WO2007042799A1 - Novel crystalline forms - Google Patents
Novel crystalline forms Download PDFInfo
- Publication number
- WO2007042799A1 WO2007042799A1 PCT/GB2006/003768 GB2006003768W WO2007042799A1 WO 2007042799 A1 WO2007042799 A1 WO 2007042799A1 GB 2006003768 W GB2006003768 W GB 2006003768W WO 2007042799 A1 WO2007042799 A1 WO 2007042799A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- topotecan hydrochloride
- crystalline form
- topotecan
- hydrochloride
- crystalline
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the present invention relates to a novel crystalline polymorphic form of 10-[(dimethylamino) methyl]- 4-ethyl 4,9dihydroxy-lH-pyrano [3',4':6,7] indolizino [1,2-b] quinoline-3, 14 (4H, 12H) dione hydrochloride (topotecan hydrochloride) and the process for the synthesis of the same.
- Topotecan hydrochloride is (10-[(dimethyl amino) memyl]-4-ethyl-4,9-dihydroxy-lH-pyrano [3', 4' : 6, 7] indolizmo[l, 2-b] quinoline-3, 14 (4H, 12H) dione hydrochloride) a compound of formula (I) .
- Topotecan is a semi-synthetic analogue of camptothecin, an agent derived from the Oriental yew tree, Camptothecan accuminata.
- the cytotoxic effects of the camptothecins are believed to be related to their activity as inhibitors of topoisomerase — I, an enzyme involved in the replication and repair of nuclear DNA.
- topoisomerase — I an enzyme involved in the replication and repair of nuclear DNA.
- topoisomerase-I acts by binding to super-coiled DNA and causing single-stranded breaks in that DNA.
- topoisomerase —I is able to relieve the torsional stresses that are introduced into DNA ahead of the replication complex or moving replication fork.
- Topotecan inhibits topoisomerase-I by stabilizing the covalent complex of. enzyme and strand-cleaved DNA, which is an intermediate of the catalytic mechanism, thereby inducing breaks in the protein-associated DNA single- strands, resulting in cell death.
- Topotecan hydrochloride stops the growth of cancer cells by preventing the development of elements necessary for cell division.
- US 5,004,758 discloses water soluble Camptothecin analogs, which includes topotecan (9- dimethylamino methyl- 10- hydroxy camptothecin), preferably (S) -topotecan and its Hydrochloride salt.
- WO2005046608 discloses a novel crystalline form of topotecan monohydrochloride pentahydrate, corresponding pharmaceutical compositions, methods of preparation and use for anti-viral and other cancer - related diseases.
- the present invention relates to the solid state physical properties of topotecan hydrochloride. These properties can be influenced by controlling the conditions under which topotecan hydrochloride is obtained in solid form.
- Solid state physical properties include, for example, the flowability of the milled solid. Flowability affects the ease with which the material is handled during processing into a pharmaceutical product.
- Rate of dissolution of a pharmaceutical compound depends upon its stable crystalline form. The rate of dissolution can have increased effect on the therapeutic efficacy of the administered drug. Hence, this property of the pharmaceutical compound is considered as an important feature in formulating syrups, elixirs and other liquid medicaments.
- the solid state form of a compound may also affect its behavior on compaction and its storage stability.
- An object of the present invention is to provide a novel crystalline polymorphic form of topotecan hydrochloride hereinafter referred to as Form-A.
- Another object of the present invention is to provide a process for preparing the novel crystalline polymorphic Form-A of topotecan hydrochloride from any crystalline form of topotecan Hydrochloride, pentahydrate or amorphous.
- Yet another object of the present invention is to provide a process for the preparation of novel crystalline polymorphic Form-A of topotecan hydrochloride from topotecan base. Summary of the invention:
- the present invention relates to a novel polymorphic form of topotecan hydrochloride which is 5 hereinafter designated as form A.
- a crystalline form A of topotecan hydrochloride having an XRPD pattern with peaks at 6.08, 6.94, 8.10, 9.96, 10.16, 11.68, 12.28, 13.08, 13.62, 14.32, 15.44, 16.46, 16.56, 17.58, 18.42, 19.32; 20.14, 21.22, 21.88, 22.54, 10 22.72, 23.38, 24.14, 24.36, 24.78, 25.02, 25.50, 26.42, 26.86, 27.18, 27.44, 28.10, 28.76, 29.42, 29.68 and 30.02 °2 ⁇ ( ⁇ 0.2°).
- a crystalline form A of topotecan hydrochloride having characteristic FT-IR peaks at 1743 , 1656 , 1596 , 1560 and 1507 cm “1 . 15
- topotecan hydrochloride form A can be formulated into 0 a variety of compositions for administration to humans and mammals.
- Dosage forms include solid dosage forms like tablets, powders, capsules, sachets, troches and lozenges as well as, liquid syrups, suspensions and elixirs.
- the active ingredient (s) and excipients can be formulated into compositions and dosage forms according to methods known in the art.
- a process for preparing crystalline form A of topotecan hydrochloride comprising: suspending topotecan hydrochloride in methanol; stirring at a temperature ranging from 25 to 3O 0 C; cooling the reaction mass to -10 to 25°C, preferably while stirring it; and recovering the topotecan hydrochloride Form A preferably by filtration and drying.
- the topotecan hydrochloride used to form the topotecan hydrochloride Form A may be formed by convention means. It may be crystalline or amorphous. It may be anhydrous or in the form of the pentahydrate.
- a process for preparing crystalline form A of topotecan hydrochloride comprises suspending topotecan base in methanol; adding aqueous HCl and stirring at 25-30°C; cooling the reaction mass to a temperature ranging from - 10 to 25 0 C, preferably while stirring it; and recovering the topotecan hydrochloride Form A preferably by filtration and drying.
- the reaction mass is preferably stirred for about one hour while at 25-30°C.
- the cooling preferably is carried out over about one hour.
- the filtration is preferably carried out over about 4-6 hours, e.g.5 hours, while the filtration is preferably carried out over 30 to 40 hours, e.g. 36 hours.
- Figure 1 shows powder X-ray diffractogram of the Form 'A' crystalline polymorph of topotecan hydrochloride.
- Figure 2 shows FT-IR (KBr) spectrum of the Form 'A' crystalline polymorph of topotecan hydrochloride.
- the present invention relates to a novel polymorphic form of topotecan hydrochloride which is hereinafter designated as form A.
- the present invention provides a novel crystalline polymorphic Form-A of topotecan hydrochloride which is characterized by an XRD pattern
- the present invention also provides a novel crystalline polymorphic Form A of topotecan hydrochloride characterized by FT-IR (KBr) spectrum as depicted in figure 2.
- Form A provides an infrared spectrum containing peaks at 1743, 1656, 1596, 1560 and 1507.
- the present invention provides a process of preparing a novel crystalline polymorphic Form-A of topotecan hydrochloride which comprises suspending topotecan base in a suitable solvent preferably methanol and adding aqueous HCl and stirring at 25-30 0 C and further cooling it, preferably while stirring, to at a temperature ranging from -10 to 25°C preferably at 10-15 0 C and filtering the solid, and drying, preferably at 25 - 30 0 C under vacuum to obtain uniform crystals of topotecan hydrochloride Form A.
- the stirring of the reaction mass at 25-30 0 C is preferably carried out for about 1 hour.
- the present invention provides a process of converting topotecan hydrochloride of any crystalline form, anhydrous, pentahydrate, or amorphous form into the novel crystalline topotecan hydrochloride Form A which comprises suspending topotecan hydrochloride in a suitable solvent preferably methanol and stirring at a temperature ranging from -10 to 25 0 C preferably at 10-15 0 C, filtering the solid, and drying at 25 - 3O 0 C under vacuum followed by drying, preferably at 30 - 35° C, for about 36 hours to obtain uniform crystals of topotecan hydrochloride Form A.
- the topotecan hydrochloride Form A of this invention has a water content in the range of 10 to 12%.
- novel crystalline polymorphic form A of topotecan hydrochloride is readily isolated, and displays uniformity, reproducibility, ease and safety of handling in manufacture and stability on isolation and drying.
- the topotecan hydrochloride form A is preferably provided in the form of the (4S)- isomer.
- the purity of the isomer may be up to about 99.5%.
- the topotecan hydrochloride according to the invention may be combined with a pharmaceutically acceptable carrier to form suitable pharmaceutical compositions. It may be used in therapy such as in a method of treating tumours.
- a method of treating a tumour comprising administering a therapeutically effective amount of a crystalline form A of topotecan hydrochloride as described above, to a patient in need thereof.
- a typical dosage would be about 4 mg, suitably provided in an injection formulation.
- topotecan base 25 10 grams was suspended in 100 ml Methanol, and 2.4 ml HCl was added at 25-30 0 C and stirred for 1 hour at 25-30 0 C, the suspension was further chilled to 10 - 15° C and stirred for 1 hour at 10 - 15° C and filtered, washed with 5 ml of methanol. The product was dried in vacuum at 25 - 30° C for 5 hours, followed by drying at 30 - 35° C for 36 hours to get 8.0 g of topotecan hydrochloride Form 'A'.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a novel crystalline form of topotecan hydrochloride, and methods of making the same. The characteristic XRPD pattern and FT-IT patterns are shown in Figs. 1 and 2.
Description
NOVEL CRYSTALLINE FORMS
Technical field:
The present invention relates to a novel crystalline polymorphic form of 10-[(dimethylamino) methyl]- 4-ethyl 4,9dihydroxy-lH-pyrano [3',4':6,7] indolizino [1,2-b] quinoline-3, 14 (4H, 12H) dione hydrochloride (topotecan hydrochloride) and the process for the synthesis of the same.
Background of the invention:
Topotecan hydrochloride is (10-[(dimethyl amino) memyl]-4-ethyl-4,9-dihydroxy-lH-pyrano [3', 4' : 6, 7] indolizmo[l, 2-b] quinoline-3, 14 (4H, 12H) dione hydrochloride) a compound of formula (I) .
Topotecan is a semi-synthetic analogue of camptothecin, an agent derived from the Oriental yew tree, Camptothecan accuminata. The cytotoxic effects of the camptothecins are believed to be related to their activity as inhibitors of topoisomerase — I, an enzyme involved in the replication and repair of nuclear DNA. As DNA is replicated in dividing cells, topoisomerase-I acts by binding to super-coiled DNA and causing single-stranded breaks in that DNA. As a result, topoisomerase —I is able to relieve the torsional stresses that are introduced into DNA ahead of the replication complex or moving replication fork. Topotecan inhibits topoisomerase-I by
stabilizing the covalent complex of. enzyme and strand-cleaved DNA, which is an intermediate of the catalytic mechanism, thereby inducing breaks in the protein-associated DNA single- strands, resulting in cell death. Topotecan hydrochloride stops the growth of cancer cells by preventing the development of elements necessary for cell division.
US 5,004,758 discloses water soluble Camptothecin analogs, which includes topotecan (9- dimethylamino methyl- 10- hydroxy camptothecin), preferably (S) -topotecan and its Hydrochloride salt.
US 5,734,056 disclose Camptothecin analogs (which include topotecan) and a process for the preparation of such analogs and its intermediates.
US 5,155,225 describes processes for making Pyrano [3',4':6,7]mdolizino-[l,2-B] quinolinones.
WO2005046608 discloses a novel crystalline form of topotecan monohydrochloride pentahydrate, corresponding pharmaceutical compositions, methods of preparation and use for anti-viral and other cancer - related diseases.
The present invention relates to the solid state physical properties of topotecan hydrochloride. These properties can be influenced by controlling the conditions under which topotecan hydrochloride is obtained in solid form. Solid state physical properties include, for example, the flowability of the milled solid. Flowability affects the ease with which the material is handled during processing into a pharmaceutical product.
Another important solid state property of a pharmaceutical compound is its rate of dissolution in aqueous fluid. The rate of dissolution of an active ingredient in a patient's body fluid can have therapeutic consequences since it imposes an upper limit on the rate at which an orally- administered active ingredient can reach the patient's bloodstream.
Topotecan Hydrochloride exhibits polymorphism. Polymorphism is the property of some molecules to adopt more than one crystalline form in the solid state. A single molecule can give rise to a variety of crystalline solids having distinct physical properties that can be measured in a laboratory like its thermal behaviour, e.g. melting point and differential scanning calorimetry (DSC) thermogram, dissolution rate, fiowability, X-ray diffraction pattern, infrared absoiption spectrum and NMR spectrum. l=1
The differences in the physical properties of polymorphs result from the conformation, orientation and intermolecular interactions of adjacent molecules in the crystalline solid. Rate of dissolution of a pharmaceutical compound depends upon its stable crystalline form. The rate of dissolution can have increased effect on the therapeutic efficacy of the administered drug. Hence, this property of the pharmaceutical compound is considered as an important feature in formulating syrups, elixirs and other liquid medicaments. The solid state form of a compound may also affect its behavior on compaction and its storage stability.
Thus, it is clear from the foregoing discussion, it would be desirable to have active pharmaceutical ingredient in a stable crystalline form having improved bulk handling and dissolution properties and this becomes the object of the present invention
Object of the Invention:
An object of the present invention is to provide a novel crystalline polymorphic form of topotecan hydrochloride hereinafter referred to as Form-A.
Another object of the present invention is to provide a process for preparing the novel crystalline polymorphic Form-A of topotecan hydrochloride from any crystalline form of topotecan Hydrochloride, pentahydrate or amorphous.
Yet another object of the present invention is to provide a process for the preparation of novel crystalline polymorphic Form-A of topotecan hydrochloride from topotecan base.
Summary of the invention:
The present invention relates to a novel polymorphic form of topotecan hydrochloride which is 5 hereinafter designated as form A.
According to one aspect of the invention there is provided a crystalline form A of topotecan hydrochloride having an XRPD pattern with peaks at 6.08, 6.94, 8.10, 9.96, 10.16, 11.68, 12.28, 13.08, 13.62, 14.32, 15.44, 16.46, 16.56, 17.58, 18.42, 19.32; 20.14, 21.22, 21.88, 22.54, 10 22.72, 23.38, 24.14, 24.36, 24.78, 25.02, 25.50, 26.42, 26.86, 27.18, 27.44, 28.10, 28.76, 29.42, 29.68 and 30.02 °2Θ (± 0.2°).
According to one aspect of the invention there is provided a crystalline form A of topotecan hydrochloride having characteristic FT-IR peaks at 1743 , 1656 , 1596 , 1560 and 1507 cm"1. 15
According to one aspect of the invention there is provided a crystalline form A of topotecan hydrochloride having an XRPD pattern as shown in Figure 1.
According to one aspect of the invention there is provided a crystalline form A of topotecan 0 hydrochloride having an FT-IR spectrum as shown in Figure 2.
In another aspect, there is provided a process of converting topotecan hydrochloride of any crystalline form, anhydrous, pentahydrate, or amorphous form into the novel crystalline topotecan hydrochloride Form A. 5
In a further aspect there is provided a process for preparation of topotecan hydrochloride form A from topotecan base by dissolving the latter in suitable organic solvent.
The compound of the present invention, topotecan hydrochloride form A can be formulated into 0 a variety of compositions for administration to humans and mammals. Dosage forms include
solid dosage forms like tablets, powders, capsules, sachets, troches and lozenges as well as, liquid syrups, suspensions and elixirs. The active ingredient (s) and excipients can be formulated into compositions and dosage forms according to methods known in the art.
According to another aspect of the invention there is provided a process for preparing crystalline form A of topotecan hydrochloride, comprising: suspending topotecan hydrochloride in methanol; stirring at a temperature ranging from 25 to 3O0C; cooling the reaction mass to -10 to 25°C, preferably while stirring it; and recovering the topotecan hydrochloride Form A preferably by filtration and drying. The topotecan hydrochloride used to form the topotecan hydrochloride Form A may be formed by convention means. It may be crystalline or amorphous. It may be anhydrous or in the form of the pentahydrate.
According to another aspect of the invention there is provided a process for preparing crystalline form A of topotecan hydrochloride, comprises suspending topotecan base in methanol; adding aqueous HCl and stirring at 25-30°C; cooling the reaction mass to a temperature ranging from - 10 to 250C, preferably while stirring it; and recovering the topotecan hydrochloride Form A preferably by filtration and drying.
The reaction mass is preferably stirred for about one hour while at 25-30°C. The cooling preferably is carried out over about one hour. The filtration is preferably carried out over about 4-6 hours, e.g.5 hours, while the filtration is preferably carried out over 30 to 40 hours, e.g. 36 hours.
Brief Description of the Drawings
The invention is illustrated by reference to the accompanying drawings described below
Figure 1 shows powder X-ray diffractogram of the Form 'A' crystalline polymorph of topotecan hydrochloride.
Figure 2 shows FT-IR (KBr) spectrum of the Form 'A' crystalline polymorph of topotecan hydrochloride.
Detailed Description of the Invention
The present invention relates to a novel polymorphic form of topotecan hydrochloride which is hereinafter designated as form A. In one aspect the present invention provides a novel crystalline polymorphic Form-A of topotecan hydrochloride which is characterized by an XRD pattern
(Figurel) having peak positions at 6.08, 6.94, 8.10, 9.96, 10.16, 11.68, 12.28, 13.08, 13.62,
14.32, 15.44, 16.46, 16.56, 17.58, 18.42, 19.32; 20.14, 21.22, 21.88, 22.54, 22.72, 23.38, 24.14,
24.36, 24.78, 25.02, 25.50, 26.42, 26.86, 27.18, 27.44, 28.10, 28.76, 29.42, 29.68 and 30.02 °2θ (± 0.2°).
The present invention also provides a novel crystalline polymorphic Form A of topotecan hydrochloride characterized by FT-IR (KBr) spectrum as depicted in figure 2. Form A provides an infrared spectrum containing peaks at 1743, 1656, 1596, 1560 and 1507.
In another aspect the present invention provides a process of preparing a novel crystalline polymorphic Form-A of topotecan hydrochloride which comprises suspending topotecan base in a suitable solvent preferably methanol and adding aqueous HCl and stirring at 25-300C and further cooling it, preferably while stirring, to at a temperature ranging from -10 to 25°C preferably at 10-150C and filtering the solid, and drying, preferably at 25 - 300C under vacuum to obtain uniform crystals of topotecan hydrochloride Form A. The stirring of the reaction mass at 25-300C is preferably carried out for about 1 hour.
In another aspect the present invention provides a process of converting topotecan hydrochloride of any crystalline form, anhydrous, pentahydrate, or amorphous form into the novel crystalline topotecan hydrochloride Form A which comprises suspending topotecan hydrochloride in a suitable solvent preferably methanol and stirring at a temperature ranging from -10 to 250C preferably at 10-150C, filtering the solid, and drying at 25 - 3O0C under vacuum followed by drying, preferably at 30 - 35° C, for about 36 hours to obtain uniform crystals of topotecan hydrochloride Form A.
The topotecan hydrochloride Form A of this invention has a water content in the range of 10 to 12%.
The novel crystalline polymorphic form A of topotecan hydrochloride is readily isolated, and displays uniformity, reproducibility, ease and safety of handling in manufacture and stability on isolation and drying.
The topotecan hydrochloride form A is preferably provided in the form of the (4S)- isomer. The purity of the isomer may be up to about 99.5%.
The topotecan hydrochloride according to the invention may be combined with a pharmaceutically acceptable carrier to form suitable pharmaceutical compositions. It may be used in therapy such as in a method of treating tumours.
According to another aspect of the invention there is provided the crystalline form A of topotecan hydrochloride as described above for use in therapy.
According to another aspect of the invention there is provided the crystalline form A of topotecan hydrochloride as described above for use in the treatment of a tumour.
According to another aspect of the invention there is provided the crystalline form A of topotecan hydrochloride as described above for use in the manufacture of a medicament for the treatment of a tumour.
According to another aspect of the invention there is provided a method of treating a tumour comprising administering a therapeutically effective amount of a crystalline form A of topotecan hydrochloride as described above, to a patient in need thereof. A typical dosage would be about 4 mg, suitably provided in an injection formulation.
The nature of the invention, its object and advantages are explained hereunder in greater detail in relation to non-limiting exemplary embodiments.
Example 1 5
Preparation of topotecan hydrochloride (Form A)
10 grams of topotecan hydrochloride amorphous form was suspended in 100 ml of Methanol at 25-300C. The mixture was stirred for 1 hour at 25-30°C and further chilled to 10 - 15° C and 10 stirred for additional 1 hour at 10 - 15° C and filtered; the solid was washed with 5 ml of methanol. The resulting product was dried under vacuum at 25 - 30° C for 5 hours, followed by drying at 30 - 35° C for 36 hours to give 9.0 g of topotecan hydrochloride Form 'A'.
Example 2
15
Preparation of topotecan hydrochloride (Form A)
10.0 g of topotecan hydrochloride pentahydrate was suspended in 100 ml of methanol and stirred at 25-300C for 1 hour and further chilled to 10 - 15° C and stirred for 1 hour at 10 - 15° C. The resulting solid was filtered and washed with 5 ml of methanol. The solid was dried in vacuum at
20 25 - 30° C for 5 hours, followed by drying at 30 - 35° C for 36 hours to get 6.0 g of Form 'A'.
Example 3
Preparation of topotecan hydrochloride (Form A)
25 10 grams of topotecan base was suspended in 100 ml Methanol, and 2.4 ml HCl was added at 25-300C and stirred for 1 hour at 25-300C, the suspension was further chilled to 10 - 15° C and stirred for 1 hour at 10 - 15° C and filtered, washed with 5 ml of methanol. The product was dried in vacuum at 25 - 30° C for 5 hours, followed by drying at 30 - 35° C for 36 hours to get 8.0 g of topotecan hydrochloride Form 'A'.
30
Claims
1. A ciystalline form A of topotecan hydrochloride having an XRPD pattern with peaks at 6.08, 6.94, 8.10, 9.96, 10.16, 11.68, 12.28, 13.08, 13.62, 14.32, 15.44, 16.46, 16.56,
5 17.58, 18.42, 19.32; 20.14, 21.22, 21.88, 22.54, 22.72, 23.38, 24.14, 24.36, 24.78, 25.02,
25.50, 26.42, 26.86, 27.18, 27.44, 28.10, 28.76, 29.42, 29.68 and 30.02 °2Θ (± 0.2°).
2. A crystalline form A of topotecan hydrochloride having characteristic FT-IR peaks at 1743 , 1656 , 1596 , 1560 and 1507 crn 1.
10
3. A crystalline form A of topotecan hydrochloride according to Claim 1 or 2, wherein the Topotecan hydrochloride has a water content in the range of about 10 to 12 wt%.
4. A crystalline form A of topotecan hydrochloride having an XRPD pattern as shown in 15 Figure 1.
5. A crystalline form A of topotecan hydrochloride having an FT-IR spectrum as shown in Figure 2.
20 6. A crystalline form of topotecan hydrochloride having a water content in the range of about 10 to 12 wt%.
7. A crystalline form A of topotecan hydrochloride according to any preceding claim, comprising (4S)-topotecan hydrochloride. 5
8. A process for preparing crystalline form A of topotecan hydrochloride, comprising: suspending topotecan hydrochloride in methanol; stirring at a temperature ranging from 25 to 300C; cooling the reaction mass to -10 to 25°C; and recovering the topotecan hydrochloride Form A by filtration and drying. 0
9. A process for preparing crystalline form A of topotecan hydrochloride, comprises suspending topotecan base in methanol; adding aqueous HCl and stirring at 25-300C; cooling the reaction mass to a temperature ranging from -10 to 25°C; and recovering the. topotecan hydrochloride Form A by filtration and diying.
10. A process according to claim 8 or 9, wherein the reaction mass is cooled to a temperature ranging from 10 to 15 0C.
11. A process according to claim 8, 9 or 10, wherein the reaction mass is stirred during said cooling step.
12. A crystalline form A of topotecan hydrochloride obtaining by a process according to any one of claims 8 to 11.
13. A pharmaceutical formulation comprising a crystalline form A of topotecan hydrochloride according to any one of claims 1 to 7, or according to claim 12, in combination with a pharmaceutically acceptable carrier.
14. A crystalline form A of topotecan hydrochloride according to any one of claims 1 to 7, or according to claim I5 for use in therapy.
15. A crystalline form A of topotecan hydrochloride according to any one of claims 1 to 7, or according to claim 12, for use in the treatment of a tumour.
16. A crystalline form A of topotecan hydrochloride according to any one of claims 1 to 7, or according to claim 12, for use in the manufacture of a medicament for the treatment of a tumour. , A method of treating a tumour comprising administering a therapeutically effective amount of a crystalline form A of topotecan hydrochloride according to any one of claims 1 to 7 or 12, to a patient in need thereof.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP06794718A EP1943253A1 (en) | 2005-10-10 | 2006-10-10 | Novel crystalline forms |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IN1274MU2005 | 2005-10-10 | ||
IN1274/MUM/2005 | 2005-10-10 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2007042799A1 true WO2007042799A1 (en) | 2007-04-19 |
Family
ID=37596204
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/GB2006/003768 WO2007042799A1 (en) | 2005-10-10 | 2006-10-10 | Novel crystalline forms |
Country Status (4)
Country | Link |
---|---|
US (1) | US8349863B2 (en) |
EP (1) | EP1943253A1 (en) |
KR (1) | KR20080068052A (en) |
WO (1) | WO2007042799A1 (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2070537A1 (en) | 2007-12-04 | 2009-06-17 | Antibioticos S.p.A. | Crystalline polymorphs of topotecan hydrochloride and methods for the preparation thereof |
EP2139899A1 (en) * | 2007-04-19 | 2010-01-06 | ScinoPharm Taiwan, Ltd. | Crystalline forms of topotecan hydrochloride and processes for making the same |
US7754733B2 (en) | 2003-11-12 | 2010-07-13 | Glaxosmithkline Llc | Crystalline topotecan hydrochloride product and process for making the same |
US8349863B2 (en) | 2005-10-10 | 2013-01-08 | Cipla Limited | Crystalline polymorphic form of a camptothecin analogue |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2012007952A1 (en) * | 2010-07-12 | 2012-01-19 | Hetero Research Foundation | Novel polymorph of irinotecan hydrochloride |
MX339926B (en) * | 2010-09-30 | 2016-06-16 | Wisconsin Alumni Res Found * | (20r,25s)-2-methylene-19,26-dinor-1î±, 25-dihydroxyvitamin d3 in crystalline form. |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005046608A2 (en) * | 2003-11-12 | 2005-05-26 | Smithkline Beecham Corporation | Novel compound, corresponding compositions, preparation and/or treatment methods |
Family Cites Families (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4290061A (en) * | 1979-08-23 | 1981-09-15 | General Electric Company | Electrically integrated touch input and output display system |
US5004758A (en) | 1987-12-01 | 1991-04-02 | Smithkline Beecham Corporation | Water soluble camptothecin analogs useful for inhibiting the growth of animal tumor cells |
CA2002912A1 (en) * | 1988-11-14 | 1990-05-14 | William A. Clough | Portable computer with touch screen and computer system employing same |
US5327161A (en) * | 1989-08-09 | 1994-07-05 | Microtouch Systems, Inc. | System and method for emulating a mouse input device with a touchpad input device |
US5155225A (en) | 1990-09-28 | 1992-10-13 | Smithkline Beecham Corporation | Method for making certain pyrano[3',4':6,7]indolizino-[1,2-B]quinolinones |
JP2848958B2 (en) | 1990-09-28 | 1999-01-20 | スミスクライン・ビーチャム・コーポレイション | Water soluble camptothecin analogs, methods and means |
US5335557A (en) * | 1991-11-26 | 1994-08-09 | Taizo Yasutake | Touch sensitive input control device |
US5369228A (en) * | 1991-11-30 | 1994-11-29 | Signagraphics Corporation | Data input device with a pressure-sensitive input surface |
US5581279A (en) * | 1991-12-23 | 1996-12-03 | Cirrus Logic, Inc. | VGA controller circuitry |
US7084859B1 (en) * | 1992-09-18 | 2006-08-01 | Pryor Timothy R | Programmable tactile touch screen displays and man-machine interfaces for improved vehicle instrumentation and telematics |
DE69432199T2 (en) * | 1993-05-24 | 2004-01-08 | Sun Microsystems, Inc., Mountain View | Graphical user interface with methods for interfacing with remote control devices |
US5581484A (en) * | 1994-06-27 | 1996-12-03 | Prince; Kevin R. | Finger mounted computer input device |
US5837947A (en) * | 1996-02-09 | 1998-11-17 | Symbios, Inc. | Method and apparatus for reducing noise in an electrostatic digitizing table |
US6061177A (en) * | 1996-12-19 | 2000-05-09 | Fujimoto; Kenneth Noboru | Integrated computer display and graphical input apparatus and method |
KR100595925B1 (en) * | 1998-01-26 | 2006-07-05 | 웨인 웨스터만 | Method and apparatus for integrating manual input |
EP1943253A1 (en) | 2005-10-10 | 2008-07-16 | Cipla Limited | Novel crystalline forms |
-
2006
- 2006-10-10 EP EP06794718A patent/EP1943253A1/en not_active Ceased
- 2006-10-10 US US11/539,932 patent/US8349863B2/en not_active Expired - Fee Related
- 2006-10-10 WO PCT/GB2006/003768 patent/WO2007042799A1/en active Application Filing
- 2006-10-10 KR KR1020087011144A patent/KR20080068052A/en not_active Application Discontinuation
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005046608A2 (en) * | 2003-11-12 | 2005-05-26 | Smithkline Beecham Corporation | Novel compound, corresponding compositions, preparation and/or treatment methods |
Non-Patent Citations (2)
Title |
---|
CHEN M. ET AL: "Studies on the polymorph of topotecan hydrochloride and its stability", CHINESE JOURNAL OF BIOCHEMICAL PHARMACEUTICS, vol. 26, no. 5, 2005, pages 279 - 281, XP001248432 * |
VOGT ET AL: "A study of variable hydration states in topotecan hydrochloride", JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS, NEW YORK, NY, US, vol. 40, no. 5, 18 March 2006 (2006-03-18), pages 1080 - 1088, XP005296966, ISSN: 0731-7085 * |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7754733B2 (en) | 2003-11-12 | 2010-07-13 | Glaxosmithkline Llc | Crystalline topotecan hydrochloride product and process for making the same |
US8158645B2 (en) | 2003-11-12 | 2012-04-17 | Glaxosmithkline Llc | Compound, corresponding compositions, preparation and/or treatment methods |
US8349863B2 (en) | 2005-10-10 | 2013-01-08 | Cipla Limited | Crystalline polymorphic form of a camptothecin analogue |
EP2139899A1 (en) * | 2007-04-19 | 2010-01-06 | ScinoPharm Taiwan, Ltd. | Crystalline forms of topotecan hydrochloride and processes for making the same |
EP2139899A4 (en) * | 2007-04-19 | 2011-01-12 | Scinopharm Taiwan Ltd | Crystalline forms of topotecan hydrochloride and processes for making the same |
EP2070537A1 (en) | 2007-12-04 | 2009-06-17 | Antibioticos S.p.A. | Crystalline polymorphs of topotecan hydrochloride and methods for the preparation thereof |
Also Published As
Publication number | Publication date |
---|---|
EP1943253A1 (en) | 2008-07-16 |
US8349863B2 (en) | 2013-01-08 |
KR20080068052A (en) | 2008-07-22 |
US20070105885A1 (en) | 2007-05-10 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US8349863B2 (en) | Crystalline polymorphic form of a camptothecin analogue | |
US8933114B2 (en) | Polymorphic forms of asenapine maleate and processes for their preparation | |
EP1951235B1 (en) | Novel crystal forms of irinotecan hydrochloride | |
JP7314319B2 (en) | Crystal polymorph of CDK9 inhibitor, method for producing the same, and use thereof | |
JP5982261B2 (en) | Stereoselective methods and crystalline forms of camptothecin | |
JP5755796B2 (en) | Camptothecin derivatives having antitumor activity | |
WO2022143897A1 (en) | POLYMORPHIC SUBSTANCE OF A-DECARBURIZATION-5α ANDROSTANE COMPOUND | |
CN103304556B (en) | Schiff bases compounds containing chromene, Preparation Method And The Use | |
WO2024067085A1 (en) | Citrate salt of cyclin-dependent kinase (cdk4/6) inhibitor, crystal form thereof, preparation method therefor and use thereof | |
WO2020156150A1 (en) | Polymorph of pomalidomide prodrug salt | |
US20080139490A1 (en) | Crystalline forms of valrubicin and processes for their preparation | |
CN114685596A (en) | Polymorphs of an a-nor-5 alpha androstane compound | |
MX2007007258A (en) | Stereoselective process and crystalline forms of a camptothecin |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
DPE1 | Request for preliminary examination filed after expiration of 19th month from priority date (pct application filed from 20040101) | ||
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2006794718 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1020087011144 Country of ref document: KR |
|
WWP | Wipo information: published in national office |
Ref document number: 2006794718 Country of ref document: EP |