Description

CRYSTALLINE SOLID FORMS OF BENIDIPINE HCI AND METHODS OF

PREPARING SAME

Technical Field

[0001] The present invention relates to novel, stable, crystalline monohydrate solid forms C, D, E, F, G, H and I of benidipine hydrochloride,

pharmaceutical compositions thereof, and processes for preparations thereof.

Background Art

[0002] Benidipine, whose chemical name is (±)-(R ^* )-1 ,

4-dihydro-2,6-dimethyl-4-(meta-nitrophenyl)-3,5-pyridinedica rbolate methyl ester [(R ^* )-1-benzyl-3-piperidine alcohol ester].

[0003] Two chiral centers are present in the structural formula; one in position of dihydropyridinic ring and one in position of piperidinic ring. Benidipine is a racemic mixture of two isomers [(S)-(S)(+)] and [(R)-(R)-(-)]. Hydrochloride salt of benidipine exists as four enantiomers and two couples of

diasteroisomers, respectively called: a-Benidipine HCI (RR, SS) and β-Benidipine HCI (RS, SR).

[0004] Benidipine hydrochloride is an odourless yellow crystalline powder. It is very soluble in formic acid, soluble in methanol, sparingly soluble in ethanol, and almost insoluble in water.

[0005] Benidipine hydrochloride is used as an antihypertensive drug similar to the structurally related compounds, nifedipine and nicardipine. Benidipine hydrochloride is a dihydropyridine calcium channel blocker and inhibits L-, N- and T-type Ca ⁺² channels. It is the only calcium antagonist that can inhibit all the three Ca ⁺² channels mentioned above. Benidipine has relatively high vascular selectivity and is expected to show protective effects on vascular endothelial cells. Renal protective effects of benidipine also have been shown in several basic and clinical studies. Moreover, anti-oxidative action and enhancing nitric oxide production have been noted with this drug, following its cardio-protective effects in patients with ischemic heart diseases. In fact, benidipine exerted a better prognostic effect than other calcium channel blockers in the therapy for patients with vasospastic angina. In addition, benidipine showed reliable antihypertensive, renoprotective effects if used in combination with angiotensin II type 1 receptor blockers (ARBs) when adequate

anti-hypertensive effects are not achieved by ARBs alone, indicating that benidipine is a useful calcium channel blocker in combination therapy for hypertension.

[0006] Benidipine is marketed under the tradename of Coniel by Kyowa Hakko Kogyo as a hydrochloride salt of benidipine. Coniel is licensed for use in Japan and selected Southeast Asian countries, where it is sold in tablet form with strengths of 2 mg, 4 mg and 8 mg, and generally prescribed in regimes of once or twice daily.

[0007] EP 63365 B (KYOWA HAKKO KOGYO KK) 15.06.1994 discloses firstly 1 , 4-dihydropyridine derivatives and pharmaceutical compositions containing the same.

[0008] EP 106275 B (KYOWA HAKKO KOGYO KK) 13.03.1991 describes the diasteomers of benidipine hydrochloride. According to EP'275 patent, benidipine hydrochloride of which has melting points of 196 °C to 202 °C is referred as (±)-a-form and benidipine hydrochloride of which has melting points of 236 °C to 242 °C is referred as (±)-p-form.

[0009] Polymorphism is defined as the ability of a substance to exist as two or more crystalline forms that have different arrangements or conformations of molecules in the crystal lattice. These different crystalline forms are known as "polymorphs" and are realized only in the crystalline state. While polymorphic forms have the same chemical composition, they differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state. As such, these modifications may have different solid-state physical properties such as shape, colour, density, hardness, deformability, stability, dissolution properties, and the like. Pharmaceutical solids can exist in different crystal forms, such as crystalline, amorphous and also in solvated or hydrated states. Solvates are crystalline solid adducts containing either stoichiometric or non-stoichiometric amounts of a solvent incorporated within the crystal structure. If the incorporated solvent is water, the solvates are also commonly known as hydrates. Polymorphism of an organic drug molecule and its consequences would be appreciated by one skilled in the pharmaceutical art.

[0010] SHOICHI, et al. Characterization of Monohydrate Form of Benidipine

Hydrochloride and Comparison of Dissolution Behaviours of Its Anhydrate and Monohyrate Form. Journal of Pharmaceutical Science and

Technology . 2003. discloses two polymorphic forms, namely monohydrate and anhydrate forms of benidipine hydrochloride. Shoichi's study describes the polymorph or hydrate form of benidipine hydrochloride though some 1 ,4-dihydropyridines polymorphs or hydrates. Said paper discloses two polymorphic forms, namely monohydrate and anhydrate forms of benidipine hydrochloride.

[001 1] JP 03763538 B (DAI TO KK) 05.04.2005 describes the industrial

preparation of high-purity benidipine hydrochloride by using a method of purification comprising benidipine hydrochloride monohydrate crystal form to obtain anhydrate benidipine hydrochloride.

[0012] Shoichi's study and JP3763538 do not disclose or refer to or even suggest the possible existence of different crystalline monohydrate forms of benidipine hydrochloride.

[0013] On the other hand, the discovery of new polymorphic forms of a

pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of the pharmaceutical product. Therefore, there is a need in the art for new polymorphs of benidipine hydrochloride and processes for the preparation of benidipine hydrochloride.

Summary of invention

[0014] This invention relates to new C, D, E,F,G,H and I crystalline monohydrate polymorphic of benidipine hydrochloride and processes for preparation thereof and pharmaceutical compositions of benidipine hydrochloride.

Technical Problem

[0015] The pharmaceutical industry has faced growing challenges in recent years as a result of increased economic and regulatory pressures.

[0016] Recently, in solid state pharmaceutical science, development and

characterization of stable crystal forms of active pharmaceutical ingredients is an ongoing challenge and it is a routine practice for scientists to invest in development of new candidates of polymorphism for active pharmaceutical ingredients.

[0017] Moreover, solid state study of an active pharmaceutical ingredient aims to widen the variety of crystalline forms that a formulation scientist has available for designing a pharmaceutical finished product with desired performance characteristics.

[0018] The new polymorphs may possess some properties can have a direct impact on the processability of drug substances and the

quality/performance of drug products, such as, dissolution and

bioavailability.

[0019] Furthermore, the solid state form of an active pharmaceutical ingredient may affect its stability as in finished product.

[0020] The stability of the active pharmaceutical ingredients (APIs) is the key

factor in stability evaluation of finished pharmaceutical products (FPPs). On this ground, stability testing of API in FPP must be conducted.

[0021] An interconversion in crystalline structure or formation new forms is highly possible during processing and storage for polymorphs of API. And, it is important to avoid any polymorphic transformation during the production stage and storage of the pharmaceutical preparation for achievement of the stability and quality standards of FPPs.

[0022] From a storage perspective, the relative humidity and/or temperature of the environment may cause polymorphic transformation of API. Thence, stable polymorphs which cannot easily convert into the other forms in case of acquirement or lost of water, are always preferred.

[0023] Since it has been done significant investment in processes for stable

polymorphs of active pharmaceutical ingredients (API), the development of new stable polymorphic forms' processes which do not require control analysis of stability of polymorphs in each step is always encouraged.

[0024] Consequently, there is a constant need for easy, simple, economic,

reliable processes for the preparation of new stable polymorphic forms of benidipine hydrochloride which may be used for commercial

manufacturing of capsule or tablets.

Solution to Problem [0025] The performance characteristics of a pharmaceutical product can be improved by means of discovery of new polymorphic forms.

[0026] It is an object of this invention to provide a crystalline monohydrate form of benidipine hydrochloride which can be produced and stored while meeting its required specifications for a pure drug substance.

[0027] Inventors have surprisingly found out new, stable crystalline forms of

benidipine hydrochloride. The newly obtained crystalline monohydrate forms have features to be stable at room and accelerated stress conditions over time.

[0028] The novel monohydrate forms of benidipine hydrochloride provide

pharmaceutically desirable properties needed for a drug to be

administered to patients, and has no colour change and thermal stability for solid dosage form and is substantially free of undesired other polymorphs.

[0029] In another aspect, the invention is also directed to methods of preparing the stable crystalline monohydrate polymorphic forms of benidipine hydrochloride. Optimization of process conditions to prepare stable crystalline monohydrate polymorphs of benidipine hydrochloride has been attempted. The method comprises basically forming a solution of the benidipine hydrochloride by heating the suspension of benidipine hydrochloride or heating the suspension optionally by adding a second solvent to complete dissolution, and then cooling the solution after distilling off second solvent or after dissolution to facilitate precipitation of the polymorph. When there is no crystallization after cooling step, specific anti solvent, such as water is used to precipitate the desired polymorph from the solution.

[0030] In the present invention, it is also aimed to develop a simple process for preparation of benidipine hydrochloride monohydrate forms with better yield.

[0031] It is a further object of this invention to provide a reliable process where, crystalline monohydrate forms of benidipine hydrochloride can be conveniently and reproducibly prepared.

Brief description of drawings [0032] Fig. 1 provides the X-ray diffractogram of crystalline C form of benidipine hydrochloride monohydrate prepared according to the process of the present invention.

[0033] Fig. 2 provides the infrared spectrum (IR) of crystalline C form of

benidipine hydrochloride monohydrate prepared according to the process of the present invention.

[0034] Fig. 3 provides the differential scanning calorimetry thermogram (DSC) crystalline C form of benidipine hydrochloride monohydrate prepared according to the process of the present invention.

[0035] Fig. 4 provides the X-ray diffractogram of crystalline D form of benidipine hydrochloride monohydrate prepared according to the process of the present invention.

[0036] Fig. 5 provides the infrared spectrum (IR) of crystalline D form of

benidipine hydrochloride monohydrate prepared according to the process of the present invention.

[0037] Fig. 6 provides the differential scanning calorimetry thermogram (DSC) crystalline D form of benidipine hydrochloride monohydrate prepared according to the process of the present invention.

[0038] Fig. 7 provides the X-ray diffractogram of crystalline E form of benidipine hydrochloride monohydrate prepared according to the process of the present invention.

[0039] Fig. 8 provides the infrared spectrum (IR) of crystalline E form of

benidipine hydrochloride monohydrate prepared according to the process of the present invention.

[0040] Fig. 9 provides the differential scanning calorimetry thermogram (DSC) crystalline E form of benidipine hydrochloride monohydrate prepared according to the process of the present invention.

[0041] Fig. 10 provides the X-ray diffractogram of crystalline F form of benidipine hydrochloride monohydrate prepared according to the process of the present invention.

[0042] Fig. 11 provides the infrared spectrum (IR) of crystalline F form of

benidipine hydrochloride monohydrate prepared according to the process of the present invention. [0043] Fig. 12 provides the differential scanning thermogram (DSC) crystalline F form of benidipine hydrochloride monohydrate prepared according to the process of the present invention.

[0044] Fig. 13 provides the X-ray diffractogram of crystalline G form of benidipine hydrochloride monohydrate prepared according to the process of the present invention.

[0045] Fig. 14 provides the infrared spectrum (IR) of crystalline G form of

benidipine hydrochloride monohydrate prepared according to the process of the present invention.

[0046] Fig. 15 provides the differential scanning calorimetry thermogram (DSC) crystalline G form of benidipine hydrochloride monohydrate prepared according to the process of the present invention.

[0047] Fig. 16 provides the X-ray diffractogram of crystalline H form of benidipine hydrochloride monohydrate prepared according to the process of the present invention.

[0048] Fig. 17 provides the infrared spectrum (IR) of crystalline H form of

benidipine hydrochloride monohydrate prepared according to the process of the present invention.

[0049] Fig. 18 provides the differential scanning calorimetry thermogram (DSC) crystalline H form of benidipine hydrochloride monohydrate prepared according to the process of the present invention.

[0050] Fig. 19 provides the X-ray diffractogram of crystalline I form of benidipine hydrochloride monohydrate prepared according to the process of the present invention.

[0051] Fig. 20 provides the infrared spectrum (IR) of crystalline I form of

benidipine hydrochloride monohydrate prepared according to the process of the present invention.

[0052] Fig. 21 provides the differential scanning calorimetry thermogram (DSC) crystalline I form of benidipine hydrochloride monohydrate prepared according to the process of the present invention.

[0053] Fig. 22 provides the X-ray diffractogram of crystalline C form of benidipine hydrochloride monohydrate at accelerated storage conditions, 40 °C, 75% relative humidity. [0054] Fig. 23 provides the X-ray diffractogram of crystalline D form of benidipine hydrochloride monohydrate at accelerated storage conditions, 40 °C, 75% relative humidity.

[0055] Fig. 24 provides the X-ray diffractogram of crystalline E form of benidipine hydrochloride monohydrate at accelerated storage conditions, 40 °C, 75% relative humidity.

[0056] Fig. 25 provides the X-ray diffractogram of crystalline F form of benidipine hydrochloride monohydrate at accelerated storage conditions 40 °C, 75% relative humidity.

[0057] Fig. 26 provides the X-ray diffractogram of crystalline G form of benidipine hydrochloride monohydrate at accelerated storage conditions, 40 °C, 75% relative humidity.

[0058] Fig. 27 provides the X-ray diffractogram of crystalline H form of benidipine hydrochloride monohydrate at accelerated storage conditions, 40 °C, 75% relative humidity.

[0059] Fig. 28 provides the X-ray diffractogram of crystalline I form of benidipine hydrochloride monohydrate at accelerated storage conditions, 40 °C, 75% relative humidity.

[0060] Fig. 29 provides the Microscopic Images of crystalline C form of benidipine hydrochloride monohydrate.

[0061] Fig. 30 provides the Microscopic Images of crystalline D form of benidipine hydrochloride monohydrate.

[0062] Fig. 31 provides the Microscopic Images of crystalline E form of benidipine hydrochloride monohydrate.

[0063] Fig. 32 provides the Microscopic Images of crystalline F form of benidipine hydrochloride monohydrate.

[0064] Fig. 33 provides the Microscopic Images of crystalline G form of benidipine hydrochloride monohydrate.

[0065] Fig. 34 provides the Microscopic Images of crystalline H form of benidipine hydrochloride monohydrate.

[0066] Fig. 35 provides the Microscopic Images of crystalline I form of benidipine hydrochloride monohydrate.

Description of embodiments [0067] The main objective of the present invention is to provide novel crystalline monohydrate forms of benidipine hydrochloride, which are described as C,

D, E, F, G, H and I forms.

[0068] Another objective of the invention is to provide processes for the

preparation of novel crystalline monohydrate forms of benidipine

hydrochloride.

[0069] In a first aspect of present invention, two different processes for the

preparation of monohydrate crystalline forms of benidipine hydrochloride are presented, respectively the process A and the process B.

C and E monohydrate forms of benidipine hydrochloride, are synthesized according to process A which comprises following steps:

[0070] (a) Preparing benidipine hydrochloride suspension in a suitable solvent at room temperature.

[0071] (b) Heating the suspension prepared in step (a) up to a suitable

temperature.

[0072] (c) Adding of a second solvent to the suspension in step (b) until complete dissolution.

[0073] (d) Distilling off the second solvent added in step (c) from the solution.

[0074] (e) After completion of the distillation, cooling the solution in step (d) to ambient temperature for crystallization.

[0075] (f) Cooling down the mixture comprising benidipine hydrochloride crystals in step (e) to suitable temperature for further crystallization.

[0076] (g) Stirring the cooled solution in step (f) for a suitable time to get better yield.

[0077] (h) In case of no crystallization in step (g), a suitable amount of water is added into the mixture in step (g) and stirred for a suitable time for crystallization.

[0078] (i) Filtering and then washing the benidipine hydrochloride monohydrate crystals with water.

[0079] (j) Drying the crystals of benidipine hydrochloride in vacuo for a suitable time.

[0080] The identification of the crystalline monohydrate forms of benidipine

hydrochloride can be performed by any suitable method, including traditional solid-state techniques e.g., infra-red spectroscopy (IR), differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD).

[0081] X-ray diffraction data are acquired using a Shimadzu X-ray diffractometer model 6100. System description: Κα1/ Κα2 ratio = 50%; Voltage = 40.0 kV; Current = 30.0 mA. Slits: Auto slit = not used; Divergence slit = 1.0°;

Scatter slit = 1.0°; Receiving slit = 0.30 mm with a Graphite

monochromator. Scanning: Drive axis = Theta-2Theta; Scan range = 3.02 - 40.00°; Scan mode = Continuous scan; Scan speed = 2.0 min;

Sampling pitch = 0.02°; Preset time = 0.60 seconds.

[0082] The infrared (IR) spectrum are recorded on a Shimadzu Fourrier-transform infra-red spectrometer model IR Prestige 21 within the range of 400 and 4000 cm ^-1 and resolution of 2 cm ^-1 . All samples are run as neat at ATR (Attenuated Total Reflectance).

[0083] The infrared spectrum of form as neat has the characteristic absorptions at the following wavelengths in cm ^-1 .

[0084] Differential scanning calorimetry (DSC) measurements are run on

Shimadzu model DSC 60. Samples are analyzed inside crimped 40 μΙ_ aluminium pans. The temperature range is 100 - 220 °C. Heating rate for all samples is 10 °C/min.

[0085] Karl Fischer titration is a classic titration method in analytical chemistry that uses coulometric or volumetric titration to determine trace amounts of water in a sample. Karl Fischer Titration (KFT) method is used to determine the presence and amount of water of monohydrate forms, respectively novel crystalline monohydrate forms C, D, E, F, G, H and I of benidipine hydrochloride. Also, KFT method is used to follow the water content or moisture uptake potential of anhydrate forms of benidipine hydrochloride.

[0086] Measurements obtained by Karl Fischer analysis showed that the

presence of water over 3.0% verifying that the monohydrate forms, C, D, E, F, G, H and I of benidipine hydrochloride.

[0087] All techniques, XRPD, IR and DSC have been evaluated together for

identification and characterization monohydrate forms. Characterization of newly synthesized monohydrate forms of benidipine hydrochloride is done not only by the comparison of all XRPD diffractograms showing similar peak positions with different relative intensities, but also by the comparison of the other parameters including thermograms obtained by DSC analysis and infrared spectra obtained by IR analysis.

[0088] One embodiment of the present invention encompasses crystalline

monohydrate form C characterized by a data selected from a group consisting of:

[0089] i) a X-ray powder diffraction pattern as depicted in Fig. 1.

[0090] ii) a powder XRD pattern having peaks and relative intensities at 7.15(33), 10.31 (100), 13.65(54), 16.4(33), 16.78(30), 17.49(29), 19.70(33),

20.10(34), 20.40(46), 20.58(27), 22.10(72), 26.11 (40) and 27.78°(24) 2 Θ±0.2°2Θ.

[0091] iii)a IR spectrum of C form is substantially in accordance with Fig. 2,

[0092] iv) a DSC thermogram of C form is substantially in accordance with Fig. 3, [0093] v) a DSC thermogram shown in Fig. 3, points with melting point: 183 °C for polymorph C of benidipine hydrochloride.

[0094] A second embodiment of the present invention encompasses crystalline monohydrate E form characterized by a data selected from a group consisting of:

[0095] i) a X-ray powder diffraction pattern as depicted in Fig. 7.

[0096] ii) a powder XRD pattern having peaks and relative intensities at 7.09(76), 10.21 (100), 13.57(63), 16.30(26), 16.69(31), 19.58(31), 20.02(27), 20.30(67), 21.45(40), 21.76(28), 22.03(40), 23.55(25), 26.62°(25)

2Θ±0.2°2Θ.

[0097] iii) a IR spectrum of E form is substantially in accordance with Fig. 8,

[0098] iv) a DSC thermogram of E form substantially in accordance with Fig. 9, [0099] v) a DSC thermogram shown in Fig. 9 points with melting point: 175 °C for polymorph E of benidipine hydrochloride.

[0100] In another aspect of the present invention, other presented monohydrate forms of benidipine hydrochloride, F, G, H and I forms are synthesized according to process B which comprises following steps of:

[0101] (a) Preparing benidipine hydrochloride suspension in a suitable solvent at room temperature.

[0102] (b) Heating the suspension prepared in step (a) up to a suitable

temperature.

[0103] (c) Adding of a second solvent into the suspension in step (b) until

complete dissolution. If the suspension dissolves in step (b), second solvent is not added at this step.

[0104] (d) Cooling down the mixture comprising benidipine hydrochloride crystals in step (c) to suitable temperature for crystallization.

[0105] (e) Stirring the cooled solution in step (d) for a suitable time to get better yield.

[0106] (f) In case of no crystallization in step (e), a suitable amount of water is added into the mixture in step (e) and stirred for a suitable time for crystallization.

[0107] (g) Filtering and then washing the benidipine hydrochloride monohydrate crystals with water or water/solvent mixture.

[0108] (h) Drying the crystals of benidipine hydrochloride in vacuo for a suitable time.

[0109] Another embodiment the present invention encompasses crystalline

monohydrate F form characterized by a data selected from a group consisting of:

[01 10] i) a X-ray powder diffraction pattern of F form as depicted in Fig. 10.

[01 1 1] ii) a powder XRD pattern having peaks and relative intensities at 7.13(42),

10.25(100), 13.62(60), 16.33(34), 16.73(32), 17.44(27), 17.83(25),

19.60(30), 20.06(31), 20.36(46), 20.56(32), 22.08(73) and

26.07°(28)2Θ±0.2°2Θ.

[01 12] iii) a IR spectrum of F form is substantially in accordance with Fig. 1 1 , [01 13] iv) a DSC thermogram of F form is substantially in accordance with Fig.

12,

[01 14] v) a DSC thermogram shown in Fig.12, points with melting point: 175 °C for F form of benidipine hydrochloride.

[01 15] One embodiment the present invention encompasses crystalline

monohydrate G form characterized by a data selected from a group consisting of: [0116] i) a X-ray powder diffraction pattern of G form as depicted in Fig. 13.

[0117] ii) a powder XRD pattern having peaks and relative intensities at 7.17(72), 10.31 (100), 13.67(70), 16.40(27), 16.79(32), 17.49(25), 19.71(33), 20.10(35), 20.40(66), 21.53(47), 22.11(59), 26.12(35) and 26.61 °(27) 2Θ±0.2°2Θ.

[0118] iii) a IR spectrum of G form is substantially in accordance with Fig. 14, [0119] iv) a DSC thermogram of G form substantially in accordance with Fig. 15, [0120] v) a DSC thermogram shown in Fig. 15 points with melting point: 183 °C for G form of benidipine hydrochloride.

[0121] Another embodiment the present invention encompasses crystalline

monohydrate H form characterized by a data selected from a group consisting of:

[0122] i) a X-ray powder diffraction pattern of H form as depicted in Fig. 16.

[0123] ii) a powder XRD pattern having peaks and relative intensities at 7.16(44),

10.27(100), 13.67(68), 16.38(34), 16.79(35), 17.50(29), 17.87(27),

19.65(34), 20.10(38), 20.42(55), 21.58(25), 22.13(84), 25.17(24) and

26.12°(33)2Θ±0.2°2Θ.

[0124] iii)a IR spectrum of H form is substantially in accordance with Fig. 17, [0125] iv) a DSC thermogram of H form is substantially in accordance with Fig.

18,

[0126] v) a DSC thermogram shown in Fig. 18 points with melting point: 172 °C for H form of benidipine hydrochloride.

[0127] Another embodiment the present invention encompasses crystalline

monohydrate I form characterized by data selected from a group consisting of:

[0128] i) a X-ray powder diffraction pattern of I form as depicted in Fig. 19.

[0129] ii) a powder XRD pattern having peaks and relative intensities at 7.11 (40),

10.26(100), 13.60(52), 20.34(50), 22.05(49), 23.58(16), 25.08(19),

26.07(31) and 27.74°(18) 2Θ±0.2°2Θ.

[0130] iii) a IR spectrum of I form is substantially in accordance with Fig. 20,

[0131] iv) a DSC thermogram of I form is substantially in accordance with Fig. 21 , [0132] v) a DSC thermogram shown in Fig. 21 , points with melting point: 179 °C for I form of benidipine hydrochloride. [0133] In a third aspect of the present invention, Form D of benidipine

hydrochloride is obtained by a process which is different from process A and B. Process to prepare form D, defined as process C, comprises following steps:

[0134] (a) Preparing benidipine hydrochloride suspension in water at room

temperature.

[0135] (b) Heating the suspension in step (a) up to a suitable temperature and stirring for a suitable time.

[0136] (c) Cooling down the suspension of benidipine hydrochloride in step (b) to ambient temperature.

[0137] (d) Further stirring the cooled suspension in step (c) for 1 to 4 hours.

[0138] (e) Filtering and then washing the benidipine hydrochloride monohydrate crystals with water.

[0139] (f) Drying the crystals of benidipine hydrochloride in vacuo for a suitable time.

[0140] Another embodiment the present invention encompasses crystalline

monohydrate D obtained by process C form characterized by a data selected from a group consisting of:

[0141] i) a X-ray powder diffraction pattern of D form as depicted in Fig. 4.

[0142] ii) a powder XRD pattern of D form having peaks and relative intensities at 7.08(50), 10.24(100), 13.57(67), 16.33(30), 16.70(31), 17.42(28),

17.78(20), 19.63(33), 20.02(38), 20.30(58), 21.42(32), 21.78(29),

22.02(66) and 26.04°(38) 2Θ±0.2°2Θ.

[0143] iii) a IR spectrum of D form is substantially in accordance with Fig. 5,

[0144] iv) a DSC thermogram of D form is substantially in accordance with Fig. 6,

[0145] v)a DSC thermogram shown in Fig. 6 points with melting point: 186 °C for polymorph D of benidipine hydrochloride.

[0146] It should be emphasized that even minor changes in crystallization

conditions, for example, super saturation, temperature or cooling rate can produce changes in the crystal structure of benidipine hydrochloride followed by formation new crystalline monohydrate forms of benidipine hydrochloride. In general aspect, both of processes to prepare

monohydrate forms of benidipine hydrochloride are similar except of the step in process B comprising of removal of second solvent.

[0147] All steps (a to j) in process A, steps (a to h) in process B and steps (a to f) in process C are individually described herein as disclosure of the present invention.

[0148] Benidipine hydrochloride in step (a), is anhydrate polymorph form of

benidipine hydrochloride.

[0149] According to Process A, suitable solvent in step (a) is water or 1-butanol.

[0150] According to Process B, suitable solvent in step (a) is selected from the group of consisting of methyl ethyl ketone, water, acetic acid or methyl ethyl ketone/water mixture.

[0151] Preparation of monohydrate forms of benidipine hydrochloride comprises a conversion reaction from anhydrate form of benidipine hydrochloride to monohydrate forms. Disruption of the crystalline structure of anhydrate benidipine hydrochloride encompasses a range of dissolution processes from complete dissolution to only slight dissolution. Degree of dissolution can be modified by selection of the appropriate solvent and/or by selection of process temperature within the specified allowable temperature ranges. Second solvent which is added in step (c) to dissolve benidipine

hydrochloride is:

[0152] -aliphatic alcohol, preferably, methanol or ethanol, for process A.

[0153] -ketone, such as, methyl ethyl ketone or acetone, for process B.

[0154] Suitable temperature in step (b) ranges from 80 to 100 °C, for process A, B and C.

[0155] Cooling temperature range in step (f) for process A and in step (d) for process B, changes from 0 to -5 °C and the time for crystallization ends up changes from 1 to 7 hours, preferably 3 hours, and most preferably 2 hours, for both of process A and B.

[0156] Suitable time for stirring in step (f) for process A, step (e) for process B and step (b) for process C changes from 30 minutes to 5 hours.

[0157] Suitable time for drying in step (j) for process A, step (h) for process B and step (f) for process C changes from 1 to 12 hours.

[0158] The present invention also provides optimized processes A and B for preparation of highly purified crystalline monohydrate forms of benidipine hydrochloride, namely C, D, E, F, G, H and I forms. The crystalline monohydrate forms of benidipine hydrochloride are obtained with a purity of over 99.9%. Also, the said process avoids multiple recrystallization cycles which are not only cause loss off the compound by recrystallization but also need a great amount of solvent which is not favourable in environmental aspect.

[0159] Another aspect of the invention relates to the preparation of stable

monohydrate polymorphs of benidipine hydrochloride.

[0160] Our inventors found that monohydrate forms of benidipine hydrochloride, C, D, E, F, G, H and I forms, possesses stability under long term and accelerated stability conditions.

[0161] Stability plays an important role in the drug development process. Stability of a pharmaceutical product may be defined as the capability of that particular formulation, in a specific container or closure system, to remain within its chemical, physical, microbiological, therapeutic and toxicological specifications to assure its attributed quality, e.g, identity, purity, strength etc. until drug expiry.

[0162] Stability of a pharmaceutical product is strongly influenced by changes in solid-state form of the API. The changes in solid state form of the API may be result from the conditions of product manufacturing process. Examples of processing that may cause polymorphic changes including grinding, milling, heating, and compressing. Manufacturing conditions that include a solvent (e.g., wet granulation, polymorphs in solution, and polymorphs in suspension) may facilitate changes in the solid-state form of API. These variations comprising polymorphic transformations, hydrate/solvate formations and dehydration/desolvation reactions in the solid-state form of API cause stability problems in FFPs.

[0163] Therefore, crystalline stability of API has a critical role on satisfying the essentialities of qualified pharmaceutical product and stable polymorphs of API should be used in pharmaceutical formulations.

[0164] For this aspect, crystalline stability of monohydrate forms of benidipine hydrochloride in its solid formulations are investigated under the conditions 25 °C, 60% relative humidity (RH) and 40 °C, 75% RH for 6 months after preparation.

[0165] The crystalline stability referred to here, is the stability of a polymorphic form of API with respect to polymorph transformations, hydration or dehydration, salt disproportionation, crystallization, or amorphization through time under the conditions 25 °C, 60% RH and 40 °C, 75% RH for 6 months after preparation.

[0166] The stability of the monohydrate forms of benidipine hydrochloride are investigated and determined by X-Ray powder diffraction method. Results show that any polymorphic transformation to another crystal form or any degradation in crystal monohydrate form has not occurred. Monohydrate crystal forms, C, D, E, F, G, H and I show crystalline stability under 25 °C, 60% relative humidity and 40 °C, 75% relative humidity for 6 months. X-Ray diffractograms of presented monohydrate forms under the conditions at 40 °C, 75% RH are given in Fig 22, Fig 23, Fig 24, Fig 25, Fig 26, Fig 27 and Fig 28, X-Ray diffractograms (Fig 22 to Fig 28) clearly show that 2-theta and intensity values of characteristic peaks did not changed when exposed to accelerated stability conditions in described monohydrate forms.

[0167] The stability of monohydrate forms of benidipine hydrochloride in finished product during room-temperature storage can be predicted from

shorter-term storage under accelerated conditions of high temperature and humidity.

[0168] In the present invention, samples of obtained crystalline monohydrate forms are stored for 6 months in stability chambers under following conditions of 25°C 60% RH and 40°C 75% RH to test stability of novel crystalline monohydrate forms of benidipine hydrochloride.

[0169] The results of stability tests for crystalline monohydrate forms of benidipine hydrochloride are summarized below in Table 1.

[0170]

Table 1 Form Water Content (%) XRD DSC (°C)

initial 25 40 25 °C 40 initial 25 40

°C °C 60% °C °C °C

60 75 RH 75% 60 75%

% % RH % RH

RH RH RH

C 3.46 3.46 3.45 stabl stabl

183 182 183 e ^* e ^*

D 3.36 3.48 3.51 stabl stabl

186 185 184 e ^* e ^*

E 3.51 3.50 3.53 stabl stabl

175 175 173 e ^* e ^*

F 3.42 3.49 3.51 stabl stabl

175 175 175 e ^* e ^*

G 3.13 3.49 3.50 stabl stabl

183 184 184 e ^* e ^*

H 3.63 3.85 3.88 stabl stabl

172 172 171 e ^* e ^*

1 3.20 3.49 3.48 stabl stabl

179 179 179 e ^* e ^*

^* 2-theta and intensity values for characteristic peaks for

described monohydrate forms did not changed after 6 months of stability test conditions: 25 °C 60% RH and 40 °C 75% RH.

[0171] According to the results shown in Table 1 , novel crystalline monohydrate forms of benidipine hydrochloride are stable under the long term and accelerated stability conditions.

[0172] Moisture interacts virtually at all stages of manufacture. Therefore,

moisture-powder interaction is a major factor in formulation, processing, and performance of solid dosage forms. The amount of moisture adsorbed by drugs and excipients affects the flow of the powder, compression characteristics, and hardness of granules and tablets. Differences in powder flow can affect content uniformity in solid processing either in the mixing process or during transfer to other processing equipment such as tablet process.

[0173] Therefore, the novel monohydrate forms of benidipine hydrochloride in pharmaceutical compositions as compared with anhydrate form are much favourable in respect of controlled moisture content.

[0174] The results of the study for determining moisture uptake potential of

anhydrate form of benidipine hydrochloride are shown in Table 2. Samples of anhydrate form of benidipine hydrochloride are stored in flasks those open to air at the conditions 25 °C 60% RH and 40 °C 75% RH for determination of the moisture uptake potential of anhydrate form of benidipine hydrochloride. According to Table 2, moisture amount of anhydrate form samples of benidipine hydrochloride is changed from 0.31 % to 1.02% at long term stability conditions, 25 °C 60% RH and to 1.10% at accelerated stability conditions, 40 °C 75% RH after 42 days. According to Japan Pharmacopoeia, moisture amount of anhydrate form of benidipine hydrochloride should be less than 0.5%. On the other hand, crystalline monohydrate forms, C, D, E, F, G, H and I forms of benidipine hydrochloride, were exposed to humidity and temperature conditions, 25 °C 60% RH and 40 °C 75% RH same with anhydrate form of benidipine hydrochloride. The results for water content of monohydrate forms are given in Table 1. In the view of moisture uptake potential, monohydrate forms of benidipine hydrochloride are more stable than anhydrate form as shown in Table 2.

[0175]

Table 2

[0176] Yet another objective of the present invention is to provide pharmaceutical compositions containing the novel benidipine hydrochloride monohydrate polymorphs C, D, E, F, G, H and I.

[0177] The compositions containing the novel crystalline monohydrate

polymorphic forms of benidipine hydrochloride may include fillers, binders, disintegrants, glidants, lubricants, flavourings.

[0178] The term 'filler' and the term 'diluent' are herein used interchangeably.

Fillers fill out the size of a composition, making it practical to produce and convenient for the consumer to use. Suitable filler/diluent includes, but are not limited, to calcium carbonate, calcium phosphate, dibasic calcium phosphate, tribasic calcium sulfate, calcium carboxymethylcellulose, cellulose, dextrin derivatives, dextrin, dextrose, fructose, lactitol, lactose (e.g. spray-dried lactose, a-lactose, β-lactose, Tablettose®, various grades of Pharmatose®, Microtose® or Fast-Floe®), methylcellulose polymers such as, e.g., Methocel A®, Methocel A4C®, Methocel A 15C®, Metocel A4M®), hydroxyethylcellulose, hydroxypropylcellulose,

L-hydroxypropylycellulose (low substituted), hydroxypropyl methylcellulose (HPMC) (e.g. Methocel E®, F and K, Metolose SH® of Shin-Etsu, grades of Methocel F® and Metolose 65 SH®, the 4,000, 15,000 and 100,000 cps grades of Methocel K®; and the 4,000, 15,000, 39,000 and 100,000 grades of Metolose 90 SH®), sodium carboxymethylcellulose,

carboxymethylene, carboxymethylhydroxyethylcellulose and other cellulose derivatives, starches or modified starches (including potato starch, wheat starch, corn starch, rice starch, pregelatinized maize starch), magnesium carbonate, magnesium oxide, maltitol, maltodextrins, maltose, sorbitol, sucrose, sugar, xylitol, and erythritol.

[0179] A binder is used to impart cohesive qualities to the solid dosage form and thus ensure that a tablet remains intact after compression. Examples of binders include, but not limited to, microcrystalline cellulose,

hydroxymethyl cellulose, hydroxypropylcellulose, starch (including corn starch and pregelatinized starch), gelatin, sugars (including sucrose, glucose, dextrose, lactose, and sorbitol), waxes, polyethylene glycol, natural and synthetic gums (e.g. acacia, tragacanth sodium alginate, celluloses, and Veegum), and synthetic polymers such as

polymetacrylates and polyvinylpyrrolidone (povidone), ethylcellulose, hydroxy ethyl cellulose, polyethylene oxide, mixtures thereof and the like.

[0180] A disintegrant is a substance which helps the composition break up once ingested. Disintegrants are, but not limited to, cross linked

polyvinylpyrolidone (crospovidone, polyplyplasdone XL®, kollidon CL®); starches such as maize starch and dried sodium starch glycolate; gums such as alginic acid, sodium alginate, guar gum; croscarmellose sodium; cellulose products such as microcrystalline cellulose and its salts, microfine cellulose, low-substituted hydroxypropylcellulose, mixtures thereof and the like.

[0181] Glidants improve the flowability of the composition. The composition may also comprise a glidant. Glidants are, but not limited to, colloidal silica, powdered cellulose, talc, tribasic calcium phosphate, mixtures thereof and the like.

[0182] The presence of a lubricant is particularly preferred when the composition is a tablet as lubricants to improve the tableting process. Lubricants prevent composition ingredients from clumping together and from sticking to the tablet punches or capsule filling machine and improve flowability of the composition mixture. Lubricants are, but not limited to sodium oleate, sodium stearate, sodium benzoate, sodium stearate, sodium chloride, stearic acid, sodium stearyl fumarate, calcium stearate, magnesium stearate, magnesium lauryl sulfate, sodium stearyl fumarate, sucrose esters or fatty acid, zinc, polyethylene glycol, talc, mixtures thereof and the like.

[0183] Flavourings are, but not limited to, cinnamon oil, essence of apple,

essence of pear, essence of peach, essence of grape, essence of strawberry, essence of raspberry, essence of cherry, essence of plum, essence of pineapple, essence of apricot, oil of wintergreen, clove oil, bay oil, anise oil, eucalyptus, thyme oil, cedar leaf oil, oil of nutmeg, oil of sage, oil of bitter almonds, cassia oil, citrus oils such as lemon, orange, grape, lime and grapefruit, vanilla, benzaldehyde, aldehyde C-8 , aldehyde C-9, aldehyde C-12 , tolyl aldehydeacacia, caraway oil, cardamom (oil, tincture, spirit), cherry syrup, citric acid syrup, citric acid, cocoa, cocoa syrup, coriander oil, dextrose, ethyl acetate, ethyl vanillin, fennel oil, ginger, glucose, glycerin, glycerrhiza, honey, lavender oil, mannitol, methyl salicylate, orange flower water, peppermint (oil, spirit, water), raspberry, rose (oil, water), rosemary oil, saccharin sodium, Sarsaparilla syrup, spearmint oil, tolu balsam, vanilla tincture, tolu balsam syrup, wild cherry syrup and mixtures thereof and the like.

[0184] Selection of excipients and amounts to use can be determined by the

scientist. One or more of these additives can be chosen and used by the artisan having regard to the particular desired properties of the solid dosage form.

[0185] Each one of the crystalline monohydrate forms of benidipine

hydrochloride, respectively C, D, E, F, G, H and I can be administered alone or in combination with other pharmaceutically active compounds.

[0186] Suitable pharmaceutical compositions include, but are not limited to,

capsules, tablets, granules, powders and unit dose pockets.

[0187] The following example is given for the purpose of illustration of the present invention and should not limit the scope of the invention.

Example 1 : Preparation of Form C:

[0188] Benidipine HCI (10 g, 18.5 mmol, anhydrate form) was suspended in water (50 ml_) at room temperature and the suspension heated up to 95 - 100 °C. At this temperature, methanol (35 ml_) was added by 5 ml_ portions until complete dissolution. After complete dissolution, methanol was distilled off from the solution. After all methanol distilled off, heating stopped and the mixture was allowed to cool to ambient temperature for crystallization. Crystallized mixture was cooled down to 0 - 5 °C and stirred at this temperature for 3 - 4 h. Afterwards product crystals were filtered and washed with water (50 ml_). Wet yellow product was dried at 80 - 85 °C in vacuo to afford a-Benidipine HCI (9.8 g, 98%; 100.00% purity by HPLC; 3.40% water content; 182 °C DSC peak) as a slightly yellowish powder.

Example 2: Preparation of Form C:

[0189] Benidipine HCI (10 g, 18.5 mmol, anhydrate form) was suspended in water (50 ml_) at room temperature and the suspension heated up to 95 - 100 °C. At this temperature, ethanol (23 ml_) was added by small portions until complete dissolution. After complete dissolution, ethanol was distilled off from the solution. After all ethanol distilled off, heating stopped and the mixture was allowed to cool to ambient temperature for crystallization. Crystallized mixture was cooled down to 0 - 5 °C and stirred at this temperature for 3 - 4 h. Afterwards product crystals were filtered and washed with water (50 mL). Wet yellow product was dried at 80 - 85 °C in vacuo to afford a-Benidipine HCI (9.5 g, 95%; 100.00% purity by HPLC; 3.46% water content; 183 °C DSC peak) as a slightly yellowish powder.

Example 3: Preparation of Form D:

[0190] Benidipine HCI (5.0 g, 9.2 mmol, anhydrate form) was suspended in water (50 mL) at room temperature and the suspension heated up to 95 - 100 °C. After stirring 30 min at this temperature, heating stopped and the mixture was allowed to cool to ambient temperature. The suspension was stirred further at room temperature for 2 - 3 h. Then, the product crystals were filtered and washed with water (70 - 80 mL). Wet yellow product was dried at 80 - 85 °C in vacuo to afford a-Benidipine HCI monohydrate (4.5 g, 90%; 99.93% purity by HPLC; 3.36% water content; 186 °C DSC peak) as a slightly yellowish powder.

Example 4: Preparation of Form E:

[0191] Benidipine HCI (10 g, 18.5 mmol, anhydrate form) was suspended in

1 -butanol (30 mL) at room temperature and the suspension heated up to 80 - 85 °C. At this temperature, methanol (15 mL) was added by 5 mL portions until complete dissolution. After complete dissolution, methanol was distilled off from the solution. After all methanol distilled off, heating stopped and the mixture was allowed to cool to ambient temperature. The mixture was cooled down to 0 - 5 °C and stirred at this temperature for 2 - 3 h but no crystallization was observed. Water (50 mL) was added into the mixture at 0 - 5 °C and stirred for 5 - 6 h for crystallization. Afterwards product crystals were filtered and washed with water (100 mL). Wet yellow product was dried at 80 - 85 °C in vacuo to afford α-Benidipine HCI (8.9 g, 89%; 100.00% purity by HPLC; 3.51 % water content; 175 °C DSC peak) as a slightly yellowish powder

Example 5: Preparation of Form F: [0192] Benidipine HCI (10 g, 18.5 mmol, anhydrate form) was suspended in methyl ethyl ketone (40 ml_) and water (10 ml_) mixture at room

temperature and the suspension heated up to 70 - 75 °C. At this temperature, complete dissolution was observed, heating stopped and the mixture was allowed to cool to ambient temperature for crystallization. Crystallized mixture was cooled down to 0 - 5 °C and stirred at this temperature for 2 - 3 h. Afterwards product crystals were filtered and washed with chilled methyl ethyl ketone/water mixture (25 ml_; 4:1 ). Wet yellow product was dried at 80 - 85 °C in vacuo to afford a-Benidipine HCI (8.7 g, 87%; 100.00% purity by HPLC; 3.42% water content; 175 °C DSC peak) as a slightly yellowish powder.

Example 6:Preparation of Form G:

[0193] Benidipine HCI (10 g, 18.5 mmol, anhydrate form) was suspended in water (50 ml_) at room temperature and the suspension heated up to 90 - 100 °C. At this temperature, methyl ethyl ketone (16 ml_) was added by 2 ml_ portions until complete dissolution. After complete dissolution, heating stopped and the mixture was allowed to cool to ambient temperature for crystallization. Crystallized mixture was cooled down to 0 - 5 °C and stirred at this temperature for 3 - 4 h. Afterwards product crystals were filtered and washed with water (25 ml_). Wet yellow product was dried at 80 - 85 °C in vacuo to afford a-Benidipine HCI (9.6 g, 96%; 100.00% purity by HPLC; 3.13% water content; 183 °C DSC peak) as a slightly yellowish powder.

Example 7:Preparation of Form H:

[0194] Benidipine HCI (10 g, 18.5 mmol, anhydrate form) was suspended in

acetic acid (20 ml_) at room temperature and the suspension heated up to 95 - 105 °C. At this temperature, complete dissolution was observed, heating stopped and the mixture was allowed to cool to ambient

temperature for crystallization. No crystallization was observed at room temperature and the solution was cooled down to 0 - 5 °C and stirred at this temperature for a while but no crystallization was observed. Water (70 ml_) was added and the product started to crystallize slowly. The mixture was stirred at 0 - 5 °C for 2 - 3 h. Afterwards product crystals were filtered and washed with chilled water (70 mL). Wet yellow product was dried at 80 - 85 °C in vacuo to afford a-Benidipine HCI (9.6 g, 96%; 100.00% purity by HPLC; 3.63% water content; 172 °C DSC peak) as a slightly yellowish powder.

Example 8:Preparation of Form I:

[0195] Benidipine HCI (10 g, 18.5 mmol, anhydrate form) was suspended in water (20 mL) at room temperature and the suspension heated up to 90 - 100 °C. At this temperature, acetone (35 mL) was added by 5 mL portions until complete dissolution. After complete dissolution, heating stopped and the mixture was allowed to cool to ambient temperature for crystallization. Crystallized mixture was cooled down to 0 - 5 °C and stirred at this temperature for 3 - 4 h. Afterwards product crystals were filtered and washed with water (25 mL). Wet yellow product was dried at 80 - 85 °C in vacuo to afford a-Benidipine HCI (8.6 g, 86%; 100.00% purity by HPLC; 3.20% water content; 179 °C DSC peak) as a slightly yellowish powder.