Martin Feth

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).

New Technology for the Investigation of Water Vapor Sorption–Induced Crystallographic Form Transformations of Chemical Compounds: A Water Vapor Sorption Gravimetry–Dispersive Raman Spectroscopy Coupling

In this study, a new dynamic water vapor sorption gravimetry (DWVSG)-Raman spectroscopy coupled system is presented and described for the investigation of water (de)sorption-induced solid-phase transition of active pharmaceutical ingredients (APIs). The innovative characteristic of the system is the possibility to measure up to 23 samples gravimetrically and spectroscopically in one sorption/desorption experiment. The used dispersive RXN1 Raman system with a 6-mm laser spot P(h) AT probe head is ideal for this kind of coupled technology, as the energy density at the point of measurement of the sample is low, which grants that gravimetrical data and the state of the sample (phase transformations or even degradation) are not influenced by the laser beam. The capabilities of the system were tested by the investigation of a crystalline, nonstoichiometric hydrate form (form 1) and the corresponding X-ray amorphous form of an API (SAR474832). For the crystalline hydrate form, it was possible to correlate the weight loss at low humidities to a crystallographic phase transition (form 2). Furthermore, it was possible to show that the phase transition is reversible upon water uptake (sorption cycle); however, a further intermediate crystal form (form 3) is involved in the rehydration process. By multivariate curve resolution analysis of the Raman spectra, the form distribution diagrams of the desorption/sorption cycle could be constructed. For the amorphous material, the recrystallization process was monitored by the changes in the Raman spectra. The recrystallization point was detected at high humidities (>90% relative humidity), the crystal phase formed was identified (form 1), and the time needed for the conversion into the crystalline state was determined. The form transformation processes were visualized by contour plots (time/humidity vs. wavenumber vs. Raman intensity). In summary, it was concluded that the presented water sorption gravimetry-Raman spectroscopy coupling is a powerful tool to study solid-state transitions of pharmaceutical compounds or galenic formulations. The information obtained can, for example, be used to optimize drying, conditioning, or rerystallization processes of chemical products or to determine their optimal storage conditions. This is especially interesting for physically and chemically labile hydrate phases.

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.