U.S. patent application number 15/133206 was filed with the patent office on 2016-10-13 for method.
The applicant listed for this patent is OPKO IRELAND GLOBAL HOLDINGS, LTD.. Invention is credited to Richard Jonathan Applewhite, James David Morrison, Maurice Sydney Newton, Nigel Peter Rhodes, Christopher John Rickard.
Application Number | 20160296557 15/133206 |
Document ID | / |
Family ID | 41129559 |
Filed Date | 2016-10-13 |
United States Patent
Application |
20160296557 |
Kind Code |
A1 |
Applewhite; Richard Jonathan ;
et al. |
October 13, 2016 |
METHOD
Abstract
There is provided a method of producing a mixed metal compound
that includes at least Mg.sup.2+ and at least Fe.sup.3+ having an
aluminum content of less than 10000 ppm, having an average crystal
size of less than 20 nm (200 .ANG.) comprising the steps of: (a)
combining a Mg.sup.2+ salt and a Fe.sup.3+ salt with
Na.sub.2CO.sub.3 and NaOH to produce a slurry, wherein the pH of
the slurry is maintained at from 9.5 to 11, and wherein the Na2CO3
is provided at an excess of 0 to 4.0 moles than is required to
complete the reaction (b) subjecting the slurry to mixing under
conditions providing a power per unit volume of 0.03 to 1.6
kW/m.sup.3 (c) separating the mixed metal compound from the slurry,
to obtain a crude product having a dry solid content of at least 10
wt % (d) drying the crude product.
Inventors: |
Applewhite; Richard Jonathan;
(Cheshire, GB) ; Morrison; James David; (Norwich,
GB) ; Newton; Maurice Sydney; (Sandbacj, GB) ;
Rhodes; Nigel Peter; (Warrington, GB) ; Rickard;
Christopher John; (Sandiway Northwich, GB) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
OPKO IRELAND GLOBAL HOLDINGS, LTD. |
Grand Cayman |
|
KY |
|
|
Family ID: |
41129559 |
Appl. No.: |
15/133206 |
Filed: |
April 19, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13388476 |
Apr 30, 2012 |
9314481 |
|
|
PCT/GB2010/051271 |
Aug 2, 2010 |
|
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15133206 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 33/06 20130101;
C01P 2006/12 20130101; A61K 33/06 20130101; A61P 3/12 20180101;
C01P 2002/22 20130101; C01P 2004/51 20130101; A61K 9/1611 20130101;
C01P 2004/61 20130101; A61K 33/26 20130101; C01P 2002/60 20130101;
A61P 7/00 20180101; C01P 2006/14 20130101; C01P 2006/11 20130101;
C01P 2002/72 20130101; A61K 6/84 20200101; A61K 33/10 20130101;
A61K 33/10 20130101; A61K 2300/00 20130101; A61K 9/1682 20130101;
A61K 9/143 20130101; A61K 2300/00 20130101; C01P 2004/64 20130101;
A61K 33/26 20130101; C01P 2006/82 20130101; C01G 49/009 20130101;
C01P 2006/80 20130101; A61K 45/06 20130101; A61K 2300/00 20130101;
B82Y 30/00 20130101 |
International
Class: |
A61K 33/26 20060101
A61K033/26; C01G 49/00 20060101 C01G049/00; A61K 9/16 20060101
A61K009/16 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 3, 2009 |
GB |
913525.2 |
Claims
1. A method of producing a mixed metal compound comprising at least
Mg.sup.2+ and at least Fe.sup.3+ having an aluminium content of
less than 10000 ppm, having an average crystal size of less than 20
nm (200 .ANG.) comprising the steps of: (a) combining a Mg.sup.2+
salt and a Fe.sup.3+ salt with Na.sub.2CO.sub.3 and NaOH to produce
a slurry, wherein the pH of the slurry is maintained at from 9.5 to
11, and wherein the Na.sub.2CO.sub.3 is provided at an excess of 0
to 4.0 moles than is required to complete the reaction (b)
subjecting the slurry to mixing under conditions providing a power
per unit volume of 0.03 to 1.6 kW/m.sup.3 (c) separating the mixed
metal compound from the slurry, to obtain a crude product having a
dry solid content of at least 10 wt % (d) drying the crude product
either by (i) heating the crude product to a temperature of no
greater than 150.degree. C. and sufficient to provide a water
evaporation rate of 0.05 to 1.5 kg water per hour per kg of dry
product, or (ii) exposing the crude product to rapid drying at a
water evaporation rate of 500 to 50000 kg water per hour per kg of
dry product.
2. A method according to claim 1 wherein the compound is of the
formula
M.sup.II.sub.1-xM.sup.III.sub.x(OH).sub.2A.sup.n-.sub.y.mH.sub.2O
(II) wherein M.sup.II is one or more bivalent metals and is at
least Mg.sup.2+; M.sup.III is one or more trivalent metals and is
at least Fe.sup.3+; A.sup.n- is one or more n-valent anions and is
at least CO.sub.3.sup.2-; x/.SIGMA.yn is from 1 to 1.2
0<x.ltoreq.0.4, 0<y.ltoreq.1 and 0<m.ltoreq.10.
3. (canceled)
4. (canceled)
5. A method according to claim 1 wherein the molar ratio of
Mg.sup.2+ to Fe.sup.3+ is 2.5:1 to 1.5:1.
6. A method according to claim 1 wherein the compound has an
average crystal size of from 10 to 20 nm (100 to 200 .ANG.).
7. (canceled)
8. (canceled)
9. A method according to claim 1 wherein the total sulphate content
of the compound is from 1.8 to 4.2 wt %.
10. A method according to claim 1 wherein the interlayer sulphate
content of the compound is from 2.1 to 5 wt %.
11.-20. (canceled)
21. A method according to claim 1 wherein in step (b) the slurry
conditions are controlled such that a d50 particle size
distribution of at least 40 .mu.m is provided.
22. A method according to claim 1 wherein in step (c) the mixed
metal compound is separated from the slurry, to obtain a crude
product having a dry solid content of at least 15 wt %.
23.-26. (canceled)
27. A method according to claim 1 wherein in step (d) the crude
product is dried to a moisture content less than 15 wt %.
28.-31. (canceled)
32. A method according to claim 1 wherein the dried crude product
is milled to a d50 average particle size of less than 200
.mu.m.
33.-39. (canceled)
40. A method according to claim 1 for the production of a mixed
metal compound having a sodium content expressed as Na.sub.2O of
less than 0.5 wt %.
41. (canceled)
42. A method according to claim 1 for the production of a mixed
metal compound having a phosphate binding capacity of more than 0.6
mmol phosphate/g mixed metal compound.
43.-47. (canceled)
48. A mixed metal compound comprising at least Mg.sup.2+ and at
least Fe.sup.3+, wherein the molar ratio of Mg.sup.2+ to Fe.sup.3+
is 2.5:1 to 1.5:1, the mixed metal compound has an aluminium
content of less than 10000 ppm, the average crystal size of the
mixed metal compound is from 10 to 20 nm (100 to 200 .ANG.), and
the d50 average particle size of the mixed metal compound is less
than 300 .mu.m.
49. A mixed metal compound according to claim 48 wherein the d50
average particle size of the mixed metal compound is less than 200
.mu.m.
50.-52. (canceled)
53. A mixed metal compound comprising at least Mg.sup.2+ and at
least Fe.sup.3+, wherein the molar ratio of Mg.sup.2+ to Fe.sup.3+
is 2.5:1 to 1.5:1, the mixed metal compound has an aluminium
content of less than 10000 ppm, the average crystal size of the
mixed metal compound is from 10 to 20 nm (100 to 200 .ANG.), and
the interlayer sulphate content of the compound is from 2 to 5 wt
%
54.-63. (canceled)
64. A compound according to claim 48 wherein the compound is of the
formula
M.sup.II.sub.1-xM.sup.III.sub.x(OH).sub.2A.sup.n-.sub.y.mH.sub.2- O
wherein M.sup.II is one or more bivalent metals and is at least
Mg.sup.2+; M.sup.III is one or more trivalent metals and is at
least Fe.sup.3+; A.sup.n- is one or more n-valent anions and is at
least CO.sub.3.sup.2-; x/.SIGMA.yn is from 1 to 1.2
0<x.ltoreq.0.4, 0<y.ltoreq.1 and 0<m.ltoreq.10.
65.-76. (canceled)
77. A mixed metal compound according to claim 48 for use in the
treatment of hyperphosphataemia.
78. A pharmaceutical composition comprising a mixed metal compound
as defined in claim 48 and optionally one or more pharmaceutically
acceptable adjuvants, excipients, diluents or carriers.
79.-82. (canceled)
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation application of U.S.
patent application Ser. No. 13/388,473 filed Apr. 30, 2012 which is
the U.S. national phase of International Application No.
PCT/GB2010/051271, filed Aug. 2, 2010, which claims the benefit of
United Kingdom Patent Application Serial No. 0913525.2, filed Aug.
3, 2009, the entire disclosures of which are hereby incorporated
herein by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to a method for producing
mixed metal compounds and to compounds prepared by these methods.
These compounds may have pharmaceutical activity, especially as
phosphate binders. The present invention further relates to novel
mixed metal compounds. Yet further the invention relates to
pharmaceutical compositions containing the above compounds and to
the pharmaceutical use of the compounds.
BACKGROUND OF THE INVENTION
Hyperphosphataemia
[0003] Hyperphosphataemia is an electrolyte disturbance in which
there is an abnormally elevated level of phosphate in blood.
Hyperphosphataemia is frequently seen in dialysis patients, as
standard dialysis regimes are unable to remove the ingested
phosphate load even with a low phosphate diet, and is associated
with an increased risk of death and the development of vascular
calcification. The presence of hyperphosphataemia leads to
hypocalcaemia, secondary hyperparathyroidism, reduced 1,25 Vit D3
and progressive metabolic bone disease. Hyperphosphataemia is
ultimately responsible for the increase in vascular calcification,
but recent studies have also suggested that the process may
additionally be influenced by 1,25 Vit D3 and an elevated
calcium-phosphate product. Patients who have chronically
uncontrolled hyperphosphataemia develop progressively extensive
soft tissue calcifications due to the deposit of Calcium/phosphate
product into skin, joints, tendons, ligaments. Eye deposits of
calcium/phosphate product have also been described.
[0004] Control of serum phosphate levels using oral phosphate
binders has, therefore, become a key therapeutic target in the
management of dialysis patients. These binders, taken with food,
render the contained phosphate insoluble and, therefore,
non-absorbable.
Phosphate Binders
[0005] Historically phosphate binders included aluminium salts.
However, use of aluminium salts was found to result in further
toxic complications due to aluminium accumulation, e.g. reduction
in haemoglobin production, impairment in natural repair and
production of bone and possible impairment of
neurological/cognitive function. Renal bone disease, osteomalacia
and dementia are the most significant toxicities related to the
absorption of aluminium. Other aluminium compounds such as
microcrystalline aluminium oxide hydroxide (boehmite) and certain
hydrotalcites were proposed for this use, such as disclosed in
Ookubo et al, Journal Pharmaceutical Sciences (November 1992), 81
(11), 1139-1140. However these suffer from the same drawbacks.
[0006] Calcium carbonate or calcium acetate are used as phosphate
binders. However these suffer from the drawback that they tend to
promote hypocalcaemia through the absorption of high amounts of
ingested calcium and are linked to accelerated cardiovascular
calcification which can cause serious side effects. Consequently,
frequent monitoring of serum calcium levels is required during
therapy with calcium-based phosphate binders. The National Kidney
Foundation Kidney Disease Quality Outcomes Initiative suggests the
limited use of calcium based salts (Clinical Practice Guidelines
for Bone Metabolism and Disease in Chronic Kidney Disease, Guide 5,
pg 1 pt 5.5). Recent efforts, therefore, have focused on the
development of phosphate binders free of calcium. More recently,
lanthanum carbonate and sevelamer HCl have been used as
calcium-free phosphate binders. Sevelamer hydrochloride is a
water-absorbing, non-absorbed hydrogel-cross-linked polyallylamine
hydrochloride but because of its structure also binds certain
fat-soluble vitamins and bile acids and is therefore reported in V.
Autissier et al, Journal of Pharmaceutical Sciences, Vol 96, No 10,
October 2007 to require large doses to be effective because it has
a higher propensity for the bound phosphate to be displaced by
these competing anions. A high pill burden or large tablets are
often associated with poor patient compliance and this type of
product is also considered relatively expensive to their calcium
counter parts. Sevelamer has also been associated with GI adverse
effects A. J. Hutchison et al, Drugs 2003; 63 (6), 577-596.
[0007] Lanthanum carbonate is a phosphate binder which has been
shown to be as effective as calcium carbonate with lower incidence
of hypocalcaemia. Long-term administration of lanthanum, a rare
earth element, continues to raise safety concerns with regards to
the potential accumulation of a rare earth metal in body tissue
which can be enhanced in renal failure--Tilman B Druke, Seminars in
Dialysis, Volume 20, Issue 4 page 329-332 July/August 2007.
[0008] Many known inorganic preparations for treatment of
hyperphosphataemia are efficient phosphate binders only over a
limited pH range. Moreover, particularly alkaline binders could
buffer the stomach pH up to a high level at which they would not
have a phosphate binding capacity.
[0009] To overcome the drawbacks associated with aluminium and also
problems of efficacy over a limited pH range, WO-A-99/15189
discloses use of mixed metal compounds which are free from
aluminium and which have a phosphate binding capacity of at least
30% by weight of the total weight of phosphate present, over a pH
range of from 2-8.
Mixed Metal Compounds
[0010] Mixed metal compounds (mixed metal compounds) exist as
so-called "Layered Double Hydroxide" (LDH) which is used to
designate synthetic or natural lamellar hydroxides with two kinds
of metallic cations in the main layers and interlayer domains
containing anionic species. This wide family of compounds is
sometimes also referred to as anionic clays, by comparison with the
more usual cationic clays whose interlamellar domains contain
cationic species. LDHs have also been reported as hydrotalcite-like
compounds by reference to one of the polytypes of the corresponding
[Mg--Al] based mineral. (See "Layered Double Hydroxides: Present
and Future", ed, V Rives, 2001 pub. Nova Science).
[0011] By mixed metal compound, it is meant that the atomic
structure of the compound includes the cations of at least two
different metals distributed uniformly throughout its structure.
The term mixed metal compound does not include mixtures of crystals
of two salts, where each crystal type only includes one metal
cation. Mixed metal compounds are typically the result of
coprecipitation from solution of different single metal compounds
in contrast to a simple solid physical mixture of two different
single metal salts. Mixed metal compounds as used herein include
compounds of the same metal type but with the metal in two
different valence states e.g. Fe(II) and Fe(III) as well as
compounds containing more than two different metal types in one
compound.
[0012] The mixed metal compound may also comprise amorphous
(non-crystalline) material. By the term amorphous is meant either
crystalline phases which have crystallite sizes below the detection
limits of x-ray diffraction techniques, or crystalline phases which
have some degree of ordering, but which do not exhibit a
crystalline diffraction pattern and/or true amorphous materials
which exhibit short range order, but no long-range order.
[0013] Mixed metal compounds provide unique challenges in using
inorganic material for pharma use and in particular for phosphate
binding and which are free of Al.
[0014] For example, use of mixed metal compound for attaining
phosphate therapeutic effects (or other pharma functional use)
depends on surface processes such as physisorption (ion-exchange)
and chemisorption (formation of a chemical bond) which is atypical
for a drug; the therapeutic activity of most drugs are based on
organic compounds which are typically more soluble.
[0015] Yet further, high daily and repeated long-term (chronic)
dosages are required for kidney patients but their total daily pill
count requires a low tablet burden due to restricted fluid intake.
Consequently, high dosage of drug substance is required in final
product (e.g. tablet) and the final product is therefore very
sensitive to the properties of the mixed metal compound drug
substance, unlike normal formulations. This means that the
properties of the tablet, including key physical properties, and
the tablet manufacturing processes, such as granulation, are often
primarily influenced by the properties of the mixed metal compound
active substance rather than solely by those of the excipients. In
order to be able to manufacture a pharmaceutical product comprising
such significant quantities of mixed metal compound with the
control and consistency necessary for pharmaceutical use, a means
of controlling an array of opposing chemical and physical
properties of the mixed metal compound is essential.
[0016] Therefore, considering these requirements, manufacture of
such materials, particularly at large scale, presents significant
problems. A number of these problems are described below.
Ageing
[0017] The ageing process (growth of crystallites) generally
increases with (unintended) increased processing and handling as
well as by the process whereby the crystallites are intentionally
grown by a combination of agitation and heat-treatment of the
reaction slurry before filtration. Control and prevention of
crystal growth can therefore be difficult.
[0018] The teachings of MgAl mixed metal compounds which are
manufactured in the aged form for medical applications such as
antacids, do not address the problems of manufacture of unaged
mixed metal compounds (on a larger scale), when the unaged form is
required, for example to maintain therapeutic activity of phosphate
binding.
[0019] Furthermore, when replacing Al for Fe we found that the
mixed metal compound changes properties such as to becoming more
difficult to wash and mill on a commercial scale.
[0020] Al-containing mixed metal compounds that are intentionally
aged to increase crystal growth have previously been manufactured
on a large scale. In contrast, there appear to be no examples of
large scale manufacture of unaged Al-free mixed metal
compounds.
[0021] The method disclosed in WO99/15189 relates to Al free mixed
metal compounds and includes examples of unaged and aged materials.
However, the products disclosed in this publication are provided at
relatively small scale. WO99/15189 does not address the problems of
provision of product at significant scale while avoiding aging of
the product.
[0022] The manufacture of unaged mixed metal Mg:Fe compounds (Mg:Fe
defined by molar ratio hereinafter) on a large scale is problematic
for a number of reasons. For example, the manufacture of unaged
mixed metal Mg:Fe compounds is problematic when using conventional
filtration methods. Unaged material results in a high pressure drop
through the filter cake during isolation leading to low filtration
rates or yield losses during conventional filtration. Furthermore,
these types of metal Mg:Fe compounds typically have small slurry
particle size and as such it is difficult to carry out isolation
whilst minimising ageing. For example, small particles can give
rise to increased processing times and/or handling issues.
[0023] Furthermore, too much processing and handling (e.g. milling
and overdrying) can present changes that are unacceptable in the
final mixed metal Mg:Fe compound. In particular with such
compounds, it is important to dry the material carefully as it is
easy to change the surface area or internal pore volume and hence
change the therapeutic activity. These typical morphology
properties are important characteristics affecting both the quality
of the final mixed metal compound and the downstream manufacturing
processes used to produce the final formulated pharmaceutical
product containing the mixed metal compound.
[0024] If processed incorrectly mixed metal compounds can become
unacceptably hard. This can lead to consequent issues of decreased
milling rates and higher energy input to achieve a given particle
size. This `knock on` effect to the processing may affect process
throughput and result in overworking the material and consequential
ageing.
[0025] Methods for lab-scale preparations of MgFe LDH's are
disclosed in art such as U.S. Pat. No. 4,629,626; Duan X, Evans D.
G., Chem. Commun., 2006, 485-496; W. Meng et al, J Chem. Sci., Vol.
117, No. 6 Nov. 2005, pp. 635-639; Carlino, Chemistry between the
sheets, Chemistry in Britain, September 1997, pp 59-62; Hashi et
al, Clays and Clay Minerals (1983) pp 152-15; Raki et al, 1995, 7,
221-224; Ookubo et al, Langmuir (1993), 9, pp 1418-14221; Zhang et
al. Inorganic Materials Vol. 4 March 132-138 (1997), Reichle, Solid
States Ionics, 22, pp 135-141 (1986); Ulibarri et al, Kinetics of
the Thermal Dehydration of some layered Hydrocycarbonates,
Thermochimica Acta, pp 231-236 (1988); Hansen et al, Applied Clay
Science 10 (1995) pp 5-19.
[0026] These methods describe lab-scale preparations only.
Furthermore, these materials are obtained via a process which
includes an ageing step (i.e. a deliberate process of increasing
crystal growth which is typically achieved by heating the reaction
slurry over a prolonged period of time such as by a hydrothermal
process). In general, the compounds of the prior art also contain
substantially more than one type of anion in the interlayer
region.
[0027] Methods for large scale manufacturing of MgAl hydrotalcites
are disclosed in art such as U.S. Pat. No. 3,650,704,
WO-A-2008/129034 and WO-A-93/22237. However, these describe the
process for obtaining materials in the aged form resulting in a
larger crystallite size (of above 200 Angstrom) and are not free of
aluminium.
[0028] Aspects of the invention are defined in the appended
claims.
SUMMARY ASPECTS OF THE INVENTION
[0029] In one aspect the present invention provides a method of
producing a mixed metal compound comprising
at least Mg.sup.2+ and at least Fe.sup.3+ having an aluminium
content of less than 10000 ppm, having an average crystal size of
less than 20 nm (200 .ANG.) comprising the steps of: [0030] (a)
combining a Mg.sup.2+ salt and a Fe.sup.3+ salt with
Na.sub.2CO.sub.3 and NaOH to produce a slurry, wherein the pH of
the slurry is maintained at from 9.5 to 11, and wherein the
Na.sub.2CO.sub.3 is provided at an excess of 0 to 4.0 moles than is
required to complete the reaction [0031] (b) subjecting the slurry
to mixing under conditions providing a power per unit volume of
0.03 to 1.6 kW/m.sup.3 [0032] (c) separating the mixed metal
compound from the slurry, to obtain a crude product having a dry
solid content of at least 10 wt % [0033] (d) drying the crude
product either by [0034] (i) heating the crude product to a
temperature of no greater than 150.degree. C. and sufficient to
provide a water evaporation rate of 0.05 to 1.5 kg water per hour
per kg of dry product, or [0035] (ii) exposing the crude product to
rapid drying at a water evaporation rate of 500 to 50000 kg water
per hour per kg of dry product.
[0036] In one aspect the present invention provides a method of
producing a mixed metal compound comprising
at least Mg.sup.2+ and at least Fe.sup.3+ having an aluminium
content of less than 10000 ppm, having an average crystal size of
less than 20 nm (200 .ANG.) comprising the steps of: [0037] (a)
combining a Mg.sup.2+ salt and a Fe.sup.3+ salt with
Na.sub.2CO.sub.3 and NaOH to produce a slurry, wherein the pH of
the slurry is maintained at from 9.5 to 11, and wherein the
Na.sub.2CO.sub.3 is provided at an excess of 2.0 to 4.0 moles than
is required to complete the reaction [0038] (b) subjecting the
slurry to mixing under conditions providing a power per unit volume
of 0.03 to 1.6 kW/m.sup.3 [0039] (c) separating the mixed metal
compound from the slurry, to obtain a crude product having a dry
solid content of at least 10 wt % [0040] (d) drying the crude
product either by [0041] (i) heating the crude product to a
temperature of no greater than 150.degree. C. and sufficient to
provide a water evaporation rate of 0.05 to 1.5 kg water per hour
per kg of dry product, or [0042] (ii) exposing the crude product to
rapid drying at a water evaporation rate of 500 to 50000 kg water
per hour per kg of dry product.
[0043] In one aspect the present invention provides a method of
producing a mixed metal compound comprising
at least Mg.sup.2+ and at least Fe.sup.3+ having an aluminium
content of less than 10000 ppm, having an average crystal size of
less than 20 nm (200 .ANG.); the method comprising the step of:
[0044] (a) combining a Mg.sup.2+ salt and a Fe.sup.3+ salt with
Na.sub.2CO.sub.3 and NaOH to produce a slurry, wherein the slurry
is maintained to a temperature between 15 and 30.degree. C., and:
[0045] (i) wherein the pH of the slurry is maintained at from 9.5
to less than 9.8, and wherein the Na.sub.2CO.sub.3 is provided at
an excess of greater than 1.0 to no greater than 5.0 moles than is
required to complete the reaction; or [0046] (ii) wherein the pH of
the slurry is maintained at from 9.5 to less than 10, and wherein
the Na.sub.2CO.sub.3 is provided at an excess of greater than 1.0
to no greater than 4.0 moles than is required to complete the
reaction; or [0047] (iii) wherein the pH of the slurry is
maintained at from 9.5 to no greater than 10.1, and wherein the
Na.sub.2CO.sub.3 is provided at an excess of greater than 1.0 to no
greater than 2.7 moles than is required to complete the reaction;
or [0048] (iv) wherein the pH of the slurry is maintained at from
9.5 to 10.5, and wherein the Na.sub.2CO.sub.3 is provided at an
excess of from greater than 1.0 to no greater than 2.0 moles than
is required to complete the reaction; or [0049] (v) wherein the pH
of the slurry is maintained at from greater than 9.5 to no greater
than 11, and wherein the Na.sub.2CO.sub.3 is provided at an excess
of from 0.0 to no greater than 1.0 moles than is required to
complete the reaction; or the method comprising the step of: [0050]
(b) combining a Mg.sup.2+ salt and a Fe.sup.3+ salt with
Na.sub.2CO.sub.3 and NaOH to produce a slurry, wherein the slurry
is maintained to a temperature from 30 to 60.degree. C., and:
[0051] (i) wherein the pH of the slurry is maintained at from
greater than 9.5 to less than 11, and wherein the Na.sub.2CO.sub.3
is provided at an excess of greater than 0 to less than 2 moles
than is required to complete the reaction; or [0052] (ii) wherein
the pH of the slurry is maintained at from greater than 9.5 to less
than 10.5, and wherein the Na.sub.2CO.sub.3 is provided at an
excess of greater than 0 to less than 2.7 moles than is required to
complete the reaction; or [0053] (iii) wherein the pH of the slurry
is maintained at from greater than 9.5 to less than 10, and wherein
the Na.sub.2CO.sub.3 is provided at an excess of greater than 0 to
less than 4 moles than is required to complete the reaction.
[0054] In one aspect the present invention provides a method of
producing a mixed metal compound comprising
at least Mg.sup.2+ and at least Fe.sup.3+ having an aluminium
content of less than 10000 ppm, having an average crystal size of
less than 20 nm (200 .ANG.); the method comprising the step of:
[0055] (a) combining a Mg.sup.2+ salt and a Fe.sup.3+ salt with
Na.sub.2CO.sub.3 and NaOH to produce a slurry, wherein the slurry
is maintained to a temperature between 15 and 30.degree. C., and:
[0056] (i) wherein the pH of the slurry is maintained at from 9.5
to less than 9.8, and wherein the Na.sub.2CO.sub.3 is provided at
an excess of greater than 2.0 to no greater than 4.0 moles than is
required to complete the reaction; or [0057] (ii) wherein the pH of
the slurry is maintained at from 9.5 to less than 10.3, and wherein
the Na.sub.2CO.sub.3 is provided at an excess of greater than 2.0
to less than 4.0 moles than is required to complete the reaction;
or [0058] (iii) wherein the pH of the slurry is maintained at from
greater than 9.8 to no greater than 10.5, and wherein the
Na.sub.2CO.sub.3 is provided at an excess of greater than 1.0 to
less than 2.7 moles than is required to complete the reaction; or
[0059] (iv) wherein the pH of the slurry is maintained at greater
than 9.8 to less than 10.3, and wherein the Na.sub.2CO.sub.3 is
provided at an excess of from 1.0 to less than 4.0 moles than is
required to complete the reaction; or the method comprising the
step of: [0060] (b) combining a Mg.sup.2+ salt and a Fe.sup.3+ salt
with Na.sub.2CO.sub.3 and NaOH to produce a slurry, wherein the
slurry is maintained to a temperature from 30 to 65.degree. C.,
and: [0061] (i) wherein the pH of the slurry is maintained at from
9.5 to no greater than 10.5, and wherein the Na.sub.2CO.sub.3 is
provided at an excess of greater than 0 to less than 2.7 moles than
is required to complete the reaction; or [0062] (ii) wherein the pH
of the slurry is maintained at from 9.5 to less than 10, and
wherein the Na.sub.2CO.sub.3 is provided at an excess of greater
than 0 to less than 4 moles than is required to complete the
reaction.
[0063] In one aspect the present invention provides a mixed metal
compound comprising
at least Mg.sup.2+ and at least Fe.sup.3+ having an aluminium
content of less than 10000 ppm, having an average crystal size of
less than 20 nm (200 .ANG.), wherein the compound is obtained or
obtainable by a method comprising the steps of: [0064] (a)
combining a Mg.sup.2+ salt and a Fe.sup.3+ salt with
Na.sub.2CO.sub.3 and NaOH to produce a slurry, wherein the pH of
the slurry is maintained at from 9.5 to 11, and wherein the
Na.sub.2CO.sub.3 is provided at an excess of 0 to 4.0 moles than is
required to complete the reaction [0065] (b) subjecting the slurry
to mixing under conditions providing a power per unit volume of
0.03 to 1.6 kW/m.sup.3 [0066] (c) separating the mixed metal
compound from the slurry, to obtain a crude product having a dry
solid content of at least 10 wt % [0067] (d) drying the crude
product either by [0068] (i) heating the crude product to a
temperature of no greater than 150.degree. C. and sufficient to
provide a water evaporation rate of 0.05 to 1.5 kg water per hour
per kg of dry product, or [0069] (ii) exposing the crude product to
rapid drying at a water evaporation rate of 500 to 50000 kg water
per hour per kg of dry product.
[0070] In one aspect the present invention provides a mixed metal
compound comprising
at least Mg.sup.2+ and at least Fe.sup.3+ having an aluminium
content of less than 10000 ppm, having an average crystal size of
less than 20 nm (200 .ANG.), wherein the compound is obtained or
obtainable by a method comprising the steps of: [0071] (a)
combining a Mg.sup.2+ salt and a Fe.sup.3+ salt with
Na.sub.2CO.sub.3 and NaOH to produce a slurry, wherein the pH of
the slurry is maintained at from 9.5 to 11, and wherein the
Na.sub.2CO.sub.3 is provided at an excess of 2.0 to 4.0 moles than
is required to complete the reaction [0072] (b) subjecting the
slurry to mixing under conditions providing a power per unit volume
of 0.03 to 1.6 kW/m.sup.3 [0073] (c) separating the mixed metal
compound from the slurry, to obtain a crude product having a dry
solid content of at least 10 wt % [0074] (d) drying the crude
product either by [0075] (i) heating the crude product to a
temperature of no greater than 150.degree. C. and sufficient to
provide a water evaporation rate of 0.05 to 1.5 kg water per hour
per kg of dry product, or [0076] (ii) exposing the crude product to
rapid drying at a water evaporation rate of 500 to 50000 kg water
per hour per kg of dry product.
[0077] In one aspect the present invention provides a mixed metal
compound comprising
at least Mg.sup.2+ and at least Fe.sup.3+ having an aluminium
content of less than 10000 ppm, having an average crystal size of
less than 20 nm (200 .ANG.), wherein the compound is obtained or
obtainable by a method comprising the steps of: [0078] (a)
combining a Mg.sup.2+ salt and a Fe.sup.3+ salt with
Na.sub.2CO.sub.3 and NaOH to produce a slurry, wherein the slurry
is maintained to a temperature between 15 and 30.degree. C., and:
[0079] (i) wherein the pH of the slurry is maintained at from 9.5
to less than 9.8, and wherein the Na.sub.2CO.sub.3 is provided at
an excess of greater than 1.0 to no greater than 5.0 moles than is
required to complete the reaction; or [0080] (ii) wherein the pH of
the slurry is maintained at from 9.5 to less than 10, and wherein
the Na.sub.2CO.sub.3 is provided at an excess of greater than 1.0
to no greater than 4.0 moles than is required to complete the
reaction; or [0081] (iii) wherein the pH of the slurry is
maintained at from 9.5 to no greater than 10.1, and wherein the
Na.sub.2CO.sub.3 is provided at an excess of greater than 1.0 to no
greater than 2.7 moles than is required to complete the reaction;
or [0082] (iv) wherein the pH of the slurry is maintained at from
9.5 to 10.5, and wherein the Na.sub.2CO.sub.3 is provided at an
excess of from greater than 1.0 to no greater than 2.0 moles than
is required to complete the reaction; or [0083] (v) wherein the pH
of the slurry is maintained at from greater than 9.5 to no greater
than 11, and wherein the Na.sub.2CO.sub.3 is provided at an excess
of from 0.0 to no greater than 1.0 moles than is required to
complete the reaction or by the method comprising the step of:
[0084] (b) combining a Mg.sup.2+ salt and a Fe.sup.3+ salt with
Na.sub.2CO.sub.3 and NaOH to produce a slurry, wherein the slurry
is maintained to a temperature from 30 to 60.degree. C., and:
[0085] (i) wherein the pH of the slurry is maintained at from
greater than 9.5 to less than 11, and wherein the Na.sub.2CO.sub.3
is provided at an excess of greater than 0 to less than 2 moles
than is required to complete the reaction; or [0086] (ii) wherein
the pH of the slurry is maintained at from greater than 9.5 to less
than 10.5, and wherein the Na.sub.2CO.sub.3 is provided at an
excess of greater than 0 to less than 2.7 moles than is required to
complete the reaction; or [0087] (iii) wherein the pH of the slurry
is maintained at from greater than 9.5 to less than 10, and wherein
the Na.sub.2CO.sub.3 is provided at an excess of greater than 0 to
less than 4 moles than is required to complete the reaction.
[0088] In one aspect the present invention provides a mixed metal
compound comprising
at least Mg.sup.2+ and at least Fe.sup.3+ having an aluminium
content of less than 10000 ppm, having an average crystal size of
less than 20 nm (200 .ANG.), wherein the compound is obtained or
obtainable by a method comprising the steps of: [0089] (a)
combining a Mg.sup.2+ salt and a Fe.sup.3+ salt with
Na.sub.2CO.sub.3 and NaOH to produce a slurry, wherein the slurry
is maintained to a temperature between 15 and 30.degree. C., and:
[0090] (i) wherein the pH of the slurry is maintained at from 9.5
to less than 9.8, and wherein the Na.sub.2CO.sub.3 is provided at
an excess of greater than 2.0 to no greater than 4.0 moles than is
required to complete the reaction; or [0091] (ii) wherein the pH of
the slurry is maintained at from 9.5 to less than 10.3, and wherein
the Na.sub.2CO.sub.3 is provided at an excess of greater than 2.0
to less than 4.0 moles than is required to complete the reaction;
or [0092] (iii) wherein the pH of the slurry is maintained at from
greater than 9.8 to no greater than 10.5, and wherein the
Na.sub.2CO.sub.3 is provided at an excess of greater than 1.0 to
less than 2.7 moles than is required to complete the reaction; or
[0093] (iv) wherein the pH of the slurry is maintained at greater
than 9.8 to less than 10.3, and wherein the Na.sub.2CO.sub.3 is
provided at an excess of from 1.0 to less than 4.0 moles than is
required to complete the reaction; or by the method comprising the
step of: [0094] (b) combining a Mg.sup.2+ salt and a Fe.sup.3+ salt
with Na.sub.2CO.sub.3 and NaOH to produce a slurry, wherein the
slurry is maintained to a temperature from 30 to 65.degree. C.,
and: [0095] (i) wherein the pH of the slurry is maintained at from
9.5 to no greater than 10.5, and wherein the Na.sub.2CO.sub.3 is
provided at an excess of greater than 0 to less than 2.7 moles than
is required to complete the reaction; or [0096] (ii) wherein the pH
of the slurry is maintained at from 9.5 to less than 10, and
wherein the Na.sub.2CO.sub.3 is provided at an excess of greater
than 0 to less than 4 moles than is required to complete the
reaction.
[0097] In one aspect the present invention provides a mixed metal
compound comprising at least Mg.sup.2+ and at least Fe.sup.3+,
wherein the molar ratio of Mg.sup.2+ to Fe.sup.3+ is 2.5:1 to
1.5:1, the mixed metal compound has an aluminium content of less
than 10000 ppm, the average crystal size of the mixed metal
compound is from 10 to 20 nm (100 to 200 .ANG.), and the d50
average particle size of the mixed metal compound is less than 300
.mu.m.
[0098] In one aspect the present invention provides a mixed metal
compound comprising at least Mg.sup.2+ and at least Fe.sup.3+,
wherein the molar ratio of Mg.sup.2+ to Fe.sup.3+ is 2.5:1 to
1.5:1, the mixed metal compound has an aluminium content of less
than 10000 ppm, the average crystal size of the mixed metal
compound is from 10 to 20 nm (100 to 200 .ANG.), and the water pore
volume of the mixed metal compound is from 0.25 to 0.7 cm.sup.3/g
of mixed metal compound.
[0099] In one aspect the present invention provides a mixed metal
compound comprising at least Mg.sup.2+ and at least Fe.sup.3+,
wherein the molar ratio of Mg.sup.2+ to Fe.sup.3+ is 2.5:1 to
1.5:1, the mixed metal compound has an aluminium content of less
than 10000 ppm, the average crystal size of the mixed metal
compound is from 10 to 20 nm (100 to 200 .ANG.), and the interlayer
sulphate content of the compound is from 1.8 to 5 wt %.
[0100] In one aspect the present invention provides a mixed metal
compound comprising at least Mg.sup.2+ and at least Fe.sup.3+,
wherein the molar ratio of Mg.sup.2+ to Fe.sup.3+ is 2.5:1 to
1.5:1, the mixed metal compound has an aluminium content of less
than 10000 ppm, the average crystal size of the mixed metal
compound is from 10 to 20 nm (100 to 200 .ANG.), and the interlayer
sulphate content of the compound is from 1.8 to 3.2 wt %.
[0101] In one aspect the present invention provides a mixed metal
compound comprising at least Mg.sup.2+ and at least Fe.sup.3+,
wherein the molar ratio of Mg.sup.2+ to Fe.sup.3+ is 2.5:1 to
1.5:1, the mixed metal compound has an aluminium content of less
than 10000 ppm, the average crystal size of the mixed metal
compound is less than 20 nm (200 .ANG.), and the interlayer
sulphate content of the compound is from 1.8 to 5 wt %.
[0102] In one aspect the present invention provides a mixed metal
compound comprising at least Mg.sup.2+ and at least Fe.sup.3+,
wherein the molar ratio of Mg.sup.2+ to Fe.sup.3+ is 2.5:1 to
1.5:1, the mixed metal compound has an aluminium content of less
than 10000 ppm, the average crystal size of the mixed metal
compound is less than 20 nm (200 .ANG.), and the interlayer
sulphate content of the compound is from 1.8 to 3.2 wt %.
[0103] In one aspect the present invention provides a mixed metal
compound comprising at least Mg.sup.2+ and at least Fe.sup.3+,
wherein the molar ratio of Mg.sup.2+ to Fe.sup.3+ is 2.5:1 to
1.5:1, the mixed metal compound has an aluminium content of less
than 10000 ppm, the average crystal size of the mixed metal
compound is less than 20 nm (200 .ANG.), and the surface area is
from 80 to 145 m.sup.2 per gram of compound.
[0104] In one aspect the present invention provides a mixed metal
compound comprising at least Mg.sup.2+ and at least Fe.sup.3+,
wherein the molar ratio of Mg.sup.2+ to Fe.sup.3+ is 2.5:1 to
1.5:1, the mixed metal compound has an aluminium content of less
than 10000 ppm, the average crystal size of the mixed metal
compound is from 10 to 20 nm (100 to 200 .ANG.), the surface area
is from 40 to 80 m.sup.2 per gram of compound.
[0105] In one aspect the present invention provides a mixed metal
compound as described herein for use as a medicament.
[0106] In one aspect the present invention provides a mixed metal
compound as described herein for binding phosphate.
[0107] In one aspect the present invention provides a mixed metal
compound as described herein for use in the treatment of
hyperphosphataemia.
[0108] In one aspect the present invention provides a
pharmaceutical composition comprising a mixed metal compound as
described herein and optionally one or more pharmaceutically
acceptable adjuvants, excipients, diluents or carriers.
Some Advantages
[0109] The present method provides a process which may be operated
on a large scale to provide for a pharmaceutical phosphate binding
drug of consistent composition which is stable upon storage and can
be easily formulated and/or packaged. Moreover, the present method
provides for control of key properties such as average crystal
size, particle size, surface area, other morphology parameters
(such as pore volume) and degree of hydration--all of which are
important for such manufacture.
[0110] Al-free mixed metal compounds containing Fe and Mg typically
have a clay-like structure. This presents limitations in view of
the difficult filtration of such products which in turn affect the
viability of a controlled process.
[0111] The present method provides a process which allows for
manufacture of a consistent `Al-free` mixed metal compounds
suitable for use in final product formulations (e.g. tablet
formulations etc). The therapeutic effect of the final products and
the ability to process the mixed metal compounds into a final
product consistently, depend on the physical (i.e. particle- and
crystallite-size) and chemical (i.e. composition) properties of the
mixed metal compound. The present process provides a method for a
consistent manufacture of pharmaceutical-grade `Al-free` mixed
metal compounds with consistent particle- and crystallite-size.
[0112] In one aspect the present invention provides a mixed metal
compound comprising at least Mg.sup.2+ and at least Fe.sup.3+,
wherein the molar ratio of Mg.sup.2+ to Fe.sup.3+ is 2.5:1 to
1.5:1, the mixed metal compound has an aluminium content of less
than 10000 ppm, the average crystal size of the mixed metal
compound is from 10 to 20 nm (100 to 200 .ANG.), and the interlayer
sulphate content of the compound is from 1.8 to 5 wt % (such as
from 1.8 to 3.2 wt %).
[0113] For mixed metal compounds, maintaining the target metal
molar ratio (Mg: Fe) during the reaction whilst meeting the above
criteria is difficult as this is affected by the way the material
is processed. We found that correct stoichiometry is not only
determined by the correct ratios of the starting materials but also
by pH for the reaction; i.e. when a pH is below pH 9.5 incomplete
precipitation of magnesium may occur and too high a pH (i.e. above
pH 11) risks loss of iron.
[0114] Mixed metal compounds can have more than one type of anion
within the interlayer region. This can introduce impurities which
are undesirable when considering pharma use and we found can also
affect therapeutic activity (of phosphate binding). We have also
found, surprisingly, that the type and amount of anions present in
the interlayer region has a marked effect on the time taken to
complete separation and washing of the unaged product, particularly
for commercial scale manufacture. For example, we have found that
at low (below 1.8% wt) interlayer sulphate levels, separation and
washing times increase significantly.
[0115] We found that when the amount of interlayer sulphate is
maintained from 1.8 to 5 wt % (such as from 1.8 to 3.2 wt %)
phosphate binding of more than 0.60 mmol phosphate/g compound can
be obtained whilst maintaining low filtration and wash times.
[0116] The combination of process parameters of the present method
provides for the preparation of mixed metal compounds which have
controlled sulphate (SO.sub.4) levels in the interlayer region.
[0117] Soluble SO.sub.4 in the form of Na.sub.2SO.sub.4 salt can be
readily removed by washing whereas the interlayer sulphate cannot
be removed by washing with water.
[0118] We found that the interlayer sulphate could be reduced
without necessarily increasing the filtration and wash times by
reslurrying the dried compound in a solution containing carbonate
enabling ion-exchange; however, this meant an additional reaction,
isolation and drying step and generally lead to a decrease in
phosphate binding. Furthermore, this route would result in a longer
overall time to manufacture. This route to control interlayer
sulphate is therefore less preferred. Alternatively, the interlayer
sulphate may be reduced by washing or reslurrying the filtercake
after isolation with a solution containing carbonate instead of
water. Again this would lead to an additional process step and is
less preferred.
[0119] We found that by control of the process parameters as
described herein, one may prepare a mixed metal compound having low
levels of impurities, and in particular heavy metal impurities,
without the need to perform purification to remove such impurities.
The present invention may provide a process for preparing a mixed
metal compound having a lead content of less than 1 ppm and/or a
chromium content of less than 30 ppm and/or a total heavy metal
content of less than 10 ppm and/or a sodium content expressed as
Na.sub.2O of less than 0.5 wt %. In one aspect the mixed metal
compound has a total heavy metal content of less than 25 ppm,
preferably less than 10 ppm. For example the present invention may
provide a process for preparing a mixed metal compound having a
total heavy metal content of less than 15 ppm, a lead content less
than 10 ppm, a chromium level less than 35 ppm and a sodium content
(expressed as Na.sub.2O) of less than 1 wt %.
[0120] Heavy metals content as referred to herein are the group
consisting of As, Cd, Pb, Hg, Sb, Mo and Cu. Thus, reference to
total heavy metal content will be understood to mean the combined
content of As, Cd, Pb, Hg, Sb, Mo and Cu.
[0121] WO99/15189 teaches the preparation of a slurry at pH above
10 using a 5 mole Na.sub.2CO.sub.3: 12 mole NaOH ratio which
equates to an excess of 4 mole Na.sub.2CO.sub.3 than required to
complete the reaction equation:
4MgSO.sub.4+Fe.sub.2(SO.sub.4).sub.3+12
NaOH+5Na.sub.2CO.sub.3->Mg.sub.4Fe.sub.2(OH).sub.12.CO.sub.3.nH.sub.2O-
+7Na.sub.2SO.sub.4+4Na.sub.2CO.sub.3.
[0122] We have found that this excess of 4 mole Na.sub.2CO.sub.3 is
not preferred, especially when precipitated at a pH of more than 10
and at room temperature. We found that this combination results in
reduced solubility of the carbonate in the reactant solution at the
desired reaction temperatures, provides poor filtration and wash
times. We have found that when preparing unaged material of 2:1
Mg:Fe molar ratio according to method of WO99/15189 that this
material was more difficult to separate and wash when manufactured
at scale whilst maintaining good phosphate binding. This resulted
in loss of batches as a result of material being out of
specification.
[0123] Sodium carbonate not only provides the carbonate for the
anion-exchange sites, but also acts as a pH buffer which assists pH
control during precipitation. The ability to maintain an accurate
precipitation pH is considerably increased when Na.sub.2CO.sub.3 is
present. However, we have also found that the filtration rate
significantly increases when Na.sub.2CO.sub.3 is reduced from a 2.7
mole excess to zero excess. A high filtration rate is advantageous
when seeking to manufacture an unaged form of the Mg Fe mixed metal
compounds. Such materials can be difficult to filter. Also
decreasing the Na.sub.2CO.sub.3 further, such as below the 2.7 mole
excess, may result in less precise pH control as well as increasing
the level of sulphate anions present in the interlayer region. As a
consequence of the above, we have identified that there is a
complex interrelationship between pH, mole excess Na.sub.2CO.sub.3
and the temperature at which the slurry is maintained, all of which
are important to maintain good phosphate binding and filtration and
or wash times. In particular we have determined that in order to
obtain phosphate binding above 0.60 mmol phosphate/g compound and
maintain good filtration and wash time it is preferred to produce a
slurry, wherein a temperature is maintained between 15 and
30.degree. C. [0124] (i) wherein the pH of the slurry is maintained
at from 9.5 to less than 9.8, and wherein the Na.sub.2CO.sub.3 is
provided at an excess of greater than 1.0 to no greater than 5.0
moles than is required to complete the reaction; or [0125] (ii)
wherein the pH of the slurry is maintained at from 9.5 to less than
10, and wherein the Na.sub.2CO.sub.3 is provided at an excess of
greater than 1.0 to no greater than 4.0 moles than is required to
complete the reaction; or [0126] (iii) wherein the pH of the slurry
is maintained at from 9.5 to no greater than 10.1, and wherein the
Na.sub.2CO.sub.3 is provided at an excess of greater than 1.0 to no
greater than 2.7 moles than is required to complete the reaction;
or [0127] (iv) wherein the pH of the slurry is maintained at from
9.5 to 10.5, and wherein the Na.sub.2CO.sub.3 is provided at an
excess of from greater than 1.0 to no greater than 2.0 moles than
is required to complete the reaction; or [0128] (v) wherein the pH
of the slurry is maintained at from greater than 9.5 to no greater
than 11, and wherein the Na.sub.2CO.sub.3 is provided at an excess
of from 0.0 to no greater than 1.0 moles than is required to
complete the reaction.
[0129] Alternatively, a Mg.sup.2+ salt and a Fe.sup.3+ salt can be
combined with Na.sub.2CO.sub.3 and NaOH to produce a slurry,
wherein the slurry is maintained to a temperature from 30 to
60.degree. C. [0130] (i) wherein the pH of the slurry is maintained
at from greater than 9.5 to less than 11, and wherein the
Na.sub.2CO.sub.3 is provided at an excess of greater than 0 to less
than 2 moles than is required to complete the reaction; or [0131]
(ii) wherein the pH of the slurry is maintained at from greater
than 9.5 to less than 10.5, and wherein the Na.sub.2CO.sub.3 is
provided at an excess of greater than 0 to less than 2.7 moles than
is required to complete the reaction; or [0132] (iii) wherein the
pH of the slurry is maintained at from greater than 9.5 to less
than 10, and wherein the Na.sub.2CO.sub.3 is provided at an excess
of greater than 0 to less than 4 moles than is required to complete
the reaction.
[0133] Furthermore, we have found that in order to avoid the
presence of additional crystalline phases in the compound (i.e.
phases other than hydrotalcite-type as detected by powder X-ray
Diffraction) it is necessary to wash the product to such an extent
that the unbound sulphate (SO.sub.4) i.e. in form of sodium
sulphate (Na.sub.2SO.sub.4) is maintained below 1.5 wt % (when
expressed as Na.sub.2SO.sub.4) and preferably less than 1 wt %
(when expressed as SO.sub.4). This conversely can only be achieved
when a small amount of the interlayer sulphate is maintained such
as to enable effective filtration and washing at commercial
scale
[0134] The present method is a co-precipitation process. Such
processes encourage the formation of different crystalline phases
in addition to the hydrotalcite phase. For use as an active in
pharmaceutical formulations, there is the requirement to be able to
identify and control the phase of interest. The present method
provides for the preparation of mixed metal compounds which contain
less of (or are substantially free of) any other crystalline phases
as determined by the absence of XRD diffraction lines except those
attributed to a hydrotalcite phase. The hydrotalcite phase had the
following diffraction X-ray diffraction analysis: dA (`d` spacings)
7.74*, 3.86*, 3.20, 2.62*, 2.33*, 1.97*, 1.76, 1.64, 1.55*, 1.52*,
1.48, 1.44*, 1.40; of which the peaks marked * are the eight most
intense peaks typically seen in the unaged samples. The remaining
five peaks are only resolved in more crystalline samples, typically
as a result of ageing.
[0135] In summary, we have found that a total process of production
(from reaction to drying) is provided such as to prevent growth of
the crystallite size (above average crystal size 200 .ANG.) in
order to maintain the phosphate binding activity without
significantly hindering the process of isolation and washing of the
compound. This was achieved by careful control of process
conditions and a specific selection of the same such as by
controlling interlayer sulphate from 1.8 to 5 wt % (such as from
1.8 to 3.2 wt %) which in turn can be controlled via selection of
excess Na.sub.2CO.sub.3, reaction pH and reaction slurry
temperature.
[0136] In one aspect the present invention provides a mixed metal
compound comprising at least Mg.sup.2+ and at least Fe.sup.3+,
wherein the molar ratio of Mg.sup.2+ to Fe.sup.3+ is 1.5:1 to
2.5:1, the mixed metal compound has an aluminium content of less
than 10000 ppm, the average crystal size of the mixed metal
compound is from 10 to 20 nm (100 to 200 .ANG.), and the d50
average particle size of the mixed metal compound is less than 300
.mu.m. We have found surprisingly that this unaged compound with
such average crystal size range and with milled particle size less
than 300 microns, has the advantages of good, controlled phosphate
binding (above 0.60 mmol phosphate/g compound) whilst maintaining
low magnesium release (less than 0.2 mmol magnesium/g compound).
Above 300 micron particle size we have found that the phosphate
binding decreases markedly and magnesium release increases to above
0.2 mmol magnesium/g compound.
[0137] We have found that an average crystal size of the mixed
metal compound of less than 20 nm (200 .ANG.) and high surface area
(80-145 m.sup.2/g) can be manufactured using a process comprising a
short residence drying step such that the resultant material has
both small average crystal size and high surface area but also
importantly has a higher phosphate binding capacity as well as a
lower magnesium release when compared at similar d50 average
particle size to that of the low surface area (40-80 m.sup.2/g)
material; even when the material is not milled further. The
requirement for no milling has the advantage of reduced processing
steps. A further advantage is that such material can be suitable
for tabletting processes without the need for wet granulation. A
further advantage is that material manufactured via the short
residence route may be exposed to temperatures above 150.degree. C.
because the residence time (less than 5 minutes) of the product in
the dryer is generally too short to enable any decomposition of the
compound.
[0138] The mixed metal compound having an average crystal size of
from 10 to 20 nm (100 to 200 .ANG.) and surface area 40-80
m.sup.2/g has the benefit of good stability in particular phosphate
binding, on storage. This product has the additional benefit of
providing a smaller tablet size (i.e. less than 500 mm.sup.3 for
500 mg compound) thereby improving tablet pill burden; a prevalent
issue within the treatment of renal patients. The material of
surface area 40-80 m.sup.2/g which required micronisation can be
manufactured at commercial scale, including milling of the
material, with minimal impact on aging of the material as reflected
in maintaining a small average crystal size of below 200 .ANG.. If
the crystallite size is less than 100 .ANG. it presents
difficulties in milling to small particle size of for example,
problems with trace metal impurities, milling rate and
decomposition of the product and over-drying of the product.
Furthermore an additional surprising benefit is that such materials
also exhibit no significant reduction in the uptake rate of
phosphate, despite the lower surface areas. This facet can be
important when considering such materials for pharmaceutical
applications in which the binding of phosphate needs to be rapid
such as renal care. We have found that the material described above
bind 80% phosphate within 10 minutes (Test Method 3).
[0139] As for the product of 10 to 20 nm (100 to 200 .ANG.) average
crystal size and 40-80 m.sup.2/g surface area, the product of low
surface area and low pore volume by water from 0.3 to 0.65
cm.sup.3/g has the additional benefit of providing a smaller tablet
size (i.e. less than 500 mm.sup.3 for 500 mg compound) thereby
improving tablet pill burden; a prevalent issues within the
treatment of renal patients. Furthermore a higher density material
is more suitable for the manufacture by wet granulation of compact
tablets.
[0140] If product is dried to less than 85 wt % dry solid content
storage problems may be observed because of water-desorption. If
product is dried to less than 80 wt % dry solid content, milling
may be problematic. If product is dried to more than 99 wt % the
phosphate binding may be reduced. If product is too dry storage
problems may also be observed because of water-adsorption.
Therefore, in one embodiment, the product is dried such that it has
80 wt % to 99 wt % dry solid content, preferably 85 wt % to 99 wt
%.
[0141] In one aspect the present invention provides a mixed metal
compound comprising at least Mg.sup.2+ and at least Fe.sup.3+,
wherein the molar ratio of Mg.sup.2+ to Fe.sup.3+ is 1.5:1 to
2.5:1, the mixed metal compound has an aluminium content of less
than 10000 ppm, the average crystal size of the mixed metal
compound is from 10 to 20 nm (100 to 200 .ANG.), and the water pore
volume of the mixed metal compound is from 0.3 to 0.65 cm.sup.3/g
of mixed metal compound. Surprisingly we have found that this low
pore volume compound has the advantage of good phosphate binding
that is essentially unchanged upon storage over periods of up to
years, making it viable as a pharmaceutically active material. It
may be expected typically that significantly higher pore volumes
would be required to attain such stability.
[0142] As used herein, the term `water pore volume` refers to the
pore volume as determined in accordance with Test Method 15.
[0143] For ease of reference, these and further aspects of the
present invention are now discussed under appropriate section
headings. However, the teachings under each section may be combined
and are not necessarily limited to each particular section.
BRIEF DESCRIPTION OF THE DRAWING
[0144] FIG. 1 is a graphical representation of data from Table 3,
demonstrating preferred range between 2-5 wt % interlay sulphate,
wherein phosphate binding is high and wash time is low.
PREFERRED ASPECTS
[0145] As discussed herein the present invention provides a method
of producing a mixed metal compound comprising
at least Mg.sup.2+ and at least Fe.sup.3+ having an aluminium
content of less than 10000 ppm, having an average crystal size of
less than 20 nm (200 .ANG.) comprising the steps of: [0146] (a)
combining a Mg.sup.2+ salt and a Fe.sup.3+ salt with
Na.sub.2CO.sub.3 and NaOH to produce a slurry, wherein the pH of
the slurry is maintained at from 9.5 to 11, and wherein the
Na.sub.2CO.sub.3 is provided at an excess of 0 to 4.0 moles than is
required to complete the reaction [0147] (b) subjecting the slurry
to mixing under conditions providing a power per unit volume of
0.03 to 1.6 kW/m.sup.3 [0148] (c) separating the mixed metal
compound from the slurry, to obtain a crude product having a dry
solid content of at least 10 wt % [0149] (d) drying the crude
product either by [0150] (i) heating the crude product to a
temperature of no greater than 150.degree. C. and sufficient to
provide a water evaporation rate of 0.05 to 1.5 kg water per hour
per kg of dry product, or [0151] (ii) exposing the crude product to
rapid drying at a water evaporation rate of 500 to 50000 kg water
per hour per kg of dry product.
[0152] It will be understood by one skilled in the art that by
"average crystal size" it is meant the crystal size as measured in
accordance with Test Method 2.
[0153] In one preferred aspect, in step (a) a Mg.sup.2+ salt and a
Fe.sup.3+ salt are combined with Na.sub.2CO.sub.3 and NaOH to
produce a slurry, wherein the pH of the slurry is maintained at
from 9.5 to 10.5. Preferably the pH of the slurry is maintained at
from 9.5 to less than 10.1. Preferably the pH of the slurry is
maintained at from 9.5 to less than 10. Preferably the pH of the
slurry is maintained at from 9.5 to less than 9.8. Preferably the
pH of the slurry is maintained at from 9.6 to 9.9. More preferably
the pH of the slurry is maintained at approximately 9.8.
[0154] In one preferred aspect, in step (a) a Mg.sup.2+ salt and a
Fe.sup.3+ salt are combined with Na.sub.2CO.sub.3 and NaOH to
produce a slurry, wherein the Na.sub.2CO.sub.3 is provided at an
excess from 2.0 to less than 4.0 moles, preferably at an excess
from 2.7 to less than 4.0 moles, preferably at an excess from 2.7
to less than 3.2 moles, preferably at an excess from 2.7 to less
than 3.0 moles. More preferably the Na.sub.2CO.sub.3 is maintained
at an excess of approximately 2.7 moles.
[0155] In one preferred aspect, in step (a) a Mg.sup.2+ salt and a
Fe.sup.3+ salt are combined with Na.sub.2CO.sub.3 and NaOH to
produce a slurry, wherein the slurry is maintained to a temperature
between 15 and 30.degree. C. [0156] (i) wherein the pH of the
slurry is maintained at from 9.5 to less than 9.8, and wherein the
Na.sub.2CO.sub.3 is provided at an excess of greater than 1.0 to no
greater than 5.0 moles than is required to complete the reaction;
or [0157] (ii) wherein the pH of the slurry is maintained at from
9.5 to less than 10, and wherein the Na.sub.2CO.sub.3 is provided
at an excess of greater than 1.0 to no greater than 4.0 moles than
is required to complete the reaction; or [0158] (iii) wherein the
pH of the slurry is maintained at from 9.5 to no greater than 10.1,
and wherein the Na.sub.2CO.sub.3 is provided at an excess of
greater than 1.0 to no greater than 2.7 moles than is required to
complete the reaction; or [0159] (iv) wherein the pH of the slurry
is maintained at from 9.5 to 10.5, and wherein the Na.sub.2CO.sub.3
is provided at an excess of from greater than 1.0 to no greater
than 2.0 moles than is required to complete the reaction; or [0160]
(v) wherein the pH of the slurry is maintained at from greater than
9.5 to no greater than 11, and wherein the Na.sub.2CO.sub.3 is
provided at an excess of from 0.0 to no greater than 1.0 moles than
is required to complete the reaction.
[0161] In one preferred aspect, in step (a) a Mg.sup.2+ salt and a
Fe.sup.3+ salt are combined with Na.sub.2CO.sub.3 and NaOH to
produce a slurry, wherein the slurry is maintained to a temperature
between 15 and 30.degree. C. [0162] i) wherein the pH of the slurry
is maintained at from 9.5 to less than 9.8, and wherein the
Na.sub.2CO.sub.3 is provided at an excess of greater than 2.0 to no
greater than 4.0 moles than is required to complete the reaction;
or [0163] (ii) wherein the pH of the slurry is maintained at from
9.5 to less than 10.3, and wherein the Na.sub.2CO.sub.3 is provided
at an excess of greater than 2.0 to less than 4.0 moles than is
required to complete the reaction; or [0164] (iii) wherein the pH
of the slurry is maintained at from greater than 9.8 to no greater
than 10.5, and wherein the Na.sub.2CO.sub.3 is provided at an
excess of greater than 1.0 to less than 2.7 moles than is required
to complete the reaction; or [0165] (iv) wherein the pH of the
slurry is maintained at greater than 9.8 to less than 10.3, and
wherein the Na.sub.2CO.sub.3 is provided at an excess of from 1.0
to less than 4.0 moles than is required to complete the
reaction;
[0166] In one preferred aspect, in step (a) a Mg.sup.2+ salt and a
Fe.sup.3+ salt are combined with Na.sub.2CO.sub.3 and NaOH to
produce a slurry, wherein the slurry is maintained to a temperature
from 30 to 60.degree. C. [0167] (i) wherein the pH of the slurry is
maintained at from greater than 9.5 to less than 11, and wherein
the Na.sub.2CO.sub.3 is provided at an excess of greater than 0 to
less than 2 moles than is required to complete the reaction; or
[0168] (ii) wherein the pH of the slurry is maintained at from
greater than 9.5 to less than 10.5, and wherein the
Na.sub.2CO.sub.3 is provided at an excess of greater than 0 to less
than 2.7 moles than is required to complete the reaction; or [0169]
(iii) wherein the pH of the slurry is maintained at from greater
than 9.5 to less than 10, and wherein the Na.sub.2CO.sub.3 is
provided at an excess of greater than 0 to less than 4 moles than
is required to complete the reaction.
[0170] In one preferred aspect, in step (a) a Mg.sup.2+ salt and a
Fe.sup.3+ salt are combined with Na.sub.2CO.sub.3 and NaOH to
produce a slurry, wherein the slurry is maintained to a temperature
from 30 to 65.degree. C. [0171] (i) wherein the pH of the slurry is
maintained at from 9.5 to no greater than 10.5, and wherein the
Na.sub.2CO.sub.3 is provided at an excess of greater than 0 to less
than 2.7 moles than is required to complete the reaction; or [0172]
(ii) wherein the pH of the slurry is maintained at from 9.5 to less
than 10, and wherein the Na.sub.2CO.sub.3 is provided at an excess
of greater than 0 to less than 4 moles than is required to complete
the reaction.
[0173] In one preferred aspect, in step (b) the slurry is subjected
to mixing under conditions providing a power per unit volume of
0.03 to 1.6 kW/m.sup.3. In one preferred aspect, in step (b) the
slurry is subjected to mixing under conditions providing a power
per unit volume of 0.03 to 0.5 kW/m.sup.3. In one preferred aspect,
in step (b) the slurry is subjected to mixing under conditions
providing a power per unit volume of 0.05 to 0.5 kW/m.sup.3.
[0174] In one preferred aspect, in step (b) the slurry is
controlled to a d50 particle size distribution (psd) of at least 40
.mu.m. Preferably, the slurry is controlled to a d50 psd of greater
than 40 .mu.m. Preferably, the slurry is controlled to a d50 psd of
at least 50 .mu.m. Preferably, the slurry is controlled to a d50
psd of at least 60 .mu.m. More preferably, the slurry is controlled
to a d50 psd of at least 70 .mu.m. Preferably, the slurry is
controlled to a d50 psd of greater than 70 .mu.m. The d50 psd of
the slurry is as measured in accordance with Test Method 9
herein.
[0175] As used herein, the term `particle size distribution` refers
to the d50 or average particle size distribution as determined in
accordance with Test Method 24. D50 refers to the 50th percentile
of that Test Method.
[0176] In one preferred aspect, in step (b) the slurry is
controlled to a d50 psd of at least 40 .mu.m after the addition of
the reactants and after an initial hold time of 30 minutes to
attain the optimum particle size distribution. Preferably, the
slurry is controlled to a d50 psd of at least 50 .mu.m after the
addition of the reactants and after an initial hold time of 30
minutes.
[0177] Preferably, the slurry is controlled to a d50 psd of at
least 60 .mu.m after the addition of the reactants and after an
initial hold time of 30 minutes. More preferably, the slurry is
controlled to a d50 psd of at least 70 .mu.m after the addition of
the reactants and after an initial hold time of 30 minutes.
[0178] In one preferred aspect, the hold time of slurry before
isolation, such as before step (c), is less than 16 hours,
preferably less than 12 hours. Preferably, the hold time is more
than 30 minutes. In one preferred aspect, the hold time of slurry
before isolation, such as before step (c), from 30 minutes to 16
hours. In one preferred aspect, the hold time of slurry before
isolation, such as before step (c), from 30 minutes to 12 hours. If
hold time increases to more than 16 hours the crystallite size may
increase and/or particle size change.
[0179] In step (c) of the present method, the mixed metal compound
is separated from the slurry, to obtain a crude product having a
dry solid content of at least 10 wt %. Preferably the mixed metal
compound is separated from the slurry, to obtain a crude product
having a dry solid content of at least 15 wt %. More preferably the
mixed metal compound is separated from the slurry, to obtain a
crude product having a dry solid content of at least 20 wt %.
[0180] In step (d) of the present method the crude product is dried
either by
(i) heating the crude product to a temperature of no greater than
150.degree. C. and sufficient to provide a water evaporation rate
of 0.05 to 1.5 kg water per hour per kg of dry product, or (ii)
exposing the crude product to rapid drying at a water evaporation
rate of 500 to 50000 kg water per hour per kg of dry product.
[0181] It will be understood by one skilled in the art that
reference to "heating the crude product to a temperature of no
greater than X.degree. C." refers to the heating the product such
that the bulk temperature of the product is no greater than
X.degree. C. It will be understood that the temperature to which
the product is exposed, for example a drum temperature in the case
of drum drying, or the temperature of the shell of the product may
be greater than X.degree. C. when the bulk temperature of the
product is X.degree. C.
[0182] It will be understood by one skilled in the art that
reference to a water evaporation rate at a rate of kg water per
hour per kg of dry product, is to be measured in accordance with
Test Method 18.
[0183] In one preferred aspect, step d(i) is followed, that is in
step (d) the crude product is dried by heating the crude product to
a temperature of no greater than 150.degree. C. and sufficient to
provide a water evaporation rate of 0.05 to 1.5 kg water per hour
per kg of dry product.
[0184] In one preferred aspect, step d(ii) is followed, that is in
step (d) the crude product is dried by exposing the crude product
to flash drying or spray drying at a water evaporation rate of 500
to 50000 kg water per hour per kg of dry product.
[0185] Preferably when step d(i) is followed, the crude product is
dried by heating the crude product to a temperature of no greater
than 150.degree. C. and sufficient to provide a water evaporation
rate of 0.05 to 1 kg water per hour per kg of dry product, more
preferably a water evaporation rate of 0.05 to 0.5 kg water per
hour per kg of dry product, even more preferably a water
evaporation rate of 0.09 to 0.5 kg water per hour per kg of dry
product, most preferred a water evaporation rate of 0.09 to 0.38 kg
water per hour per kg of dry product.
[0186] Preferably when step d(i) is followed, the crude product is
dried by heating the crude product to a temperature of no greater
than 150.degree. C., such as no greater than 140.degree. C., such
as no greater than 130.degree. C., such as no greater than
120.degree. C., such as no greater than 110.degree. C., such as no
greater than 100.degree. C., such as no greater than 90.degree. C.,
such as from 60 to 150.degree. C., such as from 70 to 150.degree.
C., such as from 60 to 140.degree. C., such as from 70 to
140.degree. C., such as from 60 to 130.degree. C., such as from 70
to 130.degree. C., such as from 60 to 120.degree. C., such as from
70 to 120.degree. C., such as from 60 to 110.degree. C., such as
from 70 to 110.degree. C., such as from 60 to 100.degree. C., such
as from 70 to 100.degree. C., such as from 60 to 90.degree. C.,
such as from 70 to 90.degree. C. Preferably when step d(i) is
followed, the crude product is dried by heating the crude product
to a temperature of from 35 to 150.degree. C., such as from 35 to
140.degree. C., such as from 35 to 130.degree. C., such as from 35
to 120.degree. C., such as from 35 to 110.degree. C., such as from
35 to 100.degree. C., such as from 35 to 90.degree. C., such as
from 35 to 80.degree. C., such as from 35 to 70.degree. C., such as
from 35 to 60.degree. C., such as from 35 to 50.degree. C.
Preferably when step d(i) is followed, the crude product is dried
by heating the crude product to a temperature of from greater than
40 to 150.degree. C., such as from greater than 40 to 140.degree.
C., such as from greater than 40 to 130.degree. C., such as from
greater than 40 to 120.degree. C., such as from greater than 40 to
110.degree. C., such as from greater than 40 to 100.degree. C.,
such as from greater than 40 to 90.degree. C., such as from greater
than 40 to 80.degree. C., such as from greater than 40 to
70.degree. C., such as from greater than 40 to 60.degree. C., such
as from greater than 40 to 50.degree. C. We have found that heating
the crude product to a temperature of no greater than 90.degree. C.
and sufficient to provide a water evaporation rate of 0.05 to 1.5
kg water per hour per kg of dry product is particularly preferred.
In this aspect, the average crystal size does not significantly
increase during drying and the advantageous average crystal sizes
described herein may be provided
[0187] Preferably when step d(i) is followed, the crude product is
dried by exposing the crude product to a temperature of no greater
than 150.degree. C., preferably exposing the crude product to a
temperature of no greater than 140.degree. C., preferably exposing
the crude product to a temperature of no greater than 130.degree.
C., preferably exposing the crude product to a temperature of no
greater than 120.degree. C., preferably exposing the crude product
to a temperature of no greater than 110.degree. C., preferably
exposing the crude product to a temperature of no greater than
100.degree. C., preferably exposing the crude product to a
temperature of no greater than 90.degree. C., preferably exposing
the crude product to a temperature of from 60 to 150.degree. C.,
preferably exposing the crude product to a temperature of from 70
to 150.degree. C., preferably exposing the crude product to a
temperature of from 60 to 140.degree. C., preferably exposing the
crude product to a temperature of from 70 to 140.degree. C.,
preferably exposing the crude product to a temperature of from 60
to 130.degree. C., preferably exposing the crude product to a
temperature of from 70 to 130.degree. C., preferably exposing the
crude product to a temperature of from 60 to 120.degree. C.,
preferably exposing the crude product to a temperature of from 70
to 120.degree. C., preferably exposing the crude product to a
temperature of from 60 to 110.degree. C., preferably exposing the
crude product to a temperature of from 70 to 110.degree. C.,
preferably exposing the crude product to a temperature of from 60
to 100.degree. C., preferably exposing the crude product to a
temperature of from 70 to 100.degree. C., preferably exposing the
crude product to a temperature of from 60 to 90.degree. C.,
preferably from 70 to 90.degree. C.
[0188] Preferably when step d(i) is followed, the crude product is
dried to between 5-10 wt % moisture by exposing the crude product
to a temperature from 35-90.degree. C. and sufficient to provide a
water evaporation rate of 0.05 to 0.5 kg water per hour per kg of
dry product.
[0189] Preferably when step d(ii) is followed, the crude product is
dried by exposing the crude product to flash drying or spray drying
at a water evaporation rate of 900 to 40000 kg water per hour per
kg of dry product.
[0190] Preferably when step d(ii) is followed, the crude product is
dried by exposing the crude product to flash drying at a water
evaporation rate from 1500 to 50000 or exposing the product to
spray drying at a water evaporation rate from 500 to 1500 kg water
per hour per kg of dry product. More preferably either from 20000
to 50000 by flash drying or from 900 to 1100 by spray drying.
[0191] Preferably when step d(ii) is followed, the crude product is
dried by exposing the crude product to flash drying or spray drying
at a water evaporation rate of 500 to 50000 kg water per hour per
kg of dry product, a delta T from 0.30 to 0.80 and residence time
of product in dryer of less than 5 minutes.
[0192] Before step (a) of the present method, after step (d) of the
present method, between any one of steps (a), (b), (c) and (d) of
the present method, one or more additional steps may be provided.
These additional steps are encompassed by the present method. For
example, in one preferred aspect, the crude product is washed prior
to step (d).
[0193] An additional process step according to one aspect of the
present invention comprises performing ion exchange on the mixed
metal compound. This may be performed at any time during the
process, such as when present in the slurry, as a crude product or
a dried product. A preferred ion exchange is in respect of sulphate
present in the mixed metal compound. Ion exchange performed in
respect of sulphate present in the mixed metal compound is
preferably performed by exchanging sulphate with carbonate, for
example by contacting the mixed metal compound with a carbonate
containing solution. Thus in this aspect, there is provided a
method of producing a mixed metal compound comprising
at least Mg.sup.2+ and at least Fe.sup.3+ having an aluminium
content of less than 10000 ppm, having an average crystal size of
less than 20 nm (200 .ANG.) comprising the steps of: [0194] (a)
combining a Mg.sup.2+ salt and a Fe.sup.3+ salt with
Na.sub.2CO.sub.3 and NaOH to produce a slurry, wherein the pH of
the slurry is maintained at from 9.5 to 11, and wherein the
Na.sub.2CO.sub.3 is provided at an excess of 0 to 4.0 moles (such
as an excess of 2.0 to 4.0 moles) than is required to complete the
reaction [0195] (b) subjecting the slurry to mixing under
conditions providing a power per unit volume of 0.03 to 1.6
kW/m.sup.3 [0196] (c) separating the mixed metal compound from the
slurry, to obtain a crude product having a dry solid content of at
least 10 wt % [0197] (d) drying the crude product either by [0198]
(i) heating the crude product to a temperature of no greater than
150.degree. C. and sufficient to provide a water evaporation rate
of 0.05 to 1.5 kg water per hour per kg of dry product, or [0199]
(ii) exposing the crude product to rapid drying at a water
evaporation rate of 500 to 50000 kg water per hour per kg of dry
product. [0200] (e) optionally contacting the slurry, the crude
product or the mixed metal compound, with a carbonate containing
solution to exchange sulphate present in the mixed metal compound
with carbonate.
[0201] The separation of the product may be performed by any
suitable method. For example the mixed metal compound may be
separated from the slurry by centrifugation. Different filtration
methods may be utilized but a preferred aspect is obtained by a
filtration method using centrifugation which combines filtration
followed by washing and de-watering in one step. Another preferred
aspect is obtained by a filtration method using a belt filter which
combines filtration followed by washing and de-watering in one
step
[0202] After step (d) the product may be further treated. The
present invention encompasses products obtained by virtue of
further treatment. In one aspect the dried crude product is
classified by sieving to a d50 average particle size of less than
300 .mu.m, more preferably the dried crude product is milled to a
d50 average particle size of less than 200 .mu.m, more preferably
the dried crude product is milled to a d50 average particle size of
less than 100 .mu.m, more preferably the dried crude product is
milled to a d50 average particle size of 2 to 50 .mu.m, more
preferably the dried crude product is milled to a d50 average
particle size of 2 to 30 .mu.m.
[0203] Preferably, as measured by sieving, less than 10% by weight
of particles are greater than 106 .mu.m in diameter, more
preferably less than 5%. Most preferably, no particles are greater
than 106 .mu.m in diameter as measured by sieving.
[0204] After step d(i) the product may be further treated. The
present invention encompasses products obtained by virtue of
further treatment. In one aspect the dried crude product is milled.
More preferably the dried crude product is milled to a d50 average
particle size of less than 10 .mu.m, yet more preferably the dried
crude product is milled to a d50 average particle size from 2-10
.mu.m. most preferred the dried crude product is milled to a d50
average particle size from 2-7 .mu.m, yet most preferred the dried
crude product is milled to a d50 average particle size of
approximately 5 .mu.m.
[0205] Preferably, after step d(i) the dried crude product is
milled to provide a surface area of 40-80 m.sup.2/g, more
preferably to a surface area of 40-70 m.sup.2/g, even more
preferably to a surface area of 45-65 m.sup.2/g, most preferred to
a surface area of 50-60 m.sup.2/g.
[0206] Preferably, after step d(i) the dried crude product is
milled to a d50 average particle size from 2-10 .mu.m and a surface
area of 40-80 m.sup.2/g compound.
[0207] Preferably, after step d(ii) the dried product is not
milled. Preferably, after step d(ii) the dried product has a d50
average particle size from 10-50 .mu.m and a surface area of 80-145
m.sup.2/g compound.
[0208] Preferably the dried crude product has a water content of
less than 15 wt %, preferably the dried crude product has a water
content of less than 10 wt %, preferably the dried crude product
has a water content from 1-15 wt %, preferably the dried crude
product has a water content from 5-15 wt %, preferably the dried
crude product has a water content from 5-10 wt %, preferably the
dried crude product has a water content from 8-15 wt %, preferably
the dried crude product has a water content from 8-11 wt %, based
on the total weight of the dried crude product.
[0209] Preferably the mixed metal compound has a dry solid content
of at least 10 wt %. Preferably the mixed metal compound has a dry
solid content of at least 15 wt %. More preferably the mixed metal
compound has a dry solid content of at least 20 wt %.
[0210] When dried, the mixed metal compound has a dry solid content
of at least 80 wt %. Preferably, the dried mixed metal compound has
a dry solid content of more than 85 wt %. Preferably the dried
mixed metal compound has a dry solid content of less than 99 wt %.
More preferably the dried mixed metal compound has a dry solid
content of less than 95 wt %. Most preferred the dried mixed metal
compound has a dry solid content from 90 to 95 wt %.
[0211] As discussed herein, the compound has a average crystal size
of less than 20 nm (200 .ANG.). Preferably the compound has a
average crystal size of from 100 to 200 .ANG.. Preferably the
compound has a average crystal size of from 155 to 200 .ANG..
Preferably the compound has a average crystal size of from 110 to
195 .ANG.. Preferably the compound has a average crystal size of
from 110 to 185 .ANG.. Preferably the compound has a average
crystal size of from 115 to 165 .ANG.. Preferably the compound has
a average crystal size of from 120 to 185 .ANG.. Preferably the
compound has a average crystal size of from 130 to 185 .ANG..
Preferably the compound has a average crystal size of from 140 to
185 .ANG.. Preferably the compound has a average crystal size of
from 150 to 185 .ANG.. Preferably the compound has a average
crystal size of from 150 to 175 .ANG.. More preferably the compound
has a average crystal size of from 155 to 175 .ANG.. More
preferably the compound has a average crystal size of from 155 to
165 .ANG..
[0212] In a further preferred embodiment there is provided for the
production of a mixed metal compound having an average crystal size
of less than 13 nm (130 .ANG.) and a phosphate binding capacity of
more than 0.65 mmol phosphate/g mixed metal compound.
[0213] In a further preferred embodiment there is provided for the
production of a mixed metal compound having an average crystal size
of less than 9 nm (90 .ANG.) and a phosphate binding capacity of
more than 0.70 mmol phosphate/g mixed metal compound.
[0214] In one preferred aspect the present invention provides a
mixed metal comprising at least Mg.sup.2+ and at least Fe.sup.3+
wherein the molar ratio of Mg.sup.2+ to Fe.sup.3+ is 2.1:1 to 1.7:1
having an aluminium content of less than 30 ppm, having a average
crystal size from 110-195 .ANG., having an interlayer sulphate from
2.1 to 5 wt % (such as from 2.1 to 3.2 wt %) comprising the steps
of
(a) combining a Mg.sup.2+ salt and a Fe.sup.3+ salt with
Na.sub.2CO.sub.3 and NaOH to produce a slurry, wherein the pH of
the slurry is maintained at from 9.6 to less than 10, and wherein
the Na.sub.2CO.sub.3 is provided at an excess of 2.7 moles than is
required to complete the reaction (b) subjecting the slurry to
mixing under conditions providing a power per unit volume of 0.05
to 0.05 kW/m.sup.3 (b1) controlling the slurry to a temperature
from 20 to 25.degree. C. (b2) optionally controlling the slurry to
a d50 psd of at least 40 .mu.m (preferably controlling the slurry
to a d50 psd of at least 40 .mu.m) (c) separating the mixed metal
compound from the slurry, to obtain a crude product having a dry
solid content of at least 10 wt % (d) (i) drying the crude product
to 5-10 wt % moisture by exposing the crude product to a
temperature from 40-90.degree. C. and sufficient to provide a water
evaporation rate of 0.05 to 0.5 kg water per hour per kg of dry
product.
[0215] The compound prepared by the present method may be any mixed
metal compound comprising Mg.sup.2+ and at least Fe.sup.3+. In one
preferred aspect, the compound is a compound having a hydrotalcite
structure. Preferably the compound is of the formula
M.sup.II.sub.1-xM.sup.III.sub.x(OH).sub.2A.sup.n-.sub.y.mH.sub.2O
(II)
wherein M.sup.II is one or more bivalent metals and is at least
Mg.sup.2+; M.sup.III is one or more trivalent metals and is at
least Fe.sup.3+; An.sup.n- is one or more n-valent anions and is at
least CO.sub.3.sup.2-; 1.0<x/.SIGMA.yn<1.2,
0<x.ltoreq.0.67, 0<y.ltoreq.1 and 0<m.ltoreq.10.
[0216] The method by which the molecular formula of a mixed metal
compound may be determined will be well known to one skilled in the
art. It will be understood that the molecular formula may
determined from the analysis of M.sup.II/M.sup.III ratio (Test
Method 1), SO.sub.4 analysis (Test Method 5), CO.sub.3 analysis
(Test Method 6) and H.sub.2O analysis (Test Method 12).
[0217] Preferably, 0<x.ltoreq.0.4, 0<y.ltoreq.1 and
0<m.ltoreq.10.
[0218] Preferably 1.05<x/.SIGMA.yn<1.2, preferably
1.05<x/.SIGMA.yn<1.15. In one preferred aspect
x/.SIGMA.yn=1.
[0219] In one preferred aspect 0.1<x, such as 0.2<x,
0.3<x, 0.4<x, or 0.5<x. In one preferred aspect
0<x.ltoreq.0.5. It will be understood that
x=[M.sup.III]/([M.sup.II]+[M.sup.III]) where [M.sup.II] is the
number of moles of M.sup.II per mole of compound of formula I and
[M.sup.III] is the number of moles of M.sup.III per mole of
compound of formula I.
[0220] In one preferred aspect 0<y.ltoreq.1. Preferably
0<y.ltoreq.0.8. Preferably 0<y.ltoreq.0.6. Preferably
0<y.ltoreq.0.4. Preferably 0.05<y.ltoreq.0.3. Preferably
0.05<y.ltoreq.0.2. Preferably 0.1<y.ltoreq.0.2. Preferably
0.15<y.ltoreq.0.2.
[0221] In one preferred aspect 0.ltoreq.m.ltoreq.10. Preferably
0.ltoreq.m.ltoreq.8. Preferably 0.ltoreq.m.ltoreq.6. Preferably
0.ltoreq.m.ltoreq.4. Preferably 0.ltoreq.m.ltoreq.2. Preferably
0.ltoreq.m.ltoreq.1. Preferably 0.ltoreq.m.ltoreq.0.7. Preferably
0.ltoreq.m.ltoreq.0.6. Preferably 0.1.ltoreq.m.ltoreq.0.6.
Preferably 0.ltoreq.m.ltoreq.0.5. Preferably 0.ltoreq.m.ltoreq.0.3.
Preferably 0.ltoreq.m.ltoreq.0.15. Preferably
0.15.ltoreq.m.ltoreq.0.5 The number of water molecules m can
include the amount of water that may be absorbed on the surface of
the crystallites as well as interlayer water. The number of water
molecules is estimated to be related to x according to:
m=0.81-x.
[0222] It will be appreciated that each of the preferred values of
x, y, z and m may be combined.
[0223] In one preferred aspect the compound has an aluminium
content of less than 5000 ppm, more preferably less than 1000 ppm,
most preferred 100 ppm, most preferably 30 ppm.
[0224] In one preferred aspect the total sulphate content of the
compound is from 1.8 to 5 wt %. By total sulphate content it is
meant content of sulphate that is present in the compound. This may
be determined by well known methods and in particular determined in
accordance with Test Method 1. Preferably the total sulphate is
from 2 to 5 wt % preferably from 2 to 3.7 wt %, preferably from 2
to 5 wt %, preferably from 2 to less than 5 wt %, preferably from
2.1 to 5 wt % preferably from 2.1 to less than 5 wt %, preferably
from 2.2 to 5 wt %, preferably from 2.2 to less than 5 wt %,
preferably from 2.3-5 wt %, preferably from 2.3 to less than 5 wt
%.
[0225] In one preferred aspect the total sulphate content of the
compound is from 1.8 to 4.2 wt %. By total sulphate content it is
meant content of sulphate that is present in the compound. This may
be determined by well known methods and in particular determined in
accordance with Test Method 1. Preferably the total sulphate is
from 2 to 4.2 wt % preferably from 2 to 3.7 wt %, preferably from 2
to 3.2 wt %, preferably from 2 to less than 3.2 wt %, preferably
from 2.1 to 3.2 wt % preferably from 2.1 to less than 3.2 wt %,
preferably from 2.2 to 3.2 wt %, preferably from 2.2 to less than
3.2 wt %, preferably from 2.3-3.2 wt %, preferably from 2.3 to less
than 3.2 wt %.
[0226] The compound will also contain an amount of sulphate that is
bound within the compound. This content of sulphate, the interlayer
sulphate, may not be removed by a washing process with water. As
used herein, amounts of interlayer sulphate are the amount of
sulphate as determined in accordance with Test Method 5. In a
preferred aspect the interlayer sulphate content of the compound is
from 1.8 to 5 wt %, preferably from 1.8 to 3.2 wt %, preferably
from 2 to 5 wt %, preferably from 2 to less than 5 wt %, preferably
from 2 to 3.2 wt %, preferably from 2 to 3.1 wt %, preferably from
2 to 3.0 wt %. Preferably the interlayer sulphate content of the
compound is from 2.1 to 5 wt %, preferably from 2.1 to 3.2 wt %,
preferably from 2.1 to less than 3.2 wt %. More preferably the
interlayer sulphate content of the compound is from 2.2 to 5 wt %,
preferably from 2.2 to 3.2 wt %, preferably from 2.2 to less than
3.2 wt %. Yet more preferably the interlayer sulphate content of
the compound is from 2.3 to 5 wt %, preferably from 2.3 to 3.2 wt
%, preferably from 2.3 to less than 3.2 wt %. Most preferably the
interlayer sulphate content of the compound is from 2.5 to 5 wt %,
preferably from 2.5 to 3.2 wt %, preferably from 2.5 to less than
3.2 wt %. Yet most preferred the interlayer sulphate content of the
compound is from 2.5 to 3.0 wt %.
[0227] As discussed herein, the present invention provides novel
compounds. As discussed herein, the present invention provides a
mixed metal compound comprising at least Mg.sup.2+ and at least
Fe.sup.3+,
wherein the molar ratio of Mg.sup.2+ to Fe.sup.3+ is 2.5:1 to
1.5:1, the mixed metal compound has an aluminium content of less
than 10000 ppm, the average crystal size of the mixed metal
compound is from 10 to 20 nm (100 to 200 .ANG.), and the d50
average particle size of the mixed metal compound is less than 300
.mu.m. Preferably the d50 average particle size of the mixed metal
compound is less than 200 .mu.m.
[0228] As discussed herein, the present invention provides a mixed
metal compound comprising at least Mg.sup.2+ and at least
Fe.sup.3+,
wherein the molar ratio of Mg.sup.2+ to Fe.sup.3+ is 2.5:1 to
1.5:1, the mixed metal compound has an aluminium content of less
than 10000 ppm, the average crystal size of the mixed metal
compound is from 10 to 20 nm (100 to 200 .ANG.), and the water pore
volume of the mixed metal compound is from 0.25 to 0.7 cm.sup.3/g
of mixed metal compound. Preferably the water pore volume of the
mixed metal compound is from 0.3 to 0.65 cm.sup.3/g of mixed metal
compound. Preferably the water pore volume of the mixed metal
compound is from 0.35 to 0.65 cm.sup.3/g of mixed metal
compound.
[0229] Preferably the water pore volume of the mixed metal compound
is from 0.3 to 0.6 cm.sup.3/g of mixed metal compound.
[0230] In further preferred embodiment of this aspect the nitrogen
pore volume of the mixed metal compound is from 0.28 to 0.56
cm.sup.3/g. As used herein, the term `nitrogen pore volume` refers
to the pore volume as determined in accordance with Test Method
14.
[0231] When the nitrogen pore volume of the mixed metal compound is
from 0.28 to 0.56 cm.sup.3/g it has been found that the close
correlation to the water pore volume is such that the water pore
volume need not be determined. Thus in a further aspect the present
invention provides a mixed metal compound comprising at least
Mg.sup.2+ and at least Fe.sup.3+,
wherein the molar ratio of Mg.sup.2+ to Fe.sup.3+ is 2.5:1 to
1.5:1, the mixed metal compound has an aluminium content of less
than 10000 ppm, the average crystal size of the mixed metal
compound is from 10 to 20 nm (100 to 200 .ANG.), and the nitrogen
pore volume of the mixed metal compound is from 0.28 to 0.56
cm.sup.3/g.
[0232] As discussed herein, the present invention provides a mixed
metal compound comprising at least Mg.sup.2+ and at least
Fe.sup.3+,
wherein the molar ratio of Mg.sup.2+ to Fe.sup.3+ is 2.5:1 to
1.5:1, the mixed metal compound has an aluminium content of less
than 10000 ppm, the average crystal size of the mixed metal
compound is from 10 to 20 nm (100 to 200 .ANG.), and the interlayer
sulphate content of the compound is from 1.8 to 5 wt % (such as
from 1.8 to 3.2 wt %). Preferably the average crystal size of the
mixed metal compound is from 12 to 20 nm (120 to 200 .ANG.).
[0233] As discussed herein, the present invention provides a mixed
metal compound comprising at least Mg.sup.2+ and at least
Fe.sup.3+,
wherein the molar ratio of Mg.sup.2+ to Fe.sup.3+ is 2.5:1 to
1.5:1, the mixed metal compound has an aluminium content of less
than 10000 ppm, the average crystal size of the mixed metal
compound is less than 20 nm (200 .ANG.), and the interlayer
sulphate content of the compound is from 2.1 to 5 wt % (such as
from 1.8 to 3.2 wt %). Preferably the average crystal size of the
mixed metal compound is from 10 to 20 nm (100 to 200 .ANG.).
[0234] As discussed herein, the present invention provides a mixed
metal compound comprising at least Mg.sup.2+ and at least
Fe.sup.3+,
wherein the molar ratio of Mg.sup.2+ to Fe.sup.3+ is 2.5:1 to
1.5:1, the mixed metal compound has an aluminium content of less
than 10000 ppm, the average crystal size of the mixed metal
compound is less than 20 nm (200 .ANG.), and the surface area is
from 80 to 145 m.sup.2 per gram of compound. Preferably the
compound has a d50 average particle size of from 10 to 350 .mu.m
(and preferably wherein the compound has not been subject to
milling). Preferably the compound has a d50 average particle size
of from 10 to 300 .mu.m Preferably the compound has a d50 average
particle size of from 10 to 210 .mu.m Preferably the compound has a
d50 average particle size of from 10 to 100 .mu.m. Preferably the
compound has a d50 average particle size of from 10 to 50 .mu.m.
Preferably the compound has a d50 average particle size of from 10
to 35 .mu.m Preferably the compound releases magnesium in an amount
is less than 0.15 mmol magnesium/g compound. The magnesium release
is determined in accordance with Test Method 3
[0235] As discussed herein, the present invention provides a mixed
metal compound comprising at least Mg.sup.2+ and at least
Fe.sup.3+,
wherein the molar ratio of Mg.sup.2+ to Fe.sup.3+ is 2.5:1 to
1.5:1, the mixed metal compound has an aluminium content of less
than 10000 ppm, the average crystal size of the mixed metal
compound is from 10 to 20 nm (100 to 200 .ANG.), the surface area
is from 40 to 80 m.sup.2 per gram of compound.
[0236] Preferably the d50 average particle size of the mixed metal
compound is less than 100 .mu.m. Preferably the d50 average
particle size of the mixed metal compound is less than 50 .mu.m.
Preferably the d50 average particle size of the mixed metal
compound is less than 20 .mu.m. Preferably the d50 average particle
size of the mixed metal compound is less than 10 .mu.m. Preferably
the d50 average particle size of the mixed metal compound is
approximately 5 .mu.m. Preferably the water pore volume of the
mixed metal compound is from 0.25 to 0.7 cm.sup.3/g of mixed metal
compound, preferably the water pore volume is from 0.3 to 0.65
cm.sup.3/g of mixed metal compound, preferably the water pore
volume is from 0.3 to 0.6 cm.sup.3/g of mixed metal compound.
Preferably the nitrogen pore volume of the mixed metal compound is
from 0.28 to 0.56 cm.sup.3/g of mixed metal compound.
[0237] In each of the aspects of the invention in which a mixed
metal compound is provided, preferably
(1) the interlayer sulphate content of the compound is from 2.2 to
5 wt % (such as from 1.8 to 3.2 wt %), and/or (2) the compound is
of the formula
M.sup.II.sub.1-xM.sup.III.sub.x(OH).sub.2A.sup.n-.sub.y.mH.sub.2O
wherein is one or more bivalent metals and is at least Mg.sup.2+;
M.sup.III is one or more trivalent metals and is at least
Fe.sup.3+; A.sup.n- is one or more n-valent anions and is at least
CO.sub.3.sup.2-; x/.SIGMA.yn is from 1 to 1.2 (preferably
x/.SIGMA.yn is from 1.05 to 1.15, preferably x/.SIGMA.yn is 1)
0<x.ltoreq.0.4, 0<y.ltoreq.1 and 0<m.ltoreq.10, and/or (3)
the compound has an aluminium content of less than 100 ppm,
preferably an aluminium content of less than 30 ppm. (4) the
interlayer sulphate content of the compound is from 1.8 to 5 wt %
(such as from 1.8 to 3.2 wt %), and/or (5) the compound has a d50
average particle size of less than 100 .mu.m. preferably the
compound has a d50 average particle size of 5 to 50 .mu.m,
preferably the compound has a d50 average particle size of
approximately 5 .mu.m and/or (6) the water pore volume of the mixed
metal compound is from 0.3 to 0.65 cm.sup.3/g of mixed metal
compound and/or (7) the compound has a dry solid content of at
least 20 wt %.
[0238] The compound may have any degree of porosity, subject to any
range specified herein. In a preferred aspect the water pore volume
of the mixed metal compound is from 0.25 to 0.7 cm.sup.3/g of mixed
metal compound. In a preferred aspect the water pore volume of the
mixed metal compound is from 0.3 to 0.65 cm.sup.3/g of mixed metal
compound.
[0239] Preferably the mixed metal compound comprises at least some
material which is a Layered Double Hydroxide (LDH). More
preferably, the mixed metal compound of formula (I) is a layered
double hydroxide. As used herein, the term "Layered Double
Hydroxide" is used to designate synthetic or natural lamellar
hydroxides with two different kinds of metallic cations in the main
layers and interlayer domains containing anionic species. This wide
family of compounds is sometimes also referred to as anionic clays,
by comparison with the more usual cationic clays whose
interlamellar domains contain cationic species. LDHs have also been
reported as hydrotalcite-like compounds by reference to one of the
polytypes of the corresponding [Mg--Al] based mineral.
[0240] A particularly preferred mixed metal compound contains at
least one of carbonate ions, and hydroxyl ions.
[0241] A particularly preferred compound contains as M.sup.II and
M.sup.III, magnesium and iron (Ill) respectively.
Process
[0242] The mixed metal compound or compounds may be suitably made
by co-precipitation from a solution, followed by centrifugation or
filtration, then drying, milling and/or sieving. The mixed metal
compound may then be rewetted as part of the wet-granulation
process and the resulting granules dried in a fluid-bed dryer. The
degree of drying in the fluid-bed is used to establish the desired
water content of the final tablet.
[0243] Two methods of coprecipitation may be used, namely one at
low supersaturation whereby the pH of the reaction solution is
maintained constant by controlling the addition of a second
solution of an alkali, or alternatively precipitation at high
supersaturation whereby the pH of the reaction solution is
continuously changed by addition of the mixed metal solution to an
alkali solution already present in the reactor vessel. The
precipitation method whereby the pH is kept constant is preferred
as this avoids the formation of single metal compounds such as
M(OH).sub.2 and/or M(OH).sub.3 phases instead of mixed metal
compound.
[0244] Other precipitation methods of the mixed metal compound may
also be possible if the crystallite size is controlled to less than
200 .ANG.. For example, a precipitation method involving separate
nucleation and aging steps, an urea hydrolysis method, an induced
hydrolysis method, a salt-oxide method, a sol-gel method, an
electrosynthesis method, an in situ oxidation of the divalent metal
ion to a trivalent metal ion, a so-called "Chimie Douce" method or
a method wherein the mixed metal compound may be formed by heating
an intimate mixture of finely divided single metal salts at a
temperature whereby solid-solid reaction can occur, leading to a
mixed metal compound formation.
[0245] Post synthesis methods that tend to promote ageing are less
preferred but may be used if crystallite size is controlled to less
than 200 .ANG.. Examples of possible post synthesis heat-treatment
steps include hydrothermal, microwave and ultrasound.
[0246] A variety of methods can be used to separate the mixed metal
compound from the reaction slurry. Different washing, drying and
milling methods are also possible where crystallite size is less
than 200 .ANG..
[0247] The substances of the invention prepared by treatment of a
suitable starting material as hereinbefore described may be
prepared by providing a first solution of a water soluble compound
of metal M.sup.II and a water soluble compound of metal M.sup.III,
the anions being chosen so as not to result in precipitation from
the first solution (A). A second solution (B) is also provided, of
a water soluble hydroxide (e.g. NaOH) and a water soluble salt of
anion A.sup.n- (the cation being chosen so as not to precipitate
with the hydroxide or the anion with the metal from the hydroxide).
The two solutions are then combined and the mixed metal compound
starting material is formed by co-precipitation. For example,
Solution A is made up by dissolving magnesium sulphate and ferric
sulphate in purified water. Solution B is made up by dissolving
sodium carbonate and sodium hydroxide in purified water. A heel of
purified water is added to a reactor, the solutions A and B are fed
in a ratio controlled manner. After the product forms in the
reactor it may comprise solid crystalline material, usually also
with the presence of some solid amorphous material. Preferably, at
least some of the material so formed is of a layered double
hydroxide and/or of a hydrotalcite structure, usually also with
some amorphous and/or poorly crystalline material, preferably after
co-precipitation, the material is then filtered or centrifuged,
washed then dried by heating. The drying is carried out either by
(i) exposing the crude product to a temperature of no greater than
150.degree. C. and sufficient to provide a water evaporation rate
of 0.05 to 1.5 kg water per hour per kg of dry product, or (ii)
exposing the crude product to flash drying or spray drying at a
water evaporation rate of 500 to 50000 kg water per hour per kg of
dry product, for example by oven drying, spray drying or fluid bed
drying.
[0248] Optionally, the dry material may be first classified, to
remove oversize particles by milling and/or sieving and/or any
other suitable technique, for example to restrict the material to
be treated to particles which are substantially no greater than 300
.mu.m in diameter.
Reaction
[0249] A wide number of options are available for carrying out the
reaction. These may be controlled in order to carry out the
reaction in the manner desired. For example, the reactant equipment
type, reactant stream composition, temperature and pH, mode of
reactant addition, agitation system, and hold time may all be
specified in order to produce a desired reaction.
[0250] Various reactor types are common in the pharmaceutical
industry, these include Batch and Continuous reactors.
[0251] The material structure and crystallite size can be
significantly determined at the reaction stage by close control of
the reactant solution concentration, the reaction temperature, the
time that the reaction mass is held following precipitation and the
mode of reactant addition. Furthermore, in order to achieve the
preferred material structure with small crystallite size, a high
solution concentration (at end of reaction period of 4.8-5.4 wt %),
low reaction temperature (15-25.degree. C.) and short hold time
(typically <12 hours) are preferred.
[0252] To prepare the mixed metal compounds to a preferred Mg:Fe
molar ratio, for example from 1.5:1 to 2.5:1 then precise control
of pH during the precipitation process is desirable. Precise pH
control is typically achieved by frequent calibration of pH
electrodes and monitoring and adjustment of the pH throughout the
precipitation process. The pH of the reaction may be controlled by
varying the relative rate of addition of Solution A to Solution B
added to the reactor. We have found that the variation of Solution
B only is preferred since this maintains the precipitate
concentration in the reaction mix at a constant level. The
variation in Solution B flow rate can be carried out manually or
using a suitable control algorithm.
[0253] We have found an optimal reactant composition, whereby
opposing requirements of maintaining a relatively low reaction
temperature, but achieving reasonable filtration rate and good pH
control, are met.
[0254] For example, the preferred M.sup.2+:M.sup.3+ molar ratio
between 1.5:1 to 2.5:1 of the mixed metal compound can be achieved
by maintaining the reactant streams in solution even at relatively
low temperatures, thereby limiting the reaction temperature. The
reaction temperature can be important in determining the extent of
crystallite growth and hence the phosphate binding activity.
[0255] The preferred method allows good filtration rates to be
achieved, this again can be important in limiting the reaction mass
storage time which in term is known to help determine the extent of
crystallite growth, and hence the phosphate binding activity.
[0256] Further, the preferred reaction conditions and recipe helps
to maintain good pH control. Good pH control is required in order
to achieve the target pH.
[0257] The mode of reactant stream addition can be important in
defining the reaction product quality. Different combinations of
addition mode are possible and may include the addition of one
reactant stream into an excess of the other reactant (either
reactant could be selected as the added stream).
[0258] We have found that simultaneous addition of a high pH
reactant stream containing carbonate and hydroxide ions, and a low
pH reactant stream containing metal and sulphate ions into a heel
provides more accurate pH control of the reaction slurry.
Therefore, in a preferred embodiment, the reaction is carried out
by simultaneous addition (co-precipitation) of a reactant stream
containing carbonate and hydroxide ions, and a reactant stream
containing metal and sulphate ions.
[0259] Similarly, the product can be removed on a continuous basis
as the reactant streams are added, or at the end of a defined
period.
[0260] Good filtration characteristics are achieved by targeting a
relatively large particle size such as of at least 40 .mu.m by
controlling the power per unit volume from 0.03 to 1.6 kW/m.sup.3.
We have identified that power per unit volume of 0.05 to 0.5
kW/m.sup.3 using impeller(s) configured for axial flow agitation,
helps to produce a slurry with further improved filtration
characteristics (such as lower filtration and washing time, and
high final solids content in cake).
[0261] Therefore, in a preferred embodiment, agitation is used to
subject the slurry to mixing under conditions providing a power per
unit volume of 0.03 to 1.6 kW/m.sup.3 provided by static mixers,
impeller agitators, pump, jet mixer or dynamic in line mixer.
Therefore, in a further preferred embodiment, axial flow agitation
is used to subject the slurry to mixing under conditions providing
a power per unit volume of 0.03 to 1.6 kW/m.sup.3 provided by an
impeller agitator. More preferably a power per unit volume of 0.05
to 0.5 kW/m.sup.3 delivered by impeller agitation. This provides
reaction slurry with the preferred filtration characteristics.
[0262] Therefore, in a separate embodiment, the reaction is
agitated using means other than a conventional impeller
agitator.
[0263] An optimum hold time has been identified as from 30 minutes
to 12 hours. For hold times of more than 16 hours, filtration
becomes difficult due to a reduction in particle size during use of
agitation in hold time and ageing occurs.
Filtration
[0264] A wide number of options are available for carrying out the
product isolation and washing steps, however the filtration
equipment type and operating process parameters should be carefully
defined and controlled.
[0265] For example, in order to limit the overall reaction slurry
hold time (and hence crystallite growth), it is beneficial to
minimise the time for cake isolation and wash time A high cake
solids content is also preferable as this reduces the drying time
and hence the propensity for crystallite growth during the drying
step.
[0266] Various filter types are used in the pharmaceutical
industry, these include: Neutsche filters, Filter dryers, Filtering
centrifuges, Belt filters, Plate and frame filters.
[0267] When isolating the unaged mixed metal compound, the overall
filtration rate can be extremely low due to the relative difficulty
of isolating and washing these unaged clay-type mixed metal
compounds making this economically unattractive if not controlled
to the preferred conditions. The unaged material of crystallite
size of less than 200 .ANG., has the tendency to result in
`blinding` of the filtration media and/or the clay-type properties
have a tendency to form a more impermeable cake.
[0268] In one preferred embodiment we have produced high filtration
rate using a belt filter.
Drying
[0269] A wide number of options are available for carrying out the
drying operation, these should be defined and controlled in order
to carry out the drying step in the best manner.
[0270] For example, the dryer type, mode of drying, and rate of
drying should be specified and controlled such that the crude
product is dried either by (i) exposing the crude product to a
temperature of no greater than 150.degree. C. and sufficient to
provide a water evaporation rate of 0.05 to 1.5 kg water per hour
per kg of dry product, or (ii) exposing the crude product to flash
drying or spray drying at a water evaporation rate of 500 to 50000
kg water per hour per kg of dry product. The rate of drying is
affected by factors including the mode of drying, heated
surface/heating medium temperature, degree of agitation, vacuum
level (if any) etc. The product temperature must be limited to no
greater than 150.degree. C. to prevent damage to the drug
substance.
[0271] Various dryer types are common in the pharmaceutical
industry, these include long residence time dryers (characterised
as typically up to 20 h residence time) such as Spherical, Conical,
Double cone, Tray dryer (vacuum, ambient pressure), and short
residence time dryers (characterised as typically up to several
minutes residence time) include; Spray, Spin flash, Etc.
[0272] We have found that of the various batch dryer designs an
agitated spherical dryer offers a large heated surface area to the
product. Therefore a higher product rate per unit area from 1 to
2.1 kg product/(m.sup.2hr) and thus high heat transfer and drying
rates are possible. Since ageing (crystallite growth) can occur
during drying, it is important to minimise the drying time/maximise
drying rate. In order to prevent decomposition of the drug
substance, where surface heating is used the drying surface
temperature is typically limited to 150.degree. C. for batch drying
and preferably 90.degree. C. or less to avoid average crystal size
growth to above 200 .ANG.. Partial evacuation of the dryer
depresses the boiling point of water in the drying mass, thereby
limiting crystal growth, this depression also serves to maximise
the drying rate. The drying rate is manipulated by maximising the
dryer vacuum and/or increasing the shell temperature up to
120.degree. C. during an initial drying phase, to remove water at
the highest possible rate, and then reducing the rate by reducing
the shell temperature to less than 90.degree. C., in order to
accurately target a defined moisture end point whilst maintaining a
crystallite size less than 200 .ANG.. The moisture end point can be
inferred by monitoring the evaporation mass, or measured directly,
by analysis of the dried contents, or other suitable methods.
[0273] Conical dryers (e.g. Nautamixer type) offer similar benefits
to the spherical dryer.
[0274] Vacuum tray dryers were found to produce an acceptable
product quality, however this type of dryer can require manual
intervention (e.g. redistribution of solids) for uniform drying,
and has limited throughput.
[0275] The long residence time batch dryers described (spherical,
conical, vacuum) all have relatively low drying rates (expressed in
normalised terms as kg evaporation per kg product per hour) when
compared to the short residence time drying methods. We have found
that the temperature of the drug substance during drying and the
drying rate can significantly influence the crystallite size and
morphology of the drug substance.
[0276] For example, long residence time batch drying tends to
produce a relatively large average crystal size and relatively low
pore volume and surface area, whereas short residence methods such
as spray drying and spin flash drying have been found to produce
relatively smaller crystals with relatively large pore volume and
surface area. Material produced using short residence time drying
can show an enhanced phosphate binding performance; this may be due
to the different crystallite and morphological properties. Spray
dried material has the additional advantage of granulation for just
dry blending (e.g. for tablet manufacture) and may be carried out
without prior milling of the drug substance.
[0277] Long residence drying time methods are typically defined as
having a residence time equal to or greater than 3 hours. Examples
of these include: tray drying, kettle drying, pan drying, rotary
(shell) drying, rotary (internal) drying, double cone drying.
[0278] We have found average evaporation rates of between 9 and 29
kg water/(hm.sup.2) are achievable using an agitated vacuum
spherical dryer. Stated on an alternative basis this is equivalent
to an evaporation rate of approximately 0.05 to 0.5 kg water per
hour per kg of dry product. The product crystallite size produced
at this range of evaporation rates is typically between 100-200
Angstroms. For a dried product of consistent quality the dryer must
be fed with a wet cake (typically >20 wt % solids).
[0279] Each of the above dryers is operated on a batch basis.
[0280] Short residence drying time method examples typically have
much lower residence times. These differ depending upon technology
types and are defined as: spin flash drying, typical residence time
of 5 to 500 seconds/spray drying, typical residence time up to 60
seconds.
[0281] Typical evaporation rates are defined as: spin flash 70-300
kg water/(hm.sup.3) vessel volume, spray 5-25 kg water/(hm.sup.3)
vessel volume. Evaporation rates for spin flash and spray dryers
are also calculated as 500 to 50000 kg water/(hkg drug). The
product crystallite size produced at this range of evaporation
rates is typically less than 140 Angstroms. The spin flash dryer
may be fed with wet cake (typically >20 wt % solids), whereas
the spray dryer must be fed with a free flowing slurry at a lower
concentration (typically to 10 wt % solids)
[0282] The above short residence time dryers may all be operated on
a continuous basis.
[0283] Various `medium` residence time technologies can be used
which predominantly rely on the use conveyors and are operated
continuously. These may be less preferred if problems occur in
terms of ensuring a consistent quality of product (variable
moisture content) and cleanliness for pharmaceutical production.
Examples of medium residence time technologies are listed as:
Rotary shelf, Trough Vibrating, Turbo type.
Uses
[0284] Preferably the compound is used in the manufacture of a
medicament for the prophylaxis or treatment of
hyperphosphataemia.
[0285] In a further aspect the present invention provides use of a
compound of the present invention or obtained/obtainable in
accordance with the present invention in the manufacture of a
medicament for the prophylaxis or treatment of any one of
hyperphosphataemia, renal insufficiency, hypoparathyroidism,
pseudohypoparathyroidism, acute untreated acromegaly, chronic
kidney disease and over medication of phosphate salts.
[0286] Examples of one or more of the symptoms which may indicate
risk for the presence of CKD: a creatine concentration of above 1.6
mg/dL, a blood phosphate level of above 4.5 mg/dL, any detectable
blood in urine, urine protein concentration above 100 mg/dL, a
urine albumin concentration above about 100 mg/dL, a glomerular
filtration rate (GFR) of below 90 mL/min/1.73 m.sup.2 or a
parathyroid hormone concentration in the blood above 150 pg/mL. The
symptoms are also defined by the National Kidney Foundation-Fidney
Disease Outcomes Quality Initiative "NKF-K/DOQI" or "K/DOQI,".
[0287] In one preferred aspect the chronic kidney disease (CKD)
treated in accordance with the presence invention is CKD having
stage one to five.
[0288] The medicament may be used on animals, preferably
humans.
Pharmaceutical Compositions
[0289] A pharmaceutically acceptable carrier may be any material
with which the substance of the invention is formulated to
facilitate its administration. A carrier may be a solid or a
liquid, including a material which is normally gaseous but which
has been compressed to form a liquid, and any of the carriers
normally used in formulating pharmaceutical compositions may be
used. Preferably, compositions according to the invention contain
0.5% to 95% by weight of active ingredient. The term
pharmaceutically acceptable carrier encompasses diluents,
excipients or adjuvants.
[0290] When the substances of the invention are part of a
pharmaceutical composition, they can be formulated in any suitable
pharmaceutical composition form e.g. powders, granules, granulates,
sachets, capsules, stick packs, battles, tablets but especially in
a form suitable for oral administration for example in solid unit
dose form such as tablets, capsules, or in liquid form such as
liquid suspensions, especially aqueous suspensions or semi-solid
formulations, e.g. gels, chewy bar, dispersing dosage, chewable
dosage form or edible sachet. Direct addition to food may also be
possible.
[0291] Dosage forms adapted for extra-corporeal or even intravenous
administration are also possible. Suitable formulations can be
produced by known methods using conventional solid carriers such
as, for example, lactose, starch or talcum or liquid carriers such
as, for example, water, fatty oils or liquid paraffins. Other
carriers which may be used include materials derived from animal or
vegetable proteins, such as the gelatins, dextrins and soy, wheat
and psyllium seed proteins; gums such as acacia, guar, agar, and
xanthan; polysaccharides; alginates; carboxymethylcelluloses;
carrageenans; dextrans; pectins; synthetic polymers such as
polyvinylpyrrolidone; polypeptide/protein or polysaccharide
complexes such as gelatin-acacia complexes; sugars such as
mannitol, dextrose, galactose and trehalose; cyclic sugars such as
cyclodextrin; inorganic salts such as sodium phosphate, sodium
chloride and aluminium silicates; and amino acids having from 2 to
12 carbon atoms such as a glycine, L-alanine, L-aspartic acid,
L-glutamic acid, L-hydroxyproline, L-isoleucine, L-leucine and
L-phenylalanine.
[0292] Auxiliary components such as tablet disintegrants,
solubilisers, preservatives, antioxidants, surfactants, viscosity
enhancers, colouring agents, flavouring agents, pH modifiers,
sweeteners or taste-masking agents may also be incorporated into
the composition. Suitable colouring agents include red, black and
yellow iron oxides and FD & C dyes such as FD & C blue No.
2 and FD & C red No. 40 available from Ellis & Everard.
Suitable flavouring agents include mint, raspberry, liquorice,
orange, lemon, grapefruit, caramel, vanilla, cherry and grape
flavours and combinations of these. Suitable pH modifiers include
sodium hydrogencarbonate, citric acid, tartaric acid, hydrochloric
acid and maleic acid. Suitable sweeteners include aspartame,
acesulfame K and thaumatin. Suitable taste-masking agents include
sodium hydrogencarbonate, ion-exchange resins, cyclodextrin
inclusion compounds, adsorbates or microencapsulated actives.
[0293] For treatment of and prophylaxis of hyperphosphataemia,
preferably amounts of from 0.1 to 500, more preferably from 1 to
200, mg/kg body weight of substance of the invention as active
compound are administered daily to obtain the desired results.
Nevertheless, it may be necessary from time to time to depart from
the amounts mentioned above, depending on the body weight of the
patient, the method of application, the animal species of the
patient and its individual reaction to the drug or the kind of
formulation or the time or interval in which the drug is applied.
In special cases, it may be sufficient to use less than the minimum
amount given above, whilst in other cases the maximum dose may have
to be exceeded. For a larger dose, it may be advisable to divide
the dose into several smaller single doses. Ultimately, the dose
will depend upon the discretion of the attendant physician.
Administration soon before meals, e.g. within one hour before a
meal or taken with food will usually be preferred.
[0294] A typical single solid unit dose for human adult
administration may comprise from 1 mg to 1 g, preferably from 10 mg
to 800 mg of substance of the invention.
[0295] A solid unit dose form may also comprise a release rate
controlling additive. For example, the substance of the invention
may be held within a hydrophobic polymer matrix so that it is
gradually leached out of the matrix upon contact with body fluids.
Alternatively, the substance of the invention may be held within a
hydrophilic matrix which gradually or rapidly dissolves in the
presence of body fluid. The tablet may comprise two or more layers
having different release properties. The layers may be hydrophilic,
hydrophobic or a mixture of hydrophilic and hydrophobic layers.
Adjacent layers in a multilayer tablet may be separated by an
insoluble barrier layer or hydrophilic separation layer. An
insoluble barrier layer may be formed of materials used to form the
insoluble casing. A hydrophilic separation layer may be formed from
a material more soluble than the other layers of the tablet core so
that as the separation layer dissolves the release layers of the
tablet core are exposed.
[0296] Suitable release rate controlling polymers include
polymethacrylates, ethylcellulose, hydroxypropylmethylcellulose,
methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose,
sodium carboxymethylcellulose, calcium carboxymethylcellulose,
acrylic acid polymer, polyethylene glycol, polyethylene oxide,
carrageenan, cellulose acetate, zein etc.
[0297] Suitable materials which swell on contact with aqueous
liquids include polymeric materials include from cross-linked
sodium carboxymethylcellulose, cross-linked hydroxypropylcellulose,
high molecular weight hydroxypropylcellulose, carboxymethylamide,
potassium methacrylatedivinylbenzene copolymer,
polymethylmethacrylate, cross-linked polyvinylpyrrolidone and high
molecular weight polyvinylalcohols.
[0298] Solid unit dose forms comprising a substance of the
invention may be packaged together in a container or presented in
foil strips, blister packs or the like, e.g. marked with days of
the week against respective doses, for patient guidance.
[0299] There is also a need for formulations which could improve
patient compliance, for example in case of elderly or paediatric
patients. A formulation in powder dose form could be either diluted
in water, reconstituted or dispersed.
Combinations
[0300] The compound of the present invention may be used as the
sole active ingredient or in combination with another phosphate
binding agent. It may also be used in combination with a
calcimimetic such as cinacalet, vitamin D or calcitriol.
[0301] In a further aspect the present invention provides use of a
compound of the present invention or obtained/obtainable in
accordance with the present invention in the manufacture of a
medicament for the prophylaxis or treatment of
hyperphosphataemia.
EXAMPLES
General Description of Reaction
[0302] The mixed metal compound is formed by the reaction of an
aqueous mixture of magnesium sulphate and ferric sulphate with an
aqueous mixture of sodium hydroxide and sodium carbonate. The
precipitation is carried out at a pH of around 9.8 and a reaction
temperature starting at around 22.degree. C. and rising to up to
30.degree. C. upon addition of reactants. The resulting precipitate
is filtered, washed, dried and milled.
[0303] The synthesis reaction is represented thus:
4MgSO.sub.4+Fe.sub.2(SO.sub.4).sub.3+12NaOH+(XS+1)Na.sub.2CO.sub.3.fwdar-
w.Mg.sub.4Fe.sub.2(OH).sub.12.CO.sub.3.nH.sub.2O+7Na.sub.2SO.sub.4+XSNa.su-
b.2CO.sub.3.
[0304] This generates a mixed metal compound with a molar ratio of
Mg:Fe of typically 2:1 and the reaction by-product sodium sulphate.
Excess (XS) sodium carbonate added to the reaction mixture along
with the sodium sulphate is washed out of the precipitate.
[0305] By changing the molar ratio of M.sup.II:M.sup.III cations to
1:1, 2:1, 3:1, 4:1 different composition materials were achieved.
The excess sodium carbonate and reaction pH were also changed in
separate experiments.
[0306] The molecular formula of layered double hydroxides can be
measured by different methods. The actual method used to determine
the molecular formula of the examples herein was determined from
the analysis of M.sup.II/M.sup.III ratio (Method 1), SO.sub.4
analysis (Method 5), CO.sub.3 analysis (Method 6) and H.sub.2O
analysis (Method 12). Formula
[M.sup.II.sub.1-xM.sup.III.sub.x(OH).sub.2][(CO.sub.3).sub.y1(SO.sub.4).s-
ub.y2.mH.sub.2O][Na.sub.2SO.sub.4], was used to describe the
composition of the examples (1-66) shown herein below in further
detail for mixed metal compound wherein:
x=[M.sup.II]/([M.sup.II]+[M.sup.III]) where [M.sup.II] is the
number of moles of bivalent metal M.sup.II per mole of compound of
formula I and [M.sup.III] is the number of moles of trivalent metal
M.sup.III per mole of compound of formula I. .SIGMA.y'=sum of the
moles interlayer anions y1' (CO.sub.3.sup.2-)+y2' (SO.sub.4.sup.2-)
or any other anions wherein
y1'=wt % CO.sub.3.sup.2-/Mw CO.sub.3.sup.2-
y2'=(wt % SO.sub.4.sup.2-total/Mw SO.sub.4.sup.2-)-(wt %
Na.sub.2O/Mw Na.sub.2O)
[0307] Interlayer anions are also defined as bound anions or anions
that cannot be removed by washing with water.
.SIGMA.y=.SIGMA.y'*f
.SIGMA.y=is the sum of moles interlayer anion corrected with the
formula normalisation factor (f).
y1=y1'*f
y2=y2'*f
f=x/(2*wt % M.sup.III.sub.2O.sub.3/Mw
M.sup.III.sub.2O.sub.3)=formula normalisation factor
m'=wt % H.sub.2O/(Mw H.sub.2O)
m=m'*f
wt % H.sub.2O=LOD (loss on drying measured at 105.degree. C.)
z=z'*f z=amount of sulphate remaining that can be removed by
washing and is calculated from the amount of Na.sub.2O the total of
which is assumed to be associated with SO.sub.4.sup.2 as soluble
Na.sub.2SO.sub.4
z'=wt % Na.sub.2O/Mw Na.sub.2O
[0308] The ratio x/.SIGMA.yn can be calculated from the values of x
and the sum of interlayer anions (.SIGMA.yn) the data for which is
inserted below into molecular formula
[Mg.sub.1-xFe.sub.x(OH).sub.2][(CO.sub.3).sub.y1(SO.sub.4).sub.y2
mH.sub.2O].[Na.sub.2SO.sub.4].sub.z.
Example 1
[0309] Prepared by the method described below for preparation of
approximately 250 gram of dried product targeted to have a Mg:Fe
molar ratio of 1:1.
[0310] The actual molecular formula found by analysis was:
[Mg.sub.0.5Fe.sub.0.5(OH).sub.2][(CO.sub.3).sub.0.14(SO.sub.4).sub.0.02.-
0.4H.sub.2O][Na.sub.2SO.sub.4].sub.0.00
[0311] Wherein x=0.5, y1=0.14, y2=0.02, m=0.4, z=0.
[0312] Two starting materials, designated solution 1 and solution 2
were prepared by the method set out below such as to provide an
Na.sub.2CO.sub.3 excess of 2.7 mole (in reaction equation 1).
[0313] Magnesium sulphate and iron sulphate were dissolved in
AnalaR.TM. water to prepare solution 1. In a separate vessel sodium
carbonate and sodium hydroxide were dissolved in AnalaR.TM. water
to prepare solution 2. The weights used were calculated to give the
desired ratio of metal cations.
[0314] For the preparation of solution 1, AnalaR.TM. water was
weighed out into a vessel and stirred using an overhead mixer, into
which was dissolved an appropriate amount of ferric sulphate
hydrate (GPR grade). Once dissolved, magnesium sulphate (Epsom
Salt) was quantitatively transferred to the stirred iron sulphate
solution and allowed to dissolve.
[0315] For the preparation of solution 2, AnalaR.TM. water was
weighed out into a vessel and stirred using an overhead mixer, into
which was dissolved an appropriate amount of sodium carbonate
(Pharmakarb). Once dissolved, sodium hydroxide (Pearl Caustic Soda)
was quantitatively transferred to the stirred sodium carbonate
solution and allowed to dissolve.
[0316] The solutions were then added simultaneously to stirred heel
water of 1100 cm.sup.3 at controlled flow rates sufficient to
maintain pH 10.3 in the reaction mixture (+/-0.2 pH units) at a
reaction temperature not exceeding 30.degree. C. The final slurry
concentration was around 5.1 wt % compound.
[0317] When the additions were complete, the reaction mixture was
mixed for another 30 minutes and then filtered using a buchner
filtration set up. The product slurry was filtered using a vacuum
pump and buchner funnel with a Whatman.TM. hardened ashless filter
paper (No 541). After filtering, the filter cake was washed with
portions of AnalaR.TM. water.
[0318] The filtered product was then washed with 220 cm.sup.3
portions of cold AnalaR.TM. water. After isolation the product was
dried using a preheated oven.
[0319] A weight of AnalaR.TM. water was placed into a vessel. Flow
control units were used to deliver the appropriate flow rates of
the alkaline carbonate and metal sulphate solutions.
[0320] After isolation the washed product was transferred to a
vessel and dried in a preheated oven at 120.degree. C. for three
hours.
[0321] Product sample for analysis were ground using a ball mill
(Retsch PM 100). The milling parameters were set depending on the
properties of the product.
[0322] Product sample for analysis was milled through a stainless
steel, 200 mm diameter, 106 .mu.m sieve, using a sieve shaker
(Retsch AS-200). Oversize material was returned to the stock dried
sample to be reground, until all material is <106 .mu.m.
Example 2
[0323] Preparation method as for Example 1 but targeted to have a
Mg:Fe molar ratio of 2:1.
[0324] The actual molecular formula found by analysis was:
[Mg.sub.0.64Fe.sub.0.36(OH).sub.2][(CO.sub.3).sub.y1(SO.sub.4).sub.0.03.-
0.20H.sub.2O][Na.sub.2SO.sub.4].sub.z
Example 3
[0325] Preparation method as for Example 1 but targeted to have a
Mg:Fe molar ratio of 3:1.
Example 4
[0326] Preparation method as for Example 1 but targeted to have a
Mg:Fe molar ratio of 4:1.
Example 5 & 6
[0327] [intentionally blank]
Example 7
[0328] Preparation method as for Example 1 but targeted to have a
Mg:Fe molar ratio of 2:1 and intended ageing (increase in
crystallite size) by introducing an additional method step
immediately after precipitation wherein the reaction slurry is aged
by heat treatment. The slurry is refluxed for 4 hours by using a
hot plate and a Liebig condenser to reflux the sample in a sealed
flask. The sample was then immediately filtered using a Buchner
funnel under vacuum. The aged compound was then isolated using the
same method as described for Example 1.
[0329] The actual molecular formula found by analysis was:
[Mg.sub.0.66Fe.sub.0.34(OH).sub.2][(CO.sub.3).sub.y1(SO.sub.4).sub.0.01.-
0 09H.sub.2O][NaSO.sub.4].sub.z
Example 8-24
[0330] Preparation method as for Example 2 but with a liquid ferric
source of 40.4 to 42.9 wt % ferric sulphate of water industry
standard suitable for human consumption conforms to BS EN
890:2004). The method was then varied in that they were conducted
at different precipitation pH, different excess of
Na.sub.2CO.sub.3, and different reaction temperature i.e. either
unaged (i.e. at relatively low reaction temperature 15, 30 or 65
Celsius) or aged (at 90 Celsius) according to examples described
below. Where the examples were unaged either the solutions were
cooled (to 15 Celsius) or no heat-treatment of reaction slurry
occurred (at 30 Celsius) or some gentle heating (at 65 Celsius);
whereas when aged, heat-treatment of the reaction slurry occurred
by using a sealed glass beaker with condenser placed on a hotplate
and reaction slurry heated at 90.degree. C. for 4 hours). Where a
reaction temperature is not mentioned the reaction was conducted at
the standard room temperature of approximately 25-30 Celsius. The
reaction slurry was cooled to 15 Celsius by placing the metal
beaker in an ice water bath; the temperature was monitored by a
thermometer and controlled by the addition and removal of ice. The
reaction slurry was heated to 65 Celsius by placing the metal
beaker in a thermostatically controlled water bath Grant W38. The
temperature was monitored by a thermometer. The reaction slurry
conducted at 30 Celsius started at room temperature but gradually
rose to a final temperature of 30 Celsius after addition of the
reagents. After the addition of the reagents the slurry was mixed
for 30 minutes before filtration with the exception of example 21
which was mixed for 960 minutes.
[0331] The actual molecular formula determined by analysis,
crystallite size, precipitation pH, slurry treatment, excess moles
of Na.sub.2CO.sub.3 in recipe are listed below for each example.
Results of examples 8-24 are shown in Table 3 and FIG. 1.
TABLE-US-00001 Example 8
[Mg.sub.0.2Fe.sub.0.8(OH).sub.2][(CO.sub.3).sub.0.16(SO.sub.4).sub.0.0.-
cndot.0.42H.sub.2O].cndot.[Na.sub.2SO.sub.4].sub.0.00 Crystallite
size: not determined (nd) Precipitation pH = 8.0; reaction
temperature is 30 Celsius: 2.7 moles excess Na.sub.2CO.sub.3 9
[Mg.sub.0.5Fe.sub.0.5(OH).sub.2][(CO.sub.3).sub.0.14(SO.sub.4).sub.0.02-
.cndot.0.39H.sub.2O].cndot.[Na.sub.2SO.sub.4].sub.0.00 Crystallite
size: >200 .ANG. Precipitation pH = 9.8; reaction temperature is
90 Celsius; 2.7 moles excess Na.sub.2CO.sub.3 9b
[Mg.sub.0.5Fe.sub.0.5(OH).sub.2][(CO.sub.3).sub.0.14(SO.sub.4).sub.0.0-
2.cndot.0.39H.sub.2O].cndot.[Na.sub.2SO.sub.4].sub.0.00 Crystallite
size: >200 .ANG. Precipitation pH = 9.8; reaction temperature is
90 Celsius; 4 moles excess Na.sub.2CO.sub.3 10
[Mg.sub.0.67Fe.sub.0.38(OH).sub.2][(CO.sub.3).sub.0.14(SO.sub.4).sub.0.-
01.cndot.0.23H.sub.2O].cndot.[Na.sub.2SO.sub.4].sub.0.00
Crystallite size: not determined (nd) Precipitation pH = 10.1;
reaction temperature is 65.degree. C.; 2.7 moles excess
Na.sub.2CO.sub.3 11
[Mg.sub.0.67Fe.sub.0.33(OH).sub.2][(CO3).sub.0.14(SO.sub.4).sub.0.01.cn-
dot.0.25H.sub.2O].cndot.[Na.sub.2SO.sub.4].sub.0.00 Crystallite
size: not determined (nd) Precipitation pH = 9.8; reaction
temperature is 65.degree. C.; 2.7 moles excess Na.sub.2CO.sub.3 12
[Mg.sub.0.67Fe.sub.0.33(OH).sub.2][(CO.sub.3).sub.0.14(SO.sub.4).sub.0.-
01.cndot.0.39H.sub.2O][Na.sub.2SO.sub.4].sub.0.00 Crystallite size:
not determined (nd) Precipitation pH = 11; reaction temperature is
30 Celsius; 4 moles excess Na.sub.2CO.sub.3 13
[Mg.sub.0.66Fe.sub.0.34(OH).sub.2][(CO.sub.3).sub.0.15(SO.sub.4).sub.0.-
02.cndot.0.39H.sub.2O].cndot.[Na.sub.2SO.sub.4].sub.0.00
Crystallite size: not determined (nd) Precipitation pH = 10.5;
reaction temperature is 30 Celsius; 2.7 moles excess
Na.sub.2CO.sub.3 14
[Mg.sub.0.66Fe.sub.0.34(OH).sub.2][(CO.sub.3).sub.0.14(SO.sub.4).sub.0.-
02.cndot.0.23H.sub.2O].cndot.[Na.sub.2SO.sub.4].sub.0.00
Crystallite size: not determined (nd) Precipitation pH = 10.3;
reaction temperature is 30 Celsius; 2.7 moles excess
Na.sub.2CO.sub.3 15
[Mg.sub.0.67Fe.sub.0.33(OH).sub.2][(CO.sub.3).sub.0.13(SO.sub.4).sub.0.-
02.cndot.0.73H.sub.2O].cndot.[Na.sub.2SO.sub.4].sub.0.00
Crystallite size: not determined (nd) Precipitation pH = 10.5;
reaction temperature is 30 Celsius; 1 moles excess Na.sub.2CO.sub.3
16
[Mg.sub.0.67Fe.sub.0.33(OH).sub.2][(CO.sub.3).sub.0.13(SO.sub.4).sub.0.-
02.cndot.0.38H.sub.2O].cndot.[Na.sub.2SO.sub.4].sub.0.00
Crystallite size: not determined (nd) Precipitation pH = 10.1;
reaction temperature is 30 Celsius; 2.7 moles excess
Na.sub.2CO.sub.3 17
[Mg.sub.0.66Fe.sub.0.34(OH).sub.2][(CO.sub.3).sub.0.16(SO.sub.4).sub.0.-
02.cndot.0.37H.sub.2O].cndot.[Na.sub.2SO.sub.4].sub.0.00
Crystallite size: <100 .ANG. Precipitation pH = 9.8; reaction
temperature is 30 Celsius 2.7 moles excess Na.sub.2CO.sub.3 18
[Mg.sub.0.66Fe.sub.0.34(OH).sub.2][(CO.sub.3).sub.0.12(SO.sub.4).sub.0.-
03.cndot.0.65H.sub.2O][Na.sub.2SO.sub.4].sub.0 Crystallite size:
not determined (nd) Precipitation pH = 9.8; reaction temperature is
30 Celsius; 4 moles excess Na.sub.2CO.sub.3 19
[Mg.sub.0.67Fe.sub.0.33(OH).sub.2][(CO.sub.3).sub.0.13(SO.sub.4).sub.0.-
03.cndot.0.38H.sub.2O].cndot.[Na.sub.2SO.sub.4].sub.0.00
Crystallite size: not determined (nd) Precipitation pH = 11;
reaction temperature is 15.degree. C.; 1 moles excess
Na.sub.2CO.sub.3 20
[Mg.sub.0.64Fe.sub.0.36(OH).sub.2][(CO.sub.3).sub.0.12(SO.sub.4).sub.0.-
03.cndot.ndH.sub.2O].cndot.[Na.sub.2SO.sub.4].sub.0.00 Crystallite
size: not determined (nd) Precipitation pH = 9.6; reaction
temperature is 30 Celsius; 2.7 moles excess Na.sub.2CO.sub.3 21
[Mg.sub.0.64Fe.sub.0.36(OH).sub.2][(CO.sub.3).sub.0.13(SO.sub.4).sub.0.-
04.cndot.0.56H.sub.2O].cndot.[Na.sub.2SO.sub.4].sub.0.00
Crystallite size: not determined (nd) Precipitation pH = 9.5;
reaction temperature is 30 Celsius; 2.7 moles excess
Na.sub.2CO.sub.3 22
[Mg.sub.0.62Fe.sub.0.38(OH).sub.2][(CO.sub.3).sub.0.12(SO.sub.4).sub.0.-
04.cndot.0.49H.sub.2O][Na.sub.2SO.sub.4].sub.0.00 Crystallite size:
not determined (nd) Precipitation pH = 9.5; reaction temperature is
30 Celsius; 4 moles excess Na.sub.2CO.sub.3 23
[Mg.sub.0.64Fe.sub.0.36(OH).sub.2][(CO.sub.3).sub.0.12(SO.sub.4).sub.0.-
04.cndot.0.52H.sub.2O][Na.sub.2SO.sub.4].sub.0.00 Crystallite size:
not determined (nd) Precipitation pH = 9.5; reaction temperature is
30 Celsius; 1 moles excess Na.sub.2CO.sub.3 24
Mg.sub.0.58Fe.sub.0.42(OH).sub.2][(CO.sub.3).sub.0.1(SO.sub.4).sub.0.05-
.cndot.0.43H.sub.2O][Na.sub.2SO.sub.4].sub.0.00 Crystallite size:
not determined (nd) Precipitation pH = 9.5; reaction temperature is
15.degree. C.; 1 moles excess Na.sub.2CO.sub.3
Example 25-27
[0332] Preparation method and Mg:Fe ratio as for Example 2 with a
ferric source of 40.4 to 42.9 wt % ferric sulphate of water
industry standard suitable for human consumption conforms to BS EN
890:2004 and with precipitation pH varied in accordance with Table
4 and filtered.
TABLE-US-00002 Example The actual molecular formula found by
analysis was: 25
[Mg.sub.0.65Fe.sub.0.35(OH).sub.2][(CO.sub.3).sub.y1(SO.sub.4).sub.y2
mH.sub.2O].cndot.[Na.sub.2SO.sub.4].sub.0.00 26
[Mg.sub.0.65Fe.sub.0.35(OH).sub.2][(CO.sub.3).sub.y1(SO.sub.4).sub.y2.c-
ndot.mH.sub.2O][Na.sub.2SO.sub.4].sub.z 27
[Mg.sub.0.65Fe.sub.0.35(OH).sub.2][(CO.sub.3).sub.0.13(SO.sub.4).sub.0.-
02 mH.sub.2O].cndot.[Na.sub.2SO.sub.4].sub.0.01
Example 28
[0333] To make 163 kg of the mixed metal compound (dry basis) two
starting solutions were prepared designated solution A and solution
B. To prepare solution A, 138 kg (dry basis) iron sulphate of 40.4
to 42.9 wt % ferric sulphate of water industry standard suitable
for human consumption conforms to BS EN 890:2004, 166 kg (dry
basis) magnesium sulphate (added as the hepta-hydrate) were
dissolved in a total of 1034 kg of water where this total water
amount includes the water associated with the ferric sulphate
solution. To prepare solution B, 173 kg sodium hydroxide and 129 kg
sodium carbonate were dissolved in 948 kg of water to provide
homogenous solutions. The reaction vessel water heel was 840 kg.
The water supplied to the heel was 30% of the total water
supplied.
[0334] The reactant solution temperatures are adjusted to around
22.degree. C. prior to addition. The reactant streams (solutions A
and B) are then simultaneously fed to the reaction vessel at a rate
such as to maintain a reaction pH of 9.8. Cooling of the vessel
contents is applied such as to maintain a temperature of
20-25.degree. C. A heel of purified water is introduced prior to
the introduction of the reactant streams in order to enable
agitation of the vessel in the initial reaction phase and to give a
final slurry concentration of around 5.1 wt % compound.
[0335] The vessel is agitated using a high turnover, low shear
axial flow agitator operating at a power per unit volume of 0.1
kW/m.sup.3 and where the reactant solutions are delivered to an
area of high turnover. The reactor is baffled in order to promote
good mixing.
[0336] The precipitate slurry is held in the reaction vessel (also
referred to as hold time) for up to 12 hours and is transferred in
aliquots to a vertical filtering centrifuge for isolation and
washing, using purified water so as to provide maximum product
rate. Washing is terminated to achieve a residual sodium content
(expressed as Na.sub.2O in the dried product) of less than 0.40 wt
%.
[0337] The wet cake is discharged from the centrifuge and is dried
in a spherical, agitated vacuum drier. Vacuum and shell temperature
are adjusted to provide a product temperature in the dryer of
approximately 72.degree. C. The rate of drying was 0.26 kg
water/(kg dried producthr) a residence time of 12 hours and a
product rate per unit area of 4.6 kg product/(m2hr).
[0338] The dried product is first coarse milled using a de-lumping
mill to a particle size distribution (Test Method 24) of typically
200 micron (D50) followed by final micronisation to a particle size
of typically 5 micron (D50).
TABLE-US-00003 Exam- ple The actual molecular formula found by
analysis was: 28
[Mg.sub.0.66Fe.sub.0.34(OH).sub.2][(CO.sub.3).sub.0.12(SO.sub.4).sub.0.-
03.cndot.0.20H.sub.2O].cndot.[Na.sub.2SO.sub.4].sub.0.00
Example 28b
[0339] Particle size distribution was measured in the reaction
slurry after the addition of the reagents and after a hold time of
4 hours and filtration rate measured during the isolation step.
Example 28c
Alternative Reaction Systems
[0340] CFD (Test Method 27) was applied to example 28 in order to
derive a mixing power per unit volume at the point of addition of
the reactant streams.
[0341] The calculations were based on system having:
Slurry density: 1200 kgm-3 Slurry viscosity: 20 cP (0.02 Pas)
Agitator Shaft speed: 100 rpm Baffling: Flat plates
[0342] The pattern of mixing is demonstrated via particle tracks
from each of the two reactant stream inlets and shows that the
streams remain effectively segregated from each other before the
fluid has dispersed widely into the bulk. Contours of concentration
were also generated and confirm that mixing into the bulk takes
place very rapidly.
[0343] To derive the requirements for the manufacture of mixed
metal compounds for alternative mixing systems (e.g. static
mixers), the findings for the conventional low shear agitated
system (described above) have been applied.
[0344] Alternative mixing systems such as static mixers, jet
mixers, or dynamic in-line mixers and in particular a Kenics KM
static mixer may be suitable to provide a volume in which the
reaction can take place and suitable to deliver the necessary
mixing regime. For example the Kenics KM static mixer using a
notional feed zone volume of 5.times.10.sup.-4 m.sup.3, to provide
a power to mass ratio (1.28 W/kg--equivalent to 1.54 kW/m.sup.3)
and residence time (1.25 sec). The length was fixed by the
recommended minimum length of 4 elements (hence L/D=6). The
resulting diameter was 100 mm and the flowrate 280 litre/min.
[0345] To summarise, for a conventionally agitated reaction systems
a power per unit volume range (mixing intensity) of 0.03 to 0.5
kW/m3 has been established as optimum. Using alternative mixing
equipment, a power per unit volume range (mixing intensity) of 0.03
to 1.6 kW/m3 has been established as optimum.
Example 29
[0346] As for example 28 but with a reaction pH of 10.3.
Example 30
[0347] As for example 28 but with a batch size of 7 kg using a
single-aliquot feed to the Neutsch filter instead of centrifuge
such that the reaction mass is isolated and washed within a time
period of no more than 16 hours, a tray oven instead of a spherical
drier and milled.
[0348] The wet cake is discharged from the Neutsch filter and is
dried in a vacuum tray oven where the oven walls are heated to 120
to 130.degree. C. and regular manual redistribution of the drying
mass is carried out. The rate of drying was 0.38 kg water/(kg dried
producthr) with a total drying time of 12 to 16 hours and a product
rate per heated dryer surface area of 0.2 kg
product/(m.sup.2h).
[0349] The dried product is micronised using an impact mill to a
particle size of typically 5 micron (D50, Test Method 24).
TABLE-US-00004 Example The actual molecular formula found by
analysis was: 30
[Mg.sub.0.65Fe.sub.0.35(OH).sub.2][(CO.sub.3).sub.0.11(SO.sub.4).sub.y2
0.49H.sub.2O].cndot.[Na.sub.2SO.sub.4].sub.z
Example 31
[0350] As for example 30 but with a reaction pH of 10.3.
TABLE-US-00005 Exam- ple The actual molecular formula found by
analysis was: 31
[Mg.sub.0.66Fe.sub.0.34(OH).sub.2][(CO.sub.3).sub.0.12(SO.sub.4).sub.0.-
02 0.28H.sub.2O].cndot.[Na.sub.2SO.sub.4].sub.0.0
Example 32
[0351] As for example 28 but with a Vacuum Belt filter instead of
centrifuge. Samples of wet cake discharged from the Vacuum Belt
filter were dried in the laboratory oven at 120.degree. C. for
three hours.
[0352] Product sample for analysis were ground using a ball mill to
allow it to pass through a 106 .mu.m sieve.
Example 33
[0353] A reaction slurry was prepared according to the method of
example 2 but with a reaction pH of 9.6, a liquid ferric source (a
solution 40.4 to 42.9 wt % ferric sulphate of water industry
standard suitable for human consumption conforms to BS EN 890:2004)
and a nominal 400 cm.sup.3 batch size. The reaction slurry was
washed using Tangential Flow Filtration (Sartorius Slice 200 bench
top system with 200 cm.sup.2 filtration area, PESU 0.1 micron
membrane) operated in constant rate mode. The system was flushed
and filled with DI water prior to filtration, the permeate rate was
regulated to prevent filter blockage. Filtration with wash water
addition (diafiltration) was carried out to achieve a residual
sodium content (expressed as Na.sub.2O in the dried product) of
less than 0.40 wt %. The washed slurry was then concentrated using
conventional vacuum filtration and dried in a laboratory oven.
TABLE-US-00006 Example The actual molecular formula found by
analysis was: 33
[Mg.sub.0.65Fe.sub.0.35(OH).sub.2][(CO.sub.3).sub.y1(SO.sub.4).sub.y2
mH.sub.2O].cndot.[Na.sub.2SO.sub.4].sub.z.
Example 34
[0354] As for example 33 but with a reaction pH of 10.1
Example 35
[0355] As for example 33 but with a reaction pH of 10.3.
TABLE-US-00007 Example The actual molecular formula found by
analysis was: 35
[Mg.sub.0.65Fe.sub.0.35(OH).sub.2][(CO.sub.3).sub.y1(SO.sub.4).sub.y2
mH.sub.2O].cndot.[Na.sub.2SO.sub.4].sub.z.
Example 36
[0356] A reaction slurry was prepared for processing according to
the method of Example 28, However, 620 kg of reaction slurry were
subsequently processed using Tangential Flow Filtration instead of
centrifugation. A reaction pH of 9.8 was used.
[0357] Prior to filtration, to reduce the risk of membrane
blockage, the reaction slurry was circulated through a wet colloid
mill in order to reduce the D50 particle size (Test Method 9) from
60 to 51 micron.
[0358] A Sartorius Sartoflow Beta filtration unit was used with
eleven Sartocon II membranes giving a total filtration area of 7.7
m2. The system was flushed and filled with DI water prior to
filtration, the permeate rate was regulated to prevent filter
blockage. A rotary lobe pump was used to circulate slurry through
the system at an inlet pressure of between 2 and 3.5 bar and a
typical retentate flow of 3400 l/h. Filtration with wash water
addition (diafiltration) was carried out until to achieve a
residual sodium content (expressed as Na.sub.2O in the dried
product) of less than 0.40 wt %.
[0359] A representative quantity of slurry was sampled and isolated
and dried in accordance with the method of Example 1 but without
additional cake washing.
Example 37
[0360] As for example 36 but with a reaction pH of 10.3. The
particle size (D50, Test Method 9) was reduced by wet milling from
47 to 44 micron.
Example 38
[0361] As for example 28 but the method was then varied in that
they were conducted with slightly different drying conditions. The
rate of drying was approximately 0.27 kg water/(kg dried
producthr), a residence time of 13 hours, a product rate per unit
area of 1.4 kg product/(m.sup.2hr), and the maximum dryer
temperature achieved is approximately 85.degree. C.
TABLE-US-00008 Exam- ple The actual molecular formula found by
analysis was: 38
[Mg.sub.0.66Fe.sub.0.34(OH).sub.2][(CO.sub.3).sub.0.13(SO.sub.4).sub.0.-
03.cndot.0.36H.sub.2O].cndot.[Na.sub.2SO.sub.4].sub.0.00
Example 39
[0362] As for example 28 but the method was then varied in that
they were conducted with different drying conditions. The rate of
drying was approximately 0.38 kg water/(kg dried producthr), a
residence time of 9 hours and a product rate per unit area of 1.2
kg product/(m.sup.2hr).
TABLE-US-00009 Exam- ple The actual molecular formula found by
analysis was: 39
[Mg.sub.0.67Fe.sub.0.33(OH).sub.2][(CO.sub.3).sub.0.13(SO.sub.4).sub.0.-
02.cndot.0.26H.sub.2O].cndot.[Na.sub.2SO.sub.4].sub.0.00
Example 40
[0363] As for example 30 but the method was then varied in that
they were conducted with different drying conditions. The rate of
drying was approximately 0.21 kg water/(kg dried producthr) a
residence time of 18 hours and a product rate per unit area of 0.1
kg product/(m.sup.2hr).
Example 41
[0364] As for example 30 but the method was then varied in that
they were conducted with different drying conditions. The rate of
drying was approximately 0.27 kg water/(kg dried producthr) a
residence time of 16 hours and a product rate per unit area of 0.2
kg product/(m.sup.2hr).
TABLE-US-00010 Example The actual molecular formula found by
analysis was: 41
[Mg.sub.0.66Fe.sub.0.34(OH).sub.2][(CO.sub.3).sub.0.13(SO.sub.4).sub.0.-
02.cndot.mH.sub.2O].cndot.[Na.sub.2SO.sub.4].sub.0.00
Example 42-47
[0365] As for example 28 but the method was then varied in that
they were conducted with different drying conditions as described
in Table 7 when dried with a spherical, agitated vacuum drier (long
residence dryer).
TABLE-US-00011 Exam- ple The actual molecular formula found by
analysis was: 43
[Mg.sub.0.66Fe.sub.0.34(OH).sub.2][(CO.sub.3).sub.0.13(SO.sub.4).sub.0.-
02.cndot.0.53H.sub.2O].cndot.[Na.sub.2SO.sub.4].sub.0.01 44
[Mg.sub.0.65Fe.sub.0.35(OH).sub.2][(CO.sub.3).sub.0.12(SO.sub.4).sub.0.-
03.cndot.mH.sub.2O].cndot.[Na.sub.2SO.sub.4].sub.0.00 45
[Mg.sub.0.67Fe.sub.0.33(OH).sub.2][(CO.sub.3).sub.0.13(SO.sub.4).sub.0.-
03.cndot.mH.sub.2O].cndot.[Na.sub.2SO.sub.4].sub.0.00 46
[Mg.sub.0.66Fe.sub.0.34(OH).sub.2][(CO.sub.3).sub.0.12(SO.sub.4).sub.0.-
03.cndot.0.29H.sub.2O].cndot.[Na.sub.2SO.sub.4].sub.0.00 47
[Mg.sub.0.65Fe.sub.0.35(OH).sub.2][(CO.sub.3).sub.0.13(SO.sub.4).sub.0.-
03.cndot.mH.sub.2O].cndot.[Na.sub.2SO.sub.4].sub.0.00
Example 48-49
[0366] As for example 28 (centrifugation) but the method was then
varied in that the filter-cake was dried using a short residence
type drier (Spin-Flash Drier, manufacturer/model; Anhydro/SFD51)
wherein the delta T was 0.40 (Example 48) or a delta T of 0.66
(Example 49).
Conditions Spray Drier
TABLE-US-00012 [0367] T.sub.in T.sub.out delta Rotor Product
Example (.degree. C.) (.degree. C.) T speed (%) rate (kg/h) 48 250
150 0.40 90 8 49 350 120 0.66 45 20
Delta T=(T.sub.in-T.sub.out)/T.sub.in
TABLE-US-00013 Exam- ple The actual molecular formula found by
analysis was: 48
[Mg.sub.0.65Fe.sub.0.35(OH).sub.2][(CO.sub.3).sub.0.15(SO.sub.4).sub.0.-
02.cndot.0.19H.sub.2O][Na.sub.2SO.sub.4].sub.0.00 49
[Mg.sub.0.66Fe.sub.0.34(OH).sub.2][(CO.sub.3).sub.0.14(SO.sub.4).sub.0.-
02.cndot.0.16H.sub.2O][Na.sub.2SO.sub.4].sub.0.00
Example 50
[0368] As for example 36 (tangential flow filtration) but the
method was then varied in that the slurry was dried using a short
residence type drier (Spray Drier, manufacturer/model;
Anhydro/CSD71) with a delta T of 0.69.
Conditions Spray Drier
TABLE-US-00014 [0369] Example T.sub.in (.degree. C.) T.sub.out
(.degree. C.) delta T Tip speed (Hz) 50 350 110 0.40 208.3
DeltaT=(T.sub.in-T.sub.out)/T.sub.in
TABLE-US-00015 Exam- ple The actual molecular formula found by
analysis was: 50
[Mg.sub.0.66Fe.sub.0.34(OH).sub.2][(CO.sub.3).sub.0.14(SO.sub.4).sub.0.-
02.cndot.0.37H.sub.2O][Na.sub.2SO.sub.4].sub.0.01
Example 51-52
[0370] As for example 28 (centrifugation) but the method was then
varied in that the filter-cake was first diluted to provide a 10.1
wt % slurry and then dried using a short residence type drier
(Spray Drier, manufacturer/model; Anhydro/CSD71) wherein the delta
T was 0.74 (Example 51) or a delta T of 0.76 (Example 52).
Conditions Spray Drier
TABLE-US-00016 [0371] Example T.sub.in (.degree. C.) T.sub.out
(.degree. C.) delta T Tip speed (Hz) 51 350 110 0.74 208.3 Hz 52
325 120 0.76 208.3 Hz
TABLE-US-00017 Exam- ple The actual molecular formula found by
analysis was: 51
[Mg.sub.0.66Fe.sub.0.34(OH).sub.2][(CO.sub.3).sub.0.14(SO.sub.4).sub.0.-
01.cndot.0.34H.sub.2O][Na.sub.2SO.sub.4].sub.0.01 52
[Mg.sub.0.65Fe.sub.0.35(OH).sub.2][(CO.sub.3).sub.0.14(SO.sub.4).sub.0.-
03.cndot.0.38H.sub.2O][Na.sub.2SO.sub.4].sub.0.00
Example 53-59
[0372] As for example 28 (centrifugation) but the method was then
varied in that instead of micronisation the dried product was only
coarse-milled to 343 micron (.mu.m) (D50) and hereafter separated
into 6 different particle size fractions by sieving. Six different
sieves were used with a sieve parameter size of respectively; base,
20 micron, 75 micron, 106 micron, 180 micron, 355 micron. The sieve
fractions were obtained by hand-sieving. The 6 different sieve
fractions (Example 53-58) obtained by this method are described in
Table 9.
TABLE-US-00018 Exam- ple The actual molecular formula found by
analysis was: 53
[Mg.sub.0.65Fe.sub.0.35(OH).sub.2][(CO.sub.3).sub.y1(SO.sub.4).sub.0.03-
.cndot.mH.sub.2O].cndot.[Na.sub.2SO.sub.4].sub.0.00 Sieve fraction:
>355 .mu.m 54
[Mg.sub.0.65Fe.sub.0.35(OH).sub.2][(CO.sub.3).sub.y1(SO.sub.4).sub.0.03-
.cndot.mH.sub.2O].cndot.[Na.sub.2SO.sub.4].sub.0.00 Sieve fraction:
180-355 .mu.m 55
[Mg.sub.0.65Fe.sub.0.35(OH).sub.2][(CO.sub.3).sub.y1(SO.sub.4).sub.0.03-
.cndot.mH.sub.2O].cndot.[Na.sub.2SO.sub.4].sub.0.00 Sieve fraction:
106-180 .mu.m 56
[Mg.sub.0.65Fe.sub.0.35(OH).sub.2][(CO.sub.3).sub.y1(SO.sub.4).sub.0.03-
.cndot.mH.sub.2O].cndot.[Na.sub.2SO.sub.4].sub.0.00 Sieve fraction:
75-106 .mu.m 57
[Mg.sub.0.65Fe.sub.0.35(OH).sub.2][(CO.sub.3).sub.y1(SO.sub.4).sub.0.03-
.cndot.mH.sub.2O].cndot.[Na.sub.2SO.sub.4].sub.0.00 Sieve fraction:
<106 .mu.m 58
[Mg.sub.0.65Fe.sub.0.35(OH).sub.2][(CO.sub.3).sub.y1(SO.sub.4).sub.0.03-
.cndot.mH.sub.2O].cndot.[Na.sub.2SO.sub.4].sub.0.00 Sieve fraction:
<20 .mu.m 59
[Mg.sub.0.66Fe.sub.0.34(OH).sub.2][(CO.sub.3).sub.0.12(SO.sub.4).sub.0.-
03.cndot.0.26H.sub.2O].cndot.[Na.sub.2SO.sub.4].sub.0.00
micronised
Example 60
[0373] As for example 28 but the method was then varied in that
they were conducted with different drying conditions. The rate of
drying was approximately 0.33 kg water/(kg dried producthr), a
residence time of 9.8 hours and a product rate per unit area of 1.6
kg product/(m.sup.2hr) and the maximum dryer temperature achieved
is approximately 76.degree. C.
TABLE-US-00019 Example The actual molecular formula found by
analysis was: 60
[Mg.sub.0.65Fe.sub.0.35(OH).sub.2][(CO.sub.3).sub.0.12(SO.sub.4).sub.0.-
03.cndot.mH.sub.2O].cndot.[Na.sub.2SO.sub.4].sub.0.00
Example 61
[0374] As for example 28 but the method was then varied in that
they were conducted with different drying conditions. The rate of
drying was approximately 0.28 kg water/(kg dried producthr), a
residence time of 10.3 hours and a product rate per unit area of
1.5 kg product/(m.sup.2hr) and the product temperature achieved is
approximately 64.degree. C.
TABLE-US-00020 Example The actual molecular formula found by
analysis was: 61
[Mg.sub.0.66Fe.sub.0.34(OH).sub.2][(CO.sub.3).sub.0.13(SO.sub.4).sub.0.-
03.cndot.mH.sub.2O].cndot.[Na.sub.2SO.sub.4].sub.0.00
Example 62-65
[0375] As for Example 2 but the method was then varied in that they
were conducted at different pH, different excess of
Na.sub.2CO.sub.3 and different ferric source in accordance with
Table 12.
[0376] Furthermore, Example 62 was prepared with aluminium sulphate
in place of iron sulphate.
[0377] Two different ferric source designated A and B were
used:
A: of GPR grade Rectapur B: a more pure ferric source such as a
solution 40.4 to 42.9 wt % ferric sulphate of water industry
standard suitable for human consumption conforms to BS EN
890:2004,
TABLE-US-00021 Exam- ple The actual molecular formula found by
analysis was: 62
[Mg.sub.0.79Al.sub.0.21(OH).sub.2][(CO.sub.3).sub.0.16(SO.sub.4).sub.0.-
02.cndot.mH.sub.2O].cndot.[Na.sub.2SO.sub.4].sub.0.00 63
[Mg.sub.0.66Fe.sub.0.34(OH).sub.2][(CO.sub.3).sub.0.14(SO.sub.4).sub.0.-
02.cndot.0.22H.sub.2O].cndot.[Na.sub.2SO.sub.4].sub.0.00 64
[Mg.sub.0.66Fe.sub.0.34(OH).sub.2][(CO.sub.3).sub.y1(SO.sub.4).sub.0.02-
.cndot.mH.sub.2O].cndot.[Na.sub.2SO.sub.4].sub.0.00 65
[Mg.sub.0.66Fe.sub.0.34(OH).sub.2][(CO.sub.3).sub.y1(SO.sub.4).sub.0.01-
.cndot.mH.sub.2O].cndot.[Na.sub.2SO.sub.4].sub.0.00
Example 66
[0378] As for example 28 but the method was then varied in that the
filter-cake was dried using a short residence type drier
(Spin-Flash Drier, manufacturer/model; Anhydro/SFD51) wherein the
delta T was 0.48.
Conditions Spin Flash Drier
TABLE-US-00022 [0379] Example T.sub.in (.degree. C.) T.sub.out
(.degree. C.) delta T Atomiser speed, Hz 66 250 130 0.48 90
Delta T=(T.sub.in-T.sub.out)/T.sub.in
TABLE-US-00023 Example The actual molecular formula found by
analysis was: 66
[Mg.sub.0.65Fe.sub.0.35(OH).sub.2][(CO.sub.3).sub.0.14(SO.sub.4).sub.0.-
03.cndot.0.31H.sub.2O].cndot.[Na.sub.2SO.sub.4].sub.0
Methods
Test Method 1 XRF Analysis
[0380] XRF analysis of the product was performed by using a Philips
PW2400 Wavelength Dispersive XRF Spectrometer. The sample was fused
with 50:50 lithium tetra/metaborate (high purity) and presented to
the instrument as a glass bead. All reagents used were analytical
grade or equivalent unless specified. AnalaR.TM. water, Lithium
tetraborate 50% metaborate 50% flux (high purity grade ICPH
Fluore-X 50). A muffle furnace capable of 1025.degree. C., extended
tongs, hand tongs, Pt/5% Au casting tray and Pt/5%/Au dish were
used. 1.5 g (+/-0.0002 g) of sample and 7.5000 g (+/-0.0002 g) of
tetra/metaborate was accurately weighed out into a Pt/5%/Au dish.
The two constituents were lightly mixed in the dish using a
spatula, prior to placement in the furnace preset to 1025.degree.
C. for 12 minutes. The dish was agitated at 6 minutes and 9 minutes
to ensure homogeneity of the sample. Also at 9 minutes the casting
tray was placed in the furnace to allow for temperature
equilibration. After 12 minutes the molten sample was poured into
the casting tray, which was removed from the furnace and allowed to
cool. The bead composition was determined using the
spectrophotometer.
[0381] The XRF method was used to determine the Al, Fe, Mg, Na and
total sulphate content of the compound as well as the MII to MIII
ratio.
Test Method 2 X-Ray Diffraction (XRD) Measurements
[0382] Data was collected for fine particulate samples from
2-70.degree. 2.theta. on a Philips automatic powder X-ray
diffractometer using Copper K alpha radiation generated at 40 kV
and 55 mA.
[0383] Powder X-ray diffraction (XRD) data were collected from 2-70
degrees 2theta on a Philips PW 1800 automatic powder X-ray
diffractometer using copper K alpha radiation generated at 40 kV
and 55 mA, a 0.02 degree 2theta step size with a 4 second per step
count time. An automatic divergence slit giving an irradiated
sample area of 15.times.20 mm was used, together with a 0.3 mm
receiving slit and a diffracted beam monochromator.
[0384] The approximate volume average crystallite size can be
determined from the width, at half peak height, of the powder X-ray
diffraction peak at about 11.5 degrees 2 theta (the peak is
typically in the range 8 to 15 degrees 2 theta for hydrotalcite
type materials) using the relationship given in Table 1 which is
derived using the Scherrer equation. The contribution to the peak
width from instrument line broadening was 0.15 degrees, determined
by measuring the width of the peak at approximately 21.4 degrees
2theta of a sample of LaB.sub.6 (NIST SRM 660) under the same
conditions.
TABLE-US-00024 TABLE 1 XRD Peak width conversion to crystallite
size using the Scherrer equation Peak width D - FWHM B B(measured)
- b Calculated (measured) (instrument) crystallite
(.degree.2.THETA.) (.degree.2.THETA.) size (.ANG.) 0.46 0.31 258
0.47 0.32 250 0.48 0.33 242 0.49 0.34 235 0.50 0.35 228 0.51 0.36
222 0.52 0.37 216 0.53 0.38 210 0.54 0.39 205 0.55 0.40 200 0.56
0.41 195 0.57 0.42 190 0.58 0.43 186 0.59 0.44 181 0.60 0.45 177
0.61 0.46 174 0.62 0.47 170 0.63 0.48 166 0.64 0.49 163 0.65 0.50
160 0.66 0.51 157 0.67 0.52 154 0.68 0.53 151 0.69 0.54 148 0.70
0.55 145 0.71 0.56 143 0.72 0.57 140 0.73 0.58 138 0.74 0.59 135
0.75 0.60 133 0.76 0.61 131 0.77 0.62 129 0.78 0.63 127 0.79 0.64
125 0.80 0.65 123 0.81 0.66 121 0.82 0.67 119 0.83 0.68 117 0.84
0.69 116 0.85 0.70 114 0.86 0.71 112 0.87 0.72 111 0.88 0.73 109
0.89 0.74 108 0.90 0.75 106 0.91 0.76 105 0.92 0.77 104 0.93 0.78
102 0.94 0.79 101 0.95 0.80 100 0.96 0.81 99 0.97 0.82 97 0.98 0.83
96 0.99 0.84 95 1.00 0.85 94 1.01 0.86 93 1.02 0.87 92 1.03 0.88 91
1.04 0.89 90 1.05 0.90 89 1.06 0.91 88 1.07 0.92 87 1.08 0.93 86
1.09 0.94 85 1.10 0.95 84 1.11 0.96 83 1.12 0.97 82 1.13 0.98 81
1.14 0.99 81 1.15 1.00 80 1.16 1.01 79 1.17 1.02 78 1.18 1.03 78
1.19 1.04 77 1.20 1.05 76 1.21 1.06 75 1.22 1.07 75 1.23 1.08 74
1.24 1.09 73 1.25 1.10 73 1.26 1.11 72 1.27 1.12 71 1.28 1.13 71
1.29 1.14 70 1.30 1.15 69 1.31 1.16 69
[0385] The values in Table 1 were calculated using the Scherrer
equation:
D=K*.lamda./.beta.*cos .THETA. Equation 1
Where:
[0386] D=crystallite size (.ANG.) [0387] K=shape factor [0388]
.lamda.=wavelength of radiation used (in .ANG.) [0389] .beta.=peak
width measured as FWHM (full width at half maximum height) and
corrected for instrument line broadening (expressed in radians)
[0390] .THETA.=the diffraction angle (half of peak position
2.THETA., measured in radians)
Shape Factor
[0391] This is a factor for the shape of the particle, typically
between 0.8-1.0, a value of 0.9 is used.
Wavelength of Radiation
[0392] This is the wavelength of the radiation used. For copper K
alpha radiation the value used is 1.54056 .ANG..
Peak Width
[0393] The width of a peak is the sum of two sets of factors:
instrumental and sample.
[0394] The instrumental factors are typically measured by measuring
the peak width of a highly crystalline sample (very narrow peaks).
Since a highly crystalline sample of the same material is not
available, LaB.sub.6 has been used. For the current measurements an
instrument value of 0.15 degrees has been used.
[0395] Thus for the most accurate measure of crystallite size using
the Scherrer equation, the peak width due to instrumental factors
should be subtracted from the measured peak width i.e.:
.beta.=B.sub.(measured)-b.sub.(instrumental)
[0396] The peak width is then expressed in radians in the Scherrer
equation.
[0397] The peak width (as FWHM) has been measured by fitting of a
parabola or another suitable method to the peak after subtraction
of a suitable background.
Peak Position
[0398] A value of 11.5.degree. 2.THETA. has been used giving a
diffraction angle of 5.75.degree.. Corresponding to 0.100
radians.
Test Method 3 Phosphate Binding Capacity and Mg Release
[0399] Phosphate buffer (pH=4) was prepared by weighing 5.520 g
(+/-0.001 g) of sodium di-hydrogen phosphate followed by addition
of AnalaR.TM. water and transferring to a 1 ltr volumetric
flask.
[0400] To the 1 litre volumetric flask was then added 1 M HCl
drop-wise to adjust the pH to pH 4 (+/-0.1) mixing between
additions. The volume was then accurately made up to 1 ltr using
AnalaR.TM. water and mixed thoroughly.
[0401] 0.5 g (+/-0.005 g) of each sample was added to a volumetric
flask (50 ml) containing 40 mM phosphate buffer solution (12.5 ml)
at 37.5.degree. C. in a Grant OLS 200 Orbital shaker. All samples
were prepared in duplicate. The vessels were agitated in the
orbital shaker for 30 minutes. The solution was then filtered using
a 0.45 .mu.m syringe filter. 2.5 cm.sup.3 aliquots of supernatant
were pipetted of the supernatant and transferred into a fresh blood
collection tubes. 7.5 cm.sup.3 of AnalaR.TM. water were pipetted to
each 2.5 cm.sup.3 aliquot and the screw cap fitted and mixed
thoroughly. The solutions were then analysed on a calibrated
ICP-OES.
[0402] The phosphate binding capacity was determined by:
Phosphate binding
(mmol/g)=S.sub.P(mmol/l)-T.sub.P(mmol/l)/W(g/l)
where: T.sub.P=Analyte value for phosphate in the phosphate
solution after reaction with phosphate binder=solution P
(mg/l)*4/30.97. S.sub.P=Analyte value for phosphate in the
phosphate solution before reaction with phosphate binder.
W=concentration binder (g/l) used in test method (i.e. 0.4 g/10
cm.sup.3=40 g/l)
[0403] Magnesium release was determined by:
Magnesium release
(mmol/g)=T.sub.Mg(mmol/l)-S.sub.Mg(mmol/l)/W(g/l)
where: T.sub.Mg=Analyte value for magnesium in the phosphate
solution after reaction with phosphate binder=solution Mg
(mg/l)*4/24.31. S.sub.Mg=Analyte value for magnesium in the
phosphate solution before reaction with phosphate binder.
[0404] Fe release was not reported as the amount of iron released
from the compound was too small and below detection limit.
Test Method 4 Phosphate Binding and Magnesium Release in Food
Slurry
[0405] MCT peptide2+, food supplement (SHS International) was mixed
to form a slurry of 20% (w/v) in 0.01 M HCl. Separate aliquots of
0.05 g dry compound were mixed with 5 cm.sup.3 of the food slurry
and constantly agitated for 30 minutes at room temperature. A 3
cm.sup.3 aliquot was removed and centrifuged at 4000 rpm for 10
minutes, and the phosphate and magnesium in solution were
measured.
Test Method 5 Sulphate Determination
[0406] Total sulphate in the compound Sulphite (SO3) is measured in
the compound by XRF measurement (Test Method 1) and expressed as
total sulphate (SO4) according to:
Total SO4(wt %)=(SO3).times.96/80.
Total SO4 (mole)=total SO4 (wt %)/molecular weight SO4
Sodium Sulphate (Soluble Form of Sulphate Present in the
Compound)
[0407] Na2O is measured in the compound by XRF measurement (Test
Method 1).
[0408] It is assumed that the Na2O is associated with the more
soluble form of SO4 in the form of Na2SO4 present in the
compound.
[0409] Consequently, the number of mole Na2O is assumed equal to
that of soluble form of sulphate and is therefore calculated
as:
soluble SO4(mole)=Na2O(mole)=wt % Na2O/molecular weight Na2O
[0410] Interlayer sulphate (insoluble form of sulphate present in
the compound also referred to as bound sulphate)
[0411] The interlayer sulphate is calculated according to:
interlayer SO4(mole)=total SO4(mole)-soluble SO4(mole)
interlayer SO4(wt %)=interlayer SO4(mole).times.molecular weight
SO4
Test Method 6 Carbon Content Analysis by the Leco Method
[0412] This method was used to determine the levels of carbon
content (indicative of the presence of the carbonate anion present
in the mixed metal compound)
[0413] A sample of known mass is combusted at around 1350.degree.
C. in a furnace in a pure oxygen atmosphere. Any carbon in the
sample is converted to CO.sub.2 which is passed through a moisture
trap before being measured by an infra-red detector. By comparing
against a standard of known concentration, the carbon content of
the sample can be found. A Leco SC-144DR carbon and Sulphur
Analyser, with oxygen supply, ceramic combustion boats, boat lance
and tongs was used. 0.2 g (+/-0.01 g) of sample was weighed into a
combustion boat. The boat was then placed into the Leco furnace and
the carbon content analysed. The analysis was performed in
duplicate.
[0414] The % C was determined by:
% C(sample)=(% C.sub.1+% C.sub.2)/2
Where C.sub.1 and C.sub.2 are individual carbon results.
[0415] The results of the carbon content measurements are seen in
Table 3 and FIG. 1 and were expressed as % CO.sub.2=%
C.times.44/12
Test Method 7 Wash Time
[0416] Wash time was measured in minutes rounded to the nearest
minute, it was the time it took for one wash (i.e. one wash volume
of water) to be drawn through the filter. The wet cake was not
allowed to dry or crack during this period. The time was measured
using a stop clock.
Test Method 8 Filtration Time (Lab Scale)
[0417] Filtration time was measured in minutes rounded to the
nearest minute, it was the time taken for the slurry to be drawn
through the filter, but the resulting wet cake was not allowed to
dry. The time was measured using a stop clock.
Test Method 9 Particle Size Distribution (PSD) by Lasentech
[0418] In process particle size distribution in the slurry was
measured using a Lasentech probe. The d50 average particle size, is
obtained as part of this analytical technique.
Test Method 10 Filtration Rate (ml/Min) Defined as the quantity of
filtrate obtained in a given time.
Test Method 11 Filtration Rate (Kb Dry Product/m.sup.2h)
[0419] Filtration Rate (kg dry product/m.sup.2h) is defined as the
mass of wet cake, expressed as dried compound, isolated, washed,
dewatered and discharged per hour, divided by the area of filter
used.
Test Method 12 Moisture Content
[0420] The moisture content of mixed metal compound is determined
from the loss of weight (LOD) following drying at 105'C for four
hours at ambient pressure in a laboratory oven.
Test Method 13 [Intentionally Left Blank]
[0421] Test Method 14 Surface Area and Pore Volume (Nitrogen Method
--N.sub.2)
[0422] Surface area and pore volume measurements were obtained
using nitrogen gas adsorption over a range of relative pressures
using a Micromeritics Tristar ASAP 3000. The samples were outgassed
under vacuum for 4 hours at 105.degree. C. before the commencement
of measurements. Typically a vacuum of <70 mTorr was obtained
after outgassing.
[0423] Surface areas were calculated by the application of
Brunauer, Emmett and Teller (BET) theory using nitrogen adsorption
data obtained in the relative pressure range of 0.08 to 0.20
P/Po.
[0424] Pore volume was obtained from the desorption loop of the
nitrogen adsorption isotherm, using the volume of gas adsorbed at a
relative pressure (P/Po) of 0.98. The quantity of gas adsorbed at
0.98 relative pressure (in cc/g at STP) is converted to a liquid
equivalent volume by multiplying by the density conversion factor
of 0.0015468. This gives the reported pore volume figure in
cm.sup.3/g.
P=partial vapour pressure of nitrogen in equilibrium with the
sample at 77K Po=saturated pressure of nitrogen gas.
Test Method 15 Pore Volume (Water Method)
[0425] Water Pore Volume
[0426] Aim
[0427] To fill internal pores of a sample (in powder form) with
water such that, when all the pores are filled, the surface tension
of the liquid causes the majority of the sample to form an
aggregate which adheres to a glass jar on inversion of the jar.
Equipment
[0428] (1) Wide neck (30 mm) clear glass 120 cm.sup.3 powder jar
with screw cap. Dimensions: Height 97 mm. Outer Diameter 50 mm.
(Fisher part number BTF-600-080) (2) 10 cm.sup.3 Grade A burette
(3) Deionised water (4) Rubber bung 74 mm diameter top tapered to
67 mm. Overall height 49 mm (5) Calibrated 4 decimal place
balance
Procedure
[0429] (1) a 5.00 g (.+-.0.01) sample in the glass jar, add a 1
cm.sup.3 aliquot of water (2) After this addition vigorously knock
the bottom end of the sealed jar against the rubber bung 4 times.
(3) Using a sharp swing of the arm, flick the jar with the wrist to
invert the jar and check the sample: a. If the sample agglomerates
and the majority (>50%) of the sample adheres to the jar this is
the end point (go to results section below). If free water is
observed with the sample, the end point has been exceeded and the
test should be discarded and started again with a new sample. b. If
the sample dislodges from the jar (even if agglomeration is
evident), add a further 0.1 cm.sup.3 of water and repeat steps (2)
to (3) above until the end point is reached(3a)).
Results
[0430] The water pore volume is calculated as follows:--
Water Pore Volume (cm.sup.3/g)=Volume of water added
(cm.sup.3)/Sample Weight(g)
Test Method 16 Total Water Added/Kg API--Granulation Point
[0431] This is the amount of water added to a dry mixture of 80 wt
% mixed metal compound and 20 wt % excipients in order to form
granulates (i.e. until a granulation point is reached).
Test Method 17 Tablet Volume
[0432] The tablet volume is calculated from the dimensions of the
tablet using a computer design package (iHolland Ltd).
Test Method 18 Rate of drying
[0433] For the calculation of rate of drying (kg water/(kg dried
producthr)) mass of water removed during drying per unit time was
divided by the mass of dry product produced. The time used to
calculate the rate of drying is the dryer residence time defined in
Test Method 19.
Test Method 19 Dryer Residence Time
[0434] For long residence dryers, the residence time is the time
during which water is removed from the material being dried.
[0435] For short residence dryers such as spray drying, the
residence time is calculated as follows.
[0436] The internal volume of the dryer is first determined. The
residence time of the air or gas fed to the dryer is then
calculated by dividing the interval volume by the air or gas flow
rate. It is assumed, since a significant build up of solids does
not occur within the dryer, that the average particle residence
time is approximately equal to the air or gas residence time.
Test Method 20 Product Rate Per Unit Area
[0437] The Product rate per unit area kg product/(m.sup.2hr) can be
calculated by dividing the mass of dry product produced per unit
time with the surface area used for heating.
Test Method 21 Delta T
[0438] Delta temperature is defined for short residence drying
processes as (T.sub.in-T.sub.out)/T.sub.in where
T.sub.in is inlet gas temperature, .degree. C. T.sub.out is the
outlet gas temperature or product temperature, .degree. C.
(assuming gas and product are at the same temperature)
Test Method 22 Tapped Bulk Density
[0439] Tapped Bulk Density was determined using a Copley JV1000
Auto tapper. The measurement was made by the addition of the
product (50.0 g, +/-5.0 g) into a clean measuring cylinder
(dedicated for the apparatus). The exact weight was noted. The
initial volume was noted. The cylinder was then placed on the auto
tapper and the machine was set for 3750 taps by entering the number
of taps required and then pressing start. The volume of the
cylinder was taken again when the total number of taps was
completed (end volume). The tapped bulk density was calculated as
follows, Tapped Bulk Density (g/ml)=weight (g)/end volume (ml)
Test Method 23 Flowability Carr Index
[0440] The Carr index was calculated using the following formula
and the data available from the Tapped Bulk Density test,
Carr Index (%)=100*((initial volume (ml)-end volume (ml))/initial
volume (ml))
[0441] A result greater than 25% indicates poor flow ability and
less than 15% indicates good flow ability.
Test Method 24 Average Particle Size Distribution (d50 PSD) of
Powders
[0442] The particle size was determined using a Mastersizer `S`
fitted with a 300 Rf lens and a DIF 2012 dispersion unit. The data
was interpreted and analysed using Malvern Mastersizer software.
The Malvern was connected to process water supply. The following
program parameters were used, 80% pump speed, 80% stirrer speed,
50% ultrasonic and 3 minute residence time. The background level
was checked to be below 100 units. When prompted by the program the
sample was added in portions to reach between 15%-25% obscuration.
The analysis commenced automatically. The residual was checked to
be less than 1%. The sample was analysed in duplicate. The results
were calculated using the software by taking the % volume under the
particle sizes between 1.85 and 184 microns. This was expressed as
percentile results with the Average Particle Size (D50, 50.sup.th
percentile), 90.sup.th Percentile (D90) and 10.sup.th Percentile
(D10).
Test Method 25 Metal Analysis of Al, Cr, Pb
[0443] Samples were acidified, diluted and the specified metals
analysed using ICP-MS. Samples were analysed in duplicate.
Test Method 26 Total Heavy Metal Content
[0444] The metals were determined by acidifying the samples first
followed by analysis using ICP-MS. Total heavy metal content (ppm)
was then calculated by summating the following metals: As (ppm)+Cd
(ppm)+Pb (ppm)+Hg (ppm)+Sb (ppm)+Mo (ppm)+Cu (ppm)
Test Method 27--Power Per Unit Volume
[0445] Computational Fluid Dynamics (CFD) software application was
used to simulate fluid flow within the reaction vessel to establish
mixing requirements in mixing equipment.
Results and Discussion
[0446] We have encountered critical problems with the larger scale
process of manufacture (defined as being from the reaction to
drying stages) when trying to prevent increase in crystallite size.
This is described in more detail below.
Phosphate Binding
[0447] For, high daily and repeated long-term (chronic) dosages
required for kidney patients total daily pill count requires a low
tablet burden due to restricted fluid intake. Consequently, high
dosage of drug substance (mixed metal compound) of up to 80 wt % is
required in final product (i.e. tablet) whilst maintaining good
therapeutic activity (such as phosphate binding) and storage
stability. We have found that the final product is therefore very
sensitive to an array of opposing chemical and physical properties
of the mixed metal compound such as composition (Mg:Fe ratio,
sulphate), crystallite size, morphological properties (surface
area, particle size, pore volume) of the mixed metal compounds.
This is unlike normal requirements imposed on pharmaceuticals which
typically contain more soluble, organic type drug substances at
lower concentrations which are less dependent on a particular
morphology.
[0448] Variants of the Mg:Fe hydrotalcite structure that had
different Mg:Fe molar ratios of 2:1, 3:1 and 4:1 were compared for
phosphate binding performance and magnesium release (Table 2). The
release of the magnesium, associated with the pharmaceutical use of
mixed metal compounds can be reduced by selecting a suitable Mg:Fe
molar ratio. Data showed that material with a ratio of 2:1 had the
highest phosphate binding per mole of magnesium released in a
phosphate binding test in the presence of a meal slurry. The data
also shows that a Mg:Fe molar ratio of 2:1 does not have the
presence of any other non-hydrotalcite phases. In addition, we have
found that unaged mixed metal compounds of crystallite size less
than 200 angstrom (.ANG.) give higher phosphate binding than those
of aged compounds which typically have a crystallite size well
above 200 .ANG..
TABLE-US-00025 TABLE 2 Selection of preferred Mg:Fe Molar ratio and
Crystallite Size Phosphate bound Additional Non- Crystallite
Phosphate per mmol/l Mg Hydrotalcite Mg:Fe Size Binding released
Phases Example Ratio Method 2 Method 3 Method 4 (food slurry)
Method 2 Number Method 1 Angstrom (.ANG.) mmol/g API (%) XRD 1 1.0
95 0.77 yes 2 2.0 69 0.73 23.00 no 3 3.0 <100 7.70 no 4 4.0
<100 0.73 5.70 no 7 2.0 258 0.45 no
[0449] However, we have found that if processed incorrectly the
mixed metal compounds crystallite size will continue to grow in
size and are difficult to filter, particularly at large scale this
presents significant problems. We have discovered a novel process
for control of different production steps (from reaction to drying)
such as to prevent growth of the crystallite size above 200 .ANG.
in order to maintain the phosphate binding activity without
significantly hindering the process of isolation, washing and
drying of the compound. This was achieved by careful selection and
control of specific process conditions. Our approach is described
in more detail by the following examples.
Precipitation
[0450] We have found that the advantages of the mixed metal
compound of Mg:Fe molar ratio of approx 2:1 such as good phosphate
binding are not only determined by crystallite size but also
preferably by low levels of interlayer sulphate and the method of
manufacture (Table 3 and FIG. 1). Furthermore, across the pH range
considered, filtration is difficult due to the typical clay-like
structure of the material.
[0451] When preparing the mixed metal compound with the carbonate
anion the presence of a second anion-type may be possible. The
presence of only one anion-type may be considered more desirable
than a mixture of anions. Surprisingly, we discovered that it is
not necessarily optimal to have no sulphate but that a small amount
of sulphate should exist as interlayer (bound) sulphate in order to
increase filtration rates of the clay-like structure whereas the
sulphate in the form of soluble salts such as Na.sub.2SO.sub.4
should be removed. We found that most of the soluble
Na.sub.2SO.sub.4 salt can be readily removed by washing whereas the
interlayer sulphate is less soluble and its levels are primarily
controlled by the amount of excess Na.sub.2CO.sub.3 in the recipe,
reaction pH and extent of ageing in the reaction slurry (i.e.
temperature of reaction slurry). For example, we have found that
the interlayer sulphate decreases when: reaction temperature of
slurry increases, the excess Na.sub.2CO.sub.3 increases, the pH
increases.
[0452] Optionally, if the interlayer sulphate needs to be reduced
further to achieve an even higher purity (i.e. less than 1.0 wt %
interlayer sulphate) and initial isolation and washing rates are
not to be reduced it may be possible to wash the filter cake again
but this time with a solution of Na.sub.2CO.sub.3 (preferably up to
1 M concentration) followed by washing with water. This process may
reduce or remove the remaining interlayer sulphate without
necessarily reducing filtration rates or phosphate binding.
However, it is preferred if most of the interlayer sulphate is
removed during the reaction stage instead of requiring the need for
washing with carbonate. Additional process steps may decrease yield
as well as encouraging crystallite size growth.
[0453] Therefore in another aspect of the invention the compound is
first washed with water to remove soluble SO.sub.4 and sodium,
followed by a wash with a Na.sub.2CO.sub.3 solution to remove the
interlayer sulphate, followed by a final wash with water to remove
any remaining soluble ions. Preferably the compound is slurried
with some Na.sub.2CO.sub.3 solution for up to 1 hour to enable
exchange of the interlayer sulphate for the carbonate. It is
believed that washing with excess Na.sub.2CO.sub.3 would encourage
removal of any remaining sulphate from the interlayer region. In
this aspect after the exchange of the interlayer sulphate for the
carbonate there may be provided an Al-free mixed metal compound
with less than 1 wt % interlayer sulphate (preferably less than 0.5
wt %) and less than 0.5 wt % soluble sulphate.
[0454] Where product is not washed with Na.sub.2CO.sub.3 solution
we have also found that phosphate binding varies as a function of
sulphate level, for example, an optimum interlayer sulphate level
exists of between 1.8 to 5% wt, wherein good phosphate binding and
filtration is maintained. Phosphate binding decreases below 1.8%
wt. Above 5% wt interlayer SO.sub.4 becomes more variable and the
SO.sub.4 level is too high to be acceptable and wash and filtration
time increases. Best results were obtained between 2.5 and 5 wt %
interlayer sulphate.
TABLE-US-00026 TABLE 3 Effect and control of interlayer sulphate on
wash time and phosphate binding ##STR00001## Area highlighted is
preferred range
Separation
[0455] The features of the Al-free mixed metal compounds resulting
from their clay-like structure, replacing Al with Fe and their
unaged form present limitations when manufactured on a commercial
scale. Limitations such as difficult filtration and material
hardness have to be resolved whilst at the same time maintaining a
process at scale and a mixed metal compounds with good phosphate
binding, storage stability and not negatively affecting the
downstream manufacturing processes used to produce the final
formulated pharmaceutical product containing the mixed metal
compound.
[0456] During scale-up we found that it was difficult to prepare
this material when using traditional filtration techniques such as
a belt filter, Neutsche pressure filter. Even a centrifugation
method did not work effectively at this large scale.
[0457] We solved this problem by selecting specific ranges from one
or more of the following: (i) selection of range of interlayer
sulphate (from 1.8 to 5 wt %) by control of Na.sub.2CO.sub.3 and pH
(ii) selection of a preferred psd of reaction slurry (D50 >40
microns, preferably greater than 70 microns) and moisture content
of reaction slurry (more than 90 wt %) and filter cake (less than
80 wt %) (iii) selection of a specific agitation regime (a power
per unit volume of 0.03 to 1.6 kW/m.sup.3), (iv) selection of a
preferred filtration method and its operation (centrifuge). In a
highly preferred aspect we selected each of the following: (i)
selection of range of interlayer sulphate (from 2 to 5 wt %) by
control of Na.sub.2CO.sub.3 and pH (ii) selection of a preferred
psd of reaction slurry (D50>40 microns, preferably greater than
70 microns) and moisture content of reaction slurry (more than 90
wt %) and filter cake (less than 80 wt %) (iii) selection of a
specific agitation regime (a power per unit volume of 0.03 to 1.6
kW/m.sup.3), (iv) selection of a preferred filtration method
(centrifuge).
(i) Interlayer Sulphate
[0458] A high filtration rate and a low wash time are advantageous
when seeking to manufacture the MgFe mixed metal compounds on a
commercial scale and to prevent crystallite growth. However, mixed
metal compounds consisting of low interlayer sulphate levels (less
than 1.8 wt %) are more difficult to filter and wash whereas if too
high in sulphate (above 5 wt %) then washtime increases again
(Table 3 and FIG. 1). We found that interlayer sulphate levels can
be maintained between 2-5 wt % by controlling the temperature of
the reaction slurry, pH during the reaction and a Na.sub.2CO.sub.3
(XS) excess range of either one of the following combinations shown
below.
[0459] When the slurry is maintained to a temperature between 15
and 30.degree. C. wherein the Na.sub.2CO.sub.3 is provided at an
excess than is required to complete the reaction and a pH at
either:
(i) 9.5<pH.ltoreq.11 and 0.ltoreq.Na.sub.2CO.sub.3.ltoreq.1
moles (ii) 9.5.ltoreq.pH.ltoreq.10.5 and
1<Na.sub.2CO.sub.3.ltoreq.2 moles (iii)
9.5.ltoreq.pH.ltoreq.10.1 and 1<Na.sub.2CO.sub.3.ltoreq.2.7
moles (iv) 9.5.ltoreq.pH<10 and 1<Na.sub.2CO.sub.3.ltoreq.4
moles (v) 9.5.ltoreq.pH<9.8 and 1<Na.sub.2CO.sub.3.ltoreq.5
moles
[0460] When the slurry is maintained to a temperature from 30 to
60.degree. C. wherein the Na.sub.2CO.sub.3 is provided at an excess
than is required to complete the reaction and a pH at either:
(i) 9.5<pH<11 and 0<Na.sub.2CO.sub.3<2 (ii)
9.5<pH<10.5 and 0<Na.sub.2CO.sub.3<2.7 moles (iii)
9.5<pH<10 and 0<Na.sub.2CO.sub.3<4 moles
[0461] Excess Na.sub.2CO.sub.3 (XS) is defined as excess than is
required to complete the reaction of:
4MgSO.sub.4+Fe.sub.2(SO.sub.4).sub.3+12
NaOH+(XS+1)Na.sub.2CO.sub.3->Mg.sub.4Fe.sub.2(OH).sub.12.CO.sub.3.nH.s-
ub.2O+7Na.sub.2SO.sub.4+(XS)Na.sub.2CO.sub.3
[0462] For mixed metal compounds, maintaining the target metal
molar ratio (Mg:Fe) at approx 2 (1.8 to 2.2, preferably 1.7 to 2.1)
during the reaction whilst controlling the interlayer sulphate is
difficult as both are opposingly affected by the way the material
is processed. Furthermore, we found that correct stoichiometry is
not only determined by the correct ratios of the starting materials
but also by pH for the reaction. For example, when the pH is too
low (pH below 9.5) incomplete precipitation of magnesium may occur
whereby Mg:Fe molar ratio falls well below the target value of 2
and is also not free of non-hydrotalcite crystalline phases. It is
therefore preferred to maintain the pH between 9.5 and 11 and
preferably between an even narrower pH range of 9.5-10 and more
preferably at 9.8 to deliver the optimum magnesium: iron ratio (1.8
to 2.2, preferably 1.7 to 2.1) whilst maintaining good filtration
rates during manufacture at scale, maintain good phosphate binding
and prevent crystal growth by control of particle size distribution
and interlayer sulphate.
[0463] The total amount of anion (C.sub.calc) predicted for a mixed
metal compound if it were of an ideal hydrotalcite type phase of a
M.sup.2+:M.sup.3+ molar ratio of 2:1 can be calculated by the
following formula: C.sub.calc=(M.sup.3+/(M.sup.2++M.sup.3+))/n
wherein n is the charge of the anion. For example, a
M.sup.2+:M.sup.3+ molar ratio of 2:1 and an assumed anion charge
n=2 (i.e. as for CO.sub.3.sup.2- or SO.sub.4.sup.2-) would result
in a predicted value for (C.sub.calc) of 0.17. The experimental
value for C.sub.exp can be determined from the sum of the amount
(mole equivalent) of sulphate and carbonate anion. The .DELTA. is
defined as the difference between the C calculated and C
experimental wherein a lower .DELTA. value indicates a more pure
hydrotalcite phase. The smallest .DELTA. value is observed when
precipitating above pH 9.5.
[0464] The data of Table 3 (shown in FIG. 1) and the description of
examples 8-24 in the example section shows that the best overall
quality (i.e. good phosphate binding, high filtration rates, low
wash times, a molar ratio of approximately 2.0, no non-hydrotalcite
crystalline phases and a small .DELTA.) are obtained for those
samples wherein the interlayer sulphate levels are between 2 and 5
wt %, and preferably a sulphate to carbonate molar ratio of between
0.14 to 0.26. The total amount of anion (sulphate and carbonate) is
preferably from 0.15 to 0.20 more preferably is of 0.19 mole
equivalent.
[0465] In order to control interlayer sulphate below 3%, the
Na.sub.2CO.sub.3 had to be of more than 2 mole excess. To maintain
the interlayer sulphate above 2 wt % the precipitation pH has to be
less than 10 and of 2.7 moles excess Na.sub.2CO.sub.3 or less.
[0466] Sodium carbonate not only provides the carbonate for the
anion-exchange sites, but also acts as a pH buffer which assists pH
control during precipitation. The ability to maintain an accurate
precipitation pH is considerably increased when Na.sub.2CO.sub.3 is
present and for that reason an excess of Na.sub.2CO.sub.3 of more
than 2 is preferred. However, we found that an excess
Na.sub.2CO.sub.3 of 4 or above is less preferred because this could
result in an increased risk of incomplete dissolution of
Na.sub.2CO.sub.3 in the reactant solution at the preferred reaction
temperatures (of less than 25.degree. C.) when preparing unaged
mixed metal compounds.
[0467] For example, during dissolution of the sodium hydroxide and
sodium carbonate in the feed-solutions, the solution temperature
may rise to 65.degree. C. and we found that an excess in
Na.sub.2CO.sub.3 of 4 or more does dissolve; however, cooling
and/or pressurisation was required during dissolution to limit
evaporation and to lower the temperature to the same value as that
required for the reaction to prevent ageing. When the
Na.sub.2CO.sub.3 solution (of more than 4 mole excess) is cooled
from 65 to 25.degree. C. partial precipitation of the
Na.sub.2CO.sub.3 occurs.
[0468] It was therefore preferred to maintain the Na.sub.2CO.sub.3
at 4 mole excess or less. We found that it was possible to lower
the excess Na.sub.2CO.sub.3 from 4 to 2.7 mole without affecting pH
control.
[0469] To summarise, the data of Table 3 suggest that when outside
a range of 1.8 to 5 wt % interlayer sulphate, phosphate binding
either decreases and/or the Mg:Fe molar ratio of 2.0 is not
maintained and/or separation of the slurry is more difficult to
achieve. A Mg:Fe molar ratio of 2.0 was targeted such as to obtain
the highest phosphate binding per mole of magnesium released. A
preferred range of between 1.8 to 5 wt % interlayer sulphate was
achieved by selection of pH and Na.sub.2CO.sub.3 excess within a
narrow range.
(ii) Reaction Slurry Psd and Filter Cake Moisture Content
[0470] Particle Size Distribution (PSD)--The particle size
distribution is an important material parameter which influences
the filtration time of the reaction precipitate slurry. In the
laboratory with similar reactant concentration, reactant addition
rate, reaction temperature and pH and water heel volume, differing
agitation configurations produced different PSDs. Thus the PSD of
the reaction precipitate is strongly influenced by the agitation
regime, the vessel configuration, and the mode of reactant
addition. We have identified the agitation conditions at commercial
scale to enable optimum filtration and washing conditions whilst
ensuring that the final product is essentially unchanged from that
at low tonnes per annum scale.
[0471] Without being bound by theory it is postulated that high
pH/sub-optimal mixing can result in a small particle size which can
block up the filter cloth, reduce the filtration rate through the
cake and limit the ultimate solids content of the filter cake. We
found that there is a significant increase in filtration time when
reaction slurry psd (d50) is reduced to less than 70 microns.
Investigations (data shown in Table 4) demonstrated that control of
particle size above approximately 70 microns is preferable in
maintaining a high filtration rate suitable for use of separation
methods on a commercial scale such as centrifuge, Neutsch and belt
filters. In addition, we found that unwanted crystal growth
(ageing) can be minimised if filtration time is kept at a minimum.
We also found that a reduction in particle size to less than 70
microns leads to an increase in moisture content of the filter cake
to more than 80 wt %. This filter cake is stickier and is therefore
more difficult to remove from the filtration equipment and will
tend to hold up in mechanical devices or containers during
handling. A preferred moisture content of the filter cake is
therefore less than 80 wt %. Consequently, separating the mixed
metal compound from reaction slurry of more than 90 wt % moisture
content is also preferred.
[0472] There is therefore a preferred combination of both a filter
cake of moisture content (less than 80 wt %) and a PSD (of more
than 70 microns) to enable manufacture on a larger scale of
compositions free of aluminium.
(iii) Agitation Regime
[0473] The results described herein demonstrate that the preferred
PSD of reaction slurry are obtainable when maintaining the reaction
pH between pH 9.5-11 (preferably at pH 9.5 to 10, more preferably
9.8). In general, the teachings of WO99/15189 would not enable
separation of the compound on a commercial scale. Furthermore, we
found that the method of agitation (power per unit volume of 0.03
to 1.6 kW/m.sup.3) during precipitation is preferred. Slow stirring
(i.e. sufficient to maintain the solution homogeneous) was then
maintained during the hold time. We found that filtration time
increased significantly when the slurry is stirred for a prolonged
period during the hold time. For example, we found that a hold time
of more than 30 minutes but less than 12 hours is preferred and the
slurry during hold time should be agitated gently. The slurry hold
time is defined as the time period between when the addition of
Solutions A and B ceases (reaction phase ends) and the last aliquot
of slurry is added to the filtration equipment. At pilot plant and
large commercial scale where centrifuges are used, the slurry hold
time is typically up to 12 hours since multiple aliquots of
reaction mass are isolated, washed, dewatered and discharged as wet
cake.
[0474] The specific reaction agitation configuration to maintain
low shear conditions whilst at the same time enabling sufficient
mixing were also found to be useful in obtaining a preferred psd of
more than 70 microns (when measured at the end of hold time). The
specific power input has to be controlled such as to avoid a rate
which is too low but not at a rate which breaks the particles down
into very fine particles of psd less than 70 microns. Evaporation
of water from the reaction slurry and ageing of crystallites was
prevented by maintaining the reaction temperature below 30 Celsius
and typically was not less than 15 Celsius to avoid unacceptable
reduction in reactant feed stream solubility.
TABLE-US-00027 TABLE 4 Effect of slurry Particle Size Distribution
(PSD) on filterability Filtration Filtration PSD Time Rate Mg:Fe
reaction (Lab (Lab Mole slurry d50 Time Slurry scale) Scale) Ratio
(Lasentec) of psd hold Method Method Example Precipitation
Filtration Method Method 9 measurement time 8 10 Number pH type 1
microns hrs hrs seconds ml/min 25 9.6 Lab 1.9 81 2 2 37 n/a Filter
26 10.1 Lab 1.9 69 4 4 177 n/a Filter 27 10.3 Lab 2.1 60 4 4 350
n/a Filter 28b 9.8 Centrifuge 1.9 45 0.75 hrs (i.e. 4 n/a n/a after
addition of reactants complete) 28b 9.8 Centrifuge 1.9 79 4 4 n/a
n/a 29 10.3 Centrifuge n/a n/a n/a n/a 30 9.8 Neutsch 1.9 0.5 n/a
n/a 31 10.3 Neutsch 2.0 0.5 n/a n/a 32 9.8 Belt 2.0 0.5 n/a n/a 33
9.6 Tangential 1.9 81 2 2 n/a 7 flow filtration 34 10.1 Tangential
1.9 69 4 4 n/a 22 flow filtration 35 10.3 Tangential 2.1 60 4 4 n/a
20 flow filtration 36 9.8 Wet 1.9 60 28 28 n/a Milled + Tangential
flow filtration 37 10.3 Wet 2.0 47 33 33 n/a Milled + Tangential
flow filtration
(iv) Selection of a Preferred Filtration Method and its
Operation.
[0475] In general, a filtration method is used to isolate the
product from slurry form, wash to a predetermined impurity end
point and de-water the cake in order to obtain a material of
sufficiently high solids content to facilitate handling and for
efficient drying. In the case of laboratory filtration equipment
de-watering is typically not carried out due to the limitations of
the equipment used and due to small quantities handled.
Tangential Flow Filtration (TFF)
[0476] A method whereby filtration rate increases when psd is less
than 70 microns is the Tangential Flow Filtration (diafiltration)
method (Table 4 and 5); however, diafiltration in general has
significantly lower filtration rates (at all psd ranges) and is
only suitable for filtration of diluted slurries of more than 94 wt
% moisture content. Reaction slurry could be washed, but not
concentrated, since moisture contents below approximately 94 wt %,
would lead to blockage of the TFF. The washed slurry would then
require much greater energy input during drying. Consequently,
separation by diafiltration is less preferred.
Neutsche Filter
[0477] Isolation and washing of the drug substance was also carried
out using a Neutsche filter at a 7 kg production scale. This
equipment gave good product separation and washing but the specific
filtration rate (kg product/m.sup.2h) was extremely slow and the
filter cake contained up to 85 wt % moisture content requiring much
increased energy usage during drying. A cake depth of .about.7 cm
was achieved in the Neutsche filter and 10 cm in a filter/drier,
whereas cake depths of 30 cm or more are not uncommon for
filter/driers in other applications. Separation, by Neutsch filter
we found to be less preferred for manufacture on a commercial scale
because of lower filtration rate and limitations in handling larger
amounts of the clay-like product.
Belt Filter
[0478] A belt filter is preferred as we found that these could be
operated with a cake depth range of 15-25 mm at relatively high
filtration rates. This filtration method provides high filtration
rates when psd is maintained above 70 microns.
Centrifuge
[0479] Different filtration methods were tested but best results
were obtained with a filtration method using centrifuge which
combines filtration followed by washing and de-watering in one
step. Centrifugal filtration is preferred and provides advantages
of high filtration rate and preferred filter cake moisture content
whilst maintaining the quality of the product (Table 4 and 5).
TABLE-US-00028 TABLE 5 Selection of filtration methods Moisture
Preferred Slurry PSD Content of Wet d50 at end of hold Cake
Preferred time Example Filtration Method 12 Precipitation pH Method
9 Number Method % Range microns 28b Centrifuge 76-78 9.5-10 >70
34 or 35 Tangential Flow 92-95 10-10.5 <70 Filtration 25 Lab
Filter 85 9.5-10 >70 30 Neutsch 85 9.5-10 >70 32 Belt 75-85
9.5-10 >70 Filter dryer 85 9.5-10 >70
Drying
[0480] We found that too much processing and handling; for example,
such as overdrying can present changes (such as growth of
crystallite size) that are unacceptable in the final mixed metal
Mg:Fe compound. How the API morphology (vi) affects storage
stability and downstream processing is shown in Table 6. How to
control drying to achieve the required porosity (vii) and
crystallite size (viii) is described in more detail in Table 7 and
8.
(vi) Morphology
[0481] High daily, repeated long-term (chronic) dosages and
restricted fluid intake are required for kidney patients.
Consequently, a high dosage of drug substance is required in the
final product (i.e. tablet) and the manufacture and qualities of
the final product is therefore sensitive to the form and shape
(morphology) properties of the mixed metal compounds drug
substance, unlike more typical formulations. This means that the
properties of the tablet, including key physical properties, and
the tablet manufacturing processes, such as granulation, are often
primarily influenced by the properties of the mixed metal compound
active substance rather than those of the excipients, as is more
typically the case. In order to be able to manufacture a
pharmaceutical product comprising such significant quantities of
mixed metal compound with the control and consistency necessary for
pharmaceutical use, a means of controlling an array of these
physical properties of the mixed metal compounds is essential.
[0482] It is important to dry the material carefully as it is easy
to change the surface area or internal pore volume and hence change
the therapeutic activity (Table 6).
TABLE-US-00029 TABLE 6 Effect of API morphology on granules and
tablets properties. Properties API Granulation Tablet Change End
Point Change Average phosphate Total water phosphate crystal Suface
Pore Pore Phosphate binding added/kg Phosphate binding size Area
volume volume binding after API in Tablet binding after Method
N.sub.2 N.sub.2 Water Method storage dry mix Volume Method storage
2 Method Method Method 3 (12 Method Method 3 (12 Example Angstrom
14 14 15 mmol/g mnths) 16 17 mmol/g months) Number (.ANG.)
m.sup.2/g cm.sup.3/g cm.sup.3/g API % dm.sup.3 mm.sup.3 API % 38
151 54 0.17 0.36 0.68 -3 0.57 470 0.67 -2 39 160 57 0.20 0.44 0.63
-5 0.60 477 0.63 -5 40 102 77 0.26 0.86 0.69 0.95 532 0.68 -2 41 97
74 0.31 1.10 0.68 N/A N/A N/A N/A 66 77 119 0.30 0.68 0.79
-12.5
[0483] Table 6 shows how pore volume and surface area affects the
control of phosphate binding capacity, storage stability, the
granulation process and the production of tablets. As a general
rule, hydrotalcite type materials of a higher surface area may be
expected to have a higher ion exchange capacity and thereby higher
phosphate binding; this can be seen from Example 66 which has a
high surface area of 119 m.sup.2/g and also a high phosphate
binding value. However, the material with the higher surface area
of 119 m.sup.2/g was found to be less stable upon storage because
phosphate binding activity decreased by 12%. We have found that a
lower surface area range of between 40 and 80 m.sup.2/g is more
preferred as it has the advantage of maintaining good phosphate
binding (more than 0.6 mmol/g API) that is importantly also
essentially unchanged (only 5% or less change) upon storage over
periods of up to years, making it more viable as a an active
pharmaceutical material. It may be expected typically that
significantly higher surface areas would be required to attain such
stable phosphate binding--such materials of lower surface areas (by
N.sub.2) of between 40-80 m.sup.2/g and have a pore volume (by
N.sub.2) of 0.10-0.28 cm.sup.3/g and/or a pore volume (by water) of
0.3-0.6 cm.sup.3/g may be expected to have greater sensitivity to
any changes in the internal structure resulting in the inhibition
of access of the phosphate ions into the material and consequential
reduction in phosphate binding capacity. Surprisingly, the data
presented in Table 6 shows that all these examples of mixed metal
compound of lower surface areas are storage stable and maintain
good phosphate binding. Furthermore, the materials of lower surface
areas, in the range of between 40-70 m.sup.2/g and low pore volume
(water) of 0.3-0.6 cm.sup.3/g offers the advantage of a denser
material that can then be processed into a dosage form that is
smaller (i.e. as can be seen from Table 6 tablet volume of less
than 500 mm.sup.3) thereby improving tablet pill burden; a
prevalent issue within the treatment of renal patients. Furthermore
an additional surprising benefit is that such materials also
exhibit no significant reduction in the uptake rate of phosphate,
despite the lower surface areas. This facet can be important when
considering such materials for pharmaceutical applications in which
the binding of phosphate needs to be rapid, such as renal care. We
have also found that the material of crystallite size less 200
.ANG. binds greater than 80% of phosphate within 10 minutes
(according to Test method 3 but measured at different time
intervals) when maintained at a average particle size less than 100
.mu.m, preferably less than 50 .mu.m, most preferred less than 10
.mu.m and a surface area more than 40 m.sup.2/g.
(vii) Manufacture of Unaged, Porous Mixed Metal Compounds
(Drying)
[0484] We have found that the surface area of the drug substance is
determined by a combination of rate of drying, residence time,
product rate per unit area and delta T (Table 7). The rate of
drying is affected by both the mode of drying and other process
parameters, such as the product temperature, heating surface/gas
temperature.
[0485] A product of crystallite size between 90 and 200 .ANG. and a
surface area (by N.sub.2) of between 40-80 m.sup.2/g, and/or pore
volume (by N.sub.2) of between 0.10-0.28 cm.sup.3/g, and/or pore
volume (by water) of between 0.3-0.6 cm.sup.3/g can be achieved by
exposing the crude product to a product temperature of more than 80
but no greater than 150.degree. C. and provide a rate of drying
(water evaporation rate) of between 0.05 to 0.5 kg water per hour
per kg of dry product and/or provide a dryer residence time of
between 10 minutes to 30 hours and/or a product rate per unit area
of between 0-7 kg product/(m.sup.2hr) typically achieved by use of
a high residence time dryer under a vacuum of pressure of 400 mbar
(absolute) or less. A product of low pore volume (by water) range
of 0.3-0.6 cm.sup.3/g can be obtained by a combination of the
centrifuge and use of agitated spherical dryer method.
[0486] Alternatively, a product of crystallite size less than 140
.ANG. and a surface area (by N.sub.2) of between 80-150 m.sup.2/g,
and/or pore volume (by N.sub.2) of between 0.28-1.0 cm.sup.3/g,
and/or pore volume (by water) of between 0.6-1.2 cm.sup.3/g can be
achieved by exposing the crude product to a product temperature of
more than 35.degree. C. but no greater than 150.degree. C. and
provide a rate of drying (water evaporation rate) of between 500 to
50000 kg water per hour per kg of dry product and/or provide a
dryer residence time of less than 10 minutes and/or a delta T of
between 0.2 to 1.0 typically achieved by use of a short residence
time dryer.
TABLE-US-00030 TABLE 7 Effect of rate of drying on morphology
Moisture Rate of Dryer Product Content Surface Pore Pore Tap Drying
Residence rate per delta T Dried Area Volume Volume Bulk
Flowability Method 18 Time unit area Method Product N.sub.2 N.sub.2
Water Density Carr kg water/ Method Method 20 21 Method Method
Method Method Method Index Example (kg dried 19 kg product/ (Tin -
Tout)/ 12 14 14 15 22 Method Number product hr) hours (m.sup.2 hr)
Tin wt % m.sup.2/g cm.sup.3/g cm.sup.3/g g/cm3 23 42 0.09 29 2.1
n/a 19 0.50 0.50 43 0.13 22 1.0 n/a 10 56 0.15 0.40 0.60 44 0.23 16
1.3 n/a 61 0.19 0.50 0.54 45 0.24 12 1.3 n/a 54 0.19 0.52 0.47 28
0.26 12 1.6 n/a 57 0.17 0.49 0.51 32 46 0.28 11 2.1 n/a 54 0.18
0.48 0.56 47 0.31 9.9 2.0 n/a 61 0.17 0.52 0.52 31 15 0.2 n/a 8 71
0.28 30 40 0.21 18 0.2 n/a 77 0.26 1.10 0.36 48 38000 0.0001 n/a
0.40 4 81 0.28 0.64 0.43 19 49 38000 0.0001 n/a 0.66 3 92 0.39 0.72
0.33 13 50 990 0.02 n/a 0.69 7 93 0.41 0.76 0.48 ND 51 990 0.02 n/a
0.74 15 97 0.47 0.72 0.55 ND 52 990 0.02 n/a 0.76 7 119 0.56 0.74
0.50 22 66 38000 0.0001 n/a 119 0.68 38 0.27 12.9 1.4 n/a 7 53 0.15
39 0.38 8.9 1.2 n/a 5 60 0.21 60 0.33 9.8 1.6 n/a 56 0.17 61 0.28
10.3 1.5 n/a 50 0.13 41 0.27 15.5 0.2 n/a 5
(viii) Effect of Rate of Drying on Crystallite Size
[0487] Table 8 shows that the drying must be sufficiently rapid so
as minimise crystal growth, however bulk product temperatures
exceeding 150.degree. C. must be avoided in order to prevent damage
to the characteristic material structure. Factors such as agitation
during drying in long residence time dryers were also found to
effect crystallite size. For example, dried samples (such as
obtained by Neutsche/Tray Oven) whereby no continuous agitation is
applied tend to show smaller crystallite size than those obtained
by a spherical drier. Therefore an optimum drying regime
exists.
TABLE-US-00031 TABLE 8 Effect of drying conditions on control of
crystallite size Rate of Product Drying temperature Average Method
18 Dryer in the crystal Phosphate kg Residence delta T dryer size
Binding water/(kg Time Method Max Method Method dried Method 21
temperature 2 3 Example Slurry Separation Dryer product 19
(T.sub.in - T.sub.out)/ achieved Angstrom mmol/g Number Treatment
Method Method hr) hours T.sub.in .degree. C. (.ANG.) API 7 aged
Buchner Tray Oven n/a 258 0.45 (lab) 42 unaged Centrifuge Agitated-
0.09 29 n/a 90 195 0.63 Spherical 44 unaged Centrifuge Agitated-
0.23 16 n/a 83 175 0.63 Spherical 45 unaged Centrifuge Agitated-
0.24 12 n/a 74 160 0.67 Spherical 38 unaged Centrifuge Agitated-
0.27 12.9 n/a 85 160 Spherical 39 unaged Centrifuge Agitated- 0.38
8.9 n/a 73 160 Spherical 43 unaged Centrifuge Agitated- 0.13 22 n/a
75 157 0.66 Spherical 60 unaged Centrifuge Agitated- 0.33 9.8 n/a
76 154 0.69 Spherical 28 unaged Centrifuge Agitated- 0.26 12 n/a 72
151 0.67 Spherical 49 Unaged Centrifuge Spin Flash 38000 0.0001
0.66 135 0.64 46 unaged Centrifuge Agitated- 0.28 11 n/a 73 133
0.69 Spherical 47 unaged Centrifuge Agitated- 0.31 9.9 n/a 65 123
0.69 Spherical 51 unaged Centrifuge Spray 990 0.02 0.74 123 0.68
Dryer 52 unaged Centrifuge Spray 990 0.02 0.76 117 0.70 Dryer 61
unaged Centrifuge Agitated- 0.28 10.3 n/a 64 109 0.73 Spherical 40
Unaged Neutsch Tray Oven 0.21 18 n/a 102 0.69 50 unaged TFF Spray
990 0.02 0.69 100 0.75 Dryer 41 unaged Neutsch Tray Oven 0.27 15.5
n/a 97 31 unaged Neutsch Tray Oven 15 n/a 94 0.66 48 unaged
Centrifuge Spin Flash 38000 0.0001 0.40 93 0.68 66 unaged TFF Spin
Flash 38000 0.0001 0.48 77 0.79 2 unaged Buchner Tray Oven n/a n/a
n/a 69 0.73 (lab)
[0488] For those compounds wherein the average crystal size of the
mixed metal compound is from 10 to 20 nm (100 to 200 .ANG.)
preferably from 12 to 20 nm, the surface area (by N.sub.2) is
between 40-80 m.sup.2/g, pore volume (by N.sub.2) is between
0.10-0.28 cm.sup.3/g and the pore volume (water) is from 0.3-0.6
cm.sup.3/g. The compounds of average crystal size between 100 to
200 .ANG. are preferably obtained by use of a long residence
agitated drying process such as an agitated spherical dryer wherein
the rate of drying is between 0.09 to 0.31 kg water/(kg dried
producthr), more preferably a rate of drying between 0.24 to 0.31
kg water/(kg dried producthr) and/or a Product rate per unit area
(kg product/m.sup.2hr) of between 1-10 more preferably between
2-7.
[0489] We have found, surprisingly that the advantages of the lower
surface area product of crystallite size between 100 and 200 .ANG.
and/or low surface area 40-80 m.sup.2/g and/or low pore volume
(water) 0.3-0.6 cm.sup.3/g prepared by a long residence drying
process are good phosphate binding, storage stability and a denser
material that can be processed into a dosage form that is smaller
thereby improving tablet pill burden. Average crystal size of less
than 200 .ANG. has the advantage of good, controlled phosphate
binding. A average crystal size of between 120-200 .ANG. is
preferred if product is dried to a moisture content less than 15 wt
% (preferably between 5-10 wt %) of a batch size of between 50 and
1000 kg when dried by a process of long residence drying with a
agitated spherical dryer and when preparing materials of a low
surface area of between 40 and 80 m.sup.2 per gram and/or pore
volume (water) of 0.3-0.6 cm.sup.3/g. The low porosity product is
preferably prepared from batch sizes between 50 and 1000 kg with a
dryer residence time of between 3-30 hours, more preferably between
5 to 30 hours and most preferred between 9 to 30 hours.
Milling
[0490] Optionally, after the drying step the dry material may be
first classified to remove oversize particles by milling and/or
sieving.
(ix) Effects of PSD on Phosphate Binding and Magnesium Release
[0491] We have found that Mg release remains constant whereas
phosphate binding changes as a function of particle size (Table 9).
This is a surprising result as a smaller particle size distribution
could be expected to have a larger surface area and therefore more
susceptible to Mg release. However, the magnesium release does not
appear to be significantly affected by changes in surface area when
maintained at less than 80 m.sup.2/g despite being milled to a
particle size distribution (psd) with a (d50) of less than 60
micron when using this route. The constant Mg release enables a
wider selection of a preferred psd range to improve phosphate
binding without compromising Mg release. The data from Table 9
shows that a preferred particle size d50 is less than 177 micron,
more preferably less than 114, most preferred less than 60
micron.
TABLE-US-00032 TABLE 9 Effect of particle size distribution of
dried product on phosphate binding and magnesium release (x) Effect
of crystallite size on milling rate. PSD Phosphate Binding Mg
Release Method 24 Method 3 Method 3 Example Number d50 (microns)
mmol/g API mmol/g API 53 487 0.39 0.17 54 315 0.52 0.18 55 177 0.63
0.17 56 114 0.64 0.17 57 60 0.67 0.19 58 9 0.68 0.19 59 4 0.67
0.18
[0492] If processed incorrectly mixed metal compounds can become
unacceptably hard. This can lead to consequent issues of decreased
milling rates and higher energy input to achieve a preferred
particle size. The consequence of this is that in achieving a given
particle size it is essential that the crystallite size is not too
low.
[0493] Table 10 shows that if the crystallite size is too low (i.e.
of 120 .ANG. or less) the milling rate will be reduced by more than
50% when compared to that of crystallite size of 195 .ANG. which
will present difficulties at scale when milling to a particle size
distribution with a d50 of less than 114 micron. For example,
problems with occurrence of non-hydrotalcite phases such as MgO
periclase, reduced milling rate or decomposition of the product
because of over-heating of the product can occur. For those mixed
metal compounds wherein the crystallite size is less than 120 .ANG.
it is preferred to use the short residence drying route which does
not require milling.
TABLE-US-00033 TABLE 10 Effect of crystallite size on milling rate
and phosphate binding Milling Rate Crystallite Quantity of
Phosphate Mg Size feed processed in a Binding Release Example
Method 2 given time Method 3 Method 3 Number Angstroms g/30 s
mmol/g API mmol/g API 42 195 650 0.63 0.18 44 175 450 0.63 0.17 45
160 430 0.67 0.15 60 154 370 0.69 0.15 47 123 300 0.69 0.15 61 110
280 0.73 0.14
[0494] If the reaction pH rises above pH 11 (and to a certain
extent above pH 10) we have found that the resultant mixed metal
compounds is a much harder material. It is therefore possible to
prepare a softer material by precipitation at pH 9.8 than at higher
pH values. Consequently, not only does precipitating at a pH of 9.8
provide the advantage of increased filterability we have also shown
this to be of benefit for achieving increased milling rates.
[0495] Control of material hardness is also important because this
may also increase the potential for pickup of low levels of
trace-metals from the milling equipment. When the material is
harder it also has to be milled harder which in turn can lead to
higher temperatures being generated during milling which provide a
milled material which can contain decomposition products or may be
too dry (less than 5 wt % moisture content as determined by LOD)
which in turn can lead to problems with handling and the downstream
processing.
(xi) Methods of Micronisation
[0496] If the moisture content of the unmilled product is above 10
wt % then the product can become too sticky for milling whereas if
less than 5 wt % the product after milling will be too dry and
would then be less stable upon storage and/or provide problems in
processing into tablet formulations. We found that the milling
process results in a further 2 wt % loss of moisture resulting in a
milled product. We therefore typically target a moisture content of
between 7 and 10 wt % for the unmilled material.
[0497] The chemical (i.e. molar ratio of Mg:Fe of 2:1) and physical
properties (i.e. surface area and particle size) of the mixed metal
compounds composition favour equilibration to a 5-8 wt % moisture
content and as such may be less stable upon storage (i.e. have a
tendency to re-hydrate) if manufactured to a moisture content less
than 5 wt %.
[0498] We have found that this compound can be manufactured using a
process comprising a short residence drying step such that the
resultant representative material has both small average crystal
size and high surface area but also importantly and surprisingly
exhibits high phosphate binding even when the material is not
milled further. The requirement for no milling has the advantage of
reduced processing steps. A further advantage is that such material
can be suitable for tabletting processes without the need for wet
granulation due to the advantageous flow properties. Therefore, in
one aspect the present invention provides a mixed metal compound
wherein the average crystal size of the mixed metal compound is
less than 20 nm (200 .ANG.); in this aspect preferably the surface
area is from 80 to 145 m.sup.2 per gram. The data from Table 11
shows that for a mixed metal compound with a surface area from 80
to 145 m.sup.2 per gram the preferred particle size d50 is less
than 343 micron, more preferably less than 296, even more
preferably less than 203, most preferred less than 31 micron.
TABLE-US-00034 TABLE 11 Micro- nisation required to achieve
Phosphate Mg good PSD Binding Release Surface phosphate Method
Method Method Area N.sub.2 binding 24 3 3 Method (>0.6 Example
Micro- d50 mmol/g mmol/g 14 mmol/g) Number nised (microns) API API
m.sup.2/g yes/no 59 no 343 0.51 0.21 67 yes 59 yes 4 0.67 0.18 52
n/a 48 no 296 0.64 0.14 81 no 49 no 203 0.68 0.15 92 no 51 no 31
0.68 0.11 97 no 52 no 27 0.7 0.11 119 no 50 no 20 0.75 0.10 93
no
[0499] The compound of higher surface area of 80-145 m.sup.2 can be
manufactured using a process comprising a short residence drying
step such that the resultant representative material has both small
average crystal size and high surface area but also importantly and
surprisingly exhibits high phosphate binding even when the material
is not milled further. The requirement for no milling has the
advantage of reduced processing steps and avoids any hardness
issues. A further advantage is that such material can be suitable
for tabletting processes without the need for wet granulation.
Impurity
[0500] Mixed metal compounds may be synthesised by various
techniques; however, it is difficult to control impurity levels of
compounds when isolated in the unaged form, to a pharmaceutical
grade and when prepared Al-free especially when considering that
mixed metal compounds are prepared from minerals containing
significant levels of trace-metal impurities some of which may be
in the form of heavy metals. In particular, compounds prepared from
iron minerals are considerably intermeshed with other metal types
as these ultimately are derived from minerals that exist in nature.
Some of these metals may compete with the magnesium and iron for
formation of the mixed metal compound and get locked into the
hydrotalcite phase instead of forming more soluble salts which are
readily washed out during the washing process. There is therefore a
need to control trace metal impurity levels by selecting preferred
conditions and recipe during the precipitation stage; this in order
to meet regulatory guidelines whilst obtained via a manufacturing
process that can deliver this at scale.
[0501] Other impurities, such as sodium and sulphate must be
controlled in order that the drug substance is of acceptable
quality for human consumption. The sodium concentration is
controlled through washing of the isolated drug substance cake.
[0502] During the filtration and washing step of the manufacturing
process, the slurry is formed into a cake (with the removal of
excess mother liquor). The resultant cake is then washed with water
to remove excess sodium, sulphate and carbonate down to levels
acceptable for the final use of the material.
[0503] For pharmaceutical use it is important to be able to
identify and control the crystal phase of interest. The way the
material is processed influences this, when preparing a compound
from 2 different metal types it is possible that it may precipitate
as a mixture of single metal compounds instead of a mixed metal
compound. Mixed metal compounds are manufactured by
co-precipitation which can encourage the formation of different
crystalline phases in addition to the hydrotalcite phase. There is
therefore the need for a Al-free mixed metal compounds which are
also free of any other crystalline phases as determined by the
absence of XRD diffraction lines except those attributed to the
hydrotalcite phase. When prepared according to the process defined
for the unaged samples of crystallite size less than 200 .ANG. we
have found that the hydrotalcite phase has the following
diffraction X-ray diffraction analysis without the presence of any
other crystalline phases: dA (`d` spacings) 7.74, 3.86, 2.62, 2.33,
1.97, 1.55, 1.52, 1.44. Five additional peaks at dA 3.20, 1.76,
1.64, 1.48, 1.40 are only resolved in more crystalline samples i.e.
of crystallite size above 200 .ANG., typically as a result of
ageing.
[0504] Trace metal impurities must be controlled in order that the
drug substance is of acceptable quality for human consumption. We
found surprisingly that trace metal concentrations can be
controlled by the reaction pH, reaction hold time (ageing) and not
only as would be expected by the selection of raw materials of
appropriate quality or washing. For example, Table 12 shows how we
have been able to further reduce the aluminium (Al) and lead (Pb)
levels by control of pH, control of sodium carbonate excess and
control of ageing.
TABLE-US-00035 TABLE 12 Effect of recipe, reaction conditions on
trace metals content mixed metal compound Excess Total Moles Heavy
Na2C Al Cr Pb Metals Na.sub.2O Trivalent Precipitation O3 in Method
Method Method Method Method Example Metal Slurry pH Recipe 25 25 25
26 1 Number Source Treatment pH Moles ppm ppm ppm ppm wt % 62 Al
source unaged 9.8 2.7 96160 n/d n/d n/d <0.5 63 Fe source unaged
10.5 4.0 52 32 7 <15 <0.5 (A) 64 Fe source unaged 10.5 2.7 56
34 3 <11 <0.5 (A) 9b Fe source unaged 9.8 2.7 58 34 <1
<9 <0.5 (A) 23 Fe source aged 9.8 4.0 78 33 <1 <10
<0.5 (A) 17 Fe source unaged 9.8 2.7 <30 1 <1 <8
<0.5 (B) 28 Fe source unaged 9.8 2.7 <30 2 <1 <9
<0.5 (B) 9 Fe source aged 9.8 2.7 57 1 <1 <9 <0.5
(B)
[0505] From Table 12 it is possible to conclude that even when
changing from a solution (A) of GPR grade Rectapur to a more pure
ferric source (B) such as a solution (40.4 to 42.9 wt % ferric
sulphate of water industry standard suitable for human consumption
conforms to BS EN 890:2004), the aluminium levels may be decreased
further (i.e. to less than 30 ppm) by avoiding excessive ageing
(i.e. wherein the crystallite size is >200 .ANG.).
[0506] Example 62 was prepared with solid aluminium sulphate of
Alfa Aesar 98% CAS 17927-65-0 instead of ferric sulphate. All other
raw materials were of the same source.
[0507] All samples shown in Table 12 were washed equally as
indicated by low (<0.5 wt %) and similar Na.sub.2O levels. The
washing process was developed such as to provide the required
Na.sub.2O levels.
[0508] As discussed herein the aluminium levels of the mixed metal
compound are less than 10000 ppm. This level is considered suitable
Al exposure for a healthy individual and is typical of
pharmaceutical grade compounds (i.e. of 99% purity). In contrast,
mixed metal compounds commercially available as antacids in the
form of a Mg:Al mole ratio of 3:1, typically contain ten times as
much Al (i.e. up to 100000 ppm aluminium) and are therefore not
suitable for long term use. Renal patients are prone to aluminium
accumulation it is therefore more preferred if the aluminium
content is less than 2000 ppm (>99.8% purity) based on a total
daily intake of 6 g/day and general regulatory guidance.
[0509] We have found that a Al level of 1000 ppm (99.9% purity) is
achievable when using a large scale process for manufacture of
unaged materials. For renal patients an aluminium content as low as
possible is preferred and therefore a aluminium content of less
than 1000 ppm is more preferable. Using our process we can
typically achieve aluminum levels less than 100 ppm; therefore
aluminium levels less than 100 ppm are even more preferred. By
careful control of reaction conditions we can achieve aluminium
levels less than 30 ppm which is most preferred.
[0510] The data of Table 12 also demonstrates that it is possible
to maintain lead (Pb) levels below the detection limit of <1 ppm
when precipitated at pH 9.8 and using an excess of 2.7 moles
Na.sub.2CO.sub.3 in the recipe instead of precipitating the mixed
metal compound at pH 10.5 and using an excess of 4.0 moles
Na.sub.2CO.sub.3 even when using a more impure source of ferric
sulphate. We also found that the total heavy metal content could be
maintained at less than 10 ppm total heavy metals (Test Method 26)
when using the preferred recipe of pH 9.8 and an excess of 2.7
moles Na.sub.2CO.sub.3.
[0511] Chromium (Cr) levels are required to be limited to <25
ppm according to the guideline of metal reagents for medicinal
compounds CHMP/CWP/QWP/4446/00. Table 12 demonstrates that we have
been able to lower the chromium levels from approximately 35 ppm to
below the detection limit (less than 1 ppm).
[0512] All publications and patents and patent applications
mentioned in the above specification are herein incorporated by
reference. Various modifications and variations of the present
invention will be apparent to those skilled in the art without
departing from the scope and spirit of the invention. Although the
invention has been described in connection with specific preferred
embodiments, it should be understood that the invention as claimed
should not be unduly limited to such specific embodiments. Indeed,
various modifications of the described modes for carrying out the
invention which are obvious to those skilled in chemistry, biology
or related fields are intended to be within the scope of the
following claims.
* * * * *