Table 6.
DDDPlus™ parameters for IR#2 formulation
| Parameter | Metronidazole | MCC | Croscarmellose | Mg stearate |
|---|---|---|---|---|
| Ingredient type | Active | Other | Disintegrant | Other |
| Amount (mg) | 50/25 | 743 | 24 | 8 |
| Molecular weight (g/mol) | 171.1534 | 36,000 | 395,000 | 591.27 |
| Reference solubility (mg/mL) | 13.6 at pH 4.5 | 0.0001 at pH 7 | 0.0001 at pH 6 | 0.03 at pH 7 |
| Density (g/mL) | 1.4535 | 1.6 | 1.54 | 1.2 |
| Precipitation time (s) | 900 | 900 | 900 | 900 |
| Diffusion coefficient (cm2/s⋅105) | 1.037 | 0.00005 | 0.00005 | 0.66 |
| Reference logD | −0.02 at pH 7.436 | – | – | – |
| Mean radius (µm)/SD/no of bins | 39.4020/2.5/8 | 10039/2.5/8 | 25/2.5/8 | 25/2.5/8 |
| Dissolution model | Nernst–Brunner | – | – | – |
| Calibration constant | a | 1 | 1 | 1 |
| Disintegration constant | – | – | 537.83 | – |
| General properties | ||||
| Tablet diameter (mm) | 12.66 | |||
| Porosity model | Ryshkewitch equation | |||
| Tablet tensile strength (MPa) | 1.1960 | |||
| Calculated from | ||||
| Tablet hardness (N) | 168.6744 | |||
| Short axis (mm) | 12.66 | |||
| Thickness (mm) | 6.99 | |||
| Wall height (mm) | 2.55 | |||
| Bonding constant | 6.7166 | |||
| Tens Str at Por =0 (MPa) | 23.7379 | |||
| Disintegration time (min) | (0) | |||
| Other properties | ||||
| .spd file metronidazole | a | |||
| Apparatus type | USP paddle | |||
| Solubility calculation | Load .spd file | |||
| Simulation length | 60 min | |||
| Dissolution model | Use microclimate pH |
Notes: Parameters without a source were part of the DDDPlus excipient database, standard values or calculated using the integrated conversion tool (diffusion coefficient). Croscarmellose disintegration constant and metronidazole mean radius were optimized to fit buffer pH 4.5 and SGFsp in vitro data via DDDPlus. Metronidazole solubility at pH 4.5 was measured via HPLC and general properties were gathered during the tablet manufacturing process. Tablet Tensile Strength was calculated using the modified Fell and Newton equation by Pitt et al.37,38
Optimized calibration constants for each medium: SGFsp: 0.3564, acetate buffer pH 4.5: 0.2330, 10% sucrose: 0.2270, 20% sucrose: 0.1910, 30% sucrose: 0.1471. ‘–’ indicates no value.
Abbreviations: DDDPlus, Dose Disintegration and Dissolution Software; HPLC, high-performance liquid chromatography; IR, immediate release; MCC, microcrystalline cellulose; SD, standard deviation; USP, United States Pharmacopeial Convention.