MICROCRYSTALLINE CELLULOSE - N-nitrosamine Risk Assessments for Oral Dosage Forms

INTRODUCTION

The effects of N-nitroso compounds on human health (par­ticularly their role in gastric cancer) are well known.¹ Certain N-nitrosamines are described as highly probable human carcinogens. They are usually formed by the reaction of second­ary or tertiary amines with a source of a nitrosating agent, typi­cally derived from nitrite.^2,3

Oral excipients are considered a potential risk factor during drug product assessment.⁴ Being an excipient manufacturer, Asahi Kasei Corp. (Japan) is focused on mitigating the risk and providing information about the safe use of excipients.

In most cases, the nitrite contribution is dominated by the highest formula percent excipients. Thus, the fillers/diluents that are typically used in larger proportions should be considered as a potential risk factor.⁵

Microcrystalline Cellulose (MCC) is widely used in pharma­ceutical development and is one of the most common fillers /dilu­ents contributed to oral solid dosage form formulations, usually present in much higher concentration compared with other excipients.⁶ Thus, the high nitrite content in MCC can be a signifi­cant risk for nitrosamine formation and consequently patient health.

Boetzel R.et al presented the results of eight excipients in­cluding their origin and different batches along with the corre­spondent statistics for the nitrite level. The evaluation of these results also showed the differences between various suppliers and between batches. In this study, the nitrite content in MCC from nine suppliers showed a spread from 0.04 μg/g to 2.4 μg/g, with a mean of 0.70 μg/g.⁵

The aim of this investigation was to test the nitrite and nitrate content in the excipients produced by Asahi Kasei Corp. to pro­vide scientifically based data for N-nitrosamine risk assessment in oral formulations.

MATERIALS & METHODS

Materials
MCC grades as Ceolus^TM KG-1000, KG-802, UF-711, UF-702, PH-101, PH-102 (Asahi Kasei Corp., Japan)

Ion Chromatography Method (IC)

Developed by Asahi Kasei in collaboration with TOYO Inspec­tion Center (Japan).

Test Methodology: Suppressed Ion Chromatography

Column: Anion Exchange Chromatography Column (4.6mm I.D×15cm)

Mobile Phase: Sodium Carbonate/Sodium Hydrogen Carbon­ate eluent solution

Flow Rate: 1.0 mL/min

Oven Temperature: 40°C

Sample Injection Volume: 30 μL-100 μL

Detector: UV-VIS detector (Wavelength 210 nm), the LOD (Limit of Detection) is 0.008 μg/g

RESULTS

The nitrite and nitrate content of Ceolus^TM KG-1000, KG-802, UF-711, UF-702, and PH-101 and PH-102 was determined by ion chromatography method and systemized (Table 1).

In accordance with the used quantification method, the LOD of nitrites comprised 0.008μg/g. In the majority of tested batches of MCC grades Ceolus^TM PH-101 and PH-102, the nitrite content was lower than LOD (0.008 μg/g). In all tested batches of grades Ceolus^TM KG-802, KG-1000, UF-702, and UF-711, the nitrite level has not been detected. At the same time, the nitrate level was very low and didn’t exceed 0.112 μg/g.

Being an MCC/Ceolus^TM manufacturer, Asahi Kasei Corp. can explain the achieved results by process features. To minimize the appearance of undesirable impurities, secondary and tertiary amines, as well as quaternary ammonium salts or amide solvents are not used in the manufacturing process of products. Further­more, sodium nitrite esters or nitrite, reagents, or catalysts are not used.

CONCLUSION

Ceolus^TM demonstrated a very low level of nitrite and nitrate (lower than 0.012 and 0.112 μg/g, respectively) that can allow mitigating nitrosamine formation in the drug products with sec­ondary or tertiary amines.

Obtained results justified with Asahi Kasei Corp.’s manufac­turing process features allow or the evidence-based choice of MCC-grades with low nitrite content for the formulation of oral dosage form formulations with low nitrosamine-associated risk.

REFERENCES

1. Bruning-Fann CS, Kaneene JB The effects of nitrate, nitrite and N-nitroso compounds on human health: a re­view. Veterinary and Human Toxicology, 01 Dec 1993, 35(6):521-538.
2. Ashworth Ian W, D O, Teasdale Andrew, Whiting Matthew. Potential for the formation of N-nitrosamines during the manufacture of active pharmaceutical ingredients: an assessment of the risk posed by trace nitrite in water. Org. Process Res. Dev. 2020;24(9):1629-1646.
3. FDA. Control of Nitrosamine Impurities in Human Drugs. 2021. Available from: https://www.fda.gov/ media/141720/download.
4. IPEC. The Role of Excipients in Determining N-Nitrosamine Risks for Drug Products. March 2022.
5. Boetzel R., Schlingemann J., Hickert, S., Korn Ch. et al. A Nitrite Excipient Database: A useful Tool to Support N-Nitrosamine Risk Assessments for Drug Products. J Pharm Sci.2022.
6. Sheskey Paul J, H BC, Moss Gary P, Goldfarb David J. Handbook of Pharmaceutical Excipients. Pharmaceutical Press; 2020.

Takako Koyamatsu is a Quality Assurance Manager of Microcrystalline Cellulose, Ceolus™. She has nearly 25 years of experience in quality assurance.

Dr. Shohei Mikami joined Asahi Kasei Corporation in 2021, and belongs to the Quality Assurance Division for the excipient business. He has a Doctor of Pharmacology degree.

Kenji Obata is a Marketing Manager of pharmaceutical excipients. He has nearly 15 years of experience in marketing excipients in Europe, India, and Asia.

Julia Shmyrova has more than 20 years of experience in the pharmaceutical industry. She joined Asahi Kasei Europe in 2019 as a Technical Marketing Manager with responsibility for the European region.