WO2016142582A1 - Process for the preparation of crystalline salmeterol and its xinafoate salt - Google Patents

Process for the preparation of crystalline salmeterol and its xinafoate salt Download PDF

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WO2016142582A1
WO2016142582A1 PCT/FI2016/050138 FI2016050138W WO2016142582A1 WO 2016142582 A1 WO2016142582 A1 WO 2016142582A1 FI 2016050138 W FI2016050138 W FI 2016050138W WO 2016142582 A1 WO2016142582 A1 WO 2016142582A1
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process according
aliphatic
ether
salmeterol
heptane
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PCT/FI2016/050138
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French (fr)
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Elina Tienari
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Fermion Oy
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/10—Separation; Purification; Stabilisation; Use of additives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/41—Preparation of salts of carboxylic acids
    • C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part

Definitions

  • the present invention relates to an improved process for the preparation of crystalline salmeterol (4-hydroxy-a 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-l,3- benzenedimethanol) and its xinafoate (l-hydroxy-2-naphthoate) salt.
  • Salmeterol is a long acting beta 2 -adrenergic receptor agonist which is used as its xinafoate salt in inhaled bronchodilator therapy in the treatment of asthma.
  • the drug is delivered from a metered-dose aerosol inhaler or from dry powder inhaler.
  • Salmeterol and the pharmaceutically acceptable salts thereof were first described in GB 2140800.
  • EP 422889 describes the preparation of xinafoate salt of salmeterol isomers.
  • (R)-salt is made in methanol and crystallized from isopropyl acetate.
  • (S)-salt is made in tert-butylmethyl ether followed by trituration with diethyl ether.
  • Another method for the preparation of (S)-salt uses diethyl ether as a solvent.
  • EP 639176 describes fast crystallization of salmeterol xinofoate by quenching hot organic solution of salmeterol xinofoate with cold organic solvent wherein particularly methanol, ethanol or isopropanol are used as organic solvents.
  • the product is said to avoid the poor micronization properties associated with salmeterol xinofoate crystals.
  • WO 2007/045857 describes crystallization of salmeterol xinofoate from methanol at 25-30 °C followed by isolation at 10 °C. Isolation of salmeterol base is also described. It was obtained by precipitation of a gummy mass from ethyl acetate with 20 % yield.
  • WO 2009/144193 describes a method of preparing crystalline salmeterol xinafoate by dissolving in methyl ethyl ketone followed by stepwise cooling (yield 91.3 %). The product has mean particle size of 11.5 ⁇ and it is said to be readily micronizable.
  • WO 2012/032546 describes preparation of crystalline salmeterol xinafoate by dissolving salmeterol and l-hydroxy-2-naphthoate in acetone and precipitating the product by addition of methyl tert-butyl ether at 25 °C followed by filtering at 10 °C. The product was recrystallized from methanol and acetone resulting in total yield of about 51 %.
  • Salmeterol xinafoate is administered in dosage strength as low as 25 ⁇ g. In order to have it distributed deeply in the lungs via inhalation a small particle size is required such as about 2 - 5 ⁇ . Such small particle size is typically achieved by micronization process which requires good flowability properties. However, salmeterol xinafoate often tends to crystallize as a product which is poorly suitable for micronization process. Moreover, the synthesis of salmeterol is typically lengthy, results in low yield and purity and is associated with process impurities that may be cumbersome to remove from the end product. As the dosage strength is small it is important to have salmeterol in high purity. Finally, salmeterol base which is used in the preparation of xinafoate salt is often obtained as a gummy or oily product which is difficult to handle.
  • salmeterol xinafoate can be isolated in high purity and yield and in easily micronizable form by crystallization from hot aliphatic ketone solvent such as methyl ethyl ketone using an antisolvent such as heptane or hexane. Recrystallizations are not needed to achieve sufficient purity.
  • the essential feature of the invention is to maintain high temperature during the crystallization and isolation.
  • salmeterol base can be isolated in powdery form and in high purity and yield by crystallization from the mixture comprising aliphatic ether and heptane in a specific ratio.
  • Salmeterol base may be synthetized by a method known in the art, e.g. as described in US 4992474. It has been found that salmeterol base can be isolated in powdery form and in high purity and yield by crystallization from the mixture comprising aliphatic ether and heptane in a specific ratio.
  • Such method for crystallizing salmeterol base comprises a) dissolving salmeterol base in a mixture of aliphatic ether and heptane under heating wherein the volume ratio of the aliphatic ether to heptane is from 40:60 to 80:20; b) cooling the mixture of step a); and c) isolating the precipitated salmeterol base.
  • the volume ratio of the aliphatic ether to heptane is from about 45 :55 to about 75:25, more preferably from about 50:50 to about 70:30, for example about 60:40.
  • Salmeterol base is suitably dissolved in the mixture of aliphatic ether and heptane by heating the mixture to the temperature which is from about 50 °C to the boiling point of the mixture, typically from 55 °C to 80 °C, for example from 60 to 70 °C, for example about 65 °C.
  • step a) is then cooled to the temperature where salmeterol base precipitates, suitably to 0 - 30 °C, for example to 10 - 25 °C, for example to 20 °C.
  • the cooling is carried out slowly, suitably at the rate of 15 - 25 °C / hour, for example about 20 °C / hour.
  • the mixture can be seeded with salmeterol base crystals at the temperature of about 45 - 55 °C, for example at about 50 °C.
  • the mixture is then suitably stirred in room temperature for about 0.5 to about 14 h, for example for about 1 to about 3 h.
  • the precipitate can be easily isolated e.g. by filtering.
  • the obtained salmeterol base product can be washed and dried in vacuum at about 40 - 60 °C for about 5 - 72 h, for example about 6 - 24 h to obtain salmeterol base in powder form.
  • the aliphatic ether can be selected, for example, from cyclopentyl methyl ether, methyl tert-butylether, diisopropyl ether and combinations thereof. Cyclopentyl methyl ether and methyl tert-butylether are preferred aliphatic ethers. Cyclopentyl methyl ether is particularly preferred.
  • salmeterol xinafoate can be isolated in high purity and yield and in easily micronizable form.
  • the process for the preparation of crystalline salmeterol xinafoate comprises a) providing a hot solution of salmeterol base and l-hydroxy-2-naphthoic acid in aliphatic ketone solvent; b) adding antisolvent slowly to the hot solution; and c) isolating the precipitated salmeterol xinafoate from the hot solution; wherein the temperature of the hot solution in steps a) to c) is higher than 55 °C.
  • the temperature of the hot solution in steps a) to c) is about 58 °C or higher, for example from about 58 °C to about the boiling point of the hot solution.
  • the temperature of the hot solution in steps a) to c) is from about 60 °C to about the boiling point of the hot solution, suitably from about 60 °C to about 73 °C, for example from about 60 °C to about 72 °C.
  • the temperature of the hot solution in steps a) to c) is 60 + 2 °C.
  • hot solution refers generally to solution having temperature higher than 55 °C, preferably about 58 °C or higher, for example from about 58 °C to about the boiling point of the hot solution, still more preferably from about 60 °C to about the boiling point of the hot solution, suitably from about 60 °C to about 73 °C, for example from about 60 °C to about 72 °C.
  • the aliphatic ketone solvent comprises suitably aliphatic ketone with
  • 0 to about 5 % of water preferably from about 0.5 to about 3 % of water, more preferably from about 0.8 to about 2 % of water, for example from about 1 to about 1.5 % of water, by volume of the aliphatic ketone solvent.
  • Water improves the solubility of salmeterol xinafoate in ketone and accordingly less solvent is needed.
  • the concentration of salmeterol xinafoate in the solution of step a) is suitably 10 - 20 g/100 ml, for example 14 - 18 g/100 ml of aliphatic ketone solvent.
  • Salmeterol base and l-hydroxy-2-naphthoic acid can be dissolved directly in the hot aliphatic ketone solvent or the components can be mixed in lower temperature and the mixture heated to the desired temperature thereby dissolving salmeterol base and l-hydroxy-2-naphthoic acid.
  • antisolvent refers to an organic solvent that when mixed with the aliphatic ketone solvent in which salmeterol xinafoate is dissolved, reduces the capacity of the aliphatic ketone solvent to dissolve salmeterol xinafoate.
  • an antisolvent when admixed with a solution of salmeterol xinafoate in the aliphatic ketone solvent, the solubility of salmeterol xinafoate can be reduced to the point at which it precipitates out of solution.
  • Preferred antisolvents are those in which salmeterol xinafoate is insoluble or only poorly soluble at temperature higher than 55 °C, particularly at temperature from about 60 °C to about 73 °C.
  • Antisolvent is suitably added to the hot solution slowly, for example dropwise, while keeping the temperature of the hot solution essentially constant during the addition.
  • the mixture can be seeded, if desired, with salmeterol xinafoate crystals after or during the addition of antisolvent.
  • part of antisolvent is added before seeding and another part after seeding.
  • the amount of antisolvent used in step b) is at least 93 %, suitably 100 - 150 %, by weight of the aliphatic ketone solvent.
  • the hot mixture can be stirred for example 0.5 - 18 h while keeping the temperature essentially constant.
  • the hot mixture is then isolated suitably by filtering.
  • the obtained crystalline salmeterol xinafoate can be washed and dried, for example in vacuum at about 40 °C for 6 - 72 h, for example 8 to 24 h, to obtain crystalline salmeterol xinafoate.
  • the aliphatic ketone can be selected from, for example, methyl ethyl ketone, acetone, methyl isobutyl ketone, ethyl butyl ketone, diethyl ketone, diisobutyl ketone and mixtures thereof.
  • methyl ethyl ketone is used.
  • the antisolvent can be selected from, for example, heptane, hexane or a mixture thereof.
  • heptane is used as an antisolvent.
  • the temperature during the crystallization and isolation is kept suitably at 58 °C or higher, but preferably below the boiling point of the solvent.
  • temperatures from 60 °C to 72 °C may be used.
  • Crystallization of salmeterol xinafoate is initiated using an antisolvent.
  • an antisolvent When aqueous methyl ethyl ketone is used as a solvent and heptane is used as an antisolvent, the amount of heptane of about 93 - 150 %, by weight of the aqueous methyl ethyl ketone, e.g. 100 -130 %, may be used.
  • the impurities of salmeterol remain in the filtrate in dissolved form and pure salmeterol xinafoate product can be isolated. After isolation the precipitate is washed and dried in vacuum overnight. The dried product has good flowability and is easily micronizable. Bulk density is typically about 0.15 g/ml, tapped density typically about 0.27 g/ml and mean particle size about 25 ⁇ .
  • Example 1 Preparation of salmeterol xinafoate
  • Salmeterol free base 1.0 g
  • l-hydroxy-2-naphthoic acid 0.475 g
  • Heptane 11 ml was added slowly to the solution at 60 °C and the mixture was seeded.
  • the mixture was stirred at 60 °C for 1 h and the precipitate was filtered from the hot solution and washed with heptane. The precipitate was dried at 40 °C overnight.
  • Example 3 Preparation of salmeterol base Oily evaporation residue of crude salmeterol base (purity 94 area-%) was dissolved in a mixture of cyclopentyl methyl ether (6 vol) and heptane (4 vol) at 65 °C. The solution was cooled to 20 °C at the rate of 20 °C/h. Seeding was carried out at 50 °C. The mixture was stirred at room temperature for 1 h. The precipitate was filtered and washed with cold cyclopentyl methyl ether (2 x 2.5 vol). The precipitate was dried in vacuum at 40 °C overnight to obtain the powdery product.

Abstract

The invention relates to an improved process for the preparation of crystalline salmeterol (4-hydroxy-α1-[[[6-(4-phenylbutoxy)hexyl]amino]methyl]- 1,3-benzenedi-methanol) and its xinafoate (1-hydroxy-2-naphthoate) salt. Salmeterol is a long acting beta2-adrenergic receptor agonist which is used as its xinafoate salt in inhaled bronchodilator therapy in the treatment of asthma.

Description

PROCESS FOR THE PREPARATION OF CRYSTALLINE SALMETEROL AND ITS XINAFOATE SALT
FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of crystalline salmeterol (4-hydroxy-a1-[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-l,3- benzenedimethanol) and its xinafoate (l-hydroxy-2-naphthoate) salt.
BACKGROUND OF THE INVENTION
Salmeterol is a long acting beta2-adrenergic receptor agonist which is used as its xinafoate salt in inhaled bronchodilator therapy in the treatment of asthma. The drug is delivered from a metered-dose aerosol inhaler or from dry powder inhaler. Salmeterol and the pharmaceutically acceptable salts thereof were first described in GB 2140800.
EP 422889 describes the preparation of xinafoate salt of salmeterol isomers. (R)-salt is made in methanol and crystallized from isopropyl acetate. (S)-salt is made in tert-butylmethyl ether followed by trituration with diethyl ether. Another method for the preparation of (S)-salt uses diethyl ether as a solvent.
EP 639176 describes fast crystallization of salmeterol xinofoate by quenching hot organic solution of salmeterol xinofoate with cold organic solvent wherein particularly methanol, ethanol or isopropanol are used as organic solvents. The product is said to avoid the poor micronization properties associated with salmeterol xinofoate crystals.
WO 2007/045857 describes crystallization of salmeterol xinofoate from methanol at 25-30 °C followed by isolation at 10 °C. Isolation of salmeterol base is also described. It was obtained by precipitation of a gummy mass from ethyl acetate with 20 % yield. WO 2009/144193 describes a method of preparing crystalline salmeterol xinafoate by dissolving in methyl ethyl ketone followed by stepwise cooling (yield 91.3 %). The product has mean particle size of 11.5 μιη and it is said to be readily micronizable. WO 2012/032546 describes preparation of crystalline salmeterol xinafoate by dissolving salmeterol and l-hydroxy-2-naphthoate in acetone and precipitating the product by addition of methyl tert-butyl ether at 25 °C followed by filtering at 10 °C. The product was recrystallized from methanol and acetone resulting in total yield of about 51 %.
Salmeterol xinafoate is administered in dosage strength as low as 25 μg. In order to have it distributed deeply in the lungs via inhalation a small particle size is required such as about 2 - 5 μιη. Such small particle size is typically achieved by micronization process which requires good flowability properties. However, salmeterol xinafoate often tends to crystallize as a product which is poorly suitable for micronization process. Moreover, the synthesis of salmeterol is typically lengthy, results in low yield and purity and is associated with process impurities that may be cumbersome to remove from the end product. As the dosage strength is small it is important to have salmeterol in high purity. Finally, salmeterol base which is used in the preparation of xinafoate salt is often obtained as a gummy or oily product which is difficult to handle.
Therefore, there is a need to isolate salmeterol and its xinafoate salt in high purity, high yield and in a form which is easy to handle in subsequent processes such as micronization.
SUMMARY OF THE INVENTION
It has been found that salmeterol xinafoate can be isolated in high purity and yield and in easily micronizable form by crystallization from hot aliphatic ketone solvent such as methyl ethyl ketone using an antisolvent such as heptane or hexane. Recrystallizations are not needed to achieve sufficient purity. The essential feature of the invention is to maintain high temperature during the crystallization and isolation. Moreover, it was found that salmeterol base can be isolated in powdery form and in high purity and yield by crystallization from the mixture comprising aliphatic ether and heptane in a specific ratio.
DETAILED DESCRIPTION OF THE INVENTION
Salmeterol base may be synthetized by a method known in the art, e.g. as described in US 4992474. It has been found that salmeterol base can be isolated in powdery form and in high purity and yield by crystallization from the mixture comprising aliphatic ether and heptane in a specific ratio.
Such method for crystallizing salmeterol base comprises a) dissolving salmeterol base in a mixture of aliphatic ether and heptane under heating wherein the volume ratio of the aliphatic ether to heptane is from 40:60 to 80:20; b) cooling the mixture of step a); and c) isolating the precipitated salmeterol base.
According to one embodiment the volume ratio of the aliphatic ether to heptane is from about 45 :55 to about 75:25, more preferably from about 50:50 to about 70:30, for example about 60:40. Salmeterol base is suitably dissolved in the mixture of aliphatic ether and heptane by heating the mixture to the temperature which is from about 50 °C to the boiling point of the mixture, typically from 55 °C to 80 °C, for example from 60 to 70 °C, for example about 65 °C.
The solution of step a) is then cooled to the temperature where salmeterol base precipitates, suitably to 0 - 30 °C, for example to 10 - 25 °C, for example to 20 °C. The cooling is carried out slowly, suitably at the rate of 15 - 25 °C / hour, for example about 20 °C / hour. If desired the mixture can be seeded with salmeterol base crystals at the temperature of about 45 - 55 °C, for example at about 50 °C. The mixture is then suitably stirred in room temperature for about 0.5 to about 14 h, for example for about 1 to about 3 h. The precipitate can be easily isolated e.g. by filtering. The obtained salmeterol base product can be washed and dried in vacuum at about 40 - 60 °C for about 5 - 72 h, for example about 6 - 24 h to obtain salmeterol base in powder form. The aliphatic ether can be selected, for example, from cyclopentyl methyl ether, methyl tert-butylether, diisopropyl ether and combinations thereof. Cyclopentyl methyl ether and methyl tert-butylether are preferred aliphatic ethers. Cyclopentyl methyl ether is particularly preferred.
It has also been found that salmeterol xinafoate can be isolated in high purity and yield and in easily micronizable form.
The process for the preparation of crystalline salmeterol xinafoate comprises a) providing a hot solution of salmeterol base and l-hydroxy-2-naphthoic acid in aliphatic ketone solvent; b) adding antisolvent slowly to the hot solution; and c) isolating the precipitated salmeterol xinafoate from the hot solution; wherein the temperature of the hot solution in steps a) to c) is higher than 55 °C.
According to a preferred embodiment, the temperature of the hot solution in steps a) to c) is about 58 °C or higher, for example from about 58 °C to about the boiling point of the hot solution. According to a still more preferred embodiment, the temperature of the hot solution in steps a) to c) is from about 60 °C to about the boiling point of the hot solution, suitably from about 60 °C to about 73 °C, for example from about 60 °C to about 72 °C. According to one preferred embodiment, the temperature of the hot solution in steps a) to c) is 60 + 2 °C.
Thus, the term "hot solution" as used herein refers generally to solution having temperature higher than 55 °C, preferably about 58 °C or higher, for example from about 58 °C to about the boiling point of the hot solution, still more preferably from about 60 °C to about the boiling point of the hot solution, suitably from about 60 °C to about 73 °C, for example from about 60 °C to about 72 °C. The aliphatic ketone solvent comprises suitably aliphatic ketone with
0 to about 5 % of water, preferably from about 0.5 to about 3 % of water, more preferably from about 0.8 to about 2 % of water, for example from about 1 to about 1.5 % of water, by volume of the aliphatic ketone solvent. Water improves the solubility of salmeterol xinafoate in ketone and accordingly less solvent is needed. The concentration of salmeterol xinafoate in the solution of step a) is suitably 10 - 20 g/100 ml, for example 14 - 18 g/100 ml of aliphatic ketone solvent.
Salmeterol base and l-hydroxy-2-naphthoic acid can be dissolved directly in the hot aliphatic ketone solvent or the components can be mixed in lower temperature and the mixture heated to the desired temperature thereby dissolving salmeterol base and l-hydroxy-2-naphthoic acid.
The term "antisolvent" refers to an organic solvent that when mixed with the aliphatic ketone solvent in which salmeterol xinafoate is dissolved, reduces the capacity of the aliphatic ketone solvent to dissolve salmeterol xinafoate. Thus, when an antisolvent is admixed with a solution of salmeterol xinafoate in the aliphatic ketone solvent, the solubility of salmeterol xinafoate can be reduced to the point at which it precipitates out of solution. Preferred antisolvents are those in which salmeterol xinafoate is insoluble or only poorly soluble at temperature higher than 55 °C, particularly at temperature from about 60 °C to about 73 °C. Antisolvent is suitably added to the hot solution slowly, for example dropwise, while keeping the temperature of the hot solution essentially constant during the addition. The mixture can be seeded, if desired, with salmeterol xinafoate crystals after or during the addition of antisolvent. Alternatively, part of antisolvent is added before seeding and another part after seeding. The amount of antisolvent used in step b) is at least 93 %, suitably 100 - 150 %, by weight of the aliphatic ketone solvent. After all antisolvent has been added, the hot mixture can be stirred for example 0.5 - 18 h while keeping the temperature essentially constant. The hot mixture is then isolated suitably by filtering. The obtained crystalline salmeterol xinafoate can be washed and dried, for example in vacuum at about 40 °C for 6 - 72 h, for example 8 to 24 h, to obtain crystalline salmeterol xinafoate.
The aliphatic ketone can be selected from, for example, methyl ethyl ketone, acetone, methyl isobutyl ketone, ethyl butyl ketone, diethyl ketone, diisobutyl ketone and mixtures thereof. Preferably, methyl ethyl ketone is used.
The antisolvent can be selected from, for example, heptane, hexane or a mixture thereof. Preferably, heptane is used as an antisolvent.
Keeping sufficiently high temperature during the crystallization and isolation is essential for obtaining pure product and also for obtaining product which is well flowing and easy to micronize. Generally, the temperature during the crystallization and isolation is kept suitably at 58 °C or higher, but preferably below the boiling point of the solvent. For example, in case aqueous methyl ethyl ketone is used as a solvent, temperatures from 60 °C to 72 °C may be used.
Crystallization of salmeterol xinafoate is initiated using an antisolvent. When aqueous methyl ethyl ketone is used as a solvent and heptane is used as an antisolvent, the amount of heptane of about 93 - 150 %, by weight of the aqueous methyl ethyl ketone, e.g. 100 -130 %, may be used. During crystallization the impurities of salmeterol remain in the filtrate in dissolved form and pure salmeterol xinafoate product can be isolated. After isolation the precipitate is washed and dried in vacuum overnight. The dried product has good flowability and is easily micronizable. Bulk density is typically about 0.15 g/ml, tapped density typically about 0.27 g/ml and mean particle size about 25 μιη.
The invention is next illustrated by the following non-limiting examples.
EXAMPLES
Example 1. Preparation of salmeterol xinafoate Salmeterol free base (1.0 g) and l-hydroxy-2-naphthoic acid (0.475 g) were dissolved in a mixture of 1.3 % water in methyl ethyl ketone (9 ml) at 60 °C. Heptane (11 ml) was added slowly to the solution at 60 °C and the mixture was seeded. The mixture was stirred at 60 °C for 1 h and the precipitate was filtered from the hot solution and washed with heptane. The precipitate was dried at 40 °C overnight. Yield 94 %, purity 99.65 %, bulk density 0.15 g/ml, tapped density 0.27 g/ml, particle size distribution: di0: 7.580 μιη, d5o: 20.92 μιη, d9o: 44.04 μιη, mean volume particle size 24.70 μιη. Purity (area-%) of the product and the amount of impurities "D" and "rt 38 min" in the product were determined by HPLC. The impurity "rt 38 min" is a dimeric impurity and has the same molecular weight as the specified impurity G of the
European Pharmacopoeia. It is identified by retention time 38 min (rrt 1,97) by the HPLC-method described in the European Pharmacopoeia.
Reference examples 1-4 and Example 2 were carried out similarly to Example 1 using heptane addition temperatures and filtration temperatures given in Table 1. Table 1. Purity of salmeterol xinafoate prepared by varying the antisolvent addition temperature and the filtration temperature
Figure imgf000008_0001
* not fully dissolved The results show that using heptane addition temperature and filtration temperature of about 60-70 °C the amount of impurities reduced to a level required by the European Pharmacopoeia.
Example 3. Preparation of salmeterol base Oily evaporation residue of crude salmeterol base (purity 94 area-%) was dissolved in a mixture of cyclopentyl methyl ether (6 vol) and heptane (4 vol) at 65 °C. The solution was cooled to 20 °C at the rate of 20 °C/h. Seeding was carried out at 50 °C. The mixture was stirred at room temperature for 1 h. The precipitate was filtered and washed with cold cyclopentyl methyl ether (2 x 2.5 vol). The precipitate was dried in vacuum at 40 °C overnight to obtain the powdery product.
The effect of the solvent ratio on the yield and purity of the obtained salmeterol base product was further studied by repeating the method of Example 3 while changing the volume ratio of cyclopentyl methyl ether (CPME) : heptane. The results are shown in Table 2. Table 2. Effect of the solvent ratio on the yield and purity of the salmeterol base product
Volume ratio of Yield / % Purity / area-%
CPME : heptane
25 : 75 83 95.1
40 : 60 71 97.1
50 : 50 77.5 97.5
60 : 40 79 97.7
70 : 30 75 98.8
100 : 0 38 98.1 The results show that the combination of high yield and purity was obtained when the CPME : heptane volume ratio was between about 40 : 60 and 70 : 30.

Claims

1. A process for the preparation of crystalline salmeterol xinafoate comprising a) providing a hot solution of salmeterol base and l-hydroxy-2-naphthoic acid in aliphatic ketone solvent; b) adding antisolvent slowly to the hot solution; and c) isolating the precipitated salmeterol xinafoate from the hot solution; wherein the temperature of the hot solution in steps a) to c) is higher than 55 °C.
2. A process according to claim 1 wherein the temperature of the hot solution in steps a) to c) is about 58 °C or higher.
3. A process according to claim 2 wherein the temperature of the hot solution in steps a) to c) is from about 60 °C to about 73 °C.
4. A process according to claim 3 wherein the temperature of the hot solution in steps a) to c) is 60 °C ± 2 °C.
5. A process according to any of the previous claims wherein the aliphatic ketone solvent comprises aliphatic ketone with 0.1 to 5 % of water by weight of the aliphatic ketone solvent.
6. A process according to claim 5 wherein the aliphatic ketone solvent comprises aliphatic ketone with 0.5 to 3 % of water by weight of the aliphatic ketone solvent.
7. A process according to claim 6 wherein the aliphatic ketone solvent comprises aliphatic ketone with 0.8 to 2 % of water by weight of the aliphatic ketone solvent.
8. A process according to any of the previous claims wherein the amount of
antisolvent used in step b) is at least 93 % by weight of the aliphatic ketone solvent.
9. A process according to claim 8 wherein the amount of antisolvent used in step b) is 100 - 150 % by weight of the aliphatic ketone solvent.
10. A process according to any of the previous claims wherein the antisolvent in step b) is added drop wise.
11. A process according to any of the previous claims wherein the hot solution is seeded after the addition of antisolvent.
12. A process according to claim 11 wherein part of antisolvent is added before
seeding and another part after seeding.
13. A process according to any of the previous claims wherein the concentration of salmeterol xinafoate in the solution of step a) is 10 - 20 g/100 ml of the aliphatic ketone solvent.
14. A process according to claim 13 wherein the concentration of salmeterol xinafoate in the solution of step a) is 14 - 18 g/100 ml of the aliphatic ketone solvent.
15. A process according to any of the previous claims wherein the aliphatic ketone is methyl ethyl ketone.
16. A process according to any of the previous claims wherein the antisolvent is
heptane or hexane or a mixture thereof.
17. A process according to claim 16 wherein the antisolvent is heptane.
18. A process according to any of the previous claims wherein the salmeterol base used in step a) has been made by a method comprising a) dissolving salmeterol base in a mixture of aliphatic ether and heptane under heating wherein the volume ratio of the aliphatic ether to heptane is from 40:60 to 80:20: b) cooling the mixture of step a); and c) isolating the precipitated salmeterol base.
19. A process according to claim 18 wherein volume ratio of the aliphatic ether to heptane is from about 45:55 to about 75 :25.
20. A process according to claim 18 or 19 wherein the aliphatic ether is cyclopentyl methyl ether, methyl tert-butylether, diisopropyl ether or a combination thereof.
21. A process according to claim 20 wherein aliphatic ether is cyclopentyl methyl ether, methyl tert-butylether or a combination thereof.
22. A process according to claim 21 wherein aliphatic ether is cyclopentyl methyl ether.
23. A process for crystallizing salmeterol base comprising a) dissolving salmeterol base in a mixture of aliphatic ether and heptane under heating wherein the volume ratio of the aliphatic ether to heptane is from 40:60 to 80:20; b) cooling the mixture of step a); and c) isolating the precipitated salmeterol base.
24. A process according to claim 23 wherein volume ratio of the aliphatic ether to heptane is from about 45:55 to about 75 :25.
25. A process according to claim 23 or 24 wherein aliphatic ether is cyclopentyl methyl ether, methyl tert-butylether, diisopropyl ether or a combination thereof.
26. A process according to claim 25 wherein aliphatic ether is cyclopentyl methyl ether, methyl tert-butylether or a combination thereof.
27. A process according to claim 26 wherein aliphatic ether is cyclopentyl methyl ether.
PCT/FI2016/050138 2015-03-11 2016-03-08 Process for the preparation of crystalline salmeterol and its xinafoate salt WO2016142582A1 (en)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2140800A (en) 1983-04-18 1984-12-05 Glaxo Group Ltd Phenethanolamine derivatives
EP0422889A2 (en) 1989-10-10 1991-04-17 Glaxo Group Limited Phenethanolamine compounds
WO1992009557A1 (en) * 1990-11-29 1992-06-11 Glaxo Croup Limited Benzenedimethanol suitable for micronisation
WO2007045857A1 (en) 2005-10-17 2007-04-26 Generics (Uk) Limited Novel process
WO2009144193A1 (en) 2008-05-26 2009-12-03 Inke, S.A. Micronisable form of salmeterol xinafoate
WO2012032546A2 (en) 2010-09-08 2012-03-15 Cadila Healthcare Limited Process for the preparation of salmeterol and its intermediates
CN103864629A (en) * 2012-12-13 2014-06-18 天津金耀集团有限公司 Refining method of Salmeterol xinafoate

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2140800A (en) 1983-04-18 1984-12-05 Glaxo Group Ltd Phenethanolamine derivatives
US4992474A (en) 1983-04-18 1991-02-12 Glaxo Group Ltd. Phenethanolamine derivatives
EP0422889A2 (en) 1989-10-10 1991-04-17 Glaxo Group Limited Phenethanolamine compounds
WO1992009557A1 (en) * 1990-11-29 1992-06-11 Glaxo Croup Limited Benzenedimethanol suitable for micronisation
EP0639176A1 (en) 1990-11-29 1995-02-22 Glaxo Group Ltd Benzenedimethanol suitable for micronisation.
WO2007045857A1 (en) 2005-10-17 2007-04-26 Generics (Uk) Limited Novel process
WO2009144193A1 (en) 2008-05-26 2009-12-03 Inke, S.A. Micronisable form of salmeterol xinafoate
WO2012032546A2 (en) 2010-09-08 2012-03-15 Cadila Healthcare Limited Process for the preparation of salmeterol and its intermediates
CN103864629A (en) * 2012-12-13 2014-06-18 天津金耀集团有限公司 Refining method of Salmeterol xinafoate

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