Mass spectrometry

High-resolution mass spectrometry (HRMS) was performed with an Agilent 6538 QTOF with an ESI MS+ ion source with high resolution, accurate mass capability. HRMS data are reported in the figure captions for Supplementary Figs. ¹ and ¹⁴–¹⁸.

Pellets for release studies. Crystalline drug dimers were weighed on a stainless steel coupon. In the case of blends with a second drug, the dimer and drug were mixed at the desired mass ratio with mortar and pestle prior to weighing. Samples were transferred to a heat press (Carver Laboratory Press). A PTFE mold containing an array of 1 mm diameter holes of 1 mm depth was placed on top of the melt, and pressure was applied for 2 min. Molded pellets were cooled to room temperature and punched out of the mold, yielding a pellet of 1 mm height × 1 mm diameter.

Spray coating and electrospinning. Dimers were dissolved in acetone or tetrahydrofuran at concentrations ranging from 100–1000 mg/ml depending on the study. The solution was injected at a rate of 0.5 ml/h onto a stationary aluminum collector plate. An 18 kV potential difference between the needle and collector plate was maintained, with the needle charge set at +17.5 kV and the collector at −0.5 kV.

Solvent-based fiber pulling. Drug dimers were dissolved in DCM at 1 g/ml. Forceps were used to pull the resulting mixture and generate fibers. Fibers were left to dry overnight at room temperature.

Emulsion and microparticle fabrication. Drug dimers were dissolved in dichloromethane at 25% w/v, and 200 µl of this solution was then added to 400 ml of an aqueous solution of 1% sodium dodecyl sulfate (SDS, Sigma-Aldrich) through a Shirasu Porous Glass membrane (SPG Technology Co., Ltd). Samples were stirred for 1 h at room temperature. Serial centrifugation was used to remove residual SDS and collect microparticles. Microparticles were re-suspended in 0.5% carboxymethylcellulose (CMC, Sigma) in Milli-Q water at a concentration of 1 g/ml. 50 μl of the microparticle suspension was deposited onto carbon tape and left to dry overnight. Once dry, the samples were sputter-coated with gold at a thickness of 15 nm. Images were obtained at ×300 magnification. Microparticle diameter measurements were obtained using ImageJ (v. 1.8.0), in which the diameters of the microparticles were determined by normalizing the scale bar on the images with the corresponding distance in pixels. All microspheres that were un-obstructed and completely visible in the images were measured. Four batches of microparticles were assessed, with a minimum 200 microparticles measured per batch.

To prepare nanoparticles, dimers were dissolved in DCM at 25% w/v, and 200 µl of the solution was added to 3.8 ml of 1% SDS and sonicated for 1 min. Samples were then washed and nanoparticles collected by serial centrifugation. Nanoparticle size distributions were assessed using a DelsaMax Pro (Beckman Coulter).

Extruded rod fabrication. Dimers were weighed on aluminum foil and transferred into a length of PTFE tubing. The material was then loaded into a brass (McMaster-Carr) piston extruder barrel pre-heated with a collar heater & controller (Omega CSi32k). The extruder motor, a syringe pump (New Era) advanced a PTFE ended 1 mL Hamilton syringe piston, driving the molten dimer from the brass die (3D printing nozzle, E3D), onto a custom linear, tensioned belt, manually controlled variable-speed draw-down system to provide further control of the rod diameter. Extrusion and draw-down rates were adjusted as needed to compensate for selected extrusion die diameter, and drug-dimer material properties.

Solvent casting. Dimers were dissolved in acetone at 100 mg/ml. 10 µl of the solution was cast onto a 1 cm × 1 cm stainless steel or glass coverslip and left to dry at room temperature overnight.

Powder coating. Electrosprayed samples were heated at 185 °C to yield a smooth conformal coating.

Heat-based fiber pulling. Crystalline drug dimers were weighed on a stainless steel coupon and transferred to a heated stainless steel block. After fully melted, forceps were used to pull the melt solution, yielding fibers.