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.
The different physical properties of the crystalline forms with respect to each other and with respect to the non-crystalline state may influence markedly the chemical and pharmaceutical processing of a compound, particularly when the compound is prepared or used on an industrial scale.
Further, in the manufacture of oral drug compositions, it is important that a reliable and reproducible plasma concentration profile of drug is provided following administration to a patient. Inter-patient variability in the absorption profile of a drug within the stomach, intestine or bloodstream can have an effect on drug safety and efficacy.
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 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 crystalline form that is also stable, one of more of 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 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 alone or in the form of a salt) will be. This can only be determined empirically.
WO2009/047563, teaches a novel group of bicyclic heterocycles which may be useful in the treatment or prevention of a disease or medical condition mediated through protein kinase B (PKB, also known as AKT).
WO2009/047563 further discloses a specific bicyclic heterocycle identified therein as (S)-4-amino-N-(1-(4-chlorophenyl)-3-hydroxypropyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (Example 9). This compound is designated herein as “Compound (I)”, and is alternatively known as “AZD5363”.

Compound (I) has been shown to exhibit potent activity against all 3 mammalian isoforms of the AKT enzyme—with an IC50 of 3 nM against AKT1, an IC50 of 7 nM against AKT2 and an IC50 of 7 nM against AKT3. Compound (I) is currently being developed as a potential new drug for the treatment of several different forms of cancer, either as a monotherapy or as part of a combination therapy.
WO2009/047563 further discloses three processes for the preparation of Compound (I)—Example 9 itself and alternative routes 1 and 2 for Example 9. “Example 9 alternative route 1” includes a slimy of Compound (I) in ethyl acetate and the other two processes isolate Compound (I) as a solid by evaporating fractions eluted from as column. The present inventor analysed (by XRD) three historical hatches of Compound (I) from our compound collection which were synthesised using a procedure identical to, or substantially similar to, one of these three processes and identified all three as being a semi-crystalline form, designated as “Form A”.
USPTO Backgrounds
USPTO Backgrounds