Method for preparing a crystalline polymorph of terazosin monohydrochloride

A crystalline polymorphous terazosine monohydrochloride is obtained by suspending and treating a crystalline addition product of terazosine hydrochloride and methanol in a polar solvent which is an alcohol with 2 to 6 carbon atoms or a ketone with 2 to 6 carbon atoms or a mixture thereof. The thus obtained crystalline polymorphous terazosine hydrochloride is characterized by a reduced hygroscopicity and solvent residue retention capacity.

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
The Invention relates to a method for preparing a crystalline polymorph of 
1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(2-tetrahydrofuroyl)-piperazine 
-monohydrochloride, hereinafter abbreviated as terazosin hydrochloride. 
2. Description of Related Art 
The compound 
1-(4-amino-6,7-dimethoxy-2-guinazolinyl)-4-(2-tetrahydrofuroyl)-piperazine 
is generally known under the name terazosin. For the monohydrochloride of 
this compound there have been known to exist a plurality of anhydrous 
crystalline modifications (polymorphs) as well as a crystalline dihydrate 
form and a crystalline adduct with methanol. The compound and the 
different polymorphs thereof are suitable for pharmaceutical use, for 
example for the treatment of hypertension. 
The Japanese Laid-Open Unexamined Patent Application 05-78352 SUMIKA 
describes a plurality of crystalline forms of terazosin hydrochloride and 
the ways of preparing them. One crystalline polymorph, denoted as type A-2 
in that document, is characterized by an X-ray powder diffraction pattern 
having characteristic peaks at 7.degree., 12.degree., 20.3.degree. and is 
believed to be identical to the product of the method according to the 
present Invention. According to the prior art document this polymorph is 
prepared as follows: First the free terazosin base is prepared. This is 
converted into the crystalline adduct of the hydrochloride thereof with 
methanol. Thereafter, the methanol included in the crystal is removed by 
drying, which necessitates temperatures around 110.degree. C. One obtains 
a substantially methanol free compound, which is very hygroscopic. This is 
further treated with ethanol or mixtures of ethanol and methylene chloride 
for obtaining the desired crystalline polymorph which is substantially not 
hygroscopic. 
U.S. Pat. No. 5,412,095 and EP 0 683 167 disclose methods for obtaining 
other crystalline forms of terazosin-hydrochloride. One of the methods 
described therein also comprises the treatment of the adduct of 
terazosin-hydrochloride and methanol in suspension in a solvent such as 
ethanol. This prior art treatment, however, is performed at a 
comparatively low temperature (50.degree. C.) and for a comparatively 
short time (10 minutes or 30 minutes), and the product is a crystalline 
polymorph, designated as Form III in this document, which differs from the 
polymorph according to the Invention with respect to its X-ray pattern and 
other parameters. 
The crystalline polymorph to which the present Invention relates is also 
described in EP-0 708 104 A1 which is not prepublished, and it is 
designated there as "Form IV". The method of preparation proposed in this 
document starts from N-(2-tetrahydrofuroyl)-piperazine (the preparation of 
which by hydrogenation of N-(2-furoyl)-piperazine has already been known 
from U.S. Pat. No. 4,026,894), which is then coupled with 
4-amino-2-chloro-6,7-dimethoxy-quinazoline, which requires a treatment 
including boiling for several hours in a solvent having a high boiling 
temperature, whereby terazosin hydrochloride in the crystalline Form IV is 
obtained. This product is then converted into the dihydrate and dried. A 
drawback of this method consists in requiring several hours of boiling in 
a solvent having a high boiling temperature (for example methoxyethanol 
which is objectionable for health reasons) whereby impurities are 
necessarily formed and an undesirable dark color is obtained. Thus, the 
crystalline Form IV is not obtained in the optimal purity which is desired 
for pharmacological uses, but requires further treatment (forming of 
dihydrate), which causes a purification, including a treatment with 
diatomaceous earth. 
Other crystalline polymorphs of terazosin hydrochloride and methods for 
their preparation are disclosed in U.S. Pat. Nos. 5,294,615, 5,362,730 and 
5,412,095 and are referred therein as Form II and Form III, respectively, 
and are characterized by the characteristic peaks of the X-ray powder 
diffraction patterns thereof. 
SUMMARY OF THE INVENTION 
It is an object of the Invention to provide a novel method of preparing the 
crystalline polymorph of terazosin hydrochloride previously known under 
the designations A-2 and Form IV, which enables to obtain this crystalline 
polymorph in a simple process and with high purity. 
The method according to the Invention starts from the stable crystalline 
adduct of terazosin hydrochloride and methanol which is then treated with 
organic polar solvents or solvent mixtures from the group of alcohols and 
ketones, without preliminary intermediate drying. It has been found that 
the methanol-wet methanol adduct, as it is obtained in the preparation of 
the adduct, can be used without disadvantages, and that the residual 
methanol content of the final product is in a range acceptable for 
pharmacological use. According to the Invention it has surprisingly been 
found that by selecting a suitably higher temperature and treatment time 
the polymorph Form IV is obtained, rather than the aforementioned 
polymorph Form III or any other known polymorph (Form I or Form II). 
A substantial advantage of the method according to the Invention as 
compared with the above-mentioned known from JP-A-05-78352 consists in 
eliminating the intermediate drying step at temperatures around 
110.degree. C. This intermediate drying step of the prior art method has 
two substantial disadvantages. On the one hand the drying results in a 
very hygroscopic product. On the other hand the treatment at the drying 
temperature over several hours results in a thermic load which can cause 
the product to decompose and impurities to be generated, which is very 
undesirable when using the product as a pharmaceutical active ingredient. 
These disadvantages are avoided by the method according to the present 
Invention. 
The polymorph prepared by the method according to the present Invention has 
substantial advantages over other anhydrous polymorphs of terazosin 
hydrochloride. It is characterized by a very low hygroscopicity as well as 
a low retention for residual solvents, which is a substantial advantage 
with respect to the use as a pharmaceutical active ingredient.

DETAILED DESCRIPTION OF THE INVENTION 
A preferred embodiment of the method according to the present Invention is 
described hereinafter. 
1. Preparation of the Crystalline Adduct of Terazosin Hydrochloride and 
Methanol 
37.6 g 4-amino-2-(1-piperazinyl)-6,7-dimethoxyquinazoline and 15.8 g 
triethylamine are suspended in 400 ml methylene chloride. The suspension 
is cooled to -5.degree. C. This suspension is stirred while 21.0 g 
tetrahydrofuran-2-carboxylic acid chloride are added drop by drop. The 
suspension is continued to be stirred for two hours at 0.degree. C., 
thereafter the solvent is distilled off under vacuum. 200 ml methanol and 
200 ml acetone are added to the residue. The resulting suspension is kept 
under reflux for 0.5 hours while stirring. Thereafter, it is cooled to 
0.degree. C. The product is isolated by filtration. 78 g of moist 
terazosin base are obtained. 
This terazosin base is suspended in 400 ml methanol and 400 ml methylene 
chloride. While stirring, 23.8 g of a 20% solution of hydrochloric acid in 
methanol are added drop by drop. One obtains a solution which is filtered 
to become clear. The methylene chloride is selectively distilled off under 
vacuum which causes precipitation of the product. The suspension is 
continued to be stirred for 3 hours at room temperature, thereafter the 
product is isolated by filtration. One obtains 74 g of moist terazosin 
hydrochloride methanol adduct which may be dried at 50.degree. C. under 
vacuum, if desired. One obtains 49.0 g of a white crystalline powder 
containing ca. 1 mol methanol per mol terazosin hydrochloride. A further 
purification of the methanol adduct is possible by re-crystallization from 
methanol. 
The method steps as described so far correspond in principle to a method 
known from the above mentioned JP-A-05-78352 for preparing the methanol 
adduct which is designated as "Type M" in this document. 
2. Preparation of the Crystalline Polymorph 
10 g of the crystalline adduct, the preparation of which has been described 
above, are suspended in 100 ml ethanol denatured with 2-butanone. The 
suspension is heated under reflux and is kept for two hours at the reflux 
of the ethanol, the reflux temperature being optionally in the range of 
78.degree. C. to 80.degree. C., or higher. Thereafter the suspension is 
cooled to 20.degree. C. The product is isolated by filtration and dried at 
50.degree. C. under vacuum. One obtains 8.4 g crystalline powder, and the 
X-ray powder diffraction pattern of this product is shown in the drawing, 
FIG. 1. A determination of the contents of residual solvents shows that 
the crystalline powder typically contains less than 100 ppm methanol and 
less than 100 ppm ethanol. 
The methanolate of the terazosin monohydrochloride, which is to be treated 
with the polar solvent, is soluble in the polar solvent only to a very 
small degree. The amount of the polar solvent used is selected so that the 
amount of methonalate which is solved in the solvent is as small as 
possible. Thus, almost the entire amount of the product to be treated will 
be suspended in the polar solvent. This provides substantial advantages 
for performing the method, especially for the retrieval of the solid 
product by simple mechanical separation such as filtration. The treatment 
in polar solvent is preferably carried out at an elevated temperature. 
The crystalline form of the product obtained by the method according to the 
Invention is characterized by the X-ray powder diffraction pattern as 
shown in the drawing. This pattern has characteristic peaks as the 
following values expressed in degrees of angle of 2 .theta.: 7.04; 10.30; 
12.02; 14.12; 14.44; 20.34; 22.34; 22.62; 23.58; 24.28 and 26.96, all 
values within a tolerance of .+-.0.2. 
The Invention is not limited to the details of the example described above. 
For example, the polar solvent for treating the crystalline methonalate of 
terazosin hydrochloride can be any solvent selected from the group of 
alcohols having two to six carbon atoms or ketones having two to six 
carbon atoms or a mixture of two or more of these solvents. 
Moreover, the Invention is not limited to the temperature and time for 
treating the crystalline adduct of terazosin-hydrochloride and methanol as 
set forth in the examples. Within the teaching of this Invention the 
person skilled in the art can easily find out other ranges of temperature 
and/or treatment time, in relation to the particular solvent used, that 
are sufficient and suitable for the desired crystalline polymorph known as 
Form IV, to be formed in the reflux of the solvent. 
Further examples of suitable ranges of temperature and treatment time for 
the treatment of the methanol adduct of terazosin-hydrochloride in the 
reflux of a polar solvent in a method according to the Invention, whereby 
the desired crystal polymorph Form IV is obtained, are the following: 
treatment in ethanol at 60.degree. C.-70.degree. C. for 1-4 hours; 
treatment in ethanol at 85.degree. C.-130.degree. C. for 1-4 hours under 
pressure in an autoclave; 
treatment in isopropanol at 70.degree. C.-130.degree. C. for 1-4 hours, if 
necessary under pressure; 
treatment in isopentanol at 80.degree. C.-130.degree. C. for 0.5-4 hours. 
Although only a limited number of specific embodiments of the present 
Invention have been expressly disclosed, it is, nonetheless, to be broadly 
construed and not to be limited except by the character of the claims 
appended hereto.