Printing of small molecular medicines from the vapor phase

There is growing need to develop efficient methods for early-stage drug discovery, continuous manufacturing of drug delivery vehicles, and ultra-precise dosing of high potency drugs. Here we demonstrate the use of solvent-free organic vapor jet printing to deposit nanostructured films of small molecular pharmaceutical ingredients, including caffeine, paracetamol, ibuprofen, tamoxifen, BAY 11-7082 and fluorescein, with accuracy on the scale of micrograms per square centimeter, onto glass, Tegaderm, Listerine tabs, and stainless steel microneedles. The printed films exhibit similar crystallographic order and chemistry as the original powders; controlled, order-of-magnitude enhancements of dissolution rate are observed relative to powder-form particles. In vitro treatment of breast and ovarian cancer cell cultures in aqueous media by tamoxifen and BAY 11-7082 films shows similar behavior to drugs pre-dissolved in dimethyl sulfoxide. The demonstrated precise printing of medicines as films, without the use of solvents, can accelerate drug screening and enable continuous manufacturing, while enhancing dosage accuracy.


Supplementary Figure 3. Evaluation of particle sizes and surface area in powders and films
Powder and particles average sizes, shapes and surface areas were evaluated using Image-J software. In each case an average of at least 30 particles was measured. Based on the particles' shape and size, their average volume and weight were calculated. This micrograph is an example of measurement of length of tamoxifen film platelets grown on glass (yellow lines are calibrated with image scale bar). In a similar manner, tamoxifen platelets' width and height were measured, and volume and weight of rectangular prisms were calculated. 3 3

Supplementary Figure 3. Evaluation of particle sizes and surface area in powders and films
Powder and particles average sizes, shapes and surface areas were evaluated using Image-J software. In each case an average of at least 30 particles was measured. Based on the particles' shape and size, their average volume and weight was calculated. Here is an example of measurement of length of tamoxifen film platelets grown on glass (yellow lines are calibrated with image scale bar). By similar manner tamoxifen platelets width and height is measured, and volume and weight of rectangular prisms are calculated.

Supplementary Figure 4. FTIR absorption spectra of BAY 11-7082.
Absorption spectra of BAY 11-7082 film and original powder showed similar peaks, indicating that no material degradation occurred due to deposition. Absorption spectra of BAY 11-7082 film and original powder showed similar peaks, assuring that no material degradation occurred due deposition.

Supplementary Figure 5. Caffeine original powder and film form compared to β-form anhydrous caffeine
For caffeine, two polymorphs are usually reported: anhydrous β-form of caffeine that typically exists at low temperature, and high temperature α-form caffeine that exist above 141°C. We compared XRD pattern of caffeine films and original powder to existing phases and found that both original powder and resulting film are in very good agreement with β-form of caffeine structure

Supplementary Figure 5. Caffeine original powder and film form compared to β-form anhydrous caffeine
For caffeine, two polymorphs are usually reported: anhydrous β-form of caffeine that typically exists at low temperature, and high temperature αform caffeine that exist above 141°C.
We compared XRD pattern of caffeine films and original powder to existing phases and found that both original powder and resulting film are in very good agreement with β-form of caffeine structure Absorption spectra of BAY 11-7082 film and original powder showed similar peaks, assuring that no material degradation occurred due deposition.

Supplementary Figure 5. Caffeine original powder and film form compared to β-form anhydrous caffeine
For caffeine, two polymorphs are usually reported: anhydrous β-form of caffeine that typically exists at low temperature, and high temperature α-form caffeine that exist above 141°C. We compared XRD pattern of caffeine films and original powder to existing phases and found that both original powder and resulting film are in very good agreement with β-form of caffeine structure

Supplementary Figure 6. Paracetamol original powder and film form compared to Form I and Form II paracetamol
Paracetamol was reported to have three common polymorphs, two of which were fully characterized: monoclinic Form I, most stable; orthorhombic Form II, less stable than I, and highly metastable Form III which is not fully characterized. Good agreement was found between the our samples and Form I paracetamol structure, both in powder and film samples, with a small amount of Form II admixed.

Supplementary Figure 6. Paracetamol original powder and film form compared to Form I and Form II paracetamol
Paracetamol was reported to have three common polymorphs, two of which were fully characterized: monoclinic Form I, most stable; orthorhombic Form II, less stable than I, and highly metastable Form III which is not fully characterized. Good agreement exists between Form I paracetamol structure, powder and film, with a small amount of Form II admixed. Paracetamol was reported to have three common polymorphs, two of which were fully characterized: monoclinic Form I, most stable; orthorhombic Form II, less stable than I, and highly metastable Form III which is not fully characterized. Good agreement exists between Form I paracetamol structure, powder and film, with a small amount of Form II admixed. In the case of BAY 11-7082, we found no previous reports of XRD data in the literature. The peak appearing below 1.8° is a measurement artifact, absent for example from the pattern from a film on a silicon substrate, also shown, which lacks this broad artifact. 8 6

Supplementary Figure 8. Detailed diffraction pattern of BAY 11-7082 original powder and resulting films on glass and silicon substrates
In case of BAY 11-7082 no previous XRD data was found in the literature. The peak appearing below 1.8° is a measurement artifact, absent for example from the pattern from a film on a silicon substrate, also shown, which lacks this broad artifact.

Supplementary Figure 9. Additional results of caffeine and ibuprofen films X-RAY diffraction
Additional results of films X-RAY diffraction. A monochromatic X-ray beam at 15 keV was used to probe the film's 3D crystal structure with the beam spot size optimized at 300 µm x 35 µm in the horizontal and vertical directions, respectively. To resolve the symmetry of the organic films, high-resolution Grazing-Incidence Wide-Angle X-ray Scattering (GIWAXS) measurements were performed. Using a PILATUS 100K area detector 51,52 , the intensity distribution was measured in a series of detector scans along the out-of-plane direction as a set of twodimensional reciprocal space slices. These were then used to reconstruct the 3D reciprocal space volume 53 from which 2D projections (reciprocal space maps) at given L values were derived as shown in the figures above. For each sample, the GIWAXS patterns were recorded at an angle of incidence of 0.1° and taken over a 2! range of 5° to 45°.GIWAXS patterns of (a) caffeine, and (b) ibuprofen films deposited on glass substrates. All films show nearly isotropic orientation with extremely broad and nearly uniform distribution of intensity for all rings in plane and out of plane. The broad rings suggest that caffeine and ibuprofen have a polycrystalline crystal structure when deposited on glass substrates. Qualitatively, caffeine films show the sharper rings than ibuprofen and are therefore more ordered. 9 11

Supplementary Figure 13. Additional results of caffeine and ibuprofen films X-RAY diffraction
Additional results of films X-RAY diffraction. A monochromatic X-ray beam at 15 keV was used to probe the film's 3D crystal structure with the beam spot size optimized at 300 µm x 35 µm in the horizontal and vertical directions, respectively. To resolve the symmetry of the organic films, high-resolution Grazing-Incidence Wide-Angle X-ray Scattering (GIWAXS) measurements were performed. Using a PILATUS 100K area detector 51,52 , the intensity distribution was measured in a series of detector scans along the out-of-plane direction as a set of two-dimensional reciprocal space slices. These were then used to reconstruct the 3D reciprocal space volume 53 from which 2D projections (reciprocal space maps) at given L values were derived as shown in the figures above. For each sample, the GIWAXS patterns were recorded at an angle of incidence of 0.1° and taken over a 2! range of 5° to 45°.GIWAXS patterns of (a) caffeine, and (b) ibuprofen films deposited on glass substrates. All films show nearly isotropic orientation with extremely broad and nearly uniform distribution of intensity for all rings in plane and out of plane. The broad rings suggest that caffeine and ibuprofen have a polycrystalline crystal structure when deposited on glass substrates. Qualitatively, caffeine films show the sharper rings than ibuprofen and are therefore more ordered. Films printed on glass substrates were immersed into cell growth medium. After 1 hour of agitation, the glass film was removed.

Supplementary Figure 12. Cancer cell growth curves -cell growth at drug-free conditions.
To ensure that glass slide doesn't affect cell growth, three drug-free control studies were performed: medium with just cancer cells, medium with just cancer cells and DMSO, medium with just cancer cells and glass slide. No effect of the presence of the bare glass slide on cell growth was observed in the case of breast cancer MCF7 (a) or ovarian cancer OVCAR (b) cell cultures.