Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
2000-08-28
2002-11-12
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C514S210010
Reexamination Certificate
active
06479078
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 comprising the active compound.
Further, in the manufacture of 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 will be. This can usually only be determined empirically.
PRIOR ART
International patent application WO 94/29336 discloses a number of compounds, which are useful as inhibitors of serine proteases, such as thrombin, including the compound,
HO
2
C—CH
2
—(R)Cgl-(S)Aze-Pab-H
wherein Cgl represents cyclohexylglycine, Aze represents azetidine-2-carboxylate and Pab-H represents 4-aminomethylamidinobenzene. The compound is also known as melagatran (glycine, N-[(1R)-2-[(2S)-2-[[[[4-(aminoiminomethyl)phenyl] methyl] amino] carbonyl]-1-azetidinyl]-1-cyclohexyl-2-oxoethyl]-).
A process for the synthesis of this compound is described in Example 1 of WO 94/29336, where it is obtained as crude material, by evaporation of reaction solvent following a final deprotection step. The compound is thus isolated in an amorphous form.
Whether it is possible to provide melagatran in a crystalline form is not disclosed in WO 94/29336. Furthermore, no information is provided in relation to how this compound may be obtained in such a form and, more particularly, how it may be obtained in a chemically, and/or solid state, stable form.
DISCLOSURE OF THE INVENTION
We have found that melagatran may be readily obtained in one or more forms that are both substantially crystalline and stable in nature.
Thus, according to a first aspect of the invention there is provided melagatran in a substantially crystalline form (hereinafter referred to as “the compounds of the invention”).
Although we have found that it is possible to produce melagatran in forms which are greater than 80% crystalline, by “substantially crystalline” we include greater than 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.
The compounds of the invention may be in the form of a solvate, a hydrate or a mixed solvate/hydrate. Solvates may be of one or more organic solvents, such as lower alkyl (e.g. C
14
alkyl) alcohols (e.g. methanol, ethanol or iso-propanol) or mixtures thereof.
We have found that the compounds of the invention have a surprisingly improved stability when compared with melagatran prepared as described in WO 94/29336.
According to a further aspect of the invention, there is thus provided a stable form of melagatran.
The term “stability” as defined herein includes chemical stability and solid state stability.
By “chemical stability”, we include that the compound can be stored in an isolated solid form, or in the form of a solid formulation in which it may be provided in admixture with pharmaceutically acceptable carriers, diluents or adjuvants, under normal storage conditions, with an insignificant degree of chemical degradation or decomposition.
By “solid state stability”, we include that the compound can be stored in an isolated solid form, or in the form of a solid formulation in which it may be provided in admixture with pharmaceutically acceptable carriers, diluents or adjuvants, 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 ambient temperature, such as between 15 and 30° C.), pressures of between 0.1 and 2 bars (preferably atmospheric pressure), 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 and pressure 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 term “normal storage conditions” may also include relative humidities of between 5 and 95% (preferably 10 to 75%). However, in the case of certain crystalline forms according to the invention, changes in conformation or crystal structure by hydration and/or dehydration may occur as a result of prolonged exposure to certain extremes of relative humidities, at normal temperatures/pressures. For example, we have found that crystalline forms of melagatran that are in the form of a hydrate (e.g. a monohydrate) may be stored at 10% relative humidity or above at ambient temperature/atmospheric pressure with an insignificant degree of dehydration. However, we have also found that crystalline forms of melagatran that are in the form of an anhydrate should be stored at less than 40% (preferably less than 30%, more preferably less than 20%) relative humidity at ambient temperature/atmospheric pressure, to maintain an insignificant degree of hydration.
Thus, although compounds of the invention possess a greater solid state stability than forms of melagatran described in the prior art, some compounds of the invention are more solid state stable than others. In this respect, it will be appreciated by the skilled person that storage conditions may be tailored to suit the crystalline form that is being stored.
The compounds of the invention may be obtained advantageously by crystallising melagatran.
According to a further aspect of the invention, there is provided a process for the production of a compound of the invention which com
Hedström Lena
Lundblad Anita
Någård Sofia
AstraZeneca AB
Nixon & Vanderhye
Page Thurman K.
Pulliam A.
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