Claims:
1. A method for efficient purification of crude beta blocker drugs comprising;
a) dissolving the crude beta blocker drug in water and adjusting the pH with an acid from 8 to 2, followed by treatment with celite to obtain clear solution of respective salt of beta blocker drug;
b) passing the clear solution through an adsorbent resin with a specific flow rate to obtain the filtrate containing acid salt of beta blocker drug with good purity; and
c) precipitating the beta blocker drug by treating the filtrate with an alkali followed by isolation of the precipitated beta blocker drug with high purity from the filtrate.
2. The method as claimed in claim 1, wherein, the beta blocker drug is selected from atenolol, propranolol, metoprolol and bisoprolol.
3. The method as claimed in claim 1, wherein, the acid is selected from mineral acid such as hydrochloric acid or an organic acid such as acetic acid, citric acid, tartaric acid or oxalic acid.
4. The method as claimed in claim 1, wherein, the adsorbent resin is selected from crosslinked methacrylate and Non Ionic Acrylic Polymers.
5. The method as claimed in claim 1, wherein, the resin treatment in step b) is conducted at ambient temperature.
6. The method as claimed in claim 1, wherein, the specific flow rate of step b) is about 10 ml / minute.
7. The method as claimed in claim 1, wherein, the method optionally comprises a step of purification of the resin for reuse in next batch.
8. The method as claimed in claim 7, wherein, the purification method comprises;
a) washing the resin column with water for injection (WFI);
b) passing 80% alcohol/acid at a rate of 5ml/min; and
c) washing the resin with water for injection (WFI) to make the column for next use.
9. The method as claimed in claim 8, wherein, the alcohol is selected from isopropanol or methanol and the acid is acetic acid.
10. The method as claimed in claim 1, wherein, the method optionally comprises a step of recovering the beta blocker drug from the filtrate (mother liquor solution), which method comprises;
a) passing the filtrate (mother liquor solution) on a styrenic adsorbent resin to adsorb the beta blocker drug present in the mother liquor; and
b) eluting the resin using 80% acetic acid to recover the beta blocker drugs.
11. The method as claimed in claim 10, wherein, the styrenic adsorbent resin is selected from Poly divinylbenzene and poly ethylvinylbenzene (styrenic) resins.

12. The method as claimed in claim 10, wherein, the beta blocker drug is selected from atenolol propranolol, metoprolol and bisoprolol.
, Description:Technical filed:
The present invention relates to process for purification of crude active pharmaceutical ingredients belonging to the group of beta blockers. More particularly, the invention relates to process for purification of crude beta blockers selected from the group consisting of atenolol, Propanolol, metoprolol, Bisoprolol etc. to improve the impurity profile of the same.
Background and prior art:
Beta-adrenergic antagonists also known as beta-blockers are a class of compounds, which are employed for management of angina pectoris, hypertension and arrhythmia. The beta-blockers are used to reduce the frequency of the anginal episodes and to improve the anginal threshold by attenuating the chronotropic and inotropic responses to adrenergic stimulation.
Atenolol is chemically known as 4-[2-hydroxy-3- [(1-methyl ethyl)amino]propoxy] benzene acetamidebelongs to the class of beta blockers and exists as a racemic mixture of (R) and (S) optical isomers due to the presence of an asymmetric centre at the hydroxy-bonded carbon of the 1-aryloxy-3-aminopropan-2-ol moiety.
There is ample literature available on the synthesis of racemic atenolol and asymmetric synthesis of (S)-atenolol.
It is known that atenolol and its analogues are prepared by reaction of a phenol compound with epihalohydrin to obtain glycidyl ether followed by reaction of the glycidyl ether with an amine compound (U.S. Pat. Nos. 3,663,607, 3,836,671 and 3,934,032) as shown by the following scheme 1.
Scheme 1

US 6982349 discloses a method for synthesis of optically active (S)-atenolol with high optical purity. According to this method, reaction of a phenol with an (R-) epichlorohydrin in the presence of an alkali metal hydroxide and a quaternary ammonium salt as a phase transfer catalyst in aqueous solution at a temperature of -10° C. to 0° C. to obtain optically active glycidyl ether, which is further reacted with isopropylamine at 10° to 40° C. to obtain (S)-atenolol with an optical purity of more than 99%.
As is evident from the cursory review of prior art that the atenolol can be synthesized in two steps from Para hydroxy phenyl acetamide (PHPA), as shown in scheme 2 below.
Scheme 2

As depicted in scheme 2 above, in stage 1, Para hydroxy phenyl acetamide is reacted with Epichlorohydrine in water to give Epoxide. In stage 2, the Epoxide obtained is reacted with the Mono Isopropyl amine to give the Atenolol.
However, the epoxide formed in the stage 1 comprises a lot of impurities that formed due to side reactions or the unreacted starting materials. These impurities if not removed carry forward to stage 2, where, the atenolol is formed. At the end of the stage 2, the product, atenolol thus obtained comprises impurities brought forwarded from stage 1 as well as other impurities formed in stage 2 in addition to the unreacted starting compounds in each stage of the process.
A few prior arts have suggested charcoal treatment of the crude atenolol or through salt formation of the crude atenolol. However both the methods have its own associated disadvantages; while charcoal treatment increases effluent problems, the salt formation is associated with the formation of additional impurities such as undesired salts of these impurities.
Metoprolol is chemically known as 1-(Isopropylamino)-3-(4-(2-methoxyethyl) phenoxy)propan-2-ol. There is ample literature available on the synthesis of metoprolol with slight variations. However, the well reported method for preparation of metoprolol includes reaction of p-(2-methoxyethyl)-phenol and epichlorohydrin to obtain 1-(2, 3-epoxypropoxy)-4-(2-methoxyethyl)-benzene, which is then reacted with isopropylamine, as shown in scheme 3 below.
Scheme 3

Bisoprolol is chemically known as 1-{4-[(2-Isopropoxyethoxy) methyl]phenoxy}-3-(isopropylamino)-2-propanol. There is ample literature available on the synthesis of Bisoprolol with slight variations. However, the well reported method for preparation of Bisoprolol includes reaction of 2- (isopropoxy)ethoxymethyl-phenol with epichlorhydrin and the ß-amino alcohol moiety is formed by the addition of iso-propylamine. Moreover, the reaction between the epoxy intermediate and isopropylamine has the potential to undergoes side reactions leading to the formation of the known impurity F (as described in the European Pharmacopeia 6.1). The reaction scheme is shown in scheme 4 below.
Scheme 4

Similarly propranolol is prepared by the reacting naphthol with epichlorohydrin and subsequent reaction with isopropylamine to obtain propranolol, as shown in scheme 5.
Scheme 5

As is evident from the scheme 2, scheme 3, scheme 4 and scheme 5 for the preparation of atenolol, metoprolol, bisoprolol, and propranolol, in all the four cases, the synthetic reactions are similar i.e., epoxide formation followed by treatment with isopropyl amine. Similar to atenolol, in the case of metoprolol, bisoprolol and propranolol synthesis also, the epoxide formed in the stage 1 comprises a lot of impurities that formed due to side reactions or the unreacted starting materials. These impurities if not removed will get carried to stage 2, where, the metoprolol, propranolol and bisoprolol are formed. At the end of the stage 2, the product, metoprolol or propranolol or bisoprolol thus obtained comprises, lot of impurities as listed in respective pharmacopeias, brought forwarded from stage 1 as well as other impurities generated in stage 2 due to side reactions in addition to the unreacted starting compounds in each stage of the process.
Surprisingly, the prior art is failed to provide any teaching or suggestion on effective removal of these impurities to improve the impurity profile of the beta blocker drugs, such as atenolol, metoprolol, bisoprolol, propranolol etc.
In the light of the above, there remains a need in the art to provide an efficient process for improving the impurity profile of beta blocker drugs, such as atenolol, propranolol, metoprolol, bisoprolol etc., by removing the impurities formed during the reactions.
Therefore, it becomes an objective of the present invention to provide an efficient and simple purification process to improve the impurity profile of the crude beta blocker drugs, obtained directly from the plant, thereby meeting the requirements of all major pharmacopeias such as IP, BP, EP and US etc.
Summary of the invention:
In line with the above, the present invention provides a method for efficient purification of crude beta blocker drugs, which method comprises;
a) dissolving the crude beta blocker drug in water and adjusting the pH with an acid from 8 to 2 followed by treatment with celite to obtain clear solution of respective salt of beta blocker drugs;
b) passing the clear solution through an adsorbent resin at a specific flow rate to obtain the filtrate containing acid salt of beta blocker drug with good purity and
c) precipitating the pure beta blocker drug by treating the filtrate with an alkali.
In an aspect, the acid is selected from mineral acid such as hydrochloric acid or an organic acid such as acetic acid, citric acid, tartaric acid or oxalic acid.
The resin used in the purification is adsorbent resin, which is selected from crosslinked methacrylate and Non Ionic Acrylic Polymers.
In an aspect, the beta blocker drugs are selected from atenolol, Propranolol, metoprolol, Bisoprolol etc.
Detailed description:
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be fully understood and appreciated.
Accordingly, the invention provides a method for efficient purification of crude beta blocker drugs, which method comprises;
a) dissolving the crude beta blocker drug in water and adjusting the pH with an acid from 8 to 2, followed by treatment with celite to obtain clear solution of respective salt of beta blocker drug; and
b) passing the clear solution through an adsorbent resin at a specific flow rate of about 10 ml / minute to obtain the filtrate containing acid salt of beta blocker drug with good purity and
c) precipitating the pure beta blocker drug by treating the filtrate with an alkali.

In an aspect, the acid is selected from mineral acid such as hydrochloric acid or an organic acid such as acetic acid, citric acid, tartaric acid or oxalic acid.
In an aspect, the adsorbent resin is selected from crosslinked methacrylate and Non Ionic Acrylic Polymers.
In an aspect, the beta blocker drugs are selected from Atenolol, Propranolol, Metoprolol, Bisoprolol etc.
In an aspect, the resin treatment reaction may be conducted at ambient temperature.
In an aspect, the clear solution passed through an adsorbent resin at a specific flow rate of about 10 ml / minute.
After the purification of the beta blocker drugs, the resin can be purified or egenerated and can be reused for further batch. Accordingly, in an additional embodiment, the invention provides purification method of the used resin which comprises;
a) washing the resin column with water for injection (WFI);
b) passing 80% alcohol or acid at a rate of 5ml/min; and
c) washing the resin with water for injection (WFI) to make the column for next use.

As referred above, “80% alcohol or acid” means 80% alcohol or 80% acid along with 20% water. According to the invention the alcohol is preferably selected from isopropanol, methanol and the acid is preferably acetic acid.
Accordingly, in an embodiment, the method for purification of resin comprises;
a) washing the resin column with WFI;
b) passing 80% isopropanol at a rate of 5ml/min; and
c) washing the resin with WFI to make the column for next use.

In a process variant, the invention provides a method for purification of resin which method comprises;
a) washing the resin column with WFI;
b) passing 80% methanol at a rate of 5ml/min; and
c) washing the resin with WFI to make the column for next use.
In another process variant, the invention provides a method for purification of resin which method comprises;
a) washing the resin column with WFI;
b) passing 80% acetic acid at a rate of 5ml/min; and
c) washing the resin with WFI to make the column for next use.
In yet another embodiment, the atenolol/ Propranolol/ metoprolol/bisoprolol from the mother liquor solution (after removal of the precipitates of the respective drugs) is recovered by neutralizing the solution with sodium hydroxide and passing the solution on a poly divinylbenzene (styrenic) resin to adsorb the atenolol/ Propranolol/metoprolol/bisoprolol present in the mother liquor and eluted using 80% acetic acid and 20% water.
According to an embodiment, in the first stage of industrial preparation of atenolol, Para hydroxy phenyl acetamide is reacted with Epichlorohydrin in presence of aqueous alkali to obtain epoxide. Basically there are two products formed in this reaction, i.e., epoxide and Chloro hydrin derivative. Both of these products get converted into atenolol on subsequent reaction with Mono Isopropyl amine.
The impurity profile of Epoxide in stage 1 of the reaction comprises the following impurities in the following amounts:
1. Unreacted Parahydroxy phenyl acetamide – 0.2 to 0.3%
2. 2-(4-(2,3-dihydroxypropoxy)phenyl)acetamide (Impurity B) - 0.25 to 0.3%
3. 2,2’-[2-Hydroxypropan-1,3-diylbis(oxy-4,1-phenylene)]diacetamide (Impurity-E)-0.75 to 1.0 %
4. Epoxide + Chlorohydrine - about 98%.
In the second stage, the Epoxide thus obtained from stage 1 is reacted with the Mono Isopropyl amine (MIPA) to afford the Atenolol. The excess of MIPA is distilled to obtain a solid residue, which is atenolol Crude. This Atenolol Crude contains following impurities in the following amounts:
1. Un reacted Parahydroxy phenyl acetamide - 0.2 to 0.3%
2. 2-(4-(2,3-dihydroxypropoxy)phenyl)acetamide (Impurity-B) - 0.25 to 0.3%
3. 2,2’-[2-Hydroxypropan-1,3-diylbis(oxy-4,1-phenylene)]diacetamide(Impurity-E)- 0.75 to 1.0%
4. 2,2'-(4,4'-(3,3'-(isopropylazanediyl)bis(2-hydroxypropane-3,1-diyl))bis(oxy)bis(4,1-phenylene))diacetamide (Impurity-F) - 0.75 to 1.0%
Total impurities in the stage 2 are about 3%, along with some other minor impurities.
The crude atenolol residue thus obtained is subjected to purification reaction. According to the purification method, water is added to the crude atenolol residue followed by addition of an acid to bring the pH of the solution from 8 to 5. At this stage the mass is smoky liquid which is filtered by treatment with celite/hyflow to get the clear solution. Then, this clear liquid is passed through the specific adsorbent resin at a specific flow rate of about 10 ml / minute to afford the solution consisting of purified atenolol salt. The adsorbent resins are selected from crosslinked methacrylate and Non Ionic Acrylic Polymers.
The impurity profile after this purification with the resin treatment comprises-
1. Un reacted Parahydroxy phenyl acetamide (PHPA) - 0.07%
2. 2-(4-(2,3-dihydroxypropoxy)phenyl)acetamide (Impurity-B) - 0.15%
3. 2,2’-[2-Hydroxypropan-1,3-diylbis(oxy-4,1-phenylene)]diacetamide (Impurity-E) - NIL
4. 2,2'-(4,4'-(3,3'-(isopropylazanediyl)bis(2-hydroxypropane-3,1-diyl))bis(oxy)bis(4,1-phenylene))diacetamide (Impurity-F) - <0.05%
The filtrate is then precipitated with Sodium Hydroxide to afford the Atenolol with more than 99% purity which is filtered and then dried. The product thus obtained is in compliance with the requirement of all pharmacopoeias viz., IN, BP, EP and US pharmacopeias.

In another embodiment, the invention provides a process for recovery of Atenolol from Mother Liquor. According to this process, the mother liquor containing about 1% Atenolol, is recovered by neutralizing the solution with sodium hydroxide and passed through a specific different grade adsorbent Resin such as styrenic adsorbent resin to capture the atenolol over Resin, which can then be eluted as Atenolol or its acid salt using 80% Acetic acid with 20% water. The specific adsorbent Resin is selected from poly divinylbenzene (styrenic) resin or poly ethylvinylbenzene (styrenic) resin.

In a further embodiment, the crude propranolol obtained from the plant is subjected to purification by using a similar process as in the case of atenolol by giving resin treatment and achieved the propranolol in more than 97.5% purity. The propranolol thus obtained is in compliance with the requirement of all IN, EP, BP and US pharmacopoeias.

In yet another embodiment, the crude metoprolol obtained from the plant is subjected to purification by using a similar process as in the case of atenolol, by giving resin treatment and achieved the metoprolol in more than 99.5% purity. The metoprolol thus obtained is in compliance with the requirement of all IN, EP, BP and US pharmacopoeias.

In yet another embodiment, the crude bisoprolol obtained from the plant is subjected to purification by using a similar process as in the case of atenolol or metoprolol or propranolol, by giving resin treatment and achieved the bisoprolol in more than 96.5% purity. The bisoprolol thus obtained is in compliance with the requirement of all IN, EP, BP and US pharmacopoeias.

In all the cases, similar to atenolol, the resin is treated and reused for the next batch. Also, the mother liquor is treated with alkali and subjected to resin treatment on styrenic adsorbent resin to capture the respective drugs such as metoprolol/ bisoprolol/propranolol and further recovered as metoprolol/ bisoprolol/propranolol or its acid salt by eluting 80% Acetic acid with 20% water.

Other features and embodiments of the invention will become apparent by the following examples which are given only for the purpose of illustration of the invention rather than limiting its intended scope. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art.
Examples
Example 1
Experiments with solid crude atenolol taken from the plant:
Taken 250gm crude Atenolol obtained from plant in 500ml water, and analyzed the same for known and unknown impurities as shown in table 1. Adjusted pH 7.2 to 7.5 with Conc. HCl at 25 – 30deg, a hazy solution was observed. Added 5gm celite / Hyflo into the hazy solution, stirred for 30 minutes at 25 deg. and filter the solution. A clear 720ml filtrate was obtained and analyzed the same for impurity profile, as shown below in table 2.
Table 1:
Stage pH IMP B PHPA UKN 1 IMP J IMP I Atenolol UKN 2 IMP F1 IMP F2 IMP G Qty.(ml)
Solid 250gm+500ml WFI 7.49 0.16 0.07 0.03 0.01 0.07 97.98 0.61 0.32 0.32 0.28 720

Resin treatment
A resin bed of 600Ml crosslinked methacrylate resin was prepared in a glass column. The resin bed was washed with WFI 300ml and passed 720 ml filtrate (FT) obtained from the previous stage through this resin with downward flow at a rate of 10 ml / minute to obtain filtrate-1(FT-1), followed by water wash (250 ml) and the results are depicted in table 2.
Table 2
Stage pH IMP B PHPA UKN 1 IMP J IMP I Atenolol UKN 2 IMP F1 IMP F2 IMP G Qty.(ml)
FT-1 7.49 0.12 0.02 0.01 0.02 0.06 99.35 0.03 0.04 0.04 0.33 720
Ist
WFI wash 250ml 0.18 0.06 0.03 0.02 0.06 99.14 0.05 0.04 0.02 0.41 250

The filtrate thus obtained was observed to be confirming with IP/EP/BP/USP requirements except Imp. “G”, which is an acid and gets removed as sodium salt, while treating the filtrate with alkali to precipitate pure atenolol.
By employing the process of the present invention, the following impurities either get eliminated or reduced thereby complying the atenolol thus obtained to all the pharmacopeas.
Impurity B: 2-(4-(2,3-dihydroxypropoxy)phenyl)acetamide
Impurity I: 2-(4-(3-(ethylamino)-2-hydroxypropoxy)phenyl)acetamide
Impurity F1 and F2: 2,2'-(4,4'-(3,3'-(isopropylazanediyl)bis(2-hydroxypropane-3,1-diyl))bis(oxy)bis(4,1-phenylene))diacetamide
Impurity G: 2-(4-(2-hydroxy-3-(isopropylamino)propoxy)phenyl)acetic acid
Impurity J: 2[4-(3-Amino-2-hydroxy-propoxy)-phenyl]-acetamide
Impurity E: 2,2’-[2-Hydroxypropan-1,3-diylbis(oxy-4,1-phenylene)]diacetamide
Impurity PHPA: unreacted Parahydroxy phenyl acetamide
Example 2
Experiments by dissolving crude solid with Acetic acid
Repeated the above experiment and used the Acetic acid instead of HCl, and passed the solution in a resin column having 600ml of crosslinked methacrylate resin.
The results are presented in below table 3, wherein, the upper row is input and the lower row is clear filtrate after treatment.
Table 3
Stage pH IMP B PHPA UKN 1 IMP J IMP I Atenolol UKN 2 IMP F1 IMP F2 IMP G Qty.(ml)
Input 7.5 0.16 0.24 0 0.01 0.01 98.21 0.2 0.34 0.38 0.35 1620
C1 FT 0.14 0.1 0 0 0.01 99.29 0 0 0 0.37 1600

Example 3
Experiment with plant Filtrate
Taken 500ml of plant batch filtrate containing crude atenolol, after Hyflo filtration to remove haziness, passed into a resin column containing 300ml of crosslinked methacrylate resin.
The results are presented in below table 4, wherein, the upper row is input and the lower row is the filtrate after treatment.
Table 4

Stage pH IMP B PHPA UKN 1 IMP J IMP I Atenolol UKN 2 IMP F1 IMP F2 IMP G Qty.(ml)
Input 6.91 0.14 0.23 0 0.04 0.04 98.02 0 0.62 0.28 0.57 500
FT-1 0.06 0.01 0 0.01 0.04 99.17 0 0.09 0.09 0.51 400

Example 4
Regeneration of Resin
Process – I
After the atenolol treatment, the resin column was washed with WFI and drained the water. Further the resin column was treated with two volumes of 80% IPA and 20% water at a rate of 5ml/min. The resin column was subsequently rinsed with WFI to make the resin column ready for next use.
Process – II
After the atenolol treatment, the resin column was washed with WFI and drained the water. Further, the resin column was treated with two volumes of 80% Methanol and 20% water at a rate of 5ml/min. The resin column was subsequently rinsed with WFI to make the resin column ready for next use.
Process – III
After the atenolol treatment, the resin column was washed with WFI and drained the water. Further, the resin column was treated with two volumes of 80% acetic acid and 20% water at a rate of 5ml/min. The resin column was subsequently rinsed with WFI to make the resin column ready for next use.
Example 5
Experiments for recovery of Atenolol from mother liquor
Taken 2800ml of mother liquor of Atenolol, adjusted pH to 7.0 to 7.5, passed through the column of 600ml of poly divinylbenzene (styrenic) resin bed at a rate of 15ml/min and analyzed the filtrate obtained after passing through the poly divinylbenzene (styrenic) resin for Atenolol content. It contains very negligible amount of Atenolol indicating that the atenolol present in the mother liquor was effectively absorbed by the resin.
The Atenolol adsorbed on the resin was further eluted with 80% Acetic and 20% water 200ml. The results are presented in table 5.
Table 5

Stage pH IMP B PHPA UKN 1 IMP J IMP I Atenolol UKN 2 IMP F1 IMP F2 IMP G Qty.(ml) Qtfn.(%)
Mother liquor 7.48 0 0 0 0 0 83.38 0 0 0 16.62 2800 1.13
FT 84.51 0 0 0 0 8.26 0 0 0 5.6 2800 0.0015
EL-1 0 0.62 0 0 0.06 82.56 0.06 0 0 16.7 240 13.1

Example 6
Purification of Metoprolol Base from plant:
Taken 50gm of crude Metoprolol base from plant and diluted with 200ml purified water and adjusted pH 5.0 to 5.5 with acetic acid at 25 – 30deg, to achieve homogeneous solution. Added 2gm celite / Hyflo into the solution, stirred the solution for 30 minutes at 25 deg. and filtered the solution. A clear 250ml filtrate was obtained and analyzed the same for impurity profile, as detailed herein below and depicted in the upper row of the table 6 given below.
1. Metoprolol tertiary amine:

2. Metoprolol Diol:

3. Metoprolol Bis Ether

4. Metoprolol Related Compound A / Metoprolol Impurity A
IUPAC Name: (2RS)-1-(Ethylamino)-3-[4-(2-methoxyethyl)phenoxy]propan-2-ol

5. Metoprolol USP Related Compound B / Metoprolol Succinate Impurity B
IUPAC Name: (+/-)1-chloro-2-hydroxy-3-[4-(2-methoxyethyl)phenoxy]-propane

6. Metoprolol Impurity C
IUPCA Name: 4-[(2RS)-2-hydroxy-3-[(1-methylethyl)amino]propoxy] benzaldehyde

7. Metoprolol EP Impurity Diol
IUPAC Name: (2RS)-3-[4-(2-Methoxyethyl) phenoxy]propane-1,2-diol

Example 7:
Resin treatment:
A resin bed of 300ml crosslinked methacrylate resin in a glass column was prepared. Washed this resin bed with WFI 150ml; started the passing of the 250 ml filtrate through this resin with downward flow at a rate of 10 ml / minute. The analysis of the feed and the filtrate (FT) after resin treatment is depicted in the lower row of the below table 6.
Table 6
Metoprolol Base Column Resin data
B.No. Content pH Diol Related comp.C Related comp.B Related comp.A Metoprolol Base Bis ether Tert. Amine1 Tert. Amine2
002/17
Feed 5.32 2.25 0 0.19 0.28 92.88 1.67 0.75 0.93
FT 0 0 0.07 0.21 99.46 0 0 0

The filtrate thus obtained is then precipitated with Sodium Hydroxide to afford the metoprolol with a purity of more than 99%.
From the above, it is evident that the diol impurity, related impurity C, bis ether impurity, ter. Amine 1, Ter. Amine 2 are completely eliminated after the resin treatment in accordance with the invention and the related compound B and related compound A are substantially reduced and the precipitated metoprolol after the treatment with alkali, obtained was observed to be in compliance with IP/EP/BP/USP requirements.
Regeneration of Resin is conducted as per the example 4 and the metoprolol is recovered from the mother as per the example 5 by modification in pH 5 to 5.5.
Example 8
Purification of Bisoprolol Base Crude from plant:
Taken 20gm Bisoprolol base crude, diluted with 200ml purified water and adjusted pH 7.0 to 7.5 with conc HCl at 25 – 30deg, hazy solution was observed. Added 2gm celite / Hyflo into the solution, stirred for 30 minutes at 25 deg. and filter the solution. A clear 250ml filtrate was obtained and analyzed the same for impurity profile, as shown in upper row of table 7.
Resin treatment:
A resin bed of 100ml crosslinked methacrylate resin in a glass column was prepared. Washed this resin bed with purified water 200ml and passed the 250 ml filtrate through this resin with downward flow at a rate of 10 ml / minute and the results are depicted in the lower row of table 7.
Table 7

Bisoprolol Base Column Resin data
B.No. Content pH UNK-1 UNK-2 Bisoprolol UNK-3
004/18
Feed 7.34 3.76 0.42 93.14 0.52
After passing nil 0.92 96.69 nil

The results show the substantial improvement of the purity of Bisoprolol and complete elimination of the unknown impurity 1 and 3. However, unkown impurity 2 is increased because, the area of impurity 2 is increased in the ratio due to the complete removal of impurity 1.
Regeneration of Resin is conducted as per the example 4 and the Bisoprolol is recovered from the mother as per the example 5 by modification in pH 7 to 7.5.

Example 9
Purification of Propranolol Base Crude:
Taken 25gm Propranolol base crude, diluted with 200ml purified water and adjusted pH 2.0 to 3.0 with conc HCl at 25 – 30deg, hazy solution was observed. Added 2gm celite / Hyflo into the solution, stirred for 30 minutes at 25 deg. and filter the solution. A clear 250ml filtrate was obtained and analyzed the same for impurity profile, as shown in upper row of table 8.
Resin treatment
A resin bed of 100ml crosslinked methacrylate resin in a glass column was prepared. Washed this resin bed with purified water 200ml and passed the 250 ml filtrate through this resin with downward flow at a rate of 10 ml / minute and the results are depicted in the lower row of table 8.
Table 8
Propranolol Base Column Resin data
B.No. Content pH UNK-1 Propanolol UNK-2
004/18
Feed 2 1.47 97.66 0.44
After passing 1.42 97.95 0.07

The results show the improvement of the purity of propranolol and reduction in unknown impurities 1 and 2.
Regeneration of Resin is conducted as per the example 4 and the propranolol is recovered from the mother as per the example 5 by modification in pH 2 to 3.