ritonavir and sorbitan-monolaurate

To understand the role of different surfactants, incorporated into amorphous solid dispersions (ASDs) of ritonavir and copovidone, in terms of their impact on release, phase behavior and stabilization of amorphous precipitates formed following drug release.. Ternary ASDs with ritonavir, copovidone and surfactants (30:70:5 w/w/w) were prepared by rotary evaporation. ASD release performance was tested using Wood's intrinsic dissolution rate apparatus and compared to the binary drug-polymer ASD with 30% drug loading. Size measurement of amorphous droplets was performed using dynamic light scattering. Solid state characterization was performed using attenuated total reflectance-infrared spectroscopy, differential scanning calorimetry and scanning electron microscopy.. All surfactant-containing ASDs showed improvement over the binary ASD. Span 85 and D-α-tocopheryl polyethylene glycol succinate (TPGS) showed complete release with no evidence of AAPS or crystallization whereas Span 20 and Tween 80 showed < 50% release with amorphous amorphous phase separation (AAPS). Span 20 also induced solution crystallization. Sodium dodecyl sulfate (SDS) showed very rapid, albeit incomplete (~ 80%) release. AAPS was not observed with SDS. However, crystallization on the dissolving solid surface was noted. Span 20 and TPGS formed the smallest and most size-stable droplets with ~ 1 µm size whereas coalescence was noted with other surfactants.. Surfactants improved the release performance relative to the binary ASD. Different surfactant types impacted overall performance to varying extents and affected different attributes. Overall, Span 85 showed best performance (complete release, no crystallization/AAPS and small droplet size). Correlation between physicochemical properties and surfactant performance was not observed.

Topics: Drug Compounding; Drug Liberation; Hexoses; HIV Protease Inhibitors; Kinetics; Polysorbates; Pyrrolidines; Ritonavir; Solubility; Surface-Active Agents; Vinyl Compounds; Vitamin E

Single-particle tracking of crystal growth performed in situ enables substantial improvements in the signal-to-noise ratio (SNR) for recovered crystal nucleation and growth rates by nonlinear optical microscopy. Second harmonic generation (SHG) is exquisitely sensitive to noncentrosymmetric crystals, including those produced by many homochiral active pharmaceutical ingredients (APIs). Accelerated stability testing at elevated temperatures and relative humidity informs design of pharmaceutical formulations. In the present work, we demonstrate reduction in the Poisson noise associated with the finite number of particles present in a given field of view through continuous monitoring during stability testing. Single-particle tracking enables recovery of crystal growth rates of individual crystallites and enables unambiguous direct detection of nucleation events. Collectively, these capabilities provide significant improvements in the signal-to-noise for nucleation and crystal growth measurements, corresponding to approximately an order of magnitude reduction in anticipated measurement time for recovery of kinetics parameters.

Topics: Colloids; Crystallization; Drug Compounding; Drug Design; Drug Stability; Hexoses; Humidity; Kinetics; Pyrrolidines; Ritonavir; Second Harmonic Generation Microscopy; Signal-To-Noise Ratio; Silicon Dioxide; Solubility; Temperature; Vinyl Compounds; Water

The objective of the study was to characterise the aqueous dispersions of ritonavir melt extrudates. More specifically to look into the particular system formed when melt extrudate of a poorly soluble drug dissolved in a hydrophilic polymer matrix containing a surfactant is dispersed in an aqueous medium. Melt extrudates with and without ritonavir were studied. The drug containing extrudate was confirmed to be molecular dispersions of drug in a polymer/surfactant matrix. Particulate dispersions were formed in water from both drug and placebo extrudates. The dispersions were investigated with respect to mean particle size and particle size distribution (photon correlation spectroscopy and optical particle counting), surface charge (zeta potential), particle composition (ultracentrifugation), tendency to form aggregates and precipitate (turbidity), in vitro dissolution rate and drug release. It was concluded that dispersion of melt extrudates in aqueous medium give rise to nano/micro-dispersions. The stability of the nano/micro-dispersion is sensitive to anions and may be subjected to association/aggregation/flocculation as time proceeds after preparation of dispersion. Melt extrudate showed improved dissolution rate and drug release properties compared to crystalline raw material. From studies of single components and physical mixtures of the formulation composition it can be concluded that the drug delivery system itself, namely solid dispersion prepared by melt extrusion technology, plays a key role for the formation of the observed particles.

Topics: Biological Availability; Buffers; Chemistry, Pharmaceutical; Crystallography, X-Ray; Drug Carriers; Drug Stability; Hexoses; Hot Temperature; Hydrogen-Ion Concentration; Hydrophobic and Hydrophilic Interactions; Nanoparticles; Nephelometry and Turbidimetry; Osmolar Concentration; Particle Size; Pharmaceutical Vehicles; Polyvinyls; Povidone; Ritonavir; Silicon Dioxide; Solubility; Static Electricity; Surface-Active Agents; Taurocholic Acid; Water