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.

Stability assessment of hypromellose acetate succinate (HPMCAS) NF for application in hot melt extrusion (HME).

HPMCAS is a widely used polymer in the pharmaceutical industry as an excipient. In this work, the physicochemical stability of HPMCAS was investigated for hot melt extrusion (HME) application. The reduction in zero rate viscosity (η0) of the polymer with the increase in temperature was determined using rheological evaluation prior to HME processing.

Hot melt extrusion for amorphous solid dispersions: temperature and moisture activated drug-polymer interactions for enhanced stability.

Hot melt extrudates (HMEs) of indomethacin (IND) with Eudragit EPO and Kollidon VA 64 and those of itraconazole (ITZ) with HPMCAS-LF and Kollidon VA 64 were manufactured using a Leistritz twin screw extruder. The milled HMEs were stored at controlled temperature and humidity conditions. The samples were collected after specified time periods for 3 months.

Highly efficient miniaturized coprecipitation screening (MiCoS) for amorphous solid dispersion formulation development.

Microprecipitated bulk powder (MBP) is a novel solid dispersion technology to manufacture amorphous formulations of poorly soluble compounds that cannot be processed by spray drying or melt extrusion. An efficient high-throughput screening method has been developed to aid the selection of polymer type, drug loading and antisolvent to solvent ratio for MBP formulation development. With a 96-well platform, the miniaturized coprecipitation screening (MiCoS) includes mixing of drug and polymer in dimethylacetamide, controlled precipitation to generate MBP, filtration/washing, drying and high throughput characterization.

Supersolubilization and amorphization of a model basic drug, haloperidol, by interaction with weak acids.

Purpose: To present a novel approach of greatly enhancing aqueous solubility of a model weakly basic drug, haloperidol, by using weak acids that would not form salts with the drug and to attain physically stable form of amorphous drug by drying such aqueous solutions.

Method: Aqueous solubility of haloperidol in presence of increasing concentrations of four different weak organic acids (malic, tartaric, citric, fumaric) were determined. Several concentrated aqueous solutions with differing drug-to-acid molar ratios were dried in vacuum oven, and dried materials were characterized by DSC, powder XRD, dissolution testing, and stability study.

Improved human bioavailability of vemurafenib, a practically insoluble drug, using an amorphous polymer-stabilized solid dispersion prepared by a solvent-controlled coprecipitation process.

The present work deals with improving the solubility of vemurafenib, a practically insoluble drug, by converting it into an amorphous-solid dispersion using a solvent-controlled precipitation process. The dispersion containing vemurafenib and hypromellose acetate succinate (HPMCAS), an enteric polymer, is termed microprecipitated bulk powder (MBP), in which the drug is uniformly dispersed within the polymeric substrate. HPMCAS was found to be the most suitable polymer for vemurafenib MBP, among a series of enteric polymers based on superior physical stability and drug-release characteristics of the MBP.

Hot melt extrusion (HME) for amorphous solid dispersions: predictive tools for processing and impact of drug-polymer interactions on supersaturation.

The processing parameters for HME have been evaluated and the impact of solid state intermolecular drug-polymer interactions on supersaturation has been investigated. Poorly water soluble drugs Indomethacin (IND), Itraconazole (ITZ), and Griseofulvin (GSF) and hydrophilic polymers - Eudragit EPO, Eudragit L-100-55, Eudragit L-100, HPMCAS-LF, HPMCAS-MF, Pharmacoat 603, and Kollidon VA-64 were selected for this study. Solubility parameters calculations (SPCs), differential scanning calorimetry (DSC), and rheological analysis of drug-polymer physical mixtures (PMs) was performed.

Understanding and optimizing the dual excipient functionality of sodium lauryl sulfate in tablet formulation of poorly water soluble drug: wetting and lubrication.

Purpose: To evaluate and optimize sodium lauryl sulfate (SLS) and magnesium stearate (Mg.St) levels, with respect to dissolution and compaction, in a high dose, poorly soluble drug tablet formulation.

Methods: A model poorly soluble drug was formulated using high shear aqueous granulation.

A method to predict the equilibrium solubility of drugs in solid polymers near room temperature using thermal analysis.

A method is presented for determining the equilibrium solubility of a drug in a solid polymer at or near room temperature, which represents a typical storage temperature. The method is based on a thermodynamic model to calculate the Gibbs energy change ΔG(SS) associated with forming a binary drug-polymer solid solution from the unmixed polymer and solid drug. The model includes contributions from heat capacity differences between the solid solution and the corresponding unmixed components, breaking up of the solid drug structure, and drug-polymer mixing.

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.

Nanoparticles in the pharmaceutical industry and the use of supercritical fluid technologies for nanoparticle production.

Poor aqueous solubility of drug candidates is a major challenge for the pharmaceutical scientists involved in drug development. Particle size reduction appears as an effective and versatile option for solubility improvement. Nanonization is an attractive solution to improve the bioavailability of the poorly soluble drugs, improved therapies, in vivo imaging, in vitro diagnostics and for the production of biomaterials and active implants.

Interplay of formulation and process methodology on the extent of nifedipine molecular dispersion in polymers.

The aim of this study is to evaluate effects of formulation and process technology on drug molecular dispersibility in solid dispersions (SDs). Nifedipine solid dispersions with ethylcellulose (EC) and/or Eudragit RL (RL) prepared by co-precipitation, co-evaporation, and fusion methods were characterized with FTIR, DSC, and XRPD for the content of nifedipine as molecular dispersion, amorphous and/or crystalline suspensions. A method was developed based on regular solution and Flory-Huggins theories to calculate drug-polymer interaction parameter in solid dispersion systems.

Influence of plasticizer type and level on the properties of Eudragit S100 matrix pellets prepared by hot-melt extrusion.

Matrix-type pellets with controlled-release properties may be prepared by hot-melt extrusion applying a single-step, continuous process. However, the manufacture of gastric-resistant pellets is challenging due to the high glass transition temperature of most enteric polymers and an unacceptably high, diffusion-controlled drug release from the matrix during the acidic phase. The objective was to investigate the influence of three plasticizers (triethyl citrate, methylparaben and polyethylene glycol 8000) at two levels (10% or 20%) on the properties of hot-melt extruded Eudragit S100 matrix pellets.

Properties of melt extruded enteric matrix pellets.

The objective of this study was to investigate the properties of enteric matrix pellets that were prepared by hot-melt extrusion in a one-step, continuous process. Five polymers (Eudragit) L100-55, L100 and S100, Aqoat grades LF and HF) were investigated as possible matrix formers, and pellets prepared with Eudragit S100 demonstrated superior gastric protection and acceptable processibility. Extruded pellets containing Eudragit S100 and up to 40% theophylline released less than 10% drug over 2h in acid, however, the processibility and yields were compromised by the high amounts of the non-melting drug material in the formulation.

Influence of an acrylic polymer blend on the physical stability of film-coated theophylline pellets.

The purpose of this study was to investigate the physical stability of a coating system consisting of a blend of two sustained release acrylic polymers and its influence on the drug release rate of theophylline from coated pellets. The properties of both free films and theophylline pellets coated with the polymer blend were investigated, and the miscibility was determined via differential scanning calorimetry. Eudragit RS 30 D was plasticized by the addition of Eudragit NE 30 D, and the predicted glass transition temperature (T(g)) of the blend was similar to the experimental values.

Functional performance of silicified microcrystalline cellulose versus microcrystalline cellulose: a case study.

Background: During the development of a tablet dosage form of an investigational compound, R411, several aspects were identified as critical quality attributes that required optimization. The use of nonsolvent processing prevented the moisture-induced physical changes in the drug product but presented manufacturing challenges related to sticking during compression and slowdown in dissolution after storage at stress conditions.

Aim: The aim of this study was to evaluate silicified microcrystalline cellulose (SMCC), microcrystalline cellulose (MCC), and physical mixture of MCC-colloidal silicon dioxide (MCC/CSD at 98:2 ratio) as extragranular compression aids to address the processing and dissolution stability issues of this formulation.

Impact of polymers on dissolution performance of an amorphous gelleable drug from surface-coated beads.

A non-ionic amorphous active API ((RR)-3((1R)-3-oxocyclopentyl)-2-[3-chloro-4-methyl sulfonyl]phenyl-N-pyrozin-2ylpropanamide) with a glass transition temperature of 60 degrees C and aqueous solubility of 0.8 mg/mL was layered on the cellulose beads by the help of an anionic (Eudragit L100) and a non-ionic (polyvinylpyrrolidone) PVP K30 polymer respectively. An "immediate" and complete release of API from the anionic (Eudragit L100), and "sustained" but incomplete release from the hygroscopic non-ionic polymer coatings were observed.

Citric acid monohydrate as a release-modifying agent in melt extruded matrix tablets.

Incomplete drug release and particle size-dependent dissolution performance can compromise the quality of controlled release matrix systems. The objective of the current study was to investigate the ability of citric acid monohydrate (CA MH) to enhance the release of diltiazem hydrochloride from melt extruded Eudragit RS PO tablets and to eliminate drug particle size effects. Preformulation studies demonstrated the thermal stability of all components, drug insolubility in the polymer but miscibility with the CA MH.

Influence of fumed silicon dioxide on the stabilization of Eudragit RS/RL 30 D film-coated theophylline pellets.

The objective of this study was to investigate the influence of various grades of fumed silicon dioxide on the drug release rate and physical aging of theophylline pellets coated with Eudragit RS 30 D and RL 30 D. Free films were assessed for both physicomechanical properties and water vapor permeability with respect to time and storage conditions. The release rate of theophylline was influenced by the physical properties of the silicon dioxide employed.

Evaluation of solid state properties of solid dispersions prepared by hot-melt extrusion and solvent co-precipitation.

The solid state properties of solid dispersions of Compound A in hypromellose acetate succinate (HPMC-AS) prepared by hot-melt extrusion (HME) and solvent co-precipitation (CP) processes were evaluated using powder X-ray diffractometry (PXRD), thermal analysis, optical microscopy, scanning electron microscopy (SEM), FT-IR and Raman spectroscopy, water vapor sorption analyzer, and surface area by BET. PXRD indicated that both processes converted the crystalline drug into amorphous solid dispersions with a glass transition temperature around 104-107 degrees C and both products have similar spectroscopic and hygroscopic properties. The two products have similar true densities; however, the CP product is more porous and has a larger specific surface area than the HME product, as indicated by the BET results and SEM micrographs.

Citric acid as a solid-state plasticizer for Eudragit RS PO.

The use of solid-state plasticizers for the hot-melt extrusion of pharmaceutical dosage forms has been shown to be beneficial compared with liquid plasticizers. The purpose of this study was to determine the suitability of citric acid (CA) as a solid plasticizer for the preparation of Eudragit RS PO extended-release matrix systems by a melt extrusion technique. The influence of increasing levels of CA monohydrate (CA MH) or anhydrous CA in the powder blend on the extrusion process parameters (screw speed and motor load) was determined as a function of temperature.

Stabilization of low glass transition temperature indomethacin formulations: impact of polymer-type and its concentration.

The objectives of this study were to formulate and stabilize amorphous formulation of low T(g) drug (Indomethacin, INM) with selected polymers and compare these formulations based on solubility and dissolution rate studies. Eudragit EPO (EPO), Polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA), and Polyvinylpyrrolidone K30 (PVPK30) were selected as hydrophilic polymers. The melt extrudates were characterized using differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), intrinsic dissolution rate and solubility studies.

Use of proteins to minimize the physical aging of EUDRAGIT sustained release films.

The objective of this study was to investigate the influence of two proteins, albumin and type B gelatin, on the physical aging of EUDRAGIT RS 30 D and RL 30 D coated theophylline pellets. The physicomechanical properties of sprayed films, thermal properties of cast films, influence of proteins on the zeta potential and particle size of the dispersion, and the release of proteins from cast films under simulated dissolution conditions were investigated. The release rate of theophylline decreased significantly over time from pellets coated with an acrylic dispersion containing 10% albumin when there was no acidification of the acrylic dispersion; however, when pellets were coated with an acidified EUDRAGIT/albumin dispersion, the theophylline release rate was stable for dosage forms stored in the absence of humidity.

Effect of formulation and processing variables on the granulation kinetics of hot melt granulation (HMG) process.

The objective of the study was to evaluate the effect of formulation factors, such as type of drug and particulate properties of a drug, and processing variables, i.e. jacket temperature, impeller speed, and scale, on granulation kinetics the of hot-melt granulation (HMG) process.

Improving the dissolution rate of poorly water soluble drug by solid dispersion and solid solution: pros and cons.

The solid dispersions with poloxamer 188 (P188) and solid solutions with polyvinylpyrrolidone K30 (PVPK30) were evaluated and compared in an effort to improve aqueous solubility and bioavailability of a model hydrophobic drug. All preparations were characterized by differential scanning calorimetry, powder X-ray diffraction, intrinsic dissolution rates, and contact angle measurements. Accelerated stability studies also were conducted to determine the effects of aging on the stability of various formulations.