Evaluation of the Crystallization Tendency of Commercially Available Amorphous Tacrolimus Formulations Exposed to Different Stress Conditions
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Tacrolimus, an immunosuppressant, is a poorly water soluble compound whereby the commercially available capsule formulations contain the drug in amorphous form. The goal of this study was to evaluate the robustness of the innovator product and five generic formulations to crystallization following storage at stress conditions.
Products were purchased from a pharmacy and stored at 40°C/75% relative humidity (RH), open dish conditions. Crystallinity was determined using X-ray diffraction. The quantity of the ingredients in the formulations were determined using different approaches and the various factors that might cause instability in the formulations were studied.
After 4 weeks of open dish storage at 40°C/75% RH, one of the generic formulations showed evidence of tacrolimus crystallization. Further investigations revealed batch-to-batch variations in crystallization tendency with the extent of crystallinity varying between 50 and 100% for different batches. Crystallization was also observed at lower storage temperatures (30°C) when the RH was maintained at 75%. It was found that crystallization could be induced in a model formulation by wet granulating an ethanolic solution of the drug with lactose and drying at 60–70°C followed by exposure to stress conditions.
It seems probable that the generic that was susceptible to crystallization contains amorphous drug physically mixed with polymeric excipients, rather than as an amorphous solid dispersion. This study highlights the importance of considering the manufacturing process on the stability of the resultant amorphous product.
Key Wordsamorphous crystallization generic stability tacrolimus
Differential scanning calorimetry
Hydroxypropylmethyl cellulose acetate succinate
Scanning electron microscopy
X-ray powder diffraction
Acknowledgments and Disclosures
The authors acknowledge the U.S. Food And Drug Administration for financial support under grant award 1U01FD005259–01. The authors would like to acknowledge Dr. Dajun Sun and Dr. Hong Wen of the FDA for helpful discussions. Ms. Chailu Que is thanked for assistance with the SEM images. This research used resources of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357. Dr. Byeongdu Lee (beamline 12-ID-B, Proposal GUP#43533, Advanced Photon Source, Argonne, Illinois) is acknowledged for his help with the X-ray measurements.
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