(M1430-02-12) Development of Combination Printlets of Sulfadiazine and Pyrimethamine Using Selective Laser Sintering 3D Printing for Pediatrics Applications

Purpose: The purpose of present study was to develop and evaluate combination printlets of sulfadiazine and pyrimethamine using selective laser sintering 3D printing techniques with a focus on pediatric applications.

Methods: Sulfadiazine, known for its poor flowability due to its fluffy nature, was granulated in combination with pyrimethamine to enhance its flowability. These two active pharmaceutical ingredients (APIs) were co-processed through wet granulation, followed by drying and size reduction via ASTM sieve #100 to get uniform particle size distribution. After performing various preliminary trials, pregelatinized starch (PGS) and Kollicoat IR (KIR) were picked as effective binders for wet granulation process. Fractional factorial design (JMP Pro 17) was used to screen process and formulation independent variables for development of quality printlets. The independent variables included surface temperature, chamber temperature, laser sintering speed, Kollidon VA64 (VA64) percentage, and type of binders (PGS and KIR). The key dependent variables for characterizing printlets’ performance included hardness, disintegration, and dissolution profile. Selected printlets were further evaluated by powder X-ray diffraction (PXRD), FTIR, DSC, and chemical imaging to assess solid state and chemical changes. Additionally, comparative analyses were performed for powders before and after printing to evaluate the impact of printing process on their physicochemical properties and overall quality.

Results: Sulfadiazine API and its granules were evaluated for flowability. The Hausner ratio and Carr’s index of the sulfadiazine API (without granulation) were recorded as 2.0±0.1 and 50±1.5%, indicating extremely poor flowability. APIs granules prepared with PGS (binder) showed Hausner ratio of 1.3±0.0 and Carr’s index of 21.4±3.1%, respectively, indicating passable flowability. However, the Hausner ratio and Carr’s index of APIs granules made with KIR as binder were 1.2±0.0 and 18.1±2.1%, which means they have decent flowability. Selected process and formulation independent variables exhibited an impact on the quality attributes of printlets. Hardness and disintegration of printlets varied from 0.6±0.0 to 15.0±2.3N, and 8.0±0.9 to 52.0±3.9s, respectively. Dissolution of sulfadiazine was varied between 81.1±6.4 and 104.7±2.0%, while that of pyrimethamine was between 90.5±3.4 and 97.3±2.4%, respectively, after 120 min. Dissolution of sulfadiazine and pyrimethamine met the USP dissolution limits of drugs, which were 75% in 60 min and 80% in 45 min, respectively. F-6 printlets printed with slow sintering speed and having maximum concentration of VA64 and KIR as a binder, showed highest hardness (15.0±2.3N) and disintegration (52.0±3.9s). From the F-6 printlet, sulfadiazine and pyrimethamine dissolved 7.3±0.9% and 30.3±1.7%, respectively, within the initial 5 min. Whereas, printlet having PGS as binder, and printed with fast laser sintering speed (F5), showed lowest hardness (0.6±0.0N), and disintegration (20.0±1.4s). F-5 printlet showed 17.2±1.0% and 56.7±2.1%, dissolution of sulfadiazine and pyrimethamine, respectively, within the initial 5 min, which was higher than F-6 printlets. These results demonstrated that the impact of laser sintering speed, where slow sintering speed produced high heat, resulting in high melting of the thermoplastic polymer, leading to the fusion of ingredients and an increase in hardness, disintegration time, and a reduction in the dissolution profile of the printlets. SEM study also confirmed fusion of excipients. PXRD diffractograms and FTIR spectra of printlets showed a reduction in the intensity of drug peaks, which revealed partial amorphization of drug. DSC thermograms of printlets did not show drugs melting peaks because of their solubilization in the melted ingredients of printlets. Hyperspectral images of printlets exhibited a uniform distribution of pixels, indicating even drug distribution. Thus, the results of the printlet evaluation showed that the printing variable, specifically laser sintering speed, was responsible for partially transforming the physical form of the drug from crystalline to amorphous, but they did not have any effect on the quality of the drug. Minor differences were observed in the PXRD diffractograms and FTIR spectra of the powders before and after printing, indicating that the process variables had a negligible impact on the quality of the non-printed powders.

Conclusion: Sulfadiazine and pyrimethamine combination printlets were successfully developed and evaluated on different parameters. Results exhibited that process and formulation variables impacted printlet quality, specifically hardness, disintegration, and dissolution profiles. Dissolution profiles of sulfadiazine and pyrimethamine meet the USP standards, which affirm their pharmaceutical acceptability. PXRD and FTIR data revealed partial amorphization of the drugs, and hyperspectral imaging confirmed a uniform distribution of the drugs throughout the printlets matrix. Additionally, results also showed that printing process variables did not affect the quality of non-printed powders after printing; hence, they could be reused. These results draw attention to the vital part of process parameters in customizing drug release and mechanical characteristics of printlets for patient-specific treatments.

Acknowledgements: This work was supported by the National Institute of Health R01 grant #1R01HD110552-01A1.