Table 3.

Recent studies of ASD API–polymer miscibility from MD-derived solubility and interaction parameters.

APIs	Polymer Carriers	Miscibility Parameter(s) Investigated	Force Field	Brief Simulation Overview 1	Experimental Miscibility Comparison	Reference
Indomethacin	PEO, glucose, sucrose	δ 2	COMPASS	2 ns NVT 3/NPT 4 equilibration, 200–500 ps NVT production (298 K, 1 fs/step)	PEO (miscible), glucose (immiscible), sucrose (borderline) predictions in agreement with thermal analysis experiments.	[57]
Artemisinin	PVP/PEG	$\delta$	COMPASS	500 ps NPT equilibration, 200 ps production (298 K, 1 fs/step)	Predicted PVP and PEG miscibility in agreement with observed drug dispersion from thermal analysis.	[62]
Gemcitabine	Chitosan	$\delta$	COMPASS	200 ps NPT equilibration, 800 ps production (298 K, 1 fs/step)	N/A	[61]
Telaprevir	Cellulose derivatives	$\delta$	CHARMM	50 ps NVE (0.5 fs/step), 5 ns NVT/NPT (310 K, 1 fs/step) equilibration, 40 ns NPT production (310 K, 1 fs/step)	N/A	[54]
Clonazepam, ibuprofen, fenofibrate, alprazolam	PVP–VA 64, HPMC, and Eudragit EPO	$\delta$	COMPASS	2 ns NPT equilibration, 500 ps NVT production (298 K, 1 fs/step)	Predicted fenofibrate/PVP-VA 64 weaker intermolecular interactions in agreement with observed recrystallization during stability experiments.	[63]
Ibuprofen, carbamazepine	SOL/PEG	$\delta$	CHARMM	2 ns NPT relaxation (393 K cooled to 298 K for ibuprofen, 474 K cooled to 298 K for carbamazepine, 10 K/step), 100 ps NPT equilibration/300 ps production at each temperature.	Both ibuprofen and carbamazepine predicted as miscible with SOL/PEG in agreement with observed single Tg values from DSC experiments.	[50]
6-Mercaptopurine	PLA, PEG-modified PLA	$\delta$	PCFF	2 ns NPT dynamics (298 K, 1 fs/step)	N/A	[58]
Olmesartan medoxomil	PVP–VA 64, SOL	$\delta$	OPLS	5 ns NPT dynamics (300 K, 1 fs/step)	Predicted high miscibility with PVP–VA 64 carrier reflected in crystallography and thermal analysis experiments.	[81]
Cyclosporin A	l/d–polylactide, chitosan, polyglycolic acid, PEG, cellulose	χ 5	PCFF	1.5 ns NPT dynamics (298 K)	N/A	[60]
Indomethacin	PEG, PLA	$\mathsf{\chi }$	COMPASS	5 ps NVT equilibration at each temperature step (298 K heated to 500 K in three steps, then cooled back to 298 K in three steps). 30 ns equilibration at the last step. 1 ns NPT production (298 K, 1 fs/step)	Predicted significant miscibility (negative interaction parameters) for indomethacin with both PEG and PLA as carriers in agreement with encapsulation efficiency experiments.	[56]
Felodipine	HPMC	$\delta$, $\mathsf{\chi }$	Amber/GLYCAM	10 ns equilibration (500–700 K), then cooled to 200 K (0.03 K/ps). 30–100 ns production (298 K, 1 fs/step).	Predicted miscibility from solubility and interaction parameters at all HPMC concentrations in agreement with observed single Tg values from DSC.	[69]
Indomethacin	PVP	$\delta$, $\mathsf{\chi }$	Amber	10 ns equilibration (600 K), then cooled to 200 K (0.03 K/ps). 100 ns production runs (298 K, 1 fs/step).	N/A	[68]
Tacrine	Chitosan, PBCA	$\delta$, $\mathsf{\chi }$	PCFF	100 ps equilibration (300 K), 5 ns NPT (298 K, 1 fs/step)	N/A	[74]
Simvastatin	PVP	$\delta$, $\mathsf{\chi }$	PCFF	5 ns NPT relaxation (600 K cooled to 200 K, 10 K/step, 1 fs/step). 400 ps NPT runs at each temperature. (1 fs/step)	Predicted miscibility from MD–based interaction parameter calculation in close agreement with measured value derived from melting point depression experiments.	[52]
Aspirin, caffeine, carbamazepine, finasteride, flufenamic acid, flutamide, mefenamic acid, salicylamide, theophylline	PVP–VA 64, poly (glycerol adipate) and derivatives	$\delta$, $\mathsf{\chi }$	CHARMM	Iterate cell volume prior to arriving at target density. At each step of the cycle, minimization, then 200 ps NVT dynamics (700 K, 1 fs/step). Cell then underwent annealing from 750 K to 300 K (0.1 K/ps). Minimization then 10 ns NPT dynamics (300 K).	Predicted solubility and interaction parameters showed no correlation to measured miscibility limits. Opposite to experimental values, MD-derived FH interaction parameters for six of nine API–PGA polymers predicted complete miscibility.	[110]

¹ See reference for more simulation details, including specific software settings, force field parameters, API–polymer cell construction, energy minimization algorithms, thermostats/barostats algorithms, periodic boundary conditions, integrators, dispersion cutoff distances, and long-range electrostatic methods. ² Solubility parameter ($\delta$), ³ Canonical ensemble conserving substance (N), volume (V), and temperature (T). ⁴ Isothermal–isobaric ensemble conserving substance (N), pressure (P), and temperature (T). ⁵ Flory–Huggins interaction parameter ($\mathsf{\chi }$). N/A: Not Applicable; PEO: polyethylene oxide; PVP-VA 64: poly(vinylpyrrolidone-co-vinyl acetate) 64; SOL: Soluplus; PBCA: polybutylcyanoacrylate; Differential scanning calorimetry: DSC.