(34f) Real-Time Monitoring of Drug Concentration in a Dropwise Additive Manufacturing System

In recent years, a changing business environment, regulatory encouragement, and novel contributions from academic/industrial researchers have spurred the pharmaceutical industry toward realization of improvements in manufacturing efficiency and product quality through implementation of on-line process analytical technologies, predictive process models and advanced production methods. Presently, innovative technologies have been developed for both drug substance and drug product manufacturing, with research focused on potential uses in continuous pharmaceutical processing, personalized medicine, and early stages of drug development. Of the new technologies which have found applications in drug product manufacturing, the use of liquid-based systems for production of solid oral doses is especially prominent; the common feature of these processes is that they rely on the precise dispensing of small volumes of liquid to produce doses, and, as such, exhibit considerable flexibility in dose strength and formulation.

For liquid dispensing technologies that produce drug products by sequential deposition of individual drops onto a specified substrate, real time process monitoring has been achieved by combining an on-line photography system with automated image analysis to record the volume of each dispensed drop [1, 2]. Given the volume dispensed in each drop, number of drops, and the fluid composition, drug amount in each dose may be accurately estimated for processes operated with homogeneous fluids comprised of active ingredient, and potentially a polymeric excipient, dissolved in a liquid. The use of drug solutions as the dosing liquid is well-suited to production of low-dose drugs (active compound <5 mg); however, for drug products which require higher dose amounts, solutions may be limited by the available capacity of a substrate to accept liquid, or by prolonged evaporation times to remove the solvent. As an alternative to solutions, delivery of active compound as a suspension of drug particles in a carrier liquid enables production of high dose drugs by dropwise dispensing, though this presents unique challenges due to the effects of non-linear flow behavior on drop formation and system operation.

With specific relevance to pharmaceutical manufacturing, the inherent heterogeneity of particulate suspensions raises questions regarding the uniformity in composition of liquid drops dispensed by such a process due to the potential for flow- or gravity-driven segregation of particles and liquid. In the suspension rheology literature, segregation effects are related to suspension properties (e.g. particle fraction, carrier viscosity), system properties (e.g. conduit diameter) and operating conditions (e.g. flow velocity), which have been explored in our previous works to identify feasible conditions for dropwise printing of non-Brownian suspensions [3]. At these operating conditions suspension-based dosing liquids were dispensed into empty capsules to create high dose drug products, which exhibited low relative standard deviation (<2.5%) in mass. However, the potential for inhomogeneity in suspensions introduces uncertainty in the amount of drug dispensed to each dose. Since on-line monitoring of drop volume is limited to estimation of deposited volume, an additional monitoring system is required to provide information on particle concentration in the printing fluid.

Process analytical technologies capable on-line monitoring of particle concentration in multi-phase mixtures include, but are not limited to, measurement techniques based on turbidity, conductivity or density. Limitations exist, however, on application of these methods to a range of processing conditions; use of turbidity measurement for optically opaque suspensions is not practical, and conductivity measurement is restricted to use in fluids which are electrically conductive. Ultrasonic-based technologies, which relate sound velocity to density and compressibility, provide a robust alternative that is capable of measuring phase volume in concentrated particle-liquid mixtures, though not without some challenges. In two-phase systems the relation between sound velocity and density is complicated by multiple scattering effects, which cause the ultrasound propagation velocity to depend on particle size and particle volume fraction [4, 5]. The calibration procedure for measurement of phase volumes depends on the system properties – when particle size distribution is fixed, correlation of ultrasound velocity with solid volume fraction has been successfully demonstrated [4, 5], but for processes (e.g. crystallizers) in which particle size distribution and particle volume fraction are expected to vary simultaneously, information obtained using an additional on-line measurement technique for particle size must be included in the model structure [6].

In this work the use of an in-line ultrasound probe is explored for monitoring of suspension density, and, by extension, particle concentration, in non-Brownian suspensions used with a dropwise additive manufacturing process for pharmaceutical solid oral dosage. For suspensions of particles with fixed size distribution, a modified form the Urick equation is used to fit experimental ultrasound velocity as a function of suspension density. Using these correlations, the in-line ultrasound probe can be used to monitor the concentration of drug particles in the suspension upstream of the printing nozzle. By conjoining real-time monitoring of particle concentration with on-line monitoring of drop volume, the drug amount in each dose can reliably be estimated. The accuracy of the on-line estimates compare very favorably to content analysis obtained using gravimetric measurements and chemical analysis performed using high performance liquid chromatography.

References

1. Hirshfield, L., Içten, E., Giridhar, A., Nagy, Z. K., & Reklaitis, G. V., 2015. Real-time process management strategy for dropwise additive manufacturing of pharmaceutical products. Journal of Pharmaceutical Innovation, 10(2), 140-155.
2. Clarke, A., Doughty, D., Khinast, J., & Rantanen, J., 2016. Development of liquid dispensing technology for the manufacture of low dose drug products. Continuous Manufacturing of Pharmaceuticals, 551-575.
3. Radcliffe, A. J., & Reklaitis, G. V., 2017. Dropwise Additive Manufacturing using Particulate Suspensions: Feasible Operating Space and Throughput Rates. In Computer Aided Chemical Engineering(Vol. 40, pp. 1207-1212). Elsevier.
4. Pinfield, V. J., Povey, M. J., & Dickinson, E., 1995. The application of modified forms of the Urick equation to the interpretation of ultrasound velocity in scattering systems. Ultrasonics, 33(3), 243-251.
5. Stolojanu, V., & Prakash, A., 2001. Characterization of slurry systems by ultrasonic techniques. Chemical Engineering Journal, 84(3), 215-222.
6. Pertig, D., Fardmostafavi, M., Stelzer, T., & Ulrich, J. 2015. Monitoring concept of single-frequency ultrasound and its application in dynamic crystallization processes. Advanced Powder Technology, 26(3), 874-881.