KR810000956B1 - Process for preparing alpha-form of prazosin hydrochloride - Google Patents

Abstract

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Description

Method for preparing α type of prazosin hydrochloride

Figure 1 shows the infrared hobbs spectrum of prazosin hydrochloride α type in KBr.

2 is the infrared absorption spectrum of prazosin hydrochloride multihydrate in KBr.

3 is an infrared absorption spectrum showing various crystalline modifications of prazosin hydrochloride.

4 is an X-ray diffraction diagram showing various crystalline modifications of prazosin hydrochloride.

5 is a powder dissolution schematic of various crystalline modifications of prazosin hydrochloride at 25 ° C. in water.

6 is a schematic diagram of powder dissolution of prazosin hydrochloride, its α-form and polyhydrate in artificial gastric juice at 25 ° C.

The present invention is characterized in that the infrared absorption spectrum in KBr has the following absorption band and also has the following structural formula: 2- [4- (2-furoyl) piperazin-1-yl] -4-amino-6, A novel method for preparing a crystalline polymorph of 7-dimethoxyquinazoline hydrochloride.

Such compounds are described herein as the α form of prazosin hydrochloride.

The present invention also provides 2- [4- (furoyl) piperazin-1-yl] -4, characterized in that the infrared absorption spectrum in KBr has the following absorption bands and also contains about 8-15% by weight of water. A novel crystalline hydrate of amino-6,7-dimethoxy quinazoline hydrochloride.

The present invention also relates to a method for exhibiting a hypotensive effect by administering the hydrate of prazosin hydrochloride to an host having hypertension in an amount capable of exhibiting a hypotensive effect.

It is known that 2- [4- (furoyl) piperazin-1-yl] -4-amino-6,7-dimethoxyquinazolin compound and its acid addition salts are valuable blood pressure lowering agents. Pharmacological studies on 2- [4- (2-furoyl) piperazin-1-yl] -4-amino-6,7-dimethoxyquinazolin hydrochloride (hereinafter referred to as generic name prazosin hydrochloride) In Sperabine et al. In Experientia, 24, 1150 (1968), and in Constantine et al., Hypertension Mechanism and Management [edit] Onsti, Grunend Stratton Incorporated, 1973, pp. 429-444. A preliminary clinical study of prazosin hydrochloride was reported by Cohen in J. Clin pharmacol 10,408 (1970). Other side effects from the initial dose of prazosin have been reported by Bendall et al. In Brit. Med. Jour 2,727 (1975).

The accompanying drawings illustrate the physical properties of prazosin hydrochloride.

형＂ 및 ＂무수물＂로 표시했다. 또한 용매화합물은 프라조신 염산염 메탄올 화합물로 표시되어 있다.The present invention is based on the discovery of two novel crystalline forms of prazosin hydrochloride, a valuable therapeutic agent for hypertension, that have certain advantages over other forms of this drug. The first of the novel crystalline forms of prazosin hydrochloride is the anhydrous form, referred to herein as "α type". This α type is known to be relatively nonhygroscopic and stable. Therefore, there is an important advantage in handling, storage and formulation. Prazosin hydrochloride Other crystalline, anhydrous, nonsolvated forms are described herein for convenience in the form of ββ, ＂

It was marked with a sentence and an anhydride. In addition, the solvate is represented by the prazosin hydrochloride methanol compound.

As used herein, “relatively non-hygroscopic” refers to substantially 1.5% or more of water when a sample containing 0.5% or less of water is initially exposed to a temperature of about 37 ° C. and a relative humidity of about 75% for about 30 days. It means that it does not contain. It is believed in the present invention that prazosin hydrochloride contains up to about 1.5% water but substantially no more.

, 무수물 및 메탄올 화합물중 어떤 형태이던지 이것을 수성 매질 또는 물과 유기용매의 혼합물로 부터 결정화시키고, 그 결과 생기는 결정의 수분 함량을 칼 휘셔(Karl Fischer)의 수분 측정법으로 약 8-15중량%의 범위 까지 건조시키면, 프라조신 염산염 다수화물을 얻을 수 있음이 발견 되었다. 수량함량 범위의 하한, 즉 약 8중량%의 수분을 함유할 경우의 화학양론은 프라조신 염산염 1몰당 약 2몰의 물을 갖고 있는 프라조신 염산염 이수화물과 일치한다. 상기 이수화물은 본 발명의 범위내에 속한다. 그러나 특히 바람직한 것은 약 12-15중량%의 물을 함유하는 프라조신 염산염 다수화물로서, 이 화합물은 쉽게 제조되며 또한 프라조신염산염의 다른 수화물보다 흡수성이 적기 때문이다. 상술한 바와 같은 ＂다수화물＂의 제조방법은 8% 이하의 물을 함유하는 프라조신 염산염의 수화 형태를 ＂다수화물＂로 변환시키는 데에도 역시 이용할 수 있다.The second novel crystalline form of prazosin hydrochloride, which has certain advantages over other forms of this drug, is referred to herein as “polyhydrate”. This form is preferable because it has a low and uniform dissolution rate. Α, β, of prazosin hydrochloride

Any form of anhydride, anhydride and methanol compound is crystallized from an aqueous medium or a mixture of water and an organic solvent, and the resulting water content of the crystals is in the range of about 8-15% by weight measurement method by Karl Fischer It has been found that by drying up, prazosin hydrochloride polyhydrate can be obtained. The lower limit of the water content range, i.e., when it contains about 8% by weight of water, is consistent with prazosin hydrochloride dihydrate having about 2 moles of water per mole of prazosin hydrochloride. Such dihydrate is within the scope of the present invention. Particularly preferred, however, is prazosin hydrochloride polyhydrate containing about 12-15% by weight of water, since this compound is easily prepared and less absorbent than other hydrates of prazosin hydrochloride. The above-mentioned method for producing "polyhydrate" can also be used to convert the hydrated form of prazosin hydrochloride containing 8% or less of water into "polyhydrate".

The polyhydrate is filtered, for example, by crystallizing prazosin hydrochloride from hot water or a mixture of water and an organic solvent and drying the crystals until the water content is about 8-15% by weight in the original range. It can manufacture by making it. As a suitable organic solvent when using a mixture of water and an organic solvent, an organic solvent which can be mixed with water such as methanol, ethanol, isopropanol, acetone, methyl ethyl ketone, etc. and water such as dichloromethane, chloroform, hexane, benzene, toluene, etc. And a mixture of an organic solvent which is not mixed with an organic solvent which may be mixed with the above water. Another method for preparing prazosin hydrochloride multihydrate is to triturate anhydrous prazosin hydrochloride with water and then dry the resulting crystals to the desired moisture content.

As mentioned above, the water content of the polyhydrate may vary from about 8% to about 15%, or more. From the X-ray diffraction data presented below, it is shown that water can only bind up to 2 molecules per mole of prazosin hydrochloride in the crystal lattice. The remaining water is free interstitial water.

Further exposure of the sample of prazosin hydrochloride polyhydrate containing about 12-15% by weight of water to dryness by heating in a vacuum oven or by standing in a drier results in the loss of moisture and ultimately about 8% of water. Dihydrate containing is obtained. This is usually sufficient as 100 ° C. in a vacuum dryer or vacuum oven as heat. Further heating gives a carbohydrate containing about 4.1% water, and heating again produces prazosin hydrochloride anhydride.

Form α of the preferred and valuable prazosin hydrochloride is in any form in the presence of an appropriate organic solvent at a temperature in the range of 100-200 ° C., more preferably in the presence of an alcoholic solvent at a temperature in the range of about 125-160 ° C. Prazosin hydrochloride can be obtained easily and reproducibly by heating together with the hydrate and the solvent compound. Preferred alcoholic solvents are aliphatic and aliphatic cyclic alcohols of about C ₅ to C ₇ . Examples of such alcohols are isoamyl alcohol, n-methanol, n-pentanol, 2-methyl-1-butanol, cyclopentanol, 1-methylcyclopentanol, 2-methylcyclopentanol, cyclohexanol, 1- Methylcyclohexanol, 3-methylcyclohexanol, 2-methyl-3-pentanol, 4-methyl-1-pentanol, 2-methyl-3-hexanol, 2-methyl-2-hexanol, cycloheptane It's coming.

Particularly good for producing the α form of prazosin hydrochloride is isoamyl alcohol, also known as 3-methyl-1-butanol, which is readily available and efficient in forming crystalline polymorphs of the desired prazosin hydrochloride. Because. The preferred temperature for forming α-form with isoamyl alcohol is about 132 ° C., which is the boiling point of isoamyl alcohol at atmospheric pressure.

In preparing the α form of prazosin hydrochloride, it is preferred to use an alcoholic solvent sufficient to at least partially solution the prazosin hydrochloride when the mixture is heated to a temperature within the desired temperature range. In some cases satisfactory results can be achieved with more or less alcohol than this amount, but in normal cases 4-25 ml of alcohol per gram of prazosin hydrochloride is sufficient.

The heating time required to form nearly the α form of prazosin hydrochloride in this manner varies from several minutes to about six hours or more. The optimal time required for a given example will vary depending on various factors such as, for example, the exact temperature, the type of alcohol used as the solvent, and the like. When carrying out the process with reflux of isoamyl alcohol, the time required for the desired α-form to be almost completely formed is usually about 2-3 hours. The degree of formation of the α form of prazosin hydrochloride can be conveniently determined by removing the sample, cooling to room temperature, isolating the precipitate by filtration, and obtaining an infrared absorption spectrum for precipitation in KBr. As can be seen in the accompanying figures, each of the non-hydrated forms of prazosin hydrochloride has a characteristic infrared absorption spectrum.

When the prazosin hydrochloride used as a starting material is a solvent compound which is a methanol compound or a kind of a hydrate, the solvation molecule is removed by, for example, removing methanol or water while heating to obtain α form of prazosin hydrochloride by the above method. Or removal of (but not necessarily) hydration molecules is preferred.

형으로 표시한 프라조신 염산염의 결정성 동질다형제이거나 또는 α형과

형의 혼합물이다.In carrying out the method, prazosin hydrochloride is used in an alcoholic solvent, such as isoamyl alcohol, at a temperature slightly lower than about 125 ° C. or within a temperature range suitable for the α-form preparation of the above mentioned prazosin hydrochloride. , And if heated only for insufficient time, the product at this time

Is a crystalline homopolymorph of prazosin hydrochloride in form or

It is a mixture of molds.

Methanol compounds of prazosin hydrochloride can be obtained by slurrying any prazosin hydrochloride that is essentially anhydrous in methanol. This is usually enough for about 3 hours at room temperature. Methanol compounds can be formed faster by heating at higher temperatures. For example, at the boiling point of methanol, the formation of the solvent is completed in about 10 minutes. The product can be isolated by standard methods. By elemental analysis of the methanol compound, it can be seen that prazosin hydrochloride and methanol are bonded at a ratio of 1 mole to 1 mole.

Exposing the methanol compound to a temperature sufficient to remove solvent compound molecules yields the β form of prazosin hydrochloride. For example, the methanol compound may be heated at 135 ° C. for about 12 hours or at 110 ° C. for about 24 hours. If the heat exposure is carried out under reduced pressure, for example in a vacuum oven, methanol can be easily removed.

Characteristic Infrared Absorption Spectra of Various Forms of Prazosin Hydrochloride

-동질다형체, 다수화물, 무수화물 및 메탄올 화합물의 적외선 흡수 스펙트럼이 제도에 비교하여 도시되어 있다. 스펙트럼은 적당한 샘플 1mg을 KBr 300mg과 함께 절구로 잘게 갈아준 후, 이 혼합물을 퍼킨-엘머 다이프레스 모델 No.1860025에 넣고 진공하에서 1분간 15000psi의 압력을 가하여 제조한 KBr펠리트를 사용하여 퍼킨-엘머 모델 21 기록식 적외선 분광계로 얻은 것중 대표적인 것이다.The infrared absorption spectra of the three anhydrous crystalline forms of prazosin hydrochloride, ie, methanol compounds, hydrates, and amorphous dehydrates, can be quickly and conveniently characterized by standard methods such as KBr pellet method or Newzolmul method. Infrared absorption spectra, however, do not distinguish between different types of sign language. The characteristic infrared absorption spectrum of prazosin hydrochloride α type is shown in FIG. The infrared absorption spectrum at 2 degrees was obtained from a sample of prazosin hydrochloride polyhydrate (12% water content). Infrared absorption spectrum according to the moisture content of the sample can be used to characterize the majority cargo. Α-, β-, and prazosin hydrochloride

Infrared absorption spectra of homopolymorphs, polyhydrates, anhydrides and methanol compounds are shown in comparison to the scheme. The spectra were finely pulverized with 1 mg of a suitable sample with 300 mg of KBr, and then the mixture was placed in a Perkin-Elmer Diepress Model No.1860025 and perkins using a KBr pellet prepared by applying a pressure of 15000 psi for 1 minute under vacuum. Representative of an Elmer Model 21 recordable infrared spectrometer.

Characteristic infrared absorption bands that distinguish the various forms of prazosin hydrochloride from one another are shown in Table 1.

TABLE 1

* Infrared absorption spectra of monohydrate (4.1% H ₂ O), dihydrate (7.9% H ₂ O) and polyhydrate are identical.

동질다형체의 샘플을 물과함께 갈았을 때, 각각의 경우에 있어서의 결과 생성물은 프라조신 염산염 수화물의 스펙트럼과 동일한 적외선 흡수 스펙트럼을 나타냈다.α-, β- and

When the sample of isopolymorph was ground with water, the resultant product in each case showed the same infrared absorption spectrum as that of prazosin hydrochloride hydrate.

[X-ray Diffraction Method]

X-ray powder rotation patterns were obtained with a copper spinner with a nickel filter and a Siemens diffractometer with a scintillation detection counter. The intensity of the beam was recorded as a function of angle 2 at a scan rate of 1 ° / min.

The characteristic diffractogram of each variant of prazosin hydrochloride is shown in FIG. The distinguishable peaks (denoted as ＂2 ° 있다) are summarized in Table 2.

TABLE 2

※ The diffractogram of the majority hydrate containing about 15% of water is not much different from that of the dihydrate. This means that only two molecules of water per molecule of prazosin hydrochloride are actually bound to the crystal lattice, and the rest of the majority of the water is the glass interspace.

형 및 무수물사이의 차이점을 더욱 확실히 나타내고 있다. 또한 X선 분석과 아울러 수분 함량을 측정하면 각종의 수화물을 구분할 수 있다.X-ray diffractograms of α, β,

The difference between the form and anhydride is more clearly shown. In addition, X-ray analysis as well as measuring the moisture content can distinguish various hydrates.

Differential Scanning Calorimetry (DSC)

Samples (1-2 mg) were analyzed with a Mettler DTA2000 calorimeter at a heating rate of 5 ° per minute at voltages ranging from 50 μV or 100 μV. The results are summarized in Tables 3 and 4.

Summary of DSC results for various types of prazosin hydrochloride samples (heating rate 5 ° per minute; sample introduction at about 40 °; temperature in ° C.)

TABLE 3

Summary of DSC results for samples of crystalline polymorphs of prazosin hydrochloride (heating rate 5 ° per minute; introduction of samples at about 250 °; temperature in ° C.)

TABLE 4

형의 이중선 패턴은 가열속도, 출발온도 및 샘플 크기의 함수에 따라 변한다는 것을 알았다.Interpretation of the differential scanning calorimetry results is complicated by the decomposition of compounds during melting. No homomorphic transformation was observed by DSC, which indicates that the polymorphs are induced into the solvent and their conversion temperature is higher than the decomposition temperature. Each form of prazosin hydrochloride has been shown to exhibit unique DSC results, but each characteristic is highly dependent on the test conditions. It has been found that by adjusting mechanical parameters, different DSC patterns can be obtained for a given isomorph or solvate. For example, prazosin hydrochloride

The double line pattern of the mold was found to vary as a function of heating rate, starting temperature and sample size.

Methanol could only be removed from the methanol compound at a temperature of about 130-140 ° C., significantly above its boiling point of 65 ° C. This suggests that for this solvent compound there is a strong binding force between methanol and prazosin hydrochloride. In contrast, the majority of water loses water rapidly at temperatures close to the boiling point of free water, which means that at least some of the water present in the water is unbound and occupies the inter-lattice position in the hydrate. Indicates only.

Hygroscopicity

결정성 동질다형체의 상대적인 흡습성을 비교했다. 각 동질 다형체의 샘플을 뚜껑이 없는 비이커에 넣고, 37℃ 및 75% 상대습도로 유지시킨 반응실에 보관했다. 그 일부분을 주기적으로 꺼내어 칼 휘셔의 방법에 따라 수분 함량을 측정하였으며, 그 결과는 표 5와 같다.As water absorption affects the integrity of drug forms, the α-, β- and

The relative hygroscopicity of crystalline homomorphs was compared. Samples of each homomorphic polymorph were placed in a lidless beaker and stored in a reaction chamber maintained at 37 ° C. and 75% relative humidity. The part was periodically taken out and the moisture content was measured according to the method of Karl Fuchsia, the results are shown in Table 5.

TABLE 5

형에 비해 상대적으로 비흡수성이다. 이와 같이 습기에 노출시킨 후의 프라조신 염산염의

형 샘플에 대한 적외선 흡수 스펙트럼(KBr 펠리트)은 원래의 스펙트럼과 형태가 달라지므로, 이에 의해 수화물이 형성되었음을 확실히 알 수 있다.As can be seen from the table, the α form of prazosin hydrochloride is β form and

It is relatively nonabsorbent compared to the mold. Of prazosin hydrochloride after exposure to moisture in this manner

Infrared absorption spectra (KBr pellets) for the mold sample differ in shape from the original spectra, and thus it can be clearly seen that hydrates are formed.

Samples of prazosin hydrochloride polyhydrate containing the first 13.7% of water were exposed to 37 ° C., 75% relative humidity. Moisture content after 10 days and 23 days was 13.2% and 13.4%, respectively. The first sample containing 13.5% water was exposed to room temperature and 20% relative humidity and found to contain 13.0 water after 18 days and 13.1% water after 35 days.

[Microscopic examination]

형과 다수화물은 모두 침상(針霜)결정이다.When examined under an optical microscope at a magnification of 200 times, it can be seen that the α-form and methanol compounds of prazosin hydrochloride are rod-shaped crystals, and the crystals of methanol compounds are much larger. β form is dark monocrystalline,

Both form and majority are acicular crystals.

형을 함유하는 3개의 현미경 슬라이드 각각에 1방울의 물을 가하면, 수화물의 날카로운 침상결정이 자라서 한데 합쳐서 액상 결정성 상(相)의 특징인 머리카락과 같은 실 형태의 배열을 형성한다. 이것은 α-, β- 및

동질다형체의 적외선 흡수 스펙트럼이 각각의 결정성 동질다형체를 물과 함께 연화시켜서 얻은 프라조신 염산염의 수화물에 해당하는 적외선 흡수 스펙트럼으로 변화한다고 하는 상술한 내용과 결과가 일치한다.Α-, β- and prazosin hydrochloride

When one drop of water is added to each of the three microscope slides containing the mold, sharp needle crystals of the hydrate grow and combine to form a hair-like yarn-like arrangement characteristic of the liquid crystalline phase. This is α-, β- and

The results are in agreement with the above description that the infrared absorption spectrum of the polymorph is changed to the infrared absorption spectrum corresponding to the hydrate of prazosin hydrochloride obtained by softening each crystalline polymorph with water.

[Stability Study]

형 및 다수화물의 다량에 대해 안정성 연구를 했다. 샘플은 50℃로 유지시킨 오븐에 보관했고, 나머지는 일광에 노출시키면서 25℃에서 보관했다.Α-, β- and prazosin hydrochloride

Stability studies were conducted for large amounts of molds and polyhydrates. Samples were stored in an oven kept at 50 ° C. and the rest were stored at 25 ° C. with exposure to sunlight.

All samples were stored in clear glass bottles. Samples were stored for 6 weeks and again for 12 weeks, after which visual or chemical changes were observed. Although all samples had good chemical stability, it can be seen that the samples of the polyhydrate exposed to daylight are somewhat photolyzed from the fact that the color changes from white to yellowish after 6 weeks of exposure and orange after 12 weeks of exposure. Another form of prazosin hydrochloride was stable to daylight during the test.

When the sample of prazosin hydrochloride polyhydrate was stored at 25 ° C. in amber glass bottles and exposed to sunlight, no change occurred after 12 weeks.

Solubility Study

형 메탄올 화합물 및 다수화물의 물에 대한 분말용해 개략도를 나타내고 있다. 다수화물에 대한 결과치가 4일간의 실험 기간동안 일정한데 비해, 다른 형태의 프라조신 염산염은 다수화물에 비해 초기 용해도는 크고 점차용해도가 감소함을 보여준다.To measure the dissolution rate of the powdered drug in water, 50 ml of water in 100 ml of a volume of 100 ml of fine powder was added. This flask was sealed and shaken with a shaker in 25 degreeC water bath. Samples were periodically taken out and filtered through a micropore filter (pore size 0.45 mυ) and subjected to spectroscopic analysis with a Beckman Acta III spectrometer. Prazosin hydrochloride was plotted on the coordinate plane at 246 nm and 330 nm according to Beer's law, and the slope was used to calculate the solubility of the powder. FIG. 5 shows α type, β type of prazosin hydrochloride,

The schematic diagram of the powder melting | dissolving with respect to the water of a type | mold methanol compound and a polyhydrate is shown. While the results for the polyhydrate are constant over the four-day experimental period, the other forms of prazosin hydrochloride show a greater initial solubility and a progressive decrease in solubility compared to the polyhydrate.

6 shows the results of powder solubility obtained in the same manner as described above except that 200 ml of solute was dissolved in 50 ml of usp artificial gastric juice (SGJ) in each case. Form α of prazosin hydrochloride showed the highest solubility after about 5 minutes, and then gradually decreased during the experiment, finally approaching the solubility of the polyhydrate. The polyhydrate also reached its maximum solubility after a few minutes, but at a much lower level, this level remained constant for the duration of the experiment.

Compressed disk solubility studies were performed according to the method of Hamlin et al., Described in J. pharm. Sci, 51, 432 (1962).

A 300 mg powder sample was compressed into a flat circular disk by compression for 2 minutes at a surface pressure of 3000 psi with a tableter 7/16 inches in diameter. The open end of the tableting machine holding the compressed disk was sealed and placed in a plastic holder. The entire assembly was then placed in a jar containing 1000 ml of water maintained at 37 ° C. The stirring speed of the teflon stirring paddle centered in the jar was maintained at 150 revolutions per minute. The solution was continuously pumped through a micropore filter (pore size 0.45 mυ) into the flow cell of a Beckman Acta III spectrometer, where the change in absorption was automatically recorded at 246 nm.

Table 6 shows the intrinsic dissolution rates of various forms of prazosin hydrochloride. The dissolution rate was determined from the slope of the compressed disk dissolution schematic between 4-10 minutes.

TABLE 6

From the above characterization studies on various forms of prazosin hydrochloride, it is clear that the α form has several important advantages over other forms. It is the only crystalline anhydride that is non-absorbent and stable under normal storage conditions, including sun exposure. And this compound can be prepared easily and reproducibly by the method described in this specification.

Polyhydrate forms of prazosin hydrochloride can also be readily prepared by the methods described herein. It is stable under normal storage conditions when stored in a container where sunlight is blocked. Examples of such containers are known amber vials with screw caps or opaque plastic bottles with screw caps. Another advantage of the multihydrate form of prazosin hydrochloride is that it has a low and uniform solubility, taking into account the fact that the rate of dissolution of a drug determines the biological effectiveness of the drug, and as a valuable antihypertensive It can be concluded that the compound of the multimodal behavior sustains blood levels per unit dose more smoothly, more gradually and for longer periods of time than other forms. Furthermore, by administering multiple cargo forms as therapeutic agents of this valuable hypertension to keep the concentration of prazosin hydrochloride in the blood smooth, any side effects that can often be caused by the initial dose of the drug may be prevented to a minimum.

As described above, the α form of prazosin hydrochloride can be converted into a polyhydrate by contact with excess water, so that the preparation containing the α form is aqueous for a sufficient time prior to or before being absorbed into the blood after administration. Exposure to the medium yields the same smooth blood levels as before.

The methanol form of prazosin hydrochloride has the disadvantage that it contains toxic methanol molecules that can adversely affect when administered to hypotensive patients.

형은 β형 보다도 더욱 흡수성이다.The β form of prazosin hydrochloride is hygroscopic and more difficult to prepare than the α form and the polyhydrate.

The type is more absorbent than the β type.

Monohydrates and anhydrides of prazosin hydrochloride can only be prepared by further drying the polyhydrate at relatively high temperatures and are less preferred than α- and polyhydrate because they return to the majority when exposed to moist air.

Preferred α and polyhydrate forms of prazosin hydrochloride can be administered to hypertensive patients alone or in combination with a pharmaceutically acceptable carrier. The proportion of active ingredient depends on the route of administration chosen and the standard pharmaceutical formulation. For example, they may be administered in tablet form with excipients such as lactose, sodium citrate, calcium carbonate and dicalcium phosphate.

Various disintegrants such as starch, alginic acid and some kinds of silica complexes can be used with lubricants such as magnesium stearate, sodium lauryl sulfate and talc. For oral administration in capsules, excipients such as lactose and high molecular weight polyethylene glycols can be added. If an aqueous suspension is required, the active ingredient may be combined with an emulsifier and / or suspending agent. Various combinations of diluents such as ethanol, propylene glycol, glycerin and various diluents are used. For parenteral administration, an α- or polyhydrate solution of prazosin hydrochloride can be used in combination with other solutes such as glucose or salts. If necessary, these aqueous solutions may be appropriately buffered so as to be isotonic.

As can be seen above, it should be noted that for formulations containing excess water, the anhydrous α form of prazosin hydrochloride is hydrogenated. The dose required to lower blood pressure in hypertensive patients will depend on the nature and extent of hypertension. In general, a small dose is initially administered and the dose is gradually increased to determine the optimal dose. When the composition is orally administered, it is common to require a larger amount of the active ingredient in order to exhibit the same level of blood pressure drop as the parenterally lowered blood pressure by a certain amount administered parenterally. Normally, administration of about 0.02-10 mg of active ingredient per kg of body weight in single or multiple dose units effectively strengthens blood pressure in hypertensive patients. Tablets containing 0.5-5 mg of active ingredient are particularly useful.

Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are intended to illustrate the present invention, but the present invention is by no means limited thereto.

Example 1

Prazosin Hydrochloride Methanol Compound

To 1000 ml of isoamyl alcohol add 65.4 g (0.272 moles) of 2-chloro-4-amino-6,7-dimethoxyquinazoline and 54.0 g (0.30 moles) of 1- (2-furoyl) -piperazine. do. The mixture is heated to reflux for 3 hours, cooled to room temperature with stirring, and further stirring is continued at room temperature for 16 hours. The reaction mixture is cooled to 15 ° C., filtered, and the filtered cake is washed with acetone and dried in air to give 107.2 g of crude material having a melting point of 272-276 ° C. (decomposition).

It is slurried with 1400 ml of methanol and heated at the limiting temperature for 3 hours and then cooled to room temperature. The solid was isolated by filtration, washed with methanol, then washed again with ether and dried in air to obtain 110 g of the title compound having large rod crystals and melting point of 276-278 ° C. (decomposition).

Analysis: C ₁₉ H ₂₁ N ₅ O ₄ ㆍ CH ₃ OH

Theoretical (%): C 53.15; H 5.80; N 15.50; Cl 7.85

Found (%): C 53.02; H 5.77; N 15.47; Cl 7.79

Thermogravimetric analysis at a heating rate of 20 ° C. per minute on a DuPont thermogravimetric system showed a 7% weight loss at 135 ° C. This corresponds to the stoichiometric ratio 1: 1 of methanol: franzosin hydrochloride and is consistent with the above elemental analysis.

Example 2

[Prazocin hydrochloride β-type]

10 g of the prazosin hydrochloride methanol compound obtained in Example 1 was placed in an oven, held at 110 ° C. for 24 hours, and then cooled to room temperature. The resulting material is a monoclinic crystal with a melting point of 278-280 ° C.

Assay: C ₁₉ H ₂₁ N ₅ O ₄ ㆍ HCI

Theoretical (%): C 54.34; H 5.28; N 16.68; Cl 8.44

Found (%): C 54.21; H 5.26; N 16.60; Cl 8.37

Example 3

[Prazocin hydrochloride γ-type]

2- (1-piperazinyl) -4-amino-6,7-dimethoxyquinazoline (57.8 g, 0.20 mole) is dissolved in 1000 ml of chloroform and 32.2 g (0.20 mole) 2-furoyl chloride is dissolved in room temperature. Gradually added. The resulting slurry was stirred for 15 minutes and 1000 ml of isoamyl alcohol was added. A sufficient amount (usually about 200 ml) of 10% (w / w) aqueous sodium hydroxide solution was added to the resulting mixture to solidify the solids and the reaction was kept at room temperature. The aqueous layer was separated and the organic phase was washed with 250 ml of water. The organic phase was dried over anhydrous MgSO 4, filtered and the filtrate was cooled to 0 ° C. For wet paper, anhydrous hydrogen chloride was passed through the solution at 0-5 ° C. until the solution showed acidic (pH about 2-2.5) (about 45 minutes). Chloroform was evaporated under reduced pressure with slow heating at 20-30 mmHg to about 45 ° C. The vacuum was released and the solution was heated to about 100 ° C. to remove the last traces of chloroform and the mixture was cooled to room temperature. The product was recovered by filtration, washed with chloroform and dried at 50-60 ° C. in a vacuum oven to give 73.9 g of the title compound isoform, which was needle crystal and had a melting point of 277-279 ° C. (decomposition).

형을 얻을 수 있었다.In addition, the β-type sample of prazosin hydrochloride obtained in Example 2 was recrystallized from isoamyl alcohol (heated to about 115 ° C and cooled to room temperature).

Could get a brother.

Example 4

[Prozosin hydrochloride α type]

The procedure of Example 3 was repeated except that after evaporating the bulk of chloroform the slurry of isoamyl alcohol was heated at reflux (130-132 ° C.) for 2 hours. The mixture was cooled to room temperature, filtered, washed with chloroform and dried at 50-60 ° C. in a vacuum oven. Melting point of the rod-shaped crystals produced at this time was 280-282 ℃ (decomposition).

Analysis: C ₁₉ H ₂₁ N ₅ O ₄ ㆍ HCI (Molecular Weight 419.87)

Theoretical (%): C 54.35; H 5.28; N 16.68; Cl 8.44

Found (%): C 54.38; H 5.56; N 16.71; Cl 8.41

If the above procedure is repeated by heating at the indicated temperature using one of the following alcohols instead of isoamyl alcohol, the resulting product is actually the same.

Example 5

[Translation of Prazosin Hydrochloride β-Type to α-Type]

5 g of β-form of prazosin hydrochloride obtained in Example 2 was stirred with 50 ml of isoamyl alcohol while heating at reflux for 2 hours. The mixture was cooled to room temperature, washed with chloroform and dried overnight in air to give rod-shaped crystals. The infrared absorption spectrum (kBr) was consistent with that of the α type of prazosin hydrochloride.

Example 6

형에서 α염으로의 변환]Prazosin Hydrochloride

Conversion from type to α salt]

형 5g을 사용하여 상기 과정을 반복했을 때에도 역시 α형의 봉상 결정을 얻었다. 또한 적외선 흡수 스펙트럼(kBr)을 실제로 프라조신 염산염 α형의 것과 일치했다.Of prazosin hydrochloride obtained in Example 3

Also when the above process was repeated using 5 g of mold, a rod-shaped crystal of α type was obtained. In addition, the infrared absorption spectrum (kBr) actually coincided with that of the prazosin hydrochloride α type.

Example 7

[Conversion of Prazosin Hydrochloride Methanol Compound to α-form]

5 g of the sample of methanol compound obtained in Example 1 was refluxed in 100 ml of 2-methylbutanol for 3 hours. The mixture was cooled to room temperature, washed with dichloromethane and dried in air to obtain α form of prazosin hydrochloride.

Example 8

[Prazocin hydrochloride hydrate and anhydride]

180 g of prazosin hydrochloride were dissolved in a mixture of 3 L methanol, 3 L chloroform and 1200 ml water. The solution was filtered and then concentrated to 1100 ml in volume at atmospheric pressure. After cooling to room temperature, the precipitated solid was collected by filtration, and the resulting cake was washed with ethanol and then with hexane, dried at 60 ° C. for 3 hours, and then melted at 265-268 ° C. (decomposed) by water using Karl Whischer. 176 g of acicular crystals having a content of 11.96% were obtained. Thin layer chromatography was performed to show agreement with the actual sample of prazosin hydrochloride. Other samples exposed to high humidity contained up to 15% moisture. This compound was named Prazosin Hydrochloride Multihydrate.

After drying the polyhydrate for 30 minutes at 100 ° C. in a vacuum drier, the water content is reduced to 7.9%, where the prazosin hydrochloride matches the water content of the hydrate.

When the sample of prazosin hydrochloride multihydrate is dried for about 60 minutes at 100 ° C. in a vacuum dryer, the moisture content is reduced to 4.1%, which is consistent with the moisture content of prazosin hydrochloride monohydrate.

Drying at 100 ° C. for 12-15 hours in a vacuum dryer yields anhydrous prazosin hydrochloride containing about 1% water.

When samples of anhydrides and monohydrates are stored at 75% relative humidity at room temperature, they rapidly absorb water and form dihydrates (8% moisture) after about 24 hours. The hydrate continues to absorb water at a slower rate, reaching an equilibrium moisture content of 13.5% after 4 days.

Example 9

[Formulation of Prazosin Hydrochloride to α-Polyhydrate]

50 g of α form of prazosin hydrochloride is added to 500 ml of water, the mixture is stirred and heated at 95 ° C. for 2 hours. After cooling to about 50 ° C., the slurry was filtered, washed with water and dried in air for 48 hours to give 50.5 g of prazosin hydrochloride polyhydrate containing 12.4% of water. The infrared absorption spectrum obtained by the KBr disk method is consistent with that shown in FIG.

Example 10

[Conversion of Prazosin Hydrochloride Dihydrate to Form α]

A sample of prazosin hydrochloride dihydrate was slurried with isoamyl alcohol, refluxed for 3 hours, cooled and filtered to form rod-shaped crystals, which are shown in FIG. 1 by comparison of infrared absorption spectra (KBr). In fact, it was found to be consistent with that of the sample of α type.

Example 11

[Tablet]

Tablet bases are prepared by mixing the following ingredients in the indicated weight ratios.

Form α of 2- [4- (2-furoyl) piperazin-1-yl] -4-amino-6,7-dimethoxyquinazolin hydrochloride; tablets containing 0.5, 1, 2 and 5 mg of active ingredient Mix in sufficient amount to the base to ensure that.

Example 12

[Capsules]

A mixture containing the following ingredients is prepared.

Capsule of the majority of 2- [4- (2-furoyl) piperazin-1-yl] -4-amino-6,7-dimethoxy quinazoline hydrochloride has 0.25, 0.5, 1, 2.5 and 5 mg of the active ingredient Sufficient amount is added to the mixture to contain.

Example 13

[Injectable preparation]

1000 g of 2- [4- (2-furoyl) piperazin-1-yl] -4-amino-6,7-dimethoxyquinazolin hydrochloride α form is mixed closely with 2500 g of sodium ascorbate. The dry mixture is filled into small bottles and sterilized by sterilization with ethylene oxide. For intravenous use, a sufficient amount of water is added to the bottle to make a solution containing 1.0 mg of active ingredient per ml.

Example 14

[Suspension]

A suspension of the polyhydrate of 2- [4- (2-furoyl) piperazin-1-yl] -4-amino-6,7-dimethoxyquinazolin hydrochloride is prepared from the following components.

Various sweeteners and fragrances may be selectively added to this suspension. This suspension contains about 2.5 mg of the antihypertensive agent per ml.

Claims (1)

2- [4- (2-furoyl) piperazin-1-yl] -4-amino-6,7-dimethoxyquinazoline hydrochloride or a hydrate or solvate thereof having an aliphatic or aliphatic ring of C ₅ to C ₇ The infrared absorption spectrum in KBr is characterized by heating in a presence of an alcoholic solvent to a temperature in the range of about 125-160 ° C. until the formation of crystalline α form of the compound is substantially complete and then precipitating this α form. A process for producing crystalline α form of 2- [4- (2-furoyl) piperazin-1-yl] -4-amino-6,7-dimethoxyquinazolin hydrochloride having the following absorption bands.