Advantages and Limitations of In Vivo Predictive Dissolution (IPD) Systems November 16 th Prof. Gregory E. Amidon - University of Michigan
What is an In vivo Predictive Dissolution (IPD) System? An IPD system is an experimental system (not necessarily simple). that closely simulates human in vivo conditions and permits the measurement of the rate and extent of dissolution of oral (solid) dosage forms and closely mimics dissolution in the human intestinal tract. Rube Goldberg
In vivo Predictive Dissolution (IPD) Methods: Advantages and Disadvantages (Potential) Advantages of an IPD method Better simulation of in vivo conditions Better experimental control compared to human studies A priori experimental conditions can be defined (physiologically relevant) Better IVIVC/IVIVR is possible Less expensive than clinical study Can be used for QbD, scale-up, formulation development, mfr. changes,. Limitations/disadvantages of an IPD method Largely unproven methodology More complicated than current compendial methods Slower throughput than compendial methods Longer experimental times Potentially conflicting results with current compendial methods or FDA Dissolution Methods Database
Percent of Ibuprofen dissolved (%) USP 2 Monograph Dissolution of 800 mg Ibuprofen tablet at ph = 7.2 (800 mg Dr. Reddy s Reference Listed Drug(RLD)) % Ibuprofen Dissolved: Normalized USP Monograph dissolution, ph=7.2 50mM Phosphate buffer, 900 ml, 50 rpm 120% 100% 80% 60% 40% 20% USP Test: NLT 80% dissolved in 60 min 0% 0 10 20 30 40 50 60 70 Time (0-60 minutes) 50% dissolved 4 min
Percent Dose Absorbed The Issue Compendial dissolution methods often do not occur in a timeframe representative of oral absorption. 100.0 800 mg Ibuprofen Oral Absorption 90.0 80.0 70.0 60.0 50.0 40.0 30.0 20.0 10.0 0.0 0 50 100 150 200 250 300 350 400 Minutes
Percent Dissolved Percent Dissolved The Solution Hypothesis: Practical, Useful, Reliable, and Efficient (PURE) dissolution methodologies that capture in vivo and physiologically relevant processes will be predictive of oral dosage form performance in vivo. 100 100.0 90 90.0 80 80.0 70 70.0 60 60.0 50 50.0 40 40.0 30.0 30 20.0 10.0 What if we could create a dissolution profile more like this? Ave % absorbed Clinical Data Fasted Ave % absorbed Clinical Data Fasted 0.00 0 50 100 150 200 250 300 350 400 Minutes
Gastric emptying and absorption rates are important determinants of in vivo dissolution rate Disintegration dm di /dt = k di M di Transport to blood Absorption dm a /dt = k a C b Gastric Dissolution dm d /dt = D/h eff A (C s C b ) Intestinal transit dm t /dt = ~0.5 ml/min Lumenal Dissolution dm d /dt = (D/h eff )A (C s C b )
Critical parameters to consider in developing an in vivo relevant dissolution method. Vessel Hydrodynamics Stirring/mixing Vessel design Dissolution Volume Rate determining steps Stomach Emptying Intestinal transit Absorption rate Physiologic parameters Fluid content (eg: buffer type, conc) Intestinal Permeability Absorptive Surface Area Bile salts/lecithin Lumenal Volume Fluid Packet size, location Motility Lumenal Hydrodynamics Viscosity ph gradient Inter & Intra-subject Variation Secretions (type, rate, volume) Dissolution Media Buffer Type Concentration Buffer capacity ph Surfactants FaSSIF, FeSSIF I, II, III viscosity API properties Solubility, pka, BCS Class Dose Particle size, distribution Formulation properties Disintegration Controlled release dosage forms Other complicated dosage forms Excipient effects Supersaturating systems Precipitation Supersaturation
Conc. Dissolved ( g/ml) Gastrointestinal System (GIS) Stomach Emptying Rate t 1/2 1 ml/min Physiologic ph, volumes, buffers, surfactants may be used. 1 ml/min Stomach Secretion ph=2.0 Stomach Duodenum Jejunum Initial: 50 ml ph=2.0 250 ml H 2 O Final: 50 ml Initial: 50 ml ph=6.5 0.1M PO 4 Maintained at 50 ml Adjusted Initial: 0 ml Final: ~350 ml Intestinal Secretion Adjustable parameters: ph Buffer species Buffer capacity Stomach emptying rate Duodenal emptying rate Secretion rate Measurable parameters Total amount/conc. Amount dissolved ph Drug = propranolol (BCS Class I) S. Takeuchi, etal. JPharmSci. 103:3416-3422 (2014).
Permeability methods Bi-phasic (octanol-water) Polymer membranes 1-octanol water co coi cwi cw } } ho hw
Future Gastrointestinal System (GIS+) with Lipid/Membrane Absorption Compartment 1 ml/min Stomach Secretion ph=2.0 Stomach Emptying Rate t 1/2 Stomach Duodenum Jejunum Initial: 50 ml ph=2.0 250 ml H 2 O Final: 50 ml Initial: 50 ml ph=6.5 0.1M PO 4 Maintained at 50 ml 1 ml/min Adjusted Initial: 0 ml Final: ~350 ml Intestinal Secretion Physiologic ph, volumes, buffers, surfactants may be used. Adjustable parameters: ph Buffer species Buffer capacity Stomach emptying rate Duodenal emptying rate Secretion rate Measurable parameters Total amount/conc. Amount dissolved ph GIS can be modified (ideally using a semipermeable membrane) to include an absorption compartment.
Percent Dissolved Predicted GIS+ (Dissolution + Absorption) 800 mg IBU. ph=6.5 10mM phosphate buffer, Hydrodynamic Shear = 10 1/s, Absorption Rate = 10 hr -1 Shown with Clinical Data: % Absorbed and % dissolved by deconvolution GIS with Absorption Compartment and Shear=10/sec 100 90 % Dissolved by deconvolution 80 70 60 50 40 30 20 10 0 % Absorbed in humans % dissolved 800 mg, 10.44/hr, 6.5 1mM 10/s Ave % absorbed Clinical Data Fasted Deconvol (W-N) Dissolution fasted Predicted 900 ml dissolution, ph=7.2, 50 mm, 200/s Predicted 900 ml dissolution, ph=6.5, 50 0 50 100 150 200 250 mm, 300 200/s 350 400 Minutes % organic 10/s GIS+ with appropriate hydrodynamic shear and absorption compartment appears promising as a way to approximate oral absorption of IBU.
Slow absorption Fast absorption In Vivo Predictive Dissolution method selection will utilize simulation tools to determine in vivo relevant processes and choose an appropriate in vitro method (example: weak acid). ~25 h -1 ~1000 mg GIS/ASD Abs Dose Effective permeation rate 10-1000 mg 0.5-12 X 10-4 cm/s Gastric Intestinal Intestinal Absorption rate coefficient (A/V* P eff ) 0.5-25 h -1 ~750 mg ~10 h -1 Abs Gastric Intestinal GIS+biphasic ~200 mg Biphasic Biphasic Abs Intestinal Intrinsic solubility Drug pk a 4.2 Median particle radius Fluid volume t 1/2 gastric emptying 0.01-1 mg/ml 25 μm 75 ml Initial bulk ph 6.5 Buffer concentration 13 min 10 mm Low Dose High Dose
In vivo Predictive Dissolution (IPD) Methods: Advantages and Disadvantages (Potential) Advantages of an IPD method Better simulation of in vivo conditions Better experimental control compared to human studies A priori experimental conditions can be defined (physiologically relevant) Better IVIVC/IVIVR is possible Less expensive than clinical study Can be used for QbD, scale-up, formulation development, mfr. changes,. Limitations/disadvantages of an IPD method Largely unproven methodology More complicated than current compendial methods Slower throughput than compendial methods Longer experimental times Potentially conflicting results with current compendial methods or FDA Dissolution Methods Database
Challenges to IPD (In vivo Predictive Dissolution)? How do current compendial QC methods link to IPD (In vivo Predictive Dissolution)? Can we have two dissolution methods: IPD and QC? How do we validate the relevance of an IPD method? Humans are not good models for humans (ie: too much variation, too complicated). Can IPD methods replace in vivo studies? Can IPD methods combined with computational tools, better predict in vivo performance?