Wantanee Phuapradit

Effect of formulation and process variables on porosity parameters and release rates from a multi unit erosion matrix of a poorly soluble drug

The effect of drug loading, water required for granulation and spheronization time on porosity parameters (intrusion-extrusion isotherms, pore size distribution, total pore surface area, mean pore diameter, shape and morphology of pores) and drug release rates from pellets of a poorly soluble drug was investigated. Porosity parameters were determined by mercury intrusion porosimetry. The drug loading was found to have a profound effect on the porosity parameters. Pellets with low drug loading showed increased pore surface area with small mean pore diameters and an increased number of total pores. On the other hand, pellets with high drug loading had decreased pore surface areas with larger mean pore diameters and a reduction in the total number of pores. With high drug loading, the drug release rate decreased. Water required for granulation had a direct effect on the total porosity of the pellets. Spheronization time from 2 to 10 min had a pronounced effect on porosity parameters and release rates. No changes in porosity parameters and release rates were observed from 10 to 20 min of spheronization time. It was shown that each porosity parameter investigated was well correlated with drug release rates and thus it is important to study the effect of porosity parameters in evaluating the in vitro performance of the multi-unit erosion matrix for the controlled release of a poorly soluble drug.

Release performance of a poorly soluble drug from a novel, Eudragit-based multi-unit erosion matrix.

Mechanisms governing the release of drugs from controlled delivery systems are mainly diffusion, osmosis and erosion. For poorly soluble drugs, the existing mechanisms are limited to osmosis and matrix erosion, that are commonly observed in single unit matrix dosage forms. This study reports formulation and dissolution performance of Eudragit L 100 55 and Eudragit S 100 based multi-unit controlled release system of a poorly soluble thiazole based leukotriene D(4) antagonist, that was obtained by an extrusion/spheronization technique. Effect of triethyl citrate, that was incorporated in the matrix, on the dissolution performance of the drug was also evaluated. In vitro matrix erosion and drug release from the pellets were determined by the use of USP Dissolution Apparatus I, pH 6.8 phosphate buffer, gravimetry and UV spectrophotometry, respectively. Results obtained demonstrated that matrix erosion and drug release occurred simultaneously from the pellets. Pellets eroded with a consequent reduction in size without any change in the pellet geometry for over 12 h. Matrix erosion and drug release followed zero order kinetics. Data obtained strongly suggested a polymer controlled, surface erosion mechanism.

Development of novel microprecipitated bulk powder (MBP) technology for manufacturing stable amorphous formulations of poorly soluble drugs.

A novel method was developed to manufacture amorphous formulations of poorly soluble compounds that cannot be processed with existing methods such as spray drying and melt extrusion. The manufacturing process and the characterization of the resulting amorphous dispersion are presented via examples of two research compounds. The novel process is utilized N,N-dimethylacetamide (DMA) to dissolve the drug and the selected ionic polymer. This solution is then co-precipitated into aqueous medium. The solvent is extracted out by washing and the co-precipitated material is isolated by filtration followed by drying. The dried material is referred to as microprecipitated bulk powder (MBP). The amorphous form prepared using this method not only provides excellent in vitro and in vivo performance but also showed excellent stability. The stabilization of amorphous dispersion is attributed to the high T(g), ionic nature of the polymer that help to stabilize the amorphous form by possible ionic interactions, and/or due to the insolubility of polymer in water. In addition to being an alternate technology for amorphous formulation of difficult compounds, MBP technology provides advantages with respect to stability, density and downstream processing.

Multi-unit controlled release systems of Nifedipine and Nifedipine:Pluronic® F-68 solid dispersions: Characterization of release mechanisms

ABSTRACT Nifedipine (N) and nifedipine:Pluronic® F-68 solid dispersion (SD) pellets were developed and characterized for drug release mechanisms from a multi-unit erosion matrix system for controlled release. Nifedipine was micronized using a jet mill. Solid dispersion with Pluronic F-68 was prepared by the fusion method. Nifedipine and SD were characterized by particle size analysis, solubility, differential scanning calorimetry (DSC), and x-ray diffraction (XRD) studies. Samples were subsequently processed into matrix pellets by extrusion/spheronization using Eudragit® L 100-55 and Eudragit® S 100 as release rate-controlling polymers. Drug release mechanisms from pellets were characterized by microscopy and mercury intrusion porosimetry; DSC and XRD studies indicated no polymorphic changes in N after micronization and also confirmed the formation of SD of N with Pluronic F-68. Pellets of N showed a 24-hr drug release profile following zero-order kinetics. Pellets of SD showed a 12-hr release profile following first-order kinetics. Aqueous solubility of N after SD formation was found to be increased 10-fold. Due to increased solubility of N in SD, the drug release mechanism from the multi-unit erosion matrix changed from pure surface erosion to an erosion/diffusion mechanism, thereby altering the release rate and kinetics.

In Vitro Characterization of Polymeric Membrane used for Controlled Release Application

AbstractThe application of a polymer film coat is a common practice in the preparation of controlled release dosage forms. In vitro characterization of the polymeric membrane is essential for optimization of the membrane formulation. Polymers selected in this study were cellulose acetate (CA), ethylcellulose (EC) and copolymers of acrylic and methacrylic esters (Eudragit RL100). Plasticizers used in this study were dibutyl sebacate (DBS), triethyl citrate (TEC) and triacetin. Polymer dispersions containing different plasticizers were cast into membranes on a tefloncoated plate. The resulting membranes were evaluated for permeability and mechanical properties. Membrane permeability was determined by quantifying the transport of a model drug, theophylline, across a circular polymeric membrane mounted in a thermostatted, twocompartment horizontal diffusion cell. Mechanical properties of the membranes, such as tensile strength, percent elongation and modulus of elasticity, were determined using an Instron 430...

Excipients for Amorphous Solid Dispersions

Pharmaceutical excipients play a significant role in stabilization of amorphous solid dispersions, as these systems are thermodynamically unstable. This chapter illustrates the challenges associated with amorphous solid dispersion stability and the role that excipients play in stabilization of amorphous solid dispersions by influencing the physicochemical properties of the drug molecule of interest. The classification of various excipients is categorized in detail, covering polymers, solubilizers, plasticizers, antioxidants, and other suitable fillers. The impact of excipients on various amorphous solid dispersion technologies is also discussed in detail. Discovery of newer polymers and greater understanding of excipients’ role in the stabilization of amorphous solid dispersion are the primary reasons for successful launch of several marketed drug products. In addition, safety and regulatory aspects of these excipients also need to be considered for the development of successful products. In summary, excipients play a significant role in stabilizing amorphous solid dispersions, maximizing bioavailability, and overcoming absorption issues associated with poorly soluble drugs.

High Energy Ordered Mixture for Improving the Dissolution Rate of Sparingly Soluble Compounds

AbstractBioavailability of a sparingly soluble drug is often limited by the rate of dissolution of the drug substance. The drug in a micronized form is generally employed to maximize the bioavailability. However, the micronized drugs tend to agglomerates and do not always exhibit an improved dissolution rate. In this study, a simple processing using a high energy mill was demonstrated as an effective means to utilize the entire surface area available for drug release of the micronized drug. An experimental hydrophobic drug in a micronized form was milled with a carrier, hydrous lactose using Micropulverizer to achieve a uniform mixture so-called “high energy ordered mixture”. The high energy ordered mixture provided a contact surface area taking part in dissolution 4-fold greater than the micronized drug agglomerates. Therefore, the dissolution was significantly improved, irrespective of test parameters such as agitation and the presence of surfactant. This high energy ordered mixture provided the advanta...

Selection of Solid-State Plasticizers as Processing Aids for Hot-Melt Extrusion

The objective of the study was to select solid-state plasticizers for hot-melt extrusion (HME) process. The physical and mechanical properties of plasticizers, in selected binary (polymer:plasticizer) and ternary (active pharmaceutical ingredient:polymer:plasticizer) systems, were evaluated to assess their effectiveness as processing aids for HME process. Indomethacin and Eudragit® E PO were selected as model active pharmaceutical ingredient and polymer, respectively. Solubility parameters, thermal analysis, and rheological evaluation were used as assessment tools. Based on comparable solubility parameters, stearic acid, glyceryl behenate, and polyethylene glycol 8000 were selected as solid-state plasticizers. Binary and ternary physical mixtures were evaluated as a function of plasticizer concentration for thermal and rheological behavior. The thermal and rheological assessments also confirmed the miscibility predictions from solubility parameters. The understanding of thermal and rheological properties of the various mixtures helped in predicating plasticization efficiency of stearic acid, glyceryl behenate, and polyethylene glycol 8000. The evaluation also provided insight into the properties of the final product. An empirical model was also developed correlating rheological property of physical mixtures to actual HME process. Based on plasticizer efficiency, solid-state plasticizers and processing conditions can be selected for a HME process.

Effect of Particle Size on Deformation and Compaction Characteristics of Ascorbic acid and Potassium Chloride: Neat and Granulated Drug

AbstractDeformation and compaction characteristics of two soluble drugs, ascorbic acid and potassium chloride, were investigated. Five different particle size fractions of ascorbic acid with mean particle size (d50) ranging from 30–300μm and four different particle size fractions of potassium chloride with d50 ranging from 20–400 μm were selected in the study. The compaction behavior of the drug substances as neat drugs or as granulated drugs were evaluated on both a Carver press and an instrumented single-punch tablet press. The results clearly show that mean particle size of the drug substances plays an important role in their compactibility. Intrinsic compactibility of both drug substances was slightly improved with increased particle size. Granulations of the drugs with polyvinyl pyrrolidone significantly improved their compactibility. However, this effect was more pronounced in the drug substance with finer particle size. The Heckel plots indicate that deformation characteristics of both granulated d...