Formulation Intervention to Overcome Decreased Kinetic Solubility of a Low Tg Amorphous Drug.

This technical note investigated the loss of dissolution rate during accelerated stability studies with a dry blend capsule formulation containing an amorphous salt of drug NVS-1 (Tg 76°C). After 6 m at 40°C/75%RH, dissolution of NVS-1 was ≤40% of initial value. Scanning electron microscope characterization of the undissolved capsule contents from samples stored at 50°C/75%RH for 3 weeks showed agglomeration with a distinct "melt and fuse" morphology of particles. At elevated temperature and humidity conditions, undesired sintering among the amorphous drug particles was observed. Humidity plasticizes the drug as the stability temperature (T) gets closer to the glass transition temperature (Tg) of the amorphous salt (i.e., smaller Tg-T); a decreased viscosity favors viscoplastic deformation and sintering of drug particles. When moisture is adsorbed onto agglomerated drug particles, partial dissolution of the drug forms a viscous surface layer, further reducing the rate of dissolution media penetration into the bulk solid, hence the slower dissolution rate. Formulation intervention focused on the use of L-HPC and fumed silica as disintegrant and glidant and the removal of the hygroscopic crospovidone. Reformulation improved dissolution performance at short-term accelerated stability conditions of 50°C (± 75%RH); however, sintering to a lesser extent was still observed at high humidity, impacting the dissolution rate. We infer reducing the impact of moisture at high humidity conditions in a formulation with a 34% drug load is challenging. Future formulation efforts will focus on the addition of water scavengers, reducing drug load by ~50% to physically separate drug particles by water-insoluble excipients, and optimizing disintegrant levels.

Best practices for the development, scale-up, and post-approval change control of IR and MR dosage forms in the current quality-by-design paradigm.

In this whitepaper, the Manufacturing Technical Committee of the Product Quality Research Institute provides information on the common, best practices in use today in the development of high-quality chemistry, manufacturing and controls documentation. Important topics reviewed include International Conference on Harmonization, in vitro-in vivo correlation considerations, quality-by-design approaches, process analytical technologies and current scale-up, and process control and validation practices. It is the hope and intent that this whitepaper will engender expanded dialog on this important subject by the pharmaceutical industry and its regulatory bodies.

Optimization of formulation and process parameters for the production of nanosuspension by wet media milling technique: effect of Vitamin E TPGS and nanocrystal particle size on oral absorption.

The purpose of this study was to develop nanosuspension formulations of a poorly soluble drug using a wet media milling technique. The milling process was optimized by studying the effects of critical process parameters on the size of nanoparticles using a factorial design approach. During the design of experiments (DOEs) study, different concentrations of Vitamin E TPGS in the suspensions were used to evaluate its influence on the stabilization of a nanosuspension. Once the final formulation was optimized, a pharmacokinetic study was performed in beagle dogs to investigate the effect of different ranges of particle size of nanocrystals on the plasma profile. A significant increase in AUC and C(max) was observed when the drug substance was converted into nanocrystals, likely due to the increase in dissolution rate. Results also revealed that the nanosuspension formulation (consists of nanocrystals with narrow size distribution, having a mean particle size<300 nm) produced less variability with regards to the individual plasma concentrations in the dogs when compared an alternate nanocrystal formulation (consists of nanocrystals with broad size distribution having a mean particle size<750 nm). This type of observation can be explained due to the Ostwald ripening phenomena between the nanocrystals when the particle size distribution was very broad (higher poly dispersity index). Surprisingly, the un-micronized suspension containing Vitamin E TPGS did not show any significant impact on pharmacokinetic parameters.

Application of spray granulation for conversion of a nanosuspension into a dry powder form.

The in vivo effect of particle agglomeration after drying of nanoparticles has not been extensively studied till date based on current literature review. The purpose of this research was to evaluate the feasibility of spray granulation as a processing method to convert a nanosuspension of a poorly water soluble drug into a solid dosage form and to evaluate the effect of the transformation into a solid powder on the in vivo exposure in beagle dogs. Formulation variables like the level of stabilizer in the nanosuspension formulation, granulation substrate and drug loading in the granulation were evaluated. The granules were characterized for moisture content, drug content, particle size, crystallinity and in vitro dissolution rate. Granulations with 10% drug loading showed dissolution profiles comparable to the nanosuspension, slightly slower dissolution profiles were observed at 20% drug loading. This can be attributed to an increase in the surface hydrophobicity at a higher drug loading and the formation of agglomerates that were harder to disintegrate, thereby compromising the dissolution rate. An in vivo PK study in beagle dogs showed an 8-fold increase and a 6-fold increase in the AUC(0-48) from the nanosuspension and dried nanosuspension formulations respectively compared to the coarse suspension. Also, the nanosuspension and dried nanosuspension formulations showed a 12-fold and 8-fold increase in the C(max) respectively compared to the coarse suspension. This shows the feasibility of using spray granulation as a processing method to convert a nanosuspension into a solid dosage form with improved in vivo exposure compared to the coarse suspension formulation.