enhanced kinetic solubility profile of indomethacin amorphous solid … · 2013-11-04 · amorphous...
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Enhanced kientic solubility of indomethacin amorphous solid dispersions in hydrogel
Dajun Sun
Supervisor: Professor Ping Lee
Department of Pharmaceutical Science
University of Toronto
April 11, 2012
Story of Itraconazole (an -azole antifungal drugs)
1960 1970s 1980s
AIDS era w/o antiretroviral treatment
Not used for a broad spectrum of fungal infections
Low therapeutic index Low potency
- Minimum inhibitory concentration: 100-fold smaller than ketoconazole - Higher therapeutic index
Solubility 0.1 mg/mL
Solubility 8 mg/mL
Absorption of Oral Dosage Form
Drugs in oral dosage forms
(tablets or capsules)
Absorbed by the body and
transferred by blood stream
to the site of action for
therapeutic purposes
Solublized in GI fluids
Cross the biological
membranes
Biopharmaceutics Classification System
Lipophilic
High Permeability
Low Solubility Flurbiprofen
Naproxen
Diclofenac
Piraxicam
Carbamazeppine
Phenytoin
Amphiphobic
Low Permeability
Low Solubility Famotidine
Atenolol
Ranitidine
Nadolol
Cimetidine
Hydrophilic
Low Permeability
High Solubility Terfenedine
Ketoprofen
Hydrochorothiazide
Furosemide
Solubility
Pe
rme
ab
ilit
y
Improvement at
chemical levels
(difficult)
Formulation design
Amphiphilic
High Permeability
High Solubility Propranolol
Metoprolol
Labetalol
Enalapril
Captopril
Diltiazem
Nortriptyline
Marketed drug
New Chemical Entity
Solubility: highest required dose is soluble in 250ml or less of
aqueous media over the pH 1 to 7.5.
Permeability: the extent of absorption in humans is determined to
be 90 % or more of the administered dose in comparison to iv. www.fda.gov/cder/guidance/2062dft.pdf
Physical modifications to improve solubility
Particle size reduction 1
Polymorph of crystal 2
Complexation / solubilization 3
Creation of salt forms 4
Amorphous solid dispersions (ASD) 5
Micronization
Nanosuspensions
Surfactants
Cyclodextrin
Solubility enhancement of ASD
Crystalline Amorphous
Metastable
(Amorphous)
Stable
(Crystalline)
Unstable
Free Energy
Yu, L Adv Drug Del Rev , Nov 48, 2000, 27-42
Amorphous: lack of long range of molecular orientation
symmetry (randomness of molecular conformation). But, it
may have short range of molecular lining.
Polymeric carriers: amorphous drugs molecularly
dispersed in polymer which retards nucleation/crystallization.
Polymeric matrix
ASD example – hard candy
Methods of preparing amorphous solid dispersions
(1) Solvent method: dissolved in solvent and dry the solvent off
(2) Melt quenching: rapid cooling after melt
Example: Hard candy – melt sugar is rapidly cooled
Crystalline sugar:
Hard, lower solubility Amorphous sugar
(hard candy):
Brittle (glass)
Higher solubility
Drug release from water-soluble polymers
Water-soluble
carriers
Body
Fluids
Polymer
matrix
Drug molecule
Curatolo et al. Pharm Res, Vol. 26, No. 6, 2009, 1419-1431
Kinetic / apparent solubility
Crosslinked Poly(2-hydroxyethyl methacrylate)
Immerse dry
beads in drug
loading
solution
Swelling
hydrogel imbibes
loading solution
Remove
excess loading
solution and
dry hydrogel
Insoluble PHEMA hydrogel beads synthesis:
Indomethacin loading process:
Physicochemical characterization of ASD
Microscopy
FTIR
DSC
Dissolution Study XRD
Drug-polymer
interaction
Appearance
Degree of
crystallinity
Tg: molecular
mobility in
polymeric matrix
Solubility
enhancement
Indomethacin-loaded PHEMA hydrogel
Sun, D.D. and P.I. Lee, Eur. J. Pharm. Biopharm. Jan 2012, accepted
Dissolution under the sink condition
- Dissolution volume is fixed (=250mL)
- Indomethacin aqueous solubility ~ 10 mg/mL
- Dose required = 20 mg
Sink Index (SI)
SI=10
Perfect sink
condition
SI=0.125
Physiological condition
with required dosage
sink condition Non-sink condition
Kinetic solubility enhancement between soluble polymers and insoluble PHEMA at low loading
Sun, D.D. and P.I. Lee, Eur. J. Pharm. Biopharm. Jan 2012, accepted
Kinetic solubility enhancement between soluble polymers and insoluble PHEMA at high loading
Sun, D.D. and P.I. Lee, Eur. J. Pharm. Biopharm. Jan 2012, accepted
Effect of drug loading on dissolution
Sun, D.D. and P.I. Lee, Eur. J. Pharm. Biopharm. Jan 2012, accepted
Effect of particle size on dissolution
Sun, D.D. and P.I. Lee, Eur. J. Pharm. Biopharm. Jan 2012, accepted
Conclusion
Insoluble PHEMA hydrogel shows a different release
mechanism of ASD drugs from soluble polymeric carriers Soluble polymers (PVP, HPMCAS): instantaneous release, resulting in an
initial surge of drug concentration, followed by rapid drop of drug
concentration due to nucleation and crystallization
Insoluble polymer (PHEMA): gradually releasing drugs to avoid a sudden
surge of supersaturation
The solubility enhancement of PHEMA falls between those
of HPMCAS and PVP at 10% loading and outperforms both
at 33%
Immediate to controlled release of ASD drugs in PHEMA
can be achieved by controlling the particle size
Dissolution rate might play a role in supersaturation and
kinetic solubility enhancement
Supervisor: Professor Ping Lee
Advisory Committee: Professors Edgar Acosta, Christine Allen & Shirley Wu
Abbott Laboratory: Dr. Rob Ju
PIL Lab Members
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