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:
The invention relates to acid addition salts and/or solvates of [6-hydroxy-2-(4-hydroxyphenyl)benzol[1)]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. 
     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. 
     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 FOR THE INVENTION 
     Raloxifene, [6-hydroxy-2-(4-hydroxyphenyl)benzol[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl-, is a well known compound having antiestrogen and antiandrogen activity. Raloxifene or raloxifene hydrochloride has proved useful for the preparation of pharmaceutical compositions for the treatment of cancer, osteoporosis and cartilage degradation. 
     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. 
     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. 
     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. 
     The obtained free base was subsequent transformed into acid addition salts using usual techniques. 
     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. 
     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. 
     In WO 96/09045 raloxifene hydrochloride in crystalline form or as a solvate is described. 
     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. 
     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. 
     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 
     The present invention relates to raloxifene acid addition salts and/or solvates having a high availability in dilute hydrochloric acid or gastric juice. 
     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. 
     In a further aspect the invention relates to new and particular useful crystal forms of said novel raloxifene acid addition salts or solvates thereof. 
     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. 
     A further aspect of the invention relates to a new and improved method for preparation of raloxifene lactate. 
    
    
     
       SHORT DESCRIPTION OF THE FIGURES 
         FIG. 1  shows a differential scanning calorimetric chart (DSC) for raloxifene DL-lactate. The chart was recorded at a rate of 20° C./min. 
         FIG. 2  shows the X-ray diffraction pattern for crystalline raloxifene DL-lactate. 
         FIG. 3  shows a DSC for raloxifene L-lactate hemihydrate. The chart was recorded at a rate of 20° C./min. 
         FIG. 4  shows the X-ray diffraction pattern for crystalline raloxifene L-lactate hemihydrate. 
         FIG. 5  shows a DSC for raloxifene L-lactate. The chart was recorded at a rate of 20° C./min. 
         FIG. 6  shows the X-ray diffraction pattern for crystalline raloxifene L-lactate. 
         FIG. 7  shows the Intrinsic Dissolution Rate for raloxifene succinate compared with raloxifene hydrochloride. 
         FIG. 8  shows the Intrinsic Dissolution Rate for raloxifene DL-lactate compared with raloxifene hydrochloride. 
         FIG. 9  shows the Intrinsic Dissolution Rate for raloxifene L-lactate compared with raloxifene hydrochloride. 
         FIG. 10  shows the Intrinsic Dissolution Rate for raloxifene L-lactate hemihydrate compared with raloxifene hydrochloride. 
         FIG. 11  shows the Intrinsic Dissolution Rate for raloxifene malonate compared with raloxifene hydrochloride. 
         FIG. 12  shows the Intrinsic Dissolution Rate for raloxifene sulphate compared with raloxifene hydrochloride. 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     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. 
     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. 
     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. 
     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. 
     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. 
     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. 
     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. 
     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. 
     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. 
     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. 
     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. 
     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. 
     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. 
     According to the invention the acid addition salts and/or solvates of raloxifene is selected among the succinate, lactate, malonate or the sulphate. 
     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. 
     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. 
     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. 
     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. 
     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. 
     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. 
     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). 
     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. 
     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. 
     Therefore the raloxifene acid addition salts and/or solvates according to the invention in crystalline form provides another aspect of the invention. 
     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. 
     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. 
     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. 
     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 excipients, such as disintegration agents, lubricants, swelling agents. The preparations may also be coated according to well-known techniques. 
     Raloxifene acid addition salts and/or solvates may be prepared using methods known for the skilled person. 
     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. 
     Usually raloxifene is prepared directly as raloxifene hydrochloride. 
     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. 
     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. 
     Thus raloxifene lactate may be prepared directly without previous isolation of free raloxifene or raloxifene hydrochloride using the following procedure: 
     To a solution of the compound having the general formula I 
     
       
                 
         
             
             
         
      
     
     wherein R represents two independently selected hydroxyl protection groups, 
     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. 
     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. 
     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). 
     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  alkoxy-phenyl, mono- or dinitrophenyl or mono- or di(chloro or fluoro)phenyl. 
     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. 
     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. 
     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. 
     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. 
     The obtained raloxifene lactate may be recrystallized in order to obtain the compound in even higher purity. 
     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. 
     As examples of preferred alcohols can be mentioned methanol, ethanol, propanol, 2-propanol, butanol, 2-butanol, neobutyl alcohol, pentanol, 2-pentanol and 3-pentanol. 
     It is within the abilities of the skilled practitioner to select a suitable solvent for crystallization of particular selected compound of the invention. 
     Ethanol is a particular preferred alcohol. 
     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. 
     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. 
     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. 
     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. 
     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 
     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. 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. 
     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. 
     Mp: dec. &gt;195° C., mp. ˜225° C. 
     Elemental analysis C 33 H 33 NO 8 S: 
     Calculated: C, 64.96%; H, 5.62%; N, 2.37%; S, 5.42%. 
     Found: C, 65.64%; H, 5.49%; N, 2.60%; S, 5.99%. 
     IR: 
     3406 cm −1 , 3145 cm −1 , 2945 cm −1 , 2691 cm −1 , 1642 cm −1 , 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 −1 , 1108 cm −1 , 1079 cm −1 , 1047 cm −1 , 1038 cm −1 , 907 cm −1 , 839 cm −1 , 807 cm −1 , 623 cm −1    
     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 
     [6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl-, malonate; Raloxifene malonate 
     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. 
     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. 
     Mp: 226-227° C. 
     Elemental analysis C 32 H 31 NO 8 S: 
     Calculated: C, 64.46%; H, 5.41%; N, 2.42%; S, 5.55%. 
     Found: C, 64.86%; H, 5.55%; N, 2.57%; S, 5.87%. 
     IR: 
     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    
     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 solvate); Raloxifene sulphate (2-propanol solvate) 
     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. 
     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. 
     Mp: 262-263° C. 
     Elemental analysis C 59 H 64 N 2 O 13 S 3 : 
     Calculated: C, 64.46%; H, 5.41%; N, 2.42%; S, 5.55%. 
     Found: C, 64.86%; H, 5.55%; N, 2.57%; S, 5.87%. 
     IR: 
     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 , 1167 cm −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 . 
     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; Raloxifene DL-lactate 
     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. 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. 
     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. 
     Mp: 196-198° C. 
     Elemental analysis C 34 H 33 NO 7 S: 
     Calculated: C, 65.00%; H, 5.98%; N, 2.45%; S, 5.60%. 
     Found: C, 65.07%; H, 5.93%; N, 2.37%; S, 5.34%. 
     IR: 
     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 . 
     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 . 
     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. 
     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; Raloxifene L-lactate 
     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. 
     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. 
     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. 
     Mp: 134-136° C. 
     Elemental analysis C 31 H 33 NO 7 S (½H 2 O): 
     Calculated: C, 65.00%; H, 5.98%; N, 2.45%; S, 5.60%. 
     Found: C, 65.08%; H, 6.14%; N, 2.58%; S, 5.78%. 
     IR: 
     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 . 
     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 . 
     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. 
     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 
     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 
     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. 
     Mp: 171-173° C.: 
     Elemental analysis C 31 H 33 NO 7 S: 
     Calculated: C, 65.52%; H, 5.94%; N, 2.47%; S, 5.64%. 
     Found: C, 65.50%; H, 5.85%; N, 2.50%; S, 5.74%. 
     IR: 
     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 . 
     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 . 
     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. 
     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 
     40 g (0.06 mol) 6-methyl sulphonyloxy-2-(4-methylsulphonyl-oxyphenyl)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 
     60 mg raloxifene HCl was transferred to a dissolution vessel containing one liter 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. 
     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 
     Using same procedures as in example 8, raloxifene succinate, raloxifene DL-lactate, raloxifene L-lactate hemihydrate, raloxifene malonate and raloxifene sulphate (2-propanol solvate) were tested for dissolution in dilute hydrochloric acid or phosphorous acid. 
     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 
     Experimental set-up: 
     The intrinsic dissolution rate of raloxifene succinate, raloxifene DL-lactate, raloxifene L-lactate, 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. 
     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. 
     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.
 
     Preparation of Standard Solution: 
     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. 
     Preparation of Buffer Solutions: 
     pH 1: a 0.1 M HCl is used. 
     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. 
     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. 
     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. 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. 
     Results 
     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. 
               
             
          
         
       
     
     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.