This blog focuses on how microscopy, hot-stage microscopy, and DSC microscopy can be used to develop co-processing strategies and relies heavily on input from Chemical Microscopy LLC, which is closely linked to Improved Pharma. Micro approaches are ideal when only limited amounts of material are available. Micro approaches also have the distinct advantage of allowing direct visual observation of how particles change under different temperatures. Several applications related to co-processing strategies are described below.
Microscopy is, of course, a widely used method for analyzing solids. It can easily be used to determine the morphology of solids, analyze amorphous forms, polymorphs, and hydrates, and directly determine particle size. Microscopy provides a visual analysis of solid materials and their behavior during co-processing. Its versatility is well-known, and it can determine whether materials are homogeneous or heterogeneous. The pioneering application of hot stage microscopy in pharmaceuticals goes back to the 1930s when Kuhnert-Brandstätter, who was in the Kofler lab, applied hot stage microscopy and the Kofler hot stage to pharmaceuticals.(Kumar et al., 2020)
Currently, large pharmaceutical companies such as Novartis, Merck, Pfizer, and Bristol Myers Squibb are significantly interested in co-processing APIs.(Erdemir et al., 2019; Schenck et al., 2020) Co-processing offers a simple way to rapidly develop products for clinical trials. Because of this advantage, many companies have ongoing co-processing studies. The concept is to process difficult-to-formulate APIs early and avoid complex sequencing involving first isolating and characterizing a drug substance and then, in a second step, processing the API into a drug product. Co-processing difficult-to-formulate pharmaceuticals can lead to an immediate composition that can be used in early trials. Amorphous materials are a clear example of co-processing, but other co-processing methods, such as milling and ball milling with other components and melt processing, are also good examples. Microscopy and hot-stage microscopy offer a strategy to develop co-processed materials from small amounts of API that are available in the early stage of development.
Co-processing is typically carried out by blending, milling, co-processing, or melting the API and a second component. Microscopy, especially when equipped with DSC (Differential Scanning Calorimetry), is a powerful method to investigate these systems. Kumar, in his review of microscopy, described the ability of microscopy to detect physical incompatibility.(Kumar et al., 2020) He noted that this method has been widely used for binary mixtures. He specifically highlighted a study involving solid aspirin and magnesium stearate. The melting points of the particles of both components can be observed visually because magnesium stearate has a very small particle size, and aspirin typically has much larger particles.(Harding et al., 2008) DSC hot-stage microscopy showed melting point depression. Heating this system to 90°C showed a liquid layer forming around the acetylsalicylic acid particles and the formation of a layer between the two components. This suggests that melt cooling could produce a co-processed composition with good flow due to the magnesium stearate molecules on the surface of the aspirin.
Roopwani and Buckner showed a very interesting application of microscopy to the co-processing of gabapentin with hydroxypropyl methylcellulose in a high shear mixer.(Roopwani & Buckner, 2019) Under these processing conditions, the finer hydroxypropyl cellulose particles were distributed on the surface of large gabapentin crystals, showing a visual appearance of specks on the crystal surface. In this case, they used a 10% weight/weight mixture. Gabapentin co-processed in this way showed decreased die wall friction and reduced tablet capping.
Although there are not many examples of the use of hot-stage microscopy combined with DSC to analyze polymers for melt extrusion, Repka’s review highlights a study by Chokshi that used DSC to determine the miscibility of a model drug, indomethacin, with PVP and several other polymers.(Chokshi et al., 2005) This study was able to verify that most of these polymers were miscible with indomethacin. The Repka review also pointed out that another study evaluated the stability of hypromellose acetate succinate (HPMCAS) for hot melt processing using DSC.(Thakkar et al., 2020) Unfortunately, none of these studies used microscopy, therefore not providing further information on the drug-polymer mixtures and their phase behavior.
Auch studied the predictability of pre-formulation screening for drug-polymer compositions and co-processed amorphous solid dispersions.(Auch et al., 2018) They found that standard methods were not as predictable as methods involving first casting films and then heating those films to remove solvent. Upon cooling, this system was more predictive of stability and behavior than the standard films prepared without this treatment. A hot stage, DSC microscopic study would follow the following procedure: first cast films, then utilize hot-stage DSC to heat the films to remove solvent, cool them, and then run a DSC to measure Tg and observe miscibility visually. Microscopy and polarized light microscopy (PLM) can also be used to observe crystalline and amorphous regions in the sample. If the drug and polymer are miscible, the mixture should appear homogeneous without distinct crystalline regions. Phase separation or crystallization of the drug would indicate immiscibility. Likewise, if the sample is miscible, there should be a single endotherm or Tg in its DSC. If the sample is phase-separated, multiple thermal events should be observed in the DSC. This approach constitutes a powerful DSC-Hot-stage microscopy method for analyzing co-processed systems, especially when limited amounts of API are available.
Forster and coworkers in the Radas lab carried out a study using small-scale fusion experiments with amorphous polymers mixed with five different drugs.(Forster et al., 2001) They used the polymer PVP for their studies, maintaining a 1:1 ratio of PVP to drug. They determined the glass transition temperature (Tg) using DSC and assessed physical stability with X-ray analysis. Chemical stability was determined using HPLC. Overall, the small-scale DSC experiments provided important information on the Tg of the system. The miscible components formed an amorphous solid solution, whereas the immiscible components resulted in crystalline particles in an amorphous background.
In conclusion, using microscopy, hot-stage microscopy, and DSC microscopy for screening co-processed systems, as described above, is a powerful approach for rapid optimization using small amounts of material. Improved Pharma and Chemical Microscopy LLC have the capability to carry out these experiments and can provide significant input into the development of co-processed systems for rapid introduction into the clinic.
Auch, C., Harms, M., & Mäder, K. (2018). Melt-based screening method with improved predictability regarding polymer selection for amorphous solid dispersions. European Journal of Pharmaceutical Sciences, 124, 339-348.
Chokshi, R. J., Sandhu, H. K., Iyer, R. M., Shah, N. H., Malick, A. W., & Zia, H. (2005). Characterization of physico-mechanical properties of indomethacin and polymers to assess their suitability for hot-melt extrusion processs as a means to manufacture solid dispersion/solution. Journal of Pharmaceutical Sciences, 94(11), 2463-2474.
Erdemir, D., Daftary, V., Lindrud, M., Buckley, D., Lane, G., Malsbury, A., Tao, J., Kopp, N., Hsieh, D. S., & Nikitczuk, W. (2019). Design and scale-up of a co-processing technology to improve powder properties of drug substances. Organic Process Research & Development, 23(12), 2685-2698.
Forster, A., Hempenstall, J., Tucker, I., & Rades, T. (2001). The potential of small-scale fusion experiments and the Gordon-Taylor equation to predict the suitability of drug/polymer blends for melt extrusion. Drug development and industrial pharmacy, 27(6), 549-560.
Harding, L., Qi, S., Hill, G., Reading, M., & Craig, D. (2008). The development of microthermal analysis and photothermal microspectroscopy as novel approaches to drug–excipient compatibility studies. International journal of pharmaceutics, 354(1-2), 149-157.
Kumar, A., Singh, P., & Nanda, A. (2020). Hot stage microscopy and its applications in pharmaceutical characterization. Applied Microscopy, 50(1), 12.
Roopwani, R., & Buckner, I. S. (2019). Co-processed particles: An approach to transform poor tableting properties. Journal of Pharmaceutical Sciences, 108(10), 3209-3217.
Schenck, L., Erdemir, D., Saunders Gorka, L., Merritt, J. M., Marziano, I., Ho, R., Lee, M., Bullard, J., Boukerche, M., & Ferguson, S. (2020). Recent advances in co-processed APIs and proposals for enabling commercialization of these transformative technologies. Molecular pharmaceutics, 17(7), 2232-2244.
Thakkar, R., Thakkar, R., Pillai, A., Ashour, E. A., & Repka, M. A. (2020). Systematic screening of pharmaceutical polymers for hot melt extrusion processing: A comprehensive review. International journal of pharmaceutics, 576, 118989.