The Relative Impact of Solubility and Mobility From

Stability of Amorphous Solid Dispersions – The

Relative Impact of Solubility and Mobility from

Molecular Dynamics Simulations — Supporting

Information

Michael Brunsteiner,† Johannes Khinast,†,‡ and Amrit Paudel∗,†,‡

Research Center Pharmaceutical Engineering, Graz, Austria, and University of Technology, Graz, Austria

∗To whom correspondence should be addressed †Research Center Pharmaceutical Engineering, Graz, Austria ‡University of Technology, Graz, Austria

1 1 Choice of Model Systems

Lidocaine (LI) Benzamide (BD) Phenacetin (PH) Bifonazole (BI)

Chlorzoxazone (CZ) Flufenamic acid (FFA) Flurbiprofen (FB) Chlorpropamide (CP)

Figure S1: Literature data1 for eight different API molecules, each formulated with four different polymer types. ASD stabilities are given as amorphicity index (AI) values that are each an average from measurements at several different API loadings.

2 2 Convergence

-100 -20 FLA PAC

-101 -21

-102 -22 [kJ/mol] [kJ/mol] -103 -23 nonb nonb E E

-104 -24

-105 -25 0 20 40 60 80 100 120 140 160 180 200 0 20 40 60 80 100 120 140 160 180 200 time [ns] time [ns]

FLA PAC 0.354 0.274

0.352 0.272 ] ] 3 3

0.35 0.27

Volume [nm 0.348 Volume [nm 0.268

0.346 0.266

0 20 40 60 80 100 120 140 160 180 200 0 20 40 60 80 100 120 140 160 180 200 time [ns] time [ns]

Figure S2: Convergence of simulations of pure APIs. Non-bonded energies (top) and volume per molecule (bottom).

20 0.4 FLA FLA PAC PAC 0 0.38

-20 0.36 ] 3 -40 0.34 [kJ/mol] -60 0.32 nonb Volume [nm E -80 0.3

-100 0.28

-120 0.26 0 20 40 60 80 100 120 140 160 180 200 0 20 40 60 80 100 120 140 160 180 200 time [ns] time [ns]

Figure S3: Convergence of simulations of pure APIs. Direct comparsion of data for the two APIs. Non-bonded energies (left) and volume per molecule (right).

3 -4200 -4600 -8600 -2680 EEC PAA PSA PVP

-4220 -4620 -8620 -2700

-4240 -4640 -8640 -2720 [kJ/mol] [kJ/mol] [kJ/mol] [kJ/mol] -4260 -4660 -8660 -2740 nonb nonb nonb nonb E E E E

-4280 -4680 -8680 -2760

-4300 -4700 -8700 -2780 0 50 100 150 200 250 300 350 400 0 50 100 150 200 250 300 350 400 0 50 100 150 200 250 300 350 400 0 50 100 150 200 250 300 350 400 time [ns] time [ns] time [ns] time [ns]

9.5 3.9 9.2 6.8 EEC PAA PSA PVP 9.45 3.85 9.15

9.4 3.8 9.1 6.75 ] ] ] ] 3 9.35 3 3.75 3 9.05 3

9.3 3.7 9 6.7

9.25 3.65 8.95 Volume [nm Volume [nm Volume [nm Volume [nm 9.2 3.6 8.9 6.65

9.15 3.55 8.85

9.1 3.5 8.8 6.6 0 50 100 150 200 250 300 350 400 0 50 100 150 200 250 300 350 400 0 50 100 150 200 250 300 350 400 0 50 100 150 200 250 300 350 400 time [ns] time [ns] time [ns] time [ns]

Figure S4: Convergence of simulations of pure polymers. Non-bonded energies (top) and volume per molecule (bottom).

12 -1000 EEC EEC PAA 11 PAA -2000 PSA PSA PVP 10 PVP -3000 ] ]

3 3 9 -4000 8 -5000 7 -6000 Volume [nm Volume [nm 6 -7000 5 -8000 4 -9000 3 0 50 100 150 200 250 300 350 400 0 50 100 150 200 250 300 350 400 time [ns] time [ns]

Figure S5: Convergence of simulations of pure polymers. Direct comparsion of data for the four polymer types. Non-bonded energies (left) and volume per molecule (right).

4 -67000 -137000 -111000 -58000 EEC PAA PSA PVP

-67500 -137500 -111500 -58500

-68000 -138000 -112000 -59000

-68500 -138500 -112500 -59500 [kJ/mol] [kJ/mol] [kJ/mol] [kJ/mol] nonb nonb nonb nonb

E -69000 E -139000 E -113000 E -60000

-69500 -139500 -113500 -60500

-70000 -140000 -114000 -61000 0 50 100 150 200 250 300 350 400 0 50 100 150 200 250 300 350 400 0 50 100 150 200 250 300 350 400 0 50 100 150 200 250 300 350 400 time [ns] time [ns] time [ns] time [ns]

163 136 141 154 EEC PAA PSA PVP

162.5 135.5 140.5 153.5 ] ] ] ]

3 162 3 135 3 140 3 153

161.5 134.5 139.5 152.5

Volume [nm 161 Volume [nm 134 Volume [nm 139 Volume [nm 152

160.5 133.5 138.5 151.5

160 133 138 151 0 50 100 150 200 250 300 350 400 0 50 100 150 200 250 300 350 400 0 50 100 150 200 250 300 350 400 0 50 100 150 200 250 300 350 400 time [ns] time [ns] time [ns] time [ns]

Figure S6: Convergence of simulations of blends of four polymer types with 25 w% FLA. Non- bonded energies (top) and volume per molecule (bottom).

-20000 170 EEC EEC PAA 165 PAA -40000 PSA PSA PVP PVP 160

-60000 ] 3 155 -80000

[kJ/mol] 150

nonb -100000 Volume [nm E 145 -120000 140

-140000 135 0 50 100 150 200 250 300 350 400 0 50 100 150 200 250 300 350 400 time [ns] time [ns]

Figure S7: Convergence of simulations of blends of four polymer types with 25 w% FLA. Di- rect comparsion of data for the four polymer types. Non-bonded energies (left) and volume per molecule (right).

5 -61000 -132000 -106000 -51000 EEC PAA PSA PVP -51500 -61500 -132500 -106500 -52000 -62000 -133000 -107000 -52500

-62500 -133500 -107500 -53000 [kJ/mol] [kJ/mol] [kJ/mol] [kJ/mol]

nonb nonb nonb nonb -53500

E -63000 E -134000 E -108000 E -54000 -63500 -134500 -108500 -54500

-64000 -135000 -109000 -55000 0 50 100 150 200 250 300 350 400 0 50 100 150 200 250 300 350 400 0 50 100 150 200 250 300 350 400 0 50 100 150 200 250 300 350 400 time [ns] time [ns] time [ns] time [ns]

170 142 147 159 EEC PAA PSA PVP

169.5 141.5 146.5 158.5 ] ] ] ]

3 169 3 141 3 146 3 158

168.5 140.5 145.5 157.5

Volume [nm 168 Volume [nm 140 Volume [nm 145 Volume [nm 157

167.5 139.5 144.5 156.5

167 139 144 156 0 50 100 150 200 250 300 350 400 0 50 100 150 200 250 300 350 400 0 50 100 150 200 250 300 350 400 0 50 100 150 200 250 300 350 400 time [ns] time [ns] time [ns] time [ns]

Figure S8: Convergence of simulations of blends of four polymer types with 25 w% PAC. Non- bonded energies (top) and volume per molecule (bottom).

-20000 EEC EEC PAA 180 PAA -40000 PSA PSA PVP PVP 170 ]

-60000 3

-80000 160 [kJ/mol] nonb Volume [nm E -100000 150

-120000 140 -140000 0 50 100 150 200 250 300 350 400 0 50 100 150 200 250 300 350 400 time [ns] time [ns]

Figure S9: Convergence of simulations of blends of four polymer types with 25 w% PAC. Di- rect comparsion of data for the four polymer types. Non-bonded energies (left) and volume per molecule (right).

6 -77000 -146000 -121000 -69000 EEC PAA PSA PVP

-77500 -146500 -121500 -69500

-78000 -147000 -122000 -70000

-78500 -147500 -122500 -70500 [kJ/mol] [kJ/mol] [kJ/mol] [kJ/mol] nonb nonb nonb nonb

E -79000 E -148000 E -123000 E -71000

-79500 -148500 -123500 -71500

-80000 -149000 -124000 -72000 0 100 200 300 400 500 600 700 800 900 1000 0 100 200 300 400 500 600 700 800 900 1000 0 100 200 300 400 500 600 700 800 900 1000 0 100 200 300 400 500 600 700 800 900 1000 time [ns] time [ns] time [ns] time [ns]

196 170 174 187 EEC PAA PSA PVP 195.5 169.5 173.5 186.5

195 169 173 186 ] ] ] ] 3 194.5 3 168.5 3 172.5 3 185.5

194 168 172 185

193.5 167.5 171.5 184.5 Volume [nm Volume [nm Volume [nm Volume [nm 193 167 171 184

192.5 166.5 170.5 183.5

192 166 170 183 0 100 200 300 400 500 600 700 800 900 1000 0 100 200 300 400 500 600 700 800 900 1000 0 100 200 300 400 500 600 700 800 900 1000 0 100 200 300 400 500 600 700 800 900 1000 time [ns] time [ns] time [ns] time [ns]

Figure S10: Convergence of simulations of blends of four polymer types with 40 w% FLA. Non- bonded energies (top) and volume per molecule (bottom).

-40000 210 EEC EEC PAA 205 PAA -60000 PSA PSA PVP 200 PVP

] 195 -80000 3 190

[kJ/mol] -100000 185 nonb

Volume [nm 180 E -120000 175

-140000 170 165 0 100 200 300 400 500 600 700 800 900 1000 0 100 200 300 400 500 600 700 800 900 1000 time [ns] time [ns]

Figure S11: Convergence of simulations of blends of four polymer types with 40 w% FLA. Di- rect comparsion of data for the four polymer types. Non-bonded energies (left) and volume per molecule (right).

7 -64000 -135000 -110000 -56000 EEC PAA PSA PVP -64500 -135500 -110500 -56500

-65000 -136000 -111000 -57000

-65500 -136500 -111500 -57500

-66000 -137000 -112000 -58000 [kJ/mol] [kJ/mol] [kJ/mol] [kJ/mol]

nonb -66500 nonb -137500 nonb -112500 nonb -58500 E E E E -67000 -138000 -113000 -59000

-67500 -138500 -113500 -59500

-68000 -139000 -114000 -60000 0 100 200 300 400 500 600 700 800 900 1000 0 100 200 300 400 500 600 700 800 900 1000 0 100 200 300 400 500 600 700 800 900 1000 0 100 200 300 400 500 600 700 800 900 1000 time [ns] time [ns] time [ns] time [ns]

211 185 189 200 EEC PAA PSA PVP

210 184 188 199 ] ] ] ]

3 209 3 183 3 187 3 198

208 182 186 197

Volume [nm 207 Volume [nm 181 Volume [nm 185 Volume [nm 196

206 180 184 195

205 179 183 194 0 100 200 300 400 500 600 700 800 900 1000 0 100 200 300 400 500 600 700 800 900 1000 0 100 200 300 400 500 600 700 800 900 1000 0 100 200 300 400 500 600 700 800 900 1000 time [ns] time [ns] time [ns] time [ns]

Figure S12: Convergence of simulations of blends of four polymer types with 40 w% PAC. Non- bonded energies (top) and volume per molecule (bottom).

220 EEC EEC -40000 PAA 215 PAA PSA PSA PVP 210 PVP -60000 ]

3 205 -80000 200

[kJ/mol] 195 -100000 nonb Volume [nm E 190 -120000 185 180 -140000 175 0 100 200 300 400 500 600 700 800 900 1000 0 100 200 300 400 500 600 700 800 900 1000 time [ns] time [ns]

Figure S13: Convergence of simulations of blends of four polymer types with 40 w% PAC. Di- rect comparsion of data for the four polymer types. Non-bonded energies (left) and volume per molecule (right).

8 3.5 EEC PAA 3 PSA PVP 2.5 /sec] 2 2 cm

-10 1.5

D [10 1

0.5

0 300 400 500 600 700 800 900 1000 1100 time [ns] Figure S14: Convergence of API mobility calculations in blends of four polymer types with 40 w% PAC.

10 EEC 9 PAA PSA 8 PVP 7 /sec]

2 6

cm 5 -10 4

D [10 3 2 1 0 400 600 800 1000 1200 1400 time [ns] Figure S15: Convergence of API mobility calculations in blends of four polymer types with 40 w% PAC.

9 References

(1) Eerdenbrugh, B. V.; Taylor, L. Small Scale Screening to Determine the Ability of Different Polymers to Inhibit Drug Crystallization upon Rapid Solvent Evaporation. Molecular Phar- maceutics 2010, 7, 1328–1337.