US20070259052A1 - Assay for lanthanum hydroxycarbonate - Google Patents

Assay for lanthanum hydroxycarbonate Download PDF

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US20070259052A1
US20070259052A1 US11/418,666 US41866606A US2007259052A1 US 20070259052 A1 US20070259052 A1 US 20070259052A1 US 41866606 A US41866606 A US 41866606A US 2007259052 A1 US2007259052 A1 US 2007259052A1
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Prior art keywords
lanthanum
hydroxycarbonate
ray diffraction
impurity
limit
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Donald Hallenbeck
Simon Bates
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Shire International Licensing BV
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Shire International Licensing BV
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Priority to US11/418,666 priority Critical patent/US20070259052A1/en
Assigned to SHIRE INTERNATIONAL LICENSING B.V. reassignment SHIRE INTERNATIONAL LICENSING B.V. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BATES, SIMON, HALLENBECK, DONALD
Priority to BRPI0710343-3A priority patent/BRPI0710343A2/pt
Priority to CA002651344A priority patent/CA2651344A1/en
Priority to SG201103215-8A priority patent/SG171656A1/en
Priority to CNA2007800245933A priority patent/CN101484798A/zh
Priority to PCT/US2007/061461 priority patent/WO2007130721A2/en
Priority to KR1020087029695A priority patent/KR20090016465A/ko
Priority to AU2007248374A priority patent/AU2007248374A1/en
Priority to JP2009509898A priority patent/JP2009536356A/ja
Priority to EA200802169A priority patent/EA200802169A1/ru
Priority to MX2008014148A priority patent/MX2008014148A/es
Priority to TW096107691A priority patent/TW200742849A/zh
Priority to US11/932,367 priority patent/US7618656B2/en
Publication of US20070259052A1 publication Critical patent/US20070259052A1/en
Priority to IL195051A priority patent/IL195051A0/en
Priority to MA31414A priority patent/MA31601B1/fr
Priority to NO20085063A priority patent/NO20085063L/no
Assigned to SHIRE INTERNATIONAL LICENSING B.V. reassignment SHIRE INTERNATIONAL LICENSING B.V. CHANGE OF ASSIGNEE ADDRESS AT REEL/FRAME 018180/0854 Assignors: SHIRE INTERNATIONAL LICENSING B.V.
Priority to US12/636,583 priority patent/US20100092576A1/en
Abandoned legal-status Critical Current

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N23/00—Investigating or analysing materials by the use of wave or particle radiation, e.g. X-rays or neutrons, not covered by groups G01N3/00 – G01N17/00, G01N21/00 or G01N22/00
    • G01N23/20—Investigating or analysing materials by the use of wave or particle radiation, e.g. X-rays or neutrons, not covered by groups G01N3/00 – G01N17/00, G01N21/00 or G01N22/00 by using diffraction of the radiation by the materials, e.g. for investigating crystal structure; by using scattering of the radiation by the materials, e.g. for investigating non-crystalline materials; by using reflection of the radiation by the materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/244—Lanthanides; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01F—COMPOUNDS OF THE METALS BERYLLIUM, MAGNESIUM, ALUMINIUM, CALCIUM, STRONTIUM, BARIUM, RADIUM, THORIUM, OR OF THE RARE-EARTH METALS
    • C01F17/00—Compounds of rare earth metals
    • C01F17/20—Compounds containing only rare earth metals as the metal element
    • C01F17/247—Carbonates
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N23/00—Investigating or analysing materials by the use of wave or particle radiation, e.g. X-rays or neutrons, not covered by groups G01N3/00 – G01N17/00, G01N21/00 or G01N22/00
    • G01N23/20—Investigating or analysing materials by the use of wave or particle radiation, e.g. X-rays or neutrons, not covered by groups G01N3/00 – G01N17/00, G01N21/00 or G01N22/00 by using diffraction of the radiation by the materials, e.g. for investigating crystal structure; by using scattering of the radiation by the materials, e.g. for investigating non-crystalline materials; by using reflection of the radiation by the materials
    • G01N23/207—Diffractometry using detectors, e.g. using a probe in a central position and one or more displaceable detectors in circumferential positions
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
    • C01P2002/00—Crystal-structural characteristics
    • C01P2002/70—Crystal-structural characteristics defined by measured X-ray, neutron or electron diffraction data
    • C01P2002/72—Crystal-structural characteristics defined by measured X-ray, neutron or electron diffraction data by d-values or two theta-values, e.g. as X-ray diagram
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
    • C01P2006/00—Physical properties of inorganic compounds
    • C01P2006/80—Compositional purity

Definitions

  • This invention relates to the quantitative analysis of rare earth compounds by X-ray diffraction. More particularly, the assay can be used to determine lanthanum hydroxycarbonate impurities in a lanthanum carbonate composition.
  • the lanthanum hydroxycarbonate may also be made in a purified form for use as a standard.
  • Lanthanum carbonate hydrate which has been used to treat hyperphosphatemia (see, e.g., U.S. Pat. No. 5,968,976) and hyperphosphatemia in patients with renal failure (see, e.g., JP 1876384), is a molecule which is prone to decarboxylation under certain stressful conditions such as high heat and elevated humidity. These conditions may be present during the manufacture of lanthanum carbonate hydrate or during the storage of the unformulated or formulated material.
  • the decarboxylation product is lanthanum hydroxycarbonate.
  • Certain forms of lanthanum carbonate have been used to treat hyperphosphatemia in patients with renal failure (see, e.g., JP 1876384).
  • U.S. Pat. No. 5,968,976 owned by the assignee of the present invention, describes the preparation and use in a pharmaceutical composition of certain hydrates of lanthanum carbonate for the treatment of hyperphosphatemia.
  • HPLC high performance liquid chromatography
  • Both La 2 (CO 3 ) 3 and LaCO 3 OH are insoluble in water and standard organic solvents. Either may be dissolved in acidic solution, but in doing so, reactions occur which form impurities in the sample. For example, dissolution of either La 2 (CO 3 ) 3 or LaCO 3 OH in aqueous hydrochloric acid results in a solution of lanthanum chloride, (LaCl 3 ). Since both materials give the same product after dissolution of a sample in acid, there is no way to distinguish La 2 (CO 3 ) 3 from LaCO 3 OH. Similarly, the same salt is formed when either material is dissolved in other aqueous acids.
  • LaCO 3 OH contains 64.3% La
  • La 2 (CO 3 ) 3 tetrahydrate contains 52.4% La
  • a mixture of 1% LaCO 3 OH in La 2 (CO 3 ) 3 tetrahydrate would contain 52.5% La.
  • XRPD x-ray powder diffraction
  • a method of assaying the purity of a rare earth compound having at least one known impurity, wherein at least one of the salt or impurity is a compound that disassociates in aqueous media comprising:
  • MQL minimum quantitation limit
  • the rare earth compound is a lanthanum carbonate composition and the known impurity is one or more polymorph of lanthanum hydroxycarbonate.
  • the method further comprises (v) classifying the predicted concentrations as:
  • the present invention also provides a method of preparing a lanthanum carbonate comprising:
  • MQL minimum quantitation limit
  • the present invention also provides a pharmaceutical composition
  • lanthanum hydroxycarbonate form (I) characterized by an X-ray powder diffraction pattern having reflections at approximately 17.7, 24.4, and 30.3° two theta, wherein the lanthanum hydroxycarbonate content of the composition comprises at least 96% lanthanum hydroxycarbonate form (I).
  • the two theta values will be within ⁇ 0.2° of the listed values, and more preferably, the two theta values will be within ⁇ 0.1° of the listed values.
  • the composition comprises at least 98% lanthanum hydroxycarbonate form (I), and even more preferably, the composition comprise at least 99% lanthanum hydroxycarbonate form (I).
  • FIG. 1 is an XRPD (x-ray powder diffraction) pattern of La 2 (CO 3 ) 3 .4H 2 O.
  • FIG. 2 is an XRPD pattern of La 2 (CO 3 ) 3 .8H 2 O.
  • FIG. 3 is an XRPD pattern of La(CO 3 )OH form (II).
  • FIG. 4 is an XRPD pattern of La(CO 3 )OH form (I).
  • FIG. 5 is an overlay of 4 XRPD patterns of La 2 (CO 3 ) 3 .4H 2 O (top pattern), La 2 (CO 3 ) 3 .8H 2 O, La(CO 3 )OH 3 form (I) and La(CO 3 )OH form (II) (bottom pattern).
  • FIG. 6 depicts the actual concentration of La(CO 3 )OH form (I) standards compared to the concentration of La(CO 3 )OH form (I) as calculated by the Rietveld method and a linear regression.
  • FIG. 7 depicts the actual concentration of La(CO 3 )OH form (II) standards compared to the concentration of La(CO 3 )OH form (II) as calculated by the Rietveld method and a linear regression.
  • FIG. 8 is an XRD Overlay of four samples containing La 2 (CO 3 ) 3 .4H 2 O and La(CO 3 )OH and a La(CO 3 )OH standard.
  • FIG. 9 is an XRD Overlay of four samples containing La 2 (CO 3 ) 3 .4H 2 O and La(CO 3 )OH and a La(CO 3 )OH standard.
  • the terms “about” or “approximately” mean within an acceptable range for the particular parameter specified as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, e.g., the limitations of the sample preparation and measurement system. Examples of such limitations include preparing the sample in a wet versus a dry environment, different instruments, variations in sample height, and differing requirements in signal-to-noise ratios. For example, “about” can mean a range of up to 20% of a given value, and more preferably means a range of up to 10%. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, preferably within 5-fold, and more preferably within 2-fold, of a value.
  • “Lanthanum carbonate” as used herein encompasses all polymorphs of hydrated forms of lanthanum carbonate and of anhydrous lanthanum carbonate.
  • hydrated lanthanum carbonate refers to lanthanum carbonate having water content approximately equivalent to 4-5 moles of water.
  • “Lanthanum hydroxycarbonate” as used herein encompasses all polymorphs of lanthanum hydroxycarbonate, including form (I) and form (II).
  • the term HC(I) refers to lanthanum hydroxycarbonate polymorphic form (I) as described by the XRD pattern in FIG. 3 .
  • the term HC(II) refers to lanthanum hydroxycarbonate polymorphic form (II) as described by the XRD pattern in FIG. 4 .
  • rare earth compound refers to a compound containing at least one rare earth element of the lanthamide series, yttrium, scandium, and thorium.
  • the lanthamide series comprises cerium, praseodymium, neodymium, samarium, europium, gadolinium, terbium, dysprosium, holmium, erbium, thulium, ytterbium, and lutetium.
  • Each of these elements closely resemble lanthanum in their chemical and physical properties, each having similar so that any given compound of the rare earths is likely to crystallize with the same structure as any other rare earth. Similar salts of these metals will have common properties including reacting with water to liberate hydrogen, binding to water, and acting as strong reducing agents.
  • Percent or “%” as used herein refers to the percentage by weight of the total composition unless otherwise noted.
  • substantially pure when referring to either lanthanum carbonate or lanthanum hydroxycarbonate, refers to the lanthanum compound having about 90% purity or greater, on an anhydrous basis.
  • the purity is about 95% or greater; more preferably, the purity is 98% or greater; even more preferably, the purity is 99% or greater. It is preferred that the purity is 99.2% or greater; more preferably, the purity is 99.4% or greater; even more preferably, the purity is 99.6%; even more preferably, the purity is 99.8% or greater; and even more preferably, the purity is 99.9% or greater.
  • salt refers to the ionic product of a reaction between a metallic oxide and an acid.
  • the salts useful in the present invention are salts of rare earth elements such as lanthanum.
  • lanthanum salt refers to lanthanum bound to a negatively charged anion to create a neutral species.
  • hydrolysable lanthanum salts include, but are not limited to lanthanum methoxyethoxide, lanthanum acetate, lanthanum acetylacetonate, lanthanum oxalate, and hydrates thereof . . .
  • the hydrolzable lanthanum salt is a lanthanum (III) salt.
  • a compound that disassociates in aqueous media means that at least some of the compound separates into two or more components such as La 2 (CO 3 ) 3 separating into La 3+ and CO 3 2 ⁇ . This disassociation may be induced by an acidic environment (e.g., aqueous HCl) and may be followed by the formation of salts such as LaCl 3 .
  • an acidic environment e.g., aqueous HCl
  • Rietveld analysis and “Rietveld method” as used herein mean the data is analyzed using the constrained, full pattern analytical model first developed by Rietveld ( Acta. Crystallogr., 22, 151-2, 1967, and J. Appl. Crystallogr., 2, 65-71, 1969).
  • Constrained analysis means that the analytical model is limited, or constrained, using one or more parameters obtained from chemical or other information about the sample.
  • the assay for the impurity lanthanum hydroxycarbonate in a lanthanum carbonate sample may be constrained using the knowledge of the crystal structure of the components in the sample: lanthanum carbonate tetrahydrate, other lanthanum carbonate hydrates, lanthanum hydroxycarbonate form (I) and lanthanum hydroxycarbonate form (II).
  • a full-pattern analysis is one in which the full XRD pattern in analyzed instead of only the more intense peaks.
  • the full pattern encompasses a range of two-theta values, and may include, for example, the range from 9 to 40 °2 ⁇ , or from 10 to 35 °2 ⁇ .
  • Rietveld analysis and “Rietveld method” also include analyses using a modification of the Rietveld method, such as those described by Bish, D. L. and Howard, S. A. 1988 ( J. Appl. Crystallography, 21, 86-91). Other modifications of the Rietveld method are also contemplated as within the scope of the Rietveld analysis.
  • Lanthanum carbonate has the general formula La 2 (CO 3 ) 3 .xH 2 O, wherein x has a value from 0 to 10.
  • a common form of the hydrate has an average x value of about between 3 and 5.
  • the hydration level of the lanthanum compound can be measured by methods well known in the art, such as thermo gravimetric analysis (TGA) or x-ray powder diffraction (XRPD).
  • La 2 (CO 3 ) 3 hydrate to hydrothermal conditions (water at high temperature and pressure) affords lanthanum hydroxycarbonate (LaCO 3 OH).
  • La 2 (CO 3 ) 3 hydrate used as an active pharmaceutical ingredient would contain the degradation product LaCO 3 OH, either as polymorph (I) or polymorph (II).
  • Lanthanum carbonate tetrahydrate and octahydrate can be made by methods known in the art including the method described in U.S. Pat. No. 5,968,976.
  • the degradation of lanthanum carbonate into lanthanum hydroxycarbonate can be observed by examining an XRPD pattern of a potentially degraded lanthanum carbonate sample.
  • the presence of observable peaks corresponding to lanthanum hydroxycarbonate in the sample pattern indicates degradation whereas the absence of observable peaks indicates no detectable degradation.
  • lanthanum hydroxycarbonate may be synthesized by methods known in to those skilled in the art including, (I) from hydrated lanthanum(III) carbonate under hydrothermal conditions as disclosed in Haschke, J., J. Solid State Chemistry, 12 (1975) 115-121; (2) from LaBr(OH) 2 treated with carbon dioxide or from hydrolysis of lanthanum carbonate as disclosed in Sun, J.; Kyotani, T.; Tomita, A. J. Solid State Chem., 65 (1986) 94; (3) the treatment of lanthanum(III) nitrate with urea or thiourea as disclosed in Han et al.
  • rare earth compounds will degrade or react to form impurities in the product sample.
  • compounds such as lanthanum citrate, acetate, lactate methoxyethoxide, acetylacetonate, oxalate, and hydrates thereof may be analyzed in the same manner as disclosed herein for the lanthanum carbonate.
  • lanthanum acetate will degrade to form a hydroxy derivative (i.e., La(OAc) 3-x (AcAc) x , will hydrolyzed into La(AcAc) 3-x (OH) x (Yin, M Z et al., J Zhejiang Univ Sci. 2004 5(6), 696-8)). It is contemplated that concentrations of lanthanum hydroxyacetate impurities can be determined in the same or similar manner as described herein for lanthanum hydroxycarbonate by replacing the hydroxycarbonate standards with hydroxyacetate standards and modifying the parameters used in the Rietveld analysis for the crystal of the hydroxyacetate isoform(s).
  • lanthanum citrate i.e., La(Hcit)(H 2 O)] n where (Hcit 3 ⁇ ) is C(OH)(COO ⁇ )(CH 2 COO ⁇ ) 2
  • Lanthamide citrate has a structure comprising chains of La(III) cations bridged by O—C—O groups with pendant Hcit anions; the Hcit ligand is involved in six La—O bonds to five different La centers.
  • concentrations of lanthanum hydroxycitrate impurities can be determined in the same or similar manner as described herein for lanthanum hydroxycarbonate by replacing the hydroxycarbonate standards with hydroxycitrate standards and modifying the parameters used in the Rietveld analysis for the crystal of the hydroxycitrate isoform(s).
  • rare earth salts will degrade similarly to lanthanum salts since these elements closely resemble lanthanum in their chemical and physical properties. Therefore, some degradation impurities of other rare earth salts may also be analyzed using the XRD analysis method of the present invention for other rare earth metal salts.
  • an XRD of both the compound and the degradation product must be obtained and the parameters used in the Rietveld analysis for the crystal structures must be obtained as appropriate for the compounds used, as described herein for the parameters used for analysis of lanthanum hydroxycarbonate.
  • the two spectra must differ in at least one structural feature. Preferably, this feature will comprise a number of unique positions (2 theta) and intensities.
  • the reference samples will span a range from 0-50% of the impurity (each polymorph if more than one polymorph is in the sample), or more preferably 0-30%. In another embodiment, the reference samples span only a narrow range of, for example, 0-10% of the impurity.
  • the standards are used to calibrate the scale factors in the analytical model described herein.
  • polymorph (II) For the more stable of the two lanthanum hydroxycarbonate polymorphs, form (II), the production of a substantially pure sample is accomplished by the methods known in the art. However, the production of polymorph (I) is not as simple since this compound is not soluble in many of the organic solutions commonly used for recrystallizing and forming different polymorphs.
  • Factors important to the synthesis of hydroxycarbonate polymorph (I) include temperature, humidity, the presence of unreacted La(OH) 3 , reaction scale, and the particle size of the starting material.
  • Ammonium carbonate was therefore used as an additive to liberate carbon dioxide as it was heated, providing a constant source of the inhibitor of the reaction leading to polymorph (II). Indeed, the major product in most of these reactions was polymorph (I). By using an amount of ammonium carbonate which was approximately 25% of the weight of La 2 (CO 3 ) 3 .8H 2 O, the formation of polymorph (II) was completely suppressed and the product was pure polymorph (I).
  • This substantially pure form (I) can then be used to create a standard used in the Rietveld analysis of the content of LaCO 3 OH form (I) in a sample. Additionally, this polymorph is useful as a pharmaceutical agent. Similar to the carboxylated salt, LaCO 3 OH form (I) can be used to treat hyperphosphatemia.
  • the substantially pure compound can optionally be mixed with one or more pharmaceutically acceptable carrier or excipient and used in the manner described for La 2 (CO 3 ) 3 hydrate.
  • substantially pure form (II) can be used as both a standard used for the Rietveld analysis to determine the content of LaCO 3 OH form (II) in a sample and as a pharmaceutical agent, such as an agent for the treatment of hyperphosphatemia.
  • This isoform can be administered to a patient as an active agent or in a pharmaceutical composition without also administering form (I) or other impurities to the patient as well.
  • a pharmaceutical agent containing a known mixture of form (I) and form (II) LaCO 3 OH can be formed and used for treating hyperphosphatemia.
  • PLS partial least squares
  • Goodness-of-fit metrics like the spectral F ratio provide a measure of how well measured data fit the model.
  • PLS is a useful approach when the components to be monitored experience severe overlap with other components in the mixture, when the correlation between concentration and absorbance is very complex, or when additional components whose concentrations are unknown may be present in the sample mixture. Since PLS is a statistical analysis technique, a large number of standards are needed in order to correlate the analytical data with concentration.
  • La 2 (CO 3 ) 3 tetrahydrate LaCO 3 OH polymorph (I), and LaCO 3 OH polymorph (II) were not available in the literature.
  • the present invention provides structural models of the latter three materials based on XRPD data and the structures of similar materials in the literature. It was found that La 2 (CO 3 ) 3 tetrahydrate is a layered structure in which the layers consist of La 2 (CO 3 ) 3 species with water bound between the layers. On the other hand, both polymorphs of LaCO 3 OH are strongly bonded in all three dimensions. The result is that La 2 (CO 3 ) 3 tetrahydrate breathes with increasing or decreasing amounts of water; the layers are further apart with increasing amounts of water.
  • the Rietveld method varies structural factors derived from the crystal structures in order to generate the best fit of measured and calculated XRPD patterns. Since the structure of La 2 (CO 3 ) 3 tetrahydrate does not change sample-to-sample, but only expands or contracts based on water content, Rietveld treatment can model the layer separation differences based on the underlying structure.
  • I j(0) and I j(c) are the intensity observed and intensity calculated by the Rietveld refinement, respectively, at the jth step in the data, and wj is the weight.
  • the refinement iteratively fits to the data by modifying the structure and instrument parameters.
  • This method is also advantageous because it uses the whole XRD pattern instead of a number of selected peaks. This, although increasing the calculation time, provides for much greater accuracy and precision of the fit.
  • the results returned from the Rietveld analysis are based on the following criteria: Predicted Concentration Reported Value ⁇ LOD “non-detectable, complies” LOD - MQL user input needed MQL -upper analytical report concentration, “does not comply” limit >upper analytical limit >upper analytical limit, “does not comply” where LOD is the limit of detection, or detection limit, given at a 99% confidence limit.
  • MQL is the minimum quantitation limit, which may also be defined as the limit of quantitation (LOQ) is the limit at which accurate quantitation is possible.
  • MQL may be expressed as 10( ⁇ /S), where ⁇ is the standard deviation of the observed response of samples free of analyte and S is the slope of the response curve.
  • the individual XRDP patterns should be co-added (when more than one XRDP was obtained) and visually examine for the presence of hydroxycarbonate versus the hydroxycarbonate reference patterns. Report either “Detected Rietveld, none detected visual-complies” or “Detected Rietveld and visual—does not comply”.
  • the assay of the present invention preferably follows the analytical guidelines provided by the International Committee on Harmonization (1CH) document (November 1996) “Guidance for Industry, Q2B Validation of Analytical Procedures: Methodology.” These guidelines include limitations on specificity, linearity and range, precision, detection limits, minimum quantitation limits, accuracy of the validation standards, system suitability, and ruggedness.
  • the assay of the present invention is particularly useful since it is able to analyze impurity content of an active agent in the presence of excipients.
  • excipients As discussed below, a tablet form of lanthanum carbonate can be tested for the relative weight percent of the hydroxycarbonate polymorphs. These excipients do not significantly interfere with the analytical measurements.
  • the starting material, La 2 (CO 3 ) 3 .4H 2 O was provided by Shire Pharmaceutical and was analyzed by XRPD to confirm its identity.
  • a mixture of about 1500 g (2.8 mol) of La 2 (CO 3 ) 3 .4H 2 O and 10 liters of water was heated to approximately 60° C. for approximately 2 h.
  • a sample was removed and analyzed by XRPD.
  • the mixture was heated to approximately 70° C. for approximately 17 h.
  • a sample was removed and analyzed by XRPD.
  • the mixture was heated to approximately 80° C. for approximately 7 h.
  • the mixture was heated to approximately 90° C. for approximately 13 h.
  • a portion of the sample was analyzed by XRPD. Another portion was analyzed by an ICP metal scan (Quantitative Technologies Inc.) to give 220 ppm K, and less than 20 ppm for each of the other quantifiable atoms tested. This sample was assayed by titration and Karl Fischer analysis for water content. The sample contained 96.3% lanthanum, 93.6% hydroxy carbonate, and a water content of ⁇ 1%.
  • a portion of the sample was analyzed by XRPD. Another portion was analyzed by an ICP metal scan (Quantitative Technologies Inc.) to give 214 ppm K, 192 ppm Si, and less than 20 ppm for each of the other quantifiable atoms tested. A 1.3 g portion of this sample was assayed by titration to give 94.6% lanthanum, 94.0% hydroxy carbonate.
  • X-ray powder diffraction was used to determine the lanthanum hydroxycarbonate (I and II) concentrations in lanthanum carbonate tetrahydrate. Quantitation was based on Rietveld modeling and calibration against a set of 28 standards. Analytical figures-of-merit (accuracy, precision, robustness) were derived from an independent data set. Reported concentrations are weight percent relative to the total drug substance. This method assumes that lanthanum carbonate tetrahydrate was the major component of the active pharmaceutical ingredient, and that the only other species present in the lanthanum carbonate were lanthanum carbonate octahydrate and hydroxycarbonate (I and II).
  • the materials used to generate calibration and validation samples were sieved using a 106 ⁇ m sieve.
  • the hydrates of La 2 (CO 3 ) 3 were prepared using methods known in the art such as those described in U.S. Pat. No. 5,968,976.
  • the pure hydroxycarbonate compounds used to make the calibration and validation samples are made in Examples 6.1 and 6.2. All sample mixtures were prepared by geometric mixing to ensure sample homogeneity. The X-ray structure of these samples are shown in FIGS. 1-4 .
  • XRPD analyses were performed using a Shimadzu XRD-6000 X-ray powder diffractometer using Cu Ka radiation.
  • the instrument was equipped with a long fine focus X-ray tube.
  • the tube voltage and amperage were set to 40 kV and 40 mA, respectively.
  • the divergence and scattering slits were set at 1° and the receiving slit was set at 0.15 mm.
  • Diffracted radiation was detected by a NaI scintillation detector.
  • a theta-two theta continuous scan at 1°/min (1.2 sec/0.02° step) from 9 to 40 °2 ⁇ was used, and the sample was rotated at 50 rpm during analysis.
  • a silicon standard was analyzed to check the instrument alignment. Data were collected and analyzed using XRD-6000 v. 4.1. Samples were analyzed in a back-fill aluminum holder.
  • the files were converted to ascii-format and the individual diffractograms were x-axis shifted as necessary using the ⁇ 18.4° reflection of lanthanum carbonate XRPD pattern as the shift reference (GRAMS) and export the files to the format used for the full-pattern analysis (pm format for the Maud Rietveld Analysis software).
  • GRAMS shift reference
  • XRPD diffractograms were converted to ASCII format using Shimadzu software (Shimadzu XRD-6000 v4.1) or File-Monkey (v1.1), and converted to .spc file format using GRAMS software (v6.0).
  • the diffractograms were examined for two-theta correspondence versus a standard pattern and if necessary, the patterns were x-axis shifted using the ⁇ 18.4° reflection as the shift reference.
  • the diffractograms were then converted to prn format using GRAMS, and Rietveld analysis was performed using Maud software (Material Analysis Using Diffraction; www.ing.unitn.it/luttero/maud/, v1.998).
  • % Recovery (Predicted % Analyze)/(Actual % Analyte) ⁇ 100%
  • FIGS. 1-4 XRPD patterns of the lanthanum carbonate tetrahydrate, octahydrate, and hydroxycarbonate (I), and hydroxycarbonate (II) used as components for calibration and validation mixtures are shown in FIGS. 1-4 .
  • Visual examination of the XRPD overlay of the four components shows regions in which any single component can be clearly differentiated from the others.
  • XRPD analysis demonstrates specificity for these components and is therefore a suitable technique for quantitation.
  • Rietveld results for the 28 mixtures used as calibration standards and the average values for the triplicate determinations are: Rietveld Rietveld Actual Avg % Actual Avg % Sample % HC(I) HC(I) Error % HC(II) HC(II) Error 1 2.54 2.36 0.03 1.20 1.58 0.15 2 0.00 0.52 0.27 3.81 3.64 0.03 3 5.00 4.35 0.43 1.20 1.54 0.12 4 0.00 0.35 0.12 1.20 1.54 0.12 5 2.49 2.40 0.01 3.76 3.59 0.03 6 1.74 1.60 0.02 2.87 2.98 0.01 7 0.00 0.41 0.17 6.39 5.58 0.66 8 0.00 0.35 0.12 5.97 5.54 0.19 9 0.00 0.15 0.02 1.13 1.35 0.05 10 4.84 4.30 0.29 6.30 5.76 0.30 11 10.05 8.23 3.31 1.13 1.57 0.19 12 5.04 4.19 0.72 1.13 1.53 0.16 13 0.00 0.57 0.32 11.31 9.66 2.75 14 3.68
  • the Rietveld hydroxycarbonate (I) response was done for the 28 calibration standards spanning 0-30% hydroxycarbonate(I).
  • the root-mean-square error of the uncalibrated Rietveld data is 1.52%.
  • the slope of the response curve is the sensitivity of the Rietveld response per unit concentration (0.8127). This slope is subsequently used in calculating the minimum quantitation limit for hydroxycarbonate (I) determination.
  • the response data were used to generate a linear regression model for hydroxycarbonate (I) determination across the full calibration range.
  • the correlation coefficient for this model is 0.9986, and the predicted values from this model exhibit a root-mean-square error of 0.27%.
  • the Rietveld hydroxycarbonate(II) response for the 28 calibration standards spanned a concentration range of 0.9-31% hydroxycarbonate.
  • the root-mean-square error of the uncalibrated Rietveld data is 1.54%.
  • the slope of this curve is the sensitivity of the Rietveld response per unit concentration (0.8199). This slope is subsequently used in calculating the minimum quantitation limit for hydroxycarbonate (II) determination.
  • the response data were used to generate a linear regression model for hydroxycarbonate (II) determination across the full calibration range.
  • the correlation coefficient for this model is 0.9955, and the predicted values from this model exhibit a root-mean-square error of 0.4861%.
  • the detection limit (LOD) was established by calculating the upper 99% confidence limit of the response observed in the 9 samples visually free of analyte. These values are: Average Predicted Concentration Standard Detection Analyte (Analyte-free Samples) Deviation Limit HC(I) ⁇ 0.13% 0.229% 0.55% HC(II) 0.02% 0.091% 0.29% H. Minimum Quantitation Limit
  • Accuracy may be reported as percent recovery by the assay of the known amount of analyte in the validation standard.
  • Six validation standards were prepared, with analyte concentrations ranging from 0.5 to 10% for HC(I) and 1.8 to 10.9% for HC(II).
  • Octahydrate was allowed to vary from 0.5 to 10%.
  • Recovery data for the validation standards for hydroxycarbonate (I) and (II), respectively are: Accuracy of Validation Standards Analyte Actual Range, % % Recovery (all data) HC(I) 4.3-10.1 90.4 ⁇ 9.0 HC(II) 1.8-10.9 98.1 ⁇ 6.4 J. System Suitability
  • This quantitative method is applicable for the determination of lanthanum hydroxycarbonate (I and II) in lanthanum carbonate tetrahydrate lanthanum carbonate samples.
  • the method is preferred for samples containing at least 68% of La 2 (CO 3 ) 3 tetrahydrate.
  • XRPD analysis can reliably determine lanthanum hydroxycarbonate (I and II) in lanthanum carbonate lanthanum carbonate as summarized below: Detection Quantitation Upper Analytical Analyte Limit (LOD) Limit (MQL) Limit Hydroxycarbonate (I) 0.55% 2.82% 30% Hydroxycarbonate (II) 0.29% 1.11% 31%
  • the tablets can be represented as % weight of LHC/weight of ingoing lanthanum carbonate hydrate.
  • Lanthanum hydroxycarbonate polymorph (I) and (II) limit of detection (LOD) and LOQ for the tablet by Rietveld analysis is provided as follows, with the number in parentheses corresponding to the equivalent percent of ingoing lanthanum carbonate hydrate.
  • Detection Limit Quantitation Limit Analyte (LOD) MQ L
  • Hydroxycarbonate (I) 0.65% (2.5%) 1.8% (6.8%) Hydroxycarbonate (II) 0.23% (0.9%) 2.0% (7.6%)

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US11/418,666 US20070259052A1 (en) 2006-05-05 2006-05-05 Assay for lanthanum hydroxycarbonate
CA002651344A CA2651344A1 (en) 2006-05-05 2007-02-01 Assay for lanthanum hydroxycarbonate
JP2009509898A JP2009536356A (ja) 2006-05-05 2007-02-01 水酸化炭酸ランタンの分析方法
MX2008014148A MX2008014148A (es) 2006-05-05 2007-02-01 Ensayo para hidroxicarbonato de lantano.
SG201103215-8A SG171656A1 (en) 2006-05-05 2007-02-01 Assay for lanthanum hydroxycarbonate
CNA2007800245933A CN101484798A (zh) 2006-05-05 2007-02-01 碱式碳酸镧的检定法
PCT/US2007/061461 WO2007130721A2 (en) 2006-05-05 2007-02-01 Assay for lanthanum hydroxycarbonate
KR1020087029695A KR20090016465A (ko) 2006-05-05 2007-02-01 란타늄 하이드록시카보네이트 분석
AU2007248374A AU2007248374A1 (en) 2006-05-05 2007-02-01 Assay for lanthanum hydroxycarbonate
BRPI0710343-3A BRPI0710343A2 (pt) 2006-05-05 2007-02-01 método para ensaio da pureza de um composto terroso raro, método para ensaio da concentração do hidroxicarbonato de lantánio em uma composição de carbonato de lantánio método para preparar carbonato de latánio e composição farmacêutica
EA200802169A EA200802169A1 (ru) 2006-05-05 2007-02-01 Способы анализа гидроксикарбоната лантана
TW096107691A TW200742849A (en) 2006-05-05 2007-03-06 Assay for lanthanum hydroxycarbonate
US11/932,367 US7618656B2 (en) 2006-05-05 2007-10-31 Method for use of lanthanum carbonate pharmaceutical compositions
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MA31414A MA31601B1 (fr) 2006-05-05 2008-11-25 Dosage pour l'hydrocarbonate de lanthane
NO20085063A NO20085063L (no) 2006-05-05 2008-12-04 Analyse for lantanhydroksykarbon
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