PATENT DOCUMENT

Abstract:
The invention provides a crystal of 2-(3,4-dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic acid (which has the chemical structure shown below) and a mixed crystal comprising such a crystal. 
     
       
                 
         
             
             
         
       
     
     The invention also provides methods of producing such crystals, pharmaceutical compositions comprising such crystals, and methods of modulating phosphodiesterase-9 activity and treating disorders such as overactive bladder syndrome by administration of an effective amount of the crystals.

Full Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
       [0001]    This patent application is a divisional of copending U.S. patent application Ser. No. 13/700,935, filed on Nov. 29, 2012, which is the U.S. national phase of International Patent Application No. PCT/JP2011/062513, filed on May 31, 2011, which claims the benefit of Japanese Patent Application No. 2010-125362, filed on May 31, 2010, which are incorporated by reference in their entireties herein. 
     
    
     TECHNICAL FIELD 
       [0002]    The present invention relates to a crystal of 2-(3,4-dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic acid (hereinafter to be referred to as “compound A”) useful as a therapeutic drug for dysuria and the like, a medicament containing the crystal and a production method of the crystal. 
       BACKGROUND ART 
       [0003]    Compound A is a compound described in WO 2006/135080 (see patent document 1), which has a high PDE9 inhibitory action as well as a mild PDE5 inhibitory action, and is useful for the treatment or procedure of dysuria and the like. 
         [0004]    However, patent document 1 does not clearly show concrete properties of the obtained compound A and does not describe or suggest the presence of crystal polymorph. 
       DOCUMENT LIST 
     Patent Document 
       [0000]    
       
         patent document 1: WO 2006/135080 
       
     
       BRIEF SUMMARY OF THE INVENTION 
     Problems to be Solved by the Invention 
       [0006]    The problem of the present invention is to provide a crystal of compound A. 
       Means of Solving the Problems 
       [0007]    In view of the above-mentioned problem, the present inventors have studied various aspects of crystallization of compound A, and successfully obtained novel amorphous form (amorphous), solvate crystals and unsolvated crystals of compound A. 
         [0008]    Particularly, they have found that an unsolvated crystal showing particular property data (Form I crystal and Form II crystal to be mentioned later) cannot be obtained by general crystallization methods such as recrystallization and the like using various organic solvents, but can unexpectedly be produced by a convenient method including heating in an aqueous suspension for a given time. 
         [0009]    This method can be performed as a work-up in the final step of industrial production, with no need to separately include a burdensome step of a crystallization step. In addition, the obtained crystal is superior in filterability. Thus, the method is suitable for large-scale production from the aspects of operability and cost. Furthermore, they have found that these crystals have superior property as a medicament, which resulted in the completion of the present invention. 
         [0010]    Accordingly, the present invention relates to 
         [0000]    [1] a crystal of 2-(3,4-dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic acid having an X-ray powder diffraction pattern showing diffraction peaks at diffraction angles 2θ of 6.7±0.2°, 8.3±0.2°, 8.9±0.2°, 14.0±0.2°, 14.8±0.2° and 26.4±0.2° in X-ray powder diffraction spectrum;
 
[2] the crystal of the above-mentioned [1], showing an endothermic peak having a peak top temperature of 362±5° C. in differential scanning calorimetry (DSC);
 
[3] a crystal of 2-(3,4-dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic acid, having an X-ray powder diffraction pattern showing diffraction peaks at diffraction angles 2θ of 7.3±0.2°, 11.2±0.2°, 13.3±0.2°, 17.0±0.2°, 25.5±0.2° and 27.5±0.2° in X-ray powder diffraction spectrum;
 
[4] the crystal of the above-mentioned [3], showing an endothermic peak having a peak top temperature of 342±5° C. in differential scanning calorimetry (DSC);
 
[5] the crystal of any of the above-mentioned [1] to [4], which is an unsolvated and unhydrated crystal;
 
[6] a mixed crystal comprising the crystal of the above-mentioned [1] or [2], and the crystal of the above-mentioned [3] or [4];
 
[7] a medicament comprising the crystal of any of the above-mentioned [1] to [6] as an active ingredient;
 
[8] a pharmaceutical composition comprising the crystal of any of the above-mentioned [1] to [6] and a pharmaceutically acceptable carrier;
 
[9] the medicament of the above-mentioned [7], which is a PDE9 inhibitor;
 
[10] the medicament of the above-mentioned [7], which is a therapeutic agent for overactive bladder syndrome, pollakiuria, urinary incontinence, dysuria in benign prostatic hyperplasia, neurogenic bladder, interstitial cystitis, urolithiasis, benign prostatic hyperplasia, erectile dysfunction, cognitive impairment, neuropathy, Alzheimer&#39;s disease, pulmonary hypertension, chronic obstructive pulmonary diseases, ischemic heart diseases, hypertension, angina, myocardial infarction, arteriosclerosis, thrombosis, embolism, and type I diabetes or type II diabetes;
 
[11] a method of producing the crystal of any of claims  1  to  6 , comprising a step of heating an aqueous suspension of 2-(3,4-dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic acid;
 
[12] a method of producing the crystal of the above-mentioned [1] or [2], comprising a step of heating an aqueous suspension of 2-(3,4-dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic acid at not less than 40° C. and less than 50° C. for 1 to 96 hr, not less than 50° C. and less than 60° C. for 0.5 to 32 hr, not less than 60° C. and less than 70° C. for 0.5 to 24 hr, not less than 70° C. and less than 80° C. for 0.1 to 12 hr, not less than 80° C. and less than 90° C. for 0.05 to 6 hr, or not less than 90° C. and not more than 100° C. for 0.01 to 3 hr;
 
[13] a method of producing the crystal of the above-mentioned [3] or [4], comprising a step of heating an aqueous suspension of 2-(3,4-dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic acid at not less than 60° C. and less than 70° C. for 144 hr or more, not less than 70° C. and less than 80° C. for 25 hr or more, not less than 80° C. and less than 90° C. for 23 hr or more, or not less than 90° C. and not more than 100° C. for 16 hr or more;
 
[14] the production method of any of the above-mentioned [11] to [13], comprising heating an aqueous suspension obtained by neutralizing or acidifying an aqueous alkaline solution of 2-(3,4-dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic acid; and the like.
 
       Effect of the Invention 
       [0011]    According to the present invention, a novel unsolvated crystal of compound A can be obtained. This crystal can be produced by a convenient method suitable for industrial large-scale production. In addition, the obtained crystal can be easily filtered as compared to amorphous form, and is suitable for industrial large-scale production. Furthermore, the crystal of the present invention is also suitable as an active ingredient of a medicament in stability, solubility, absorbability and the like. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0012]      FIG. 1  shows an X-ray powder diffraction pattern of Form I crystal of compound A (Example 1). 
           [0013]      FIG. 2  shows an infrared absorption spectrum (paste method) of Form I crystal of compound A (Example 1). 
           [0014]      FIG. 3  shows an X-ray powder diffraction pattern of Form II crystal of compound A (Example 2). 
           [0015]      FIG. 4  shows an infrared absorption spectrum (paste method) of Form II crystal of compound A (Example 2). 
           [0016]      FIG. 5  shows an X-ray powder diffraction pattern of a crystal of an isopropanol solvate of compound A (Reference Example 1). 
           [0017]      FIG. 6  shows an infrared absorption spectrum (paste method) of a crystal of an isopropanol solvate of compound A (Reference Example 1). 
           [0018]      FIG. 7  shows an X-ray powder diffraction pattern of a crystal of a dimethylacetamide solvate of compound A (Reference Example 2). 
           [0019]      FIG. 8  shows an infrared absorption spectrum (paste method) of a crystal of a dimethylacetamide solvate of compound A (Reference Example 2). 
           [0020]      FIG. 9  shows an X-ray powder diffraction pattern of a crystal of a dimethylformamide solvate of compound A (Reference Example 3). 
           [0021]      FIG. 10  shows an infrared absorption spectrum (paste method) of a dimethylformamide solvate of compound A (Reference Example 3). 
           [0022]      FIG. 11  shows an X-ray powder diffraction pattern of a crystal of a 1,3-dimethyl-2-imidazolidinone solvate of compound A (Reference Example 4). 
           [0023]      FIG. 12  shows an infrared absorption spectrum (paste method) of a crystal of a 1,3-dimethyl-2-imidazolidinone solvate of compound A (Reference Example 4). 
           [0024]      FIG. 13  shows an X-ray powder diffraction pattern of a crystal of an N-methylpyrrolidone solvate of compound A (Reference Example 5). 
           [0025]      FIG. 14  shows an infrared absorption spectrum (paste method) of a crystal of an N-methylpyrrolidone solvate of compound A (Reference Example 5). 
           [0026]      FIG. 15  shows a DSC chart of Form I crystal of compound A (Example 1). 
           [0027]      FIG. 16  shows a DSC chart of Form II crystal of compound A (Example 2). 
           [0028]      FIG. 17  shows an HPLC chart showing the photostability of compound A (Experimental Example 7). 
       
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
       [0029]    A production method of compound A is disclosed in Example 36-a) of patent document 1, wherein production in the same manner as in Example 1 is described. In Example 1 of the patent document 1, it is described that an ester compound is ester-hydrolyzed by heating under reflux in an aqueous alkaline solution to give carboxylic acid, which is acidified with dilute hydrochloric acid, and the precipitated crystals are collected by filtration. However, compound A having what property was obtained in Example 36-a) is not clearly shown. 
         [0030]    Thus, the present inventors first conducted a replication study of the above-mentioned experiment. Compound A was produced by a method similar to that specifically disclosed in Example 1 of patent document 1. As a result, although crystals were precipitated in said Example 1, an aggregate was in fact suspended. When the aggregate was filtrated by suction, the filter was clogged, and the filtration took an extremely long time. The aggregate was measured by X-ray powder diffraction, but a clear peak showing the presence of crystal was not found, which has clarified that this production method only affords a simple aggregate (amorphous form) or a powder having low crystallinity, rather than a crystal. 
         [0031]    Amorphous forms generally have low stability to light and heat, and have defects in that they are difficult to handle because of being glassy and the like. In addition, amorphous forms tend to allow presence of impurity as compared to crystal. As mentioned above, moreover, since compound A obtained in an amorphous form causes clogging during filtration by suction, it is not suitable for industrial large-scale production. To use compound A as a pharmaceutically active ingredient, and for industrial large-scale production, production of compound A in a crystal form is desired. 
         [0032]    Therefore, the present inventors have tried crystallization of compound A using various solvents. As a result, pseudo crystals of various organic solvent solvates of compound A were obtained, but a crystal free of an organic solvent could not be obtained. 
         [0033]    In general, crystal of solvate often has problems of stability such as easy transformation due to dissociation of solvent and the like, as compared to unsolvated crystals and, unless a stable crystal such as hydrate crystal and the like is obtained, difficulty of handling as a medicament is feared. In addition, since a substantial amount of organic solvent is contained, the safety of the solvent itself should also be considered, and various difficulties are expected in the development as a medicament. 
         [0034]    Furthermore, the present inventors have conducted various studies in an attempt to obtain an unsolvated crystal, and unexpectedly found that a novel unsolvated crystal of compound A can be produced by a convenient operation of heating an aqueous suspension of compound A for a given time, and further, the obtained crystal can be easily filtered as compared to amorphous forms and is suitable for industrial large-scale production. 
         [0035]    Furthermore, they have found that two novel unsolvated crystals of compound A (hereinafter to be referred to as Form I crystal and Form II crystal) and a mixed crystal thereof can be produced separately by appropriately adjusting the heating temperature and duration. 
         [0036]    Moreover, the thus-obtained Form I crystal and Form II crystal have preferable properties as a medicament in terms of solubility, stability, absorbability and the like. 
         [0037]    The detail is explained in the following. 
       1. Production of Amorphous Compound A 
       [0038]    An amorphous compound A can be obtained as a precipitated aggregate by neutralizing or acidifying an aqueous alkaline solution of compound A with an acid. Examples of the method for obtaining the aggregate from water suspension include collection by filtration, centrifugation, a method including precipitation and decanting supernatant and the like. Of these, collection by filtration is convenient and preferable. However, this method has a room for improvement for application to industrial production since it requires an extremely long time due to the clogging of filter, and shows poor dewatering. 
         [0039]    The aqueous alkaline solution of compound A may contain an organic solvent miscible with water. Examples of the organic solvent include alcohols (e.g., methanol, ethanol, propanol, isopropanol etc.), amides (e.g., N,N-dimethylformamide, N,N-dimethylacetamide etc.), ethers (e.g., tetrahydrofuran, dioxane etc.) and the like. The amount of the solvent to be used is preferably 0.01- to 0.1-fold (v/v) relative to water. 
         [0040]    The aqueous alkaline solution of compound A can be prepared by dissolving compound A or a salt thereof (e.g., sodium salt, potassium salt etc.) in an aqueous alkaline solution. Examples of the aqueous alkaline solution include aqueous solutions of sodium hydroxide, potassium hydroxide, potassium carbonate and the like. While the amount of alkali to be used can be about 1 to 5 mol per 1 mol of compound A, 2 mol or more is preferable, and 2 to 2.4 mol is particularly preferable. When the amount of alkali to be used is less than this range, compound A is not easily dissolved in an aqueous alkaline solution. 
         [0041]    In addition, as an aqueous alkaline solution of compound A, a reaction solution obtained by alkaline hydrolysis of an ester form of compound A (e.g., C 1-6  alkyl ester form of compound A such as ethyl 2-(3,4-dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate and the like produced in Production Example 10 of patent document 1) may be used. 
         [0042]    Hydrolysis of an ester form of compound A can be performed according to a method known per se, for example, suspending or dissolving an ester form of compound A in water or a mixed solvent of alcohols such as methanol, ethanol, isopropanol and the like added with water, in the presence of alkali such as sodium hydroxide, potassium hydroxide, potassium carbonate and the like at 0° C. to the refluxing temperature of the reaction mixture, preferably within the range of room temperature to the refluxing temperature of the reaction mixture. While the ratio of alkali to be used relative to an ester form of compound A is not particularly limited, alkali can be generally used within the range of about 1 to 20 mol per 1 mol of an ester form of compound A. 
         [0043]    The concentration of the aqueous alkaline solution of compound A is preferably about 0.5 to 2 mol/L. 
         [0044]    Examples of the acid to be used for neutralization or acidification of an aqueous alkaline solution of compound A include hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, oxalic acid and the like, with preference given to dilute hydrochloric acid. 
         [0045]    For neutralization, an equivalent amount of an acid relative to the base contained in the aqueous alkaline solution only needs to be added. For acidification, the pH thereof is not particularly limited, but an acid is preferably added to adjust pH to about 5 to 7. 
         [0046]    The precipitated aggregate is obtained by collection by filtration, centrifugation and the like, and washed and dried to give an amorphous compound A. When an amorphous aggregate is obtained by collection by filtration, the filter is easily clogged and the filtration takes time even when suctioned during filtration. Therefore, obtainment by collection by filtration is not suitable for industrial production. 
       2. Production Method of Form I Crystal and Form II Crystal 
       [0047]    The Form I crystal and Form II crystal of compound A can be produced by heating an aqueous suspension of compound A for a given time. 
         [0048]    The aqueous suspension of compound A may contain an organic solvent miscible with water. Examples of the organic solvent include alcohols (e.g., methanol, ethanol, propanol, isopropanol etc.) and the like. Since production of a crystal of the organic solvent solvate contained is feared, it is preferable to not contain an organic solvent. 
         [0049]    The amount of the solvent to be used when an organic solvent is contained is preferably 0.001- to 0.3-fold (v/v) relative to water. When the amount of the organic solvent is greater than this range, production of a crystal of the organic solvent solvate is feared. 
         [0050]    While the form of compound A in the suspension in the above-mentioned “aqueous suspension of compound A” is not particularly limited, an amorphous form is preferable. 
         [0051]    The aqueous suspension of compound A can be prepared by adding compound A to water or a mixed solvent of water and an organic solvent, and stirring them. 
         [0052]    Alternatively, preferably, the suspension wherein an amorphous compound A is precipitated by adding an acid to an aqueous alkaline solution of compound A, in the production method of the amorphous compound A explained in the above-mentioned 1., can be used as an aqueous suspension of compound A. 
         [0053]    Particularly preferably, a suspension wherein an amorphous compound A is precipitated, which is obtained by adding an acid to a reaction solution obtained by alkaline hydrolysis of an ester form of compound A, can be used as an aqueous suspension of compound A. This method is particularly advantageous for industrial production since, in alkaline hydrolysis of an ester form, which is the final step of industrial production of compound A in this method, 
         [0000]    Form I crystal and Form II crystal of compound A can be prepared in one pot by work-up, without once taking out compound A from the reaction container. 
         [0054]    In the heating conditions of the aqueous suspension of compound A, Form I crystal and Form II crystal, or a mixed crystal thereof can be produced separately by appropriately adjusting heating duration and heating temperature. That is, by heating an aqueous suspension of compound A in a given temperature range for a given time, Form I crystal can be first produced. Furthermore, by heating at a higher temperature and/or for a longer time, Form I crystal is converted to Form II crystal, whereby Form II crystal or a mixed crystal of Form I crystal and Form II crystal can be obtained. 
         [0055]    In the following, heating an aqueous suspension of compound A in a given temperature range and for a given time is referred to as “maturation”. 
         [0056]    During maturation, an aqueous suspension may be left standing, or can be, for example, stirred, shaken or convected, with preference given to stirring. 
         [0057]    When Form I crystal is produced by maturation of an aqueous suspension of compound A, the relationship between maturation temperature and time is that a lower temperature requires maturation for a comparatively long time, and a higher temperature can afford Form I crystal by maturation for a comparatively short time. 
         [0058]    Specifically, Form I crystal can be obtained by setting the maturation temperature and time to, for example, not less than 40° C. and less than 50° C. and 1 to 96 hr (more preferably 8 to 48 hr), not less than 50° C. and less than 60° C. and 0.5 to 32 hr (more preferably 4 to 24 hr), not less than 60° C. and less than 70° C. and 0.5 to 24 hr (more preferably 2 to 6 hr), not less than 70° C. and less than 80° C. and 0.1 to 12 hr (more preferably 1.5 to 4 hr), not less than 80° C. and less than 90° C. and 0.05 to 6 hr (more preferably 0.5 to 3 hr), not less than 90° C. and not more than 100° C. and 0.01 to 3 hr (more preferably 0.1 to 2 hr) or the like. In consideration of the production efficiency, crystallinity, possibility of mixing of other crystal form and the like, of these, maturation at not less than 70° C. and less than 80° C. for 0.1 to 12 hr is preferable, and maturation at not less than 70° C. and less than 80° C. for 1.5 to 4 hr is particularly preferable. In some cases when a higher temperature (e.g., not less than 90° C. and not more than 100° C.) is used, maturation is completed during temperature rise, and Form I crystal is obtained at the time point when said temperature is reached. 
         [0059]    In another embodiment, Form I crystal can be obtained by setting the maturation temperature and time to, for example, not less than 40° C. and less than 50° C. and 1 to 96 hr (more preferably 8 to 48 hr), not less than 50° C. and less than 60° C. and 0.5 to 48 hr (more preferably 4 to 24 hr), not less than 60° C. and less than 70° C. and 0.5 to 24 hr (more preferably 2 to 6 hr), not less than 70° C. and less than 80° C. and 0.1 to 12 hr (more preferably 1.5 to 4 hr), not less than 80° C. and less than 90° C. and 0.05 to 6 hr (more preferably 0.5 to 3 hr), not less than 90° C. and not more than 100° C. and 0.01 to 3 hr (more preferably 0.1 to 2 hr) or the like. 
         [0060]    In a third embodiment, Form I crystal can also be obtained by setting the maturation temperature and time to, for example, not less than 40° C. and less than 50° C. and 1 to 96 hr (more preferably 8 to 48 hr), not less than 50° C. and less than 60° C. and 0.5 to 32 hr (more preferably 4 to 24 hr), not less than 60° C. and less than 70° C. and 0.5 to 24 hr (more preferably 2 to 6 hr), not less than 70° C. and less than 80° C. and 0.1 to 12 hr (more preferably 1.5 to 4 hr), not less than 80° C. and less than 90° C. and 0.05 to 6 hr (more preferably 0.5 to 3 hr), not less than 90° C. and not more than 100° C. and 0.01 to 4 hr (more preferably 0.1 to 2 hr) or the like. 
         [0061]    The maturation time to obtain Form I crystal may vary somewhat depending on the difference in the experiment conditions. 
         [0062]    Furthermore, by heating at a higher temperature and/or for a longer time than the above-mentioned ranges, Form I crystal is converted to Form II crystal, or amorphous form is converted to Form II crystal via Form I crystal, whereby Form II crystal can be obtained. 
         [0063]    Specifically, Form II crystal can be obtained by setting the maturation temperature and time to, for example, not less than 60° C. and less than 70° C. and 144 hr or more (more preferably not less than 155 hr), not less than 70° C. and less than 80° C. and 25 hr or more (more preferably not less than 30 hr), not less than 80° C. and less than 90° C. and 23 hr or more (more preferably not less than 25 hr), not less than 90° C. and not more than 100° C. and 16 hr or more (more preferably not less than 20 hr) or the like. Of these, maturation at not less than 90° C. and not more than 100° C. for 16 hr or more is preferable, and maturation at not less than 90° C. and not more than 100° C. for 20 hr or more is particularly preferable. 
         [0064]    In another embodiment, Form II crystal can be obtained by setting the maturation temperature and time to, for example, not less than 60° C. and less than 70° C. and 70 hr or more (more preferably not less than 80 hr), not less than 70° C. and less than 80° C. and 25 hr or more (more preferably not less than 30 hr), not less than 80° C. and less than 90° C. and 12 hr or more (more preferably not less than 15 hr), not less than 90° C. and not more than 100° C. and 5 hr or more (more preferably not less than 8 hr) or the like. Of these, maturation at not less than 90° C. and not more than 100° C. for 5 hr or more is preferable, and maturation at not less than 90° C. and not more than 100° C. for 8 hr or more is particularly preferable. 
         [0065]    While the upper limit of the maturation time for obtaining Form II crystal is not particularly limited, maturation may be further continued for about 1 to 2 hr from the lower limit of the above-mentioned maturation time. 
         [0066]    In addition, the maturation time for obtaining Form II crystal may vary somewhat depending on the experiment conditions thereof. 
         [0067]    A mixed crystal of Form I crystal and Form II crystal can be obtained by discontinuing the maturation of an aqueous suspension of compound A during conversion of Form I crystal to Form II crystal. 
         [0068]    A mixed crystal of Form I crystal and Form II crystal at a desired mixing ratio can be obtained by, for example, sampling within the range of further maturation conditions after production of Form I crystal, and monitoring the amount ratio of Form I crystal and Form II crystal by X-ray powder diffraction, DSC and the like. 
         [0069]    After producing Form I crystal and/or Form II crystal by maturation under the above-mentioned respective conditions, the crystals can be collected by filtration by a general method, washed with water and the like as necessary, and further dried. 
         [0070]    As an analysis method of the thus-obtained crystals, X-ray powder diffraction is preferable. In addition, infrared absorption spectrum, solid-state NMR, differential scanning calorimetry (DSC), thermogravimetry/differential thermal analysis (TG-DTA) and the like may be used in combination. While measurement conditions of these are not particularly limited, measurement under the measurement conditions described in the present specification is preferable. 
         [0071]    Each spectrum obtained by such analysis methods has a certain measurement error caused by the nature thereof. A crystal having a peak with a spectrum error within the error range is also encompassed in the scope of the present invention. For example, in the case of a measurement by X-ray powder diffraction, a crystal having a peak within the error range of ±0.2° at diffraction angles 2θ is contained in the present invention. 
         [0072]    An error range of ±5° C. is acceptable in differential scanning calorimetry (DSC), and an error range of ±0.5% is acceptable in infrared absorption spectrum. 
         [0073]    The Form I crystal of the present invention shows an X-ray powder diffraction pattern having characteristic diffraction peaks at diffraction angles 2θ of 6.7°, 8.3°, 8.9°, 14.0°, 14.8° and 26.4° (each ±0.2°), using CuKα radiation as X-ray, preferably an X-ray powder diffraction pattern having diffraction peaks at 6.7°, 8.3°, 8.9°, 13.1°, 13.4°, 14.0°, 14.8°, 17.9°, 21.6° and 26.4° (each ±0.2°). 
         [0074]    In addition, Form I crystal of the present invention has an endothermic peak showing a peak top temperature of about 362° C. (±5° C.) in differential scanning calorimetry (DSC), and an infrared absorption spectrum pattern showing absorption peaks at 1713, 1673, 1643, 1590, 1532, 1421, 1265, 1214 and 1034 cm −1  (each ±0.5%) in infrared absorption spectrum (paste method). 
         [0075]    The Form II crystal of the present invention shows an X-ray powder diffraction pattern having characteristic diffraction peaks at diffraction angles 2θ of 7.3°, 11.2°, 13.3°, 17.0°, 25.5° and 27.5° (each)±0.2°, using CuKα radiation as X-ray, preferably an X-ray powder diffraction pattern having diffraction peaks at 7.3°, 11.2°, 13.3°, 17.0°, 22.4°, 23.1°, 25.5° and 27.5° (each ±0.2°). 
         [0076]    The Form II crystal of the present invention has an endothermic peak having a peak top temperature of about 342° C. (±5° C.) in differential scanning calorimetry (DSC), and shows an infrared absorption spectrum pattern having absorption peaks at 1706, 1669, 1649, 1584, 1530, 1283, 1271, 1260, 1215, 1203, 1137, 1033 cm −1  (each ±0.5%) in infrared absorption spectrum (paste method). 
       3. Production of Solvate Crystal of Compound A 
       [0077]    Solvate crystal of compound A can be prepared by a cooling method (slow cooling) or a heating suspension stirring method using various organic solvents. Specific procedures of each method are as described below. 
       (Cooling Method) 
       [0078]    Compound A is dissolved by heating in a soluble organic solvent, and cooled slowly to room temperature to allow precipitation of crystals. 
       (Heating Suspension Stirring Method) 
       [0079]    Compound A is suspended in a poorly soluble organic solvent, and the mixture is suspended and stirred with heating. 
         [0080]    To be specific, an isopropanol solvate can be obtained by a heating suspension stirring method of isopropanol, a dimethylacetamide solvate can be obtained by a heating suspension stirring method of dimethylacetamide-acetone, a dimethylformamide solvate can be obtained by a cooling method of dimethylformamide-water, a 1,3-dimethyl-2-imidazolidinone solvate can be obtained by a cooling method of 1,3-dimethyl-2-imidazolidinone, and an N-methylpyrrolidone solvate can be obtained by a cooling method of N-methylpyrrolidone, as respective pseudo crystal forms. The detail of the production method of each solvate crystal and the property data of the obtained solvate crystals are as described in the below-mentioned Reference Examples. 
         [0081]    Form I crystal and Form II crystal of the present invention, and a mixed crystal thereof (hereinafter to be referred to as the crystal of the present invention) have a superior PDE9 inhibitory action and a mild PDE5 inhibitory action, and is useful as a medicament for the treatment and procedure of diseases wherein decomposition of cGMP due to PDE9 is involved; for example, overactive bladder syndrome, pollakiuria, urinary incontinence, dysuria in benign prostatic hyperplasia, neurogenic bladder, interstitial cystitis, urolithiasis, benign prostatic hyperplasia, erectile dysfunction, cognitive impairment, neuropathy, Alzheimer&#39;s disease, pulmonary hypertension, chronic obstructive pulmonary diseases, ischemic heart diseases, hypertension, angina, myocardial infarction, arteriosclerosis, thrombosis, embolism, type I diabetes, type II diabetes and the like. 
         [0082]    Use of compound A as an agent for the treatment or procedure of dysuria and the like is disclosed in detail in patent document 1, and similarly, the crystal of the present invention can be administered orally or parenterally (e.g., intramuscular injection, intravenous injection, rectal administration, transdermal administration etc.) for the treatment, procedure and the like of dysuria and the like in human and other mammals. All disclosures of patent document 1 are encompassed in full in the disclosure of the present specification as reference. 
         [0083]    The crystal of the present invention can be formulated, together with non-toxic excipients, into any preparation form such as solid (e.g., tablet, hard capsule, soft capsule, granule, powder, fine granule, pill, troche etc.); semi-solid (e.g., suppository, ointment etc.); or liquid (e.g., injection, emulsion, suspension, lotion, spray etc.). Particularly, a solid preparation is preferable. 
         [0084]    Examples of the non-toxic excipients usable for the above-mentioned preparations include starch, gelatin, glucose, lactose, fructose, maltose, magnesium carbonate, talc, magnesium stearate, methyl cellulose, carboxymethyl cellulose and salts thereof, gum Arabic, polyethylene glycol, p-hydroxybenzoic acid alkyl ester, syrup, ethanol, propylene glycol, vaseline, Carbowax, glycerine, sodium chloride, sodium sulfite, sodium phosphate, citric acid and the like. These preparations may also contain other therapeutically useful drugs. 
         [0085]    While the content of the crystal of the present invention in these preparations varies depending on the dosage form, it can be generally contained at a concentration of 0.1-50 wt % in solid and semi-solid forms, and 0.05-10 wt % in liquid form. 
         [0086]    While the dose of the crystal of the present invention varies widely according to the kind of warm-blooded animals including human to be the subject, the kind of the target disease, administration route, seriousness of symptoms, doctor&#39;s diagnosis and the like, it can be generally within the range of 0.01-5 mg/kg per day, preferably 0.02-2 mg/kg per day. It is obviously possible to administer a dose smaller than the above-mentioned lower limit or more than the above-mentioned upper limit, depending on seriousness of the symptom of patients, doctor&#39;s diagnosis and the like. The above-mentioned dose can be administered once a day or in several portions per day. 
         [0087]    An example of a preparation containing Form I crystal of the present invention is shown below. 
         [0000]    
       
         
               
               
               
             
               
               
               
             
           
               
                   
                 TABLE 1 
               
               
                   
                   
               
               
                   
                 5 mg tablet  
                 mg/tablet 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 Form I crystal 
                 5.0 
               
               
                   
                 starch 
                 10.0 
               
               
                   
                 lactose 
                 73.0 
               
               
                   
                 carboxymethylcellulose calcium 
                 10.0 
               
               
                   
                 talc 
                 1.0 
               
               
                   
                 magnesium stearate 
                 1.0 
               
               
                   
                   
                 100.0 
               
               
                   
                   
               
             
          
         
       
     
         [0088]    Form I crystal is pulverized to a particle size 70 μm or less, starch, lactose and carboxymethylcellulose calcium are added thereto, and the mixture is mixed well. 10% Starch glue is added to the above-mentioned mixed powder, the mixture is mixed by stirring to produce granules. The granules are sieved to a particle size after drying of about 1000 μm, talc and magnesium stearate are admixed therewith, and the mixture is tableted. 
       EXAMPLES 
       [0089]    The present invention is more specifically explained in the following by referring to Examples, which are not to be construed as limitative. 
       Production Example 1 
     Production of amorphous 2-(3,4-dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic acid 
       [0090]    A mixture of ethyl 2-(3,4-dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate (20.03 g), 5 mol/L aqueous sodium hydroxide solution (30 mL), water (50 mL) and isopropanol (30 mL) was heated under reflux for 1 hr. The reaction mixture was ice-cooled, acidified with dilute hydrochloric acid, and stirred for 2 hr under ice-cooling. The precipitated solid was collected by filtration, washed with water, and dried under reduced pressure at 80° C. for 24 hr to give a solid (17.39 g). The time necessary for collection by filtration was about 90 min. 
         [0091]    By  1 H-NMR and MS, the solid obtained in Production Example 1 was confirmed to be the same compound as 2-(3,4-dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic acid described in Example 36-a) of patent document 1. 
         [0092]      1 H-NMR (DMSO-d 6 ) δ: 2.79 (3H, s), 3.99 (2H, s), 7.3-7.7 (3H, m), 12.71 (1H, br s), 13.33 (1H, br s) MS (m/z): 370 (M + +2), 368 (M + ) 
       Example 1 
     Production of Form I crystal of 2-(3,4-dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic acid 
       [0093]    A mixture of amorphous 2-(3,4-dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic acid (4.995 g) obtained in Production Example 1, 1 mol/L aqueous sodium hydroxide solution (27.1 mL) and water (32 mL) was heated for 1 hr, and dissolution was confirmed. The reaction mixture was allowed to cool under room temperature, acidified with dilute hydrochloric acid, and stirred at 75° C. for 1.5 hr. The obtained crystals were collected by filtration, washed with water, and draught-dried at 40° C. for 19 hr to give the title crystal (4.835 g). The time necessary for collection by filtration was about 5 min. 
         [0094]    By  1 H-NMR and MS, the crystal obtained in Example 1 was confirmed to be the same compound as 2-(3,4-dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic acid described in Example 36-a) of patent document 1. 
         [0095]      1 H-NMR (DMSO-d 6 ) δ: 2.79 (3H, s), 3.99 (2H, s), 7.3-7.7 (3H, m), 12.71 (1H, br s), 13.33 (1H, br s) MS (m/z): 370 (M + +2), 368 (M + ) 
         [0096]    The X-ray powder diffraction pattern of the crystal obtained in Example 1 is shown in  FIG. 1 , and the peaks and peak intensities at diffraction angle (2θ) are shown in Table 2. Furthermore, the infrared absorption spectrum is shown in  FIG. 2 . 
         [0000]    
       
         
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 2 
               
               
                   
               
               
                 Peak 
                   
                 Setting width 
                   
                   
                 Relative 
               
               
                 No. 
                 2 θ 
                 for peak search 
                 d value 
                 Intensity 
                 intensity 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 1 
                 6.720 
                 0.165 
                 13.1426 
                 52347 
                 100 
               
               
                 2 
                 8.250 
                 0.188 
                 10.7084 
                 15366 
                 30 
               
               
                 3 
                 8.930 
                 0.188 
                 9.8944 
                 17464 
                 34 
               
               
                 4 
                 12.190 
                 0.200 
                 7.2547 
                 8197 
                 16 
               
               
                 5 
                 13.110 
                 0.176 
                 6.7476 
                 9829 
                 19 
               
               
                 6 
                 13.430 
                 0.200 
                 6.5875 
                 10120 
                 20 
               
               
                 7 
                 14.040 
                 0.200 
                 6.3026 
                 27104 
                 52 
               
               
                 8 
                 14.840 
                 0.200 
                 5.9646 
                 33271 
                 64 
               
               
                 9 
                 16.520 
                 0.176 
                 5.3616 
                 7506 
                 15 
               
               
                 10 
                 17.880 
                 0.365 
                 4.9568 
                 11807 
                 23 
               
               
                 11 
                 20.160 
                 0.165 
                 4.4010 
                 6716 
                 13 
               
               
                 12 
                 21.300 
                 0.129 
                 4.1680 
                 6955 
                 14 
               
               
                 13 
                 21.550 
                 0.165 
                 4.1202 
                 10723 
                 21 
               
               
                 14 
                 24.790 
                 0.306 
                 3.5885 
                 8788 
                 17 
               
               
                 15 
                 26.400 
                 0.388 
                 3.3732 
                 48325 
                 93 
               
               
                 16 
                 27.070 
                 0.235 
                 3.2912 
                 8288 
                 16 
               
               
                 17 
                 28.320 
                 0.306 
                 3.1488 
                 8741 
                 17 
               
               
                 18 
                 28.930 
                 0.235 
                 3.0837 
                 6232 
                 12 
               
               
                   
               
             
          
         
       
     
       Example 2 
     Production of Form II crystal of 2-(3,4-dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic acid 
       [0097]    A mixture of amorphous 2-(3,4-dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic acid (5.671 g) obtained in Production Example 1, 1 mol/L aqueous sodium hydroxide solution (30.8 mL) and water (54 mL) was heated for 1 hr, and dissolution was confirmed. The reaction mixture was allowed to cool under room temperature, acidified with dilute hydrochloric acid, and stirred at 75° C. for 25 hr. The obtained crystals were collected by filtration, washed with water, and draught-dried at 40° C. for 19 hr to give the title compound (5.331 g). The time necessary for collection by filtration was about 5 min. 
         [0098]    By  1 H-NMR and MS, the crystal obtained in Example 2 was confirmed to be the same compound as 2-(3,4-dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic acid described in Example 36-a) of patent document 1. 
         [0099]      1 H-NMR (DMSO-d 6 ) δ: 2.79 (3H, s), 3.99 (2H, s), 7.3-7.7 (3H, m), 12.71 (1H, br s), 13.33 (1H, br s) 
         [0100]    MS (m/z): 370 (M + +2), 368 (M + ) 
         [0101]    The X-ray powder diffraction pattern of the crystal obtained in Example 2 is shown in  FIG. 3 , and the peaks and peak intensities at diffraction angle (2θ) are shown in Table 3. Furthermore, the infrared absorption spectrum is shown in  FIG. 4 . 
         [0000]    
       
         
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 3 
               
               
                   
               
               
                 Peak 
                   
                 Setting width 
                   
                   
                 Relative 
               
               
                 No. 
                 2 θ 
                 for peak search 
                 d value 
                 Intensity 
                 intensity 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 1 
                 7.250 
                 0.176 
                 12.1830 
                 18986 
                 29 
               
               
                 2 
                 11.210 
                 0.200 
                 7.8866 
                 24968 
                 38 
               
               
                 3 
                 13.330 
                 0.212 
                 6.6367 
                 40132 
                 60 
               
               
                 4 
                 14.350 
                 0.153 
                 6.1672 
                 6774 
                 11 
               
               
                 5 
                 14.490 
                 0.188 
                 6.1079 
                 8676 
                 13 
               
               
                 6 
                 17.030 
                 0.224 
                 5.2022 
                 22985 
                 35 
               
               
                 7 
                 17.870 
                 0.212 
                 4.9595 
                 11704 
                 18 
               
               
                 8 
                 18.500 
                 0.188 
                 4.7920 
                 6558 
                 10 
               
               
                 9 
                 20.200 
                 0.176 
                 4.3924 
                 5993 
                 9 
               
               
                 10 
                 20.370 
                 0.200 
                 4.3561 
                 6465 
                 10 
               
               
                 11 
                 21.810 
                 0.200 
                 4.0717 
                 6112 
                 10 
               
               
                 12 
                 22.390 
                 0.341 
                 3.9675 
                 18571 
                 28 
               
               
                 13 
                 23.070 
                 0.235 
                 3.8521 
                 26730 
                 40 
               
               
                 14 
                 23.740 
                 0.259 
                 3.7448 
                 9886 
                 15 
               
               
                 15 
                 24.630 
                 0.259 
                 3.6115 
                 11312 
                 17 
               
               
                 16 
                 24.960 
                 0.176 
                 3.5645 
                 10264 
                 16 
               
               
                 17 
                 25.490 
                 0.212 
                 3.4916 
                 67301 
                 100 
               
               
                 18 
                 27.470 
                 0.271 
                 3.2442 
                 42854 
                 64 
               
               
                 19 
                 30.000 
                 0.200 
                 2.9761 
                 6616 
                 10 
               
               
                 20 
                 31.630 
                 0.224 
                 2.8264 
                 5372 
                 8 
               
               
                   
               
             
          
         
       
     
       Reference Example 1 
     Production of crystal of isopropanol solvate of 2-(3,4-dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic acid 
       [0102]    Amorphous 2-(3,4-dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic acid (1 g) obtained in Production Example 1 was suspended in isopropanol (25 mL), and the suspension was heated under reflux for 1 hr. After cooling to room temperature, the precipitate was collected by filtration, and draught-dried at 40° C. for 14 hr to give the title crystal (1.136 g). 
         [0103]      1 H-NMR (DMSO-d 6 ) δ: 1.04 (6H, d, J=6.2 Hz), 2.79 (3H, s), 3.7-3.8 (1H, m), 3.99 (2H, s), 4.2-4.4 (1H, m), 7.3-7.7 (3H, m), 12.70 (1H, br s), 13.34 (1H, br s) 
         [0104]    According to the above-mentioned NMR data, the obtained crystal is considered to be a mono isopropanol solvate of compound A. 
         [0105]    The X-ray powder diffraction patterns thereof are shown in  FIG. 5 , the peaks and peak intensities at diffraction angle (2θ) are shown in Table 4, and the infrared absorption spectrum is shown in  FIG. 6 . 
         [0000]    
       
         
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 4 
               
               
                   
               
               
                 Peak 
                   
                 Setting width 
                   
                   
                 Relative 
               
               
                 No. 
                 2 θ 
                 for peak search 
                 d value 
                 Intensity 
                 intensity 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 1 
                 7.120 
                 0.165 
                 12.4051 
                 33839 
                 56 
               
               
                 2 
                 7.970 
                 0.176 
                 11.0839 
                 21152 
                 35 
               
               
                 3 
                 13.990 
                 0.141 
                 6.3250 
                 8027 
                 14 
               
               
                 4 
                 14.230 
                 0.165 
                 6.2189 
                 22834 
                 38 
               
               
                 5 
                 14.770 
                 0.176 
                 5.9927 
                 26316 
                 44 
               
               
                 6 
                 15.490 
                 0.188 
                 5.7158 
                 15104 
                 25 
               
               
                 7 
                 15.850 
                 0.224 
                 5.5867 
                 12555 
                 21 
               
               
                 8 
                 16.690 
                 0.176 
                 5.3074 
                 8433 
                 14 
               
               
                 9 
                 19.810 
                 0.176 
                 4.4780 
                 11945 
                 20 
               
               
                 10 
                 20.130 
                 0.188 
                 4.4075 
                 20146 
                 34 
               
               
                 11 
                 22.610 
                 0.188 
                 3.9294 
                 18646 
                 31 
               
               
                 12 
                 23.340 
                 0.188 
                 3.8081 
                 16153 
                 27 
               
               
                 13 
                 24.210 
                 0.165 
                 3.6732 
                 9881 
                 17 
               
               
                 14 
                 25.280 
                 0.294 
                 3.5201 
                 60914 
                 100 
               
               
                 15 
                 25.820 
                 0.188 
                 3.4477 
                 6903 
                 12 
               
               
                 16 
                 26.490 
                 0.188 
                 3.3620 
                 18926 
                 32 
               
               
                 17 
                 27.650 
                 0.188 
                 3.2235 
                 8502 
                 14 
               
               
                 18 
                 28.980 
                 0.188 
                 3.0785 
                 23265 
                 39 
               
               
                 19 
                 31.700 
                 0.165 
                 2.8203 
                 10297 
                 17 
               
               
                 20 
                 31.900 
                 0.153 
                 2.8031 
                 11660 
                 20 
               
               
                 21 
                 32.070 
                 0.188 
                 2.7886 
                 9615 
                 16 
               
               
                 22 
                 33.850 
                 0.212 
                 2.6459 
                 8341 
                 14 
               
               
                   
               
             
          
         
       
     
       Reference Example 2 
     Production of crystal of dimethylacetamide solvate of 2-(3,4-dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic acid 
       [0106]    In the same manner as in Reference Example 1 except that dimethylacetamide (6 mL) and acetone (12 mL) were used instead of isopropanol, the title crystal was produced. 
         [0107]      1 H-NMR (DMSO-d 6 ) δ: 1.96 (3H, s), 2.7-2.9 (6H, m), 2.95 (3H, s), 3.99 (2H, s), 7.3-7.7 (3H, m), 12.70 (1H, br s), 13.34 (1H, br s) 
         [0108]    According to the above-mentioned NMR data, the obtained crystal is considered to be a mono dimethylacetamide solvate of compound A. 
         [0109]    The X-ray powder diffraction pattern is shown in  FIG. 7 , the peaks and peak intensities at diffraction angle (2θ) are shown in Table 5, and the infrared absorption spectrum is shown in  FIG. 8 . 
         [0000]    
       
         
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 5 
               
               
                   
               
               
                 Peak 
                   
                 Setting width 
                   
                   
                 Relative 
               
               
                 No. 
                 2 θ 
                 for peak search 
                 d value 
                 Intensity 
                 intensity 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 1 
                 5.330 
                 0.165 
                 16.5665 
                 28442 
                 32 
               
               
                 2 
                 9.360 
                 0.165 
                 9.4408 
                 9230 
                 11 
               
               
                 3 
                 12.840 
                 0.188 
                 6.8888 
                 14564 
                 17 
               
               
                 4 
                 16.020 
                 0.059 
                 5.5278 
                 7933 
                 9 
               
               
                 5 
                 16.410 
                 0.176 
                 5.3973 
                 89400 
                 100 
               
               
                 6 
                 17.320 
                 0.200 
                 5.1157 
                 22311 
                 25 
               
               
                 7 
                 19.790 
                 0.271 
                 4.4825 
                 18273 
                 21 
               
               
                 8 
                 20.970 
                 0.271 
                 4.2328 
                 18373 
                 21 
               
               
                 9 
                 21.370 
                 0.188 
                 4.1545 
                 6820 
                 8 
               
               
                 10 
                 23.380 
                 0.165 
                 3.8017 
                 13066 
                 15 
               
               
                 11 
                 23.710 
                 0.224 
                 3.7495 
                 28662 
                 33 
               
               
                 12 
                 24.800 
                 0.212 
                 3.5871 
                 12585 
                 15 
               
               
                 13 
                 25.500 
                 0.200 
                 3.4902 
                 8943 
                 10 
               
               
                 14 
                 26.520 
                 0.153 
                 3.3582 
                 11336 
                 13 
               
               
                 15 
                 26.710 
                 0.212 
                 3.3348 
                 12896 
                 15 
               
               
                 16 
                 27.520 
                 0.200 
                 3.2384 
                 25663 
                 29 
               
               
                 17 
                 27.960 
                 0.224 
                 3.1885 
                 29102 
                 33 
               
               
                 18 
                 33.130 
                 0.329 
                 2.7018 
                 7264 
                 9 
               
               
                   
               
             
          
         
       
     
       Reference Example 3 
     Production of crystal of dimethylformamide solvate of 2-(3,4-dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic acid 
       [0110]    Amorphous 2-(3,4-dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic acid (1 g) obtained Production Example 1 was dissolved in dimethylformamide (14 mL) and water (1 mL), and the mixture was left standing at room temperature for 24 hr. The precipitated crystals were collection by filtration, draught-dried at 40° C. for 14 hr to give the title crystal (904 mg). 
         [0111]      1 H-NMR (DMSO-d 6 ) δ: 2.73 (3H, s), 2.79 (3H, s), 2.89 (3H, s), 3.99 (2H, s), 7.3-7.7 (3H, m), 7.95 (1H, s), 12.70 (1H, br s), 13.34 (1H, br s) 
         [0112]    According to the above-mentioned NMR data, the obtained crystal is considered to be a mono dimethylformamide solvate of compound A. 
         [0113]    The X-ray powder diffraction pattern is shown in  FIG. 9 , the peaks and peak intensities at diffraction angle (2θ) are shown in Table 6, and the infrared absorption spectrum is shown in  FIG. 10 . 
         [0000]    
       
         
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 6 
               
               
                   
               
               
                 Peak 
                   
                 Setting width 
                   
                   
                 Relative 
               
               
                 No. 
                 2 θ 
                 for peak search 
                 d value 
                 Intensity 
                 intensity 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 1 
                 5.370 
                 0.165 
                 16.4432 
                 39234 
                 100 
               
               
                 2 
                 10.130 
                 0.176 
                 8.7249 
                 17628 
                 45 
               
               
                 3 
                 10.730 
                 0.176 
                 8.2383 
                 6294 
                 17 
               
               
                 4 
                 13.060 
                 0.176 
                 6.7733 
                 9536 
                 25 
               
               
                 5 
                 13.970 
                 0.188 
                 6.3341 
                 17868 
                 46 
               
               
                 6 
                 16.480 
                 0.188 
                 5.3746 
                 38805 
                 99 
               
               
                 7 
                 16.970 
                 0.188 
                 5.2205 
                 27192 
                 70 
               
               
                 8 
                 17.680 
                 0.188 
                 5.0124 
                 32972 
                 85 
               
               
                 9 
                 18.610 
                 0.176 
                 4.7639 
                 6592 
                 17 
               
               
                 10 
                 19.050 
                 0.176 
                 4.6549 
                 5605 
                 15 
               
               
                 11 
                 20.140 
                 0.235 
                 4.4054 
                 22011 
                 57 
               
               
                 12 
                 20.650 
                 0.282 
                 4.2977 
                 20563 
                 53 
               
               
                 13 
                 22.530 
                 0.165 
                 3.9431 
                 5409 
                 14 
               
               
                 14 
                 23.030 
                 0.094 
                 3.8587 
                 5981 
                 16 
               
               
                 15 
                 23.240 
                 0.259 
                 3.8243 
                 10257 
                 27 
               
               
                 16 
                 24.820 
                 0.188 
                 3.5843 
                 10746 
                 28 
               
               
                 17 
                 25.030 
                 0.129 
                 3.5547 
                 5637 
                 15 
               
               
                 18 
                 27.010 
                 0.224 
                 3.2984 
                 12703 
                 33 
               
               
                 19 
                 21.370 
                 0.235 
                 3.2558 
                 22120 
                 57 
               
               
                 20 
                 27.870 
                 0.224 
                 3.1986 
                 8421 
                 22 
               
               
                   
               
             
          
         
       
     
       Reference Example 4 
     Production of crystal of 1,3-dimethyl-2-imidazolidinone solvate of 2-(3,4-dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic acid 
       [0114]    In the same manner as in Reference Example 3 except that 1,3-dimethyl-2-imidazolidinone was used as a solvent, the title crystal was produced. 
         [0115]      1 H-NMR (DMSO-d 6 ) δ: 2.63 (12H, s), 2.79 (3H, s), 3.20 (8H, 5), 3.99 (2H, s), 7.3-7.7 (3H, m), 12.70 (1H, br s), 13.34 (1H, br s) 
         [0116]    According to the above-mentioned NMR data, the obtained crystal is considered to be a di 1,3-dimethyl-2-imidazolidinone solvate of compound A. 
         [0117]    The X-ray powder diffraction pattern is shown in  FIG. 11 , the peaks and peak intensities at diffraction angle (2θ) are shown in Table 7, and the infrared absorption spectrum is shown in  FIG. 12 . 
         [0000]    
       
         
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 7 
               
               
                   
               
               
                 Peak 
                   
                 Setting width 
                   
                   
                 Relative 
               
               
                 No. 
                 2 θ 
                 for peak search 
                 d value 
                 Intensity 
                 intensity 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 1 
                 6.220 
                 0.176 
                 14.1979 
                 15695 
                 13 
               
               
                 2 
                 8.350 
                 0.188 
                 10.5803 
                 52228 
                 43 
               
               
                 3 
                 12.390 
                 0.176 
                 7.1380 
                 41419 
                 34 
               
               
                 4 
                 12.960 
                 0.212 
                 6.8253 
                 8788 
                 8 
               
               
                 5 
                 14.600 
                 0.188 
                 6.0621 
                 121811 
                 100 
               
               
                 6 
                 15.480 
                 0.165 
                 5.7194 
                 23445 
                 20 
               
               
                 7 
                 15.790 
                 0.188 
                 5.6078 
                 33098 
                 28 
               
               
                 8 
                 18.060 
                 0.200 
                 4.9078 
                 16881 
                 14 
               
               
                 9 
                 18.680 
                 0.212 
                 4.7462 
                 14142 
                 12 
               
               
                 10 
                 18.920 
                 0.176 
                 4.6866 
                 14090 
                 12 
               
               
                 11 
                 21.650 
                 0.200 
                 4.1014 
                 10804 
                 9 
               
               
                 12 
                 22.200 
                 0.224 
                 4.0010 
                 28053 
                 24 
               
               
                 13 
                 24.050 
                 0.235 
                 3.6973 
                 41921 
                 35 
               
               
                 14 
                 24.740 
                 0.118 
                 3.5957 
                 9582 
                 8 
               
               
                 15 
                 25.040 
                 0.224 
                 3.5533 
                 65992 
                 55 
               
               
                 16 
                 25.470 
                 0.224 
                 3.4943 
                 9860 
                 9 
               
               
                 17 
                 25.980 
                 0.224 
                 3.4268 
                 26529 
                 22 
               
               
                 18 
                 26.240 
                 0.129 
                 3.3934 
                 11253 
                 10 
               
               
                 19 
                 28.060 
                 0.259 
                 3.1773 
                 13615 
                 12 
               
               
                 20 
                 29.040 
                 0.224 
                 3.0723 
                 18423 
                 16 
               
               
                 21 
                 31.340 
                 0.353 
                 2.8519 
                 16219 
                 14 
               
               
                   
               
             
          
         
       
     
       Reference Example 5 
     Production of crystal of N-methylpyrrolidone solvate of 2-(3,4-dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic acid 
       [0118]    In the same manner as in Reference Example 3 except that N-methylpyrrolidone was used as a solvent, the title crystal was produced. 
         [0119]      1 H-NMR (DMSO-d 6 ) δ: 1.8-2.0 (3H, m), 2.1-2.3 (3H, m), 2.69 (4.5H, s), 2.79 (3H, s), 3.2-3.4 (3H, m), 3.99 (2H, s), 7.3-7.7 (3H, m), 12.70 (1H, br s), 13.34 (1H, br s) 
         [0120]    According to the above-mentioned NMR data, the obtained crystal is considered to be a sesqui N-methylpyrrolidone solvate of compound A. 
         [0121]    The X-ray powder diffraction pattern is shown in  FIG. 13 , the peaks and peak intensities at diffraction angle (2θ) are shown in Table 8, and the infrared absorption spectrum is shown in  FIG. 14 . 
         [0000]    
       
         
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 8 
               
               
                   
               
               
                 Peak 
                   
                 Setting width 
                   
                   
                 Relative 
               
               
                 No. 
                 2 θ 
                 for peak search 
                 d value 
                 Intensity 
                 intensity 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 1 
                 5.320 
                 0.188 
                 16.5976 
                 13478 
                 13 
               
               
                 2 
                 5.920 
                 0.176 
                 14.9167 
                 109648 
                 100 
               
               
                 3 
                 11.800 
                 0.165 
                 7.4935 
                 28799 
                 97 
               
               
                 4 
                 14.460 
                 0.176 
                 6.1205 
                 13122 
                 12 
               
               
                 5 
                 15.240 
                 0.165 
                 5.8090 
                 19620 
                 18 
               
               
                 6 
                 15.750 
                 0.165 
                 5.6220 
                 31601 
                 29 
               
               
                 7 
                 16.600 
                 0.188 
                 5.3360 
                 40775 
                 38 
               
               
                 8 
                 17.450 
                 0.176 
                 5.0779 
                 23183 
                 22 
               
               
                 9 
                 17.730 
                 0.153 
                 4.9984 
                 13302 
                 13 
               
               
                 10 
                 19.780 
                 0.165 
                 4.4847 
                 13353 
                 13 
               
               
                 11 
                 20.150 
                 0.176 
                 4.4032 
                 20094 
                 19 
               
               
                 12 
                 20.460 
                 0.212 
                 4.3372 
                 15586 
                 15 
               
               
                 13 
                 21.470 
                 0.165 
                 4.1354 
                 16776 
                 15 
               
               
                 14 
                 22.140 
                 0.176 
                 4.0117 
                 59636 
                 55 
               
               
                 15 
                 22.420 
                 0.153 
                 3.9622 
                 49753 
                 46 
               
               
                 16 
                 22.930 
                 0.259 
                 3.8753 
                 19478 
                 18 
               
               
                 17 
                 23.700 
                 0.176 
                 3.7511 
                 66432 
                 61 
               
               
                 18 
                 24.650 
                 0.176 
                 3.6086 
                 31269 
                 29 
               
               
                 19 
                 27.190 
                 0.212 
                 3.2770 
                 65626 
                 60 
               
               
                 20 
                 28.570 
                 0.200 
                 3.1218 
                 23291 
                 22 
               
               
                 21 
                 30.720 
                 0.200 
                 2.9080 
                 12884 
                 12 
               
               
                   
               
             
          
         
       
     
         [0122]    The X-ray powder diffraction measurement of the crystal obtained in each Example was performed under the following conditions. 
         [0123]    X-ray: CuKα/40 kV/40 mA 
         [0124]    scan axis: 2θ/θ 
         [0125]    scanning range: 5.0000-45.0000° 
         [0126]    sampling width: 0.0100° 
         [0127]    scan speed: 10.000° per minute 
         [0128]    The infrared absorption spectrum (paste method) measurement of the crystal obtained in each Example was performed under the following conditions. That is, liquid paraffin was added to a sample and kneaded well on an agate mortar, and infrared absorption spectrum was measured. 
         [0000]    infrared absorption spectrum measuring apparatus: FT/IR-470 (JASCO Corporation) 
         [0129]      1 H-NMR was measured using JNM-ECP400 (JEOL Ltd.) in DMSO-d 6  at 400 Mz. 
       Example 3 
     Consideration of maturation temperature and maturation time of aqueous suspension 2-(3,4-dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic acid 
       [0130]    A mixture of 2-(3,4-dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic acid mono sodium salt (4.992 g) produced from amorphous 2-(3,4-dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic acid produced by the method described in Production Example 1 and sodium hydroxide by a conventional method, 1 mol/L aqueous sodium hydroxide solution (12.8 mL) and water (45 mL) was heated, and dissolution was confirmed. The reaction mixture was allowed to cool under room temperature, acidified with dilute hydrochloric acid and matured at the temperature described in Table 9. The precipitated crystals were sampled over time, and production and disappearance of Form I crystal and Form II crystal was measured by X-ray powder diffraction. To be specific, as for Form I crystal, appearance and disappearance of characteristic X-ray powder diffraction peaks 2θ of about 14.8° and about 26.4° were analyzed, and as for Form II crystal, appearance of characteristic X-ray powder diffraction peaks 2θ of about 11.2° and about 25.5° was analyzed. The results are shown in Table 9. 
         [0000]    
       
         
               
               
               
               
             
           
               
                 TABLE 9 
               
               
                   
               
               
                   
                   
                 appearance of 
                   
               
               
                   
                 observation  
                 Form II crystal  
                 observation 
               
               
                 temperature  
                 of Form I  
                 (mixture of Form  
                 of Form II 
               
               
                 (° C.) 
                 crystal alone 
                 I and Form II) 
                 crystal alone 
               
               
                   
               
             
             
               
                 45 
                 1 h, 72 h, 96 h 
                 312 h 
                 408 h 
               
               
                 55 
                 0.5 h, 24 h, 32 h 
                 48 h, 168 h 
                 192 h 
               
               
                 65 
                 0.5 h, 24 h 
                 120 h 
                 144 h 
               
               
                 75 
                 0.1 h, 12 h 
                   
                  25 h 
               
               
                 85 
                 0.05 h, 5 h, 6 h 
                 15 h, 22 h 
                  23 h 
               
               
                 95 
                 0.01 h, 4 h 
                 5 h, 10 h 
                  16 h 
               
               
                   
               
             
          
         
       
     
       Experimental Example 1 
     Thermal Stability 
       [0131]    Form I crystal obtained in Example 1 and Form II crystal obtained in Example 2 and amorphous compound A obtained in Production Example 1 were heated at 100° C. for 6 hr or 200° C. for 6 hr, and the amount of the decomposition product 2-(3,4-dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine (decarboxylation substance of compound A) was measured by HPLC. The results thereof and the color of each sample then are shown in the following Table 10. In the HPLC measurement, the sample was suspended in a mobile phase, dissolved by adding 1 equivalent of aqueous sodium hydroxide and then applied. 
       HPLC Measurement Condition 
       [0132]    measuring apparatus: Waters Alliance HPLC system
 
detector: ultraviolet absorption spectrophotometer (measurement wavelength 225 nm)
 
column: XBridge C18 (Waters)
 
column temperature: constant temperature near 30° C.
 
mobile phase A: acetonitrile
 
mobile phase B: 5 mmol/L ammonium hydrogen carbonate (pH 8.0) gradient method of mobile phase A and mobile phase B: mobile phase A 23% (0 to 15 min), mobile phase A 23%→55% (15 to 30 min), mobile phase A 55% (30 to 50 min)
 
flow rate: 1.0 mL/min
 
         [0000]    
       
         
               
               
               
               
               
             
           
               
                   
                 TABLE 10 
               
               
                   
                   
               
               
                   
                 temperature 
                 Form I 
                 Form II 
                 Amorphous 
               
               
                   
                 and time 
                 crystal 
                 crystal 
                 form 
               
               
                   
                   
               
             
             
               
                   
                 100° C.,  
                 0%, white 
                 0%, white 
                 0.006%, 
               
               
                   
                 6 hr 
                   
                   
                 slight brown 
               
               
                   
                 200° C.,  
                 0.05%,  
                 0.07%,  
                  3.42%,  
               
               
                   
                 6 hr 
                 slight brown 
                 slight brown 
                 pale-brown 
               
               
                   
                   
               
             
          
         
       
     
       Experimental Example 2 
     Solubility 
       [0133]    Form I crystal obtained in Example 1, Form II crystal obtained in Example 2 and amorphous compound A obtained in Production Example 1 (each 50 mg) were suspended in 0.5% aqueous Tween80 solution (20 mL), sonicated, aqueous 0.5% Tween80 solution (180 mL) was added and the mixture was stirred at 37° C. 
         [0134]    The solubility was measured by HPLC under the same conditions (isocratic method using acetonitrile/5 mmol/L ammonium hydrogen carbonate (pH 8.0) (27:73) for mobile phase) as in Experimental Example 1 at the time points of 0.5 hr, 1 hr, 2 hr, 3 hr, 4 hr, 5 hr, and 6 hr from the start of stirring. As a result, amorphous compound A reached near saturation at about 0.5 hr, Form I crystal reached near saturation at about 1 hr and Form II crystal reached near saturation at about 2 hr. Therefore, the value of 3 hr was taken as the solubility. The results are shown in Table 11 below together with the results of the following Experimental Example 3. 
       Experimental Example 3 
     Dissolution Rate 
       [0135]    Form I crystal obtained in Example 1, Form II crystal obtained in Example 2 and amorphous compound A obtained in Production Example 1 (each 100 mg) were compression molded by a tableting machine for IR measurement having a metal mold pre-treated with magnesium stearate, and formed into discs (diameter 12 mm). Each disc was added to 0.5% aqueous Tween80 solution (900 mL, 37° C.), the concentration was measured every 10 minutes up to 1 hr, and every 1 hour after 1 hr up to 3 hr, by HPLC under the same conditions as in Experimental Example 1 (isocratic method using acetonitrile/5 mmol/L ammonium hydrogen carbonate (pH 8.0) (27:73) for mobile phase) while maintaining the temperature at 37° C. according to the dissolution test apparatus Paddle Method (50 rpm), and each dissolution rate was calculated. The results are shown in Table 11 below together with the results of the above-mentioned Experimental Example 2. 
         [0000]    
       
         
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                   
                 TABLE 11 
               
               
                   
                   
               
               
                   
                   
                 Form I 
                 Form II 
                 Amorphous 
               
               
                   
                   
                 crystal 
                 crystal 
                 form 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 solubility (μg/mL) 
                 15 
                 10 
                 37 
               
               
                   
                 dissolution rate 
                 0.0017 
                 0.0011 
                 0.0052 
               
               
                   
                 (μg/mL/min) 
               
               
                   
                   
               
             
          
         
       
     
         [0136]    From the results of Experimental Examples 1 to 3, it is clear that Form I crystal is superior to Form II crystal in the thermal stability, and higher in the solubility and dissolution rate than Form II crystal. The results show that Form I crystal is more superior when used as, for example, a pharmaceutically active ingredient of oral administration preparations such as tablet and the like, an adhesive preparation and the like. On the other hand, when used as a pharmaceutically active ingredient of a sustained-release preparation, Form II crystal is useful since its concentration does not become high, which leads to the reduction of side effects. 
       Experimental Example 4 
     Thermoanalysis 
       [0137]    Form I crystal obtained in Example 1 and Form II crystal obtained in Example 2 were subjected to the measurement of differential scanning calorimetry (DSC) using aluminum oxide as a control. The measurement conditions are as follows. 
         [0138]    sample container: open 
         [0139]    heating temperature: 10.0° C./min up to 400° C. 
         [0140]    measurement temperature range: 50 to 400° C. 
         [0141]    atmospheric gas: nitrogen gas 
         [0142]    The DSC chart of each crystal is shown in  FIG. 15  and  FIG. 16 . 
       Experimental Example 5 
     Comparison of Filtration Speed 
       [0143]    Form I crystal, Form II crystal and amorphous compound A were subjected to the measurement of the speed of filtration from a water suspension. In the test, the same synthesis scale, the same solvent amount, the same filtration apparatus (glass filter) and the same level of reduced pressure were used for comparison. Experimental Examples are shown in the following and the results thereof are shown in Table 12 below. 
       Experimental Example 5-a 
     Filtration speed of amorphous 2-(3,4-dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic acid 
       [0144]    A mixture of 2-(3,4-dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic acid mono sodium salt (2.501 g), 1 mol/L aqueous sodium hydroxide solution (9.6 mL) and water (39.4 mL) was dissolved by stirring. The reaction mixture was ice-cooled, ethanol (10 mL) was added, the inside temperature was set to about 2° C., neutralized with 1 mol/L hydrochloric acid (16.0 mL), water (25.0 mL) was added (solvent amount was set to 100 mL), and the mixture was stirred under ice-cooling to confirm that the inside temperature was about 1° C. The suspension was poured into a G2 glass filter (diameter 3 cm), and the pressure reduction was started at 50 hpa. The time necessary to the increase of pressure by the completion of filtration was 42 minutes 52 seconds. The height of the solid at that time was 4.3 cm (bulk 30.4 cm 3 ). Washing with water was not possible due to clogging. 
       Experimental Example 5-b 
     Filtration speed of Form I crystal of 2-(3,4-dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic acid 
       [0145]    A mixture of 2-(3,4-dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic acid mono sodium salt (2.502 g), 1 mol/L aqueous sodium hydroxide solution (6.4 mL) and water (22.5 mL) was dissolved by stirring with heating. The reaction mixture was allowed to cool under room temperature, neutralized with 1 mol/L hydrochloric acid (12.8 mL), and water (8.3 mL) was added. The mixture was stirred at about 75° C. for 1.5 hr, water (50 mL) was added (solvent amount was set to 100 mL), and the mixture was cooled to about 21° C. The suspension was poured into a G2 glass filter (diameter 3 cm), and the pressure reduction was started at 50 hpa. The time necessary to the increase of pressure by the completion of filtration was 4 minutes 14 seconds. The height of the solid at that time was 2.3 cm (bulk 16.2 cm 3 ). Then, an operation of washing the obtained solid with water (25 mL), followed by reduced pressure filtration at 50 hpa was repeated 3 times to confirm that the filtrate had pH 7. At this point, the total filtration time necessary for increasing the pressure was 10 minutes 2 seconds and the height of the final solid was 1.5 cm (bulk 10.6 cm 3 ). 
       Experimental Example 5-c 
     Filtration speed of Form II crystal of 2-(3,4-dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic acid 
       [0146]    A mixture of 2-(3,4-dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic acid mono sodium salt (2.503 g), 1 mol/L aqueous sodium hydroxide solution (6.4 mL) and water (22.5 mL) was dissolved by stirring with heating. The reaction mixture was allowed to cool under room temperature, neutralized with 1 mol/L hydrochloric acid (12.8 mL), and water (8.3 mL) was added. The mixture was stirred with heating under reflux for 8 hr, and further at about 70° C. for 8 hr. Water (50 mL) was added (solvent amount was set to 100 mL), and the mixture was cooled to about 21° C. The suspension was poured into a G2 glass filter (diameter 3 cm), and the pressure reduction was started at 50 hpa. The time necessary to the increase of pressure by the completion of filtration was 4 minutes 5 seconds. The height of the solid at that time was 2.1 cm (bulk 14.8 cm 3 ). Then, an operation of washing the obtained solid with water (25 mL), followed by reduced pressure filtration at 50 hpa was repeated 3 times to confirm that the filtrate had pH 7. At this point, the total filtration time necessary for increasing the pressure was 6 minutes 33 seconds and the height of the final solid was 1.6 cm (bulk 11.3 cm 3 ). 
         [0000]    
       
         
               
               
               
               
               
               
             
               
               
               
               
               
               
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 12 
               
               
                   
               
               
                   
                   
                   
                 time of 
                   
                   
               
               
                   
                   
                   
                 washing  
                 bulk 
                   
               
               
                   
                   
                 bulk 
                 with water  
                 after 
                   
               
               
                   
                 filtration 
                 after 
                 (25 mL × 3, 
                 washing 
                   
               
               
                   
                 operation 
                 filtration 
                 washed until 
                 with 
                   
               
               
                 form 
                 time 
                 operation 
                 pH 7) 
                 water 
                 note 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 amorphous 
                 42  
                 min 
                 30.4 cm 3   
                 washing 
                 — 
                 amorphous 
               
               
                   
                 52  
                 sec 
                   
                 impossible 
                   
                 form turned 
               
             
          
           
               
                   
                   
                   
                 due to 
                   
                 into a gel 
               
               
                   
                   
                   
                 clogging 
                   
                 by water 
               
               
                   
                   
                   
                   
                   
                 absorption, 
               
               
                   
                   
                   
                   
                   
                 and solid- 
               
               
                   
                   
                   
                   
                   
                 liquid 
               
               
                   
                   
                   
                   
                   
                 separation 
               
               
                   
                   
                   
                   
                   
                 was 
               
               
                   
                   
                   
                   
                   
                 difficult 
               
             
          
           
               
                 Form I 
                 4  
                 min 
                 16.2 cm 3   
                 10  
                 min  
                 10.6 cm 3   
                   
               
               
                   
                 14  
                 sec 
                   
                 2  
                 sec 
                   
                   
               
               
                 Form II 
                 4  
                 min  
                 14.8 cm 3   
                 6  
                 min  
                 11.3 cm 3   
                   
               
               
                   
                 5  
                 sec 
                   
                 33  
                 sec 
               
               
                   
               
             
          
         
       
     
       Experimental Example 6 
     Dog Absorption Test 
       [0147]    Form I crystal, Form II crystal and amorphous form of compound A were subjected to a dog absorption test under the following conditions. The results are shown in Table 13. Form I crystal, Form II crystal and amorphous form of compound A showed good pharmacokinetics as a medicament. 
         [0000]    sample: except for amorphous form, samples of Form I crystal and Form II crystal sieved to have a particle size of 20 to 63 μm by wet classification (two kinds of sieves and flowing water were used) were used.
 
Preparation method: 25 mL of water was added to a sample (3 g), and the mixture was gently pulverized in a mortar, classified under pressurization, and draught-dried. As amorphous form, a sample pulverized in agate mortar was used.
 
method: 9 dogs, 3×3 crossover, 0.3 mg/kg oral administration
 
         [0000]    
       
         
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                   
                 TABLE 13 
               
               
                   
                   
               
               
                   
                   
                   
                 Form I 
                 Form II 
                 amorphous 
               
               
                   
                 Parameters 
                 units 
                 average 
                 average 
                 average 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 T 1/2   
                 hr 
                 3.50 
                 3.32 
                 3.05 
               
               
                   
                 Tmax 
                 hr 
                 3.06 
                 3.44 
                 3.78 
               
               
                   
                 Cmax 
                 ng/mL 
                 9.1 
                 3.7 
                 10.3 
               
               
                   
                 AUC 0-t   
                 ng · hr/mL 
                 64.6 
                 24.2 
                 62.9 
               
               
                   
                 AUC inf   
                 ng · hr/mL 
                 65.6 
                 24.2 
                 63.4 
               
               
                   
                 MRT 
                 hr 
                 6.73 
                 6.89 
                 6.31 
               
               
                   
                   
               
             
          
         
       
     
       Experimental Example 7 
     Photostability Test 
       [0148]    Form I crystal, Form II crystal and amorphous form of compound A were subjected to a photostability test under the following conditions. The results are shown in  FIG. 17 . 
         [0000]    light source: xenon lamp 18 million Lxs
 
conditions: sample (6 mg) was weighed in a transparent sample bottle, and exposed to light for 8 hr.
 
HPLC conditions: same as in Experimental Example 1
 
         [0149]    Form I and Form II crystals were comparatively stable, but the amorphous form contained impurity exceeding 0.2%. 
       INDUSTRIAL APPLICABILITY 
       [0150]    The crystal of the present invention is suitable as an active ingredient of a medicament for the treatment, procedure and the like of dysuria and the like, since it can be produced by a convenient method suitable for industrial large-scale production, and is stable. 
         [0151]    This application is based on patent application No. 2010-125362 filed in Japan, the contents of which are encompassed in full herein. 
         [0152]    Although the present invention have been presented or described by referring to preferred embodiments of this invention, it will, however, be understood by those of ordinary skill in the art that various modifications may be made to the forms and details without departing from the scope of the invention as set forth in the appended claims. All patents, patent publications and other publications indicated or cited in the Specification are hereby incorporated in their entireties by reference.