An example of how to establish the thermodynamic stability relationship between two polymorphs of a compound highly prone to solvate formation.

Upon transition from research to development, a new chemical entity, which acts upon the Kv1.5-potassium channel and blocks potassium flow in the atrium of the human heart, has been subjected to a crystallization screen. The sodium salt of an anthranilic acid amide with a heteroarylsulfonyl side chain forms solvates from all tested organic solvents. Solvent-free crystalline phases can only be obtained by drying certain solvates under suitable conditions. Two well crystalline solvent-free phases can be obtained this way. Three different methods were applied to determine their thermodynamic stability relationship from melting, solution and eutectic melting data. The different approaches are discussed and compared with respect to their accuracy and limitations.

An example of how to handle amorphous fractions in API during early pharmaceutical development: SAR114137--a successful approach.

The so-called pharmaceutical solid chain, which encompasses drug substance micronisation to the final tablet production, at pilot plant scale is presented as a case study for a novel, highly potent, pharmaceutical compound: SAR114137. Various solid-state analytical methods, such as solid-state Nuclear Magnetic Resonance (ssNMR), Differential Scanning Calorimetry (DSC), Dynamic Water Vapour Sorption Gravimetry (DWVSG), hot-stage Raman spectroscopy and X-ray Powder Diffraction (XRPD) were applied and evaluated to characterise and quantify amorphous content during the course of the physical treatment of crystalline active pharmaceutical ingredient (API). DSC was successfully used to monitor the changes in amorphous content during micronisation of the API, as well as during stability studies. (19)F solid-state NMR was found to be the method of choice for the detection and quantification of low levels of amorphous API, even in the final drug product (DP), since compaction during tablet manufacture was identified as a further source for the formation of amorphous API. The application of different jet milling techniques was a critical factor with respect to amorphous content formation. In the present case, the change from spiral jet milling to loop jet milling led to a decrease in amorphous API content from 20-30 w/w% to nearly 0 w/w% respectively. The use of loop jet milling also improved the processability of the API. Stability investigations on both the milled API and the DP showed a marked tendency for recrystallisation of the amorphous API content on exposure to elevated levels of relative humidity. No significant impact of amorphous API on either the chemical stability or the dissolution rate of the API in drug formulation was observed. Therefore, the presence of amorphous content in the oral formulation was of no consequence for the clinical trial phases I and II.

From laboratory to pilot plant: the solid-state process development of a highly potent cathepsin S/K inhibitor.

The solid-state development for the low dose drug molecule SAR114137, a selective and reversible inhibitor of cysteine cathepsin S/K, is reported. Six polymorphic forms as well as various solvate phases were discovered by an extensive polymorphism screening. The solid phase characterizations revealed that phase 1, from which a single crystal structure could be obtained, is the thermodynamically most stable form and therefore it was chosen for pharmaceutical development. The successful scale-up from development laboratory into pilot plant for the crystallization and drying processes is presented. Testing of different drying techniques, like agitated drying in conical or filter dryers as well as spray drying, proved them to be very promising alternatives to the conventional tray drying process and might be used during the industrialization phase of the project. The use of online analytical tools (e.g., Raman spectroscopy) for a better process understanding and as tools for process optimization is shown. Furthermore, wet milling by ultrasound was performed on laboratory scale and discussed as potential option to reach the desired particle size distribution necessary for a good content uniformity of the API in an oral formulation.

Challenges in the development of hydrate phases as active pharmaceutical ingredients--an example.

The challenges during pilot plant scale-up of the SAR474832 API (active pharmaceutical ingredient) production in view of crystallization, isolation, drying and micronization are reported. A variety of different solid-state analytical and spectroscopic techniques (also coupled methods) were applied in order to understand the complex phase transition behaviour of the crystallographic phase (form 1) chosen for development: a partially non-stoichiometric channel-hydrate (x (1+1.25) H(2)O) crystallizing from pure water in the crystal habit of fine needles, which tend to agglomerate upon isolation and drying. Processes have been developed for drying, sieving and micronization by jetmilling to avoid non-desired phase transitions (overdrying effects) into other hydrate forms. Special methods have been established to minimize, monitor and control the formation of amorphous content during the particle size reduction steps. By optimizing all production parameters it was possible to produce API batches in 10 kg scale with physical quality suitable for oral formulations (e.g. particle size d 90 value<20 µm, water content and crystallographic phase corresponding to desired form 1 of SAR474832).

Indexing powder patterns in physical form screening: instrumentation and data quality.

Two multisample laboratory powder diffractometers have been evaluated for the purpose of pattern indexing in the context of physical form screening. Both diffractometers utilise foil transmission geometry, primary monochromated radiation, and a position-sensitive detector. Data collected from six compounds (sotalol hydrochloride, hydroflumethiazide, verapamil hydrochloride, captopril, clomipramine hydrochloride, and famotidine) showed good angular resolution (FWHM as small as ca. 0.06 degrees ) and lattice parameters were easily obtained using the indexing program DICVOL-91. The extent of preferred orientation in each pattern was estimated using the DASH implementation of the March-Dollase function and is most evident with clomipramine hydrochloride and famotidine. Otherwise, the data compare favorably with reference capillary data sets. In conclusion, where there is a requirement to analyze 20-30 samples per day, with an emphasis on obtaining the high-quality data that are important in pattern recognition and imperative in indexing, the combination of foil transmission geometry, primary monochromated radiation, plus a position-sensitive detector is highly effective. The data also afford opportunities for crystal structure determination.