EP1523302A2 - Procede de production de cristaux de principes actifs de medicaments, cristaux ainsi obtenus et leur utilisation dans les formulations pharmaceutiques - Google Patents

Procede de production de cristaux de principes actifs de medicaments, cristaux ainsi obtenus et leur utilisation dans les formulations pharmaceutiques

Info

Publication number
EP1523302A2
EP1523302A2 EP03747106A EP03747106A EP1523302A2 EP 1523302 A2 EP1523302 A2 EP 1523302A2 EP 03747106 A EP03747106 A EP 03747106A EP 03747106 A EP03747106 A EP 03747106A EP 1523302 A2 EP1523302 A2 EP 1523302A2
Authority
EP
European Patent Office
Prior art keywords
particle size
crystals
active pharmaceutical
suspension
solvent
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP03747106A
Other languages
German (de)
English (en)
Inventor
Detlef Grawe
Hagen Gerecke
Peter Hösel
Annette Eichardt
Sabine Gliesing
Uwe Müller
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer Pharma AG
Original Assignee
Schering AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Schering AG filed Critical Schering AG
Publication of EP1523302A2 publication Critical patent/EP1523302A2/fr
Withdrawn legal-status Critical Current

Links

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

Abstract

L'invention concerne un procédé de production de cristaux de principes actifs de médicaments, dont la taille moyenne des particules se situe dans une plage donnée et dont la taille maximale des particules ne dépasse pas une valeur donnée. Une solution sursaturée pendant la cristallisation est soumise à un broyage humide à l'aide d'un dispositif de broyage humide, ce qui permet d'obtenir une suspension de grains primaire. L'invention concerne également les cristaux obtenus selon ce procédé et les formulations pharmaceutiques les contenant.
EP03747106A 2002-04-23 2003-04-22 Procede de production de cristaux de principes actifs de medicaments, cristaux ainsi obtenus et leur utilisation dans les formulations pharmaceutiques Withdrawn EP1523302A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10218106 2002-04-23
DE10218106A DE10218106A1 (de) 2002-04-23 2002-04-23 Verfahren zum Herstellen von Kristallen von Arzneimittelwirkstoffen, danach erhältliche Kristalle und deren Verwendung in pharmazeutischen Formulierungen
PCT/EP2003/004153 WO2003090721A2 (fr) 2002-04-23 2003-04-22 Procede de production de cristaux de principes actifs de medicaments, cristaux ainsi obtenus et leur utilisation dans les formulations pharmaceutiques

Publications (1)

Publication Number Publication Date
EP1523302A2 true EP1523302A2 (fr) 2005-04-20

Family

ID=29264786

Family Applications (1)

Application Number Title Priority Date Filing Date
EP03747106A Withdrawn EP1523302A2 (fr) 2002-04-23 2003-04-22 Procede de production de cristaux de principes actifs de medicaments, cristaux ainsi obtenus et leur utilisation dans les formulations pharmaceutiques

Country Status (16)

Country Link
US (1) US20030215516A1 (fr)
EP (1) EP1523302A2 (fr)
JP (1) JP2005535577A (fr)
KR (1) KR20050003388A (fr)
CN (1) CN1812767A (fr)
AU (1) AU2003232490A1 (fr)
BR (1) BR0309358A (fr)
CA (1) CA2480130A1 (fr)
DE (1) DE10218106A1 (fr)
IL (1) IL163984A0 (fr)
MX (1) MXPA04010466A (fr)
NO (1) NO20045071L (fr)
PL (1) PL371518A1 (fr)
RU (1) RU2004134321A (fr)
WO (1) WO2003090721A2 (fr)
ZA (1) ZA200409398B (fr)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TWI415603B (zh) * 2005-05-20 2013-11-21 Merck Sharp & Dohme １，８－辛二醯基苯胺羥胺酸（ｓｕｂｅｒｏｙｌａｎｉｌｉｄｅ ｈｙｄｒｏｘａｍｉｃ ａｃｉｄ）之調配物及其製配方法
EP1993513A4 (fr) * 2006-03-14 2012-06-27 Merck Sharp & Dohme Procédés et appareils permettant de produire des compositions de microparticules organiques cristallines par micro-broyage et cristallisation sur micro-grain et utilisation correspondante
DE102010003711B4 (de) * 2010-04-08 2015-04-09 Jesalis Pharma Gmbh Verfahren zur Herstellung kristalliner Wirkstoffpartikel
EP3143001B1 (fr) 2014-05-13 2018-07-18 Akzo Nobel Chemicals International B.V. Procédé pour cristalliser des agents de chélation
CN108031142A (zh) * 2017-12-13 2018-05-15 上海合全药物研发有限公司 一种简化的利用湿磨来制备大量微晶种的装置及方法

Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB838654A (en) * 1956-02-08 1960-06-22 Upjohn Co Steroids and the production thereof
US3226389A (en) * 1962-01-04 1965-12-28 Du Pont 11,11,12,12-tetracyano-naphtho-2,6-quinodimethan and its anion-radical salts
CH627449A5 (de) * 1977-03-25 1982-01-15 Hoffmann La Roche Verfahren zur herstellung von mikrokristallinem vitamin a-acetat, sowie von trockenen, frei-fliessenden praeparaten, in welchen vitamin a-acetat in mikrokristalliner form vorliegt.
DE2801705A1 (de) * 1978-01-16 1979-07-19 Metallgesellschaft Ag Verfahren zur gewinnung von kaliumchlorid
DE3014160A1 (de) * 1979-04-16 1980-10-30 Lummus Co Kristallisationsverfahren
DE3306250A1 (de) * 1983-02-23 1984-08-23 Basf Ag, 6700 Ludwigshafen Sphaerische einkristalle fuer pharmazeutische zwecke
US4997637A (en) * 1989-05-09 1991-03-05 Occidental Chemical Corporation Digestive crystallizing process and apparatus for purification of KC1
FR2668945B1 (fr) * 1990-11-12 1993-02-19 Theramex Nouveau procede de cristallisation des substances organiques et les composes ainsi obtenus.
DE4117717C1 (en) * 1991-05-30 1992-12-17 Dynamit Nobel Ag, 5210 Troisdorf, De Finely crystalline priming explosive prodn. - by comminuting to specified grain size in non-solvent using high speed stirrer
DE4244466C2 (de) * 1992-12-24 1995-02-23 Pharmatech Gmbh Verfahren zur Herstellung von Pseudolatices und Mikro- oder Nanopartikeln und deren Verwendung zur Herstellung von pharmazeutischen Präparaten

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
None *
See also references of WO03090721A3 *

Also Published As

Publication number Publication date
MXPA04010466A (es) 2004-12-13
CA2480130A1 (fr) 2003-11-06
DE10218106A1 (de) 2003-11-20
PL371518A1 (en) 2005-06-27
AU2003232490A1 (en) 2003-11-10
NO20045071L (no) 2005-01-21
KR20050003388A (ko) 2005-01-10
WO2003090721A2 (fr) 2003-11-06
RU2004134321A (ru) 2005-10-10
US20030215516A1 (en) 2003-11-20
ZA200409398B (en) 2006-06-28
JP2005535577A (ja) 2005-11-24
WO2003090721A3 (fr) 2005-02-24
CN1812767A (zh) 2006-08-02
IL163984A0 (en) 2005-12-18
BR0309358A (pt) 2005-02-22

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