The Application of Scientific
Principles to Pharmaceutical
Formulation Design
Stephen R. Wicks PhD FAPS FRPharmS
University of Greenwich
Science and Formulation Design
• The Team
• Human
Biology
• The Drug
• The Dosage
Form
Khartoum, November 2015 - Stephen Wicks
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Science and Formulation Design
• The Team
• Human
Biology
• The Drug
• The Dosage
Form
Khartoum, November 2015 - Stephen Wicks
3
Decision-making in the
Pharmaceutical Industry
Drug Safety
Clinical
Toxicology
Stakeholders
Patient
Payer
Shareholder
Biology
Clinical
Development
Research
Sales/
Marketing
API
Pharmaceutical Science
Process Chemistry
Formulation
Analytical
Drug Metabolism
Manufacturing
Khartoum, November 2015 - Stephen Wicks
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Critical Transactions in Successful Drug Development
General Pharmacology
Drug Safety
Clinical
Toxicology
Patient
Safety
Biology
Drug
Design
API
Clinical
Development
Research
Label
Clinical
Pharmacology
Market Stakeholders
Sales/ Research Patient
Marketing
Payer
Shareholder
Output
Label
Pharmaceutical Science
Process Chemistry
Formulation
Manufacturing
Analytical
‘Preformulation’ Drug Metabolism Technology
Transfer
Khartoum, November 2015 - Stephen Wicks
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• Drug Development
– Does the molecule have drug-like properties?
– What is the mechanism of action in animal/in vitro
models?
• Main effect
• Side effect
– Can I formulate the molecule into a medicine?
– Is my dosage form design relevant to clinical use?
– Is the formulated molecule safe to give to
humans?
– Will the formulated molecule meet clinical need?
• Is it safe in humans?
– Can I mass produce the medicine?
– Can the rate of manufacture meet demand?
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Decision Making in Dosage Form Design
Drug Safety
Clinical
Toxicology
Biology
Clinical
Development
Research
Sales/
Marketing
API design
Pharmaceutical Science
Process Chemistry
Formulation
Analytical
Drug Metabolism
Manufacturing
Khartoum, November 2015 - Stephen Wicks
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Stakeholders
Patient
Payer
Shareholder
Critical Transactions in Dosage Form Design
Drug
Product
Safety
Biology
Drug Safety
Clinical
Toxicology
Clinical
Development
Research
Drug
Delivery
API
Pharmaceutical Science
Process Chemistry
Formulation
Analytical
Drug Metabolism
Sales/
Marketing
Drug
Product
Design
Manufacturing
Mass Production
Khartoum, November 2015 - Stephen Wicks
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Stakeholders
Patient
Payer
Shareholder
• Dosage Form Design
– Is my dosage form safe?
– Does my dosage form express optimum
biology?
– Does my dosage form meet the needs of
the market?
• Unmet clinical need
• Satisfactory dosage form
– Can it be mass produced?
•
•
•
•
•
Quality
Robust, well-understood process
Consistent API and excipients
Acceptable cost
Manufacturing capital equipment available
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Science and Formulation Design
• The Team
• Human
Biology
• The Drug
• The Dosage
Form
Khartoum, November 2015 - Stephen Wicks
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Reliable Once Daily ACE Inhibition: Addition of 1(methylsulphonyl)piperidine enhances angiotensin
converting enzyme (ACE) inhibition
EtO
EtO
O
NH
O
NH
O
Me
N
CO2H
Enalapril – Merck
60% oral bioavailablity
O
O
S
O
N
N
CO2H
UK-64,143 – Pfizer
Not orally bioavailable
UK-64,143 and enalapril structures from Peter Dunn and Michael Williams courtesy of Pfizer Ltd.
Khartoum, November 2015 - Stephen Wicks
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Drug-like Properties
•
•
•
•
•
•
Compounds having MWs not exceeding 450 Da,
cLogP values between 4.5 and 3.5
A maximum of four rings
A maximum of ten non-terminal single bonds
No more than five hydrogen-bond donors, and
A maximum of eight hydrogen-bond acceptors
Oprea TI: Current trends in lead discovery: Are we looking for the appropriate
properties? J Comput Aided Mol Des (2002) 16(5-6):325-334.
Khartoum, November 2015 - Stephen Wicks
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Drug Absorption
Physicochemical
Properties
Gut Anatomy and Physiology
Cell Monolayer
Permeability
Gastrointestinal Transit
•
Gastric emptying is unpredictable
–
–
–
•
In humans, transit in the small intestine is
constant
–
•
Transit is 3 hours
Although the colon is shorter, the transit time is
much longer
–
•
It depends on whether the subject is fed or has
been fasting
Objects less than 10mm can empty from a fed
stomach
Objects >20mm in size will be retained in the fed
stomach
Transit can be 20 hours or, in some cases,
longer
In the fasted state, a dosage form can reach
the ileo-caecal junction in 4-5 hours
Biopharmaceutical Evaluation
•
The starting point is generally a reference oral liquid formulation
–
–
–
–
•
•
Late Phase I crossover studies with the oral liquid formulation and an evaluable
Phase II dosage form, e.g. tablet or hard gelation capsule
Absolute bioavailability
–
•
•
Ideal for rapid, low-cost entry into Phase I studies
Based on solutions or oral suspensions, these systems avoid solid dosage form
complications, e.g. disintegration and dissolution (solutions)
API may be fluid energy milled (‘micronized’) if low solubility and dissolution rate is
suspected.
Caution: there are reports in the literature of oral liquid formulations being less
bioavailable than tablets and capsules
If an IV injection formulation is feasible
Crossover studies if formulation changes are made
Studies aimed to establish an in vivo-in vitro relationship or correlation
Preformulation Studies
•
The Distribution Coefficient (Log D) and the Partition Coefficient (Log P)
are important starting points:
– Referenced to the octanol:water partition coefficient
– Many alternative high-throughput methods now available, e.g. reverse phase
HPLC
– Public domain algorithms now available for reliable calculation
•
Solubility
– Particularly pH-solubility relationships
•
•
Dissolution rate
Permeability studies in Caco-2 or other cell monolayers
– The process can now be automated
•
Permeability and solubility estimates will allow determination of the
Biopharmaceutics Classification System (BCS) profile
Biopharmaceutics Classification System
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The pH Partition Hypothesis
Plasma
Compartment
Lipid
Barrier
Gut Compartment
R – NH2
R – NH2
R – NH+
R – NH+
pH = 7.0
pH = 1.0
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The Caco-2 Monolayer and absorption
EtO
EtO
O
NH
Me
O
Passive
Active
Transcellular
Facilitate
N
NH
O
O
S
O
O
N
N
CO2H
Passive
Efflux
Paracellular
CO2H
Gut
Khartoum, November 2015 - Stephen Wicks
Receptor
Mediated
19
Physicochemical and Cell Monolayer Prediction
Salicylate Cohort
High Molecular Weight
Cohort
Drug Efflux
Drug Transporters
UK-64,143: Addition of 1-(methylsulphonyl)piperidine
enhances angiotensin converting enzyme (ACE)
inhibition
EtO
EtO
O
NH
O
NH
O
Me
N
CO2H
Enalapril – Merck
60% oral bioavailablity
O
O
S
O
N
N
CO2H
UK-64,143 – Pfizer
Not orally bioavailable
UK-64,143 and enalapril structures from Peter Dunn and Michael Williams courtesy of Pfizer Ltd.
Khartoum, November 2015 - Stephen Wicks
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Differential Solubility, Stability and Absorption:
The ‘Absorption Window’
•
‘Absorption windows’ can arise from a number of physiological and
physical reasons
–
Environmental changes in the gut
•
–
–
–
–
•
pH, gut enzymes, bile
Active transporters
Paracellular absorption
Gut wall metabolism (Cytochrome P450 3A4)
Efflux pumps, e.g. P-glycoprotein
In general
–
–
Drugs absorbed by passive diffusion can be absorbed from the small intestine and the
colon
Drugs absorbed via the paracellular route or by active transporters are absorbed
from the small intestine only. i.e. they appear to have an absorption window of about 4-5
hours at which point absorption rates reduce dramatically or absorption ceases
Absorption Windows Frustrate Controlled
Release
•
•
•
•
•
•
•
•
•
•
Acyclovir
Bisphosphonates
ACE inhibitors
Frusemide
Metformin
Gabapentin
Penicillin and Cephalosporin antibiotics
Levodopa
Baclofen
Ciprofloxacin
ACE Inhibitors
Name
Activity
Hepatic
Metabolism
Excretion
F
t1/2
(hr)
Captopril
Active
Yes
Renal
70-75%
1.9
Enalaprilat
Active
Yes
Renal
Nil
11.0
Enalapril
Enalaprilat
prodrug
Yes
Renal
60%
n/a
Lisinopril
Active
No
Renal unchanged
25%
(6-60%)
12.0
Science and Formulation Design
• The Team
• Human
Biology
• The Drug
• The Dosage
Form
Khartoum, November 2015 - Stephen Wicks
31
Polymorphism: a philosophy of science
problem
• Fewer, smaller API batches being manufactured due to minimalism
• Poor analytical characterisation
– Limited to IR spectroscopy and thermal analysis
• Understanding of the importance of polymorphism
• Lack of control
– Manage the problem when it happens
– Damage limitation
Khartoum, November 2015 - Stephen Wicks
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Norvir®
•
1998 — Abbott Laboratories announced that it was experiencing
manufacturing difficulties with the capsule formulation of its HIV protease
inhibitor, Norvir®.
•
"We have encountered an undesired formation of a Norvir® (Ritonavir)
crystalline structure (Form II) that affects how the capsule form of Norvir®
dissolves”
•
“In Form II all of the strong hydrogen bond donors and acceptors have
been satisfied and are strong….Since the strength and completeness of the
hydrogen bonding has attained the maximum possible in the Form II lattice,
it is not thought possible that another undiscovered polymorph of ritonavir
would exist with equivalent or lower solubility than that of Form II’’
•
In 2003, it was reported that 2000 high throughput crystallisations had
identified two new solvates plus an additional anhydrous form.
Chemburkar, et al. (2000) Org. Process Res. Dev. 4(5), 413.
Bauer, et al. (2001) Pharm. Res. 18(6), 859.
Morissette, et al. (2003) PNAS. 100, 2180.
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Conventional Solid State Unit Processing
Compression
Mixing and
Granulation
Coating
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Structural Frequency Analysis
Solid Form
Data Mining
2.415 Å
2.454 Å
Crystallisation Experiments
• 3-Centred
interaction absent
from the database
2.241 Å
• Linear Interaction
more common and
shorter
• First Form Crystallised
• A more stable form
predicted
• Second Form Crystallised
• Weak H-Bonding
• Stronger, Linear H-Bonding
• ‘3-Centred’ Architecture
• More stable form
Khartoum, November 2015 - Stephen Wicks
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Courtesy – R. Docherty, Pfizer Ltd
Robotic Screening
Solids Dosing Robot
Sitting Drop Robot
Polymorph/Hydrate
hunting- Robot
Crystallisation
Robustness Robot
Image
Analysis
From 10 to 100 to 1000
crystallisations
Increase in diversity of
experiments (robustness)
Khartoum, November 2015 - Stephen Wicks
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Courtesy – R. Docherty, Pfizer Ltd
Optimisation of Properties
• Met demands of
dynamic fast moving
program
•
Solubility/Stability
Lead and CAN
Nomination
DS Technology
Embraced the
technology
opportunity
Science Of Scale
Tablet Dosage
Form Design
Solid Form
Selection
Solid Form Screening Informatics
Clinical Commercial
Manufacture
Expert Systems
120.00
100.00
% Theory
80.00
T1
T2
60.00
T3
T4
T5
40.00
T6
20.00
0.00
0
5
10
15
20
25
30
35
40
45
50
Time (mins)
Khartoum, November 2015 - Stephen Wicks
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Courtesy – R. Docherty, Pfizer Ltd
Pharmaceutical Materials Science
Crystal
structure
Crystallization,
spray drying,
lyophilization
QUANTUM
MOLECULAR
(CRYSTAL)
PARTICULATE
Scale-up
Blending,
granulation,
compression
SINGLE
TABLET
Khartoum, November 2015 - Stephen Wicks
BULK
TABLET
38
Courtesy – R. Docherty, Pfizer Ltd
Select crystal
form
2.415 Å
Model crystal
form
Modify
Physical
properties
Maraviroc:
Putting it all
together
Manufacturing
simulation
Data mine test
for precedence
Robotic
screening
Courtesy : Pfizer Ltd; Cambridge Crystallographic Database
Khartoum, November 2015 - Stephen Wicks
39
2.454 Å
Thank You
Khartoum, November 2015 - Stephen Wicks
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