Application and Methodology of the Non-destructive 19F Time-domain NMR Technique to Measure the Content in Fluorine-containing Drug Products

Summary

A simple and non-destructive technique that measures the average content of drug substances in formulated drug products containing fluorine using low-field fluorine-19 (¹⁹F) time-domain (TD) nuclear magnetic resonance (NMR) is presented here. The technique can be applied to the development and manufacturing of drugs in the pharmaceutical industry.

Abstract

Here, we describe a protocol developed by our group that uses low-field fluorine-19 (¹⁹F) time-domain (TD) nuclear magnetic resonance (NMR) to measure the average content of fluorinated drugs in their formulated drug product forms: tablets or capsules. This method is specific to fluorinated drugs because it detects only the content of fluorine, avoiding interference from the excipients that lack fluorine. The advantages of measuring the active content of fluorinated drugs using low-field ¹⁹F TD-NMR versus high-field ¹⁹F solid-state (SS) NMR are the simplicity of the method; the low cost; and the non-destructive nature of the technique, with all samples recoverable in intact forms (e.g., powders, tablets, and capsules), making this technique affordable for any laboratory.

We have tested the method with three fluorinated drug products available on the market - cinacalcet, lansoprazole, and ciprofloxacin - with doses ranging from 15 to 500 mg. The results of the analyses, measured by low-field ¹⁹F TD-NMR, supported the reported label claims for the average drug content.

Based on the simplicity and reproducibility of the analysis, we envision this methodology being implemented in any laboratory, including manufacturing plants, as a process analytical technology (PAT) tool in the pharmaceutical industry.

Introduction

In the pharmaceutical industry, the content of drug substances in their unit-of-dosage forms (e.g., tablets and capsules) must be within the range on the label claim to meet quality control and performance guidelines. High-performance liquid chromatography (HPLC) is the conventional analytical technique used to measure the content uniformity of drugs in their formulated forms. However, the method is lengthy and destructive, requiring the dissolution of the drug into its formulated form using the appropriate solvents prior to analysis. Even with automation, the process can take 1 - 3 h per sample, depending on the development of the appropriate analytical meth....

Protocol

Caution: Please consult all relevant material safety data sheets (MSDS) before using any chemicals. Drug substances in general are toxic and should be handled with the appropriate personal protective equipment (PPE; e.g., gloves, safety glasses, lab coat, full-length pants, and closed-toe shoes), with special caution when weighing powder materials. It is recommended to use a balance placed in a hood with good air flow to minimize the powder from solid materials disseminating out of the area surrounding the balance.

NOTE: The software instructions are specific for RINMR, RI Calibration, and Mnova. For other TD-NMR vendor instruments....

Results

We have tested low-field ¹⁹F TD-NMR with three commercial drug products (cinacalcet, lansoprazole, and ciprofloxacin) to measure the average drug content of the fluorinated drug products. Figure 1 shows the structures of the tested drugs, displaying the locations of the fluorine atoms.

We tested several lots and dosage forms (i.e., 30, 60, and 90 mg) of cinacalcet tablets, one do.......

Discussion

As more fluorinated drugs are becoming available in the market, we have developed a specific and simple methodology to measure the average drug content of fluorinated drug products using low-field ¹⁹F TD-NMR⁵. We tested this method on three commercial drug products: tablets containing cinacalcet HCl, capsules containing lansoprazole, and tablets containing ciprofloxacin HCl monohydrate. The advantages of this method are its specificity due to the lack of fluorine in the excipients and i.......

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
MQC-23	Oxford Instruments	52-AM4044	23.4 MHz for 1H and 22.0 MHz for 19F
26 mm Probe (19F)	Oxford Instruments	52-AM4061	19F NMR probe
Cinacalcet HCl	Amgen	Lot 005002 M	Purity 99.8%
Cinacalcet commercial tablets	Amgen	Lot 0010021308	30 mg tablets
Cinacalcet commercial tablets	Amgen	Lot D1026396	30 mg tablets
Cinacalcet commercial tablets	Amgen	Lot D118714	30 mg tablets
Cinacalcet commercial tablets	Amgen	Lot D061829	60 mg tablets
Cinacalcet commercial tablets	Amgen	Lot 00100213	90 mg tablets
Cinacalcet commercial tablets	Amgen	Lot D064074	90 mg tablets
Cinacalcet commercial tablets	Amgen	Lot 1026356	90 mg tablets
Lansoprazole	Fluka	Lot LRAA1897	Purity 99.7%
Brand name Lansoprazole	Novartis	Lot DV1891	15 mg capsules
Lansoprazole generic	SUPERVALUE INC	Lot 2GE2027	15 mg capsules
Ciprofloxacin free base	Fluka	Lot BCBM7969V	99.9% purity
Ciprofloxacin HCl monohydrate	Fluka	Lot P500044	94% purity as HCl salt
Cipro generic	Pack Pharmaceuticals	Lot PUB3033	500 mg tablets
25 mm NMR tube	New Era Enterprises	NE-25TD-200-FB
18 mm NMR tube	New Era Enterprises	NE-18TD-200-FB
10 mm NMR tube	New Era Enterprises	NE-10TD-200-FB
5 mm NMR tube	New Era Enterprises	NE-HL5-7
3 mm NMR tube	New Era Enterprises	NE-H3-7
2.5 mm NMR tube	New Era Enterprises	NE-H5/2.5