Biorelevant Dissolution Method in Early Phase Drug Development

Yun Mao Merck and Co. Inc AAPS Short Course Developing Biorelevant Dissolution Test Methods with an Emphasis on QbD 08Nov2009

Outline
Challenges in early phase formulation development Overview of Bio-relevant Dissolution Case studies of using dissolution in bio-relevant medium to guide formulation selection
Neutral Compounds Acidic Compounds Basic Compounds

Conclusions
Dissolution in bio-relevant medium can be a useful tool for early formulation selection IVIVR established can be leveraged for future formulation development and quality control method development

Challenges in Early Phase Development

Majority of the drug candidates have poor aqueous solubility Early phase formulations need to maximize bioavailability to ensure that API is delivered to the intended target
Many formulation approaches available Limited time and limited API amount

In-vitro dissolution, if reflecting in-vivo performance, can be used to guide formulation development

Oral Bioavailability How to Formulate the Drug to Reach Target

Ingestion Target

Distribution
Dissolution

Absorption

In-vivo dissolution is the pre-requisite for drug absorption

Bio-relevant Dissolution: Predict Formulation Bio-performance

BCS II/IV Dissolution rate limited In-vivo dissolution IVIVC Bioavailability BCS III/IV Permeation rate limited In-vivo permeation

In-vitro dissolution

Simulate gastrointestinal hydrodynamics

Simulate Gastrointestinal fluids

Bio-relevant apparatus and hydrodynamics

Bio-relevant medium

Bio-relevant Apparatus and Hydrodynamics

USP IV-flow through

USP III-reciprocating cylinder Bio-Dis

TIM gastrointestinal model

Transfer Model

Crescent brush model

Bio-relevant Medium
Simulated Gastric Fluid (SGF)

HCl (mL)
NaCl (g) Deionized water

1.4 mL (conc. 12N HCl)

2.0 g (34.2 mM) 1L

Fasted Simulated Small Intestinal Fluid (FaSSIF) Na Taurocholate 1.61 g (3 mM) Lecithin 0.56 g (0.75 mM) KH2PO4 3.9 g KCl 7.7 g NaOH qs pH 6.5 Deionized water 1L
1 Galia E, Nicolaides E, Horter D, Lobenberg R, Reppas C, Dressman JB. 1998. Evaluation of various dissolution media for predicting in vivo performance of class I and II drugs. Pharm Res 15:698705.

Bio-relevant Dissolution

Meaningful

Simplicity

Predict in-vivo performance Provide feedback on formulation

Use common apparatus Turn around data fast (automation)

Simple Bio-relevant Dissolution Models

In-vivo
Stomach

In-vitro models
250mL SGF (pH 1.8) 500mL FaSSIF (pH 6.5)

Two-stage model
30min in 250mL SGF Add 2X FaSSIF +NaOH 120min in FaSSIF

Intestine

Bio-relevant Medium Volume

Projected human dose Target Concentration= Volume of bio-relevant medium

Micro Dissolution 4-20 mL

Vessel Type Micro Dissolution Volume 4-20mL

200mL
1L
Agitation Stir bar

USP II Paddle

Vankel 200mL
Vankel 1000mL

50-200mL
250-1000mL

Paddle
Paddle

Bio-relevant Dissolution of API Select API Phase

Select appropriate API phase
Salt form Particle size

Considerations
pH of the medium API with small PSD can agglomerate
Solubility of Acid and Base
100.0

Impact of PSD on dissolution Small PSD

Average % Dissolved
80.0 60.0

Base
Solubility

pKa/b=4

Acid

40.0

20.0

Large PSD

0.0

4
pH

20

40

60

80

100

Bio-relevant Dissolution of API Guide Formulation Development

Extent of release
API Dissolved

Time

Formulation goals Fast release rate for IR formulations Solublize maximum amount of API Maintain the API in solution

Formulation approaches super-disintegrant, surfactant, water-soluble excipients, API PSD reduction Solid dispersion (amorphous API), lipid-based formulation (pre-dissolve API), API PSD reduction Anti-nucleating agent, pH-modifying agent

Early Phase Formulation Development

Understand drug product requirements
Desired PK profile Projected human dose Food effect restriction Needs to combine with existing therapy

Evaluate formulation risks

Do= (Dose/250mL)/ SGF or FaSSIF solubility High Do leads to higher risk and needs more effort Relative dissolution/solubility in FeSSIF and FaSSIF forecasts potential food effect

Value of Bio-relevant Dissolution for Early Phase Formulation Development

Develop prototype formulations Low Bio-performance Risk (modeling) Conduct In-vitro bio-relevant dissolution testing Evaluate lead prototype(s) in animals and compare bioavailability to benchmark toxicology formulation Adequate in-vivo bioavailability in animals? Yes Evaluate lead formulation in Phase I human studies

No

Value of Bio-relevant Dissolution Save animal resources by screening out poor-performance formulations Evaluate more formulation approaches to enhance formulation quality Potential IVIVR to guide further formulation development

Design of Bio-relevant Dissolution for Neutral Drug

Neutral drug
Minimal pH dependent solubility

Formulation approaches
Dose number low
Conventional formulations

Neutral compound

Dose number high

Lipids based formulation Solid dispersions PSD reduction

Drug solubility
pH: stomach to small intestines

Bio-relevant dissolution considerations

Generally sufficient to assess dissolution in FaSSIF

Case 1: Formulation Development for a Poorly Soluble Neutral Compound-Solid Dispersion

Merck compound A has very low solubility (0.4 ug/mL) from pH 1 to 8 Solubility in FaSSIF is 4.6ug/mL (Do=87) BCS II with high permeability Conventional formulation has low bioavailability and food effect Four solid dispersion formulations (SD 1-4) developed Different polymer/surfactant types and processes Bio-relevant Dissolution FaSSIF at 100RPM

Case 1: Formulation Development for A Poorly Soluble Neutral Compound-Solid Dispersion

Formulation SD-1 SD-2 SD-3 SD-4 % release at 60min 50.27% 5.60% 2.28% 1.93%

Small vial experiments to evaluate the SD materials SD-1 provides more than ten-fold increase in apparent solubility

FaSSIF (USP II) Dissolution of SD-1 vs. conventional 100.0 80.0 % Claim 60.0 40.0 20.0 0.0 0 20 40 Time (Min) 60 SD-1 Formulation Conventional Formulation SD-1 Formulation Diluted with Organic

Dissolution of SD-1 drug product confirms the enhanced API release

Case 1: Formulation Development for A Poorly Soluble Neutral Compound-Solid Dispersion

5.0 4.5 4.0 3.5 Mean Cp (uM) 3.0 Conventional SD-1 SD-2

2.5
2.0 1.5 1.0 0.5 0.0 0 10 20

50.27% dissolved

5.6% dissolved 1.6% dissolved

30 40 Time (hr) 50 60 70 80

SD-1 outperform SD-2 and conventional formulation SD-1 has 10-fold increase in exposure with no food effect IVIVR established

Design of Bio-relevant Dissolution for Acidic Compounds

Acidic drug
High solubility in small intestine (pka<5) Salts can disproportionate to neutral form in stomach (pka>2) Solubility of Acid pKa 1 2 3
Solubility

Formulation approaches

Low Do in FaSSIF: conventional formulations High Do FaSSIF: Free acid: same approach as neutral drug 1 Salt of acid (pKa>5): exhibit high initial dissolution in stomach. Maintaining API in solution is critical

4
pH

Bio-relevant dissolution considerations

Free acid: sufficient to assess dissolution in FaSSIF Salt of the weak acid:
SGF: evaluate initial release of salt form and potential disproportionation FaSSIF or two-stage model: may be used if dissolution in SGF is not discriminating

Case 2: Formulation Development of a Weak Acidic Compound

Merck compound B was a acidic compound with pka of 6.3 Solubility is low (< 0.1 mg/mL) at pH below pKa Potassium salt of the acid was chosen for development, which has high (70mg/mL) water solubility High clinical doses are projected and fixed dose combination potentially needed Maximize bioavailability is critical for the success of the program Dry filled capsule has less exposure comparing to safety assessment (SA) formulation (methocel solution)
Formulation (Dog PK, 10MPK) Methocel Solution of K-salt Simple DFC of K-salt AUC (mM*hr)SD 47.9 17.7 21.2 6.01

Why and how to improve the formulation exposure?

Case 2: Dissolution of API and Safety Assessment Formulation in SGF using uDissolution
120

Micro Dissolution
Sample: 8mg API 8mg API in water 8mg API in methocel Medium: 20mL SGF

100

80

% released

60

API Solid API in water API in Methocel

40

20

0 0 20 40 60 80

Time (min)

Salt disproportionates to free acid in SGF and precipitates in < 30min Methocel formulation maintains the API in solution at low pH up to 90min, creating longer absorption window

Case 2: Excipients Screening for Formulation Development

120 100

80 API Solid API in water HPC HPMC Methocel Poloxamer 407

API: 8mg solid or dissolved in water Excipients: 1mg of each Medium: 20mL SGF

% released

60

40

20

Poloxamer 407 did not sustain super-saturation of API in acid HPC and HPMC maintain API super-saturation up to 90 min

0 0 20 40 60 80

Time (min)

Formulation (Dog PK, 10MPK) Methocel Solution of K-salt Simple DFC of K-salt Tablet with 5% HPMC

AUC (mM*hr)SD 47.9 17.7 21.2 6.01 55.0 20.5

Design of Bio-relevant Dissolution for Basic Compounds

Basic drug
High solubility in stomach Limited solubility in small intestine (pKb<7) 3
Solubility

Solubility of Base 4 5 6 7 pKb

Formulation approaches
Weak base (7> pKb > 4)
Fast initial release in stomach May disproportionate in small intestine

Very weak base (pKb<4)

Strong pH dependent solubility in stomach Include acidifying agent to facilitate initial dissolution

Bio-relevant dissolution considerations

Dissolution in SGF is generally recommended Two stage dissolution is recommended If SGF dissolution is not discriminating

Case 3: Formulation Development for a Free Base Compound

Merck compound C is a free base High solubility in SGF (1.0 mg/mL) and low solubility in FaSSIF (0.02mg/mL) BCS II with good permeability 10% tween was used as vehicle for safety assessment formulation Three solid dosage formulations were developed
Formulation A with surfactant A Formulation B with surfactant B Formulation C with surfactant C

2-stage dissolution (SGF followed by FaSSIF) was conducted with 200mL volume dissolution vessel

Case 3: Formulation Selection with 2-stage Bio-relevant Dissolution

SGF
120 100

FaSSIF

%Dissolved

80 60 40 20 0 0 30 60 90

SA Formulation Form A Form B Form C

120

150

Time (min)

Dissolution was conducted in 90mL SGF and 180mL of FaSSIF with USP II paddle (100rpm) The safety formulation (10% tween) remain supersaturated in SGF and FaSSIF Formulation A has the highest release in SGF and FaSSIF In-vivo animal study showed that solid formulation A has slightly lower, but comparable exposure to safety formulation

20 18 16 14 12 10 8 6 4 2 0 0 4 8

Plasma Conc (uM)

SA formulation Form A

12 Time (hr) 10 % Tween

16

20

24

DFC_P407

Case 4: Formulation Selection for A Very Weak Base

Merck compound D is a weak base with pKa of 2.2
SGF solubility: 28 mg/mL FaSSIF solubility: 0.07mg/mL Solubility pH at pH 3 : 3.4mg/mL

Formulation 1 contains amorphous HCl salt Formulation 2 contains crystalline free base Conventional solid dosage forms are used Initial fast release is important for the program Biorelevant Dissolution
Medium: SGF

Case 4: In-vitro and In-vivo Comparison of Two Formulations

Dissolution in SGF (pH 1.2)
Dissolution Comparison Plot
110 100 90 80
%Claim (Active)

70 60 50 40 30 20 10 0 0 10 20

Initial (125820, 50mg FFP)) Initial (127398, 100mg PMF)

Formulation-1 Formulation-2

30 Time (Minutes)

40

50

60

No dissolution difference in SGF No bioavailability difference in acidified dogs Formulation-1 has a fast release and higher bioavailability than formulation-2 in human Hypothesis: steep solubility-pH profile pH in human stomach might be variable and higher than SGF Human PK data
Formulation-1 Formulation-2 Ratio (F2/F1) 0.84 (0.75, 0.95) 0.61 (0.41, 0.91)

PK data in Acidified dog

AUC0-8hr (Mhr) Formulation-1 2.00 0.571 Formulation-2 1.87 0.471

AUC0- (nMhr) AUC0-2 (nMhr)

1711.88 (30.22%) 566.84 (41.40%)

1443.95 (38.85%) 346.43 (56.40%)

Case 4: Impact of Medium pH on Dissolution

SGF over-predict the release and is not bio-relevant for compound D Evaluate the impact of dissolution medium pH Dissolution in pH 3.5 medium best correlates with human PK
Dissolution Profile at pH 1.2
100 80 60 40 20 0 0 10 20 30 Time (min) 40 50 60

1.2
100 80 60 40 20 0 0
% Claim

Dissolution Profile at pH 1.8

1.8
Formulation-1 Formulation-2

% Claim

10

20

30 Time (min)

40

50

60

Dissolution Profile at pH 2.5

100 80 60 40 20 0 0 10 20 30 Time (min) 40

2.5
100
% Released

Dissolution Profile at pH 3.5

3.5

80 60 40 20 0 0 10 20 30 Time (min) 40 50 60

% Claim

50

60

Bio-relevant Dissolution and Quality Control (QC) Dissolution

Bio-relevant Dissolution Quality Control Dissolution

Purpose
Method development Profiles

Predicting bio-performance
Universal: conditions chosen to mimic in-vivo GI tract non-sink, ranking order

Ensuring batch-to-batch consistency

Product-specific: condition chosen to detect process and stability changes 3-5 sink, full release

Early Phase Development Few batches manufactured, formulation will evolve

Recommend using bio-relevant dissolution to monitor product bio-performance and using disintegration tests to monitor batch-to-batch consistency

Late Phase Development Many batches are manufactured and simple/robust QC method is needed
QC method should be the same or correlate with bio-relevant dissolution method

Conclusions
Dissolution in bio-relevant medium is proven to be a useful tool for formulation development
Select formulation types and excipients

Medium and dissolution model are selected based on API and formulation characteristics Bio-relevant dissolution provides value in
saving animal resources (w/screening out poor-performance formulations) evaluating more formulation approaches (w/enhanced bioavailability) fast turn around time (w/standard apparatus, medium and methods) potential IVIVR to guide further formulation development

Future development areas

Understand in-vivo disproportionation of salts Simulate fast absorption in small intestine for BCS II compound Interface with simulation

Acknowledgements
Jennifer Broyles Michael Wang Russ Maus Li Li Laura Sharon Filippos Kesisoglou Mark Mowery Bruce Acken Henry Wu Bio-relevant Dissolution Team Members