Bernard Van Eerdenbrugh

Top-down production of drug nanocrystals: Nanosuspension stabilization, miniaturization and transformation into solid products

During the last 10-15 years, the formulation of drugs as nanocrystals has rapidly evolved into a mature drug delivery strategy, with currently five products on the market. The major characteristic of these systems is the rapid dissolution velocity, enabling bioavailability enhancement after oral administration. This mini-review focuses on recent advances with respect to three topics considering drug nanocrystals. The first topic is nanosuspension stabilization. A current literature status is provided and special attention is given to studies attempting to extend our physicochemical understanding of the underlying principles. The second part describes recent advances on miniaturization of nanosuspension production, to enable formulation screening during preclinical development. Finally, literature available on further nanosuspensions solidification is discussed, focussing on the maintenance of the preservation of the rapid dissolution properties of the nanocrystals after further downstream processing.

A screening study of surface stabilization during the production of drug nanocrystals

In order to establish a knowledge base for nanosuspension production, a screening was performed on 13 different stabilizers at 3 concentrations for 9 structurally different drug compounds. Concerning the stabilizers tested, the group of semi-synthetic polymers was the least performant (stable nanosuspensions were obtained in only 1 out of 10 cases). For the linear synthetic polymers, better results were obtained with povidones, however poly(vinyl alcohol) did not result in adequate stabilization. The synthetic copolymers showed even higher success rates, resulting in nanosuspensions in two out of three cases when applied at a 100 wt% concentration (relative to the drug weight). Finally, the surfactants gave the best results, with TPGS being successful at concentrations of 25 or 100 wt% of the drug weight for all compounds tested. From the point of view of drug compound, large differences could be observed upon evaluation of the relative number of formulations of that compound resulting in nanosuspensions. It was found that the hydrophobicity of the surfaces, as estimated by the adsorbed amount of TPGS per unit of surface area of nanosuspensions stabilized with 25 wt% TPGS, was decisive for the agglomeration tendency of the particles and hence the ease of nanosuspensions stabilization.

Drying of crystalline drug nanosuspensions-the importance of surface hydrophobicity on dissolution behavior upon redispersion.

d-alpha-Tocopherol polyethylene glycol 1000 succinate (TPGS)-stabilized nanosuspensions (25wt%, relative to the drug weight) were produced by media milling for 9 model drug compounds [cinnarizine, griseofulvin, indomethacin, itraconazole, loviride, mebendazole, naproxen, phenylbutazone and phenytoin]. After 3 months of storage at room temperature, Ostwald ripening occurred in all of the samples, except for indomethacin. Whereas lowering the temperature could slow down the ripening, it markedly increased upon storage at 40 degrees C. As for ripening, settling generally became more pronounced at 40 degrees C compared to 4 degrees C. As the nanosuspensions were afflicted by Ostwald ripening and settling, we explored nanosuspension drying as a strategy to circumvent these stability issues. Spray-drying and freeze-drying were evaluated for nanosuspensions and coarse reference suspensions of the compounds. Nanoparticle agglomeration could be visually observed in all of the powders. To evaluate the effect of agglomeration on the key characteristic of drug nanocrystals (i.e. rapid dissolution), dissolution experiments were performed under poor sink conditions. It was found that the compounds could be categorized into 3 groups: (i) compounds for which it was impossible to differentiate between coarse and nanosized products (griseofulvin, mebendazole, naproxen), (ii) compounds that gave clear differences in dissolution profiles between the nanosized and the coarse products, but for which drying of the nanosuspensions did not decrease the dissolution performance of the product (indomethacin, loviride, phenytoin) and (iii) compounds that showed differences between coarse and nanosized products, but for which drying of the nanosuspensions resulted in a significant decrease of the dissolution rate (cinnarizine, itraconazole, phenylbutazone). To gain insight on the influence of the drug compound characteristics on the dissolution of the dried products, the dissolution behavior of the compounds of the second and the third group was linked to the compounds characteristics. It was found that compounds with a more hydrophobic surface resulted in agglomerates which were harder to disintegrate, for which dissolution was compromised upon drying. The same was found for compounds having higher logP values.

Small Scale Screening To Determine the Ability of Different Polymers To Inhibit Drug Crystallization upon Rapid Solvent Evaporation

In this study, the ability of 7 chemically diverse polymers [Eudragit E100 (E100), poly(acrylic acid) (PAA), poly(vinylpyrrolidone) (PVP), poly(vinylpyrrolidone-vinyl acetate) (PVPVA), poly(styrene sulfonic acid) (PSSA), hydroxypropylmethylcellulose (HPMC) and hydroxypropylmethylcellulose acetate succinate (HPMCAS)] to inhibit the crystallization of 8 readily crystallizable model compounds [benzamide (BD), phenacetin (PH), flurbiprofen (FB), flufenamic acid (FFA), chlorpropamide (CP), chlorzoxazone (CZ), bifonazole (BI) and lidocaine (LI)] was investigated. Films of the different drug-polymer combinations were prepared by rapid evaporation from solution, using a spin coating method. A total of 7 different drug/polymer weight ratios [90/10, 75/25, 60/40, 50/50, 40/60, 25/75 and 10/90 (w/w)] were evaluated for each drug-polymer combination. Crystallization behavior of the films was monitored using polarized light microscopy over 7 days of room temperature storage under dry conditions. It was observed that compounds having a higher crystallization tendency for the pure compound tended to be more difficult to stabilize using the polymeric additives; more polymer was required. In addition, the stabilizing ability of the polymers varied considerably for the individual compounds, with the acidic polymers PAA and PSSA showing the most extreme behavior. The acidic polymers were good stabilizers for the drugs with basic and amide functional groups, but extremely poor stabilizers for acidic drugs. A reasonable correlation between crystallization inhibition in spin coated films versus bulk powders (prepared by rotary evaporation) was observed. The small scale screening method is thus a potentially useful technique to evaluate the role of drug-polymer chemistry in the stabilization of amorphous solid dispersions.

Solubility increases associated with crystalline drug nanoparticles: methodologies and significance.

In this manuscript, the determination of solubility of crystalline drug nanosuspensions by a range of methods is critically investigated. As the determinations of solubility were performed in the presence of the solubilizing nanosuspension stabilizer d-α-tocopherol polyethylene glycol 1000 succinate (TPGS), the potential effects of this excipient on the measurements were studied first. Solubility data of nanosuspensions of itraconazole, loviride, phenytoin and naproxen were generated using different methodologies. Data obtained using separation-based methodologies (centrifugation, filtration and ultracentrifugation) proved to be of limited use, due to poor nanoparticle separation efficiencies and/or significant adsorption of TPGS onto the nanoparticle surfaces. Light scattering and turbidity were found to be more suitable for the determination of nanosuspension solubility. The obtained data show that, unlike earlier reports, the solubility increases due to nanosizing are small, with measured increases of only 15%. These solubility increases are in fair agreement with what would be predicted based on the Ostwald-Freundlich equation.

Alternative matrix formers for nanosuspension solidification: Dissolution performance and X-ray microanalysis as an evaluation tool for powder dispersion

Four alternative matrix formers [Avicel PH101, Fujicalin (CaHPO(4)), Aerosil 200 (SiO(2)) and Inutec SP1] were evaluated for their capability in preserving rapid dissolution after spray-drying of nanosuspensions. Model drug compounds selected were cinnarizine (CIN), itraconazole (ITR) and phenylbutazone (PHB) as they showed a decrease in dissolution rate upon spray-drying in the absence of additional matrix formers, yielding release values after 5min of dissolution (release(5min)) of 57.7+/-1.0% (CIN), 56.3+/-3.8% (ITR) and 67.4+/-1.3% (PHB). Compared to the situation without matrix former inclusion, the performance of Avicel PH101 was good for CIN (release(5min)=90.9+/-7.7%), intermediate for PHB (release(5min)=81.0+/-6.4%) and poor for ITR (release(5min)=42.1+/-4.2%). For Fujicalin, intermediate (PHB: release(5min)=87.7+/-3.0%) or poor (CIN: release(5min)=66.1+/-3.4%; ITR: release(5min)=55.9+/-5.2%) performance was seen. Results for Aerosil 200 were good for all compounds (CIN: release(5min)=91.5+/-2.5%; ITR: release(5min)=83.8+/-3.4%; PHB: release(5min)=95.5+/-2.4%), indicating that the large specific surface area was in this case translated into good matrix forming capabilities. Finally, the best results were obtained for Inutec SP1 (CIN: release(5min)=88.7+/-1.2%; ITR: release(5min)=93.4+/-2.4%; PHB: release(5min)=101.3+/-4.9%). Except for Avicel PH101, Cl-maps from X-ray microanalysis of the itraconazole powders supported the hypothesis that better dispersion of drug in the powders results in faster dissolution.

Itraconazole/TPGS/Aerosil ® 200 solid dispersions Characterization, physical stability and in vivo performance

Solid dispersions were successfully prepared by co-spray-drying of TPGS-stabilized itraconazole nanosuspensions with Aerosil200, followed by heat treatment of the powders. The itraconazole/Aerosil200 weight ratios amounted to 50/50, 30/70, 40/60 and 20/80. The itraconazole content of the powders was close to the expected value, with relative errors between 0.3% and 7.8%. X-ray powder diffraction (XRPD), solid state NMR (SSNMR) and differential scanning calorimetry (DSC) evaluation on the powders revealed the formation of amorphous itraconazole and the absence of glassy itraconazole. Dissolution of the powders was enhanced compared to crystalline and glassy itraconazole (a 2-dimensional structured form of itraconazole). However, no clear trend could be observed between drug loading and dissolution performance of the solid dispersions. Upon storage, conversion to crystalline itraconazole was observed for the 50/50 powder based on XRPD, SSNMR and DSC measurements. Although the 40/60 powder remained X-ray amorphous upon storage, DSC did reveal that a small fraction (7.5+/-1.6% after 10 months of storage) of itraconazole crystallized upon storage. For the 30/70 and 20/80 dispersions, no crystallization could be seen. After 10 months of storage, important changes in the dissolution behavior of the powders were observed. A decrease in dissolution performance was seen for the 50/50 dispersion, which could be attributed to the crystallization of itraconazole. On the other hand, the 40/60, 30/70 and 20/80 dispersions showed an increase in dissolution rate (more than 60% after 10 min). Although not completely clear at this stage, adsorption of itraconazole onto the Aerosil200 surface during storage might be responsible for this behavior. Finally, in vivo experiments were performed in the rat. Oral bioavailability of the 30/70 dispersion was, although lower compared to the marketed Sporanox formulation, significantly enhanced compared to the crystalline drug.

Nanoscale Mid-Infrared Evaluation of the Miscibility Behavior of Blends of Dextran or Maltodextrin with Poly(vinylpyrrolidone)

Determining the extent of miscibility of amorphous components is of great importance for certain pharmaceutical systems, in particular for polymer-polymer and polymer-small molecule blends. In this study, the application of standard atomic force microscopy (AFM) measurements combined with nanoscale mid-infrared (mid-IR) spectroscopy was explored to evaluate miscibility in binary polymer blends. The miscibility characteristics of a set of 50/50 (w/w) polymer blends comprising of poly(vinylpyrrolidone) (PVP) with dextran or maltodextrin (DEX) of varying molecular weights (MWs) were investigated. Standard AFM characterization results show good agreement with inferences drawn from differential scanning calorimetry (DSC) analysis in terms of forming either single or two phase systems. AFM analysis also provided insight into the microstructure of the two phase systems and how domain sizes varied as a function of polymer MWs. Nanoscale mid-IR evaluation of the blends, performed by collecting local mid-IR spectra or spectral maps, provided an extra dimension of information about the dependence of polymer MWs on chemical composition of the different phases. AFM, combined with nanoscale mid-infrared analysis, thus appears to be a promising technique for the evaluation of miscibility in certain pharmaceutical blends.