Enhancing Solid Dosage Bioavailability with Size, Crystal Form, and Formulation
Second U.S.-Korea Nano Forum
Tony Meehan, Ph.D.Director, Pharmaceutical DevelopmentFebruary 17, 2005
The Impact of Size on Efficacy
• Most drugs in solid form fall in the range of 10-500 microns
• Poor aqueous solubility may limit oral bioavailability or ability to deliver as a parenteral formulation
• Absorption may depend on rate of dissolution, which in turn is controlled by particle size, crystalline form, and aqueous environment
Drug dissolved in gastric fluid
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NanoCrystals
µm sizedrugparticles
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Dissolved drug is absorbed
Dissolved drug uptakeinto mixed micelles of bilesalts & lipid digestion products
Drug is absorbed
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MK-869 Particle Size Effects in Dogs
0
200
400
600
800
1000
1200
1400
0 4 8 12 16 20 24
NanoCrystal, 0.12 umWet-Milled, 0.48 umJet-Milled, 1.85 um004H004, 5.49 um
ng/m
L M
K-0
869
Hours (Expanded View, 0-24 Hours)
Total Exposure (AUC) in Humans
0
2 0
4 0
6 0
8 0
1 00
1 20
0 5 0 1 0 0 1 5 0 2 0 0 2 5 0 3 00 3 5 0
AU
C, u
g hr
/mL
Dos e (m g)
Nanoc aps u le Fed
NanoC rys ta l Susp ens ionFas ted
NanoCaps u le , Fas ted
Tab let Fe d
Table t, f as ted
Improving Oral Bioavailability
• Particle Size Reduction– Jet-milling, high energy ball milling– Spray drying– Super critical fluid extraction– High supersaturation crystallization
• Solid Form Thermodynamics– Amorphous– Salts– Higher Free Energy Polymorphs
• Improve Solubility
Jet Milling
• Relies on particle-particle interaction• Narrow size distribution• Minimal heating• Mean size 1-10 microns
www.comex-group.com
Oct: Beclomethasone Dipropionate (after micronization) - Jet-milling
Beclomethasone Dipropionate (after micronization), www.hovione.com
High Energy Ball Milling• Mean size range from 100 o 1000 nm • Particles stabilized via adsorbed GRAS excipients • (Nanosystems’ technology)• Enhances dissolution rate of oral drugs• Enables parenteral forms of poorly soluble drugs
Asada
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Other Methods of Size Reduction
Spray Drying Supercritical Fluid Extraction
• PSD < 1,000 nm
• Applicable for pulmonary, oral, or parenteral delivery.
• Generally amorphous; may agglomerate or pick up moisture; less chemically stable
Particle Size Reduction Summary
• Particle size reduction generally successful in improving oral, pulmonary, and parenteral bioavailability
• However, problems exist…– Downstream processing, material handling– Chemical and physical stability
• Manufacturing processes for crystalline particles < 100 nm really don’t yet exist, but could present an opportunity for improving drug delivery efficacy
Improving Oral Bioavailability
• Particle Size Reduction– Jet-milling, high energy ball milling– Spray drying– Super critical fluid extraction– High supersaturation crystallization
• Solid Form Thermodynamics– Amorphous– Salts– Higher Free Energy Polymorphs
• Improve Short Term Solubility
CrystalMaxCrystalMaxTMTM
Solid Oral Forms
FASTFASTTMTM/SFinX/SFinXTMTM
Liquid/Injectable Formulations
DerMaxDerMaxTMTM
Transdermal
TransForm Pharmaceuticals Platforms
HTE in Pharmaceutical Formulations
Parallel experimentation: > 10,000 crystallizations/week Typically 0.25 - 2 mg of compound per testCooling, evaporative, melt, anti-solvent, and other modes
CrystalMaxTM Process Flow
Clustering of Glycine Polymorph Raman Spectra
α
γ
Rapid, automated crystal form classificationMethod can be used with other types of data
Each dot = value of ‘similarity’ for a pair of spectra
High
Low
Similarity measure
Pharmaceutical Co-Crystals
Pure drugCo-crystal with new structure, properties
Co-crystal former
Can impact:SolubilityDissolution rateHygroscopicityStabilityHabitProcessability
Many of the potential benefits of a salt, without the limitations
> 30% of compounds lack “saltable” functional groups
Broad potential applicability
A stable higher energy form
Itraconazole: Succinic Acid Co-Crystal
Remenar, J. F. et al. J. Am. Chem. Soc. 125, 8456 (2003)
The acid groups of the co-crystal former do not interact with the strongest base on itraconazoleGeometry of co-crystal former drives crystal formation
a=30.145(4)Åb=5.7435(7)Å β=105.133(2)ºc=21.580(3)Å
P21/c
Improved Dissolution of Itraconazole
50µm8x10-4
6
4
2
0
[1] (M
)
4003002001000Time (min)
■ Sporanox® beadsl-malic acid co-crystal
● l-tartaric acid co-crystalsuccinic acid co-crystal
◆ cis-itraconazole
Co-crystals of itraconazole showed improved dissolution compared to the free baseEnables alternative formulation options
New Crystal Form of Celecoxib
40% bioavailableSlow onsetNon-linear PK
Issues Impact~95% bioavailableFaster onsetLinear PK
Potential implication
0
500
1000
1500
2000
0 5 10 15 20 25
TPI-336Marketed product
t, hours
Lower doseNew indication7+ years add’l patent life
Approach Novel crystal forms enable new formulation technique
Precipitation Inhibition: Spring and Parachute
Concentration
New Form
Free drug in equilibrium
Time
“Spring” “Parachute”
Problem: API with poor solubility & low bioavailability
PrecipitationInhibition
Solution: “Spring” and “parachute” concept
Poor Solubility Problem
• Compound PropertiesCrystallineVery low aqueous solubilityUnstable salts(pKa compound 0.9, 14.6)
Room Temperature Solubility
< 25
28Ethanol
71PEG 400
0.000060Water, pH 3-7
Solubility (mg/ml)Vehicle
triglycerides
28Ethanol
71PEG 400
0.000060Water, pH 3-7
Solubility (mg/ml)Vehicle
Challenge: Poorly soluble drug crashes out instantly upon dilution, limiting bioavailability
Approach:HT formulation studies to identify excipient combinations that delay precipitation or accelerate resolubilization in SGF
Precipitation Inhibition Solution
• Compound used: <5 g• Project duration: 8
weeks• >4,500 experiments
– 2 HT studies– Optimization
Dissolution Profiles of 2 Lead Formulations in SGF(20 mg/ml, 10X dilution, 37C)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0 20 40 60 80 100 120 140time (min)
API
(mg/
ml)
AV21
AV22
PEG400
• Solubility improvement vs. diluted PEG400: > 19,000X at 2 hours• Enabled > 50% improvement in bioavailability
Parenteral Reformulation: PropofolParenteral Reformulation: Propofol
• Very effective I.V. anesthetic• Formulated as a lipid emulsion
• Complex / expensive manufacturing process• Thermodynamically metastable• Difficult to handle aseptically• Risk of contamination
• Opportunity for improved product
• Lipid-free, preserved formulation• Thermodynamically stable pluronic
based colloidal self assembly• Equivalent PK to Diprivan• Enables multi-dose vials
Marketed product TPI-213M
Enabling Transdermal Technology
ALZA in 2002 • Limited screening capacity• Few transdermal candidates• Slow formulation
development
TransForm + ALZA in 2004• 100x conventional capabilities • Improved/enabled transdermal
products with broad IP
SkinReceptor
compartment
Transdermalpatch
Franz Diffusion Cell
1 – 2 experiments / in2
of skin
Adhesive formulations
25 – 100 experiments / in2 of skin
Skin
Receptor compartment
TransForm Permeation Cell Array
Summary
• Form, size, and environment impact the rate and extent of drug bioavailability
• Manufacturing processes for creating crystalline pharmaceuticals actives < 100 nm do not exist, yet may represent the next tool to improve drug delivery
• High throughput experimental methods present new opportunities to enable effective but poor performing molecules with new crystalline forms and formulations
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