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A Design of Experiment Study Applied to a New Nano Spray Drying Technic and Nanoprecipitation for Producing PLGA Drug Delivery Systems with Defined Sizes and Size Distributions
| Content Provider | Semantic Scholar |
|---|---|
| Author | Draheim, Christina Crecy, François De Hansen, S. Collnot, E.-M. Lehr, C.-M. |
| Copyright Year | 2013 |
| Abstract | SUMMARY In a design of experiment study (DOE) two processes (nanoprecipitation and nano spray drying) for producing poly (lactic-co-glycolic acid) (PLGA) nano-/ microspheres as drug delivery systems were investigated focusing on factors which control size and size distribution. INTRODUCTION PLGA is one of the most widely used synthetic polymers for drug delivery systems and used in many approved medical and drug products. Essentially, it is biodegradable and biocompatible. 1 For the preparation of nano-/ microspheres a new nano spray drying method represented by the Büchi Nano Spray Dryer B-90 (Büchi B-90) and the classical nanoprecipitation method were studied. The novel vibration mesh spray technology of the Büchi B-90 offers a direct production of dry nano-/ microsized product without requiring a special drying step. For the nanoprecipitation method a high-accuracy syringe pump (HARVARD® apparatus) was used to minimize effects due to individual handling. The two methods were chosen for performing a DOE as in both processes the nano-/ microsphere formation can be automatized. The DOE should help to understand for the Büchi B-90 controllability and limitations of the process to control size and size distribution, whereas in the nanoprecipitation method the main focus lay on the production of particles between 150 200 nm with a narrow size distribution (PDI < 0.150). EXPERIMENTAL METHODS Design of Experiments Design Expert® software was used to perform a design of experiments. For the nanoprecipitation method we have 3 continuous factors (polymer concentration, inner diameter and injection speed) and 2 two level categoric factors: nature of the stabilizer (Poloxamer-407 or Tween® 80) and nature of the solvent (pure acetone or a mixture of acetone/ ethanol). We chose an IV-optimal design for surface response with 34 experimental points. For the nano spray drying we have 5 continuous factors (temperature, polymer concentration, concentration of stabilizer and spray rate) and 3 level categoric factors (nature of organic solvent, pumping rate and nature of stabilizer). A IV-optimal design for surface response were chosen with 56 experimental points. Nanoprecipitation method PLGA was dissolved in acetone or a mixture of acetone/ ethanol (16/ 3 v/v), the solution was injected with a Hamilton syringe at 0.25 – 10 ml/ min into double distilled water containing either Poloxamer-407 (1 % m/ v) or Tween® 80 (1 % wt/ v) as stabilizer. The organic solvent was evaporated by stirring overnight. Nano spray drying method PLGA together with Span ®60 or Lutrol ® F 127 as stabilizer were dissolved or suspended in either acetone, dichloromethane or ethylacetate. Afterwards the feeding solution was sprayed under ice cooling in the Büchi B-90. The yield was defined as wt starting material/ wt spray dried product. The yield was corrected for the death volume. Characterization of size and size distribution Hydrodynamic diameter and polydispersity index of nanospheres were measured by dynamic light scattering (Zetasizer® Nano ZS, Malvern). The spray dried microspheres were characterized by laser diffraction (Mastersizer ® 2000, Malvern). Additionally nano-/ microspheres were visualized by scanning electron microscopy (SEM). RESULTS AND DISCUSSION Nanoprecipitation Using the nanoprecipitation method nanospheres in a range of 50 177 nm were produced with a narrow size distribution (PDI < 0.1) within the used parameters. Evaluation of the DOE showed that the polymer concentration is the main factor influencing size and size distribution (~ 90%, 80 % respectively, described by Sobol's analysis of variance) (Table 1). When polymer concentration increases, size increases and size distribution decreases. Stabilizer and injection speed have a moderate to weak influence, whereas the inner diameter of needle showed almost no effect. The organic solvent only had an influence on the size. Table 1 Nanoprecipitation Influence of factors varied in the DOE size size distribution polymer concentration +++ +++ nature of stabilizer + + organic solvent + inner diameter of needle injection speed + + +++ strong influence, + weak influence, almost no influence The statistical properties are rather good; R2=0.973 and predicted_R2=0.95 for size, R2=0.971 and predicted_R2=0.928 for size distribution. At the lowest polymer concentrations (~ 0.1 % wt/ v) the PDI increases to 0.13 – 0.29 indicating a wider size distribution. This was also obvious in SEM images. Spray drying With the spray drying technic stable redispersable microspheres could be prepared with the lowest mean size of 2 – 6 μm. Size and yield (1 – 54 %) of the microspheres are most effected by the nature of stabilizer and the organic solvent (Table 2). The other factors had no or only a weak influence. The size distribution (2 – 207) is driven by the polymer concentration, the pumping rate and the organic solvent, whereas other factors have no influence. No main influence factor for size, size distribution or yield could be determined. Table 2 Nano spray drying Influence of factors varied in the DOE size size distribution yield polymer concentration ++ + conc. of stabilizer + nature of stabilizer ++ ++ spray rate + pumping rate ++ organic solvent ++ ++ ++ inlet temperature +++ strong influence, ++ medium influence, + weak influence, no influence CONCLUSION The nanoprecipitation is essentially controlled by only one factor, which is the polymer concentration. In contrast, the formation of microspheres with the spray drying technique is influenced by various factors and therefore more difficult to control. |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | http://www.controlledreleasesociety.org/meetings/Documents/2013Abstracts/100632.pdf |
| Language | English |
| Access Restriction | Open |
| Content Type | Text |
| Resource Type | Article |
