Title of Invention

NOVEL PROCESS FOR THE PREPARATION OF BETA- POLYMORPHIC FORM OF IMATINIB MESYLATE

Abstract

The invention relates to novel processes for the preparation of Imatinib mesylate, beta form suitable for industrial operations which comprises slurrying Imatinib base in a solvent selected from acetone, acetonitrile, mixture of Isopropyl alcohol and water, Methanol and methylene chloride, Methanol and isopropanol at room temperature followed by addition of methane sulfonic acid and maintaining at room temperature (or) 50-60degreeeC followed by filtration.

Full Text

Field of invention : The present invention relates to improved processes for the preparation of p-polymorphic form of Imatinib mesylate. The invention particularly relates to an improved process for the preparation of p~form of Imatinib mesylate . which has the formula given below The invention also provides a novel, stable cx2-form of Imatinib mesylate and a process for its preparation This invention also relates to pharmaceutical compositions containing the novel stable (X2 form of Imatinib mesylate useful in the treatment of Chronic Myelogenous Leukemia p-form of Imatinib mesylate . which has the formula given below (CML). Background of the invention: Imatinib mesylate which is N-{5-[4-(4-methylpiperazino-methyl)- benzoylamido]-2-methylphenyl}-4- (3-pyridyl) 2-pyrimidine -amine, having the formula given above is approved under the trademark "Gleevec ®" by the US Food and Drug Administration for the treatment of Chronic Myelogenous Leukemia before and after the failure of interferon alpha. It has also been approved for the treatment of patients with kit (CD117) positive unresectable and / or metastatic malignant Gastro Intestinal Stromal Tumors (GISTs). Recently it has been approved for the treatment of pediatric patients with Philadelphia chromosome positive (Ph+) Chronic Myeloid Leukemia (CML)^ chronic phase. It is known that Imatinib mesylate exists in two polymorphic forms a and p (WO 99/03854). The preparation of Imatinib mesylate a and (5 forms are disclosed in WO99/03854 issued on 28th January 1999. In the Examples 1 to 3 of the said patent the process for the preparation of Imatinib mesylate p-form has been described using a maximum of 50 gms Imatinib base in solution. In the Example-2 of the said patent a process has been described for the preparation of the P-form which involves suspending Imatinib base in methanol, adding methane sulfonic acid in methanol, heating to 50°C, followed by carbon treatment and distilling off methanol. Then dissolving the residue in minimum methanol and inoculation by some seeding crystals of Imatinib mesylate P-form. In Examples land 3 of the said patent, two processes are described for the conversion of a-polymorphic form to P-polymorphic form. The first process (Example-1) involves (i) Digesting a-modification with methanol solvent at 25°C for 2 days. The second process (Example-3) involves (i) Heating a modification in methanol to 60°C and inoculating with p- modification. In the same Example-1, the a-crystal form is prepared as follows: Imatinib base was suspended in ethanol, methane sulfonic acid was added and heated under reflux for 20 minutes and then filtered at 65°C. The filtrate was evaporated down to 50% and the residue filtered off at 25°C (filter material A). The mother liquor was evaporated to dryness. The residue and filter material A were suspended in ethanol dissolved under reflux with addition of water. Cooling overnight to 25°C, filtration and drying yielded Imatinib mesylate a-crystal form. These processes suffers from the following disadvantages 1. In Examples 2 and 3 seed crystals of p-form are required to crystallize out the product 2. The process for preparing a-crystal form given under Example-1 is not reproducible. Repetition of the experiment exactly under identical conditions as reported in the above patent (WO 99/03854) resulted only in the p-form 3. Thus, there is currently no available process to prepare the a-crystal modification. Important solid state properties of a pharmaceutical substance are its rate of dissolution in aqueous fluid. The rate of dissolution of an active ingredient in a patients stomach fluid may have therapeutic consequences because it imposes an upper limit on the rate at which an orally-administered active ingredient may reach the blood stream. The solid state form of a compound may also affect its behavior on compaction and its storage stability. These practical physical characteristics are influenced by the conformation and orientation of molecules in the unit cell, which defines a particular polymorph form of a substance. The polymorphic form may give rise to thermal behavior different form that of the amorphous material (or) another polymorphic form. Thermal behaviour is measured in the laboratory by such techniques as capillary melting point, Thermo Gravimetric Analysis (TGA) and Differential Scanning Calorimetry (DSC), and may be used to distinguish some polymorphic forms from others. A particular polymorphic form may also give rise to distinct properties that may be detectable by powder x-ray diffraction (XRPD) solid state ,3CNMR spectrometry and infrared spectrometry. The various characteristics and properties of the polymorpohic forms of a substance, e.g. shape, colour, density and the like, will make one polymorphic form preferable over the others for production and /or pharmaceutical compounding. As a result, a very first step in the processes of product development of a new pharmaceutical agent is the determination of whether it exists in polymorphic forms and if so which of such form possesses advantages for the eventual commercial pharmaceutical application. In the case of Imatinib mesylate, p form is offered commercially under the trade name Gleevec ®./Glivec® In the patent mentioned above (WO 99/03854), p-form was selected over a-form based on the following observations and conclusions. (i) p-form is thermodynamically stable at room temperature and at temperatures below 140°C. Greater stability of the p-form is thus expected, (ii) p-crystal form is less hygroscopic than the a-crystal form, (iii) a-crystal form is meta stable at room temperature (iv) p-crystal has the advantage that its flow properties are substantially more favourable than those of that the a-crystal form. Based on the above information, we undertook a detailed study of the solid state physical properties of the polymorphic forms of Imatinib mesylate. The presumption was that these properties may be influenced by controlling the conditions under which Imatinib mesylate is obtained in solid form. Our studies on a and p-crystal forms of Imatinib Mesylate, surprisingly we could prepare a novel stable -form of Imayininb Mesylate which is also as good as the p-form for commercial pharmaceutical applications. We have designated this new form as a2 polymorphic form. Based on the above findings the need for a thorough investigation on a -form of Imatinib Mesylate was felt, as the prior art on this polymorphic form, is either inadequate or erroneously documented. Accordingly we focused our R&D efforts in taking up an elaborate study on the polymorphism of Imatinib Mesylate with particular reference to a -form. Surprisingly, these studies also resulted in developing an improved process for the preparation of P-crystal form as well. The focused R&D program undertaken revealed that: (i) the new ot2 form is not meta stable and is stable at room temperature and even at higher temperatures like 120°C. (ii) 0&2 form is stable at normal and accelerated stress conditions both in bulk and formulated capsule form. (iii) ot2 form is as freely soluble in water as is the P-form. The rate of dissolution of ot2 form in the formulation is comparable and even better than that of the P-form. (iv) Flow properties of the formulations prepared with the new ot2 are comparable with that of p form as the same excipient composition is employed in both cases. Determination of presence of Imatinib mesylate form-p in Imatinib mesylate form ai may be made by analysis for the presence of various peaks associated with form-p particularly at 9.7, 13.9, 18.2, 20.0, 20.6, 21.1, 22.1, 22.7, 23.8, 29.8, 30.8 ± 0.2 degree 26.(WO99/03854). Therefore we focussed our R&D efforts in taking up an elaborate study on the polymorphism of Imatinib Mesylate with particular reference to stable forms.. Such a stable ct2 form of imatinib Mesylate is not hitherto known and is a novel polymorphic form. Our copending application No. A describes and claims the novel, stable form and deals with the on form of imatinib Mesylate and a pharmaceutical composition containing the novel ot2 form Imatinib Mesylate which is stable and less hygroscopic and water soluble and having the XRPD characteristics shown in Table 1. In addition, the form prepared by us now is also suitable for developing a pharmaceutical composition. Such a pharmaceutical composition containing ct2 form is also not known and is novel is the subject matter of our above mentioned co pending application no A.. Therefore the main objective of the present invention is to provide an improved process for the preparation of Beta form of Imatinib Mesylate Another objective of the present invention is to provide a novel az crystalline form oi Imatinib Mesylate which is stable at room temperature and even at higher temperatures like 120°C and accelerated stress conditions, freely soluble in water and having tfa characteristics given in Table 1 given below Yet another objective of the present invention is to provide a process for the preparation of novel ot2 form of Imatinib Mesylate which is stable and less hygroscopic and water soluble having the characteristics given in table 1 Still another objective of the present invention is to provide a pharmaceutical composition useful for the treatment of Chronic Myeloid Leukemia which comprises novel (X2 form of Imatinib Mesylate which is stable and less hygroscopic and water soluble having the characteristics given in table 1 and a commonly employed pharmaceutically acceptable excipients. Accordingly the present invention there is provided an improved process for the preparation of Imatinib mesylate form-p which comprises suspending Imatinib base in a solvent selected from methanol, acetone, acetonitrile, mixture of methanol and isopropanol and mixture of isopropanol and water and adding methane sulfonic acid to the resulting solution at room temperature and maintaining the solution at the reflux temperature of the solvent (or) at room temperature and filtering the p-crystal form. According to another embodiment of the present invention there is provide a novel (X2 crystalline form of Imatinib Mesylate which is stable at room temperature and even at higher temperatures like 120°C and accelerated stress conditions, freely soluble in water and having the characteristics given in Table 1 . According to still another embodiment of the present invention there is provided a process for the preparation novel α2 crystalline form of Imatinib Mesylate which is stable at room temperature and even at higher temperatures like 120°C and accelerated stress conditions, freely soluble in water and having the characteristics given in Table 1 which comprises suspending Imatinib base in isopropanol and adding methane sulfonic acid at room temperature and maintaining the reaction mixture at a temperature in the range of 40-80°C, for a period in the range of 20-30 minutes, cooling and filtering to obtain the α2 crystal form. According to yet another embodiment of the present invention there is provided a pharmaceutical composition useful for the treatment of Lukemia which comprises novel ot2 form of Imatinib Mesylate which is stable and less hygroscopic and water soluble having the characteristics given in table 1 and a commonly employed pharmaceutically acceptable exepients It is to be noted that the ot2 form of Imatinib mesylate of the present invention does not substantially convert over time to form p, either as such in bulk form or after formulation in the dosage form, upon storage at about 40° and about 75% relative humidity for at least about 6 months. We have also observed that the pharmaceutical formulation, particularly oral dosage forms such as capsules containing fine crystals of novel Imatinib mesylate form α2 along with other usually employed pharmaceutically acceptable excipients. The dosage form of the formulation of the present invention may be a capsule containing the composition preferably a powdered on granulated solid composition of the invention, within either a hard (or) soft shell. The shell may be made from gelatine and optionally contain a plasticizer such as glycerin and sorbitol and an opacifying agent (or) colorant. Storage of capsule containing highly pure Imatinib mesylate form α2 at about 40° C and about 75% relative humidity for about 3-4 months, does not show any significant conversion to p-polymorphic form of Imatinib mesylate preferably less than about 5%. The detection of Imatinib mesylate form-p in a pharmaceutical formulation to the extent about 1% w/w or more may be accomplished by use of x-ray powder diffraction. Pharmaceutical composition contains the new α2 form Imatinib mesylate as the active ingredient and one or more excipients conventionally used in such compositions. Excipients are added to the composition for a variety of purposes. Methods known in the art, may be used to prepare the composition. Accordingly the composition may be prepared by mixing the active ingredient with a combination of excipients including micro crystalline cellulose, lactose, crospovidone XL, colloidal silicon dioxide magnesium stearate and talc. Table-2 shows suitable ranges of active ingredients and excipients (weight %) and the preferred amounts for the present pharmaceutical formulations. Same ranges of active ingredients and excipients (weight %) is applicable for P-crystal pharmaceutical formulations as well. The pharmaceutical formulations are useful in the treatment of Chroma ITVW*V&W»VM» Leukemia. The oral pharmaceutical dosage forms of the present invention preferably contain about 100 mg of the base equivalent. The industrial sized batch of novel Imatinib mesylate form-α2 does not substantially convert over time to form p, either as such in bulk form or after formulation in the dosage form, upon storage at about 40° and about 75% relative humidity for at least about 6 months. The above novel α2 form of Imatinib Mesylate and the pharmaceutical composition containing the novel form and the process of its preparation has been made the subject matter of the applications Nos. A & B respectively which are divided out of this application. Table - 3 shows two typical examples of the capsule formulation containing Imatinib Mesylate α2 - form and their dissolution and stability characteristics. Table-3 PHARMACEUTICAL COMPOSITIONS CONTAINING IMATINIB MESYLATE a2 -FORM Dissolution and stability characteristics Inference: Two typical batch formulations of Imatinib a2-form are prepared. The dissolution and stability characteristics indicate that (X2-form has excellent formulation characteristics. TabIe-4 shows the heat stability of α2 form over the temperature range 110-120°C. The α2 form is shown to be non-metastable and stable when heated at 120°C for 6 hours. Stability of c^-crystal form Pure oc2-crystal polymorph 1 gm prepared by the process described in Example 1 was taken in a boiling test tube and heated gradually in oil bath and the substance was examined by XRPD. The results are tabulated below * The presence of form-p was below the detection level in these examples. Inference: The a2 form of Imatinib mesylate is not metastable. It is fairly stable to heat even at 120°C/ 6 hours. Table-5 shows the stability of ai form under accelerated stress conditions (45±2°C, 75 ±5% RH, 6 months) in the bulk and capsule formulation * The presence of form-p was below the detection level in these examples showing that α2 form is not converted to p- form over a time period. The stability of oc2 form in bulk and in the formulated capsule is thus established. Table-6 shows comparative dissolution data of Imatinib capsule formulation containing α2 form and p-form. The formulation with α2 form is found to have better dissolution characteristics. Table-6 Comparative dissolution data for Imatinib mesylate capsules 100 mg* (CLI and B-forms) Test parameters 1. Dissolution medium : 0.1 N HC1 2. Dissolution volume : 900ml 3. RPM (Revolutions Per Minute) : 50 4. Wave length : 240 nm (for assay determination) * The capsules contain Imatinib Mesylate equivalent of 100 mg of Imatinib base. The excipients are as per the Example - 11 Inference : The release profile and dissolution data show that the capsule formulation with α2 -form is better than the formulation with p-form Storage of capsule containing pure Imatinib mesylate α2 form prepared by the process of the present invention at about 40° C and about 75% relative humidity for 6 months. does not show any significant conversion to p-polymorphic form of Imatinib mesylate preferably less than about 5%. The detection of Imatinib mesylate form-p in a pharmaceutical formulation to the extent about 1% w/w or more may be accomplished by use of x-ray powder diffraction. The pharmaceutical formulations containing the novel, stable a2 form prepared by the process of the present invention are useful in the treatment of Chronic Myelogenous Leukemia. The oral pharmaceutical dosage forms preferably contain about 100 mg of the base equivalent. The preparative aspects, physical and functional properties of novel Imatinib mesylate α2 form prepared by the process of the present invention are compared with the properties of a form described in the prior art (WO 99/03854) and tabulated in Table-7. The tabulated data clearly demonstrates the stability and functional superiority of the novel The present invention provides an improved process for the preparation of a stable crystalline Imatinib mesylate p Form, which is useful for batch wise industrial production The term "batch" is used herein to refer to a pharmaceutical bulk preparation. 'Preferably on an industrial scale' means "A specific quantity of a drug of uniform specified quantity produced according to a single manufacturing operation during the same cycle of manufacture". The term "reproducible process" means a process that produces a product of a specified quantity and quality on a consistent basis. Therefore the main objective of the present invention is to provide an improved reproducible processes suitable for industrial scale operations for the manufacture of P-crystal form of Imatinib Mesylate. The process for the preparation of the novel, stable α2 form of Imatinib mesylate, comprises suspending Imatinib base in isopropanol and adding methane sulfonic acid at room temperature and maintaining the reaction mixture at a temperature in the range of 40-80°C, for a period in the range of 20-30 minutes, cooling and filtering the α2-crystal form. According to the present invention there is provided an improved process for the preparation of Imatinib mesylate Form-P which comprises suspending Imatinib base in a solvent selected from methanol, acetone, acetonitrile, mixture of methanol and isopropanol and mixture of isopropanol and water and adding methane sulfonic acid to the resulting solution at room temperature and maintaining the solution at the reflux temperature of the solvent (or) at room temperature and filtering the P-crystal form. The details of the invention are provided in the examples given below which are provided to illustrate the invention only and therefore they should not be construed to limit the scope of the invention. Examnle-1 Preparation of novel Imatinib mesylate form-a 2 in lab scale Imatinib base (200 gms) obtained directly from the synthesis was suspended in 2.5 L of isopropanol. Methane sulfonic acid (38.9 gms) in 400ml anhydrous Isopropanol was added slowly during 20 minutes at room temperature. Reaction mass was heated to 75-80°C for 30 minutes and slowly cooled to 40-45°C during 45 minutes. Filtered at 40-45°C and washed with 250 ml Isopropanol. The wet cake was dried for 6 hours at 80°C. The yield was 170 gms (71%) Melting range - 226-227°C (DSC) The Fig 1 of the drawings accompanying this specification shows the X-Ray Powder Diffraction (XRPD) pattern which substantially depicts a typically pure sample of Imatinib mesylate of form-012 prepared as per the process disclosed in this Example The 29 values and intensities are tabulated in Table-1. 3 Fig - 2 shows the IR spectrum of α2 form prepared by the process described in this Example. Fig - 3 shows the DSC thermogram of α2 form prepared by the proicess described in this Example Fig. - 4 shows the XRD spectrum of cc2 form from capsules stored for 6 months at 40° ± 2° / 75 ± 5% (Table-5) Example-2 Preparation of novel Imatinib mesylate form-a 2 on industrial scale Imatinib base (10 Kg) obtained directly from the synthesis was suspended in 125 L of Isopropanol. Methane sulfonic acid (1.94 Kg) in 20L Isopropanol was added slowly during 40-60 minutes at room temperature. Reaction mass was heated to 75-80°C for 30 minutes and slowly cooled to 40-45°C during 45 minutes. Filtered at 40-45°C and washed with 12 L Isopropanol. The wet cake was dried for 6 hours at 80°C. The yield was 8.6 Kg (72%) Melting range - 225-226°C (DSC) XRPD matches Standard 012 form as given in Example-1 above Example-3 Preparation of Imatinib mesylate form-B in isopropanol: methanol mixture Imatinib base (0.5 Kg) was suspended in 6 L of isopropanol at room temperature. Methane sulfonic acid (97.2 gms) in 1 L isopropanol was added slowly during 30 minutes. Reaction mass was heated to 80-85°C and 2.5 L of methanol was added through the condenser at reflux temperature. Maintained for 6 hours at 70-75°C and slowly brought to RT during 1 hour. Filtered and washed with mixture of isopropanol.(1.5 L) and methanol (0.5 L). Dried for 6 hours at 65°C. The yield was 0.51 Kg (85%) Melting range - 215-217°C (DSC) XRPD spectrum as given in figure-5 XRPD matches standard p-form ExampIe-4 Preparation of Imatinib mesylate form-B in acetone with heating Imatinib base (0.25 Kg) was suspended in 12 L of acetone Methane sulfonic acid (48.6 gms) in 0.5 L acetone was added slowly during 30 minutes at room temperature. The reaction mass was heated to reflux temperature for 30 minutes and was slowly brought to room temperature during 45 minutes. Filtered and washed with 1 L acetone and dried for 6 hours at 65°C. The yield was 255 gms (85%) Melting range-215-217°C (DSC) XRPD spectrum as given in figure-6 XRPD matches standard p-form. Example-5 Preparation of Imatinib mesylate form-B in acetone at room temperature Imatinib base (0.25 Kg) was suspended in 12 L acetone. Methane sulfonic acid (48.6 gms) in 0.5 L acetone was added slowly during 30 minutes at room temperature. The suspension was stirred at room temperature for 1 hour. Filtered and washed with 1 L acetone and dried for 6 hours at 65°C. The yield was 270 gms (90%) Melting range - 207-212°C (DSC) XRPD matches standard p-form Example-6 Preparation of Imatinib mesylate form-B in acetonitrile with heating Imatinib base (0.25 Kg) was suspended in 12 L acetonitrile. Methane sulfonic acid (48.6 gms) in 0.5 L acetonitrile was added slowly during 30 minutes at room temperature. The reaction mass was heated to reflux temperature for 30 minutes and was slowly brought to room temperature slowly during 45 minutes. The suspension was stirred at room temperature for 1 hour. Filtered and washed with 1 L acetonitrile and dried for 6 hours at 65°C. The yield was 260 gms (86.6%) Melting range - 208-211°C (DSC) XRPD spectrum as given in figure-7 XRPD matches standard p-form Example-7 Preparation of Imatinib mesylate form-B in acetonitrile at room temperature Imatinib base (0.25 Kg) was suspended in 12 L acetonitrile. Methane sulfonic acid (48.6 gms) in 0.5 L acetonitrile was added slowly during 30 minutes at room temperature. The suspension was stirred at room temperature for 3 hours. Filtered and washed with 1 L acetonitrile and dried for 6 hours at 65°C. The yield was 265 gms (88.0%) Melting range - 211-215°C (DSC) XRPD matches standard P-form Example-8 Preparation of Imatinib mesylate form-B in isopropanol and water Imatinib base (0.5 Kg) was suspended in 6 L of isopropanol. Methane sulfonic acid (97.2 gms) in 0.5 L DM water was added slowly during 30 minutes. The reaction mass was maintained over night at room temperature under stirring. Filtered and washed with mixture of Isopropanol and water, dried for 6 hours at 65°C. The yield was 0.41Kg (68%) Melting range - 210-216°C DSC XRPD spectrum as given in figure-8 XRPD matches standard p-form Example-9 Preparation of Imatinib mesylate form-B in methanol at room temperature Imatinib base (0.1 Kg) was suspended in 0.3 L of Methanol. Methane sulfonic acid (19.4 gms) was added slowly during 15 minutes. Reaction mass was stirred for 5 hours at room temperature. Filtered, washed with methanol and dried for 5 hours at 65°C. The yield was 96 gm (80%) Melting range - 213.7-217.7°C (DSC) XRPD matches standard P-form Example-10 Preparation of Imatinib mesylate form-B in methanol and methylene chloride Imatinib base (0.1 Kg) was suspended in 0.8 L of methanol. Methane sulfonic acid (19.4 gms) in 0.2 L methanol was added slowly during 20 minutes. Reaction mass was heated to reflux temperature for 30 minutes. Distilled off methanol completely under reduce pressure. Charged 0.3 L methylene chloride to the residue and stirred 3 hours at room temperature. Filtered and washed with 0.2 L Methylene chloride and dried for 5 hours at 65°C. The yield was 0.1 Kg (83%) Melting range - 216.6°C (DSC) XRPD matches standard p-form Example-11 Capsules containing 120 mg of active ingredient of the compound describe in the Example-1 and having the following composition are prepared in customary manner. Average weight: 230 * Equivalent to 100 mg Advantages of the invention 1. Provides improved process for the manufacture of P-polymorphic form on an industrial scale. 2. The process produces novel stable α2 polymorphic form of imatinib mesylate consistently. 3. The α2 polymorphic form of Imatinib mesylate produced is stable and compares well with the p-polymorphic form in stability. 4. The process results in the preparation of a stable dosage form (capsule) incorporating the novel α2 polymorph form . We Claim An improved process for the preparation of Imatinib mesylate form-P which comprises suspending Imatinib base in a solvent selected from methanol, acetone, acetonitrile, mixture of methanol and isopropanol and mixture of isopropanol and water and adding methane sulfonic acid to the resulting solution at room temperature and maintaining the solution at the reflux temperature of the solvent (or) at room temperature and filtering the P-crystal form. An improved process for the preparation of Imatinib mesylate form-p substantially as herein described with reference to the Examples 3 to 10 .

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