The active ingredient in the preparation (API) is intended to be used in any substance or mixture of substances in the manufacture of pharmaceuticals, and pharma intermediates are important raw materials for the production of API. The production of drugs depends on the custom synthesis of intermediates. After the synthesis of APIs, the industrialized large-scale production should also be considered. Often there are multiple technological routes for a drug. When preparing kilogram-scale candidate drugs and active ingredients, it is necessary to select efficient technological research and development routes of API and intermediates, ensuring the speed of drug development and saving research and development costs.
Generally speaking, according to the development stage of drug development, the technological route is generally divided into two types: the emergency route in the early stage of drug screening and the cost-effective route for the formal project approval of drug development.
(1) The selected route must be technically feasible
After the API is produced through the custom synthesis of intermediates, subsequent scale-up production of the API may be required.
(2) The selected route must have suitable and available equipment
Route selection should prioritize existing equipment, but some special reactions may involve proprietary equipment.
(3) Pay attention to the patent protection of the production route
Anyone who uses the materials and technologies described in others' patents must be legally authorized, otherwise they will be prosecuted for infringement.
(4) Post-process by using compression
Separation of intermediates results in material loss and increased costs, so in addition to purification of key intermediates, we can properly use compression to avoid separation. As a result, product is directly put into the next step without separation, so proper compression can greatly improve the total yield.
(5) Minimize the design steps of API and intermediates
Design the reaction route with the least steps or optimize the reaction process. In addition, use one-step method for multiple reactions.
(6) Minimize the influence of protecting groups
In view of atom economy, the introduction and removal of protecting groups increase the cost, so the number of protecting groups should be minimized.
(11) Minimize environmental impact
Reducing environmental impact is becoming more and more important, and the "greenness" of environmental impact can be measured by technological route, atom economy, ecological efficiency, and the number of three wastes.
The screening of cost-effective development routes for API and intermediates can be assessed by cost accounting at the end. Cost estimates can show which types of costs contribute the most to the product and where optimization is needed, including the cost of raw materials, the yield of qualified quality products, the total amount of intermediates required per kilogram of product, capacity, processing costs, the amount of raw and auxiliary materials for recovery and recycling. Sometimes it is necessary to calculate the fixed expenses and labor costs. On this basis, consider the characteristics of each route and select a reliable technology.