By Marc Taraban
Variable temperature time-domain benchtop NMR (VT-NMR) instrument with attainable temperature range from -70 °C to +80 °C allows to perform the measurements not only at a fixed temperature value but is also capable to scan the temperature in the above range with predetermined ramp synchronized with different NMR experiments.
Two non-biological complex drugs Diprivan® and its generic Propofol® formulated as oil-in-water emulsions are intravenous sedative agents used to induce anesthesia. Due to known restricted window of safety and serious side effects, it is of utmost importance to understand the factors affecting the stability and quality of these drugs. E.g., it is known that Diprivan® and Propofol® are freeze-sensitive, therefore the detection of their prior freeze history will allow to avoid using the damaged and dangerous drug products.
Using VT-NMR, we monitored the freezing process of drug product, noninvasively, in the original drug container, observing the changes in the ratio of FID/Spin Echo intensity vs. temperature. Freezing point is characterized by the abrupt drop in the FID/Spin Echo ration at ca. -14 °C.
We also developed new pulse sequence for the fast measurements of the longitudinal relaxation time/rate (T1/R1). The results are obtained much faster compared to the traditional approaches (~ 15–18 sec vs. 2–4 hrs for the same level of precision). We used this approach to analyze Diprivan® and Propofol® in their original containers (20 mL) at 25 °C. We also compared the results observed for intact drug products and those previously subjected to the freezing stress (18 hrs @ -30 °C). We found that freezing has no effect on water R1 which remains unchanged in both drug products before and after freezing stress. However, noticeable effect of freezing is observed for oil component with the oil R1 consistently decreasing in the stressed vials. Freezing potentially results in the coalescence of the emulsion droplets, and larger droplets will demonstrate slower R1. This assumption agrees with fundamental understanding of the size dependence of longitudinal relaxation rates.
Analysis of the longitudinal relaxation profiles also allows to obtain relative contributions of two main drug components—aqueous and oil components. The resulting relative percent fraction of oil in all vials was (9.5–9.7)% ± 0.2% which is in a good agreement with the published formulation data for both drugs, containing 100 mg/mL of soybean oil. We also explored this approach to analyze fat fraction in the dietary supplement MicrolipidTM and found that our result is in a good agreement with the manufacturer data (fat content ca. 50%).
Our observations show that longitudinal relaxation measurements could serve as noninvasive and quick control method for the formulation consistency and quality of complex emulsion drug products.
Session #9: Proteins, Peptides, Genes/Vaccines – With our Magnets Now You’re Seen