Title of Invention	"A PROCESS FOR PREPARING ALUMINIUM CITRATE IN ORALLY ADMINISTRABLE FORM EFFECTIVE AGAINST GASTROINTESTINAL DISORDERS" .
Abstract	Heretofore aluminium citrate was prepared from aluminium chloride by interacting them under vigorous agitation, preferably at low temperatures. Aluminium chloride of desirable grade is not readily available in this part of the country and this route is found to be lacking in cost effectiveness. As alternative route was being searched and this led to the present invention which relates to a process for preparing aluminium citrate in orally administrable form effective against gastrointestinal disorders, characterized in that the said process comprises - (a) dissolving potash alum [K2 Al2 (SO4)3, 24 H2O] by heating in water until a clear solution results; (b) adding solid or powdery sodium bicarbonate in water and boiling the mixture until dissolution results; (c) mixing solutions (a) and (b) in stoichiometric proportions under stirring and allowing the thus formed precipitate to settle for a period varying between 6 and 8 hours without agitation; (d) decanting the supernatant liquid followed by washing of the precipitate with distilled water until the wash liquid is free from SO4" ions; (e) adding citric acid solution to the reaction mass obtained from step (d), boiling the reaction medium to a temperature not exceeding 90°C under gentle stirring, and adjusting the pH between 6 and 7; (f) cooling the reaction medium to ambient temperature, filtering if necessary, and storing the final solution of aluminium citrate in orally administrable form followed by transferring the solution into suitable receptacles in predetermined volumes prior to dispatch to outlets.

Title of Invention

"A PROCESS FOR PREPARING ALUMINIUM CITRATE IN ORALLY ADMINISTRABLE FORM EFFECTIVE AGAINST GASTROINTESTINAL DISORDERS" .

Abstract

Heretofore aluminium citrate was prepared from aluminium chloride by interacting them under vigorous agitation, preferably at low temperatures. Aluminium chloride of desirable grade is not readily available in this part of the country and this route is found to be lacking in cost effectiveness. As alternative route was being searched and this led to the present invention which relates to a process for preparing aluminium citrate in orally administrable form effective against gastrointestinal disorders, characterized in that the said process comprises - (a) dissolving potash alum [K2 Al2 (SO4)3, 24 H2O] by heating in water until a clear solution results; (b) adding solid or powdery sodium bicarbonate in water and boiling the mixture until dissolution results; (c) mixing solutions (a) and (b) in stoichiometric proportions under stirring and allowing the thus formed precipitate to settle for a period varying between 6 and 8 hours without agitation; (d) decanting the supernatant liquid followed by washing of the precipitate with distilled water until the wash liquid is free from SO4" ions; (e) adding citric acid solution to the reaction mass obtained from step (d), boiling the reaction medium to a temperature not exceeding 90°C under gentle stirring, and adjusting the pH between 6 and 7; (f) cooling the reaction medium to ambient temperature, filtering if necessary, and storing the final solution of aluminium citrate in orally administrable form followed by transferring the solution into suitable receptacles in predetermined volumes prior to dispatch to outlets.

Full Text	The present invention relates to a novel process for preparing aluminium citrate in orally administrable form effective against gastro intestinal disorders. More particularly, this invention pertains to a new cost-effective route for arriving at a valuable ingredient like aluminium citrate showing pronounced effectiveness against gastro-intestinal disorders, which is capable of controlling and modulating the absorption of non-essential and potentially toxic trace elements from the gastro- intestinal tract. It has been observed that at least two factors assume importance if enhanced gastrointestinal absorption of aluminium is to occur. First, the aluminium compound must be soluble at the pH of the intestinal fluid, and second, the compound in question must result in the opening of cellular tight junctions. Aluminium citrate's high formation constant, which precludes the formation of insoluble aluminium hydroxide or phosphate in association with its ability to open junctions, probably accounts for its high degree of gastrointestinal absorption. Aluminium also binds to mucus glycoproteins, at least at acid pH, probably via sialic acid end-groups, even though this aspect is still being studied, so direct interaction with monomeric aluminium, or stabilization of a polymeric, probably colloidal, species are both possible. Hence, the solution chemistry of dietary aluminium in the lumen of the gastro intestinal track will be dictated by competition from endogenous factors, such as mucins, albumin and citrate and exogenous (dietary) factors. Other potential routes for uptake of aluminium include perception, endocytosis by mucosal cells or conventional transcellular transport of hydrophobic or very small hydrophilic species. Certain dietary cofactors undoubtedly affect absorption of aluminium, although their role in the diet may be considerably less that when studied in isolation. In conclusion, it has been established that citric acid promotes systemic absorption of aluminium. Heretofore aluminium citrate was prepared from aluminium chloride employed as the starting compound. Apart from being a partially co-valent compound, its degree of hydrolysis with subsequent reaction with free citric acid was considerably time consuming. The chloride route had another drawback in view of the release of a strong acid like hydrochloric acid in the course of reaction. Besides, in this part of India, cost of aluminium chloride is quite considerable, which factor plays a major role in commercial production of aluminium citrate. Heretofore liquid aluminium citrate in a stabilized solution state was being prepared and used for arriving at ethical, pharmaceutical and/or veterinary preparations. In European Patent No. 0040763 there is described a method involving combining a solution of aluminium chloride with a solution of citric acid under vigorous agitation. After formation of aluminium citrate solution, sufficient quantity of alkali metal or ammonium hydroxide was added to the reaction mixture to raise the pH to a level of 5.0 to 7.0. During addition of the base, agitation was continued and temperature was kept low. As discussed earlier, accessing the starting material, namely, aluminium chloride posed a difficulty and the reaction parameters also needed close monitoring. Such conditions pose difficulty in translating the conventional procedure into commercial scale in this part of the country. The principal object of the present invention is to evolve a procedure to overcome the difficulties envisaged in the prior art. A further object of this invention is to provide a process which employs an easily accessible, inexpensive starting compound like potash alum and citric acid of C.P. grade. A still further object of this invention is to provide a process for preparing orally administrable aluminium citrate solution which is both storage stable and cost effective. The foregoing objects are achieved by the present invention which relates to a process for preparing aluminium citrate in orally administrable form effective against gastrointestinal disorders, characterized in that the said process comprises - (a) dissolving potash alum [K2 Al2 (SO4)3, 24 H2O] by heating in water until a clear solution results; (b) adding solid or powdery sodium bicarbonate in water and boiling the mixture until dissolution results; (c) mixing solutions (a) and (b) in stoichiometric proportions under stirring and allowing the thus formed precipitate to settle for a period varying between 6 and 8 hours without agitation; (d) decanting the supernatant liquid followed by washing of the precipitate with distilled water until the wash liquid is free from SO4" ions; (e) adding citric acid solution to the reaction mass obtained from step (d), boiling the reaction medium to a temperature not exceeding 90° under gentle stirring, and adjusting the pH between 6 and 7; (f) cooling the reaction medium to ambient temperature, filtering, if necessary, and storing the final solution of aluminium citrate in orally administrable form followed by transferring the solution into suitable receptacles in predetermined volumes prior to dispatch to outlets. In the sequence of reactions as outlined above, stirring is needed in a couple of constituent steps. The speed of stirring is primarily dependent on the degree of viscosity of the reaction medium, which is optimally adjusted at around 50 r.p.m. The aqueous solutions resulting from both steps (a) and (b) are subjected to filtration to remove undissolved impurities by employing a filtering medium of clear membrance with an optimum pore size of 0.25µ. The pH of the final solution of aluminium citrate is allowed to revert to 4-5, and the specific gravity of the solution sent for storage is adjusted to a value of approximately 1.02. Furthermore, the precipitate of aluminium hydroxide formed in step (c) stated above is allowed to be converted into aluminium hydroxide gel in the course of washing with water to render it free from SO4" ions, prior to reaction with citric acid. Testing procedure: About 0.2 gm is weighed accurately and dissolved in 3.4 ml of hydrochloric acid (1:1) and 50 ml. of water. 50 ml. of 0.05 M EDTA is added. The solution is rendered neutral to methyl red/ethanol T.S. with sodium hydroxide solution. The solution is heated on a water bath for 30 minutes, cooled and about 50 mg of xylenol orange indicator mixture R and 5gm of methenamine R are added and the excess EDTA is back titrated with 0.05 lead nitrate solution till the yellow solution turns pink violate. Each ml. of 0.05 EDTA v.s. is equivalent to 1.349 mg. of aluminium. While the invention has been described in detail and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications may be made therein without deviating or departing from the scope and spirit of the invention. Thus the disclosure contained herein includes within its ambit the obvious equivalents and substitutes as well. Having described the invention in detail with particular reference to the illustrations given above, it will now be more specifically defined by means of claims appended hereafter. We claim: 1. A process for preparing aluminium citrate in orally administrable form effective against gastrointestinal disorders, characterized in that the said process comprises (a) dissolving potash alum [K2 Al2 (SO4)3, 24 H2O] by heating in water until a clear solution results; (b) adding solid or powdery sodium bicarbonate in water and boiling the mixture until dissolution results; (c) mixing solutions (a) and (b) in stoichiometric proportions under stirring and allowing the thus formed precipitate to settle for a period varying between 6 and 8 hours without agitation; (d) decanting the supernatant liquid followed by washing of the precipitate with distilled water until the wash liquid is free from SO4" ions; (e) adding citric acid solution to the reaction mass obtained from step (d), boiling the reaction medium to a temperature not exceeding 90°C under gentle stirring, and adjusting the pH between 6 and 7; (f) cooling the reaction medium to ambient temperature, filtering if necessary, and storing the final solution of aluminium citrate in orally administrable form followed by transferring the solution into suitable receptacles in predetermined volumes prior to dispatch to outlets. 2. A process as claimed in Claim 1, wherein degree of stirring is determined by the degree of viscosity of the reaction medium, optimally adjusted at around 50 r. p.m. 3. A process as claimed in Claim 1, wherein aqueous solutions resulting from both steps (a) and (b) are subjected to filtration to remove undissolved impurities by employing a filtering medium of clear membrane with an optimum pore size of 0.25µ. 4. A process as claimed in Claims 1 to 3, wherein pH of the stored solution of aluminium citrate is allowed to revert to 4 to 5 and the specific gravity thereof is adjusted to a value of approximately 1.02. 5. A process as claimed in Claim 1, wherein the precipitate of aluminium hydroxide formed in step (c) is allowed to be converted into aluminum hydroxide gel in the course of washing with water to render it free from SO4" -ions, prior to reaction with citric acid. 6. A process for preparing aluminium citrate in orally administrable form effective against gastro-intestinal disorders, substantially as hereinbefore described. Heretofore aluminium citrate was prepared from aluminium chloride by interacting them under vigorous agitation, preferably at low temperatures. Aluminium chloride of desirable grade is not readily available in this part of the country and this route is found to be lacking in cost effectiveness. As alternative route was being searched and this led to the present invention which relates to a process for preparing aluminium citrate in orally administrable form effective against gastrointestinal disorders, characterized in that the said process comprises - (a) dissolving potash alum [K2 Al2 (SO4)3, 24 H2O] by heating in water until a clear solution results; (b) adding solid or powdery sodium bicarbonate in water and boiling the mixture until dissolution results; (c) mixing solutions (a) and (b) in stoichiometric proportions under stirring and allowing the thus formed precipitate to settle for a period varying between 6 and 8 hours without agitation; (d) decanting the supernatant liquid followed by washing of the precipitate with distilled water until the wash liquid is free from SO4" ions; (e) adding citric acid solution to the reaction mass obtained from step (d), boiling the reaction medium to a temperature not exceeding 90°C under gentle stirring, and adjusting the pH between 6 and 7; (f) cooling the reaction medium to ambient temperature, filtering if necessary, and storing the final solution of aluminium citrate in orally administrable form followed by transferring the solution into suitable receptacles in predetermined volumes prior to dispatch to outlets.

Full Text

The present invention relates to a novel process for preparing
aluminium citrate in orally administrable form effective against gastro
intestinal disorders. More particularly, this invention pertains to a new
cost-effective route for arriving at a valuable ingredient like aluminium
citrate showing pronounced effectiveness against gastro-intestinal
disorders, which is capable of controlling and modulating the absorption
of non-essential and potentially toxic trace elements from the gastro-
intestinal tract.
It has been observed that at least two factors assume
importance if enhanced gastrointestinal absorption of aluminium is to
occur. First, the aluminium compound must be soluble at the pH of the
intestinal fluid, and second, the compound in question must result in the
opening of cellular tight junctions. Aluminium citrate's high formation
constant, which precludes the formation of insoluble aluminium
hydroxide or phosphate in association with its ability to open junctions,
probably accounts for its high degree of gastrointestinal absorption.
Aluminium also binds to mucus glycoproteins, at least at acid
pH, probably via sialic acid end-groups, even though this aspect is still
being studied, so direct interaction with monomeric aluminium, or
stabilization of a polymeric, probably colloidal, species are both possible.
Hence, the solution chemistry of dietary aluminium in the lumen of the
gastro intestinal track will be dictated by competition from endogenous
factors, such as mucins, albumin and citrate and exogenous (dietary)
factors. Other potential routes for uptake of aluminium include perception,
endocytosis by mucosal cells or conventional transcellular transport of
hydrophobic or very small hydrophilic species. Certain dietary cofactors
undoubtedly affect absorption of aluminium, although their role in the
diet may be considerably less that when studied in isolation. In conclusion,
it has been established that citric acid promotes systemic absorption of
aluminium.
Heretofore aluminium citrate was prepared from aluminium
chloride employed as the starting compound. Apart from being a partially
co-valent compound, its degree of hydrolysis with subsequent reaction
with free citric acid was considerably time consuming. The chloride route
had another drawback in view of the release of a strong acid like
hydrochloric acid in the course of reaction. Besides, in this part of India,

cost of aluminium chloride is quite considerable, which factor plays a
major role in commercial production of aluminium citrate.
Heretofore liquid aluminium citrate in a stabilized solution
state was being prepared and used for arriving at ethical, pharmaceutical
and/or veterinary preparations. In European Patent No. 0040763 there is
described a method involving combining a solution of aluminium chloride
with a solution of citric acid under vigorous agitation. After formation of
aluminium citrate solution, sufficient quantity of alkali metal or
ammonium hydroxide was added to the reaction mixture to raise the pH
to a level of 5.0 to 7.0. During addition of the base, agitation was continued
and temperature was kept low.
As discussed earlier, accessing the starting material, namely,
aluminium chloride posed a difficulty and the reaction parameters also
needed close monitoring. Such conditions pose difficulty in translating the
conventional procedure into commercial scale in this part of the country.
The principal object of the present invention is to evolve a
procedure to overcome the difficulties envisaged in the prior art.
A further object of this invention is to provide a process which
employs an easily accessible, inexpensive starting compound like potash
alum and citric acid of C.P. grade.
A still further object of this invention is to provide a process
for preparing orally administrable aluminium citrate solution which is
both storage stable and cost effective.
The foregoing objects are achieved by the present invention
which relates to a process for preparing aluminium citrate in orally
administrable form effective against gastrointestinal disorders,
characterized in that the said process comprises -
(a) dissolving potash alum [K2 Al2 (SO4)3, 24 H2O] by heating in
water until a clear solution results;
(b) adding solid or powdery sodium bicarbonate in water and
boiling the mixture until dissolution results;

(c) mixing solutions (a) and (b) in stoichiometric proportions
under stirring and allowing the thus formed precipitate to
settle for a period varying between 6 and 8 hours without
agitation;
(d) decanting the supernatant liquid followed by washing of the
precipitate with distilled water until the wash liquid is free
from SO4" ions;
(e) adding citric acid solution to the reaction mass obtained
from step (d), boiling the reaction medium to a temperature
not exceeding 90° under gentle stirring, and adjusting the
pH between 6 and 7;
(f) cooling the reaction medium to ambient temperature,
filtering, if necessary, and storing the final solution of
aluminium citrate in orally administrable form followed by
transferring the solution into suitable receptacles in
predetermined volumes prior to dispatch to outlets.
In the sequence of reactions as outlined above, stirring is
needed in a couple of constituent steps. The speed of stirring is primarily
dependent on the degree of viscosity of the reaction medium, which is
optimally adjusted at around 50 r.p.m.
The aqueous solutions resulting from both steps (a) and (b)
are subjected to filtration to remove undissolved impurities by employing
a filtering medium of clear membrance with an optimum pore size of
0.25µ.
The pH of the final solution of aluminium citrate is allowed to
revert to 4-5, and the specific gravity of the solution sent for storage is
adjusted to a value of approximately 1.02.
Furthermore, the precipitate of aluminium hydroxide formed
in step (c) stated above is allowed to be converted into aluminium
hydroxide gel in the course of washing with water to render it free from
SO4" ions, prior to reaction with citric acid.

Testing procedure:
About 0.2 gm is weighed accurately and dissolved in 3.4 ml of
hydrochloric acid (1:1) and 50 ml. of water. 50 ml. of 0.05 M EDTA is
added. The solution is rendered neutral to methyl red/ethanol T.S. with
sodium hydroxide solution. The solution is heated on a water bath for 30
minutes, cooled and about 50 mg of xylenol orange indicator mixture R
and 5gm of methenamine R are added and the excess EDTA is back
titrated with 0.05 lead nitrate solution till the yellow solution turns pink
violate.
Each ml. of 0.05 EDTA v.s. is equivalent to 1.349 mg. of
aluminium.
While the invention has been described in detail and with
reference to specific embodiments thereof, it will be apparent to one skilled
in the art that various changes and modifications may be made therein
without deviating or departing from the scope and spirit of the invention.
Thus the disclosure contained herein includes within its ambit the obvious
equivalents and substitutes as well.
Having described the invention in detail with particular
reference to the illustrations given above, it will now be more specifically
defined by means of claims appended hereafter.

We claim:
1. A process for preparing aluminium citrate in orally
administrable form effective against gastrointestinal
disorders, characterized in that the said process comprises
(a) dissolving potash alum [K2 Al2 (SO4)3, 24 H2O] by
heating in water until a clear solution results;
(b) adding solid or powdery sodium bicarbonate in
water and boiling the mixture until dissolution
results;
(c) mixing solutions (a) and (b) in stoichiometric
proportions under stirring and allowing the thus
formed precipitate to settle for a period varying
between 6 and 8 hours without agitation;
(d) decanting the supernatant liquid followed by
washing of the precipitate with distilled water until
the wash liquid is free from SO4" ions;
(e) adding citric acid solution to the reaction mass
obtained from step (d), boiling the reaction medium
to a temperature not exceeding 90°C under gentle
stirring, and adjusting the pH between 6 and 7;
(f) cooling the reaction medium to ambient
temperature, filtering if necessary, and storing the
final solution of aluminium citrate in orally
administrable form followed by transferring the
solution into suitable receptacles in predetermined
volumes prior to dispatch to outlets.
2. A process as claimed in Claim 1, wherein degree of stirring is
determined by the degree of viscosity of the reaction
medium, optimally adjusted at around 50 r. p.m.

3. A process as claimed in Claim 1, wherein aqueous solutions
resulting from both steps (a) and (b) are subjected to
filtration to remove undissolved impurities by employing a
filtering medium of clear membrane with an optimum pore
size of 0.25µ.
4. A process as claimed in Claims 1 to 3, wherein pH of the
stored solution of aluminium citrate is allowed to revert to 4
to 5 and the specific gravity thereof is adjusted to a value of
approximately 1.02.
5. A process as claimed in Claim 1, wherein the precipitate of
aluminium hydroxide formed in step (c) is allowed to be
converted into aluminum hydroxide gel in the course of
washing with water to render it free from SO4" -ions, prior
to reaction with citric acid.
6. A process for preparing aluminium citrate in orally
administrable form effective against gastro-intestinal
disorders, substantially as hereinbefore described.

Heretofore aluminium citrate was prepared from aluminium
chloride by interacting them under vigorous agitation, preferably at low
temperatures. Aluminium chloride of desirable grade is not readily
available in this part of the country and this route is found to be lacking in
cost effectiveness.
As alternative route was being searched and this led to the present
invention which relates to a process for preparing aluminium citrate in
orally administrable form effective against gastrointestinal disorders,
characterized in that the said process comprises -
(a) dissolving potash alum [K2 Al2 (SO4)3, 24 H2O] by heating in
water until a clear solution results;
(b) adding solid or powdery sodium bicarbonate in water and
boiling the mixture until dissolution results;
(c) mixing solutions (a) and (b) in stoichiometric proportions
under stirring and allowing the thus formed precipitate to
settle for a period varying between 6 and 8 hours without
agitation;
(d) decanting the supernatant liquid followed by washing of the
precipitate with distilled water until the wash liquid is free
from SO4" ions;
(e) adding citric acid solution to the reaction mass obtained
from step (d), boiling the reaction medium to a temperature
not exceeding 90°C under gentle stirring, and adjusting the
pH between 6 and 7;
(f) cooling the reaction medium to ambient temperature,
filtering if necessary, and storing the final solution of
aluminium citrate in orally administrable form followed by
transferring the solution into suitable receptacles in
predetermined volumes prior to dispatch to outlets.

Documents:

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Patent Number

279879

Indian Patent Application Number

797/KOL/2010

PG Journal Number

05/2017

Publication Date

03-Feb-2017

Grant Date

31-Jan-2017

Date of Filing

22-Jul-2010

Name of Patentee

PATHAK PREM SHANKAR

Applicant Address

119E, MANCHESWAR INDUSTRIAL ESTATE, BHUBANESWAR-751010, ORISSA. INDIA

Inventors:

#	Inventor's Name	Inventor's Address
1	PATHAK PREM SHANKAR	119E, MANCHESWAR INDUSTRIAL ESTATE, BHUBANESWAR-751010, ORISSA. INDIA
2	BHARDWAJ HARSHVARDHAN	119E, MANCHESWAR INDUSTRIAL ESTATE, BHUBANESWAR-751010, ORISSA. INDIA
3	BHARDWAJ GAURAVARDHAN	119E, MANCHESWAR INDUSTRIAL ESTATE, BHUBANESWAR-751010, ORISSA. INDIA

PCT International Classification Number

C07C51/41

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA