An example of how to handle amorphous fractions in API during early pharmaceutical development: SAR114137 – A successful approach

Petzoldt, Christine; Bley, O.; Byard, Stephen J.; Andert, Doris; Baumgärtner, B.; Nagel, Norbert; Tappertzhofen, Christoph; Feth, Martin P.

doi:10.1016/j.ejpb.2013.09.015

Cited by 12 publications

(11 citation statements)

References 41 publications

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“…Approximately 80−110 mg of powder samples were packed into 4.0 mm ZrO 2 rotors. Spectra were acquired at 293 K and a MAS frequency of 12 kHz, with 16 to 512 numbers of scans for 19 F ssNMR and 1024 for 13 C ssNMR. The 13 C and 19 F chemical shift were referenced externally to the α-Gly 13 C′ resonance at 176.49 ppm on the TMS scale and isotropic 19 F signal at −122 ppm for the Teflon standard, respectively.…”

Section: Methodsmentioning

confidence: 99%

“…A 100 kHz TPPM 1 H decoupling was applied during acquisition of all experiments. 13 C cross-polarization (CP) MAS experiments were conducted with 1 ms contact time and 25 ms acquisition time. 19 F-detected direct polarization MAS ( 19 F DP) experiment was conducted with a relatively long recycle delay (D 1 ) of 60 s optimized to allow for relaxation of the crystalline fractions.…”

Section: Methodsmentioning

confidence: 99%

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Understanding Compression-Induced Amorphization of Crystalline Posaconazole

et al. 2018

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Process-induced phase transformations (PIPTs) of active pharmaceutical ingredients (APIs) can alter APIs’ physicochemical properties and impact performance of pharmaceutical drug products. In this study, we investigated compression-induced amorphization of crystalline posaconazole (POSA), where the impact of mechanical stresses and excipients on amorphization were explored. 19F solid-state NMR (ssNMR) was utilized to detect and quantify amorphous content in the compressed tablets, and finite element analysis (FEA) was conducted to understand stress distributions in the compression process. Both applied macroscopic axial stress and shear stress were found to be important to amorphization of crystalline POSA. Punch velocity, an important compression process parameter, had negligible effect on amorphization up to 100 mm/s. Two diluents, microcrystalline cellulose (MCC) and dibasic calcium phosphate anhydrous (DCPA), and one lubricant, magnesium stearate (MgSt), were evaluated for their impact on amorphization in this study. It was found that both MCC and DCPA significantly enhanced amorphization of POSA at a low drug loading (5% w/w). The 1% (w/w) blended lubricant effectively reduced the amorphous content in MCC-POSA tablets; however, it had minimal effect on either neat POSA or DCPA-POSA tablets. Drug loading, or excipient concentration, was demonstrated to have a significant impact on the extent of amorphization. These observed excipient effects support the important role of interparticulate stresses in amorphization of crystalline POSA.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Understanding Compression-Induced Amorphization of Crystalline Posaconazole

et al. 2018

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“…Cathepsin S is currently being studied for its involvement in a number of diseases and inflammatory conditions from cancer to rheumatoid arthritis to chronic pain (Fonovic and Turk 2014). There are numerous cathepsin S inhibitors available and some are already approved for human therapeutic applications (Payne et al 2014; Petzoldt et al 2014). Similarly, cathepsin K inhibitors are in various stages of clinical trials (Brömme and Lecaille 2009; Helali et al 2013).…”

Section: Particle-induced Lysosomal Membrane Permeability (Lmp)mentioning

confidence: 99%

Engineered nanomaterial-induced lysosomal membrane permeabilization and anti-cathepsin agents

Bunderson-Schelvan

Holian

Hamilton

2017

Journal of Toxicology and Environmental Health, Part B

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Engineered nanomaterials (ENMs), or small anthropogenic particles approximately < 100 nm in size and of various shapes and compositions, are increasingly incorporated into commercial products and used for industrial and medical purposes. There is an exposure risk to both the population at large and individuals in the workplace with inhalation exposures to ENMs being a primary concern. Further, there is increasing evidence to suggest that certain ENMs may represent a significant health risk, and many of these ENMs exhibit distinct similarities with other particles and fibers that are known to induce adverse health effects, such as asbestos, silica, and particulate matter (PM). Evidence regarding the importance of lysosomal membrane permeabilization (LMP) and release of cathepsins in ENM toxicity has been accumulating. The aim of this review was to describe our current understanding of the mechanisms leading to ENM-associated pathologies, including LMP and the role of cathepsins with a focus on inflammation. In addition, anti-cathepsin agents, some of which have been tested in clinical trials and may prove useful for ameliorating the harmful effects of ENM exposure are examined.

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“…The authors stated that the reliability of this method for the characterization of amorphous forms of fluorinated APIs in drug products with concentrations down to 1%–5%. Recently, 19 F MAS NMR proved to be the best quantitative method for the determination of the amorphicity of an investigational drug, SAR114137, induced by different unit operations (e.g., milling, tableting) during the development of tablets . Among the different analytical tools, SS‐NMR was able to precisely quantify the amorphous content in the tablet generated by compression, even at a drug content as low as 0.5% (w/w).…”

Section: Crystallinity/crystallization Studies In Asd By Ss‐nmr Spectmentioning

confidence: 99%

Structural and Dynamic Properties of Amorphous Solid Dispersions: The Role of Solid-State Nuclear Magnetic Resonance Spectroscopy and Relaxometry

Paudel

Geppi

Mooter

2014

Journal of Pharmaceutical Sciences

114

103

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An example of how to handle amorphous fractions in API during early pharmaceutical development: SAR114137 – A successful approach

Cited by 12 publications

References 41 publications

Understanding Compression-Induced Amorphization of Crystalline Posaconazole

Understanding Compression-Induced Amorphization of Crystalline Posaconazole

Engineered nanomaterial-induced lysosomal membrane permeabilization and anti-cathepsin agents

Structural and Dynamic Properties of Amorphous Solid Dispersions: The Role of Solid-State Nuclear Magnetic Resonance Spectroscopy and Relaxometry

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