A drug-excipient interaction impurity of bromhexine hydrochloride injection: Structure and formation mechanism elucidation.

A long-term stability study using high performance liquid chromatography (HPLC) revealed an unidentified impurity in the bromhexine hydrochloride injection, which was employed as a mucolytic agent. Investigations into stress degradation and elemental impurities revealed one of the elemental impurities Fe3+ in this injection as the primary generator of these impurities. This impurity, named N-carboxymethyl bromhexine, was a product formed during drug-excipient interaction between bromhexine and tartaric acid with Fe3+. The structure of the impurity was identified through ultra-high-performance liquid chromatography with diode array detector (UHPLC-DAD), liquid chromatograph mass spectrometer (LC-MS). Further, the formation mechanism of the impurity was discussed. Overall, this study elucidates the cause, origin, and mechanism of an unknown impurity in bromhexine hydrochloride injection, providing a basis for quality control for bromhexine hydrochloride injections and drug products containing both amine and tartaric acid.

Monitoring of Essential and Toxic Elements in Multivitamin/Mineral Effervescent Tablet Supplements and Safety Assessment.

Multivitamin/mineral (MVM) supplements are the most commonly utilized dietary supplements by many populations. However, there is a severe concern about their adverse effects due to elemental impurities. In the present study, it was aimed to determine the levels of 11 elemental impurities (Cd, Pb, As, Hg, Co, V, Ni, Se, Mo, Cu, and Cr) by inductively coupled plasma-mass spectrometry (ICP-MS) and evaluate the human health risk associated with the consumption of 33 MVM effervescent tablet supplements available in Turkey. The precision of the method in terms of relative standard deviation (RSD) was less than 4.6%. The accuracy of the method was tested with recovery experiments, and the results ranged between 86 and 107%. The impurity levels for Cd, Pb, As, Co, V, Ni, Se, Mo, Cu, and Cr were found between 0.011-0.050, 0.025-0.098, 0.018-0.056, 0.010-0.626, 0.027-0.290, 0.026-1.65, 1.92-21.83, 0.034-34.09, 0.140-183.9, and 0.033-13.10 µg/g, respectively, and Hg was not detected in any sample. The calculated concentrations for elemental impurities complied with EMA and USP guidelines, except one supplement for Se (21.83 µg/g) with a permitted limit of 15 µg/g. The hazard quotient (HQ) and hazard index (HI) levels were below 1 for all samples within the ranges of 3.4 × 10-1-1.4 × 10-6 for HQ and 7.8 × 10-1-1.4 × 10-6 for HI indicating that there is no risk for consumption. The carcinogenic risk (CR) of As was between 1.7 × 10-6 and 5.9 × 10-6, below the threshold value of 1 × 10-4. The results showed that there is no risk to human health.

Comparison of Regulations for Arsenic and Heavy Metals in Herbal Medicines Using Pharmacopoeias of Nine Counties/Regions.

INTRODUCTION: Standardization is an import factor in ensuring the safety, efficacy, and quality of herbal medicines, and facilitates their international commerce. Heavy metal poisoning due to herbal medicines has been reported in many countries. Here, to better understand the current state of harmonization, we compared regulations for arsenic and heavy metals in herbal medicines across seven countries and two regions with two international standards. METHODS: We studied the monographs of herbal medicines of seven countries and two regions, as well as the WHO guidelines and ISO standards. We then compared the limits and test methods adopted for elemental impurities in herbal medicines listed in the monographs and standards among countries. RESULTS: The number of herbal medicines assessed amounted to over 2000. Limits and test methods adopted for elemental impurities in herbal medicines varied by country/region and organization. Although WHO recommends a uniform upper limit for lead and cadmium for all herbal medicines, some countries set unique upper limits for individual herbal medicines. ISO 18664:2015 lists only instrumental analysis methods, whereas Japan and India list only chemical methods. CONCLUSIONS: Many countries do not adhere to the WHO or ISO recommendations on elemental impurities in herbal medicines. These findings suggest the presence of differences in regulations for herbal medicines among countries/regions, likely rooted in cultural differences and policies aimed at maintaining the diversity of herbal medicines. Regulatory convergence by "loose harmonization" to internationally agreed standards appears a feasible option to maintain diversity and safety, and promote international trade in herbal medicines.

Analysis of non-carcinogenic health risk assessment of elemental impurities in vitamin C supplements.

Objectives: Elemental impurity exposure that may occur in the use of supplements has the potential to pose a risk to human health. Vitamin C supplements are among the most commonly used supplements on a daily basis and in the long-term due to the pharmacological properties of vitamin C. In this study, we aimed to evaluate the non-carcinogenic health risk of elemental impurities that may cause contamination in orally administered vitamin C supplements. Materials and Methods: Ten elemental impurities (Cd, Pb, As, Hg, Co, V, Ni, Cr, Sb, and Sn) in 12 supplements were analyzed using ICP-MS. The estimated daily intake (EDI), hazard quotient (HQ), and hazard index (HI) values of elemental impurities were calculated for non-carcinogenic risk assessment. Cancer risk (CR) was additionally calculated for elemental impurities with carcinogenic properties detected in the samples. Results: Low levels of Cr and Hg were detected in some samples. While the HQ values of sample 1, sample 2, sample 8, and sample 9 for Hg were calculated as 0.054, 0.096, 0.064, and 0.086, respectively, the HQ values of sample 5, sample 10, and sample 11 for Cr were calculated as 0.011, 0.017, and 0.014, respectively. Since only Hg or only Cr was detected in samples with elemental impurity, the HI values in the samples are the same as the HQ values. Since the HQ and HI values calculated from the samples are not≥1, there is no elemental impurity at a level that will hazard human health through supplement use. Other carcinogenic elements were not detected in the samples except Cr. In sample 5, sample 10, and sample 11, the CR values for Cr were 1.767.10-5, 2.571.10-5, and 2.089.10-5, respectively. In probability simulation, while HQ and CR values of Cr did not exceed the allowable value, the HQ level for Hg in the 95% slice was higher than the allowable value. Conclusion: There is no risk to human health and there is no critical difference between the supplements considering the elemental pollutant content among the vitamin C supplements of different trademarks. However, in order to keep the Hg level, which has a potential risk capacity, at low limits, it is recommended that the necessary risk-reducing measures be taken by the authorities and further studies be carried out.

Quantitative X-ray fluorescence analysis: Trace level detection of toxic elemental impurities in drug product by ED-XRF spectrometer.

Inorganic impurity analysis of pharmaceutical drug products is of paramount importance at trace levels due to the availability of toxic metals. The existing techniques require extensive development and chemical treatment to evaluate the presence of class I (Pb, Cd, Hg and As) and class II (Co, V and Ni) heavy metal elements which are harmful to the environment. To overcome these issues, a cost and time effective wavelength dispersive X-ray fluorescence spectrometry (XRF) was introduced to determine the concentration of trace elements in one of the angiotensin receptor blocker (ARB) (tablet sample 300 mg) according to guidelines addressed in ICH Q3D and USP. The validation study focused on class I and class II elements are also in accordance with regulatory guidelines. Overall it includes the comprehensive characterization of analytical method which is compliant with the requirement of USP. The novelty of this work includes the application of EDXRF in routine analysis of trace elements (especially volatile Hg) present in the pharmaceutical product beyond the previously published studies for the limited number of the non-pharmaceutical regime. Apart from this it also requires minimal sample preparation and method development and is able to quantify toxic impurities which are present in the sample in less than 20 ppm concentration, with the lowest level of detection up to 0.1 ppm.

Profiling extractable and leachable inorganic impurities in ophthalmic drug containers by ICP-MS.

In this study, we investigated the elemental impurities present in the plastic material of ophthalmic eye drop bottles using inductively coupled plasma-mass spectrometry (ICP-MS). Metallic contaminations, especially localized within the small cavity of the eye, can significantly perturb the ocular metallome. The concern is two-fold: first certain elements, for example heavy metals, can be toxic to humans at even trace levels, and second, these contaminations can have adverse reactions with other medicines or enzymatic processes in the eye. The implication of redox-active metals in cataract formation is one such biological consequence. The analysis demonstrated the effect of aggressive storage and transportation conditions on elemental extractable and leachable contamination, and posits that release of these elemental impurities can disrupt metallome equilibrium in the ocular compartment, leading to toxicity and disease.