Crystalline forms

Details Crystalline forms Crystalline forms

2001-01-04

2002-08-27

Russel, Jeffrey E. (Department: 1653)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C549S315000

Reexamination Certificate

active

06440939

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to new solid state forms of a drug, to pharmaceutical compositions containing them, and to processes for obtaining them.
BACKGROUND OF THE INVENTION
In the formulation of drug compositions, it is important for the drug substance to be in a form in which it can be conveniently handled and processed. This is of importance, not only from the point of view of obtaining a commercially viable manufacturing process, but also from the point of view of subsequent manufacture of pharmaceutical formulations (e.g. oral dosage forms such as tablets) comprising the active compound.
Further, in the manufacture of oral drug compositions, it is important that a reliable, reproducible and constant plasma concentration profile of drug is provided following administration to a patient. This is of particular importance in the manufacture of compositions comprising antithrombotic agents.
Chemical stability, solid state stability, and “shelf life” of the active ingredients are also very important factors. The drug substance, and compositions containing it, should be capable of being effectively stored over appreciable periods of time, without exhibiting a significant change in the active component's physico-chemical characteristics (e.g. its chemical composition, density, hygroscopicity and solubility).
Moreover, it is also important to be able to provide drug in a form which is as chemically-pure as possible.
Amorphous materials may present significant problems in this regard. For example, such materials are typically difficult to handle and to formulate, provide for unreliable solubility, and are often found to be unstable and chemically impure.
The skilled person will appreciate that, if a drug can be readily obtained in a stable crystalline form, the above problems may be solved.
Thus, in the manufacture of commercially viable, and pharmaceutically acceptable, drug compositions, it is important, wherever possible, to provide drug in a substantially crystalline, and stable, form.
It is to be noted, however, that this goal is not always achievable. Indeed, typically, it is not possible to predict, from molecular structure alone, what the crystallisation behaviour of a compound, either as such or in the form of a salt, will be. This can only be determined empirically.
PRIOR ART
International patent application WO 97/23499 discloses a number of compounds, which have been found to be useful as prodrugs of thrombin inhibitors, which thrombin inhibitors are of the general formula:
R
a
O
2
C—CH
2
—(R)Cgl—Aze—Pab—H
wherein R
a
represents H, benzyl or C
1-6
alkyl, Cgl represents cyclohexylglycine, Aze represents S-azetidine-2-carboxylic acid and Pab—H represents 4-aminomethyl-amidinobenzene. The active thrombin inhibitors are themselves disclosed in the earlier international patent application WO 94/29336.
WO 97/23499 also contains a specific disclosure of the compound:
EtO
2
C—CH
2
—(R)Cgl—Aze—Pab—OH
wherein Pab—OH represents 4aminomethyl-benzeneamidoxime. A process for the synthesis of this compound is described in Example 17 of WO 97/23499, where it is purified by preparative RPLC and isolated in an amorphous form.
Whether it is possible to provide EtO
2
C—CH
2
—(R)Cgl—Aze—Pab—OH in a crystalline form is not disclosed in WO 97/23499. Furthermore, no information is provided in relation to how this compound may be obtained in such a form.
DISCLOSURE OF THE INVENTION
Surprisingly, we have found that EtO
2
C—CH
2
—(R)Cgl—Aze—Pab—OH may be obtained in one or more forms that are substantially crystalline in nature.
Thus, according to a first aspect of the invention there is provided EtO
2
C—CH
2
—(R)Cgl—Aze—Pab—OH, or a pharmaceutically-acceptable salt thereof, in a substantially crystalline form (hereinafter referred to as “the compounds of the invention”).
Although we have found that it is possible to produce EtO
2
C—CH
2
—(R)Cgl—Aze—Pab—OH, and salts thereof, in forms which are greater than 80% crystalline, by “substantially crystalline” we include greater than 10% (e.g. greater that 20%), preferably greater than 30%, and more preferably greater than 40% crystalline. The degree (%) of crystallinity may be determined by the skilled person using X-ray powder diffraction (XRPD). Other techniques, such as solid state NMR, FT-IR, Raman spectroscopy, differential scanning calorimetry (DSC) and microcalorimetry, may also be used.
Suitable pharmaceutically-acceptable salts which may be mentioned include inorganic, and organic, acidic and basic addition salts, such as hydrogen halide salts (e.g. HBr salts), carboxylic acid salts, lower alkanesulphonate salts (e.g. linear or branched C
1-6
alkanesulphonate, preferably C
1-3
alkanesulphonate, and especially ethane- and methanesulphonate salts) and ammonium and amine salts. Toluenesulphonate salts may also be mentioned. For a full list of salts that may be mentioned see Berge et al, J. Pharm. Sci., 66, 1 (1977). However, we prefer that the compounds of the invention are not in the form of a salt.
The compounds of the invention may be in the form of a solvate (by which we include a hydrate) or otherwise.
We have found, surprisingly, that the compounds of the invention have an improved stability when compared with EtO
2
C—CH
2
—(R)Cgl—Aze—Pab—OH prepared as described in WO 97/23499.
According to a further aspect of the invention, there is thus provided a stable form of EtO
2
C—CH
2
—(R)Cgl—Aze—Pab—OH, or a pharmaceutically-acceptable salt thereof.
The term “stability” as defined herein includes chemical stability and solid state stability.
By “chemical stability”, we include that the compound, or salt, can be stored in an isolated form, or in the form of a formulation in which it is provided in admixture with pharmaceutically acceptable carriers, diluents or adjuvants (e.g. in an oral dosage form, such as tablet, capsule etc.), under normal storage conditions, with an insignificant degree of chemical degradation or decomposition.
By “solid state stability”, we include that the compound, or salt, can be stored in an isolated solid form, or in the form of a solid formulation in which it is provided in admixture with pharmaceutically acceptable carriers, diluents or adjuvants (e.g. in an oral dosage form, such as tablet, capsule etc.), under normal storage conditions, with an insignificant degree of solid state transformation (e.g. crystallisation, recrystallisation, solid state phase transition, hydration, dehydration, solvatisation or desolvatisation).
Examples of “normal storage conditions” include temperatures of between minus 80 and plus 50° C. (preferably between 0 and 40° C. and more preferably room temperatures, such as 15 to 30° C.), pressures of between 0.1 and 2 bars (preferably at atmospheric pressure), relative humidities of between 5 and 95% (preferably 10 to 75%), and/or exposure to 460 lux of UV/visible light, for prolonged periods (i.e. greater than or equal to six months). Under such conditions, compounds of the invention may be found to be less than 15%, more preferably less than 10%, and especially less than 5%, chemically degraded/decomposed, or solid state transformed, as appropriate. The skilled person will appreciate that the above-mentioned upper and lower limits for temperature, pressure and relative humidity represent extremes of normal storage conditions, and that certain combinations of these extremes will not be experienced during normal storage (e.g. a temperature of 50° C. and a pressure of 0.1 bar).
The compounds of the invention may be obtained advantageously by crystallising EtO
2
C—CH
2
—(R)Cgl—Aze—Pab—OH, or a salt of EtO
2
C—CH
2
—(R)Cgl—Aze—Pab—OH.
According to a further aspect of the invention, there is provided a process for the production of a compound of the invention which comprises crystallising EtO
2
C—CH
2
—(R)Cgl—Aze—Pab—OH, or a pharmaceutically-acceptable salt thereof.
It is possible to crystallise EtO
2
C—CH
2
—(R)Cgl—Aze—Pab—OH and pharmaceutically-acceptable salts thereof with or without the presence of a solvent system (e.g. crystallisation may be from a melt, und

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