A thermodynamic-based approach to analyzing a highly solvating polymorphic system: the desolvation window method.

There are two major challenges in developing a solid form: (1) identifying the thermodynamically stable form and (2) determining the method used to crystallize that form. Often experiments performed to address these challenges have different objectives and use separate experimental techniques. The thermodynamically stable form is usually found on small scale, utilizing slurries or crystallizations. Subsequently, a crystallization process is developed to purge impurities and to increase yield and these experiments are typically conducted on medium to large scale (greater than 10 g). Axitinib, a research compound for the treatment of cancer, forms solvates in most solvents to which it is exposed, presenting a problem in discovering and making a desirable anhydrous phase. A method has been developed that will give the best chance of making a thermodynamic stable form of the anhydrous material, necessarily not a desolvated form. This approach relies on solvent mediated transformation (thermodynamic control), rather than crystallization or solid-to-solid phase desolvation (generally kinetic control). Experimental conditions (a desolvation window) to produce an anhydrous solid form for this compound that shows predominance for solvate formation is detailed.

Development of a targeted polymorph screening approach for a complex polymorphic and highly solvating API.

Elucidation of the most stable form of an active pharmaceutical ingredient (API) is a critical step in the development process. Polymorph screening for an API with a complex polymorphic profile can present a significant challenge. The presented case illustrates an extensively polymorphic compound with an additional propensity for forming stable solvates. In all, 5 anhydrous forms and 66 solvated forms have been discovered. After early polymorph screening using common techniques yielded mostly solvates and failed to uncover several key anhydrous forms, it became necessary to devise new approaches based on an advanced understanding of crystal structure and conformational relationships between forms. With the aid of this analysis, two screening approaches were devised which targeted high-temperature desolvation as a means to increase conformational populations and enhance overall probability of anhydrous form production. Application of these targeted approaches, comprising over 100 experiments, produced only the known anhydrous forms, without appearance of any new forms. The development of these screens was a critical and alternative approach to circumvent solvation issues associated with more conventional screening methods. The results provided confidence that the current development form was the most stable polymorph, with a low likelihood for the existence of a more-stable anhydrous form.

Pyrazolinone-piperidine dipeptide growth hormone secretagogues (GHSs). Discovery of capromorelin.

Novel pyrazolinone-piperidine dipeptide derivatives were synthesized and evaluated as growth hormone secretagogues (GHSs). Two analogues, capromorelin (5, CP-424391-18, hGHS-R1a K(i)=7 nM, rat pituicyte EC(50)=3 nM) and the des-methyl analogue 5c (hGHS-R1a K(i)=17 nM, rat pituicyte EC(50)=3 nM), increased plasma GH levels in an anesthesized rat model, with ED(50) values less than 0.05 mg/kg iv. Capromorelin showed enhanced intestinal absorption in rodent models and exhibited superior pharmacokinetic properties, including high bioavailabilities in two animal species [F(rat)=65%, F(dog)=44%]. This short-duration GHS was orally active in canine models and was selected as a development candidate for the treatment of musculoskeletal frailty in elderly adults.