WO2023277172A1 - Procédé de préparation de sels pharmaceutiques de dérivés de pyrimidine - Google Patents

Procédé de préparation de sels pharmaceutiques de dérivés de pyrimidine Download PDF

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WO2023277172A1
WO2023277172A1 PCT/JP2022/026431 JP2022026431W WO2023277172A1 WO 2023277172 A1 WO2023277172 A1 WO 2023277172A1 JP 2022026431 W JP2022026431 W JP 2022026431W WO 2023277172 A1 WO2023277172 A1 WO 2023277172A1
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compound
composition
mixture
minutes
temperature
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PCT/JP2022/026431
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English (en)
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Justin L. QUON
Charles D. PAPAGEORGIOU
Landon J. DURAK
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Takeda Pharmaceutical Company Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

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  • compositions comprising Compound 1.
  • present disclosure further relates to processes for the preparation of Compound 1.
  • BACKGROUND Lung cancer is composed of non-small-cell lung cancer (NSCLC), small-cell lung cancer (SCLC), and neuroendocrine tumors. Approximately 10% of patients with NSCLC in the US (10,000 cases/year) and 35% in East Asia are reported to have tumor-associated epidermal growth factor receptor (EGFR) mutations. New England J. Med. 2004; 350(21):2129-39.
  • NSCLC non-small-cell lung cancer
  • SCLC small-cell lung cancer
  • EGFR tumor-associated epidermal growth factor receptor
  • EGFR (alternatively named ErbB1 or HER1) is part of the ErbB family of transmembrane receptor tyrosine kinases involved in signal transduction pathways that regulate proliferation and apoptosis.
  • Inhibitors of the EGFR have emerged as effective therapies for some patients and represent an important target for therapeutic intervention in oncology.
  • the development and clinical application of inhibitors that target EGFR provide important insights for new lung cancer therapies, as well as for the broader field of targeted cancer therapies. Nature Review Cancer 2007; 7, 169-181 (March 2007).
  • a primary concern for the manufacture of pharmaceutical compounds is the stability of an active substance.
  • An active substance ideally has a stable crystalline morphology to ensure consistent processing parameters and pharmaceutical quality. Unstable active substances may affect the reproducibility of the manufacturing process and thus lead to final formulations which do not meet the high quality and stringent requirements imposed on formulations of pharmaceutical compositions.
  • the present disclosure provides a composition comprising wherein Compound 1 has a bulk density of from about 0.18 g/mL to about 0.55 g/mL, and/or a tapped density of from about 0.32 g/mL to about 0.61 g/mL.
  • Compound 1 comprises particles having a d 10 of about 10 ⁇ m to about 54 ⁇ m, a d 50 of from about 31 ⁇ m to about 137 ⁇ m, and/or a d 90 of from about 76 ⁇ m to about 353 ⁇ m.
  • the present disclosure provides a milled form of Compound 1.
  • the present disclosure provides a pharmaceutical composition comprising Compound 1.
  • the pharmaceutical composition is in a capsule.
  • the capsule comprises Compound 1 that is equivalent to 40 mg of Compound (A).
  • the capsule does not contain pharmaceutical excipients.
  • the present disclosure provides a composition of Compound 1 prepared by a process comprising the steps of: (i) mixing Compound (A) with succinic acid in the presence of a solvent; (ii) heating the mixture of step (i); (iii) adding a seeding material to the mixture of step (ii); (iv) thermal cycling the mixture at a temperature of between about 45 °C-75 °C; (v) repeating the (iv) thermal cycling step; (vi) performing a cool-heat step at a temperature of between about 15 °C-45 °C; (vii) collecting solids to provide Compound 1; and (viii) optionally, milling the solids obtained in step (vii) to provide a milled form of Compound 1.
  • the seeding material is in an amount of about 0.5% to about 1.5% by weight of Compound (A).
  • the process comprises the optional milling step (viii). In some embodiments, the milling is pin-milling.
  • the present invention comprises the following.
  • (Item 1) A composition comprising Compound 1 wherein Compound 1 has a) a bulk density of from about 0.18 g/mL to about 0.55 g/mL, and/or b) a tapped density of from about 0.32 g/mL to about 0.61 g/mL.
  • (Item 2) The composition of any one of the preceding items, wherein Compound 1 has a bulk density higher than 0.22 g/mL and less than 0.55 g/mL.
  • (Item 3) The composition of any one of the preceding items, wherein Compound 1 has a bulk density higher than 0.30 g/mL and less than 0.40 g/mL.
  • composition of any one of the preceding items, wherein the milled form is pin-milled.
  • composition of any one of the preceding items, wherein Compound 1 comprises particles having a d 10 of about 10 ⁇ m to about 54 ⁇ m.
  • composition of any one of the preceding items, wherein Compound 1 comprises particles having a d 50 of from about 31 ⁇ m to about 137 ⁇ m.
  • composition of any one of the preceding items, wherein Compound 1 comprises particles having a d 90 of from about 76 ⁇ m to about 353 ⁇ m.
  • a pharmaceutical composition comprising the composition of any one of the preceding items.
  • the pharmaceutical composition of any one of the preceding items, wherein the pharmaceutical composition is in a capsule.
  • a composition of Compound 1 prepared by a process comprising the steps of: (i) mixing Compound (A) with succinic acid in the presence of a solvent (ii) heating the mixture of step (i), (iii) adding a seeding material to the mixture of step (ii), (iv) thermal cycling the mixture at a temperature of between about 45 °C-75 °C, (v) repeating the (iv) thermal cycling step, (vi) performing a cool-heat step at a temperature of between about 15 °C-45 °C, (vii) collecting solids to provide Compound 1, and (viii) optionally, milling the solids obtained in step (vii) to provide a milled form of Compound 1.
  • step (Item 16) The compound of any one of the preceding items, wherein after step (ii) and before step (iii), the process further comprises a clarifying filtration step, an ethanol rinse step, and a distillation to a target volume step.
  • step 17) The composition of any one of the preceding items, wherein the seeding material is a crystalline succinate salt suspended in an organic solvent.
  • the organic solvent is ethanol.
  • seeding material is in an amount of about 0.5% to about 1.5% by weight of Compound (A).
  • (Item 20) The composition of any one of the preceding items, wherein the seeding material is in an amount of about 1.0% by weight of Compound (A).
  • (Item 21) The composition of any one of the preceding items, wherein after the addition of the seeding material, the mixture is kept at a temperature of about 70 °C for about 30 to 60 minutes prior to proceeding to step (iv).
  • (Item 22) The composition of any one of the preceding items, wherein each thermal cycle of step (iv) has a duration of about 160 minutes to about 280 minutes.
  • (Item 23) The composition of any one of the preceding items, wherein each thermal cycle has a duration of about 200 minutes to about 250 minutes.
  • step (vi) The composition of any one of the preceding items, wherein each thermal cycle has a duration of about 200 minutes.
  • the cool-heat cycle of step (vi) comprises: (vi.1) slow-cooling the mixture to between about 15 °C and about 25 °C, (vi.2) holding the temperature for about 15-75 minutes, (vi.3) slow-heating the mixture to between about 35 °C and about 45 °C, (vi.4) holding the temperature for about 15-75 minutes, and (vi.5) cooling the mixture to between about 10 °C to about 20 °C.
  • (Item 27) The composition of any one of the preceding items, comprising the optional milling step (viii).
  • (Item 28) The composition of any one of the preceding items, wherein the milling occurs at a speed of 2700 rotations per minute (RPM) to 4700 RPM.
  • (Item 29) The composition of any one of the preceding items, wherein the milling occurs at 2700 RPM.
  • (Item 30) The composition of any one of the preceding items, wherein the milling is pin-milling.
  • (Item 31) The composition of any one of the preceding items, wherein Compound 1 has a bulk density of 0.18 g/mL to 0.55 g/mL.
  • (Item 32) The composition of any one of the preceding items, wherein Compound 1 has a bulk density higher than 0.22 g/mL and less than 0.55 g/mL.
  • (Item 33) The composition of any one of the preceding items, wherein Compound 1 has a bulk density of higher than 0.30 g/mL and less than 0.40 g/mL.
  • (Item 34) The composition of any one of the preceding items, wherein Compound 1 has a tapped density of from 0.32 g/mL to 0.61 g/mL.
  • (Item 35) The composition of any one of the preceding items, wherein Compound 1 has a tapped density of from 0.32 g/mL to 0.51 g/mL.
  • composition of any one of the preceding items, wherein Compound 1 has a tapped density of from 0.33 g/mL to 0.44 g/mL.
  • Compound 1 comprises particles having a d 10 of from about 10 ⁇ m to about 54 ⁇ m.
  • Compound 1 comprises particles having a d 50 of from about 31 ⁇ m to about 137 ⁇ m.
  • Compound 1 comprises particles having a d 90 of from about 76 ⁇ m to about 353 ⁇ m.
  • a process for preparing Compound 1 comprising: (i) mixing Compound (A) with succinic acid in the presence of a solvent (ii) heating the mixture of step (i), (iii) adding a seeding material to the mixture of step (ii), (iv) thermal cycling the mixture at a temperature of between about 45 °C-75 °C, (v) repeating the (iv) thermal cycling step, (vi) performing a cool-heat step at a temperature of between about 15 °C-45 °C, (vii) collecting solids to provide Compound 1, and (viii) optionally, milling the solids obtained in step (vii) to provide a milled form of Compound 1.
  • step (Item 41) The process of any one of the preceding items, wherein after step (ii) and before step (iii), the process further comprises a clarifying filtration step, an ethanol rinse step, and a distillation to a target volume step.
  • step 42) The process of any one of the preceding items, wherein the seeding material is a jet-milled seed.
  • the seeding material is a crystalline succinate salt suspended in an organic solvent.
  • the organic solvent is ethanol.
  • step 45 The process of any one of the preceding items, wherein the seeding material is in an amount of about 0.5% to 1.5% by weight Compound (A).
  • step 46 The process of any one of the preceding items, wherein after the addition of the seeding material, the mixture is kept at a temperature of about 70 °C for about 30 to 60 minutes prior to proceeding to step (iv).
  • step 47 The process of any one of the preceding items, wherein each thermal cycle of step (iv) has a duration of about 160 minutes to about 280 minutes.
  • step 48 The process of any one of the preceding items, wherein each thermal cycle has a duration of about 200 minutes to about 250 minutes.
  • step (vi) The process of any one of the preceding items, wherein each thermal cycle has a duration of about 200 minutes.
  • the process comprises 3 (iv) thermal cycles.
  • the cool-heat cycle of step (vi) comprises: (vi.1) slow-cooling the mixture to between about 15 °C and about 25 °C, (vi.2) holding the temperature for about 15-75 minutes, (vi.3) slow-heating the mixture to between about 35 °C and about 45 °C, (vi.4) holding the temperature for about 15-75 minutes, and (vi.5) cooling the mixture to between about 10 °C to about 20 °C.
  • (Item 52) The process of any one of the preceding items, comprising the optional milling step (viii).
  • (Item 53) The process of any one of the preceding items, wherein the milling occurs at a speed of 2700 rotations per minute (RPM) to 4700 RPM.
  • (Item 54) The process of any one of the preceding items, wherein the milling occurs at 2700 RPM.
  • (Item 55) The process of any one of the preceding items, wherein the milling is pin-milling.
  • (Item 56) The process of any one of the preceding items, wherein Compound 1 has a bulk density of 0.18 g/mL to 0.55 g/mL.
  • FIG. 1 is an exemplified process workflow for the process of Example 1.
  • FIG. 2 is an exemplified process workflow for the process of Example 2.
  • FIG. 3 is an exemplified process workflow for the process of Example 5.
  • FIG. 4 is microscopy and particle size distribution (PSD) data for particles of Compound 1 produced by different processes of the present invention.
  • FIG. 5 is microscopy and PSD data for particles of Compound 1 produced by a 1 wt% seeded process of Example 6.
  • FIG. 6A-B are microscopy and PSD data for particles of Compound 1 produced by a 1 wt% seeded process of Example 6 with (A) heat cycling between 60-70 °C and (B) heat cycling between 50-70 °C.
  • FIG. 7 is a bar graph showing the variance analysis of distribution for d 10 .
  • FIG. 8 is a bar graph showing the variance analysis of distribution for d 50 .
  • FIG. 9 is a bar graph showing the variance analysis of distribution for d 90 .
  • FIG. 10 is a bar graph showing the variance analysis of distribution for bulk density.
  • FIG. 11 is a bar graph showing the variance analysis of distribution for tapped density.
  • FIG. 12 is a bar graph showing the variance analysis of distribution for yield.
  • pharmaceutically acceptable carrier or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like.
  • the pharmaceutically acceptable carrier or excipient does not destroy the pharmacological activity of the disclosed compound and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound.
  • the use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions as disclosed herein is contemplated.
  • Non-limiting examples of pharmaceutically acceptable carriers and excipients include sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as polyethylene glycol and propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate; coloring agents
  • Cyclodextrins such as ⁇ -, ⁇ -, and ⁇ -cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-cyclodextrins, or other solubilized derivatives can also be used to enhance delivery of compounds described herein.
  • crystalline refers to a solid in which the constituent atoms, molecules, or ions are packed in a regularly ordered, repeating three-dimensional pattern having a highly regular chemical structure.
  • a crystalline compound or salt might be produced as one or more crystalline forms.
  • polymorphic form polymorph or “crystalline form” are synonymous.
  • solution refers to a solvent containing a substance(s) that is at least partially dissolved; and which may contain undissolved substance(s).
  • room temperature and “ambient temperature” are used interchangeably herein. These terms refer to the temperature of the surrounding environment.
  • seeding or “seeding material” refers to the addition of a small amount of a crystalline material to a solution or mixture to initiate crystallization.
  • Compound 1 has the following structure:
  • Compound 1 is a succinate salt of propan-2-yl 2-[5-(acryloylamino)-4- ⁇ [2-(dimethylamino)ethyl](methyl)amino ⁇ -2-methoxyanilino]-4-(1-methyl-1H-indol-3-yl)pyrimidine-5-carboxylate.
  • Compound (A) is the freebase of propan-2-yl 2-[5-(acryloylamino)-4- ⁇ [2-(dimethylamino)ethyl](methyl)amino ⁇ -2-methoxyanilino]-4-(1-methyl-1H-indol-3-yl)pyrimidine-5-carboxylate.
  • Compound (A) has the following structure:
  • Compound 1 is provided as a polymorphic form of the succinate salt of Compound 1.
  • Compound 1 is provided as a pharmaceutically acceptable form, e.g., pharmaceutically acceptable salts, hydrates, solvates, isomers, or prodrugs.
  • Compound 1 and Compound (A) or pharmaceutically acceptable salts, hydrates, solvates, isomers, or prodrugs thereof, may be produced according to the methods described in WO2015/195228 and/or WO2019/222093, each of which is incorporated herein by reference in its entirety.
  • Compound 1 is provided in a composition as a solid form.
  • solid form refers to a drug substance having the physical properties (e.g., bulk density, tap density, particle size distribution, and/or compressibility) described herein.
  • Compound 1 has a bulk density of from about 0.18 g/mL to about 0.55 g/mL. In some embodiments, Compound 1 has a bulk density of from about 0.22 g/mL to about 0.55 g/mL. In some embodiments, Compound 1 has a bulk density of from about 0.30 g/mL to about 0.40 g/mL. In some embodiments, Compound 1 has a bulk density of from about 0.18 g/mL to about 0.33 g/mL.
  • “Bulk density” is the ratio of the mass of a bulk solid to its volume, and it determines the space occupied by a given amount of material.
  • Compound 1 has a tapped density of from about 0.32 g/mL to about 0.61 g/mL. In some embodiments, Compound 1 has a tapped density of from about 0.32 g/mL to about 0.51 g/mL. In some embodiments, Compound 1 has a tapped density of from about 0.33 g/mL to about 0.44g/mL.
  • Tapped density is the ratio of the mass of a compound to its volume (measured in a container) after the container has been tapped for a defined period of time.
  • the tapped density represents its random dense packing.
  • Compound 1 has a bulk density of from about 0.18 g/mL to about 0.55 g/mL, and/or a tapped density of from about 0.32 g/mL to about 0.61 g/mL. In some embodiments, Compound 1 has a bulk density of from about 0.18 g/mL to about 0.55 g/mL, or a tapped density of from about 0.32 g/mL to about 0.61 g/mL. In some embodiments, Compound 1 has a bulk density of from about 0.18 g/mL to about 0.55 g/mL, and a tapped density of from about 0.32 g/mL to about 0.61 g/mL.
  • Compound 1 is in a milled form. In some embodiments, Compound 1 is in a pin-milled form.
  • compositions described herein comprise particles of Compound 1.
  • the particles comprise an un-milled form of Compound 1.
  • the particles comprise a milled form of Compound 1. In some embodiments, the particles comprise a pin-milled form of Compound 1.
  • PSD measurable particle size distribution
  • D10, D50 and D90 and d 10 , d 50 and d 90 are used interchangeably and are commonly used to represent the particle size distribution of a given sample.
  • D10 is the value in which 10% of the particles are equal to or smaller than a defined measurement, for example a particle diameter.
  • D50 is the value in which 50% of the particles are equal to or smaller than a defined measurement, for example a particle diameter.
  • D60 is the value in which 60% of the particles are equal to or smaller than a defined measurement, for example a particle diameter.
  • D70 is the value in which 70% of the particles are equal to or smaller than a defined measurement.
  • D80 is the value in which 80% of the particles are equal to or smaller than a defined measurement, for example a particle diameter.
  • D90 is the value in which 90% of the particles are equal to or smaller than a defined measurement, for example a particle diameter.
  • the particle size distribution is generally measured via laser diffraction and the PSD is determined by application of the Mie Theory.
  • Mie Theory uses an optical scattering model based on refractive indices of the particle and dispersion medium and particle absorption values to calculate particle size distribution.
  • the particles have a D10 from about 5 ⁇ m to about 54 ⁇ m. In some embodiments, the particles have a D10 from about 8.5 ⁇ m to about 30 ⁇ m. In some embodiments, the particles have a D10 from about 6.6 ⁇ m to about 30.5 ⁇ m. In some embodiments, the particles have a D10 from about 5 ⁇ m to about 16 ⁇ m. In some embodiments, the particles have a D50 from about 15 ⁇ m to about 137 ⁇ m. In some embodiments, the particles have a D50 from about 28 ⁇ m to about 74 ⁇ m. In some embodiments, the particles have a D50 from about 23 ⁇ m to about 81.1 ⁇ m.
  • the particles have a D50 from about 18 ⁇ m to about 29 ⁇ m. In some embodiments, the particles have a D50 from about 15 ⁇ m to about 48 ⁇ m. In some embodiments, the particles have a D90 from about 32 ⁇ m to about 353 ⁇ m. In some embodiments, the particles have a D90 from about 70 ⁇ m to about 142 ⁇ m. In some embodiments, the particles have a D90 from about 54.6 ⁇ m to about 156.4 ⁇ m. In some embodiments the particles have a D90 from about 38 ⁇ m to about 57 ⁇ m. In some embodiments, the particles have a D90 from about 45 ⁇ m to about 55 ⁇ m. In some embodiments, the particles have a D90 from about 32 ⁇ m to about 95 ⁇ m.
  • the particles have a D10 from about 5 ⁇ m to about 16 ⁇ m, a D50 from about 15 ⁇ m to about 48 ⁇ m, and a D90 from about 32 ⁇ m to about 95 ⁇ m. In some embodiments, the particles have a D10 from about 6.6 ⁇ m to about 30.5 ⁇ m, a D50 from about 23 ⁇ m to about 81.1 ⁇ m, and a D90 from about 54.6 ⁇ m to about 156.4 ⁇ m.
  • the particles comprise an un-milled form of Compound 1. In some embodiments, the particles comprise an un-milled form of Compound 1 and said particles have a D10 from about 8.5 ⁇ m to about 30 ⁇ m. In some embodiments, the particles comprise an un-milled form of Compound 1 and said particles have a D50 from about 28 ⁇ m to about 74 ⁇ m. In some embodiments, the particles comprise an un-milled form of Compound 1 and said particles have a D90 from about 69 ⁇ m to about 142 ⁇ m.
  • the particles comprise a milled form of Compound 1. In some embodiments, the particles comprise a milled form of Compound 1 and said particles have a D10 from about 5 ⁇ m to about 10 ⁇ m. In some embodiments, the particles comprise a milled form of Compound 1 and said particles have a D50 from about 18 ⁇ m to about 29 ⁇ m. In some embodiments, the particles comprise a milled form of Compound 1 and said particles have a D90 from about 38 ⁇ m to about 57 ⁇ m.
  • the density at 15kPa, also referred to as “compressibility,” of Compound 1 is measured.
  • Compound 1 has a compressibility of from about 0.55 g/mL to about 0.65 g/mL. In some embodiments, Compound 1 has a compressibility of from about 0.56 g/mL to about 0.62 g/mL.
  • Compound 1 can be formulated as pharmaceutical compositions for administration in solid or liquid form, including those adapted for the following: oral administration, for example, tablets, capsules, boluses, powders, granules, or pastes; intravaginally or intrarectally, for example, as a pessary, cream, stent or foam; sublingually; ocularly; pulmonarily; local delivery by catheter or stent; intrathecally, or nasally.
  • oral administration for example, tablets, capsules, boluses, powders, granules, or pastes
  • intravaginally or intrarectally for example, as a pessary, cream, stent or foam
  • sublingually ocularly
  • pulmonarily local delivery by catheter or stent
  • intrathecally or nasally.
  • Compound 1 is formulated as pharmaceutical composition for administration in the form of a capsule.
  • compositions comprise Compound 1, and optionally one or more pharmaceutically acceptable excipients, carriers, including inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants.
  • a pharmaceutical composition described herein includes a second active agent such as an additional therapeutic agent, (e.g., a chemotherapeutic).
  • compositions comprise Compound 1 together with a pharmaceutically acceptable carrier, which, as used herein, includes any and all solvents, diluents, or other vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • a pharmaceutically acceptable carrier which, as used herein, includes any and all solvents, diluents, or other vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • compositions comprise Compound 1 filled in a capsule without any excipients.
  • Compound 1 may be filled directly into hard gelatin capsules, with no excipients.
  • compositions may be formulated as a drug-in-capsule without excipients.
  • the drug-in-capsule composition comprises Compound 1 that is equivalent to 20 mg of Compound (A).
  • the drug-in-capsule composition comprises Compound 1 that is equivalent to 40 mg of Compound (A).
  • aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions can also contain adjuvants such as preservatives, wetting agents, emulsifying agents, dispersing agents, lubricants, and/or antioxidants.
  • adjuvants such as preservatives, wetting agents, emulsifying agents, dispersing agents, lubricants, and/or antioxidants.
  • Prevention of the action of microorganisms upon Compound 1 can be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like.
  • isotonic agents such as sugars, sodium chloride, and the like into the compositions.
  • prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
  • Methods of preparing these formulations or compositions include the step of bringing into association Compound 1 and/or the chemotherapeutic with the carrier and, optionally, one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association Compound 1 with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • the present disclosure provides processes for preparing Compound 1. Exemplary processes, as described herein, for preparing Compound 1 are shown in FIG. 1 and FIG. 2.
  • the process for the preparation of Compound 1 comprises: (i) mixing Compound (A) with succinic acid in the presence of a solvent (ii) heating the mixture of step (i), (iii) adding a seeding material to the mixture of step (ii), (iv) thermal cycling the mixture at a temperature of between about 45 °C-75 °C (v) repeating the (iv) thermal cycling step, (vi) performing a cool-heat step at a temperature of between about 20 °C-40 °C, (vii) collecting solids to provide Compound 1, and (viii) optionally, milling the solids obtained in step (vii) to provide a milled form of Compound 1.
  • the solvent in step (i) is acetone, acetone/water (3:1), acetonitrile, anisole, methanol, ethanol, propanol, 1-butanol, dimethylacetamide, dimethylformamide, dimethylsulfoxide, 1,4-dixoane, ethyl acetate, a mixture of methanol and water (3:1), 2-methoxyethanol, methyltetrahydrofuran, tetrahydrofuran, a mixture of tetrahydrofuran and water (3:1), a mixture of methyltetrahydrofuran and water (96:4), methyl acetate, methylethyl ketone, methyl isobutyl ketone, N-methyl-2-pyrrolidone, or a mixture thereof.
  • the solvent in step (i) is an alcohol, such as methanol, ethanol, propanol, or 1-butanol.
  • the solvent in step (i) is ethanol.
  • the temperature of step (ii) is from about 73°C to about 83 °C. In some embodiments, the temperature of step (ii) is about 78°C. In some embodiments, the temperature of step (ii) has a 5 °C variation. In some embodiments, the temperature of step (ii) is 78 ⁇ 5 °C.
  • the amount of solvent in step (i) ranges from about 28.5 liters of solvent per kilogram of Compound (A) to about 31.5 liters of solvent per kilogram of Compound (A).
  • an optional clarifying filtration step is performed on the resulting mixture of, followed by a solvent rinse.
  • the solvent rinse is between about 1.9 liters of solvent per kilogram of Compound (A) and about 2.1 liters of solvent per kilogram of Compound (A).
  • the temperature of the clarifying filtration step is from about 73°C to about 83 °C. In some embodiments, the temperature the clarifying filtration step about 78°C. In some embodiments, the temperature the clarifying filtration step has a 5 °C variation. In some embodiments, the temperature of the clarifying filtration step is 78 ⁇ 5 °C.
  • the mixture after step (ii) or after the optional clarifying filtration is distilled to a target volume.
  • the target volume is about 11 liters of solvent per kilogram of Compound (A) to about 15 liters of solvent per kilogram of Compound (A).
  • the target volume is about 12 liters of solvent per kilogram of Compound (A) to about 14 liters of solvent per kilogram of Compound (A).
  • the target volume is about 13 liters of solvent per kilogram of Compound (A).
  • the mixture is cooled to a temperature of about 73°C to about 77 °C, and held until the temperature is stabilized. In some embodiments, the mixture is cooled down to a temperature of about 75°C.
  • a seeding material is added to the mixture of step (ii). In some embodiments, about 0.5%, about 0.75%, about 1.0%, about 1.25%, or about 1.5% by weight of seeding material is added to the mixture. In some embodiments, about 0.75%, about 1.0%, or about 1.25% by weight of seeding material is added to the mixture. In some embodiments, about 1.0% by weight of seeding material is added to the mixture.
  • the seeding material is Compound 1 in milled form. In some embodiments, the seeding material is Compound 1 in jet-milled form. In some embodiments, Compound 1 is suspended in an organic solvent. In some embodiments, the organic solvent in which Compound 1 is suspended in is an alcohol, such as methanol, ethanol, propanol, or 1-butanol. In some embodiments, the organic solvent in which Compound 1 is suspended in is ethanol. In some embodiments, the seeding material is a jet-milled form of Compound 1 suspended in ethanol.
  • the seeding material has a particle size distribution defined by a D90.
  • the D90 of the seeding material is about 3 ⁇ m (micron) to about 8 ⁇ m (micron).
  • the seeding material has a particle size distribution defined by surface area.
  • the seed surface area of the seeding material is between about 3 m 2 /g and about 11 m 2 /g. In some embodiments, the seed surface area of the seeding material is between about 4 m 2 /g and about 7 m 2 /g.
  • the resulting slurry is held at a stable temperature for a period of about 15 min to about 60 minutes. In some embodiments, the resulting slurry is held at a stable temperature for about 30 min. In some embodiments, the resulting slurry is held at a stable temperature for about 60 min.
  • the resulting mixture is placed under “thermal cycling” at a temperature of between about 45 °C-75 °C.
  • thermal cycling refers to the process of cooling the mixture to a low temperature point of the cycle over a fixed period of time, holding the mixture at that low temperature for a fixed period of time, heating the mixture to the high temperature point of the cycle over a fixed period of time, and holding the mixture at that high temperature for a fixed period of time.
  • the temperature cycling is conducted, meaning that the temperature is increased or decreased depending on the point of the cycle, at a rate of from about 0.05 to about 0.5 °C per minute.
  • thermal cycling is conducted at a rate of from about 0.1 to about 0.3 °C per minute.
  • thermal cycling is conducted at a rate of about 0.1 °C per minute.
  • the mixture is slow-cooled to about 45 °C to about 55 °C. In certain embodiments, during the thermal cycle, the mixture is slow-cooled to about 48 °C to about 52 °C. In certain embodiments, during the thermal cycle, the mixture is slow-cooled to about 50 °C. In certain embodiments, the slow-cooling is conducted at a rate of from about 0.1 to about 0.5 °C per minute. In certain embodiments, the slow-cooling period is between about 200 and about 350 minutes. In certain embodiments, the slow-cooling period is between about 250 and about 300 minutes. In certain embodiments, the slow-cooling period is about 250 minutes. In certain embodiments, the slow-cooling period is about 200 minutes. In certain embodiments, the resulting mixture is slow-cooled to about 50 °C over a period of about 250 minutes. In certain embodiments, the resulting mixture is slow-cooled to about 50 °C over a period of about 200 minutes.
  • the mixture is held at the low temperature of the cycle. In certain embodiments, following the slow-cooling, the mixture is held for a period of about 15 minutes to about 75 minutes. In certain embodiments, following the slow-cooling, the mixture is held for a period of about 30 minutes to about 60 minutes. In certain embodiments, following the slow-cooling, the mixture is held for a period of about 30 minutes.
  • the mixture is slow-heated to about 65 °C to about 75 °C. In certain embodiments, during the temperature cycle, the mixture is slow-heated to about 68 °C to about 72 °C. In certain embodiments, during the temperature cycle, the resulting mixture is slow-heated to about 70 °C. In certain embodiments, the slow-heating period is between about 160 and about 280 minutes. In certain embodiments, the slow-heating period is between about 200 and about 250 minutes. In certain embodiments, the slow-heating period is about 200 minutes. In certain embodiments, the resulting mixture is slow-heated to about 70 °C over a period of at least 200 minutes.
  • the mixture is held at the high temperature of the cycle. In certain embodiments, following the slow-heating, the mixture is held for a period of about 15 minutes to about 75 minutes. In certain embodiments, following the slow-heating, the mixture is held for a period of about 30 minutes to about 60 minutes. In certain embodiments, following the slow-heating, the mixture is held for a period of about 30 minutes.
  • the thermal cycling step is repeated one to three times. In certain embodiments, the thermal cycling step is repeated once for a total of two cycles. In certain embodiments, the thermal cycling step is repeated twice for a total of three cycles. In certain embodiments, the thermal cycling step is repeated three times for a total of four cycles.
  • a (vi) cool-heat step is performed at a temperature of between about 15 °C-45 °C.
  • the cool-heat step comprises a (vi.1) slow-cooling step, (vi.2) a hold time at a low temperature, a (vi.3) heating step, (vi.4) a hold time at high temperature, and a (vi.5) final cooling step.
  • the (vi) cool-heat step comprises the steps of: (vi.1) slow-cooling the mixture to a temperature between about 15 °C and about 25 °C over a period of about 400 to about 700 minutes, (vi.2) holding the temperature for about 15 minutes to about 75 minutes (vi.3) slow-heating the mixture to a temperature between about 35 °C and about 45 °C over a period of about 150 to about 250 minutes (vi.4) holding the temperature for about 15 minutes to about 75 minutes, and (vi.5) cooling the mixture to a temperature between about 10 °C and about 20 °C over a period of about 160 to about 280 minutes.
  • step (vi.1) comprises slow-cooling the mixture between a temperature of about 18 °C and about 22 °C. In certain embodiments, step (vi.1) comprises slow-cooling the mixture to about 20 °C. In certain embodiments, step (vi.1) comprises slow-cooling the mixture over a period of about 500 to about 600 minutes. In certain embodiments, step (vi.1) comprises slow-cooling the mixture over a period of about 500 minutes.
  • step (vi.2) comprises holding the mixture at about 15 °C and about 25 °C for about 30 minutes to about 60 minutes. In certain embodiments, step (vi.2) comprises holding the mixture at about 15 °C and about 25 °C for about 30 minutes.
  • step (vi.3) comprises slow-heating the mixture to a temperature between about 38 °C and about 42 °C. In certain embodiments, step (vi.3) comprises slow-heating the mixture to about 40 °C. In certain embodiments, step (vi.3) comprises slow-heating the mixture over a period of about 200 to about 250 minutes. In certain embodiments, step (vi.3) comprises slow-cooling the mixture over a period of about 200 minutes.
  • step (vi.4) comprises holding the mixture at a temperature between about 35 °C and about 45 °C for about 30 minutes to about 60 minutes. In certain embodiments, step (vi.4) comprises holding the mixture at about 15 °C and about 25 °C for about 30 minutes.
  • step (vi.5) comprises cooling the mixture to a temperature between about 18 °C and about 22 °C. In certain embodiments, step (vi.5) comprises cooling the mixture to about 20 °C. In certain embodiments, step (vi.5) comprises cooling the mixture over a period of about 200 to about 250 minutes. In certain embodiments, step (vi.5) comprises cooling the mixture over a period of about 200 minutes
  • the resulting mixture Upon completion of the (vi) cool-heat step, the resulting mixture is held at the final temperature for a period of about 1 hour to about 48 hours. In certain embodiments, the resulting mixture is held for a period of about 3 hours to about 24 hours. In certain embodiments, the resulting mixture is held for a period of about 3 hours
  • aging As used herein, holding a mixture for a period of time is sometimes referred to as “aging” the mixture. Accordingly, these two terms are used interchangeably.
  • the solvent is an alcohol, such as methanol, ethanol, propanol, or 1-butanol. In some embodiments, the solvent is ethanol.
  • the process comprises an optional (viii) milling step.
  • An exemplary process comprising this step is shown in FIG. 2.
  • milling occurs at a speed of 2700 rotations per minute (RPM) to 4700 RPM. In some embodiments, milling occurs at a speed of 2700 RPM. In some embodiments, the milling is pin-milling.
  • Compound 1 is made by the process shown in FIG. 1.
  • Compound 1 is made by: (i) mixing Compound (A) with succinic acid in the presence of a solvent (ii) heating the mixture of step (i) to 78 ⁇ 5 °C in solvent at a concentration of about 30 liters of solvent per kg of Compound (A), (iii) performing a clarifying filtration, (iv) distilling the mixture to a concentration of about 13 liters of solvent per kg of Compound (A), (v) cooling the mixture to 75 ⁇ 2 °C, (vi) adding 1 wt% of a seeding material to the mixture, (vii) aging the mixture for 30-60 minutes, (viii) cooling the mixture to 50 ⁇ 5 °C at a rate of 0.1 °C/min, (ix) aging the mixture for 30-60 minutes, (x) thermal cycling the mixture at a temperature of between 50 ⁇ 5 °C and 70 ⁇ 5 °C, (xi) aging the mixture for 30 minutes each time the temperature reaches 50 ⁇ 5 °C and
  • Compound 1 is made by the process shown in FIG. 2.
  • Compound 1 is prepared by a process comprising: (i) mixing Compound (A) with succinic acid in the presence of a solvent (ii) heating the mixture of step (i) to 78 ⁇ 5 °C in solvent at a concentration of about 30 liters of solvent per kg of Compound (A), (iii) performing a clarifying filtration, (iv) distilling the mixture to a concentration of about 13 liters of solvent per kg of Compound (A), (v) cooling the mixture to 75 ⁇ 2 °C, (vi) adding 1 wt% of a seeding material to the mixture, (vii) aging the mixture for 30-60 minutes, (viii) cooling the mixture to 50 ⁇ 5 °C at a rate of 0.1 °C/min, (ix) aging the mixture for 30-60 minutes, (x) thermal cycling the mixture at a temperature of between 50 ⁇ 5 °C and 70 ⁇ 5 °C, (xi) aging the mixture for 30 minutes each time the temperature reaches 50 ⁇ 5 °
  • Compound 1 obtained by the processes described herein is in a substantially crystalline form.
  • substantially crystalline form refers to at least a particular percentage by weight of Compound 1 that is crystalline. Particular weight percentages include at least about 50%, 60%, 70%, 75%, 80%, 85%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5% and 99.9%.
  • Bulk and Tap Density Bulk and Tap Analysis is performed using a Copley Tap Density Analyzer. First, the bulk density is assessed using a 25ml graduated cylinder. A graduated cylinder is placed on a balance and tared. The cylinder is then held horizontally, and sample is scooped from the powder container directly into the graduated cylinder. Powder is added into the graduated cylinder, with care being taken to avoid tapping or jostling the cylinder to prevent consolidation. When the cylinder is almost full, the cylinder is carefully rotated to the vertical position, and a volume reading is taken. If the powder is unevenly distributed at the top of the cylinder, an average line can be used between the peaks and troughs to estimate the total volume.
  • the sample is placed on the balance and the net weight of powder is recorded.
  • the sample is then placed on the Tap Density Analyzer, under a protective ring.
  • the cylinder is then automatically tapped a total of 2000 times. After tapping is complete, the protective rings are removed and the volume of the powder in the cylinder is recorded.
  • the bulk density is calculated by dividing the mass by the pre-tap volume, while the tap density is calculated by dividing the mass by the post-tap volume.
  • Compressibility begins by measuring condition bulk density first. Before each test is run, the powder is first conditioned. This is to standardize the powder packing of each sample as the process removes any compaction or excess air, it also removes variability introduced by the operator during loading of the sample.
  • a conditioning cycle comprises a traverse of the blade downward and then a traverse upward. This is repeated 3 times. For the compressibility test, the sample is then split such that the top, excess portion of the sample is removed. Since the volume and weight of the sample is then known, the conditioned bulk density can then be calculated. After the conditioning steps, the stirrer blade is replaced with a piston that then applies force to the sample.
  • a standardized method incrementally applies forces of 0.5, 1, 2, 4, 6, 8, 10, 12, 15kPa on a 50mm vessel. Other methods may be used to measure compressibility, such as varying the applied force. Pin-Milling
  • Un-milled Compound 1 is poured into a hopper and then conveyed to the pin-mill via a vibratory feeder at a set feed rate (center-point 3.6 kg/hr). The mill is run at a set speed (center-point 3700 RPM), and the milled product is collected in a bag. An intermediate process control (IPC) sample is removed from the product, and the particle size of the product is tested against the d 90 target size range. If necessary, the milling speed is then adjusted to achieve the desired particle size.
  • IPC intermediate process control
  • Particle size distribution is measured via laser diffraction.
  • the particle size distribution may be measured via laser diffraction using the Malvern Mastersizer 3000 optical bench equipped with a Hydro MV wet dispersion unit.
  • the particle size distribution is determined by application of the Mie Theory.
  • Mie theory uses an optical scattering model based on refractive indices of the particle and dispersion medium and particle absorption values to calculate particle size distribution.
  • Sample measurement (a) Gently rotate and invert the sample container to ensure the sample is homogenous. (b) Weigh approximately 100 mg of sample into a 20 mL scintillation vial. (c) Add approximately 20 mL of toluene to the vial. Gently swirl and invert the vial to mix. (d) Vortex the vial for 15 seconds. (e) Align the instrument laser and measure the background. (f) Immediately prior to analysis, aspirate the sample with a plastic transfer pipette to ensure a uniformly-dispersed suspension. (g) Add the sample suspension drop-wise to the sample well until the obscuration is within the range, making sure to continue aspiration of the sample suspension so as to not allow for sedimentation in the pipette tip.
  • FIG. 1 is a graphic representation of the process described below.
  • a clean and dry reactor is charged with Compound (A) (1.0 eq), succinic acid (1.02 eq) and ethanol (30.0 L/kg).
  • the resultant slurry is agitated and heated to 78 °C, at which point a clear solution is obtained.
  • a clarifying filtration is performed, followed by a 2.0 L/kg ethanol vessel rinse.
  • the solution is distilled down to 13 volumes (13L/kg).
  • the solution is cooled to 75 °C and held until the temperature is stable.
  • a slurry of 1 wt% Compound 1 jet-milled seed in ethanol is charged to the reactor and the slurry is held for 30 minutes to ensure the seeds hold.
  • the batch is subjected to 3 heating and cooling cycles between 50 °C and 70 °C at a rate of 0.1 °C/min with 30 minute holds each time the temperature reaches both 50 °C and 70 °C.
  • the temperature of the batch is reduced to 20 °C at approximately 0.1 °C/min.
  • the solution is held for 30 minutes, followed by heating the batch to 40 °C at approximately 0.1 °C/min, held for 30 minutes, then cooled to 20 °C at 0.1 °C/min.
  • the batch is held for 3-24 hours.
  • the solids are collected by filtration, washed with ethanol (2 x 3 L/Kg) and dried under vacuum at 55-65 °C.
  • the values for the factors were selected based on the typical settings in the manufacturing settings. Seed surface area from production ranged from 4 to 7 m 2 /g, so a wider range of seed surface area was chosen. Variation of the seed loading at production is ⁇ 0.003 wt%, but due to the scale, this was deemed infeasible to accurately charge, so the range was increased to ⁇ 0.5 wt%. Distillation accuracy is ⁇ 1 volume, a double range was selected. For temperature, the process has a ⁇ 2 °C tolerance, so this was doubled to roughly ⁇ 4 °C. The high-end and low-end of the thermocycling have a ⁇ 2°C tolerance but a ⁇ 5 °C tolerance was selected. A ⁇ 15-minute range hold time was used. The tolerance for time of the temperature adjustments used was a non-linear range of -20% and +40%.
  • the primary responses from the DoE were the particle size d 10 , d 50 , and d 90 . Additional responses were yield, bulk density, and tapped density.
  • the d 10 varied across the DoE design space from 9.8 to 53.6 ⁇ m, with a median of 22.3 ⁇ m (FIG. 7).
  • the d 50 varied across the DoE design space from 30.9 to 136.7 ⁇ m, with a median of 67.5 ⁇ m (FIG. 8).
  • the d 90 varied across the DoE design space from 76.9 to 352.6 ⁇ m, with a median of 152.1 ⁇ m (FIG. 9).
  • the bulk density varied across the DoE design space from 0.14 to 0.33 g/mL, with a median of 0.22 g/mL (FIG. 10).
  • the tapped density varied across the DoE design space from 0.26 to 0.47 g/mL, with a median of 0.36 g/mL (FIG. 11).
  • the yield varied across the DoE design space from 77.3 to 92.0%, with a median of 84.8% (FIG. 12).
  • the DoE ranges were set to be significantly wider than the typical tolerance during routine manufacturing.
  • the results of the maximization and minimization of the PSD parameters can be seen in Table 4.
  • a calculation was made assuming that the PSD would be reduced by 50% after going through an agitated filter dryer. From these more reasonable ranges for the factors, and assuming a 50% reduction of the PSD, the d 10 now ranges from 8.2 to 20.2 ⁇ m, the d 50 ranges from 26.1 to 53.9 ⁇ m, and the d 90 ranges from 65.5 to 124.3 ⁇ m.
  • Compound 1 can be made by a process where Compound (A) (25.6 kg), Succinic Acid (1.02 eq, approx.. 5.3 kg), and Ethanol (approx. 607 kg), are charged to a reactor and are heated to reflux until dissolution is achieved. The contents of the reactor are transferred to a second reactor by passing the solution through a filter. Additional EtOH (approximately 41 kg) is added to the first reactor to rinse it of residue, and the rinsate is filtered and charged to the second reactor. The reaction mixture is heated to reflux and distilled to approximately 333 L. Upon completion of the distillation, the temperature is adjusted to 75°C. A seed slurry is prepared in a suitable container by mixing micronized Compound 1 (approx.
  • FIG. 2 is a graphic representation of Example 2, wherein Compound 1 is pin-milled to the d 90 target size range of 45-55 ⁇ m.
  • Example 3 Milling and Bulk Density.
  • Table 6 shows various process parameters and sample properties of Compound 1 produced by the processes described above with the modifications shown in Table 6.
  • FIG. 3 is a graphic representation of Example 5.
  • Seeds were generated using 3 different configurations (coarse, medium and fine) having particle size distributions shown in Table 9.
  • the 3 lots of product were used as seed input to crystallizations at both 1 and 5 wt% loadings.
  • the resulting physical properties from the crystallizations can be seen in Table 10.
  • un-milled seeds were used as input as well.
  • bulk density and d 90 particle size did not have a direct correlation with the seed input size. Because of the shape of the size distributions, the inconsistency and bi-modality of the size distributions likely resulted in material that could not pack together well, resulting in the poor bulk density.
  • the conditions that gave the highest bulk density of product was a 5 wt% loading of fine material. While the 5 wt% fine material loading provided a reasonable bulk density, seeding alone was insufficient to produce a reasonable bulk density.
  • Example 1 The learnings from the seeding, heat cycling, and seed surface area studies were applied to produce the process in Example 1.
  • the batch was seeded with 1 wt% medium sized seed and the thermalcycling was performed between 50-70 °C with a heating/cooling rate of 0.1 °C/min. Additionally, each time the crystallization reached 50 and 70 °C, a 30 minute hold was implemented. A final thermal cycle between 20 and 40 °C was also implemented.

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Abstract

La présente invention concerne des compositions du composé 1 et des procédés de préparation de compositions du composé 1.
PCT/JP2022/026431 2021-06-30 2022-06-30 Procédé de préparation de sels pharmaceutiques de dérivés de pyrimidine WO2023277172A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015195228A1 (fr) 2014-06-19 2015-12-23 Ariad Pharmaceuticals, Inc. Composés hétéroaryle d'inhibition de la kinase
WO2019222093A1 (fr) 2018-05-14 2019-11-21 Ariad Pharmaceuticals, Inc. Sels pharmaceutiques de dérivés de pyrimidine et méthode de traitement d'affections

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015195228A1 (fr) 2014-06-19 2015-12-23 Ariad Pharmaceuticals, Inc. Composés hétéroaryle d'inhibition de la kinase
WO2019222093A1 (fr) 2018-05-14 2019-11-21 Ariad Pharmaceuticals, Inc. Sels pharmaceutiques de dérivés de pyrimidine et méthode de traitement d'affections

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"Basic and Clinical Pharmacology", 2003, MCGRAW HILL
"Handbook of Clinical Drug Data", 2002, MCGRAW-HILL
"Principles of Drug Action", 1990, CHURCHILL LIVINGSTON
"The Pharmacological Basis of Therapeutics", 2000, LIPPINCOTT WILLIAMS & WILKINS
MARTINDALE: "The Extra Pharmacopoeia", 1999, THE PHARMACEUTICAL PRESS
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