CROSS-REFERENCE TO RELATED APPLICATIONS 0001 This application claims the benefit of provisional applications Serial No. 60/372,465, filed Apr. 11, 2002; Serial No. 60/404,174, filed Aug. 16, 2002, and Serial No. 60/405,668, filed Aug. 22, 2002.

FIELD OF THE INVENTION 0002 The present invention relates to novel polymorphs and pseudopolymorphs of risedronate sodium and methods of making them. The invention further relates to pharmaceutical compositions containing risedronate sodium in various polymorphic or pseudopolymorphic forms.

BACKGROUND OF THE INVENTION 0003 Osteoporosis is a disease characterized by a progressive loss of bone mineral. Osteoporosis is also characterized by low bone mass and architectural deterioration of bone tissue leading to enhanced bone fragility and increase in the risk of fracture. The goal of therapy in treatment of osteoporosis is to improve calcium absorption and decrease urinary excretion of calcium thus reversing secondary hyperparathyroidism. Calcium supplements are widely used in managing established osteoporosis but there have been few satisfactory prospective studies of calcium supplementation on bone density or the risk of further fracture. The bisphosphonates, for example etidronate, pamidronate, and risedronate are useful in treating osteoporosis. Risedronate sodium 1-hydroxy-2(3-pyridinyl)ethylidene bis phosphonic acid monosodium salt), the subject of the present invention, is presently marketed under the tradename Actonel for treatment of osteoporosis. 0004 Many pharmacologically active substances can exist in more than one crystalline form. The discovery of a new crystalline form of a pharmaceutically useful compound provides an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic. It is clearly advantageous when this repertoire is enlarged by the discovery of new crystalline forms of a useful compound. For a general review of polymorphs and the pharmaceutical applications of polymorphs consult G. M. Wall, Pharm Manuf. 3, 33 (1986); J. K. Haleblian and W. McCrone, J. Pharm. Sci., 58, 911 (1969); and J. K. Haleblian, J. Pharm. Sci., 64, 1269 (1975), all of which are incorporated herein by reference. 0005 In some cases, foreign molecules, for example solvent molecules, can be regularly incorporated into the crystal structure of a compound. Strictly speaking, such compounds are not true polymorphs and are often referred to as pseudopolymorphs. 0006 The present invention relates to the solid state forms (i.e. polymorphs and pseudopolymorphs) of risedronate sodium that can be prepared by any of the methods herein described. The polymorphs and pseudopolymorphs can be influenced by controlling the conditions under which the salt is obtained in solid form. Solid state physical properties that can differ from one polymorph (or pseudopolymorph) to the next include, for example, the flowability of the milled solid. Flowability affects the ease with which the material is handled during processing into a pharmaceutical product. When particles of the powdered compound do not flow past each other easily, a formulation specialist must take that fact into account in developing a tablet or capsule formulation, which may necessitate the use of glidants such as colloidal silicon dioxide, talc, starch, or tribasic calcium phosphate. 0007 Another important solid state property of a pharmaceutical compound that can depend on crystal structure is its rate of dissolution in aqueous media. The rate of dissolution of an active ingredient in a patient's stomach fluid can have therapeutic consequences because it imposes an upper limit on the rate at which an orally-administered active ingredient can reach the patient's bloodstream. The rate of dissolution is also a consideration in formulating syrups, elixirs and other liquid medicaments. The solid state form of a compound can also affect its behavior on compaction and its storage stability. 0008 These practical physical characteristics can be influenced by the conformation and orientation of molecules in the unit cell, which defines a particular polymorphic form of a substance. The polymorphic form may give rise to thermodynamic properties that are different from those of the amorphous material or another polymorphic (or pseudopolymorphic) form. Thermodynamic properties can be used to distinguish between polymorphs and pseudopolymorphs. Thermodynamic properties that can be used to distinguish between polymorphs can be measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and differential thermal analysis (DTA). 0009 A particular polymorphic form can also possess distinct spectroscopic properties that may be detectable by, for example, solid state 13C NMR spectroscopy and infrared (IR) spectroscopy. 0010 X-ray crystallography on powders (powder diffractometry) can be used to obtain x-ray diffractograms unequivocally distinguish among the crystal structure of different polymorphs and pseudopolymorphs. 0011 U.S. Pat. No. 6,410,520 (the '520 patent) describes selective crystallization of risedronate sodium as a monohydrate or hemipentahydrate (pseudopolymorphs). At page 1, the application states, without citation, It is known in the literature that some bisphonic sic acids and their salts are capable of forming hydrates, risedronate sodium exists in three hydration states: mono, hemipenta and anhydrous. The publication also states that the mono and hemipentahydrates were characterized by various means including x-ray diffraction. However, the present inventors have found no such characterization data in the literature for the monohydrate. Also, the present inventors are not aware of any teach in the prior art where a process to make the monohydrate is shown. 0012 In the '520 patent it is written that the monohydrate and the hemipentahydrate are preferred forms and that the hemipentahydrate is the thermodynamically preferred crystalline form under processing conditions based on the observation that the monohydrate crystals convert to the hemipentahydrate form. 0013 The '520 patent also discloses that the monohydrate has a water content from about 5.0% to about 7.1%, more preferably about 5.6% to about 6.5%, and most preferably 5.6%. 0014 The application also discloses that the hemipentahydrate has a water content from about 11.9% to about 13.9%, more preferably about 12.5% to about 13.2%, and most preferably 12.9%. The monohydrate and the hemipentahydrate are further characterized by single crystal X-Ray crystallography, and thermogravimetric analysis, but x-ray results were not disclosed. The present inventors collected x-ray diffraction and TGA data for the forms disclosed in the '520 patent. 0015 In the '520 patent, a process for preparation of the hemipentahydrate form is disclosed. Also, a pharmaceutical composition comprising risedronate from about 50% to about 100% hemipentahydrate and from about 50% to about 0% monohydrate is disclosed. 0016 The '520 patent also discloses methods to selectively make the monohydrate. The present inventors have repeated example 2 of the '520 patent. The product we obtained following the teachings of the '520 patent are a mixture of forms B, A, BB, by x-ray analysis.

SUMMARY OF THE INVENTION 0017 In one aspect, the present invention provides risedronate sodium having at least one characteristic of form B, which is characterized by x-ray diffraction peaks (reflections) at 2 values of about 6.0, 14.4, 19.6, 24.9, and 25.4 degrees, or by FTIR absorption bands at about 624, 951, 796, 912, 931, 1046, 1105, 1123, 1323, and 1641 cm1. Form B is a monohydrate as proved by single crystal x-ray analysis. 0018 In another aspect, the present invention relates to pure risedronate sodium form B. 0019 In another aspect, the present invention relates to risedronate sodium form B, stable against transformation to form A. 0020 In a further aspect, the present invention relates to a method of making risedronate sodium having at least one characteristic of form B, especially pure form B, including the step of refluxing a combination of risedronic acid, a sodium base, especially sodium hydroxide, and a mixture of an alcohol, especially ethanol, and water (40-60% water, v/v in alcohol), methanol and water (20%-70% water, v/v, in alcohol), or isopropanol and water (40%-60% water, v/v, in alcohol). Form B so made is stable against transformation to form A. 0021 In another aspect, the present invention relates to a method of making risedronate sodium having at least one characteristic of form B including the step of exposing risedronate sodium form D to an atmosphere of 80% to 100% RH. The product so made is stable against transformation to form A. 0022 In another aspect, the present invention relates to a method of making risedronate sodium having at least one characteristic of form B including the step of treating risedronate sodium form A with a lower alkanol at a temperature between about room temperature and reflux. 0023 In still another aspect, the present invention provides a method for preparation of risedronate sodium form B by exposing to high relative humidity of 60-100% RH, more preferably 80% RH, risedronate sodium form D for a period of time between 3 and 20 days, more preferably 5-10 days. 0024 In still another aspect, the present invention provides pure risedronate sodium form B. Pure risedronate sodium form B has less than about 2% by weight of form A. 0025 In another aspect, the present invention provides stable risedronate sodium form B. Stable form B does not transform to form A even when exposed to high relative humidity. 0026 In yet another aspect, the present invention relates to risedronate sodium in crystalline form B that is stable against transformation to risedronate sodium in crystalline form A. 0027 In still a further aspect, the present invention relates to risedronate sodium in crystalline form B, stable against transformation to risedronate sodium in crystalline form A when exposed to 75% RH at 40 C. for at least three months. 0028 In another aspect, the present invention provides risedronate sodium having at least one characteristic of form B1. Form B1 has characteristic x-ray diffraction peaks (reflections) at 2 values of about 6.5, 14.7, 21.2, 27.7, and 32.4 degrees 2. 0029 In a further aspect, the present invention relates to a method of making risedronate sodium having at least one characteristic of form B1 including the step of refluxing a combination of risedronic acid, at least about two equivalents of a sodium base, and a liquid that is a mixture of an alcohol, especially ethanol, and water (5-25% ethanol, v/v in alcohol). The method can further include one or more cooling steps to room temperature or 5 C. or less. 0030 In another aspect, the present invention relates to a method of making risedronate sodium having at least one characteristic of form B1 including the steps of refluxing a suspension of risedronic acid and at least about two equivalents of a sodium base in a mixture of water and ethanol, 50/50 v/v, cooling the suspension to a temperature of about room temperature, further cooling the suspension to a temperature of about 5 C. or less, and isolating risedronate sodium having at least one characteristic of form B1 from the suspension. 0031 In another aspect, the present invention relates to a method of making risedronate sodium having at least one characteristic of form B1 including the steps of refluxing a mixture of risedronic acid, at least about two equivalents of a sodium base, and a liquid comprising water and ethanol, 50/50 v/v, and isolating risedronate disodium having at least one characteristic of form B1 from the mixture. 0032 In yet another aspect, the present invention relates to a method of making risedronate sodium form B in admixture with form B1 including the steps of refluxing a combination of risedronic acid and a sodium base in a liquid made-up of between about 5% and about 25%, v/v, ethanol, the remainder essentially water, and isolating the risedronate sodium form the combination. 0033 In still another aspect, the present invention relates to risedronate sodium having at least one characteristic of form BB, which is characterized by x-ray diffraction peaks (reflections) at 2 values of about 8.5, 9.1, and 9.5, degrees 2 . X-ray peaks at 5.9, 16.7, 22.0, 24.7, and 28.0 degrees 2 is a further characteristic of form BB. 0034 In another aspect, the present invention relates to risedronate sodium form BB. 0035 In another aspect, the present invention relates to a method of making risedronate sodium having at least one characteristic of form BB including the steps of providing a solution of risedronate sodium in water at a temperature of about 70 C. or more, adding iso-propanol to the solution to obtain a solid-in-liquid suspension, isolating the solid from the suspension, refluxing the isolated solid in suspension in iso-propanol for at least about 10, hours, and isolating risedronate sodium having at least one characteristic of form BB from the suspension. 0036 In yet another aspect, the present invention relates to a method of making risedronate sodium having at least one characteristic of from BB including the steps of exposing risedronate sodium having at least one characteristic of form F to an atmosphere having a relative humidity of at least about 80%. 0037 In yet another aspect, the present invention relates to risedronate sodium having at least one characteristic of form C, which characterized by x-ray diffraction peaks (reflections) at 2 values of about 5.6, 10.3, 12.9, 26.5, and 30.9 degrees 2, or by FTIR absorption bands at about 615, 666, 1089, 1563, and 1615 cm1. 0038 In another aspect, the present invention relates to a method of making risedronate sodium having at least one characteristic of form C including the step of refluxing a combination of risedronic acid, a sodium base (especially sodium hydroxide), and an alcoholwater mixture, especially an ethanolwater mixture having about 3%, v/v, ethanol, the remainder being water. The method can include one or more cooling steps, for example cooling the mixture to a temperature of 5 C. or less. 0039 In a further aspect, the present invention relates to risedronate sodium having at least one characteristic of form D, which can be characterized by x-ray diffraction peaks (reflections) at about 9.9, 17.2, 22.1, 27.9, and 29.2 degrees 2, or by FTIR absorption bands at about 697, 807, 854, 955, 1187, 1218, 1576, 1646, and 1719 cm1. 0040 In yet another aspect, the present invention relates to a method of making risedronate sodium having at least one characteristic of form D including the step of refluxing a combination of risedronic acid, a sodium base (especially sodium hydroxide), and an alcohol or an alcohol/water mixture, especially methanol or a mixture of methanol and water, wherein the mixture is made-up of 1 to about 11 %, v/v, water. The method can include one or more cooling steps prior to isolating the risedronate sodium, for example cooling to room temperature or to a temperature of about 5 C. or less. 0041 In another aspect, the present invention relates to risedronate sodium having at least one characteristic of form E. Form E is characterized by x-ray diffraction peaks (reflections) at 2 values of about 8.4, 8.9, 13.6, 27.6, and 27.9 degrees, or by FTIR absorption bands at about 801, 890, 935, 1656, and 1689 cm1. 0042 In another aspect, the present invention relates to a method of making risedronate sodium having at least one characteristic of form E including the step of refluxing a combination of risedronic acid, a sodium base and an alcoholwater mixture selected from: ethanol containing up to about 80% (v/v) water and methanol containing up to about 80% (v/v) water. The method can include one or more cooling steps before isolating the risedronate sodium, for example cooling to a temperature of about 5 C. or less. 0043 In a further aspect, the present invention relates to risedronate sodium having at least one characteristic of form F. Form F can be characterized by x-ray diffraction peaks (reflections) at 2 values of about 6.6, 8.4, 8.9, 12.2, and 18.6 degrees, or by FTIR absorption bands at about 971, 1133, and 1306 cm1. Form F is stable against transformation to form A hemipentahydrate when exposed to high relative humidity. 0044 In another aspect, the present invention relates to a method of making form F including the step of heating risedronate sodium forms B and A to a temperature between about 120 and 180 C. for about 2 to about 10 hours. 0045 In still another aspect, the present invention relates to risedronate sodium having at least one characteristic of form G. Form G is characterized by x-ray diffraction peaks at 2 values of about 8.0, 9.9, 12.2, 15.2, and 19.6 degrees, or by FTIR absorption band s at about 724, 871, 1174, and 1285 cm1. 0046 In another aspect, the present invention relates to a method of making risedronate sodium having at least one characteristic of form G including the step of heating a combination of risedronate forms A and E at a temperature of between about 120 and 180 C. In another aspect, the present invention relates to the just-recited method for making form G wherein the temperature is about 160 C. and the time of heating is between about 5 and about 8 hours. 0047 In still a further aspect, the present invention relates to risedronate sodium having at least one characteristic of form H. Form H is characterized by x-ray diffraction peaks (reflections) at 2 values of about 6.9, 9.8, 10.9, 13.7, 16.0, and 18.0 degrees. 0048 In another aspect, the present invention relates to a method of making risedronate sodium having at least one characteristic of form H including the step of exposing risedronate sodium form C to high relative humidity (>60% RH) for about 3 to about 20 days. In still another aspect, the present invention relates to the just-recited method for making form H wherein the percent relative humidity is >80% and the risedronate sodium is exposed for a period of about 7 to about 14 days. 0049 In another aspect, the invention provides a method for preparation of risedronate sodium having at least one characteristic of form A by combining at reflux temperature risedronic acid and sodium hydroxide in water or water solutions of isopropanol or ethanol (e.g., 20%, v/v, isopropanol and water) to yield product having at least one characteristic of form A, the reaction taking place for a period of at least about 1 hour. The method can further include one or more cooling steps prior to isolating risedronate sodium, for example cooling to a temperature of about 5 C. or less. 0050 In yet another aspect, the present invention provides a method for preparation of form A by exposing to high relative humidity of 60-100% RH risedronate sodium form G for a period of time between 3 and 10 days. In another aspect, the present invention provides a method of making form A according to the just-recited method wherein the % RH is greater that about 80% and the exposure is for a time of about 7 days. 0051 In still another aspect, the present invention provides a method for preparation of form A by exposing to high relative humidity of 60-100% RH, more preferrably 80% RH, form E or form G for a period of time between 3 and 10 days, more preferrably 7 days. 0052 In yet a further aspect, the present invention relates to a method of making risedronate sodium having at least one characteristic of form A including the step of treating risedronate sodium with water at a temperature between about room temperature and reflux temperature. 0053 In still a further aspect, the present invention provides a method for preparation of form H by exposing to high relative humidity of 60-100% RH, more preferrably 80% RH, form C for a period of time between 3 and 20 days, more preferrably 5-10 days. 0054 Another aspect of the present invention is preparation of form A by heating form E at temperatures in the range 30-100 C. 0055 In yet another aspect, the present invention relates to pharmaceutical compositions, suitable for administration to a host in need of treatment for disorders relating to, for example, calcium homeostasis or bone density, containing one or more of forms A, B, B1, BB, C, D, E, F, G, and H of risedronate sodium and at least one pharmaceutically acceptable excipient. 0056 In still another aspect, the present invention provides a pharmaceutical composition containing pure risedronate sodium form B. 0057 In another aspect, the present invention provides a pharmaceutical composition containing risedronate sodium form B, stable against transformation to form A. 0058 In yet another aspect, the present invention provides a pharmaceutical composition containing stable risedronate sodium form B. Upon exposure to 75% RH at 40 C. for a period of about 6 months, less than 40% by weight of the risedronate sodium in this composition transforms to form A.

BRIEF DESCRIPTION OF THE DRAWINGS 0059 FIG. 1 is the x-ray powder diffraction diagram of risedronate sodium form A hemipentahydrate. 0060 FIG. 2 is the TGA curve of Risedronate sodium form A hemipentahydrate. 0061 FIG. 3 is the FTIR spectrum of Risedronate sodium form A hemipentahydrate. 0062 FIG. 4 is the X-Ray powder diffraction of Risedronate sodium form B. 0063 FIG. 5 is the TGA curve of Risedronate sodium form B. 0064 FIG. 6 is the FTIR spectrum of Risedronate sodium form B. 0065 FIG. 7 is the X-Ray powder diffraction of Risedronate sodium form BB. 0066 FIG. 8 is the TGA curve of Risedronate sodium form BB. 0067 FIG. 9 is the X-Ray powder diffraction of Risedronate sodium form B1. 0068 FIG. 10 is the TGA curve of Risedronate sodium form B1. 0069 FIG. 11 is the X-Ray powder diffraction of Risedronate sodium form C. 0070 FIG. 12 is the TGA curve of Risedronate sodium form C. 0071 FIG. 13 is the FTIR spectrum of Risedronate sodium form C. 0072 FIG. 14 is the X-Ray powder diffraction of Risedronate sodium form D. 0073 FIG. 15 is the TGA curve of Risedronate sodium form D. 0074 FIG. 16 is the FTIR spectrum of Risedronate sodium form D. 0075 FIG. 17 is the X-Ray powder diffraction of Risedronate sodium form E. 0076 FIG. 18 is the TGA curve of Risedronate sodium form E. 0077 FIG. 19 is the FTIR spectrum of Risedronate sodium form E. 0078 FIG. 20 is the X-Ray powder diffraction of Risedronate sodium form F. 0079 FIG. 21 is the TGA curve of Risedronate sodium form F. 0080 FIG. 22 is the FTIR spectrum of Risedronate sodium form F. 0081 FIG. 23 is the X-Ray powder diffraction of Risedronate sodium form G. 0082 FIG. 24 is the TGA curve of Risedronate sodium form G. 0083 FIG. 25 is the FTIR spectrum of Risedronate sodium form G. 0084 FIG. 26 is the FTIR spectrum of risedronate sodium form H.

DETAILED DESCRIPTION OF THE INVENTION 0085 As used herein, risedronate sodium and sodium risedronate refer to the monosodium salt of risedronic acid, i.e., 1-hydroxy-2(3-pyridinyl)ethylidene bis phosphonic acid monosodium salt. Risedronate sodium has the empirical formula C7H10NO7P2Na. 0086 Unless otherwise required by the context, as used herein risedronate sodium and sodium risedronate do not denote the material in any particular physical state and include amorphous material as well as material in any crystalline form. 0087 As used herein in connection with a measured quantity, the term about indicates that variation in the measured quantity as would be expected by the skilled artisan making the measurement or determination and exercising a level of care commensurate with the objective of the measurement and the precision of the measuring apparatus being used. 0088 As used herein, the term sodium base refers to a base having sodium as a cation. Examples of sodium bases include NaOH, Na2CO3, and Na HCO3. NaOH is the preferred sodium base. 0089 As used herein, the term lower alkanol refers to compounds of the general formula ROH, where R is a linear or branched alkyl group having up to 6 carbon atoms. 0090 As used herein in connection with liquids that are mixtures, v/v and volume/volume refer to the ratio of volumes of liquids (e.g. alcohols and water) that are combined to make the liquid. Thus, 50/50, v/v, refers to a mixture made by combining approximately equal volumes of two liquids. 0091 As used herein TGA weight loss is determined by calculating the weight loss over the temperature range up to about 200 by 220 C. at the inflection point of the weight loss curve (see Figures). 0092 The abbreviations RH and %RH have the customary meanings and denote the percent relative humidity of an atmosphere. 0093 The term room temperature refers to a temperature of about 25 C. 0094 X-ray diffraction data described herein was obtained by the powder diffraction method. X-Ray powder diffraction data were obtained using methods known in the art with a SCINTAG powder X-Ray diffractometer model X'TRA equipped with a solid state detector. Copper radiation of 1.5418 was used. A round aluminum sample holder with a round zero background quartz plate, with cavity of 25 mm0.5 mm. 0095 X-ray diffraction analysis can be used to detect and quantify one crystalline form of risedronate sodium in another. Using x-ray diffraction analysis, the presence of about 1% by weight or less of form A in form B can be detected. 0096 Fourier Transform Inrfared spectroscopy (FTIR) is an analytical technique well known in the art employing polychromatic radiation and Fourier transformation of the interferogram obtained. FTIR spectra disclosed herein were recorded for nujol mulls of samples using a Perkin Elmer Spectrum 1 instrument. 0097 Thermogravimetric analysis (TGA) is a technique of thermal analysis well known in the art and measures the change in weight of a sample as a function of temperature. The technique is particularly well suited for measurement of, for example, decomposition and desolvation. TGA results reported herein were obtained using a Mettler TG50. Sample size was between about 6 and about 15 mg. Samples were analyzed at a heating rate of 10 C./min from 25 C. to 250 C. The oven was purged with nitrogen gas at a flow rate of 40 ml/min. Standard alumina crucibles covered by lids with one hole were used. 0098 As used herein, the phrase having at least one characteristic of form , where is a letter or letter and Arabic numeral (e.g. form B, form B1, etc.), refers to a crystalline form of risedronate sodium that exhibits at least the characteristic x-ray peaks or the characteristic FTIR absorption bands of form . 0099 As used herein in connection with a crystalline form (polymorph or pseudopolymorph) of risedronate sodium, the phrase does not substantially convert to the hemipentahydrate form means that not more than about 20% of the polymorph or pseudopolymorph converts or rearranges to hemipentahydrate (risedronate sodium form A). 0100 As used herein in connection with risedronate sodium form B, the term pure denotes form B substantially free of risedronate sodium hemipentahydrate form A. Substantially free means less than about 1% on a weight basis as determined by, for example, x-ray diffraction analysis. 0101 As used herein in connection with form B, stable against transformation to form A means that not more than about 20% of form B transforms to form A under the specified conditions. When made according to the preferred embodiments of the present invention, less than 20% of form B transforms to form A upon exposure to a RH of 75% at 40 C. for a period of at least three months. 0102 The stability of crystalline forms of risedronate sodium against transformation to form A is measured by exposing a sample to an atmosphere having a percent relative humidity (RH or %RH) of at least about 50% at a temperature greater than room temperature for a period of time. It is convenient to evaluate the stability of a crystalline form of risedronate sodium against transformation to form A by exposing a sample to an atmosphere having RH of about 75% at a temperature of 40 C. for a period of at least 3 months. The experience of the skilled artisan teaches that a pharmaceutical that is stable under these conditions will be stable for at least 2 years at room temperature. Hence, the skilled artisan would anticipate, with reasonable expectation of being correct, that form B stable against transformation to form A when exposed to 40 C./75% RH for six months would not substantially convert to form A when stored at room temperature for four years. 0103 Hemipentahydrate reference material was prepared according to the procedure of example 1 in the '520 patent. The hemipentahydrate was denominated by us form A, and was identified as the crystal form present in the commercial tablet ACTONEL. 0104 Form A hemipentahydrate, prepared according to the procedure of example 1 in the '520 patent, has been characterized by X-Ray, FTIR, and TGA. 0105 One characteristic of form A is its x-ray diffraction pattern. The x-ray diffraction diagram of form A is shown in FIG. 1, and the TGA curve obtained is shown in FIG. 2. Form A hemipentahydrate is characterized by x-ray peaks at 8.9, 12.2, 24.6 degrees 2-theta and other peaks at 12.9, 13.5, 15.4, 15.7, 27.8, 28.1, 31.3 degrees 2-theta. The TGA curve shows multiple weight loss steps, for an overall weight loss of 12-14%, which conforms to the value of 11.9-13.9% water content reported in the '520 patent. 0106 Another characteristic of form A is its absorption bands in FTIR spectroscopy. The FTIR spectrum of form A shows characteristic peaks at 800, 889, 935, 1132, 1637, 1657, 1689 cm1. 0107 The procedure of examples 1 and 2 of the '520 patent for the preparation of the so called monohydrate form was repeated and, in our hands, consistently led to a product that included forms B, BB and A. The X-Ray powder diffraction pattern of form BB differs from that of form A. The TGA thermogram shows multiple weight loss steps, for an overall weight loss of 9.5-10.0%, which does not conform to the value of 5.0-7.1% for the monohydrate reported in the '520 patent. 0108 In one embodiment, the present invention provides risedronate sodium having the characteristics of form B that was shown to be monohydrate by single crystal x-ray analysis. Form B has a weight loss in TGA of between about 5% and about 8%. The TGA weight loss step of monohydrate form B is larger than the expected based on theoretical water content of 5.6%; presumably due in the fact that the TGA weight loss step also reflects decomposition processes. 0109 One characteristic of form B is its x-ray diffraction pattern. Form B is characterized by x-ray diffraction peaks at 2 values of about 6.0, 14.4, 19.6, 24.9, and 25.4 degrees. The x-ray diffraction diagram for form B is shown in FIG. 4. Principle x-ray diffraction peaks (reflections) for risedronate sodium form B are collect with those of other crystal forms in Table I. 0110 Another characteristic of form B is its absorption bands in FTIR. The FTIR spectrum of form B is shown in FIG. 6. Absorption bands characteristic of form B include those at 624, 951, 796, 912, 931, 1046, 1105, 1123, 1323, and 1641 cm1. FTIR absorption bands characteristic for form B are collected with those of other crystalline forms of risedronate sodium in Table III. 0111 In another embodiment the present invention provides pure risedronate sodium form B. Pure risedronate sodium form B of the present invention is also physically stable and does not substantially convert (transform) to form A hemipentahydrate when exposed to 75% to 100% RH for one week or more; or upon storage at 40 C. and 75% RH for 6 months. Pure risedronate sodium has less than about 1% by weight form A. 0112 In another embodiment, the present invention provides risedronate sodium form B that is stable against transformation to form A. 0113 In another embodiment, the present invention provides risedronate sodium having the characteristics of form BB. Form BB has a TGA weight loss between about 9% and about 11%. 0114 One characteristic of form BB is its x-ray diffraction pattern. Form BB has characteristic x-ray diffraction peaks at 2 values of about 8.5, 9.1, 9.5, and 12.2 degrees and other peaks at 14.3, 16.9, 19.7, 23.5, 28.8, and 33.6 degrees 2. The x-ray diffraction diagram of form BB is shown in FIG. 7. The TGA curve for risedronate sodium form BB is shown in FIG. 8. 0115 In another embodiment, the present invention provides risedronate sodium having characteristics of form B1. One characteristic of form B1 is its x-ray diffraction diagram. Form B1 is characterized by x-ray diffraction peaks at 2 values at about 6.5, 14.7, 21.2, 27.7, and 32.4 degrees 2 and is further characterized by x-ray diffraction peaks at 14.3, 16.9, 19.7, 23.5, 28.8, and 33.6 degrees 2. The x-ray diffraction diagram of form B1 is shown in FIG. 9. The characteristic x-ray diffraction peaks for form B1 are collected with those for other risedronate sodium crystal forms in Table II. Form B1 is a disodium salt. 0116 The TGA thermogram for form B1 is shown in FIG. 10. 0117 In another embodiment, the present invention provides risedronate sodium having the characteristics of form C. Form C has a TGA weight loss of about 7%. The TGA curve for form C is shown in FIG. 12. Form C is characterized by x-ray diffraction peaks at 2 values of about 5.6, 10.3, 12.9, 16.5, and 30.9. The locations of characteristic x-ray peaks for form C are collected with those of other crystal forms of risedronate sodium in Table II. 0118 Another characteristic of form C is its absorption bands in FTIR spectroscopy. Risedronate sodium form C is characterized through its FTIR spectrum. Characteristic absorption band for form C include those at 615, 666, 1089, 1563, and 1625 cm1. FTIR absorption bands characteristic of form C are collected with those of other crystalline forms of risedronate sodium in Table III. 0119 Form C does not substantially convert (transform) to form A in high humidity atmosphere of 80%-100% at room temperature, preferably 80% relative humidity humidities for at least a period of one week. 0120 In another embodiment, the present invention provides risedronate sodium having the characteristics of form D, which has a TGA weight loss of not more than about 3%. The TGA curve for form D is shown in FIG. 15. One characteristic of form D is its x-ray diffraction pattern. Form D is characterized by x-ray diffraction peaks at 2 values of about 9.9, 17.2, 22.1, 27.9, and 29.2 degrees. The x-ray diffraction diagram of form D is shown in FIG. 14. The locations of characteristic x-ray peaks for form D are collected with those of other polymorphs of risedronate sodium in Table II. 0121 Another characteristic of form D is its absorption bands in FTIR. Risedronate sodium form D is characterized by means of its FTIR spectrum. The FTIR spectrum for form D is shown in FIG. 16. Absorption bands characteristic of form D include those at 697, 807, 854, 955, 1187, 1218, 1576, 1646, and 1719 cm1. FTIR absorption bands for form D are collected with those of other crystalline forms of risedronate sodium in Table III. 0122 Form D does not substantially convert (transform) to form A in high humidity atmosphere of 80%-100% RH at room temperature for at least a period of one week. Form D can be converted to form B by exposing it to an atmosphere of 80% to 100% RH for at least about one week. 0123 In yet another embodiment, the present invention provides risedronate sodium having the characteristics of form E, which can be characterized by x-ray diffraction peaks at 2 values of about 8.4, 8.9, 13.6, 27.6, and 27.9 degrees and a TGA weight loss of 9% to 12%. The locations of the characteristic diffraction peaks for form E are collected with those of other crystalline forms of risedronate sodium in Table II. 0124 Another characteristic of form E is its absorption bands in FTIR spectroscopy. The FTIR spectrum for form E is shown in FIG. 19. Absorption bands characteristic of form E include those at 801, 890, 935, 1656, and 1689 cm1. Characteristic FTIR absorption bands for form E are collected with those of other crystalline forms of risedronate sodium in Table III. 0125 In another embodiment, the present invention provides risedronate sodium having the characteristics of form F, which has a TGA weight loss between about 4% and about 6%. The TGA curve for form F is shown in FIG. 21. 0126 One characteristic of form F is its x-ray diffraction pattern. Risedronate sodium form F is characterized by x-ray diffraction peaks at values of 2 of about 6.6, 8.4, 8.9, 12.2, and 18.6 degrees. The x-ray diffraction diagram of form F is shown in FIG. 20. The locations of characteristic x-ray peaks for form F are collected with those of other crystalline forms of risedronate sodium in Table II. 0127 Risedronate sodium form F can be further characterized by means of FTIR spectroscopy. The FTIR spectrum of form F is shown in FIG. 22. Absorption bands characteristic of form F include those 971, 1133, and 1306 cm1. Characteristic absorption bands of FTIR absorptions for form F are collected with those of other crystalline forms of risedronate sodium in Table III. 0128 Form F does not substantially rearrange (transform) to the hemipentahydrate form at up to 100% relative humidity during one week storage. In high humidity atmosphere of 80%-100% RH form F transforms to form BB during storage of one week or more. 0129 In yet another embodiment, the present invention provides risedronate sodium having the characteristics of form G, which has a TGA weight loss between about 9% and about 11%. The TGA curve of form G is shown in FIG. 24. 0130 One characteristic of form G is its x-ray diffraction pattern. Risedronate sodium form G is characterized by x-ray diffraction peaks at 2 values of about 8.0, 9.9, 12.2, 15.2, and 19.6 degrees. The x-ray diffraction diagram of form G is shown in FIG. 23. The locations of the characteristic diffraction peaks of form G are collected with those of other crystalline forms of risedronate sodium in Table II. 0131 Another characteristic of form G is its absorption bands in FTIR spectroscopy. Risedronate sodium form G can be further characterized by FTIR spectroscopy. The FTIR spectrum of form G is shown in FIG. 25. Characteristic FTIR absorption bands of form G include those at 724, 871, 1174, and 1285 cm1. Characteristic FTIR absorption bands for form G are collected with those for other crystalline forms of risedronate sodium in Table III. 0132 In yet another embodiment, the present invention provides risedronate sodium having the characteristics of form H, which can be characterized by x-ray diffraction peaks at values of 2 of about 6.9, 9.8, 10.9, 13.7, 16.0, and 18.0 degrees. The characteristic x-ray diffraction peaks for form H are collected with those of other crystalline forms of risedronate sodium in Table II. 0133 Form H is further characterized by a TGA weight loss of 22%, which corresponds to the water content of pentahydrate. 1TABLE IIRisedronate sodium XRD peaks (degrees 2-theta)Form A(hemipenta)Form BForm B1Form BBForm CForm DForm EForm FForm GForm8.96.06.55.95.69.96.58.08.06.912.212.014.38.510.313.87.48.48.39.812.913.414.79.112.914.28.48.98.910.913.514.416.99.515.216.58.912.29.913.715.416.519.712.216.517.213.614.012.216.015.717.121.216.717.618.314.415.613.517.219.818.123.522.017.818.516.416.913.818.022.919.027.724.720.322.120.119.815.219.024.619.628.828.020.922.722.918.617.119.527.821.832.420.521.223.623.921.519.620.928.124.933.623.926.024.324.627.823.723.231.325.424.626.724.727.624.625.236.526.527.828.827.927.925.225.930.230.229.629.228.527.826.430.933.930.232.427.530.0

0134

2TABLE IIIRisedronate FTIR Peaks (in cm1)Pentahydrate(form A)Form BForm CForm DForm EForm FForm G60461061560860460460762962466663063066162366066081566066069465968769288869768779169480095197280780182472479610168258198887928188171052854890937822889858108988993497185988411519151033106187191591212739551212113388693593115639851275127591610239451615101712121306934103298316821052127515689451061104610821318162897011321080113615699851212110511871638104312751123121816561060131911521283168911741568121015761285163712761627156716571323164616271689156717191641

0135 The novel crystal forms (polymorphs and pseudopolymorphs) of the present invention can be prepared by several methods. These methods include a reflux method, an annealing (thermal) method, and a humidification method. 0136 The reflux method is preferred when risedronate sodium having the characteristics of any of forms B, BB, B1, C, D, or E is desired. In the reflux method, risedronic acid is combined with a suitable base having sodium as a counterion (cation) and a reflux medium that can be water, an alcohol, or a mixture of an alcohol and water. Sodium hydroxide is a preferred sodium base. The particular alcohol and the composition of the alcoholwater mixture are chosen according to the form desired. The following table (Table III) will provide guidance to the skilled artisan in selecting the appropriate reflux medium. The composition of reflux media are expressed on a volume/volume basis. (abbreviated v/v). That is, 50% v/v means a mixture of approximately equal volumes. 3TABLE IIIPolymorph Produced in the Reflux Method Using Various Reflux Media(Alcohols and Alcohol - Water Mixtures)% H2O (v/v)MeOHEtOHIPA0DDRisedronic acid3C10DB >> B1B risedronic acid20BB >> B1B risedronic acid40BBB60BBB70BB A80EA EA100A E

0137 Generally, 1 to 2 equivalents of sodium hydroxide are combined with risedronic acid and water, alcohol, or an alcohol-water mixture. The total volume of reflux medium is not critical and can be, for example, between about 15 and about 25 milliliters per gram of risedronic acid used. In preferred embodiments, a solution of sodium hydroxide in the chosen reflux medium is added to a suspension of risedronic acid in the reflux medium (12 to 22 mL per gram of risedronic acid are convenient). The mixture is refluxed for 0.5 to 30 hours, preferably 3 to 24 hours. Optionally but preferably, the mixture is then cooled to room temperature and then to less than about 5 C., most preferably to about 0 C. The solids are separated and collected by any suitable means, such as filtration (gravity or suction) or centrifugation, to mention just two. 0138 The annealing (incubating) method is preferred when forms F and G are desired. Annealing can be accomplished by exposing the starting risedronate sodium to the desired temperature for the desired time using, for example, an oven. The skilled artisan will know to adjust the annealing time according to the temperature chosen. Lower annealing temperatures generally require longer annealing times. 0139 In the practice of the present invention, risedronate sodium having at least one characteristic of form B can be made by refluxing a combination of risedronic acid, a sodium base, and a liquid that is a mixture with water of an alcohol selected from methanol, ethanol, n-propanol, and iso-propanol. 0140 In a particular embodiment, the present invention provides a process by which form B is obtained, by combining at reflux temperature a suspension of risedronic acid in a mixture of water and an alcohol, preferably ethanol, methanol, or isopropanol with a solution of sodium hydroxide in a mixture of alcohol and water. The reaction to yield product having the characteristics of form B takes place for a period of 0.5-30 hours, more preferably 20 hours. 0141 In another embodiment, the present invention provides a process by which form B is obtained by combining, at reflux temperature, risedronic acid and about one to about one-and-one half equivalents of sodium hydroxide in mixture of water and ethanol (40% to 60%, especially 50%, v/v, water in ethanol, see Table III), wherein the combination is a suspension. 0142 In another embodiment, the present invention provides a process by which risedronate sodium having at least one characteristic of form B is obtained, by combining at reflux temperature a suspension of risedronic acid in a mixture of water and methanol (20% to 70%, v/v, methanol, see Table III) with a solution of about one to about one-and-one half equivalents of sodium hydroxide in a mixture of alcohol and water. 0143 In another embodiment, the present invention provides a process by which risedronate sodium having at least one characteristic of form B is obtained, by combining at reflux temperature a suspension of risedronic acid in a liquid that is a mixture of water and isopropanol (40% to 60%, v/v, isopropanol) with a solution of sodium hydroxide in a mixture of alcohol and water. 0144 In yet another embodiment, the present invention provides a method of making risedronate sodium having at least one characteristic of form B including the step of treating risedronate sodium with a lower alkanol at a temperature between about room temperature and reflux temperature. Treatment can be effected by agitating a combination of risedronate sodium having at least one characteristic of form A and a lower alkanol for a time sufficient to effect the transformation. The skilled artisan will know to optimize the treatment time by routine experimentation by monitoring the transformation using, for example, x-ray diffraction analysis. 0145 Another embodiment of the invention provides a process by which form B, alone or in admixture with form B1 is obtained, by combining at reflux temperature risedronic acid and one equivalent sodium hydroxide in an ethanol water mixture (5%-25%, v/v, water in ethanol) for a period of 5-20 hours, most preferably 10 hours. 0146 In another embodiment, the present invention provides a method for making risedronate sodium having at least one characteristic of form B1 including the step of refluxing risedronic acid and two equivalents of an inorganic base, having sodium as the cation preferably NaOH in a 50/50 (v/v), alcohol/water, for 5 to 20, preferably 10 hours. With the appropriate reflux medium, use of at least about 2 equivalents of an inorganic base having sodium as the cation (e.g. NaOH) ensures that the product having the characteristics of B1 is formed in preference to form B. 0147 Another aspect of the invention is the process by which risedronate sodium having at least one characteristic of form C is obtained, by combining at reflux temperature risedronic acid and sodium hydroxide in an ethanol-water mixture (3% water in ethanol, v/v) for a period of 10-30 hours, most preferably about 20 hours. 0148 In another embodiment, the present invention provides a process by which risedronate sodium having at least one characteristic of form D is obtained by combining, at reflux temperature, risedronic acid and sodium hydroxide in methanol or ethanol or in a mixture of methanol and water (up to 11% water v/v) for a period of 10-30 hours, most preferably about 20 hours. 0149 In yet another embodiment the present invention provides a method by which form E, alone or in admixture with form A, is obtained by combining at reflux temperature risedronic acid and sodium hydroxide in a liquid that is water or a mixture of alcohols, preferably ethanol or methanol more preferably ethanol in water (up to 20% v/v ethanol) or methanol in water (up to 20% v/v methanol). The reaction to yield a product exhibiting the characteristics of form E takes place for a period of at least 1 hour. 0150 In another embodiment, the present invention provides a method by which risedronate sodium having at least one characteristic of form BB is obtained by providing a solution of risedronate sodium in water at elevated temperature, preferably at 70 C., and adding IPA to the solution to obtain a suspension, isolating the suspended solid, drying the isolated precipitate, and suspending the dried precipitate in IPA at reflux for at least about 10 hours, especially about 17 hours. 0151 Another aspect of the invention is the process by which risedronate sodium having at least one characteristic of form F is obtained, by heating a mixture of forms B and A at temperatures in the range 100-200 C., most preferably 120-180 C., most preferably 160 C. The time needed for the conversion depends on the temperature. At 160 C. a period of 2-10 hours is used, preferably 5-8 hours. 0152 Another embodiment of the invention is the process by which risedronate sodium having at least one characteristic of form G is obtained, by heating a mixture of forms A and E at temperatures in the range 100-200 C., most preferably 120-180 C., most preferably 160 C. The time needed for the conversion depends on the temperature. At 160 C. a period of 2-10 hours is used, preferably 5-8 hours. 0153 Another embodiment of the invention is the process by which risedronate sodium having at least one characteristic of form H is obtained, by exposing at high relative humidity, in the range 60-100% relative humidity, preferably 80% relative humidity, risedronate sodium form C. The period needed for the conversion is 3-20 days, preferably 7-14 days. 0154 In another embodiment, the present invention provides a method for preparation of risedronate sodium having at least one characteristic of form A by combining at reflux temperature risedronic acid and sodium hydroxide in aqueous solution of isopropanol(80-100% v/v water). Under these conditions, formation of product exhibiting the characteristics of form A is usually complete in about 2 hours or less. 0155 In another embodiment, the present invention provides a method for the preparation of form BB by exposing form F to high relative humidity of 60-100% RH, more preferrably 80% RH, for a period of time between 3 and 10 days, more preferrably 7 days. 0156 In still another embodiment, the present invention provides a method for the preparation of risedronate sodium having at least one characteristic of form A by exposing form G to high relative humidity of 60-100% RH, more preferrably 80% RH, for a period of time between 3 and 10 days, more preferrably 7 days. 0157 In yet another embodiment, the present invention provides a method for the preparation of risedronate sodium having at least one characteristic of form A by exposing to high relative humidity of 60-100% RH, more preferrably 80% RH, risedronate sodium having at least one characteristic of either form E or form G for a period of time between 3 and 10 days, more preferably 7 days. 0158 Another embodiment of the invention is preparation of risedronate sodium having at least one characteristic of form B by exposing risedronate sodium having at least one characteristic of form D to high relative humidity of 60-100% RH, more preferrably 80% RH, for a period of time between 3 and 20 days, more preferably 5-10 days. 0159 In another embodiment, the present method provides a method for the preparation of risedronate sodium having at least one characteristic of form H by exposing form C to high relative humidity of 60-100% RH, more preferrably 80% RH, for a period of time between 3 and 20 days, more preferably 5-10 days. 0160 The humidification method is preferred when form H is desired. 0161 In still a further embodiment, the present invention provides a method for the preparation of a risedronate sodium having at least one characteristic of form A by incubating form E at temperatures in the range 30-100 C., most preferably 50-80 C., most preferably 60 C. The time needed for the conversion depends on the temperature. At 60 C. a period of 10-30 hours is used, preferably 20 hours. 0162 In another embodiment, the present invention provides a method of making risedronate sodium having at least one characteristic of form A including the steps of treating risedronate sodium form B or form D with water at a temperature from room temperature up to about reflux temperature. Treatment can be by agitation of a mixture of form B or D and water as a slurry or suspension. The risedronate sodium is treated for a time sufficient to effect the transformation. The skilled artisan will know to optimize the treatment time by routine experimentation by monitoring the transformation by, for example, x-ray diffraction analysis. 0163 In still another embodiment, the present invention provides a pharmaceutical composition including at least one of risedronate sodium forms B, B1, BB, C, D, E, F, G, or H and at least one pharmaceutically acceptable excipient. Preferably the pharmaceutical composition is in the form of an oral solid dosage form. 0164 In yet another embodiment, the present invention provides a pharmaceutical composition including stable risedronate sodium form B and at least one pharmaceutically acceptable excipient. Preferably the pharmaceutical composition is in the form of an oral solid dosage form. 0165 Tablets were prepared according to standard formulations and form B in the tablets was found to be stable for 5 months under stressed conditions of 40 C. and 75% RH. The stability of risedronate sodium form B in tablets is not limited to particular formulations. 0166 In yet another embodiment, the present invention provides a pharmaceutical composition including pure risedronate sodium form B and at least one pharmaceutically acceptable excipient. Preferably the pharmaceutical composition is in the form of an oral solid dosage form. 0167 Risedronate sodium having at least one characteristic of any form herein described may be formulated into a variety of pharmaceutical compositions and dosage forms that are useful in treating patients afflicted with, for example, osteoporosis. 0168 Pharmaceutical compositions of the present invention contain one or more of the herein described polymorphs of risedronate sodium. In addition to the active ingredient(s), risedronate sodium pharmaceutical compositions of the present invention may contain one or more excipients. Excipients are added to the composition for a variety of purposes. 0169 Diluents increase the bulk of a solid pharmaceutical composition and may make a pharmaceutical dosage form containing the composition easier for the patient and caregiver to handle. Diluents for solid compositions include, for example, microcrystalline cellulose (e.g. AVICEL, microfine cellulose, lactose, starch, pregelitinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g. EUDRAGIT), potassium chloride, powdered cellulose, sodium chloride, sorbitol and talc. 0170 Solid pharmaceutical compositions that are compacted into a dosage form like a tablet may include excipients whose functions include helping to bind the active ingredient and other excipients together after compression. Binders for solid pharmaceutical compositions include acacia, alginic acid, carbomer (e.g. carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. KLUCEL), hydroxypropyl methyl cellulose (e.g. METHOCEL), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g. KOLLIDON, PLASDONE), pregelatinized starch, sodium alginate and starch. The dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach may be increased by the addition of a disintegrant to the composition. 0171 Disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g. AC-DI-SOL, PRIMELLOSE), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g. KOLLIDON, POLYPLASDONE), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g. EXPLOTAB) and starch. 0172 Glidants can be added to improve the flow properties of non-compacted solid compositions and improve the accuracy of dosing. Excipients that may function as glidants include colloidal silicon dixoide, magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate. 0173 When a dosage form such as a tablet is made by compaction of a powdered composition, the composition is subjected to pressure from a punch and die. Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and die, which can cause the product to have pitting and other surface irregularities. A lubricant can be added to the composition to reduce adhesion and ease release of the product from the die. Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc and zinc stearate. 0174 Flavoring agents and flavor enhancers make the dosage form more palatable to the patient. Common flavoring agents and flavor enhancers for pharmaceutical products that may be included in the composition of the present invention include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid ethyl maltol, and tartaric acid. 0175 Compositions may also be colored using any pharmaceutically acceptable colorant to improve their appearance and/or facilitate patient identification of the product and unit dosage level. 0176 Selection of excipients and the amounts to use may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field. 0177 The solid compositions of the present invention include powders, granulates, aggregates and compacted compositions. The dosages include dosages suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalant and ophthalmic administration. Although the most suitable route in any given case will depend on the nature and severity of the condition being treated, the most preferred route of the present invention is oral. The dosages may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the pharmaceutical arts. 0178 Dosage forms include solid dosage forms like tablets, powders, capsules, suppositories, sachets, troches and lozenges as well as liquid syrups, suspensions and elixirs. An especially preferred dosage form of the present invention is a tablet. 0179 The present invention can be further demonstrated with the following non-limiting examples. 0180 In the following examples, the identity of the particular polymorph formed was determined by x-ray diffraction and, where appropriate, TGA and FTIR. 0181 Preparation of Crystal Form B in Aqueous Ethanol

EXAMPLE 1 0182 A solution of sodium hydroxide (1.18 g, 1 eq.) in a mixture of water/ethanol (32% v/v) (18.5 ml) was added dropwise to a suspension of risedronic acid (8.35 g) in a mixture of water/ethanol (32% v/v) (105 ml) at reflux temperature. The reaction mixture was heated at reflux temperature for 18 hours. The reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed with ethanol (210 ml) and dried in a vacuum oven at 50 C. for 24 hours to give 8.77 g (91%) of sodium risedronate crystal form B.

EXAMPLE 2 0183 A solution of sodium hydroxide (1.47 g, 1 eq.) in water (100 ml) was added in one portion to a suspension of Risedronic acid (10.0 g) in Ethanol (100 ml) at reflux temperature. The reaction mixture was heated at reflux temperature for additional 18 hours. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed with Ethanol (115 ml) and dried in a vacuum oven at 50 C. for 27 hours to give 9.35 g of Sodium Risedronate crystal form B.

EXAMPLE 3 0184 A solution of sodium hydroxide (1.18 g, 1 eq.) in a mixture of water/Ethanol (60% v/v) (126 ml) was added in one portion to dry solid risedronic acid (8.35 g) at room temperature. The reaction mixture was then heated to reflux temperature for 18 hours. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed with Ethanol (110 ml) and dried in a vacuum oven at 50 C. for 24 hours to give 8.04 g (84%) of Sodium Risedronate crystal form B (LOD by TGA6.22%).

EXAMPLE 4 0185 A solution of sodium hydroxide (1.38 g, 1 eq.) in a mixture of water/Ethanol (50% v/v) (30 ml) was added dropwise to a suspension of Risedronic acid (10.0 g) in a mixture of water/Ethanol (50% v/v) (170 ml) at reflux temperature. The reaction mixture was heated at reflux temperature until the pH was 4.10-4.30 (about 1 hour). The reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then collected by filtration, washed with a mixture of water/Ethanol (1:1) (120 ml), and dried in a vacuum oven at 50 C. for 14 hours to give 7.50 g of Sodium Risedronate crystal form B.

EXAMPLE 5 0186 A solution of sodium hydroxide (1.18 g, 1 eq.) in a mixture of water/ethanol (39% v/v) (20.5 ml) was added dropwise to a suspension of risedronic acid (8.35 g) in a mixture of water/ethanol (39% v/v) (116 ml) at reflux temperature. The reaction mixture was heated at reflux temperature for 18 hours. The reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed with ethanol (210 ml) and dried in a vacuum oven at 50 C. for 24 hours to give 8.50 g (88%) of sodium risedronate crystal form B.

EXAMPLE 6 0187 A solution of sodium hydroxide (1.18 g, 1 eq.) in a mixture of water/ethanol (60% v/v) (31 ml) was added dropwise to a suspension of risedronic acid (8.35 g) in a mixture of water/ethanol (60% v/v) (178 ml) at reflux temperature. The reaction mixture was heated at reflux temperature for 19 hours. The reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed with ethanol (120 ml) and dried in a vacuum oven at 50 C. for 20 hours to give 7.55 g of sodium risedronate crystal form B. 0188 Preparation of Crystal Form B in Aqueous Methanol

EXAMPLE 7 0189 A solution of sodium hydroxide (1.18 g, 1 eq.) in a mixture of water/methanol (24% v/v) (16.6 ml) was added dropwise to a suspension of risedronic acid (8.35 g) in a mixture of water/methanol (24% v/v) (94 ml) at reflux temperature. The reaction mixture was heated at reflux temperature for 18.5 hours. The reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed with methanol (210 ml) and dried in a vacuum oven at 50 C. for 19 hours to give 8.69 g of sodium risedronate crystal form B.

EXAMPLE 8 0190 A solution of sodium hydroxide (1.18 g, 1 eq.) in a mixture of water/methanol (39% v/v) (20.6 ml) was added dropwise to a suspension of risedronic acid (8.35 g) in a mixture of water/methanol (39% v/v) (117 ml) at reflux temperature. The reaction mixture was heated at reflux temperature for 18.5 hours. The reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed with methanol (210 ml) and dried in a vacuum oven at 50 C. for 19 hours to give 8.30 g of sodium risedronate crystal form B.

EXAMPLE 9 0191 A solution of sodium hydroxide (1.18 g, 1 eq.) in a mixture of water/methanol (60% v/v) (31.3 ml) was added dropwise to a suspension of risedronic acid (8.35 g) in a mixture of water/methanol (60% v/v) (178 ml) at reflux temperature. The reaction mixture was heated at reflux temperature for 18 hours. The reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed with methanol (210 ml) and dried in a vacuum oven at 50 C. for 22 hours to give 7.75 g of sodium risedronate crystal form B.

EXAMPLE 10 0192 A solution of sodium hydroxide (1.18 g, 1 eq.) in a mixture of water/methanol (70% v/v) (41.8 ml) was added dropwise to a suspension of risedronic acid (8.35 g) in a mixture of water/methanol (70% v/v) (237 ml) at reflux temperature. The reaction mixture was heated at reflux temperature for 19 hours. The reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed with methanol (210 ml) and dried in a vacuum oven at 50 C. for 23 hours to give 6.55 g of sodium risedronate crystal form B. 0193 Preparation of Crystal Form B in Aqueous 2-Propanol (IPA)

EXAMPLE 11 0194 A solution of sodium hydroxide (1.18 g, 1 eq.) in a mixture of water/IPA (40% v/v) (21 ml) was added dropwise to a suspension of risedronic acid (8.35 g) in a mixture of water/IPA (40% v/v) (119 ml) at reflux temperature. The reaction mixture was heated at reflux temperature for 19 hours. The reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed with IPA (125 ml) and dried in a vacuum oven at 50 C. for 27 hours to give 8.53 g of sodium risedronate crystal form B.

EXAMPLE 12 0195 A solution of sodium hydroxide (1.18 g, 1 eq.) in a mixture of water/IPA (60% v/v) (31 ml) was added dropwise to a suspension of risedronic acid (8.35 g) in a mixture of water/IPA (60% v/v) (178 ml) at reflux temperature. The reaction mixture was heated at reflux temperature for 19 hours. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed with IPA (125 ml) and dried in a vacuum oven at 50 C. for 23 hours to give 8.09 g of sodium risedronate crystal form B. 0196 Preparation of Crystal Form C in Aqueous Ethanol

EXAMPLE 13 0197 A solution of sodium hydroxide (1.18 g, 1 eq.) in a mixture of water/ethanol (3% v/v) (12.4 ml) was added dropwise to a suspension of risedronic acid (8.35 g) in a mixture of water/ethanol (3% v/v) (70 ml) at reflux temperature. The reaction mixture was heated at reflux temperature for 18 hours. The reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed with ethanol (210 ml) and dried in a vacuum oven at 50 C. for 22 hours to give 8.20 g (89%)of sodium risedronate crystal form C. 0198 Preparation of Crystal Form D in Aqueous Methanol

EXAMPLE 14 0199 A solution of sodium hydroxide (1.18 g, 1 eq.) in a mixture of water/methanol (11% v/v) (14 ml) was added dropwise to a suspension of risedronic acid (8.35 g) in a mixture of water/methanol (11% v/v) (80 ml) at reflux temperature. The reaction mixture was heated at reflux temperature for 18 hours. The reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed with methanol (110 ml) and dried in a vacuum oven at 50 C. for 20 hours to give 8.20 g (90%)of sodium risedronate crystal form D. 0200 Preparation of Crystal Form E in Aqueous Methanol

EXAMPLE 15 0201 A solution of sodium hydroxide (1.18 g, 1eq.) in a mixture of water/methanol (80% v/v) (62.6 ml) was added dropwise to a suspension of risedronic acid (8.35 g) in a mixture of water/methanol (80% v/v) (355 ml) at reflux temperature. The reaction mixture was heated at reflux temperature for 2 hours. The reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed with methanol (110 ml) and dried in a vacuum oven at 50 C. for 24 hours to give 5.27 g (51%)of sodium risedronate crystal form E. 0202 Preparation of Crystal Form E in Aqueous Ethanol

EXAMPLE 16 0203 A solution of sodium hydroxide (1.18 g, 1 eq.) in a mixture of water/ethanol (80% v/v) (63 ml) was added dropwise to a suspension of risedronic acid (8.35 g) in a mixture of water/ethanol (80% v/v) (354.5 ml) at reflux temperature. The reaction mixture was heated at reflux temperature for 19 hours. The reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed with ethanol (120 ml) and dried in a vacuum oven at 50 C. for 20 hours to give 6.17 g of sodium risedronate crystal form E in a mixture with form A. 0204 Preparation of Crystal Form E in Water

EXAMPLE 17 0205 A solution of sodium hydroxide (1.18 g, 1 eq.) in water (12.5 ml) was added dropwise to a suspension of risedronic acid (8.35 g) water (71 ml) at reflux temperature. The reaction mixture was heated at reflux temperature for 1 hour. The reaction mixture was cooled to room temperature and stirred at this temperature for 16 hours. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed with ethanol (120 ml) and dried in a vacuum oven at 50 C. for 19 hours to give 6.01 g of sodium risedronate crystal form E in a mixture with crystal form A. 0206 Preparation of Crystal Form A in Aqueous 2-Propanol (IPA)

EXAMPLE 18 0207 A solution of sodium hydroxide (1.18 g, 1 eq.) in a mixture of water/EPA (80% v/v) (63 ml) was added dropwise to a suspension of risedronic acid (8.35 g) in a mixture of water/IPA (80% v/v) (354.5 ml) at reflux temperature. The reaction mixture was heated at reflux temperature for 2 hours. The reaction mixture was cooled to room temperature and stirred at this temperature for 16 hours. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed with IPA (120 ml) and dried in a vacuum oven at 50 C. for 24 hours to give 6.09 g of sodium risedronate crystal form A. 0208 Preparation of Sodium Risedronate Crystal Form BB

EXAMPLE 19 0209 A suspension of sodium risedronate (10.0 g) in water (220 mL) was heated to 70 C. and maintained at that temperature for two hours. Cold (0 C.) IPA (1600 mL) was added, in one portion, to the hot solution to obtain a precipitate. The mixture was then cooled in an ice bath for 1.5 hours. The precipitate was then filtered, washed with IPA (230 mL), and dried in a vacuum oven at 50 C. for 25 hours to yield 8.8 g (92%) of sodium risedronate for BB. The obtained risedronate sodium we stirred in IPA (150 mL) at reflux temperature for 17 hours. The solid was then isolated by filtration, washed with IPA (217 mL) and dried in vacuo at 50 C. for 27 hours to give 7.9 g (90%) of sodium risedronate crystal form BB. 0210 Preparation of Crystal Form B1 in Aqueous Ethanol

EXAMPLE 20 0211 A solution of sodium hydroxide (2.77 g, two equivalents) in a mixture of water/Ethanol (50% v/v) (30 ml) was added dropwise to a suspension of Risedronic acid (10.0 g) in a mixture of water/Ethanol (50% v/v) (170 ml) at reflux temperature. The reaction mixture was held at reflux temperature for 24 hours. The reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was collected by filtration, washed with Ethanol (110 ml) and dried in a vacuum oven at 50 C. for 24 hours to give 7.80 g of sodium risedronate crystal form B1. 0212 Preparation of Mixtures of Forms B and B1

EXAMPLE 21 0213 A solution of sodium hydroxide (1.18 g, 1 eq.) in a mixture of water/ethanol (24% v/v) (16.5 ml) was added dropwise to a suspension of risedronic acid (8.35 g) in a mixture of water/ethanol (24% v/v) (94 ml) at reflux temperature. The reaction mixture was heated at reflux temperature for 19 hours. The reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed with ethanol (210 ml) and dried in a vacuum oven at 50 C. for 24 hours to give 8.84 g (92%) of sodium risedronate mixture of crystal form B1 and B (LOD by TGA6.9%).

EXAMPLE 22 0214 A solution of sodium hydroxide (1.18 g, 1 eq.) in a mixture of water/ethanol (6% v/v) (13.3 ml) was added dropwise to a suspension of risedronic acid (8.35 g) in a mixture of water/ethanol (6% v/v) (75.5 ml) at reflux temperature. The reaction mixture was heated at reflux temperature for 18 hours. The reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed with ethanol (210 ml) and dried in a vacuum oven at 50 C. for 41 hours to give 8.96 g (90%) of sodium risedronate mixture of crystal form B1 and B (LOD by TGA6.65%).

EXAMPLE 23 0215 A solution of sodium hydroxide (1.18 g, 1 eq.) in a mixture of water/ethanol (11% v/v) (14 ml) was added dropwise to a suspension of risedronic acid (8.35 g) in a mixture of water/ethanol (11% v/v) (80 ml) at reflux temperature. The reaction mixture was heated at reflux temperature for 19 hours. The reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed with ethanol (210 ml) and dried in a vacuum oven at 50 C. for 41 hours to give 8.67 g of sodium risedronate mixture of crystal form B1 and B.

EXAMPLE 24 0216 A solution of sodium hydroxide (1.18 g, 1 eq.) in a mixture of water/ethanol (16% v/v) (15 ml) was added dropwise to a suspension of risedronic acid (8.35 g) in a mixture of water/ethanol (16% v/v) (84.5 ml) at reflux temperature. The reaction mixture was heated at reflux temperature for 21 hours. The reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed with ethanol (210 ml) and dried in a vacuum oven at 50 C. for 24 hours to give 8.73 g (90%) of sodium risedronate mixture of crystal form B1 and B (LOD by TGA7.1%).

EXAMPLE25 0217 A solution of sodium hydroxide (1.18 g, 1 eq.) in a mixture of water/ethanol (20% v/v) (15.7 ml) was added dropwise to a suspension of risedronic acid (8.35 g) in a mixture of water/ethanol (20% v/v) (89 ml) at reflux temperature. The reaction mixture was heated at reflux temperature for 20 hours. The reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed with ethanol (120 ml) and dried in a vacuum oven at 50 C. for 24 hours to give 8.75 g of sodium risedronate mixture of crystal form B1 and B. 0218 Preparation of Crystal Form D in Ethanol

EXAMPLE 26 0219 1.23 g (1 eq.) of sodium hydroxide were added to a suspension of risedronic acid (8.35 g) in ethanol (834 ml) at room temperature. The reaction mixture was heated to reflux temperature for 13 days. The reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed with ethanol (115 ml) and dried in a vacuum oven at 50 C. for 48 hours to give 7.28 g of sodium risedronate crystal form D. 0220 Preparation of Crystal Forms by Heat

EXAMPLE 27 0221 About 100 mg of a mixture of risedronate forms B and A was kept in an open bottle in the oven at 160 C. 5 hours, to yield form F.

EXAMPLE 28 0222 About 100 mg risedronate mixture of forms A and E was kept in an open bottle in the oven at 160 C. 5 hours, to yield form G.

EXAMPLE 29 0223 About 100 mg risedronate form E was kept in an open bottle in the oven at 60 C. 20 hours, to yield a mixture of form E and form A. 0224 Preparation of Crystal Forms by Exposure at High Relative Humidity

EXAMPLE 30 0225 About 100 mg risedronate form C was spread in a petri dish at a controlled relative humidity (5%) of 80% for a period of one week, to yield a mixture of form C and form H.

EXAMPLE 31 0226 About 100 mg risedronate form D was spread in a petri dish at a controlled relative humidity (5%) of 80% for a period of one week, to yield a mixture of form D and form B.

EXAMPLE 32 0227 About 100 mg risedronate form E was spread in a petri dish at a controlled relative humidity (5%) of 80% for a period of one week, to yield form A with a small quantity of form D.

EXAMPLE 33 0228 About 100 mg risedronate form F was spread in a petri dish at a controlled relative humidity (5%) of 80% for a period of one week, to yield a mixture of form BB.

EXAMPLE 34 0229 About 100 mg risedronate form F was spread in a petri dish at a controlled relative humidity (5%) of 100% for a period of one week, to yield form BB.

EXAMPLE 35 0230 About 100 mg risedronate form G was spread in a petri dish at a controlled relative humidity (5%) of 100% for a period of one week, to yield a mixture of form G and form A. 4TABLE VSummary of physical stability at high relative humidity(One week storage at relative humidities)RelativeResultingTGA WeightCrystal Formhumidity (%)formLoss (%)A (LB-91)80A13.6B (LB-89)80B6.5C (LB-87)80H16.0D (MS-273)80D > B1.1%E (MS-277)80A14.0F (LB-10420-60F4-6160 C. 8 hr)80-100BB > A11.3-12.3G (MS-25720-80G9.4-10.2160 C. 8 hr)100G A12.6

0231 Polymorphic Transformations by Slurries in Water, Ethanol and IPA Formation of Crystal Form B by Slurry of Sodium Risedronate Hemipentahydrate (A) in EtOH/water (1:1)

EXAMPLE 36 0232 Sodium Risedronate hemipentahydrate (10.0 g) was stirred in a mixture of water/Ethanol (1:1, 200 ml). The suspension was heated at reflux temperature for 19 hours and then cooled to room temperature. The solid was filtered, washed with Ethanol (120 ml) and dried in a vacuum oven at 50 C. for 24 hours to give 8.78 g of sodium risedronate crystal form B. 0233 Form D to Form A (in Water at Reflux)

EXAMPLE 37 0234 Sodium Risedronate crystal form D (3.0 g) was stirred in water (30 ml). The suspension was heated to reflux temperature to obtain a clear solution. Then the solution was cooled to room temperature. The resulting precipitate was filtered, washed with water (15 ml), and dried in a vacuum oven at 50 C. for 29 hours to give 1.58 g of sodium risedronate crystal form A.

EXAMPLE 38 0235 Sodium Risedronate crystal form D (2.0 g) was stirred in water (30 ml) at room temperature for 16 hours. The solid was then collected by filtration, washed with water (12 ml) and dried in a vacuum oven at 50 C. for 23 hours to give 0.25 g of sodium risedronate crystal form A. 0236 The mother-liquid was evaporated to dryness to give 1.30 g of Sodium Risedronate crystal form B.

EXAMPLE 39 0237 Sodium Risedronate crystal form B (2.0 g) was stirred in water (20 ml). The suspension was heated to reflux temperature to obtain a clear solution. Then the solution was cooled to room temperature. Further cooling was performed using an ice-bath. The resulting precipitate was filtered, washed with water (110 ml), and dried in a vacuum oven at 50 C. for 72 hours to give 0.58 g of sodium risedronate crystal form A.

EXAMPLE 40 0238 Sodium Risedronate crystal form BB>A (2.0 g) was stirred in water (25 ml). The suspension was heated at reflux temperature for 18 hours to obtain a turbid solution and the turbid solution was cooled to room temperature. Further cooling was performed using an ice-bath. The resulting precipitate was filtered, washed with water (25 ml) and dried in a vacuum oven at 50 C. for 22 hours to give 0.22 g of sodium risedronate crystal form A.

EXAMPLE 41 0239 Sodium risedronate crystal form BB>A (3.0 g) was stirred in Ethanol (45 ml). The suspension was heated at reflux temperature for 18 hours to. The resulting solution was cooled to room temperature. The resulting precipitate was filtered, washed with water (115 ml) and dried in a vacuum oven at 50 C. for 26 hours to give 2.71 g of sodium risedronate crystal form D.

EXAMPLE 42 0240 Stability Test of Risedronate Tablets 0241 A tablet containing Risedronate sodium active ingredient (about 12% w/w of the tablet) was kept in a securitainer at 40 degrees, 75% relative humidity for 6 months. The crystal form (detected from X-Ray powder diffraction data) of Risedronate active ingredient in the tablet are shown in the following table. 5Crystal form of Risedronate sodium active ingredientin a pharmaceutical tablet kept at 40 C., 75% RHTime IntervalCrystal formt 0B2 WeeksB1 MonthB2 MonthsB5 MonthsB6 MonthsB

EXAMPLE 43 0242 Stability Test of Risedronate Tablets 0243 A tablet containing Risedronate sodium active ingredient (about 12% w/w of the tablet) was kept in a securitainer at ambient temperature for 4 months. The crystal form (detected from X-Ray powder diffraction data) of Risedronate active ingredient in the tablet are shown in the following table. 6Crystal form of Risedronate sodium active ingredientin a pharmaceutical tablet kept at ambient temperatureTime IntervalCrystal formt 0B4 MonthsB