Transcript Dissolution – where biology and physicochemistry meet

Dissolution – where physiochemistry
meets biology
PhysChem Forum, 20th Sept 2011
Nottingham
Dr Brian Henry
Pharmaceutical Science
Pfizer Global Research and Development
[email protected]
Today’s Talk
Biology
Physiochemistr
y
2
Drug Absorption
sampling
3
Dosage Form Performance1
Pharmacokinetic
Measurement
Clinical / PD
Measurement
Solubility Permeability
Drug in
Solution
Dissolution
Gut Wall
Dosage
Form
Blood
Site of
Action
Therapeutic
Effect
What is dissolution?
1 Based
on a slide from 2007 AAPS-FDA BCS, BE, and Beyond Workshop Presentation, entitled General BA/BE Issues,
Dale Conner, Division of Bioequivalence, Office of Generic Drugs, CDER, FDA
4
Dissolution Testing of Oral Dosage Form
What is Dissolution?
• Dissolution is the rate at which a substance dissolves in a fluid.
• In pharmaceutical practice, dissolution is the rate at which a drug in a
dosage form dissolves into the fluid surrounding it.
• In the case of modified release dosage forms dissolution rate and
release rate of drug are controlled by the design of drug product
5
Two Very Different Purposes of Dissolution Test
As a quality control measure for dosage form
• Batch to batch reproducibility to assure consistency in quality of
manufactured product
• Shelf life stability
• Assure manufacturing process changes do not impact performance
(typically requires BE study)
To predict dosage form PK performance in vivo
• Guide formulation selection, design and scale-up during development
– Quality by design and support regulatory filings
• Help select and set specifications for API form and particle size
• Guide bioequivalence strategy
6
Disintegration and Dissolution
D
D
D
D
D
D
..
...
7
Dissolution Model
Noyes and Whitney Equation
dM DS

(Cs  C )
dt
h
Diffusion
Layer
Cs
• M: the mass of solute dissolved at time t
Solid
Surface
Bulk
solution
C
x=0
x=h
• dM/dt: the mass rate of dissolution
• D: diffusion coefficient of the solute in
solution
• S: the surface area of the exposed solid
• h: the thickness of the diffusion layer
• Cs: the solubility of the solid
• C: the concentration of solute in the bulk
solution and at time t
8
What Factors Influence Dissolution?
The properties of drug
• Solubility of the API in the dissolution medium
• Whether the API is hydrophilic or hydrophobic (ease of surface wetting)
• The particle size/shape of the API
• Whether the API is crystalline or amorphous in the drug product
• If there are polymorphs, which polymorph is present
• If a salt form is used
The quality and design of the drug product
• The composition of the drug product and how they are added
• Manufacturing processes and steps
• Whether the product is designed to immediately release the API, to delay release,
or to release the drug over time.
The condition of dissolution tested
9
USP Dissolution apparatus
USP I/II
USP III
USP IV
10
Dissolution of different 250 mg Crizotinib dosage
forms
Dissolution for Multiple Crizotinib Dosage Forms in 0.1N HCl
Method conditions: 0.1N HCl, Baskets 100 RPM
120
Note: 75
minutes is an
infinity spin, 15
minutes at 200
RPM
% Dissolved
100
80
PIC pH 1
60
MST pH 1
40
ICH pH 1
20
0
0
10
20
30
40
50
60
70
80
Time (mins)
11
Crizotinib ‘Powder in Capsule’ vs Tablet BA study
50
100
250 mg IR TABLET
250 mg SD PIC
0
PF-02341066 Median Concentration
150
A8081008
0
20
40
60
80
100
Time (hr)
12
Bridging in vitro to in vivo
in vitro performance
In vivo performance
0.02
120
0.018
100
Plasma conc (ug/ml)
80
% released
formulation 1
0.016
formulation1
60
formulation 2
formulation 3
40
formulation 2
0.014
formulation 3
0.012
0.01
0.008
0.006
0.004
20
0.002
0
0
0
1
2
Time (hour)
3
4
0
5
10
15
20
25
30
Tim e (hour)
How can we ensure the low risk of failing to achieve the desired in vivo performance?
13
13
In vitro/In vivo correlations (IVIVC) Definition5
Definition
A predictive mathematical treatment describing the relationship
between an in vitro property of a dosage form (usually the rate or
extent of drug release) and a relevant in vivo response (e.g. drug
concentration in plasma or amount of drug absorbed).
… to accurately and precisely predicting expected bioavailability characteristics for an ER
product from dissolution profile characteristics …
5
Guidance for Industry: Extended Release Oral Dosage Forms: Development, Evaluation, and Application of In Vitro/ In Vivo
Correlations, September 1997
14
14
Concept of Convolution and Deconvolution
Convolution
The convolution method is a simulation method used to predict the
blood/plasma concentration when a drug is administered orally.
Deconvolution
Deconvolution is the process to obtain input function with known
plasma concentrations
Deconvolution is the reverse process of convolution
120
Convolution
In vivo dissolution
% drug absorbed
100
80
60
Deconvolution
40
Pharmacokinetic
profile
20
0
0
5Time (hrs)10
15
15
IVIVC Model
Rsq=0.9937 slope=0.884
1.0
0.8
Fabs vs Fdiss 1*100 mg SR 186
0.6
Fabs vs Fdiss 2*50 mg SR 190
Fabs vs Fdiss 200 mg A61138
0.4
Fabs vs Fdiss 200 mg A61140
Fabs vs Fdiss 200 mg Target
Line of Unity
0.2
Regression
0.0
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Fraction Dissolved
16
16
So that’s about it for dissolution, Dinner?
…well, it’s rarely that straight forward
17
The problems with predicting dissolution are very
fundamental
Consider what is happening at the primary particle surface
dM DS

(Cs  C )
dt
h
Surface area
Particle size distribution
Particle shape
Wetting and aggregation
Diffusion
Layer
Bulk solution solubility
Cs
pH differences/precipitation
Bile solubilisation
Solid
Surface
Bulk
solution
C
x=0
x=h
Dissolution vs absorption rates
Unstirred Water layer
pH gradient
Bile micelle migration
Mix hydrodynamics
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Intrinsic dissolution rate; the simplest form of
dissolution testing
• Constant surface area compact
(ensure solid form remains intact
after compression)
• Rotating disk (or static disk &
rotating fluid)
– Well defined hydrodynamics
• Detection methodology (on-line or
off line)
• Temperature controlled
• Means to assess solid form after
experiment
19
Example experimental data for a drug
HCl Salt
RDD of Test Compound 3 at pH2
25
Data collected ~every 5 seconds
Slope is proportional to dissolution
rate
Curvature of concentration profile
indicates a phase transformation
Concentration
If well behaved, (no change in
solid form) linear dissolution is
expected
20
15
0.01 N HCl
+ 0.1 M NaCl
+ 0.2 M NaCl
10
5
0
0
5
10
15
20
25
30
Time (min)
20
Basic compound, pKa~4.5
Intrinsic solubility
(~1µg/mL)
Salt solubility about 200
mg/mL
Developed as a mesylate
salt but has erratic
bioavailability
Total Concentration of Delavirdine (µg/mL)
Delavirdine – NNRTI for the treatment of HIV
100000
Salt Solubility
10000
1000
Free Base Solubility
100
10
1
1
2
3
4
5
6
7
8
pH
21
Intrinsic Dissolution Rate of Delavirdine Mesylate
As the pH increased, the
dissolution rate decreased
Free base precipitation on the
compact confirmed by PXRD
-1
• Should dissolve quickly
• Should be pH independent
-2
Salt very soluble
Dissolution Rate (µgcm sec )
Calculated salt dissolution rates
Measured disolution rates
1
2
3
4
5
6
Bulk Solution pH
22
What is happening?
B(aq)+ H3O+ Prec
ipit
atio
n
BH+(aq)+ H2O
BH+A-(solid) Dissolution
Hydrolysis
B(solid)
A-(aq)+ H2O
HA(aq)+ OH-
23
Free base precipitation
24
Impact of Free Base on the dissolution rate of
Delavirdine Mesylate at pH 2 dissolution
Small amount of free base in the compact has a dramatic impact on dissolution
30
Delavirdine Mesylate only
Concentration (µg/mL)
25
20
15
10
With 0.6%
free base
5
With 0.1% free base
0
0
2
4
6
8
10
12
14
Time (min)
25
Impact of citric acid in the compact on the dissolution rate of
Delavirdine Mesylate - Diffusion Layer Modulation
30
Delavirdine Mesylate, pH 2
Concentration (µg/mL)
25
20
DLpHM
Delavirdine Mesylate
+ Citric Acid at pH 6
15
10
5
Delavirdine Mesylate
pH 6
0
0
2
4
6
8
10
12
14
Time (min)
Figure 7: RDD profiles for a delavirdine mesylate DLM solid pre
at pH 6 as compared to the dissolution of delavirdine mesylate alon
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Rat Study Results
• Diffusion Layer modification increases oral bioavailability
Delavirdine Formulations in Rat with pH 5 Stomach
Delavirdine Concentration (µg/mL)
7
6
5
CA Granules
Tablet
4
3
2
1
0
0
5
10
15
20
25
Time (hr)
27
New technologies to provide a greater understanding of
dissolution mechanisms
SDI300 Surface Dissolution
Imaging System: A powerful
new tool for formulations
optimization
28
The Artificial Stomach Duodenal (ASD) model to
investigate the impact of pH change on dissolution
Gastric
Fluid
Stomach
Duodenal
Fluid
Gastric
Empty Pump
Duodenum
Duodenal
Empty Pump
29
Typical ASD dissolution profiles
Formulation
disintegration
dissolution
solid
pH 2-4
precipitation
solid
transport
Duodenum
pH ~6-7
soln
Stomach
liquid
transport
dissolution
solid
precipitation
soln
solubilization
solid
transport
Duodenum
Concentration
Stomach
bioavailable
liquid
transport
-20
0
20
40
60
80
100
120
140
160
180
200
Time (min)
waste
30
In vitro/in vivo correlation for ASD
• Correlation of ASD AUC to in vivo data for carbamazepine polymorphs:
(Carino, S.R., D.C. Sperry, and M. Hawley, Relative bioavailability estimation of carbamazepine crystal
31
forms using an artificial stomach-duodenum model. J. Pharm. Sci., 2006, 95(1), 116-125.)
Formulations of compound X were being
developed for rapid oral onset of action
• Weak based with low solubility >pH4.5 ~10ug/mL
• High solubility at gastric pH (>5mg/mL)
• Three crystalline solid forms were available
– Free base
• Intrinsic solubility of 10ug/mL
– Citrate salt
• Intrinsic solubility of 20mg/mL
– Mesylate salt
• Intrinsic solubility of 80mg/mL
32
ASD data for Compound X solid forms with a pH 4 stomach.
UNTITLED
Concentration in solution in the Stomach
Free Base
Citrate
Mesylate
0.40
0.25
Concentration, mg/ml
Concentration, mg/ml
0.30
stomach@pH 4
0.50
Concentration in solution in the Duodenum
0.30
0.20
0.10
0.00
0
30
60
90
120
Time, min
stomach@pH 4
duodenum
Free Base
Citrate
Mesylate
0.20
0.15
0.10
0.05
0.00
0
30
60
90
120
Time, min
•The mesylate performed poorly in the duodenum with a gastric of pH4.0
•Precipitation to free base?
•The citrate salt performs the best in the duodenum compartment
•Slower dissolution leading to less precipitation at higher pH
33
pH modulated dog model to monitor oral absorption of
Compound X salts from stomachs of low and high pH
Pentagastrin treated dogs
• Good precedent for use in dogs to reduce stomach pH
• 10mcg/kg im
Medtronic Bravo pH
telemetry systems
– 15 minutes prior to dosing and 30 minutes post dosing
Pantoprazole treated dogs
• Low hepatic drug interaction potential and used in veterinary
practise with dogs
• 1mg/kg iv 12 hours pre dose and 1 hour post dose
Compound X formulated as rapidly disintegrating tablets of the
the free base, mesylate and citrate salts
Tablets dose with the Bravo capsule on a fasted stomach with
a small volume of water
34
Measurement of the pH of the gastrointestinal tract of
male Beagle dogs using Bravo pH telemetry Capsules
Pantoprazole treated
Pentagastrin treated
001M
001M
002M
002M
003M
003M
004M
8
004M
pH
0
Time (hrs)
35
Gastric pH in male beagle dogs after the different
pretreatments to control Gastric pH
8
Mean = 4.6 + 2.7
Mean = 6.6 + 0.7
7
6
pH
5
4
3
Mean = 1.3 + 0.2
2
1
0
No treatment
Pentagastrin
Pantoprazole
Treatment
36
Comparison of mean maximum plasma concentrations (Cmax) of Compound X
following a single oral administration of Compound X free-base, mesylate and
citrate with no medication, pentagastrin medication and pantoprazole
Free base
Mesylate
Citrate
700
600
Cmax (ng/mL) .
500
400
300
200
100
0
None
Pentagastrin
Pantoprazole
37
Comparison of the mean time (tmax) to reach the maximum plasma
concentration of Compound X following a single oral administration of
Compound X free-base, mesylate and citrate with no medication, pentagastrin
medication and pantoprazole medication
Free base
Mesylate
Citrate
3.00
2.50
tmax (h) .
2.00
1.50
1.00
Pha
se 1
Pha
se 2
Pha
se 3
Pha
se 4
Pha
se 6
Pha
se 8
Pha
se 5
Pha
se 7
Pha
se 9
0.50
0.00
None
Pentagastrin
Pantoprazole
38
pH modulated dog model to monitor oral absorption of
Compound X salts from stomachs of low and high pH
•All Compound X salts performed better at lower stomach pH
• Faster absorption as measured by shorter Tmax and Higher Cmax
•Trend for the citrate salt to have more reliable performance across a wider pH
range
•Supported by the ASD in vitro dissolution/precipitation model
•Bravo pH telemetry capsule worked successfully in this dog model
•Drug pre-treatments successfully controlled dog stomach pH to desired level
• Fasted dog stomach highly variable
39
Conventional USP dissolution approaches do not mimic
the dynamic conditions of the intralumenal environment
+
≠
(*1 - Using models of the human digestive process to simulate the fate of dosage forms, M.
Wickham & H. Parry, APS Biopharmaceutics & Drug Delivery Meeting, Dec 07)
(*1)
(*2)
(*2 - Picture supplied by Prof. Christos Reppas, National & Kapodistrian 40
University of Athens, Greece)
New technologies now provide a view from the
tablets perspective
Daniel Bar-Shalom
Faculty of Pharmaceutical Sciences
University of Copenhagen
41
What is really happening in the GI tract?
DOG 05AA7
pH
Temp
Pressure
13
5
18
0
22
5
27
0
31
5
36
0
40
5
45
0
49
5
54
0
58
5
63
0
90
45
0
40
35
30
25
20
15
10
5
0
time (mins)
New technologies now provide a view from the Tablets perspective
42
Typical daily variation in gastric pH in a
health subject
43
Reduced acid secretion in the Stomach
Hypochlorhydria and Achlorhydria
Disease states know to be associated with reduced acid production
•
•
•
•
•
•
Malnutrition
HIV/AIDs
Gastric infections (incl H Pylori)
Gastric inflammation and cancer
Autoimmune diseases (pernicious anaemia, thyroid disorders)
Genetic Disorders
Surgical induced hypochlorhydria
• Gastric resection, Vagotomy
Drug induced hypochlorhydria
• H2 antagonists, Proton Pump Inhibitors, Antacids
• Cannabis
• Aspirin, alcohol
Aged associated hypochlorhydria
44
Gastritis and Acid Secretion in the Elderly
•Prevalence of gastric cancer and peptic ulcers more common and severe with advancing aging
•Well established that gastric pH in the elderly can be more variable and higher then young
•50% of all people over 65 have H pylori infection and with prevalence increasing with advancing age
•30% of all people over 60 have atrophic gastritis
‘Free-living Boston Elderly’ atrophic gastritis rates
– 60-60
– 70-79
– >80
21%
31%
37%
•High Gastric pH in the elderly
• Quinine resin release study in 258 people over 65s
– 67% normal
– 22% intermittent secretors
– 11% had consistently pH>3.5
• pH telemetry study in 79 people over 65
– 11% had pH consistently pH>5.0
– Equated to ~5M Americans in 2020
•Achlorhydria in the elderly associated with poor absorption of nutrients
– Ca, Fe, folic acid, Vit B6 and B12
45
Mapping the real the world of the Gastrointestinal
environment
Tablet Velocity and pressure in the GI tract
Gastric emptying
Fluid volume within the gastrointestinal organs
during fasting and after a meal by MRI.
Werner Weitschies
Institute of Pharmacy
University of Greifswald
46
What should a biorelevant dissolution
system consider?
• Changing pH, digestive enzyme and bile levels
• Removal of dissolved drugs from the intestinal lumen
• Discontinuity of movement of the dosage forms
→ Velocities of dosage forms up to 50 cm/s
• Simulation of pressure waves of physiological power
→ Pressure values up to 300 mbar (~230 mm Hg)
• Interrupted contact of the dosage form to the medium
• Device should be able to operate with small fluid
volumes
47
Dynamic Gastric Model
Fully automated, computer controlled dynamic model of
human stomach
System modelled closely on the human stomach
Can process real food and drugs in real time
Includes stomach volume, peristaltic motion and
continuous gastric secretions, simulating physical and
biochemical processes
Has been used for some time in food research
Application to pharmaceutical products more recent.
Can be applied to a variety of the dissolution challenges.
48
TNO TIM-1 dynamic dissolution model
Stomach and small intestinal model which
mimics key aspects of intestinal physiology
including:
• GI pH profiles and transit times
• Secretion of gastric acid and enzymes
(pepsin, lipase)
• Secretion of bile, pancreatic juice
• Absorption of digested products via dialysis
Provides information on release kinetics in
the intestinal lumen and availability for
absorption (bioaccessibility)
Fed/fasted studies completed with
micronized tablet, SDD tablet and
nanomilled suspension
49
In vitro formulation comparison
Formulations tested in the TNO TIM-1 fed/fasted in vitro model of a low
solubility drug at 100mg and 300mg doses
The drug has a pronounced Fed/Fasted effect in human PK studies
100mg tablet
(fasted)
100mg SDD (fasted)
100mg Nano (fasted)
300mg Nano
(fasted)
100mg tablet (fed)
100mg SDD (fasted)
50
In vivo formulation comparison
Formulations tested in fed/fasted dog model at a 100mg dose
51
TNO TIM-1 summary
• Strong positive food effect seen in the clinic with high fat meals
replicated in the TNO TIM-1 model
• Recovery results for formulations tested typically >75%
• Formulation ranking
– TNO TIM-1
• SDD > nanomilled suspension > micronised tablet
– In vivo dog model
• Nano Milled > SDD > micronised tablet
– In addition, both demonstrated reduced variability
• Still need to prove relevance to clinical performance in humans
52
University of Greifswald – Dissolution Stress
Tester
Developed specifically to mimic GI specific pressure events, GI motility
and intermittent contact of dosage form with water.
Garbacz et al. Eur J Pharm Biopharm (2008) 70:421-428
Werner Weitschies
Institute of Pharmacy
University of Greifswald
53
The influence of different hydrodynamic mixing conditions on
the dissolution of diclofenac controlled release formulations
Garbacz et al. Eur J Pharm Biopharm
(2008) 70:421-428
Werner Weitschies
Institute of Pharmacy
University of Greifswald
54
Summary
Dissolution testing has served us well over the years
Provide the quality controlled required to help ensure patients get the full
benefits of the medicines we develop
Catalysed the debate leading to SUPAC, IVIVC, BCS, QbD solutions
Greater scientific understanding is going to be required moving forward
More tricky compounds and formulations coming through
Enable robust formulation development and commercialisation
Still struggling to predict clinical outcomes
pH dependant and low solubility compounds
Integrate dissolution data into predictive PK packages
Robustness of some controlled release technologies
We are now developing a much better understanding of the GI environment
Better dissolution tools in development
Going to be tough validating with new compounds and formulations
55
Many thanks to
Pfizer Sandwich Mark McAllister, Mei
Wong, Kiyo Sugano, Kelly Jones
Pfizer Groton Michael Hawley, Rong Li,
Kazuko Sagawa
56