US20130172376A1 - Solid dosage forms of (s)-ethyl 2-amino-3-(4-(2-amino-6-((r)-1-(4-chloro-2-(3-methyl-1h-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoate - Google Patents

Solid dosage forms of (s)-ethyl 2-amino-3-(4-(2-amino-6-((r)-1-(4-chloro-2-(3-methyl-1h-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoate Download PDF

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US20130172376A1
US20130172376A1 US13/652,527 US201213652527A US2013172376A1 US 20130172376 A1 US20130172376 A1 US 20130172376A1 US 201213652527 A US201213652527 A US 201213652527A US 2013172376 A1 US2013172376 A1 US 2013172376A1
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tablet
phenyl
amino
magnesium stearate
telotristat
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US13/652,527
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Jinling Chen
Matthew S. DEAVER
Richard J. Holl
Kalyan NUGURU
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Lexicon Pharmaceuticals Inc
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Lexicon Pharmaceuticals Inc
Catalent Pharma Solutions Inc
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Priority to US13/652,527 priority Critical patent/US20130172376A1/en
Assigned to LEXICON PHARMACEUTICALS, INC. reassignment LEXICON PHARMACEUTICALS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CHEN, JINLING
Assigned to CATALENT PHARMA SOLUTIONS, INC. reassignment CATALENT PHARMA SOLUTIONS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: DEAVER, Matthew S., HOLL, RICHARD J., NUGURU, Kalyan
Assigned to LEXICON PHARMACEUTICALS (NEW JERSEY), INC. reassignment LEXICON PHARMACEUTICALS (NEW JERSEY), INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CATALENT CTS, LLC
Assigned to LEXICON PHARMACEUTICALS, INC. reassignment LEXICON PHARMACEUTICALS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: LEXICON PHARMACEUTICALS (NEW JERSEY), INC.
Publication of US20130172376A1 publication Critical patent/US20130172376A1/en
Priority to US14/619,150 priority patent/US20150157632A1/en
Priority to US15/613,458 priority patent/US20190000843A1/en
Priority to US16/688,658 priority patent/US11406635B2/en
Abandoned legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • 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
    • A61K31/495—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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2893—Tablet coating processes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C07D403/12—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 linked by a chain containing hetero atoms as chain links

Definitions

  • This invention relates to solid pharmaceutical dosage forms of (S)-ethyl 2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoate (telotristat).
  • telotristat The compound (S)-ethyl 2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoate (telotristat) is an inhibitor of tryptophan hydroxylase, the enzyme responsible for the rate-limiting step in biosynthesis of 5-hydroxytryptamine (serotonin). See, e.g., U.S. Pat. No. 7,709,493.
  • the compound is believed to be useful in the treatment of diseases and disorders associated with abnormal levels of serotonin, such as diarrhea-predominant irritable bowel syndrome and carcinoid syndrome.
  • serotonin such as diarrhea-predominant irritable bowel syndrome and carcinoid syndrome.
  • telotristat's physicochemical properties make its incorporation into a commercially viable dosage form difficult.
  • Telotristat hydrolyzes when contacted with water. Dosage forms comprising it must, therefore, limit this degradation as much as possible, and must be made using methods that limit the compound's exposure to moisture. The poor flowability of telotristat's crystalline hippurate salt (telotristat etiprate) further complicates the manufacture of dosage forms comprising it. Further adding to the problem is the desire to provide single unit dosage forms that contain at least 100 mg of the compound, and that rapidly release it upon oral administration.
  • telotristat that can be stored at typical temperatures and humidity levels for a commercially viable period of time, and for methods of their manufacture.
  • Preferred dosage forms should be capable of rapidly delivering the compound upon oral administration.
  • This invention is directed to solid dosage forms of telotristat.
  • Particular dosage forms are tablets made with the hippurate salt of telotristat (telotristat etiprate).
  • One embodiment of the invention encompasses a tablet suitable for administration to a patient comprising at least 100, 200, or 300 mg of an active pharmaceutical ingredient (API), which tablet has a disintegration time of less than 10, 5.0, 2.3, 2.0, or 1.8 minutes in water, wherein the API is telotristat or a pharmaceutically acceptable salt thereof.
  • API active pharmaceutical ingredient
  • Another embodiment encompasses a tablet suitable for administration to a patient comprising at least 100, 200, or 300 mg of an API based on free base, which tablet comprises a coating and has a disintegration time of less than 5.5, 4.5, or 4.0 minutes in water, wherein the API is telotristat or a pharmaceutically acceptable salt thereof.
  • Another embodiment encompasses a tablet having a core consisting essentially of telotristat hippurate, lactose, hyrdroxy propyl cellulose, croscarmellose sodium, magnesium stearate, and silicon dioxide.
  • Another embodiment encompasses a tablet comprising telotristat or a pharmaceutically acceptable salt thereof, which forms less than 1.0, 0.8 or 0.5 percent (S)-2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid when stored at about 40° C. and about 75% relative humidity for six months.
  • Another embodiment encompasses a tablet comprising telotristat or a pharmaceutically acceptable salt thereof, which forms less than 0.5 or 0.4 percent (S)-2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid when stored at about 40° C. and about 75% relative humidity for three months.
  • Another embodiment encompasses a granule comprising telotristat etiprate, lactose, hydroxyl propyl cellulose, croscarmellose sodium, magnesium stearate, and silicon dioxide.
  • Another embodiment encompasses a method of making a tablet, which comprises: combining granules comprising intragranular ingredients with at least one extragranular ingredient, and compressing the granules to provide a tablet; wherein the intragranular ingredients comprise telotristat or a pharmaceutically acceptable salt thereof, magnesium stearate, and lactose; and at least one extragranular ingredient is lactose.
  • FIG. 1 shows an X-ray powder diffraction (XRPD) pattern of a crystalline form of telotristat.
  • the diffractogram was obtained using a Rigaku MiniFlex diffractometer (copper K ⁇ radiation).
  • FIG. 2 provides an XRPD pattern of a crystalline form of telotristat etiprate.
  • the diffractogram was obtained using a Bruker D8 Advance (copper K ⁇ radiation).
  • FIG. 3 shows the effects of temperature, humidity and time on the formation of the hydrolysis product (S)-2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid in different dosage forms of telotristat.
  • This invention is directed to solid pharmaceutical dosage forms in which an active pharmaceutical ingredient (API) is (S)-ethyl 2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoate (telotristat):
  • Particular dosage forms comprise crystalline telotristat freebase.
  • One form of this compound has a melting point of about 104° C. as determined by differential scanning calorimetry (DSC) (onset temperature).
  • DSC differential scanning calorimetry
  • the term “about” means ⁇ 3° C.
  • This form provides an X-ray powder diffraction (XRPD) pattern that contains peaks at about 10.7, 12.2, 12.8, 17.7 and/or 22.0 degrees 20.
  • XRPD peaks As used in connection with XPRD peaks, the term “about” means ⁇ 0.3 degrees 20.
  • the relative intensities of peaks in an XRPD pattern of a crystalline material can vary depending on how the sample is prepared and how the data is collected. With this in mind, an example of an XRPD pattern of this crystalline form is provided in FIG. 1 .
  • Particular dosage forms comprise the hippurate salt of telotristat (telotristat hippurate; telotristat etiprate).
  • a particular crystalline form of this salt has a melting point of about 142° C. (DSC onset temperature, with a peak at about 147° C.).
  • a particular crystalline form provides an XRPD pattern that contains peaks at about 8.2, 9.5, 12.6, 16.9, 21.8, 22.0, 22.7, 24.3 and/or 29.1 degrees 20.
  • An example of an XRPD pattern of this form is provided in FIG. 2 .
  • telotristat When contacted with water, telotristat can hydrolyze to form (S)-2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid.
  • Preferred dosage forms of this invention minimize this degradation.
  • FIG. 3 shows the difference between two tablets of the invention—formulations 6 and 8, described in the examples below—and a capsule dosage form that was used in human Phase 1 and 2 clinical trials.
  • the capsules contained a mixture of 250 mg telotristat and 2% magnesium stearate. Both tablet formulations are clearly more stable than the capsule formulation.
  • the bioavailability of an API can greatly depend on the formulation in which it is delivered to a patient.
  • tablets that rapidly disintegrate when administered to a patient are desired.
  • Particular non-coated tablets of this invention have a disintegration time of less than 2.3, 2.0, or 1.8 minutes in water, or less than 4.0, 3.0, or 2.7 minutes in 0.1 N HCl.
  • Particular-film coated tablets of the invention have a disintegration time of less than 5.5, 4.5, or 4.0 minutes in water, or less than 5.4, 5.0, or 4.8 minutes in 0.1 N HCl.
  • disintegration time refers to disintegration time in 100 mL of purified water or 0.1 N HCl as measured according to test USP ⁇ 701>.
  • the disintegration of a tablet can be affected by the disintegrants it contains.
  • disintegrants include alginates, celluloses, croscarmellose sodium, crospovidone, and sodium starch glycolate.
  • a preferred disintegrant is croscarmellose sodium.
  • tablettes of the invention have a hardness greater than 8, 9, or 10 kP, and a friability of less than 0.4, 0.3, or 0.25 (percent loss).
  • telotristat etiprate cellulose, lactose, croscarmellose sodium, magnesium stearate, and silicon dioxide
  • This invention encompasses methods of making solid dosage forms of telotristat and salts thereof that limit the compound's exposure to water and address the poor flow properties exhibited by many of its forms.
  • roller compaction is used to prepare a granular material (“granulate”) made of up granules comprising the compound, which is then combined with additional excipients and compressed to provide a tablet core. The core is then optionally coated to increase the stability of the resulting tablet.
  • Particulate granules comprise telotristat etiprate, hydroxypropyl cellulose, lactose, croscarmellose sodium, magnesium stearate, and silicon dioxide. Preferred granulates flow and compress well, allowing the ready manufacture of tablets possessing the desired hardness, stability, and disintegration properties described herein.
  • the solid dosage forms (e.g., tablets) of the invention can be packaged by methods and using containers known in the art.
  • the packaging material may form a plurality of divided containers such as a divided bottle or a divided foil packet.
  • the container can be in any conventional shape or form as known in the art which is made of a pharmaceutically acceptable material, for example a paper or cardboard box, a glass or plastic bottle or jar with or without desiccant, a re-sealable bag (for example, to hold a “refill” of tablets for placement into a different container), or a blister pack (e.g., Aclar blisters or foil/foil blisters) with individual doses for pressing out of the pack according to a therapeutic schedule.
  • tablets are stored in an induction-sealed HDPE bottle with a desiccant pack.
  • Disintegration testing was performed as per USP ⁇ 701> using the test for uncoated tables and plain coated tablets. The disintegration was performed in 1000 mL purified water or 0.1 N HCl. Disintegration endpoint was determined visually.
  • Dissolution was determined in 900 mL of 0.1 N HCl at 37° C. using USP Apparatus 2 (paddles) set at 50 rpm. Filtrates of the dissolution test solution were collected at specific time intervals. The samples were analyzed by high performance liquid chromatography (HPLC) using a PhenomenexSynergi 4 ⁇ Max-RP column and a mobile phase of 70/30/0.2 (v/v/v) methanol/water/phosphoric acid at a flow rate of 1.0 mL/min. The HPLC system utilized ultraviolet (UV) detection at a wavelength of 237 nm.
  • UV ultraviolet
  • Granulation particle size was determined using a sieve method, wherein the tare weight of each of several sieves (mesh 25, 40, 60, 100, 140, 230, and Fines) was recorded, the sieves were stacked in order of the coarsest sieve on top and the finest on bottom, and approximately 5 grams of the granulate material was transferred to the top sieve.
  • the assembly was secured and placed in an ATM Sonic sifter, the pulse amplitude and sift amplitudes both set to 5. After 5 minutes, the assembly was removed and the individual sieves weighed.
  • Flow properties were determined using a J.R. Johanson Flow Indicizer.
  • Tablets comprising 300 mg (measured as free base) of the API telotristat in the hippurate salt form were made in two general steps. First, granules comprising crystalline telotristat etiprate and selected excipients (intragranular components) were prepared. The material was compressed using a roller compactor and milled. The intragranular material was then combined with additional excipients (“extragranular components”), and the resulting mixture was compressed to provide the tablets. In some cases, the tablets were coated.
  • Batches were prepared by screening all intragranular materials except magnesium stearate through a 20-mesh screen. Components were blended in an appropriately sized V-blender for 10 minutes. Intragranular magnesium stearate was combined with a portion of the blend and co-screened through a 20-mesh screen. The screened magnesium stearate blend was then charged into the V-blender and blended for an additional three minutes. The blend was then roller compacted using a Vector TF-Mini roller compactor with a target ribbon thickness of 1.5 mm. The ribbons were milled by sequentially oscillating them through a 14-mesh and 20-mesh screen. All extragranular components except magnesium stearate were combined and screened through a 20-mesh screen.
  • tablets were made from the ingredients listed below in Table 1:
  • the intragranular components were mixed and roller compacted with a roller pressure of 70 kg/cm 2 .
  • the ribbons were 0.99-1.42 mm in thickness.
  • a bench-top ribbon disintegration test was performed by placing a one inch section of ribbon in a beaker containing approximately 500 mL of DI water and allowed to disintegrate. The ribbon disintegrated in 12.5 minutes. Inspection of the roller compactor rollers indicated that some sticking had occurred. Ribbons were milled by oscillating sequentially through a 14-mesh and 20-mesh screen. The granulation was blended with extragranular components and physical tests were performed. The granules flowed poorly, and the initial tablets exhibited weight variations and low average tablet weight.
  • tablets were made from the ingredients listed below in Table 4:
  • the intragranular components were mixed and roller compacted with a roller pressure of 45 kg/cm 2 .
  • the ribbon thicknesses ranged from 1.16-1.46 mm.
  • Bench-top ribbon disintegration test resulted in a disintegration time of 3 minutes. Some sticking was noted during the roller compaction of the blend.
  • the ribbons were milled by oscillating sequentially through a 14-mesh and 20-mesh screen. The ribbons were hard and more difficult to mill. Approximately 0.75% of the batch did not pass through the oscillator.
  • the granulation was blended with extragranular components and physical tests were performed. Granulation exhibited poor flow characteristics, although the compression was manageable. Some sticking to tablet punches was observed initially during compression, which subsided after the punches were cleaned. The tablets exhibited a dull appearance, which did not improve when the compression force was increased.
  • tablets were prepared using the ingredients listed below in Table 5:
  • the mixture of intragranular components was roller compacted with a roller pressure of 50 kg/cm 2 .
  • the ribbon thicknesses ranged from 1.40-1.90 mm.
  • Bench-top ribbon disintegration test resulted in an undesirable disintegration time of 11 minutes. Some sticking was observed during the roller compaction process.
  • the ribbons were similar to Formulation 2 and were difficult to mill.
  • Granulation was blended with extragranular components and physical tests were performed. The granulation exhibited poor flow, and some rat-holing was observed in the hopper during compression, which was overcome by agitating the hopper. Tablet compression was completed with no observable problems.
  • tablet disintegration testing in water and 0.1N HCl resulted in disintegration times significantly longer than those observed the other formulations, suggesting that in these formulations, crospovidone is a less effective disintegrant than croscarmellose sodium.
  • tablets were prepared using the ingredients listed below in Table 7:
  • the mixture of intragranular components was roller compacted with a roller pressure of 50 kg/cm 2 .
  • the ribbon thickness ranged from 1.37-1.83 mm.
  • Bench-top ribbon disintegration time was 1 minute. Minor sticking was observed throughout the roller compaction process.
  • the granulation was blended with the extragranular components and physical tests were performed. The granulation exhibited poor flow, but tablet compression was completed with no observable problems.
  • the formulation was capable of achieving hardnesses exceeding 18 kP. Tablet disintegration testing in water and 0.1N HCl resulted in acceptable disintegration times for an immediate release tablet: 2.0 minutes in water, 4.0-5.25 minutes in 0.1N HCl.
  • assay and related substance testing indicated that an unacceptable amount of what is believed to be a hydrolysis product of the API increased significantly at the one-month time point when stored at 40° C./75% RH without desiccant.
  • the resulting tablets were coated to a 4% weight gain.
  • the dissolution profile of these tablets was acceptable, although the disintegration times in water and 0.1 N HCl were significantly longer than the uncoated tablets.
  • tablets were prepared using the ingredients listed below in Table 8:
  • the mixture of intragranular components was roller compacted with a roller pressure of 50 kg/cm 2 .
  • the ribbon thickness ranged from 1.11-1.52 mm.
  • Bench-top ribbon disintegration time was 1 minute. Very little sticking was observed throughout the roller compaction process. Although the granulation exhibited poor flow, it was blended and compressed into tablets, during which some sticking was observed. Tablets exhibited some chipping during friability testing. Dissolution and disintegration times were: 1.3-1.5 minutes in water; 1.5-2.8 minutes in 0.1 N HCl. These tablets particularly stable (0.23 area percent after 1 month at 40° C./75% relative humidity), and more so when stored with desiccant (0.16 area percent after 1 month at 40° C./75% relative humidity).
  • tablets were prepared using the ingredients listed below in Table 9:
  • the mixture of intragranular components was roller compacted with a roller pressure of 50 kg/cm 2 .
  • the ribbon thickness ranged from 1.45-1.63 mm.
  • Bench-top ribbon disintegration time was 3 minutes. Very little sticking was observed during roller compaction. Granulation, which exhibited poor flow, was blended and compressed into tablets. Sticking was observed on the punch faces and die walls during tablet compression. Chipping was also noted during friability testing. Dissolution and disintegration times were acceptable, although assay and related substance testing indicated a significant increase in apparent API hydrolysis product when stored for one month under accelerated conditions without desiccant (1.01 area percent after 1 month at 40° C./75% relative humidity). Desiccant decreased the observed level of hydrolysis product to 0.16.
  • tablets were prepared using the ingredients listed below in Table 10:
  • the mixture of intragranular components was roller compacted with a roller pressure of 55 kg/cm 2 .
  • the ribbon thickness ranged from 1.07-1.52 mm.
  • the material processed very well, yielding long ribbons.
  • Bench-top ribbon disintegration time was 2.5 minutes. Approximately 2% of the ribbons did not pass through the 20-mesh oscillating screen. Granulation was blended and compressed into tablets. The blend compressed well and no sticking was observed. Some minor picking was observed.
  • the tablets' disintegration profile was acceptable: uncoated tablets disintegrated in 1.8-2.3 minutes in water and 2.7-4.0 minutes in 0.1N HCl; coated tablets disintegrated in 3.1-5.5 minutes in water and 4.4-5.4 minutes in 0.1N HCl.
  • the dissolution profile of the tablets is shown below in Table 12:
  • a standard solution was prepared by dissolving telotristat etiprate in THF with a concentration of approximately 0.25 ⁇ g/mL.
  • Samples were prepared from 300 mg tablets as follows: 1) at least 4 tablets were weighed; 2) then crushed using a mortar and pestle; 3) an amount of equivalent to about 50 mg drug substance (i.e., about 117 mg) was weighed and transferred to a 100-mL volumetric flask; 4) then diluted to about 1/2 to 2/3 volume with diluent (THF); 5) the flask was then placed on a shaker for at least 20 minutes at low speed; 6) the volume was then further diluted with diluent and mixed well; 7) an aliquot was centrifuged for about 5 minutes at approximately 3000 RPM; 8) an aliquot of the supernate was then withdrawn for injection; 9) steps 3 through 8 were repeated for a total of two replicates for injection; 10) the average retention time of the API peak was then determined for the first six injections of the standard solution; and 2) the ratio of the retention time of any peaks in the sample preparation to the average retention time of the API peak in the first six injections of the standard was
  • API (mg) per tablet ( A sample *W total )/( RF std *W sample *N total )* DF sample
  • a sample API sample peak area
  • W total total weight of the tablets (mg)
  • DF sample sample dilution volume in mL (100 mL for the 300-mg tablets)
  • RF std standard average response factor (1 st 6 injections)
  • W sample Individual sample weight (mg)
  • N total Number of tablets used (at least 4). Individual impurities were determined as a percent of the total integrated peak area.

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US13/652,527 2011-10-17 2012-10-16 Solid dosage forms of (s)-ethyl 2-amino-3-(4-(2-amino-6-((r)-1-(4-chloro-2-(3-methyl-1h-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoate Abandoned US20130172376A1 (en)

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