Track: Formulation and Delivery - Chemical - Formulation - Preformulation
Category: Poster Abstract
High Temperature Measurement of API Solubility in Spray Drying Solutions by NMR
Purpose: Heating spray solutions prior to atomization during the spray drying process enhances API solubility in the spray solvent and increases process throughput for compounds with low organic solubility. Tuning the spray solution temperature in the range of approximately 25 – 130°C1 allows optimization of critical parameters such as active loading and solution stability. The solubility of API in a solvent as a function of temperature is critical information for optimization of processing conditions for low solubility compounds.
An NMR method has been developed to generate API solubility curves from room temperature to superheated conditions under pressure. Additionally, the experiment directly measures degradation and therefore provides immediately insight into spray solution stability at elevated temperatures. This technique uses standard NMR pulse sequences, requires minimal operator time, and is material-sparing, using approximately 500 mg API. The approach solves challenges related to solution turbidity and opacity which confound visual or optical assessment of solubility. We propose that the high temperature NMR technique is a valuable tool for spray drying process development of APIs having low organic solubility. Methods: A high-pressure 10 mm glass NMR tube is filled with the desired solvent and polymer solution. API is added in excess of the expected solubility at the highest temperature to be tested. A small amount of internal standard such as imidazole or sodium trimethylsilylpropionate is also added to the suspension. 100 psig head pressure of nitrogen is introduced into the tube to maintain a low solvent vapor concentration in the headspace. Samples are heated to the temperature of interest using a standard variable temperature probe, equilibrated for 40 minutes, then measured by taking a spectrum. Only dissolved API is measured (solids do not contribute to the signal), and the internal standard allows for direct and absolute quantitation of dissolved API. Results: Work was performed to ensure mixing is sufficient to permit measurement of thermodynamic solubility at each temperature, since NMR tubes do not have internal agitators. One driver for mixing is convection due to temperature gradients in the tube. NMR diffusion experiments were used for estimation of linear convective velocity values in 5 and 10 mm NMR tubes, and it was found that the 10 mm tube allows for significantly greater convection velocity than the 5 mm tube (Table 1). Figure 1 shows that the convection velocity in a 10 mm tube effectively suspends particles of various sizes in fluids of different viscosities. The particle size of an API may be reduced through micronization if there is concern that it may not suspend and mix during the NMR experiment. Further, additional mixing energy can be generated by spinning the tubes in the magnet. The combination of spinning, convective mixing, and a 40 minute equilibration time at each temperature point enables measurement of accurate solubility values.
Figure 2 compares the solubility of Compound X found using the NMR method to data gathered using an orthogonal technique in which an API suspension of fixed composition is placed into a pressure vessel with a sight glass and heated with mixing. The temperature at which the API visually fully dissolves is recorded as the solubility temperature. The data shows that the NMR method produced results consistent with the orthogonal technique, indicating that the mixing kinetics in the NMR technique are acceptable. Conclusion: An NMR method was developed which accurately measures the solubility of APIs in spray drying solutions as a function of temperatures up to approximately 130°C. It was shown that convection velocity from temperature gradients in the tube provide adequate mixing for particles in suspension. Molar quantitation of API in solution is possible using an internal standard, and thermal degradation information is available from the spectra. The NMR experiment is setup to ramp stepwise through the desired temperature range, equilibrating and taking spectra at each temperature of interest to minimize both API use and operator input. The method can be performed on a hazy material, so solutions may contain polymer in order to ascertain any affect on solubility.
References: 1Friesen, et. al. 2016. High-temperature spray drying process and apparatus. US9248584B2.