Process for the preparation of cysteamine bitartrate and product so obtained

A process for purifying crude cysteamine bitartrate, comprising:

• h1) preparing a solution of crude cysteamine bitartrate (I) in water
• h2) pouring said water solution of crude cysteamine bitartrate (I) into 2-propanol, thus precipitating crystalline cysteamine bitartrate (I) from the admixture,
• h3) isolating crystalline cysteamine bitartrate (I) from the crystallization medium and, optionally,
• i) drying the isolated crystalline cysteamine bitartrate (I),
• to obtain pure cysteamine bitartrate (I).

A process for the preparation of crystalline anhydrous cysteamine bitartrate (I) polymorph L2 comprising:

• 1) contacting a cysteamine salt with a base in an aqueous medium at a pH of not less than 10.5, to obtain cysteamine free base of formula (I-B)
• 2) reacting in one-pot the cysteamine free base (I-B), in the same aqueous medium, with a compound of formula (III)
• R1-CO—R2 (III)
• in which R1 and R2 are each independently selected from H, linear or branched C1-C20 alkyl, optionally substituted C6-C20 aryl and optionally substituted heteroaryl,
• to obtain a crude thiazolidine of formula (II)
• in which R1 and R2 have the meanings reported above,
• 3) reacting the crude thiazolidine (II) with L(+)-tartaric acid in an aqueous medium, to obtain crude cysteamine bitartrate of formula (I)
• 4) precipitating the crude cysteamine bitartrate (I) from the aqueous medium from 3) by pouring it into 2-propanol optionally in admixture with water and then c) isolating the precipitated crude wet cysteamine bitartrate (I) from the aqueous medium,
• 5) preparing a solution of said crude wet cysteamine bitartrate (I) in water,
• 6) pouring said water solution of crude cysteamine bitartrate (I) into 2-propanol optionally in admixture with water thus precipitating crystalline cysteamine bitartrate (I),
• 7) isolating said crystalline cysteamine bitartrate (I) from the crystallization medium and
• 8) drying the isolated crystalline cysteamine bitartrate (I) up to a water content lower than 1.0% ww, measured by Karl-Fischer method,
• to obtain crystalline anhydrous cysteamine bitartrate (I) polymorph L2.

A process for the preparation of crystalline anhydrous cysteamine bitartrate (I) polymorph L2 comprising:

• 1) preparing a solution of cysteamine bitartrate (I) in water,
• 2) pouring said water solution of cysteamine bitartrate (I) into 2-propanol optionally in admixture with water thus precipitating crystalline cysteamine bitartrate (I) from the admixture,
• 3) isolating crystalline Cysteamine Bitartrate (I) from the crystallization medium, and,
• 4) drying the isolated crystalline cysteamine bitartrate (I), up to a water content lower than 1.0% ww, measured by Karl-Fischer method,
• to obtain crystalline anhydrous cysteamine bitartrate (I) polymorph L2.

A process for the preparation of crystalline monohydrate cysteamine bitartrate (I) polymorph L1 comprising:

• 1) contacting a cysteamine salt with a base in an aqueous medium at a pH of not less than 10.5, to obtain cysteamine free base of formula (I-B)
• 2) reacting one-pot the cysteamine free base (I-B), in the same aqueous medium, with a compound of formula (III)
• R1-CO—R2 (III)
• in which R1 and R2 are each independently selected from H, linear or branched C1-C20 alkyl, optionally substituted C6-C20 aryl, and optionally substituted heteroaryl,
• to obtain a crude thiazolidine of formula (II)
• in which R1 and R2 have the meanings reported above,
• 3) reacting the crude thiazolidine (II) with L(+)-tartaric acid in an aqueous medium, to obtain crude cysteamine bitartrate of formula (I)
• 4) precipitating the crude cysteamine bitartrate (I) from the aqueous medium from 3) by pouring it into 2-propanol and then c) isolating the precipitated crude wet cysteamine bitartrate (I) from the aqueous medium,
• 5) preparing a solution of said crude wet cysteamine bitartrate (I) in water,
• 6) pouring said solution of crude cysteamine bitartrate (I) in water into 2-propanol thus precipitating crystalline cysteamine bitartrate (I),
• 7) isolating said crystalline cysteamine bitartrate (I) from the crystallization medium and
• 8) drying the isolated crystalline cysteamine bitartrate (I) up to a water content from 7.0% to 8.0% ww, measured by Karl-Fischer method,
• to obtain crystalline monohydrate cysteamine bitartrate (I) polymorph L1.

A process for the preparation of crystalline monohydrate cysteamine bitartrate (I) polymorph L1 comprising:

• 1) preparing a solution of cysteamine bitartrate (I) in water,
• 2) pouring said water solution of cysteamine bitartrate (I) into 2-propanol optionally in admixture with water thus precipitating crystalline cysteamine bitartrate (I) from the admixture,
• 3) isolating crystalline cysteamine bitartrate (I) from the crystallization medium, and,
• 4) drying the isolated crystalline cysteamine bitartrate (I), up to a water content from 7.0% to 8.0% ww, measured by Karl-Fischer method,
• to obtain crystalline monohydrate cysteamine bitartrate (I) polymorph L1.

A crystalline anhydrous cysteamine bitartrate (I) polymorph L2 powder, said powder being characterized by

• a water content lower than 1.0%, measured by Karl-Fischer method,
• a volumetric particle size distribution (PSD), without micronization and after a pre-sieving with a sieve with openings of 600 microns, characterized by D50 not greater than 150 microns and D90 not greater than 250 microns,
• a bulk density from 0.28 g/ml to 0.35 g/ml, measured according to Ph. Eur. 2.9.34,
• a tapped density from 0.40 g/ml to 0.43 g/ml, measured according to Ph. Eur. 2.9.34 and/or
• a Hausner ratio from 1.30 to 1.55.

A one-pot process for manufacturing a thiazolidine of formula (II)

• in which R1 and R2 are independently selected from H, linear or branched C1-C20 alkyl, optionally substituted C6-C20 aryl, and optionally substituted heteroaryl that comprises:
• 1) contacting a cysteamine salt with a base in an aqueous medium at a pH of not less than 10.5, to obtain cysteamine free base of formula (I-B)
• 2) reacting in one-pot the cysteamine free base (I-B), in the same aqueous medium, with a compound of formula (III)
• R1-CO—R2 (III)
• in which R1 and R2 have the meanings reported above, thus providing the crude thiazolidine (II) and, optionally,
• 3) purifying the thiazolidine of formula (II).