Crystallization and Polymorphism

Crystallization and Polymorphism

Prof. Attilio Citterio

Dipartimento CMIC “Giulio Natta”

http://iscamap.chem.polimi.it/citterio/dottorato// “Scale up of a crystallisation process is probably MORE difficult than any other

J.W. Mullin

PhD

IN INDUSTRIAL CHEMISTRY AND CHEMICAL ENGINEERING (CII)

Crystallization

http://aiche.confex.com/aiche/2005/techprogram/images/21810-0.jpg

Spheres Needles Cubes

Solubility Curve and Metastable Zone

temperature

or solvent composition

concentration

B A C

Metastable zone

Rapid

nucleation

Supersaturation

Induction time Metastable zone

temperature

concentration

temperature

concentration

Unseed system with slow cooling One nucleation event gives small crystals of uniform size

Unseed system with fast cooling Several nucleation event gives a wide distribution of small crystals

Supersaturation Path (unseed)

temperature

concentration

Seeded system with slow cooling

No nucleation event, the crystal size depend on the number and size of seeds added

Supersaturation Path (seeded)

temperature

concentration

temperature

concentration

System with a phase transition temperature

M may be isolated by seeding within the narrow range region between the solubility curve of M and the metastable zone of S

Solubility curve of M

Solubility curve of S

T₁ T₂

Metastable zone of S Metastable

zone of M

Solubility curve of M Solubility

curve of S

Metastable Zones of Polymorph

temperature

concentration

M cannot be isolated by seeding

Crystallising a 50:50 mixture of diastereoisomers, the yield of the less soluble can be increased using the metastable zone of the more soluble diastereoisomer

temperature

concentration

Metastable zone of S Metastable

zone of M

Solubility curve of M Solubility

curve of S

diastereoisomers

T₁ T₂ T₃

∆G₁

∆G₂

Metastable Zones

~ 5 cm

Light in from colorimeter Light out to

colorimeter

Fibre-optic cable Fibre-optic cable

Flange for lid with thermometer and condenser

Jacketed Vessel for Metastable Zone

Measurement

Agitated Drying of Crystals

Crystal Size Distribution:

Attrition decreases the size.

Agglomeration increases the size.

Lekhal et al. Powder

Drying Parameters:

Drying Temperature Agitation Speed

Drying time Vacuum

Drying

• Freeze Drying

• Spray Drying

solvent evaporation

http://www.malvern.com/ProcessEng/images/processes/spray_drying_overview1.gif

Spray drying consists of the following unit operations:

Pre-concentration of liquid

Atomization (creation of droplets)

Drying in stream of hot, dry gas (usually air) Separation of powder from moist gas

Cooling

Packaging of product

Factors Affecting Crystal Habit

Variations in

 Temperature

 Level of supersaturation

 Rate of cooling

 Rate of agitation

 Solvent polarity and viscosity

 Water content

 Impurities

- Nature

- Concentration

Example

• Final product insoluble in most solvents

• ^Normally

- crystallised from reaction mixture (methanol - ethyl acetate) - Needles obtained

- Sufficient purity

- Solvent removed by extensive drying

• If batch not pure enough

- Recrystallisation from DMF required - Different crystal habit obtained - prisms - 1 mole DMF incorporated in crystal

• Other solvents give plates or rods

L. Shimon, Chapter 6 In “Organic Crystal Chemistry” ed.

Garbarczyk and Jones, Oxford University Press 1991

a) from methanol b) in presence of traces of methyl ester

c) in presence of R isomer d) from acetic acid

(111) (121)

(111) (121)

(001) (010)

(001)

(111) (111)

(011)

(033) (033)

(010)

(001)

(010)

(112) (112

)

(122) (122)

(001) (010)

(010)

(111) (111)

Crystals of

N-(E-cinnamoyl)-S-alanine

from aqueous solution from 90:10 methanol:water -c

b

(110)

(011) (011)

(001) (011)

(011)

(110)

-c b

(110)

(100)

(110) (011)

(011)

Crystals of α-Rhamnose

Solvates

 Molecular complexes incorporating solvent

 Desolvation may lead to a new polymorph

 Solvates are generally more soluble and dissolve faster than the pure substance

 Hydrates are usually less soluble

 Characterised by

- DSC-TGA - GLC

- NMR

Substance Medium Temp Solubility (mg/ml) Form I Form II Form III

Ampicillin Water 37 10* 8 +

Chloramphenicol t-BuOH/water 30 0.1 0.4 Palmitate

Codeine Water 25 8.13 11.16 80.7

Diflunisal Water 25 0.014 0.026

Mebendazole Water 25 0.01 0.07 0.04

Sulphathiazole 95% EtOH 20 7.1 13.1 40 14.0 21.0 Tetracycline water 37 27.5 35.0

Solubility of Different Crystal Form

During Crystallisation

• Nucleation rate affected by

- Agitation rate

- Supersaturation level - Seeding

- Trace impurities - Temperature

• Rate of crystal growth affected by

- Agitation rate

- Density and viscosity of solvent - Temperature

• Optimum temperature for nucleation may not be the

optimum for crystal growth

Polymorphism

• Defined as “the ability of a compound to exist in more than one crystal form”

• Internal arrangement of atoms is different

• Caused by a molecule’s ability to change conformation

• Hydrogen bonding very significant

Different Polymorphs

May have different

§

 Solubilities

§

 Rates of dissolution

§

 Melting points

§

 Heats of solution

§

 Spectra (IR, X-ray)

§

 Solid state (rheological) properties

- e.g. bulk density, wettability, ease of milling, granulation, compression

-All important in formulation

Polymorphism

Affected by

§

 Level of supersaturation

§

 Temperature

§

 Rate of cooling

§

 Rate of agitation

§

 Seeding

§

 Impurities

§

 Nature of solvent (polarity)

References 1. R. Bouche

J. Pharm Belg 1977, 32, 23 2. M. Schikata

J Pharm SCI 1983, 72, 1436 3. M. Kuhnert-Brandstatter

Z Anal Chem 1985,322,164 4. A. Burger

Acta Pharm Technol 1979. supp 7,107 5. T. Umeda

Chem Pharm Bull. 1984, 2. 1637 ibid. 1986, 3. 917 6. A K. Jarn

Indian Drugs. 1986, 3, 315 Drug Polymorph Other Form Ref.

(solvates, etc.)

Ampicillin 1 1 1

Barbital 6 1

Benoxaprofen 2 5

Cephaloridine 4 2 1

Codeine 3 1

Cortisone 2 1 1

Cortisone AcO 8 1

Fluocortolone 2 19 1

Nicotinamide 7 4

Sulphaguanidine 4 1 1

Sulphamethazine 2 1

Sulphapyridine 6 1

Testosterone 3 1

Tolbutamide 3 1

Cimetidine 4 2

Propanolol 2 3

Piroxicam 3 3

Trimethoprim 3 1 6

Drugs Which Show Polymorphism

50% of manufactured compounds in the above groups were NOT in the most stable polymorphic form

How Widespread is Polymorphism?

Estimate - 1 in 3 compounds

Sulphonamides 60% of compounds

Barbiturates 70% investigated exhibited

Steroids 60% polymorphism

P

a

b

c d

Solid

Liquid

Vapour

T

ab represents the variation of vapour pressure with temp.

bc represents the variation of boiling point with pressure bd represents the variation of imp with pressure

(i.e. almost invariant). b.

is the triple point, the only temp and pressure at which solid, liquid and vapour

coexist at equilibrium.

Phase Diagram for Single Compound

P

b

b'

c d

solid II

liquid

vapour

T solid

I

a T₁ T₂

T₁ is the transition temp for the forms I and II

Below T₁ I is the stable solid and II is metastable with respect to I.

Between T₁ and T₂ II is the stable solid and I is

metastable with respect to II.

P-T Diagram for Compound with

Enantiotropic Crystals

P

b' b

c d

solid II

liquid

vapour

T solid

I

a a’

d'

In this case solid II is

metastable at all temps with respect to I.

If this stable form obtained during chemical manufacture, few problems should be

encountered.

If the metastable form is obtained there is danger of reversion to stable form under certain conditions (i.e. during formulation or storage)

particularly in presence of solvents.

P-T Diagram for Compound with Monotropic

Crystals

Properties Affected by Polymorphism

 Colour of a dye

 Light stability

 Activity of a drug

 Power of an explosive

 Quality of food

- Graininess of margarine

- Blooming of chocolate

Polymorphism - Important in 3 Areas of Processing

 Solid handling

- Filtration - Washing

 Drying

 Reactivity and stability

- Stability to heat - penicillin G

- Stability to light - corticosteroids

Examples of Polymorphic Change During Formulation

 Phenylbutazone compression

 Methisathone grinding

 Sulphanilamide grinding

 Digoxin grinding

 Spironolactone grinding

 Oestradiol grinding

A.K. Jain, Indian Drugs, 1986, 23, 315

Recryst. Speed of Polymorph Crystallisation

Toluene slow or fast B

Chloroform slow A

fast B

Acetone slow or fast A

Ethanol slow or fast A

(in H₂O, 25°C) A m.p. 153-4°C

sol. 0,13 g·L^-1 B m.p. 150-3°C sol. 0.23 g·L^-1 Cl

Cl

O CO₂H

O S

Tienilic Acid (Selacryn)

Behaviour of Polymorph B when stirred in water at room and elevated temperatures

Time of stirring Polymorph Temperature

15 minutes B RT

5 hours B RT

7 hours A RT

1 hour A 90-100°C

Tienilic Acid (Selacryn)

Checking for Polymorphism

 Observation

 Melting point determination under a microscope

 Suspension/heating

 Change solvent of recrystallisation

 DSC

Characterization of Polymorphs

 Melting point

 DSC - TGA

 IR

 X-ray

 Solid state NMR

(investigating the need to set acceptance criteria for polymorphism) in drug substances or drug products

Drug substance

1.

Conduct polymorphism screen on drug substance

Can

different poly- morph be

formed?

NO FURTHER ACTION

Characterize the form:

e.g. - X-ray Powder Diffraction - DSC / Thermo analysis - Microscopy

- Spectroscopy

Yes

No

GO TO 2

Decision Tree

Can

different poly- morph be

formed?

Yes

Can

different poly- morph be

formed?

Set acceptance criterion for polymorph

content in drug substance GO TO 2

NO FURTHER TEST OR ACCEPTANCE CRITERION FOR DRUG

SUBTANCE

No

No 2.

Decision Tree (2)

H.G. Brittain, K.R. Morris, D.E.

Bugay, A.B. Thakur, A.T.M. Serajuddin J. Biom. Pharm. Anal. 1993, 11, 1063

P N

O O

O

O o

COO Na

1

2 3

5 4 6 7 8

9 10

11 18 19 20

21

22 23

24 25

S

15

16 17 12

13 14 14

Diffuse reflectance mid-IR spectra

Polymorph of Fosinopril Sodium IR-Spectra

Polymorph of Fosinopril Sodium Powder X-

Ray Diffraction Patterns

35P-NMR spectra ¹³C CP/MAS NMR spectra

Polymorph of Fosinopril Sodium

P- and

13

C-NMR Spectra

NO₂

Zn dust NH₄Cl/H₂O

65°C

Pyridine/ 0°C Acetyl Chloride

NaOMe MeOH25-30°C

NaOMe/MeOH + DMF (55°C)

NHOH N

N

N N

OAc Ac

Ac OH

Cl NHCOCH₃

N

NH

O By-products: 2 ortho isomers

Synthesis of 94120

Interconversion of Forms

NHCOCH₃

N

NH O

H⁺, pH = 6

Hydrate B

Water slurry Hydrate A

Water slurry

> 85 °C Polymorph I

∆

Polymorph II Pseudomorph

∆

∆

Temperature (°C)

mcal/sec

WT 2.92 mg

SSCAN RATE 10.00 °/min Max 288.03

Min 286.35

Min 291.48

210 230 250 270 290 310

0.00 0.50 1.00 1.50 2.00 2.50 3.00 3.50 4.00 4.50 5.00

DSC Analysis

Temperature (°C)

mcal/sec

WT 4.70 mg

SSCAN RATE 10.00 °/min

Min 291.4

210 230 250 270 290 310

0.00 0.50 1.00 1.50 2.00 2.50 3.00 3.50 4.00 4.50 5.00

mcal/sec

WT 2.61 mg

SSCAN RATE 10.00 °/min

Min 290.134

210 230 250 270 290 310

0.00 1.00 2.00 3.00 4.00 5.00 6.00 7.00 8.00

DSC Analysis

0.00 0.50 1.00 1.50 2.00

Temperature (°C)

mcal/sec

Min 291.679

30 80 130 180 230 280 330

Min 284.826

Min 100.267 WT 2.35 mg

SSCAN RATE 10.00 °/min

Temperature (°C)

mcal/sec

WT 2.09 mg

SSCAN RATE 10.00 °/min

Min 275.995

0.00 0.20 0.40 0.60 0.80 1.00 1.20 1.40 1.60 1.80 2.00

80 130 180 230 280 330

Min 106.038

Max 171.6

DSC Analysis

G.B. Woodward J. Appl. Cryst. 1975, 8, 2.

“The seeds of crystallisation, as dust, are carried upon the winds, from end to end of the earth”

EXAMPLES:

Ampicillin

Ethylenediamine tartrate D-Galacto-α-lactone

Xilitol

β-D-Mannose Turanose

10-Methylbenzochrysene Pentaerythritol