An investigation of the adsorption of hydroxypropylmethyl cellulose 2910 5 mPa s and polyvinylpyrrolidone K90 around Naproxen nanocrystals.

The selection of the appropriate stabilizer for a nanosuspension is still based on trial-and-error and the amount of stabilizer is mostly determined as the lowest amount that results in a stable nanosuspension. Although nanosuspensions are often dried, it is currently not known if the stabilizer remains associated with the surface after drying. Hence, the purpose of this study was to investigate the association of two common pharmaceutical stabilizers [hydroxypropylmethyl cellulose (HPMC) 2910 5 mPa s and polyvinylpyrrolidone (PVP) K90] with the surface of Naproxen crystals. The association between drug and polymer after drying was investigated by evaluating the mixing glass transition temperature using modulated differential scanning calorimetry. Dynamic laser scattering was used to study the Naproxen-polymer association in suspension state. Association with the Naproxen surface was proven after drying for both polymers. A difference in behavior between HPMC and PVP was observed at the liquid-particle interface. In suspension state, the HPMC layer continuously increases in thickness when adding more polymer, whereas in contrast for PVP, the surface can become saturated. The conclusion is that the behavior in suspension determines the behavior of the stabilizer after drying and it is governed by the physicochemical properties of the polymers.

Is the amorphous fraction of a dried nanosuspension caused by milling or by drying? A case study with Naproxen and Cinnarizine.

One of the benefits of nanocrystals is their positive effect on the solubility and dissolution rate without alterations to the solid state. Up to now, amorphization of nanocrystals after milling or drying has only rarely been described. The results we present in this article prove that amorphization occurs in some specific cases. This conclusion is based on careful investigation of two different drugs and one polymeric stabilizer. Milling is often mentioned as the prime suspect for solid-state alterations; however, milling proved to be an unlikely cause as the water present in the nanosuspensions acts as a plasticizer that triggers recrystallization. The cause of amorphization can instead be found in the interplay between drug and stabilizer after drying. If a drug is soluble in the stabilizer in the solid state, an amorphous solid dispersion is formed at the interface. Calculations show that the total amount of amorphous material is rather low, but even a small amount could have an influence on both chemical and physical stability or influence the bioavailability if uncontrolled crystallization occurs during storage. In general, those results prove that in depth testing and characterization of the solid state of a dried nanocrystal formulation remains very important.

Bead layering as a process to stabilize nanosuspensions: influence of drug hydrophobicity on nanocrystal reagglomeration following in-vitro release from sugar beads.

OBJECTIVES: In this article the feasibility of fluidized bed bead coating of nanosuspensions of drugs with significantly different physicochemical properties was investigated as a process to transform nanosuspensions into a solid dosage form. The second aim was to see how those physicochemical properties affect the coating process and the subsequent in-vitro dissolution process. METHODS: Naproxen and cinnarizine were used as model drugs. A fluidized bed pellet coater with Würster insert was used to coat the nanosuspensions prepared by media milling on sugar beads. KEY FINDINGS: Bead layering of cinnarizine nanosuspensions resulted in a complete dissolution in 15 min, compared to only 11% in 1 h for the unmilled powder. Naproxen also dissolved three times faster when formulated on a bead. A difference could be observed between naproxen and cinnarizine. Cinnarizine nanocrystals reagglomerate when released from the coating, resulting in a slower release when compared to the original nanosuspension. No agglomeration and no delay could be observed for naproxen. These differences are most likely caused by the difference of surface hydrophobicity between naproxen and cinnarizine. CONCLUSION: This study confirms that bead layering is a valuable drying technique that could complement spray drying and freeze drying, but more important is that we prove that drug physicochemical properties have a significant influence on in-vitro dissolution performance after bead layering and this is not readily predictable from the information obtained from the original nanosuspension itself.

Comparison between hot-melt extrusion and spray-drying for manufacturing solid dispersions of the graft copolymer of ethylene glycol and vinylalcohol.

PURPOSE: To investigate the effect of the manufacturing method (spray-drying or hot-melt extrusion) on the kinetic miscibility of miconazole and the graft copolymer poly(ethyleneglycol-g-vinylalcohol). The effect of heat pre-treatment of solutions used for spray-drying and the use of spray-dried copolymer as excipient for hot-melt extrusion was investigated. METHOD: The solid dispersions were prepared at different drug-polymer ratios and analyzed with modulated differential scanning calorimetry and X-ray powder diffraction. RESULTS: Miconazole either mixed with the PEG-fraction of the copolymer or crystallized in the same or a different polymorph as the starting material. The kinetic miscibility was higher for the solid dispersions obtained from solutions which were pre-heated compared to those spray-dried from solutions at ambient temperature. Hot-melt extrusion resulted in an even higher mixing capability. Here the use of the spray-dried copolymer did not show any benefit concerning the kinetic miscibility of the drug and copolymer, but it resulted in a remarkable decrease in the torque experienced by the extruder allowing extrusion at lower temperature and torque. CONCLUSION: The manufacturing method has an influence on the mixing capacity and phase behavior of solid dispersions. Heat pre-treatment of the solutions before spray-drying can result in a higher kinetic miscibility. Amorphization of the copolymer by spray-drying before using it as an excipient for hot-melt extrusion can be a manufacturing benefit.

Characterization of the copolymer poly(ethyleneglycol-g-vinylalcohol) as a potential carrier in the formulation of solid dispersions.

In order to fully exploit the graft copolymer poly(ethyleneglycol-g-vinylalcohol) (EG/VA) in the formulation of solid dispersions, a characterization of its phase behavior before, during and after spray-drying and hot-melt extrusion is performed. Solid state characterization was performed using MDSC and XRPD. The effect of heating/cooling rate on the degree of crystallinity was studied using HPer DSC and ultra-fast chip calorimetry. EG/VA consists of two semi-crystalline fractions, one corresponding to the polyethyleneglycol (PEG) fraction (T(g)=-57 degrees C, T(m)=15 degrees C) and one corresponding to the polyvinylalcohol (PVA) fraction (T(g)=45 degrees C, T(m)=212 degrees C). XRPD analysis confirmed its semi-crystallinity, and EG/VA showed Bragg reflections comparable to those of PVA. Spray-drying at a temperature lower than 170 degrees C resulted in amorphization of the PVA fraction, while after hot-melt extrusion at different temperatures, the crystallinity of this fraction increases. In both cases, the PEG fraction is not influenced. Plasticization of the amorphous domains of the PEG or PVA fraction of the copolymer was dependent on the type and concentration of plasticizer, suggesting that also other small organic molecules like drugs may not homogeneously mix with both amorphous domains. A controlled cooling rate of 3000 degrees C/s was necessary to make the copolymer completely amorphous.

Ordered mesoporous silica induces pH-independent supersaturation of the basic low solubility compound itraconazole resulting in enhanced transepithelial transport.

The majority of innovative drug candidates are poorly water soluble and exhibit basic properties. This makes them highly dependent on the in vivo encountered acid-neutral pH sequence to achieve a sufficient dissolution and thus absorption. In this study, we evaluated the pH-independent generation of intraluminally induced supersaturation of the model compound itraconazole and its beneficial effect on the extent of absorption in the Caco-2 system and the rat in situ perfusion system. Local supersaturation was obtained by means of a solvent shift method and a novel formulation strategy based on ordered mesoporous silica (OMS) as a carrier. In vitro results evidenced that both methods were capable of creating a supersaturated state of itraconazole in fasted state simulated intestinal fluid (FaSSIF) when no preceding acidic dissolution was simulated. The extent of supersaturation exceeded 21.9 and 9.6 during at least 4h for the solvent shift method and OMS as a carrier, respectively. As compared to saturation conditions (0.09+/-0.01 microg), supersaturation induced by the solvent shift method as well as by the use of OMS increased transport across a Caco-2 cell monolayer more than 16-fold, resulting in the basolateral appearance of 2.20+/-0.29 microg and 1.46+/-0.03 microg itraconazole after 90 min, respectively. In the absence of an acid-neutral pH sequence, the performance of the marketed product Sporanox was inferior with total transport amounting to 0.12+/-0.03 microg after 90 min. Enhanced absorption was confirmed in the in situ perfusion model where OMS was able to boost total transport of itraconazole after 60 min from 0.03+/-0.01 nmol cm(-1) to 0.70+/-0.09 nmol cm(-1) compared to saturated equilibrium conditions in FaSSIF. The solid dosage form Sporanox again failed to achieve a similar extent of absorption enhancement (0.29+/-0.01 nmol cm(-1)). These findings suggest that intraluminal supersaturation can be created by the use of OMS and that preceding dissolution of basic compounds in the acidic medium of the stomach is not required to allow for efficient intestinal absorption. The use of OMS appears to be a promising strategy for the delivery of especially basic low solubility compounds in patients suffering from hypochlorhydria; the pH independency may also result in a more reproducible systemic exposure.