Hisham Al-Obaidi

Anomalous properties of spray dried solid dispersions

The use of solid dispersions for oral dosage forms can increase the dissolution rate of poorly soluble drugs. Spray drying is one process that can be used to prepare solid dispersions. Spray dried solid dispersions of griseofulvin, poly[N-(2-hydroxypropyl)methacrylate] (PHPMA) and polyvinylpyrrolidone (PVP) were prepared from acetone and water. When methanol was substituted for water, the morphology, stability and dissolution properties of the solid dispersion changed dramatically. The glass transition temperature for the ternary solid dispersion (GF, PHPMA, and PVP) shifted from 83 degrees C (acetone/water) to 103 degrees C for the acetone/methanol system. These differences in the dispersions are thought to derive from conformational variations of the polymers in solution prior to spray drying. Both PHPMA and PVP formed globules in solution of a size range between 16 and 33 nm. The effect of drug and polymer concentration in solution (before spray drying) on the properties of the solid dispersion was studied. It was found that solid dispersions that were prepared using lower concentrations of drug and polymers in solutions resulted in the formation of particles that display a lower relaxation rate. This result supports the hypothesis that the polymer conformation may significantly change the properties of the solid dispersion.

Characterization and stability of ternary solid dispersions with PVP and PHPMA

The effect of adding a third polymer to immiscible binary solid dispersions was investigated. The model actives griseofulvin (GF), progesterone (PG) and phenindione (PD) were selected because they exemplify a key property of many poorly soluble molecules of having at least one hydrogen bonding acceptor moiety while not having any hydrogen bond donating moieties. Ternary solid dispersions of the drug, PVP (polyvinylpyrrolidone) (proton acceptor) and PHPMA (poly[2-hydroxypropyl methacrylate]) (proton acceptor and donor) were prepared by spray drying. Stability results showed that binary solid dispersions (API and PVP) of GF and PVP crystallized quickly while the amorphous form was not possible to prepare for PG and PD. The amorphous form was prolonged upon the incorporation of PHPMA in the solid dispersion (API, PHPMA and PVP). Based on measuring the melting points, the energy of mixing the drug with the polymer was calculated using the Flory-Huggins theory. The results showed that GF had the lowest free energy followed by PG and finally PD which agreed well with the stability results. These results suggest that the addition of a third polymer to immiscible binary solid dispersions can significantly improve the stability of the amorphous form.

Investigation of preparation methods on surface/bulk structural relaxation and glass fragility of amorphous solid dispersions

The objective of this study was to investigate the effect of preparation methods on the surface/bulk molecular mobility and glass fragility of solid dispersions. Solid dispersions containing indomethacin and PVP K30 were chosen as the model system. An inverse gas chromatography method was used to determine the surface structural relaxation of the solid dispersions and these data were compared to those for bulk relaxation obtained by DSC. The values of τ(β) for the surface relaxation were 4.6, 7.1 and 1.8h for melt quenched, ball milled and spray dried solid dispersions respectively, compared to 15.6, 7.9 and 9.8h of the bulk. In all systems, the surface had higher molecular mobility than the bulk. The glass fragility of the solid dispersions was also influenced by the preparation methods with the most fragile system showing the best stability. The zero mobility temperature (T(0)) was used to correlate with the physical stability of the solid dispersions. Despite having similar T(g) (65°C), the T(0) of the melt quenched, ball milled and spray dried samples were 21.6, -4.2 and 16.7°C respectively which correlated well with their physical stability results. Therefore, T(0) appears to be a better indicator than T(g) for predicting stability of amorphous materials.

Investigation of griseofulvin and hydroxypropylmethyl cellulose acetate succinate miscibility in ball milled solid dispersions.

Solid dispersions of varying weight ratios compositions of the nonionic drug, griseofulvin and the hydrophilic, anionic polymer, hydroxylpropylmethyl cellulose acetate succinate, have been prepared by ball milling and the resulting samples characterized using a combination of Fourier transform infra-red spectroscopy, X-ray powder diffraction and differential scanning calorimetry. The results suggest that griseofulvin forms hydrogen bonds with the hydroxylpropylmethyl cellulose acetate succinate polymer when prepared in the form of a solid dispersion but not when prepared in a physical mixture of the same composition. As anticipated, the actual measured glass transition temperature of the solid dispersions displayed a linear relationship between that predicted using the Gordon-Taylor and Fox equations assuming ideal mixing, but interestingly only at griseofulvin contents less than 50 wt%. At griseofulvin concentrations greater than this, the measured glass transition temperature of the solid dispersions was almost constant. Furthermore, the crystalline content of the solid dispersions, as determined by differential scanning calorimetry and X-ray powder diffraction followed a similar trend in that the crystalline content significantly decreased at ratios less than 50 wt% of griseofulvin. When the physical mixtures of griseofulvin and the hydroxylpropylmethyl cellulose acetate succinate polymer were analyzed using the Flory-Huggins model, a negative free energy of mixing with an interaction parameter of -0.23 were obtained. Taken together these results suggest that anionic hydrophilic hydroxylpropylmethyl cellulose acetate succinate polymer is a good solvent for crystalline nonionic griseofulvin with the solubility of griseofulvin in the solid dispersion being was estimated to be within the range 40-50 wt%. Below this solubility limit, the amorphous drug exists as amorphous glassy solution while above these values the system is supersaturated and glassy suspension and solution may coexist.

Effect of drug-polymer interactions on the aqueous solubility of milled solid dispersions

The role of molecular interactions in ball milled solid dispersions in determining the aqueous solubility of the poorly water-soluble drug, griseofulvin (GF) has been examined. Ball milled solid dispersions of GF and hydroxypropylmethylcellulose acetate succinate (HPMCAS) and GF and polyvinylpyrrolidone (PVP) were prepared and characterized by laser diffraction, scanning electron microscopy and X-ray powder diffraction and the aqueous saturation solubility measured and analyzed using one way ANOVA. The results showed that solid dispersions of GF and HPMCAS possessed an aqueous GF saturation solubility of about ten times higher than the GF solubility achieved from PVP-based solid dispersions. Furthermore, although the aqueous solubility of GF did not vary with the milling conditions used to prepare the solid dispersions with PVP, significant changes in solubility were observed upon changing the milling conditions for preparation of the GF/HPMCAS solid dispersions. Surprisingly, the GF/HPMCAS solid dispersion prepared using spray drying exhibited a significantly lower aqueous solubility than those prepared by bead milling despite their smaller particle size and GF being fully in its amorphous form. It is thought that the higher surface energy of the spray-dried solid dispersions negatively affected the aqueous solubility of GF. In conclusion, the results suggest that the molecular interactions occurring between GF and HPMCAS affect the aqueous solubility of GF and that the molecular interactions appear to remain in the liquid state. In contrast no molecular interactions were evident in the GF/PVP solid dispersions.

Dynamics of microparticles inside lipid vesicles: movement in confined spaces

Microparticles and nanoparticles used in drug delivery frequently depend on their movement in confined spaces such as cells. Liposomes containing small numbers of 1-µm diameter polystyrene particles were used to study the dynamics of their movement within the confined space of the liposome interior. The analysis of the trajectories of single and multiple entrapped particles revealed that the particles were largely localized toward the periphery of the liposome with a rare presence in the centre. Interparticle interactions were studied by calculating interparticle distances, ranging from close to zero to around 8 µm with a mean of ∼4 µm. The diffusion coefficient of a single entrapped particle was D = 0.27 × 10−9 cm2 s−1 when compared with 5.1 × 10−9 cm2 s−1 free in water. When more than one particle was entrapped, the calculated diffusion coefficients were D = 0.61 × 10−9 cm2 s−1 for two particles, D = 1.26 × 10−9 cm2 s−1 for three particles, and D = 1.3 × 10−9 cm2 s−1 for multiple particles). Particle movement was found to be distinctly faster at the periphery (average velocity 21.4 μm s−1) than at the centre of the vesicle (average velocity 14.2 μm s−1). These results demonstrate the significance of particle–particle interactions as well as particle–surface interactions, which is evident here in some systems by particle aggregation close to the liposome membrane.

Atypical effects of incorporated surfactants on stability and dissolution properties of amorphous polymeric dispersions

To understand the impact of ionic and non‐ionic surfactants on the dissolution and stability properties of amorphous polymeric dispersions using griseofulvin (GF) as a model for poorly soluble drugs.

Fabrication of inhaled hybrid silver/ciprofloxacin nanoparticles with synergetic effect against Pseudomonas aeruginosa

Graphical abstract Figure. No caption available. Abstract Ciprofloxacin (CFX) is a fluoroquinolone antibiotic used as a first line treatment against infections caused by Pseudomonas aeruginosa and Streptococcus pneumonia that are commonly acquired by cystic fibrosis (CF) patients. However, no inhalation formulation is currently available for ciprofloxacin. Hybrid silica coated silver nanoparticles were prepared using Stöber reaction and the optimum ratio of chitosan and sodium tripolyphosphate was used to encapsulate CFX. Particle deposition was assessed in vitro using twin stage impinger while antimicrobial activity was evaluated based on the planktonic growth of P. aeruginosa as well as against P. aeruginosa sp biofilm formation. In vitro deposition results showed significant deposition in stage 2 using twin stage impinger (TSI) (˜70%). Compared to CFX, the formed hybrid nanoparticles were 3–4 folds more effective against inhibiting growth and biofilm formation by P. aeruginosa PAO1 and P. aeruginosa NCTC 10662.

Amorphous and Crystalline Particulates: Challenges and Perspectives in Drug Delivery

Crystalline and amorphous dispersions have been the focus of academic and industrial research due to their potential role in formulating poorly water-soluble drugs. This review looks at the progress made starting with crystalline carriers in the form of eutectics moving towards more complex crystalline mixtures. It also covers using glassy polymers to maintain the drug as amorphous exhibiting higher energy and entropy. However, the amorphous form tends to recrystallize on storage, which limits the benefits of this approach. Specific interactions between the drug and the polymer may retard this spontaneous conversion of the amorphous drug. Some studies have shown that it is possible to maintain the drug in the amorphous form for extended periods of time. For the drug and the polymer to form a stable mixture they have to be miscible on a molecular basis. Another form of solid dispersions is pharmaceutical co-crystals, for which research has focused on understanding the chemistry, crystal engineering and physico-chemical properties. USFDA has issued a guidance in April 2013 suggesting that the co-crystals as a pharmaceutical product may be a reality; but just not yet! While some of the research is still oriented towards application of these carriers, understanding the mechanism by which drug-carrier miscibility occurs is also covered. Within this context is the use of thermodynamic models such as Flory-Huggins model with some examples of studies used to predict miscibility.