Method for the preparation of cysteamine tartrate and resulting products

Abstract

The present invention relates to a new and improved process for the preparation of cysteamine tartrate (I) and its key intermediate thiazolidine (II). Furthermore, it relates to a new process for the preparation of crystalline anhydrous cysteamine tartrate (polymorph L2) and cysteamine tartrate monohydrate (polymorph L1). The crystalline anhydrous cysteamine tartrate thus obtained (polymorph L2) is characterized by a particularly fine particle size and good appearance.

Description

[Technical field]

[0001] The present disclosure relates to an improved process for the preparation of cysteamine tartrate and the resulting crystalline anhydrous stable polymorphic powder. [Background technology]

[0002] Cysteamine tartrate of formula (I) TIFF2025500525000002.tif52143(I) (MW227.24, C6H 13 NO6S) is a cystine-depleting agent that reduces cellular cystine content in patients with cystinosis, an inherited lysosomal transport disorder, indicated for the management of nephropathic cystinosis in children and adults.

[0003] According to the literature and the applicant's experience, it is not practical to prepare cysteamine tartrate starting from commercially available cysteamine hydrochloride by simple exchange of the chloride-tartrate counterion, but rather requires passing through cysteamine free base.

[0004] Thus, cysteamine tartrate is typically prepared by salification with L(+)-tartaric acid of the cysteamine free base, which is released from the cysteamine salt by basic treatment, starting from the hydrochloride salt, as illustrated in Scheme 1 below: Method 1 TIFF2025500525000003.tif37156

[0005] For example, US10251850 describes the preparation of cysteamine tartrate from cysteamine free base or its salts, starting from a specific cysteamine hydrochloride.Furthermore, this document describes the preparation of cysteamine tartrate crystalline polymorphs L1 and L2 by crystallization from methanol at -5 / -25°C and -25 / -30°C, respectively, and their analytical characterization.

[0006] US10221132 discloses the preparation of cysteamine tartrate (I) by starting from cysteamine hydrochloride, liberating the cysteamine free base with tributylamine, followed by salification with L(+)-tartaric acid (Example 5). Cysteamine tartrate is then crystallized from a mixture of methanol / 2-propanol (1:1).

[0007] Acta Cyst. (2013), 658-664, under the experimental section, describes the preparation and crystallization of cysteamine tartrate monohydrate by reacting cysteamine free base with L(+)-tartaric acid in a 1:1 ratio in ethanol.

[0008] One of the key problems in the above synthesis of cysteamine tartrate is obtaining and maintaining a high purity product, since cysteamine salt is unstable and easily oxidized to disulfide cystamine, especially in a basic environment or in the presence of metal ions (see, for example, Journal of Pharmaceutical Analysis 2020, 10 499-516, par. 3). In addition to not being pharmacologically active, cystamine is difficult to remove by extraction, crystallization or distillation, since its molecular weight and acid-base properties are similar to those of cysteamine.

[0009] In this respect, EP3842418A1 discloses a method for the purification of cysteamine or its salts from polysolfurica impurities, in particular cystamine, by treatment with dithiothreitol. Example 2 describes the purification of crude cysteamine tartrate containing 2.5% cystamine via dissolution in water and precipitation by addition of an antisolvent (2-propanol) to the aqueous solution. The resulting solid still contains 0.19% cystamine (HPLC).

[0010] Another method for the synthesis of cysteamine uses 2-substituted thiazolidines as convenient, purifiable and stable cysteamine precursors that are ring-opened under acidic conditions, e.g., with hydrohalic acid, HX, as shown in Scheme 2 below: Method 2 TIFF2025500525000004.tif34140

[0011] For example, GB 2054573A discloses reacting a 2,2-disubstituted thiazolidine with a mineral acid, such as HCl or HBr, in the presence of water to provide the corresponding cysteamine salt.

[0012] No. 5,017,725 describes the acid hydrolysis of the intermediate 2,2-disubstituted thiazolidine by reaction with ammonium or metal hydrogen sulfide with the mediated addition of a medium to strong acid, preferably hydrochloric acid, to provide cysteamine hydrochloride.

[0013] EP54409A1 relates to the preparation of 2-monosubstituted-thiazolidines, such as 2-phenylthiazolidine, and their use as intermediates in a number of preparation processes, including the preparation of cysteamine hydrochloride by ring opening with hydrochloric acid or an organic acid such as acetic acid or oxalic acid, which is then converted to the hydrochloride salt.

[0014] 2-Substituted thiazolidines can then be prepared from precursors such as ethanolamine derivatives, aldehydes and sulfur donors as described for example in EP 54409 A1, or possibly from cysteamine salts and ketones as described in the following documents under reported conditions: - CN106146427A, starting from cysteamine hydrochloride by reaction with acetone in cyclohexane at a pH of about 7 (see Example 1, soda dropwise until neutral); - Agric. Biol. Chem (1989), vol. 53, 8, 2273-2274, starting with an aqueous solution of cysteamine hydrochloride, brought to pH 6.2 by addition of dilute soda, which was then reacted with an aqueous methanolic solution of the selected aldehyde or ketone; - US 4,011,233, starting from cysteamine free base by reaction with an aldehyde or ketone; -J.Het.Chem.(2019),vol.56,1,180-187 and Chem.A Eur.J.(2019),vol.25,24,6113-6118, from cysteamine HCl in methanol or toluene under acid catalysis; -J.Agric. and food chemistry (1998), vol.46,1,224-227, A higher pH such as pH 10.3 in carbonate buffer is discouraged because it generates significant amounts of thiazoline by-products from cysteamine and aldehydes in phosphate buffer, preferably at pH 7.2 (see the last 5 lines of the right column on page 226 of the first paragraph).

[0015] In conclusion, according to the above mentioned state of the art, the preparation of cysteamine tartrate starting from the viable and cheap raw material cysteamine salt via the intermediate thiazolidine is rather long and has poor overall yields, since it completely comprises at least the following steps: - preparation of intermediate thiazolidines (II) from, for example, starting cysteamine or its salts by reaction with aldehydes or ketones under neutral or slightly acidic conditions followed by purification; - by hydrolysis of the thiazolidine, typically by ring opening with hydrohalic acid, to form and isolate the corresponding cysteamine salt; - release of cysteamine free base from the salt by treatment with base; - Cysteamine free base is salified with L(+)-tartaric acid to provide cysteamine tartrate (I), as summarized in Scheme 3 below: Method 3 TIFF2025500525000005.tif50156

[0016] A more simple preparation recently described is based on the direct ring-opening of an intermediate thiazolidine with L(+)-tartaric acid to provide cysteamine tartrate in fewer steps.

[0017] In this regard, "Improved Process for the Preparation of Cysteamine Tartrate" (Technical Disclosure Commons, Srinivasan Tirumala Rajang, MSN Laboratories Private Limited, R&D Centre, January 2021) and related patent application IN202041000697A describe the preparation of cysteamine tartrate by direct ring opening of substituted thiazolidines, in particular 2-methyl 2-ethyl-thiazolidine (Examples 8-9), with L(+) tartaric acid.

[0018] However, these methods show some drawbacks, especially for large-scale production: in fact, the crude 2,2-disubstituted thiazolidines prepared from ethanolamines by the formation of 2-aminoethyl hydrogen sulfate and subsequent reaction with ketones under acid catalysis contain undesirable by-products that interfere with the preparation, and as a result, the overall process yield and purity of the crude cysteamine tartrate are not entirely satisfactory, as confirmed in this experimental section.

[0019] These references (see Examples 6 and 10) also describe the preparation of polymorph M of cysteamine tartrate by addition of the antisolvent 2-propanol to an aqueous solution of crude cysteamine tartrate.

[0020] The addition of antisolvent to an aqueous solution of cysteamine tartrate is referred to herein as "direct" addition. According to the applicant's evaluation (see the experimental part, Example 10 and the comments below), the final crystalline powder obtained by direct addition may be endowed with non-optimal flow properties. Summary of the Invention

[0021] The Applicant envisages a particularly advantageous synthetic route with the aim of improving known processes for the preparation of cysteamine tartrate, with fewer and simpler steps, with few intermediate manipulations and purifications, and starting from the raw cysteamine salt, which provides cysteamine tartrate in high yield, high purity and, after crystallization under new conditions, an improved polymorph.

[0022] The overall method of the present invention is summarized in Scheme 4 below: Method 4 TIFF2025500525000006.tif73148

[0023] First, Applicants have identified particularly preferred conditions for the preparation of the intermediate 2,2-disubstituted-thiazolidines (II) and have discovered that the conventional reaction of a cysteamine salt with the requisite ketone, when carried out in one pot at highly basic pH, provides smooth ring closure to the thiazolidine at mild temperatures and in short times.

[0024] In a highly basic environment, the ring closure is fast, complete removal of water is not necessary, the presence of by-products is minimized, and the resulting thiazolidine is stable. Moreover, the high purity and stability of the 2,2-disubstituted-thiazolidine so prepared allows simple and fast isolation of the product by liquid / liquid separation instead of requiring longer purification procedures, which often imply high thermal stress, such as high temperature distillation. Advantageously, the starting thiazolidine (II) is obtained in high yield and purity and can be used directly in the subsequent reaction.

[0025] Further, the applicant has found that reaction of intermediate crude thiazolidine (II) prepared according to the present process with L(+)-tartaric acid directly provides cysteamine tartrate under the present process conditions, not only simplifying the process and significantly reducing the number of steps, but also providing crude cysteamine tartrate (I) in high purity and high yield. Thus, as demonstrated in the experimental section below, the overall process of the present invention is generally more advantageous than prior art processes, in particular over the technical disclosure commented above and the closest known synthetic route as shown in Indian patent application IN202041000697A.

[0026] Finally, the applicant has developed a method for crystallization of cysteamine tartrate, characterized by particle size and shape, which provides an advantageous crystalline anhydrous cysteamine tartrate (polymorph L2) powder. This powder of cysteamine tartrate of the present invention shows superior purity and stability compared to commercially available crystalline cysteamine tartrate batches prepared according to different synthetic routes and crystallized from other solvents, as shown in the experimental part.

[0027] In addition, the unique powder morphology obtained thanks to the crystallization conditions is characterized by the addition of an aqueous solution of cysteamine tartrate to the anti-solvent 2-propanol (referred to herein as "reverse addition"), providing a cysteamine tartrate powder with improved appearance, increased bulk density and finer particles compared to the product obtained according to the prior art by "direct addition". These powder characteristics predict better rheological properties, especially better flowability.

[0028] The object of the present invention is therefore a process for the preparation of crude cysteamine tartrate of formula (I), comprising the steps of: TIFF2025500525000007.tif50141(I) a) providing a thiazolidine of formula (II), TIFF2025500525000008.tif4240(II) (Wherein, R1 and R2 are independently selected from H, linear or branched C1-C20 alkyl, optionally substituted C6-C20 aryl, and optionally substituted heteroaryl.) b) reacting said thiazolidine (II) with L(+)-tartaric acid in an aqueous medium to provide crude cysteamine tartrate (I) in said aqueous medium; and c) isolating crude cysteamine tartrate (I) from said aqueous medium; wherein said thiazolidine of formula (II) is prepared in a one-pot process, d) providing a cysteamine salt; e) contacting the cysteamine salt with a base in an aqueous medium having a pH of 10.5 or greater to provide cysteamine free base of formula (IB); TIFF2025500525000009.tif3063(IB) f) reacting said cysteamine free base (IB) with a compound of formula (III) in the same aqueous medium; R1-CO-R2 (III) wherein R1 and R2 have the meanings reported above and therefore provide crude thiazolidine (II), and, optionally, g) purifying said crude thiazolidine of formula (II), method.

[0029] Preferably, the process for the preparation of crude cysteamine tartrate of formula (I) further comprises, after step b), a step h) of precipitating the crude cysteamine tartrate (I) by pouring said aqueous medium from step b) into 2-propanol (reverse addition) and then c) isolating the precipitated crude wet cysteamine tartrate (I) from the aqueous medium.

[0030] The above process may further comprise, after step c), step i) of drying the precipitated crude wet cysteamine tartrate (I), thereby providing crude cysteamine tartrate (I).

[0031] A further object of the present invention is a one-pot process for preparing the thiazolidine of formula (II) according to the above process, comprising the steps of: TIFF2025500525000010.tif4240(II) wherein R1 and R2 are independently selected from H, linear or branched C1-C20 alkyl, optionally substituted C6-C20 aryl, and optionally substituted heteroaryl. d) providing a cysteamine salt; e) contacting said cysteamine salt with a base in an aqueous medium with a pH of 10.5 or greater, preferably 11 or greater, more preferably 12 or greater, even more preferably 12.5 or greater, to provide cysteamine free base of formula (IB); TIFF2025500525000011.tif3063(IB) f) reacting the cysteamine free base (IB) with a compound of formula (III) in one pot in the same aqueous medium; R1-CO-R2 (III) wherein R1 and R2 have the meanings reported above, and thus provide said crude thiazolidine (II), and, optionally, g) purifying said crude thiazolidine of formula (II), One-pot method.

[0032] A further object of the present invention is a process for purifying crude cysteamine tartrate, preferably obtained according to the present invention, comprising the steps of: h1) providing an aqueous solution of crude cysteamine tartrate (I); h2) pouring said aqueous solution of crude cysteamine tartrate (I) into 2-propanol, optionally mixed with water (reverse addition), thus precipitating crystalline cysteamine tartrate (I) from the mixture; h3) isolating the crystalline cysteamine tartrate (I) from the crystallization medium, and preferably i) drying the isolated crystalline cysteamine tartrate (I), thus providing pure cysteamine tartrate (I); method.

[0033] A further object of the present invention is a process for the preparation of crystalline anhydrous cysteamine tartrate (I) (polymorph L2), comprising the steps of: d) providing a cysteamine salt; e) contacting said cysteamine salt with a base in an aqueous medium at a pH of 10.5 or greater, preferably 11 or greater, more preferably 12 or greater, even more preferably 12.5 or greater, to provide cysteamine free base of formula (IB); TIFF2025500525000012.tif3063(IB) f) reacting said cysteamine free base (IB) with a compound of formula (III) in one pot in the same aqueous medium; R1-CO-R2 (III) wherein R1 and R2 are independently selected from H, linear or branched C1-C20 alkyl, optionally substituted C6-C20 aryl, and optionally substituted heteroaryl, and thus a) providing a crude thiazolidine of formula (II), TIFF2025500525000013.tif4240(II) where R1 and R2 have the meanings reported above, b) reacting the crude thiazolidine (II) with L(+)-tartaric acid in an aqueous medium, thereby providing crude cysteamine tartrate of formula (I); TIFF2025500525000014.tif50141(I) h) precipitating the crude cysteamine tartrate (I) from the aqueous medium from step b) by optionally mixing it with water and pouring it into 2-propanol (reverse addition), and then c) isolating the precipitated crude wet cysteamine tartrate (I) from the aqueous medium; h1) providing an aqueous solution of the crude wet cysteamine tartrate (I); h2) pouring said aqueous solution of crude cysteamine tartrate (I), optionally mixed with water, into 2-propanol (reverse addition), thereby precipitating crystalline cysteamine tartrate (I); h3) isolating the crystalline cysteamine tartrate (I) from the crystallization medium; and i) drying the isolated crystalline cysteamine tartrate (I) to a water content of less than 1.0% ww, as determined by Karl Fischer method, thus providing crystalline anhydrous cysteamine tartrate (I) (polymorph L2), method.

[0034] A further object of the present invention is a process for the preparation of crystalline cysteamine tartrate monohydrate (I) (polymorph L1), comprising the steps of: d) providing a cysteamine salt; e) contacting the cysteamine salt with a base in an aqueous medium having a pH of 10.5 or greater to provide cysteamine free base of formula (IB); TIFF2025500525000015.tif3063(IB) f) reacting said cysteamine free base (IB) with a compound of formula (III) in one pot in the same aqueous medium; R1-CO-R2 (III) wherein R1 and R2 are independently selected from H, linear or branched C1-C20 alkyl, optionally substituted C6-C20 aryl, and optionally substituted heteroaryl, and thus a) providing a crude thiazolidine of formula (II), TIFF2025500525000016.tif4240(II) where R1 and R2 have the meanings reported above, b) reacting the crude thiazolidine (II) with L(+)-tartaric acid in an aqueous medium, thereby providing crude cysteamine tartrate of formula (I); TIFF2025500525000017.tif50141(I) h) precipitating the crude cysteamine tartrate (i) from the aqueous medium from step b) by pouring it into 2-propanol (reverse addition) and then c) isolating the precipitated crude wet cysteamine tartrate (i) from the aqueous medium; h1) providing an aqueous solution of the crude wet cysteamine tartrate (i); h2) pouring the aqueous solution of crude cysteamine tartrate (i) into 2-propanol (reverse addition), thereby precipitating crystalline cysteamine tartrate (i); h3) isolating the crystalline cysteamine tartrate (i) from the crystallization medium; and i) drying the isolated crystalline cysteamine tartrate (i) to a water content of 7.0% to 8.0% ww, as measured by Karl Fischer method, thus providing crystalline anhydrous cysteamine tartrate (I) (polymorph L1), method.

[0035] A further object of the present invention is a process for the preparation of crystalline anhydrous cysteamine tartrate (I) (polymorph L2), comprising the steps of: h1) providing an aqueous solution of cysteamine tartrate (I); h2) pouring said aqueous solution of cysteamine tartrate (I) into 2-propanol, optionally mixed with water (inverse addition), thus precipitating crystalline cysteamine tartrate (I) from the mixture, preferably by cooling; h3) isolating the crystalline cysteamine tartrate (I) from the crystallization medium; and i) drying the isolated crystalline cysteamine tartrate (I) to a water content of less than 1.0% ww, as measured by Karl Fischer method, thus providing crystalline anhydrous cysteamine tartrate (I) (polymorph L2); method.

[0036] A further object of the present invention is a process for the preparation of crystalline cysteamine tartrate monohydrate (I) (polymorph L1), comprising the steps of: h1) providing an aqueous solution of cysteamine tartrate (I); h2) pouring said aqueous solution of cysteamine tartrate (I), optionally mixed with water, into 2-propanol (inverse addition), thereby precipitating crystalline cysteamine tartrate (I) from the mixture, preferably by cooling; h3) isolating the crystalline cysteamine tartrate (I) from the crystallization medium; and i) drying the isolated crystalline cysteamine tartrate (I) to a water content of 7.0% to 8.0% ww, as determined by Karl Fischer method, thereby providing crystalline cysteamine tartrate monohydrate (I) (polymorph L1); method.

[0037] A further object of the present invention is a method for converting crystalline cysteamine tartrate monohydrate (I) (polymorph L1) into crystalline anhydrous cysteamine tartrate (I) (polymorph L2), comprising the steps of: drying crystalline cysteamine tartrate monohydrate (I) (polymorph L1) by heating at a temperature of at least 45° C. and preferably at a pressure of less than 200 mbar to a water content of less than 1.0% ww, preferably less than 0.5% ww, as measured by the Karl Fischer method; method.

[0038] A further object of the present invention is cysteamine tartrate obtainable according to any one of the processes of the present invention.

[0039] A further object of the present invention is a crystalline anhydrous cysteamine tartrate (I) (polymorph L2) powder, preferably obtainable according to the process of the present invention, said powder having Water content of less than 1.0% as measured by Karl Fischer method; A volumetric particle size distribution (PSD) of D50 not greater than 150 microns and D90 not greater than 250 microns, measured according to the method reported herein after pre-sieving through a sieve with 600 micron openings without micronization; a bulk density, measured according to Ph.Eur.2.9.34, of 0.28 g / ml to 0.35 g / ml, preferably about 0.30 g / ml; and / or a tap density, measured according to Ph.Eur.2.9.34, of 0.40 g / ml to 0.43 g / ml, preferably about 0.42 g / ml; and / or characterized by a Hausner ratio of 1.30 to 1.55, preferably about 1.40; powder. [Brief description of the drawings]

[0040] [Figure 1]Figure 1 shows the diffractogram of crystalline anhydrous cysteamine tartrate (I) (polymorph L2) from Example 4. The analysis was performed immediately after opening the vial at room conditions (T=22.2°C, RH=28.5%). [Diagram 2] FIG. 2 is a DSC thermogram of crystalline anhydrous cysteamine tartrate (I) (polymorph L2) of Example 4. [Diagram 3] FIG. 3 shows the DVS graph of crystalline anhydrous cysteamine tartrate (I) (polymorph L2) of Example 4. [Figure 4] FIG. 4 shows the 1H-NMR spectrum of the crystalline anhydrous cysteamine tartrate (I) of Example 4 (polymorph L2). [Diagram 5] FIG. 5 shows the 13C-NMR spectrum of the crystalline anhydrous cysteamine tartrate (I) (polymorph L2) of Example 4. [Figure 6] FIG. 6 shows the IR spectrum of the crystalline anhydrous cysteamine tartrate (I) (polymorph L2) of Example 4. [Figure 7] FIG. 7 shows the mass spectrum of crystalline anhydrous cysteamine tartrate (I) (polymorph L2) of Example 4. [Figure 8] FIG. 8 shows the XRPD diffractogram of cysteamine tartrate crystallized from water / 2-propanol by direct addition according to Example 10 of IN202041000697A after drying under vacuum at 30° C. (this Example 10B, polymorph M, monohydrate). [Figure 9] FIG. 9 discloses optical microscope images of A) cysteamine tartrate powder of Example 10A (E44-18-085) prepared according to the present invention and B) cysteamine tartrate powder of Example 10B (E44-18-095) prepared according to the prior art. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0041] The objects of the present invention are characterized by the following features, taken alone or in combination: The preferences expressed in the following description of intermediates, process step conditions, and products can be applied to the intermediates, conditions, and products of any embodiment of the invention.

[0042] The object of the present invention is therefore a process for the preparation of crude cysteamine tartrate of formula (I), comprising the steps of: TIFF2025500525000018.tif50141(I) a) providing a thiazolidine of formula (II), TIFF2025500525000019.tif4240(II) (Wherein, R1 and R2 are independently selected from H, linear or branched C1-C20 alkyl, optionally substituted C6-C20 aryl, and optionally substituted heteroaryl.) b) reacting said thiazolidine (II) with L(+)-tartaric acid in an aqueous medium to provide crude cysteamine tartrate (I) in said aqueous medium; and c) isolating crude cysteamine tartrate (I) from said aqueous medium; wherein said thiazolidine of formula (II) is prepared in a one-pot process, d) providing a cysteamine salt; e) contacting the cysteamine salt with a base in an aqueous medium having a pH of 10.5 or greater to provide cysteamine free base of formula (IB); TIFF2025500525000020.tif3063(IB) f) reacting said cysteamine free base (IB) with a compound of formula (III) in the same aqueous medium; R1-CO-R2 (III) wherein R1 and R2 have the meanings reported above and therefore provide crude thiazolidine (II), and, optionally, g) purifying said crude thiazolidine of formula (II), method.

[0043] In the process of the present invention, the thiazolidine of formula (I) has identical or different R1 and R2, preferably selected from H, C1-C3 alkyl, e.g. methyl, ethyl, propyl or isopropyl, C6-C10 aryl, e.g. phenyl or benzyl. Preferably at least one of R1 and R2 is different from H, more preferably R1 and R2 are both different from H, even more preferably R1 and R2 are selected from C1-C3 alkyl, most preferably R1 and R2 are both methyl.

[0044] The thiazolidine of formula (II) in step a) is prepared according to the method of the invention comprising steps d) to f) and, optionally, g) as described below. Preferably, the thiazolidine (II) in step a) has a purity of more than 70%, more preferably more than 80%, even more preferably more than 90%, as measured by GC according to the method described in this experimental part.

[0045] The thiazolidine of formula (II) and L(+)-tartaric acid are reacted in step b) in a stoichiometric ratio of preferably 1:1 to 1:2, more preferably 1:1 to 1:1.5, even more preferably 1:1 to 1:1.1, or most preferably about 1:1. As the skilled person knows, the same reaction can be carried out with D(-)-tartaric acid or (±)-tartaric acid, but is preferably carried out with L(+)-tartaric acid, since this optical isomer is a natural product, easily available, and inexpensive. The reaction of thiazolidine (II) with L(+)-tartaric acid can be carried out in suspension or, preferably, in solution.

[0046] Step b) of the process for the preparation of cysteamine tartrate (I) from thiazolidine (II) is carried out in an aqueous medium, which may comprise a mixture of water and at least a solvent.

[0047] The amount of water in the reaction medium will be at least the stoichiometric amount required for the hydrolytic opening of the thiazolidine ring, although preferably an excess of water is used and, more preferably, the aqueous medium consists of water.

[0048] The optional solvent may preferably be selected from alcohols such as methanol, ethanol, butanol, propanol, etc.; nitriles such as acetonitrile, propionitrile, butyronitrile, etc.; ethers such as tetrahydrofuran, dioxane, dimethoxyethane, etc.; esters such as ethyl acetate, ethyl acetoacetate, butyl acetate, propyl acetate, etc.; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, etc.; other polar solvents such as dimethylformamide, dimethylsulfoxide, and mixtures thereof.

[0049] Preferably, the concentration of thiazolidine (II) in the reaction medium in step b) is between 15 and 30% by weight, more preferably between 20 and 25% by weight, relative to the weight of the reaction medium.

[0050] Preferably, since cysteamine is readily oxidized to cystamine (the disulfide by-product 2,2'-dithio-bis-ethanamine), the treatment is carried out under an inert atmosphere, e.g., nitrogen or argon, and / or in the presence of an antioxidant, e.g., butylated hydroxyanisole, butylated hydroxytoluene, thiosulfates, and the like.

[0051] The applicant has found that the reaction of step b) carried out under acidic conditions, preferably at a pH of 2.0-5.0, more preferably at a pH of 3.5-4.0, and in an inert atmosphere, minimizes cystamine formation. Thus, the content of cystamine in crude cysteamine tartrate prepared according to the method of the present invention, as measured by HPLC as described in the methods of the experimental part, is preferably less than 1.0%, more preferably less than 0.5% or less than 0.3%.

[0052] In the present process, thiazolidine (II) can be used as a free base or as a salt. In the case of a salt, the thiazolidine free base can be released in advance or in situ by the addition of a suitable base prior to the addition of L(+)-tartaric acid.

[0053] Preferably, the thiazolidine of formula (II) and L(+) tartaric acid are reacted in step b) at a temperature between 40° C. and 55° C., more preferably between 48° C. and 52° C., preferably for at least 3 hours, more preferably about 3 hours to 5 hours.

[0054] Preferably, the reaction of step b) is completed by removing the compounds of formula (III) R1-CO-R2 produced in the hydrolysis, preferably by distillation for the low boiling compounds.

[0055] When R1-CO-R2 is acetone (R1 = R2 = CH3), the distillation is preferably carried out at a temperature below 50°C to prevent distillation of the starting thiazolidine (II).

[0056] Preferably, the removal of ketone (III) by distillation is repeated more than once, each time replacing the volume removed with an equivalent volume of medium, preferably water.

[0057] Finally, according to step c), the crude cysteamine tartrate can be isolated from the reaction residue by conventional work-up methods, such as removal of the aqueous solvent by evaporation, preferably forming an azeotrope with a suitable solvent to facilitate evaporation, as known in the art, or more preferably by extraction in an organic phase, followed by anhydrification of the solvent and concentration by distillation.

[0058] In one embodiment, according to the purification method object of the present invention comprising direct precipitation according to step h), preferably followed by steps h1 to h3), crude cysteamine tartrate is isolated from the aqueous reaction medium, preferably by one or more crystallizations, and then preferably dried according to step i) to provide first crude cysteamine tartrate and then pure crystalline cysteamine tartrate.

[0059] In a preferred embodiment of step c), the aqueous reaction medium from step b), after complete removal of the compound of formula (III) by distillation, is poured into 2-propanol (reverse addition) and crude cysteamine tartrate is directly precipitated from this mixture (step h).

[0060] Preferably, the volume ratio of 2-propanol to water at the end of the reverse addition of step h) above is between 10:1 and 2.5:1, more preferably between 5:1 and 2.8:1, even more preferably about 3:1.

[0061] Preferably, in step h), the concentration of crude cysteamine tartrate in the aqueous solution is from 520 to 330 g / kg, more preferably from 500 to 440 g / kg.

[0062] In this reverse addition of step h), 2-propanol may be mixed with small amounts of other solvents, such as for example less than 50%, 40%, 30%, 20%, 10% or 5% of polar solvents, such as water, nitriles or other short chain alcohols, such as ethanol, methanol, etc.

[0063] In one embodiment of step h), 2-propanol is not used in admixture with any other solvent.

[0064] The precipitated crude cysteamine tartrate can be separated from the medium by conventional techniques, such as filtration or centrifugation.

[0065] The crude wet cake of cysteamine tartrate (I) can be dried to provide crude cysteamine tartrate (I) or can be further purified by crystallization. In a preferred embodiment, the process provides a yield of typically at least 72 mol%, preferably at least 77 mol%, from thiazolidine (II) to crude cysteamine tartrate (I) obtained by direct precipitation from the reaction medium after distillation of the ketone (steps a)-i) as described above.

[0066] Crude cysteamine tartrate precipitated directly from a mixture of water and 2-propanol typically has a purity of at least 97%, preferably at least 98%, more preferably at least 99%, as measured by HPLC according to the methods described in this experimental section.

[0067] A preferred process for the preparation of crude cysteamine tartrate of formula (I) according to the present invention comprises: - the thiazolidine of formula (II) has R1=R2=methyl, - reacting the thiazolidine of formula (II) and L(+) tartaric acid in step b) in a molar ratio of 1:1 to 1:1.5, preferably 1:1 to 1:1.1, - reacting thiazolidine of formula (II) and L(+) tartaric acid in step b) at a temperature between 45°C and 55°C, characterised in that after complete removal of the compound of formula (III) by distillation, the crude cysteamine tartrate is isolated from the aqueous reaction medium from step b) by pouring said aqueous reaction medium into 2-propanol, thus directly precipitating the crude cysteamine tartrate.

[0068] A further object of the present invention is a process for preparing a thiazolidine of formula (II) comprising TIFF2025500525000021.tif4240(II) A useful intermediate for the preparation of cysteamine tartrate according to the present invention.

[0069] In the thiazolidine of formula (II), R1 and R2 are preferably independently selected from H, C1-C3 alkyl, such as methyl, ethyl, propyl or isopropyl, C6-C10 aryl, such as phenyl or benzyl. Preferably, at least one of R1 and R2 is different from H, more preferably R1 and R2 are both different from H, even more preferably R1 and R2 are selected from C1-C3 alkyl, and most preferably R1 and R2 are both methyl.

[0070] The present method for producing thiazolidine (II) comprises the steps of: d) providing a cysteamine salt; e) contacting the cysteamine salt with a base in an aqueous medium at a pH of 10.5 or greater to provide the cysteamine free base of formula (IB); TIFF2025500525000022.tif3063(IB) f) reacting cysteamine free base (IB) with the compound of formula (III) in the same aqueous medium in one pot; R1-CO-R2 (III) wherein R1 and R2 preferably have the meanings reported above and therefore provide a crude thiazolidine (II), and, optionally, g) purifying the thiazolidine of formula (II).

[0071] The starting cysteamine salt in step d) can be selected from inorganic or organic salts. Inorganic salts can be selected, for example, from hydrochloride, hydrobromide, hydroiodide, etc. Organic salts can be selected, for example, from formate, acetate, fumarate, propionate, butyrate, valerate, oxalate, maleate, citrate, glutarate, succinate, salicylate, etc.

[0072] Preferably, the cysteamine salt is selected from the hydrochloride, hydrobromide, hydroiodide salts, more preferably cysteamine hydrochloride.

[0073] Preferably, the cysteamine salt is suspended or preferably dissolved in an aqueous solvent, preferably selected from water, methanol, ethanol, 2-propanol and mixtures thereof, more preferably in water.

[0074] Preferably, the cysteamine salt is present in the reaction medium in a concentration ranging from 10 to 50% by weight, preferably from 15 to 30% by weight.

[0075] Unlike the previous method, in this method the pH of the reaction medium of step e) is greater than or equal to 10.5, preferably greater than or equal to 11, more preferably greater than or equal to 12, even more preferably greater than or equal to 12.5.

[0076] Unlike the previous method, in the present method, the pH of the reaction medium in step e) is 10.5 or more, preferably 11 or more, more preferably 12 or more, even more preferably 12.5 or more. Preferably, the pH of the reaction medium is 12-14, more preferably 12.5-13.5. Advantageously, a pH of 10.5 or more provides easy and fast ring closure to the desired thiazolidine (II). The applicant has observed that a lower pH can cause incomplete release of the cysteamine free base, which, in addition to causing a loss of yield, can also result in a lower purity of the desired thiazolidine due to side reactions. Indeed, due to incomplete cysteamine release, the resulting excess acetone can self-condense or provide other impurities such as thiazepine.

[0077] At the pH of the process of the present invention, the SH function of the cysteamine free base is also partially deprotonated. Moreover, at the pH values ​​of the process of the present invention, the thiazolidine is present as a free base that can be easily purified by simple direct extraction from the aqueous phase into the organic phase during processing.

[0078] Preferably, the base used to bring the pH of the reaction medium in step e) to a value greater than or equal to 10.5 is selected from organic bases such as NaOMe, NaOEt, NaOi-Pr, Et3N, (i-Pr)2NEt (DIPEA) or inorganic bases such as NaOH, Na2CO3, NaHCO3, more preferably the base is selected from NaOEt, Na2CO3 and NaOH, even more preferably NaOH.

[0079] In the present method, with respect to the cysteamine salt, the base is used in a molar ratio at least sufficient to completely release the cysteamine free base (IB) from the salt. Preferably, the base is used in excess, more preferably in a 10% molar excess, to provide a pH of the medium of 10.5 or greater, preferably 11 or greater, more preferably 12 or greater, even more preferably 12.5 or greater.

[0080] In this process, the cysteamine free base (IB) is not isolated but is reacted in situ, in the same aqueous medium, with the desired compound of formula (III) R1-CO-R2 (one-pot reaction) in process f).

[0081] Suitable aldehydes and ketones of formula R1-CO-R2 (III) are for example formaldehyde, acetaldehyde, acetone, methyl ethyl ketone, benzaldehyde, vanillin, preferably acetone.

[0082] Preferably, the molar ratio of R1-CO-R2 (III) to cysteamine is from 2:1 to 1:1, more preferably from 1.2:1 to 1:1, even more preferably from 1.1:1 to 1:1.

[0083] Preferably, the reaction is carried out at a temperature below 25° C., more preferably below 18° C., and most preferably between 10 and 15° C. Applicants have noted that temperatures above 25° C. increase the formation of by-products.

[0084] Preferably, the reaction is carried out under an inert atmosphere, for example under nitrogen, and / or in the presence of an antioxidant, for example sodium thiosulfate.

[0085] The final thiazolidine can be isolated from the reaction medium and optionally purified by conventional methods (step g).

[0086] Preferably, the aqueous reaction medium is extracted with a water-immiscible organic solvent, such as dichloromethane or cyclohexane, preferably cyclohexane, which is more selective than other solvents in extracting the desired product.

[0087] Preferably, prior to extraction, the aqueous phase is salted out by addition of a conventional salt such as NaCl to facilitate salting out and extraction of the thiazolidine into the organic phase.

[0088] Preferably, prior to removing the organic solvent by distillation, the organic phase is anhydrified by conventional techniques, e.g., by addition of sodium sulfate, etc. Applicants have observed that removing water prior to commencing the concentration and distillation operations is desirable to minimize decomposition of the final product.

[0089] The organic phase, after removal of the solvent by distillation, gives crude thiazolidine (II) which can be advantageously used as such in the preparation of cysteamine tartrate, without further purification, according to steps a) to c) of the present process.

[0090] Preferably, in order to minimize losses of thiazolidine and thus obtain a high yield and recycle the organic solvent, the distillation is carried out in two or more steps recovering the organic solvent separately from the azeotrope of the solvent and ketone (III) under temperature and pressure conditions that, as the skilled person will know, depend on the solvent and the ketone used in the particular reaction. Preferably, in the case of 2,2-dimethylthiazolidine, the distillation is carried out at a temperature below 40° C. and a pressure below 80 mbar.

[0091] Advantageously, the process is carried out at a pH of 10.5 or more, preferably 11 or more, more preferably 12 or more, even more preferably 12.5 or more, and provides a crude thiazolidine having unexpected purity and a thiazolidine content of at least 98%, preferably at least 99%, as measured by GC, as described in the experimental section.

[0092] Preferably, the process provides thiazolidine with a yield of more than 70%, more preferably more than 72%. The advantages of the process for the preparation of thiazolidine (II) and the thiazolidine (II) so obtained are evident from the experimental section which describes the prior art preparation of thiazolidine (II) and its conversion to crude cysteamine tartrate (see Examples 7A and 7C).

[0093] Preferred process conditions for the preparation and use of thiazolidine (II) in the preparation of crude cysteamine tartrate of formula (I) according to the present invention are: - the cysteamine salt of step d) is cysteamine hydrochloride, the pH of the aqueous medium of step e) is between 12.5 and 13.5, in step f) the compound of formula R1-CO-R2 (III) is acetone, - the reaction of step f) is carried out at a temperature below 25°C, - the crude thiazolidine (II) obtained from steps d) to f) is used as such in the preparation of crude cysteamine tartrate according to steps a) to c).

[0094] In a particularly preferred embodiment, the process for the preparation of thiazolidine (II) is carried out under the following conditions: a pH of about 13, a production temperature of 10-15° C., and a molar ratio of cysteamine hydrochloride to acetone of about 1:1.

[0095] A preferred overall process for the preparation of crude cysteamine tartrate of formula (I) from steps a) to i) according to the present invention comprises: - the cysteamine salt of step d) is cysteamine hydrochloride, the pH of the aqueous medium of step e) is between 12.5 and 13.5, the compound of formula R1-CO-R2 (III) in step f) is acetone, the reaction of step f) is carried out at a temperature below 25° C., the crude thiazolidine (II) obtained from steps d) to f) is used as such in the preparation of crude cysteamine tartrate according to steps a) to c), the thiazolidine of formula (II) has R1=R2=methyl; - the thiazolidine of formula (II) and L(+) tartaric acid are reacted in step b) in a molar ratio of 1:1 to 1:1.5, preferably 1:1 to 1:1.1, - isolating the crude cysteamine tartrate from the aqueous reaction medium from step b) by pouring said aqueous reaction medium directly into 2-propanol, after complete removal of the compound of formula (III) by distillation, thereby directly precipitating the crude cysteamine tartrate, It is characterized by:

[0096] The crude cysteamine tartrate prepared according to the present process is preferably further purified by crystallization to provide the desired pure crystalline cysteamine tartrate.Preferably, the purification is carried out according to the present invention by dissolving the crude cysteamine tartrate in water and then pouring this aqueous solution of cysteamine tartrate into 2-propanol (reverse addition, steps h1 and h2), followed by isolating the product (step h3) and preferably drying (step i).

[0097] Therefore, a further object of the present invention is a process for purifying crude cysteamine tartrate, preferably obtained according to the present invention, comprising: h1) providing an aqueous solution of crude cysteamine tartrate (I), h2) pouring said aqueous solution of crude cysteamine tartrate (I) into 2-propanol (reverse addition), thus precipitating crystalline cysteamine tartrate (I) from the mixture; h3) isolating the crystalline cysteamine tartrate (I) from the crystallization medium, preferably i) drying the isolated crystalline cysteamine tartrate (I), thus providing pure cysteamine tartrate (I).

[0098] In the present purification process, the aqueous solution of crude cysteamine tartrate (I) in step h1) can be directly the aqueous reaction medium of step b) above, an aqueous solution prepared by dissolution in water of the precipitated crude cysteamine tartrate isolated from step h) above, or any suitable aqueous solution of any crude cysteamine tartrate.

[0099] Preferably, the crude cysteamine tartrate (I) has an HPLC purity of at least 90%, preferably at least 95%, more preferably at least 97%.

[0100] Preferably, the volume ratio of 2-propanol to water at the end of the reverse addition of step h2) above is between 10:1 and 2.5:1, more preferably between 5:1 and 2.8:1, even more preferably about 3:1.

[0101] Preferably, the concentration of crude cysteamine tartrate in the aqueous solutions of steps h1) and h2) is 1100-500 g / l, more preferably 1000-800 g / l or 520-330 g / kg, more preferably 500-440 g / kg.

[0102] In this reverse addition of step h2), 2-propanol may be admixed with small amounts of other solvents, such as, for example, less than 50%, 40%, 30%, 20%, 10% or 5% of polar solvents such as water, nitriles or other short chain alcohols such as ethanol, methanol, etc.

[0103] Depending on the conditions of step i), the crystalline cysteamine tartrate wet cake is dried to provide crystalline cysteamine tartrate monohydrate (polymorph L1) or crystalline anhydrous cysteamine tartrate (polymorph L2).

[0104] Preferably, crystalline cysteamine tartrate (L1) is formed by heating the wet cake from step h3) at a temperature below 40°C, preferably below 35°C, preferably above 25°C, at a pressure below 200mbar, preferably below 100mbar, more preferably below 50mbar, preferably for a period of 2 to 24 hours.

[0105] Preferably, the crystalline cysteamine tartrate monohydrate (L1) is prepared by drying the wet cake to a moisture content of 7.0% to 7.5% ww, more preferably about 7.3% ww, as measured by the Karl Fischer method.

[0106] Water contents even higher than 8% are, of course, possible if the crystalline cysteamine tartrate monohydrate (L1) is not completely dried.

[0107] Preferably, crystalline anhydrous cysteamine tartrate (L2) is prepared by heating the wet cake from step h3) or the cake of crystalline cysteamine tartrate monohydrate (L1) at a temperature of at least 40°C, preferably at least 45°C, more preferably at least 50°C and not more than 70°C, preferably not more than 60°C, at a pressure of less than 200mbar, preferably less than 100mbar, more preferably less than 50mbar, preferably for 2 to 24 hours (step i). Preferably, crystalline anhydrous cysteamine tartrate (L2) is prepared by drying the wet cake to a moisture content of less than 1.0% ww, more preferably less than 0.9% ww or less than 0.5% ww, as measured by Karl Fischer method.

[0108] Advantageously, the above process can be used to purify crude cysteamine tartrate obtained according to the process of the present invention or any other process. The crystalline anhydrous cysteamine tartrate (I) has an HPLC purity of more than 98.0%, preferably more than 99.0%, more preferably more than 99.7%.

[0109] As used herein, the term "pure cysteamine tartrate" refers to cysteamine tartrate having an HPLC purity, measured according to the method reported in the experimental section, generally greater than 98.0%, preferably greater than 99.0%, more preferably greater than 99.7%.

[0110] A further object of the present invention is a process for the preparation of crystalline anhydrous cysteamine tartrate (I) (polymorph L2), comprising the steps of: d) providing a cysteamine salt; e) contacting said cysteamine salt with a base in an aqueous medium at a pH of 10.5 or greater, preferably 11 or greater, more preferably 12 or greater, even more preferably 12.5 or greater, to provide cysteamine free base of formula (IB); TIFF2025500525000023.tif3063(IB) f) reacting said cysteamine free base (IB) with a compound of formula (III) in one pot in the same aqueous medium; R1-CO-R2 (III) wherein R1 and R2 are independently selected from H, linear or branched C1-C20 alkyl, optionally substituted C6-C20 aryl, and optionally substituted heteroaryl, and thus a) providing a crude thiazolidine of formula (II), TIFF2025500525000024.tif4240(II) where R1 and R2 have the meanings reported above, b) reacting the crude thiazolidine (II) with L(+)-tartaric acid in an aqueous medium, thereby providing crude cysteamine tartrate of formula (I); TIFF2025500525000025.tif50141(I) h) precipitating the crude cysteamine tartrate (I) from the aqueous medium from step b) by optionally mixing it with water and pouring it into 2-propanol (reverse addition), and then c) isolating the precipitated crude wet cysteamine tartrate (I) from the aqueous medium; h1) providing an aqueous solution of the crude wet cysteamine tartrate (I); h2) pouring said aqueous solution of crude cysteamine tartrate (I), optionally mixed with water, into 2-propanol (reverse addition), thereby precipitating crystalline cysteamine tartrate (I); h3) isolating the crystalline cysteamine tartrate (I) from the crystallization medium; and i) drying the isolated crystalline cysteamine tartrate (I) to a water content of less than 1.0% ww, as determined by Karl Fischer method, thus providing crystalline anhydrous cysteamine tartrate (I) (polymorph L2), method.

[0111] Preferably, in step i), the isolated crystalline cysteamine tartrate (I) is dried to a moisture content of less than 0.9%, or less than 0.5% ww, as measured by the Karl Fischer method.

[0112] Preferably, in drying step i), the isolated crystalline cysteamine tartrate (I) is dried by heating at a temperature of at least 40°C, preferably at least 45°C, more preferably at least 50°C, but not exceeding 70°C, preferably not exceeding 60°C.

[0113] Preferably, in drying step i), the isolated crystalline cysteamine tartrate (I) is dried by heating at a pressure of less than 200 mbar, preferably less than 100 mbar, more preferably less than 50 mbar, even more preferably less than 10 mbar.

[0114] Preferably, in the drying step i), the isolated crystalline cysteamine tartrate (I) is dried by heating for 2 to 24 hours.

[0115] The preferences and conditions previously reported for the partial methods above, either alone or in combination, apply equally to this overall method.

[0116] The final crystalline anhydrous cysteamine tartrate (I) (polymorph L2) prepared according to this method typically has an HPLC purity of greater than 98%, preferably greater than 99%.

[0117] The purity of the final cysteamine tartrate can be further increased by repeating the crystallization method several times.

[0118] Due to the direct reaction of L(+)-tartaric acid with the intermediate thiazolidine (II) and the minimization of intermediate work-up and purification steps, the overall process for the preparation of cysteamine tartrate according to the present invention provides high yields.

[0119] The overall yield of the present process from cysteamine salt to crystalline anhydrous cysteamine tartrate (I) (polymorph L2) is typically at least 35 mol % ww, preferably at least 45 mol %, even more preferably at least 55 mol %.

[0120] Advantageously, inert gas can be applied throughout the synthesis process and even in packaging operations to preserve intermediate and final products from undesirable oxidative side reactions.

[0121] A further object of the present invention is a process for the preparation of crystalline cysteamine tartrate monohydrate (I) (polymorph L1), comprising the steps of: d) providing a cysteamine salt; e) contacting the cysteamine salt with a base in an aqueous medium having a pH of 10.5 or greater to provide cysteamine free base of formula (IB); TIFF2025500525000026.tif3063(IB) f) reacting said cysteamine free base (IB) with a compound of formula (III) in one pot in the same aqueous medium; R1-CO-R2 (III) wherein R1 and R2 are independently selected from H, linear or branched C1-C20 alkyl, optionally substituted C6-C20 aryl, and optionally substituted heteroaryl, and thus a) providing a crude thiazolidine of formula (II), TIFF2025500525000027.tif4240(II) where R1 and R2 have the meanings reported above, b) reacting the crude thiazolidine (II) with L(+)-tartaric acid in an aqueous medium, thereby providing crude cysteamine tartrate of formula (I); TIFF2025500525000028.tif50141(I) h) precipitating the crude cysteamine tartrate (i) from the aqueous medium from step b) by pouring it into 2-propanol (reverse addition) and then c) isolating the precipitated crude wet cysteamine tartrate (i) from the aqueous medium; h1) providing an aqueous solution of the crude wet cysteamine tartrate (i); h2) pouring the aqueous solution of crude cysteamine tartrate (i) into 2-propanol (reverse addition), thereby precipitating crystalline cysteamine tartrate (i); h3) isolating the crystalline cysteamine tartrate (i) from the crystallization medium; and i) drying the isolated crystalline cysteamine tartrate (i) to a water content of 7.0% to 8.0% ww, as measured by Karl Fischer method, thus providing crystalline cysteamine tartrate monohydrate (I) (polymorph L1), method.

[0122] Preferably, in the drying step i) the isolated crystalline cysteamine tartrate (I) is dried by heating to a moisture content of 7.0% to 7.5% ww, more preferably about 7.3% ww.

[0123] Preferably, in the drying step i), the isolated crystalline cysteamine tartrate (I) is dried by heating at a temperature below 40°C, more preferably below 35°C, preferably above 25°C.

[0124] Preferably, in the drying step i) the isolated crystalline cysteamine tartrate (I) is dried by heating at a pressure of less than 200 mbar, preferably less than 100 mbar, more preferably less than 50 mbar.

[0125] Preferably, in the drying step i), the isolated crystalline cysteamine tartrate (I) is dried by heating for 2 to 24 hours.

[0126] The same preferences in the conditions of steps h1) to i) described above or below apply here as well.

[0127] A further object of the present invention is a process for the preparation of crystalline cysteamine tartrate monohydrate (i) (polymorph L1), comprising the steps of: h1) providing an aqueous solution of cysteamine tartrate (I); h2) pouring said aqueous solution of cysteamine tartrate (I), optionally mixed with water, into 2-propanol (inverse addition), thereby precipitating crystalline cysteamine tartrate (I) from the mixture, preferably by cooling; h3) isolating the crystalline cysteamine tartrate (I) from the crystallization medium; and i) drying the isolated crystalline cysteamine tartrate (I) to a water content of 7.0% to 8.0% ww, as determined by Karl Fischer method, thereby providing crystalline cysteamine tartrate monohydrate (I) (polymorph L1); method.

[0128] A further object of the present invention is a process for the preparation of crystalline anhydrous cysteamine tartrate (I) (polymorph L2), comprising the steps of: h1) providing an aqueous solution of cysteamine tartrate (I); h2) pouring said aqueous solution of cysteamine tartrate (I) into 2-propanol, optionally mixed with water (inverse addition), thus precipitating crystalline cysteamine tartrate (I) from the mixture, preferably by cooling; h3) isolating the crystalline cysteamine tartrate (I) from the crystallization medium; and i) drying the isolated crystalline cysteamine tartrate (I) to a water content of less than 1.0% ww, as measured by Karl Fischer method, thus providing crystalline anhydrous cysteamine tartrate (I) (polymorph L2); method.

[0129] The same preferences in the conditions of steps h1) to i) described above or below apply here as well.

[0130] The crystallization methods of cysteamine tartrate described in the prior art used methanol (US10251850), a mixture of methanol and 2-propanol (US10221132), ethanol (Acta Cryst. 2013, 658-664) or 2-propanol added as anti-solvent to an aqueous mixture (direct addition, IN202041000697A) as the crystallization solvent.

[0131] The commercially available anhydrous cysteamine tartrate referred to in Example 5 was crystallized from ethanol, whereas the product of Example 10B was crystallized from 2-propanol / water (direct addition) (comparative product).

[0132] The applicant has conducted experimental studies and found that polymorph L1 of cysteamine tartrate described in US10251850 corresponds to polymorph of cysteamine tartrate monohydrate, also characterized in Acta Cryst. (2013), C69, 658-664 as polymorph M and IN202041000697A, while polymorph L2 of cysteamine tartrate described in US10251850 is an anhydrous polymorph.

[0133] Advantageously, the present crystallization method results in crystalline cysteamine tartrate of superior purity, stability and improved powder appearance. In particular, the present crystallization method by inverse addition of an aqueous solution of cysteamine tartrate to 2-propanol removes impurities very effectively and provides a powder with better properties when compared to previous powders, especially when compared to the powder obtained by direct addition of 2-propanol as described above.

[0134] As used herein, the terms "polymorph" and "polymorph powder" both refer to crystalline polymorphic solid forms.

[0135] According to the present crystallization process, in step h1), said solution of cysteamine tartrate (I) in water can be either the same aqueous reaction medium containing crude cysteamine tartrate (I) obtained after step b) of the present process, or any other aqueous solution of cysteamine tartrate freshly prepared from isolated crude or partially purified cysteamine tartrate.

[0136] In one embodiment, said aqueous solution is prepared by isolating crude cysteamine tartrate (I) from said aqueous reaction medium after steps b) and c), and subsequently dissolving the isolated crude cysteamine tartrate (I) in water.

[0137] In step h1) of the crystallization method, the concentration of cysteamine tartrate (I) in the aqueous solution before contact with 2-propanol is preferably 1100-500 g / l, more preferably 1000-800 g / l (g of product per liter of solvent), or 520-330 g / Kg, more preferably 500-440 g / Kg (g of product per kg of mixture).

[0138] In one embodiment, in step h1) of the process, cysteamine tartrate (I) is dissolved in water, preferably at a temperature below 60° C., more preferably at a temperature between 45 and 55° C., preferably by heating.

[0139] According to the method, the solution of cysteamine tartrate in water in step h1) can be prepared by dissolving cysteamine tartrate in any form or by forming cysteamine tartrate in situ, for example from cysteamine and L(+) tartaric acid, preferably in a molar ratio of 1:2 to 1:1, more preferably in equimolar amounts.

[0140] Preferably, the solution of cysteamine tartrate in water of step h1) can be prepared starting from the isolated cysteamine tartrate of step h3), or more preferably by directly using the reaction aqueous medium containing crude cysteamine tartrate obtained from step b).

[0141] According to the present crystallization method, in step h2), an aqueous solution of cysteamine tartrate, optionally mixed with water, is contacted by inverse addition with 2-propanol, whereby crystalline cysteamine tartrate (I) is precipitated, preferably by cooling.

[0142] Preferably, at the end of the reverse addition of step h2), the volume ratio of 2-propanol to water in the crystallization mixture of step h2) is from 10:1 to 2.5:1, more preferably from 5:1 to 2.8:1, even more preferably about 3:1.

[0143] The crystallization mixture may contain small amounts of other solvents, but the solvent mixture preferably consists of 2-propanol and water, preferably in the ratios specified above.

[0144] In step h2), the aqueous solution of cysteamine tartrate, optionally mixed with water or small amounts of other solvents as described above (reverse addition), is poured into 2-propanol, thereby providing, after isolation and drying to a water content of less than 1% by weight, a powder of crystalline anhydrous cysteamine tartrate (I) (polymorph L2) which is particularly fine, non-sticky and has improved appearance.

[0145] Preferably, the addition of the aqueous solution back into the 2-propanol is done slowly, over a period of time that depends on the scale of the reaction, but can range from 30 minutes to 2 hours or more. Preferably, the mixture is kept under vigorous stirring during the addition. Applicants have noted that slow addition with vigorous stirring advantageously provides a non-sticky powder having a low particle size.

[0146] In one embodiment, particularly for recrystallization of crystalline highly pure cysteamine tartrate to further increase purity, the reverse addition of the aqueous solution is performed to a mixture of 2-propanol and water.

[0147] Preferably, precipitation of the desired crystalline form is facilitated by seeding with pure crystals of that form, such as crystals of crystalline anhydrous cysteamine tartrate (I) (polymorph L2).

[0148] Crystalline cysteamine tartrate may be precipitated from the mixture of step h2) by cooling to a temperature preferably between 15 and 35°C, more preferably between 15 and 25°C, even more preferably between 18 and 22°C.

[0149] In step h3) of the process, the crystalline cysteamine tartrate can be isolated from the crystallization mixture by applying one or more conventional techniques known in the art, such as filtration, concentration, removal of the solvent by evaporation, distillation, centrifugation, decantation, cooling, flash evaporation, rotary evaporation, etc.

[0150] Preferably, the isolated crystalline cysteamine tartrate is dried in step i) by conventional techniques, for example in an oven under vacuum at a residual pressure of 200 mbar, preferably 100 mbar, more preferably 50 mbar, at 25-60° C. for 2-24 hours.

[0151] Depending on the drying conditions, it is possible to obtain monohydrate or anhydrous cysteamine tartrate with a water content of 7.0%-8.0% ww or less than 1.0% ww, respectively, as determined by Karl Fischer method.

[0152] According to the present invention, one or more of steps h1), h2), h3) and i) may advantageously be carried out under an inert atmosphere, such as under nitrogen.

[0153] The dried crystalline anhydrous cysteamine tartrate can preferably be sieved to remove coarse particles, if present (e.g., particles having at least one dimension above 600 microns), and / or can be micronized in accordance with conventional techniques to provide finer particles of a size more suitable for the particular end use.

[0154] A particularly preferred method for preparing crystalline anhydrous cysteamine tartrate (I) (polymorph L2) according to the present invention is: h1) providing an aqueous solution of cysteamine tartrate (I) in water having a concentration of 1100-800 g / l or 500-440 g / kg of cysteamine tartrate (I); h2) contacting said solution of cysteamine tartrate (I) in water with 2-propanol in a volume ratio of 2-propanol to water of 11:1 to 3:1; The contact may include: - slowly adding said aqueous solution of cysteamine tartrate (I) to 2-propanol (reverse addition) at a temperature between 20 and 35°C under stirring, preferably for at least 1 hour, - preferably maintaining under stirring for at least 30 minutes at a temperature between 30 and 35°C, then cooling, preferably at a temperature between 18 and 22°C, preferably for about 2 hours, keeping under stirring at -18 to 22°C, preferably for at least 16 hours, thus precipitating crystalline cysteamine tartrate (I); h3) isolating the crystalline cysteamine tartrate from the crystallization medium; i) The isolated crystalline cysteamine tartrate (I) is dried to a water content of less than 1.0% ww as determined by Karl Fischer method, thereby obtaining crystalline anhydrous cysteamine tartrate (I) (polymorph L2).

[0155] The duration of addition of the aqueous solution, the temperature and time of decomposition and precipitation indicated above provide an improved crystalline powder morphology, with better filterability and flowability upon visual inspection.

[0156] Advantageously, crystalline anhydrous cysteamine tartrate (I) (polymorph L2), when prepared according to the process of the present invention by pouring an aqueous solution of cysteamine tartrate into 2-propanol (reverse addition), is in the form of a particularly fine powder, finer than the powders obtained from other conventional solvent mixtures.

[0157] A further object of the present invention is a process for converting crystalline cysteamine tartrate monohydrate (I) (polymorph L1) into crystalline anhydrous cysteamine tartrate (I) (polymorph L2), comprising drying the crystalline cysteamine tartrate monohydrate (I) (polymorph L1) by heating at a temperature of at least 45°C and preferably at a pressure of less than 200 mbar to a water content of less than 1.0% ww, preferably less than 0.5% ww, as measured by the Karl Fischer method. With regard to the conversion step i), the temperature to which the crystalline cysteamine tartrate monohydrate (I) (polymorph L1) is heated is preferably at least 50°C. Preferably, the heating temperature is not more than 70°C, more preferably not more than 60°C.

[0158] Heating is preferably carried out at a pressure of less than 100 mbar, more preferably less than 50 mbar, even more preferably less than 10 mbar, for a period of preferably 2 to 24 hours.

[0159] Heating is preferably carried out to a moisture content of less than 0.9% or 0.5% ww, as measured by the Karl Fischer method.

[0160] A further object of the present invention is cysteamine tartrate obtainable according to any one of the processes of the present invention.

[0161] In particular, a further object of the present invention is a crystalline anhydrous cysteamine tartrate (I) (polymorph L2) powder, preferably obtainable according to the process of the present invention, said powder having a volumetric particle size distribution (PSD) after pre-sieving through a sieve with 600 micron openings, preferably having a D50 less than or equal to 100 microns and a D90 less than or equal to 150 microns, measured according to the method reported in the experimental part; Water content less than 0.5% as determined by Karl Fischer method; a bulk density measured according to PhEur 2.9.34 of 0.29 g / ml to 0.32 g / ml, preferably about 0.30 g / ml; a tap density measured according to PhEur 2.9.34 of 0.41 g / ml to 0.43 g / ml, preferably about 0.42 g / ml; a Hausner ratio of 1.30 to 1.45, preferably about 1.40; It is characterized in that:

[0162] The powders of the invention are made of particles characterized by a small particle size (granulometry), advantageously obtained without the need for any micronization, have a uniform distribution and have a particle shape (morphology) particularly suitable for pharmaceutical applications. As is known in the art, the technical properties of powders (bulk density, flowability, surface area, etc.) and their areas of application strictly depend on the particle properties.

[0163] In a preferred embodiment, the crystalline anhydrous cysteamine tartrate (I) (polymorph L2), preferably prepared according to the inverse addition method of the present invention (steps h1 to h3 followed by drying in step i), does not require micronization and has, after pre-sieving through a sieve with 600 micron openings, a volumetric particle size distribution (PSD) characterized by a D50 of 150 microns or less and a D90 of 250 microns or less, preferably a D50 of 100 microns or less and a D90 of 150 microns or less, measured according to the method reported in the experimental part.

[0164] Preferably, sieving is carried out using a sieve with 600 micron openings to remove coarse particles.

[0165] The powder of crystalline anhydrous cysteamine tartrate (I) (polymorph L2) obtained by the present inverse addition method is non-sticky and shows improved appearance. Furthermore, the powder properties e morphology predict better filterability, stirrability, stability and flowability, which are of great value for drug development.

[0166] The bulk density of a powder is the ratio of the mass of an unused powder sample to its volume. It depends on both the density of the powder particles and the spatial arrangement of the particles in the powder bed. Preferably, the crystalline anhydrous cysteamine tartrate (I) (polymorph L2) powder is characterized by a bulk density, measured according to Ph.Eur2.9.34, of more than 0.28 g / ml, more preferably more than 0.29 g / ml, even more preferably more than 0.30 g / ml.

[0167] Preferably, the crystalline anhydrous cysteamine tartrate (I) (polymorph L2) powder is characterized by a tap density of 0.40 g / ml to 0.43 g / ml, preferably about 0.42 g / ml, measured according to Ph.Eur.2.9.34.

[0168] Preferably, the crystalline anhydrous cysteamine tartrate (I) (polymorph L2) powder is characterized by a Hausner ratio of 1.30 to 1.55, preferably about 1.40.

[0169] Preferably, the crystalline anhydrous cysteamine tartrate (I) (polymorph L2) powder of the present invention is obtained according to the present preparation and crystallization method.

[0170] The crystalline anhydrous cysteamine tartrate (I) (polymorph L2) has been characterized by XRPD, DSC, DVS, IR, UV, 1 H-NMR, 13 The compound was analyzed by C-NMR, mass spectrometry and HPLC.

[0171] The present crystalline anhydrous cysteamine tartrate (I) (polymorph L2) is - an X-ray powder diffraction pattern having characteristic diffraction peaks as shown in Figure 1; - a characteristic DSC peak at about 122°C, measured according to the method and conditions reported in this experimental part, as shown in Figure 2; -Characteristic DVS graph shown in Figure 3; -Characteristics shown in Figure 4 1 H-NMR spectrum; -Characteristics shown in Figure 5 13 C-NMR spectrum; - an IR spectrum based on the IR spectrum of standard crystalline anhydrous cysteamine tartrate shown in FIG. 6; and - the mass spectrum shown in Figure 7, It is characterized by:

[0172] The crystalline anhydrous cysteamine tartrate (I) (polymorph L2) obtained according to the present process is a white crystalline powder, preferably characterized by one or more of the following properties: Melting point in the range of -118 to 122°C, preferably 120 to 122°C The water content measured by the Karl Fischer method is 1.0% or less, preferably 0.8% or less. - total impurity content at release of max. 1.5% by HPLC, preferably max. 1.0%, more preferably max. 0.5%; - A volumetric particle size distribution (PSD) without micronization and after preliminary sieving using a sieve with 600 micron openings to remove coarse particles, characterized by a D50 less than or equal to 150 microns and a D90 less than or equal to 250 microns, preferably a D50 less than or equal to 100 microns and a D90 less than or equal to 150 microns, measured according to the method reported in the Experimental Section.

[0173] According to DVS analysis (see FIG. 3), the present crystalline anhydrous cysteamine tartrate (I) (polymorph L2) began to convert to a hydrate form at 25% RH and 25° C., yielding 7.5% w / w water (approximately 1 mol HO).

[0174] Thus, the present crystalline anhydrous cysteamine tartrate (I) (polymorph L2) is stable and does not rapidly convert to a hydrate form when stored at a temperature below 25°C and under an atmosphere having a RH% below 25% ww.

[0175] The crystalline anhydrous cysteamine tartrate (I) of the present invention (polymorph L2) can be advantageously stored for long periods of time, according to the stability data reported in this experimental part, where the impurity content and profile remain constant.

[0176] The present crystallization method provides cysteamine tartrate (I) as an anhydrous crystalline polymorph L2 with improved purity, stability, bulk density and particle size distribution.

[0177] Without being bound to any particular theory, the applicant believes that the high purity of the crystalline cysteamine tartrate and the crystallization conditions of the method of the present invention likely affect the solid state properties resulting in very fine particles, in particular preventing the formation of particle agglomerates and keeping the particle size distribution constant over time.

[0178] Applicants have realised that the present crystalline anhydrous cysteamine tartrate (I) (polymorph L2) prepared according to the present method is characterised by a remarkable stability of powder properties over time.

[0179] Applicants speculate that the advantageous particle size distribution stability of the present crystalline anhydrous cysteamine tartrate (I) (polymorph L2) powder, in terms of the absence of aggregates over other cysteamine tartrate polymorph L2 powders, may result from, for example, a different form or different impurity profile of the present crystalline anhydrous cysteamine tartrate (I) (polymorph L2) (e.g., different types and / or amounts of impurities as shown in the present experimental part, Example 5), which, at the crystalline level, reduces the tendency of the particles to aggregate.

[0180] As one skilled in the art would know, these differences may relate to the presence or absence in the final product of certain by-products or solvents, which may depend primarily on the specific synthesis and / or crystallization methods.

[0181] Furthermore, the smaller particle size of the present crystalline anhydrous cysteamine tartrate (I) (polymorph L2) powder obtained by the reverse addition method may also result in a lower tendency of the powder to aggregate, which may be associated with a better dissolution profile compared to prior art powders.

[0182] The present invention is further illustrated by the following representative examples, which are provided for purposes of illustration only.

[0183] Experimental part Analysis method Cysteamine tartrate determination: The titration with potassium iodate was carried out according to European Pharmacopoeia 2.2.20 under the following conditions: A potassium iodate 0.1N solution (3.567 g potassium iodate already dried to a constant volume at 110° C. and 1000 ml water) was prepared.

[0184] 500.0 mg of sample was weighed into a 250 ml flask. 100 ml of water, 10 ml of sulfuric acid 3.6N, 1.0 g of KI and 2.0 ml of starch solution were added to the flask. The solution was titrated with potassium iodate solution to the end point (light blue persistent color for more than 30 seconds). In parallel, a blank titration was performed.

[0185] 1.0 ml of the 0.1 N potassium iodate solution was equivalent to 22.72 mg of cysteamine tartrate. Assay % = {[(Vc-Vb) x 22.72 x N] / [mg sample x 0.1]} x 100 where: Vc = volume of potassium iodate solution used to titrate the sample Vb = volume of potassium iodide solution used to titrate the blank N = normality of potassium iodate solution

[0186] Free tartaric acid (TA assay) was evaluated by titration with NaOH and potassium iodide. Free tartaric acid was calculated by the difference between the volume title with 3 t.q. KIO and the title with NaOH 0.1 N according to the following formula: Free tartaric acid = (Assay NaOH% - Assay KIO3) / 2

[0187] If the KIO3 assay was higher than the sodium hydroxide assay, free cysteamine was present.

[0188] Cysteamine, cystamine and impurity content by HPLC Cysteamine and impurity content was assessed by HPLC according to the European Pharmacopeia.2.2.29 method using the following conditions: Chromatography Systems Column: Alltima C18 LL, l=250mm, Φ=4.6mm, 5μm or equivalent Column temperature: 25°C, Mobile phase A: 380 ml water, 300 ml acetonitrile, 320 ml methanol and 1.4 ml H3PO4 85%; stirred to obtain a clear solution, then added 11.52 g sodium dodecyl sulfate; Mobile phase B: Acetonitrile Flow rate: 1.4 ml / min; Detector: UV at 210 nm; Run time: 35 min; Injection volume: 20 μl The gradients reported in Table 1 below:

[0189] [Table 1] and elution times are as shown in Table 2:

[0190] [Table 2]

[0191] solution a. Test solution: Prepared by dissolving approximately 100.0 mg of sample in 5.0 ml of water. b. Cystamine 2-HCl reference solution (0.1%) was prepared by dissolving approximately 150.0 mg of cystamine 2-HCl in 200.0 ml of water (cystamine 2-HCl standard mother liquor). 2.0 ml of this solution was then diluted to 50.0 ml with water. c. Cystamine 2-HCl standard solution (0.5%) was prepared by diluting 2.0 ml of Cystamine 2-HCl standard solution to 10.0 ml with water. d. Cysteamine reference solution (0.10%) was prepared by dissolving approximately 100.0 mg of working standard in a 5 ml volumetric flask and bringing to volume with water for HPLC. 1.0 ml of this solution was diluted to 100.0 ml with water, then 1 ml of this final solution was diluted to 10.0 ml with water. (Comparison 0.02 mg / ml).

[0192] 2,2-Dimethylthiazolidine Assay by Gas Chromatography The purity of 2,2-dimethylthiazolidine was assessed by GC according to the following method and conditions: Capillary column: Ultra 2 or equivalent; stationary phase: 5% phenyl, 95% dimethylpolysiloxane; column length 25 m; column diameter 0.32 mm; film thickness 0.52 μm; column temperature: 50 °C to 280 °C at 10 °C / min, 2 min at 280 °C; injector temperature 200 °C; detector temperature 290 °C; carrier P helium = 50 KPa; internal standard solution: 0.4 ml toluene diluted to 250 ml with methanol; reference standard solution: 100 mg 2,2-dimethylthiazolidine diluted to 25 ml with internal standard solution; injection: 0.5 μl.

[0193] water content The water content was determined by the Karl Fischer method on 250.0 mg of the product using standard methanol with added N-ethylmaleimide according to the European Pharmacopoeia (2.5.12.), the water content having been previously determined.

[0194] X-ray powder diffraction (XRPD): Range 3~40°2θ; 3~80°2θ X-ray powder diffraction patterns were recorded at room temperature on an X'Pert PRO PANalytical Instrument, Application SW with Cu Kα radiation (λ=1.54060 Å), run at 45 kV and 40 mA, and a single continuous scan in reflection mode. To avoid conversion of crystalline anhydrous cysteamine tartrate polymorph L2 to the monohydrate polymorph L1, sample preparation and analysis were performed at temperatures below 25° C. and RH% below 25%.

[0195] Differential scanning calorimetry (DSC): Range 20-350°C, Speed: 10°K / min; Instrument: Mettler Toledo DSC1

[0196] Dynamic Vapor Sorption (DVS): Range 0-90% RH, Process: 5% RH, Equipment Type: SMS-DVS specific, Temperature 25°C

[0197] Melting Range The apparatus (Buchi 545-B or equivalent) is preheated to 108° C., and after reaching 113° C., the capillary tube containing the product is inserted and the temperature is increased at 1° C. / min until complete melting (decomposition).

[0198] Infrared absorption spectrum Attenuated total reflectance (ATR) method, PerkinElmer Spectrum 2 instrument, range 650-4000 cm -1 .

[0199] drying loss Weight loss of the samples was assessed by drying 1.00 g of material under vacuum at 60° C. for 3 h according to the method described in the European Pharmacopoeia (2.2.32).

[0200] Particle size distribution The particle size distribution was evaluated according to European Pharmacopoeia 2.9.31 using an instrument according to the sample preparation and test conditions reported in Table 3 below:

[0201] [Table 3]

[0202] 1 H NMR spectrum :The nuclear magnetic resonance spectrum of cysteamine tartrate in DMSO was recorded on a Bruker CAB AV4 400 MHZ NMR spectrometer.

[0203] 13 C NMR spectrumNMR 13 C spectrum of cysteamine tartrate in DMSO was recorded on a Bruker CAB AV4 400 MHZ NMR spectrometer.

[0204] MS spectrum : Mass spectra of cysteamine tartrate were performed on a Thermo Fisher LCQ-Fleet by dissolving the sample in methanol using ESI (+) ionization technique.

[0205] Bulk and tapped density : Measured according to the method of the Pharmacopoeia (PhEur.2.9.34). 100g of sample was weighed and then placed in a test tube and the apparent volume was recorded without any kind of treatment on the sample. After that, using an automatic volumetric meter (model: Schleuniger JV2000, instrument code: CE9), 10, 500 and 1250 taps were made and the apparent volumes obtained in these three tests were recorded. If the difference in the volumes obtained for the 500 and 1250 taps was more than 2ml, the operation was repeated by 1250 taps until the difference in the measurements was less than 2ml. For each batch, the test was performed twice.

[0206] The bulk density and tapped density were calculated according to the following formulas: Bulk density: δ0=m / V0(g / ml) where m is the weighed amount of sample in grams and V is the apparent uncompressed volume in milliliters. Tap density: δ=m / V 1250 (g / ml) or δ=m / V 2500 (g / ml) Here, V 1250 and V 2500 is the compressed apparent volume at 1250 and 2500 taps.

[0207] Optical microscopeThe powders were observed with an Optech SL Dual trinocular stereomicroscope equipped with polarized light, camera Optech 318CU 3.2M CMOS (photo software: Micrometrics SE Premium). The samples were observed directly under the microscope without further preparation.

[0208] Preparation of Cysteamine Tartrate Cysteamine tartrate was prepared according to the steps reported in Scheme 5 below: Method 5 TIFF2025500525000032.tif166170

[0209] Example 1 Preparation and workup of 2,2-dimethylthiazolidine(II). In this example, cysteamine hydrochloride (I-HCl) was reacted with acetone in the presence of sodium hydroxide and sodium thiosulfate to provide 2,2-dimethylthiazolidine (II) as shown below.

[0210] The starting material, cysteamine hydrochloride (I-HCl), was prepared according to J Chem Soc. C, (1967), 1373-1376 (HPLC purity approximately 99.0%).

[0211] A first reactor (800 l) equipped with stirrer, reflux condenser and distillation apparatus was charged with purified water (128 l) and sodium thiosulfate pentahydrate (606 g, 2.44 mol) and purged with vacuum / nitrogen three times while stirring.

[0212] Cysteamine hydrochloride (I-HCl, 80 kg, 0.704 Kmol) was added under stirring and the mass was cooled to about 10-15° C. while maintaining nitrogen flow.

[0213] A solution containing purified water (72 L, 0.9 vol to I-HCl), sodium hydroxide (31 Kg, 0.775 Kmol) and sodium thiosulfate pentahydrate (513 g, 2.07 mol) was prepared in a second reactor (500 L) and cooled to about 5-10° C. This solution was then added slowly to the first reactor while maintaining the temperature at 10-23° C.

[0214] After stirring for at least 10 min, the pH in the first reactor was checked (pH of about 13 by litmus paper) and the solution was cooled to 10-15 °C.

[0215] Acetone (43 Kg, 0.740 Kmol) was pre-cooled at 10-15 °C and added with stirring at 14-18 °C for the other 2 h at least 1 h.

[0216] Sodium chloride (3.8 Kg, 0.065 Kmol) and cyclohexane (237 Kg, 3.8 vol. to I-HCl) were then charged into the first reactor with stirring at 14-18° C. for 15 minutes and then it was allowed to stand for 20 minutes.

[0217] The aqueous phase was removed and the organic cyclohexane phase containing the product was sent to a third reactor, where anhydrous sodium sulfate (1.6 Kg, 0.011 Kmol) was added and the mixture was stirred at 15-20°C for at least 1 hour, then filtered through a filter filled with 6.4 Kg of anhydrous sodium sulfate.

[0218] The filter was washed with cyclohexane (13 Kg). The combined dry organic phase was distilled under vacuum at a pressure decreasing from 250 to 80 mbar without exceeding 50°C to minimize product loss by evaporation. Acetone (34 l) was added to the distillation residue containing 2,2-dimethylthiazolidine in cyclohexane and distilled again under the same conditions.

[0219] Removal of the acetone / cyclohexane mixture provided a residue of 2,2-dimethylthiazolidine (II) as a colorless liquid (Yield: 74%, 60.7 kg at 100%).

[0220] Analysis: IR spectrum is equivalent to the reference standard spectrum, and GC purity is 98.5%.

[0221] Example 2 Preparation of crude cysteamine tartrate (I) from 2,2-dimethylthiazolidine (II) 85.7 Kg of L(+)-tartaric acid (0.57 Kmol) and 120 L of purified water were placed in a first reactor and stirred under nitrogen until completely dissolved. After three vacuum / nitrogen flushes, crude 2,2-dimethylthiazolidine (II) (60.7 Kg at 100%, 0.518 Kmol) prepared according to Example 1 was added to the solution. The aqueous mass was heated to 48-52°C and held under these conditions for at least 3 hours.

[0222] Acetone formed as a reaction by-product was removed in the next step by distillation under vacuum without exceeding 50° C. First, 36 l of the solvent mixture was distilled off and then the reactor was charged with purified water (34 l).

[0223] The process was then repeated until the acetone was completely removed, each time distilling approximately 21 liters of the solvent mixture and replenishing with 17 liters of water.

[0224] In a second reactor, 2-propanol (364 l) and crystalline anhydrous cysteamine tartrate (I) (polymorph L2) (10 g) were charged as seeds and then degassed with vacuum / nitrogen cycles.

[0225] The cysteamine tartrate aqueous solution previously prepared in the first reactor was then transferred into the second reactor under stirring for at least 1 hour while maintaining the temperature at 20-35°C.

[0226] The first reactor was washed with 8.6 liters of water and the wash was sent to the second reactor.

[0227] The mass in the second reactor was stirred at 30-35° C. for at least 30 minutes and then cooled to 18-22° C. in about 2 hours. It was then maintained under stirring at 18-22° C. for at least 16 hours. The slurry was centrifuged and washed twice with a mixture of 15 liters of water and 45 liters of 2-propanol.

[0228] The cake was removed to obtain wet crude cysteamine tartrate, and a sample of the wet crude cysteamine tartrate was dried overnight under vacuum (about 3 mbar) at 30° C. and submitted for XRPD analysis to obtain crude monohydrate cysteamine tartrate (polymorph L1). The remaining cake was dried under vacuum at 40÷60° C. to a final moisture content of less than 2% ww, thereby providing crude anhydrous cysteamine tartrate polymorph L2 (XRPD analysis). After drying at 40-60° C., 102 Kg of crude cysteamine tartrate was obtained with a yield of about 87 mol % to 100% 2,2-dimethylthiazolidine.

[0229] Analysis: The crude cysteamine tartrate was characterized as shown in Table 4 below:

[0230] [Table 4]

[0231] key: 1 pH was measured potentiometrically using a solution of 100 mg of sample dissolved in 10 ml of water; HPLC purity is expressed as area percentage (peak area / total area x 100); DMT: 2,2-dimethylthiazolidine

[0232] As can be seen from Table 4, the crude cysteamine tartrate already had high HPLC purity and low cystamine content (0.04%).

[0233] After drying at 40–60 °C, the predominant crystalline form observed in the diffractogram of crude cysteamine tartrate corresponded to polymorph L2.

[0234] Example 3: Crystallization test Several cysteamine tartrate crystallization tests were performed on approximately 100 g of product using the following solvents and conditions: Example 3a Cysteamine tartrate was dissolved in water and EtOH was added dropwise to the aqueous solution of cysteamine tartrate as an antisolvent. Poor yields were obtained due to the high solubility of the product in the water-EtOH crystallization mixture. Example 3b -Cysteamine tartrate was dissolved in water and added dropwise to the aqueous solution of cysteamine tartrate using 2-propanol as a poor solvent. A sticky solid was obtained that was difficult to handle. Example 3c -Cysteamine tartrate was dissolved in one volume of water at about 50° C., and then the concentrated solution was added dropwise onto a solution of 2-propanol and water at room temperature for about 1 hour with vigorous stirring. The product immediately began to precipitate.

[0235] After the addition was completed, the suspension under stirring was warmed to 30-35°C to improve the crystal morphology, homogenized, cooled and further kept at 20°C under stirring, thus providing an easily filtered and washed crystal morphology.

[0236] Example 4 Scale-up preparation of crystalline anhydrous cysteamine tartrate (polymorph L2) by crystallization from 2-propanol-water (reverse addition) A glass-lined reactor (500 L) equipped with stirrer, reflux condenser and distillation apparatus was charged with crude cysteamine tartrate (100 kg, 0.44 Kmol) prepared according to Example 2 and purified water (100 L). The reactor was vacuum / nitrogen flushed three times and then heated at 48-52°C under stirring for at least 30 min until complete dissolution.

[0237] A second reactor was charged with 2-propanol (525 l), purified water (50 l) and crystalline anhydrous cysteamine tartrate (polymorph L2) (10 g) as seeds, washed with vacuum / nitrogen three times and then the mass was heated to 20-35°C.

[0238] The solution in the first reactor was transferred to the second reactor under stirring for at least 1 hour while maintaining the temperature at 20-35° C. The first reactor was washed with 10 l of purified water, which was then added to the mass in the second reactor.

[0239] The mass in the second reactor was stirred at 30-35°C for at least 30 minutes, cooled to 18-22°C in about 2 hours and then kept stirring at 18-22°C for at least 16 hours.

[0240] The slurry was centrifuged and washed twice with a mixture of 15 L of purified water and 45 L of 2-propanol.

[0241] The cake was removed to give wet cysteamine tartrate (100 kg).

[0242] The wet cysteamine tartrate was charged into a dryer and dried under vacuum at 40-60°C, about 25 mbar to a moisture content of less than 0.5% ww and finally sieved through a sieve having 600 micron openings to provide 72.5 Kg of crystalline anhydrous cysteamine tartrate (yield from DMT to crystalline anhydrous cysteamine tartrate: 62 mol %; crystallization yield: 78.9 mol %). The final properties of the product are summarized in Table 5 below:

[0243] [Table 5] na:Not rated

[0244] The crystalline anhydrous cysteamine tartrate prepared as described above in Example 4 was analyzed by XRPD, DSC, DVS, 1 H-NMR, 13 Further analysis was performed by C-NMR, IR and mass spectrometry (see Figures 1 to 9).

[0245] Thermal analysis by DSC showed endothermic transitions at approximately 56, 121, 160, and 190° C. due to small amounts of water loss, melting, and subsequent decomposition above 140° C., as shown in FIG.

[0246] The XRPD analysis showed no significant differences compared to the XRPD spectrum of polymorph L2 published in US10251850, as evident from the spectrum in FIG.

[0247] 1 H-NMR spectra, chemical shifts and spectral assignments of hydrogen at 400 MHz in DMSO-d6 are reported in Table 6 below:

[0248] [Table 6]

[0249] The crystalline anhydrous cysteamine tartrate obtained by the method of the present invention 1 The H-NMR spectrum is shown in Figure 4.

[0250] at 100 MHz in DMSO-d6 13 The chemical shifts and spectral assignments of the carbons in the C-NMR spectra are reported in Table 7 below:

[0251] [Table 7]

[0252] The crystalline anhydrous cysteamine tartrate obtained by the method of the present invention 13 The C-NMR spectrum is shown in Figure 5.

[0253] The infrared absorption spectrum of the crystalline anhydrous cysteamine tartrate obtained by the method of the present invention exhibits a maximum, as shown in FIG.

[0254] The full scan mass spectrum (range 50-300 m / z) of the crystalline anhydrous cysteamine tartrate obtained by the method of the present invention shows the quasimolecular ion of cysteamine, [M+H]+, with m / z of 78.

[0255] The mass spectrum of the crystalline anhydrous cysteamine tartrate obtained by the method of the present invention is shown in FIG.

[0256] DVS analysis 0%-90%, step 5% DVS analysis was performed on a sample of anhydrous cysteamine tartrate prepared according to Example 4 to assess at what RH% the conversion to the hydrate form had begun. A plot of the water sorption isotherm is shown in Figure 3. The hydration process started at 25% RH and ended at 35% RH, and it can be seen that the sample gained 7.5% w / w water (compatible with 1 mol of water) during this process. XRPD analysis performed on the sample after the DVS analysis confirmed that it had been converted to the hydrate form.

[0257] Example 5 :Stability test Cysteamine tartrate batches (three batches for testing) prepared according to Example 4 were subjected to stability testing as described below. - long term stability : Stability samples were stored under controlled conditions at 25±2°C and 60±5% RH packaged in the same container type as for shipping, in accordance with current ICH stability guidelines.

[0258] At six month intervals, volumetric assays (on anhydrous or dried basis), HPLC related substances, and loss on drying or water content by Karl Fischer were evaluated on the three batches according to previously reported methods, with the results shown in Tables 8A-8C below:

[0259] [Table 8A] NMT: Below

[0260] [Table 8B]

[0261] [Table 8C] The long-term stability data reported above in accordance with ICH guidelines for stability indicates that no significant degradation has occurred after 36 months.

[0262] -Accelerated stability test: Stability samples will be stored under controlled conditions at 40±2°C and 75±5% RH and packaged in the same container type as will be shipped in accordance with current ICH stability guidelines.

[0263] At three month intervals, the three batches were evaluated for volumetric analysis, HPLC related substances and loss on drying according to previously reported methods, with the results shown in Tables 9A-9C below:

[0264] [Table 9A]

[0265] [Table 9B]

[0266] [Table 9C]

[0267] Accelerated stability data reported above in accordance with ICH guidelines for stability indicates that no significant degradation has occurred after 6 months.

[0268] Example 6: Comparison of crystalline anhydrous cysteamine tartrate prepared according to the present invention with commercially available cysteamine tartrate

[0269] In this study, three batches of crystalline anhydrous cysteamine tartrate prepared according to Example 4 (Recordati R1-R3) were analyzed in comparison with three batches of commercially available cysteamine tartrate (Comparative C1-C3).

[0270] Commercially available cysteamine tartrate was crystallized from ethanol.

[0271] The approved specifications, analyses and results for the batches according to the invention and the comparative batches are summarized in Table 10 below:

[0272] [Table 10]

[0273] Key: OK means compliant; ND: not detectable; § 2% aqueous solution (500 mg sample in 25 ml water).

[0274] As can be seen from Table 10 above, the three batches R1 to R3 of cysteamine tartrate according to the invention always complied with the specification, whereas comparative examples C1 to C3 showed out-of-spec results for melting point, assay (dry basis), cystamine and free tartaric acid content.

[0275] Concerning PSD, the commercial batches only partially met the requirement of D50<150 microns, whereas the batches according to the invention always met all PSD specifications.

[0276] In conclusion, compared to the commercial comparative product, the cysteamine tartrate of the present invention has higher HPLC purity, longer stability (up to at least 36 months) and, unlike the commercial comparative batch, has a particle size distribution that is 100% in accordance with the specification.

[0277] The crystalline anhydrous cysteamine tartrate of the present invention, thanks to its high purity and also thanks to the particular small size of the particles which makes unnecessary further micronization steps, is particularly stable and, when stored in a sealed dark container under inert gas, is capable of maintaining its characteristic analytical parameters unchanged and complying with the accepted standard regulatory requirements for up to more than 36 months and even longer.

[0278] Example 7 : Preparation of crude cysteamine tartrate according to IN202041000697A (Comparative Example) Crude cysteamine tartrate (I) was prepared following the procedure described in Examples 7-9 of Indian Patent Application IN202041000697A.

[0279] Example 7A: Preparation of 2-aminoethyl sulfate hydrogel (Example 7 of IN202041000697A) TIFF2025500525000044.tif30156 method 6

[0280] Sulfuric acid (1.1 equiv, 96.5 ml) was added slowly to a pre-cooled mixture of toluene (6 volumes, 600 ml), ethanolamine (100 g), and tetra-n-butylammonium bromide (0.19 equiv, 100 g) at 10-15 °C, the mixture was stirred at 25-30 °C for 15 min, and then heated at reflux temperature with stirring overnight. The reaction mixture was cooled at 25-30 °C and 2-propanol was added at 25-30 °C (4 volumes) and stirred. The precipitated solid was filtered, washed with 2-propanol (1 volume), slurried in 2-propanol (5 volumes) at room temperature for 2 h, and finally filtered to give the title compound (92% yield). 1 H-NMR detected only the title compound.

[0281] Example 7B Preparation of 2-ethyl-2-methylthiazolidine (Example 8 of IN202041000697A) Method 7 TIFF2025500525000045.tif35156

[0282] Sodium hydroxide (1.0 eq., 76.0 g) was added to a mixture of 2-aminoethyl hydrogen sulfate (268 g) obtained in Example 7A, aqueous sodium hydrosulfide (2.0 eq., 213 g, in 4 volumes of water), and methyl ethyl ketone (4 eq., 680 ml) at 25-30°C with stirring. Paratoluenesulfonic acid monohydrate (0.1 eq.) was added at 25-30°C, then the mixture was heated to 80-85°C and kept stirring at the same temperature overnight. The mixture was then cooled at 25-30°C, stirred, filtered, and washed with methyl ethyl ketone. The organic layer was separated and the aqueous phase was extracted with methyl ethyl ketone. The combined organic layers were washed with aqueous sodium hydroxide and then with aqueous sodium chloride. Finally, the solvent of the organic layer was completely distilled off to obtain the title compound (60% yield). On the final compound 1 H-NMR detected 5% w / w MEK.

[0283] By comparing the results of this process for the preparation of 2,2-disubstituted thiazolidines with the one according to the invention of Example 1, carried out under highly basic conditions and with cysteamine instead of 2-aminoethyl hydrogen sulfate as starting material, it becomes clear that the process according to the invention is advantageous both in terms of yield and purity (yield: 74% vs. 60%; GC purity: 98% vs. 93%).

[0284] Example 7C Preparation of crude cysteamine tartrate monohydrate (Example 9 of IN202041000697A)

[0285] 2-Methyl 2-ethyl thiazolidine (1 eq. 100 g) prepared in Example 7B was added under nitrogen for 30 min at 25-30° C. to a solution of L-(+)-tartaric acid (1.1 eq. 126 g) in 2-propanol (11.2 vol. 1120 ml) and water (2.2 vol. 220 ml) prepared at 25-30° C. and stirred at the same temperature. The mixture was stirred overnight and the precipitated solid was filtered, washed with 2-propanol (1 vol. 100 ml) and dried under vacuum (approx. 3 mbar) at 30° C. overnight (HPLC purity 95.5%) (yield: 70%).

[0286] Example 8: using 2,2-dimethylthiazolidine (DMT) instead of 2-methyl-2-ethylthiazolidine (MET) as the starting material; Preparation of crude cysteamine tartrate as described in IN202041000697A (Example 9).

[0287] Crude cysteamine tartrate was prepared according to the same procedure as in Example 7C, except starting with 100 g of 2,2-dimethylthiazolidine (DMT) prepared according to Example 1. The final crude cysteamine tartrate showed an HPLC purity of 98.5% (yield: 85%).

[0288] Example 9 Using 2-methyl-2-ethylthiazolidine (MET) from Example 7B as starting material, Preparation of crude cysteamine tartrate according to the present invention.

[0289] Crude cysteamine tartrate was prepared following the same procedure as in Example 2, but starting from 2-methyl-2-ethylthiazolidine (MET) prepared according to Example 7B. The final crude cysteamine tartrate showed an HPLC purity of 95.6% (yield: 65%).

[0290] Both the crude cysteamine tartrate obtained according to Example 7C and Example 9 contained cystamine (RRT 3.3, HPLC % 3.9-4.0).

[0291] Because cystamine was difficult to remove by crystallization from water / 2-propanol (see Table 12), it was important to avoid or minimize its presence in the crude cysteamine tartrate, for example, by using the present DMT as the thiazolidine instead of MET in Example 7B. The results of the above experiments are summarized in Table 11 below:

[0292] [Table 11] Key: THIAZ: thiazolidine; TA: tartaric acid; DMT: 2,2-dimethylthiazolidine; MET: 2,2-methylethyl-thiazolidine; INV: invention; COMP: comparison; CB cysteamine tartrate; cystamine (RRT 3.3 min); nd: undetectable.

[0293] According to the above data, the process for preparing crude cysteamine tartrate according to the present invention (Example 2) provided the best yield and purity.

[0294] In particular, comparing the results of Example 7C and Example 8, it appears that the chemical purity of the crude cysteamine tartrate obtained by using MET as starting material prepared according to the prior art is clearly lower (HPLC purity about 95.5%) than that of the product obtained by the same method but starting from the present DMT (HPLC purity 98.5%). The yield of crude cysteamine tartrate was also increased from 70% to 85% with respect to the teaching of the prior art.

[0295] Instead, by comparing the results of Examples 7C and 9, the chemical purity and yield of crude cysteamine tartrate obtained starting from the same prior art MET appeared to be comparable for these processes.

[0296] By comparing the analysis of the product obtained according to the method of Example 8 (comparative) with that of the product from Example 2 (inventive), both methods starting from the same DMT but applying different reaction and isolation conditions, it appears that the inventive method provided a purer crude cysteamine tartrate (99.90% vs. 98.6%), with a lower content of cystamine (0.04% vs. 0.82%) and a slightly increased yield (87% vs. 85%). In addition, the inventive method provided a virtually complete conversion of the starting DMT (residual DMT 0.01% vs. 0.45%).

[0297] Finally, by comparing the overall process of Example 7C (IN202041000697A) and Example 2 (invention) (including reaction with tartaric acid and the following crude cysteamine tartrate precipitate from the respective thiazolidine), it appears that a significant increase in yield and purity was obtained in the present invention (yield 70% to about 87%; HPLC purity 95.5% to 99.9%).

[0298] In conclusion, taking into account the data reported in Table 11 above, the process according to the invention appears to provide crude cysteamine tartrate with higher yield and purity compared to the process described in IN202041000697A.

[0299] Example 10 : Crystallization of crude cysteamine tartrate (Invention vs. IN202041000697A)

[0300] Crude cysteamine tartrate was prepared according to Example 2. Samples from the same batch were subjected to different crystallization conditions from water / 2-propanol, as detailed in the following examples.

[0301] Example 10A : Crystallization of crude cysteamine tartrate by reverse addition (invention)

[0302] Crude cysteamine tartrate (100 g) was crystallized as described in Example 4 (reverse addition, i.e., aqueous cysteine ​​tartrate solution added dropwise into 2-propanol seeded with anhydrous cysteamine tartrate polymorph L2). The cysteamine tartrate cake was dried under vacuum (about 3 mbar) at 50° C. overnight to provide 86 g of cysteamine tartrate. Yield: 86%; Purity by HPLC: 99.6% XRPD: Anhydrous polymorph L2

[0303] Example 10B Crystallization of crude cysteamine tartrate by direct addition (Comparison, Example 10 of IN202041000697A)

[0304] L(+)-Tartaric acid (0.1 equiv., 6.6 g) was added to nitrogen gas purged water (2 volumes, 200 ml) at 25-30 °C and stirred under nitrogen atmosphere. Cysteamine tartrate (0.1 equiv., 100 g) was added and stirred until dissolved. The solution was filtered and then 2-propanol (9.5 volumes, 950 ml) was added to the aqueous solution at room temperature for 1 h. The mixture was cooled at 7-10 °C, stirred and stirred at the same temperature for 2 h, then the precipitated solid was filtered, washed with 2-propanol (1 volume, 100 ml) and dried overnight under vacuum (approximately 3 mbar) at 30 °C and then dried to constant weight at 50 °C to provide 91 g of cysteamine tartrate.

[0305] Yield: 91%; Purity by HPLC: 99.4% (dry solid at 30°C), 99.3% (dry solid at 50°C) XRPD: polymorph L1 monohydrate (solid dried at 30° C., designated “polymorph M”) (see FIG. 8), polymorph L2 anhydrate (solid dried at 50° C.).

[0306] The relevant analytical data (average of analyses for three samples) determined for the crude and crystallized cysteamine tartrate of Examples 10A and 10B after drying overnight under vacuum at the reported temperatures are shown in Table 12 below:

[0307] [Table 12] Key: CB cysteamine tartrate.

[0308] From the data reported above, it is clear that the method according to the present invention (reverse addition) provides slightly purer CB and is more effective at removing cystamine than the prior art method (direct addition).

[0309] Moreover, the bulk density of the solids obtained by indirect addition according to the invention was clearly higher than that of the solids prepared by direct addition according to the prior art. Since bulk density is usually a good indicator of powder flowability, with low values ​​indicating poor flow and vice versa, it followed that the flowability of the powders of the invention was predictably higher than that of the powders of the prior art. This property is known to be advantageous from the point of view of pharmaceutical formulations.

[0310] The powders recovered from Examples 10A and 10B were also observed by optical microscopy (Figure 9). Very elongated prisms exhibiting a needle-like morphology (i.e., needle-like crystals) were observed in both cases. Large needle-like crystals can be undesirable in the pharmaceutical industry, as they can exhibit poor flow properties that complicate operations such as filtration, drying, and mixing (Crystals 2020, 10, 925). The elongated particles likely interdigitate with each other, increasing the agglomeration strength and thus resisting powder flow.

[0311] However, as is evident from Figure 9, the crystal size of the anhydrous cysteamine tartrate (I) (polymorph L2) powder according to the present invention (Example 10A, Figure 9A) was much smaller than that of the prior art (Example 10B, Figure 9B). The large elongated crystals of the prior art powder were responsible for the lower bulk density and worse flowability predicted above.

[0312] Another parameter relevant for evaluating powder flowability is the Hausner ratio, i.e. the ratio between tapped density and bulk density. Generally, a Hausner ratio higher than 1.50 indicates very poor flowability (Powder Properties in Food Production Systems, Handbook of Food Powders, Ed.: Bhesh Bhandari, Nidhi Bansal, Min Zhang, Pierre Schuck, Woodhead Publishing, 2013, chapter 12, page 298).

[0313] From the Hausner ratio values ​​reported in Table 12 above, the polymorphic cysteamine tartrate crystals obtained according to the present invention appear to have better flowability than the prior art powder (Hausner ratio 1.41 vs. 1.58).

[0314] In conclusion, taking into account the above, cysteamine tartrate crystallized according to the prior art method (direct addition) showed, in particular, worse properties compared to cysteamine tartrate crystallized according to the method of the present invention: Slightly lower chemical purity (99.3 vs. 99.6% a / a HPLC) Higher cystamine content (0.52% vs. 0.39%) Lower bulk density (0.279 vs. 0.301 g / mL) A higher Hausner ratio (1.58 vs. 1.41) predicts worse liquidity

Claims

1. 1. A process for the preparation of crude cysteamine tartrate of formula (I), comprising the steps of: (I) a) providing a thiazolidine of formula (II), (II) wherein R1 and R2 are independently selected from H, linear or branched C1-C20 alkyl, optionally substituted C6-C20 aryl, and optionally substituted heteroaryl. b) reacting said thiazolidine (II) with L(+)-tartaric acid in an aqueous medium to provide crude cysteamine tartrate (I) in said aqueous medium; and c) isolating crude cysteamine tartrate (I) from said aqueous medium; wherein the thiazolidine of formula (II) is prepared in a one-pot process, d) providing a cysteamine salt; e) contacting the cysteamine salt with a base in an aqueous medium having a pH of 10.5 or greater to provide cysteamine free base of formula (IB); (IB) f) reacting said cysteamine free base (IB) with a compound of formula (III) in the same aqueous medium; R1-CO-R2 (III) wherein R1 and R2 have the meanings reported above, and thus provide crude thiazolidine (II), and optionally g) purifying said crude thiazolidine of formula (II), method.

2. after step b), further comprising step h) of precipitating the crude cysteamine tartrate (I) by pouring the aqueous medium from step b) into 2-propanol (reverse addition), and then c) isolating the precipitated crude cysteamine tartrate (I) from the aqueous medium. The method of claim 1.

3. after step c), further comprising step i) drying the precipitated crude wet cysteamine tartrate (I), thereby providing crude cysteamine tartrate (I); The method of claim 2.

4. The pH of the aqueous medium in step e) is 11 or more, preferably 12 or more, more preferably 12.5 or more; 4. The method according to any one of claims 1 to 3.

5. The thiazolidine of formula (II) has identical or different R1 and R2 selected from H, C1-C3 alkyl, C6-C10 aryl, preferably with R1=R2=methyl; or said thiazolidine of formula (II) and said L(+) tartaric acid are reacted in step b) in a molar ratio of 1:1 to 1:2, 1:1 to 1:1.5, even more preferably 1:1 to 1:1.1; or The thiazolidine of formula (II) and the L(+) tartaric acid are reacted in step b) at a temperature of 45°C to 55°C, preferably 48°C to 52°C, or The reaction of step b) is completed by removing by distillation the compound of formula (III) R1-CO-R2, preferably when R1=R2=CH3, or the crude cysteamine tartrate is isolated from the aqueous medium from step b) by pouring the aqueous medium into 2-propanol, thereby directly precipitating the crude cysteamine tartrate, after complete removal of the compound of formula (III), preferably by distillation, or the cysteamine salt of step d) is cysteamine hydrochloride; or The pH of the aqueous medium in step e) is between 12 and 14, preferably between 12.5 and 13. said compound of formula R1-CO-R2 (III) in step f) is acetone, or The reaction of step f) is carried out at a temperature of 25° C. or less; or The crude thiazolidine (II) obtained in steps d) to f) is directly used for the preparation of said crude cysteamine tartrate according to steps a) and b).

4. The method according to any one of claims 1 to 3.

6. said thiazolidine of formula (II) has R1 = R2 = methyl; said thiazolidine of formula (II) and said L(+) tartaric acid are reacted in step b) in a molar ratio of 1:1 to 1:1.5, preferably 1:1 to 1:1.1, said thiazolidine of formula (II) and said L(+) tartaric acid are reacted in step b) at a temperature of 45°C to 55°C; the crude cysteamine tartrate is isolated by completely removing the compound of formula (III) from the aqueous medium from step b) by distillation, followed by pouring the aqueous medium into 2-propanol, thereby directly precipitating crude cysteamine tartrate; said cysteamine salt in step d) is cysteamine hydrochloride; the pH of the aqueous medium in step e) is 12.5 to 13.5; said compound of formula R1-CO-R2 (III) in step f) is acetone; The reaction of step f) is carried out at a temperature of 25° C. or less, and The crude thiazolidine (II) obtained from steps d) to f) is directly used for the preparation of crude cysteamine tartrate according to steps a) and b). The method of claim 5.

7. A process for purifying crude cysteamine tartrate, preferably obtained according to the process of any one of claims 1 to 3, comprising the steps of: h1) providing an aqueous solution of crude cysteamine tartrate (I); h2) pouring said aqueous solution of crude cysteamine tartrate (I) into 2-propanol, optionally mixed with water (inverse addition), thus precipitating crystalline cysteamine tartrate (I) from the mixture; h3) isolating the crystalline cysteamine tartrate (I) from the crystallization medium, and preferably i) drying the isolated crystalline cysteamine tartrate (I), thus providing pure cysteamine tartrate (I); method.

8. The aqueous solution of crude cysteamine tartrate (I) in step h1) can be either the aqueous medium from step b) of the process according to any one of claims 1 to 3, or an aqueous solution prepared by isolation of crude cysteamine tartrate from step c) of the process according to any one of claims 1 to 3, followed by dissolution of the isolated crude cysteamine tartrate in water. The method of claim 7.

9. 1. A process for the preparation of crystalline anhydrous cysteamine tartrate (I) (polymorph L2), comprising the steps of: d) providing a cysteamine salt; e) contacting the cysteamine salt with a base in an aqueous medium at a pH of 10.5 or greater, preferably 11 or greater, more preferably 12 or greater, even more preferably 12.5 or greater, to provide cysteamine free base of formula (IB); (IB) f) reacting said cysteamine free base (IB) with a compound of formula (III) in one pot in the same aqueous medium; R1-CO-R2 (III) wherein R1 and R2 are independently selected from H, linear or branched C1-C20 alkyl, optionally substituted C6-C20 aryl, and optionally substituted heteroaryl; a) providing a crude thiazolidine of formula (II), (II) where R1 and R2 have the meanings reported above. b) reacting the crude thiazolidine (II) with L(+)-tartaric acid in an aqueous medium, thereby providing crude cysteamine tartrate of formula (I); (I) h) precipitating the crude cysteamine tartrate (I) from the aqueous medium from step b) by pouring it into 2-propanol, optionally mixed with water (reverse addition), and then c) isolating the precipitated crude wet cysteamine tartrate (I) from the aqueous medium; h1) providing an aqueous solution of said crude wet cysteamine tartrate (I); h2) pouring the aqueous solution of crude cysteamine tartrate (I), optionally mixed with water, into 2-propanol (inverse addition), thereby precipitating crystalline cysteamine tartrate (I); h3) isolating the crystalline cysteamine tartrate (I) from the crystallization medium; and i) drying the isolated crystalline cysteamine tartrate (I) to a water content of less than 1.0% ww, as determined by Karl Fischer, thus providing crystalline anhydrous cysteamine tartrate (I) (polymorph L2), method.

10. 1. A process for the preparation of crystalline anhydrous cysteamine tartrate (I) (polymorph L2), comprising: h1) providing an aqueous solution of cysteamine tartrate (I); h2) pouring said aqueous solution of cysteamine tartrate (I) into 2-propanol, optionally mixed with water (inverse addition), thus precipitating crystalline cysteamine tartrate (I) from the mixture, preferably by cooling; h3) isolating the crystalline cysteamine tartrate (I) from the crystallization medium; and i) drying the isolated crystalline cysteamine tartrate (I) to a water content of less than 1.0% ww, as determined by Karl Fischer method, thus providing crystalline anhydrous cysteamine tartrate (I) (polymorph L2), method.

11. In step h1), the concentration of the cysteamine tartrate (I) in the aqueous solution is 1100-500 g / l, preferably 1000-800 g / l, or 520-330 g / Kg, preferably 500-440 g / Kg, or In step h1), cysteamine tartrate (I) is dissolved in water by heating at a temperature of 60°C or less, or In step h2), the volume ratio of 2-propanol to water in the mixture is from 20:1 to 2:1, preferably from 15:1 to 2.5:1, more preferably from 11:1 to 3.0:1; or In step h2), the aqueous solution of cysteamine tartrate is poured into 2-propanol under stirring (reverse addition), or In step h2), precipitating crystalline cysteamine tartrate from the mixture is carried out by seeding the mixture with crystalline anhydrous cysteamine tartrate (I) (polymorph L2); or In step h2), precipitating crystalline cysteamine tartrate from the mixture is carried out by cooling to a temperature of 15-30°C.

11. The method according to claim 9 or 10.

12. In step h1), the concentration of the cysteamine tartrate (I) in the aqueous solution is 1100-500 g / l or 500-440 g / kg; In step h2), the volume ratio of 2-propanol and water in the mixture is 11:1 to 3.0:1; In step h2), the aqueous solution of cysteamine tartrate is poured into 2-propanol under stirring (reverse addition), In step h2), precipitating crystalline cysteamine tartrate (I) from the mixture is carried out by seeding the mixture with crystals of crystalline anhydrous cysteamine tartrate (I) (polymorph L2).

11. The method according to claim 9 or 10.

13. 1. A process for the preparation of crystalline cysteamine tartrate monohydrate (I) (polymorph L1), comprising the steps of: d) providing a cysteamine salt; e) contacting the cysteamine salt with a base in an aqueous medium having a pH of 10.5 or greater to provide the cysteamine free base of formula (IB); (IB) f) reacting said cysteamine free base (IB) with a compound of formula (III) in one pot in the same aqueous medium; R1-CO-R2 (III) wherein R1 and R2 are independently selected from H, linear or branched C1-C20 alkyl, optionally substituted C6-C20 aryl, and optionally substituted heteroaryl; a) providing a crude thiazolidine of formula (II), (II) where R1 and R2 have the meanings reported above. b) reacting the crude thiazolidine (II) with L(+)-tartaric acid in an aqueous medium, thereby providing crude cysteamine tartrate of formula (I); (I) h) precipitating the crude cysteamine tartrate (i) from the aqueous medium from step b) by pouring it into 2-propanol (reverse addition), and then c) isolating the precipitated crude wet cysteamine tartrate (i) from the aqueous medium; h1) providing an aqueous solution of said crude wet cysteamine tartrate (i); h2) pouring the aqueous solution of crude cysteamine tartrate (i) into 2-propanol (inverse addition), thereby precipitating crystalline cysteamine tartrate (i); h3) isolating the crystalline cysteamine tartrate (i) from the crystallization medium; and i) drying the isolated crystalline cysteamine tartrate (i) to a water content of 7.0% to 8.0% ww, as determined by Karl Fischer method, thus providing crystalline cysteamine tartrate monohydrate (I) (polymorph L1), method.

14. 1. A process for the preparation of crystalline cysteamine tartrate monohydrate (I) (polymorph L1), comprising: h1) providing an aqueous solution of cysteamine tartrate (I); h2) pouring said aqueous solution of cysteamine tartrate (I), optionally mixed with water, into 2-propanol (inverse addition), thereby precipitating crystalline cysteamine tartrate (I) from the mixture, preferably by cooling; h3) isolating the crystalline cysteamine tartrate (I) from the crystallization medium; and i) drying the isolated crystalline cysteamine tartrate (I) to a water content of 7.0% to 8.0% ww, as determined by Karl Fischer, thereby providing crystalline cysteamine tartrate monohydrate (I) (polymorph L1), method.

15. 1. A process for converting crystalline cysteamine tartrate monohydrate (I) (polymorph L1) into crystalline anhydrous cysteamine tartrate (I) (polymorph L2), comprising the steps of: drying crystalline cysteamine tartrate monohydrate (I) (polymorph L1) by heating at a temperature of at least 45°C and preferably at a pressure of less than 200 mbar to a water content of less than 1.0% ww, preferably less than 0.5% ww, as measured by Karl Fischer method, method.

16. In the drying step i), the temperature is at least 50° C. and the pressure is less than 100 mbar, preferably less than 50 mbar; 16. The method of any one of claims 9, 10 or 15.

17. 16. Cysteamine tartrate obtainable according to the method of any one of claims 1 to 3, 9, 10, or 13 to 15.

18. Preferably, a crystalline anhydrous cysteamine tartrate (I) (polymorph L2) powder obtained according to the method of any one of claims 9, 10 or 15, said powder comprising: a water content of less than 1.0% as measured by Karl Fischer; a volume particle size distribution (PSD) of D50 not greater than 150 microns and D90 not greater than 250 microns, measured according to the method reported herein after pre-sieving through a sieve with 600 micron openings without micronization, a bulk density, measured according to Ph. Eur. 2.9.34, of 0.28 g / ml to 0.35 g / ml, preferably about 0.30 g / ml; a tap density, measured according to Ph. Eur. 2.9.34, of 0.40 g / ml to 0.43 g / ml, preferably about 0.42 g / ml, and / or characterized by a Hausner ratio of 1.30 to 1.55, preferably about 1.40; powder.

19. 14. A one-pot process for preparing thiazolidins of formula (II) according to any one of claims 1 to 3, 9 or 13, comprising: (II) wherein R1 and R2 are independently selected from H, linear or branched C1-C20 alkyl, optionally substituted C6-C20 aryl, and optionally substituted heteroaryl. d) providing a cysteamine salt; e) contacting the cysteamine salt with a base in an aqueous medium having a pH of 10.5 or greater, preferably 11 or greater, more preferably 12 or greater, even more preferably 12.5 or greater, to provide cysteamine free base of formula (IB); (IB) f) reacting the cysteamine free base (IB) with a compound of formula (III) in one pot in the same aqueous medium; R1-CO-R2 (III) wherein R1 and R2 have the meanings reported above, and accordingly provide said crude thiazolidine (II), and optionally g) purifying said crude thiazolidine of formula (II), One-pot method.

20. One or more steps are carried out under an inert atmosphere and / or in the presence of at least an antioxidant; 16. The method of any one of claims 1 to 3, 9, 10, or 13 to 15.

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