On the Usefulness of Two Small-Scale In Vitro Setups in the Evaluation of Luminal Precipitation of Lipophilic Weak Bases in Early Formulation Development
Abstract
:1. Introduction
2. Materials and Methods
2.1. Materials
2.2. Methods
2.2.1. Physicochemical and Pharmacokinetic Properties of Model Drugs
2.2.2. Preparation of Level II FaSSIF V2 × 10 Concentrated for Biphasic Dissolution Experiments
2.2.3. Preparation of Level II FaSSIF V2 × 4 Concentrated for D-P Experiments
2.2.4. Dose Selection
2.2.5. Biphasic Dissolution Test
2.2.6. Biphasic Emulsification Risk Investigation
2.2.7. D-P Experiments
2.2.8. PBPK Modelling
3. Results and Discussion
3.1. Data on the Emulsification Risk in the Biphasic Experiments
3.2. Data from the Biphasic Experiments
3.3. Data from the D-P Experiments
3.4. Limitations of UV Probes
3.5. PBPK Modelling
4. Concluding Remarks
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Parameter (Units) | Values Used | Refs/Comments |
---|---|---|
Physchem and Blood Binding Parameters | ||
Mol wt (g/mol) | 504.6 | |
Log Po:w | 3.97 | In house experimental database |
Compound type | Monoprotic base | In house experimental database |
pKa | 6.07 | In house experimental database |
Fraction unbound in plasma | 0.002 | Pathak et al. [25] |
Blood plasma ratio | 0.56 | Predicted in Simcyp |
Fraction unbound in enterocyte | 1 | Simcyp compound file |
Drug Absorption Parameters (ADAM Model) | ||
Apparent Caco-2 cell permeability (×10−6 cm/s) apical pH 7.4 - basolateral pH 7.4 | 11.24 | Skolnik et al. [26] |
Calibrator compounds Caco-2 cell permeability (×10−6 cm/s) | Cimetidine 1.64 Propranolol 21.29 Verapamil 22.68 Metoprolol 17.74 | Skolnik et al. [26] |
PredictedPeff,man (×10−4 cm/s) | 2.90 | Predicted in Simcyp using Caco-2 cell permeability |
Aqueous (Aq) intrinsic solubility (mg/mL) | 0.0065 | Calculated used pH solubility profile |
Solubility Factor (SF) | 1081 | Estimated in Simcyp |
Diffusion Layer Model (DLM) scalar | 1 | Simcyp default value |
Particle density (g/mL) | 1.2 | Default Simcyp value |
Particle size distribution | Monodispersed | Default Simcyp value |
Particle radius (µm) | 10 | Default Simcyp value |
Log bile micellar: buffer partition coefficient (Log Km:w) neutral | 4.65 | Estimated in Simcyp in vitro analysis (SIVA) toolkit |
Log Km:w ion | 4.07 | Estimated in SIVA |
Particle diffusion layer thickness (heff) prediction | Hintz–Johnson method | Default Simcyp method [27] |
Critical Supersaturation Ratio (CSR) | 13.33 | Calculated from experimental data, this study |
Precipitation Rate Constant (PRC) (1/h) | 1.08 (from biphasic exp)/2.02 (from D-P exp) | Calculated from experimental data, this study |
Secondary PRC (sPRC) (1/h) | N/A | |
Monomer diffusion coeff (10−4 cm2/min) | 3.70 | Predicted in Simcyp |
Micelle diffusion coeff (10−4 cm2/min) | 0.78 | Default Simcyp value |
Distribution Parameters | ||
Model | Full PBPK Model | |
Method | Method 3 | |
Tissue-plasma partition coefficient (Kp) scalar | 1 | Pathak et al. [25] |
Steady State Volume of Distribution (Vss) (L/kg) | 0.41 | Predicted within Simcyp |
Elimination Parameters | ||
Intravenous clearance (CLiv) (L/h) | 12 | Persantin® Ampoules 10 mg/2 mL solution for infusion product information [19] |
Renal clearance (L/h) | 0 | Nielsen-Kudsk and Pedersen [28] |
Parameter (Units) | Values Used | Refs/Comments |
---|---|---|
Physchem and Blood Binding Parameters | ||
Mol wt (g/mol) | 531.4 | |
Log Po:w | 3.84 | In house experimental database |
Compound type | Diprotic base | In house experimental database |
pKa | 3.16, 6.13 | In house experimental database |
Fraction unbound in plasma | 0.029 | Martinez-Jorda et al. [29] |
Blood plasma ratio | 0.62 | Simcyp inhibitor compound file |
Fraction unbound in enterocyte | 0.06 | Simcyp inhibitor compound file |
Drug Absorption Parameters (ADAM Model) | ||
Apparent Caco-2 cell permeability (×10−6 cm/s) apical pH 7.4 - basolateral pH 7.4 | 15.95 | Skolnik et al. [26] |
Calibrator compounds Caco-2 cell permeability (×10−6 cm/s) | Cimetidine 1.64 Propranolol 21.29 Verapamil 22.68 Metoprolol 17.74 | Skolnik et al. [26] |
PredictedPeff,man (×10−4 cm/s) | 3.70 | Predicted in Simcyp using Caco-2 cell permeability |
Aq intrinsic solubility (mg/mL) | 0.0064 | Back calculated using pH solubility data |
Solubility factor | 2167 | Estimated in SIVA |
DLM scalar | 1 | Simcyp default value |
Particle density (g/mL) | 1.2 | Simcyp default value |
Particle size distribution | Monodispersed | Default Simcyp |
Particle radius (µm) | 12 | Pathak et al. [30] |
Log Km:w neutral | 4.30 | Estimated in SIVA |
Log Km:w ion | 4.28 | Estimated in SIVA |
Particle heff prediction | Hintz–Johnson method | Default Simcyp method [27] |
CSR | 16.93 | Calculated from experimental data, this study |
PRC (1/h) | 2.02 (from biphasic exp)/6.14 (from D-P exp) | Calculated from experimental data, this study |
sPRC (1/h) | N/A | |
Monomer diffusion coeff (10−4 cm2/min) | 3.62 | Predicted in Simcyp |
Micelle diffusion coeff (10−4 cm2/min) | 0.78 | Default Simcyp Value |
Distribution Parameters | ||
Model | Full PBPK Model | |
Method | Method 2 | |
Kp scalar | 0.012 | Cristofoletti et al. [31] |
Vss (L/kg) | 0.2 | Predicted within Simcyp |
Elimination Parameters | ||
CLiv (L/h) | 14.4 | Huang et al. [20] |
Renal clearance (L/h) | 0.15 | Pathak et al. [30] |
Parameter (Units) | Values Used | Refs/Comments |
---|---|---|
Physchem and Blood Binding Parameters | ||
Mol wt (g/mol) | 704.64 | |
Log Po:w | 5.66 | FDA Label Sporanox |
Compound type | Monoprotic base | In house experimental database |
pKa | 3.87 | In house experimental database |
Fraction unbound in plasma | 0.002 | FDA Label Sporanox |
Blood plasma ratio | 0.58 | Simcyp inhibitor compound file |
Fraction unbound in enterocyte | 0.016 | Simcyp inhibitor compound file |
Drug Absorption Parameters (ADAM Model) | ||
MCDK II (×10−6 cm/s) | 57.1 | Simcyp inhibitor compound file |
Calibrator compounds MCDK II permeability (×10−6 cm/s) | Cimetidine 2.00 Propranolol 49.60 Verapamil 59.10 | Simcyp inhibitor compound file |
PredictedPeff,man (×10−4 cm/s) | 9.85 | Predicted in Simcyp using MCDK cell permeability |
Aq intrinsic solubility (mg/mL) | 8.94E-05 | Back calculated using pH solubility data |
Solubility factor | 222.37 | Estimated in SIVA |
DLM scalar | 1 | Simcyp default value |
Particle density (g/mL) | 1.2 | Simcyp default value |
Particle size distribution | Monodispersed | Simcyp default value |
Particle radius (µm) | 10 | Simcyp default value |
Log Km:w neutral | 5.62 | Predicted in SIVA |
Log Km:w ion | 5.48 | Predicted in SIVA |
Particle heff prediction | Hintz–Johnson method | Default Simcyp method [27] |
CSR | 44.97 | Calculated from experimental data, this study |
PRC (1/h) | 1.98 (OS), 2.11 (capsules) | Calculated from experimental data, this study |
sPRC (1/h) | N/A | |
Monomer diffusion coeff (10−4 cm2/s) | 3.17 | Predicted within Simcyp |
Micelle diffusion coeff (10−4 cm2/s) | 0.78 | Default Simcyp Value |
Solid state 2 (Capsules only) | ||
Aq. intrinsic solubility (mg/ml) | 0.001 | Matsui et al. [32] |
DLM scalar | 0.69 | Estimated in SIVA from dissolution profile |
Excipient Mediated Solubility (OS only) | ||
Binding constant (M−1) | 1654 (K1:1), 13 (K1:2) | Peeters et al. [33] |
Binding constant (M−1) stomach | 9895 (K1:1), 23 (K1:2) | Peeters et al. [33] |
Distribution Parameters | ||
Model | Full PBPK Model | |
Method | Method 2 | |
Kp scalar | 0.19 | Poirier et al. [34] |
Vss (L/kg) | 11.06 | Predicted within Simcyp |
Elimination Parameters | ||
CLiv (L/h) | 22.9 | Heykants et al. [21] |
Renal clearance (L/h) | 0 | Simcyp inhibitor compound file |
PK Parameter | Ricevuti et al. ± SD | PBPK Using Experimental Biphasic InForm PRC Value ± SD (% PE) | PBPK Using Experimental D-P PRC Value ± SD (% PE) | PBPK Using Default Simulator Precipitation Values ± SD (% PE) | PBPK with no Precipitation ± SD (% PE) |
---|---|---|---|---|---|
AUC (mg/L h) | 4.13 ± 0.52 | 4.12 ± 1.49 (0.24%) | 3.58 ± 1.32 (13.32%) | 2.81 ± 1.13 (31.96%) | 5.28 ± 1.98 (27.85%) |
Cmax (mg/L) | 0.93 ± 0.13 | 0.83 ± 0.21 (10.75%) | 0.71 ± 0.18 (23.66%) | 0.49 ± 0.15 (47.31%) | 1.14 ± 0.29 (22.58%) |
PK Parameter. | Daneshmend et al. ± SD | PBPK Using Biphasic Experimental Biphasic InForm PRC Value ± SD (% PE) | PBPK Using Experimental D-P PRC Value ± SD (% PE) | PBPK Default Simulator Precipitation Values ± SD (% PE) | PBPK with no Precipitation ± SD (% PE) |
---|---|---|---|---|---|
AUC (mg/L h) | 12.9 ± 1.50 | 10.49 ± 4.37 (18.68%) | 7.08 ± 3.27 (45.12%) | 7.44 ± 3.41 (42.33%) | 17.93 ± 7.87 (38.99%) |
Cmax (mg/L) | 4.36 ± 0.54 | 4.01 ± 1.23 (8.03%) | 2.52 ± 0.99 (42.20%) | 2.80 ± 1.00 (35.78%) | 6.53 ± 2.06 (49.77%) |
PK Parameter | Brouwers et al. ± SD | PBPK Using Experimental Biphasic InForm PRC and CSR Values ± SD (% PE) | PBPK Using Experimental D-P PRC Value ± SD (% PE) | PBPK Using Default Simulator Precipitation Values ± SD (% PE) | PBPK with no Precipitation ± SD (% PE) |
---|---|---|---|---|---|
AUC (mg/L h) | 3.64 | 3.32 ± 1.12 (8.79%) | D-P PRC value not available * | 2.18 ± 0.78 (40.11%) | 3.52 ± 1.17 (3.30 %) |
Cmax (mg/L) | 0.54 | 0.84 ± 0.23 (55.56%) | 0.37 ± 0.14 (31.48%) | 1.10 ± 0.28 (103.70%) |
PK Parameter | Brouwers et al. ± SD | PBPK Using Experimental Biphasic InForm PRC Value ± SD (% PE) | PBPK Using Experimental D-P PRC Value ± SD (% PE) | PBPK Using Default Simulator Precipitation Values ± SD (% PE) | PBPK with No Precipitation ± SD (% PE) |
---|---|---|---|---|---|
AUC (mg/L h) | 0.87 | 0.67 ± 0.35 (22.99%) | D-P PRC value not available * | 0.58 ± 0.31 (33.33%) | 0.70 ± 0.36 (19.54%) |
Cmax (mg/L) | 0.084 | 0.089 ± 0.045 (5.95%) | 0.076 ± 0.037 (9.52%) | 0.092 ± 0.047 (9.52%) |
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O’Dwyer, P.J.; Imanidis, G.; Box, K.J.; Reppas, C. On the Usefulness of Two Small-Scale In Vitro Setups in the Evaluation of Luminal Precipitation of Lipophilic Weak Bases in Early Formulation Development. Pharmaceutics 2020, 12, 272. https://doi.org/10.3390/pharmaceutics12030272
O’Dwyer PJ, Imanidis G, Box KJ, Reppas C. On the Usefulness of Two Small-Scale In Vitro Setups in the Evaluation of Luminal Precipitation of Lipophilic Weak Bases in Early Formulation Development. Pharmaceutics. 2020; 12(3):272. https://doi.org/10.3390/pharmaceutics12030272
Chicago/Turabian StyleO’Dwyer, Patrick J., Georgios Imanidis, Karl J. Box, and Christos Reppas. 2020. "On the Usefulness of Two Small-Scale In Vitro Setups in the Evaluation of Luminal Precipitation of Lipophilic Weak Bases in Early Formulation Development" Pharmaceutics 12, no. 3: 272. https://doi.org/10.3390/pharmaceutics12030272
APA StyleO’Dwyer, P. J., Imanidis, G., Box, K. J., & Reppas, C. (2020). On the Usefulness of Two Small-Scale In Vitro Setups in the Evaluation of Luminal Precipitation of Lipophilic Weak Bases in Early Formulation Development. Pharmaceutics, 12(3), 272. https://doi.org/10.3390/pharmaceutics12030272