Abstract:
Raloxifene acid addition salts or solvates thereof, having improved dissolution properties in media comprising hydrochloric acid are described, compared with similar preparations based on raloxifene or raloxifene hydrochloride. The disclosed acid addition salts or solvates thereof show an improved bioavailability in media comprising hydrochloric acid, such as the gastric juice. The acid addition salts or solvates thereof are addition salts or solvates of raloxifene and a pharmaceutical acceptable acid selected among succinic acid, lactic acid, malonic acid or sulphuric acid. Further, crystalline forms of the raloxifene salts and solvates thereof are disclosed. The raloxifene acid addition salts and/or solvates thereof are useful for the preparation of pharmaceutical composition for oral administration capable of fast and reliable release of the active ingredients in the stomach of the patient, in particular for the treatment of cancer or osteoporosis, or for inhibiting cartilage degradation. A new method for preparation of raloxifene lactate is also disclosed.

Description:
[0001]     The invention relates to acid addition salts and/or solvates of [6-hydroxy-2-(4-hydroxyphenyl)benzol[b]thien-3-yl][4-[2-(1-piperidinyl)-ethoxy]phenyl-, raloxifene, having high availability from media comprising dilute hydrochloric acid, such as gastric juice. In addition useful crystal forms of the acid addition salts and/or solvates are disclosed.  
         [0002]     In another aspect the invention relates to pharmaceutical composition for oral administration comprising said novel acid addition salts and/or solvates thereof, preferably in crystalline form. The pharmaceutical compositions according to the invention are useful because the high availability from dilute hydrochloric acid, such as gastric juice, secures a high and reliable release of the active ingredient, raloxifene, in the stomach of the patient to whom said pharmaceutical composition have been administered.  
         [0003]     Further the invention provides an improved method for preparation and purification of said acid addition salts and/or solvates thereof, which method provides for a quick and highly efficient purification of the crude raloxifene product.  
       BACKGROUND OF THE INVENTION  
       [0004]     Raloxifene, [6-hydroxy-2-(4-hydroxyphenyl)benzol[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl-, is a well known compound having antiestrogene and antiandrogene activity. Raloxifene or raloxifene hydrochloride has proved useful for the preparation of pharmaceutical compositions for the treatment of cancer, osteoporosis and cartilage degradation.  
         [0005]     Raloxifene, [6-hydroxy-2-(4-hydroxyphenyl)benzol[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl-, is also known as 6-hydroxy-2-(4-hydrophenyl)-3-[4-(2-piperidinoethoxy)-benzoyl]benzo-[b]-thiophene. Other names for raloxifene may also be found in the literature.  
         [0006]     EP 62 503 A1 discloses benzothiophene compounds and process for preparing them. The disclosed compounds have antiestrogenic and antiandrogenic activity. Pharmaceutical preparation comprising said benzothiophene compounds are described, which preparations are useful for the treatment of cancers. A particular preferred compound is Raloxifene. Acid addition salts of the benzothiophene compounds with physiologically acceptable acids are also disclosed. As examples of physiologically acceptable acids are mentioned among others sulphuric acid, succinic acid and lactic acid.  
         [0007]     In the manufacture of raloxifene the crude product in the reaction mixture was evaporated to dryness, redissolved and purified in several steps before the pure product was recovered as a crude product that was further purified to provide the desired compound.  
         [0008]     The obtained free base was subsequent transformed into acid addition salts using usual techniques.  
         [0009]     EP 584 952 discloses use of raloxifene or acid addition salts thereof for the treatment of osteoporosis. It is preferred to use an acid addition salt of raloxifene instead of raloxifene as a free base because the acid addition salts generally have improved dissolution properties compared to the free base. As examples of acids used for the acid addition salts are mentioned among others: hydrochloric acid, sulphuric acid, lactic acid, malonic acid and succinic acid. Raloxifene hydrochloride is the preferred acid addition salt.  
         [0010]     EP 652 002 A1 discloses use or 2-phenyl-3-aroylbenzothiephenes or pharmaceutical acceptable acid addition salts thereof, such as raloxifene and raloxifene hydrochloride respectively, for the inhibition of cartilage degradation.  
         [0011]     In WO 96/09045 raloxifene hydrochloride in crystalline form or as a solvate is described.  
         [0012]     EP 910 369 discloses raloxifene hydrochloride in crystal form where the crystals are smaller than 50 microns, and EP 826 682 discloses raloxifene in an amorphous form having enhanced solubility.  
         [0013]     At present most commercial available pharmaceutical compositions comprising raloxifene as active ingredient comprises raloxifene hydrochloride, because raloxifene hydrochloride is fairly soluble in aqueous solvents whereas raloxifene as free base is only sparingly soluble in aqueous solvents.  
         [0014]     Despite the extensive experimentation of increasing the bioavailability of raloxifene there is still a need for providing the active compound in a form having increased availability of the active compound in order to provide pharmaceutical preparations for oral administration, which composition have a high availability of the active compound raloxifene from the upper gastrointestinal tract.  
       BRIEF DESCRIPTION OF THE INVENTION  
       [0015]     The present invention relates to raloxifene acid addition salts and/or solvates having a high availability in dilute hydrochloric acid or gastric juice.  
         [0016]     The present inventors have surprisingly discovered that the raloxifene acid addition salts and solvates according to the invention have high bioavailability of the active compound soon after ingestion. In particular the raloxifene salts and/or solvates according to the invention have improved intrinsic dissolution properties in the presence of hydrochloric acid such as in gastric juice, compared with the commonly used raloxifene acid addition salt, raloxifene hydrochloride.  
         [0017]     In a further aspect the invention relates to new and particular useful crystal forms of said novel raloxifene acid addition salts or solvates thereof.  
         [0018]     In an even further aspect the invention relates to pharmaceutical compositions comprising said novel raloxifene acid addition salts and solvates thereof, which compositions after the ingestion thereof is capable of releasing the active compound raloxifene in higher amounts, compared with the frequently used compound raloxifene hydrochloride.  
         [0019]     A further aspect of the invention relates to a new and improved method for preparation of raloxifene lactate. 
     
    
     SHORT DESCRIPTION OF THE FIGURES  
       [0020]      FIG. 1  shows a differential scanning calorimetric chart (DSC) for raloxifene DL-lactate hemihydrate. The chart was recorded at a rate of 20° C./min.  
         [0021]      FIG. 2  shows the X-ray diffraction pattern for crystalline raloxifene DL-lactate hemihydrate.  
         [0022]      FIG. 3  shows a DSC for raloxifene L-lactate hemihydrate. The chart was recorded at a rate of 20° C./min.  
         [0023]      FIG. 4  shows the X-ray diffraction pattern for crystalline ralbxifene L-lactate hemihydrate.  
         [0024]      FIG. 5  shows a DSC for raloxifene L-lactate ¼-hydrate. The chart was recorded at a rate of 20° C./min.  
         [0025]      FIG. 6  shows the X-ray diffraction pattern for crystalline raloxifene L-lactate ¼-hydrate.  
         [0026]      FIG. 7  shows the Intrinsic Dissolution Rate for raloxifene succinate compared with raloxifene hydrochloride.  
         [0027]      FIG. 8  shows the Intrinsic Dissolution Rate for raloxifene DL-lactate hemihydrate compared with raloxifene hydrochloride.  
         [0028]      FIG. 9  shows the Intrinsic Dissolution Rate for raloxifene L-lactate ¼-hydrate compared with raloxifene hydrochloride.  
         [0029]      FIG. 10  shows the Intrinsic Dissolution Rate for raloxifene L-lactate hemihydrate compared with raloxifene hydrochloride.  
         [0030]      FIG. 11  shows the Intrinsic Dissolution Rate for raloxifene malonate compared with raloxifene hydrochloride.  
         [0031]      FIG. 12  shows the Intrinsic Dissolution Rate for raloxifene sulphate compared with raloxifene hydrochloride. 
     
    
     DETAILED DESCRIPTION OF THE INVENTION  
       [0032]     The inventors have realized that even though raloxifene hydrochloride is fairly soluble in aqueous media the solubility appear to decreases significant in aqueous media comprising hydrochloric acid.  
         [0033]     By the term “dilute hydrochloric acid” or “media comprising hydrochloric acid” as used herein is meant an acidic aqueous solution containing chloride ions. Gastric juice is a preferred example of dilute hydrochloric acid.  
         [0034]     The skilled person will appreciate that gastric juice contains hydrochloric acid. Further the skilled person will appreciate that the composition of gastric juice apart from individual variations depends on various factors such as time of day, time since last meal and size and composition of said last meal. However for the purpose of the present description, the gastric juice can be regarded as a dilute solution of hydrochloric acid usually having a pH value in the range of approximately 1-3, possible also containing sodium chloride in an amount of 1-3% w/w. In the duodenum and the upper part of the small intestines the pH raises up to approximately 4-6 or even higher.  
         [0035]     The raloxifene acid addition salts and/or solvates thereof according to the invention have dissolution properties in dilute hydrochloric that secure a high bioavailability of these compounds. In particular the compounds according to the invention have higher intrinsic dissolution rates in dilute hydrochloric acid compared with free raloxifene or raloxifene hydrochloride.  
         [0036]     The terms “high availability”, “high bioavailability” or grammatical equivalent expressions are according to the invention intended to mean that the raloxifene salts and/or solvates thereof are available for assimilation from the gastro intestinal tract to the circulation of the body in high amount soon after ingestion. In particular the raloxifene salts and/or solvates thereof have higher bioavailability compared with the presently frequently used raloxifene compounds, i.e. raloxifene as free base or raloxifene hydrochloride.  
         [0037]     In accordance with the present invention the term “upper gastrointestinal tract” is intended to mean the oesophagus, the stomach, the duodenum and the upper part of the small intestines. It is believed that the assimilation of raloxifene mainly takes place in the upper gastrointestinal tract.  
         [0038]     The inventors have surprisingly discovered that acid addition salts and/or solvates thereof according to the invention appear to have a higher bioavailability from acidic solutions comprising sodium chloride compared to raloxifene as free base or raloxifene hydrochloride in crystalline or amorphous form. Consequently, pharmaceutical preparations for oral administration comprising acid addition salts and /or solvates thereof according to the invention will provide the active compound raloxifene faster and/or in an higher amount compared with pharmaceutical preparations comprising raloxifene hydrochloride or raloxifene as free base.  
         [0039]     Thus in one aspect the invention provides pharmaceutical preparations for oral administration comprising a raloxifene acid addition salt and/or solvate thereof according to the invention as the active ingredient. These preparations provide the active compound raloxifene in a form having high bioavailability when said preparations are ingested and dispersed in gastric juice.  
         [0040]     The high availability of the active compound secures that a therapeutic regimen using the pharmaceutical preparations according to the invention may be performed with higher accuracy because the attending physician will know that the complete dose or at least a major part thereof will be available for assimilation from the gastro intestinal tract soon after the ingestion the pharmaceutical preparations according to the invention.  
         [0041]     Therefore pharmaceutical compositions comprising such compounds may provide for a higher efficiency of the of said compounds by the individuals to whom said compositions are administered, compared with corresponding pharmaceutical compositions based on raloxifene or raloxifene hydrochloride.  
         [0042]     Thus the pharmaceutical preparations according to the invention provide a fast and high availability of the active compound in the stomach soon after intake of the preparation.  
         [0043]     Alternatively or additionally, the high availability of the active compounds according to the invention may render the need for micronization superfluous, which micronization in the prior art have been used to increase the bioavailability of raloxifene compounds, cf. EP 910 369.  
         [0044]     Therefore in one aspect the present invention relates to pharmaceutical compositions for oral administration comprising raloxifene acid addition salts and/or solvates thereof, having fast and high bioavailability of the active compound raloxifene.  
         [0045]     According to the invention the acid addition salts and/or solvates of raloxifene is selected among the succinate, lactate, malonate or the sulphate.  
         [0046]     The lactate may be in the D or L form or a mixture thereof such as racemic mixtures. Further the lactate may be isolated as a solvate.  
         [0047]     Because succinic acid, malonic acid and sulphuric acid have two acid groups per molecule, compounds of these acids and raloxifene may be isolated as either mono or di acid addition salts and/or solvates thereof having either one or two raloxifene molecules per acid molecule respectively.  
         [0048]     In a preferred embodiment the acid addition salt and/or solvates thereof according to the invention is raloxifene DL-lactate, and in a particular preferred embodiment the acid addition salt is raloxifene L-lactate.  
         [0049]     The skilled person will appreciate that the acid addition salts according to the invention may be isolated as solvates, which in the present description is to be understood as compounds where solvate molecules are included in the solid compounds, usually in defined stoichiometric amounts.  
         [0050]     For some compounds more that one solvate may be isolated, which solvates differ only with respect of the solvent incorporated in the solid and the number of solvate molecules per molecule of the acid addition salt.  
         [0051]     Preferred solvates according to the invention are solvates with pharmaceutically acceptable solvents such as water or alcohols having less than 5 carbon atoms, even more preferred selected among water, methanol, ethanol, propanol and 2-propanol.  
         [0052]     Examples of solvates according to the invention include raloxifene L-lactate hemihydrate, raloxifene D-lactate hemihydrate, raloxifene DL-lactate hemihydrate, raloxifene L-lactate ¼-hydrate, raloxifene D-lactate ¼-hydrate, raloxifene DL-lactate ¼-hydrate and raloxifene sulphate (2-propanol solvate).  
         [0053]     Preferred compounds according to the invention include raloxifene D-lactate hemihydrate, raloxifene DL-lactate hemihydrate, raloxifene L-lactate hemihydrate and raloxifene L-lactate ¼-hydrate, where raloxifene L-lactate hemihydrate and raloxifene L-lactate ¼-hydrate is particular preferred.  
         [0054]     It is well known that organic compounds may be isolated in crystalline form or in amorphous form. Generally it is preferred to provide compounds in crystalline form because crystallisation usually is accompanied by a purification of the compound, and further, because crystals are more well defined solids than amorphous materials the properties of compounds in-crystalline form varies less than materials in amorphous form.  
         [0055]     Therefore the raloxifene acid addition salts and/or solvates according to the invention in crystalline form provides another aspect of the invention.  
         [0056]     The raloxifene acid addition salts in crystalline form according to the invention are raloxifene lactate, raloxifene malonate and raloxifene succinate, which all exist as distinct crystalline compounds, and raloxifene sulphate, which may be isolated in crystalline form as a 2-propanol solvate having one molecule of 2-propanol incorporated per two raloxifene molecules.  
         [0057]     For some of the raloxifene acid addition salts and/or solvates thereof according to the invention more that one crystal form may be possible, where the different crystal forms may be prepared dependent on the solvent, temperature etc, as it will be known within the area.  
         [0058]     Pharmaceutical preparations for oral administration comprising raloxifene salts and/or solvates thereof according to the invention may be prepared using pharmaceutical techniques well known within the area e.g. from text books such as Remington&#39;s manual.  
         [0059]     For example may the raloxifene compounds according to the invention be formed for oral administration into tablets, capsules etc. In forming the pharmaceutical preparations the compounds according to the invention may be mixed with usual fillers and excipiens, such as disintegration agents, lubricants, swelling agents. The preparations may also be coated according to well-known techniques.  
         [0060]     Raloxifene acid addition salts and/or solvates may be prepared using methods known for the skilled person.  
         [0061]     For example may any acid addition salt be converted into the free base and subsequently the free base may be converted into another acid addition salt by known procedures.  
         [0062]     Usually raloxifene is prepared directly as raloxifene hydrochloride.  
         [0063]     The present inventors have observed that in contrast to raloxifene and previously tested acid addition salts thereof e.g. raloxifene hydrochloride, raloxifene lactate can easily be crystallized in high yield and high purity from an alcoholic solution.  
         [0064]     It has been realized that this property may be used for a quick and high efficient purification of raloxifene lactate from an intermediate in the synthesis of raloxifene.  
         [0065]     Thus raloxifene lactate may be prepared directly without previous isolation of free raloxifene or raloxifene hydrochloride using the following procedure:  
         [0066]     To a solution of the compound having the general formula I  
                         
 
         [0067]     wherein R represents two independently selected hydroxyl protection groups,  
         [0068]     in a solvent a suitable reagent is added in order to remove the protection groups. Next the pH of the mixture is adjusted to neutral reaction using lactic acid, and thereafter raloxifene lactate may be precipitated and isolated.  
         [0069]     This procedure according to the invention is beneficial because raloxifene lactate is easily crystallized from such a mixture, particular if the solvent is an alcohol having 1-5 carbon atoms. The easy crystallisation of raloxifene lactate represents a high and easy purification of the raloxifene from the reaction mixture. The crystallized raloxifene lactate may be further purified by recrystallization from an alcohol.  
         [0070]     The compound having the formula I is known within the art from e.g EP 875 511 A1, where it is called formula VII, and from EP 62 503, where it is prepared by the reaction scheme (B).  
         [0071]     The group R may be any hydroxyl protection group known to the skilled person. For example, R may be selected from C 1 -C 4  alkyl, C 5 -C 7  cycloalkyl, benzyl —COR 2  or SO 2 R 2 , wherein R 2  is C 1 -C 4  primary or secondary alkyl, C 1 -C 3  fluoroalkyl, C 1 -C 3  chloroalkyl, C 1 -C 4  alkylphenyl, C 1 -C 4  alkoxyphenyl, mono- or dinitrophenyl or mono- or di(chloro or fluoro)phenyl.  
         [0072]     The two R groups may be the same or different. It is preferred that the two R groups are selected so that the similar conditions are needed to remove the two groups.  
         [0073]     The term “neutral reaction” is intended to mean that the mixture has a pH value in the range of 6-8, preferably 7.0-7.5.  
         [0074]     The chemical used to remove the protection groups may be any chemical known to be able to remove the particular used protection groups. It is within the skills of the practitioner to select a suitable chemical to remove the protection group for each selected protection group.  
         [0075]     The solvent used for the reaction may in principle be any solvent that is capable of dissolving the reagents and does not participate in reactions with any of the ingredients of the reaction mixture under the conditions applied. Preferred solvents are alcohols having 1 to 5 carbon atoms. Particular preferred solvents are monovalent alcohols having 1 to 5 carbon atoms, where methanol, ethanol, propanol and 2-propanol are the most preferred solvents.  
         [0076]     The obtained raloxifene lactate may be recrystallized in order to obtain the compound in even higher purity.  
         [0077]     As solvent for the crystallization may in principle be used any alcohol having suitable melting and boiling temperatures. Alcohols having 1 to 5 carbon atoms and one hydroxyl group are preferred.  
         [0078]     As examples of preferred alcohols can be mentioned methanol, ethanol, propanol, 2-propanol, butanol, 2-butanol, neobutyl alcohol, pentanol, 2-pentanol and 3-pentanol.  
         [0079]     It is within the abilities of the skilled practitioner to select a suitable solvent for crystallization of particular selected compound of the invention.  
         [0080]     Ethanol is a particular preferred alcohol.  
         [0081]     The concentration of alcohol in the crystallization mixture should be higher that 90%, preferably higher that 95%. A particular preferred solvent for the crystallisation reaction is 96% ethanol.  
         [0082]     The crystallisation may be performed using procedures known within the area. Further as it will be known for the skilled person it may be advantageous to add seeding crystals to the crystallization mixture to promote crystallisation.  
         [0083]     Thus in another aspect the invention relates to a method for purification of raloxifene lactate from an alcoholic solution of raloxifene comprising addition of lactate, adjusting pH and temperature of the obtained mixture and isolation of the formed crystalline raloxifene lactate.  
         [0084]     In a preferred embodiment the alcoholic solution of raloxifene is the reaction mixture of the synthesis of raloxifene if necessary after a change of solvent.  
         [0085]     The invention is further illustrated by way of examples, which are solely provided for illustration and should not be considered at limiting in any way.  
       EXAMPLES  
     Example 1  
     [6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl-, succinate; Raloxifene succinate  
       [0086]     37.9 g (˜0.6 mol) pulverized potassium hydroxide (&gt;85%) is dissolved in 1250 ml 2-propanol, with stirring and addition of nitrogen, over approximately 30 minutes. 100 g (0.196 mol) raloxifene hydrochloride is added in small portions in such a way that temperature is kept below 36° C. After addition of raloxifene hydrochloride, the deep red suspension is stirred for 30-45 minutes until a deep red solution appears. Reminiscence of insoluble product may be filtered off. 1 L of a solution of 70.85 g (0.6 mol) succinic acid in 2-propanol/water (80:20) is added with violent stirring during 1-1.5 hours. The mixture is now stirred further at room temperature for 18 hours, and the precipitate is filtered off as white/yellowish crystals. The product is now washed 2 times with 40 ml 2-propanol and then dried in vacuo at 55-65° C. for 16 hours to give 178.5 g crude product.  
         [0087]     The crude product is stirred with 890 ml of water for 3 hours and then filtered off and washed 3 times with 100 ml of water. The product is dried in vacuo at 55-65° C. for 16 hours to give 89.7 g (77.3% yield) of product.  
         [0088]     Mp: dec. &gt;195° C., mp. ˜225° C.  
         [0089]     Elemental analysis C 33 H 33 NO 8 S:  
         [0090]     Calculated: C, 64.96%; H, 5.62%; N, 2.37%; S. 5.42%  
         [0091]     Found: C, 65.64%; H, 5.49%; N, 2.60%; S, 5.99%  
         [0092]     IR:  
         [0093]     3406 cm −1 , 3145 cm −1 , 2945 cm −1 , 2691 cm − , 1642 cm − , 1597 cm −1 , 1541 cm −1 , 1501 cm −1 , 1457 cm −1 , 1430 cm −1 , 1421 cm −1 , 1356 cm −1 , 1259 cm −1 , 1234 cm −1 , 1171 cm −1 , 1125 cm − , 1108 cm −1 , 1079 cm −1 , 1047 cm −1 , 1038 cm −1 , 907 cm −1 , 839 cm −1 , 807 cm −1 , 623 cm −1    
         [0094]     XRD:  
                                                                     D   2Theta   I(rel)   I(abs))   FWHM                                13.195230   6.6933   20.78   8475   0.1400       9.695642   9.1137   13.43   5476   0.0300       9.304945   9.4972   18.19   7419   0.1300       8.394523   10.5300   13.26   5407   0.1000       7.944460   11.1283   14.15   5768   0.1000       7.708667   11.4699   17.61   7180   0.1200       7.526675   11.7482   12.32   5023   0.0898       7.323294   12.0756   15.22   6205   0.1000       7.160495   12.3512   13.04   5316   0.0800       6.926815   12.7696   23.68   9655   0.1300       6.606409   13.3917   29.08   11856   0.1400       6.463392   13.3894   14.45   5891   0.0898       6.285432   14.0789   21.24   8662   0.1200       6.127742   14.4432   63.63   25947   0.1200       5.961999   14.8469   15.55   6342   0.0900       5.875574   15.0665   15.77   6430   0.0898       5.788967   15.2933   16.15   6585   0.1400       5.624221   15.7441   34.74   14167   0.1200       5.453763   16.2394   22.89   9334   0.1300       5.276560   16.7887   12.71   5182   0.1200       5.095057   17.3913   14.19   5786   0.1100       5.020392   17.6520   11.12   4535   0.0898       4.835944   18.3309   18.30   7461   0.1200       4.765096   18.6059   18.62   7591   0.1100       4.630456   19.1519   65.88   26864   0.1600       4.525518   19.6003   15.16   6180   0.0800       4.484997   19.7792   24.48   9982   0.1000       4.376528   20.2745   18.78   7659   0.1000       4.352225   20.3889   19.11   7790   0.1000       4.227757   20.9959   29.39   11984   0.1000       4.191265   21.1808   56.82   23171   0.0800       4.158052   21.3520   40.16   16377   0.0898       4.101947   21.6475   17.14   6988   0.0800       4.062068   21.8626   19.79   8072   0.1000       4.010082   22.1496   11.70   4771   0.0600       3.921660   22.6556   100.00   40776   0.1300       3.860487   23.0194   29.04   11842   0.1100       3.813566   23.3066   19.25   7850   0.1100       3.732687   23.8189   19.33   7884   0.1300       3.694791   24.0669   22.47   9161   0.1100       3.644300   24.4054   18.84   7680   0.1400       3.544078   25.1067   13.63   5556   0.0700       3.496160   25.4565   16.28   6637   0.0898       3.446458   25.8299   20.36   8300   0.2100       3.398344   26.2021   12.35   5036   0.1200       3.373032   26.4022   8.82   3597   0.0898       3.305938   26.9481   14.08   5741   0.1100       3.281940   27.1489   10.08   4112   0.0898       3.260437   27.3314   9.66   3937   0.0898       3.227083   27.6194   19.22   7838   0.1200       3.179256   28.0434   16.28   6640   0.2600       3.146269   28.3435   8.89   3627   0.0898       3.121159   28.5764   9.58   3907   0.0900       3.097691   28.7975   10.64   4337   0.0400       3.074307   29.0213   19.64   8008   0.1200       3.032262   29.4328   10.17   4148   0.1300       3.010128   29.6541   9.43   3847   0.0898                  
 
       Example 2  
     16-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl-, malonate; Raloxifene malonate  
       [0095]     37.9 g (˜0.6 mol) pulverized potassium hydroxide (&gt;85%) is dissolved in 1250 ml 2-propanol, with stirring and addition of nitrogen, over approximately 30 minutes. 100 g (0.196 mol) raloxifene hydrochloride is added in small portions in such a way that temperature is kept below 30° C. After addition of raloxifene hydrochloride, the deep red suspension is stirred for 30-45 minutes until a deep red solution appears. Reminiscence of insoluble product may be filtered off. 260 ml of a solution of 62.76 g (0.6 mol) malonic acid in 2-propanol/water is added with violent stirring during 1-1.5 hours. The mixture is now stirred further at room temperature for 18 hours, and the precipitate is filtered off as white/yellowish crystals. The product is now washed 2 times with 40 ml 2-propanol and then dried in vacuo at 55-65° C. for 16 hours to give 182.4 g crude product.  
         [0096]     The crude product is stirred with 912 ml of water for 3 hours and then filtered off and dried in vacuo at 55-65° C. for 16 hours to give 98.7 g (87.2% yield) of crude product. The crude product is boiled for 5 minutes in 500 ml 2-propanol and then cooled at 10° C. for 30 minutes. The product is filtered off and washed with 100 ml 2-propanol and then dried in vacuo to give 90.8 g (97%) of the product.  
         [0097]     Mp:. 226-227° C.  
         [0098]     Elemental analysis C 32 H 31 NO 8 S:  
         [0099]     Calculated: C, 64.46%; H, 5.41%; N, 2.42%; S, 5.55%  
         [0100]     Found: C, 64.86%; H, 5.55%; N, 2.57%; S, 5.87%  
         [0101]     IR:  
         [0102]     3388 cm −1 , 3199 cm −1 , 2950 cm −1 , 2683 cm −1 , 2543 cm −1 , 1643 cm −1 , 1597 cm −1 , 1539 cm −1 , 1502 cm −1 , 1467 cm −1 , 1421 cm −1 , 1355 cm −1 , 1306 cm −1 , 1255 cm −1 , 1169 cm −1 , 1038 cm −1 , 952 cm −1 , 907 cm −1 , 839 cm −1 , 808 cm −1 , 645 cm −1 , cm −1 , 623 cm −1    
         [0103]     XRD:  
                                                                     D   2Theta   I(rel)   I(abs)   FWHM                                14.385166   6.1391   36.51   6471   0.0100       13.125024   6.7292   38.91   6896   0.1300       10.305386   8.5734   37.32   6614   0.1700       9.279238   9.5236   39.85   7062   0.1300       8.860721   9.9745   34.60   6133   0.0900       8.510328   10.3863   33.27   5895   0.0900       8.314361   10.6318   33.02   5852   0.0800       7.947949   11.1234   41.61   7375   0.1600       7.265135   12.1727   35.79   6343   0.1300       6.882996   12.8512   29.65   5254   0.0300       6.537915   13.5326   60.19   10667   0.1800       6.258251   14.1404   61.12   10833   0.2100       6.003203   14.7444   31.92   5657   0.1200       5.877911   15.0605   29.17   5170   0.0600       5.794580   15.2784   29.33   5198   0.0200       5.663226   15.6349   49.63   8796   0.1300       5.550457   15.9547   36.61   6487   0.0800       5.354103   16.5438   55.84   9897   0.2200       5.134028   17.2583   30.18   5349   0.1378       5.023848   17.6397   55.21   9784   0.2100       4.836637   18.3283   36.13   6404   0.1400       4.700761   18.8628   71.64   12696   0.1600       4.644808   19.0922   86.46   15323   0.1500       4.538522   19.5436   61.36   10874   0.1300       4.472256   19.8361   50.40   8931   0.1000       4.347111   20.4132   37.86   6709   0.1000       4.247918   20.8951   88.12   15616   0.2300       4.161428   21.3344   73.93   13101   0.1600       4.085803   21.7341   37.19   6591   0.1100       4.019584   22.0966   35.60   6309   0.1500       3.921695   22.6554   100.00   17722   0.1700       3.765729   23.6059   50.70   8986   0.2000       3.703455   24.0097   34.79   6166   0.1200       3.638542   24.4446   47.30   8382   0.1900       3.499221   25.4339   44.29   7849   0.2000       3.426872   25.9801   43.63   7732   0.2200       3.292398   27.0610   23.39   4145   0.1000       3.253755   27.3886   25.03   4435   0.1400       3.192249   27.9269   22.18   3931   0.1400       3.094846   28.8246   28.68   5083   0.3000       3.034329   29.4123   27.30   4338   0.1900                  
 
       Example 3  
     [6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl- sulphate (2-propanol solvat); Raloxifene sulphate (2-propanol solvate)  
       [0104]     3.79 g (˜0.06 mol) pulverized potassium hydroxide (&gt;85%) is dissolved in 125 ml 2-propanol, with stirring and addition of nitrogen, over approximately 30 minutes. 10 g (0.0196 mol) raloxifene hydrochloride is added in small portions in such a way that temperature is kept below 30° C. After addition of raloxifene hydrochloride, the deep red suspension is stirred for 30-45 minutes until a deep red solution appears. Reminiscence of insoluble product may be filtered off. A solution of 6.5 g 96% (0.6 mol) sulphuric acid in 15 ml 2-propanol and 12 ml of water is added with violent stirring during 1-1.5 hours (weakly exothermic). The mixture is now stirred further at room temperature for 18 hours, and the precipitate is filtered off as white crystals. The product is now washed 2 times with 4 ml 2-propanol and then dried in vacuo at 55-65° C. for 16 hours to give 15 g crude product.  
         [0105]     The crude product is stirred with 76 ml of water for 3 hours and then filtered off and washed 3 times with 100 ml of water. The product is dried in vacuo at 55-65° C. for 16 hours to give 8.6 g (% yield) of product. The product is boiled with 38 ml of 2-propanol for 5 minutes and then cooled on to 0-5° C. for 30 minutes and filtered. The product is washed with 2 times with 5 ml 2-propanol, and dried in vacuum at 70-75° C.  
         [0106]     Mp:. 262-263° C.  
         [0107]     Elemental analysis C 59 H 64 N 2 O 13 S 3 :  
         [0108]     Calculated: C, 64.46%; H, 5.41%; N, 2.42%; S, 5.55%  
         [0109]     Found: C, 64.86%; H, 5.55%; N, 2.57%; S, 5.87%  
         [0110]     IR:  
         [0111]     3199 cm −1 , 2963 cm −1 , 2723 cm −1 , 2693 cm −1 , 2659 cm −1 , 2559 cm −1 , 1653 cm −1 , 1597 cm −1 , 1547 cm −1 , 1501 cm −1 , 1467 cm −1 , 1437 cm −1 , 1419 cm −1 , 1344 cm −1 , 1308 cm −1 , 1268 cm −1 , 1251 cm −1 , 1233 cm −1 , 1167cm −1 , 1037 cm −1 , 1020 cm −1 , 952 cm −1 , 907 cm −1 , 839 cm −1 , 823 cm −1 , 809 cm −1 , 627 cm −1 , 524 cm −1 .  
         [0112]     XRD:  
                                                                     D   2Theta   I(rel)   I(abs)   FWHM                                14.374007   6.1439   26.57   5009   0.0900       10.303750   8.5748   29.62   5583   0.1300       9.201529   9.6042   26.22   4942   0.1100       8.871726   9.9621   29.84   5624   0.1300       8.569965   10.3138   22.25   4195   0.0400       8.320378   10.6241   25.97   4896   0.1200       7.945119   11.1274   38.65   7286   0.1300       7.514174   11.7678   20.56   3876   0.1041       7.205108   12.2745   25.04   4721   0.1400       6.537437   13.5336   66.78   12590   0.1400       6.228787   14.2076   21.88   4126   0.1100       5.628329   15.7325   20.71   3904   0.0900       5.540447   15.9837   27.40   5166   0.1100       5.322476   16.5489   64.98   12249   0.1500       5.138694   17.2425   21.65   4082   0.1100       5.020317   17.6522   64.05   12074   0.1400       4.706881   18.8381   100.00   18851   0.1300       4.618097   19.2036   60.47   11400   0.0800       4.538129   19.5453   59.35   11189   0.1100       4.471816   19.8381   67.03   12636   0.1200       4.261964   20.8255   54.78   10327   0.1100       4.204757   21.1121   51.35   9680   0.1600       4.156029   21.3625   46.65   8794   0.1041       4.093305   21.6938   25.93   4888   0.0900       4.035960   22.0058   24.21   4563   0.1800       3.937182   22.5651   25.37   4784   0.1200       3.835400   23.1721   22.17   4179   0.0900       3.796528   23.4127   40.94   7718   0.0900       3.767170   23.5978   61.03   11505   0.1100       3.691303   24.0899   20.10   3790   0.1500       3.639317   24.4393   47.20   8897   0.1200       3.590489   24.7769   28.23   5321   0.1600       3.511060   25.3467   29.66   5592   0.1100       3.478586   25.5873   23.70   4468   0.1041       3.416539   26.0601   37.38   7047   0.1900       3.355389   26.5436   20.28   3823   0.1300       3.314637   26.8760   17.08   3220   0.1200       3.271015   27.2413   15.24   2874   0.0600       3.252583   27.3987   14.71   2773   0.1041       3.100446   28.7714   23.04   4344   0.1200       3.079703   28.9694   19.73   3720   0.1041       3.033828   29.4172   29.23   5511   0.1300       3.009744   29.6580   15.28   2880   0.1041       2.937725   30.4024   13.30   2507   0.1700                  
 
       Example 4  
     [6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl-, DL-lactate hemihydrate; Raloxifene DL-lactate hemihydrate  
       [0113]     37.9 g (˜0.6 mol) pulverized potassium hydroxide (&gt;85%) is dissolved in 1250 ml 2-propanol, with stirring and addition of nitrogen, over approximately 30 minutes. 100 g (0.196 mol) raloxifene hydrochloride is added in small portions in 30 such a way that temperature is kept below 30° C. After addition of raloxifene hydrochloride, the deep red suspension is stirred for 30-45 minutes until a deep red solution appears. Reminiscence of insoluble product may be filtered off. A solution of 67.6 g 85% DL-lactic acid (0.6 mol) in 200 ml of 2-propanol is added with violent stirring during 1-1.5 hours. The mixture is now stirred further at room temperature for 18 hours, and the precipitate is filtered off as white/yellowish crystals. The product is now washed 2 times with 40 ml 2-propanol and then dried in vacuo at 55-65° C. for 16 hours to give 109 g crude product.  
         [0114]     The crude product is stirred with 545 ml of water for 3 hours and then filtered off and washed 2 times with 75 ml of water. The product is dried in vacuo at 75-80° C. for 16 hours to give 92.7 g (83.9% yield) of product.  
         [0115]     Mp: 196-198° C.  
         [0116]     Elemental analysis C 34 H 33 NO 7 S (½H 2 O):  
         [0117]     Calculated: C, 65.00%; H, 5.98%; N, 2.45%; S, 5.60%  
         [0118]     Found: C, 65.07%; H, 5.93%; N, 2.37%; S, 5.34%  
         [0119]     IR:  
         [0120]     3385 cm −1 , 3223 cm −1 , 2940 cm −1 , 2675 cm −1 , 1641 cm −1 , 1598 cm −1 , 1542 cm −1 , 1502 cm −1 , 1467 cm −1 , 1421 cm −1 , 1349 cm −1 , 1307 cm −1 , 1253 cm −1 , 1171 cm −1 , 1123 cm −1 , 1038 cm −1 , 953 cm −1 , 908 cm −1 , 837 cm −1 , 808 cm −1 , 649 cm −1 , 623 cm −1 , cm −1 , 532 cm −1 , 514 cm −1 .  
         [0121]     The product was further analysed using differential scanning calorimetry using a METTLER TOLEDO STAR® system, according to the instructions of the manufacturer. The differential scanning calorimetric chart (DSC) is shown in  FIG. 1 .  
         [0122]     Further the product was analysed by X-ray diffraction analysis using the STOE Powder diffraction system. The result is shown in  FIG. 2 , and is also listed numerically below.  
         [0123]     XRD:  
                                                                     D   2Theta   I(rel)   I(abs)   FWHM                                13.595814   6.4959   28.40   12683   0.1400       10.855533   8.1382   16.15   7211   0.1200       9.849394   8.9711   32.17   14369   0.1000       9.534325   9.2682   66.95   29898   0.1300       8.150249   10.8465   45.20   20188   0.1300       7.240730   12.2138   63.53   28374   0.1400       6.769843   13.0670   18.42   8227   0.1500       6.272666   14.1077   75.67   33794   0.1900       5.818832   15.2143   13.28   5933   0.2000       5.657337   15.6513   18.07   8070   0.1300       5.505030   16.0872   10.51   4692   0.1000       5.261933   16.8357   17.48   7806   0.1400       5.089504   17.4104   16.14   7210   0.1000       5.001569   17.7189   41.94   18732   0.0900       4.958950   17.8725   29.16   13023   0.1148       4.797388   18.4795   19.39   8660   0.1100       4.669322   18.9910   49.20   21972   0.1400       4.574684   19.3876   63.21   28227   0.1000       4.533019   19.5676   44.94   20071   0.1148       4.440548   19.9792   32.70   14604   0.1200       4.301886   20.6301   100.00   44659   0.1500       4.155406   21.3657   78.00   34833   0.1600       4.059049   21.8797   27.53   12296   0.1800       3.960846   22.4285   25.59   11427   0.1000       3.907408   22.7393   83.48   37282   0.1200       3.865461   22.9894   16.46   7350   0.1148       3.828892   23.2120   17.46   7798   0.0900       3.773130   23.5599   50.71   22649   0.1200       3.716486   23.9243   23.06   10300   0.1300       3.652238   24.3515   15.79   7053   0.1800       3.584725   24.8174   12.91   5764   0.1500       3.486791   25.5261   30.45   13600   0.1200       3.439149   25.8858   22.21   9919   0.1300       3.396267   26.2184   17.86   7978   0.1100       3.370045   26.4261   12.48   5572   0.1148       3.329320   26.7553   9.21   4113   0.1100       3.292728   27.0582   11.81   5274   0.1000       3.278070   27.1815   11.25   5026   0.1148       3.218620   27.6935   21.24   9485   0.1900       3.167986   28.1452   13.80   6162   0.0900       3.143230   28.3715   30.33   13546   0.1000       3.095423   28.9191   14.02   6260   0.1200       3.024921   29.5058   11.56   5161   0.1400       3.007253   29.6831   13.40   5984   0.1300                  
 
       Example 5  
     [6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl-, L-lactate hemihydrate; Raloxifene L-lactate hemihydrate  
       [0124]     37.9 g (˜0.6 mol) pulverized potassium hydroxide (&gt;85%) is dissolved in 1250 ml 2-propanol, with stirring and addition of nitrogen, over approximately 30 minutes. 100 g (0.196 mol) raloxifene hydrochloride is added in small portions in such a way that temperature is kept below 30° C. After addition of raloxifene hydrochloride, the deep red suspension is stirred for 30-45 minutes until a deep red solution appears. Reminiscence of insoluble product may be filtered off.  
         [0125]     A solution of 67.6 g 85% L-lactic acid (0.6 mol) is added with violent stirring during 1-1.5 hours. The mixture is now stirred further at room temperature for 18 hours, and the precipitate is filtered off as white/yellowish crystals. The product is now washed 2 times with 40 ml 2-propanol and then dried in vacuo at 55-65° C. for 16 hours to give 109 g crude product.  
         [0126]     The crude product is stirred with 545 ml of water for 3 hours and then filtered off and washed 2 times with 75 ml of water. The product is dried in vacuo at 75-80° C. for 16 hours to give 92.7 g (83.9% yield) of product.  
         [0127]     Mp:. 134-136° C.  
         [0128]     Elemental analysis C 31 H 33 NO 7 S (½H 2 O):  
         [0129]     Calculated: C, 65.00%; H, 5.98%; N, 2.45%; S, 5.60%  
         [0130]     Found: C, 65.08%; H, 6.14%; N, 2.58%; S, 5.78%  
         [0131]     IR:  
         [0132]     3167 cm −1 , 2934 cm −1 , 1641 cm −1 , 1627 cm −1 , 1593 cm −1 , 1543 cm −1 , 1500 cm −1 , 1469 cm −1 , 1433 cm −1 , 1350 cm −1 , 1314 cm −1 , 1259 cm −1 , 1170 cm −1 , 1128 cm −1 , 1103 cm −1 , 1033 cm −1 , 908 cm −1 , 836 cm −1 , 809 cm −1 .  
         [0133]     The product was analysed using differential scanning calorimetry using a METTLER TOLEDO STAR® system, according to the instructions of the manufacturer. The differential scanning calorimetric chart (DSC) is shown in  FIG. 3 .  
         [0134]     Further the product was analysed by X-ray diffraction analysis using the STOE Powder diffraction system. The result is shown in  FIG. 4 , and is also listed numerically below.  
         [0135]     XRD:  
                                                                     D   2Theta   I(rel)   I(abs)   FWHM                                14.639874   6.0322   17.56   6122   0.1200       13.207421   6.6871   15.07   5254   0.1200       10.875932   8.1229   80.41   28029   0.1200       9.268456   9.5347   22.67   7903   0.1200       8.140638   10.8593   17.92   6247   0.1200       7.488503   11.8083   15.59   5433   0.1000       7.310331   12.0971   12.47   4347   0.0800       7.089508   12.4754   25.79   8991   0.1000       6.931874   12.7603   12.78   4454   0.0900       6.723932   13.1566   27.83   9701   0.1300       6.551458   13.5045   14.20   4949   0.0900       6.359432   13.9143   30.57   10656   0.1100       6.130010   14.4378   21.33   7435   0.1300       5.853018   15.1249   36.40   12687   0.1100       5.626204   15.7385   15.49   5401   0.1300       5.507643   16.0795   23.25   8106   0.1000       5.447238   16.2590   13.21   4606   0.0870       5.224449   16.9573   19.21   6697   0.1100       5.160516   17.1690   17.10   5961   0.0870       5.083475   17.4312   14.74   5137   0.1100       4.954247   17.8896   19.64   6848   0.1000       4.863750   18.2252   28.34   9879   0.0800       4.805168   18.4494   46.26   16125   0.0700       4.756883   18.6383   49.99   17425   0.0800       4.656926   19.0420   19.10   6659   0.1900       4.630194   19.1530   17.96   6260   0.0870       4.566015   19.4248   21.34   7438   0.1000       4.487514   19.7680   12.76   4447   0.1000       4.347753   20.4101   11.69   4074   0.1100       4.301465   20.6322   19.17   6682   0.0900       4.224555   21.0120   14.55   5072   0.0870       4.186561   21.2049   23.33   8134   0.1700       4.065767   21.8425   26.06   9084   0.1000       4.015560   22.1190   17.10   5929   0.1000       3.976949   22.3365   14.98   5223   0.0500       3.935785   22.5732   34.50   12028   0.1100       3.867038   22.9799   100.00   34859   0.1000       3.779481   23.5198   40.14   13991   0.0800       3.742319   23.7567   59.68   20805   0.1000       3.710418   23.9640   13.17   4591   0.0870       3.645564   24.3968   11.19   3902   0.0800       3.621808   24.5593   18.71   6524   0.1000       3.552536   25.0459   16.01   5581   0.1000       3.516088   25.3098   13.46   4691   0.0600       3.498357   25.4402   12.66   4413   0.0700       3.467075   25.6737   10.74   3745   0.0500       3.418947   26.0414   21.49   7491   0.1000       3.395298   26.2260   12.12   4225   0.0870       3.369948   26.4268   15.48   5369   0.0700       3.358554   26.5181   14.33   4995   0.0600       3.244985   27.4641   11.90   4149   0.0700       3.229427   27.5990   9.63   3356   0.0870       3.177657   28.0578   15.07   5253   0.1200       3.144884   28.3562   32.65   11381   0.1000       3.106130   28.7176   9.83   3425   0.0800       3.082970   28.9380   9.00   3138   0.0870       3.056106   29.1980   8.56   2984   0.0870       3.032184   29.4335   8.74   3048   0.1100       2.994539   29.8121   8.27   2884   0.0700       2.979114   29.9700   9.26   3229   0.0800       2.924922   30.5387   9.19   3203   0.1800       2.870290   31.1346   16.32   5689   0.1400       2.828902   31.6019   13.59   4737   0.1100       2.762611   32.3808   10.83   3775   0.1000                  
 
       Example 6  
     [6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl-,; Raloxifene L-lactate (¼ H 2 O)  
       [0136]     37.9 g (˜0.6 mol) pulverized potassium hydroxide (&gt;85%) is dissolved in 1250 ml 2-propanol, with stirring and addition of nitrogen, over approximately 30 minutes. 100 g (0.196 mol) raloxifene hydrochloride is added in small portions in such a way that temperature is kept below 30° C. After addition of raloxifene hydrochloride, the deep red suspension is stirred for 30-45 minutes until a deep red solution appears. Reminiscence of insoluble product may be filtered off  
         [0137]     A solution of 67.6 g 85% L-lactic acid (0.6 mol) is added with violent stirring during 1-1.5 hours. The mixture is now stirred further at room temperature for 18 hours. If no or very little precipitate appears in the solution the reaction mixture is filtered and 2-propanol is evaporated off. To the reminisce is now added 150 ml of water with stirring and the precipitated product is collected by filtration and dried in vacuo at 55-65° C. Next the crude product is recrystallized from 160 ml 96% ethanol (if necessary seeding crystals are added) to give 62.8 g (56.4%) of the product.  
         [0138]     Mp: 171-173° C.:  
         [0139]     Elemental analysis C 31 H 33 NO 7 S (¼H 2 O):  
         [0140]     Calculated: C, 65.52%; H, 5.94%; N, 2.47%; S, 5.64%  
         [0141]     Found: C, 65.50%; H, 5.85%; N, 2.50%; S, 5.74%  
         [0142]     IR:  
         [0143]     3159 cm −1 , 2935 cm −1 , 2806 cm −1 , 2672 cm −1 , 1643 cm −1 , 1598 cm −1 , 1574 cm −1 , 1547 cm −1 , 1501 cm −1 , 1466 cm −1 , 1422 cm −1 , 1347 cm −1 , 1308 cm −1 , 1269 cm −1 , 1229 cm −1 , 1171 cm −1 , 1119 cm −1 , 1067 cm −1 , 1037 cm −1 , 1006 cm −1 , 908 cm −1 , 835 cm −1 , 807 cm −1 , 665 cm −1 , 649 cm −1 , 634 cm −1 , 623 cm −1 , 513 cm −1 .  
         [0144]     The product was analysed using differential scanning calorimetry using a METTLER TOLEDO STAR® system, according to the instructions of the manufacturer. The differential scanning calorimetric chart (DSC) is shown in  FIG. 5 .  
         [0145]     Further the product was analysed by X-ray diffraction analysis using the STOE Powder diffraction system. The result is shown in  FIG. 6 , and is also listed numerically below.  
         [0146]     XRD:  
                                                                     D   2Theta   I(rel)   I(abs)   FWHM                                14.079244   6.2726   45.93   16568   0.1300       9.974912   8.8580   32.43   11699   0.1100       9.526523   9.2758   71.31   25721   0.1200       8.215598   10.7600   47.82   17248   0.1100       7.246270   12.2045   80.04   28871   0.1100       7.065557   12.5178   16.17   5832   0.0700       6.878001   12.8606   22.74   8201   0.1200       6.283709   14.0828   66.27   23901   0.0800       6.194698   14.2862   53.98   19470   0.0984       5.859529   15.1080   11.17   4028   0.0984       5.744935   15.4112   16.16   5828   0.1200       5.312222   16.6751   18.02   6499   0.1200       5.046910   17.5585   34.26   12356   0.0900       4.978933   17.8001   54.66   19715   0.1000       4.918535   18.0205   17.40   6277   0.0984       4.746264   18.6804   26.77   9655   0.1000       4.712771   18.8143   46.35   16716   0.0900       4.569429   19.4101   57.60   20777   0.1000       4.455985   19.9093   53.60   19332   0.1200       4.345589   20.4204   12.70   4579   0.0900       4.268096   20.7952   86.33   31139   0.0900       4.106332   21.6241   20.17   7274   0.1100       4.042283   21.9710   22.73   8197   0.1200       3.944656   22.5218   23.46   8462   0.1000       3.913129   22.7056   100.00   36069   0.1100       3.831706   23.1947   15.49   5586   0.0900       3.777075   23.5350   69.72   25148   0.1400       3.735872   23.7983   14.85   5358   0.0984       3.667856   24.2463   11.94   4305   0.0900       3.639035   24.4413   13.87   5001   0.0800       3.589918   24.7809   9.38   3383   0.0984       3.545715   25.0949   23.58   8505   0.0800       3.505655   25.3864   33.63   12131   0.1100       3.442223   25.8622   22.60   8152   0.1100       3.411017   26.1030   10.82   3901   0.0984       3.371851   26.4117   44.16   5108   0.1000       3.280618   27.1600   15.23   5494   0.1100       3.251104   27.4114   14.23   5134   0.0800       3.232072   27.5760   19.25   6943   0.1100       3.153056   28.2812   12.42   4479   0.1900       3.143130   28.3724   12.29   4432   0.0984       3.081939   28.9479   17.16   6189   0.2200       3.040378   29.3524   9.73   3510   0.1300       2.990508   29.8532   15.29   5514   0.1400       2.929711   30.4876   11.37   4102   0.1200       2.892397   30.8906   18.91   6822   0.1200       2.856192   31.2922   8.91   3214   0.1100       2.818108   31.7261   14.79   5336   0.2500       2.765584   32.3450   15.86   5720   0.1300                  
 
       Example 7  
     Preparation of [6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl-, L-lactate; Raloxifene L-lactate  
       [0147]     40 g (0.06 mol) 6-methylsulphonyloxy-2-(4-methylsulphonyloxyphenyl)benzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl-, hydrochlorid, having the structural formula below  
                         
 
 is suspended in 385 ml 2-propanol. 21.75 g (0.33 mol) powdered 85% potassium hydroxide is added with stirring, and the mixture is heated to reflux for 2 hour. The deep red solution is cooled to room temperature, and a solution of 20.3 g 85% L-lactic acid (0.18 mol) is added with violent stirring during 1-1.5 hours, and thereafter the 2-propanol is evaporated off to give the crude product. The product is recrystallized from approximately 50 ml 96% ethanol to give the title compound. 
 
       Example 8 (Comparative Example)  
     Dissolution of Raloxifene Hydrochloride in Dilute Hydrochloric Acid or Phosphoric Acid  
       [0148]     60 mg raloxifene HCl was transferred to a dissolution vessel containing one litre 0.1 M HCl. The mixture was vigorously mixed and left at room temperature over night. Subsequently the dissolution was evaluated visually. Very little of the initial added amount of raloxifene hydrochloride was dissolved shown by the presence of solid material at the bottom of the vessel and essentially no colouring of the fluid.  
         [0149]     A similar dissolution test was performed using 60 mg raloxifene hydrochloride in 0.1 M phosphoric acid. In this case all raloxifene hydrochloride seemed to be dissolved indicated by the absence of solids on the bottom of the vessel and a strong yellow colouring of the fluid in the vessel.  
       Example 9  
     Dissolution of Raloxifene Acid Addition Salts or Solvates in Dilute Hydrochloric Acid or Phosphoric Acid  
       [0150]     Using same procedures as in example 8, raloxifene succinate, raloxifene DL-lactate hemihydrate, raloxifene L-lactate hemihydrate, raloxifene malonate and raloxifene sulphate (2-propanol solvate) were tested for dissolution in dilute hydrochloric acid or phosphorous acid.  
         [0151]     All these tests showed complete dissolution shown be absence of solids in the vessel and strong colouring of the liquid.  
       Example 10  
     Intrinsic Dissolution Rate of Raloxifene Acid Addition Salts in Dilute Phosphoric Acid Compared with Dilute Hydrochloric Acid  
       [0152]     Experimental set-up:  
         [0153]     The intrinsic dissolution rate of raloxifene succinate, raloxifene DL-lactate hemihydrate, raloxifene L-lactate ¼-hydrate, raloxifene L-lactate hemihydrate, raloxifene malonate, raloxifene sulphate (2-propanol solvate) and raloxifene hydrochloride were tested in dilute solutions of hydrochloric acid and in dilute solutions of phosphorous acid containing NaCl in amounts so the chloride ion concentration in each solution was 0.1 M. The tests were performed at 37° C. and at pH of 1, 2, 3, 4, and 5, respectively. The raloxifene hydrochloride salt used in these experiments was purchased from Otto Bradt GmbH (batch MA/RF/12003) while the rest of the raloxifene acid additions salts were prepared according to Example 1-6.  
         [0154]     The experiments were carried out following the procedure of Rotation Disc Method (USP 1087) using Vankel VK 7000 Intrinsic dissolution apparatus (Vankel Technology group, W. Vankelion) equipped with Vankel 12-4120 intrinsic disc having a surface area of 0.5 cm 2 , Vankel 12-4130 surface plate, Vankel 12-4140 punch, and Vankel shaft and holder (surface area: 0.5 cm 2 ) and operating at a rotation rate of 100 rpm.  
         [0155]     The buffer solution is handled in a 750 ml measuring bottle, degassed and transferred into a dissolution vessel. Approximately 100 mg compound is weighed out and transferred into an intrinsic disc. Said disc is then assembled, and to said disc a disc is applied in the IR-press at a pressure of 5 kN for 1 minute. The disc is started and samples of 10 ml are collected by use of “pressure vials” after 1, 10, 20, 30, 45, and 60 minutes. The change of volume is corrected using the equation: 
 
 Q=Vs ×(sum Cn− 1)+ Cn×Vt  
 
 wherein Q designates the volume at the time t, C designates the concentration of the sample n, Vt designates the volume of the liquid collected at the time t, and Vs designates the volume of the sample collected. The sample is measured against a standard using HPLC. In these measurements a 5 microns 3.9×150 mm column filled with symmetrical material is employed and as eluant a 20 mM phosphate buffer KH 2 PO 4 , pH 6.8 mixed with acetonitrile and tetrahydrofuran in the ratio 55:35:10 is used. 
 
         [0156]     Preparation of Standard Solution:  
         [0157]     The standard is prepared by use of following procedure: 20 mg of salt is dissolved initially in 100 ml of MeOH and then 1 ml of this solution is transferred to a 50 ml flask with water and then 2 ml to a 20 ml flask of buffer in question.  
         [0158]     Preparation of Buffer Solutions:  
         [0159]     pH 1: a 0.1 M HCl is used.  
         [0160]     0.025 M Phosphate buffer solution pH 2.0: 3.40 g of potassium dihydrogen phosphate is dissolved in 900 ml of water. Then pH is adjusted to 2.0 with phosphoric acid and diluted to 1000.0 ml with water. Exactly 5.85 g of NaCl is added to 1 L of buffer.  
         [0161]     0.025 M Phosphate buffer solution pH 3.0: 3.40 g of potassium dihydrogen phosphate is dissolved in 900 ml of water. Then pH is adjusted to 3.0 with phosphoric acid and diluted to 1000.0 ml with water. Exactly 5.85 g of NaCl is added to 1 L of buffer.  
         [0162]     0.022 M Phosphate buffer solution pH 4.0: 3.0 g of potassium dihydrogen phosphate is dissolved in 800 ml of water. Then pH is adjusted with 1 M potassium hydroxide and phosphoric acid and diluted to 1000.0 ml with water. Exactly 5.85 g of NaCl is added to 1 L of buffer.  
         [0163]     0.02 M Phosphate buffer solution pH 5.0: 2.72 g of potassium dihydrogen phosphate is dissolved in 800 ml of water. Then pH is adjusted with 1 M potassium hydroxide and diluted to 1000.0 ml with water. Exactly 5.85 g of NaCl is added to 1 L of buffer.  
         [0164]     Results  
         [0165]     The results from above described experiment comparing the ID of the various raloxifene acid addition salts in dilute solutions of phosphorous acid and hydrochloric acid, respectively, is given in the table below. The numbers in the table represent the average of two measurements.  
                                                                   DL-lactate       L-lactate                           hemi-   L-Lactate   hemi-       Buffer solution   Succinate   hydrate   ¼-hydrate   hydrate   Malonate   Sulphate   Hydrochloride                   Hydrochloride,   0.0550   0.0056   0.0035   0.0475   0.0229   0.0036   0.0022       pH 1       Phosphate,   0.0228   0.0119   0.0028   0.0453   0.0173   0.0137   0.0026       pH 2       Phosphate,   0.0271   0.0062   0.0067   0.0403   0.0148   0.0052   0.0022       pH 3       Phosphate,   0.0127   0.0212   0.0324   0.0190   0.0136   0.0109   0.0022       pH 4       Phosphate,   0.0119   0.0215   0.0247   0.0091   0.0112   0.0081   0.0044       pH 5                 The intrinsic dissolution rate (IDR) in (μmol/min * cm 2 ) of various acid addition salts of raloxifene determined by the method described above.            The numbers represent the average of two measurements.             
 
         [0166]     Graphic displays of the results are shown in the  FIGS. 7-12 . The results show very clearly that the intrinsic dissolution rate is markedly higher for the raloxifene acid addition salts and/or solvates thereof according to the invention compared with raloxifene hydrochloride.