ES2637113T3 - Procedimientos para preparar isoquinolinonas y formas sólidas de isoquinolinonas - Google Patents

Procedimientos para preparar isoquinolinonas y formas sólidas de isoquinolinonas Download PDF

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ES2637113T3
ES2637113T3 ES12734039.6T ES12734039T ES2637113T3 ES 2637113 T3 ES2637113 T3 ES 2637113T3 ES 12734039 T ES12734039 T ES 12734039T ES 2637113 T3 ES2637113 T3 ES 2637113T3
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peak
polymorph
integral
normalized
dimethylaminoethyl
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Pingda Ren
Michael Martin
Paul Isbester
Benjamin S. Lane
Jason KROPP
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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    • A—HUMAN NECESSITIES
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    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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Abstract

Polimorfo de un compuesto de fórmula (I):**Fórmula** en el que dicho polimorfo es la "forma C" de polimorfo, que tiene los siguientes picos de XRPD característicos: 2θ >= 10,4º (+- 0,2º), 13,3º (+- 0,2º) y 24,3º (+- 0,2º).

Description

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DESCRIPCION
Procedimientos para preparar isoquinolinonas y formas solidas de isoquinolinonas Descripcion
La actividad de las celulas puede regularse mediante senales externas que estimulan o inhiben acontecimientos intracelulares. El proceso mediante el cual las senales estimuladoras o inhibidoras se transmiten al interior o dentro de una celula para provocar una respuesta intracelular se denomina transduccion de senales. A lo largo de las ultimas decadas, se han esclarecido las cascadas de los acontecimientos de transduccion de senales y se ha encontrado que desempenan un papel crucial en una variedad de respuestas biologicas. Se ha encontrado que los defectos en diversos componentes de las rutas de transduccion de senales son responsables de un gran numero de enfermedades, que incluyen numerosas formas de cancer, trastornos inflamatorios, trastornos metabolicos, enfermedades vasculares y neuronales (Gaestel et al. Current Medicinal Chemistry (2007) 14:2214-2234).
Las cinasas representan una clase de importantes moleculas de senalizacion. Las cinasas pueden clasificarse en general en protema cinasas y en lfpido cinasas, y ciertas cinasas presentan especificidades dobles. Las protema cinasas son enzimas que fosforilan a otras protemas y/o a sf mismas (es decir, autofosforilacion). Las protema cinasas pueden clasificarse en general en tres grupos principales basados en la utilizacion de sus sustratos: tirosina cinasas, que fosforilan de forma predominante sustratos en los residuos de tirosina (por ejemplo, erb2, receptor de PDGF, receptor de EGF, receptor de VEGF, src, abl, serina/treonina cinasas, que fosforilan de forma predominante sustratos en residuos de serina y/o treonina (por ejemplo, mTorCI, mTorC2, ATM, ATR, ADN-PK, Akt), y cinasas de especificidad doble, que fosforilan sustratos en residuos de tirosina, serina y/o treonina.
Las lfpido cinasas son enzimas que catalizan la fosforilacion de lfpidos. Estas enzimas, y los lfpidos fosforilados y moleculas organicas biologicamente activas procedentes de lfpidos resultantes, desempenan un papel en numerosos procesos fisiologicos diferentes, incluyendo la proliferacion, migracion, adhesion y diferenciacion celulares. Ciertas lfpido cinasas estan asociadas a la membrana y catalizan la fosforilacion de los lfpidos contenidos en o asociados a las membranas celulares. Los ejemplos de tales enzimas incluyen fosfoinosttido(s) cinasas (por ejemplo, PI3-cinasas, PI4-cinasas), diacilglicerol cinasas y esfingosina cinasas.
Las fosfoinosttido 3-cinasas (PI3K) constituyen una familia unica y altamente conservada de lfpido cinasas intracelulares que fosforilan el grupo 3'-OH en fosfatidilinositoles o fosfoinosftidos. La familia de PI3K comprende 15 cinasas con distintas especificidades de sustrato, patrones de expresion y modos de regulacion. Las PI3K de clase I (p110a, p110p, p110S y p110y) se activan normalmente mediante tirosina cinasas o receptores acoplados a protemas G para generar un producto lipfdico denominado PIP3, que se acopla a efectores posteriores tales como los de la ruta Akt/PDK1, mTOR, las cinasas de la familia Tec, y las GTPasas de la familia Rho. Las PI3K de clase II y III desempenan un papel en el trafico intracelular a traves de la smtesis de PI(3)P y PI(3,4)P2.
La ruta de senalizacion de las fosfoinosftido 3-cinasas (PI3K) es uno de los sistemas mas mutados en los canceres humanos. La senalizacion de PI3K tambien es un factor clave en muchas otras enfermedades de los seres humanos. La senalizacion PI3K esta implicada en numerosos estados patologicos incluyendo dermatitis alergica por contacto, artritis reumatoide, artrosis, enfermedades inflamatorias intestinales, trastorno pulmonar obstructivo cronico, psoriasis, esclerosis multiple, asma, trastornos relacionados con complicaciones de la diabetes y complicaciones inflamatorias del sistema cardiovascular, tales como smdrome coronario agudo.
Se han generado muchos inhibidores de PI3K. Aunque tales compuestos a menudo se evaluan inicialmente para determinar su actividad cuando estan disueltos en disolucion, algunas caractensticas de estado solido tales como polimorfismo desempenan un papel importante. Las formas polimorficas de un principio activo, tal como un inhibidor de PI3K, pueden tener diferentes propiedades qrnmicas y ffsicas, incluyendo cristalinidad, punto de fusion, reactividad qrnmica, solubilidad, velocidad de disolucion, propiedades opticas y mecanicas, presion de vapor y densidad. Estas propiedades pueden tener un efecto directo sobre la capacidad para procesar o fabricar un principio activo y el producto terminado. Ademas, el polimorfismo es a menudo un factor en la revision reguladora de la “igualdad” de productos terminados de diversos fabricantes. Por ejemplo, se ha evaluado el polimorfismo en compuestos tales como warfarina sodica, famotidina y ranitidina. El polimorfismo puede afectar a la calidad, seguridad y/o eficacia de un producto terminado, tal como un inhibidor de cinasa. Por tanto, la investigacion dirigida a polimorfos de inhibidores de PI3K y a procedimientos para preparar polimorfos de inhibidores de PI3K representa un campo de investigacion significativamente util en el desarrollo de principios activos farmaceuticos (API).
Ademas, se han usado inhibidores de PI3K para tratar diversas enfermedades y trastornos en seres humanos (por ejemplo, en ensayos clmicos). Para la produccion de un principio activo destinado para su uso en seres humanos, son aplicables las Buenas Practicas de Fabricacion (BPF) actuales. Es necesario implementar procedimientos que puedan controlar los niveles de impurezas y garantizar que se producen productos de API que cumplen sistematicamente sus especificaciones predeterminadas. Por tanto, existe una necesidad importante de un procedimiento para preparar inhibidores de PI3K adecuados para uso en seres humanos, particularmente a escala comercial, es decir entre otros, seguros, ampliables a escala, eficaces, economicamente viables y/o que tengan
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otras propiedades deseables. Entre otras entidades, se dan a conocer en el presente documento las formas polimorficas de inhibidores de PI3K que abordan estas necesidades y proporcionan ventajas a modo de ejemplo.
Sumario
En una realizacion, se proporciona en el presente documento una forma polimorfica de un compuesto de formula (I):
imagen1
en la que dicha forma polimorfica es la “forma C” de polimorfo, que tiene los siguientes picos de XRPD caractensticos: 20 = 10,4° (+ 0,2°), 13,3° (+ 0,2°) y 24,3° (+ 0,2°).
En una realizacion, se proporciona en el presente documento un metodo de preparacion de un polimorfo de la forma C de un compuesto de formula (I):
imagen2
En una realizacion, el metodo comprende una cualquiera, dos, tres, cuatro, cinco, seis, siete u ocho o mas de las siguientes etapas:
O
imagen3

Claims (109)

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    1. Polimorfo de un compuesto de formula (I):
    imagen1
    en el que dicho polimorfo es la “forma C” de polimorfo, que tiene los siguientes picos de XRPD caractensticos: 20 = 10,4° (+ 0,2°), 13,3° (+ 0,2°) y 24,3° (+ 0,2°).
  2. 2. Polimorfo segun la reivindicacion 1, en el que dicho polimorfo comprende ademas al menos un pico de XRPD caractenstico seleccionado de 20 = 6,6° (+ 0,2°) y 12,5° (+ 0,2°).
  3. 3. Polimorfo segun la reivindicacion 1, en el que dicho polimorfo tiene los siguientes picos de XRPD caractensticos: 20 = 6,6° (+ 0,2°), 10,4° (+ 0,2°), 12,5° (+ 0,2°), 13,3° (+ 0,2°) y 24,3° (+ 0,2°) en combinacion con al menos un pico de XRPD seleccionado de 20 = 8,8° (+ 0,2°), 9,9° (+ 0,2°), 13,4° (+ 0,2°), 15,5° (+ 0,2°), 16,9° (+ 0,2°), 19,8° (+ 0,2°), 21,3° (+ 0,2°), 23,6° (+ 0,2°), 25,3° (+ 0,2°) y 27,9° (+ 0,2°).
  4. 4. Polimorfo segun la reivindicacion 1, en el que dicho polimorfo tiene sustancialmente todos los picos en su espectro de XRPD tal como se muestra en la figura 3.
  5. 5. Polimorfo segun la reivindicacion 1, en el que dicho polimorfo tiene un pico endotermico a
    aproximadamente 203°C.
  6. 6. Polimorfo segun la reivindicacion 1, en el que dicho polimorfo tiene un pico endotermico a
    aproximadamente 206°C o aproximadamente 208°C.
  7. 7. Polimorfo segun la reivindicacion 1, en el que dicho polimorfo tiene un pico endotermico en el intervalo de aproximadamente 203°C a aproximadamente 208°C, y al menos un pico seleccionado de un pico exotermico en el intervalo de aproximadamente 251°C a aproximadamente 254°C y un pico endotermico en el intervalo de aproximadamente 281°C a aproximadamente 283°C.
  8. 8. Polimorfo segun la reivindicacion 1, en el que dicho polimorfo tiene un pico endotermico a
    aproximadamente 208°C, un pico exotermico a aproximadamente 254°C y un pico endotermico a aproximadamente 283°C.
  9. 9. Polimorfo segun la reivindicacion 1, en el que el polimorfo de la forma C es un hidrato con canales.
  10. 10. Metodo de preparacion de un polimorfo de la forma C de un compuesto de formula (I) segun la reivindicacion 1:
    imagen2
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    en el que el metodo comprende:
    (i) exponer una composicion que comprende uno o mas polimorfos distintos a la forma C seleccionados de la forma A, la forma B, la forma D, la forma E, la forma F, la forma G, la forma H, la forma I, la forma J y una forma amorfa de un compuesto de formula (I) o una sal, un solvato o hidrato del mismo a condiciones no anhidras durante un periodo de tiempo suficiente para convertir al menos aproximadamente el 50% de la cantidad total de polimorfo(s) distinto(s) a la forma C en la forma C de un compuesto de formula (I); y
    (ii) recuperar dicho polimorfo de la forma C; en el que:
    la forma A de polimorfo tiene los siguientes picos de XRPD caractensticos: 20 = 9,6° (+ 0,2°), 12,2° (+ 0,2°) y 18,3° (+ 0,2°);
    la forma B de polimorfo tiene los siguientes picos de XRPD caractensticos: 20 = 7,9° (+ 0,2°), 13,4° (+ 0,2°) y 23,4° (+ 0,2°);
    la forma D de polimorfo tiene los siguientes picos de XRPD caractensticos: 20 = 11,4° (+ 0,2°), 17,4° (+ 0,2°) y 22,9° (+ 0,2°);
    la forma E de polimorfo tiene los siguientes picos de XRPD caractensticos: 20 = 6,7° (+ 0,2°), 9,3° (+ 0,2°) y 24,4° (+ 0,2°);
    la forma F de polimorfo tiene los siguientes picos de XRPD caractensticos: 20 = 9,6° (+ 0,2°), 17,3° (+ 0,2°) y 24,6° (+ 0,2°);
    la forma G de polimorfo tiene los siguientes picos de XRPD caractensticos: 20 = 6,7° (= 0,2°), 9,5° (+ 0,2°) y 19,0° (+ 0,2°);
    la forma H de polimorfo tiene los siguientes picos de XRPD caractensticos: 20 = 8,9° (+ 0,2°), 9,2° (+ 0,2°) y 14,1° (60,2°);
    la forma I de polimorfo tiene los siguientes picos de XRPD caractensticos: 20 = 9,7° (+ 0,2°), 19,3° (+ 0,2°) y 24,5° (+ 0,2°); y
    la forma J de polimorfo tiene los siguientes picos de XRPD caractensticos: 20 = 9,1° (+ 0,2°), 17,3° (+ 0,2°) y 18,3° (+ 0,2°).
    Metodo de preparacion de un polimorfo de la forma C de un compuesto de formula (I) segun la reivindicacion 1:
    imagen3
    en el que el metodo comprende: i) combinar un compuesto de formula (Ia):
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    imagen4
    en la que:
    PG2 es un grupo protector seleccionado de metilsulfonilo, metilsulfonilo sustituido, bencenosulfonilo, bencenosulfonilo sustituido, benciloxicarbonilo, benciloxicarbonilo sustituido, 2,2,2-tricloroetoxicarbonilo, 2- trimetilsililetoxicarbonilo, t-butoxicarbonilo, 1-adamantiloxicarbonilo, 2-adamantiloxicarbonilo, alquilo, alquilo sustituido, t-butildimetilsililo, triisopropilsililo, alilo, bencilo, bencilo sustituido, hidroximetilo, metoximetilo, dietoximetilo, (2-cloroetoxi)metilo, t-butoximetilo, t-butildimetilsiloximetilo, pivaloiloximetilo, benciloximetilo, dimetilaminometilo, 2-tetrahidropiranilo, alcoximetilo sustituido y ariloximetilo sustituido, y
    en donde los sustituyentes se seleccionan de alquilo, heteroalquilo, alquenilo, alquinilo, cicloalquilo, heterociclilo, arilo, arilalquilo, heteroarilo, heteroarilalquilo, alcoxilo, cicloalcoxilo, heterocicliloxilo, ariloxilo, heteroariloxilo, amido, amino, acilo, aciloxilo, alcoxicarbonilo, ester, eter, tio, sulfinilo, sulfonilo, sulfonamido, halo, ciano, hidroxilo, nitro, fosfato, urea, carbamato y carbonato; con uno o mas reactivos para eliminar el grupo protector PG2 para formar el compuesto de formula (I); y
    ii) recuperar el polimorfo de la forma C del compuesto de formula (I);
    en el que al menos una de las etapas i) y ii) se produce en condiciones no anhidras.
    Metodo de preparacion de un polimorfo de la forma C de un compuesto de formula (I) segun la reivindicacion 1:
    imagen5
    en el que el metodo comprende:
    (i) preparar una primera suspension espesa de un polimorfo de la forma C en diclorometano;
    (ii) recuperar los solidos en la primera suspension espesa mediante filtracion;
    (iii) preparar una segunda suspension espesa de los solidos recuperados en la etapa ii) en agua o disolvente que contiene agua; y
    (iv) recuperar los solidos en la segunda suspension espesa mediante filtracion para dar el polimorfo de la forma C.
    Metodo de preparacion de un polimorfo de la forma C de un compuesto de formula (I) segun la
    reivindicacion 1:
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    imagen6
    en el que el metodo comprende poner el polimorfo de la forma A de un compuesto de formula (I) en agua o un sistema de disolventes que contiene agua;
    en el que la forma A de polimorfo tiene los siguientes picos de XRPD caractensticos: 20 = 9,6° (+ 0,2°), 12,2° (+ 0,2°) y 18,3° (+ 0,2°).
    Metodo segun la reivindicacion 10 o la reivindicacion 11, en el que las condiciones no anhidras incluyen agua lfquida.
    Metodo segun la reivindicacion 14, en el que las condiciones no anhidras incluyen un disolvente miscible en agua y sistema de disolventes con agua lfquida.
    Metodo segun la reivindicacion 14 o la reivindicacion 15, en el que esta presente el agua lfquida en una cantidad seleccionada de aproximadamente el 1%, aproximadamente el 5%, aproximadamente el 10%, aproximadamente el 15%, aproximadamente el 20%, aproximadamente el 25%, aproximadamente el 30%,
    aproximadamente el 35%, aproximadamente el 40%, aproximadamente el 45%, aproximadamente el 50%,
    aproximadamente el 55%, aproximadamente el 60%, aproximadamente el 65%, aproximadamente el 70%,
    aproximadamente el 75%, aproximadamente el 80%, aproximadamente el 85%, aproximadamente el 90%,
    aproximadamente el 95% y aproximadamente el 100% en volumen del sistema de disolventes.
    Metodo segun la reivindicacion 14 o la reivindicacion 15, en el que esta presente dicha agua lfquida en una cantidad de entre aproximadamente el 85% y aproximadamente el 95% en volumen del sistema de disolventes.
    Metodo segun la reivindicacion 10, en el que el uno o mas polimorfos distintos a la forma C comprenden al menos aproximadamente el 50% en peso de la forma A de polimorfo o comprenden una forma amorfa;
    en el que la forma A de polimorfo tiene los siguientes picos de XRPD caractensticos: 20 = 9,6° (+ 0,2°), 12,2° (+ 0,2°) y 18,3° (+ 0,2°).
    Metodo segun la reivindicacion 11, en el que la etapa (ii) implica cristalizar en un sistema de mono o multidisolvente, en el que cristalizar implica anadir un antidisolvente o bien con o bien sin una etapa de enfriamiento para provocar la precipitacion de la forma C.
    Metodo segun la reivindicacion 19, en el que las condiciones de cristalizacion son no anhidras.
    Metodo segun la reivindicacion 11, en el que el uno o mas reactivos para eliminar el grupo protector PG2 se seleccionan de acidos, bases de carbonato, bases de hidroxido, bases de litio, oxidantes, condiciones de hidrogenacion, TBAF y BF3-Et2O.
    Metodo segun la reivindicacion 21, en el que el reactivo para eliminar el grupo protector PG2 es un acido y PG2 es 2-tetrahidropiranilo.
    Metodo segun la reivindicacion 22, en el que el acido es HCl, HBr, TFA, acido perclorico, acido sulfurico, acido mtrico o acido fosforico.
  18. 24. Metodo segun la reivindicacion 23, en el que el acido es HCl.
  19. 25. Metodo segun la reivindicacion 13, en el que el sistema de disolventes comprende agua y 2-propanol. 55
  20. 26. Metodo segun la reivindicacion 13, en el que la forma A de polimorfo se pone en agua o un sistema de disolventes que contiene agua para formar una suspension espesa durante aproximadamente 18-24 horas.
  21. 27. Metodo segun la reivindicacion 13, en el que la forma A se pone en agua o un sistema de disolventes que
    5 contiene agua para formar una suspension espesa durante de menos de aproximadamente una hora a
    aproximadamente 24 horas.
  22. 28. Metodo segun la reivindicacion 13, en el que la forma A de polimorfo se prepara volviendo a formar una suspension espesa de uno o mas polimorfo(s) distinto(s) a la forma A en un disolvente anhidro.
    10
  23. 29. Metodo segun la reivindicacion 28, en el que el disolvente anhidro se selecciona de cloroformo, diclorometano, alcohol isopropflico, etanol o una mezcla de los mismos.
  24. 30. Metodo segun la reivindicacion 11, en el que el compuesto de formula (la) se prepara combinando el
    15 compuesto 9 de formula:
    imagen7
    20
    con un compuesto de cloropurina protegido de formula:
    imagen8
    en presencia de Et3N en un disolvente alcoholico seleccionado de MeOH, EtOH, PrOH e iPrOH.
    25 31. Metodo segun la reivindicacion 11, la reivindicacion 21 o la reivindicacion 30, en el que el uno o mas
    reactivos para eliminar el grupo protector PG2 se seleccionan de HCl, HBr, TFA, Na2CO3 y K2CO3, NaOH, KOH, metil-litio, etil-litio, propil-litio, n-butil-litio, n-pentil-litio, n-hexil-litio, nitrato cerico amonico, ciclohexadieno/negro de Pd, H/Pd sobre carbono, TBAF y BF3'Et2O.
    30 32. Metodo segun la reivindicacion 30, en el que PG2 es 2-tetrahidropiranilo.
  25. 33. Metodo segun la reivindicacion 30, en el que el compuesto 9 se prepara mediante la conversion de un compuesto 8 de formula:
    35
    imagen9
    en presencia de un acido seleccionado de acido trifluoroacetico y acido metanosulfonico en un disolvente seleccionado de metanol, alcohol isopropflico, anisol, y THF, o una mezcla de los mismos.
    40 34. Metodo segun la reivindicacion 33, en el que el acido es acido trifluoroacetico.
    10
    Metodo segun la reivindicacion 33 o la reivindicacion 34, en el que el compuesto 8 se prepara combinando el compuesto 7 de formula:
    imagen10
    con n-hexil-litio, y anadiendo el compuesto 2 de formula:
    imagen11
    en el que el compuesto 2 se combina previamente con reactivo de Grignard de isopropilo.
  26. 36. Composicion farmaceutica que comprende un polimorfo de la forma C segun una cualquiera de las reivindicaciones 1 a 9, y uno o mas excipientes farmaceuticamente aceptables.
    15
  27. 37. Composicion farmaceutica segun la reivindicacion 36, en el que el uno o mas excipientes farmaceuticamente aceptables se seleccionan de celulosa microcristalina silicificada, lactosa, manitol, almidon, sorbitol, sacarosa, fosfato de dicalcio, celulosa microcristalina, crospovidona, croscarmelosa sodica y glicolato sodico de almidon, dioxido de silicio, dioxido de silicio, silicato de magnesio, talco,
    20 estearato de magnesio, estearil-fumarato de sodio, acido estearico, laurilsulfato de sodio, dodecilsulfato de
    sodio, Tween® 80 y Lutrol®.
  28. 38. Composicion farmaceutica segun la reivindicacion 36 o la reivindicacion 37, que comprende ademas una forma amorfa de un compuesto de formula (I).
    25
  29. 39. Composicion farmaceutica segun la reivindicacion 36, la reivindicacion 37 o la reivindicacion 38, que comprende ademas al menos un polimorfo distinto de la forma C seleccionado de la forma A, la forma B, la forma D, la forma E, la forma F, la forma G, la forma H, la forma I, la forma J y una forma amorfa de un compuesto de formula (I) o una sal, un solvato o hidrato del mismo.
    30
  30. 40. Composicion farmaceutica segun la reivindicacion 39, que comprende polimorfo de la forma C y la forma A de polimorfo en una razon forma C:forma A mayor de aproximadamente 9:1.
  31. 41.
    35
    Polimorfo segun una cualquiera de las reivindicaciones 1 a 9, para su uso en un metodo de tratamiento de un trastorno mediado por Pl3K.
  32. 42. Polimorfo segun la reivindicacion 41, en el que el trastorno es cancer, una enfermedad inflamatoria o una enfermedad autoinmunitaria
    40 43.
    Polimorfo segun una cualquiera de las reivindicaciones 1 a 9, para su uso en un metodo de tratamiento de un cancer.
    Cuentas
    imagen12
    Fig. 1
    Cuentas
    imagen13
    Fig. 2
    Cuentas
    imagen14
    Fig. 3
    Cuentas
    imagen15
    Fig. 4
    Cuentas
    imagen16
    Fig. 5
    Cuentas
    imagen17
    Fig. 6
    Cuentas
    imagen18
    Posicion [°2 Theta] (Cobre (Cu)) Forma G de polimorfo
    Fig. 7
    Cuentas
    imagen19
    Fig. 8
    Cuentas
    imagen20
    Fig. 9
    Cuentas
    imagen21
    Fig. 10
    Intensidad (CPS)
    imagen22
    imagen23
    mW-
    -2r
    -3-j'
    -4-
  33. -7.32 m
    Integral
    normalizado -1.02 Jq A-1
  34. 277.77 °C
    Imcio
  35. 280.23 °C
    Pico
    10
  36. -340.80 mJ
    Integral
    normalizado -47.57 JqA-1
  37. 232.22 °C
    Inicio
  38. 238.88 °C
    Pico
    2-
    Forma A
    Fig. 12
    imagen24
    imagen25
    Inicio
    Forma C
    Fig. 14
  39. 253.44 °C
    Pico extrapol
    mW
    Valor de pico 0.58 mW
  40. 253.70 °C
    Pico
    Pico extrapol. 208.44 C
    Valor de pico -4.26 mW
  41. 207.78
    Pico
    10-
    Pico extrapol. 283.57 C
    Valor de pico -13.22 mW
  42. 283.05
    Pico
    4-
    imagen26
    -6,62 m
    Integral
    normalizado -1.71 JgM
  43. 281.48 C
    Imcio
  44. 282.88 °C
    Pico
    12-
  45. -290.13 mJ
    Integral
    -14-
    normalizado -75.05 JgA-1
  46. 257.9
    Imcio
    16-
  47. 260.40
    Pico
    -18
    40 60 80 100 120 140 160 180 200 220 240 260 280 300 320 340°C
    Forma D
    Fig. 15
    imagen27
    MCL-E-100(1) DSC, 09.04.2010 12:32:40
    mWH
    MCL-E-100(1) DSC, 3.5530 mg
    Integral
  48. 21.14 mJ
    Metodo: 30-350/ 0
    normalizado
  49. 5.95 JgA-1
  50. 30.0-350.0
  51. 10.00 C/min
    Imcio
  52. 264.85 °C
    Pico
  53. 266.67
    mJ
  54. 48.6
    Integral
  55. 13.68 JgA
    normalizado
    - 0.40 mJ
    Integral
  56. 107.66 °C
    nicio
  57. -2.93 JgA-1
    normalizado
    37 X
    31
    Pico
  58. 257.74
    nicio
  59. 320.99 mJ
    Integral
  60. 262.9
    0-
    Pico
    normalizado -90.34 JgA-1
    Inicio
  61. 281.10 C
    Pico
  62. 282.07 C
    15-
    20
    40 60 80 100 120 140 160 180 200 220 240 260 280 300 320 340X
    Forma E
    Fig. 16
    imagen28
  63. 8.95 mJ
    Integral
    normalizado 20.41 JgA
  64. 252.25
    Imcio
  65. 266.36 °C
    Pico
    3-
  66. 115.92 mJ
    Integral
    normalizado -124.78 JgA-1
  67. 68.79 °C
    Imcio
  68. 181.19 C
    Pico
  69. 15.37 mJ
  70. -49.12 m
    Integral
    Integral
    16,54Jgf
    normalizado -51.80 Jq -1
    normalizado
    Imcio
  71. 280.84 5C
  72. 258.59 SC
    Imcio
    28225’C
    Pico
  73. 260.04 °C
    40 60 80 100 120 140 160 180 200 220 240 260 280 300 °C
    Forma F
    Fig. 17
    imagen29
  74. -210.15 mJ
    Integral
    nomnalizado -133.60 JgA-1
  75. 147.17 °C
    Inicio
  76. 161.66
    Pico
  77. -107.12 mJ
    Integral
    normalizado -58.10 JgA-1
  78. 278.68 °C
    Inicio
  79. 281.18 °C
    Pico
    Forma G
    Fig. 18
    Integral
  80. 85.40 mJ
    normalizado 54.29 JgA-1
    Inicio
  81. 233.18 C
    Pico
  82. 241.45 °C
    imagen30
  83. -36.94 mJ
    Integral
    normalizado -30.78 JgA-1
  84. 96. 3
    Imcio
  85. 27.92
    Pico
  86. 0.44 m
    Integral
    normalizado -8.70 JgA
    Imcio
    28C.30 C
    Pico
  87. 281.94 C
  88. -79.26 mJ
    Integral
    normalizado -66.05 Jg A-1
  89. 253.86 °C
    Imcio
    6-
  90. 258.0 °C
    Pico
    Forma H
    Fig. 19
    imagen31
    3-
    Integral -5.02 mJ
    4-
  91. 205.21 °C
    Inicio
  92. 208.01 °C
    Pico
    5-
    Integral -62.50 mJ
    Inicio 258.45 °C
    Pico 262.67 °C
    Forma
    Fig
    ia. 20
    imagen32
    2-
  93. -20.45 m
    Integral
    JgM
    normalizado -26.
  94. 2.91 mJ
    Integral
    Imcio
  95. 98.41
    normalizado -3.72 JgA-1
  96. 121.26 °C
    Pico
  97. 72.80 °C
    nicio
  98. 184.57 °C
    Pico
  99. -0.46 mJ
    Integral
    normalizado -0.59 Jg A-
    4-
    Integral
  100. 47.16 mJ
    Imcio
  101. 280.70
    normalizado -60.23 JgA
    Pico
  102. 282.33
    Imcio
  103. 254.98 T
    Pico
  104. 258.75
    Forma J
    Fig. 21
    imagen33
    100
    20
    140
    160
    ISO
    200
    220
    I GA de forma
    Fig
    Integral
    normaliiado
    9-
    imcio
    Pico
    10
    - 748,00 mJ
    Integral
    -8737 JgM
    normal izado
    Initio
  105. 238.29
    Pico
  106. 336.85
    12-
    DSC de forma A
    imagen34
    Initio 240j&7"C
    3-
    Integral
    norma izado
    4-
    Inicio
    Pico
    Integral
    normalizado
    Inicio
    Integral
    Pica
    normalizado
    Inicio
    8-
    Pico
    DSC de forma C
    mW
    Pico extrapol. 251 S3 C
    120 mW
    Valor de picO
    nomnalizado -1.07wgM
    -2
    Inicio 193.07 C
    25 ,32VC
    4-
    Picd extrapol.
  107. 204.74 t
    valor de pico
  108. 6.33 mW
    normalizadD
    -ZllWgA-1
  109. 205.35
    0
    Pico
    12-
    Pico extrapol. 283.53 X
    Valor depioo -15.71 mW
    H-
    narmalizado -5.24 Wq^
    283,40 C
    Pico
    16-
    DSC do forma C
    Fig. 23
    imagen35
    mw
    Pico extra pol
    10-
    Valor de pica
    normalizado
    Pico
    Pico extrapol
    Valor de pico
    normalizado
    Pico
    Pico exlrapol
    Pico extrapol
    valor de pico
    Valor de pico
    normalizado
    Pico
    normalrzado
    Pico
    DSC de forma F
    mW
    .7-
    1.6 -
    1.5-
    1.4-
    1.3-
    1.2-
    40 60 80 100 120 140 160 180 200 220 PC
    TGA de forma F
    Fig. 24
    169
    imagen36
    n-BuOH
    Acetona
    MEK Disolvente
    O; THF
    ^ h
    Contraion
    ro i
    ■l
    3 & i
    3. 3' o D Ei
    fp ex
    3 c
    CU 3 £
    if c
    Q W Cl ffl
    & □
    C a- Z
    s
    3 L
    8
    . DMF
    h
    Fig.25
    imagen37
    imagen38
    t-OEftf
    imagen39
    2000 1500
    Nunnei'os de onda (cm-1)
    Fig. 27
    1000
    800
    imagen40
    imagen41
    Fig. 29
    imagen42
    % disuello % disuelto
    imagen43
    Formula 11Leapsulas.dej QPrng
    imagen44
    RgT31
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