WO2014188226A2 - Lapatinib salts - Google Patents
Lapatinib salts Download PDFInfo
- Publication number
- WO2014188226A2 WO2014188226A2 PCT/HU2014/000047 HU2014000047W WO2014188226A2 WO 2014188226 A2 WO2014188226 A2 WO 2014188226A2 HU 2014000047 W HU2014000047 W HU 2014000047W WO 2014188226 A2 WO2014188226 A2 WO 2014188226A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- lapatinib
- salt
- acid
- ray powder
- powder diffraction
- Prior art date
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- 150000004927 Lapatinib derivatives Chemical class 0.000 title claims abstract description 33
- 239000002136 L01XE07 - Lapatinib Substances 0.000 claims abstract description 177
- 229960004891 lapatinib Drugs 0.000 claims abstract description 174
- BCFGMOOMADDAQU-UHFFFAOYSA-N lapatinib Chemical compound O1C(CNCCS(=O)(=O)C)=CC=C1C1=CC=C(N=CN=C2NC=3C=C(Cl)C(OCC=4C=C(F)C=CC=4)=CC=3)C2=C1 BCFGMOOMADDAQU-UHFFFAOYSA-N 0.000 claims abstract description 162
- 150000003839 salts Chemical class 0.000 claims abstract description 154
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims abstract description 86
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 35
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
Definitions
- the invention lies in the broad field of pharmaceuticals specifically in the field of small molecule tyrosine kinase inhibitors. More specifically the invention lies in the field of lapatinib salts and polymorphic forms thereof and processes for their preparation.
- 6-[5-[(2-methylsulfonylethylamino)methyl]-2-furyl] quinazolin-4-amine is a pharmaceutical active ingredient acting by the tyrosine kinase mechanism both on the epidermal growth factor receptor (EGFR/ErbBl) and the human epidermal growth factor receptor (HER-2/ErbB2).
- This active ingredient can be effectively used against locally advanced or metastatic HER-2 -positive breast cancer (MBC, metastatic breast cancer).
- MBC metastatic breast cancer
- the treatment by lapatinib of further ErbBl and/or ErbB2 overexpressing tumors are also suggested, such tumors are e.g. head, neck and lung tumors and renal cell carcinomas.
- Lapatinib ditosylate monohydrate [CAS: 388082-78-8] is marketed as Tykerb ® in the USA since March 2007 and in the EU since June 2008.
- Lapatinib of formula 1 was first disclosed in WO 1999/035146. This international application discloses in Example 29 the synthesis of lapatinib free base and the product is characterized by ⁇ -NMR and MS data. Furthermore it describes that it is possible to produce the hydrochloride salt of lapatinib. However there is no specific measurement or data regarding lapatinib hydrochloride or its chemical properties.
- EP 1294715 discloses quinazoline ditosylate salt compounds and hydrates and anhydrates thereof methods for their production and pharmaceutical compositions comprising them.
- This patent further discloses the advantages of the use of lapatinib tosylate as a pharmaceutical active ingredient as well as the disadvantages of the lapatinib hydrochloride salt. It discloses that "problems exist with the di-HCI salt in that it sorbs very large amounts of water at the humidities to which it might be exposed (e.g. 20-75% relative humidity (RH)) if utilized in a medicament.” and draws the conclusion that the suitability of the hydrochloride salt compound as a medicament could be compromised unless special handling and storage procedures were instituted.
- RH relative humidity
- WO 2010/027848 discloses the following lapatinib salts (in the brackets are the names of the polymorphic forms) monotosylate (Ml), furnarate (Fl), succinate (SI), sulphate (amorphous and U1-U7), dihydrochloride (amorphous and CI), dihydrobromide (amorphous), phosphate (P2-P4), maleate (LI), Z-tartarate (amorphous).
- the object of the present invention was to provide a process for the preparation of morphologically pure new lapatinib salts of high purity which possess more favourable physical- chemical properties than the known salts and have at least as high chemical stability as the known salts and can be prepared in a reproducible manner suitable fore industrial scale manufacture.
- a lapatinib ditosylate monohydrate is poorly soluble in aqueous medium which restricts the bioavailability thereof.
- the low solubility also limits the route of administration and the finishing of the active ingredient into solid pharmaceutical compositions.
- lapatinib namely lapatinib salts formed by (15)-(+)-camphorsulfonic acid, 2,5 dihydroxy benzoic acid, hydrogen bromide, malonic acid, naphtalene 1,5 disulfonic acid, naphtalene 2 sulfonic acid, nitric acid, citric acid and hydrochloric acid.
- the common inventive idea of the present invention resides in the preparation of new lapatinib salts which are more soluble in aqueous medium than the lapatinib ditosylate monohydrate salt.
- the invention relates to normal or acidic salts of lapatinib and the hydrate and solvate forms thereof.
- the invention relates to crystalline lapatinib naphtalene 1,5 disulfonic acid (1 : 1) salt which has the following characteristic X-ray powder diffraction peaks: °2 ⁇ ( ⁇ 0.2 °20): 4.925; 9.680; 10.446; 14.877; 15.702; 19.727; 22.266; 23.165; 24.324; 25.455; 26.323; 27.635.
- this product can be characterized by the following characteristic X-ray powder diffraction peaks: °20 ( ⁇ 0.2 °20): 4.925; 9.680; 10.446; 10.910; 14.877; 15.702; 16.820; 17.575; 18.707; 19.727; 20.624; 21.275; 21.850; 22.266; 23.165; 24.324; 25.455; 26.323; 27.635; 28.155; 29.928; 30.284; 30.974; 32.160; 32.792; 34.198.
- the characteristic X-ray powder diffractogram of the product is shown on Figure 1 and the signals having an intensity larger than 5% are summarized in Table 1 below:
- the invention further relates to lapatinib naphtalene 1,5 disulfonic salt dimethylformamide solvate (1 :1 :1) which has the following characteristic X-ray powder diffraction peaks: °20 ( ⁇ 0.2 °20): 4.341; 6.431 ; 8.899; 12.556; 16.796; 18.435; 19.635; 21.112; 23.211 ; 25.481 ; 27.397.
- this product can be characterized by the following characteristic X-ray powder diffraction peaks: °2 ⁇ ( ⁇ 0.2 °2 ⁇ ): 4.341; 6.049; 6.431 ; 7.488; 8.899; 12.556; 13.001; 13.370; 13.995; 15.132; 16.340; 16.796; 18.027; 18.435; 18.952; 19.635; 21.1 12; 23.211; 24.027; 24.728; 25.481; 26.171 ; 27.397; 28.527; 29.292.
- the invention further relates to lapatinib (lS)-(+)-camphorsulfonic acid (1 :1) salt which has the following characteristic X-ray powder diffraction peaks: °2 ⁇ ( ⁇ 0.2 °20): 4.569; 5.811; 7.828; 1 1.403; 12.991 ; 14.182; 15.008; 16.635; 17.730; 19.731 ; 22.066; 23.689; 25.228; 26.161 ; 26.693.
- this product can be characterized by the following characteristic X-ray powder diffraction peaks: °2 ⁇ ( ⁇ 0.2 °2 ⁇ ): 4.569; 5.811 ; 6.813; 7.828; 11.403; 12.380; 12.991 ; 13.840; 14.182; 15.008; 16.300; 16.635; 17.263; 17.730; 18.283; 18.728; 19.362; 19.731 ; 20.677; 21.030; 22.066; 22.763; 23.140; 23.689; 24.254; 25.228; 26.161; 26.693; 27.430; 27.936; 28.746; 29.752; 30.435; 31.373.
- the characteristic X-ray powder diffractogram of the product is shown on Figure 3 and the signals having an intensity larger than 9% are summarized in Table 3 below:
- the invention further relates to crystalline lapatinib 2,5 dihydroxy benzoic acid (1 :1) salt which has the following characteristic X-ray powder diffraction peaks: °2 ⁇ ( ⁇ 0.2 °2 ⁇ ): 5.449; 5.917; 6.376; 11.012; 12.341; 14.432; 16.475; 17.958; 19.065; 20.620; 21.332; 22.573; 25.296; 26.049; 28.107.
- this product can be characterized by the following characteristic X-ray powder diffraction peaks: °2 ⁇ ( ⁇ 0.2 °2 ⁇ ): 5.449; 5.917; 6.376; 9.497; 1 1.012; 12.341 ; 13.375; 14.060; 14.432; 14.913; 15.385; 16.475; 16.771 ; 17.571; 17.958; 19.065; 19.640; 20.620; 21.332; 22.180; 22.573; 23.239; 23.995; 24.383; 25.296; 26.049; 27.058; 27.922; 28.107.
- the characteristic X-ray powder diffractogram of the product is shown on Figure 4 and the signals having an intensity larger than 4% are summarized in Table 4 below:
- the invention further relates to crystalline lapatinib malonic acid (1 : 1) salt which has the following characteristic X-ray powder diffraction peaks: °2 ⁇ ( ⁇ 0.2 °2 ⁇ ): 4.833; 9.787; 12.027; 14.767; 16.968; 19.269; 20.088; 21.563; 22.942; 24.871.
- this product can be characterized by the following characteristic X-ray powder diffraction peaks: °2 ⁇ ( ⁇ 0.2 °2 ⁇ ): 4.833; 6.176; 7.524; 9.787; 10.084; 11.788; 12.027; 12.473; 14.767; 16.164; 16.968; 18.855; 19.269; 20.088; 21.563; 22.420; 22.942; 23.772; 24.337; 24.871 ; 26.443; 26.953; 27.612; 28.689; 29.822.
- the characteristic X-ray powder diffractogram of the product is shown on Figure 5 and the signals having an intensity larger than 7% are summarized in Table 5 below:
- the invention further relates to crystalline lapatinib malonic acid methanol solvate (1 :1 :1) salt which has the following characteristic X-ray powder diffraction peaks: °20 ( ⁇ 0.2 °2 ⁇ ): 4.848; 9.842; 12.010; 14.498; 15.884; 16.774; 17.197; 18.128; 18.812; 20.588; 21.870; 24.934; 26.670; 27.632; 31.050.
- this product can be characterized by the following characteristic X-ray powder diffraction peaks: °20 ( ⁇ 0.2 °2 ⁇ ): 4.848; 9.842; 12.010; 13.151 ; 14.498; 15.884; 16.774; 17.197; 18.128; 18.812; 19.302; 19.833; 20.588; 21.200; 21.870; 22.280; 22.936; 23.194; 23.562; 23.818; 24.245; 24.934; 26.347; 26.670; 27.632; 28.333; 29.331; 30.299; 31.050; 31.907; 34.424; 34.656.
- the characteristic X-ray powder diffractogram of the product is shown on Figure 6 and the signals having an intensity larger than 4% are summarized in Table 6 below:
- the invention further relates to crystalline lapatinib malonic acid (1 :2) salt which has the following characteristic X-ray powder diffraction peaks: °2 ⁇ ( ⁇ 0.2 °2 ⁇ ): 8.198; 10.189; 10.523; 11.950; 13.208; 14.932; 15.899; 17.255; 17.762; 18.631 ; 20.584; 21.225; 23.715; 26.690; 32.605.
- this product can be characterized by the following characteristic X-ray powder diffraction peaks: °20 ( ⁇ 0.2 °2 ⁇ ): 7.840; 8.198; 10.189; 10.523; 10.880; 11.950; 13.208; 14.932; 15.899; 17.255; 17.762; 18.631 ; 19.679; 20.584; 21.225; 21.968; 22.601 ; 23.715; 24.729; 25.066; 25.560; 26.690; 27.223; 27.944; 28.294; 28.790; 29.925; 30.266; 31.155; 32.605.
- the characteristic X-ray powder diffractogram of the product is shown on Figure 7 and the signals having an intensity larger than 5% are summarized in Table 7 below:
- the invention further relates to crystalline lapatinib nitric acid (1 :1) salt which has the following characteristic X-ray powder diffraction peaks: °2 ⁇ ( ⁇ 0.2 °2 ⁇ ): 7.346; 9.611; 12.083; 12.869; 14.824; 16.652; 17.020; 17.372; 18.541 ; 19.405; 19.761 ; 20.094; 22.31 1 ; 23.161 ; 23.870; 25.657; 26.050; 31.306.
- this product can be characterized by the following characteristic X-ray powder diffraction peaks: °2 ⁇ ( ⁇ 0.2 °2 ⁇ ): 7.346; 9.611; 12.083; 12.869; 14.824; 15.806; 16.652; 17.020; 17.372; 18.541; 19.405; 19.761 ; 20.094; 20.540; 21.113; 21.887; 22.311 ; 22.798; 23.161; 23.521 ; 23.870; 24.287; 25.033; 25.657; 26.050; 26.368; 26.981 ; 27.078; 28.020; 28.503; 29.798; 30.042; 31.306; 31.874.
- the characteristic X-ray powder diffractogram of the product is shown on Figure 8 and the signals having an intensity larger than 3% are summarized in Table 8 below:
- the invention further relates to crystalline lapatinib citric acid (1 : 1) salt which has the following characteristic X-ray powder diffraction peaks: °2 ⁇ ( ⁇ 0.2 °20): 5.339; 10.693; 12.639; 13.738; 16.063; 16.289; 17.259; 18.507; 19.712; 20.331 ; 20.746; 21.067; 21.585; 21.826; 22.676; 23.160; 23.542; 23.972; 25.438; 27.495; 28.918; 30.183; 33.059.
- this product can be characterized by the following characteristic X-ray powder diffraction peaks: °2 ⁇ ( ⁇ 0.2 °2 ⁇ ): 5.339; 9.937; 10.693; 10.938; 11.697; 11.953; 12.639; 13.738; 15.382; 15.649; 16.063; 16.289; 17.259; 17.857; 18.507; 19.322; 19.712; 20.331 ; 20.746; 21.067; 21.585; 21.826; 22.094; 22.676; 23.160; 23.542; 23.972; 24.500; 25.1 14; 25.438; 25.666; 26.035; 27.495; 28.365; 28.658; 28.918; 29.759; 30.183; 31.071 ; 31.919; 32.474; 33.059; 34.486.
- the characteristic X-ray powder diffractogram of the product is shown on Figure 9 and the signals having an intensity larger than 3% are summarized in Table 9 below:
- the invention further relates to crystalline lapatinib hydrogen bromide (1 :1) salt which has the following characteristic X-ray powder diffraction peaks: °2 ⁇ ( ⁇ 0.2 °20): 7.305; 9.551 ; 12.809; 15.013; 16.503; 18.455; 19.259; 21.423; 22.154; 23.610; 24.409; 25.443; 27.185; 27.776; 28.634; 29.967.
- this product can be characterized by the following characteristic X-ray powder diffraction peaks: °2 ⁇ ( ⁇ 0.2 °2 ⁇ ): 5.574; 7.305; 9.551 ; 12.004; 12.809; 14.753; 15.013; 15.745; 16.503; 16.941 ; 17.223; 18.455; 19.259; 19.791 ; 20.102; 20.260; 20.576; 20.865; 21.423; 22.154; 22.674; 23.030; 23.610; 24.409; 25.443; 25.892; 26.573; 26.805; 27.185; 27.776; 28.240; 28.634; 29.536; 29.967; 30.340; 30.656; 31.049; 31.637; 31.978.
- the characteristic X-ray powder diffractogram of the product is shown on Figure 10 and the signals having an intensity larger than 3% are summarized in Table 10 below:
- the invention further relates to lapatinib hydrogen bromide (1 :2) amorphous salt, which can be characterized by the X-ray powder diffractogram shown on figure 11.
- the invention further relates to crystalline lapatinib naphtalene 2 sulfonic acid (1 : 1) salt Form I which has the following characteristic X-ray powder diffraction peaks: °2 ⁇ ( ⁇ 0.2 °2 ⁇ ): 4.793; 6.865; 12.029; 13.116; 17.992; 18.915; 20.049; 20.455; 20.702; 21.413; 21.695; 24.319; 28.266; 28.607.
- this product can be characterized by the following characteristic X-ray powder diffraction peaks: °2 ⁇ ( ⁇ 0.2 °2 ⁇ ): 4.793; 6.865; 7.821 ; 9.375; 11.369; 12.029; 13.116; 14.614; 16.327; 16.650; 17.149; 17.992; 18.580; 18.915; 20.049; 20.455; 20.702; 21.413; 21.695; 22.930; 23.372; 23.700; 24.319; 25.379; 25.707; 26.449; 27.026; 28.266; 28.607; 28.800; 29.579; 29.974; 30.547; 32.213; 32.988; 33.346.
- the characteristic X-ray powder diffractogram of the product is shown on Figure 12 and the signals having an intensity larger than 3% are summarized in Table 12 below:
- the invention further relates to crystalline lapatinib naphtalene 2 sulfonic acid (1 :1) salt Form II which has the following characteristic X-ray powder diffraction peaks: °2 ⁇ ( ⁇ 0.2 °2 ⁇ ): 4.91 1; 7.077; 11.776; 11.940; 13.414; 14.279; 16.909; 18.528; 19.140; 19.923; 20.402; 21.161; 22.860; 23.431; 25.181 ; 25.966; 27.140; 28.514; 29.147.
- this product can be characterized by the following characteristic X-ray powder diffraction peaks: °2 ⁇ ( ⁇ 0.2 °20): 4.911; 5.826; 7.077; 7.977; 9.672; 9.922; 11.776; 11.940; 12.433; 13.414; 14.279; 15.308; 16.909; 17.755; 18.220; 18.528; 19.140; 19.923; 20.140; 20.402; 20.783; 21.161 ; 21.564; 21.842; 22.096; 22.307; 22.860; 23.431 ; 24.136; 24.388; 25.181 ; 25.966; 26.481 ; 27.140; 28.514; 28.997; 29.147; 32.358.
- the characteristic X-ray powder diffractogram of the product is shown on Figure 13 and the signals having an intensity larger than 4% are summarized in Table 13 below:
- the invention further relates to crystalline lapatinib hydrochloride (1 : 1) salt which has the following characteristic X-ray powder diffraction peaks: °2 ⁇ ( ⁇ 0.2 °2 ⁇ ): 5.543; 9.663; 12.129; 14.883; 16.636; 17.368; 18.566; 19.398; 20.073; 20.499; 22.258; 23.351 ; 23.833; 24.578; 25.637; 27.963; 28.959; 30.1 1 1 ; 30.812.
- this product can be characterized by the following characteristic X-ray powder diffraction peaks: °2 ⁇ ( ⁇ 0.2 °2 ⁇ ): 5.543; 7.417; 9.663; 9.972; 11.073; 11.370; 12.129; 12.932; 14.883; 15.133; 16.636; 17.068; 17.368; 18.566; 19.398; 20.073; 20.499; 21.298; 21.813; 22.258; 22.900; 23.351; 23.833; 24.144; 24.578; 24.898; 25.637; 26.032; 26.927; 27.386; 27.963; 28.504; 28.959; 30.1 1 1 ; 30.51 1 ; 30.812; 31.161 ; 31.744; 32.879.
- Table 14 The characteristic X-ray powder diffractogram of the product is shown on Figure 14 and the signals having an intensity larger than 2% are summarized in Table 14 below:
- the invention further relates to crystalline lapatinib hydrochloride (1 :1) dihydrate salt which has the following characteristic X-ray powder diffraction peaks: °2 ⁇ ( ⁇ 0.2 °2 ⁇ ): 5.050; 6.768; 10.100; 10.835; 11.738; 15.165; 15.500; 17.625; 19.178; 20.272; 20.905; 21.458; 21.754; 22.691 ; 23.249; 24.435; 24.973; 26.070; 26.507; 28.038.
- this product can be characterized by the following characteristic X-ray powder diffraction peaks: °2 ⁇ ( ⁇ 0.2 °2 ⁇ ): 5.050; 6.768; 7.487; 7.726; 8.223; 10.100; 10.835; 11.738; 12.620; 13.555; 14.057; 15.165; 15.500; 17.625; 18.200; 18.527; 19.178; 19.493; 19.991 ; 20.272; 20.905; 21.458; 21.754; 22.691; 23.249; 24.435; 24.973; 25.458; 26.070; 26.507; 27.517; 28.038; 29.179; 29.842; 30.281 ; 30.483; 31.763; 32.101; 33.068.
- the characteristic X-ray powder diffractogram of the product is shown on Figure 15 and the signals having an intensity larger than 2% are summarized in Table 15 below:
- the invention further relates to crystalline lapatinib hydrochloride (1 :2) trihydrate salt which has the following characteristic X-ray powder diffraction peaks: °2 ⁇ ( ⁇ 0.2 °2 ⁇ ): 4.826; 5.153; 10.322; 12.474; 18.898; 19.208; 20.726; 21.828; 23.644; 23.847; 24.614; 25.236; 26.225; 27.363; 30.013; 33.289.
- this product can be characterized by the following characteristic X-ray powder diffraction peaks: °2 ⁇ ( ⁇ 0.2 °2 ⁇ ): 4.826; 5.153; 7.905; 10.322; 12.081 ; 12.474; 15.332; 15.855; 16.493; 17.406; 18.898; 19.208; 19.822; 20.726; 21.355; 21.828; 23.081 ; 23.644; 23.847; 24.142; 24.614; 25.236; 25.786; 26.225; 26.533; 27.363; 27.676; 28.093; 28.328; 28.671; 29.038; 30.013; 30.801 ; 31.145; 31.815; 32.431 ; 33.014; 33.289; 33.826.
- the characteristic X-ray powder diffractogram of the product is shown on Figure 16 and the signals having an intensity larger than 3% are summarized in Table 16 below:
- the invention further relates to crystalline lapatinib hydrochloride (1 :2) anhydrate salt which has the following characteristic X-ray powder diffraction peaks: °20 ( ⁇ 0.2 °20): 4.180; 6.424; 11.509; 12.646; 15.174; 16.706; 18.631 ; 19.018; 20.554; 21.460; 21.889; 23.070; 24.002; 25.177; 25.909; 26.808; 27.394; 27.801 ; 28.890; 32.534.
- this product can be characterized by the following characteristic X-ray powder diffraction peaks: °2 ⁇ ( ⁇ 0.2 °20): 4.180; 6.424; 8.319; 11.509; 12.492; 12.646; 12.860; 13.771; 14.314; 15.174; 15.951 ; 16.706; 18.631 ; 19.018; 19.635; 20.554; 20.853; 21.460; 21.889; 22.649; 23.070; 24.002; 24.645; 25.177; 25.909; 26.549; 26.808; 27.394; 27.801 ; 28.890; 29.350; 30.090; 30.702; 31.109; 31.486; 32.534; 32.896; 33.689; 34.184.
- Table 17 The characteristic X-ray powder diffractogram of the product is shown on Figure 17 and the signals having an intensity larger than 2% are summarized in Table 17 below:
- a process for the preparation of lapatinib salts which comprises reacting an amorphous or crystalline form of lapatinib or an anhydrous form, hydrate or solvate thereof in a suitable organic solvent with the desired acid and separating the lapatinib salt formed.
- the salts according to the present invention can be prepared by reacting lapatinib free base in an organic solvent with the desired acid, separating the crystallized salt and if desired washing with organic solvent.
- the salts according to the present invention can also be prepared by reacting the free lapatinib base without isolation in an organic solvent with the desired acid, separating the crystallized salt and if desired washing it with an organic solvent.
- the salt can be separated by known methods of pharmaceutical industry suitable for the separation of a solid phase and a liquid, such as filtration which is optionally carried out under atmospheric pressure or in vacuo or under pressure or by using a centrifuge.
- mono-or polybasic organic or inorganic acids can be used, such as by (15)-(+)-camphorsulfonic acid, 2,5 dihydroxy benzoic acid, hydrogen bromide, malonic acid, naphtalene 1 ,5 disulfonic acid, naphtalene 2 sulfonic acid, nitric acid, citric acid and hydrochloric acid.
- the process can be carried out in an organic solvent, e.g. C 1-4 aliphatic alcohols, Q.5 linear or ring ethers, Ci_6 esters and acetonitrile or mixtures thereof.
- organic solvent e.g. C 1-4 aliphatic alcohols, Q.5 linear or ring ethers, Ci_6 esters and acetonitrile or mixtures thereof.
- organic solvent a C 1-4 ether, ester or alcohol or a dipolar-aprotic solvent, particularly tetrahydrofurane, diethyl ether, ethyl acetate, acetonitrile, methanol, ethanol or 2-propanol or mixtures thereof or optionally aqueous mixtures thereof.
- salts of the present invention may be prepared with different stochiometry.
- 'mono' salt refers to a ratio of 1 : 1 of lapatinib and the corresponding salt
- 'di' salt refers to a ratio of 1 :2 of lapatinib and the corresponding salt
- 'hemi' salt refers to a ratio of 2: 1 of lapatinib and the corresponding salt.
- the salt forming acid is preferably applied in a 0.3-3.0 molar equivalent amount related to the amount of the lapatinib.
- the precipitated product is separated preferably by filtration.
- the new lapatinib salts of the present invention can be prepared by dissolving lapatinib base in a suitable solvent, preferably a C 1- alcohol, particularly ethanol, methanol or isopropanol at a temperature between 0 °C and the reflux temperature of the solvent and adding a 0.5-3.0, preferably a 0.5-2.5 molar equivalent amount of an acid in solid form or as a solution. If the salt precipitates at the temperature of the addition or under cooling it is filtered, if desired purified by digestion or recrystallization and finally filtered, washed and dried. If the precipitation does not spontaneously take place, the solvent is removed in vacuo and the residue is crystallized by adding a suitable solvent or solvent mixture, if desired purified by digestion or recrystallization and finally filtered, washed and dried.
- a suitable solvent preferably a C 1- alcohol, particularly ethanol, methanol or isopropanol
- Lapatinib naphtalene 1,5 disulfonic acid (1 : 1) salt is preferably prepared by stirring the solution of the formed lapatinib base with an alcohol type solvent, preferably methanol and adding the methanolic solution of naphtalene 1,5 disulfonic acid at a temperature between 0°C and the boiling point of the solvent, preferably at a temperature between 0°C and 80°C, more preferably at 70°C. If necessary the reaction mixture is cooled to 5-25°C, the precipitated crystals are filtered, optionally washed and dried. Optionally the product is recrystallized from an alcohol type solvent or a mixture thereof formed with water, preferably from methanol.
- Lapatinib naphtalene 1 ,5 disulfonic dimethylformamide solvate (1 : 1 : 1) salt is preferably prepared by stirring lapatinib naphtalene 1,5 disulfonic acid (1 : 1) salt in N,N-dimethylformamide for 96 hours at a temperature from 10°C to 50°C, preferably at room temperature. The obtained reaction mixture is filtered and optionally the precipitated crystals are washed and dried.
- Lapatinib (15)-(+)-camphorsulfonic acid salt (1 :1) is preferably prepared in a similar way as described for naphtalene 1 ,5 disulfonic (1 : 1) salt with the difference that instead of methanol acetone is used as solvent and instead of naphtalene- 1 ,5-disulfonic acid tetrahydrate an acetonic solution of (15)-(+)-camforsulfonic acid monohydrate is used.
- Lapatinib 2,5 dihydroxy benzoic acid (1 : 1) salt is preferably prepared in a similar way as described for naphtalene 1 ,5 disulfonic (1 : 1) salt with the difference that instead of methanol ethanol is used as solvent and instead of naphtalene- 1 ,5 -disulfonic acid tetrahydrate an ethanolic solution of 2,5 dihydroxy benzoic acid is used.
- Lapatinib malonic acid (1 : 1) salt is preferably prepared by is preferably prepared by stirring the solution of the lapatinib base with an alcohol type solvent, preferably ethanol and adding solid malonic acid at a temperature between 0°C and the boiling point of the solvent, preferably at a temperature between room temperature and 80°C, more preferably at 70°C. Then it is preferably stirred further overnight at room temperature. The precipitated crystals are filtered, optionally washed and dried.
- Lapatinib malonic acid salt methanol solvate (1 :1 :1) is preferably prepared by stirring lapatinib malonic acid (1 : 1) salt in methanol at a temperature between 50 °C and 80 °C, preferably at the boiling point of the solvent, then for a further one hour at room temperature. The precipitated crystals are filtered, optionally washed and dried.
- Lapatinib malonic acid (1 :2) salt is preferably prepared by stirring lapatinib free base in an alcoholic type solvent, preferably in ethanol and solid malonic acid is added to the mixture at a temperature between 0 °C and the boiling point of the solvent, preferably between room temperature and 80 °C, more preferably at 70 °C. Then after cooling it is stirred further preferably at room temperature for 24 hours. The precipitated crystals are filtered, optionally washed and dried.
- Lapatinib nitric acid (1 :1) salt may be prepared preferably in a similar way as described for naphtalene 1,5 disulfonic acid (1 :1) salt with the difference that methanol is used as solvent instead of acetonitrile and nitric acid solution (65%) is added to the mixture instead of naphtalene 1,5 disulfonic acid.
- Lapatinib citric acid (1 : 1) salt is preferably prepared by stirring lapatinib free base in an alcohol type solvent, preferably in methanol then citric acid monohydrate is added to the mixture at a temperature between 0°C and the boiling point of the solvent, preferably between room temperature and 80°C, more preferably at 70 °C then after cooling it is stirred further preferably at room temperature for 24 hours.
- the precipitated crystals are filtered, optionally washed and dried.
- Lapatinib hydrogen bromide (1 :1) salt may be prepared in a similar way as described for the citric acid (1 :1) salt with the difference that instead of citric acid monohydrate hydrogen bromide 47% aqueous solution is added.
- Lapatinib hydrogen bromide (1 :2) amorphous salt may be prepared in a similar way as described for the citric acid (1 :1) salt with the difference that instead of citric acid monohydrate hydrogen bromide 47% aqueous solution is added and the reaction mixture is stirred for 48 hours at room temperature.
- Lapatinib naphtalene 2 sulfonic acid (1 :1) Form I is preferably prepared by stirring lapatinib free base in an alcohol type solvent, preferably in ethanol then naphtalene 2 sulfonic acid monohydrate is added to the mixture at a temperature between 0°C and the boiling point of the solvent, preferably between room temperature and 80°C, more preferably at 70 °C then after cooling it is stirred further preferably at room temperature for 20 hours.
- the reaction mixture is optionally cooled to a temperature from 5 to 25°C.
- the precipitated crystals are filtered, optionally washed and dried then it is recrystallized from a dipolar-aprotic type solvent or an aqueous mixture thereof, preferably from acetonitrile or from a mixture of acetonitrile and water.
- Lapatinib naphtalene 2 sulfonic acid (1:1) is preferably prepared by stirring lapatinib free bas in a dipolar aprotic type solvent, preferably in acetonitrile then naphtalene 2 sulfonic acid monohydrate is added to the mixture at a temperature between 0°C and the boiling point of the solvent, preferably between room temperature and 90°C, more preferably at 80 °C then after cooling it is stirred further preferably at room temperature for 20 hours. The precipitated crystals are filtered, optionally washed and dried.
- Lapatinib hydrochloride (1 :1) may be prepared in a similar way as described for citric acid (1 :1) salt with the difference that instead of citric acid monohydrate aqueous hydrochloride solution is added to the reaction mixture.
- Lapatinib hydrochloride (1 :1) dihydrate salt is preferably prepared by stirring lapatinib hydrochloride (1 :1) salt in a dipolar aprotic type solvent or aqueous mixtures thereof, preferably in acetonitrile-water at a temperature from 50°C to 110 °C, preferably at the boiling point of the solvent mixture, then it is stirred further for 20 hours at room temperature. The precipitated crystals are filtered, optionally washed and dried.
- Lapatinib hydrochloride (1 :2) trihydrate salt is preferably prepared by stirring lapatinib free base in an alcohol type solvent, preferably in methanol at a temperature between 0°C and the boiling point of the solvent, preferably between room temperature and 80°C, more preferably at 70°C then after cooling it is stirred further preferably at room temperature for 24 hours.
- the reaction mixture is optionally cooled to a temperature from 5 to 25°C.
- the precipitated crystals are filtered, optionally washed and dried then it is recrystallized from a dipolar-aprotic type solvent or an aqueous mixture thereof, preferably from acetonitrile or from a mixture of acetonitrile and water.
- Lapatinib hydrochloride (1 :2) anhydrate salt is preferably prepared by drying lapatinib hydrochloride (1 :2) trihydrate salt in vacuo at a temperature form 50°C to 100°C, preferably at 80°C, under a pressure of 1-10 mbar, preferably at a pressure of 8 mbar for 24 hours.
- the decompositions in a pharmaceutical composition occurring during storage are constructed essentially in an accelerated manner.
- the results of these tests predicted that under normal storage conditions the new lapatinib salts of the present invention would be more stable than the salts used in the marketed pharmaceutical compositions and those known from the prior art.
- the advantageous properties of the new lapatinib salts of the present invention are significant from the point of view of the formulation of pharmaceutical compositions, the storage and the minimalization of the harmful effects exerted in the human body.
- the stability of the new lapatinib salts of the present invention was subjected to detailed tests.
- As referent product the lapatinib ditosylate monohydrate salt contained in the Tykerb ® or Tyverb ® medicine of the originator was used.
- lapatinib salts of the present invention show a higher stability than the salts known from prior art in the storage tests carried out under various conditions. It has been found that from the new salts of the present invention lapatinib citrate (1 :1) salt, hydrochloride (1 :2) dihydrate salt and the hydrochloride (1 :2) anhydrate salt salts proved to be particularly stable. Said salts are particularly useful in the preparation of pharmaceutical compositions.
- the lapatinib hydrochloride (1 :2) trihydrate salt and the lapatinib hydrochloride (1 :2) anhydrate salt produced therefrom are new compounds of the present invention and they have the biologically advantageous property that both of them are hydrochloride salts thus these compounds do not contain any ballast material. Therefore their use in highly preferable compared to the presently used compound in which the salt forming component is the less favourable para-toluenesulfonic acid.
- a further general disadvantage of /j ra-toluenesulfonic acid salts is that extreme care should be taken during the production of the active ingredient.
- the presence of alcohols, especially the presence of ethanol in certain steps of the active ingredient production, or the technological steps attached thereto may result in the production of genotoxic alkyl- (in the case of ethanol ethyl-) /> ra-toluolsulfonate.
- the latter compound is a mutagenic and carcinogenic substance well known in the literature.
- compositions comprising a therapeutically effective amount of a lapatinib salt of the present invention and if desired a pharmaceutically active carrier.
- compositions of the present invention may be administered preferably orally.
- Such oral compositions may be e.g. tablets, capsules, dragees, solutions, elixirs, suspensions or emulsions.
- the pharmaceutical compositions according to the present invention may contain conventional pharmaceutical carriers and/or auxiliary agents.
- carrier e.g. magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, low melting wax, PEG, cocoa butter etc.
- carrier often serves as the capsule wall material so that no additional carrier is required.
- Chartula and lozenge are further oral pharmaceutical compositions. Particularly preferred oral administration forms are the powders, pirules, chartula and lozenges.
- the tablets are prepared by admixing the active ingredient with suitable carriers in an appropriate ratio and from this mixture tablets of desired shape and size are pressed.
- the powders are prepared by admixing the finely powdered active ingredient with the carriers.
- the liquid compositions may be solutions, suspensions and emulsions which can also be sustained release compositions.
- Aqueous solutions and aqueous propylene glycol solutions proved to be advantageous.
- Compositions suitable for parenteral administration can be prepared preferably in the form of aqueous polyethylene glycol solutions.
- compositions of the invention can be preferably prepared in the form of dosage units which contain the desired amount of the active ingredient.
- the dosage units can be put on the market in the form of packages comprising separated amounts of the compositions e.g. packed tablets, capsules, vials or ampoules which contain the powder.
- the term "dosage unit" relates to the capsules, chartula, lozenge and also to the package comprising a suitable amount of dosage units.
- a process for the preparation of the above pharmaceutical compositions which comprises admixing a lapatinib salt according to the invention or a mixture thereof with pharmaceutically acceptable solid or liquid diluents and/or auxiliary agents and bringing the mixture to a galenic composition.
- compositions of the present invention can be prepared by conventional methods of pharmaceutical industry.
- the pharmaceutical compositions of the present invention may contain further pharmaceutical active ingredients which are compatible with the new lapatinib salts according to the invention or mixtures thereof.
- the lapatinib salts according to the invention as pharmaceutical active ingredient.
- the use of any of the lapatinib salts for the treatment or prophylaxis of locally advanced or metastatic HER-2- positive breast cancer (MBC, metastatic breast cancer) furthermore for the treatment or prophylaxis of other cancers such as head-neck, lung and renal cell carcinoma.
- any of the lapatinib salts for the preparation of pharmaceutical compositions for the treatment or prophylaxis of locally advanced or metastatic HER-2-positive breast cancer (MBC, metastatic breast cancer) furthermore for the treatment or prophylaxis of other cancers such as head-neck, lung and renal cell carcinoma.
- the advantage of the present invention is that the new lapatinib salt compounds of the present invention are substances of uniform morphology and have an advantageous crystal form. For this reason the salts of the present invention possess preferable and reproducible properties, such as dissolving velocity, bioavailability, chemical stability and processing characteristics e.g. filtration, drying and tabletting properties.
- the active ingredients of the present invention may be prepared by procedures readily suitable for industrial scale manufacture.
- the lapatinib base used in the following examples was prepared from lapatinib ditosylate monohydrate by general methods well known for the person skilled in the art. NMR
- Soller source side: 2,5 °; detector side: 5 °
- Orifices source side: automatic and 1,25 ° divergence
- Measuring range continuous ⁇ /2 ⁇ scan, 3 - 35 °2 ⁇
- Sample preparation the powdered sample was leveled on a zero background Si single crystal sample holder
- lapatinib hydrochloride (1 :2) anhydrate salt.
- Orifices source side: 0.6 mm divergence slit
- Measuring range continuous ⁇ /2 ⁇ scan, 4 - 35 °2 ⁇
- Step interval 0,02 °2 ⁇ Sample preparation: not powdered sample between Mylar foils, room temperature
- Atmosphere N 2 stream 40 ml/minute
- IR (KBr, cm- 1 ): 3451, 3010, 2804, 1619, 1582, 1561, 1530, 1499, 1444, 1401, 1384, 1367, 1301, 1242, 1219, 1174, 1151, 1062, 1030, 996, 970, 954, 916, 881, 840, 802, 766, 748, 706, 683, 664, 610, 566, 528, 500, 478.
- IR (KBr, cm '1 ): 3425, 3314, 3011, 2929, 2813, 1655, 1636, 1621, 1581, 1561, 1529, 1500, 1449, 1402, 1384, 1312, 1293, 1277, 1242, 1220, 1180, 1158, 1138, 1102, 1078, 1063, 1031, 953, 927, 900, 879, 841, 803, 765, 748, 694, 684, 665, 610, 565, 524, 463, 444.
- the reaction mixture is allowed to cool to room temperature under stirring, then 15 cm 3 tert- butyl methyl ether is added thereto and further stirred. Slowly crystals start to appear then it is stirred for 24 hours under room temperature then for a further one hour under external ice/water cooling. The precipitated crystalline product is filtered and washed with a little cold acetone and tert-butyl methyl ether.
- IR (KBr, cm “1 ): 3026, 2922, 2727, 2625, 1592, 1561, 1498, 1462, 1419, 1384, 1368, 1349, 1334, 1307, 1257, 1241, 1177, 1 131, 1089, 1077, 1059, 1042, 1026, 1001, 973, 948, 927, 877, 845, 827, 81 1, 794, 782, 717, 705, 686, 661, 641, 622, 556, 541 , 519, 490, 481, 456, 415.
- Lapatinib malonic acid (1 :1) salt (lapatinib monomalonate)
- IR (KBr, cm “1 ): 3444, 3286, 3019, 2989, 2939, 2758, 2564, 2416, 1935, 1702, 1630, 1594, 1571, 1545, 1529, 1497, 1445, 1424, 1388, 1367, 1323, 1292, 1272, 1213, 1141, 1059, 1030, 996, 974, 955, 931, 913, 891, 865, 844, 836, 811, 794, 750, 708, 682, 665, 634, 624, 607, 582, 566, 553, 534, 521, 509, 497, 480, 467, 440, 414.
- IR (KBr, cm “1 ): 3425, 3124, 3011, 2926, 2859, 2597, 2456, 1948, 1711, 1604, 1593, 1571, 1545, 1524, 1498, 1448, 1422, 1382, 1367, 1320, 1293, 1276, 1213, 1139, 1061, 1024, 968, 955, 928, 897, 870, 838, 789, 749, 685, 662, 639, 625, 582, 551, 523, 494, 478, 443, 408.
- Lapatinib malonic acid (1 :2) salt (lapatinib dimalonate)
- IR (KBr, cm “1 ): 3433, 3010, 2930, 2603, 1731, 1610, 1591, 1559, 1529, 1501, 1444, 1413, 1380, 1328, 1288, 1275, 1212, 1159, 1136, 1062, 1031, 954, 927, 893, 874, 842, 809, 783, 752, 683, 660, 582, 535, 523, 504, 443.
- IR (KBr, cm “1 ): 3491, 3358, 3124, 3021 , 2928, 2859, 1735, 1699, 1609, 1592, 1560, 1533, 1499, 1451 , 1427, 1369, 1340, 1307, 1266, 1219, 1 135, 1099, 1080, 1061, 1025, 996, 972, 949, 927, 902, 846, 823, 795, 739, 710, 683, 627, 578, 569, 521 , 501 , 479, 442, 423.
- Lapatinib hydrogen bromide (1 : 1) salt Into an apparatus 40 cm 3 methanol is weighed in whereupon 0.700 g (1.21 mmol) lapatinib base is dissolved therein under intensive stirring and reflux. To the reaction mixture 0.140 cm 3 (1.21 mmol) 47 % aqueous hydrogen bromide is added. The solution immediately starts to turn opal, the precipitation starts to appear. The reaction mixture is stirred and allowed to cool to room temperature then it is stirred for a further 24 hours. The precipitated crystalline product is filtered and washed with a little cold ethanol and tert-butyl methyl ether. Well filterable crystalline product is obtained. The product is dried on 40 °C for 24 hours under 5.2 mbar pressure.
- IR (KBr, cm “1 ): 2988, 2923, 2742, 2398, 1615, 1574, 1557, 1532, 1499, 1443, 1382, 1365, 1297, 1272, 1136, 1061, 1029, 968, 955, 925, 862, 841, 802, 780, 747, 681, 665, 583, 533, 517, 502, 441.
- the obtained salt is recrystallized according to the following: 0.400 g material is recrystallized from 22 cm 3 acetonitrile/water 9:1 mixture. After cooling to room temperature the mixture is further stirred for one hour, then for 30 minutes on a temperature of 0-5 °C. The precipitated product is filtered then washed with a little cold solution then with tert-buthyl methyl ether. The product is dried on 50 °C for 4 days under 3.9 mbar pressure.
- Lapatinib hydrochloride (1 :1) salt (lapatinib monohydrochloride)
- hydrochloride salt of example 13 is recrystallized according to the following: 1.500 g
- IR (KBr, cm “1 ): 3473, 3397, 3132, 3031, 3015, 2929, 2771, 2721, 2610, 2413, 1666, 1601, 1571, 1545, 1528, 1508, 1497, 1464, 1448, 1423, 1395, 1365, 1333, 1324, 1285, 1258, 1215, 1 198, 1160, 1 140, 1079, 1059, 1024, 975, 957, 936, 927, 904, 884, 871, 840, 820, 804, 787, 749, 733, 687, 663, 625, 594, 578, 563, 548, 535, 518, 507, 451, 435.
- Lapatinib hydrochloride (1 :2) trihydrate salt (lapatinib dihydrochloride trihydrate (1 :2:3) a) Lapatinib hydrochloride salt (1 :2)
- IR (KBr, cm -1 ): 3426, 3258, 3126, 2987, 2928, 2712, 2604, 2426, 1635, 1617, 1592, 1574, 1557, 1533, 1505, 1489, 1445, 1413, 1383, 1369, 1328, 1302, 1276, 1266, 1223, 1189, 1176, 1131, 1063, 1031, 969, 955, 925, 895, 870, 842, 818, 749, 735, 703, 693, 682, 668, 663, 639, 625, 582, 562, 552, 548, 543, 533, 517.
- the dihydrochloride salt of example 14 is recrystallized according to the following: 2.200 gram (3,36 mmol) salt may be recrystallized from 130 cm 3 acetonitrile/water 2: 1. After cooling to room temperature the mixture is stirred for further 48 hours then with ice/water cooling for further 2 hours. The precipitated crystalline product is filtered and washed with a little cold solution mixture then with tert-butyl methyl ether. The product is dried on air.
- the measurement was done by an isochratic method with an external standard. Lapatinib base was the used standard. The differences resulting from the different molar weight of the salt forms were corrected for. As a result of the measurement the concentration of the salt solutions were obtained in mg salt/ml solution form which is the solubility of the given salt in water (mg salt/ml water).
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Abstract
Disclosed are new lapatinib salts and polymorphic forms thereof and processes for their preparation. More specifically disclosed are new salts of lapatinib, namely lapatinib salts formed by (1S)-(+)-camphorsulfonic acid, 2,5 dihydroxy benzoic acid, hydrogen bromide, malonic acid, naphtalene 1,5 disulfonic acid, naphtalene 2 sulfonic acid, nitric acid, citric acid and hydrochloric acid.
Description
LAPATINIB SALTS
Field of the invention The invention lies in the broad field of pharmaceuticals specifically in the field of small molecule tyrosine kinase inhibitors. More specifically the invention lies in the field of lapatinib salts and polymorphic forms thereof and processes for their preparation.
Background of the invention
It is known in the art that lapatinib e.g. N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-
6-[5-[(2-methylsulfonylethylamino)methyl]-2-furyl] quinazolin-4-amine (CAS: 231277-92-2) is a pharmaceutical active ingredient acting by the tyrosine kinase mechanism both on the epidermal growth factor receptor (EGFR/ErbBl) and the human epidermal growth factor receptor (HER-2/ErbB2). This active ingredient can be effectively used against locally advanced or metastatic HER-2 -positive breast cancer (MBC, metastatic breast cancer). The treatment by lapatinib of further ErbBl and/or ErbB2 overexpressing tumors are also suggested, such tumors are e.g. head, neck and lung tumors and renal cell carcinomas.
Lapatinib ditosylate monohydrate [CAS: 388082-78-8] is marketed as Tykerb® in the USA since March 2007 and in the EU since June 2008.
Lapatinib of formula 1 was first disclosed in WO 1999/035146. This international application discloses in Example 29 the synthesis of lapatinib free base and the product is characterized by ^-NMR and MS data. Furthermore it describes that it is possible to produce the hydrochloride salt of lapatinib. However there is no specific measurement or data regarding lapatinib hydrochloride or its chemical properties.
EP 1294715 discloses quinazoline ditosylate salt compounds and hydrates and anhydrates thereof methods for their production and pharmaceutical compositions comprising them. This patent further discloses the advantages of the use of lapatinib tosylate as a pharmaceutical active ingredient as well as the disadvantages of the lapatinib hydrochloride salt. It discloses that "problems exist with the di-HCI salt in that it sorbs very large amounts of water at the humidities to which it might be exposed (e.g. 20-75% relative humidity (RH)) if utilized in a medicament." and draws the conclusion that the suitability of the hydrochloride salt compound as a medicament could be compromised unless special handling and storage procedures were instituted.
WO 2010/027848 discloses the following lapatinib salts (in the brackets are the names of the polymorphic forms) monotosylate (Ml), furnarate (Fl), succinate (SI), sulphate (amorphous
and U1-U7), dihydrochloride (amorphous and CI), dihydrobromide (amorphous), phosphate (P2-P4), maleate (LI), Z-tartarate (amorphous).
In EP 2468745 in Example 6 a process is set forth for the preparation of lapatinib hydrochloride. In the final coupling step of 4-chloro-quinazoline and the substituted amine the monohydrochloride salt of lapatinib is produced. However this salt is not characterized by melting point or any spectroscopic data.
Recently serious demand has occurred in pharmaceutical industry on the reproducible manufacture of morphologically uniform products. This is a fundamental-condition for active ingredients needed to meet the requirements of the formulation of medicines. It is well-known that various salts and polymorphs differ from each other in important properties such as solubility, chemical stability, polymorph stability, bioavailability, filtration, drying and tabletting properties.
From economical point of view of the manufacturing process it is highly important that the product should be prepared by a process suitable for industrial scale manufacture in a reproducible manner to provide a morphologically uniform salt free of contaminations.
Brief description of the invention
The object of the present invention was to provide a process for the preparation of morphologically pure new lapatinib salts of high purity which possess more favourable physical- chemical properties than the known salts and have at least as high chemical stability as the known salts and can be prepared in a reproducible manner suitable fore industrial scale manufacture.
A lapatinib ditosylate monohydrate is poorly soluble in aqueous medium which restricts the bioavailability thereof. The low solubility also limits the route of administration and the finishing of the active ingredient into solid pharmaceutical compositions.
The above object is solved according to the present invention by the preparation of new salts of lapatinib, namely lapatinib salts formed by (15)-(+)-camphorsulfonic acid, 2,5 dihydroxy benzoic acid, hydrogen bromide, malonic acid, naphtalene 1,5 disulfonic acid, naphtalene 2 sulfonic acid, nitric acid, citric acid and hydrochloric acid.
The common inventive idea of the present invention resides in the preparation of new lapatinib salts which are more soluble in aqueous medium than the lapatinib ditosylate monohydrate salt.
Detailed description of the invention
The invention relates to normal or acidic salts of lapatinib and the hydrate and solvate forms thereof.
More specifically the invention concerns:
- lapatinib naphtalene 1,5 disulfonic (1 :1) salt,
- lapatinib naphtalene 1,5 disulfonic salt dimethylformamide solvate (1:1 :1),
- lapatinib (lS)-(+)-camphorsulfonic acid (1 :1) salt,
- lapatinib 2,5 dihydroxy benzoic acid (1 : 1) salt,
- lapatinib malonic acid (1: 1) salt,
- lapatinib malonic acid salt methanol solvate (1 :1 :1),
- lapatinib malonic acid (1:2) salt,
- lapatinib nitric acid (1 :1) salt,
- lapatinib citric acid (1 : 1) salt,
- lapatinib hydrogen bromide (1 :1) salt,
- lapatinib hydrogen bromide (1 :2) amorphous salt,
- lapatinib naphtalene 2 sulfonic (1 :1) salt Form I and Form II,
- lapatinib hydrochloride (1 :1) salt,
- lapatinib hydrochloride (1 : 1) salt dihydrate,
- lapatinib hydrochloride (1 :2) salt trihydrate,
- lapatinib hydrochloride (1 :2) salt anhydrate.
More specifically the invention relates to crystalline lapatinib naphtalene 1,5 disulfonic acid (1 : 1) salt which has the following characteristic X-ray powder diffraction peaks: °2Θ (±0.2 °20): 4.925; 9.680; 10.446; 14.877; 15.702; 19.727; 22.266; 23.165; 24.324; 25.455; 26.323; 27.635. More particularly this product can be characterized by the following characteristic X-ray powder diffraction peaks: °20 (±0.2 °20): 4.925; 9.680; 10.446; 10.910; 14.877; 15.702; 16.820; 17.575; 18.707; 19.727; 20.624; 21.275; 21.850; 22.266; 23.165; 24.324; 25.455; 26.323; 27.635; 28.155; 29.928; 30.284; 30.974; 32.160; 32.792; 34.198. The characteristic X-ray powder diffractogram of the product is shown on Figure 1 and the signals having an intensity larger than 5% are summarized in Table 1 below:
Table 1 : Lapatinib naphtalene 1,5 disulfonic acid salt (1 :1) salt (relative intensity >5%)
Peak 2Θ (°) d (A) Relative intensity (%)
1 4.925 17.9281 10
2 9.680 9.1295 9
3 10.446 8.4615 13
4 10.910 8.1030 7
5 14.877 5.9501 51
6 15.702 5.6393 100
7 16.820 5.2668 32
8 17.575 5.0421 25
9 18.707 4.7395 38
10 19.727 4.4969 98
11 20.624 4.3032 47
12 21.275 4.1730 54
13 21.850 4.0644 62
14 22.266 3.9894 72
15 23.165 3.8366 93
16 24.324 3.6563 87
17 25.455 3.4964 100
18 26.323 3.3830 54
19 27.635 3.2253 52
20 28.155 3.1669 46
21 29.928 2.9832 22
22 30.284 2.9489 21
23 30.974 2.8848 19
24 32.160 2.7811 1 1
25 32.792 2.7289 8
26 34.198 2.6199 6
The invention further relates to lapatinib naphtalene 1,5 disulfonic salt dimethylformamide solvate (1 :1 :1) which has the following characteristic X-ray powder diffraction peaks: °20 (±0.2 °20): 4.341; 6.431 ; 8.899; 12.556; 16.796; 18.435; 19.635; 21.112; 23.211 ; 25.481 ; 27.397. More particularly this product can be characterized by the following characteristic X-ray powder diffraction peaks: °2Θ (±0.2 °2Θ): 4.341; 6.049; 6.431 ; 7.488; 8.899; 12.556; 13.001; 13.370; 13.995; 15.132; 16.340; 16.796; 18.027; 18.435; 18.952; 19.635; 21.1 12; 23.211; 24.027; 24.728; 25.481; 26.171 ; 27.397; 28.527; 29.292. The characteristic X-ray powder diffractogram of the product is shown on Figure 2 and the signals having an intensity larger than 4% are summarized in Table 2 below:
Table 2: Lapatinib naphtalene 1,5 disulfonic acid salt (1 :1) DMF solvate (relative intensity >4%)
The invention further relates to lapatinib (lS)-(+)-camphorsulfonic acid (1 :1) salt which has the following characteristic X-ray powder diffraction peaks: °2Θ (±0.2 °20): 4.569; 5.811; 7.828; 1 1.403; 12.991 ; 14.182; 15.008; 16.635; 17.730; 19.731 ; 22.066; 23.689; 25.228; 26.161 ; 26.693. More particularly this product can be characterized by the following characteristic X-ray powder diffraction peaks: °2Θ (±0.2 °2Θ): 4.569; 5.811 ; 6.813; 7.828; 11.403; 12.380; 12.991 ; 13.840; 14.182; 15.008; 16.300; 16.635; 17.263; 17.730; 18.283; 18.728; 19.362; 19.731 ;
20.677; 21.030; 22.066; 22.763; 23.140; 23.689; 24.254; 25.228; 26.161; 26.693; 27.430; 27.936; 28.746; 29.752; 30.435; 31.373. The characteristic X-ray powder diffractogram of the product is shown on Figure 3 and the signals having an intensity larger than 9% are summarized in Table 3 below:
Table 3: Lapatinib (15)-(+)-camphorsulfonic acid (1 : 1) salt (relative intensity >9%)
Peak 2Θ (°) d (A) Relative intensity (%)
1 4.569 19.3252 24
2 5.811 15.1974 15
3 6.813 12.9630 10
4 7.828 11.2855 13
5 11.403 7.7540 18
6 12.380 7.1439 17
7 12.991 6.8094 42
8 13.840 6.3934 50
9 14.182 6.2398 76
10 15.008 5.8983 63
11 16.300 5.4336 73
12 16.635 5.3251 92
13 17.263 5.1325 78
14 17.730 4.9985 80
15 18.283 4.8485 76
16 18.728 4.7344 73
17 19.362 4.5808 77
18 19.731 4.4958 93
19 20.677 4.2923 65
20 21.030 4.2211 64
21 22.066 4.0251 62
22 22.763 3.9034 54
23 23.140 3.8407 52
24 23.689 3.7529 60
25 24.254 3.6666 61
26 25.228 3.5273 100
27 26.161 3.4036 69
28 26.693 3.3369 70
29 27.430 3.2489 38
30 27.936 3.1912 36
31 28.746 3.1032 27
32 29.752 3.0004 16
33 30.435 2.9347 12
34 31.373 2.8490 10
The invention further relates to crystalline lapatinib 2,5 dihydroxy benzoic acid (1 :1) salt which has the following characteristic X-ray powder diffraction peaks: °2Θ (±0.2 °2Θ): 5.449; 5.917; 6.376; 11.012; 12.341; 14.432; 16.475; 17.958; 19.065; 20.620; 21.332; 22.573; 25.296; 26.049; 28.107. More particularly this product can be characterized by the following characteristic X-ray powder diffraction peaks: °2Θ (±0.2 °2Θ): 5.449; 5.917; 6.376; 9.497; 1 1.012; 12.341 ; 13.375; 14.060; 14.432; 14.913; 15.385; 16.475; 16.771 ; 17.571; 17.958; 19.065; 19.640; 20.620; 21.332; 22.180; 22.573; 23.239; 23.995; 24.383; 25.296; 26.049; 27.058; 27.922; 28.107. The characteristic X-ray powder diffractogram of the product is shown on Figure 4 and the signals having an intensity larger than 4% are summarized in Table 4 below:
Table 4: Lapatinib 2,5 dihydroxy benzoic acid (1 : 1) salt (relative intensity >3%)
Peak 2Θ (°) d (A) Relative intensity (%)
1 5.449 16.2042 100
2 5.917 14.9253 13
3 6.376 13.8507 7
4 9.497 9.3055 4
5 11.012 8.0279 6
6 12.341 7.1666 10
7 13.375 6.6145 7
8 14.060 6.2939 6
9 14.432 6.1325 14
10 14.913 5.9357 9
11 15.385 5.7545 10
12 16.475 5.3765 7
13 16.771 5.2822 10
14 17.571 5.0432 9
15 17.958 4.9356 16
16 19.065 4.6513 18
17 19.640 4.5165 5
18 20.620 4.3040 18
19 21.332 4.1619 35
20 22.180 4.0047 6
21 22.573 3.9358 7
22 23.239 3.8245 6
23 23.995 3.7057 5
24 24.383 3.6475 5
25 25.296 3.5179 8
26 26.049 3.4180 11
27 27.058 3.2928 13
28 27.922 3.1929 8
29 28.107 3.1722 9
The invention further relates to crystalline lapatinib malonic acid (1 : 1) salt which has the following characteristic X-ray powder diffraction peaks: °2Θ (±0.2 °2Θ): 4.833; 9.787; 12.027; 14.767; 16.968; 19.269; 20.088; 21.563; 22.942; 24.871. More particularly this product can be characterized by the following characteristic X-ray powder diffraction peaks: °2Θ (±0.2 °2Θ): 4.833; 6.176; 7.524; 9.787; 10.084; 11.788; 12.027; 12.473; 14.767; 16.164; 16.968; 18.855; 19.269; 20.088; 21.563; 22.420; 22.942; 23.772; 24.337; 24.871 ; 26.443; 26.953; 27.612; 28.689; 29.822. The characteristic X-ray powder diffractogram of the product is shown on Figure 5 and the signals having an intensity larger than 7% are summarized in Table 5 below:
Table 5: Lapatinib malonic acid (1 : 1) salt (relative intensity >7%)
Peak 2Θ (°) d (A) Relative intensity (%)
1 4.833 18.2689 32
2 6.176 14.2990 8
3 7.524 11.7403 10
4 9.787 9.0298 23
5 10.084 8.7652 15
6 11.788 7.5014 19
7 12.027 7.3530 21
8 12.473 7.0908 10
9 14.767 5.9941 29
10 16.164 5.4791 11
11 16.968 5.2212 100
12 18.855 4.7026 31
13 19.269 4.6026 31
14 20.088 4.4167 40
15 21.563 4.1179 41
16 22.420 3.9623 38
17 22.942 3.8733 54
18 23.772 3.7400 44
19 24.337 3.6544 34
20 24.871 3.5771 31
21 26.443 3.3679 18
22 26.953 3.3054 16
23 27.612 3.2280 12
24 28.689 3.1091 10
25 29.822 2.9936 8
The invention further relates to crystalline lapatinib malonic acid methanol solvate (1 :1 :1) salt which has the following characteristic X-ray powder diffraction peaks: °20 (±0.2 °2Θ): 4.848; 9.842; 12.010; 14.498; 15.884; 16.774; 17.197; 18.128; 18.812; 20.588; 21.870; 24.934; 26.670; 27.632; 31.050. More particularly this product can be characterized by the following characteristic X-ray powder diffraction peaks: °20 (±0.2 °2Θ): 4.848; 9.842; 12.010; 13.151 ; 14.498; 15.884; 16.774; 17.197; 18.128; 18.812; 19.302; 19.833; 20.588; 21.200; 21.870; 22.280; 22.936; 23.194; 23.562; 23.818; 24.245; 24.934; 26.347; 26.670; 27.632; 28.333; 29.331; 30.299; 31.050; 31.907; 34.424; 34.656. The characteristic X-ray powder diffractogram of the product is shown on Figure 6 and the signals having an intensity larger than 4% are summarized in Table 6 below:
Table 6: Lapatinib malonic acid methanol solvate (1 :1 :1) salt (relative intensity >4%)
Peak 2Θ (°) d (A) Relative intensity (%)
1 4.848 18.2131 32
2 9.842 8.9796 74
3 12.010 7.3631 35
4 13.151 6.7268 5
5 14.498 6.1047 13
6 15.884 5.5751 63
7 16.774 5.2810 53
8 17.197 5.1523 23
9 18.128 4.8896 100
10 18.812 4.7132 59
11 19.302 4.5948 19
12 19.833 4.4730 17
13 20.588 4.3106 25
14 21.200 4.1876 9
15 21.870 4.0606 45
16 22.280 3.9869 13
17 22.936 3.8744 19
18 23.194 3.8318 24
19 23.562 3.7729 21
20 23.818 3.7328 19
21 24.245 3.6680 17
22 24.934 3.5682 52
23 26.347 3.3800 17
24 26.670 3.3398 32
25 27.632 3.2256 14
26 28.333 3.1474 8
27 29.331 3.0425 6
28 30.299 2.9475 5
29 31.050 2.8780 15
30 31.907 2.8026 5
31 34.424 2.6032 7
32 34.656 2.5863 7
The invention further relates to crystalline lapatinib malonic acid (1 :2) salt which has the following characteristic X-ray powder diffraction peaks: °2Θ (±0.2 °2Θ): 8.198; 10.189; 10.523; 11.950; 13.208; 14.932; 15.899; 17.255; 17.762; 18.631 ; 20.584; 21.225; 23.715; 26.690; 32.605. More particularly this product can be characterized by the following characteristic X-ray powder diffraction peaks: °20 (±0.2 °2Θ): 7.840; 8.198; 10.189; 10.523; 10.880; 11.950; 13.208; 14.932; 15.899; 17.255; 17.762; 18.631 ; 19.679; 20.584; 21.225; 21.968; 22.601 ; 23.715;
24.729; 25.066; 25.560; 26.690; 27.223; 27.944; 28.294; 28.790; 29.925; 30.266; 31.155; 32.605. The characteristic X-ray powder diffractogram of the product is shown on Figure 7 and the signals having an intensity larger than 5% are summarized in Table 7 below:
Table 7: Lapatinib malonic acid (1 :2) salt (relative intensity >5%)
Peak 2Θ (°) d (A) Relative intensity (%)
1 7.840 1 1.2677 20
2 8.198 10.7762 86
3 10.189 8.6748 22
4 10.523 8.4004 26
5 10.880 8.1253 9
6 11.950 7.4001 18
7 13.208 6.6979 16
8 14.932 5.9281 74
9 15.899 5.5699 23
10 17.255 5.1350 58
11 17.762 4.9895 100
12 18.631 4.7588 36
13 19.679 4.5076 13
14 20.584 4.3115 48
15 21.225 4.1826 90
16 21.968 4.0429 24
17 22.601 3.9311 20
18 23.715 3.7488 84
19 24.729 3.5973 33
20 25.066 3.5498 30
21 25.560 3.4823 25
22 26.690 3.3374 31
23 27.223 3.2732 18
24 27.944 3.1903 16
25 28.294 3.1516 16
26 28.790 3.0985 13
27 29.925 2.9835 8
28 30.266 2.9507 7
29 31.155 2.8684 6
30 32.605 2.7441 11
The invention further relates to crystalline lapatinib nitric acid (1 :1) salt which has the following characteristic X-ray powder diffraction peaks: °2Θ (±0.2 °2Θ): 7.346; 9.611; 12.083; 12.869; 14.824; 16.652; 17.020; 17.372; 18.541 ; 19.405; 19.761 ; 20.094; 22.31 1 ; 23.161 ; 23.870; 25.657; 26.050; 31.306. More particularly this product can be characterized by the following characteristic X-ray powder diffraction peaks: °2Θ (±0.2 °2Θ): 7.346; 9.611; 12.083; 12.869; 14.824; 15.806; 16.652; 17.020; 17.372; 18.541; 19.405; 19.761 ; 20.094; 20.540; 21.113; 21.887; 22.311 ; 22.798; 23.161; 23.521 ; 23.870; 24.287; 25.033; 25.657; 26.050; 26.368; 26.981 ; 27.078; 28.020; 28.503; 29.798; 30.042; 31.306; 31.874. The characteristic X-ray powder diffractogram of the product is shown on Figure 8 and the signals having an intensity larger than 3% are summarized in Table 8 below:
Table 8: Lapatinib nitric acid (1 :1) salt (relative intensity >3%)
Relative
Peak 2Θ (°) d (A)
intensity (%)
1 7.346 12.0236 21
2 9.611 9.1951 58
3 12.083 7.3186 46
4 12.869 6.8737 26
5 14.824 5.9713 12
6 15.806 5.6023 4
7 16.652 5.3194 63
8 17.020 5.2055 23
9 17.372 5.1006 29
10 18.541 4.7816 17
11 19.405 4.5706 29
12 19.761 4.4892 21
13 20.094 4.4153 45
14 20.540 4.3206 4
15 21.113 4.2047 5
16 21.887 4.0577 19
17 22.311 3.9815 100
18 22.798 3.8974 11
19 23.161 3.8372 30
20 23.521 3.7793 8
21 23.870 3.7248 11
22 24.287 3.6618 10
23 25.033 3.5543 13
24 25.657 3.4693 15
25 26.050 3.4180 15
26 26.368 3.3774 9
27 26.981 3.3020 10
28 27.078 3.2904 10
29 28.020 3.1819 11
30 28.503 3.1290 11
31 29.798 2.9959 14
32 30.042 2.9721 11
33 31.306 2.8549 19
34 31.874 2.8053 4
The invention further relates to crystalline lapatinib citric acid (1 : 1) salt which has the following characteristic X-ray powder diffraction peaks: °2Θ (±0.2 °20): 5.339; 10.693; 12.639; 13.738; 16.063; 16.289; 17.259; 18.507; 19.712; 20.331 ; 20.746; 21.067; 21.585; 21.826; 22.676; 23.160; 23.542; 23.972; 25.438; 27.495; 28.918; 30.183; 33.059. More particularly this product can be characterized by the following characteristic X-ray powder diffraction peaks: °2Θ (±0.2 °2Θ): 5.339; 9.937; 10.693; 10.938; 11.697; 11.953; 12.639; 13.738; 15.382; 15.649; 16.063; 16.289; 17.259; 17.857; 18.507; 19.322; 19.712; 20.331 ; 20.746; 21.067; 21.585; 21.826; 22.094; 22.676; 23.160; 23.542; 23.972; 24.500; 25.1 14; 25.438; 25.666; 26.035; 27.495; 28.365; 28.658; 28.918; 29.759; 30.183; 31.071 ; 31.919; 32.474; 33.059; 34.486. The characteristic X-ray powder diffractogram of the product is shown on Figure 9 and the signals having an intensity larger than 3% are summarized in Table 9 below:
Table 9: Lapatinib citric acid (1 :1) salt (relative intensity >3%)
Peak 2Θ (°) d (A) Relative intensity (%)
1 5.339 16.5403 44
2 9.937 8.8943 4
3 10.693 8.2667 30
4 10.938 8.0821 16
5 11.697 7.5594 12
6 11.953 7.3982 15
7 12.639 6.9981 25
8 13.738 6.4407 18
9 15.382 5.7559 19
10 15.649 5.6582 8
11 16.063 5.5133 48
12 16.289 5.4372 81
13 17.259 5.1338 27
14 17.857 4.9632 8
15 18.507 4.7902 95
16 19.322 4.5900 10
17 19.712 4.5002 100
18 20.331 4.3645 43
19 20.746 4.2782 25
20 21.067 4.2137 59
21 21.585 4.1137 52
22 21.826 4.0687 35
23 22.094 4.0200 16
24 22.676 3.9182 57
25 23.160 3.8373 49
26 23.542 3.7760 49
27 23.972 3.7092 26
28 24.500 3.6304 8
29 25.114 3.5431 20
30 25.438 3.4987 46
31 25.666 3.4681 30
32 26.035 3.4198 23
33 27.495 3.2414 25
34 28.365 3.1439 23
35 28.658 3.1125 18
36 28.918 3.0851 35
37 29.759 2.9997 10
38 30.183 2.9586 29
39 31.071 2.8760 6
40 31.919 2.8015 7
41 32.474 2.7549 5
42 33.059 2.7075 15
43 34.486 2.5986 5
The invention further relates to crystalline lapatinib hydrogen bromide (1 :1) salt which has the following characteristic X-ray powder diffraction peaks: °2Θ (±0.2 °20): 7.305; 9.551 ; 12.809; 15.013; 16.503; 18.455; 19.259; 21.423; 22.154; 23.610; 24.409; 25.443; 27.185; 27.776; 28.634; 29.967. More particularly this product can be characterized by the following characteristic X-ray powder diffraction peaks: °2Θ (±0.2 °2Θ): 5.574; 7.305; 9.551 ; 12.004; 12.809; 14.753; 15.013; 15.745; 16.503; 16.941 ; 17.223; 18.455; 19.259; 19.791 ; 20.102; 20.260; 20.576; 20.865; 21.423; 22.154; 22.674; 23.030; 23.610; 24.409; 25.443; 25.892; 26.573; 26.805; 27.185; 27.776; 28.240; 28.634; 29.536; 29.967; 30.340; 30.656; 31.049; 31.637; 31.978. The characteristic X-ray powder diffractogram of the product is shown on Figure 10 and the signals having an intensity larger than 3% are summarized in Table 10 below:
Table 10: Lapatinib hydrogen bromide (1 :1) salt (relative intensity >3%)
Peak 20 (°) d (A) Relative intensity (%)
1 5.574 15.8423 5
2 7.305 12.0917 28
3 9.551 9.2524 31
4 12.004 7.3669 7
5 12.809 6.9055 29
6 14.753 5.9998 20
7 15.013 5.8966 27
8 15.745 5.6237 4
9 16.503 5.3673 28
10 16.941 5.2295 9
11 17.223 5.1446 13
12 18.455 4.8037 65
13 19.259 4.6050 55
14 19.791 4.4824 21
15 20.102 4.4138 25
16 20.260 4.3797 25
17 20.576 4.3131 13
18 20.865 4.2539 13
19 21.423 4.1444 29
20 22.154 4.0094 51
21 22.674 3.9186 25
22 23.030 3.8587 33
23 23.610 3.7652 100
24 24.409 3.6437 61
25 25.443 3.4979 43
26 25.892 3.4383 22
27 26.573 3.3517 13
28 26.805 3.3233 15
29 27.185 3.2776 30
30 27.776 3.2092 34
31 28.240 3.1576 10
32 28.634 3.1150 38
33 29.536 3.0219 5
34 29.967 2.9794 22
35 30.340 2.9436 10
36 30.656 2.9140 9
37 31.049 2.8780 17
38 31.637 2.8259 15
39 31.978 2.7965 4
The invention further relates to lapatinib hydrogen bromide (1 :2) amorphous salt, which can be characterized by the X-ray powder diffractogram shown on figure 11. The invention further relates to crystalline lapatinib naphtalene 2 sulfonic acid (1 : 1) salt Form I which has the following characteristic X-ray powder diffraction peaks: °2Θ (±0.2 °2Θ): 4.793; 6.865; 12.029; 13.116; 17.992; 18.915; 20.049; 20.455; 20.702; 21.413; 21.695; 24.319; 28.266; 28.607. More particularly this product can be characterized by the following characteristic X-ray powder diffraction peaks: °2Θ (±0.2 °2Θ): 4.793; 6.865; 7.821 ; 9.375; 11.369; 12.029; 13.116; 14.614; 16.327; 16.650; 17.149; 17.992; 18.580; 18.915; 20.049; 20.455; 20.702; 21.413; 21.695; 22.930; 23.372; 23.700; 24.319; 25.379; 25.707; 26.449; 27.026; 28.266; 28.607; 28.800; 29.579; 29.974; 30.547; 32.213; 32.988; 33.346. The characteristic X-ray powder
diffractogram of the product is shown on Figure 12 and the signals having an intensity larger than 3% are summarized in Table 12 below:
Table 12: Lapatinib naphtalene 2 sulfonic acid (1 :1) salt Form I (relative intensity >3%)
Peak 20 (°) d (A) Relative intensity (%)
1 4.793 18.4231 37
2 6.865 12.8650 57
3 7.821 11.2949 10
4 9.375 9.4257 6
5 11.369 7.7767 4
6 12.029 7.3516 17
7 13.116 6.7449 23
8 14.614 6.0565 4
9 16.327 5.4248 16
10 16.650 5.3202 8
11 17.149 5.1665 16
12 17.992 4.9264 100
13 18.580 4.7717 22
14 18.915 4.6880 53
15 20.049 4.4252 71
16 20.455 4.3384 38
17 20.702 4.2872 38
18 21.413 4.1463 33
19 21.695 4.0931 39
20 22.930 3.8753 19
21 23.372 3.8030 20
22 23.700 3.7512 17
23 24.319 3.6571 30
24 25.379 3.5067 19
25 25.707 3.4626 15
26 26.449 3.3672 13
27 27.026 3.2966 7
28 28.266 3.1547 19
29 28.607 3.1179 16
30 28.800 3.0974 13
31 29.579 3.0176 5
32 29.974 2.9788 7
33 30.547 2.9242 5
34 32.213 2.7766 4
35 32.988 2.7131 5
36 33.346 2.6848 5
The invention further relates to crystalline lapatinib naphtalene 2 sulfonic acid (1 :1) salt Form II which has the following characteristic X-ray powder diffraction peaks: °2Θ (±0.2 °2Θ): 4.91 1; 7.077; 11.776; 11.940; 13.414; 14.279; 16.909; 18.528; 19.140; 19.923; 20.402; 21.161; 22.860; 23.431; 25.181 ; 25.966; 27.140; 28.514; 29.147. More particularly this product can be characterized by the following characteristic X-ray powder diffraction peaks: °2Θ (±0.2 °20): 4.911; 5.826; 7.077; 7.977; 9.672; 9.922; 11.776; 11.940; 12.433; 13.414; 14.279; 15.308; 16.909; 17.755; 18.220; 18.528; 19.140; 19.923; 20.140; 20.402; 20.783; 21.161 ; 21.564; 21.842; 22.096; 22.307; 22.860; 23.431 ; 24.136; 24.388; 25.181 ; 25.966; 26.481 ; 27.140; 28.514; 28.997; 29.147; 32.358. The characteristic X-ray powder diffractogram of the product is shown on Figure 13 and the signals having an intensity larger than 4% are summarized in Table 13 below:
Table 13: Lapatinib naphtalene 2 sulfonic acid (1 : 1) salt Form II (relative intensity >4%)
Peak 20 (°) d (A) Relative intensity (%)
1 4.911 17.9797 45
2 5.826 15.1566 8
3 7.077 12.4814 64
4 7.977 11.0748 9
5 9.672 9.1370 12
6 9.922 8.9076 7
7 11.776 7.5091 17
8 11.940 7.4062 12
9 12.433 7.1138 10
10 13.414 6.5955 13
11 14.279 6.1980 14
12 15.308 5.7836 8
13 16.909 5.2392 77
14 17.755 4.9914 13
15 18.220 4.8651 22
16 18.528 4.7850 38
17 19.140 4.6332 100
18 19.923 4.4529 61
19 20.140 4.4055 38
20 20.402 4.3494 22
21 20.783 4.2707 17
22 21.161 4.1952 33
23 21.564 4.1176 25
24 21.842 4.0658 20
25 22.096 4.0197 27
26 22.307 3.9821 25
27 22.860 3.8870 77
28 23.431 3.7935 57
29 24.136 3.6844 21
30 24.388 3.6469 19
31 25.181 3.5338 21
32 25.966 3.4287 30
33 26.481 3.3632 15
34 27.140 3.2830 20
35 28.514 3.1279 16
36 28.997 3.0768 17
37 29.147 3.0613 16
38 32.358 2.7645 5
The invention further relates to crystalline lapatinib hydrochloride (1 : 1) salt which has the following characteristic X-ray powder diffraction peaks: °2Θ (±0.2 °2Θ): 5.543; 9.663; 12.129; 14.883; 16.636; 17.368; 18.566; 19.398; 20.073; 20.499; 22.258; 23.351 ; 23.833; 24.578; 25.637; 27.963; 28.959; 30.1 1 1 ; 30.812. More particularly this product can be characterized by the following characteristic X-ray powder diffraction peaks: °2Θ (±0.2 °2Θ): 5.543; 7.417; 9.663; 9.972; 11.073; 11.370; 12.129; 12.932; 14.883; 15.133; 16.636; 17.068; 17.368; 18.566; 19.398; 20.073; 20.499; 21.298; 21.813; 22.258; 22.900; 23.351; 23.833; 24.144; 24.578; 24.898; 25.637; 26.032; 26.927; 27.386; 27.963; 28.504; 28.959; 30.1 1 1 ; 30.51 1 ; 30.812; 31.161 ;
31.744; 32.879. The characteristic X-ray powder diffractogram of the product is shown on Figure 14 and the signals having an intensity larger than 2% are summarized in Table 14 below:
Table 14: Lapatinib hydrochloride (1 :1) salt (relative intensity >2%)
Peak 2Θ (°) d (A) Relative intensity (%)
1 5.543 15.9315 8
2 7.417 11.9095 3
3 9.663 9.1459 47
4 9.972 8.8627 5
5 11.073 7.9839 1 1
6 11.370 7.7760 5
7 12.129 7.2909 52
8 12.932 6.8402 13
9 14.883 5.9477 29
10 15.133 5.8500 8
1 1 16.636 5.3248 17
12 17.068 5.1908 6
13 17.368 5.1020 20
14 18.566 4.7753 24
15 19.398 4.5723 35
16 20.073 4.4201 25
17 20.499 4.3290 89
18 21.298 4.1684 9
19 21.813 4.0712 19
20 22.258 3.9908 45
21 22.900 3.8804 8
22 23.351 3.8064 29
23 23.833 3.7305 100
24 24.144 3.6831 24
25 24.578 3.6191 59
26 24.898 3.5733 20
27 25.637 3.4720 43
28 26.032 3.4202 5
29 26.927 3.3085 9
30 27.386 3.2540 10
31 27.963 3.1882 23
32 28.504 3.1289 10
33 28.959 3.0808 25
34 30.111 2.9655 1 1
35 30.511 2.9275 4
36 30.812 2.8996 8
37 31.161 2.8679 7
38 31.744 2.8166 6
39 32.879 2.7219 4
The invention further relates to crystalline lapatinib hydrochloride (1 :1) dihydrate salt which has the following characteristic X-ray powder diffraction peaks: °2Θ (±0.2 °2Θ): 5.050; 6.768; 10.100; 10.835; 11.738; 15.165; 15.500; 17.625; 19.178; 20.272; 20.905; 21.458; 21.754; 22.691 ; 23.249; 24.435; 24.973; 26.070; 26.507; 28.038. More particularly this product can be characterized by the following characteristic X-ray powder diffraction peaks: °2Θ (±0.2 °2Θ): 5.050; 6.768; 7.487; 7.726; 8.223; 10.100; 10.835; 11.738; 12.620; 13.555; 14.057; 15.165; 15.500; 17.625; 18.200; 18.527; 19.178; 19.493; 19.991 ; 20.272; 20.905; 21.458; 21.754; 22.691; 23.249; 24.435; 24.973; 25.458; 26.070; 26.507; 27.517; 28.038; 29.179; 29.842; 30.281 ; 30.483; 31.763; 32.101; 33.068. The characteristic X-ray powder diffractogram of the product is shown on Figure 15 and the signals having an intensity larger than 2% are summarized in Table 15 below:
Table 15: Lapatinib hydrochloride (1 :1) dihydrate salt (relative intensity >2%)
Peak 2Θ (°) d (A) Relative intensity (%)
1 5.050 17.4862 40
2 6.768 13.0494 3
3 7.487 11.7980 18
4 7.726 1 1.4344 5
5 8.223 10.7439 13
6 10.100 8.7510 38
7 10.835 8.1591 35
8 11.738 7.5333 18
9 12.620 7.0084 9
10 13.555 6.5273 4
11 14.057 6.2950 9
12 15.165 5.8375 27
13 15.500 5.7123 30
14 17.625 5.0282 54
15 18.200 4.8704 13
16 18.527 4.7851 3
17 19.178 4.6243 62
18 19.493 4.5503 12
19 19.991 4.4380 28
20 20.272 4.3771 34
21 20.905 4.2459 69
22 21.458 4.1378 34
23 21.754 4.0821 100
24 22.691 3.9156 82
25 23.249 3.8229 30
26 24.435 3.6399 36
27 24.973 3.5628 87
28 25.458 3.4959 18
29 26.070 3.4153 59
30 26.507 3.3600 58
31 27.517 3.2389 13
32 28.038 3.1798 35
33 29.179 3.0580 16
34 29.842 2.9916 17
35 30.281 2.9492 12
36 30.483 2.9301 13
37 31.763 2.8150 10
38 32.101 2.7860 7
39 33.068 2.7067 4
The invention further relates to crystalline lapatinib hydrochloride (1 :2) trihydrate salt which has the following characteristic X-ray powder diffraction peaks: °2Θ (±0.2 °2Θ): 4.826; 5.153; 10.322; 12.474; 18.898; 19.208; 20.726; 21.828; 23.644; 23.847; 24.614; 25.236; 26.225; 27.363; 30.013; 33.289. More particularly this product can be characterized by the following characteristic X-ray powder diffraction peaks: °2Θ (±0.2 °2Θ): 4.826; 5.153; 7.905; 10.322;
12.081 ; 12.474; 15.332; 15.855; 16.493; 17.406; 18.898; 19.208; 19.822; 20.726; 21.355; 21.828; 23.081 ; 23.644; 23.847; 24.142; 24.614; 25.236; 25.786; 26.225; 26.533; 27.363; 27.676; 28.093; 28.328; 28.671; 29.038; 30.013; 30.801 ; 31.145; 31.815; 32.431 ; 33.014; 33.289; 33.826. The characteristic X-ray powder diffractogram of the product is shown on Figure 16 and the signals having an intensity larger than 3% are summarized in Table 16 below:
Table 16: Lapatinib hydrochloride (1 :2) trihydrate salt (relative intensity >3%)
Peak 20 (°) d (A) Relative intensity (%)
1 4.826 18.2971 9
2 5.153 17.1341 100
3 7.905 11.1749 5
4 10.322 8.5635 25
5 12.081 7.3198 4
6 12.474 7.0904 58
7 15.332 5.7743 4
8 15.855 5.5853 11
9 16.493 5.3706 5
10 17.406 5.0908 26
1 1 18.898 4.6922 62
12 19.208 4.6172 44
13 19.822 4.4755 25
14 20.726 4.2822 73
15 21.355 4.1574 4
16 21.828 4.0684 44
17 23.081 3.8504 21
18 23.644 3.7599 39
19 23.847 3.7284 41
20 24.142 3.6835 20
21 24.614 3.6139 72
22 25.236 3.5262 67
23 25.786 3.4523 9
24 26.225 3.3954 29
25 26.533 3.3567 15
26 27.363 3.2568 32
27 27.676 3.2206 16
28 28.093 3.1738 12
29 28.328 3.1480 10
30 28.671 3.1111 13
31 29.038 3.0725 17
32 30.013 2.9750 20
33 30.801 2.9006 5
34 31.145 2.8693 7
35 31.815 2.8104 7
36 32.431 2.7585 5
37 33.014 2.7111 10
38 33.289 2.6893 29
39 33.826 2.6478 6
The invention further relates to crystalline lapatinib hydrochloride (1 :2) anhydrate salt which has the following characteristic X-ray powder diffraction peaks: °20 (±0.2 °20): 4.180; 6.424; 11.509; 12.646; 15.174; 16.706; 18.631 ; 19.018; 20.554; 21.460; 21.889; 23.070; 24.002; 25.177; 25.909; 26.808; 27.394; 27.801 ; 28.890; 32.534. More particularly this product can be characterized by the following characteristic X-ray powder diffraction peaks: °2Θ (±0.2 °20): 4.180; 6.424; 8.319; 11.509; 12.492; 12.646; 12.860; 13.771; 14.314; 15.174; 15.951 ; 16.706; 18.631 ; 19.018; 19.635; 20.554; 20.853; 21.460; 21.889; 22.649; 23.070; 24.002; 24.645; 25.177; 25.909; 26.549; 26.808; 27.394; 27.801 ; 28.890; 29.350; 30.090; 30.702; 31.109; 31.486; 32.534; 32.896; 33.689; 34.184. The characteristic X-ray powder diffractogram of the product is shown on Figure 17 and the signals having an intensity larger than 2% are summarized in Table 17 below:
Table 17: Lapatinib hydrochloride (1 :2) anhydrate salt (relative intensity >2%)
Peak 2Θ (°) d (A) Relative intensity (%)
1 4.180 21.1223 7
2 6.424 13.7476 20
3 8.319 10.6197 6
4 11.509 7.6823 98
5 12.492 7.0801 11
6 12.646 6.9941 20
7 12.860 6.8785 6
8 13.771 6.4252 6
9 14.314 6.1828 4
10 15.174 5.8341 32
11 15.951 5.5516 15
12 16.706 5.3025 48
13 18.631 4.7587 44
14 19.018 4.6628 41
15 19.635 4.5177 16
16 20.554 4.3177 74
17 20.853 4.2565 26
18 21.460 4.1373 55
19 21.889 4.0572 46
20 22.649 3.9228 33
21 23.070 3.8522 88
22 24.002 3.7047 55
23 24.645 3.6094 14
24 25.177 3.5344 39
25 25.909 3.4361 100
26 26.549 3.3547 28
27 26.808 3.3229 50
28 27.394 3.2531 23
29 27.801 3.2064 26
30 28.890 3.0880 18
31 29.350 3.0406 3
32 30.090 2.9675 7
33 30.702 2.9098 9
34 31.109 2.8726 6
35 31.486 2.8390 12
36 32.534 2.7500 24
37 32.896 2.7205 4
38 33.689 2.6583 13
39 34.184 2.6209 5
According to a further aspect of the present invention there is provided a process for the preparation of lapatinib salts which comprises reacting an amorphous or crystalline form of
lapatinib or an anhydrous form, hydrate or solvate thereof in a suitable organic solvent with the desired acid and separating the lapatinib salt formed.
The salts according to the present invention can be prepared by reacting lapatinib free base in an organic solvent with the desired acid, separating the crystallized salt and if desired washing with organic solvent.
The salts according to the present invention can also be prepared by reacting the free lapatinib base without isolation in an organic solvent with the desired acid, separating the crystallized salt and if desired washing it with an organic solvent.
The salt can be separated by known methods of pharmaceutical industry suitable for the separation of a solid phase and a liquid, such as filtration which is optionally carried out under atmospheric pressure or in vacuo or under pressure or by using a centrifuge.
For the salt formation according to the present invention mono-or polybasic organic or inorganic acids can be used, such as by (15)-(+)-camphorsulfonic acid, 2,5 dihydroxy benzoic acid, hydrogen bromide, malonic acid, naphtalene 1 ,5 disulfonic acid, naphtalene 2 sulfonic acid, nitric acid, citric acid and hydrochloric acid.
The process can be carried out in an organic solvent, e.g. C1-4 aliphatic alcohols, Q.5 linear or ring ethers, Ci_6 esters and acetonitrile or mixtures thereof.
It is preferred to use as organic solvent a C1-4 ether, ester or alcohol or a dipolar-aprotic solvent, particularly tetrahydrofurane, diethyl ether, ethyl acetate, acetonitrile, methanol, ethanol or 2-propanol or mixtures thereof or optionally aqueous mixtures thereof.
Naturally lapatinib has more than one basic centres therefore the salts of the present invention may be prepared with different stochiometry. Throughout the description 'mono' salt refers to a ratio of 1 : 1 of lapatinib and the corresponding salt; 'di' salt refers to a ratio of 1 :2 of lapatinib and the corresponding salt; and 'hemi' salt refers to a ratio of 2: 1 of lapatinib and the corresponding salt.
The salt forming acid is preferably applied in a 0.3-3.0 molar equivalent amount related to the amount of the lapatinib. One may proceed preferably by using the solution of the organic acid and carrying out the reaction at a temperature between 0°C and the boiling point of the solvent.
One may particularly preferably proceed by reacting the methanolic solution of lapatinib with a solution containing a 0.3-3.0 molar equivalent of the acid at a temperature near to the boiling point of the solvent. The precipitated product is separated preferably by filtration.
One may also proceed by using the acid in solid crystalline form and performing the reaction at a temperature between 0°C and the boiling point of the mixture or at the boiling point of the solvent.
The new lapatinib salts of the present invention can be prepared by dissolving lapatinib base in a suitable solvent, preferably a C1- alcohol, particularly ethanol, methanol or isopropanol at a temperature between 0 °C and the reflux temperature of the solvent and adding a 0.5-3.0, preferably a 0.5-2.5 molar equivalent amount of an acid in solid form or as a solution. If the salt precipitates at the temperature of the addition or under cooling it is filtered, if desired purified by digestion or recrystallization and finally filtered, washed and dried. If the precipitation does not spontaneously take place, the solvent is removed in vacuo and the residue is crystallized by adding a suitable solvent or solvent mixture, if desired purified by digestion or recrystallization and finally filtered, washed and dried.
Lapatinib naphtalene 1,5 disulfonic acid (1 : 1) salt is preferably prepared by stirring the solution of the formed lapatinib base with an alcohol type solvent, preferably methanol and adding the methanolic solution of naphtalene 1,5 disulfonic acid at a temperature between 0°C and the boiling point of the solvent, preferably at a temperature between 0°C and 80°C, more preferably at 70°C. If necessary the reaction mixture is cooled to 5-25°C, the precipitated crystals are filtered, optionally washed and dried. Optionally the product is recrystallized from an alcohol type solvent or a mixture thereof formed with water, preferably from methanol.
Lapatinib naphtalene 1 ,5 disulfonic dimethylformamide solvate (1 : 1 : 1) salt is preferably prepared by stirring lapatinib naphtalene 1,5 disulfonic acid (1 : 1) salt in N,N-dimethylformamide for 96 hours at a temperature from 10°C to 50°C, preferably at room temperature. The obtained reaction mixture is filtered and optionally the precipitated crystals are washed and dried.
Lapatinib (15)-(+)-camphorsulfonic acid salt (1 :1) is preferably prepared in a similar way as described for naphtalene 1 ,5 disulfonic (1 : 1) salt with the difference that instead of methanol acetone is used as solvent and instead of naphtalene- 1 ,5-disulfonic acid tetrahydrate an acetonic solution of (15)-(+)-camforsulfonic acid monohydrate is used.
Lapatinib 2,5 dihydroxy benzoic acid (1 : 1) salt is preferably prepared in a similar way as described for naphtalene 1 ,5 disulfonic (1 : 1) salt with the difference that instead of methanol ethanol is used as solvent and instead of naphtalene- 1 ,5 -disulfonic acid tetrahydrate an ethanolic solution of 2,5 dihydroxy benzoic acid is used.
Lapatinib malonic acid (1 : 1) salt is preferably prepared by is preferably prepared by stirring the solution of the lapatinib base with an alcohol type solvent, preferably ethanol and adding solid malonic acid at a temperature between 0°C and the boiling point of the solvent,
preferably at a temperature between room temperature and 80°C, more preferably at 70°C. Then it is preferably stirred further overnight at room temperature. The precipitated crystals are filtered, optionally washed and dried.
Lapatinib malonic acid salt methanol solvate (1 :1 :1) is preferably prepared by stirring lapatinib malonic acid (1 : 1) salt in methanol at a temperature between 50 °C and 80 °C, preferably at the boiling point of the solvent, then for a further one hour at room temperature. The precipitated crystals are filtered, optionally washed and dried.
Lapatinib malonic acid (1 :2) salt is preferably prepared by stirring lapatinib free base in an alcoholic type solvent, preferably in ethanol and solid malonic acid is added to the mixture at a temperature between 0 °C and the boiling point of the solvent, preferably between room temperature and 80 °C, more preferably at 70 °C. Then after cooling it is stirred further preferably at room temperature for 24 hours. The precipitated crystals are filtered, optionally washed and dried.
Lapatinib nitric acid (1 :1) salt may be prepared preferably in a similar way as described for naphtalene 1,5 disulfonic acid (1 :1) salt with the difference that methanol is used as solvent instead of acetonitrile and nitric acid solution (65%) is added to the mixture instead of naphtalene 1,5 disulfonic acid.
Lapatinib citric acid (1 : 1) salt is preferably prepared by stirring lapatinib free base in an alcohol type solvent, preferably in methanol then citric acid monohydrate is added to the mixture at a temperature between 0°C and the boiling point of the solvent, preferably between room temperature and 80°C, more preferably at 70 °C then after cooling it is stirred further preferably at room temperature for 24 hours. The precipitated crystals are filtered, optionally washed and dried.
Lapatinib hydrogen bromide (1 :1) salt may be prepared in a similar way as described for the citric acid (1 :1) salt with the difference that instead of citric acid monohydrate hydrogen bromide 47% aqueous solution is added.
Lapatinib hydrogen bromide (1 :2) amorphous salt may be prepared in a similar way as described for the citric acid (1 :1) salt with the difference that instead of citric acid monohydrate hydrogen bromide 47% aqueous solution is added and the reaction mixture is stirred for 48 hours at room temperature.
Lapatinib naphtalene 2 sulfonic acid (1 :1) Form I is preferably prepared by stirring lapatinib free base in an alcohol type solvent, preferably in ethanol then naphtalene 2 sulfonic acid monohydrate is added to the mixture at a temperature between 0°C and the boiling point of the solvent, preferably between room temperature and 80°C, more preferably at 70 °C then after
cooling it is stirred further preferably at room temperature for 20 hours. The reaction mixture is optionally cooled to a temperature from 5 to 25°C. The precipitated crystals are filtered, optionally washed and dried then it is recrystallized from a dipolar-aprotic type solvent or an aqueous mixture thereof, preferably from acetonitrile or from a mixture of acetonitrile and water.
Lapatinib naphtalene 2 sulfonic acid (1:1) Form II salt is preferably prepared by stirring lapatinib free bas in a dipolar aprotic type solvent, preferably in acetonitrile then naphtalene 2 sulfonic acid monohydrate is added to the mixture at a temperature between 0°C and the boiling point of the solvent, preferably between room temperature and 90°C, more preferably at 80 °C then after cooling it is stirred further preferably at room temperature for 20 hours. The precipitated crystals are filtered, optionally washed and dried.
Lapatinib hydrochloride (1 :1) may be prepared in a similar way as described for citric acid (1 :1) salt with the difference that instead of citric acid monohydrate aqueous hydrochloride solution is added to the reaction mixture.
Lapatinib hydrochloride (1 :1) dihydrate salt is preferably prepared by stirring lapatinib hydrochloride (1 :1) salt in a dipolar aprotic type solvent or aqueous mixtures thereof, preferably in acetonitrile-water at a temperature from 50°C to 110 °C, preferably at the boiling point of the solvent mixture, then it is stirred further for 20 hours at room temperature. The precipitated crystals are filtered, optionally washed and dried.
Lapatinib hydrochloride (1 :2) trihydrate salt is preferably prepared by stirring lapatinib free base in an alcohol type solvent, preferably in methanol at a temperature between 0°C and the boiling point of the solvent, preferably between room temperature and 80°C, more preferably at 70°C then after cooling it is stirred further preferably at room temperature for 24 hours. The reaction mixture is optionally cooled to a temperature from 5 to 25°C. The precipitated crystals are filtered, optionally washed and dried then it is recrystallized from a dipolar-aprotic type solvent or an aqueous mixture thereof, preferably from acetonitrile or from a mixture of acetonitrile and water.
Lapatinib hydrochloride (1 :2) anhydrate salt is preferably prepared by drying lapatinib hydrochloride (1 :2) trihydrate salt in vacuo at a temperature form 50°C to 100°C, preferably at 80°C, under a pressure of 1-10 mbar, preferably at a pressure of 8 mbar for 24 hours.
In course of the thermal stress test and the forced stability test the decompositions in a pharmaceutical composition occurring during storage are constructed essentially in an accelerated manner. The results of these tests predicted that under normal storage conditions the new lapatinib salts of the present invention would be more stable than the salts used in the marketed pharmaceutical compositions and those known from the prior art. The advantageous
properties of the new lapatinib salts of the present invention are significant from the point of view of the formulation of pharmaceutical compositions, the storage and the minimalization of the harmful effects exerted in the human body.
The stability of the new lapatinib salts of the present invention was subjected to detailed tests. As referent product the lapatinib ditosylate monohydrate salt contained in the Tykerb® or Tyverb® medicine of the originator was used.
It has been surprisingly found that some of the lapatinib salts of the present invention show a higher stability than the salts known from prior art in the storage tests carried out under various conditions. It has been found that from the new salts of the present invention lapatinib citrate (1 :1) salt, hydrochloride (1 :2) dihydrate salt and the hydrochloride (1 :2) anhydrate salt salts proved to be particularly stable. Said salts are particularly useful in the preparation of pharmaceutical compositions.
Importantly the lapatinib hydrochloride (1 :2) trihydrate salt and the lapatinib hydrochloride (1 :2) anhydrate salt produced therefrom are new compounds of the present invention and they have the biologically advantageous property that both of them are hydrochloride salts thus these compounds do not contain any ballast material. Therefore their use in highly preferable compared to the presently used compound in which the salt forming component is the less favourable para-toluenesulfonic acid.
This advantage is extremely important in the case of lapatinib since the daily dosage of Tykerb® or Tyverb® preparations is 1500 mg (counted as free base) thus in the therapeutic use of different salts their individual toxicology should be taken into account.
A further general disadvantage of /j ra-toluenesulfonic acid salts is that extreme care should be taken during the production of the active ingredient. The presence of alcohols, especially the presence of ethanol in certain steps of the active ingredient production, or the technological steps attached thereto may result in the production of genotoxic alkyl- (in the case of ethanol ethyl-) /> ra-toluolsulfonate. The latter compound is a mutagenic and carcinogenic substance well known in the literature.
According to a further aspect of the present invention there are provided pharmaceutical compositions comprising a therapeutically effective amount of a lapatinib salt of the present invention and if desired a pharmaceutically active carrier.
According to a further aspect of the present invention there is provided the use of the lapatinib salts of the present invention for the preparation of pharmaceutical compositions.
The pharmaceutical compositions of the present invention may be administered preferably orally. Such oral compositions may be e.g. tablets, capsules, dragees, solutions, elixirs, suspensions or emulsions.
The pharmaceutical compositions according to the present invention may contain conventional pharmaceutical carriers and/or auxiliary agents. As carrier e.g. magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, low melting wax, PEG, cocoa butter etc. can be used. In case of capsules the carrier often serves as the capsule wall material so that no additional carrier is required. Chartula and lozenge are further oral pharmaceutical compositions. Particularly preferred oral administration forms are the powders, pirules, chartula and lozenges.
The tablets are prepared by admixing the active ingredient with suitable carriers in an appropriate ratio and from this mixture tablets of desired shape and size are pressed.
The powders are prepared by admixing the finely powdered active ingredient with the carriers. The liquid compositions may be solutions, suspensions and emulsions which can also be sustained release compositions. Aqueous solutions and aqueous propylene glycol solutions proved to be advantageous. Compositions suitable for parenteral administration can be prepared preferably in the form of aqueous polyethylene glycol solutions.
The pharmaceutical compositions of the invention can be preferably prepared in the form of dosage units which contain the desired amount of the active ingredient. The dosage units can be put on the market in the form of packages comprising separated amounts of the compositions e.g. packed tablets, capsules, vials or ampoules which contain the powder. The term "dosage unit" relates to the capsules, chartula, lozenge and also to the package comprising a suitable amount of dosage units.
According to a further aspect of the present invention there is provided a process for the preparation of the above pharmaceutical compositions which comprises admixing a lapatinib salt according to the invention or a mixture thereof with pharmaceutically acceptable solid or liquid diluents and/or auxiliary agents and bringing the mixture to a galenic composition.
The pharmaceutical compositions of the present invention can be prepared by conventional methods of pharmaceutical industry. The pharmaceutical compositions of the present invention may contain further pharmaceutical active ingredients which are compatible with the new lapatinib salts according to the invention or mixtures thereof.
According to a further aspect of the present invention there is provided the use of the lapatinib salts according to the invention as pharmaceutical active ingredient.
According to a further aspect of the present invention there is provided the use of any of the lapatinib salts for the treatment or prophylaxis of locally advanced or metastatic HER-2- positive breast cancer (MBC, metastatic breast cancer) furthermore for the treatment or prophylaxis of other cancers such as head-neck, lung and renal cell carcinoma.
According to a further aspect of the present invention there is provided the use of any of the lapatinib salts for the preparation of pharmaceutical compositions for the treatment or prophylaxis of locally advanced or metastatic HER-2-positive breast cancer (MBC, metastatic breast cancer) furthermore for the treatment or prophylaxis of other cancers such as head-neck, lung and renal cell carcinoma.
The advantage of the present invention is that the new lapatinib salt compounds of the present invention are substances of uniform morphology and have an advantageous crystal form. For this reason the salts of the present invention possess preferable and reproducible properties, such as dissolving velocity, bioavailability, chemical stability and processing characteristics e.g. filtration, drying and tabletting properties.
The active ingredients of the present invention may be prepared by procedures readily suitable for industrial scale manufacture.
Brief description of the drawings
All figures show X-ray powder diffracto grams of the named compounds.
Figure 1 - lapatinib naphtalene 1,5 disulfonic acid (1 : 1) salt
Figure 2 - lapatinib naphtalene 1,5 disulfonic acid salt dimethylformamide solvate (1: 1 :1)
Figure 3 - lapatinib (15)-(+)-camphorsulfonic acid (1 :1) salt
Figure 4 - lapatinib 2,5 dihydroxy benzoic acid (1 :1) salt
Figure 5 - lapatinib malonic acid (1 :1) salt
Figure 6 - lapatinib malonic acid salt methanol solvate (1 :1 :1)
Figure 7 - lapatinib malonic acid (1 :2) salt
Figure 8 - lapatinib nitric acid (1 :1) salt
Figure 9 - lapatinib citric acid (1 :1) salt
Figure 10 - lapatinib hydrogen bromide (1 :1) salt
Figure 11 - lapatinib hydrogen bromide (1 :2) amorphous salt
Figure 12 - lapatinib naphtalene 2 sulfonic acid (1 : 1) salt Form I
Figure 13 - lapatinib naphtalene 2 sulfonic acid (1 : 1) salt Form II
Figure 14 - lapatinib hydrochloride (1 : 1) salt
Figure 15 - lapatinib hydrochloride (1 : 1) salt dihydrate
Figure 16 - lapatinib hydrochloride (1 :2) salt trihydrate
Figure 17 - lapatinib hydrochloride (1 :2) salt anhydrate
Further details of the present invention are to be found in the following Examples without limiting the scope of protection to said Examples which serve the purpose of illustration only.
EXAMPLES
The lapatinib base used in the following examples was prepared from lapatinib ditosylate monohydrate by general methods well known for the person skilled in the art. NMR
The following NMR apparatuses were used:
- VARIAN INOVA 500 (500 MHz); BRUKER AVANCE III 400 (400 MHz)
X-ray powder diffraction measurements
The X-ray powder diffraction data of
lapatinib (15)-(+)-camphorsulfonic acid (1 :1) salt,
lapatinib 2,5 dihydroxy benzoic acid (1 :1) salt,
lapatinib hydrogen bromide (1 :1) salt,
lapatinib hydrogen bromide (1 :2) amorphous salt,
lapatinib malonic acid (1 :1) salt,
lapatinib malonic acid methanol solvate (1 :1 :1) salt,
lapatinib malonic acid (1 :2) salt,
lapatinib naphtalene 1,5 disulfonic (1 : 1) salt,
lapatinib naphtalene 1,5 disulfonic dimethylformamide solvate (1 :1 :1) salt,
lapatinib naphtalene 2 sulfonic (1 :1) salt Form I and Form II, and
lapatinib nitric acid (1 :1) salt were obtained under the following measuring conditions:
Apparatus: Rigaku Miniflex2 X-ray powder diffractometer
Radiation: CuKai (λ=1, 54060 A), CuKcc2 (λ=1,54439 A)
Accelerating voltag 30 kV
Anode current: 15 mA
Arrangement: Bragg-Brentano parafocusing geometry, 6-position sample changer, reflexive measurement setup
Detector: D/teX Ultra
Soller: source side: 2,5 °; detector side: 5 °
Orifices: source side: automatic and 1,25 ° divergence
detector side: 8 mm scattering slit
Measuring range: continuous Θ/2Θ scan, 3 - 35 °2Θ
Uptake velocity: 1 °/minute
Step interval: 0,02 °2Θ
Sample preparation: the powdered sample was leveled on a zero background Si single crystal sample holder
Rotation speed of the sample holder: 1 rotation/sec
Measurement cycles: 1
Measurement time: 32 minutes
The X-ray powder diffraction data of
Lapatinib citric acid (1 :1) salt, lapatinib hydrochloride (1 :1) salt,
lapatinib hydrochloride (1 :1) dihydrate salt,
lapatinib hydrochloride (1 :2) salt,
lapatinib hydrochloride (1 :2) trihydrate salt and
lapatinib hydrochloride (1 :2) anhydrate salt.
were obtained under the following measuring conditions:
Apparatus: Bruker D8 Advance X-ray powder diffractometer
Radiation: CuKcci (λ=1, 54060 A), CuKa2 (λ=1, 54439 A)
Accelerating voltagi 40 kV
Anode current: 40 mA
Arrangement: Gobel-mirror (parallel radiation), 9-position sample changer, transmissive arrangement
Detector: Bruker LynxEye
Soller: 2,5 °
Orifices: source side: 0.6 mm divergence slit
detector side: 8 mm slit
Measuring range: continuous Θ/2Θ scan, 4 - 35 °2Θ
Time for one step: 1.2 sec
Step interval: 0,02 °2Θ
Sample preparation: not powdered sample between Mylar foils, room temperature
Rotation speed of the sample holder: 0.5 rotation/sec
Measurement cycles: 1
Measurement time: 35 minutes
Thermogravimetric measuring conditions
Apparatus: Perkin Elmer Pyris 1 TGA thermogravimetric analyzer
Heating speed: 10 °C/minute
Atmosphere: N2 stream 40 ml/minute
Pan: open Pt pan
Example 1
Lapatinib naphtalenee-1,5 disulfonic acid (1 :1) salt
Into an apparatus 40 cm3 methanol is weighed in whereupon 0.582 g (1.00 mmol) lapatinib base is dissolved therein under intensive stirring and reflux. To the reaction mixture
0.360 g (1.00 mmol) naphtalene-l,5-disulfonic acid tetrahydrate (Armstrong-acid) in 10 cm3 methanol solution is added at this temperature. After some seconds crystal precipitation begins.
Stirring is continued until the reaction mixture cools to room temperature. After stirring for 20 hours the precipitated crystalline product is filtered and washed with a little cold methanol and ter/-butyl methyl ether.
Yield: 0,815 g (86,5 %)
Melting point: 240-245 °C
IR (KBr, cm-1): 3451, 3010, 2804, 1619, 1582, 1561, 1530, 1499, 1444, 1401, 1384, 1367, 1301, 1242, 1219, 1174, 1151, 1062, 1030, 996, 970, 954, 916, 881, 840, 802, 766, 748, 706, 683, 664, 610, 566, 528, 500, 478.
1H-NMR (DMSO-c/6, 500 MHz): 11.31 (b, 1H), 9.33 (b), 9.01 (d, J=1.3 Hz, 1H), 8.91 (s, 1H), 8.89 (m, 2H), 8.55 (dd, J^l .5 Hz, J2=8.6 Hz, 1H), 7.95 (m, 2H), 7.91 (d, J=2.6 Hz, 1H), 7.83 (d, J=8.8 Hz, 1H), 7.46 (m, 1H), 7.45 (m, 1H), 7.38 (m, 2H), 7.35 (m, 1H), 7.34 (m, 1H), 7.18 (m, 1H), 7.17 (d, J=3.6 Hz, 1H), 7.13 (d, J=9.0 Hz, 1H), 6.82 (d, J=3.5 Hz, 1H), 5.27 (s, 2H), 4.48 (s, 2H), 3.61 (m, 2H), 3.49 (m, 2H), 3.12 (s, 3H).
13C-NMR (DMSO-i/6, 125 MHz): 163.31, 161.37, 159.55, 152.50, 151.92, 151.23, 146.67, 143.47, 139.59, 139.53, 138.48, 131.42, 130.74, 130.68, 130.25, 129.77, 129.63, 129.23, 126.35,
124.49, 124.41, 124.24, 123.50, 123.48, 121.34, 121.19, 118.56, 115.22, 114.96, 114.79, 1 14.29, 114.14, 114.1 1, 109.53, 69.54, 49.78, 42.88, 40.91, 40.03.
Example 2
Lapatinib naphthalene 1,5 disulfonic acid dimethylformaniide solvate (1 : 1 : 1) salt
Into an apparatus 10 cm dimethylformaniide is weighed in whereupon 0,700 g lapatinib naphthalene 1,5 disulfonic acid is dissolved therein under intensive stirring and reflux. Then it is stirred for further four days under room temperature. The precipitated crystalline product is filtered and washed with a little dimethylformaniide and tert-butyl methyl ether. It is dried on air under room temperature.
Yield: 0.450 g (60.5 %).
Melting point: 235-241 °C
IR (KBr, cm'1): 3425, 3314, 3011, 2929, 2813, 1655, 1636, 1621, 1581, 1561, 1529, 1500, 1449, 1402, 1384, 1312, 1293, 1277, 1242, 1220, 1180, 1158, 1138, 1102, 1078, 1063, 1031, 953, 927, 900, 879, 841, 803, 765, 748, 694, 684, 665, 610, 565, 524, 463, 444.
1H-NMR (DMSO-ifc, 500 MHz): 11.30 (b, 1H), 9.33 (b), 9.00 (s, 1H), 8.91 (s, 1H), 8.89 (m, 2H), 8.35 (d, J=8.8 Hz, 1H), 7.95 (s, 1H), 7.94 (m, 2H), 7.91 (d, J=2.4 Hz, 1H), 7.84 (d, J=8.8 Hz, 1H), 7.47 (m, 2H), 7.38 (m, 2H), 7.35 (m, 1H), 7.34 (m, 1H), 7.18 (m, 1H), 7.17 (m, 2H), 6.83 (d, J=3.4 Hz, 1H), 5.28 (s, 2H), 4.47 (s, 2H), 3.59 (m, 2H), 3.48 (m, 2H), 3.13 (s, 3H), 2.89 (s, 3H), 2.73 (s, 3H).
Example 3
Lapatinib (l,SV(+ -camphorsulfonic acid salt (1 :1)
Into an apparatus 30 cm3 acetone is weighed in whereupon 0.885 g (1.52 mmol) lapatinib base is dissolved therein under intensive stirring and reflux. To the hot solution under stirring
0.381 g (1.52 mmol) (15)-(+)-camphorsulfonic acid monohydrate in 10 cm3 acetone is added.
The reaction mixture is allowed to cool to room temperature under stirring, then 15 cm3 tert- butyl methyl ether is added thereto and further stirred. Slowly crystals start to appear then it is stirred for 24 hours under room temperature then for a further one hour under external ice/water cooling. The precipitated crystalline product is filtered and washed with a little cold acetone and tert-butyl methyl ether.
Yield: 1.110 g (89.8 %).
Melting point: 123.0-130.8 °C
1H-NMR (DMSO-d6, 500 MHz): 10.07 (b, 1H), 9.40 (b), 8.88 (d, J=1.5 Hz, 1H), 8.61 (s, 1H), 8.25 (dd, Ji=1.7 Hz, J2=8.6 Hz, 1H), 8.00 (d, J=2.4 Hz, 1H), 7.86 (d, J=8.8 Hz, 1H), 7.75 (dd, Ji=2.6 Hz, J2=9.0 Hz, 1H), 7.48 (m, 1H), 7.34 (m, 1H), 7.33 (m, 1H), 7.30 (d, J=9.0 Hz, 1H), 7.18 (m, 2H), 6.85 (d, J=3.5 Hz, 1H), 5.28 (s, 2H), 4.43 (s, 2H), 3.61 (m, 2H), 3.45 (m, 2H), 3.14 (s, 3H), 2.99 (d, J=14.6 Hz, 1H), 2.62 (m, 1H), 2.48 (d J=14.1 Hz, 1H), 2.24 (m, 1H), 1.93 (m, 1H), 1.82 (m, 2H), 1.35 (m, 1H), 1.25 (m, 1H), 0.99 (s, 3H), 0.72 (s, 3H).
13C-NMR (DMSO-t¾, 125 MHz): 216.20, 162.36 (d, J=243.7 Hz), 158.3, 154.33, 153.55, 150.24, 148.21, 146.60, 139.78 (d, J=7.3 Hz), 132.88, 130.70 (d, J=8.3 Hz), 129.18, 128.00, 127.86, 124.82, 123.43 (d, J=2.4 Hz), 123.05, 121.29, 117.73, 115.33, 114.83 (d, J=21.0 Hz), 114.70, 1 14.47, 114.13 (d, J=22.0 Hz), 108.27, 72.19, 69.59, 58.27, 50.02, 48.85, 47.25, 47.02, 43.09, 42.37, 42.23, 40.95, 26.97, 26.53.
Example 4
Lapatinib 2,5 dihydroxy benzoic acid (1 : 1) salt
Into an apparatus 50 cm ethanol is weighed in whereupon 0.797 g (1.37 mmol) lapatinib base is dissolved therein under intensive stirring and reflux. To the reaction mixture 0.211 g (1.37 mmol) 2,5 dihydroxy benzoic acid in 10 cm3 ethanol is added. The reaction mixture is allowed to cool to room temperature under stirring then it is stirred for a further 20 hours. The precipitated crystalline product is filtered and washed with a little cold ethanol and fert-butyl methyl ether. Dried in vacuo for one day under room temperature.
Yield: 0.705 g (70.5 %)
Melting point: 121.3-124.9 °C
Analysis calculated for C29H26C1FN404S-C7H604 (735.19):
Calculated C: 58.81 H: 4.39 N: 7.62 CI: 4.82 S: 4.36
Measured C: 58.15 H: 4.33 N: 7.52 CI: 4.88 S: 4.32
IR (KBr, cm"1): 3026, 2922, 2727, 2625, 1592, 1561, 1498, 1462, 1419, 1384, 1368, 1349, 1334, 1307, 1257, 1241, 1177, 1 131, 1089, 1077, 1059, 1042, 1026, 1001, 973, 948, 927, 877, 845, 827, 81 1, 794, 782, 717, 705, 686, 661, 641, 622, 556, 541 , 519, 490, 481, 456, 415.
1H-NMR (DMSO-t¾, 500): 9.93 (b, 1H), 8.78 (s, 1H), 8.58 (s, 1H), 8.17 (dd, J^O.9 Hz, J2=8.6 Hz, 1H), 8.03 (d, J=2.2 Hz, 1H), 7.81 (d, J=8.8 Hz, 1H), 7.76 (dd, Ji=2.2 Hz, J2=8.8 Hz, 1H), 7.48 (m, 1H), 7.34 (m, 1H), 7.33 (m, 1H), 7.29 (d, J=9.0 Hz, 1H), 7.20 (m, 1H), 7.19 (m, 1H), 7.08 (d, J=3.3 Hz, 1H), 6.86 (dd, 1^3.1 Hz, J2=8.8 Hz, 1H), 6.70 (d, J=8.8 Hz, 1H), 6.63 (d,
J=3.1 Hz, 1H), 5.27 (s, 2H), 4.08 (s, 2H), 3.44 (t, J=7.1 Hz, 2H), 3.20 (t, J=7.1 Hz, 2H), 3.08 (s, 3H).
13C-NMR (DMSO-t¾, 125 MHz): 172.27, 162.37 (d, J=243.7 Hz), 157.74, 154.45, 154.41, 152.40, 151.80, 149.98, 149.02, 148.99, 139.80 (d, J=7.8 Hz), 133.25, 130.69 (d, J=8.3 Hz), 128.77, 128.56, 128.25, 124.49, 123.47 (d, J=2.9 Hz), 122.67, 122.22, 121.27, 1 17.18, 1 17.00, 1 15.52, 1 15.18, 1 14.83 (d, J=21.0 Hz), 1 14.51, 114.18 (d, J=22.0 Hz), 11 1.54, 108.02, 69.61 (d, J=1.5 Hz), 52.40, 44.37, 41.39.
Example 5
Lapatinib malonic acid (1 :1) salt (lapatinib monomalonate)
Into an apparatus 60 cm3 ethanol is weighed in whereupon 0.822 g (1.45 mmol) lapatinib base is dissolved therein under intensive stirring and reflux. To the reaction mixture 0.147 g
(1.45 mmol) malonic acid is added then it is allowed to cool to room temperature under stirring.
Meanwhile precipitation starts. Then the reaction mixture is stirred for a further 24 hours. The precipitated crystalline product is filtered and washed with a little cold ethanol and tert-butyl methyl ether. Dried under a pressure of 7.8 mbar and at a temperature of 25 °C.
Yield: 0.793 g (82,1 %)
Melting point: 157.8-161.2 °C
Analysis calculated for C29H26C1FN404S-C3H404 (685.13):
Calculated C: 56.10 H: 4.41 N: 8.18 CI: 5.17 S: 4.68
Measured C: 55.97 H: 4.46 N: 8.07 CI: 5.29 S: 4.41
IR (KBr, cm"1): 3444, 3286, 3019, 2989, 2939, 2758, 2564, 2416, 1935, 1702, 1630, 1594, 1571, 1545, 1529, 1497, 1445, 1424, 1388, 1367, 1323, 1292, 1272, 1213, 1141, 1059, 1030, 996, 974, 955, 931, 913, 891, 865, 844, 836, 811, 794, 750, 708, 682, 665, 634, 624, 607, 582, 566, 553, 534, 521, 509, 497, 480, 467, 440, 414.
1H-NMR (DMSO-<¾, 400): 9.91 (b, 1H), 8.75 (s, 1H), 8.56 (s, 1H), 8.18 (d, J=8.8 Hz, 1H), 8.01 (d, J=2.1 Hz, 1H), 7.82 (d, J=8.7 Hz, 1H), 7.74 (dd, J]=2.1 Hz, J2=8.9 Hz, 1H), 7.48 (m, 1H), 7.34 (m, 1H), 7.32 (m, 1H), 7.29 (m, 1H), 7.19 (m, 1H), 7.08 (d, J=3.3 Hz, 1H), 6.58 (d, J=3.2 Hz, 1H), 5.27 (s, 2H), 3.98 (s, 2H), 3.35 (t, J=6.9 Hz, 2H), 3.13 (s, 2H), 3.11 (t, J=7.0 Hz, 2H), 3.06 (s, 3H).
13C-NMR (DMSO-<¾, 125 MHz): 169.45, 169.44, 162.41 (d, J=243.7 Hz), 157.79, 154.53, 152.82, 152.23, 150.00, 149.08, 139.85 (d, J=7.3 Hz), 133.22, 130.79 (d, J=8.1 Hz), 128.84, 128.69, 128.36, 124.56, 123.56 (d, J=2.9 Hz), 122.76, 121.24, 116.88, 115.55, 114.93 (d, J=20.7
Hz), 114.48, 114.27 (d, J=21.9 Hz), 111.13, 108.12, 69.57 (d, J=1.5 Hz), 52.81, 44.77, 41.68, 41.52, 41.42.
Example 6
Lapatinib malonic acid methanol solvate (1 : 1 : 1) salt
Into an apparatus 27 cm methanol is weighed in whereupon 0.440 g (0.64 mmol) lapatinib malonic acid is dissolved in it. The reaction mixture is allowed to cool down to room temperature, the slow crystallization process starts. The reaction mixture is stirred for one hour under room temperature then for one hour under external ice/water cooling. The precipitated crystalline product is filtered and washed with a little cold ethanol and tert-butyl methyl ether. Yield: 0.425 g (96.6 %).
Melting point: 158.1-161.7 °C
Analysis calculated for C29H26C1FN404S · C3H404 · CH4O (717.17):
Calculated C: 55.27 H: 4.78 N: 7.81 CI: 4.94 S: 4.47
Measured C: 54.60 H: 4.30 N: 7.90 CI: 5.11 S: 4.47
IR (KBr, cm"1): 3425, 3124, 3011, 2926, 2859, 2597, 2456, 1948, 1711, 1604, 1593, 1571, 1545, 1524, 1498, 1448, 1422, 1382, 1367, 1320, 1293, 1276, 1213, 1139, 1061, 1024, 968, 955, 928, 897, 870, 838, 789, 749, 685, 662, 639, 625, 582, 551, 523, 494, 478, 443, 408.
1H-NMR (DMSO-c¼, 400 MHz): 9.91 (b, 1H), 8.76 (s, 1H), 8.57 (s, 1H), 8.18 (d, J=8.8 Hz, 1H), 8.02 (d, J=1.8 Hz, 1H), 7.82 (d, J=8.7 Hz, 1H), 7.75 (dd, J,=1.6 Hz, J2=8.8 Hz, 1H), 7.48 (m, 1H), 7.35 (m, 1H), 7.34 (m, 1H), 7.30 (d, 1H), 7.19 (m, 1H), 7.08 (d, J=3.1 Hz, 1H), 6.60 (d, J=3.0 Hz, 1H), 5.27 (s, 2H), 4.01 (s, 2H), 3.37 (t, J=6.8 Hz, 2H), 3.18 (s, 3H), 3.13 (s, 2H), 3.13 (t, 2H), 3.08 (s, 3H).
Example 7
Lapatinib malonic acid (1 :2) salt (lapatinib dimalonate)
Into an apparatus 50 cm3 ethanol is weighed in whereupon 0.776 g (1.34 mmol) lapatinib base is dissolved therein under intensive stirring and reflux. To the reaction mixture 0.279 g (2.68 mmol) malonic acid is added. The reaction mixture under stirring is allowed to cool to room temperature then it is stirred for a further 24 hours. The precipitated crystalline product is filtered and washed with a little cold ethanol and tert-butyl methyl ether and yellow crystalline product is obtained.
Yield: 0.883 g (83.4 %).
Melting point: 166.3-169.5 °C
Analysis calculated for C29H26C1FN404S-C6H808 (789.20):
Calculated C: 53.27 H: 4.34 N: 7.10 CI: 4.49 S: 4.06
Measured C: 53.12 H: 4.33 N: 7.15 CI: 4.57 S: 4.19
IR (KBr, cm"1): 3433, 3010, 2930, 2603, 1731, 1610, 1591, 1559, 1529, 1501, 1444, 1413, 1380, 1328, 1288, 1275, 1212, 1159, 1136, 1062, 1031, 954, 927, 893, 874, 842, 809, 783, 752, 683, 660, 582, 535, 523, 504, 443.
1H-NMR (DMSO-<¾, 500 MHz): 9.90 (b, 1H), 8.76 (d, J=1.3 Hz, 1H), 8.56 (s, 1H), 8.18 (dd, Hz, J2=8.6 Hz, 1H), 8.02 (d, J=2.4 Hz, 1H), 7.82 (d, J=8.6 Hz, 1H), 7.75 (dd, J,=2.4 Hz, J2=8.8 Hz, 1H), 7.48 (m, 1H), 7.34 (m, 1H), 7.33 (m, 1H), 7.30 (d, J=9.0 Hz, 1H), 7.18 (m, 1H), 7.08 (d, J=3.3 Hz, 1H), 6.62 (d, J=3.3 Hz, 1H), 5.27 (s, 2H), 4.06 (s, 2H), 3.39 (t, J=7.0 Hz, 2H), 3.17 (m, 2H), 3.16 (s, 4H), 3.08 (s, 3H).
13C-NMR (DMSO-c¾, 125 MHz): 169.10, 163.34, 161.40, 157.75, 154.47, 152.39, 151.95, 150.00, 149.03, 139.84, 139.78, 133.24, 130.74, 130.67, 128.78, 128.59, 128.26, 124.50, 123.49, 123.47, 122.69, 121.29, 116.98, 1 15.53, 114.93, 114.77, 114.53, 114.27, 1 14.10, 111.52, 108.06, 69.63, 52.47, 44.52, 41.60, 41.43, 39.7.
Example 8
Lapatinib nitric acid CI :1 salt
Into an apparatus 18 cm3 acetonitrile is weighed in whereupon 0.760 g (1.31 mmol) lapatinib base is dissolved therein under intensive stirring and reflux. To the reaction mixture
0.0907 cm 65 % aqueous nitric acid solution (1,31 mmol) is added. Yellow precipitate appears then the reaction mixture is allowed to cool to room temperature while stirred then it is stirred for further 20 hours. The precipitated crystalline product is filtered and washed with a little cold acetonitrile and tert-butyl methyl ether.
Yield: 0.808 g (95.8 %).
Melting point: 212.0-214.0 °C
Analysis calculated for
(644.08):
Calculated C: 54.08 H: 4.23 N: 10.87 CI: 5.50 S: 4.98
Measured C: 53.70 H: 4.14 N: 10.84 CI: 5.58 S: 4.79
IR (KBr, cm"1): 3403, 3021, 2984, 2898, 2815, 2628, 2425, 1916, 1601, 1592, 1568, 1542, 1530, 1496, 1454, 1438, 1420, 1384, 1365, 1341, 1331, 1290, 1282, 1268, 1235, 1212, 1 197, 1169,
1158, 1 137, 1081, 1062, 1035, 983, 966, 955, 923, 901 , 886, 873, 843, 836, 873, 843, 836, 816, 799, 788, 776, 748, 724, 692, 681 , 665, 594, 582, 566, 546, 536, 524, 515, 506, 447, 416.
1H-NMR (DMSO-£¾, 400 MHz): 10.01 (b, 1H), 9.20 (b), 8.84 (s, 1H), 8.62 (s, 1H), 8.24 (d, J=8.8 Hz, 1H), 8.02 (d, J=1.8 Hz, 1H), 7.86 (d, J=8.8 Hz, 1H), 7.74 (dd, Ji=1.7 Hz, J2=8.8 Hz, 1H), 7.48 (m, 1H), 7.34 (m, 1H), 7.33 (m, 1H), 7.30 (d, 1H), 7.19 (m, 1H), 7.15 (d, J=3.4 Hz, 1H), 6.85 (d, J=3.3 Hz, 1H), 5.28 (s, 2H), 4.41 (s, 2H), 3.55 (m, 2H), 3.45 (m, 2H), 3.15 (s, 3H).
Example 9
Lapatinib citric acid (1 : 1) salt
Into an apparatus40 cm3 methanol is weighed in whereupon 0.800 g (1.38 mmol) lapatinib base is dissolved therein under intensive stirring and reflux. To the reaction mixture 0.290 g (1.38 mmol) crystalline citric acid monohydrate is added. The reaction mixture is stirred for 1 hour on its boiling point, the it is stirred and allowed to cool to room temperature then it is stirred for a further 24 hours. The precipitated crystalline product is filtered and washed with a little cold ethanol and rt-butyl methyl ether. The product is dried on 45 °C for 24 hours under 6,8 mbar pressure.
Yield: 0.940 g (86.2 %).
Melting point: 196.8-21 1 °C
Analysis calculated for C29H26C1FN404S-C5H807 (773.20):
Calculated C: 54.37 H: 4.43 N: 7.25 CI: 4.59 S: 4.15
Measured C: 54.29 H: 4.34 N: 7.16 CI: 4.54 S: 4.04
IR (KBr, cm"1): 3491, 3358, 3124, 3021 , 2928, 2859, 1735, 1699, 1609, 1592, 1560, 1533, 1499, 1451 , 1427, 1369, 1340, 1307, 1266, 1219, 1 135, 1099, 1080, 1061, 1025, 996, 972, 949, 927, 902, 846, 823, 795, 739, 710, 683, 627, 578, 569, 521 , 501 , 479, 442, 423.
1H-NMR (DMSO-c¾, 400 MHz): 9.90 (b, 1H), 8.75 (s, 1H), 8.56 (s, 1H), 8.17 (d, J=8.7 Hz, 1H), 8.01 (d, J=2.3 Hz, 1H), 7.82 (d, J=8.7 Hz, 1H), 7.75 (dd, Ji=2.2 Hz, J2=8.8 Hz, 1H), 7.48 (m, 1H), 7.34 (m, 1H), 7.33 (m, 1H), 7.29 (d, J=9.1 Hz, 1H), 7.19 (m, 1H), 7.08 (d, J=3.2 Hz, 1H), 6.57 (d, J=3.2 Hz, 1H), 5.27 (s, 2H), 3.96 (s, 2H), 3.34 (t, J=6.8 Hz, 2H), 3.09 (t, J=6.8 Hz, 2H), 3.06 (s, 3H), 2.72 (d, J=15.3 Hz, 2H), 2.63 (d, J=15.3 Hz, 2H).
Example 10
Lapatinib hydrogen bromide (1 : 1) salt
Into an apparatus 40 cm3 methanol is weighed in whereupon 0.700 g (1.21 mmol) lapatinib base is dissolved therein under intensive stirring and reflux. To the reaction mixture 0.140 cm3 (1.21 mmol) 47 % aqueous hydrogen bromide is added. The solution immediately starts to turn opal, the precipitation starts to appear. The reaction mixture is stirred and allowed to cool to room temperature then it is stirred for a further 24 hours. The precipitated crystalline product is filtered and washed with a little cold ethanol and tert-butyl methyl ether. Well filterable crystalline product is obtained. The product is dried on 40 °C for 24 hours under 5.2 mbar pressure.
Yield: 0.668 g (83.4 %).
Melting point: 239-243 °C
Analysis calculated for C29H27BrClFN404S (661.98):
Calculated: C: 52.62 H: 4.11 N: 8.46 CI: 5.36 Br: 12.07 S: 4.84
Measured: C: 52.63 H: 4.16 N: 8.55 CI: 5.21 Br: 12.24 S: 4.73 IR (KBr, cm"1): 3421, 3023, 2983, 2896, 2851, 2731, 2696, 2589, 2377, 1630, 1599, 1568, 1544, 1530, 1505, 1496, 1453, 1438, 1420, 1389, 1377, 1366, 1329, 1285, 1270, 1249, 1215, 1196, 1162, 1135, 1081, 1062, 1035, 1025, 981, 967, 953, 922, 900, 887, 873, 838, 815, 801, 786, 747, 727, 691, 681 , 664, 634, 608, 590, 582, 534, 513, 462, 444, 436, 426, 415.
1H-NMR (DMSO- 6, 400 MHz): 10.81 (bs, 1H), 9.41 (b), 9.14 (s, 1H), 8.80 (s, 1H), 8.35 (d, J=8.7 Hz, 1H), 8.00 (d, J=2.4 Hz, 1H), 7.91 (d, J=8.8 Hz, 1H), 7.75 (dd, Ji=2.4 Hz, J2=8.9 Hz, 1H), 7.49 (m, 1H), 7.35 (d, 1H), 7.34 (m, 2H), 7.30 (d, J=3.4 Hz, 1H), 7.20 (m, 1H), 6.89 (d, J=3.4 Hz, 1H), 5.31 (s, 2H), 4.47 (s, 2H), 3.62 (m, 2H), 3.48 (m, 2H), 3.16 (s, 3H).
Example 11
Lapatinib hydrogen bromide (1 :2) amorphous salt
Into an apparatus 40 cm3 methanol is weighed in whereupon 0.701 g (1.21 mmol) lapatinib base is dissolved therein under intensive stirring and reflux. To the reaction mixture 0.280 cm (2.42 mmol) 47 % aqueous hydrogen bromide solution is added. Precipitate starts to appear, then we allow the reaction mixture to cool to room temperature, then the mixture is stirred for a further 48 hours. From the reaction mixture ethanol is evaporated to half volume. The precipitated crystalline product is filtered and washed with a little cold ethanol and tert-butyl methyl ether. Well filterable crystalline product is obtained. The product is dried on 40 °C for 24 hours under 3.8 mbar pressure.
Yield: 0.707 g (78.9 %).
Melting point: 225.0-234.0 °C
Analysis calculated for C29H28Br2ClFN404S (742.89):
Calculated: C: 46.89 H: 3.80 N: 7.54 CI: 4.77 Br: 21.51 S: 4.32
Measured: C: 46.22 H: 3.77 N: 7.44 CI: 4.64 Br: 21.23 S: 4.22
IR (KBr, cm"1): 2988, 2923, 2742, 2398, 1615, 1574, 1557, 1532, 1499, 1443, 1382, 1365, 1297, 1272, 1136, 1061, 1029, 968, 955, 925, 862, 841, 802, 780, 747, 681, 665, 583, 533, 517, 502, 441.
1H-NMR (DMSO- ¾, 400 MHz): 1 1.45 (b, 1H), 9.44 (b), 9.29 (s, 1H), 8.96 (s, 1H), 8.44 (d, J=8.8 Hz, 1H), 7.95 (d, J=8.3 Hz, 1H), 7.95 (d, J=2.7 Hz, 1H), 7.71 (dd, 1^2.4 Hz, J2=8.9 Hz, 1H), 7.49 (m, 1H), 7.38 (d, J=9.0 Hz, 1H), 7.35 (m, 3H), 7.20 (m, 1H), 6.91 (d, J=3.4 Hz, 1H), 5.33 (s, 2H), 4.48 (s, 2H), 3.63 (m, 2H), 3.49 (m, 2H), 3.17 (s, 3H).
Example 12
Lapatinib naphtalene 2 sulfonic acid (1 : 1) salt Form I and Form II
1) Form I
Into an apparatus 80 cm3 ethanol is weighed in whereupon 0.800 g (1.38 mmol) lapatinib base is dissolved therein under intensive stirring and reflux. To the reaction mixture 0.312 g (1.38 mmol) naphtalene-2-sulfonic acid monohydrate is added. Immediately precipitate starts to appear, to the reaction mixture further 30 cm3 ethanol is added then it is stirred and allowed to cool to room temperature, the it is stirred for a further 20 hours. The precipitated crystalline product is filtered and washed with a little cold ethanol and tert-butyl methyl ether. The product is dried on 25 °C for 24 hours under 6.1 mbar pressure.
Yield: 1.023 g (93.9 %).
The obtained salt is recrystallized according to the following: 0.400 g material is recrystallized from 22 cm3 acetonitrile/water 9:1 mixture. After cooling to room temperature the mixture is further stirred for one hour, then for 30 minutes on a temperature of 0-5 °C. The precipitated product is filtered then washed with a little cold solution then with tert-buthyl methyl ether. The product is dried on 50 °C for 4 days under 3.9 mbar pressure.
Yield: 0.337 g (84.3 %).
Melting point: 194.8-199.0 °C
Analysis calculated for C29H26ClFN4O4S-C10H8O3S (789.31):
Calculated: C: 59.35 H: 4.34 N: 7.10 CI: 4.49 S: 8.12
Measured: C: 58.94 H: 4.36 N: 7.00 CI: 4.46 S: 7.96
IR (KBr, cm"1): 3416, 3017, 2771, 1592, 1567, 1526, 1503, 1448, 1420, 1386, 1297, 1271, 1248, 1139, 1092, 1059, 1032, 966, 922, 868, 836, 787, 749, 676, 623, 567, 523, 503.
1H- MR (DMSO-ffc, 400 MHz): 10.00 (b, 1H), 9.12 (b, 1H), 8.86 (s, 1H), 8.61 (s, 1H), 8.23 (d, J=8.8 Hz, 1H), 8.15 (s, 1H), 8.00 (d, J=1.6, Hz, 1H), 7.95 (m, 1H), 7.89 (m, 1H), 7.85 (d, J=8.9 Hz, 1H), 7.85 (d, J=8.5 Hz, 1H), 7.72 (m, 2H), 7.52 (m, 2H), 7.47 (m, 1H), 7.34 (m, 1H), 7.32 (m, 1H), 7.28 (d, J=9.0 Hz, 1H), 7.19 (m, 1H), 7.16 (d, J=3.4 Hz, 1H), 6.84 (d, J=3.2 Hz, 1H), 5.27 (s, 2H), 4.41 (s, 2H), 3.55 (m, 2H), 3.45 (m, 2H), 3.14 (s, 3H). 2) Form II
Into an apparatusl5 cm3 acetonitrile is weighed in whereupon 0.600 g (1.03 mmol) lapatinib base is dissolved therein under intensive stirring and reflux. To the reaction mixture 0.234 g (1.03 mmol) naphtalene-2-sulfonic acid monohydrate in 5 cm3 acetonitrile is added. Precipitate starts to appear the reaction mixture is stirred for a further 20 hours. The precipitated crystalline product is filtered and washed with a little cold acetonitrile and tert-butyl methyl ether. The product is dried on 50 °C for 48 hours under 2.8 mbar pressure.
Yield: 0.694 g (85.4 %)
Melting point: 200-205 °C IR (KBr, cm"1): 3379, 2764, 1602, 1567, 1541, 1525, 1496, 1450, 1421, 1296, 1246, 1139, 1089, 1028, 958, 922, 904, 839, 783, 747, 676, 623, 565, 518, 504, 477.
Example 13
Lapatinib hydrochloride (1 :1) salt (lapatinib monohydrochloride)
Into an apparatus 200 cm methanol is weighed in whereupon 5.000 g (8.60 mmol) lapatinib base is dissolved therein under intensive stirring and reflux. To the reaction mixture 6.720 cm (8.60 mmol) 1.28 N aqueous hydrogen chloride solution is added. Immediately precipitate appears then by stopping the heating the reaction mixture is stirred further for 24 hours under room temperature. From the reaction mixture approximately 80 cm3 methanol is evaporated, then the mixture is stirred further with external ice/water cooling. The precipitated crystalline product is filtered and washed with a little cold methanol and tert-butyl methyl ether. The product is dried on 40 °C for 24 hours under 3.0 mbar pressure.
Yield: 5.058 g (95.2 %).
Melting point: 235-238 °C
Analysis calculated for C29H27C12FN404S (617.53):
Calculated: C: 56.41 H: 4.41 N: 9.07 CI: 11.48 S: 5.19
Measured: C: 56.64 H: 4.27 N: 9.12 CI: 11.57 S: 5.14 IR (KBr, cm"1): 3432, 3128, 3025, 2986, 2898, 2813, 2738, 2695, 2593, 2406, 1918, 1844, 1734, 1718, 1700, 1684, 1653, 1631, 1599, 1590, 1569, 1545, 1530, 1506, 1496, 1455, 1437, 1421, 1395, 1389, 1376, 1340, 1328, 1288, 1271, 1249, 1215, 1196, 1 161, 1136, 1081, 1062, 1036, 1024, 984, 970, 953, 939, 923, 900, 888, 873, 857, 838, 816, 801, 787, 746, 727, 690, 681, 668, 663, 634, 609, 590, 583, 545, 535, 512, 494, 458, 449, 444, 436, 423, 419, 414.
1H-NMR (DMSO-<¾, 400 MHz): 10.22 (b, 1H), 9.80 (b), 9.26 (s, 1H), 8.62 (s, 1H), 8.24 (d, J=8.7 Hz, 1H), 8.18 (d, J=2.2 Hz, 1H), 7.91 (dd,
Hz, J2=8.9 Hz, 1H), 7.84 (d, J=8.7 Hz, 1H), 7.48 (m, 1H), 7.34 (m, 1H), 7.31 (m, 1H), 7.30 (d, J=9.1 Hz, 1H), 7.21 (d, J=3.2Hz, 1H), 7.19 (m, 1H), 6.82 (d, J=3.3 Hz, 1H), 5.28 (s, 2H), 4.42 (s, 2H), 3.67 (m, 2H), 3.44 (m, 2H), 3.15 (s, 3H).
Example 14
Lapatinib hydrochloride (1 : 1) dihydrate salt (lapatinib monohydrochloride dihydrate (1 : 1 :2)]
The hydrochloride salt of example 13 is recrystallized according to the following: 1.500 g
(2.43 mmol) material may be recrystallized from 150 cm3 acetonitrile/water 2.5: 1. After cooling to room temperature the mixture is further stirred for 20 hours, then for 2 hours with ice/water cooling. The precipitated product is filtered then washed with a little cold solution then with tert- buthyl methyl ether. The product is dried on air.
Yield: 1.419 g (89.3 %).
Melting point: 235-238 °C
Analysis calculated for C29H31C12FN406S (653.56):
Calculated: C: 53.30 H: 4.78 N: 8.57 CI: 10.85 S: 4.91
Measured: C: 53.30 H: 4.80 N: 8.50 CI: 10.76 S: 4.87
IR (KBr, cm"1): 3473, 3397, 3132, 3031, 3015, 2929, 2771, 2721, 2610, 2413, 1666, 1601, 1571, 1545, 1528, 1508, 1497, 1464, 1448, 1423, 1395, 1365, 1333, 1324, 1285, 1258, 1215, 1 198, 1160, 1 140, 1079, 1059, 1024, 975, 957, 936, 927, 904, 884, 871, 840, 820, 804, 787, 749, 733, 687, 663, 625, 594, 578, 563, 548, 535, 518, 507, 451, 435.
1H-NMR (DMSO-ifc, 400 MHz): 10.21 (b, 1H), 9.76 (b), 9.26 (s, 1H), 8.61 (s, 1H), 8.23 (dd, Ji=1.2 Hz, J2=8.7 Hz, 1H), 8.18 (d, J=2.3 Hz, 1H), 7.91 (dd,
Hz, J2=8.9 Hz, 1H), 7.83 (d,
J=8.7 Hz, 1H), 7.48 (m, 1H), 7.34 (m, 1H), 7.33 (m, 1H), 7.30 (d, J=9.1 Hz, 1H), 7.21 (d, J=3.3 Hz, 1H), 7.19 (m, 1H), 6.80 (d, J=3.3 Hz, 1H), 5.27 (s, 2H), 4.41 (s, 2H), 3.67 (m, 2H), 3.42 (m, 2H), 3.15 (s, 3H). Example 15
Lapatinib hydrochloride (1 :2) trihydrate salt (lapatinib dihydrochloride trihydrate (1 :2:3) a) Lapatinib hydrochloride salt (1 :2)
Into an apparatus 200 cm3 methanol is weighed in whereupon 5.000 g (8.60 mmol) lapatinib base is dissolved therein under intensive stirring and reflux. To the reaction mixture 14.781 cm (18.92 mmol, 2.2 equivalent) 1.28 N aqueous hydrogen chloride solution is added. Yellow precipitate appears then by stopping the heating the reaction mixture is stirred further for 24 hours under room temperature. From the reaction mixture approximately 80 cm methanol is evaporated, then the mixture is stirred further for one hour with external ice/water cooling. The precipitated crystalline product is filtered and washed with a little cold methanol and tert-butyl methyl ether. The product is dried on 40 °C for 24 hours under 7.0 mbar pressure.
Yield: 5.426 g (96.5 %).
Melting point: 253-260 °C
Analysis calculated for C29H28C13FN404S (653.99):
Calculated: C: 53.26 H: 4.32 N: 8.57 CI: 16.26 S: 4.90
Measured: C: 53.21 H: 4.26 N: 8.57 CI: 16.11 S: 4.87
IR (KBr, cm-1): 3426, 3258, 3126, 2987, 2928, 2712, 2604, 2426, 1635, 1617, 1592, 1574, 1557, 1533, 1505, 1489, 1445, 1413, 1383, 1369, 1328, 1302, 1276, 1266, 1223, 1189, 1176, 1131, 1063, 1031, 969, 955, 925, 895, 870, 842, 818, 749, 735, 703, 693, 682, 668, 663, 639, 625, 582, 562, 552, 548, 543, 533, 517.
1H-NMR (DMSO- , 400 MHz): 11.70 (b, 1H), 9.97 (b, 1H), 9.61 (s, 1H), 8.82 (s, 1H), 8.34 (d, J=8.8 Hz, 1H), 7.99 (d, J=2.5 Hz, 1H), 7.92 (d, J=8.8 Hz, 1H), 7.76 (dd, Ji=2.4 Hz, J2=8.9 Hz, 1H), 7.41 (m, 1H), 7.30 (d, J=3.4 Hz, 1H), 7.27 (m, 3H), 7.12 (m, 1H), 6.88 (d, J=3.4 Hz, 1H), 5.24 (s, 2H), 4.38 (s, 2H), 3.66 (m, 2H), 3.38 (m, 2H), 3.08 (s, 3H). b) Recrystallization of lapatinib hydrochloride salt (1 :2) from acetonitrile/water
The dihydrochloride salt of example 14 is recrystallized according to the following: 2.200 gram (3,36 mmol) salt may be recrystallized from 130 cm3 acetonitrile/water 2: 1. After cooling to room temperature the mixture is stirred for further 48 hours then with ice/water cooling for
further 2 hours. The precipitated crystalline product is filtered and washed with a little cold solution mixture then with tert-butyl methyl ether. The product is dried on air.
Yield: 1.798 g (75.5 %).
Melting point: 257-263 °C
Analysis calculated for C29H34C13FN407S (708.04):
Calculated: C: 49.20 H: 4.84 N: 7.91 CI: 15.02 S: 4.53
Measured: C: 49.01 H: 4.75 N: 7.95 CI: 14.89 S: 4.43
1H-NMR (DMSO-i/6, 400 MHz): 11.90 (bs, IH), 10.00 (b, 2H), 9.71 (s, IH), 8.93 (s, IH), 8.44 (d, J=8.7 Hz, IH), 8.05 (d, J=2.4 Hz, IH), 7.99 (d, J=8.8 Hz, IH), 7.81 (dd, ^=2.4 Hz, J2=8.9 Hz, IH), 7.48 (m, IH), 7.39 (d, J=3.4 Hz, IH), 7.35 (m, IH), 7.33 (m, IH), 7.20 (m, IH), 6.85 (d, J=3.3 Hz, IH), 5.32 (s, 2H), 4.46 (s, 2H), 3.72 (m, 2H), 3.45 (m, 2H), 3.15 (s, 3H).
Example 16
Lapatinib hydrochloride (1 :2) anhydrate salt (lapatinib dihydrochloride anhydrate (1 :2:0)
The drying of the dihydrochloride trihydrate salt of example 15 gave the anhydrate form:
0.395 g (0.56 mmol) dihydrochloride trihydrate was dried at a temperature of 80°C at a pressure of 8 mbar for 24 hours.
Yield: 0.362 g (99.2 %).
Melting point: 242-262 °C
Analysis calculated for C29H28C13FN404S (653.99):
Calculated: C: 53.26 H: 4.32 N: 8.57 CI: 16.26 S: 4.90
Measured: C: 53.27 H: 4.35 N: 8.55 CI: 16.11 S: 4.84 IR (KBr, cm"1): 3418, 2984, 2924, 2662, 2591, 2420, 1617, 1575, 1557, 1530, 1500, 1467, 1446, 1382, 1363, 1336, 1305, 1271, 1260, 1214, 1130, 1064, 1027, 968, 926, 867, 844, 807, 799, 775, 748, 734, 681, 668, 622, 564, 532, 524, 503, 435.
Example 17
Liberation of lapatinib base from lapatinib ditosylate monohydrate
5.400 g (5.72 mmol) lapatinib ditosylate monohydrate salt was vigorously stirred in 100 cm3 ethyl acetate for 60 minutes (Heidolph MR 3001, 500 rpm) at room temperature. 50 cm3 10 w/w% aqueous sodium carbonate solution is added thereto then the mixture is stirred for a
further hour. After separation of the phases 35 cm3 water is added to the ethyl acetate phase then at 50 °C it is stirred for a further 15 minutes. The phases are separated, the organic phase is dried on magnesium sulphate. After filtering out the drying material the obtained clear solution is evaporated. The residue is stirred with tert-buthyl methyl ether for 20 minutes then the solid material is filtered and dried on air.
Yield: 3.200 g (96.2 %)
Melting point: 142.3-145.5 °C
Example 18
Salt formation in an orfianic solvent mixture without preparation of the free base
Salt formation by citric acid monohydrate
To the -100 cm3 ethyl acetic solution of example 17 obtained after the separation of the phases a mixture of 70 cm tetrahydrofurane and 2 cm 2-propanol is added then under vigorous stirring (Heidolph MR 3001, 500 rpm) at a temperature of 60 °C 1.200 g (5.72 mmol) citric acid monohydrate is added. After the start of precipitation the mixture is further stirred at room temperature for 24 hours. Then in vacuo it is evaporated to roughly half volume and stirred for further 2 hours at a temperature of 5-10 °C. The precipitated crystals are filtered and washed with 20 cm3 tert-bufhyl methyl ether. It is dried for 20 hours at 50 °C and 6,0 mbar.
Yield: 4.16 g (94.0 %)
Melting point: 196.2-210 °C
Analysis calculated for C29H26C1FN404S-C5H807 (773.20):
Calculated C: 54.37 H: 4.43 N: 7.25 CI: 4.59 S: 4.15
Measured C: 54.46 H: 4.43 N: 7.21 CI: 4.74 S: 4.10 Example 19
Measuring the solubility of lapatinib salts
The solubility in water of the new lapatinib salts of the invention was also tested. It has been surprisingly found that some of the new lapatinib salts of the present invention show a better solubility than the ditosylate monohydrate salt known from the prior art.
From each of the lapatinib salts according to the invention 100 mg was measured into glass vials and 8 ml was added thereto. The vials were closed and the samples were stirred at room temperature for 30 minutes (Heidolph MR 3001, 375 rpm), then we checked whether there was any solid material left. If all of the solid material went into solution then a further 100 mg was added to the vial as long as there was any not solved material left. Then the mixtures were
stirred at room temperature then we further checked for the presence of any leftover solid material. From each sample 4 ml is taken and the aqueous suspension is filtered through a 0.22 micron filter. From the obtained filtrate 1 ml is taken and is diluted with eluent„A". Apparatus: Waters Acquity UPLC
Colonna: BEH C-18 (1,7 μπι; 50x2,1 mm)
Eluent: A 70 % buffer solution/30 % acetonitrile (V V)
B 20 % buffer solution/80 % acetonitrile (V/V)
Buffer solution: 10 mM ammonium formate, pH=4.0
The measurement was done by an isochratic method with an external standard. Lapatinib base was the used standard. The differences resulting from the different molar weight of the salt forms were corrected for. As a result of the measurement the concentration of the salt solutions were obtained in mg salt/ml solution form which is the solubility of the given salt in water (mg salt/ml water).
nd - not detectable
Claims
1. Lapatinib salt selected from the group consisting of the naphtalene 1,5 disulfonic salt, (15 - (+)-camphorsulfonic acid salt, 2,5 dihydroxy benzoic acid salt, malonic acid salt, nitric acid salt, citric acid salt, hydrogen bromide salt, naphtalene 2 sulfonic acid salt, hydrochloride salt and amorphous and crystalline forms, hydrates and solvates thereof.
2. The lapatinib naphtalene 1,5 disulfonic acid (1 :1) salt according to claim 1 which has the following characteristic X-ray powder diffraction peaks: °2Θ (±0,2 °2Θ): 4,925; 9,680; 10,446; 14,877; 15,702; 19,727; 22,266; 23,165; 24,324; 25,455; 26,323; 27,635.
3. The lapatinib naphtalene 1,5 disulfonic acid dimethylformamide solvate (1 :1 : 1) salt according to claim 1 which has the following characteristic X-ray powder diffraction peaks: °2Θ (±0,2 °2Θ): 4,341; 6,431 ; 8,899; 12,556; 16,796; 18,435; 19,635; 21,112; 23,211 ; 25,481 ; 27,397.
4. The lapatinib (lS)-(+)-camphorsulfonic acid (1 : 1) salt according to claim 1 which has the following characteristic X-ray powder diffraction peaks: °2Θ (±0,2 °2Θ): 4,569; 5,811 ; 7,828; 11,403; 12,991; 14,182; 15,008; 16,635; 17,730; 19,731; 22,066; 23,689; 25,228; 26,161; 26,693.
5. The lapatinib 2,5 dihydroxy benzoic acid (1 :1) salt according to claim 1 which has the following characteristic X-ray powder diffraction peaks: °2Θ (±0,2 °2Θ): 5,449; 5,917; 6,376; 11,012; 12,341 ; 14,432; 16,475; 17,958; 19,065; 20,620; 21,332; 22,573; 25,296; 26,049; 28,107.
6. The lapatinib malonic acid (1 :1) salt according to claim 1 which has the following characteristic X-ray powder diffraction peaks: °2Θ (±0,2 °2Θ): 4,833; 9,787; 12,027; 14,767; 16,968; 19,269; 20,088; 21,563; 22,942; 24,871.
7. The lapatinib malonic acid methanol solvate (1 :1) salt according to claim 1 which has the following characteristic X-ray powder diffraction peaks: °20 (±0,2 °2Θ): 4,848; 9,842; 12,010; 14,498; 15,884; 16,774; 17,197; 18,128; 18,812; 20,588; 21,870; 24,934; 26,670; 27,632; 31,050.
8. The lapatinib malonic acid (1 :2) salt according to claim 1 which has the following characteristic X-ray powder diffraction peaks: °2Θ (±0,2 °2Θ): 8,198; 10,189; 10,523; 1 1,950; 13,208; 14,932; 15,899; 17,255; 17,762; 18,631 ; 20,584; 21,225; 23,715; 26,690; 32,605.
9. The lapatinib nitric acid (1 :1) salt according to claim 1 which has the following characteristic X-ray powder diffraction peaks: °20 (±0,2 °20): 7,346; 9,61 1; 12,083; 12,869; 14,824; 16,652; 17,020; 17,372; 18,541 ; 19,405; 19,761; 20,094; 22,31 1 ; 23,161; 23,870; 25,657; 26,050; 31,306.
10. The lapatinib citric acid (1 : 1) salt according to claim 1 which has the following characteristic X-ray powder diffraction peaks: °2Θ (±0,2 °20): 5,339; 10,693; 12,639; 13,738; 16,063; 16,289; 17,259; 18,507; 19,712; 20,331; 20,746; 21,067; 21,585; 21,826; 22,676; 23,160; 23,542; 23,972; 25,438; 27,495; 28,918; 30,183; 33,059.
11. The lapatinib hydrogen bromide (1: 1) salt which has the following characteristic X-ray powder diffraction peaks: °20 (±0,2 °2Θ): 7,305; 9,551 ; 12,809; 15,013; 16,503; 18,455; 19,259; 21,423; 22,154; 23,610; 24,409; 25,443; 27,185; 27,776; 28,634; 29,967.
12. The lapatinib hydrogen bromide (1 :2) amorphous salt according to claim 1.
13. The lapatinib hydrogen bromide amorphous salt according to claim 12 which has the characteristic X-ray powder diffraction peaks show non figure 11.
14. The lapatinib naphtalene 2 sulfonic acid (1 :1) salt Form I according to claim 1 which has the following characteristic X-ray powder diffraction peaks: °20 (±0,2 °2Θ): 4,793; 6,865; 12,029;
13,116; 17,992; 18,915; 20,049; 20,455; 20,702; 21,413; 21,695; 24,319; 28,266; 28,607.
15. The lapatinib naphtalene 2 sulfonic acid (1 :1) salt Form II according to claim 1 which has the following characteristic X-ray powder diffraction peaks: °2Θ (±0,2 °2Θ): 4,91 1 ; 7,077; 1 1,776; 11,940; 13,414; 14,279; 16,909; 18,528; 19,140; 19,923; 20,402; 21,161; 22,860; 23,431 ; 25,181 ; 25,966; 27,140; 28,514; 29,147.
16. The lapatinib hydrochloride (1 :1) salt according to claim 1 which has the following characteristic X-ray powder diffraction peaks: °2Θ (±0,2 °2Θ): 5,543; 9,663; 12,129; 14,883;
16,636; 17,368; 18,566; 19,398; 20,073; 20,499; 22,258; 23,351; 23,833; 24,578; 25,637; 27,963; 28,959; 30,111; 30,812.
17. The lapatinib hydrochloride (1 :1) dihydrate salt according to claim 1 which has the following characteristic X-ray powder diffraction peaks: °2Θ (±0,2 °2Θ): 5,050; 6,768; 10,100; 10,835;
11,738; 15,165; 15,500; 17,625; 19,178; 20,272; 20,905; 21,458; 21,754; 22,691; 23,249; 24,435; 24,973; 26,070; 26,507; 28,038.
18. The lapatinib hydrochloride (1 :2) trihydrate salt according to claim 1 which has the following characteristic X-ray powder diffraction peaks: °20 (±0,2 °2Θ): 4,826; 5,153; 10,322; 12,474;
18,898; 19,208; 20,726; 21,828; 23,644; 23,847; 24,614; 25,236; 26,225; 27,363; 30,013; 33,289.
19. The lapatinib hydrochloride (1 :2) anhydrate salt according to claim 1 which has the following characteristic X-ray powder diffraction peaks: °2Θ (±0,2 °2Θ): 4,180; 6,424; 1 1,509;
12,646; 15,174; 16,706; 18,631; 19,018; 20,554; 21,460; 21,889; 23,070; 24,002; 25,177; 25,909; 26,808; 27,394; 27,801 ; 28,890; 32,534.
20. Method for the preparation of lapatinib salts according to any of Claims 1 to 19, characterized in that it comprises reacting lapatinib base with an organic acid in an organic solvent or a mixture of an organic solvent and water and separating the lapatinib salt formed.
21. The method of claim 20 characterized in that it comprises using the acid in a 0.3-3.0 molar equivalent amount, preferably in a 0.5-2.5 molar equivalent amount.
22. The method according to any of Claims 20 and 21 characterized in that the used organic solvent is a C alcohol, an ether, ester or a dipolar aprotic solvent or a mixture thereof or mixtures thereof with water.
23. The method according to Claim 22 which is characterized in that the used solvent is tetrahydrofurane, diethyl ether, ethyl acetate, acetonitrile, methanol, ethanol, 2-propanol or a mixture thereof or a mixtures thereof with water.
24. The method according to any of Claims 20 to 23 characterized in that the reaction is carried out at a temperature between 0°C and the boiling point of the solvent, preferably between room temperature and 80°C.
25. Pharmaceutical composition comprising a lapatinib salt according to any of Claims 1 to 19 in an admixture with conventional pharmaceutical auxiliary agents.
26. Method for the preparation of pharmaceutical compositions according to Claim 25 characterized in that it comprises admixing a therapeutically effective amount of a lapatinib salt according to any of Claims 1 to 19 with a pharmaceutically acceptable carrier and optionally with further pharmaceutically acceptable auxiliary agents and bringing the mixture into a galenic form.
27. Lapatinib salts according to any of Claims 1 to 19 for use in medicine.
28. Lapatinib salts according to any of Claims 1 to 19 for use in the treatment or prophylaxis of locally advanced or metastatic HER-2 -positive breast cancer (MBC, metastatic breast cancer) furthermore for the treatment or prophylaxis of other cancers such as head-neck, lung and renal cell carcinoma.
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| RU2603943C1 (en) * | 2016-02-01 | 2016-12-10 | Индивидуальный предприниматель Михайлов Олег Ростиславович | CRYSTALLINE γ-MODIFICATION OF N-{3-CHLORO-4-[(3-FLUOROBENZYL)OXY]PHENYL}-6-[5-({[2-(METHYLSULFONYL)ETHYL]AMINO}METHYL)-2-FURYL]-4-QUINOLINE AMINE OF BIS (4-METHYLBENZENESULFONATE) MONOHYDRATE, METHOD OF ITS PRODUCTION AND PHARMACEUTICAL COMPOSITION BASED THEREON |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999035146A1 (en) | 1998-01-12 | 1999-07-15 | Glaxo Group Limited | Bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors |
| EP1294715A1 (en) | 2000-06-30 | 2003-03-26 | Glaxo Group Limited | Quinazoline ditosylate salt compounds |
| WO2010027848A2 (en) | 2008-08-26 | 2010-03-11 | Teva Pharmaceutical Industries Ltd. | Forms of lapatinib compounds and processes for the preparation thereof |
| EP2468745A1 (en) | 2011-03-25 | 2012-06-27 | F.I.S. Fabbrica Italiana Sintetici S.p.A. | Process for the preparation of lapatinib and the salts thereof |
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| EP2166859A4 (en) * | 2007-06-11 | 2011-09-07 | Smithkline Beecham Cork Ltd | Quinazoline salt compounds |
| WO2012017448A2 (en) * | 2010-08-03 | 2012-02-09 | Hetero Research Foundation | Salts of lapatinib |
| CN102964339A (en) * | 2012-11-19 | 2013-03-13 | 北京阜康仁生物制药科技有限公司 | Novel pharmaceutical salt of lapatinib |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999035146A1 (en) | 1998-01-12 | 1999-07-15 | Glaxo Group Limited | Bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors |
| EP1294715A1 (en) | 2000-06-30 | 2003-03-26 | Glaxo Group Limited | Quinazoline ditosylate salt compounds |
| WO2010027848A2 (en) | 2008-08-26 | 2010-03-11 | Teva Pharmaceutical Industries Ltd. | Forms of lapatinib compounds and processes for the preparation thereof |
| EP2468745A1 (en) | 2011-03-25 | 2012-06-27 | F.I.S. Fabbrica Italiana Sintetici S.p.A. | Process for the preparation of lapatinib and the salts thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2603943C1 (en) * | 2016-02-01 | 2016-12-10 | Индивидуальный предприниматель Михайлов Олег Ростиславович | CRYSTALLINE γ-MODIFICATION OF N-{3-CHLORO-4-[(3-FLUOROBENZYL)OXY]PHENYL}-6-[5-({[2-(METHYLSULFONYL)ETHYL]AMINO}METHYL)-2-FURYL]-4-QUINOLINE AMINE OF BIS (4-METHYLBENZENESULFONATE) MONOHYDRATE, METHOD OF ITS PRODUCTION AND PHARMACEUTICAL COMPOSITION BASED THEREON |
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