Comparing failure tests on pharmaceutical tablets: Interpretation using experimental results and a numerical approach with cohesive zone models

The mechanical strength is an important quality attribute of pharmaceutical tablets. It can be determined using different failure tests like the Brazilian test or the three-point bending test. Nevertheless, literature shows that different failure tests often give conflicting values of tensile strengths (TS), which are generally calculated using the maximum stress criterion as a failure criterion. This work started from the hypothesis that these discrepancies are in fact due to the application of this criterion which is not suited to study pharmaceutical tablets, first due to heterogeneity of the stress distributions during the tests and second due to the quasi-brittle nature of pharmaceutical tablets. As an alternative, a numerical fracture criterion which is known to be well-suited for quasi-brittle solids (cohesive zone model, CZM) was used and calibrated using experiments. Using this approach, the breaking forces obtained numerically were shown to be in fair agreement with the experimental ones. Above all, the numerical results made it possible to catch the trends when comparing the different failure tests one to another. Especially, the model made it possible to retrieve the factor 2 between the TS obtained by three-point bending and by diametral compression found in the literature

MYH7 p.(Arg1712Gln) is pathogenic founder variant causing hypertrophic cardiomyopathy with overall relatively delayed onset

Introduction: The MYH7 c.5135G &gt; A p.(Arg1712Gln) variant has been identified in several patients worldwide and is classified as pathogenic in the ClinVar database. We aimed to delineate its associated phenotype and evaluate a potential founder effect.Methods: We retrospectively collected clinical and genetic data of 22 probands and 74 family members from an international cohort.Results: In total, 53 individuals carried the MYH7 p.(Arg1712Gln) variant, of whom 38 (72%) were diagnosed with hypertrophic cardiomyopathy (HCM). Mean age at HCM diagnosis was 48.8 years (standard deviation: 18.1; range: 8–74). The clinical presentation ranged from asymptomatic HCM to arrhythmias (atrial fibrillation and malignant ventricular arrhythmias). Aborted sudden cardiac death (SCD) leading to the diagnosis of HCM occurred in one proband at the age of 68 years, and a family history of SCD was reported by 39% (5/13) probands. Neither heart failure deaths nor heart transplants were reported. Women had a generally later-onset disease, with 14% of female carriers diagnosed with HCM at age 50 years compared with 54% of male carriers. In both sexes, the disease was fully penetrant by age 75 years. Haplotypes were reconstructed for 35 patients and showed a founder effect in a subset of patients.Conclusion: MYH7 p.(Arg1712Gln) is a pathogenic founder variant with a consistent HCM phenotype that may present with delayed penetrance. This suggested that clinical follow-up should be pursued after the seventh decade in healthy carriers and that longer intervals between screening may be justified in healthy women &lt; 30 years.</p

MYH7 p.(Arg1712Gln) is pathogenic founder variant causing hypertrophic cardiomyopathy with overall relatively delayed onset

Introduction: The MYH7 c.5135G &gt; A p.(Arg1712Gln) variant has been identified in several patients worldwide and is classified as pathogenic in the ClinVar database. We aimed to delineate its associated phenotype and evaluate a potential founder effect.Methods: We retrospectively collected clinical and genetic data of 22 probands and 74 family members from an international cohort.Results: In total, 53 individuals carried the MYH7 p.(Arg1712Gln) variant, of whom 38 (72%) were diagnosed with hypertrophic cardiomyopathy (HCM). Mean age at HCM diagnosis was 48.8 years (standard deviation: 18.1; range: 8–74). The clinical presentation ranged from asymptomatic HCM to arrhythmias (atrial fibrillation and malignant ventricular arrhythmias). Aborted sudden cardiac death (SCD) leading to the diagnosis of HCM occurred in one proband at the age of 68 years, and a family history of SCD was reported by 39% (5/13) probands. Neither heart failure deaths nor heart transplants were reported. Women had a generally later-onset disease, with 14% of female carriers diagnosed with HCM at age 50 years compared with 54% of male carriers. In both sexes, the disease was fully penetrant by age 75 years. Haplotypes were reconstructed for 35 patients and showed a founder effect in a subset of patients.Conclusion: MYH7 p.(Arg1712Gln) is a pathogenic founder variant with a consistent HCM phenotype that may present with delayed penetrance. This suggested that clinical follow-up should be pursued after the seventh decade in healthy carriers and that longer intervals between screening may be justified in healthy women &lt; 30 years.</p

MYH7 p.(Arg1712Gln) is pathogenic founder variant causing hypertrophic cardiomyopathy with overall relatively delayed onset

Introduction: The MYH7 c.5135G &gt; A p.(Arg1712Gln) variant has been identified in several patients worldwide and is classified as pathogenic in the ClinVar database. We aimed to delineate its associated phenotype and evaluate a potential founder effect.Methods: We retrospectively collected clinical and genetic data of 22 probands and 74 family members from an international cohort.Results: In total, 53 individuals carried the MYH7 p.(Arg1712Gln) variant, of whom 38 (72%) were diagnosed with hypertrophic cardiomyopathy (HCM). Mean age at HCM diagnosis was 48.8 years (standard deviation: 18.1; range: 8–74). The clinical presentation ranged from asymptomatic HCM to arrhythmias (atrial fibrillation and malignant ventricular arrhythmias). Aborted sudden cardiac death (SCD) leading to the diagnosis of HCM occurred in one proband at the age of 68 years, and a family history of SCD was reported by 39% (5/13) probands. Neither heart failure deaths nor heart transplants were reported. Women had a generally later-onset disease, with 14% of female carriers diagnosed with HCM at age 50 years compared with 54% of male carriers. In both sexes, the disease was fully penetrant by age 75 years. Haplotypes were reconstructed for 35 patients and showed a founder effect in a subset of patients.Conclusion: MYH7 p.(Arg1712Gln) is a pathogenic founder variant with a consistent HCM phenotype that may present with delayed penetrance. This suggested that clinical follow-up should be pursued after the seventh decade in healthy carriers and that longer intervals between screening may be justified in healthy women &lt; 30 years.</p

MYH7 p.(Arg1712Gln) is pathogenic founder variant causing hypertrophic cardiomyopathy with overall relatively delayed onset

Introduction: The MYH7 c.5135G &gt; A p.(Arg1712Gln) variant has been identified in several patients worldwide and is classified as pathogenic in the ClinVar database. We aimed to delineate its associated phenotype and evaluate a potential founder effect.Methods: We retrospectively collected clinical and genetic data of 22 probands and 74 family members from an international cohort.Results: In total, 53 individuals carried the MYH7 p.(Arg1712Gln) variant, of whom 38 (72%) were diagnosed with hypertrophic cardiomyopathy (HCM). Mean age at HCM diagnosis was 48.8 years (standard deviation: 18.1; range: 8–74). The clinical presentation ranged from asymptomatic HCM to arrhythmias (atrial fibrillation and malignant ventricular arrhythmias). Aborted sudden cardiac death (SCD) leading to the diagnosis of HCM occurred in one proband at the age of 68 years, and a family history of SCD was reported by 39% (5/13) probands. Neither heart failure deaths nor heart transplants were reported. Women had a generally later-onset disease, with 14% of female carriers diagnosed with HCM at age 50 years compared with 54% of male carriers. In both sexes, the disease was fully penetrant by age 75 years. Haplotypes were reconstructed for 35 patients and showed a founder effect in a subset of patients.Conclusion: MYH7 p.(Arg1712Gln) is a pathogenic founder variant with a consistent HCM phenotype that may present with delayed penetrance. This suggested that clinical follow-up should be pursued after the seventh decade in healthy carriers and that longer intervals between screening may be justified in healthy women &lt; 30 years.</p

ERRα promotes breast cancer cell dissemination to bone by increasing RANK expression in primary breast tumors

Bone is the most common metastatic site for breast cancer. Estrogen-related-receptor alpha (ERRα) has been implicated in cancer cell invasiveness. Here, we established that ERRα promotes spontaneous metastatic dissemination of breast cancer cells from primary mammary tumors to the skeleton. We carried out cohort studies, pharmacological inhibition, gain-of-function analyses in vivo and cellular and molecular studies in vitro to identify new biomarkers in breast cancer metastases. Meta-analysis of human primary breast tumors revealed that high ERRα expression levels were associated with bone but not lung metastases. ERRα expression was also detected in circulating tumor cells from metastatic breast cancer patients. ERRα overexpression in murine 4T1 breast cancer cells promoted spontaneous bone micro-metastases formation when tumor cells were inoculated orthotopically, whereas lung metastases occurred irrespective of ERRα expression level. In vivo, Rank was identified as a target for ERRα. That was confirmed in vitro in Rankl stimulated tumor cell invasion, in mTOR/pS6K phosphorylation, by transactivation assay, ChIP and bioinformatics analyses. Moreover, pharmacological inhibition of ERRα reduced primary tumor growth, bone micro-metastases formation and Rank expression in vitro and in vivo. Transcriptomic studies and meta-analysis confirmed a positive association between metastases and ERRα/RANK in breast cancer patients and also revealed a positive correlation between ERRα and BRCA1mut carriers. Taken together, our results reveal a novel ERRα/RANK axis by which ERRα in primary breast cancer promotes early dissemination of cancer cells to bone. These findings suggest that ERRα may be a useful therapeutic target to prevent bone metastases

Réévaluation du test de compression diamétrale comme test de rupture pour comprimé pharmaceutique : introduction de méplats et de défauts de taille contrôlée

Le comprimé est la forme pharmaceutique la plus répandue. Comme tout produit pharmaceutique, il doit remplir un certain nombre d'exigences. Parmi elles, la résistance mécanique représente un attribut qualité considéré comme critique. La pratique courante dans le domaine pharmaceutique, consiste à utiliser le test de compression diamétrale (test brésilien) pour calculer la résistance à la traction. Néanmoins, dans sa forme classique ce test présente un problème de singularité des contraintes aux contacts entre les plateaux et le comprimé. Ceci est dû aux faibles surfaces de contact entre ces derniers et peut remettre en cause la validité des résultats obtenus au cours du test. Pour pallier ce problème de contact, une géométrie contenant des méplats a été utilisée pour mesurer plus précisément la résistance à la traction des comprimés. Dans un premier temps, des simulations numériques (FEM) du test de compression diamétrale ont été réalisées pour les deux géométries. Ces dernières montrent clairement que, pour la géométrie contenant des méplats, la déformation maximale et la contrainte de traction maximale sont situées au centre du comprimé, ce qui n'est pas le cas pour la géométrie standard. Ces résultats ont été confortés expérimentalement grâce à l'utilisation d'une caméra rapide durant le test de compression diamétrale. Les acquisitions vidéo confirment que l'utilisation de comprimés parfaitement cylindriques ne permet pas d'assurer l'amorçage de la fissure au centre du comprimé, au contraire de la géométrie contenant des méplats. Par ailleurs, le comprimé pharmaceutique est formé à partir d'une compression de poudres. Le matériau final est donc un solide poreux qui contient intrinsèquement des défauts de structure. Il est bien connu que la présence de défauts conduit à un affaiblissement de la structure, en raison de concentrations de contraintes au niveau local. Comme il est parfois difficile de quantifier correctement les défauts dans une structure, la pratique courante est d'insérer des défauts d'une taille plus grande que celle des défauts intrinsèquement présents dans le matériau. Dans ce contexte, à la fois les formalismes de la MMC et de la MELR sont applicables, ce qui conduit aux concepts de facteurs de concentration de contraintes (SCF). Cependant, contrairement à ce qui aurait pu être attendu en ne considérant que le SCF, la force nécessaire pour rompre le comprimé dépend de la taille du trou, même lorsque le rapport entre le rayon du trou et le rayon du comprimé est suffisamment petit pour que la valeur du SCF soit constante. Cette dépendance est due à la variation de la distribution des contraintes autour du trou lorsque l'on fait varier sa taille. Il a donc été décidé de transposer à notre problème, des critères prenant en compte la capacité supposée du matériau à redistribuer les concentrations de contraintes locales. Les critères communément appelés « Point-stress » et « Average-stress », issus du domaine de la rupture des matériaux composites, ont ainsi pu être appliqués avec succès au cas de la rupture du comprimé pharmaceutique

Quantification of tablet sensitivity to a stress concentration: Generalization of Hiestand's approach and link with the microstructure

Sensitivity to a stress concentration is important for the development of pharmaceutical tablets as it is related to defects like capping. The Brittle Fracture Index (BFI) was introduced by Hiestand et al. to test this sensitivity. Recently, a more general index, based on the average stress criterion, was proposed as a generalized Hiestand approach. In this work, this new approach is tested on tablets obtained for several products and pressure levels, and results show the wide applicability of the new criterion. Furthermore, X-ray micro-computed tomography was used to link the tablet microstructure and the sensitivity to a stress concentration. A strong correlation was found between the size of the largest pores in the structure and the value of a(0) which quantify the sensitivity to a stress concentration in the generalized Hiestand approach. These results constitute the first attempt to link the brittle fracture propensity of tablets with their effective microstructure

Dynamic fracture analysis in Brazilian test: application to pharmaceutical tablets

In this paper, the flattened disk Brazilian test was used to evaluate the critical fracture parameter of a pharmaceutical tablet made of compressed anhydrous lactose powder. Following previous works, the energy release rate function was build thanks to experimental tests and numerical simulations. During the experimental tests, a high speed camera was used to capture the crack tip location during the dynamic propagation and Rapid Crack Propagation mechanisms were observed. A numerical analysis was thus used to evaluate the dynamic correction factor needed to take into account the inertia effects due to the crack tip velocity. The results were then compared to those obtained with the classical analytic relation related to a crack propagation in a semi-infinite plate. After giving a range of fracture energy for the material, the necessity to take into account inertia effects in the estimate of the fracture energy of the material was finally discussed in the case of the Brazilian test.Clivage en compression pharmaceutiqu

Breaking pharmaceutical tablets with a hole: Reevaluation of the stress concentration factor and influence of the hole size

Mechanical strength is an important property for pharmaceutical tablets. Its study using the theory of linear elastic fracture mechanics has been introduced in the pharmaceutical field through the Brittle Fracture Index (BFI). This index is based on the stress concentration factor (SCF) and contradictory results have been published in the pharmaceutical literature about the value of the SCF during the diametral compression of a disc with a hole. In this work, thanks to the use of numerical simulations (FEM) and analytical results, the value of the SCF was proved to be equal to 6. The result was also applicable for the case of the flattened disc geometry that was introduced in a previous work. The value of the SCF is found to be nearly independent of the hole size if the ratio between the hole and the tablet diameterswas lower than 0.1. Nevertheless, experimental results presentedin this paper show that the load needed to break a compact varieswith the hole size. This influence is due to the change in the stress distribution around the hole when the hole size is changing. Criteria such as the average stress criterion, which takes into account the stress distribution, made it possible to explain the influence of the hole on the breaking load