To evaluate hot melt extruder as a novel technique to dry nanosuspension and develop a mechanistic understanding of polymeric factors influencing the stabilization of nanosuspension

Most of the current NCEs (New chemical entities) in research pipeline belongs to the brick-dust category of drugs, which faces solubility and dissolution rate limited bioavailability concerns. Presystemic metabolism and food effects further lead to increased inter-patient variability in terms of drug's absorption and systemic circulation. Higher doses have to be administered to achieve desired therapeutic plasma concentrations. Low solubility and dissolution rate have been counterbalanced by techniques such complexation, salt formation, micronization, nanonization, cocrystallization and melt granulation. Techniques such as amorphization and nanonization of drugs are currently one of the most explored formulation strategies, wherein, amorphization leads to increased apparent saturation solubility of the drug by converting it to high energy form and nanonization leading to increase in drug surface area promoting dissolution rate. Nanoamorphous formulation strategy is one such promising approach which involves precipitating drug molecules in nanonized amorphous form. The high amount of polymers and surfactants are frequently incorporated in the formulation to prevent crystallization and aggregation of nanoamorphous drug particles. Nanoamorphous formulation can apparently assist in achieving relatively higher drug absorption and faster rate of dissolution compared to conventional nanocrystalline and solid dispersion formulation strategies.;Nanonized amorphous drug particles were produced by sonoprecipitation technique. It involved introducing solvent phase consisting of drug molecules into an antisolvent phase comprising of aqueous polymeric phase, under constant agitation and sonication. Polymers are subjectively selected for stabilization of nanosuspension without any underlying rationale. Thus, the primary aim of the current work was to understand the underlying mechanism governing particle aggregation and agglomeration mechanistically. Commonly used polymers for steric stabilization, such as HPMC E15, Soluplus, HPC-SL, Kollidon VA64, PVP K30 and were used in the preliminary experimental study. Computational studies were performed simultaneously to complement and supplement the experimental nanoprecipitation studies. Multiple Linear Regression models were developed to mathematically correlate the response variables (particle size, zeta potential, and PDI) and polymeric input variables such as torsion energy, the radius of gyration, molecular surface area, volume, surface tension, viscosity and molecular weight. According to the developed and validated mathematical models, molecular weight, torsion energy, and radius of gyration significantly controlled aggregation of nanoparticle upon sonoprecipitation. Additionally, Soluplus with relatively higher torsion energy, the radius of gyration and molecular weight led to nanosuspension with smallest particle size and lower PDI value. Poloxamer 407 compared to SLS, Docusate sodium, Tween 80 and TPGS proved to be a better surfactant in synergistically controlling aggregation and agglomeration of nanoparticles. Thus, Soluplus and Poloxamer 407 were selected for future optimization studies.;Drug concentration, soluplus and poloxamer 407 concentration, and antisolvent: solvent ratio were optimized by DOE methodology to evaluate main and interaction effects of input variables. From the DOE studies, it was identified that low drug concentration resulted in smaller nanoparticles with narrower particle size distribution, high soluplus concentration facilitated essential shielding of precipitated nanoparticles and prevented aggregation of particles. Antisolvent: solvent (AS:S) ratio was the most significant process parameter affecting the precipitation of drug molecules. At low AS: S ratio, Ostwald ripening was accelerated due to a higher concentration of organic solvent, resulting in solvation of smaller particles and their adsorption on to the existing particles. On the contrary, at high AS: S ratio, Ostwald ripening is not favored resulting in uniformly precipitated nano-sized drug particles. Moreover, poloxamer 407 ironically didn't impact the response variables significantly (p>0.05) and was excluded from the final optimized formulation. The optimized nanosuspension was further dried using a novel HME drying technique and a conventionally used spray drying technique. A Quality by Design (QbD) approach was adopted to optimize the drying of nanosuspensions, using both the technologies. Box-Behnken design was used to model the response variables (RDI, zeta potential and PDI) and identify the main and interaction effects of the input variables (Spray drying: Atomization, Feed rate, and Input temperature; HME drying: Feed rate, Input temperature, and screw speed). Optimized HME-dried and Spray dried nanosuspension from chapter 4 and 5 respectively, were selected to evaluate the effect of different processing techniques on the physicochemical properties of the nanoamorphous drug product. Optimized formulations were further stored at different stability conditions (25°C/60% RH & 40°C/75% RH). Characterization studies, sink and non-sink in-vitro dissolution studies were performed on the stored samples at days 1, 7, 14 and 28. Spray dried, and HME dried nanosuspension didn't exhibit any significant difference in the dissolution rate enhancement during sink condition. At 25% and 50% non-sink dissolution condition, HME-dried formulation fared poorly and failed to maintain the supersaturation advantage imparted by amorphous nano-sized drug particles. Nevertheless, spray dried nanosuspension successfully achieved and maintained supersaturation during non-sink dissolution condition, possibly due to better shielding of drug particles by soluplus, lower residence time and minimal exposure to thermal energy during drying. Similarly, spray dried nanosuspension proved to be more robust and performed well compared to HME dried nanosuspension during stability studies.;In summary, it can be inferred that the drying of amorphous nanosuspension might be possible by HME, but spray drying technology remains the method of choice due to the attainment of higher stability compared to the HME-dried end product. The novel HME drying technique can also be successfully used by researchers to solidify crystalline nanosuspension, which are apparently less prone to instability compared to amorphous nanosuspension.