is needed in order to scale up co-crystal systems and implement manufacturing of final dosage forms on large scale.

Towards fabrication of 3D printed medical devices to prevent biofilm formation

The use of three-dimensional (3D) printing technologies is transforming the way that materials are turned into functional devices. We demonstrate in the current study the incorporation of anti-microbial nitrofurantoin in a polymer carrier material and subsequent 3D printing of a model structure, which resulted in an inhibition of biofilm colonization. The approach taken is very promising and can open up new avenues to manufacture functional medical devices in the future.

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.

Ethylene vinyl acetate (EVA) as a new drug carrier for 3D printed medical drug delivery devices

The main purpose of this work was to investigate the printability of different grades of ethylene vinyl acetate (EVA) copolymers as new feedstock material for fused-deposition modeling (FDM™)-based 3D printing technology in fabrication of custom-made T-shaped intrauterine systems (IUS) and subcutaneous rods (SR). The goal was to select an EVA grade with optimal properties, namely vinyl acetate content, melting index, flexural modulus, for 3D printing of implantable prototypes with the drug incorporated within the entire matrix of the medical devices. Indomethacin was used as a model drug in this study. Out of the twelve tested grades of the EVA five were printable. One of them showed superior print quality and was further investigated by printing drug-loaded filaments, containing 5% and 15% indomethacin. The feedstock filaments were fabricated by hot-melt extrusion (HME) below the melting point of the drug substance and the IUS and SR were successfully printed at the temperature above the melting point of the drug. As a result, the drug substance in the printed prototypes showed to be at least partly amorphous, while the drug in the corresponding HME filaments was crystalline. This difference affected the drug release profiles from the filaments and printed prototype products: faster release from the prototypes over 30days in the in vitro tests. To conclude, this study indicates that certain grades of EVA were applicable feedstock material for 3D printing to produce drug-loaded implantable prototypes.

Perspective: Concepts of printing technologies for oral film formulations

Different types of printing methods have recently attracted interest as emerging technologies for fabrication of drug delivery systems. If printing is combined with different oral film manufacturing technologies such as solvent casting and other techniques, multifunctional structures can be created to enable further complexity and high level of sophistication. This review paper intends to provide profound understanding and future perspectives for the potential use of printing technologies in the preparation of oral film formulations as novel drug delivery systems. The described concepts include advanced multi-layer coatings, stacked systems, and integrated bioactive multi-compartments, which comprise of integrated combinations of diverse materials to form sophisticated bio-functional constructs. The advanced systems enable tailored dosing for individual drug therapy, easy and safe manufacturing of high-potent drugs, development and manufacturing of fixed-dose combinations and product tracking for anti-counterfeiting strategies.

Three-Dimensional Printing of Drug-Eluting Implants: Preparation of an Antimicrobial Polylactide Feedstock Material

The aim of the present work was to investigate the potential of three-dimensional (3D) printing as a manufacturing method for products intended for personalized treatments by exploring the production of novel polylactide-based feedstock materials for 3D printing purposes. Nitrofurantoin (NF) and hydroxyapatite (HA) were successfully mixed and extruded with up to 30% drug load with and without addition of 5% HA in polylactide strands, which were subsequently 3D-printed into model disc geometries (10 × 2 mm). X-ray powder diffraction analysis showed that NF maintained its anhydrate solid form during the processing. Release of NF from the disks was dependent on the drug loading in a concentration-dependent manner as a higher level of released drug was observed from disks with higher drug loads. Disks with 30% drug loading were able to prevent surface-associated and planktonic growth of Staphylococcus aureus over a period of 7 days. At 10% drug loading, the disks did not inhibit planktonic growth, but still inhibited surface-associated growth. Elemental analysis indicated the presence of microdomains of solid drug supporting the observed slow and partial drug release. This work demonstrates the potential of custom-made, drug-loaded feedstock materials for 3D printing of pharmaceutical products for controlled release.

Near infrared spectroscopy in the development of solid dosage forms.

The use of near infrared (NIR) spectroscopy has rapidly grown partly due to demands of process analytical applications in the pharmaceutical industry. Furthermore, newest regulatory guidelines have advanced the increase of the use of NIR technologies. The non‐destructive and non‐invasive nature of measurements makes NIR a powerful tool in characterization of pharmaceutical solids. These benefits among others often make NIR advantageous over traditional analytical methods. However, in addition to NIR, a wide variety of other tools are naturally also available for analysis in pharmaceutical development and manufacturing, and those can often be more suitable for a given application. The versatility and rapidness of NIR will ensure its contribution to increased process understanding, better process control and improved quality of drug products. This review concentrates on the use of NIR spectroscopy from a process research perspective and highlights recent applications in the field.

The influence of various excipients on the conversion kinetics of carbamazepine polymorphs in aqueous suspension.

The influence of various excipients on the conversion of carbamazepine polymorphs to the dihydrate in aqueous suspension has been investigated. Ten excipients having functional groups which were potentially able to form hydrogen bonds with carbamazepine (group 1: methylcellulose, hypromellose (hydroxypropyl methylcellulose), hydroxypropylcellulose (HPC), 2‐hydroxyethylcellulose (HEC), carmellose sodium (sodium carboxymethylcellulose), cellobiose; group 2: povidone (polyvinylpyrrolidone), povidone‐vinyl acetate copolymer (povidone/VA) and N‐methyl‐2‐pyrrolidone; group 3: macrogol (polyethylene glycol) and polyethylene oxide‐polypropylene oxide copolymer (PEO/PPO)) were selected. Carbamazepine polymorphic forms III and I were dispersed separately into each aqueous excipient solution (0.1%, w/v) for 30 min at room temperature. The inhibition effect of each excipient was quantified using Raman spectroscopy combined with multivariate analyses. The solubility parameter of each excipient was calculated and used for categorizing excipients. Excipients in groups 1 and 2, which had both low solubility parameters (< 27.0 MPa½) and strong hydrogen bonding groups, inhibited the conversion completely. With increasing solubility parameter, the inhibition effect decreased for group 1 excipients, especially for carbamazepine form I, which had a higher specific surface area. Also, the excipients of group 3, lacking strong hydrogen bonding groups, showed poor inhibition although they had low solubility parameters (< 21.0 MPa½). This study indicated the importance of both hydrogen bonding interaction and a suitable hydrophobicity (expressed by the solubility parameter) in the inhibition of the conversion of carbamazepine to the dihydrate.

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.

Particle sizing measurements in pharmaceutical applications: comparison of in-process methods versus off-line methods.

It has been previously described that when a samples particle size is determined using different sizing techniques, the results can differ considerably. The purpose of this study was to review several in-process techniques for particle size determination (Spatial Filtering Velocimetry, Focused Beam Reflectance Measurements, Photometric Stereo Imaging, and the Eyecon® technology) and compare them to well-known and widespread off-line reference methods (laser diffraction and sieve analysis). To start with, a theoretical explanation of the working mechanism behind each sizing technique is presented, and a comparison between them is established. Secondly, six batches of granules and pellets (i.e., spherical particles) having different sizes were measured using these techniques. The obtained size distributions and related D10, D50, and D90 values were compared using the laser diffraction wet dispersion method as reference technique. As expected, each technique provided different size distributions with different D values. These dissimilarities were examined and explained considering the measurement principles behind each sizing technique. The particle property measured by each particle size analyzer (particle size or chord length) and how it is measured as well as the way in which size information is derived and calculated from this measured property and how results are presented (e.g., volume or mass distributions) are essential for the interpretation of the particle size data.