An investigation into the formations of the internal microstructures of solid dispersions prepared by hot melt extrusion.

Hot melt extrusion (HME) is a widely used manufacturing process for pharmaceutical solid dispersions. The complexity of the HME formulations and the number of excipients used in the process are increasing with the advancement of the relevant knowledge. However, one of the areas that is still significantly lacking understanding is the control of internal microstructure of extrudates. Internal microstructure, consisting of voids, in hot melt extruded amorphous solid dispersions is often observed without the causes having been systemically investigated in the literature. In this study, we investigated a range of factors that demonstrated their impacts on the formation of the voids. These include the effect of the types of the materials (i.e. drug, polymer and additive) used in the formulation, the quantity of the drug and the additives used, the key extrusion processing parameters, the type of extruder, and the drying of the raw materials prior to extrusion. The results indicate that the appropriate viscosity and the presence of phase-separated particulates are essential for the formation of the voids. The particulates act as nuclei for the entrapped gas bubbles and the viscosity of the mixture during extrusion governs the collapse/escape of the bubbles. To minimise void formation, the results of this study indicate that slow screw speed, low moisture content of the raw materials, fewer particulates and the addition of lubricants, such as low melting lipid excipients, could be beneficial. This study systematically examines the mechanism of void formation in HME extrudates and generates new strategies that can be used to manage such void formations.

Mechanism of synergistic interactions and its influence on drug release from extended release matrices manufactured using binary mixtures of polyethylene oxide and sodium carboxymethylcellulose.

The ability of anionic polymer sodium carboxymethylcellulose to influence the release of four model cationic drugs (chlorpheniramine maleate, venlafaxine hydrochloride, propranolol hydrochloride and verapamil hydrochloride) from extended release (ER) hydrophilic matrices based on non-ionic polymer polyethylene oxide was investigated by X-ray photoelectron spectroscopy (XPS), isothermal titration calorimetry (ITC) and differential scanning calorimetry (DSC). For all studied APIs, a combination of polyethylene oxide with sodium carboxymethylcellulose produced slower drug release compared to the matrices of single polymers. This behaviour was mainly attributed to the interaction of ester/carboxylic acid functionalities to yield H-bonding between the anionic polymer groups and the additionally protonated N-atoms of the active substances. X-ray photoelectron and isothermal titration calorimetry studies confirmed drug-polymer interaction and polymer-polymer interaction (i.e. the PEO binding with negatively charged NaCMC), whilst differential scanning calorimetry indicated the existence of both crystalline and molecularly dispersed active forms in the created complexes. The drug release mechanisms were fitted to various models suggesting diffusion control for the majority of the formulations. The Korsmeyer-Peppas model was found to be the most suitable for description of release profiles of all formulations. The present study showed that XPS and ITC in combination with DSC can be valuable tool to investigate the presence and nature (mechanism) of synergistic interactions between polymers and drugs in extended release matrix tablets.

Preparation and optimization of PMAA-chitosan-PEG nanoparticles for oral drug delivery.

The objective of this study was to develop pH sensitive polymethacrylic acid-chitosan-polyethylene glycol (PCP) nanoparticles. This was achieved by dispersion polymerization of methacrylic acid (MAA), polyethylene glycol (PEG) and different chitosan (CS) grades in the presence of cross linking agent ethylene dimethacrylate (EDMA) and polymer initiator potassium persulphate. Method development was carried out by varying formulation parameters such as type of CS, ratio of PEG to CS, quantity of solvent and polymer initiator. Metoprolol (MTP) tartrate was incorporated into the nanoparticles (NPs) as a model drug. Laser diffraction, scanning electron microscopy (SEM) and transmission electron microscopy (TEM) studies revealed that the NPs were spherical with smooth surfaces ranging in size from 190 to 450 nm. X-ray diffraction (XRD) and differential scanning calorimetry (DSC) findings showed the presence of amorphous MTP in PCP NPs. The MTP loading of PCP and glycol chitosan (GC) NPs varied from 10 to 45% depending on the CS grade while both types of NPs showed excellent binding efficiency on mucin from porcine stomach. The in vitro dissolution study showed pH dependent release profiles suggesting that the PCP NPs system have great potential for oral controlled drug delivery as an alternative to conventional dosage forms.

Development and evaluation of cetirizine HCl taste-masked oral disintegrating tablets.

The purpose of the current study was to mask the taste of cetirizine HCl and to incorporate the granules produced in oral disintegrating tablets (ODT). The bitter, active substance was coated by fluidized bed coating using Eudragit® RL30-D at levels between 15% and 40% w/w. The ODTs were developed by varying the ratio of superdisintegrants such as sodium croscarmellose, crospovidone grades and low substituted hydroxypropyl cellulose (L-HPC). A direct compression process was used to compress the ODTs under various compaction forces to optimize tablet robustness. The properties of the compressed tablets including porosity, hardness, friability and dissolution profiles were further investigated. The in vitro and in vivo evaluation of the tablet disintegration times showed almost identical rapid disintegration below 10 s at the optimal levels of each superdisintegrant. Finally, the taste and sensory evaluation in human volunteers demonstrated excellence in masking the bitter active and tablet palatability.

Development and release mechanism of diltiazem HCl prolonged release matrix tablets.

A coated matrix tablet formulation has been used to develop controlled release diltiazem HCl (DIL) tablets. The developed drug delivery system provided prolonged drug release rates over a defined period of time. DIL tablets prepared using dry mixing and direct compression and the core consisted of hydrophilic and hydrophobic polymers such as hydroxypropylmethylcellulose (HPMC), Eudragits RLPO/RSPO, microcrystalline cellulose, and lactose. Tablets were coated with Eudragit NE 30D, and the influence of varying the inert hydrophobic polymers and the amount of the coating polymer were investigated. The release profile of the developed formulation was described by the Higuchi model. Stability trials up to 6 months displayed excellent reproducibility.

Diameter-selective solubilization of carbon nanotubes by lipid micelles.

The one-step dispersion of HiPco single-walled carbon nanotubes in aqueous media with the use of a synthetic lyso-phosphatidylcholine was studied. Solubilization occurs through wrapping of lipid molecules around the circumference of the tubes, yielding lipid monolayers on the graphitic sidewalls as evidenced by atomic force microscopy imaging and dynamic light scattering measurements. Raman spectroscopy showed that the dispersion and centrifugation process leads to an effective enrichment of the stable aqueous suspension in carbon nanostructures with smaller diameters.

In vitro-in vivo correlations of self-emulsifying drug delivery systems combining the dynamic lipolysis model and neuro-fuzzy networks.

The aim of the current study was to evaluate the potential of the dynamic lipolysis model to simulate the absorption of a poorly soluble model drug compound, probucol, from three lipid-based formulations and to predict the in vitro-in vivo correlation (IVIVC) using neuro-fuzzy networks. An oil solution and two self-micro and nano-emulsifying drug delivery systems were tested in the lipolysis model. The release of probucol to the aqueous (micellar) phase was monitored during the progress of lipolysis. These release profiles compared with plasma profiles obtained in a previous bioavailability study conducted in mini-pigs at the same conditions. The release rate and extent of release from the oil formulation were found to be significantly lower than from SMEDDS and SNEDDS. The rank order of probucol released (SMEDDS approximately SNEDDS > oil formulation) was similar to the rank order of bioavailability from the in vivo study. The employed neuro-fuzzy model (AFM-IVIVC) achieved significantly high prediction ability for different data formations (correlation greater than 0.91 and prediction error close to zero), without employing complex configurations. These preliminary results suggest that the dynamic lipolysis model combined with the AFM-IVIVC can be a useful tool in the prediction of the in vivo behavior of lipid-based formulations.

Using a modified shepards method for optimization of a nanoparticulate cyclosporine a formulation prepared by a static mixer technique.

An innovative methodology has been used for the formulation development of Cyclosporine A (CyA) nanoparticles. In the present study the static mixer technique, which is a novel method for producing nanoparticles, was employed. The formulation optimum was calculated by the modified Shepard's method (MSM), an advanced data analysis technique not adopted so far in pharmaceutical applications. Controlled precipitation was achieved injecting the organic CyA solution rapidly into an aqueous protective solution by means of a static mixer. Furthermore the computer based MSM was implemented for data analysis, visualization, and application development. For the optimization studies, the gelatin/lipoid S75 amounts and the organic/aqueous phase were selected as independent variables while the obtained particle size as a dependent variable. The optimum predicted formulation was characterized by cryo-TEM microscopy, particle size measurements, stability, and in vitro release. The produced nanoparticles contain drug in amorphous state and decreased amounts of stabilizing agents. The dissolution rate of the lyophilized powder was significantly enhanced in the first 2 h. MSM was proved capable to interpret in detail and to predict with high accuracy the optimum formulation. The mixer technique was proved capable to develop CyA nanoparticulate formulations.

Practical approaches of taste masking technologies in oral solid forms.

In the pharmaceutical industry, taste masking techniques are applied to prevent active pharmaceutical ingredients exhibiting a bitter and unpleasant taste. The oral administration of bitter drugs through solid dosage forms requires an acceptable degree of palatability, patient tolerance and significant therapeutic value. In the recent years, enormous progress in taste masking technologies has given rise to novel strategies such as fast dissolving dosage forms, chewable tablets and coating of molten materials. Similarly, common technologies applying double coating layers, microencapsulation or even chemical modification have been employed to improve patient compliance. This review endeavours to present the practical technologies and platforms applied for taste masking and indicate the most interesting features of each approach.

Physicochemical characterization of solid dispersions of three antiepileptic drugs prepared by solvent evaporation method.

We have investigated the solid dispersion and dissolution profiles of three antiepileptic drugs (carbamazepine (CBZ), oxcarbazepine (OXC) and rufinamide (RFN)) with different aqueous solubilities, prepared by the solvent evaporation method. Solid dispersions of the three drugs in hydroxy-propylmethylcellulose (HPMC), with drug:polymer ratios of 1:4, were prepared and characterized by differential scanning calorimetry (DSC), Fourier transformation infrared (FTIR) spectroscopy, X-ray diffraction (XRD) and scanning electron microscopy. The release mechanism was also investigated and the kinetic order of the solid dispersions was evaluated. It appeared that the dissolution behaviour depended on the physicochemical properties of the drug and drug-polymer interactions. DSC thermographs showed amorphous forms for all drugs confirmed by XRD patterns. The FTIR spectra of CBZ and OXC demonstrated drug interactions with HPMC through hydrogen polymer bonds. Thus, solid dispersions of these drugs had an improved dissolution profile. In contrast, solid dispersions of RUF showed modest enhancement of dissolution, suggesting negligible drug-polymer interactions. The different dissolution behaviour is attributed to the extent of interactions between the polymer hydroxyl group and the drug amide groups.

Drug release from differently structured monoolein/poloxamer nanodispersions studied with differential pulse polarography and ultrafiltration at low pressure.

Aqueous colloidal monoolein/poloxamer dispersions are under investigation as drug delivery systems. Depending on the composition and preparation procedure these dispersions may either contain predominantly vesicular particles or nanoparticles of cubic inner structure. To study the influence of ultrastructure on drug release, corresponding dispersions loaded with the model drugs diazepam (two different concentrations) and chloramphenicol were prepared by high-pressure homogenization with or without subsequent heat treatment. The dispersions were characterized with regard to particle size and their ultrastructure was confirmed with small angle X-ray diffractometry. Two techniques with high time resolution, differential pulse polarography (DPP) and ultrafiltration at low pressure were compared for their suitability to monitor rapid release from the dispersions. Instantaneous release was found for both drugs independent on the type of particle structure with the amount of released drug being controlled by the partition coefficient. Both release methods were suitable to monitor the rapid appearance of the releasable drug in the release medium.

Colloidal stability of carbon nanotubes in an aqueous dispersion of phospholipid.

Within the family of nanomaterials, carbon nanotubes (CNTs) have emerged as a new efficient scaffold for studying molecular interactions at interfaces. Poor dispersability of CNTs in any solvent presents a considerable drawback for the development of novel functional composite structures. Previous studies have demonstrated that the solubility of CNTs can be greatly enhanced by employing appropriate surfactants, some of them being biological molecules. In this work, we study the noncovalent wrapping of lipid chains onto the graphitic surface of single-walled material (SWCNTs) by electron microscopy and Raman spectroscopy. Stable and homogenous aqueous suspensions of SWCNTs in the presence of lipids have been prepared, whereas their electrophoretic mobility was confirmed by zeta-potential measurements. Raman measurements revealed that smaller diameter SWCNTs are preferentially dispersed by lipid molecules in the aqueous supernatant part of the prepared suspension.

Adaptive neuro-fuzzy modeling of poorly soluble drug formulations.

PURPOSE: The purpose of this study was to evaluate the efficiency of a neuro-fuzzy logic-based methodology to model poorly soluble drug formulations and predict the development of the particle size that has been proven to be an important factor for long-term stability. METHODS: An adaptive neuro-fuzzy inference system was used to model the natural structures within the data and construct a set of fuzzy rules that can subsequently used as a predictive tool. The model was implemented in Matlab 6.5 and trained using 75% of an experimental data set. Subsequently, the model was evaluated and tested using the remaining 25%, and the predicted values of the particle size were compared to the ones from the experimental data. The produced adaptive neuro-fuzzy inference system-based model consisted of four inputs, i.e., acetone, propylene glycol, POE-5 phytosterol (BPS-5), and hydroxypropylmethylcellulose 90SH-50, with four membership functions each. Moreover, 256 fuzzy rules were employed in the model structure. RESULTS: Model training resulted in a root mean square error of 4.5 x 10(-3), whereas model testing proved its highly predictive efficiency, achieving a correlation coefficient of 0.99 between the actual and the predicted values of the particle size (mean diameter). CONCLUSIONS: Neuro-fuzzy modeling has been proven to be a realistic and promising tool for predicting the particle size of drug formulations with an easy and fast way, after proper training and testing.