It is estimated that up to 90% of emerging drug candidates have significantly less than optimal aqueous solubility, which will impede their efficient delivery to the body. Amorphous solid dispersions (ASDs) have emerged as an important approach to improve oral bioavailability of low solubility drugs. However, the interplayofmanufacturingconditions,polymerchoice,andstorageconditionsonthecriticalqualityattributes ofASDsthatimpactdissolution,precipitationandultimatelyinvivoperformanceispoorlyunderstood.There is also concern within the medical community that generic ASD products may not perform as well as brand products. The objective of the current proposal is to evaluate the impact of formulation components, processing parameters and storage conditions on the in vitro and in vivo performance of ASDs of relevant poorly water soluble drugs. The rationale for this research is that its successful completion will enable an understanding of processing and formulation factors that impact the robustness of brand and generic ASD formulations,insuringproductquality.
The specificaims areto: 1) Demonstrate that drug?polymer miscibility depends both on drug and polymer chemistry and on processingconditions,comparingASDspreparedwithspraydryingandmeltextrusion. 2) Using innovative analytical approaches, show that differences in product performance for ASDs preparedwithspraydryingversushotmeltextrusiondependoncriticalqualityattributesthatinclude, drug?polymer homogeneity, residual crystallinity and dissolution performance. Determine critical process parameters specific to each manufacturing technique that impact these critical quality attributes. Demonstrate that precipitation behavior can be modified by formulation components and that precipitation to a non?crystalline form has very different consequences for product performance comparedtocrystallization. 3) Compare and contrast the quality attributes of brand and generic ASD products in terms of assay, relatedsubstances,dissolutionperformanceandothercriticalqualityattributes. 4) Compare and contrast brand and generic ASD formulations in terms of the robustness of the formulation to stressed storage conditions. Performance attributes that will be assessed include evolution of crystallinity with time as a function of moisture content, as well as dissolution rate and precipitationtendency/outcomeatdifferenttimepoints. 5) Conduct a clinical trial to evaluate the in vivo performance of fresh and aged brand and generic ASD preparations.
Sophisticatedformulationsareneededfordrugswhicharenotverywatersolubleinorderto deliverthemtothebodyfollowingoralingestion.Thisresearchwillexplorecriticalfactorsthat impacttheeffectivenessoftheseformulations.Thiswillhelpinsurethatbrandandgeneric productsofpoorlywatersolubledrugsaresafeandefficaciousthroughouttheirshelf-life.