Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J75/00—Processes for the preparation of steroids in general
• • 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

Definitions

• the invention relates to a method for producing crystals of active pharmaceutical ingredients whose average particle size is in a predetermined range and whose maximum particle size does not exceed a predetermined value, crystals obtainable by this method and their use in pharmaceutical formulations, in particular low dose formulations.
• the method according to the invention it is surprisingly possible to obtain crystals which are sufficiently stable and which, with regard to the parameters of their particle size distribution, meet the pharmaceutical requirements with regard to homogeneity of the active ingredient distribution (CUT) and dissolution kinetics for low-dose formulations and can therefore meet them.
• a grain size distribution that is suitable for the respective dose can be produced with high accuracy and reproducibility.
• the method according to the invention can be carried out in a simple, quick and inexpensive manner.
• the crystals obtainable by the process according to the invention can be isolated from the suspension and dried without impairing their particle size distribution
• the average particle size is preferably 1 ⁇ m to 25 ⁇ m, in particular 7 ⁇ m to 15 ⁇ m.
• the maximum particle size preferably does not exceed 100 ⁇ m, in particular 80 ⁇ m.
• maximum particle size means that no particle is larger than the specified value.
• a supersaturated solution of an active pharmaceutical ingredient is used in the method according to the invention.
• the solution contains as a solution the active pharmaceutical ingredient which is dissolved in a solvent for it. Mixtures of different solvents are also understood as solvents.
• the supersaturated solution contains 1% by weight to 60% by weight, in particular 5% by weight to 35% by weight, based on the supersaturated solution, of the active pharmaceutical ingredient.
• T ma ⁇ is preferably chosen such that 10% by weight to 95% by weight, in particular 20% by weight to 50% by weight, very particularly approximately 30% by weight, of the primary grains are dissolved in the solvent.
• the proportion of the quantity of primary grains to be dissolved is selected as a function of the specified grain size, which in turn is determined by the type of low dose formulation. If a high proportion of the primary grains is dissolved, a coarser grain is obtained.
• T min is chosen so that the dissolved primary grains essentially crystallize again. Conveniently, in order to keep the loss of active ingredient low, almost all of the primary granules dissolved should crystallize on the remaining primary granules.
• the pharmaceutically required particle size distribution of the active pharmaceutical ingredients can be produced with high reproducibility.
• 1 and 2 show the development of the grain size in the crystallization process.
• the advantage here is that the scatter in the particle size distribution is significantly reduced and the maximum grain size increases significantly less despite the multiplication of the average grain size. This supports the achievement of good CUT values even in low dose formulations.
• the suspension is then filtered through a frit and washed with 100 ml of MtBE.
• the filter cake is washed very thoroughly with 1000 ml of water and then slurried in 300 g of water.
• the suspension is spray dried under the following conditions in a laboratory spray dryer with a two-fluid nozzle (2 mm) (QVF / Yamato) Drying gas_ inlet temperature: 170 ° C Drying gas_ outlet temperature: 60 ° C Throughput drying gas: 0.23 m3 / min

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Organic Chemistry (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Epidemiology (AREA)
• Pharmacology & Pharmacy (AREA)
• Medicinal Chemistry (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicinal Preparation (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Steroid Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Applications Claiming Priority (3)

Publications (1)

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Family Applications (1)

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Families Citing this family (5)

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• 2002
  • 2002-04-23 DE DE10218106A patent/DE10218106A1/de not_active Ceased
• 2003
  • 2003-04-17 US US10/417,556 patent/US20030215516A1/en not_active Abandoned
  • 2003-04-22 AU AU2003232490A patent/AU2003232490A1/en not_active Abandoned
  • 2003-04-22 RU RU2004134321/15A patent/RU2004134321A/ru not_active Application Discontinuation
  • 2003-04-22 CA CA002480130A patent/CA2480130A1/en not_active Abandoned
  • 2003-04-22 KR KR10-2004-7017080A patent/KR20050003388A/ko not_active Application Discontinuation
  • 2003-04-22 IL IL16398403A patent/IL163984A0/xx unknown
  • 2003-04-22 EP EP03747106A patent/EP1523302A2/de not_active Withdrawn
  • 2003-04-22 JP JP2003587358A patent/JP2005535577A/ja not_active Withdrawn
  • 2003-04-22 PL PL03371518A patent/PL371518A1/xx not_active Application Discontinuation
  • 2003-04-22 WO PCT/EP2003/004153 patent/WO2003090721A2/de active Application Filing
  • 2003-04-22 BR BR0309358-1A patent/BR0309358A/pt not_active IP Right Cessation
  • 2003-04-22 CN CNA038092123A patent/CN1812767A/zh active Pending
  • 2003-04-22 MX MXPA04010466A patent/MXPA04010466A/es unknown
• 2004
  • 2004-11-22 ZA ZA200409398A patent/ZA200409398B/en unknown
  • 2004-11-22 NO NO20045071A patent/NO20045071L/no not_active Application Discontinuation

Non-Patent Citations (2)

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