Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1991-04-19
1993-07-27
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
544 82, 544134, C07D41704, A61K 31535
Patent
active
052310957
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The object of the present invention is a novel crystalline S-timolol derivative, in particular a novel hydrate form of S-timolol. The object of the invention is also a process for the preparation of this novel S-timolol derivative.
S-timolol, i.e., S-(-)-3-morpholino-4-(3-tert-butyl-amino-2-hydroxypropoxy)-1,2,5-thiadiazo le and its acid addition salts, are known pharmacologically valuable .beta.-blocking agents. In pharmaceutical preparations S-timolol is, as a rule, used as maleate salt, which, being a well crystallizing salt, has clear advantages compared to the free S-timolol base. The free S-timolol base is namely an oily sticky substance and thus difficult to process further, for example to purify and to dose. The use of the free S-timolol base in certain pharmaceutical preparations, especially in so called transdermal medicated patches or bandages, involves, however, advantages as compared to the acid addition salts as regards their penetration through the skin. Thus, the EP publication A2 0197504 discloses a transdermal delivery system, wherein use is made of i.a. timolol maleate, which is transformed to the nonionic, more easily absorbed timolol base form with a buffer. In the delivery system a solvent is used in which both the salt form and the free base form are soluble. The concentration of the timolol base form in the system is regulated with the pH of the buffer. From the viewpoint of easy manufacture of e.g. the transdermal system, it would be of advantage to prepare a S-timolol compound in the base form which crystallizes well in a non-sticky manner, which may be isolated in a pure form and which may be exactly dosed, and which at the same time exhibits a good penetration capacity when used in medicated bandages.
BRIEF SUMMARY OF THE INVENTION
Now it has surprisingly been discovered that S-timolol may easily be crystallized as the hemihydrate compound. Thus, the object of the invention is, as a novel compound, S-(-)-3-morpholino-4-(3-tert-butyl-amino-2-hydroxypropoxy)-1,2,5-thiadiazo le hemihydrate of the formula ##STR1## This compound, as obtained in a stable crystalline form, and the preparation thereof, are not known from the prior art. The well-crystallized and stable compound according to the invention may thus find use in applications, e.g., medicated bandages, where the exact dosing of the active ingredient in base form is of importance.
The structure of the compound has been elucidated using X-ray diffraction. The results indicate for the compound a crystal structure wherein four S-timolol base molecules and two water molecules are situated in the same unit cell, the hydrophilic parts (--NH, --OH) of each pair of two S-timolol molecules being arranged around one water molecule. The hydrogen bridges formed by the water molecule and the two polar groups, along with the favourable lipophilic intermolecular forces, existing in the crystal lattice provide for optimal packing of the molecules. Because of the above-mentioned molecular arrangement, S-timolol hemihydrate may be crystallized in an optical purity of 100% e.e., which means that S-timolol hemihydrate and the crystallization procedure may also be used for purification purposes, e.g., small amounts of the corresponding R-timolol enantiomer generally encountered in the starting material prepared by any current method, may be removed completely. The molecular arrangement in the crystal lattice along with easily controlled crystal growth is the reason for this surprisingly simple removal of impurities in one single crystallization step.
BRIEF DESCRIPTION OF THE DRAWING
The appended FIG. 1 discloses the arrangement of S-timolol hemihydrate in the unit cell, omitting the hydrogen atoms.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
The crystal structure for S-timolol hemihydrate (single crystals from water-methylene chloride) was measured with a Enraf-Nonius CAD-4 diffractometer using graphite-monochromatized MoK.sub..alpha. (0.71073 .ANG.) and .omega.-2.theta. method at 21.degree. C. The cell p
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The Merck Index, 11th Ed. (1989), Budavari; editor, p. 1488.
Datlow Philip
Leiras Oy
Shah Mukund J.
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