Evaluation of the Physicochemical Properties of the Iron Nanoparticle Drug Products: Brand and Generic Sodium Ferric Gluconate.

Complex iron nanoparticle-based drugs are one of the oldest and most frequently administered classes of nanomedicines. In the US, there are seven FDA-approved iron nanoparticle reference drug products, of which one also has an approved generic drug product (i.e., sodium ferric gluconate (SFG)). These products are indicated for the treatment of iron deficiency anemia and are administered intravenously. On the molecular level, iron nanomedicines are colloids composed of an iron oxide core with a carbohydrate coating. This formulation makes nanomedicines more complex than conventional small molecule drugs. As such, these products are often referred to as nonbiological complex drugs (e.g., by the nonbiological complex drugs (NBCD) working group) or complex drug products (e.g., by the FDA). Herein, we report a comprehensive study of the physiochemical properties of the iron nanoparticle product SFG. SFG is the single drug for which both an innovator (Ferrlecit) and generic product are available in the US, allowing for comparative studies to be performed. Measurements focused on the iron core of SFG included optical spectroscopy, inductively coupled plasma mass spectrometry (ICP-MS), X-ray powder diffraction (XRPD), 57Fe Mössbauer spectroscopy, and X-ray absorbance spectroscopy (XAS). The analysis revealed similar ferric-iron-oxide structures. Measurements focused on the carbohydrate shell comprised of the gluconate ligands included forced acid degradation, dynamic light scattering (DLS), analytical ultracentrifugation (AUC), and gel permeation chromatography (GPC). Such analysis revealed differences in composition for the innovator versus the generic SFG. These studies have the potential to contribute to future quality assessment of iron complex products and will inform on a pharmacokinetic study of two therapeutically equivalent iron gluconate products.

[Study on quality status of mineral medicine Calamina].

In this paper, some quality problems of mineral medicine Calamina and calcined Calamina have been discussed after determination and analysis of the quality parameters of a large number of market samples, and the countermeasures are put forward. According to the XRD results, as well as the results of tests included in Chinese Pharmacopoeia(2015 edition), the authenticity of Calamina and calcined Calamina samples were identified. The content of zinc oxide in samples were determined by the method of determination in Chinese Pharmacopoeia. Individually, inductively coupled plasma mass spectrometry(ICP-MS), inductively coupled plasma atomic emission spectrometry(ICP-AES) and atomic fluorescence spectrometry(AFS) methods were used for the determination of impurity elements and harmful elements in Calamina and calcined Calamina samples. Four kinds of impurity elements of magnesium(Mg), iron(Fe), aluminum(Al), calcium(Ca) and five harmful elements such as lead(Pb), cadmium(Cd), arsenic(As), copper(Cu), mercury(Hg) were measured. The study showed that: ① Fake Calamina products on the market were overflowing; ② The mineral origin of the mainstream Calamina in the market is inconsistent with that stipulated in Chinese Pharmacopoeia(2015 edition); ③ The contents of harmful elements Pb and Cd in Calamina and calcined Calamina are generally higher, while the contents of harmful elements As and Cu in some inferior Calaminae are higher; ④ Parts of calcined Calamina were improperly or inadequately processed. In view of these quality problems, the countermeasures are put forward as follows: ① It is suggested that hydrozincite should be approved as the mineral source of Calamina, and be included by Chinese Pharmacopoeia; ② Strengthen the research on the specificity of Calamina identification methods to improve the quality control level; ③ Strengthen the research on the processing of Calamina, and formulate the limit standards for the content of Pb and Cd in Calamina; ④ Carry out research on the artificial synthesis of Calamina and calcined Calamina, in order to cope with the current shortage of Calamina resources and ensure the sustainable development of Calamina medicinal materials.

Study on quality status of mineral medicine Calamina / 中国中药杂志

In this paper, some quality problems of mineral medicine Calamina and calcined Calamina have been discussed after determination and analysis of the quality parameters of a large number of market samples, and the countermeasures are put forward. According to the XRD results, as well as the results of tests included in Chinese Pharmacopoeia(2015 edition), the authenticity of Calamina and calcined Calamina samples were identified. The content of zinc oxide in samples were determined by the method of determination in Chinese Pharmacopoeia. Individually, inductively coupled plasma mass spectrometry(ICP-MS), inductively coupled plasma atomic emission spectrometry(ICP-AES) and atomic fluorescence spectrometry(AFS) methods were used for the determination of impurity elements and harmful elements in Calamina and calcined Calamina samples. Four kinds of impurity elements of magnesium(Mg), iron(Fe), aluminum(Al), calcium(Ca) and five harmful elements such as lead(Pb), cadmium(Cd), arsenic(As), copper(Cu), mercury(Hg) were measured. The study showed that: ① Fake Calamina products on the market were overflowing; ② The mineral origin of the mainstream Calamina in the market is inconsistent with that stipulated in Chinese Pharmacopoeia(2015 edition); ③ The contents of harmful elements Pb and Cd in Calamina and calcined Calamina are generally higher, while the contents of harmful elements As and Cu in some inferior Calaminae are higher; ④ Parts of calcined Calamina were improperly or inadequately processed. In view of these quality problems, the countermeasures are put forward as follows: ① It is suggested that hydrozincite should be approved as the mineral source of Calamina, and be included by Chinese Pharmacopoeia; ② Strengthen the research on the specificity of Calamina identification methods to improve the quality control level; ③ Strengthen the research on the processing of Calamina, and formulate the limit standards for the content of Pb and Cd in Calamina; ④ Carry out research on the artificial synthesis of Calamina and calcined Calamina, in order to cope with the current shortage of Calamina resources and ensure the sustainable development of Calamina medicinal materials.

Synthesis of diatom-FeOx composite for removing trace arsenic to meet drinking water standards.

This study presents the synthesis of diatom-FeOx composite as a novel sorbent for arsenic removal from water. The unique porous architecture of the diatom was utilized to immobilize iron oxide to form the composite. The surface area was as high as 70 m(2)/g. The adsorption isotherms for As (III) and As (V) followed the Langmuir, Freundlich and D-R models. Langmuir monolayer adsorption capacity for arsenite (As III) was 10,000 µg/g and arsenate (As V) was 12,500 µg/g. The pseudo-second order rate equation was found to effectively describe the kinetics of arsenic adsorption. This study opens the door for the development of bio derived materials for environmental remediation.

Pharmaceutical characterization and thermodynamic stability assessment of a colloidal iron drug product: iron sucrose.

The study objective was to evaluate the thermodynamic stability of iron sucrose complexes as determined by molecular weight (m.w.) changes. The first part of the study focused on the effect of thermal stress, pH, electrolyte or excipient dilution on the stability of a colloidal iron drug product. Part two focused on the physical and chemical evaluation of the colloidal nature of iron sucrose using a series of characterization experiments: ultracentrifugation, dialysis, particle size, zeta potential, and osmotic pressure analysis. A validated Taguchi-optimized high performance gel permeation chromatography method was used for m.w. determinations. Results indicate m.w. of the iron sucrose complex remained unchanged after excipient dilution, ultracentrifugation, dialysis, and electrolyte dilution. Electrolyte dilution studies indicated the lyophilic nature of the iron sucrose colloid with a particle size of 10nm and zeta potential of 0 mV. The complex deformed at low pH and reformed back at the formulation pH. The complex is stable under mild-to-moderate temperature <50°C but aggregates following prolonged exposure to high temperatures >70°C. In conclusion, the resistance of the complex to breakdown by electrolytic conditions, excipient dilution, ultracentrifugation and the reversible complexation after alteration of formulation pH suggest iron sucrose is a lyophilic colloid in nature and lyophilic colloidals are thermodynamically stable.

Chewability testing in the development of a chewable tablet for hyperphosphatemia.

The official Pharmacopeia does not include a test procedure for the in vitro estimation of the chewability of tablets and publications in the scientific literature on this subject are rare. The purpose of this study was to evaluate a number of different test procedures for assessing chewability, starting from standard breaking force and strength testing and progressing to develop new procedures that simulate the actual chewing action on tablets. A further goal was to apply these test procedures to characterize the chewability of the novel phosphate binder PA21 in comparison with a commercially available phosphate binder chewable tablet product based on lanthanum (Fosrenol®) and a chewable tablet product containing calcium (Calcimagon®) - the latter being used as a standard for its very good chewability. For this purpose, a number of development formulations (different batches of PA21) were tested. The radial or diametrical tablet breaking force offers a poor means of assessing chewability while the axial breaking force was concluded to better reflect the effect of chewing on the tablet. Measurement of tablet behavior upon repeated loading afforded the best simulation of the actual chewing action and was found to have a good discriminating power with respect to chewability of the tested tablets, especially when the tablet was moistened with artificial saliva. The developed tests are shown to be more suitable for evaluating chewing properties of tablets than currently used Pharmacopeial tests. Following ICHQ6, which calls for specification of hardness for chewable tablets, these test procedures enabled the optimal chewability features of PA21 tablets in development to be confirmed whilst still maintaining capabilities for robust production and transportation processes.

Thermodynamic stability assessment of a colloidal iron drug product: sodium ferric gluconate.

A high performance gel permeation chromatography (HP-GPC) method was developed, validated and used to determine the molecular weight (MW) of sodium ferric gluconate following various stress conditions. The intra-day accuracy (90-103%), intra-day precision (1.5-2.7%), inter-day accuracy (91-105%), inter-day precision (1.3-3.2%) were within acceptable range stated in FDA guidance. The MW of sodium ferric gluconate remained unchanged after: (1) autoclaving (121 degrees C), (2) moderate thermal stress (30 days at 50 degrees C or 7 days at 70 and 90 degrees C), (3) excipient dilution, (4) basic buffer dilution (pH of 8 and 9), (5) ultracentrifugation, (6) dialysis, and (7) electrolyte dilution. However sodium ferric gluconate showed signs of instability at higher temperatures (>90 degrees C) after 30 days and at pH of 10-11. Sodium ferric gluconate was found to be a lypophilic colloidal solution with an average particle size of 10 nm and a zeta potential of -13 mV. The colloid osmotic pressure was 3.5 mmHg and remained unchanged after moderate thermal stress. Additionally, in-house drug products with similar MW to sodium ferric gluconate were produced by three different synthetic procedures, suggesting that this colloidal iron drug product might be thermodynamically stable.

Negative gastrointestinal contrast enhancement and image distortion induced by superparamagnetic particles at 0.02 Tesla.

Gastrointestinal contrast enhancement and image distortion induced by superparamagnetic particles were evaluated in vitro and in rabbits at 0.02 Tesla. Test tubes containing 0.01-1.0 mg particles/ml were imaged in an oil or water bath in order to demonstrate the concentration-dependent signal void and image distortion in vitro at several pulse sequences. The lowest concentration of particles tested clearly decreased the signal intensity. Image distortion was observed when the concentration exceeded 0.07 mg/ml and was more pronounced on the T2-weighted images. The in vitro T2 relaxation time decreased from 122 ms to 56 ms with an increase in the particle concentration from 0.01 to 0.06 mg/ml. A loss of the GI-tract signal was observed in rabbits after the administration of 1 mg particles/kg, given as a 0.03 mg/ml suspension. At a dose of 20 mg/kg (0.6 mg/ml suspension) significant image distortion was observed.