When active pharmaceutical ingredients (APIs) are produced in multiple lots, it is possible for inconsistencies to develop in the quality (i.e. physical and chemical properties) of the drug substance. A major pharmaceutical company came to SSCI, A Division of Aptuit, when confronted with such a problem. The problem arose in the manufacture of the API for an antibiotic drug product that had been on the market for more than twenty years.

A third-party contract manufacturer was responsible for the production of the client’s API. Problems with the flow properties of the drug substance were encountered during the manufacturing of different lots using the same process. Similar crystal morphologies were obtained from the different lots, and x-ray powder diffraction (XRPD) analysis indicated the same form was presented in all lots. However, a large number of fine particles were observed in the problem lots.

The client came to Aptuit to determine why the API manufacturing process was not producing consistent API even though no major changes in the process had been detected, and to learn if a new polymorphic form was being produced. Aptuit took a dual approach to the problem, conducting both polymorph screening of the API and an investigation of the crystallization process. During the polymorph screen, SSCI scientists identified three additional forms that were unknown to the client and the API manufacturer. The development of these forms during production was at the basis of the inconsistent production lots. Using crystallization analysis, SSCI scientists were able to determine that slight variations in the crystallization conditions during the manufacturing process caused an alternate form to develop, the presence of which contributed to the flow problems of the final product. The SSCI scientists provided a controlled crystallization process that ensured the formation of the desired substance.

As a global leader in drug development services, Aptuit has the resources and capabilities to analyze existing drug substances and solve development problems. Aptuit can provide complete integrated drug development services, from API development to pharmaceutics, physical and analytical chemistry, preclinical and clinical technologies and clinical packaging and logistics.

The Challenge

A contract manufacturer’s production of an API for a commercialized antibiotic was yielding poor results after approximately 20 years of production without manufacturing problems. The client reported one crystal form for all lots, but discovered that some lots of the drug substance were exhibiting flow problems. Analysis of the API from multiple development batches showed similar morphologies, and XRPD analysis indicated the same crystalline form. The problem lots exhibited larger numbers of small particles, and suggested possible solid state issues. In short, an improved development process that yielded API with consistent physical and chemical properties was required.

The Aptuit Solution

SSCI scientists decided to take a dual approach by conducting polymorph screening on the material while also investigating the crystallization process. During screening, numerous experimental methods and patented techniques were used, as well as a wide selection of solvents that were not limited to those used during manufacture.

From Figure 1 it can be seen that Forms A, B and C were observed. In addition to these three, a fourth, Form D, was produced by lyophilization. It was also determined that different forms were generated from the same experiment in a 2-propanol/water mixture.

As shown in Figure 2, the manufacturer was able to isolate the desired Form A through crystallization from 2-propanol/water, followed by recovery via filtration and drying. At low nucleation temperature, Form A crystals could be harvested.

The effect of temperature on the API crystallization was examined by SSCI scientists. Figure 3 shows the effect of crystallization temperature on the formation of anhydrate Form A and the hydrate Form C when the temperature was changed from 15°C to 5°C.

At the higher temperature, Form A particles of 40 microns were formed. At the lower temperature, Form C particles of 690 microns were formed (Figure 4).

Figure 5 demonstrates the problem being faced by the API manufacturer. If the crystallization temperature is not controlled, and nucleation occurs at a lower temperature, the Form C hydrate is produced. Once the Form C hydrate is dried, it converts to a very fragile crystal of Form A, which produces very small particles. However, if a higher temperature allows Form A to nucleate, there is no conversion or change in particle size during drying. The fine particles are produced in the problem lots due to uncontrolled crystallization temperatures during API production. The produced Form C during the uncontrolled crystallization converts to Form A upon drying, forming fines, and resulting in poor flow. Therefore, controlling the temperature is the key to consistently high quality API production.

Conclusion

The polymorph screening and crystallization process control done by Aptuit clearly identified the flaw in the development process that was resulting in poor lot-to-lot API quality. SSCI scientists were able to demonstrate that the client in fact had multiple API forms instead of one, and that the crystallization process being used by the client’s API supplier was inefficient in forming only the desired product. Aptuit provided a manufacturing solution that resulted in clear efficiencies, which translated to less waste, reduced cost and improved production time.

By bringing your API requirements to Aptuit at the early stages of development, we can help you not only develop the most stable and consistent form of your compound, we can also help you develop an API synthesis process that leads to this desired form. In scaling up from grams to commercial production, Aptuit’s solid state chemistry capabilities will ensure that the product form remains consistent throughout the development process.

As a global provider of fully integrated pharmaceutical services, Aptuit can assist clients across the entire drug development continuum. At Aptuit, it’s all about the science.