Advantages and Limitations of In Vivo Predictive Dissolution (IPD) Systems

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1 Advantages and Limitations of In Vivo Predictive Dissolution (IPD) Systems November 16 th Prof. Gregory E. Amidon - University of Michigan

2 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

3 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

4 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% Percent of Ibuprofen dissolved (%) 100% 80% 60% 40% 20% USP Test: NLT 80% dissolved in 60 min 0% Time (0 60 minutes) 50% dissolved 4 min

5 The Issue Compendial dissolution methods often do not occur in a timeframe representative of oral absorption mg Ibuprofen Oral Absorption Percent Dose Absorbed Minutes

6 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. Percent Dissolved Percent Dissolved What if we could create a dissolution profile more like this? Ave % absorbed Clinical Data Fasted Ave % absorbed Clinical Data Fasted Minutes

7 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 )

8 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

9 Gastrointestinal System (GIS) 1 ml/min Stomach Secretion ph=2.0 Stomach Emptying Rate t 1/2 Stomach Duodenum Jejunum Initial: 50 ml ph= ml H 2 O Final: 50 ml Initial: 50 ml ph= M PO 4 Maintained at 50 ml Drug = propranolol (BCS Class I) S. Takeuchi, etal. JPharmSci. 103: (2014). 1 ml/min Adjusted Initial: 0 ml Final: ~350 ml Conc. Dissolved (μg/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

10 Permeability methods Bi phasic (octanol water) Polymer membranes

11 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= ml H 2 O Final: 50 ml Initial: 50 ml ph= M 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.

12 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 % Dissolved by deconvolution Percent Dissolved % 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, mm, /s Minutes % organic 10/s GIS+ with appropriate hydrodynamic shear and absorption compartment appears promising as a way to approximate oral absorption of IBU.

13 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). Fast absorption Slow absorption ~25 h -1 ~1000 mg GIS/ASD Gastric Intestinal ~750 mg ~10 h -1 Abs Gastric Intestinal GIS+biphasic ~200 mg Biphasic Low Dose High Dose Abs Intestinal Biphasic Abs Intestinal Dose Effective permeation rate Absorption rate coefficient (A/V* P eff ) Intrinsic solubility Drug pk a 4.2 Median particle radius Fluid volume mg X 10-4 cm/s h mg/ml 25 μm 75 ml t 1/2 gastric 13 min emptying Initial bulk ph 6.5 Buffer concentration 10 mm

14 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

15 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?

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Advantages and Limitations of In Vivo Predictive Dissolution (IPD) Systems

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