Alfuzosin hydrochloride is stabilized as alfuzosin hydrochloride dihydrate, which is useful for the production of antihypertensive agents or dysuria curing agents.

The present invention belongs to the field of synthetic medicinal 
chemistry, and it relates. to the stabilization of the publicly known 
compound, alfuzosin hydrochloride. Particularly, the present invention 
relates to a hydrate of alfuzosin hydrochloride. 
Alfuzosin hydrochloride is a compound represented by the formula: 
##STR1## 
and is described in Japanese Examined Patent Application Publication SHO 
No. 60-23114. This compound is known to be an antagonist of .alpha..sub.1 
-adrenergic receptor, and is useful as antihypertensive agent and dysuria 
curing agent (see also Japanese Examined Patent Application Publication 
HEI No. 5-64930). 
Generally, it is known that active components or excipients undergo crystal 
transition due to moisture absorption, which results in their volumetric 
change, leading to a change in hardness or cracking of the tablets. To 
establish appropriate bioavailability, such changes are extremely 
troublesome phenomena, particularly in the case of sustained release 
preparations. When anhydrous alfuzosin hydrochloride is preserved under 
conditions with the relative humidity exceeding 75%, the crystal structure 
of the anhydrous formchanges, thereby providing a trihydrate, which is 
accompanied by a change in volume. No reports have been made concerning 
the change in the preparation properties of tablets comprising crystals of 
anhydrous alfuzosin which are observed in long period stability tests, 
etc. To avoid the realization of the above-mentioned anxiety, however, it 
is useful to have an alfuzosin compound in a crystal state which does not 
suffer from the change in the crystal form under influence of humidity and 
temperature during the preparation process and storage of the 
preparations. 
After repeated zealous investigations, we the present inventors have found 
that alfuzosin hydrochloride can take forms of mono-, di-, tri- and 
tetrahydrate, with confirmation that the dihydrate is the stablest of them 
during the usual preparation process and under usual preservation 
conditions, thus the present invention has been completed. Alfuzosin 
hydrochloride dihydrate is produced by recrystallization of anhydrous 
alfuzosin hydrochloride from an 80:20 mixture solution of acetone and 
water at 6.degree. C. 
The tetrahydrate of alfuzosin hydrochloride is produced by 
recrystallization under room temperature conditions in the same manner as 
its dihydrate. 
The trihydrate of alfuzosin hydrochloride is produced by keeping anhydrous 
alfuzosin hydrochloride at 25.degree. C. and at a relative humidity of 93% 
for three days. Here the monohydrate is believed to be obtained by 
allowing the trihydrate to stand under the conditions of 25.degree. C. and 
at a relative humidity of 0% for two or more days.

EXAMPLES 
Hereunder the present invention will be explained in detail with reference 
to the Examples, without limiting the scope of the present invention 
thereto. 
Anhydrous alfuzosin hydrochloride and various hydrates thereof may be 
distinguished from each other by means of X-ray powder diffraction, IR 
spectra or thermal analysis. In the present examples, the distinguishing 
was conducted using X-ray powder diffraction capable of characterizing 
crystal structures, with investigation of moisture content carried out 
appropriately. 
Here, the X-ray powder diffraction was carried out using Phillips MPD1880 
X-ray diffraction apparatus system which uses CuK.alpha. radiation. This 
apparatus was set up as follows: tube voltage 40 kV, tube current 50 mA, 
scanning rate 0.02.degree./s, sampling time 0.2 seconds, measurement range 
2.theta.=2.5-32.5.degree.. 
Patterns of X-ray powder diffraction for the anhydrous form, dihydrate, 
trihydrate and tetrahydrate of alfuzosin hydrochloride are shown in FIG. 
1, FIG. 2, FIG. 3 and FIG. 4, respectively. The respective characteristic 
diffractometric peaks are as follows: 
Anhydrous form: 2.theta.=7.56.degree. 
Dihydrate: 2.theta.=6.36.degree., 8.07.degree., 9.78.degree. 
Trihydrate: 2.theta.=6.12.degree., 8.96.degree. 
Tetrahydrate: 2.theta.=6.04.degree., 8.37.degree. 
The moisture content was measured with Karl Fischer Aquameter (Kyoto 
Electron Industry, MK-AII) for about 100 mg of a sample dissolved in 
methanol for moisture measurement. In turn, the dehydration behavior of 
the crystal water was measured by thermogravimetry and differential 
thermal analysis using TG/DTA200 thermogravimetric apparatus and SSC5030 
Disc Station (Seiko). Concretely, approximately 5 mg of a sample was 
weighed into an open aluminum pan and analyzed at a rate of temperature 
increase of 10.degree. C./m or 1.degree. C./m. This analysis was carried 
out in a nitrogen atmosphere (flow rate: 100 ml/m). 
Example 1 
Preparation of Alfuzosin Hydrochloride Dihydrate 
To 2g of alfuzosin hydrochloride (anhydrous form) produced as described in 
Japanese Examined Patent Application Publication SHO No. 60-23114, was 
added 20 ml of an acetone/water (4:1) mixture solution, and the mixture 
was heated to reflux at approximately 60.degree. C. until the anhydrous 
form was completely dissolved. After confirmation of the complete 
dissolution of the anhydrous form, the mixture was gradually cooled to 
room temperature, and the resulting precipitate was filtered off on filter 
paper, followed by air-drying at room temperature for 24 hours. 
The obtained substance was confirmed to be alfuzosin hydrochloride 
dihydrate by X-ray powder diffraction. 
Reference 1 
Preparation of atfuzosin hydrochloride tetrahydrate 
To 2 g of alfuzosin hydrochloride (anhydrous form) described in Japanese 
Examined Patent Application Publication SHO No. 60-23114, was added 20 ml 
of an acetone/water (4:1) mixture solution, after which themixture was 
shaken for mixing at room temperature. 
The anhydrous formwas dissolved, but a precipitate was observed immediately 
upon stoppage of stirring. The resulting precipitate was filtered off on 
filter paper and air-dried at room temperature for 24 hours. 
The obtained substance was confirmed to be alfuzosin hydrochloride 
tetrahydrate by X-ray powder diffraction. 
The stability of alfuzosin hydrochloride dihydrate of the present invention 
was evaluated according to the following tests. 
Test 1 
Hygroscopicity Test 
A 0.2 g-portion of a sample of each of the anhydrous form and respective 
hydrates of alfuzosin hydrochloride was placed in a desiccator containing 
a saturated solution of the salts listed hereunder (at 25.degree. C.), and 
the relationship between the relative humidity at which the hydrated 
states of the respective compounds become. stable physically and the 
hygroscopicity of polymorphic hydrated forms of those compounds was 
investigated. The respective samples were brought to equilibrium by 
storage for 10 days under the respective conditions. For the setting up of 
the relative humidity (RH: %) was used a saturated solution of salts 
listed below: 
RH 0%, dry P.sub.2 O.sub.5 ; RH 11%, LiCl; RH 22%, CH.sub.3 COOK; RH 33%, 
MgCl.sub.2 ; RH 43%, K.sub.2 CO.sub.3.2H.sub.2 O; RH 53%, 
Mg(NO.sub.3).sub.2 ; RH 64%, CoCl.sub.2.6H.sub.2 O; RH 75%, NaCl; RH 84%, 
KCl; RH 93%, KNO.sub.3 ; RH 100%, water. 
The obtained results were graphed and shown in FIG. 5 attached hereto. 
The anhydrous form of alfuzosin hydrochloride was stable at an RH of 75% or 
less. When preserved under conditions where the RH was over 75%, however, 
the moisture content increased significantly. This increasing continued 
until the moisture content attained the equilibrium of 12%, which is 
equivalent to 3 moles of water. 
Under all the conditions relating to the relative humidity at 25.degree. 
C., with exception under drying conditions (RH: 0%), all the hydrates did 
not undergo moisture absorption. With consideration for the fact that the 
relative humidity usually ranges from about 40% to about 80%, it may be 
concluded that all the hydrates including the dihydrate of the present 
invention do not cause moisture absorption at usual relative humidity at 
normal temperature. 
Test 2 
Drying Test 
Different from the hygroscopicity test mentioned above, the various 
hydrates of alfuzosin hydrochloride were kept under drying conditions for 
the monitoring of the change in moisture content. 
The obtained results are shown in FIG. 6 attached hereto. FIG. 6 shows that 
the dehydration process of alfuzosin hydrochloride dihydrate goes very 
slowly. That is, although the trihydrate and tetrahydrate lost most of the 
water in 1 day, no significant change in moisture content was observed for 
the dihydrate according to the present invention even in 3 days. This 
evidences that the interaction between alfuzosin hydrochloride and water 
molecules is stronger in the case where the former is a dihydrate than in 
the case of a trihydrate or tetrahydrate. 
In this connection, simultaneously in the present test, also the crystal 
state of dried samples after a three-days' drying was investigated for the 
dihydrate of the present invention by X-ray powder diffraction under 
drying conditions, for comparison with patterns of X-ray powder 
diffraction under normal conditions. As a result, it has been revealed 
that the dihydrate of the present invention retains its original crystal 
form, with some drop in degree of crystallization (data not shown). 
Test 3 
Test on Stability to Heating, Humidifying and Light 
The stability test was carried out following the procedures described 
below. 
A 0.3 g-portion of each of the anhydrous form and respective hydrates of 
alfuzosin hydrochloride in crystal forms was placed in a glass bottle 
(sealed) and in a desiccator filled with a NaCl saturated solution, and 
preserved at 70.degree. C. with a heater (Toyama Industry), after which 
the physicochemical stability of each compound was evaluated by X-ray 
powder diffraction and high performance liquid chromatography (HPLC). 
Separately, 0.3 g of each of the anhydrous form and respective hydrates of 
alfuzosin hydrochloride in crystal forms was placed in a plastic dish 
which was then covered with a polyvinylidene chloride film, followed by 
irradiation with a chemical lamp (dominant wavelength: 365 nm) for 24 
hours, for the evaluation of the light stability in the same manner as in 
the above. 
The obtained results are shown in the following table 1. Table 1 includes 
the moisture content of the respective crystal forms as well. Here, the 
HPLC was carried out under the following conditions: 
HPLC apparatus (manufactured by Shimazu) 
Detection with UV (at 254 nm); column (Nucleosil 5C.sub.18, 150 mm.times.4 
mm, M, Nagel; flow rate 1.0 ml/m; room temperature; eluent, NaClO.sub.4 
(in 1000 ml of water, 7 g, pH 3.5)- acetonitrile-THF (155:55:45): internal 
standard, p-chloroacetanilide (0.5 mg/ml). 
[TABLE 1] 
__________________________________________________________________________ 
Results of the stability test 
70.degree. C. 70.degree. C. 
Crystal forms 
9 days 9 days at RH 75% 
Chemical lamp 
(moisture 
(moisture (moisture (moisture 
content: 
content: content: content: 
%) %) %) %) 
__________________________________________________________________________ 
Anhydrous 
Stable Stable Stable 
(0.1%) (1.33%) (0.7%) (0.66%) 
Dihydrate (DI) 
Stable Stable Stable 
(8.14%) (8.41%) (8.48%) (8.40%) 
Trihydrate 
DI = 37% + TRI = 68% 
DI = 16% + TRI = 84% 
Stable 
(TRI) (11.05%) (12.03%) (12.87%) 
(12.75%) 
Tetrahydrate 
DI = 26% + TETRA = 74% 
DI = 98% + TETRA = 2% 
Stable 
(TETRA) (13.19%) (8.25%) (15.18%) 
(14.93%) 
__________________________________________________________________________ 
The above table 1 proves that the anhydrous form and dihydrate are 
extremely stable under all these conditions. On the other hand, both the 
trihydrate and tetrahydrate changed partially into the dihydrate, so they 
are considered unstable under the two conditions mentioned above. 
To light, neither chemical decomposition nor physical change was found for 
all the samples. 
Test 4 
Accelerated Test 
A 0.3 g-portion of each of the hydrates of alfuzosin hydrochloride was 
preserved in heaters (Sanyo) set to 100.degree. C. and 120.degree. C., for 
the confirmation of the stability of the respective hydrates. The physical 
stability of the respective samples was confirmed by X-ray powder 
diffraction. 
The obtained results are shown in the following tables 2 and 3. 
[TABLE 2] 
______________________________________ 
Accelerated test at 100.degree. C. 
Preservation time 
Crystal forms 
30 min. 60 min. 90 min. 
120 min. 
______________________________________ 
Dihydrate (DI) 
DI DI DI DI 
Trihydrate (TRI) 
TRI TRI + TRI + TRI + 
DI DI DI 
Tetrahydrate 
TETRA + DI DI DI DI 
(TETRA) 
______________________________________ 
In this test, the crystal state of the respective hydrates was monitored by 
X-ray powder diffraction every 30 minutes for 2 hours. 
The dihydrate was stable for 2 hours. 
The trihydrate changed into the dihydrate by degrees. 
Also the tetrahydrate changed into the dihydrate by degrees. 
[TABLE 3] 
______________________________________ 
Accelerated test at 120.degree. C. 
Preservation time 
Crystal forms 45 min. 
______________________________________ 
Dihydrate (DI) DI 
Trihydrate (TRI) AN + DI + TRI 
Tetrahydrate (TETRA) DI 
______________________________________ 
[wherein AN stands for anhydrous form.] 
The dihydrate was stable for 45 minutes. 
The trihydrate changed into a mixture of the anhydrous form, dihydrate and 
trihydrate. 
The tetrahydrate changed into the dihydrate. 
With the results of the above-mentioned tests 1-4, it may be concluded that 
the stablest crystal form of alfuzosin hydrochloride under normal 
preservation conditions for the preparations (e.g., 25.degree. C., 
relative humidity 40-80%) and under heating (drying) condition (e.g., 
50.degree.-60.degree. C.) to be expected for the preparation process is 
that of the dihydrate. 
Test 5 
Dissolution Test 
Water at 37.degree. C. was used to study the dissolution profiles of the 
respective hydrates of alfuzosin hydrochloride. The results are shown in 
FIG. 7. FIG. 7 proves that the respective hydrates have dissolution 
profiles which are very similar to those of anhydrous alfuzosin 
hydrochloride . This is indicative of the fact that all the hydrates, 
including the dihydrate of the present invention, may be used for the 
preparation of alfuzosin hydrochloride preparations in the same manner as 
its anhydrous form. 
Accordingly, the dihydrate according to the present invention may be used 
for the production of antihypertensive agents or dysuria curing agents. 
BRIEF DESCRIPTION OF DRAWINGS 
FIG. 1 is a chart showing the X-ray powder diffraction pattern of anhydrous 
alfuzosin hydrochloride. 
FIG. 2 is a chart showing the X-ray powder diffraction pattern of alfuzosin 
hydrochloride dihydrate. 
FIG. 3 is a chart showing the X-ray powder diffraction pattern of alfuzosin 
hydrochloride trihydrate. 
FIG. 4 is a chart showing the X-ray powder diffraction pattern of alfuzosin 
hydrochloride tetrahydrate. 
FIG. 5 is a graph showing the hygroscopicity of the anhydrous form of 
alfuzosin hydrochloride and its various hydrates. 
FIG. 6 is a graph showing the change in the moisture contents of the 
hydrates of alfuzosin hydrochloride under drying conditions. 
FIG. 7 is a graph showing the dissolution profiles of the anhydrous form 
and respective hydrates of alfuzosin hydrochloride in water at 37.degree. 
C.