Process for the preparation of S(+)-ibuprofen-particles

Details Process for the preparation of S(+)-ibuprofen-particles Process for the preparation of S(+)-ibuprofen-particles

1996-07-12

1999-02-09

Page, Thurman K.

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Particulate form

424494, 424480, 424488, A61K 914

Patent

active

058691014

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/AT95/00014 filed Jan. 26, 1995.
The invention relates to a process for the preparation of S(+)-ibuprofen-particles having improved flow properties, in particular suitable for filling capsules or for pressing tablets.
As it is well known, the particle size and the crystalline form are decisive parameters for the pharmaceutic-technologic properties of racemic or, respectively, optically pure ibuprofen. It is also known that ibuprofen obtained by different reaction processes shows crystals having the shape of a needle so that they have very poor flow properties or pourability. By these reasons, difficulties occur in connection with galenically processing, for example when pressing tablets or producing capsules. There have been attempts to overcome these difficulties by processing racemic ibuprofen by a crystallisation step (EP-A 120,587, WO 90/03782, WO 92/08686), or by processing it by melting (EP-A 362,728). The first-named kind of processing requires the use of organic solvents what frequently causes problems by environmental reasons. This disadvantage is indeed avoided by the second-named kind of processing, however, the process described there requires considerable effort in apparatus, because the racemic mixture is molten and then cooled on a contact surface. Thereby, scaly-shaped structures are obtained that must be comminutated considering special grinding conditions. For this an effort in apparatus is necessary that is too great in order to allow an economical process.
Further, S(+)-ibuprofen, the pharaceutic activity thereof considerably exceeds that of the racemic mixture, has not only a melting point (50.degree.-54.degree. C.) that is substantially lower than that of the racemic mixture (75.degree.-78.degree. C.), but also shows completely different physical properties, for example a different solvent power inconventional solvents, so that also by these reasons S(+)-ibuprofen cannot be processed along the above described processes.
The invention has at its object to provide a process for the production of S(+)-ibuprofen-particles having improved flow properties, in particular for filling in capsules or for pressing tablets, which process operates economically and, therefore, can be economically carried out in a large scale and without substantial use of organic solvents and therefore without environmental impact, requires less effort in apparatus and also enables a continuous processing. The invention solves this task by the features that granular crystalline S(+)-ibuprofen is molten and then in molten condition is finely distributed in a non-solvent medium, preferably in cold water, and is rapidly chilled for obtaining a fine-grained crystalline primary structure, whereupon the product obtained in agglomerates as a secondary structure is filtered out and dried. The sudden fall of temperature caused by the action of the non-solvent medium on the molten S(+)-ibuprofen, causes that the molten active substance solidifies and crystallizes in a particle shape that in a surprising manner is considerably similar to the shape of granules. Within this, it is over all surprising that a primary structure in form of irregularly shaped crystallites is obtained, which have a ratio of length to width of not more of about 1:2. These crystallites agglomerate to a secondary structure in form of granules having generally a diameter of less than 1 mm and being substantially spheroid and, therefore, have a good pourability. Such particles can be directly pressed in tablets using conventional additives, or, respectively, an exact apportioning can take place for the production of tablets, capsules or other galenic forms. As a rule, it is no more necessary to comminute the obtained granules, only if it is desired to obtain particles of substantially uniform size, a sizing step may be used if necessary, or example, by screening.
FIGS. 1 and 2 represent a graph of the release rate of a tablet prepared according to the invention.
FIG. 3 represents a graph of the release rate of a tablet prep

REFERENCES:
patent: 4086346 (1978-04-01), Bocker et al.
patent: 4609675 (1986-09-01), Franz
patent: 5191114 (1993-03-01), Chen
patent: 5198568 (1993-03-01), Zepp et al.
Database WPI, Week 7744, Derwent Publications Ltd., London, GB; AN 77-78258Y (44) & JP,A,52 111 533, Sep. 19, 1977.

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