Plasticizers

A search of the published literature on the use of phthalates in orally ingested medications suggested that phthalates are frequently included as inactive ingredients in modified-release drug formulations (i.e., controlled-release, delayed-release, or targeted-release systems), as well as in formulations for film coatings. Drug products using these formulations rely on the integrity of their coating systems for proper delivery of their active ingredients and therefore should not be crushed or chewed. Lists of drug products that are not recommended to be crushed or chewed have been published for reference by health care professionals to ensure their proper administration (Mitchell 2011 ; Thomson PDR 2006). We used these lists, which included approximately 450 product names, to complete an initial screen of drug product labeling for the inclusion of phthalates as excipients.
All inactive ingredients for RX medications on the “do not crush list” were first reviewed using a combination of print and electronic resources including the Physicians’ Desk Reference (Thomson Healthcare 1995–2010a), FDA Approved Drug Products database (Drugs@FDA; FDA 2011b), DailyMed [National Library of Medicine (NLM) 2011a], and LabelDataPlus (Reed Technology and Information Services Inc. 2011 ). Canadian products with comparable active ingredients and formulations were researched by using any available monographs from the Health Canada Drug Product Database (Health Canada 2011a ) and the CPS: Compendium of Pharmaceuticals and Specialties (Canadian Pharmaceutical Association 1995–2006). Names of brand and generic drug products marketed since 1995 appearing on the lists were searched within each available electronic or print reference, and all potential modified-release formulations were selected from the results. Once a label was located, we searched the document for all inactive ingredients. If multiple labels were available within a database, we investigated all potential inactive ingredient formulation changes by reviewing the older labels. If an older formulation of the product contained phthalates but the newer formulations did not, we searched all available labels by revision date to determine when the formulation changed. If none of the available compendia provided sufficient label information for a product, we searched the manufacturer or distributor website. If no label was found, we contacted the manufacturer and requested a copy of the package insert.
We performed further Internet searches using terms containing “phthalate” and “medication,” or suspected medication names and drug classes (e.g., bisacodyl, enzyme), to locate additional products and product categories. Patents for proprietary drug delivery systems were reviewed for the use of phthalate plasticizers in specific drug products or groups of products.
Several OTC medications and dietary supplement products were listed on the “do not crush” list; however, most available references including the Physicians’ Desk Reference for Nonprescription Drugs, Dietary Supplements, and Herbs (Thomson Healthcare 1995–2010b), Drugs@FDA, LabelDataPlus, DailyMed, and Dietary Supplements Labels Database (NLM 2011b) either did not include these products or did not provide complete, searchable label information on their inactive ingredients. For these products, we obtained detailed information on inactive ingredients from manufacturer and distributor web sites, or if possible, directly from product package labeling retrieved from store shelves. Canadian dietary supplement products were searched using the Health Canada Licensed Natural Health Products Database (LNHPD; Health Canada 2011b ), which currently contains information on approximately 16,000 licensed dietary supplements available in solid oral dosage forms.

The dogbone samples for tensile tests were printed on PRUSA i3 MK2 3D printer (Prusa Research s.r.o., Praha, Czech Republic) by the FDM technology from PHB/PLA/plasticizer filaments with defined diameter, as mentioned above. AutoCAD (ver. 2018, Autodesk Inc., San Rafael, CA, USA) and Slic3r (software version 1.3.0, free software, developed by Alessandro Ranellucci) program were used for 3D virtual modeling and mathematical slicing. The dogbones were printed at 190 °C (195 °C during the first layers printing for better adhesion to the printing bed), at ambient conditions, without additional air cooling and bed heating. 3D printing was executed approximately six months after the filaments preparation.
The evolution of 3D printed dogbone models that were prepared for further tensile tests can be seen in Figure 2.
The Version I was created by simple import of fabricated model to Slic3r program and uploading to the printer. But, during the tensile test with dogbones of Version I, the delamination of perimeters occurred (illustrated by yellow color), and so the measured samples did not provide relevant results. To solve this problem, Version II was designed, where the perimeters of dogbone neck were elongated up to the upper part. The paddleboards were created from two parts. Unfortunately, during the tensile test, the defect at the point of paddleboard and neck connection occurred, because the printer created an inclusion in the paddleboard corner by releasing a large amount of melting. The inclusion acted as a disruption initiator and cracked untimely. The aim of Version III was to eliminate this problem, but the pressure of grips was not strong enough to hold the sample. The deformation then occurred in upper cross-sectional part and disagreed with real dogbone strength. The final Version (that could not be illustrated in Figure 2) was created by the combination of 10 laminas of Version I and IV, which alternate regularly (five from each Version). The delamination of the neck in its extending part was eliminated by the insertion of vertical infill (illustrated by red color) and the vertical fracture of samples was eliminated by the combination with horizontal infill.