Understanding and optimizing the dual excipient functionality of sodium lauryl sulfate in tablet formulation of poorly water soluble drug: wetting and lubrication.

PURPOSE: To evaluate and optimize sodium lauryl sulfate (SLS) and magnesium stearate (Mg.St) levels, with respect to dissolution and compaction, in a high dose, poorly soluble drug tablet formulation. METHODS: A model poorly soluble drug was formulated using high shear aqueous granulation. A D-optimal design was used to evaluate and model the effect of granulation conditions, size of milling screen, SLS and Mg.St levels on tablet compaction and ejection. The compaction profiles were generated using a Presster(©) compaction simulator. Dissolution of the kernels was performed using a USP dissolution apparatus II and intrinsic dissolution was determined using a stationary disk system. RESULTS: Unlike kernels dissolution which failed to discriminate between tablets prepared with various SLS contents, the intrinsic dissolution rate showed that a SLS level of 0.57% was sufficient to achieve the required release profile while having minimal effect on compaction. The formulation factors that affect tablet compaction and ejection were identified and satisfactorily modeled. The design space of best factor setting to achieve optimal compaction and ejection properties was successfully constructed by RSM analysis. CONCLUSIONS: A systematic study design helped identify the critical factors and provided means to optimize the functionality of key excipient to design robust drug product.

Development of novel microprecipitated bulk powder (MBP) technology for manufacturing stable amorphous formulations of poorly soluble drugs.

A novel method was developed to manufacture amorphous formulations of poorly soluble compounds that cannot be processed with existing methods such as spray drying and melt extrusion. The manufacturing process and the characterization of the resulting amorphous dispersion are presented via examples of two research compounds. The novel process is utilized N,N-dimethylacetamide (DMA) to dissolve the drug and the selected ionic polymer. This solution is then co-precipitated into aqueous medium. The solvent is extracted out by washing and the co-precipitated material is isolated by filtration followed by drying. The dried material is referred to as microprecipitated bulk powder (MBP). The amorphous form prepared using this method not only provides excellent in vitro and in vivo performance but also showed excellent stability. The stabilization of amorphous dispersion is attributed to the high T(g), ionic nature of the polymer that help to stabilize the amorphous form by possible ionic interactions, and/or due to the insolubility of polymer in water. In addition to being an alternate technology for amorphous formulation of difficult compounds, MBP technology provides advantages with respect to stability, density and downstream processing.

Functional performance of silicified microcrystalline cellulose versus microcrystalline cellulose: a case study.

BACKGROUND: During the development of a tablet dosage form of an investigational compound, R411, several aspects were identified as critical quality attributes that required optimization. The use of nonsolvent processing prevented the moisture-induced physical changes in the drug product but presented manufacturing challenges related to sticking during compression and slowdown in dissolution after storage at stress conditions. AIM: The aim of this study was to evaluate silicified microcrystalline cellulose (SMCC), microcrystalline cellulose (MCC), and physical mixture of MCC-colloidal silicon dioxide (MCC/CSD at 98:2 ratio) as extragranular compression aids to address the processing and dissolution stability issues of this formulation. METHODS: The compactibility and stickiness upon compression over extended period of time as well as the dissolution of R411 formulations incorporating the aforementioned compression aids were investigated. In addition, the water sorption/desorption properties of these compression aids were determined. RESULTS: All formulations showed comparable compactibility irrespective of the compression aid used. Nevertheless, MCC alone or in a physical mixture with CSD showed sticking of the lower punches, whereas SMCC resulted in clean punch surface during extended compression runs. Furthermore, the three compression aids were compared for their effect on dissolution stability after storage at stress conditions. The formulations containing SMCC provided superior dissolution stability over the other compression aids evaluated in the study. CONCLUSIONS: Novel functionalities of SMCC are presented in terms of sticking prevention while having the most beneficial effect on dissolution stability in R411 formulation.

Evaluation of solid state properties of solid dispersions prepared by hot-melt extrusion and solvent co-precipitation.

The solid state properties of solid dispersions of Compound A in hypromellose acetate succinate (HPMC-AS) prepared by hot-melt extrusion (HME) and solvent co-precipitation (CP) processes were evaluated using powder X-ray diffractometry (PXRD), thermal analysis, optical microscopy, scanning electron microscopy (SEM), FT-IR and Raman spectroscopy, water vapor sorption analyzer, and surface area by BET. PXRD indicated that both processes converted the crystalline drug into amorphous solid dispersions with a glass transition temperature around 104-107 degrees C and both products have similar spectroscopic and hygroscopic properties. The two products have similar true densities; however, the CP product is more porous and has a larger specific surface area than the HME product, as indicated by the BET results and SEM micrographs. Dissolution study using USP apparatus 2 showed that the CP product had a faster dissolution profile, but slower intrinsic dissolution rate than the HME product. The two products have acceptable physical stability after storage in 40 degrees C/75% RH chamber for 3 months. However, the HME product is more stable than the CP product in aqueous suspension formulation.

Effect of formulation and processing variables on the granulation kinetics of hot melt granulation (HMG) process.

The objective of the study was to evaluate the effect of formulation factors, such as type of drug and particulate properties of a drug, and processing variables, i.e. jacket temperature, impeller speed, and scale, on granulation kinetics the of hot-melt granulation (HMG) process. Two model active pharmaceutical ingredients (API) Ro-A and indomethacin were selected for this evaluation using poloxamer 188 as a meltable binder. The effect of solid-state properties of API was investigated for Ro-A, whereas the binder properties were maintained constant. General factorial design was used to investigate the effect of independent process variables, impeller speed and jacket temperature using impeller motor power consumption as response variable. Consistent granulation could be developed for Ro-A by optimizing the binder level and impeller speed, however, the addition of third excipient was necessary for indomethacin. The granulation rate was related to the bulk density and the surface area of the drug. The jacket temperature affected overall granulation time but had no significant effect on the granulation kinetics, suggesting that faster heating rate is desirable for optimal productivity. A significant increase in the granulation rate was observed with increase in impeller speed. The effect of impeller speed was further confirmed at 5 L and 25 L scale. From the formulation prospective, the critical factors were the level of binder, inherent binding properties of the API, the solid-state properties of API and binder. From processing perspectives, the impeller speed had a significant effect on the granulation kinetics.