HK1160782A - Medicaments containing vardenafil hydrochloride trihydrate - Google Patents

Description

Medicament comprising vardenafil hydrochloride trihydrate

The present application is a divisional application of an invention patent application having an application number of 03821144.0 and an application date of 2003, 7/3.

Technical Field

The present application relates to medicaments comprising vardenafil hydrochloride in solid form, essentially in the form of the trihydrate, and to processes for the preparation thereof.

Background

The pharmaceutically active ingredients vardenafil (IUPAC-name: 2-ethoxy-5- [ (4-ethyl-1-piperazinyl) sulfonyl ] phenyl } -5-methyl-7-propylimidazo [5, 1-f ] [1, 2, 4] triazin-4 (3H) -one), vardenafil hydrochloride and vardenafil hydrochloride trihydrate and their use for the treatment of erectile dysfunction are described in WO 99/24433 in the form of examples 19, 20 and 336.

Vardenafil hydrochloride has been found to exist in the form of four different polymorphs (anhydrous modification I having a melting point of 217 ℃, modification II having a melting point of 190 ℃, modification III having a melting point of 183-186 ℃, modification IV having a transformation point of 166 ℃) and preferably does not form any of these polymorphs at room temperature. Furthermore, each polymorph form may have a different amount of water depending on the humidity and temperature of the surrounding environment, and may form, together with water, another polymorph form known as a pseudopolymorph form.

Since the dissolution behavior of different polymorphic forms of a substance often differs, these differences may manifest themselves, for example, in birthBioavailability (AUC), maximum plasma concentration (C)_max) And time to appearance of maximum plasma concentration (AUC)_max) In (1). It may also reduce absorption, thereby rendering the effect insufficient or completely absent.

One problem is therefore that the solid drug must contain the active ingredient vardenafil hydrochloride in a well-defined reproducible form. However, on the other hand, the polymorphic form of vardenafil HCl cannot be prepared or isolated in pure form because it each absorbs small amounts of water and thus exists in the form of a mixture of polymorphic form and hydrates.

For these reasons, vardenafil hydrochloride is not suitable as an ingredient of a drug in which the active ingredient should be present in solid form.

Disclosure of Invention

It has now been found that when vardenafil hydrochloride in its trihydrate form is used, a homogeneous and reproducible form of the solid drug can be obtained when these drugs are wetted during or after their preparation.

The present invention therefore relates to a process for the preparation of a medicament comprising vardenafil hydrochloride trihydrate in solid form, characterized in that

a) In the preparation of the medicament, vardenafil hydrochloride having any water of crystallization content is used,

b) converting the vardenafil hydrochloride into the trihydrate form in an intermediate processing step or in the final product, and

c) optionally, the process conditions in the following process steps are controlled such that the variation of the water of crystallization content of vardenafil hydrochloride trihydrate can be neglected.

Vardenafil hydrochloride having any water content, i.e. as trihydrate or in a form whose water of crystallization is substantially different from 9.3% by weight, can be used in this process.

Vardenafil hydrochloride is converted into the trihydrate form in one of the following process stages or in the final product and, optionally, the process conditions in the following process steps are controlled such that the water of crystallization of vardenafil hydrochloride trihydrate does not change.

According to the invention, the conversion to the trihydrate form is carried out by contacting the intermediate process stages or the end product with moist gas in a suitable system until the trihydrate of vardenafil hydrochloride is substantially formed.

Moist gases are in particular air with a relative humidity of 35% to 100%, particularly preferably 50% to 99%. Suitable systems are all systems or chambers into which the moist gas can be introduced or supplied and which can be brought into as homogeneous contact as possible with the pharmaceutical form or which can be incubated under the conditions specified. The residence time of the moist gas through or in the system, or the residence time of the pharmaceutical form in the system and the relative humidity of the gas, depends on the initial water content of the pharmaceutical form and the ratio between the amount of moist gas and pharmaceutical form. It can be from a few minutes up to several days, in most cases 0.5-12 hours being sufficient. In the case of packaged pharmaceutical forms, a period of 1 day to 6 months is usually sufficient.

Solid medicaments are all pharmaceutical forms comprising vardenafil hydrochloride trihydrate in solid form, such as powders, granules, tablets, film-coated tablets, dragees, fast-dissolving tablets or hard gelatine capsules.

The solid pharmaceutical substances used for the purposes of the present invention are preferably tablets, in particular coated tablets, since the active ingredient is present again inhomogeneously in the form of various polymorphs and pseudopolymorphs, since the vardenafil hydrochloride trihydrate is partially or completely dehydrated to a particular extent during the processing of the tablets by conventional methods, in particular during the coating of the tablets.

In addition to vardenafil hydrochloride trihydrate, which is present only in one crystalline modified form at room temperature (vardenafil hydrochloride trihydrate having a water content of 9.3% by weight), the pharmaceutical products prepared according to the invention also comprise further pharmaceutical auxiliaries which are known to the person skilled in the art.

In addition to vardenafil hydrochloride trihydrate, the tablets of the invention preferably comprise fillers, disintegrants and lubricants and, optionally, further adjuvants. The tablet of the present invention preferably contains 0.1 to 70% by weight of vardenafil hydrochloride trihydrate, 0.1 to 10% by weight of a disintegrant, 0.1 to 2% by weight of a lubricant, and optionally, further contains an auxiliary agent, and a filler as the remaining ingredients.

The tablet preferably comprises microcrystalline cellulose as filler, crospovidone as disintegrant, magnesium stearate as lubricant.

Further adjuvants which may optionally be added to the tablets are, for example and preferably, flow regulators such as highly dispersed silicon dioxide, for example.

Particularly preferred are coated tablets (also in a form that is easy to administer) comprising as active ingredient vardenafil hydrochloride, which is reproducible in the trihydrate modification.

The european pharmacopoeia, 3 rd edition 1997, page 1852, clearly defines coated tablets: "coated tablets" are tablets which are covered with a mixture of one or more layers of various substances, such as natural or synthetic resins, gums, gelatins, inactive and insoluble fillers, sugars, plasticizers, polyols, waxes, coloring substances approved by the authorities and optionally also flavoring and active substances. The substances used as coatings are usually applied in the form of solutions or suspensions under conditions under which evaporation of the solution or dispersion can occur. When the coating is a very thin polymer coating, the tablet is referred to as a film coated tablet. "

Reference may also be made to the definition of tablets in the european pharmacopoeia, 3 rd edition, 1997.

The loss of water of crystallization of the active ingredient is particularly high when coated tablets comprising vardenafil hydrochloride trihydrate are produced in a conventional manner, since the aim in the processing is to dry off the solution or dispersant and form a film with the coating material.

Thus, a preferred embodiment of the present invention is a process for the preparation of vardenafil hydrochloride trihydrate coated tablets comprising reproducible vardenafil hydrochloride in the trihydrate form and also in a form which is easy to administer.

In this preferred process, the coated vardenafil HCl tablet is treated with a rehydration process. In this respect, the same vardenafil HCl trihydrate is surprisingly formed in the coated tablet in all cases, regardless of whether the polymorphic form or the mixture of polymorphic forms of vardenafil hydrochloride is initially present in the coated tablet.

Thus, another aspect of the present invention is a process for the preparation of coated tablets comprising vardenafil hydrochloride trihydrate, characterized in that coated tablets comprising vardenafil hydrochloride in any (hydrate) modified form or forms prepared by conventional processes are subjected to a rehydration process.

The rehydration process is preferably carried out by contacting the coated tablet with a humid gas in a suitable system until the pharmaceutical form of vardenafil HCl trihydrate is formed.

Suitable systems in which the rehydration process may be carried out are for example and preferably environmentally controlled chambers, environmentally controlled rooms, fluid bed granulators, coating apparatus or drums.

Examples of moist gases are, preferably, air with a relative humidity of 35% to 100%, particularly preferably 50% to 99%.

During the rehydration process, the coated tablets may be left in the system, for example on a tray in an environmentally controlled chamber or at the bottom of a fluid bed granulator or continuously or occasionally agitated to provide better mixing, for example, agitation may be provided in a drum or coating system. The rehydration process may also be carried out after the coated tablets have been packaged in a package that is permeable to water vapor. For this purpose, the packaged coated tablets are incubated in an environmentally controlled room.

The duration of said rehydration depends on the initial water content of the coated tablets, the relative humidity of the humid gas and the dose ratio between the humid gas and the coated tablets. It can range from a few minutes up to several days, and in most cases a rehydration time of 0.5-12 hours is sufficient. In the case of rehydration of said tablets after packaging in a moisture permeable package, the rehydration time will also depend on the permeability of the packaging material to moisture. In the case of pharmaceutically conventional blister packs, a period of 1 day up to 6 months is usually sufficient.

If this rehydration is carried out in an intermediate processing stage, the subsequent processing conditions are controlled such that the water of crystallization of vardenafil hydrochloride trihydrate does not change. For this purpose, the subsequent processing steps are carried out with a relative humidity of the air in contact with the product of 30 to 100%, preferably 35 to 99%.

It is also surprising that the process of the present invention allows the complete conversion of the poorly defined modified mixture of vardenafil hydrochloride into the trihydrate form even in the case of a dense structure of the finally finished coated tablet. Furthermore, there are no unwanted side effects on the quality of the coated tablets, such as, for example, coating layer breakage, cracking or a reduced release rate of the active ingredient.

It has also been found that the tablets prepared by the process of the present invention have many advantages over coated tablets prepared by conventional methods using vardenafil trihydrate hydrochloride.

The present application therefore also relates to tablets prepared by the process of the invention.

The tablets according to the invention or the tablets prepared by the process according to the invention have the advantage that the crystal structure of the active ingredient in the medicament is well-defined, reproducible and stable over a wide range of air humidity, the corresponding coated tablets have a faster disintegration and, contrary to what was expected in the prior art so far (David j.w.grant, t.higuchi, Techniques of Chemistry, Volume XXI, pages 38, 42 and 43), the dissolution rate of the active ingredient from the tablets according to the invention or the tablets prepared by the process according to the invention is constantly fast.

Can be obtained from Raman spectroscopy (FT Raman spectrum of vardenafil hydrochloride trihydrate at 1701cm^-1Showing a significant peak. In contrast, the polymorphic and pseudopolymorphic forms with low water content and mixtures thereof were found to be 1692cm^-1Having a band), IR spectrum, NIR spectrum, FIR spectrum,¹³The crystal structure determined by the C solid state NMR spectrum and X-ray diffraction pattern (see appended FIGS. 2, 4-8 and tables 3-8) clearly defines the tablets of the invention or tablets prepared by the process of the invention.

For the preparation of vardenafil hydrochloride and vardenafil hydrochloride trihydrate, reference may be made to the disclosure of WO 99/24433, in particular examples 20 and 336 thereof.

Vardenafil hydrochloride in the medicament is preferably at least 90 mol%, particularly preferably at least 95 mol%, in the form of the trihydrate.

The medicaments of the invention and the medicaments which can be prepared by the process of the invention, in particular the tablets of the invention or the tablets prepared by the process of the invention, are suitable for the treatment and/or prophylaxis of human and/or animal diseases, in particular for the treatment of sexual dysfunction, more particularly for the treatment of erectile dysfunction.

The medicaments of the present invention exhibit a number of unexpected advantages:

1. the medicament comprises vardenafil hydrochloride in only one crystalline modification. Thus, the drug can be prepared reproducibly and it releases vardenafil at a reproducible and uniform rate.

2. The release rate of the active ingredient from the medicament of the invention can be compared with medicaments comprising an active ingredient without solvates. From inclusion of the solvate in its solvent, herein in water, the release rate in the crystal, herein comprising water, is generally lower than from a crystal without solvate.

3. The drug, especially the coated tablet, has a shorter disintegration time. The medicament is therefore particularly suitable for the treatment of diseases for which a rapid onset of action is desired, such as, for example, for the treatment of erectile dysfunction.

4. In contrast to the high hygroscopicity of the drug of vardenafil hydrochloride without solvate, the drug of the present invention is stable upon long-term storage and its composition, in particular its water content, hardly changes.

The medicament of the present invention can be administered in various ways. Examples which may be mentioned are: oral, sublingual, buccal, nasal, inhalation, subcutaneous, or topical administration. Oral administration is preferred.

It has proven generally advantageous to administer amounts of about 0.001 to 10mg/kg of body weight, preferably about 0.005 to 3mg/kg of body weight to achieve effective results in oral application.

However, it may optionally be desirable to deviate from the stated amounts, which are influenced in particular by the body weight or the nature of the route of administration, the individual's response to the drug, its formulation properties and the time or time interval taken for administration. Thus, in some cases less than the minimum number of doses described above may be used, while in other cases the number used must exceed the upper limit described. If larger quantities are administered, it is also preferable to divide the quantity into a plurality of single doses within the day.

Description of the drawings:

FIG. 1a different Raman spectra of tablets of example 6 before rehydration of anhydrous vardenafil HCl non-rehydrated tablets (spectrum of the tablet-vardenafil HCl 3H)₂Spectrum of O).

FIG. 1b different Raman spectra of tablets of example 6 after rehydration of anhydrous vardenafil HCl non-rehydrated tablets (spectrum of the tablet-vardenafil HCl 3H)₂Spectrum of O).

FIG. 2: vardenafil HCl 3H₂Raman spectrum of O.

FIG. 3: detection of the trihydrate form of vardenafil HCl in a 20mg tablet.

FIG. 4: vardenafil HCl 3H₂IR spectrum of O.

FIG. 5: vardenafil HCl 3H₂NIR spectrum of O.

FIG. 6: vardenafil HCl 3H₂FIR spectrum of O.

FIG. 7: vardenafil HCl 3H₂Of O¹³C solid state NMR spectrum.

FIG. 8: vardenafil HCl 3H₂X-ray diffraction pattern of O.

The invention is further illustrated by the following examples, which are not intended to be limiting.

Detailed Description

Examples

Comparative example 1 and example 2: tablets prepared by conventional methods of manufacture using drum granulation and coating, and improved disintegration of the tablets of the invention

216g of micronized vardenafil HCl was mixed with 605g of microcrystalline cellulose and 43.2g of crospovidone. 2101g of microcrystalline cellulose and 132g of crospovidone were added thereto and mixed, and then, it was mixed with 350g of microcrystalline cellulose, 17.5g of highly dispersed silicon dioxide and 35g of magnesium stearate. The mixture was compressed with a rotary tablet press into tablets having a diameter of 6mm and a tablet weight of 87mg (corresponding to 5mg vardenafil base). In the coating apparatus, 43.5mg of coating suspension containing 4.5% hypromellose, 1.5% polyethylene glycol 400, 1.23% titanium dioxide, 0.25% yellow iron oxide and 0.02% red iron oxide was sprayed to each tablet.

Comparative example 1

Vardenafil hydrochloride present in the tablets is partly trihydrate and partly in dehydrated form (1 to 4 modification). The disintegration time of the tablet was 2 minutes.

Example 2

The tablets are prepared by mixing the above powders at a ratio of 150m³Rehydrated in a fluidized bed granulator at a temperature of 30 ℃ and an inlet air water content of 19g/kg for 4 hours (corresponding to a relative air humidity of 70%). Thus, the modification of vardenafil HCl in the tablets of the invention corresponds to the trihydrate. The tablet now has a disintegration time of only 1/2 minutes.

Example 3:stability of the tablets prepared according to the invention

28.4kg micronized vardenafil HCl trihydrate were mixed with 69.6kg microcrystalline cellulose and 5.16kg sieved crospovidone in a mechanical mixer. This mixture was mixed with 182kg microcrystalline cellulose and 9.84kg crospovidone in a container mixer and granulated using drum dry granulation. After mixing in 1.50kg of highly disperse silicon dioxide and 3.00kg of magnesium stearate, tablets having a mass of 125mg and a diameter of 7mm are prepared on a rotary tablet press. The uncoated tablets were coated with a suspension of 5.74kg hypromellose, 1.91kg polyethylene glycol 400, 1.57kg titanium oxide, 319g yellow iron oxide, 25.5g red iron oxide and 118kg purified water in a commercially available coating system. The modified form of vardenafil HCl in this coated tablet is not consistent with the trihydrate form, thus it represents an undefined mixture of anhydrous and aqueous forms of vardenafil HCl. The coated tablets were treated in a coating system at 25 ℃ for 5 hours with air having a water content of 16g water/kg (corresponding to a relative air humidity of 80%). The vardenafil HCl modification in the rehydrated tablet is consistent with the trihydrate phase.

And (3) stability test: the tablets with vardenafil HCl trihydrate were stored in an oven at 25 ℃ and 30% relative humidity for one week. Despite the low air humidity, no loss of water of crystallization occurs during this process, and the vardenafil HCl active ingredient modification is still consistent with the trihydrate form.

Example 4:release of active ingredients from tablets prepared according to the invention

336g of vardenafil HCl was mixed together with 2216g of microcrystalline cellulose and 134g of crospovidone and dry granulated. The granules were transferred and then mixed with 283g microcrystalline cellulose, 16g crospovidone and 15g magnesium stearate and compressed into tablets with a diameter of 5mm and a mass of 48mg (corresponding to 5mg vardenafil base per tablet). The tablets were provided with a white coating of 57.4g hypromellose, 19.1g polyethylene glycol 4000 and 19.1g titanium dioxide and stored in an oven at 25 ℃ and 80% relative air humidity for 4 days. The modification of vardenafil HCl in the tablets is consistent with the trihydrate form.

As shown by the release data in table 1, the tablets of the invention prepared in this way release the active ingredient very rapidly, although vardenafil HCl in the final tablet reverts to the trihydrate form.

Table 1: release of active ingredient from the tablet of example 4

Time of day

Active ingredient release

5 minutes	100％
		10 minutes	101％
30 minutes	101％
		45 minutes	101％

Releasing conditions are as follows: n-6, USP paddle method, 900ml 0.1-M-HCl, 75rpm, 10 μ M filter.

Example 5Minor differences in relative bioavailability of the tablets of the invention

0.645kg vardenafil HCl was mixed with 2.42kg microcrystalline cellulose and 161 crospovidone, sieved and dry granulated with a drum. The granulate is then mixed with 0.339kg microcrystalline cellulose, 18.8g crospovidone and 18g magnesium stearate and compressed into round tablets with a diameter of 7mm and a mass of 120mg (equal to 20mg vardenafil base). The tablets were coated with 0.765mg polyethylene glycol 4000, 2.295mg hypromellose and 0.765mg titanium dioxide (in each case in the amount per tablet). It was exposed to an ambient controlled room on a plate at 16-24 ℃ and 60-75% relative humidity for 72 hours to produce the trihydrate form of vardenafil HCl in the finished tablet.

For comparison, a solution of composition 21.49mg vardenafil HCl (equivalent to 20mg vardenafil base), 38.69mg methylparaben, 4.298mg propylparaben, 6448mg sucrose, 17419mg water and lactic acid to pH 3.9 was prepared. Pharmacokinetics were compared with 12 male subjects in an open randomized crossover study after dosing the tablets and solution (table 2).

Table 2: pharmacokinetic parameters (geometric mean/geometric standard deviation) after administration of the tablets and solutions of example 5

Parameter(s)	Tablets corresponding to example 5	Comparative solution
			AUC(μg×h/L)	60.2/1.64	64.6/1.78

Cmax(μg/L)

21.1/1.86

22.5/2.09

The results show that the relative bioavailability of the tablets of the invention compared to an aqueous solution is 93%. Since the geometric standard deviation of bioavailability and maximum plasma concentration is less than the value after aqueous solution administration, it can rule out differences caused by variable polymorphic or pseudopolymorphic forms of vardenafil HCl as solid form in the tablet.

Example 6

0.871kg vardenafil HCl trihydrate, 2.13kg microcrystalline cellulose and 0.158kg of sieved crospovidone were mixed vigorously in a plowshare mixer. This mixture was mixed with 3.08kg microcrystalline cellulose and 0.167kg crospovidone, drum granulated and then mixed with 0.0325kg highly disperse silicon dioxide and 0.0650kg magnesium stearate.

The mixture was compressed with a rotary tablet press into tablets of 8kg diameter and a mass of 177mg (corresponding to 20mg vardenafil base) and coated with 2.76kg of an aqueous coating suspension with 4.5% hypromellose, 1.5% polyethylene glycol 400, 1.23% titanium dioxide, 0.25% yellow iron oxide and 0.02% red iron oxide in a coating pan. The modification of vardenafil HCl in the tablets did not correspond to the trihydrate form (fig. 1 a).

By introducing the coated tablets into a fluid bed granulator model Glatt GPCG 1/3 and using a 150m granulator³Rehydration was carried out by treatment for 4 hours with inlet air at a temperature of 25 ℃ and a relative humidity of 16g/kg (corresponding to a relative air humidity of 80%). Improved and trihydrate forms of vardenafil HCl in tablets treated in this wayThe formulae are identical (FIG. 1 b).

Example 7

After coating, 37kg of the coated tablets prepared according to example 6 are introduced in a tablet drum (tablettenloss) with 40m of air introduced through an air duct³Per 3 days of inlet air treatment at 21 ℃ and 84% relative humidity.

Example 8

12.3kg vardenafil HCl trihydrate, 30.2kg microcrystalline cellulose and 2.24kg of sieved crospovidone were mixed. The mixture was then mixed with a further 238kg of microcrystalline cellulose and 12.8kg of sieved crospovidone, granulated with a drum and then mixed with 1.5kg of highly disperse silicon dioxide and 3.0kg of sieved magnesium stearate. The mixture was compressed with a rotary tablet press into round tablets having a diameter of 5.5mm and a mass of 72 mg. The tablets were provided with a coating of 5.74kg hypromellose, 1.91kg polyethylene glycol 400, 1.57kg titanium dioxide, 319g yellow iron oxide and 25.5g red iron oxide. The coated tablets were rehydrated twice in batches of about 140kg by 2000m in a Glatt 1250 type coating system³The reaction was carried out by treating the inlet air with a humidity of 16g/kg (corresponding to a relative air humidity of 80%) at 25 ℃ for 5 hours.

Example 9

600g tablets consisting of 5.926mg vardenafil HCl trihydrate, 4.35mg crospovidone, 0.87mg magnesium stearate, 75.419mg microcrystalline cellulose and 0.435mg colloidal silicon dioxide were coated in a Kugelcoat with an organic coating solution consisting of 6.65% cellulose acetate, 0.35% PEG 3350, 92.535% acetone and 0.465% water until 82.76g of coating had been applied. The coated tablets were treated on a tray at 25 ℃/80% relative air humidity for 24 hours.

Example 10

Tablets were prepared as described in example 6. After coating, the tablets were sealed into blister packs consisting of 20 μm combined with 3.5g/m²Aluminum sheets of PP sheets, and colorless and transparent PP sheets of 300 μm. The blister pack was incubated at 25 ℃ and 60% relative air humidity for more than 6 months. The vardenafil HCl modification in tablets treated in this way is consistent with the trihydrate form.

Example 11

2.96kg vardenafil hydrochloride trihydrate, 7.25kg microcrystalline cellulose and 538g crospovidone were mixed in a plowshare mixer. The mixture was mixed in a free fall mixer with 26.1kg microcrystalline cellulose and 1.64kg crospovidone. The mixture was dry granulated in a drum granulator and then mixed with 4.35kg of microcrystalline cellulose, 218g of highly disperse silicon dioxide and 435g of magnesium stearate. This mixture was compressed into round tablets with a diameter of 6mm using a rotary tablet press. The tablets were coated in a coating pan with a coating dispersion having the following ingredients: 832g of hypromellose, 277g of polyethylene glycol 400, 227g of titanium dioxide, 17.1kg of water, 46.2g of yellow and 3.70g of red iron oxide.

The finished tablets were sealed into blister packs made with 300 μm colorless transparent PP pieces and 20 μm aluminium pieces with a sealing layer. In this state, the modification of vardenafil HCl in the tablet does not correspond to the trihydrate form. The blister packages were then incubated at 25 ℃ and 80% air humidity for three days. The active ingredient in the tablet is then in phase with vardenafil hydrochloride trihydrate.

Example 12

FT Raman spectroscopy was used to investigate the vardenafil HCl trihydrate form present in the finished coated tablets. The FT Raman spectrum of the vardenafil HCl trihydrate tablet is in contrast to the corresponding placebo tablet, with the difference that the band is 1701cm^-1、1624cm^-1、1594cm^-1、1580cm^-1、1561cm^-1And 1518cm^-1Here (fig. 2). These bands are clearly illustrated with the active ingredient vardenafil HCl trihydrate, as demonstrated below. There is a single crystal X-ray structural analysis of vardenafil HCl trihydrate and with its help a theoretical two-dimensional X-ray powder diffraction pattern was calculated. If the experimentally obtained X-ray powder diffraction pattern of a given sample of active ingredient corresponds to this theoretical diffraction pattern, the given sample is clearly vardenafil HCl trihydrate. Thus, this FT raman spectrum of the same sample is clearly the spectrum of vardenafil HCl trihydrate (table 3). If this material is dried, 1 to 4 dehydration modified bands appear in the FT Raman spectrum, for example at about 1692cm^-1And 1599cm^-1To (3). Depending on the amount remaining in the sample, the band intensities belonging to vardenafil HCl trihydrate decreased in the FT raman spectrum (fig. 3). Thus, it can be used in FT Raman spectra at about 1692cm^-1And 1599cm^-1The absence of spectra resulted in testing for complete rehydration of vardenafil HCl trihydrate. The practical operation is as follows: the FT raman spectrum of vardenafil HCl trihydrate and the FT raman spectrum of the tablet without active ingredient of the corresponding formulation were subtracted from the FT raman spectrum of a given tablet. The remaining raman intensity above the spectral noise and > 0 is the band of the other ingredients than these present in the tablets without active ingredient and vardenafil HCl trihydrate. In the case of vardenafil HCl tablets, there are, for example, bands with improved dehydration in vardenafil HCl 1 to 4.

Table 3: vardenafil HCl 3H₂Band tablet of Raman spectrum of O

Table 4: vardenafil HCl 3H₂Tablet of O in IR spectral band

Table 5: vardenafil HCl 3H₂Tablets of O in the NIR spectral band

Table 6: vardenafil HCl 3H₂Tablet of O in the FIR spectral band

Table 7: vardenafil HCl 3H₂O is at¹³Tablets in C solid NMR spectral band

Table 8: vardenafil HCl 3H₂List of peaks in X-ray diffraction pattern of O

Claims (10)

1. A process for the preparation of a medicament comprising vardenafil hydrochloride trihydrate in solid form,

a) in the preparation of the medicament, vardenafil hydrochloride having any water content is used,

b) in an intermediate processing stage or in the final product, vardenafil hydrochloride is converted substantially to the trihydrate form, characterized in that the intermediate processing stage or the final product, or the coated tablets, is brought into contact with a moist gas until 90 mol% of the trihydrate is formed.

2. The method of claim 1, wherein the processing with the humid gas is performed for 0.5 hours to 6 months.

3. A method according to claim 1 or 2, characterized in that humid air is used as the gas with a relative humidity of 35% to 100%.

4. A method according to claim 1 or 2, characterized in that the gas used has a relative humidity of 50% to 99%.

5. The method of claim 1 or 2, wherein the processing is performed at a temperature of 16-30 ℃.

6. A process according to claim 1 or 2, wherein the rehydration is carried out in an intermediate processing stage, the subsequent processing conditions are controlled such that the vardenafil hydrochloride trihydrate has a water of crystallisation content of at least 90 mol%, and the subsequent processing steps are carried out with a relative humidity of air of 30-100%.

7. Coated tablets obtainable by the process according to claim 1 or 2.

8. A coated tablet as claimed in claim 7, which comprises vardenafil hydrochloride trihydrate in an amount of 0.1 to 70% by weight, a disintegrant in an amount of 0.1 to 10% by weight, a lubricant in an amount of 0.1 to 2% by weight, and optionally, further comprises an auxiliary agent, and a filler as the remaining ingredients.

9. A coated tablet according to any one of claims 7 and 8 for use in the treatment and/or prevention of sexual dysfunction.

10. A coated tablet according to any one of claims 7 and 8 for use in the treatment and/or prevention of erectile dysfunction.