Very-Rapidly Dissolving Printlets of Isoniazid Manufactured by SLS 3D Printing: In Vitro and In Vivo Characterization.

The focus of this research was to understand the effects of formulation and processing variables on the very-rapidly dissolving printlets of isoniazid (INH) manufactured by the selective laser sintering (SLS) three-dimensional (3D) printing method, and to characterize their physicochemical properties, stability, and pharmacokinetics. Fifteen printlet formulations were manufactured by varying the laser scanning speed (400-500 mm/s, X1), surface temperature (100-110 °C, X2), and croscarmellose sodium (CCS, %, X3), and the responses measured were weight (Y1), hardness (Y2), disintegration time (DT, Y3), and dissolution (Y4). Laser scanning was the most important processing factor affecting the responses. DT was very rapid (≥3 s), and dissolution (>99%) was completed within 3 min. The root-mean-square error in the studied responses was low and analysis of variance (ANOVA) was statistically significant (p < 0.05). X-ray micro-computed tomography (micro-CT) images showed very porous structures with 24.6-34.4% porosity. X-ray powder diffraction and differential scanning calorimetry data indicated partial conversion of the crystalline drug into an amorphous form. The printlets were stable at 40 °C/75% RH with no significant changes in assay and dissolution. Pharmacokinetic profiles of the printlets and compressed tablets were superimposable. In conclusion, the rapidly dissolving printlets of the INH were stable, and oral bioavailability was similar to that of compositionally identical compressed tablets.

Formulation Optimization of Selective Laser Sintering 3D-Printed Tablets of Clindamycin Palmitate Hydrochloride by Response Surface Methodology.

The aims of the current study were to develop and evaluate clindamycin palmitate hydrochloride (CPH) 3D-printed tablets (printlets) manufactured by selective laser sintering (SLS). Optimization of the formulation was performed by studying the effect of formulation and process factors on critical quality attributes of the printlets. The independent factors studied were laser scanning speed, microcrystalline cellulose (MCC), and lactose monohydrate (LMH) concentration. The responses measured were printlets weight, hardness, disintegration time (DT), and dissolution in 30 min. The printlets were characterized for content uniformity, chemical interactions, crystallinity, drug distribution, morphology, and porosity. The laser scanning speed showed statistically significant effects on all the studied dependent responses (p < 0.05). MCC showed statistically significant effects on hardness, DT, and dissolution (p < 0.05), while LMH showed statistically significant effect on hardness and dissolution (p < 0.05). The model was validated by an independent formulation, and empirical values were in close agreement with model-predicted values. X-ray powder diffraction and differential scanning calorimetry data suggested a decrease in crystallinity of the LMH in the printlets. X-ray micro-CT scanning showed porous microstructure of the printlets with a porosity 24.4% and 31.1% for the printlets printed at 200 and 300 mm/s laser speed, respectively. In summary, the SLS method provides an opportunity to fabricate customized dosage forms as per patients' need.

Selective laser sintering 3D printing - an overview of the technology and pharmaceutical applications.

Food and Drug Administration (FDA) has approved a drug product (Spritam®) and many medical devices manufactured by three-dimensional printing (3DP) processes for human use. There is immense potential to print personalized medicines using 3DP. Many 3DP methods have been reported in the literature for pharmaceutical applications. However, selective laser sintering (SLS) printing has remained least explored for pharmaceutical applications. There are many advantages and challenges in adopting a SLS method for fabrication of personalized medicines. Solvent-free nature, availability of FDA approved thermoplastic polymer/excipients (currently used in hot melt-extrusion process), minimal/no post-processing step, etc. are some of the advantages of the SLS printing process. Major challenges of the technology are requirement of at least one thermoplastic component in the formulation and thermal stability of drug and excipients. This review provides an overview of the SLS printing method, excipient requirements, process monitoring, quality defects, regulatory aspects, and potential pharmaceutical applications.

Understanding the effects of formulation and process variables on the printlets quality manufactured by selective laser sintering 3D printing.

The focus of the study was to understand the effects of formulation and process variables on the printlets quality manufactured by selective laser sintering (SLS) 3D printing. The Box-Behnken response surface methodology was used to evaluate effects of individual variables and combinations thereof. The formulation and process variables studied were printing chamber temperature (°C, X1), laser scanning speed (mm/sec, X2) and lactose monohydrate concentration (%, X3). The responses studied were weight of printlets (mg, Y1), hardness (N, Y2), disintegration time (sec, Y3) and dissolved drug fraction in 15 min (%, Y4). The values of Y1, Y2, Y3 and Y4 varied from 170.2-257.0 mg, 5.5-32.0 N, 20-120 s and 64.4-97.5%, respectively. The studied factors showed statistically significant effects on the dependent variables (p < 0.04). The correlation coefficient between empirical and model predicted values for Y1, Y2, Y3 and Y4 were 0.999, 0.992, 0.998 and 0.983, respectively. The model was validated by an independent experiment and actual values of the responses were in close agreement with model predicted values. Fourier transformed infrared spectroscopy indicated no chemical interactions between the components of the formulation during printing process. X-ray powder diffractograms suggested a decrease in crystallinity of the drug and lactose in the printlets. Chemical images indicated uniform distribution of the drug. Scanning electron microscopy and X-ray micro-CT scanning showed a very porous microstructure of the printlets with a porosity of about 37.89%. In conclusion, the SLS method of manufacturing provides a feasible and flexible avenue for fabricating dosage forms with tailored characteristics.

Additive Manufacturing with 3D Printing: Progress from Bench to Bedside.

Three-dimensional (3D) printing was discovered in the 1980s, and many industries have embraced it, but the pharmaceutical industry is slow or reluctant to adopt it. Spiritam® is the first and only 3D-printed drug product approved by FDA in 2015. Since then, the FDA has not approved any 3D-printed drug product due to technical and regulatory issues. The 3D printing process cannot compete with well-established and understood conventional processes for making solid dosage forms. However, pharmaceutical companies can utilize it where mass production is not required; rather, consistency, precision, and accuracy in quality are paramount. There are many 3D printing technologies available, and not all of them are amenable to pharmaceutical manufacturing. Each 3D technology has certain prerequisites in terms of material that it can handle. Some of the pertinent technical and regulatory issues are as follows: Current Good Manufacturing Practice, in-process tests and process control, and cleaning validation. Other promising area of 3D printing use is printing medications for patients with special needs in a hospital and/or pharmacy setting with minimum regulatory oversight. This technology provides a novel opportunity for in-hospital compounding of necessary medicines to support patient-specific medications. However, aspects of the manufacturing challenges and quality control considerations associated with the varying formulation and processing methods need to be fully understood before 3D printing can emerge as a therapeutic tool. With these points in mind, this review paper focuses on 3D technologies amenable for pharmaceutical manufacturing, excipient requirement, process understanding, and technical and regulatory challenges.