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

Working with Amorphous Forms

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

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