ES2552219T3 - Proceso para preparar bisulfato de atazanavir y nuevas formas - Google Patents

Proceso para preparar bisulfato de atazanavir y nuevas formas Download PDF

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Publication number
ES2552219T3
ES2552219T3 ES05744537.1T ES05744537T ES2552219T3 ES 2552219 T3 ES2552219 T3 ES 2552219T3 ES 05744537 T ES05744537 T ES 05744537T ES 2552219 T3 ES2552219 T3 ES 2552219T3
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time
atazanavir
crystals
atazanavir bisulfate
bisulfate
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Soojin Kim
Bruce T. Lotz
Mary F. Malley
Jack Z. Gougoutas
Martha Davidovich
Sushil K. Srivastava
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Bristol Myers Squibb Holdings Ireland ULC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
    • C07D213/127—Preparation from compounds containing pyridine rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/42—Radicals substituted by singly-bound nitrogen atoms having hetero atoms attached to the substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/56—Amides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
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  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
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  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Communicable Diseases (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • Oncology (AREA)
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  • AIDS & HIV (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Pyridine Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Medicines Containing Plant Substances (AREA)

Abstract

Un proceso para preparar bisulfato de atazanavir en la forma de cristales de Forma A, que comprende hacer reaccionar una solución de base libre de atazanavir en un disolvente orgánico, que es acetona o una mezcla de acetona y N-metilpirrolidona, con una primera porción de ácido sulfúrico concentrado en una cantidad para reaccionar con menos de aproximadamente el 15 % en peso de la base libre de atazanavir, agregar semillas de los cristales de Forma A de bisulfato de atazanavir a la mezcla de reacción, como cristales de forma de bisulfato de atazanavir, agregar ácido sulfúrico concentrado adicional en etapas múltiples a una velocidad incrementada de acuerdo con la siguiente ecuación**Fórmula** donde Vtiempo >= Volumen de ácido sulfúrico agregado durante el período de tiempo transcurrido Vtotal >= Volumen total de ácido que representa el 90 % de carga tiempo >= Tiempo transcurrido en la cristalización tiempototal >= Tiempo de cristalización total o tiempo total para cargado de ácido para efectuar la formación de cristales de bisulfato de atazanavir, y secar el bisulfato de atazanavir para formar los cristales de Forma A.

Description

imagen1
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imagen7
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imagen9
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Se adicionó el ácido sulfúrico restante (17,8 g) durante casi 5 h en cinco etapas de acuerdo con el siguiente protocolo, definido por una ecuación cúbica, mientras se mantiene la temperatura a 40-50 ºC.
La velocidad de cada etapa de adición se determinó de acuerdo con la ecuación cúbica descrita antes y se muestra en la tabla posterior.
TABLA 1
Etapa
ml/kg/h ml(H2SO4)/h g(H2SO4)/h Duración (min)
1
4,62 0,579 1,065 60
2
6,93 0,868 1,597 60
3
16,55 2,073 3,814 60
4
30,26 3,790 6,974 60
5
48,47 6,071 11,171 23
Después de que la adición de H2SO4 se completó, la mezcla se enfrió a 20-25 ºC por al menos 1 h con agitación. La
10 mezcla se agitó a 20-25 ºC por al menos 1h. La sal de bisulfato se filtró y el licor madre se recirculó cuando se necesitó para efectuar la transferencia completa. La torta de filtro se lavó con acetona (5-10 ml/g de base libre; 1200 ml de acetona). La sal de bisulfato se secó en NMT 55 ºC bajo vacío hasta el LOD <1 % para producir un material cristalino.
15 El producto cristalino se analizó por configuraciones de DRXP, CED y AGT y espectro de RMNES y se encontró que son cristales de Forma A (no solvatados) del bisulfato del título (véase Figuras 1 a 5).
TABLA 2
Tabla de Datos Cristalográficos Forma A
T ºC
a(Å) b(Å) c(Å) αº βº γº V(Å3) Z' sg dcalc R
+22
9,861(5) 29,245(6) 8,327(2) 93,56(2) 114,77(3) 80,49(3) 2150(2) 2 P1 1,240 0,06
T = temp ( ºC) para los datos cristalográficos. Z' = número de moléculas de fármaco por unidad asimétrica
20 TABLA 3
Tabla de Parámetros Fraccionales y Sus Desviaciones Estándar Estimadas para la Forma A
Átomo
x y z B(A2)
S1
0,3230(4) 0,5467(1) 0,5608(5) 8,0(1)
O100
0,431(1) 0,5060(3) 0,649(1) 11,1(3)
O102
0,335(1) 0,5498(4) 0,383(1) 12,0(4)
O103
0,360(1) 0,5877(4) 0,655(2) 12,0(4)
O104
0,176(1) 0,5384(4) 0,528(1) 11,8(4)
S51
0,6177(4) 0,4505(1) 0,4003(5) 7,2(1)
O150
0,596(1) 0,4430(4) 0,564(1) 12,5(4)
O152
0,518(1) 0,4921(4) 0,317(1) 13,8(4)
O153
0,588(1) 0,4121(3) 0,289(2) 12,2(4)
O154
0,768(1) 0,4587(4) 0,454(1) 12,1(4)
O4
0,6985(7) 0,1753(3) 0,6456(9) 5,7(2)
O7
0,1687(8) 0,1941(3) 0,3411(9) 6,5(2)
O11
-0,0352(7) 0,2482(3) 0,0308(8) 5,7(2)
O14
0,2280(7) 0,1769(3) -0,233(1) 6,1(2)
O15
0,0399(8) 0,1335(3) -0,330(1) 6,4(2)
O17
0,6169(7) 0,2821(3) 0,963(1) 7,1(2)
O18
0,3750(7) 0,2905(3) 0,9136(9) 6,2(2)
N2
0,5015(9) 0,2182(3) 0,902(1) 4,5(2)
N5
0,4642(8) 0,1647(3) 0,6001(9) 4,2(2)
N9
0,2317(9) 0,2788(3) 0,256(1) 5,1(2)
N10
0,1820(9) 0,2760(3) 0,069(1) 4,6(2)
N13
-0,0148(8) 0,2083(3) -0,280(1) 4,6(2)
N39
-0,087(1) 0,5265(3) 0,272(1) 6,1(3)
C1
0,491(1) 0,2627(4) 0,924(1) 5,5(3)
C3
0,6381(9) 0,1908(3) 0,892(1) 4,0(2)
C4
0,600(1) 0,1764(4) 0,702(1) 4,6(3)
C6
0,420(1) 0,1551(4) 0,403(1) 5,1(3)
C7
0,295(1) 0,1936(4) 0,297(1) 5,1(3)
C8
0,357(1) 0,2400(4) 0,346(2) 5,4(3)
C11
0,051(1) 0,2592(4) -0,028(1) 4,9(3)
16
C12
0,024(1) 0,2531(4) -0,223(1) 4,5(3)
C14
0,094(1) 0,1732(4) -0,280(1) 4,7(3)
C16
0,146(2) 0,0943(5) -0,342(2) 10,9(5)
C19
0,616(1) 0,3313(4) 0,996(2) 8,1(4)
C20
0,701(1) 0,1485(4) 1,025(1) 5,8(3)
C21
0,842(1) 0,1219(5) 1,007(2) 7,9(4)
C22
0,583(2) 0,1160(5) 0,997(2) 8,0(4)
C23
0,748(2) 0,1713(5) 1,215(1) 8,2(4)
C24
0,365(1) 0,1079(4) 0,356(2) 6,6(4)
C25
0,484(1) 0,0691(4) 0,470(1) 6,5(3)
C26
0,643(2) 0,0684(5) 0,520(2) 8,4(5)
C27
0,753(2) 0,0293(6) 0,622(2) 11,4(6)
C28
0,709(3) -0,0044(7) 0,691(3) 15,0(9)
C29
0,553(2) -0,0032(5) 0,644(2) 14,2(7)
C30
0,441(2) 0,0343(5) 0,534(2) 10,8(4)
C31
0,291(1) 0,3229(4) 0,311(2) 5,7(3)
C32
0,177(1) 0,3650(4) 0,259(1) 5,4(3)
C33
0,224(1) 0,4064(4) 0,262(2) 6,3(3)
C34
0,122(1) 0,4487(5) 0,233(2) 6,9(4)
C35
-0,031(1) 0,4469(4) 0,189(1) 4,8(3)
C36
-0,081(1) 0,4043(4) 0,180(1) 5,6(3)
C37
0,019(1) 0,3629(4) 0,218(1) 5,4(3)
C38
-0,136(1) 0,4918(4) 0,170(1) 5,3(3)
C40
-0,170(1) 0,5683(4) 0,279(2) 7,8(4)
C41
-0,318(2) 0,5736(5) 0,158(2) 9,1(5)
C42
-0,376(2) 0,5403(5) 0,035(2) 9,0(5)
C43
-0,283(1) 0,4964(5) 0,039(2) 8,1(4)
C44
-0,096(1) 0,2937(4) -0,345(1) 6,2(3)
C45
-0,258(1) 0,2901(5) -0,366(2) 8,5(4)
C46
-0,085(2) 0,2890(6) -0,530(2) 10,8(5)
C47
-0,057(2) 0,3393(5) -0,265(2) 8,9(5)
O54
0,2347(7) 0,8167(3) 0,8392(8) 5,3(2)
O57
0,7713(8) 0,7950(3) 1,0561(9) 5,9(2)
O61
0,9725(7) 0,7436(3) 0,9141(8) 5,3(2)
O64
0,7062(7) 0,8164(3) 0,427(1) 5,9(2)
O65
0,8911(8) 0,8598(2) 0,535(1) 6,1(2)
O67
0,3150(8) 0,7090(3) 1,184(1) 6,4(2)
O68
0,5587(9) 0,6986(3) 1,377(1) 6,6(2)
N52
0,4313(9) 0,7713(3) 1,271(1) 4,9(2)
N55
0,4709(8) 0,8265(3) 1,0332(9) 4,2(2)
N60
0,7555(8) 0,7179(3) 0,728(1) 4,6(2)
N63
0,9491(8) 0,7852(3) 0,601(1) 4,4(2)
N89
1,026(1) 0,4719(3) 0,711(1) 6,0(3)
C51
0,442(1) 0,7247(4) 1,282(1) 5,4(3)
C53
0,296(1) 0,7996(4) 1,141(1) 5,1(3)
C54
0,3347(9) 0,8159(3) 0,989(1) 4,1(3)
C56
0,519(1) 0,8353(4) 0,887(1) 4,7(3)
C57
0,644(1) 0,7959(4) 0,886(1) 4,5(3)
C58
0,587(1) 0,7494(4) 0,854(1) 5,2(3)
C61
0,884(1) 0,7334(4) 0,766(1) 4,2(3)
C62
0,914(1) 0,7392(4) 0,603(1) 4,4(3)
C64
0,839(1) 0,8196(4) 0,513(1) 4,6(3)
C66
0,785(2) 0,8996(5) 0,433(3) 12,1(7)
C69
0,323(1) 0,6588(4) 1,202(2) 8,8(5)
C70
0,237(1) 0,8409(4) 1,232(1) 5,6(3)
C71
0,092(1) 0,8701(5) 1,080(2) 7,6(4)
C72
0,352(1) 0,8744(4) 1,328(2) 7,1(4)
C73
0,187(1) 0,8195(6) 1,362(1) 8,9(4)
C74
0,570(1) 0,8825(4) 0,907(2) 6,4(3)
C75
0,450(1) 0,9206(4) 0,919(1) 6,3(3)
C76
0,296(2) 0,9236(5) 0,813(2) 8,1(4)
C77
0,188(2) 0,9614(6) 0,826(2) 11,2(5)
C78
0,244(2) 0,9942(6) 0,960(2) 15,2(7)
17
imagen15
imagen16
producto fue 47,7 g (0,0594 mol, 74,3 % mol) de Forma E3 de bisulfato de atazanavir (solvato de trietanol) con CLAR HI = 100,0 (véase Figuras 9 y 10).
TABLA 5
Tabla de Datos Cristalográficos Forma E3
T ºC
a(Å) b(Å) c(Å) αº βº γº V(Å3) Z' sg dcalc R
-23
10,749(5) 13,450(4) 9,250(2) 98,33(2) 95,92(3) 102,82(3) 1277(2) 1 P1 1,223 0,06
T = temp ( ºC) para los datos cristalográficos. Z' = número de moléculas de fármaco por unidad asimétrica
TABLA 6
Tabla de Parámetros Fraccionales y Sus Desviaciones Estándar Estimadas para la Forma E3
Átomo
x y z B(A2) Ocupancia si no es igual a 1
S99
0,5568(1) 0,0760(1) 0,5936(1) 3,45(2)
O1
0,4200(5) 0,5541(4) 0,8496(5) 6,9(1)
O2
0,2889(5) 0,6016(4) 1,0066(6) 8,1(1)
O4
0,7004(4) 0,4509(3) 1,0233(4) 4,23(8)
O8
0,2913(4) 0,2932(3) 1,1074(4) 4,23(8)
O12
0,1057(4) 0,1088(3) 0,9299(4) 4,16(8)
O15'
0,329(1) -0,0602(9) 1,064(1) 4,8(3)* 0,3
O15"
0,324(2) -0,156(1) 1,003(2) 3,2(3)* 0,17
O15
0,3312(7) -0,1150(6) 1,0380(8) 4,9(1)* 0,53
O16
0,1810(5) -0,1433(3) 1,1819(4) 5,7(1)
O86
0,391(1) 0,6646(7) 0,6196(9) 11,5(4)
O89
0,3714(7) 0,5646(5) 0,3408(6) 6,5(2)
O90
0,7502(4) 0,2721(3) 0,8957(5) 4,99(9)
O95
0,4984(4) 0,0446(3) 0,7188(4) 4,50(8)
O96
0,6644(4) 0,0315(3) 0,5660(4) 4,83(8)
O97
0,4651(4) 0,0667(3) 0,4636(4) 5,08(9)
O98
0,6112(5) 0,1957(3) 0,6332(5) 5,9(1)
N2
0,4938(5) 0,6229(3) 1,0921(5) 4,8(1)
N5
0,5365(4) 0,4385(3) 1,1609(4) 3,16(8)
N10
0,2952(4) 0,2239(3) 0,8056(4) 3,17(8)
N11
0,2716(4) 0,1163(3) 0,7961(4) 3,08(8)
N14
0,1336(5) -0,0874(4) 0,9743(5) 4,9(1)
N38
-0,2764(4) 0,0574(3) 0,2878(4) 3,24(8)
C1
0,4011(6) 0,5893(4) 0,9712(7) 5,3(1)
C3
0,6225(5) 0,6026(4) 1,0813(5) 3,9(1)
C4
0,6231(5) 0,4896(3) 1,0873(5) 3,19(9)
C6
0,5220(5) 0,3284(3) 1,1691(5) 3,14(9)
C8
0,4026(5) 0,2632(3) 1,0653(5) 3,21(9)
C9
0,4165(5) 0,2747(4) 0,9050(5) 3,6(1)
C12
0,1740(5) 0,0661(4) 0,8596(5) 3,4(1)
C13
0,1592(5) -0,0523(4) 0,8367(5) 3,8(1)
C15
0,2248(6) -0,1124(5) 1,0627(6) 4,6(1)
C17
0,2720(9) -0,1732(6) 1,2842(7) 7,3(2)
C18
0,1818(9) 0,5715(9) 0,894(1) 11,2(3)
C19
0,7292(7) 0,6818(4) 1,1928(7) 5,8(2)
C20
0,725(1) 0,7914(6) 1,169(1) 10,7(3)
C21
0,8613(9) 0,6645(8) 1,165(1) 10,5(3)
C22
0,710(1) 0,6694(7) 1,3507(8) 10,2(3)
C23
0,5158(5) 0,3135(4) 1,3298(5) 3,8(1)
C24
0,6305(6) 0,3765(4) 1,4359(5) 4,0(1)
C25
0,7519(7) 0,3708(6) 1,4192(7) 6,1(2)
C26
0,8581(7) 0,4279(7) 1,5213(9) 7,9(2)
C27
0,8398(8) 0,4935(6) 1,6375(8) 8,6(2)
C28
0,715(1) 0,5002(6) 1,6576(7) 8,0(2)
C29
0,6112(8) 0,4430(5) 1,5589(6) 6,0(2)
C30
0,3043(5) 0,2519(4) 0,6582(5) 3,6(1)
C31
0,1813(5) 0,2051(4) 0,5532(5) 3,4(1)
C32
0,0645(5) 0,2123(4) 0,5934(5) 3,9(1)
C33
-0,0489(5) 0,1725(4) 0,4957(5) 3,8(1)
20
C34
-0,0441(5) 0,1243(4) 0,3503(5) 3,16(9)
C35
0,0756(5) 0,1176(4) 0,3097(5) 3,9(1)
C36
0,1867(5) 0,1568(4) 0,4095(5) 3,9(1)
C37
-0,1615(5) 0,0853(4) 0,2417(4) 3,11(9)
C39
-0,3885(5) 0,0247(4) 0,1969(5) 3,9(1)
C40
-0,3891(5) 0,0200(4) 0,0470(5) 4,2(1)
C41
-0,2737(6) 0,0469(4) -0,0057(5) 4,1(1)
C42
-0,1596(5) 0,0781(4) 0,0890(5) 3,7(1)
C43
0,0488(6) -0,1114(4) 0,7094(6) 4,6(1)
C44
-0,0819(7) -0,0958(6) 0,7378(9) 6,8(2)
C45
0,0496(9) -0,2266(5) 0,6929(9) 7,8(2)
C46
0,0797(8) -0,0738(5) 0,5667(7) 6,2(2)
C84
0,569(1) 0,7880(9) 0,725(1) 6,3(3)
C85
0,448(1) 0,7726(9) 0,673(2) 8,4(4)
C87
0,204(1) 0,449(1) 0,405(2) 10,6(4)
C88
0,240(1) 0,517(1) 0,316(1) 8,6(3)
C91
0,8826(7) 0,2919(5) 0,8896(8) 5,8(2)
C92
0,9613(7) 0,3439(6) 1,035(1) 7,8(2)
H381
-0,275 0,053 0,403 3,2
H891
0,397 0,602 0,446 6,6
H981
0,658 0,219 0,717 6,6
La mayoría de los hidrógenos se ha omitido; solamente los hidrógenos en N9 y el ácido se incluyen.
Los átomos anisotrópicamente refinados se dan en la forma de parámetro de desplazamiento equivalente isotrópico 5 definido como: (4/3)*[a2*B(1,1) + b2*B(2,2) + c2*B(3,3) + ab(cos gamma)*B(1,2)x + ac(cos beta)*B(1,3) + bc(cos alfa)*B(2,3)].
La Forma E3 se caracteriza por el termograma de calorimetría de exploración diferencial que tiene una endoterma normalmente dentro del intervalo de aproximadamente 89,4 ºC a aproximadamente 96,6 como se muestra en la 10 Figura 11.
La Forma E3 también se caracteriza por una curva de análisis gravimétrico térmico que tiene una pérdida de peso desde aproximadamente 14,7 % a aproximadamente 150 ºC como se muestra en la Figura 11.
15 EJEMPLO 4
Se prepararon formulaciones de cápsula de Configuración C de bisulfato de atazanavir que tienen las siguientes composiciones como se describe posteriormente.
Ingrediente
Granulación Basea ( % p/p) Cápsula de 50 mg (mg/Cápsula) Cápsula de 100 mg (mg/Cápsula) Cápsula de 200 mg (mg/Cápsula)
Bisulfato de atazanavir
63,2 56,84b 113,67b 227,34b
Lactosa, Monohidrato, NF
30,4 27,33c 54,69c 109,35c
Crospovidona, NF
6,0 5,39 10,79 21,58
Estearato de Magnesio, NF
0,4 0,36d 0,72d 1,44d
Agua Purificada, USP o Agua para Inyección, USP
c.s.e c.s.e c.s.e c.s.e
Cápsula Tamaño #4
- 1 cada una - -
Cápsula Tamaño #2
- - 1 cada una -
Cápsula Tamaño #0
- - - 1 cada una
Peso de Relleno Total
100,0 89,9 179,9 359,7
a La Granulación Base de bisulfato de atazanavir para cápsulas (55,5 % p/p como la Base Libre) se utilizó para manufacturar las cápsulas de 50 mg, 100 mg y 200 mg. b Esta cantidad se expresa en los términos de bisulfato de atazanavir a 100 % de potencia, y es igual a 55,5 % p/p como la Base Libre. C La cantidad de lactosa, hidratada variará dependiendo de la pureza de bisulfato de atazanavir y la cantidad de estearato de magnesio usada. d La cantidad de estearato de magnesio usada puede variar desde 0,4 % p/p a 0,8 % p/p. e Esto se usa solamente para procesamiento y se remueve por secado.
La granulación base de bisulfato de atazanavir se preparó como sigue, en la cual el material de Configuración C se formó.
21
imagen17

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