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Assay for lanthanum hydroxycarbonate

a technology of lanthanum hydroxycarbonate and xray diffraction, which is applied in the direction of instruments, drug compositions, extracellular fluid disorders, etc., can solve the problems of inability to develop quantitative methods to monitor the presence of degradants, inability to distinguish pure pharmaceutical agents from pharmaceutical agents containing, and inability to use chromatographic techniques such as hplc to develop quantitative methods

Inactive Publication Date: 2007-11-08
SHIRE INT LICENSING
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0036] The above features and many other attendant advantages of the invention will be better understood by reference to the following detailed description.

Problems solved by technology

Since both materials give the same product after dissolution of a sample in acid, there is no way to distinguish La2(CO3)3 from LaCO3OH.
Because of the insolubility of La2(CO3)3 and LaCO3OH in standard solvents, and the fact that each substance reacts to form the same material in acidic solvents, chromatographic techniques such as HPLC cannot be used to develop quantitative methods to monitor the presence of degradants.
However, this is impractical because the lanthanum content of both species is very similar.
Thus, one would be unable to distinguish pure pharmaceutical agent from pharmaceutical agents containing, for example, 1% degradant, which is an amount of degradant in excess of amounts typically allowed by regulations.
However, most of these techniques are not capable of differentiating LaCO3OH from La2(CO3)3 hydrates.

Method used

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  • Assay for lanthanum hydroxycarbonate
  • Assay for lanthanum hydroxycarbonate
  • Assay for lanthanum hydroxycarbonate

Examples

Experimental program
Comparison scheme
Effect test

example 6.1

Preparation of Pure Hydroxycarbonate Polymorph (II)

[0090] The starting material, La2(CO3)3.4H2O, was provided by Shire Pharmaceutical and was analyzed by XRPD to confirm its identity. A mixture of about 1500 g (2.8 mol) of La2(CO3)3.4H2O 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. A sample was removed and analyzed by XRPD. The mixture was heated to approximately 90° C. for approximately 13 h. A sample was removed, analyzed by XRPD, and found to be completely hydroxycarbonate polymorph (II). The mixture was allowed to cool to ambient temperature and filtered. The solid was dried under vacuum pump pressure for approximately three days to give 1151 g of hydroxycarbonate polymorph (II).

[0091] A portion of the sample was analy...

example 6.2

Preparation of Pure Hydroxycarbonate Polymorph (I)

[0092] A mixture of 15.0 g of La2O3, 24.7 mL of 37.7% hydrochloric acid, and 42 mL of water was cooled to ice bath temperature and filtered. To the cold filtrate was added, dropwise, a solution of 15.7 g of ammonium carbonate in 70 mL of water. The resulting slurry was allowed to warm to ambient temperature and stirred overnight. The solids were recovered by vacuum filtration, washed with three 50-mL portions of water, allowed to dry in the air, and added to a solution of 6.31 g of ammonium carbonate in 107 mL of water. The resulting slurry was heated to reflux for approximately 24 h. A portion of solid was removed, analyzed by XRPD, and found to contain only hydroxycarbonate polymorph (I). The reaction slurry was vacuum filtered and the solids were allowed to dry in the air, washed with 76 mL of water, recovered by vacuum filtration, and again allowed to dry in the air to give 17.7 g of hydroxycarbonate polymorph (I).

[0093] A port...

example 6.3

XRD Using Visual and PLS Models

[0094] Lanthanum hydroxycarbonate was first analyzed using a visual and partial least squares method using the XRD data. The analytical method for lanthanum hydroxycarbonate in lanthanum carbonate was done as a 2-state process: a visual one and a quantitative one. Stage 1 was the visual evaluation of the XRD spectra to determine if any LHC was visible. The visual technique was used because this gave the lowest limit of detection (LOD) possible, certainly lower than a typical calculation modeling method such as PLS. However PLS modeling and analysis was used for the second stage to provide quantitation of the impurities. This gives LOD and limit of quantitation (LOQ) as follows:

Lanthanum hydroxycarbonate polymorph (I): LOD 1.7% visual LOQ 2% PLS

Lanthanum hydroxycarbonate polymorph (II): LOD 0.3% visual LOQ 3.4% PLS

[0095] Similarly, tablet samples were prepared and the LOD for each polymorph was estimated at 0.5% w / w of tablet weight (actually 0.39...

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Abstract

An assay for analytically determining the amount of an impurity in a solid sample is provided. This X-ray diffraction method preferably uses the Rietveld refinement.

Description

1. FIELD OF THE INVENTION [0001] 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. 2. BACKGROUND OF THE INVENTION [0002] 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. [0003] Certain forms of lanthanum carbonate have been used to treat hyperphosphate...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K33/24A61K33/244
CPCA61K33/24C01F17/005G01N23/207C01P2006/80C01P2002/72C01F17/247A61P7/00A61K33/244G01N23/20
Inventor HALLENBECK, DONALDBATES, SIMON
Owner SHIRE INT LICENSING
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