Knowledge of the potential degradation products of active pharmaceutical ingredients (APIs) is of major interest for the development and approval of new drugs. Therefore, methodologies for the time-efficient and precise prediction of degradation products and pathways are of great importance. Traditional degradation assessments typically involve solution-based forced degradations under acidic, basic, thermal, or photolytic conditions. However, such conditions often fail to accurately replicate degradation pathways relevant to solid-state formulations. A promising addition to the established solvent-based approaches are forced degradation processes in the solid-state using mechanochemistry. The newly developed methodologies enable a time-efficient and accurate simulation of degradation pathways under mild reaction conditions in the solid-state. Herein, the general principles of forced mechanochemical degradations will be discussed on the basis of published case studies involving marketed drugs.

To ensure the efficacy, safety, and quality of drugs, several national and international guidelines and regulatory requirements exist. The most important international regulatory framework for quality is the collection of the guidelines ICH Q1-Q14 (International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use), which form the basis for the development and approval of medicinal products. Additionally, international and national pharmacopoeias and national regulatory authorities like Food and Drug Administration (FDA) and European Directory for the Quality of Medicines and HealthCare (EDQM) have to be considered during the lifecycle of a drug. Further, regular updates and optimization of processes and methods together with periodic audits and inspections of the manufacturing plants help to ensure compliance with the complex regulatory requirements for medicinal products. Although the pharmaceutical world seems to be very well regulated and controlled, several drug recalls per year have to be announced and conducted to remove defect products from the market and protect the patient from any potential health risk. This review article provides an overview of the most common reasons for such recalls presenting several historical and current cases with a detailed discussion of root causes. A specific focus lies on quality issues like drug degradation, impurity and nitrosamine contamination, lack of drug stability, occurrence and transformation of polymorphs, contamination with particulates and foreign matters, amongst others. The role of APIs, excipients and packaging will be discussed as well as the analytical challenges to detect, control and mitigate such quality issues. A final chapter will discuss the current situation and an outlook on emerging topics and future challenges for drug quality.

For the approval of a drug, the stability data must be submitted to regulatory authorities. Such analyses are often time-consuming and cost-intensive. Forced degradation studies are mainly carried out under harsh conditions in the dissolved state, often leading to extraneous degradation profiles for a solid drug. Oxidative mechanochemical degradation offers the possibility of generating realistic degradation profiles. In this study, a sustainable mechanochemical procedure is presented for the degradation of five active pharmaceutical ingredients (APIs) from the sartan family: losartan potassium, irbesartan, valsartan, olmesartan medoxomil, and telmisartan. High-resolution mass spectrometry enabled the detection of impurities already present in untreated APIs and allowed the elucidation of degradation products. Significant degradation profiles could already be obtained after 15-60 min of ball milling time. Many of the identified degradation products are described in the literature and pharmacopoeias, emphasizing the significance of our results and the applicability of this approach to predict degradation profiles for drugs in the solid state.

A new strategy to identify, assess, and mitigate the nitrosamine formation in APIs during storage was developed and demonstrated on sitagliptin hydrochloride monohydrate, in which an increase in nitrosamine content was observed during stability studies. Comprehensive stress tests and stability assessments were carried out to evaluate the influence of various internal and external stimuli. Air exposure, secondary amine content, and optimum pH conditions emerged as the principal trigger factors. The results were consistent across all four distinct types of sitagliptin hydrochloride monohydrate tested, which were synthesized at different manufacturing sites and via diverse synthetic routes. A mitigation strategy was developed in which the secondary packaging material was modified to effectively prevent the ingress of air. This change yielded a clear reduction in nitrosamine formation, confirmed by 6-month stability studies at 40 °C.

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 Ticlopidin-neuraxpharm 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.

A method for forced oxidative mechanochemical degradation of active pharmaceutical ingredients (APIs) using clopidogrel hydrogensulfate as a model compound is presented. Considerable and selective formation of degradants occurs already after very short reaction times of less than 15 minutes and the nature of the products is strongly dependent on the used oxidant.

Pain is the most common reason for patients seeking medical care resulting in an estimated world market for analgesics of more than USD 50 billion. Pain is a highly complex, heterogeneous and dynamic process characterized by specific patterns of phenotypic sensory neuronal change. Current treatment options for pain include opioids and non-opioid analgesics, acetaminophen and non-steroidal anti-inflammatory drugs and other drug classes such as antidepressants and anticonvulsants and a combination thereof. Novel approaches are focusing on the optimization of side-effect profiles of opioid based analgesics, the improvement of selectivity for specific opioid receptors, or by addressing molecular gateways implicated in pain. Promising candidates in development target various types of voltage-gated ion channels and receptors for capsaicin and analogs. Currently, after decades of pain research it has to be stated that the assessment, prevention and treatment of pain in industrialized countries as well as in low-income and middle-income countries are neither adequate nor equitable. Further research is needed so that specifically chronic pain control can be improved and individualized.

La presente invention concerne un compose represente par la formule generale (I), eventuellement sous la forme d'un sel, d'un solvate, d'un polymorphe, d'un promedicament, d'un tautomere, d'un racemate, d'un comedicament, d'un cocristal, d'un enantiomere, d'un diastereoisomere ou d'un melange associe pharmaceutiquement acceptable, qui est utile pour traiter, soulager ou prevenir la grippe. En outre, l'invention concerne des polytherapies specifiques.