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BCS Class 2 Immediate Release (IR) Dissolution in Two-Phase Media

Richard (Rik) Lostritto, Ph.D. Associate Director for Science (acting)

Office of Policy for Pharmaceutical Quality (OPPQ) Center for Drug Evaluation and Research (CDER), FDA

3rd FDA / PQRI Conference on Advancing Product Quality

Rockville, MD March 22-24, 2017

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Outline • Background

– Definitions and Focus on BCS 2 – Solubility enhancement limitations – Surfactants in dissolution media as a sink

• The basics of the two-phase media approach – A more relevant alternative to the sink condition – Potential to better understand dissolution and absorption

• Three case studies • Summary • Next steps

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Background: Definitions • Highly soluble is when highest strength is

soluble in < 250 mL water over pH 1.0 to 7.5 • Highly permeable is when 90% of a dose is

absorbed (compared to intravenous reference) • Today’s focus is on immediate release BCS -2

drugs where low solubility is the primary concern in terms of in vitro dissolution and oral absorption.

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Background: Solubility • Many approaches to improve solubility involve

salts or meta-stable higher energy solid forms – Salt formation (for weak acids and bases) – Amorphous solid forms – Selected higher solubility polymorph – Co-crystals – Polymer / API mixtures

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Background: Solubility • Meta-stable solid state forms may revert to

lower energy, less soluble forms on the shelf or during dissolution.

• For salts of weak acids and weak bases, depending upon the media pH, buffer strength, pKa of the API, etc., precipitation of the less soluble neutral form may occur (which must then re-dissolve)

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Background: Surfactants • Typically, surfactants such as SLS and Tweens

may be used to increase solubility in dissolution media and serve as a sink

• While surfactants such as SLS may increase total apparent solubility through micelle formation, they limit diffusible / absorbable / free drug.

• Thus, exogenous surfactant use has low physiological relevance.

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Background Summing up the issues for BCS class 2 Dissolution

• Formulation strategies to increase solubility may be

unstable on the shelf or revert to lower energy forms of lower solubility in situ.

• 900 mL is too large to be bio-relevant; yet it still too low a volume for maintaining sink conditions for most BCS class 2 drugs.

• Non biologically relevant surfactants in dissolution media may provide a sink, but do not adequately address how the drug product will perform in vivo

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The Two-Phase Media Approach

• Two immiscible phases (e.g., aqueous and 1-octanol) remain in constant contact throughout the dissolution run.

• The 1-octanol phase may simulate absorption and maintain a sink for BCS Class 2 drugs

• Each phase is stirred (e.g., paddle) and sampled • The pH of the aqueous phase can be manipulated.

• Is a relationship to in vivo absorption possible? – Three case studies follow

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Two-Phase Dissolution Approach 1 From: Kathrin Locher, et al., Eur J Pharm And Biopharm 105 (2016) 166-75

50 mL

30 mL

25-100 rpm

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Four Compartments were considered

Drugs studied: dipyridamole, telmisartan, ibuprofen, griseofulvin, fenofibrate, and itraconazole. Several surfactants were studied (below their CMC) with drug saturated solutions (50 mL) at pH 6.5 The in situ change in pH from 2.2 to 6.5 was studied with dipyridamole

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• Summary of results – Ka (rate of partitioning into 1-octanol) is relatively

unaffected by drug concentration at 75 rpm – For dipyridamole, Ka is smaller at and below 50 rpm

at constant pH • 60 – 75 rpm considered optimal

– Surfactants (below CMC) had a general increasing (e.g., SLS) or decreasing (e.g., Tween 80) impact on ka up to approximately 25%

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• Summary of results – Dissolution of intact dipyridamole (pKa 6.4) capsule – 60 min at pH 2.2 (aqueous only) – At 60 min, 2M NaOH added to change pH to 6.5 then 1-

ocatnol layer adeed – Supersaturation of approx 2X declines over several

hours • All results except the initial supersaturation phase

are reasonably accounted for by the four compartment model

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Two-Phase Dissolution Approach 2 From: Yi Shi, et al., J Pharm Sci 105 (2016) 2886-95

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• Candidate molecule “ABT-072” (ABT) • MW = 470 • diacid pKa1 = 8.5, pKa2 = 9.6 • BCS class 2 • Target dose is 400 mg • Intrinsic solubility approx 0.01 ug/mL

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Two-Phase Dissolution Approach 2

From: Yi Shi, et al., J Pharm Sci 105 (2016)

2886-95

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Two-Phase Dissolution Approach 3: Partitioning From: Deanna M. Mudie, et.al., Biopharm Drug Dispos 33 (2012) 378-402

Kinetics of drug partitioning between buffer and 1-octanol.

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• Studied the kinetics of drug substance partitioning between buffer and 1-octanol

• BCS Class 2 weak acids: – ibuprofen – nimesulide – piroxicam

• Proposed a mechanistic model

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• Investigations included: – Three apparatus variations (vessel shape and paddle

position), – Multiple phase volumes (150-250mL) – Stirring rate 40 - 77 rpm – pH range 1.5 - 7.5 – Multiple strengths (as initial concentration in aqueous phase)

• Scaled in vitro results to reflect in vivo absorption kinetics

• Which drug substances may be appropriate for two-phase dissolution testing?

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pH 1.5 pH 4.3

pH 4.4 pH 6.3

(a) through (d) here are with the same apparatus, each phase (buffer and 1-octanol) at 150 mL, each phase stirred at 77 rpm, 2.5 mg dose (lowest studied)

For (a) - (d), partitioning kinetics are not sensitive to aqueous pH. Under these conditions for ibuprofen, partitioning kinetics are controlled by diffusivity and hydrodynamics (boundary layers)

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• Scaled in vitro results to reflect in vivo absorption kinetics – Aqueous phase concentration should reflect in vivo – Scale partitioning rate coefficient (kp) to the known or

expected absorption rate constant in vivo (ka) • Which drug substances may be appropriate for

two-phase dissolution testing? – Hydrophobic – Highly permeable – Dissolution is limited by solubility

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Summary

• Dissolution in the aqueous phase (with or without change in pH) and partitioning into the 1-octanol layer have been scientifically modeled.

• For cases where solubility is low and permeability is high (BCS class 2 drugs); two Phase (1-octanol / aqueous) dissolution approaches show promise for: – Research (in-house and public domain) – Development with bio-relevant rank ordering / scaling – Quality control with improved bio-relevance

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Summary

• The octanol layer serves as a sink obviating the need for non bio-relevant surfactant use

• Two phase dissolution approaches for BCS class 2 drugs have the potential to: – more relevantly link in vitro dissolution performance

to in vivo absorption – predictively rank order (or scale) the effect of

formulation changes on in vivo performance

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Next Steps

• Working together, identify, develop, and refine science-based, two phase dissolution approaches such that the: – apparatus is simple, well defined, and standardized – geometry and hydrodynamics are well characterized – phase volume and phase ratios are standardized – The methodologies are more bio relevant than

current one phase systems for BCS class 2 drugs

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Next Steps

• A self-consistent body of published data spanning the scope of BCS class 2 drugs becomes available

• Propose a 2 phase dissolution approach in a regulatory submission (e.g., IND)

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Thank You!

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