Crystal of monohydrate of heterocyclic bis(phosphonic acid) deri

Details Crystal of monohydrate of heterocyclic bis(phosphonic acid) deri Crystal of monohydrate of heterocyclic bis(phosphonic acid) deri

1994-12-21

1996-01-02

Ivy, C. Warren

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Phosphorus containing other than solely as part of an...

546 23, C07D47104

Patent

active

054808758

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/JP93/00821 filed Jun. 18, 1993.


TECHNICAL FIELD

This invention relates to novel crystals D and E of a novel monohydrate of 1-hydroxy-2-(imidazo[1,2-a]pyridin-3-yl)ethane-1,1-bis(phosphonic acid), to be referred to as compound (I) hereinafter, and to a stable solid pharmaceutical preparation containing the same.


BACKGROUND ART

Compound (I) is a compound represented by the following formula (I), which has excellent bone resorption inhibitory activity, anti-inflammatory activity and analgesic-antipyretic activity and is useful for the treatment of diseases in which increased bone resorption participates, such as Paget's disease, hypercalcemia, bone metastasis of cancer and osteoporosis, as well as progress in the bone resorption (induction of osteoporosis) caused by inflammatory joint diseases such as rheumatoid arthritis and the like (cf. JP-A-2-138288). (The term "JP-A" as used herein means an "unexamined published Japanese patent application.) ##STR1##
Example 5 in the aforementioned published patent application describes that this free acid compound (I) is isolated and purified in the form of colorless needle crystals which are obtained by recrystallization from water-methanol, and the thus obtained crystals contain 0.5 mole of water according to the result of elemental analysis.
However, the aforementioned published patent application does not describe about certain properties of the crystal obtained in the Example 5 which are not desirable when compound (I) is made into a pharmaceutical preparation, with respect to the presence of compound (I) monohydrate which has two novel crystalline forms and about utility of the novel monohydrate crystals.
According to the studies conducted by tile inventors of the present invention, it was confirmed that the crystalline form of the crystal produced in accordance with the procedure described in Example 5 of the aforementioned published patent application (to be referred to as crystal C hereinafter, Lot No. 49-1 in the table) was physically unstable, because it has such a strong hygroscopic property that it absorbs 1% of moisture in a day under a relative humidity condition of 93% (cf. crystal C in Table 3) and the crystalline form was changed and converted into monohydrate in the presence of water (cf. Test Example 3 which will be described later). In consequence, it was revealed that this crystal has serious problems in putting it into practical use as a solid pharmaceutical preparation because of various limitations in the preservation of the crystal and in the pharmaceutical manufacturing steps.
When the crystal C was examined in detail, it was confirmed that the crystal C was an anhydride crystal containing 0.5 mole of free water, because its thermal analysis does not show an endothermic peak due to dehydration of water of crystallization and its powder X-ray diffraction pattern did not change even after removal of the 0.5 mole equivalent water by 3 hours of drying at 150.degree. C. In addition, though the crystal C was the same colorless needle crystal as the crystal of Example 5 of the aforementioned published patent application when observed by the naked eye, it was a lump of minute plate crystals when examined microscopically under a polarization microscope (cf. the photograph of the crystal).
In consequence, the present inventors have attempted to produce crystals of sodium salts which are commonly used to give the crystalline form of phosphoric acid compounds, but such crystals, except for monosodium salt, were not able to be produced even in an amount useful examination, because disodium salt did not crystallize and trisodium salt did not give a stable crystal.
On the contrary, the monosodium salt gave relatively stable crystals as a dihydrate (to be referred to as crystal A hereinafter, Lot No. T-8 in the table) and a trihydrate (to be referred to as crystal B hereinafter, Lot No. T-10 in the table), but each of these crystals was disadvantageously apt to release water of crystallization. It was found that these cr

REFERENCES:
patent: 4990503 (1991-02-01), Isomura et al.
patent: 5039669 (1991-08-01), Isomura et al.

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