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TRANSCRIPT
Co-‐crystals, Salts and Polymorph screening of
o-‐Desmethyl Venlafaxine and other APIs
6th PCL WORKSHOP Bologna 19-‐21 January 2012
Polymorphism -‐ in pharmaceu2cal industry -‐ Ed. by R. Hilfiker (2006)
ACTIVE MOLECULE
M
M M
M M M
M
M
M
M
M
M
M
POLYMORPHS
M M
AMORPHOUS
POLYMORPHISM
S S O L V E N T MOLECULE
S M
M
M
M
S
M M
SOLVATE S
50 solvents are usually used, chosen on the basis of their:
§ Dielectric constants
§ Boiling point
§ Solubility
THE CHOICE OF SOLVENT
1 Cyclohexane (1.4), mesitylene (8.3), cis-‐decalin (10.5), p-‐xylene (14.7), m-‐xylene (15.9), carbon tetrachloride (28.0), toluene (34.1), n-‐pentane (54.7), n-‐hexane (55.5), n-‐heptane (55.7), n-‐octane (60.3), tetrachloroethene (60.7), benzene (61.7), n-‐decane (69.1), n-‐dodecane (70.5), carbon disulfide 147.0)
2 Butylamine (27.8), diethyl ether (38.9), methyl terGary-‐butyl ether (43.2), triethylamine (64.5), diisopropyl ether (81.1), dibutylether (96.1), 1,4-‐dioxane (103.8)
3
Tetrahydrofuran (5.1), chloroform (5.8), anisole (7.7), o-‐dichlorobenzene (10.5), ethyl formate (11.6), trichloroethene (12.3), methyl benzoate (12.3), iodobenzene (12.6), chlorobenzene (13.2), methyl ethanoate (18.7), dimethyl disulfide 20.1), 1,1-‐dichloroethane (22.2), fluorobenzene (28.8), ethyl phenyl ether (32.3), ethyl acetate (34.7), 1,2-‐dichloroethane (34.8), 1,2-‐dibromoethane (43.2), 1-‐iodobutane (51.2), 1,1,1-‐trichloroethane (59.1), propyl ethanoate (61.5), diethyl sulfide (63.8), dichloromethane (66.4), butyl ethanoate (77.4), methyl methanoate (79.0), bromoform (95.4), dibromomethane (103.8)
4 2-‐methyl-‐1-‐propanol (6.4), 2-‐butanol (11.4), m-‐cresol (17.0), 2-‐methoxyethanol (19.0), 1-‐butanol (19.8), propanoic acid (28.8), morpholine (34.0), 2-‐methyl-‐2-‐propanol (38.1), 1-‐pentanol (39.4), pentanoic acid (45.3), aceGc acid (56.4), 2-‐propanol (63.2), 1-‐ propanol (94.1), 1-‐octanol (144.9), ethanol (192.7)
5 Butanone (9.0), 2,4-‐dimethylpyridine (10.0), acetophenone (17.3), 2,6-‐dimethylpyridine (20.4), 3-‐pentanone (27.6), 2-‐pentanone (31.4), 4-‐methylpyridine (39.4), acetone (42.9), cyclohexanone (45.4), 2-‐hexanone (46.1), cyclopentanone (62.2), 2-‐heptanone (66.3), 4-‐methyl-‐2-‐pentanone (68.1), pyridine (85.0)
6 N-‐methyl-‐2-‐pyrrolidone (21.0), N,N-‐dimethylformamide (35.1), N,N-‐dimethylacetamide (59.1), dimethylsulfoxide (74.7)
7 Benzonitrile (38.7), propanenitrile (46.3), acetonitrile (61.3), butanenitrile (103.8), nitromethane (125.6)
8 Aniline (13.3), benzyl alcohol (13.3)
9 Formic acid
10 Ethylene glycol
11 Methanol
12 Diethylamine
13 Diiodomethane
14 Glycerol
15 Water
• EVAPORATION
a. Evapora2on at ambient pressure (Low T – Room T – High T)
b. Evapora2on at low pressure (Room T – High T)
• PRECIPITATION
a. An2-‐solvent precipita2ons
b. Super-‐satured solu2ons
• SLURRY
a. Aqueous solvents to iden2fy the most stable hydrate form and the possible forma2on of more
stable hydrated forms
b. Non-‐aqueous solvents (to iden2fy the most stable anhydrous form)
POLYMORPH SCREENING
C O F O R M E R MOLECULE
C
CM
CM
CM
S A L T / C O -‐CRYSTAL
Handbook of Pharmaceu2cal Salts: Proper2es, Selec2on, and Use (Eds.: P. H. Stahl, C. G. Wermuth), Wiley VCH, Weinheim, 2008
ACTIVE MOLECULE
M
SALTS/ CO-‐CRYSTALS
• Polymorphism problems can be circumvented;
• Amorphous material may be turned into a crystalline salt;
• Taste and smell problems can be minimized;
• The melGng point can be raised to improve mechanical properGes;
• A drug substance can be purified;
• AdsorpGon rate can be controlled: retardaGon of gastrointesGnal adsorpGon by salts with low solubility/low dissoluGon rate;
• Two pharmacological principles can be combined.
ADVANTAGES:
SALT/CO-‐CRYSTAL SCREENING
CrystallizaJon by soluJon Grinding/Kneading Solid – Gas ReacJon
Solid
API Coformer (Solid or liquid)
Salt/Co-‐crystal
CO-‐CRYSTAL VS. MOLECULAR SALT
Paracetamol 4,4’-‐ bipyridine adduct
Glycine HCl
SALT/CO-‐CRYSTAL SCREENING
Adenine
Ascorbic Acid
Folic Acid
NicoJnic Acid
C
B9
B3
ACIDS AceGc Acid (d=1.05)
Adipic Acid L-‐AsparGc Acid Citric Acid
Formic Acid (99%, d=1,22) Fumaric Acid
L-‐Glutamic Acid Glycolic Acid Hippuric Acid
Hydrochloric acid (0.1 N) Maleic Acid L-‐Malic Acid Malonic Acid
DL-‐Mandelic Acid Methanesulfonic Ac (d=1,48)
Oxalic Acid Phosphoric
Acid(M=14,65;d=1,689) Salicylic Acid Sebacic Acid Succinic Acid L-‐Tartaric Acid Glutaric Acid Cinnamic Acid
BASES Adenine L-‐Arginine
Calcium Hydroxide N-‐methyl-‐Glucamine
Imidazole L-‐Lysine
Magnesium Hydroxide Piperazine
Potassium Hydroxide Sodium Hydroxide (0,1 N)
Triethanolamine (85% d=1,124) NH3 (d=0,9)
Diethanolamine(d=1) Diethylamine(d=0,704)
Morpholine (d=1) Pyrrolidine (d=0,86)
VITAMINS
PharmaceuGcal Salts Handbook P.Heinrich Stahl, Camille G. Wermuth (Eds.) WILEY-‐VCH, 2008
Nalidixic Acid O-‐Desmethylvenlafaxine
Lidocaine Sulfadiazine
INTERESTING PHARMACEUTICAL MOLECULES
O-‐DESMETHYLVENLAFAXINE
• SyntheGc form of the major acGve metabolite
of venlafaxine
• A selecGve serotonin and norepinephrine
reuptake inhibitor useful for the treatment of
depression O-‐desmethylvenlafaxine
Salt Screening
US 2008/0015259 A1
Fumarate (US 4,535,186)
Succinate (Pris2q-‐Pfizer US 7,291,347)
O-‐DESMETHYLVENLAFAXINE (ODV) SALT SCREENING
Acids List Bases List L-‐LacGc Acid Diethylamine
Fumaric Acid Diethanolamine
Succinic Acid Imidazole
L-‐Maleic Acid Morfoline
Hippuric Acid Piperazine
Malonic Acid Triethanolamine
Mandelic Acid 2-‐(diethylamino)-‐Ethanol
NicoGnic Acid L-‐Lysine
OroGc Acid Pyrrolidine
Oxalic Acid L-‐Arginine
Piroglutammico
Salicilic Acid
L-‐Tartaric Acid
Adipic Acid
Suberic Acid
Sebacic Acid
Pimelic Acid
ODV-‐OXALATE
Known ODV salts
NEW ODV salt
O-‐DESMETHYLVENLAFAXINE OXALATE SALT
Position [∞2Theta] (Copper (Cu))
10 20 30
Counts
0
400
1600
3600
6400
PCL01_OX Form A
FORM A 2
O-‐DESMETHYLVENLAFAXINE OXALATE SALT: POLYMORPH SCREENING
Form F
Solvent EvaporaJon LT EvaporaJon RT EvaporaJon HT
1,4-‐Dioxane Mix-‐Form A/C Mix-‐Form A/C Viscous liquid
Acetonitrile Mix-‐Form A/C Mix-‐Form A/C Form C
Acetone Mix-‐Form A/C Mix-‐Form A/C
Ethyl Acetate Mix-‐Form A/C Mix-‐Form A/C
Water Form D Mix-‐Form A/C Amorphous
Nitromethane Mix-‐Form A/C Mix-‐Form A/C Viscous liquid
1-‐Propanol Form C -‐ Viscous liquid
1,2-‐Dimethoxy Ethane -‐ -‐ Amorphous
Dichloromethane Form A Form A
Ethanol Form A Form A
Methanol Form A Form A
Solvent for Slurry EvaporaJon LT
Acetonitrile Form A
Acetone Form E
Di Ethyl Ether Form A
1-‐Propanol Form B
Form B (200°C ) then slowly cooled.
O-‐DESMETHYLVENLAFAXINE OXALATE SALT: FORM B
Position [∞2Theta] (Copper (Cu))
10 20 30
Counts
0
100
400
900
PCL01_OX Form B
1,5
O-‐DESMETHYLVENLAFAXINE OXALATE SALT: FORM C
Position [∞2Theta] (Copper (Cu))
10 20 30
Counts
0
400
1600
3600
6400
PCL01-OX Form C
2
O-‐DESMETHYLVENLAFAXINE OXALATE SALT: FORM D
Position [∞2Theta] (Cobalt (Co))
10 20 30 40
Counts
0
2500
10000 pcl01_ox_lt_b in P-1
2,5
O-‐DESMETHYLVENLAFAXINE OXALATE SALT: FORM E
Position [∞2Theta] (Copper (Cu))
10 20 30
Counts
0
400
1600
3600
6400
PCL01-OX-SL-ACT-100C
O-‐DESMETHYLVENLAFAXINE OXALATE SALT: FORM F
Position [∞2Theta] (Copper (Cu))
10 20 30
Counts
0
400
1600
3600
DEP001 Form B
FORM E
FORM B FORM B – 100 Deg
FORM A + C 40°C – 75%RH
RT (25°C – 40%RH)
FORM E + B
LT (4°C – 80%RH)
100°C
40°C – 75%RH
FORM D recrystallizaGon experiments
FORM F
200°C + cooling
O-‐DESMETHYLVENLAFAXINE OXALATE: STABILITY TESTS
FORM A FORM C
Colourless needles approximate dimensions: 0.2 x 0.2 x 0.3 mm Triclinic system with cell parameter a = 9.4342(6) Å b = 13.0621(9) Å c= 18.0686(12) Å α = 109.701(6) deg. β = 96.728(5) deg. γ = 99.120(5) deg. V = 2034.62 Å3 space group P-‐1.
O-‐DESMETHYLVENLAFAXINE OXALATE SALT: FORM D SINGLE CRYSTAL
CalibraGon eqn Abs = 1002.4*Conc R2 0.99189
CalibraGon of ODV_OX (Form A) CalibraGon of ODV_SUCC (Form B)
CalibraGon eqn Abs = 1141.4*Conc
R2 0.99638
Salt DissoluGon Rate Abs/min
ODV-‐SUCC 0.0049 ODV-‐OXA Form A 0.0053 ODV-‐OXA Form B 0.0083 ODV-‐OXA Form C 0.0110
KINETIC DISSOLUTION TESTS
THERMODINAMIC DISSOLUTION TESTS
Salt Abs/min Thermodynamic Solubility (g/L)
ODV-‐SUCC
1.00
70
ODV-‐OXA
1.31
142
The samples were suspended in a sodium chloride soluGon 0.9%.
SGrred at 500 rpm for 24 h at 37°C.
Then filtered, diluted and analyzed by UV.
WO 2009/155488 A2
• ODV oxalate (Form A) and other five different crystal forms (Form B, C, D, E and F). • TGA : four polymorphs are hydrates and two (Form E and Form F) are anhydrous. • The stability tests (40°C and 75%RH): Forms A, C, and D are stable. • A significant increase in solubility for the ODV-‐OX (142 g/L) compared with the ODV-‐SUCC (70 g/L).
O-‐DESMETHYLVENLAFAXINE-‐OXALATE SALT: CONCLUSIONS
Nalidixic Acid
Lidocaine Sulfadiazine
OTHER INTERESTING PHARMACEUTICAL MOLECULES
• SyntheGc quinolone anGbioGc, anGbacterial agent
• Used for urinary tract infecGons
• One crystal form of API was found in the CSD (FORM I) Nalidixic Acid
NALIDIXIC ACID
Polymorph Screening
NAL-‐FORM I
EvaporaGon RT Acetone
NAL-‐FORM II
Sigma Aldrich
NAL-‐FORM III
EvaporaGon RT Dichloromethane
NALIDIXIC ACID -‐ DIETHANOLAMINE
NALIDIXIC ACID -‐ PYRROLIDINE
NALIDIXIC ACID: SALT/CO-‐CRYSTAL SCREENING WITH BASES
NALIDIXIC ACID SCREENING: CONCLUSION
• A new crystal form of Nalidixic Acid was obtained and
characterized: NAL-‐Form III (by recrystallizaJon from
dichloromethane).
• Two new SALTS were obtained: with diethanolamine
and with pyrrolidine.
Nalidixic Acid
SULFADIAZINE
• SyntheGc sulfonamide anGbioGcs
• Used in treaGng urinary tract infecGon
• One crystal form of API was found in the CSD (FORM
I) Sulfadiazine (Sulfa)
• EvaporaGon experiments: Form I • Slurry experiments: Form I
Polymorph Screening
SULFADIAZINE: SALT/CO-‐CRYSTAL SCREENING WITH ACIDS
Sulfa
Salt
Salt
Salt Co-‐crystal
HCl
Methanesulfonic acid
Formic Acid
H3PO4
SULFADIAZINE: SALT/CO-‐CRYSTAL SCREENING WITH BASES
Salt
Salt
KOH
Pyrrolidine
Salt
NaOH
Sulfa
SULFADIAZINE SCREENING: CONCLUSION
A Co-‐crystal was obtained:
• SULFA-‐FORMIC ACID
Six Salts were obtained:
• SULFA-‐HCL
• SULFA-‐PYRROLIDINE
• SULFA-‐METHANSULFONIC ACID
• SULFA-‐KOH
• SULFA-‐H3PO4
• SULFA-‐NaOH
Sulfadiazine
LIDOCAINE
• The first amino amide-‐type local anestheGc.
• Typically used to relieve itching, burning and pain from skin
inflammaGons, injected as a dental anestheGc or as a local
anestheGc for minor surgery.
• Used intravenously for the treatment of ventricular arhytmias.
• One crystal form of API was found in the CSD (FORM I).
• One HCl salt of API was found in the CSD.
• EvaporaGon experiments: Form I • Slurry experiments: Form I
Polymorph Screening
5 10 15 20 25 30 35 402Theta (°)
0
400
1600
3600
6400
10000In
tens
ity (c
ount
s)
FUMARIC ACID
LIDOCAINE: SALT/CO-‐CRYSTAL SCREENING WITH ACIDS
5 10 15 20 25 30 35 402Theta (°)
0
400
1600
3600
6400
10000
Inte
nsity
(cou
nts)
OXALIC ACID
MALONIC ACID
SUCCINIC ACID
LIDOCAINE SCREENING: CONCLUSION
Two Salts were obtained:
• LIDOCAINE-‐FUMARIC ACID
• LIDOCAINE-‐OXALIC ACID
Two Co-‐crystal was obtained:
• LIDOCAINE-‐SUCCINIC ACID
• LIDOCAINE-‐MALONIC ACID
Lidocaine
CONCLUSIONS
ü A new salt of O-‐Desmethylvenlafax and another five crystal forms of it were discovered.
ü A new crystal form and two salts of Nalidixic Acid were discovered.
ü Six new salts and a co-‐crystal of Sulfadiazine were discovered.
ü Four new salts of Lidocaine were discovered.
Via F.S. Fabri, 127/1 – Medicina (BO) -‐Tel. +39 051 6970791 – Fax. +39 051 851847 E-‐mail: [email protected] Website: www.polycrystalline.it Via F.S. Fabri, 127/1 – Medicina (BO) -‐Tel. +39 051 6970791 – Fax. +39 051 851847
E-‐mail: [email protected] Website: www.polycrystalline.it
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