FIELD OF THE INVENTION

The present invention is directed to crystalline vinorelbine monotartrate and its use for the prevention and treatment of cancer, particularly non-small cell lung cancer or breast cancer.

The present invention also relates to a corresponding method for the manufacture of crystalline vinorelbine monotartrate.

BACKGROUND OF THE INVENTION

Vinca alkaloids, including the natural compounds vincristine and vinblastine as well as semisynthetic derivatives, such as vindesine and vinorelbine, are antimitotic drugs that are widely used in the retreatment of cancer. In general, vinca alkaloids are known to be inhibitors of mitosis and cellular proliferation. In particular, the anti-proliferative activity of the vinca alkaloid class of drugs has been shown to be due to their ability to bind tubulin.

Vinblastine and vincristine were first isolated from the leaves of Catharanthus roseus G. Don or Vinca rosea L. These alkaloids are dimers consisting of two indole units: catharanthine and vindoline. Vinblastine and vincristine first became available on the market in France in 1963 and 1964 under the brand names VELBE® and ONCOVIN®, respectively.

Vinorelbine was originally synthesized by Pierre Potier and co-workers in the 1980s. The compound is cell cycle phase-specific and interferes with the cell's ability to reproduce. Vinorelbine is commonly used in the treatment of advanced non-small cell lung cancer (single agent or as part of a combination therapy) and of metastatic breast cancer after failure of standard first line chemotherapy or after relapse within 6 months of anthracycline based adjuvant therapy and aggressive fibromatosis.

In all known pharmaceutical formulations, vinorelbine is used in form of a bitartrate salt. Vinorelbine bitartrate is a white to yellow or light brown amorphous powder that is particularly unstable in solid form being sensitive to both humidity and light. Hence, it has to be kept in tightly closed, light-resistant containers and stored in a freezer below −15° C. However, solutions of vinorelbine bitartrate can be kept at temperatures between 3-5° C. This is the case for both water-based solutions for injectable preparations, and for soft capsules filling solutions composed of liquid polyethylene glycol, glycerol, ethanol, and water.

An injectable formulation of vinorelbine was launched in France in 1989 under the brand name Navelbine®. However, in order to avoid problems associated with intravenous drug delivery route, there was a continued need for an oral vinorelbine dosage form with similar efficacy as the intravenous formulation. However, it has turned out to be difficult to develop such oral dosage form, primarily due to the instability of vinorelbine.

International patent publication WO 2003/101383 A2 describes the first oral formulation available on the market, a soft gelatin capsule containing vinorelbine bitartrate dissolved in an excipient mixture comprising polyethylene glycol, glycerol, ethanol, and water. This formulation is known under the brand name Navelbine Oral®. Although commercially successful, the soft gelatin capsules filled with a liquid vinorelbine composition provides for a rather challenging and costly technology requiring the active ingredient to be continuously maintained in solution inside the capsule. This capsules have low stability under ambient conditions and have to be stored in the refrigerator at 5° C. Furthermore, after long-term storage at this temperature the total amount of impurities has been shown to be significantly increased.

Another approach how to stabilize vinorelbine bitartrate was its dispersion in a mixture with polyethylene glycol, preferably in a mass ratio of 1:3 to 1:6, as described in International patent publication WO 2006/069938 A1. The dispersion can be distributed in a hard gelatin capsule, as divided pellets or associated with compression excipients in form of a tablet. But again, the task of this formulation can be seen in the amount of impurities after long-term storage, thus resulting in complex logistics with respect to continuous supply with vinorelbine.

International patent publication WO 2009/007389 A1 describes a solid dosage form made from conventional excipients and a water-soluble vinorelbine salt in order to facilitate manufacture. Manufacturing methods may include wet granulation or dry mixing of different components followed filling them into hard gelatin capsules or by compressing them into film-coated tablets. The oral dosage form according to WO 2009/007389 A1 comprises, in addition to the vinorelbine salt, at least one diluent and at least one lubricant. However, these solid dosage forms still have low stability under normal conditions and are stable only at 5° C. for a period of 12 months.

Despite these achievements with respect to pharmaceutical formulation, however, the clinical applicability of vinorelbine bitartrate as active pharmaceutical ingredient for the production of stable oral dosage form still remains hampered due to persistent problems with the stability, solubility and/or bioavailability of the compound. Thus, there is still an ongoing need for alternative to vinorelbine bitartrate, that is, a water-soluble vinorelbine salt that is stable in solid form, and thus can be directly formulated in a pharmaceutical composition in a comparably simple and cost-efficient manner without compromising for solubility and/or bioavailability of the active ingredient.

It is therefore an objective of the present invention to provide pharmaceutically acceptable forms of vinorelbine monotartrate having a good chemical and/or physical stability and/or good processability, both during its preparation as an active pharmaceutical ingredient as well as in the preparation of pharmaceutical compositions containing vinorelbine.

It was found that crystalline vinorelbine monotartrate forms as described below may provide beneficial properties especially regarding stability issues and may furthermore enhance the performance of oral dosage forms comprising said vinorelbine monotartrate crystalline forms.

In addition, combined with suitable excipients, the crystalline vinorelbine may provide a good means for development of oral pharmaceutical formulation as well as the process.

Accordingly, it is an object of the present invention to provide for a stable vinorelbine salt that overcomes the above limitations as well as a corresponding method for its production.

SUMMARY OF THE INVENTION

The invention relates to crystalline vinorelbine monotartrate forms including different solvates and hydrate forms, processes for the preparation thereof, as well as pharmaceutical compositions and formulations comprising said crystalline forms.

In another aspect, the present invention relates to stable crystalline forms of vinorelbine, comprised as active ingredient in pharmaceutical compositions, preferably for oral administration, wherein the crystalline forms of vinorelbine is a monotartrate represented as solvates or a hydrate.

The pharmaceutical composition of the present invention may comprise a mixture of one or more excipients.

In yet another aspect, the pharmaceutical composition consists of crystalline vinorelbine monotartrate and one excipient, and in particularly consists of crystalline vinorelbine monotartrate and one co-processed excipient.

In a further aspect, the present invention relates to the pharmaceutical composition as defined herein for use in the prevention and/or treatment of cancer, in particular non-small cell lung cancer and breast cancer.

Further embodiments of the present invention become apparent from the following detailed description and the appended drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts the results of X-ray powder diffraction analysis of crystalline vinorelbine monotartrate acetone solvate.

FIG. 2 depicts the results of X-ray powder diffraction analysis of crystalline vinorelbine monotartrate diethyl ketone solvate.

FIG. 3 depicts the results of X-ray powder diffraction analysis of crystalline vinorelbine monotartrate ethyl acetate solvate.

FIG. 4 depicts the results of X-ray powder diffraction analysis of crystalline vinorelbine monotartrate isopropanol solvate.

FIG. 5 depicts the results of X-ray powder diffraction analysis of crystalline vinorelbine monotartrate hydrate.

FIG. 6 depicts the results of X-ray powder diffraction analysis of amorphous vinorelbine monotartrate.

FIG. 7 depicts representative thermogravimetric analysis (TGA) for crystalline vinorelbine monotartrate hydrate according to the present invention.

FIG. 8 depicts representative differential scanning calorimetry (DSC) analysis (closed CSC cells) of crystalline vinorelbine monotartrate hydrate according to the present invention.

FIG. 9 depicts the results of dissolution test of HG capsules comprising crystalline vinorelbine monotartrate acetone solvate in three different dissolution media.

FIG. 10 depicts the results of dissolution test of HG capsules comprising crystalline vinorelbine monotartrate hydrate in three different dissolution media.

FIG. 11 depicts the results of a representative X-ray powder diffraction analysis for the mixture of crystalline vinorelbine monotartrate hydrate and excipient filling in capsules according to the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is based on the unexpected finding that vinorelbine monotartrate can be readily provided in crystalline form and that such crystalline vinorelbine monotartrate represents a superior active ingredient (as compared to the commonly used vinorelbine bitartrate) for the treatment of cancer, particularly non-small cell lung cancer or breast cancer, which exhibits pronounced thermo- and photostability without compromising for solubility and/or bioavailability, thus facilitating long-term storage. Furthermore, it has been found that crystalline vinorelbine monotartrate can be directly processed and formulated in a pharmaceutical composition, which results in a simple and cost-effective manufacturing process for providing a vinorelbine containing medicament, preferably an oral dosage form.

The present invention will be described in the following with respect to particular embodiments and with reference to certain drawings but the invention is to be understood as not limited thereto but only by the appended claims. The drawings described are only schematic and representative and are to be considered non-limiting.

Where the term “comprising” is used in the present description and claims, it does not exclude other elements or steps. For the purposes of the present invention, the term “consisting of” is considered to be a preferred embodiment of the term “comprising”. If hereinafter a group is defined to comprise at least a certain number of embodiments, this is also to be understood to disclose a group, which preferably consists only of these embodiments.

Where an indefinite or definite article is used when referring to a singular noun e.g. “a”, “an” or “the”, this includes a plural of that noun unless specifically stated otherwise.

In case, numerical values are indicated in the context of the present invention the skilled person will understand that the technical effect of the feature in question is ensured within an interval of accuracy, which typically encompasses a deviation of the numerical value given of +10%, and preferably of 5%.

Furthermore, the terms first, second, third, (a), (b), (c), and the like in the description and in the claims, are used for distinguishing between similar elements and not necessarily for describing a sequential or chronological order. It is to be understood that the terms so used are interchangeable under appropriate circumstances and that the embodiments of the invention described herein are capable of operation in other sequences than described or illustrated herein.

Further definitions of term will be given in the following in the context of which the terms are used. The following terms or definitions are provided solely to aid in the understanding of the invention. These definitions should not be construed to have a scope less than understood by a person of ordinary skill in the art.

The term “solvate”, as used herein and unless indicated otherwise, refers to a crystal form that incorporates a solvent in the crystal structure. When the solvent is water, the solvate is referred to as a “hydrate”. The solvent in a solvate may be present in either a stoichiometric or in a non-stoichiometric amount.

Typically, the crystalline vinorelbine monotartrate solvate comprises less than 25% (w/w) or less than 20% (w/w) residual solvents included in the crystal structure (i.e., weight of total residual solvents based on the total weight of the crystalline form), that is, solvent molecules being integrated in or associated to the crystal structure.

In particular embodiments, the crystalline vinorelbine monotartrate solvate comprises less than 15% (w/w) or less than 13% (w/w) or less than 11% (w/w) residual solvents, such as 14.5%, 14.0%, 13.5%, 13.0%, 12.5%, 12.0%, 11.5%, 11.0%, 10.5% or 10.0% (w/w each). In preferred embodiments, the crystalline vinorelbine monotartrate solvate comprises less than 10% (w/w) or less than 7% (w/w) or less than 3% (w/w) residual solvents, such as 9.5%, 9.0%, 8.5%, 8.0%, 7.5%, 7.0%, 6.5%, 6.0%, 5.5%, 5.0%, 4.5%, 4.0%, 3.5%, 3.0%, 2.5%, 2.0%, 1.5%, 1.0%, or 0.5% (w/w each). The solvent is typically water or an organic solvent, such as an alcohol, ester, an ether or a ketone or a mixture thereof. In preferred embodiments, the organic solvent is selected from the group consisting of acetone, diethyl ketone, ethyl acetate or isopropanol or a mixture thereof.

In specific embodiments, the vinorelbine monotartrate solvate comprises a molar ratio of vinorelbine monotartrate to solvent in the range from 4:1 to 1:6 or in the range from 2:1 to 1:5, and preferably in the range from 1:1 to 1:3.

The term “crystalline”, as used herein, is to be understood in the common sense, that is, that the vinorelbine monotartrate is present in crystalline (i.e. non-amorphous) form being obtained for example by crystallization of the compound from a solvent.

The term “photostability”, as used herein, is to be understood such that a sample of the product to be analyzed in a quantity of about 14 mg is placed in a 10 ml light glass volumetric flask and is exposed in a photo chamber to a xenon lamp (wave length 300-800 nm; fluence rate 250-765 W/m2). The amount of the known photo-degradation product 3,6-epoxy vinorelbine is determined after a specific amount of time of exposure by means of HPLC (High-performance liquid chromatography). The described photostability test procedure corresponds to the photostability determining method described in European Pharmacopoeia 7.0 using exposure time 2 hours.

The term “thermostability”, as used herein, is to be understood such that a sample of the product to be analyzed is incubated at a certain temperature. The degradation impurities are determined after a specific amount of time of incubation by means of HPLC.

The term “degradation impurities”, as used herein, is to be understood such a sample of the relevant product is subjected to HPLC analysis and calculation of the content of impurities in Vinorelbine is performed according to the method described in European Pharmacopoeia 7.0.

Only one method for the preparation of vinorelbine monotartrate in a solid state has been reported in the art (CN1437942A), and that is by precipitation with diethyl ether from acetone solution containing vinorelbine monotartrate. The reproduction of process described in CN 1437942A results in an amorphous solid. The addition of different anti-solvents to a solution of vinorelbine monotartrate in an organic solvent also leads to the formation of an amorphous solid.

The amorphous vinorelbine monotartrate has been found to be unstable upon exposure to elevated temperature and humidity for an extended period, therefore amorphous vinorelbine monotartrate cannot be used for the preparation of the stable oral dosage formulations.

It has been unexpectedly found that in contrast to vinorelbine bitartrate, vinorelbine monotartrate can form a variety of crystal forms. Such crystal forms include organic solvate and hydrate forms. Crystalline forms of vinorelbine monotartrate can be used as an excellent active ingredient (either in form of organic solvates or in form of a hydrate) for the manufacture of a pharmaceutical composition with pronounced thermo- and photostability without affecting solubility and/or bioavailability of the active ingredient.

Crystalline vinorelbine monotartrate organic solvates (e.g. acetone solvate, diethyl ketone solvate, isopropanol solvate, ethyl acetate solvate) may be prepared by a process comprising:

(a) providing a solution of vinorelbine monotartrate in a liquid containing at least one organic solvent (for example in methylene chloride);

(b) drying the solution of vinorelbine monotartrate in a liquid containing at least one organic solvent until a dry residue is obtained;

(c) dissolving the dry residue in a liquid containing at least one organic solvent to obtain a mixture;

(d) maintaining the mixture under heating and stirring to obtain a solid precipitate;

(e) isolating the solid precipitate;

(f) drying the solid precipitate.

The obtained crystalline solvates contain organic solvent in either a stoichiometric or in a non-stoichiometric amount and do not desolvate during drying under vacuum at 60° C.

Crystalline vinorelbine monotartrate solvates are characterized by a powder X-ray diffraction pattern comprising peaks at average diffraction angles (20). The XRD patterns of some crystalline vinorelbine monotartrate solvates are presented in the Table 1.

TABLE 1

XRD patterns of some crystalline vinorelbine

monotartrate solvates

Type of
Significant peaks at average diffraction angles

solvate
(2Θ)

Acetone
7.9
9.5
10.1
13.2
13.4
14.4
16.7
16.9
19.1
20.7

solvate

Diethyl
5.4
9.5
10.1
10.4
10.8
12.9
13.1
14.8
16.2
20.2

ketone

solvate

Ethyl
9.4
9.9
10.0
10.7
10.9
13.0
14.1
15.6
16.2
20.2

acetate

solvate

Iso-
8.0
9.2
10.3
10.8
10.9
13.4
14.6
16.9
19.3
22.9

propanol

solvate

It has been surprisingly found that the obtained crystalline vinorelbine monotartrate solvates have a high stability.

In further preferred embodiments, the crystalline vinorelbine monotartrate solvate according to the present invention is characterized by its stability, that is, the compound can be stored under typical storage conditions for at least three months or for at least six months, and without appreciable degradation (in particular, thermodegradation and/or photodegradation). In specific embodiments, the compound can be stored for at least 24 months without appreciable degradation.

In particular embodiments, the crystalline vinorelbine monotartrate acetone solvate according to the present invention is characterized by a thermostability of less than 0.10% degradation after 6 months at 5° C.±3° C.).

The term “degradation”, as used herein, is to be understood to relate to the total amount of identified (e.g. 3,6-epoxy vinorelbine, 4-O-deacetylvinorelbine and vinorelbine N-oxide) and unidentified degradation products that form in a sample after a particular incubation period.

Typically, degradation after 3 months at 5° C.±3° C. is less than 0.02% or less than 0.01%. Preferably, degradation after 6 months at 5° C.±3° C. is less than 0.10% or less than 0.05%.

In preferred embodiments, the crystalline vinorelbine monotartrate acetone solvate according to the present invention is further characterized by a thermostability of less than 0.10% degradation after 6 month at 25° C.±2° C. Particularly preferably, the crystalline vinorelbine monotartrate is further characterized by a thermostability of less than 0.20% degradation after 2 months at 40° C.±2° C.

Particularly preferably, the crystalline vinorelbine monotartrate according to the present invention is further characterized by a thermostability of less than 0.10% or less than 0.05% degradation after 6 months at 25° C.±2° C. Typically, degradation after 6 months at 25° C.±2° C. is less than 0.05% or less than 0.02%.

In further preferred embodiments, the crystalline vinorelbine monotartrate according to the present invention is further characterized by a thermostability of less than 0.20% or less than 0.15% degradation after 2 months at 40° C.±2° C.

Various types of vinorelbine monotartrate solvates remain stable even under stressing conditions at 60° C. After one week storage of acetone solvate and isopropanol solvate at 60° C. they didn't show any chemical degradation in contrast to the vinorelbine bitartrate.

However, organic solvates are rarely used in pharmaceuticals because the number of pharmaceutically acceptable solvents is very small and the solvents are volatile thus making it difficult to maintain the solvent in the crystal.

It was surprisingly found that a crystalline vinorelbine monotartrate hydrate can be obtained from any of the vinorelbine monotartrate solvates by exposing solvate forms to air with different relative humidity levels and temperatures. Air or an inert gas with different relative humidity levels and temperatures is also referred to as “water vapour”.

The present invention provides a process for the preparation of vinorelbine monotartrate hydrate by exposing solvate forms to water vapour. The hydrate forms prepared from different solvates have the same crystal structure and the content of the residual solvents was found to be within ICH limits.

Conversion of solvates into hydrate is performed in different controlled conditions. The temperature during conversion is in an interval from 20 to 70° C., preferable from 40 to 60° C., relative humidity is from 30% RH to 75% RH, preferably from 40 to 60% RH. The conversion time is between 8 and 48 hours, preferably between 16 and 32 hours.

Vinorelbine monotartrate hydrate is obtained as a result of a substitution of organic solvents with water. The water content after such substitution is between 0.5 and 10 w/w %, preferable, between 3 and 7 w/w %.

The crystalline vinorelbine monotartrate hydrate according to the present invention is characterized by a x-ray powder diffraction pattern comprising significant peaks at average diffraction angles (2Θ) of 7.9°, 9.5°, 10.3°, 10.8°, and 13.4°, 13.6°, 14.5° and (each ±0.2°).

In a specific embodiment, the crystalline vinorelbine monotartrate hydrate is characterized by a powder X-ray diffraction pattern as illustrated in Table 2 and FIG. 5.

TABLE 2

PXRD peak table for crystalline

vinorelbine monotartrate hydrate

Pos.
Height
FWHM
d-spacing
Rel. Int.

[°2θ]
[cts]
Left [°2θ]
[Å]
[%]

5.6603
155.39
0.0640
15.61370
9.70

6.3047
64.91
0.0640
14.01933
4.05

7.8920
1601.52
0.0640
11.20280
100.00

9.5022
619.80
0.0768
9.30778
38.70

9.6400
526.70
0.0512
9.17505
32.89

10.3129
1349.49
0.1151
8.57780
84.26

10.7438
1179.93
0.0895
8.23476
73.68

10.8241
803.11
0.0640
8.17386
50.15

11.0432
149.93
0.0640
8.01218
9.36

11.4028
398.03
0.0895
7.76029
24.85

12.0440
46.35
0.0768
7.34854
2.89

13.4144
1450.23
0.0640
6.60074
90.55

13.5607
1344.16
0.0895
6.52987
83.93

13.9826
253.57
0.1279
6.33378
15.83

14.1259
211.20
0.0512
6.26981
13.19

14.5737
764.07
0.1151
6.07818
47.71

15.4909
82.37
0.0640
5.72031
5.14

15.8024
114.03
0.1023
5.60824
7.12

16.2052
242.01
0.0895
5.46972
15.11

16.5319
99.57
0.0512
5.36236
6.22

17.1502
389.84
0.0640
5.17042
24.34

17.2971
364.86
0.0640
5.12684
22.78

18.3869
191.25
0.1535
4.82534
11.94

18.9855
427.01
0.0768
4.67454
26.66

19.4119
655.89
0.0640
4.57280
40.95

19.5577
490.86
0.0512
4.53904
30.65

20.0486
75.58
0.2558
4.42900
4.72

20.7169
244.33
0.0640
4.28761
15.26

21.1602
278.41
0.1023
4.19877
17.38

21.4709
224.42
0.0768
4.13871
14.01

22.2069
220.45
0.0640
4.00318
13.76

22.7214
119.84
0.1023
3.91369
7.48

23.1938
350.58
0.0512
3.83504
21.89

23.5706
93.54
0.1279
3.77457
5.84

24.1472
87.34
0.0768
3.68573
5.45

24.7625
234.71
0.1535
3.59552
14.66

25.1137
105.37
0.1535
3.54604
6.58

25.7867
191.69
0.0895
3.45499
11.97

26.4846
207.94
0.1535
3.36551
12.98

26.8187
116.81
0.1279
3.32434
7.29

27.4412
100.78
0.3582
3.25033
6.29

28.2760
47.50
0.3070
3.15624
2.97

28.7915
81.31
0.2558
3.10089
5.08

29.4985
48.48
0.1535
3.02816
3.03

30.3843
100.92
0.0768
2.94186
6.30

30.8031
46.71
0.1535
2.90282
2.92

32.2225
32.43
0.1535
2.77812
2.03

32.8210
16.73
0.2047
2.72881
1.04

33.3521
10.14
0.1535
2.68656
0.63

34.3526
60.81
0.1791
2.61058
3.80

35.1208
29.33
0.2558
2.55522
1.83

36.1536
42.01
0.1535
2.48456
2.62

The crystalline vinorelbine monotartrate hydrate of the present invention is also characterized by its differential scanning calorimetry (DSC) thermogram as depicted in FIG. 8, with sharp endothermic signal at 179.4° C. The crystalline vinorelbine monotartrate hydrate of the present invention is characterized by a Thermogravimetric Analysis (TGA) thermogram as depicted in FIG. 7.

Stability studies supported surprisingly a very high stability of crystalline vinorelbine monotartrate hydrate.

The crystalline vinorelbine monotartrate hydrate according to the present invention is characterized by its stability, that is, the compound can be stored under typical storage conditions for at least three months or for at least six months, and without appreciable degradation (in particular, thermodegradation and/or photodegradation). In specific embodiments, the compound can be stored for at least 24 months without appreciable degradation.

In particular embodiments, the crystalline vinorelbine monotartrate hydrate according to the present invention is characterized by a thermostability of less than 0.05% degradation after 6 months at 25° C.).

The term “degradation”, as used herein, is to be understood to relate to the total amount of identified (e.g. 3,6-epoxy vinorelbine, 4-O-deacetylvinorelbine and vinorelbine N-oxide) and unidentified degradation products that form in a sample after a particular incubation period.

Typically, degradation after 3 months at 25° C. is less than 0.10% or less than 0.05%. Preferably, degradation after 6 months at 25° C. is less than 0.05% or less than 0.02%.

In preferred embodiments, the crystalline vinorelbine monotartrate is further characterized by a thermostability of less than 0.15% degradation after 2 months at 40° C.±2° C.

Various types of vinorelbine monotartrate solvates as well as hydrate remain stable even under stressing conditions at 60° C. After one week storage at 60° C. vinorelbine monotartrate hydrate is characterized by a thermostability of less than 0.10% degradation.

In further particular embodiments, the crystalline vinorelbine monotartrate solvate or hydrate according to the present invention is further characterized by a photostability (as determined by the amount of 3,6-epoxy vinorelbine produced) of less than 0.3% or less than 0.2% degradation after 30 min of illumination of samples or less than 0.7% or less than 0.5% degradation after 120 min of illumination of samples in contrast with vinorelbine bitartrate as shown in Table 11.

In a further aspect, the present invention relates to the crystalline vinorelbine monotartrate of the present invention for use in the prevention and/or treatment of cancer. In preferred embodiments, the crystalline vinorelbine monotartrate of the present invention is for use in the prevention and/or treatment of non-small cell lung cancer or breast cancer.

In yet another aspect, the present invention relates to a pharmaceutical composition comprising the crystalline vinorelbine monotartrate of the present invention.

The pharmaceutical composition can be formulated employing conventional solid or liquid vehicles or diluents and pharmaceutical additives of a type appropriate to the mode of desired administration.

Due to the crystalline nature of the vinorelbine monotartrate the pharmaceutical composition is typically a solid composition, with the active pharmaceutical ingredient vinorelbine monotartrate being provided in crystalline form (FIG. 11). The pharmaceutical composition may be administered via any route of administration, local or systemic, such as parenteral, topical, and oral, with oral administration being particularly preferred. In other preferred embodiments, the pharmaceutical composition is provided as dosage form, that is, as a ready-to-use formulation.

Particularly preferably, the pharmaceutical composition in accordance with the present invention is a solid oral dosage form, that is, a formulation that is ready-to-use for oral administration. In preferred embodiments, the solid oral dosage form is selected from the group consisting of capsules, tablets, pills, granules, pellets, and powder, with capsules and tablets being most preferred. In highly preferred embodiments, the capsules are gelatin hydroxypropylmethyl cellulose or pullan, capsules, with hard gelatin capsules being particularly preferred. In other highly preferred embodiments, the tablets are obtained by direct compression or dry compaction.

Both capsules and tablets may be uncoated or coated including a tablet core and an inner seal coating layer coated on the tablet core.

All these oral dosage forms are well established in the art (see, e.g., Gennaro, A. L. and Gennaro, A. R. (2000), Remington: The Science and Practice of Pharmacy, 20th Ed., Lippincott Williams & Wilkins, Philadelphia, Pa.; Crowder, T. M. et al. (2003) A Guide to Pharmaceutical Particulate Science. Interpharm/CRC, Boca Raton, Fla.; Niazi, S. K. (2004) Handbook of Pharmaceutical Manufacturing Formulations, CRC Press, Boca Raton, Fla.; Podczeck, F. and Jones, B. E. (2004) Pharmaceutical Capsules, 2nd Ed., Pharmaceutical Press, London).

The amount of crystalline vinorelbine monotartrate present in the pharmaceutical composition typically corresponds to an equivalent of 5-250 mg vinorelbine base or of 10-200 mg vinorelbine base, and preferably to an equivalent of 15-150 mg vinorelbine base. In particular embodiments, the amount of active ingredient present in the pharmaceutical composition corresponds to an equivalent of 20-100 mg vinorelbine base, such as an amount corresponding to an equivalent of 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg or 100 mg vinorelbine base. The molecular weight of vinorelbine base is 778.93, whereas the molecular weight of vinorelbine monotartrate is 929.03.

According to the present invention, it is to be understood that the active ingredient is present in the pharmaceutical composition in any amount being effective to achieve the desired pharmacological effect such as to stop tumor progression or to induce an apoptotic effect in tumor cells when administered to a patient. Effective amounts are generally chosen in accordance with a number of factors, e.g., the age, size and general condition of the patient and the medical condition being treated, and determined by a variety of means, for example, dose ranging trials, well known to, and readily practiced by persons of ordinary skill in art. The daily dosage of crystalline vinorelbine monotartrate to be administered to a subject typically corresponds to an equivalent of 5-1000 mg vinorelbine base or of 10-500 mg vinorelbine base or of 10-200 mg vinorelbine base, and preferably to an equivalent of 20-100 mg vinorelbine base.

In yet other preferred embodiments, the pharmaceutical composition of the present invention, such as a solid oral dosage form, is characterized by a thermostability of less than 0.15% or less than 0.10% or less than 0.05% degradation after 2 months at 25° C.±2° C. Particularly, degradation after six months is less than 0.2% or less than 0.15% or less than 0.10%, and particularly preferably degradation after six months is less than 0.15% or less than 0.10%.

In further particularly preferred embodiments, the pharmaceutical composition of the present invention, such as a solid oral dosage form, is characterized by a thermostability of less than 0.2% or less than 0.15% or less than 0.10% degradation after 3 months at 40° C.±2° C.

A pharmaceutical composition of the present invention may comprise at least one excipient, particularly at least one co-processed excipient. Typically, the pharmaceutical composition of the present invention comprises a single excipient but may also comprise a mixture of two or more excipients, for example in form of a co-processed excipient. In preferred embodiments, the pharmaceutical composition is devoid of polyethylene glycol.

The term “excipient”, as used herein, refers to any substances, other than the active ingredients, in a pharmaceutical composition, which have been appropriately evaluated for safety and are included in a drug delivery system to either aid the processing or to aid manufacture, protect, support, enhance stability, bioavailability or patient acceptability, assist in product identification, or enhance any other attributes of the overall safety and effectiveness of the drug delivery system during storage or use.

The term “co-processed excipient”, as used herein, can be defined as combining two or more established excipients. Co-processing of excipients could lead to the formation of excipients with superior properties compared to the simple physical mixtures of their components, for example, with respect to better flowability, improved compressibility, better dilution potential, reworkability, stability, fewer fill weight variation, and controlled particle size. The aim of co-processing is to obtain a product with added value related to the ratio of its functionality/price.

The development of co-processed excipients starts with the selection of the excipients to be combined, their targeted proportion, selection of preparation method to get optimized product with desired physico-chemical parameters and it ends with minimizing avoidance with batch-to-batch variations. An excipient of reasonable price has to be combined with the optimal amount of a functional material in order to obtain integrated product, with superior functionality than the simple mixture of components. Co-processing is interesting because the products are physically modified in a special way without altering the chemical structure. A fixed and homogenous distribution for the components is achieved by embedding them within mini-granules. Segregation is diminished by adhesion of the actives on the porous particles making process validation and in process control easy and reliable (reviewed inter alia in Gohel, M. C. and Jogani, P. D. (2005) J. Pharm. Pharmaceut. Sci. 8, 76-93).

Commercially available examples of “co-processed excipients” to be employed in the pharmaceutical composition of the present invention include inter alia fructose/starch (Advantose FS-95; SPI Polyols, France), microcrystalline cellulose/guar gum (Avicel CE-15; FMC, USA), microcrystalline cellulose/lactose (Cellactose; Meggle, Germany), sucrose/dextrin (DI-PAC; American Sugar, USA), lactose/PVP/crospovidone (Ludipress; BASF, Ludwigshafen), granulated mannitol (Pearlitol SD; Roquette, France), anhydrous lactose/lactitol (Pharmatose DCL40; DMV, Netherlands), vinyl acetate/vinyl pyrollidone (Plasdone S-630; ISP, USA), microcrystalline cellulose/colloidal silica (Prosolv, Pen West, USA), and lactose/maize starch (Starlac; Roqette, France). The respective brand names and exemplary manufacturers are given in examples of “co-processed excipient” being specifically adapted to the production of oral dosage forms include inter alia mannitol/cellulose (for example, 50:50 (w/w); 60:40 (w/w), or 70:30 (w/w)), dicalcium phosphate/starch (for example, 25:75 (w/w)), lactose/mannitol (e.g., 1:1, 1:2, 2:1, 1:3 or 3:1), mannitol/microcrystalline cellulose/aerosol (for example, 70:29:1 or 30:69:1), crospovidone/sodium starch glycolate (for example, 1:1, 1:2, or 1:3), and chitosan/aerosol (for example, 1:1).

In a further preferred embodiment, the co-processed excipient is a mixture of corn starch and pre-gelatinized starch. The corn starch and the pre-gelatinized starch may be mixed in any ratio (based on the total weight of the final mixture). However, preferably the portion of corn starch is more than 50% (w/w), for example 60% (w/w), 70% (w/w), 80% (w/w), 85% (w/w), 90% (w/w) or 95% (w/w). Particularly preferably, the co-processed excipient represents a mixture of 85-95% (w/w) corn starch and 5-15% (w/w) pre-gelatinized starch. For example, such mixture can be prepared by co-spray drying. The latter mixture is commercially available from various suppliers, for example from Colorcon, West Point, Pa., USA marketed under the brand name StarCap 1500. In a specific embodiment, the weight ratio between the crystalline vinorelbine monotartrate and StarCap 1500 is in the range between 1:1 (w/w) and 1:10 (w/w), and preferably between 1:1 (w/w) and 1:5 (w/w).

In a further aspect, the present invention relates to the pharmaceutical composition, and particularly the solid oral dosage form, of the present invention for use in the prevention and/or treatment of cancer. In preferred embodiments, the pharmaceutical composition, and particularly the solid oral dosage form, of the present invention is for use in the prevention and/or treatment of non-small cell lung cancer or breast cancer.

In yet another aspect, the present invention relates to a method for the manufacture of the pharmaceutical composition, and particularly the solid oral dosage form, as defined herein, comprising:

(a) providing crystalline vinorelbine monotartrate; and

(b) formulating the crystalline vinorelbine monotartrate in a solid oral dosage form.

Particularly preferably, the crystalline vinorelbine monotartrate is formulated in pulverized form in a capsule, especially a hard gelatin capsule. Alternatively, the crystalline vinorelbine monotartrate is formulated in a tablet by direct compression or dry compaction. All these techniques are well established in the art.

The invention is further described by the figures and the following examples, which are solely for the purpose of illustrating specific embodiments of this invention, and are not to be construed as limiting the claimed subject matter in any way.

EXAMPLES
Materials and Methods

X-ray powder diffraction analysis was performed using a STOE-STADI P transmission diffractometer with the following setup: nCu-Kα₁radiation (λ=1.54056 Å); U=40 kV; I=35 mA; primary beam monochromator (curved Ge(111)); linear position sensitive detector; slits: 1 mm; d=8 mm; angle region: 2Θ=2 to 38; step width Δ2Θ=0.02°; 25 s/0.2° step.

The powder is originally filled between two Mylar foils and then into the sample holder having a d=8 mm mask.

Thermogravimetric analysis (TGA; for determining the content of residual solvents) was performed by precise sample weighing into alumina crucibles (100 μl, sealed with an alumina lid having a laser drilled 50 μm hole) by using a calibrated ultra-micro balance. Measurement: Mettler TGA/DSC1, large oven; gas control-box (purging gas: N₂, 80 ml/min, mass-flow controlled).

Differential scanning calorimetry (DSC; for determining the melting point) was performed by precise sample weighing into alumina crucibles (70 μl, hermetically closed with an alumina lid) by using a calibrated ultra-micro balance. Measurement: Mettler TC11-TA-Processor with DSC 30 module or Mettler DSC 25 with silver-oven and ceramic sensor crystal and Mettler TC15A-TA-Controller (25° C. to 250° C., 10° C./min). Purging gas: N₂, 80 ml/min, mass-flow controlled. Calibration: Performed directly before the sample measurement with ultrapure Indium (In) as a reference material (temperature scale, heat-flow scale).

HPLC analysis and calculation of the content of impurities in Vinorelbine were performed according to the method described in European Pharmacopoeia 7.0.

Example 1: Preparation of Crystalline Vinorelbine Monotartrate Acetone Solvate from Vinorelbine Bitartrate

Vinorelbine bitartrate (1000 g) was dissolved in water (10 L) and the pH was adjusted to 6.0 with NaOH. The mixture was treated with CH₂Cl₂(10 L) and stirring was continued for a further 10 min. The organic phase was separated and treated with water (3 L). Stirring was continued for a further 10 min and the organic phase (8-12 L) was separated. The solvent was evaporated (40° C., 380-400 torr, then down to <25 torr). The residue was dissolved in acetone (7 L). L(+)-tartaric acid in the calculated amount needed for the preparation of vinorelbine monotartrate (according to the titration results) was added. The obtained vinorelbine monotartrate solution was heated to reflux and stirring was continued for about 1 h. The mixture was concentrated in vacuum (70-100 torr; about 1 L of acetone was evaporated). The resulting mixture was filtered and precipitate was washed with acetone (1 L) and dried in vacuum (40-50° C., 25 torr, 2-4 h). Yield—905 g, HPLC purity—99.9%, acetone content—9.5% (GC(gas chromatography)).

The obtained sample was characterized by powder X-ray diffraction and a PXRD pattern as depicted in FIG. 1 with peaks as listed in Table 3 was obtained.

TABLE 3

PXRD peak table for crystalline vinorelbine

monotartrate acetone solvate

Pos.
Height
FWHM
d-spacing
Rel. Int.

[°2θ]
[cts]
Left [°2θ]
[Å]
[%]

5.6054
546.07
0.0512
15.76664
24.18

6.4609
83.64
0.0768
13.68074
3.70

7.9212
2258.58
0.0640
11.16156
100.00

9.1633
517.82
0.0512
9.65126
22.93

9.5573
821.26
0.0895
9.25423
36.36

9.7065
184.16
0.0512
9.11228
8.15

10.0853
1320.51
0.0895
8.77085
58.47

10.5932
685.83
0.0768
8.35144
30.37

10.7238
638.00
0.0512
8.25002
28.25

11.0545
445.22
0.0768
8.00396
19.71

11.2152
693.81
0.0640
7.88965
30.72

11.9540
74.17
0.0640
7.40367
3.28

12.8359
245.98
0.0512
6.89688
10.89

13.2416
2197.05
0.0768
6.68650
97.28

13.3568
1426.23
0.0512
6.62909
63.15

13.7171
54.85
0.0768
6.45574
2.43

13.9961
587.62
0.0768
6.32768
26.02

14.1349
255.75
0.0512
6.26586
11.32

14.3848
1055.76
0.0895
6.15758
46.74

15.2099
196.42
0.0768
5.82535
8.70

15.8701
210.95
0.0512
5.58447
9.34

16.1017
308.06
0.0768
5.50465
13.64

16.4361
504.84
0.0895
5.39341
22.35

16.7608
1278.60
0.0895
5.28964
56.61

16.8570
1051.35
0.0512
5.25966
46.55

17.6794
74.40
0.0768
5.01683
3.29

18.0195
133.67
0.0640
4.92289
5.92

18.2914
116.58
0.1023
4.85033
5.16

18.6251
115.81
0.0895
4.76417
5.13

18.9071
585.25
0.0895
4.69374
25.91

19.1306
798.17
0.0895
4.63940
35.34

19.4524
278.90
0.0895
4.56336
12.35

19.7038
100.61
0.0768
4.50572
4.45

19.9887
181.38
0.1151
4.44214
8.03

20.5121
286.29
0.0640
4.32996
12.68

20.7307
945.30
0.1023
4.28478
41.85

21.0029
341.46
0.0895
4.22987
15.12

21.5075
284.46
0.0895
4.13176
12.59

22.2002
231.05
0.0640
4.00438
10.23

22.7048
629.50
0.1023
3.91651
27.87

22.9812
159.40
0.0768
3.87003
7.06

23.3779
130.97
0.1023
3.80524
5.80

23.9488
523.75
0.1151
3.71581
23.19

24.2961
166.68
0.0640
3.66347
7.38

24.7640
299.93
0.0895
3.59531
13.28

25.0276
89.12
0.0768
3.55804
3.95

25.5884
432.27
0.1151
3.48132
19.14

26.0488
397.87
0.1151
3.42083
17.62

26.2298
313.05
0.1023
3.39763
13.86

26.6679
117.47
0.1279
3.34280
5.20

27.6944
209.73
0.1151
3.22119
9.29

28.2577
83.62
0.0768
3.15825
3.70

29.1130
76.89
0.2047
3.06737
3.40

29.5362
113.22
0.1279
3.02438
5.01

29.9278
117.80
0.1279
2.98569
5.22

30.4595
65.59
0.0468
2.93234
2.90

30.5471
63.69
0.1535
2.92656
2.82

31.0502
32.60
0.0768
2.88028
1.44

32.1358
95.29
0.1535
2.78542
4.22

33.1254
73.27
0.1535
2.70443
3.24

33.9048
68.75
0.1535
2.64403
3.04

34.7395
45.37
0.2303
2.58238
2.01

35.5866
52.92
0.2047
2.52283
2.34

35.9330
37.32
0.4093
2.49930
1.65

36.2278
106.54
0.0768
2.47964
4.72

36.9643
64.14
0.2558
2.43191
2.84

37.4205
50.27
0.2558
2.40330
2.23

Example 2: Preparation of Crystalline Vinorelbine Monotartrate Diethyl Ketone Solvate

1.5 g of vinorelbine monotartrate acetone solvate as prepared in example 1 was dissolved in 20 mL of dichlomethane. The resulting solution was evaporated to dryness under reduced pressure at 40° C. The residue was dissolved in 17 mL of diethyl ketone under stirring at 40° C. The resulting mixture was stirred for 2 hours at 50-55° C. until the crystallization completed. After cooling to room temperature the crystals were filtered, washed with diethyl ketone and dried under vacuum for 2 hours at about 55° C. 1.4 g of vinorelbine monotartrate diethyl ketone solvate with HPLC purity—99.9% and diethyl ketone content—9.4% (GC) was obtained. The obtained sample was characterized by powder X-ray diffraction and a PXRD pattern as depicted in FIG. 2 with peaks as listed in Table 4 was obtained.

TABLE 4

PXRD peak table for crystalline vinorelbine

monotartrate diethyl ketone solvate

Pos.
Height
FWHM
d-spacing
Rel. Int.

[°2θ]
[cts]
Left [°2θ]
[Å]
[%]

5.4322
238.16
0.0895
16.26880
26.12

6.0603
124.60
0.0384
14.58412
13.67

6.2281
160.05
0.0768
14.19148
17.55

7.6486
169.84
0.0640
11.55881
18.63

8.9803
207.68
0.0895
9.84752
22.78

9.5121
481.78
0.0895
9.29809
52.84

10.0506
911.81
0.0768
8.80112
100.00

10.3530
299.51
0.0512
8.54473
32.85

10.5087
114.56
0.0640
8.41843
12.56

10.8324
422.95
0.0768
8.16755
46.39

11.8135
71.28
0.0895
7.49142
7.82

12.1053
22.47
0.1023
7.31143
2.46

12.4340
66.60
0.0384
7.11892
7.30

12.7216
212.76
0.0640
6.95863
23.33

12.9317
391.81
0.0512
6.84604
42.97

13.0902
678.07
0.0768
6.76350
74.36

13.5542
49.81
0.0512
6.53296
5.46

14.1548
112.50
0.0768
6.25710
12.34

14.8028
288.34
0.0895
5.98463
31.62

15.6304
46.90
0.2047
5.66957
5.14

15.7775
112.78
0.0768
5.61701
12.37

16.2191
568.21
0.0895
5.46508
62.32

16.5148
195.24
0.0768
5.36787
21.41

17.3592
121.62
0.0895
5.10863
13.34

17.5835
140.36
0.0640
5.04396
15.39

18.0223
178.60
0.0895
4.92214
19.59

18.2024
175.47
0.0512
4.87384
19.24

18.8281
171.61
0.1279
4.71326
18.82

19.2623
72.49
0.0768
4.60797
7.95

19.6168
70.39
0.0768
4.52551
7.72

20.1526
226.77
0.0512
4.40638
24.87

20.3930
216.82
0.0768
4.35497
23.78

20.8221
76.12
0.1023
4.26618
8.35

21.1076
193.31
0.0895
4.20913
21.20

21.9443
110.20
0.0768
4.05049
12.09

22.2489
155.79
0.0768
3.99572
17.09

22.5867
178.45
0.1023
3.93672
19.57

22.7677
116.05
0.0768
3.90584
12.73

23.1250
54.75
0.0768
3.84629
6.00

23.6966
96.70
0.2047
3.75478
10.60

24.4980
119.33
0.1279
3.63374
13.09

25.1266
53.78
0.1535
3.54424
5.90

25.3505
41.65
0.0640
3.51344
4.57

25.5926
87.65
0.0768
3.48075
9.61

25.8438
83.76
0.1279
3.44750
9.19

26.0984
60.49
0.0768
3.41443
6.63

26.9579
53.91
0.0384
3.30749
5.91

27.3227
129.77
0.0384
3.26416
14.23

28.8302
68.84
0.0768
3.09682
7.55

29.3425
37.47
0.3070
3.04390
4.11

30.1656
22.61
0.3070
2.96269
2.48

31.4341
5.83
0.6140
2.84597
0.64

33.0439
16.97
0.3070
2.71091
1.86

34.2809
4.58
0.4093
2.61587
0.50

Example 3: Preparation of Crystalline Vinorelbine Monotartrate Ethyl Acetate Solvate

1.5 g of vinorelbine monotartrate acetone solvate as prepared in example 1 was dissolved in 20 mL of dichlomethane. The resulting solution was evaporated to dryness under reduced pressure at 40° C. The residue was dissolved in 40 mL of ethyl acetate under stirring at 40° C. The resulting mixture was stirred for 2 hours at 50-55° C. until the crystallization completed. After cooling to room temperature the crystals were filtered, washed with ethyl acetate and dried under vacuum for 2 hours at about 55° C. 1.2 g of vinorelbine monotartrate ethyl acetate solvate with HPLC purity—99.9% and ethyl acetate content—14.2% (GC) was obtained. The obtained sample was characterized by powder X-ray diffraction and a PXRD pattern as depicted in FIG. 3 with peaks as listed in Table 5 was obtained.

TABLE 5

PXRD peak table for crystalline vinorelbine monotartrate

ethyl acetate solvate

Height
FWHM
d-spacing
Rel.

Pos. [°2θ]
[cts]
Left [°2θ]
[Å]
Int. [%]

5.4294
689.76
0.1151
16.27716
21.31

6.0307
352.73
0.0895
14.65556
10.90

6.5111
34.38
0.1023
13.57527
1.06

7.5178
258.05
0.0768
11.75957
7.97

7.8826
469.71
0.0768
11.21613
14.51

8.8474
84.17
0.0768
9.99514
2.60

9.0307
130.74
0.0512
9.79260
4.04

9.3732
1217.63
0.0768
9.43553
37.61

9.5284
669.55
0.0640
9.28218
20.68

9.9644
1249.54
0.0768
8.87703
38.60

10.0981
1047.17
0.0640
8.75976
32.35

10.5044
380.12
0.0640
8.42191
11.74

10.7257
1308.07
0.0768
8.24857
40.41

10.8696
975.63
0.0512
8.13975
30.14

11.0511
452.46
0.1023
8.00643
13.98

11.6551
186.10
0.0895
7.59286
5.75

11.9357
129.31
0.1023
7.41496
3.99

12.0576
91.63
0.0768
7.34025
2.83

12.6717
657.45
0.0640
6.98590
20.31

12.7846
686.64
0.0256
6.92444
21.21

13.0371
3237.16
0.0895
6.79092
100.00

13.2157
556.86
0.0768
6.69953
17.20

13.4745
213.78
0.1023
6.57144
6.60

14.0552
808.92
0.1023
6.30122
24.99

14.2248
577.55
0.0895
6.22648
17.84

14.8772
420.59
0.0768
5.95487
12.99

15.0941
146.26
0.0768
5.86977
4.52

15.6461
972.99
0.1279
5.66391
30.06

16.2364
1189.45
0.0895
5.45928
36.74

16.5391
1208.19
0.0895
5.36004
37.32

17.3417
767.49
0.1023
5.11373
23.71

17.5265
648.27
0.0768
5.06025
20.03

18.1034
756.87
0.1151
4.90027
23.38

18.3968
254.40
0.0640
4.82276
7.86

18.6356
922.41
0.1023
4.76149
28.49

19.1410
257.45
0.0640
4.63691
7.95

19.6147
98.29
0.1279
4.52599
3.04

19.9770
444.91
0.0640
4.44471
13.74

20.2478
957.12
0.0640
4.38587
29.57

20.4682
725.32
0.0640
4.33915
22.41

20.7102
517.28
0.1023
4.28898
15.98

21.1079
543.29
0.1407
4.20906
16.78

21.9959
399.90
0.0768
4.04111
12.35

22.2168
581.76
0.1279
4.00142
17.97

22.6634
484.58
0.1151
3.92357
14.97

23.3790
324.86
0.1279
3.80507
10.04

23.6560
528.46
0.1279
3.76114
16.32

23.8446
452.32
0.0768
3.73181
13.97

24.4786
527.95
0.0768
3.63658
16.31

25.2045
410.29
0.0640
3.53346
12.67

25.9496
271.22
0.1791
3.43368
8.38

26.2679
109.74
0.1023
3.39278
3.39

26.8010
132.74
0.0768
3.32650
4.10

27.1254
159.67
0.0768
3.28745
4.93

27.4072
387.05
0.1151
3.25429
11.96

28.3327
116.86
0.0768
3.15005
3.61

28.7856
170.72
0.1279
3.10151
5.27

29.2461
193.32
0.1023
3.05372
5.97

29.4963
136.38
0.1023
3.02838
4.21

29.9778
45.20
0.1279
2.98082
1.40

30.6234
17.92
0.1791
2.91944
0.55

30.8915
42.39
0.1279
2.89472
1.31

31.4969
111.69
0.1791
2.84044
3.45

31.8710
42.71
0.1535
2.80795
1.32

33.4623
105.00
0.1023
2.67797
3.24

33.9398
65.06
0.1791
2.64138
2.01

34.6635
42.63
0.1279
2.58787
1.32

35.5644
50.66
0.3070
2.52436
1.56

36.0214
49.30
0.2047
2.49337
1.52

36.7783
46.37
0.2047
2.44378
1.43

37.4700
49.54
0.1023
2.40024
1.53

Example 4: Preparation of Crystalline Vinorelbine Monotartrate Isopropanol Solvate

1.5 g of vinorelbine monotartrate acetone solvate as prepared in example 1 was dissolved in 20 mL of dichlomethane. The resulting solution was evaporated to dryness under reduced pressure at 40° C. The residue was dissolved in 40 mL of isopropanol under stirring at 45-50° C. The mixture was slowly evaporated under reduced pressure at 45-50° C. to 50% of the initial volume. The resulting mixture was stirred for 2 hours at 50-55° C. until the crystallization completed. After cooling to room temperature the crystals were filtered, washed with isopropanol and dried under vacuum for 2 hours at about 55° C. 1.3 g of vinorelbine monotartrate isopropanol solvate with HPLC purity—99.9% and isopropanol content—8.4% (GC) was obtained. The obtained sample was characterized by powder X-ray diffraction and a PXRD pattern as depicted in FIG. 4 with peaks as listed in Table 6 was obtained.

TABLE 6

PXRD peak table for crystalline vinorelbine

monotartrate isopropanol solvate

Pos.
Height
FWHM
d-spacing
Rel.

[°2θ]
[cts]
Left [°2θ]
[Å]
Int. [%]

8.0129
1903.57
0.0640
11.03407
91.93

9.1809
749.59
0.0640
9.63282
36.20

9.7761
424.06
0.0768
9.04761
20.48

10.2899
1571.44
0.0768
8.59692
75.89

10.8003
1145.83
0.0768
8.19182
55.34

10.8819
791.14
0.0384
8.13053
38.21

11.3103
521.37
0.0640
7.82351
25.18

12.2000
18.07
0.3070
7.25490
0.87

13.4317
2070.70
0.1151
6.59229
100.00

14.2650
512.67
0.0768
6.20902
24.76

14.5880
804.73
0.0895
6.07225
38.86

15.2858
210.61
0.0768
5.79660
10.17

16.0847
117.63
0.0512
5.51042
5.68

16.3481
501.44
0.0768
5.42225
24.22

16.7267
360.77
0.0640
5.30034
17.42

16.9188
615.54
0.0895
5.24060
29.73

17.8557
46.11
0.1535
4.96768
2.23

18.4670
281.01
0.1279
4.80460
13.57

19.3367
821.47
0.1151
4.59041
39.67

19.7750
407.57
0.0895
4.48965
19.68

20.1040
86.52
0.0895
4.41691
4.18

20.6233
138.24
0.1023
4.30686
6.68

20.9202
438.44
0.1279
4.24640
21.17

21.2237
439.89
0.0895
4.18636
21.24

21.6569
184.35
0.1023
4.10358
8.90

21.8446
116.57
0.0512
4.06875
5.63

22.3243
68.95
0.1535
3.98239
3.33

22.7100
324.34
0.0768
3.91562
15.66

22.8892
559.79
0.1279
3.88537
27.03

23.3789
163.57
0.1279
3.80508
7.90

23.9938
338.01
0.0895
3.70895
16.32

24.5439
89.84
0.1279
3.62705
4.34

24.8749
130.45
0.0640
3.57954
6.30

25.1658
301.50
0.1151
3.53881
14.56

25.7526
183.09
0.0512
3.45949
8.84

26.1873
102.54
0.1023
3.40305
4.95

26.5238
406.86
0.1023
3.36064
19.65

27.0243
144.78
0.1279
3.29952
6.99

27.9588
74.02
0.1279
3.19132
3.57

28.4395
77.97
0.1279
3.13847
3.77

28.7491
84.79
0.1279
3.10537
4.09

29.5508
87.79
0.3070
3.02292
4.24

29.9281
103.23
0.1023
2.98566
4.99

31.1594
137.20
0.1023
2.87044
6.63

32.6595
76.23
0.1535
2.74194
3.68

33.2338
62.45
0.1023
2.69586
3.02

33.7939
106.13
0.1279
2.65245
5.13

35.2115
58.01
0.1023
2.54884
2.80

36.2464
20.06
0.2047
2.47841
0.97

36.6244
156.76
0.1023
2.45369
7.57

Example 5: Preparation of Crystalline Vinorelbine Monotartrate Hydrate

150 g of vinorelbine monotartrate acetone solvate obtained as described in example 1 was incubated at 60° C. and a relative humidity of about 40% for 16 hours. Finally, 140 g of crystalline vinorelbine monotartrate hydrate with HPLC purity—99.9% and residual acetone content—0.16% (GC) was obtained. The obtained sample was characterized by powder X-ray diffraction and a PXRD pattern as depicted in FIG. 5 with peaks as listed in Table 7 was obtained.

TABLE 7

PXRD peak table for crystalline vinorelbine

monotartrate hydrate

Pos.
Height
FWHM
d-spacing
Rel.

[°2θ]
[cts]
Left [°2θ]
[Å]
Int. [%]

5.6603
155.39
0.0640
15.61370
9.70

6.3047
64.91
0.0640
14.01933
4.05

7.8920
1601.52
0.0640
11.20280
100.00

9.5022
619.80
0.0768
9.30778
38.70

9.6400
526.70
0.0512
9.17505
32.89

10.3129
1349.49
0.1151
8.57780
84.26

10.7438
1179.93
0.0895
8.23476
73.68

10.8241
803.11
0.0640
8.17386
50.15

11.0432
149.93
0.0640
8.01218
9.36

11.4028
398.03
0.0895
7.76029
24.85

12.0440
46.35
0.0768
7.34854
2.89

13.4144
1450.23
0.0640
6.60074
90.55

13.5607
1344.16
0.0895
6.52987
83.93

13.9826
253.57
0.1279
6.33378
15.83

14.1259
211.20
0.0512
6.26981
13.19

14.5737
764.07
0.1151
6.07818
47.71

15.4909
82.37
0.0640
5.72031
5.14

15.8024
114.03
0.1023
5.60824
7.12

16.2052
242.01
0.0895
5.46972
15.11

16.5319
99.57
0.0512
5.36236
6.22

17.1502
389.84
0.0640
5.17042
24.34

17.2971
364.86
0.0640
5.12684
22.78

18.3869
191.25
0.1535
4.82534
11.94

18.9855
427.01
0.0768
4.67454
26.66

19.4119
655.89
0.0640
4.57280
40.95

19.5577
490.86
0.0512
4.53904
30.65

20.0486
75.58
0.2558
4.42900
4.72

20.7169
244.33
0.0640
4.28761
15.26

21.1602
278.41
0.1023
4.19877
17.38

21.4709
224.42
0.0768
4.13871
14.01

22.2069
220.45
0.0640
4.00318
13.76

22.7214
119.84
0.1023
3.91369
7.48

23.1938
350.58
0.0512
3.83504
21.89

23.5706
93.54
0.1279
3.77457
5.84

24.1472
87.34
0.0768
3.68573
5.45

24.7625
234.71
0.1535
3.59552
14.66

25.1137
105.37
0.1535
3.54604
6.58

25.7867
191.69
0.0895
3.45499
11.97

26.4846
207.94
0.1535
3.36551
12.98

26.8187
116.81
0.1279
3.32434
7.29

27.4412
100.78
0.3582
3.25033
6.29

28.2760
47.50
0.3070
3.15624
2.97

28.7915
81.31
0.2558
3.10089
5.08

29.4985
48.48
0.1535
3.02816
3.03

30.3843
100.92
0.0768
2.94186
6.30

30.8031
46.71
0.1535
2.90282
2.92

32.2225
32.43
0.1535
2.77812
2.03

32.8210
16.73
0.2047
2.72881
1.04

33.3521
10.14
0.1535
2.68656
0.63

34.3526
60.81
0.1791
2.61058
3.80

35.1208
29.33
0.2558
2.55522
1.83

36.1536
42.01
0.1535
2.48456
2.62

Example 6: Preparation of Crystalline Vinorelbine Monotartrate Hydrate from Ethyl Acetate Solvate

1.0 g of vinorelbine monotartrate ethyl acetate solvate obtained as described in example 3 was incubated at 30° C. and a relative humidity of about 60% for 120 hours. Finally, 0.9 g of crystalline vinorelbine monotartrate hydrate with HPLC purity—99.9% and residual ethyl acetate content—0.05% (GC) was obtained. The obtained sample was characterized by powder X-ray diffraction and a PXRD pattern is the same as for vinorelbine monotartrate hydrate obtained from acetone solvate depicted in FIG. 5.

Example 7: Preparation of Crystalline Vinorelbine Monotartrate Hydrate by Crystallization from Wet Ethanol

1.5 g of vinorelbine monotartrate acetone solvate as prepared in example 1 was dissolved in 20 mL of dichlomethane. The resulting solution was evaporated to dryness under reduced pressure at 40° C. The residue was dissolved in 30 mL of absolute ethanol under stirring at 40° C. The obtained solution was vacuum evaporated to 10 mL and 0.2 mL of water was added. Afterwards 20 mg of seeds of crystalline vinorelbine monotartrate hydrate were added and the resulting mixture was stirred for 2 hours at room temperature. The precipitate formed was filtered, washed with absolute ethanol and dried under vacuum for 1 hour at about 55° C. Finally, 0.8 g of crystalline vinorelbine monotartrate hydrate with HPLC purity—99.9% was obtained. The obtained sample was characterized by powder X-ray diffraction and a PXRD pattern is the same as for vinorelbine monotartrate hydrate obtained according to example 5 depicted in FIG. 5.

Example 8: Stability of the Crystalline Vinorelbine Monotartrate Organic Solvates

Three further representative batches of crystalline vinorelbine monotartrate acetone solvate being produced according to Example 1 were analyzed for stability (i.e. batches no. 011213, no. 021213, and no. 010414). The samples were exposed to temperatures of 5° C. and 25° C. for three and six months, respectively. Batch no. 010414 was also exposed to a temperature of 40° C. (at 60%±2% relative humidity) for 15 days, 1 month, and two months, respectively.

Exemplary results are summarized in the following Table 8.

TABLE 8

Stability data of crystalline vinorelbine monotartrate acetone

solvate at 5° C., 25° C., and 40° C.

Degradation products (%)

Photodegradation
Thermodegradation

(3.6-epoxy
(4-deacetyl

vinorelbine)
vinorelbine)
Total

Specification limits
NMT 0.15
NMT 0.15
NMT 0.70

batch no. 011213
storage conditions 5° C.

initial
LT 0.05
0.06
0.14

3 months
0.07
0.05
0.15

6 months
LT 0.05
0.06
0.15

batch no. 021213
storage conditions 5° C.

initial
LT 0.05
0.06
0.06

3 months
LT 0.05
0.08
0.08

6 months
LT 0.05
0.09
0.09

batch no. 010414
storage conditions 5° C.

initial
LT 0.05
LT 0.05
0.07

3 months
0.07
LT 0.05
0.07

6 months
LT 0.05
LT 0.05
0.07

batch no. 011213
storage conditions 25° C.

initial
LT 0.05
0.06
0.14

3 months
LT 0.05
0.06
0.16

6 months
LT 0.05
0.06
0.16

batch no. 021213
storage conditions 25° C.

initial
LT 0.05
0.06
0.06

3 months
0.06
0.07
0.07

6 months
LT 0.05
0.07
0.07

batch no. 010414
storage conditions 25° C.

initial
LT 0.05
LT 0.05
0.07

3 months
LT 0.05
LT 0.05
0.06

6 months
LT 0.05
LT 0.05
0.08

batch no. 010414
storage conditions 40° C.

initial
LT 0.05
LT 0.05
0.07

1 month
LT 0.05
LT 0.05
0.08

2 months
0.05
LT 0.05
0.13

All three batches of crystalline vinorelbine monotartrate acetone solvate tested exhibited almost no degradation after six months storage both at 5° C.+3° C. and 25° C.±2° C., and only minimal degradation after two months storage at 40° C.

Hence, the stability of crystalline vinorelbine monotartrate solvates is significantly improved as compared to vinorelbine bitartrate as shown in Table 9.

TABLE 9

Comparable stressing stability study of Vinorelbine Monotartrate

organic solvates and Vinorelbine Bitartrate at 60° C.

Total degradation impurities, %

Vinorelbine
Vinorelbine

Time
Monotartrate
Monotartrate
Vinorelbine

(weeks)
acetone solvate
isopropanol solvate
Bitartrate

1
LT 0.05
LT 0.05
9.8

3
0.08
0.05
—

8
0.24
0.15
—

Example 9: Stability of Crystalline Vinorelbine Monotartrate Hydrate

Crystalline vinorelbine monotartrate hydrate being produced according to Example 5 were analyzed for stability. The samples were exposed to temperatures of 25° C. and 40° C. for three and six months, respectively.

The overall accumulation of degradation impurities for crystalline vinorelbine monotartrate hydrate does not exceed 0.15% after 6 months at 40° C. and 0.02% at 25° C. (Table 10).

TABLE 10

Stability data of crystalline vinorelbine monotartrate hydrate at

25° C., and 40° C.

Degradation products (%)

Photodegradation
Thermodegradation

(3,6-epoxy
(4-deacetyl

vinorelbine)
vinorelbine)
Total

Specification limits
NMT 0.15
NMT 0.15
NMT 0.70

batch no. 010615
storage conditions 25° C.

initial
0.05
LT 0.05
0.05

3 months
0.05
LT0.05
0.05

6 months
0.05
LT0.05
0.06

batch no. 010615
storage conditions 40° C.

initial
0.05
LT 0.05
0.05

3 months
0.05
0.06
0.13

6 months
0.07
0.07
0.16

Furthermore, a comparative photo-degradation analysis of crystalline vinorelbine monotartrate hydrate, according to the present invention and vinorelbine bitartrate was performed.

The samples (about 14 mg each) were placed in 10 ml light glass volumetric flasks and exposed in a photo chamber to a xenon lamp (wave length 300-800 nm; fluence rate 250-765 W/m²). The amount of the known photo-degradation product 3,6-epoxy vinorelbine was determined at various time points by means of HPLC.

The obtained results are shown in Table 11. The peak due to the known photo degradation product (3,6-Epoxy vinorelbine) was detected in the chromatograms obtained with all the solutions of the illuminated samples. The observed accumulation of 3,6-epoxy vinorelbine was significantly more intense in vinorelbine bitartrate.

TABLE 11

Photo degradation products accumulation during illumination of samples of

vinorelbine bitartrate and crystalline vinorelbine monotartrate hydrate

Photodegradation product
Total impurities (excluding

(3,6-epoxy vinorelbine), %
photodegradation product), %

Vinorelbine

Vinorelbine

Exposure.
Vinorelbine
Monotartrate
Vinorelbine
Monotartrate

min
Bitartrate
Hydrate
Bitartrate
Hydrate

0
0.05
0.03
0.10
0.10

15
0.16
0.08
0.10
0.10

30
0.24
0.14
0.16
0.10

60
0.35
0.28
0.20
0.10

120
0.72
0.44
0.27
0.17

Example 10: Preparation of Amorphous Vinorelbine Monotartrate

As a comparative example, amorphous vinorelbine monotartrate was prepared according to the following procedure: 2.0 g of vinorelbine monotartrate was dissolved in 5 ml of dichloromethane (DCM) and evaporated to dryness in vacuum at 40° C. for 30 min. Then, the residue was dissolved in 5 ml of DCM. The solution was added to 50 ml of heptane and stirred for about 5 min. The precipitate was filtered, washed with heptane, and dried at 40° C. in vacuum for 20 min. Finally, the sample was analyzed by HPLC. FIG. 6 depicts the results of an exemplary X-ray powder diffraction analysis for representative batch of amorphous vinorelbine monotartrate. No peaks are detectable.

In order to evaluate the thermostability and photostability of the compound the sample was exposed to a temperature of 40° C. for 2 weeks analyzed by HPLC. The results are summarized in Table 12.

TABLE 12

Stability data of amorphous vinorelbine monotartrate at 40° C.

Degradation products (%)

3,6-epoxy
vinorelbine

vinorelbine
N-oxide
Total

Specification limits
NMT 0.15
NMT 0.15
NMT 0.70

initial
LT 0.05
LT 0.05
0.13

15 days
0.13
0.33
1.08

From the data it is apparent that the amorphous vinorelbine monotartrate (in contrast to the crystalline form of the present invention) exhibits significant degradation already after incubation for two weeks at 40° C. Accordingly, the improved thermo- and photostability data shown above can be specifically assigned to the crystalline form of vinorelbine monotartrate according to the present invention.

Example 11. Preparation of Vinorelbine Monotartrate Acetone Solvate/StarCap 40 mg HGCs (Hard Gelatin Capsule)

Capsule formulation Vinorelbine monotartrate was premixed with approximately half of the dispensed StarCap 1500, passed through a screen and collected in an intermediate bulk container. The screen was flushed with the remaining StarCap 1500 and collected. The contents of the intermediate bulk container were blended until the contents were uniform. A hard gelatin size 2 was filled with vinorelbine monotartate and co-processed mixture of corn starch and pregelatinized starch. The capsule contained approximately 48 mg of vinorelbine monotartrate (corresponding to 40.00 mg of vinorelbine) and approximately 72.00 mg of StarCap 1500. Bulk characteristics were as follows: angle of response 24, bulk density 0.581 g/ml, tapped density 0.714 g/ml, Hausner ratio 1.229, LoD determination 3.79%. Bulk particle distribution data showed about 60% of particles to be of size of 0.08 mm, 18% of size 0.125 mm.

Dissolution of vinorelbine monotartrate HGC has been tested in 900 ml 0.1 N HCl at 75 rpm at 37° C. and compared with commercial batch of Navelbine Oral 30 mg SGC (soft gelatin capsule). The dissolution profile shows vinorelbine monotartrate HGC achieved a release of about 98% after 45 min while the vinorelbine SGC achieved a release of 97% after 45 min (Table 13).

TABLE 13

Comparison of dissolution kinetics of Navelbine Oral and

the hard gelatin capsules according to the present invention

Time (min)
0
10
20
30
45

Amount of dissolved API (%) Navelbine Oral
0
93
95
95
97

Amount of dissolved API (%) hard gelatin capsules
0
93
95
97
98

When dissolution profiles of 30 mg HGCs in three different dissolution media were compared, no significant difference has been identified. In all three media the HGCs dissolution complies with a general requirement NLT (not less than) 85% in NMT (not more than) 15 min (FIG. 9).

Example 12. Preparation of Vinorelbine Monotartrate Hydrate/StarCap 30 mg HGCs

Capsule formulation Vinorelbine monotartrate hydrate was premixed with approximately half of the dispensed StarCap 1500, passed through a screen and collected in an intermediate bulk container. The screen was flushed with the remaining StarCap 1500 and collected. The contents of the intermediate bulk container were blended until the contents were uniform. A hard gelatin size 3 was filled with vinorelbine monotartate and co-processed mixture of corn starch and pre-gelatinized starch. The capsule contained approximately 36.00 mg of vinorelbine monotartrate (corresponding to 30.00 mg of vinorelbine base) and approximately 114.00 mg of StarCap 1500. Bulk characteristics were as follows: flowability 1.2-2 sec/100 g, angle of response 26, bulk density 0.51 g/ml, tapped density 0.66 g/ml, Hausner ratio 1.29, LoD determination 1.0%. Bulk particle distribution data showed about 20% of particles to be of size of 0.2 mm, 18% of size 0.31 mm and more than 50% of size of 0.5 mm.

Dissolution of vinorelbine monotartrate HGCs has been tested in 900 ml 0.1 N HCl at 75 rpm at 37° C. and compared with commercial batch of Navelbine Oral 30 mg SGC. The dissolution profile shows vinorelbine monotartrate HGC achieved a release of about 97% after 45 min while the vinorelbine SGC achieved a release of 98% after 45 min (Table 13).

When dissolution profiles of 30 mg HGCs in three different dissolution media were compared, no significant difference has been identified. In all three media the HGCs dissolution complies with a general requirement NLT 85% in NMT 15 min (FIG. 10).

As evident from Table 14 and Table 15 analytical data showed the formulation complied with all studied requirements, including content uniformity, assay/purity, water disintegration.

TABLE 14

Content Uniformity (limits142.5 to 157.5 mg)

Capsule filling weight

Sample
Assay [%]*
[mg]

1
99.40
153.7

2
96.60
149.1

3
95.44
148.9

4
92.88
146.2

5
95.59
145.8

6
101.27
156.3

7
94.74
147.1

8
94.10
146.6

9
103.18
153.2

10
97.60
149.2

mean
97.08
149.6

SD [%]
3.29

RSD [%]
3.39

AV
9.3

TABLE 15

Disintegration in Water

Sample
1
2
3
4
5
6
Mean

Time
1:51
2:57
2:07
1:47
2:03
1:43
2:04

[min]

(max)

(min)

The results of the examples 11 and 12 showed crystalline vinorelbine monotartrate can be formulated with co-processed starch, providing simple and robust formulation, free from other excipients, ready for scale up.

Example 13: Stability of Crystalline Vinorelbine Monotartrate Hydrate Containing Capsule Formulation

The stability of the vinorelbine monotartrate hydrate containing capsule formulation was determined at temperatures of 25° C. and of 40° C., respectively. The results obtained are summarized in Table 16. As evident from the table, the product remained stable during 6 months and at 25° C. and during 3 months at 40° C.

TABLE 16

Stability of capsule formulation at 25° C. and 40° C.

Degradation products (%)

Photo degradation
Thermodegradation

(3,6-epoxy
(4-deacetyl
Total

vinorelbine)
vinorelbine)
Limit

Limit NMT 0.30
Limit NMT 0.15
0.70

storage conditions 25° C.

initial
LT 0.05
0.06
0.06

15 days
LT 0.05
0.06
0.06

1 month
LT 0.05
0.06
0.07

2 months
LT 0.05
0.07
0.07

6 months
0.05
0.07
0.12

storage conditions 40° C.

initial
LT 0.05
LT 0.05
0.06

15 days
LT 0.05
LT 0.05
0.06

1 month
LT 0.05
LT 0.05
0.08

2 months
LT 0.05
LT 0.05
0.10

3 months
LT 0.05
LT 0.05
0.10

TABLE 17 shows the results of a comparison of the stability of Navelbine Oral soft gelatin capsules and hard gelatin capsules of the present invention. Incubation was performed for six months at 25° C.±2° C. and 60%±2% relative humidity, as described above.

TABLE 17

Comparison of long-term stability at 25° C. of Navelbine

Oral soft gelatin capsules and hard gelatin capsules according to the

present invention

Navelbine Oral soft gelatin capsule

Photodegradation
Thermodegradation

(%)
(%)
Total

(3,6-epoxy
(4-deacetyl
(%)

vinorelbine)
vinorelbine)
Limit

Limit NMT 0.30
Limit NMT 0.15
0.70

initial
0.06
0.05
0.20

6 months
0.23
0.46
1.40

Hard gelatin capsule of the present invention

Photo degradation
Thermodegradation

(3,6-epoxy
(4-deacetyl
Total

vinorelbine)
vinorelbine)
Limit

Limit NMT 0.30
Limit NMT 0.15
0.70

initial
LT 0.05
0.06
0.06

6 months
0.05
0.07
0.12

The results obtained again reveal the virtual absence of degradation for the hard gelatin capsule formulation, whereas substantial degradation was observed for the established soft gelatin capsule.

Example 14: Tablet Formulation
14.1 Direct Compression

Tablets employing as active ingredient vinorelbine monotartrate were produced by means of direct compression. Tablet cores containing approximately 36 mg of crystalline vinorelbine monotartrate (corresponding to 30 mg vinorelbine base), 85 mg microcrystalline cellulose (Avicel PH 102; Sigma-Aldrich, Munich, Germany), 10 mg StarCap 1500 (Colorcon, West Point, Pa., USA), 0.5 mg colloidal silica dioxide, and 1 mg magnesium stearate were prepared. The disintegration time of the tablets was determined to be approximately two minutes with a dissolution of >85% in 15 minutes. Furthermore, film coated tablets were prepared using the Opadry Film Coating System (Colorcon, West Point, Pa., USA).

14.2 Roller Compaction

Roller compaction dry granulation was used to prepare vinorelbine tablets. 36 mg of crystalline vinorelbine monotartrate (corresponding to 30 mg vinorelbine base), 85 mg microcrystalline cellulose (Avicel PH 102; Sigma-Aldrich, Munich, Germany), and 10 mg StarCap 1500 (Colorcon, West Point, Pa., USA) were mixed for 10 min. Intra-granular magnesium stearate was purified through a 250 μm sieve, added to a mixture and mixed for additional 5 min. The resulting mixture was compacted on a roller compactor. Colloidal silicon dioxide and few grams of granules were de-lumped by passing them through a 30 mesh screen. The mixture was added to the granules and blended for additional 5 min. Extra-granular magnesium stearate was also purified as described above, added and mixed for additional five minutes prior to compression. The disintegration time of the tablets was determined to be less than three minutes with a dissolution of >85% in 15 minutes.

The present invention illustratively described herein may suitably be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein. Thus, for example, the terms “comprising”, “including”, “containing”, etc. shall be read expansively and without limitation. Additionally, the terms and expressions employed herein have been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed. Thus, it should be understood that although the present invention has been specifically disclosed by embodiments and optional features, modifications and variations of the inventions embodied therein may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention.

The invention has been described broadly and generically herein. Each of the narrower species and sub-generic groupings falling within the generic disclosure also form part of the invention. This includes the generic description of the invention with a proviso or negative limitation removing any subject matter from the genus, regardless of whether or not the excised material is specifically recited herein.