Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Reexamination Certificate
2001-06-22
2002-04-16
Aulakh, Charanjit S. (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
C560S196000
Reexamination Certificate
active
06372940
ABSTRACT:
The present invention relates to a process for the preparation of non-hygroscopic salts of L(−)-carnitine. More precisely, the present invention relates to an improved process for the preparation of L(−)-carnitine acid fumarate (1:1) and of L(−)-carnitine L(+)-tartrate (2:1) by “humid melting”, as it will be further specified in the following.
The high hygroscopicity of L(−)-carnitine inner salt recognizedly causes complex problems of processability, stability and storage both of the raw materials and of the finished products. For example, L(−)-carnitine inner salt tablets have to be packaged in blisters to prevent contact with the air, since, otherwise, even in the presence of normal humidity conditions, they would undergo alterations, swelling up and becoming pasty and sticky. However, the solid orally administrable compositions are the preferred presentation form, inasmuch as they make it particularly easy for users to take the substances and comply with optimum dosage regimens.
Up to now, the problem of L(−)-carnitine inner salt hygroscopicity has been approached by transforming it into salts with pharmacologically acceptable acids, provided these salts have the same therapeutical
utritional activities of the inner salt and do not have unwanted toxic or side effects.
There is now an extensive body of literature, particularly patents, disclosing the production of stable, non-hygroscopic salts of L(−)-carnitine.
U.S. Pat. No. 4,602,039 (Sigma-Tau) discloses L(−)-carnitine acid fumarate (1:1) as a non-hygroscopic, pharmacologically acceptable L(−)-carnitine salt. EP 0,434,088 (Lonza) discloses the use of L(−)-carnitine tartrate (2:1), the preparation and physico-chemical characterization of which were, on the other hand, described by D.Muller and E.Strack in Hoppe Seyler's Z.
Physiol. Chem. 353, 618-622, April 1972, for the preparation of solid forms suitable for the oral administration, such as tablets, capsules, powders or granulates, as said salts are capable of resisting at about 60% relative humidity.
The traditional processes for the industrial production of the two above mentioned salts (the only ones developed and marketed, up to now) have remarkable drawbacks in that they involve the use of large amounts of water or hydroalcoholic solutions in which L(−)-carnitine and the suitable acid are dissolved for carrying out the salification, and of organic solvents (such as methanol, ethanol and isobutanol) for the subsequent crystallization. For instance, according to the previously cited EP 0,434,088, L(−)-carnitine inner salt is added to a boiling solution of L(+)tartaric acid in aqueous 90% ethanol. This makes it necessary to concentrate large volumes of the solution containing the desired L(−)-carnitine at 50-60° C. and under reduced pressure (about 200 Torr, 26664 Pa) for carrying out the crystallization, with remarkable energy waste and no quantitative yield.
In order to drastically reduce said energy waste and to avoid the use of organic solvents, WO 98/38157 discloses a process in which L(−)-carnitine inner salt is mixed at room temperature with the minimum amount of water necessary to obtain a slurry of semiliquid/pasty consistency which is added, at room temperature, with an equimolar amount of fumaric acid or one-half the equimolar amount of L(+)-tartaric acid with respect to L(−)-carnitine inner salt (in L(−)-carnitine acid fumarate the L(−)-carnitine/fumarate molar ratio is 1:1, whereas in L(−)-carnitine tartrate the L(−)-carnitine/tartrate molar ratio is 2:1). The above pasty mixture (containing 10 to 30% by weight of water) is blended at room temperature with formation of a solid mass consisting of the desired salt (100% yield) which is subsequently ground to the wanted particle size.
However, the absence of hygroscopicity and a suitable particle size distribution are not yet sufficient to provide an excellent processability of said compounds on standard devices for the preparation of finished pharmaceutical forms, in that the above processes do not always provide reproducible, steady and optimum density values of the products. It is in fact known that an inadequately low density (for example, for L(−)-carnitine acid fumarate, a tapped density value below 0.7 g/mL) provides a too light and flaky product which involves serious processability problems. The bulk density is not a reliable parameter for granulated or powdery products, in that even imperceptible perturbations of the test sample can give rise to remarkably different bulk density values. For the characterization of the density of said materials the tapped density is preferably used, which is the limit density obtained after tapping down the material by subjecting a graduated cylinder containing the granulate or powder to strokes, namely by hoisting the cylinder to a fixed height then dropping it for a fixed number of times.
The tapped density is usually determined according to the method described in U.S. Pharmacopoeia, National Formulary, Supplement, USP 23, NF 18, Nov. 15, 1997, pages 3976-3977. Said method is herein incorporated by reference.
The material is passed through a 1 mm (n. 18 mesh) sieve to crush any agglomerates formed during storage. About 100 g (M) of the test material are placed without tapping down in a 250 mL graduated cylinder.
Using a suitable device, the cylinder is hoisted then dropped under the action of its own weight, from a height of 14+2 mm, with a 300 times/minute fall frequency. The volume of the material after a first 500 fall cycle is then measured. After a second 750 fall cycle, the volume of material is measured again, and this is considered the final volume (V
f
) if it does not differ from the first volume by more than 2%. Otherwise, one or more further 1250 fall cycles are carried out until the final volume does not differ from the previous value by more than 2%. The tapped density, in g/mL, is expressed by the formula: M/V
f
.
Whereas the known processes do not provide granulates or powders of the above mentioned L(−)-carnitine salts, particularly of L(−)-carnitine acid fumarate, with tapped density values reproducible and suitable for a satisfactory processability in standard devices, the process of the present invention attains said object while overcoming other drawbacks, as it will be further described in details hereinbelow.
The process of the invention for the preparation of a stable, non-hygroscopic L(−)-carnitine salt selected from the group consisting of L(−)-carnitine acid fumarate (1:1) and L(−)-carnitine L(+)-tartrate (2:1), comprises:
(a) mixing at room temperature, in any desired order,
(1) L(−)-carnitine inner salt;
(2) fumaric acid or L(+)-tartaric acid, respectively in equimolar amount or in half the equimolar amount to L(−)-carnitine inner salt; and
(3) 5-9%, preferably 6-8%, by weight of water calculated on the weight of the (1)+(2)+(3) mixture;
(b) heating under stirring the above mixture at a temperature of 100-120° C. to obtain a substantially colourless, transparent molten mass;
(c) cooling the molten mass until complete solidification; and
(d) grinding the solidified mass to obtain a granulate or powder having the desired particle size.
In step (a), water, in amount only 5-9%, preferably 6-8%, by weight calculated on the weight of the (1)+(2)+(3) mixture, cannot be considered either “the minimum amount of water necessary to obtain a mixture of semiliquid/pasty consistency ”of L(−)-carnitine inner salt and fumaric or L(+)-tartaric acid, according to the teachings of the above mentioned WO 98/38157 (in fact the mixture of step (a) is not in such form), or, even less, a solvent for said reagents. In the process according to the invention, water rather acts as an adjuvant for the subsequent melting step (b) which, due to the presence of water, takes place at a temperature (100-120° C.) lower than the melting points o
Aulakh Charanjit S.
Nixon & Vanderhye
Sigma-Tau Industrie Farmaceutiche Riunite S.p.A
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