Specification
NOVEL POLYMORPHS AND PSEUDOPOLYMORPHS OF RISEDRONATE SODIUM
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of provisional applications Serial No. 60/372,465, filed April 11,2002; Serial No. 60/404,174, filed August 16,2002, and Serial No. 60/405,668, filed August 22,2002.
FIELD OF THE INVENTION
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
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-pyridmyI)ethylidene] bis phosphonic acid monosodium salt), the subject of the present invention, is presently marketed under the tradename Actonel® for treatment of osteoporosis.
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, Plimtn Manuf. 3, 33 (1986); J.K.Haleblian and W. McCrone, J. Pharm. Sci., 58,911 (1969); and J.K. Haleblian, J. Pharm. Scl, 64,1269 (1975), all of which are incorporated herein by reference.
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.
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. Flowabih'ty 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.
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.
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 pseudopolyrnorphs, Thermodynamic properties that can be used to distinguishbetween-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).
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.
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.
United States Patent 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.
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.
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%.
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.
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.
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
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 θ 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 cm' l Form B is a monohydrate as proved by single crystal x-ray analysis.
In another aspect, the present invention relates to pure risedronate sodium form B.
In another aspect, the present invention relates to risedronate sodium form B, stable against transformation to form A.
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.
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.
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 atkanol at a temperature between about room temperature and reflux.
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.
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.
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.
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.
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.
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 29 values of about 6.5,14.7,21.2,27.7, and 32.4 degrees 29.
In a further aspect, the present invention relates to a method of making risedronate sodium having at least one characteristic of form Bl 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.
In another aspect, the present invention relates to a method of making risedronate sodium having at least one characteristic of form Bl 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 Bl from the' suspension.
In another aspect, the present invention relates to a method of making risedronate sodium having at least one characteristic of form Bl 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.
In yet another aspect, the present invention relates to a method of making risedronate sodium form B in admixture with form Bl 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.
la 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 29 values of about 8.5,9.1, and 9.5, degrees 2 0. X-ray peaks at 5.9,16.7, 22.0,24.7, and 28.0 degrees 26 is a further characteristic of form BB.
In another aspect, the present invention relates to risedronate sodium form BB.
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.
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%.
In yet another aspect, the present invention relates to risedronate sodium having at least one characteristic of form C, which characterized by x-raytftfiraction peaks . (reflections) at 29 values of about 5.6,10.3,12.9,26.5, and 30.9 degrees 29, or by FTIR" absorption bands at about 615, 666,1089,1563, and 1615 cm-1.
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 alcohol - water mixture, especially an ethanol - water 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.
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 29, or by FTIR absorption bands at about 697, 807,854,955,1187,1218,1576,1646, and 1719 cm-1.
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), andean 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.
In another aspect, the present invention relates to risedronate sodium.having at least one characteristic of form E. FormE is characterized by x-ray diffraction peaks (reflections) at 20 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 cm-1.
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 alcohol - water 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.
In a further aspect, the present invention relates to risedronate sodium having at least one characteristic of farm F.~ Form F can'be characterized by x-ray diffraction peaks (reflections) at 29 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 cm-1. Form F is stable against transformation to form A hemipentahydrate when exposed to high relative humidity.
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.
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 20 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.
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.
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 26 values of about 6.9, 9.8,10.9,13.7,16.0, and 18.0 degrees.
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.
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.
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 risedronatb 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.
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.
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. ;
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.
Another aspect of the present invention is preparation of form A by heating form E at temperatures in the range 30-100°C.
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, Bl, BB, C, D, E, F, G, and H of risedronate sodium and at least one pharmaceutically acceptable excipient.
In still another aspect, the present invention provides a pharmaceutical composition containing pure risedronate sodium form B.
In another aspect, the present invention provides a pharmaceutical composition containing risedronate sodium form B, stable against transformation to form A.
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
Figure 1 is the x-ray powder diffraction diagram of risedronate sodium form A hemipentahydrate.
Figure 2 is the TGA curve of Risedronate sodium form A hemipentahydrate.
Figure 3 is the FTIR spectrum of Risedronate sodium form A hemipentahydrate.
Figure 4 is the X-Ray powder diffraction of Risedronate sodium form B.
Figure 5 is the TGA curve of Risedronate sodium form B. '
Figure 6 is the FTIR spectrum of Risedronate sodium form B.
Figure 7 is the X-Ray powder diffraction of Risedronate sodium form BB.
Figure 8 is the TGA curve of Risedronate sodium form BB..
Figure 9 is the X-Ray powder diffraction of Risedronate sodium form B1.
Figure 10 is the TGA curve of Risedronate sodium form Bl.
Figure 11 is the X-Ray powder diffraction of Risedronate sodium form C.
Figure 12 is the TGA curve of Risedronate sodium form C.
Figure 13 is the FTIR spectrum of Risedronate sodium form C.
Figure 14 is the X-Ray powder diffraction of Risedronate sodium form D.
Figure 15 is the TGA curve of Risedronate sodium form D.
Figure 16 is the FTIR spectrum of Risedronate sodium formD.
Figure 17 is the X-Ray powder diffraction of Risedronate sodium form E.
Figure 18 is the TGA curve of Risedronate sodium form E.
Figure 19 is the FTIR spectrum of Risedronate sodium form E.
Figure 20 is the X-Ray powder diffraction of Risedronate sodium form F.
Figure 21 is the TGA curve of Risedronate sodium form F.
Figure 22 is the FTIR spectrum of Risedronate sodium form F.
Figure 23 is the X-Ray powder diffraction of Risedronate sodium form G. Figure 24 is the TGA curve of Risedronate sodium form G. Figure 25 is the FTIR spectrum of Risedronate sodium form G. Figure 26 is the FTTR spectrum of risedronate sodium form H.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, risedronate sodium and sodium risedronate refer to the monosodium salt of risedronic acid, i.e., 1-hydroxy-2(3-pyrid!myl)emylidene bis phosphonic acid monosodium salt. Risedronate sodium has the empirical formula C7H10NO7P2Na.
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.
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 deterrnination and exercising a level of care commensurate with the objective of the measurement and the precision of the measuring apparatus being used.
As used herein, the term sodium base refers to a base having sodium as a cation. Examples of sodium bases include NaOH, NajCOs, and Na HCOs, NaOH is the preferred sodium base.
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.
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.
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).
The abbreviations "RH" and "%RH" have the customary meanings and denote the percent relative humidity of an atmosphere.
The term room temperature refers to a temperature of about 25° C.
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 A was used. A round aluminum sample holder with a round zero background quartz plate, with cavity of 25mm x 0.5 mm.
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.
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.
Thermogravimeuic 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 250C. The oven was purged with nitrogen gas at a flow rate of 40 ml/min. Standard alumina crucibles covered by Hds with one hole were used.
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 Bl, 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 "#"
As used herein inconnection 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).
As used herein in connection with risedronate sodium form B, the term pure denotes form B substantially free of risedronate sodium hernipentahydfate form A. Substantially free means less than about 1% on a weight basis as determined by, for example, x-ray diffraction analysis.
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.
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.
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.
Form A hemipentahydrate, prepared according to the procedure of example 1 in the '520 patent, has been characterized by X-Ray, FITR, and TGA.
One characteristic of form A is its x-ray diffraction pattern. The x-ray diffraction diagram of form A is shown in Fig.l, and the TGA curve obtained is shown in FigJZ. 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
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, 1657,1689cm-1.
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.
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.
One characteristic of form B is its x-ray diffraction pattern. Form B is characterized by x-ray diffraction peaks at 20 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 Figure 4. Principle x-ray diffraction peaks (reflections) for risedronate sodium form B are collect with those of other crystal forms in Table I.
Another characteristic of form B is its absorption bands in FTIR. The FTIR spectrum of form B is shown in figure 6. Absorption bands characteristic of form B include those at 624,951,796,912,931,1046,1105,1123,1323, and 1641 cm-1. FTIR absorption bands characteristic for form B are collected with those of other crystalline forms of risedronate sodium in Table III.
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.
In another embodiment, the present invention provides risedronate sodium form B that is stable against transformation to form A.
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%.
One characteristic of form BB is its x-ray diffraction pattern. Form BB has characteristic x-ray diffraction peaks at 29 values of about 8.5, 9.1,9.5, and 12.2 degrees 9 and other peaks at 14.3,16.9,19.7,23.5,28.8, and 33.6 degrees 29. . The x-ray diffraction diagram of form BB is shown in Figure 7. The TGA curve for risedronate sodium form BB is shown in Figure 8.
In another embodiment, the present invention provides risedronate sodium having characteristics of form Bl. One characteristic of form Bl is its x-ray diffraction diagram. FormBl is characterized by x-ray diffraction peaks at 29 values at about 6.5,14.7,21.2, 27.7., and 32.4 degrees 29 and is further characterized by x-ray diffraction peaks at 14.3, 16.9,19.7,23.5,28.8, and 33.6 degrees 29. The x-ray diffraction diagram of form Bl is shown in Figure 9. The characteristic x-ray diffraction peaks for form Bl are collected with those for other risedronate sodium crystal forms in Table II. Form Bl is a disodium salt
The TGA thermogram for form B1 is shown in Figure 10.
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 Figure 12. Form C is characterized by x-ray diffraction peaks at 29 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 E.
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 cm-'1. FTIR absorption bands characteristic of form C are collected with those of other crystalline forms of risedronate sodium in Table III.
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.
In another embodiment, the present invention provides risedronate sodium having the characteristics of form D, which has a TGA weight loss~of not more 'triari about 3%. The TGA curve for form D is shown in Figure 15. One characteristic of form D is "its x-ray diffraction pattern. Form D is characterized by x-ray diffraction peaks at 29 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 Figure 14. The locations of characteristic x-ray peaks for form D are 'collected with those of other polymorphs of risedronate sodium in Table H
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 Figure 16. Absorption bands characteristic of form D include those at 697, 807,854,955,1187,1218, 1576,1646, and 1719 cm-1. FTIR absorption bands for form D are collected with those of other crystalline forms of risedronate sodium in Table
m. 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.
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 29 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 H
Another characteristic of form E is its absorption bands in FTIR spectroscopy. The FTIR spectrum for form E is shown in Figure 19. Absorption bands characteristic of form E include those at 801,890,935,1656, and 1689 cm-1. Characteristic FTIR absorption bands for form E are collected with those of other crystalline forms of risedronate sodium in Table III.
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 figure 21.
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 20 of about 6.6, 8.4,8.9,
12.2, and 18.6 degrees. The x-ray diffraction diagram of forin F is shown in Figure 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
Risedronate sodium form F can be further characterized by means of FTIR spectroscopy. The FTIR spectrum of form F is shown in figure 22. Absorption bands characteristic of form F include those 971,1133, and 1306 cm-1. Characteristic absorption bands of FTIR absorptions for form F are collected with those of other crystalline forms of risedronate sodium in Table III
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.
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 Figure 24.
One characteristic of form G is its x-ray diffraction pattern. Risedronate sodium form G is characterized by x-ray diffraction peaks at 26 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 figure 23. The locations of the characteristic diffraction peaks of form G are collected with those of other crystalline forms of risedronate sodium in Table EL
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 Figure 25. Characteristic FTIR absorption bands of form G include those at 724,871,1174,and 1285 cm-1. Characteristic FTIR absorption bands for form G are collected with those for other crystalline forms of risedronate sodium in Table III.
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 20 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 It.
Form H is further characterized by a TGA weight loss of 22%, which corresponds to the water content of pentahydrate.
TableIII Riscdronatc sodium XRD peaks (degrees 2-theta)
(Table Removed)
Table III Risedronate FTIR Peaks (in cm-1)
(Table Removed)
The novel crystal forms (polyrnorphs and pseudopolymorphs) of the present invention can be prepared by several methods. These methods include a reflux metiod, an annealing (thermal) method, and ahumidiflcation method.
The reflux method is preferred when risedronate sodium having the characteristics of any of forms B, BB, Bl, C, D, or E is desired. In the reflux method, risedronic aA (2.0g) was stirred in water (25ml). 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 (2x5ml) and dried in a vacuum oven at 50°C for 22 hours to give 0.22g of sodium risedronate crystal form A.
Example 41
Sodium risedronate crystal form BB>A (3 .Og) was stirred in Ethanol (45ml). 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 (Ixl5ml) and dried in a vacuum oven at 50°C for 26 hours to give 2Jlg of sodium risedionate crystal form D,
Example 42
Stability test of Risedronate tablets
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.
Crystal form of Risedronate sodium active ingredient in a pharmaceutical tablet kept at
400C.75%RH
(Table Removed)
Example 43
Stability test of Risedronate tablets
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.
Crystal form of Risedronate sodium active ingredient in a pharmaceutical tablet kept at
ambient temperature
(Table Removed)
We claim:
1. A process of making risedronate sodium in crystalline in form B in
admixture with crystalline form Bl comprising the steps of:
refluxing a combination of risedronic acid and a sodium base in a liquid comprising between about 5% and about 25%, v!v, ethanol, the remainder consisting essentially of water, cooling the combination to a temperature of about room temperature, and isolating the risedronate sodium form B from the combination.
2. The process as claimed in claim 1, wherein it comprises the step of,
before isolating the risedronate sodium, further cooling the combination
to a temperature of about 5°C or less.
3. The process as claimed in claim 1 wherein the sodium base is sodium
hydroxide.
4. A process of making risedronate sodium in crystalline in form B in admixture with crystalline form Bl substantially as herein described with reference to the foregoing description and accompanying drawings.