Co-processed pharmaceutical solids are rising to the forefront as an important concept in pharmaceutical development. This general introduction is the first in a planned series of blogs delving into this exciting area.
Schenck and coworkers reviewed co-processed API, suggesting co-processing would lead to sustainability improvements and emissions reductions. (Schenck et al., 2023) He indicated that co-processing API would accelerate development by reducing the classical linear development of drug substance and then drug product by blurring the difference between drug substance and drug product. He defined co-processed API as materials produced by adding non-covalently bound, non-active components to the API during drug substance manufacturing. Schenck and coworkers described a number of applications of coprocessing including (1) particle engineering to reduce emissions and improve sustainability; (2) lower energy processing such as dry powder coating to improve flow; (3) targeted coating to overcome compressibility problems; (4) composite particles to mitigate content uniformity issues; (5) loading onto carriers to reduce content uniformity issues; and (6) stability improvement to avoid expensive packaging such as antioxidant packaging instead of co-processing with antioxidants or atomic layer deposition or coating.
Crystallization methods with a second component and co-precipitation, including amorphous drug-polymer mixture systems, fall into the category of co-processed materials. Improved Pharma described numerous studies on amorphous co-processed forms and strategies for analyzing amorphous materials. SSCI, Inc. introduced an amorphous screen in the 1990s, and Improved Pharma also offers this type of screen, as well as expanded options. Solvent-based amorphous co-processing screens, high-throughput co-precipitation screens, melt-based co-processing screens, and milling-based co-processing screens are some examples.
Spherical crystallization is another related co-processing method. Dhondale and coworkers reviewed spherical crystallization and co-precipitation techniques to alleviate problems with robustness and costs in drug product manufacture. (Dhondale et al., 2023) They indicated that solvent-mediated techniques streamline operations and result in robust, low-cost solutions to problems. They suggested these methods could circumvent the granulation step and reduce variability. They also discussed how to select the correct co-processing method. Co-process development with downstream processing in mind could avoid numerous problems. They described the co-processing of vermurafenib into the drug product Zelboraf as an example of co-processing. (Shah et al., 2013) In this case, the highly-insoluble API is co-processed with the cellulosic polymer HPMCAS in a 3:7 ratio in a solvent-mediated process to achieve a 4-5 fold increase in solublity. Co-precipitation, another co-processing method, involves rapid precipitation of the API in the presence of excipients. It is a simple alternative to spray drying. The preparation of Zelboraf can be classified as co-precipitation. Dhondale also described spherical agglomeration. These methods are unique and powerful techniques for developing solubilized products.
Although not specifically described by Schenck as co-processed systems, HME-prepared solids fit well into the category of co-processed systems. Sarabu and coworkers described hot-melt extrusion (HME) as an advanced technology to advance drug delivery. (Sarabu et al., 2019) HME is a solvent-free green technology for formulation with low investment costs. HME can also be operated continuously further reducing costs and improving quality. HME can also improve the solubility of poorly soluble drugs with methods such as twin-screw wet and dry granulation, co-extrusion, and solid SEDDS systems. Sarabu also described some interesting salt preparations by HME to improve solubility, including a haloperidol maleic acid salt. Narala and coworkers reviewed pharmaceutical co-amorphous systems and other multi-pharmaceutical systems with respect to hot melt extrusion. (Narala et al., 2021). They suggested that hot melt extrusion was a viable alternative to solvent-based studies. In their review, they briefly mentioned microscopy as an alternative.
In the 1980s, the co-processing of a statin with BHT was used to provide stability to the API (private observation). Iyer showed that co-processing oxidation-sensitive drugs with antioxidants is a powerful way to reduce oxidation. BHT is known as an antioxidant for the inhibition of the autoxidation of solid-state pharmaceuticals. Comilling of amorphous olanzapine with BHT reduced oxidation significantly.(Iyer et al., 2023)
Dhondale, M. R., Nambiar, A. G., Singh, M., Mali, A. R., Agrawal, A. K., Shastri, N. R., Kumar, P., & Kumar, D. (2023). Current trends in API co-processing: spherical crystallization and co-precipitation techniques. Journal of Pharmaceutical Sciences.
Iyer, J., Barbosa, M., Saraf, I., Pinto, J. F., & Paudel, A. (2023). Mechanoactivation as a Tool to Assess the Autoxidation Propensity of Amorphous Drugs. Molecular Pharmaceutics, 20(2), 1112-1128.
Narala, S., Nyavanandi, D., Srinivasan, P., Mandati, P., Bandari, S., & Repka, M. A. (2021). Pharmaceutical Co-crystals, Salts, and Co-amorphous Systems: A novel opportunity of hot-melt extrusion. Journal of drug delivery science and technology, 61, 102209.
Sarabu, S., Bandari, S., Kallakunta, V. R., Tiwari, R., Patil, H., & Repka, M. A. (2019). An update on the contribution of hot-melt extrusion technology to novel drug delivery in the twenty-first century: part II. Expert opinion on drug delivery, 16(6), 567-582.
Schenck, L., Risteen, B., Johnson, L. M., Koynov, A., Bonaga, L., Orr, R., & Hancock, B. (2023). A Commentary on Co-Processed API as a Promising Approach to Improve Sustainability for the Pharmaceutical Industry. Journal of Pharmaceutical Sciences.
Shah, N., Iyer, R. M., Mair, H.-J., Choi, D., Tian, H., Diodone, R., Fahnrich, K., Pabst-Ravot, A., Tang, K., & Scheubel, E. (2013). Improved human bioavailability of vemurafenib, a practically insoluble drug, using an amorphous polymer-stabilized solid dispersion prepared by a solvent-controlled coprecipitation process. Journal of Pharmaceutical Sciences, 102(3), 967-981.