Table 1.
Overview of studies using molar ratio optimization to find the optimal molar ratio for the investigated amorphous systems. Y: Yes, N: No. *ROY: 5-methyl-2 [(2-nitrophenyl)-amino]-3-thiophenecarbonitrile. DSC: Differential scanning calorimetry. DMA: Dynamical mechanical analysis. PCA: Principal component analysis. XRPD: X-ray powder diffractometry. FTIR: Fourier-transform infrared spectroscopy. Tg: glass transition temperature.
| Amorphous Systems | Preparation Method | Compositions of the Systems |
Optimization Methods | The Optimal Molar Ratio(s) |
Physical Stability to Confirm the Optimal Molar Ratio | Reference |
|---|---|---|---|---|---|---|
| Atenolol- Urea |
Melt-quench | Molar ratios of 1:1, 1:2, 1:4, 1:6, 1:8, 1:10, 1:12 | Thermal analysis by DSC; Precipitation test | Atenolol–Urea 1:4 for CAMS; Atenolol–Urea 1:8 for super-saturation maintenance | N | [44] |
| Carvedilol– Aspartic acid |
Spray drying | Molar ratios of 2:1, 1:1, 1:1.25, 1:1.5, 1:1.75, 1:2, 1:2.25, 1:2.5, 1:3, 1:4 | Data fitting methods of Tgs; FTIR-PCA | 1:1.46 (mathematically); 1:1.5 (experimentally) |
Y | [72] |
| Carvedilol– Benzoic acid |
Spray drying | Molar ratios of 1:4, 1:3, 1:2, 1:1, 1.5:1, 2:1, 4:1 | Determination of the highest Tg |
1.5:1 | Y | [39] |
| Carvedilol– Citric acid |
Spray drying | Molar ratios of 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 4:1 | Determination of the highest Tg |
2:1 | Y | [39] |
| Carvedilol– Glutamic acid |
Spray drying | Molar ratios of 2:1, 1:1, 1:1.25, 1:1.5, 1:1.75, 1:2, 1:2.25, 1:2.5, 1:3, 1:4 |
Data fitting methods of Tgs; FTIR-PCA | 1:1.43 (mathematically); 1:1.5 (experimentally) |
Y | [72] |
| Carvedilol– Malic acid |
Spray drying | Molar ratios of 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 4:1 | Determination of the highest Tg |
2:1 | Y | [39] |
| Carvedilol– Tryptophan |
Ball milling | Molar fractions 0.1–0.9, at an interval of 0.1 | Determintion of Tgβ by DMA; thermal analysis by DSC (lack of any endothermic or exothermic events) | The molar fractions of carvedilol were 34–52% (equal to the molar ratio of Carvedilol–Tryptophan from 1:0.92 to 1:1.94). | Y | [73] |
| Ezetimibe– Lovastatin– Soluplus® |
Spray drying | Ezetimibe–Lovastatin at the weight ratios of 1:1, 1:2, 1:4. The weight fractions of soluplus® were 50 wt %, 75 wt %, 90 wt %. |
Physical stability | Weight ratio of 12.5:12.5:75. | Y | [78] |
| Ezetimide–Simvastatin– Kollidon® VA64 |
Melt-quench | Ezetimibe–Simvastatin at the weight ratios of 1:1. The weight fractions of polymer were 5 wt %, 20 wt %, 40 wt %, 60 wt % |
The viscoelastic properties measured by oscillatory shear rheology | Minimal 40 wt % polymer required | N (only confirmed CAMS with 40 wt % polymer was stable) | [79] |
| Furosemide– Arginine |
Ball milling | Molar fractions of furosemide from 0.09 to 0.9 | Comparison of the experimental Tgs to the theoretical Tgs for the largest deviation | 1:1 | N | [30] |
| Furosemide– Tryptophan |
Ball milling | Molar fractions of furosemide from 0.09 to 0.9 | Comparison of the experimental Tgs to the theoretical Tgs for the largest deviation | 1:1 | N | [30] |
| Indomethacin– Arginine |
Ball milling | Molar fractions of indomethacin from 0.09 to 0.9 | Comparison of the experimental Tgs to the theoretical Tgs for the largest deviation | 1:1 | N | [30] |
| Indomethacin–Naproxen | Melt-quench | Molar fractions 0.1–0.9, at an interval of 0.1 | Phase diagrams to determine the eutectic point | 1:1.5 | Y | [73] |
| Indomethacin–Tryptophan | Ball milling | Molar fractions of indomethacin from 0.09 to 0.9 | Comparison of the experimental Tgs to the theoretical Tgs for the largest deviation | 1:1 | N | [30] |
| Indomethacin–Tryptophan | Ball milling | Molar fractions 0.1–0.9, at an interval of 0.1 | Determintion of Tgβ by DMA; thermal analysis by DSC (lack of any endothermic or exothermic events) | The molar fractions of indomethacin were 5–25% (equal to the molar ratio of Indomethacin–Tryptophan from 1:3 to 1:19). | Y | [76] |
| Naproxen– Indomethacin |
Melt-quench | Molar fractions 0.1–0.9, at an interval of 0.1 | XRP–diffractograms–PCA; FTIR–PCA; Phase diagrams | 1.5:1 | Y | [74] |
| Naproxen– Meglumine |
Melt-quench | Molar ratios of 10:1, 2.5:1, 10:7, 1:1, 7:10, 1:2.5, 1:10 | Determination of the highest glass transition temperature; Physical stability |
1:1 | Y | [80] |
| Naproxen–Sodium– Indomethacin |
Melt-quench | Molar fractions 0.1–0.9, at an interval of 0.1 | Physical stability | Naproxen–Sodium: 0.1–0.4 (equal to the molar ratio Naproxen–Sodium:Indomethacin from 1:9 to 1:1.5) |
Y | [81] |
| Naproxen–Sodium– Naproxen–Indomethacin |
Melt-quench | Molar ratio of Naproxen–Sodium:Naproxen fixed at 1:1; Molar fractions of Indomethacin: 0.1–0.9, at an interval of 0.1 |
Physical stability | Indomethacin: 0.3–0.9 (equal to the molar ratio Naproxen–Sodium:Naproxen:Indomethacin from 1:1:0.86 to 1:1:1.8) | Y | [81] |
| Nifedipine– Cimetidine |
Melt-quench | Molar fractions 0.1–0.9, at an interval of 0.1 | DSC thermograms of both freshly prepared samples and stored sample (increased Tg, and lack of crystallization and melting endotherms) | The molar fractions of cimetidine were 0.3–0.9 (equal to Nifedipine–Cimetidine from 2.3:1 to 1:9). | N (only for the sample at the 1:1 molar ratio) | [77] |
| Nifedipine– Paracetamol |
Melt-quench | Molar fractions 0.1–0.9, at an interval of 0.1 | Phase diagrams to determine the eutectic point | 1:1.5 | Y | [73] |
| Nimesulide– Carvedilol |
Melt-quench | Molar fractions 0.1–0.9, at an interval of 0.1 | DSC thermograms of both freshly prepared samples and stored sample (increased Tg, and lack of crystallization and melting endotherms) | The molar fractions of carvedilol were 0.3–0.8 (equal to Nimesulide–Carvedilol 2.3:1 to 1:4). | N (only for the sample at the 1:1 molar ratio) | [77] |
| Ofloxacin– Tryptophan |
Freeze-drying | Molar ratios of 1:1, 1:2, 1:3, and also weight fractions 0.5–0.95 |
Kinetic solubility measurements of drug for freeze-dried samples; Comparison of the experimental Tgs to the theoretical Tgs for the largest deviation | Best solubility was found at the molar ratio of 1:1.76; highest positive deviation in Tg values was also found at a molar ratio of 1:1.76. | N (only for the CAMS at the 1:1.76 molar ratio) | [82] |
| Paracetamol– Antipyrine |
Melt-quench | Molar fractions 0.1–0.9, at an interval of 0.1 | Thermal analysis during physical stability | 1:2 | Y | [83] |
| Paracetamol–Celecoxib | Melt-quench | Molar fractions 0.1–0.9, at an interval of 0.1 | Phase diagrams to determine the eutectic point | 1:1 | Y | [73] |
| ROY*– Pyrogallol |
Melt-quench | Weight fractions 0–100 wt %, at an interval of 5 wt % | Thermal analysis by DSC (lack of any endothermic or exothermic events) | Pyrogallol content 25–35 wt % (equal to the molar ratio ROY*:Pyrogallol from 1:0.69 to 1:1.11) | N | [75] |
| Simvastatin– Nifedipine |
Melt-quench | Molar fractions 0.1–0.9, at an interval of 0.1 | Physical stability; phase diagram |
CAMS at the molar ratio of 2:1 to 1:2 were all stable for at least one year (Eutectic composition: 5.375:1) |
Y | [84] |
| Ursolic acid– Piperine |
Solvent evaporation |
3:1, 2:1, 1.5:1, 1:1 and 1:2 | Determination of the highest Tg; physical stability | 2:1 showed the highest Tg; 1.5:1 was the most stable CAMS | Y | [85] |
| Valsartan– Nifedipine |
Melt-quench | Weight ratios of valsartan/nifedipine at 90:10, 80:20, 80:30 (molar 1:1), 60:40, 50:50, 40:60 | Physical stability; in vitro dissolution test | CAMS at all molar ratios were stable; CAMS at the weight fractions of 80:30, 80:20, and 90:10 showed better drug release of both drugs (equal to the molar ratio 1:1, 1:0.67, and 1:0.3) | Y | [86] |