An investigation on the correlation between drug dissolution properties and the growth behaviour of granules in high shear mixer

Objectives The aim of this study was to investigate the correlation between the growth behaviour and in‐vitro dissolution rate of water‐insoluble drugs prepared with high‐shear wet granulation. Methods Granules containing nimodipine, microcrystalline cellulose, low‐substituted hydroxypropylcellulose and aqueous solution of hydroxypropylcellulose were prepared and the effects of independent process variables, including impeller speed and liquid‐to‐solid ratio were taken into consideration. The mean granule size, granule‐size distribution (GSD), porosity and surface properties were monitored at different kneading times to identify the granule‐growth mechanisms simultaneously. A computer‐based method was applied to simulate the dissolution behaviour of polydisperse granules based on the GSD data. Key findings The in‐vitro dissolution rate of drug was high for the early stages of granulation and sharply decreased when coalescence and consolidation of granules started, approaching a flat and low level when granules were sufficiently consolidated. The simulated dissolution results were in agreement with experimental observations and were significantly affected by the GSD, porosity and surface properties of granules during the granulation process. Moreover the GSD was directly related to the granule‐growth behaviour and mechanisms. Conclusions In general, it was concluded that the dissolution properties of nimodipine basically correlated with the growth behaviour of granules in a high‐shear mixer. The simulation method based on GSD can be used as a convenient and rapid way to predict the dissolution properties for formulation development and granulation optimization.     

Engineering polymer blend microparticles: An investigation into the influence of polymer blend distribution and interaction

The aim of this work was to understand the influence of polymer interaction and distribution on drug release from microparticles fabricated from blends of polymers. Blends of pH dependent polymer (Eudragit S, soluble above pH 7) and pH independent polymer (Eudragit RL, Eudragit RS or ethylcellulose) were incorporated into prednisolone loaded microparticles using a novel emulsion solvent evaporation method. Microparticles fabricated from blends of Eudragit S and Eudragit RL or RS did not modify drug release compared to microparticles fabricated from Eudragit S alone. This can be attributed to the high degree of miscibility of Eudragit S with Eudragit RS or Eudragit RL within the microparticles as confirmed by glass transition temperature measurements and confocal laser scanning microscopy. In contrast, microparticles prepared from blends of Eudragit S (75%) and ethylcellulose (25%) extended the release of prednisolone at pH 7.4 (compared to Eudragit S microparticles). This change in release profile was related to the immiscibility of Eudragit S and ethylcellulose as assessed by thermal analysis, and confirmed by microscopy which showed pores within the microparticle structures following dissolution of the Eudragit S domains. The ability of water insoluble polymers to extend drug release from enteric polymer microparticles is dependent on the miscibility and interaction of the polymers. This knowledge is important in the design of pH responsive microparticles capable of extending drug release in the gastrointestinal tract.     

An investigation into the critical surfactant concentration for solid solubility of hydrophobic drug in different polyethylene glycols

Solid dispersions of 10% w/w griseofulvin in different polyethylene glycols (PEGs) with or without incorporation of alkali dodecyl sulphates (MDS) were prepared by the melting method. The investigations concerned the solid state (X-ray powder diffraction), the transition from solid to liquid state (Oscillating DSC) and the liquid state (low frequency dielectric spectroscopy). The critical concentrations of SDS for the formation of solid solutions in varying PEGs were evaluated. In PEG 3000 this formation occurs at 1.4% w/w SDS, whereas PEG 6000 and PEG 20 000 require solely 1.0% w/w SDS to transfer a dispersion into a solid solution. PEG 3000 was also investigated with the addition of MDS. The critical surfactant concentrations for the formation of solid solutions with the counterions Li ⁺, Na ⁺ and K ⁺ were 1.0%, 1.4% and 2.1% w/w, respectively. The investigated systems had varying degrees of crystallinity. With the addition of SDS to PEGs with a range of molecular weights, the highest crystallinity was seen in the PEG 3000 sample. The different polymers contained different amounts of folded and extended chains which influences the amount of amorphous material within the polymer structure. When surfactants with different counterions were added to PEG 3000, the lithium sample showed the highest crystallinity. In the melt the Li ⁺ sample showed the lowest dielectric mobility. The results show that concentration and structure of surfactant together with the presence of folded and extended chains form the conditions for the formation of solid solutions.     

An investigation into the characteristics and drug release properties of multiple W/O/W emulsion systems containing low concentration of lipophilic polymeric emulsifier

Multiple W/O/W emulsions with high content of inner phase (Phi1=Phi2=0.8) were prepared using relatively low concentrations of lipophilic polymeric primary emulsifier, PEG 30-dipolyhydroxystearate, and diclofenac diethylamine (DDA) as a model drug. The investigated formulations were characterized and their stability over the time was evaluated by dynamic and oscillatory rheological measurements, microscopic analysis and in vitro drug release study. In vitro release profiles of the selected model drug were evaluated in terms of the effective diffusion coefficients and flux of the released drug. The multiple emulsion samples exhibited good stability during the ageing time. Concentration of the lipophilic primary emulsifier markedly affected rheological behaviour as well as the droplet size and in vitro drug release kinetics of the investigated systems. The multiple emulsion systems with highest concentration (2.4%, w/w) of the primary emulsifier had the lowest droplet size and the highest apparent viscosity and highest elastic characteristics. Drug release data indicated predominately diffusional drug release mechanism with sustained and prolonged drug release accomplished with 2.4% (w/w) of lipophilic emulsifier employed.     

Influence of sulfobutyl ether beta-cyclodextrin (Captisol) on the dissolution properties of a poorly soluble drug from extrudates prepared by hot-melt extrusion

The aim of this study was to investigate the influence of sulfobutyl ether β-cyclodextrin (SBE₇-β-CD; Captisol^®) on the dissolution properties of a poorly water-soluble drug from extrudates prepared by hot-melt extrusion. Ketoprofen was employed as a model drug. Extrudates containing the parent β-cyclodextrin (β-CD) were also produced for comparative evaluation to assess the benefits of SBE₇-β-CD. Hot-melt extrudates were produced at 100 °C, which was close to the melting point of ketoprofen. The physiochemical properties and the in vitro drug release properties of ketoprofen from extrudates were investigated and compared with samples prepared by physical mixing, co-grinding, freeze-drying and heat-treatment. The solubilizing effects and the interactions of ketoprofen with SBE₇-β-CD and β-CD were investigated using phase solubility and NMR studies, respectively. The dissolution rate of ketoprofen from samples prepared by hot-melt extrusion with SBE₇-β-CD was significantly faster than both the physical mixture and the hot-melt extrudates prepared with the parent β-CD. Moisture absorption studies revealed that the hygroscopic nature of SBE₇-β-CD led to particle aggregation and a corresponding decrease in drug release rate for all samples. However, the samples prepared by melt extrusion were least affected by exposure to elevated humidity.     

Modeling heterogeneity of properties and random effects in drug dissolution

Purpose. To investigate new models characterizing dissolution data obtained for heterogenous materials (model I) and under randomly time-varying conditions (model II). Methods. In model I, the heterogeneity of the dissolving substance introduces variation of the fractional dissolution rate. In model II, the fractional dissolution rate evolves randomly, and thus the dissolution has the characteristics of a stochastic process. This situation is studied for the constant and time-dependent means of the dissolution rate. Results. The time dynamics of the dissolved fraction is presented for model I. The standard characteristics of dissolution are derived under general conditions and for several examples. One of them is in accordance with a function found empirically (1). A duality between the time-dependency of the fractional dissolution rate and the heterogeneity of the substance is investigated. The mean and variance of the dissolved fraction are calculated for model II. A method for estimating the mean dissolution rate is proposed and illustrated using Monte-Carlo experiments. Conclusions. It follows from model I that the heterogeneity, with the same mean properties, slows down the dissolution with respect to the homogeneous case. The second approach permits predictions about the role of the stochastic fluctuations of the dissolution rate and to establish the boundaries for the dissolution profiles.     

An in vitro investigation for vaginal bioadhesive formulations: bioadhesive properties and swelling states of polymer mixtures

Bioadhesive tablet formulations have been developed for mucosal application. Sixteen different bioadhesive tablet formulations were prepared and evaluated. Their bioadhesion to vaginal mucosa were studied by tensile testing method. The swelling behaviour of the tablets in three different solutions was also investigated. In addition, the effect of the formulations on pH of the medium was followed. The most favorable formulation resulted a mixture of Carbopol 934 and Pectin (2:1). The highest bioadhesive strength, the highest swelling volume and the lowest pH reduction were obtained with this formulation.     

Amphetamine and N-acetylamphetamine incorporation into hair: an investigation of the potential role of drug basicity in hair color bias

To elucidate the role of drug basicity in the preferential incorporation of certain drugs into dark hair rather than light hair, Long-Evans rats were dosed with amphetamine or its non-basic analogue N-acetylamphetamine (N-AcAp) and their hair evaluated for drug content. Rats were shaved prior to dosing. On the 14th day after dosing, hair from the same area that was shaved prior to dosing was shaved and collected. After the addition of amphetamine-d3 or N-AcAp-d3 as an internal standard, hair samples (20 mg) were digested in 1M NaOH at 37 degrees C. Digested solutions were then extracted with n-butyl chloride/chloroform (4:1, v/v). After drying and reconstituting, samples were injected onto a ThermoQuest TSQ liquid chromatography-tandem mass spectrometry instrument for analysis. Black hair from rats dosed with amphetamine (n = 8) was found to contain 6.44 +/- 1.31 (SD) ng amphetamine/mg hair. White hair from the same rats contained 2.04 +/- 0.58 ng amphetamine/mg hair. In contrast, no difference in N-AcAp content was found between black hair (0.87 +/- 0.08 ng N-AcAp/mg hair) and white hair (0.83 +/- 0.15 ng N-AcAp/mg hair) from rats dosed with N-AcAp (n = 8).     

An investigation into the mechanisms of drug release from taste-masking fatty acid microspheres

Fatty acid microspheres based on stearic and palmitic acids are known to form effective taste masking systems, although the mechanisms by which the drug is preferentially released in the lower gastrointestinal tract are not known. The objective of the present study was to identify the mechanisms involved, with a particular view to clarify the role of acid soap formation in the dissolution process. Microspheres were prepared by a spray chilling process. Using benzoic acid as a model drug and an alkaline dissolution medium, a faster drug release was observed in the mixed fatty acid formulation (50:50 stearic:palmitic acid (w/w)) compared to the single fatty acid component systems. Thermal and powder X-ray diffraction studies indicated a greater degree of acid soap formation for the mixed formulation in alkaline media compared to the single fatty acid systems. Particle size and porosity studies indicated a modest reduction in size for the mixed systems and an increase in porosity on immersion in the dissolution medium. It is proposed that the mixed fatty acid system form a mixed crystal system which in turn facilitates interaction with the dissolution medium, thereby leading to a greater propensity for acid soap formation which in turn forms a permeable liquid crystalline phase through which the drug may diffuse. The role of dissolution of palmitic acid into the dissolution medium is also discussed as a secondary mechanism.     

Novel treatments for allergic rhinitis: An investigation into the role of bradykinin in the human nasal airway

This paper presents a review of the current literature concerning bradykinin and allergic rhinitis and presents novel data investigating the role of bradykinin in the human nasal airway. Studies are being carried out at the present time to investigate the effect of L-NAME on challenge with antigen in subjects with seasonal and perennial allergic rhinitis. No final data are yet available but initial results indicate that, in seasonal allergic rhinitis, L-NAME antagonizes the increase in vascular permeability induced by grass challenge. Future advances in understanding allergic rhinitis will be targeted at a number of inflammatory mediators; however, this paper demonstrates the role bradykinin plays in inflammation of the nasal tissues.     

An investigation into the release of cefuroxime axetil from taste-masked stearic acid microspheres: Part 1: The influence of the dissolution medium on the drug release profile and the physical integrity of the microspheres

The dissolution properties of stearic acid-coated cefuroxime axetil (SACA) systems have been studied with a view to investigating the effects of the dissolution medium on both the release rate and the physical integrity of the microspheres. The release from the spheres was found to be highly dependent on the media used, with systems in distilled water (pH 6.8) and pH 5.9 Sorensens modified buffer showing a relatively slow release which exhibited linearity with the square root of time, implying a diffusion process. The rate of release from systems in pH 7.0 and 8.0 buffer was considerably faster and did not follow simple diffusion kinetics. Examination of the microspheres after immersion in the various media indicated a change in the integrity of the spheres in those media which showed the most rapid release. This was particularly marked when the systems were dried in buffer, with disintegration seen in the higher pH systems. It is suggested that the release of the drug is dependent both on diffusion through the intact microspheres and changes in the physical integrity of the spheres as a result of a reaction with the surrounding medium.     

An investigation into the influence of binary drug solutions upon diffusion and partition processes in model membranes

Few studies have assessed the impact of binary systems on the fundamental mathematical models that describe drug permeation. The aim of this work was to determine the influence of varying the proportions of prilocaine and lidocaine in a binary saturated solution on mass transfer across synthetic membranes. Infinite‐dose permeation studies were performed using Franz diffusion cells with either regenerated cellulose or silicone membranes, and partition coefficients were determined by drug loss over 24 h. There was a linear relationship between the flux of prilocaine and lidocaine through regenerated cellulose membrane (R² ≥ 0.985, n = 5) and their normalised ratio in solution. This linear model was also applicable for the permeation of prilocaine through silicone membrane (R² = 0.991, n = 5), as its partition coefficient was independent of the drug ratio (15.84 ± 1.41). However, the partition coefficient of lidocaine increased from 27.22 ± 1.68 to 47.03 ± 3.32 as the ratio of prilocaine increased and this resulted in a non‐linear relationship between permeation and drug ratio. Irrespective of the membrane used, the permeation of one drug from a binary system was hindered by the presence of the second, which could be attributed to a reduction in available membrane diffusion volume.     

An investigation into the adjuvanticity and immunogenicity of zein microspheres being researched as drug and vaccine carriers

We have determined whether zein microspheres could act as vaccine adjuvants i.e. increase the immune responses to co-administered immunogens. Ovalbumin (model antigen)-loaded zein microspheres, blank zein microspheres and ovalbumin solution were intramuscularly administered to mice and the sera antibody levels were determined by ELISA. Another group of mice was orally dosed with blank zein microspheres, and serum and faecal antibody levels were determined. As expected, negligible antibody titres were obtained with the ovalbumin solution. Surprisingly, intramuscular administrations of blank zein microspheres elicited high levels of serum IgG which bound to the ovalbumin antigen coated on ELISA microtitre plates. This indicated that anti-zein antibodies had been elicited by blank zein microspheres and that these antibodies were cross-reacting with ovalbumin antigen coated onto ELISA plates. Such cross-reactivity inhibited the determination of the adjuvant activity of zein microspheres, if any. Additional ELISA assays, where zein was used as the coating antigen, confirmed the generation of anti-zein antibodies by blank zein microspheres i.e. zein microspheres were immunogenic following intramuscular administration. Upon oral administration of blank zein microspheres, serum IgG levels remained low but intestinal IgA levels increased following booster doses i.e. systemic tolerance, but not mucosal tolerance, to oral zein particles was achieved. Zein microspheres were immunogenic when administered intramuscularly and orally.     

Drugs and sexual effects: role of drug type and gender

This study investigated gender differences in the relationship between psychoactive substance use and sexual thoughts, feelings, and behaviors. Participants (N = 464) were male and female alcohol, opiate, cocaine, and methamphetamine users enrolled in an outpatient treatment program at any of 8 sites. A self-report survey that inquired about the specific sexual thoughts, feelings, and behaviors of the participant during previous instances of being under the influence of their primary drug of dependence served as the data source. The results indicate that different categories of psychoactive agents were associated with different effects on sexual behavior, and that those effects vary by gender. Development of a valid measure assessing the type and strength of these relationships may be beneficial for use by treatment programs in promoting abstinence from drug and alcohol use and preventing relapse.     

An investigation into the effect of formulation variables and process parameters on characteristics of granules obtained by in situ fluidized hot melt granulation

The aim of this study was to investigate the influence of binder content, binder particle size, granulation time and inlet air flow rate on granule size and size distribution, granule shape and flowability, as well as on drug release rate. Hydrophilic (polyetilenglycol 2000) and hydrophobic meltable binder (glyceryl palmitostearate) were used for in situ fluidized hot melt granulation. Granule size was mainly influenced by binder particle size. Binder content was shown to be important for narrow size distribution and good flow properties. The results obtained indicate that conventional fluid bed granulator may be suitable for production of highly spherical agglomerates, particularly when immersion and layering is dominant agglomeration mechanism. Granule shape was affected by interplay of binder content, binder particle size and granulation time. Solid state analysis confirmed unaltered physical state of the granulate components and the absence of interactions between the active and excipients. Besides the nature and amount of binder, the mechanism of agglomerate formation seems to have an impact on drug dissolution rate. The results of the present study indicate that fluidized hot melt granulation is a promising powder agglomeration technique for spherical granules production.     

Viscosimetric investigation of the interaction between sodium dodecylsulfate micelles and a polymer drug carrier

The viscosities of aqueous sodium dodecyl sulfate solutions with and without α,β-poly(N-hydroxyethyl)-dl-aspartamide (PHEA), at 15, 25 and 35°C are reported. The viscosities of SDS and of PHEA aqueous solutions are discussed in terms of the parameter − 1)/φ] describing the non-ideal behavior of SDS micelles and of PHEA macromolecules. The viscosities of SDS plus PHEA aqueous solutions, discussed in terms of the parameter F [F = η_rel(PHEA) + η_rel(SDS) − η_rel(SDS + PHEA)]M, demonstrate the occurrence of interactions between SDS micelles and the PHEA macromolecule. Both D and F are scarcely influenced by temperature variation.