Ball milling – a new concept for predicting degradation profiles in active pharmaceutical ingredients

Kaiser, Rudolf; Krake, Everaldo F.; Backer, Laura; Urlaub, Jonas; Baumann, Wolfgang; Handler, Norbert; Buschmann, Helmut; Beweries, Torsten; Holzgrabe, Ulrike; Bolm, Carsten

doi:10.1039/d1cc04716g

Cited by 13 publications

(15 citation statements)

References 33 publications

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“…This approach resulted in CLP conversions of 30–50%. In line with previous data, longer reaction times resulted in higher degrees of degradation of CLP , producing less defined degradation profiles. Similarly, milling frequencies of less than 25 Hz gave no conversion of the API.…”

Section: Resultssupporting

confidence: 91%

“…In general, all thienopyridines discussed in this study show similar degradation profiles. As discussed before, 11,14 hydroxylation of the N-heterocycle is common for forced oxidative degradation of CLP and TIC. Formation of endo-iminium species occurs for all APIs, as the carbon atom bridging the thiophene and the nitrogen atom is highly susceptible to oxidation.…”

Section: Stability Ofmentioning

confidence: 88%

“…Our previous work used Clopidogel hydrogen sulfate ( CLP ), a compound present in antiplatelet drugs, as a thienopyridine containing model compound. Different degradation products could be selectively obtained by ball-milling in short reaction times of less than 15 min.…”

Section: Introductionmentioning

confidence: 99%

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Mechanochemical Oxidative Degradation of Thienopyridine Containing Drugs: Toward a Simple Tool for the Prediction of Drug Stability

et al. 2023

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The long-term stability of an active-pharmaceutical ingredient and its drug products plays an important role in the licensing process of new pharmaceuticals and for the application of the drug at the patient. It is, however, difficult to predict degradation profiles at early stages of the development of new drugs, making the entire process very time-consuming and costly. Forced mechanochemical degradation under controlled conditions can be used to realistically model long-term degradation processes naturally occurring in drug products, avoiding the use of solvents, thus excluding irrelevant solution-based degradation pathways. We present the forced mechanochemical oxidative degradation of three platelet inhibitor drug products, where the drug products contain thienopyridine. Model studies using clopidogrel hydrogen sulfate (CLP) and its drug formulation Plavix show that the controlled addition of excipients does not affect the nature of the main degradants. Experiments using drug products Ticlopidinneuraxpharm and Efient show that significant degradation occurs after short reaction times of only 15 min. These results highlight the potential of mechanochemistry for the study of degradation processes of small molecules relevant to the prediction of degradation profiles during the development of new drugs. Furthermore, these data provide exciting insights into the role of mechanochemistry for chemical synthesis in general.

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Section: Resultssupporting

confidence: 91%

Section: Stability Ofmentioning

confidence: 88%

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Mechanochemical Oxidative Degradation of Thienopyridine Containing Drugs: Toward a Simple Tool for the Prediction of Drug Stability

et al. 2023

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“…Besides these approaches, solid-state mechanochemical catalysis has recently been reported as a rapid method for assessing the drug degradation in the solid state via dry milling the drug powder with hydrolytic and oxidative catalysts as stressing agents . Mechanochemistry is widely used as a solvent-free (green technology) avenue for solid-state synthesis, including that of pharmaceuticals. − The milling process transforms a solid reactant to the desired product due to the reduced activation energy of the reaction .…”

Section: Introductionmentioning

confidence: 99%

Mechanoactivation as a Tool to Assess the Autoxidation Propensity of Amorphous Drugs

et al. 2023

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Mechanoactivation has attracted considerable attention in the pharmaceutical sciences due to its ability to generate amorphous materials and solid-state synthetic products without the use of solvent. Although some studies have reported drug degradation during milling, no studies have systematically investigated the use of mechanoactivation in predicting drug degradation in the solid state. Thus, this work explores the autoxidation of drugs in the solid state by comilling amorphous mifepristone (MFP):polyvinylpyrrolidone vinyl acetate (PVPVA) and amorphous olanzapine (OLA):PVPVA. MFP was amorphized by ball milling and OLA by quench cooling techniques. Subsequently, comilling the amorphous drugs in the presence of a 10-fold weight ratio of PVPVA (the excipient containing reactive free radicals) was performed at several milling frequencies to identify the kinetics of mechano-autoxidation over milling durations. Overall, milling led to the degradation of up to 5% drug in the solid state. The autoxidation mechanism was confirmed by performing a stress study in the solution at 50 °C for 5 h, by using a 10 mM azo-bis(isobutyronitrile) (AIBN) as a stressing agent. By deconvoluting the effect of milling frequency and the energy on the extent and kinetics of milling-induced autoxidation of amorphous drugs, it was possible to fit an extended Arrhenius model that allowed extrapolation of mechanoactivated degradation rates (K m) to zero milling frequencies. Further, the autoxidation rates of drugs stored at high temperatures were observed to follow an Arrhenius behavior. A good degree of agreement was observed between the model predictions obtained by mechanoactivation (K m) to the reaction rates observed under accelerated temperatures. Additionally, the impact of adding an antioxidant (e.g., butylated hydroxytoluene) to the mixture during comilling was also examined. This study can be helpful in evaluating the stability of amorphous solids stored in accelerated (non-hermetic) conditions, in screening solid-state autoxidation propensity of drugs, and for the rational selection of antioxidants.

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“…[26] A related study focused on the oxidative degradation of clopidogrel hydrogensulfate, and there, ATR IR spectroscopy was used to directly analyze the crude reaction mixtures. [27] In all of the aforementioned examples, the mechanochemical processes intended to reach high conversions. However, IR spectroscopy can also be applied for analyzing mechanochemical surface modifications of solids.…”

Section: Introductionmentioning

confidence: 99%

Opportunities and Challenges in Applying Solid-State NMR Spectroscopy in Organic Mechanochemistry

Silva

Bartalucci

Bolm

et al. 2023

Preprint

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In recent years it was shown that mechanochemical strategies can be beneficial in directed conversions of organic compounds. Finding new reactions proved difficult, and due to the lack of mechanistic understanding of mechanochemical reaction events, respective efforts have mostly remained empirical. Spectroscopic techniques are crucial in shedding light on these questions. In this overview, we discuss the opportunities and challenges of solid-state nuclear magnetic resonance (NMR) spectroscopy in the field of organic mechanochemistry. After a brief discussion of the basics of high-resolution solid-state NMR under magic-angle spinning (MAS) conditions, we present seven opportunities for solid-state NMR in the field of organic mechanochemistry, ranging from ex-situ approaches to structurally elucidate reaction products obtained by milling to the potential and limitations of in-situ solid-state NMR approaches. Particular strengths of solid-state NMR, for instance in differentiating polymorphs, in NMR-crystallographic structure-determination protocols, or in detecting weak noncovalent interactions in molecular-recognition events employing proton-detected solid-state NMR experiments at fast MAS frequencies, are discussed.

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Ball milling – a new concept for predicting degradation profiles in active pharmaceutical ingredients

Abstract: Forced oxidative mechanochemical degradation of clopidogrel hydrogensulfate as a model compound leads to selective formation of degradants in less than 15 minutes.

Cited by 13 publications

References 33 publications

Mechanochemical Oxidative Degradation of Thienopyridine Containing Drugs: Toward a Simple Tool for the Prediction of Drug Stability

Mechanochemical Oxidative Degradation of Thienopyridine Containing Drugs: Toward a Simple Tool for the Prediction of Drug Stability

Mechanoactivation as a Tool to Assess the Autoxidation Propensity of Amorphous Drugs

Opportunities and Challenges in Applying Solid-State NMR Spectroscopy in Organic Mechanochemistry

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