Working with Amorphous API’s
Edwin Aret
Avantium Technologies BV
Drug Development of Tomorrow
Tuohilampi / Vihti, Finland
28-29 January 2009
Agenda
• Solid form selection
• Marketed examples
• Amorphous state
• Properties and generation of amorphous material
• Amorphous Solid Dispersion Screen
• Case study 1 (solution process)
• Case study 2 (melt process)
Candidate MoleculesPfizer candidate molecules
Source: Chris Lipinski, J. Pharm. Tox. Meth, 44, 2000
• Increasing lipophillicity• Increasing number of neutral compounds
Formulation strategies that can influencethe drug properties (solubility……..)
• Micronization
• Solubility enhancers (complexing agents)
• Pro drugs
• Solid formsPolymorphs
Salts
Co-crystals
Amorphous forms
Polymorphs and hydrates
Pudipeddi & Serajuddin, J. Pharm. Sc 94(5), 2005
Polymorphs0.
5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5
5.0
0
10
20
30
solubility ratio's
Num
ber o
f com
poun
ds(o
r po
lym
orph
s)
anhydrate/hydrate
0 10 20 300
10
20
30
compound numberso
lubi
lity
ratio
(anh
ydro
us/h
ydra
te)
Polymorphs (55 compounds, 81 solubility ratios): improvement trend 1-5 x
Hydrates (17 compounds, 24 ratios): improvement only in exceptional cases
Benefits of Salts
Solubility of saccharin salts
Haloperidol Mirtazapine Quininie0
1
2
3
4
5
6
7marketedsaccharin
600 x
40 x
3 x
drug products
solu
bilit
y (m
g/m
l)
Pudipeddi & Serajuddin, J. Pharm. Sc 94(5), 2005Bhatt et al., Chem. Commun., 2005
Benefits of Co-crystals
0.0 0.1 0.2 0.30
10
20
30
40
50
60
70
80
90
100
110
Lactamide:carbamazepineGlycolamide:carbamazepinecarbamazapine
Time (h)
% d
isol
ved
Dissolution rate of carbamazepine co-crystals increased.
Avantium Study
1) Processing induced disorder- milling,- granulation
2) Stabilising macromolecules
3) Naturally Amorphous excipients- polymers: PVP, HPMC
4) Rendered amorphous excipients- spray dried lactose for direct compression
5) Amorphous API
Amorphous in pharmaceuticaldevelopment
Amorphous API(products for oral use)
Compound (Discoverer/Manufacturer) Year licensed Comments
Lopinavir (Abbot)
USA 2000
Europe 2001
Co-formulated with ritonavir as Kaletra to treatHIV/AIDS.Lopinavir exists as an amorphous form and 4crystalline forms. The commercial material is amixture of the amorphous form and Form Icrystals.
Cefuroxime axetil (GSK)
USA 1977
Second generation cephalosporin antibiotic,trade names Ceftin, Zinacef, Zinnat.Crystalline form is a mixture of twodiastereomers.Amorphous form recently dispersed withHPMC 2910 / PVP K-30 to increasedissolution rate.
Zafirlukast (Astra-Zeneca)
1999
Oral leukotriene receptor agonist formaintenance treatment of asthma, tradenames Accolate, Accoleit, Vanticon.Forms A (amorphous), B (unstable crystal), X(stable crystal) discovered, also ethanol &methanol solvates.X has poor bioavailability, B is difficult toprepare reliably. A is used in formulations.
Amorphous API(products for oral use)
Compound (Discoverer/Manufacturer) Year licensed Comments
Rosuvastatin calcium (Astra-Zeneca)
USA 2003
154 othercountries 2004
High potency statin for reducing high bloodcholesterol levels, trade name Crestor.Amorphous solid, slightly soluble in water (7.8mg.mL-1 @ 37oC).
Itraconazole (Janssen Pharmaceutica)
Europe 1987
USA 1992
Triazole antifungal agent, trade nameSporanox.Absorption in the body is difficult andunreliable, and dosing with a solutioncontaining cyclodextrin is employed.
Quinapril hydrochloride (Pfizer)
N
OH
O
O
HN
O
O
.HCl
1989
ACE (angiotensin converting enzyme) inhibitorfor treating hypertension and congestive heartfailure, trade name Accupril.Amorphous powder, freely soluble in waterand organic solvents.
Useful properties of the Amorphous state
- Higher dissolution rate (can give better bioavailability)
- Better compression characteristics
- Optimum stability of macromolecules (freeze dried systems are generally more stable thana liquid formulation)
Problems with Amorphous state
- Lower physical and chemical stability than crystalline state
- Higher Hygroscopicity (water absorption vs water adsorption of a crystalline form)
- Variability (batch to batch, change with time)
Amorphous state
Amorphous Crystalline
H, V
TTm
Crystal
Liquid
Supercooled liquid
Glass
TgTk
PropertiesGlass:
> 1013 P- molecular motion second to years- High temperature dependence of
and molecular motions
PropertiesSupercooled liquid:
~ 10-2 P- molecular motion pico-nanoseconds- Lower temperature dependenceof and molecular motions
50 K below Tg molecular mobility (Kauzmann temperature) can beconsidered low enough to ensure stability
Glass versus supercooled liquid
Manipulating Tg of the API by mixingwith a higher Tg excipient
Gordon-Taylor equation, and others to predict Tg of a mixed system
100% 0%A
Tg A
Tg B
Glass
Supercooled liquid
Gordon-Taylor equation assumes volume additivity and no interactions
Tg of the system different than predicted: interactions excipient-API and/or phase separation
Solid line: predictedData points: experimental Tg valueHPMC-Itraconazole(Six et al. (2003) Pharm Res 20:1047-1054
TempTemp
One phase systemOne glass transition
Two phase systemGlass transitions of eachphase
Multiple phase system
Van Drooge et al (2006) Macromol 27:1149-1155
Drug Drug DrugDispersion
medium
Dispersionmedium
Dispersionmedium
DispersionDispersion Dispersion
Amorphous Solid Dispersions
Vasanthavada et al (2005) 22:440-448
Carbonyl stretching region
Molecular Interactions:API - excipient/polymer
Felodipine
PVP
Patterson et al. IJP (2006)
10% API
30% API
50% API
Ratio I1643/I934
Karavas et al. (2007) IJP 340:76-83
Raman Mapping
Felodipine
PVP
Patterson et al. IJP (2006)
10% API
30% API
50% API
Ratio I1643/I934
Karavas et al. (2007) IJP 340:76-83
Raman Mapping
Methods to prepare solid dispersions (API dispersed into a polymer/excipient)
Solvent removal method Cooling from the melt
PolymerAPI
In solution
Lab scale: vacuum drying
Larger scale: Spray drying
MeltedPolymer and
API
cooling
Larger scale: hot stage extrusion
- Milling- Supercooling of the melt- Vapor condensation- Precipitation from solution
Ways to generate amorphousmaterial
Examples of API’s prepared asamorphous forms
API Preparation method API Preparation method(1) Separation / precipitation of solid from liquid
(1a) Solidification from the melt (1b) Spray dryingIndomethacin Quench cooling with liquid N2;
slow cooling from the meltover 30 min.
4"-O-(4-methoxyphenyl)acetyltylosin
Spray drying adichloromethane solution.
Felodipine Cooling in liquid N2 or atambient temperature.
Salbutamol sulfate Spray-drying aqueous solutionin a Buchi 90 spray dryer.
Nifedipine Melting at 180 C, immersion inliquid N2.
Furosemide Spray-drying a 4:1chloroform:methanol solution.
Lovostatin Melting under N2, rapid coolingto 20 C below glass transition.
Digoxin Spray-drying an aqueoussolution with hydroxypropylmethylcellulose
(1c) Freeze drying (lyophilization)Dirithromycin Freeze drying from methylene
chloride solutionAspirin Freeze drying an aqueous
solution with 1%hydroxypropyl- -cyclodextrin.
Sodiumethacrynate
Rapid freezing of an aqueoussolution to -50 C, freeze-drying.
Cephalothinsodium;Cefamandolsodium
Freeze-drying from a 25%aqueous solution.
Examples of API’s prepared asamorphous forms
API Preparation method API Preparation method(2) Mechanical disruption of an ordered structure
(2a) Milling (2b) DesolvationCimetidine Ball milling. Tranilast anhydrate Dehydration of the
monohydrate over P2O5.Calcium gluceptate Milling in a Pulverisette 2
grinder (Fritsch) for 4 hours.Erythromycin Heating the dihydrate for 2
hours at 135 C, and thencooling to room temperature
Chloramphenicolpalmitate
Milling in a Pulverisette 0grinder (Fritsch) for 85 hours.
Calcium DL-pantothenate
Drying the methanol:water 4:1solvate in vacuo at 50-80 C.
Digoxin Milling in a Glen CrestonModel M270 ball mill for 8hours.
Factors that can be varied during the preparation of soliddispersion from solution by solvent removal method:
- Type of polymer- Drug to polymer ratio- Solvent system- 3rd component (surfactant, 2nd polymer, etc)- Evaporation rate- etc
Screen
Polymers
DrugLoading
Solventsystem
A
Solventsystem
B
Solid dispersion screening bysolvent removal method
Factors that can be varied during the preparation of soliddispersion by melt method:
- Type of polymer- Drug to polymer ratio- Melting temperature- 3rd component (surfactant, 2nd polymer, etc)- Holding time- etc
Screen
Polymers
DrugLoading
Temp. A
Temp. B
Solid dispersion screening bymelt method
Prerequisites and timelines
- number of experiments: 80-160 at ml scale
- Amount of API: minimum 0.5 g (depending on the number of experiments)
- Stress conditions stability study (usually several weeks)
- Drug loading (10-30%)
- Timelines: 5 weeks (assuming a 1 week stability study)
Solid dispersion screening bysolvent removal and melt methods
• XRPD for first selection of amorphous systems
• Storage at stress conditions (high temperature and humidity)
• XRPD for selection of what remained amorphous
• Further characterization of the stable amorphous systems(thermal analysis, spectroscopy, solubility & dissolution)
Amorphous SolidDispersion Screen
Conclusion
• The selection of the appropriate API solid formto optimize the properties of the drug as neededfor further development
• Solubility enhancement by selecting appropriatesolid forms such as polymorphs, salts, co-crystals or amorphous
• Stabilization of amorphous solids in dispersion
• Developing/scalability practical solid dispersion
Working with Amorphous API’s
Avantium TechnologiesAmsterdam, The Netherlandshttp://www.avantium.com
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