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. Extrusion experiments showed that all plasticizers produced similar reductions in polymer melt viscosity. Differential scanning calorimetry and powder X-ray diffraction demonstrated that the solid state plasticizers were present in the amorphous state. The drug release in acidic medium was influenced by the aqueous solubility of the plasticizer. Less than 10% drug was released after 2 h at pH 1.2 when triethyl citrate or methylparaben was used, independent of the plasticizer level. Drug release at pH 7.4 resulted from polymer dissolution and was not influenced by low levels of plasticizer, but increased significantly at the 20% level. Mechanical testing by diametral compression demonstrated the high tensile strength of the hot-melt extruded pellets that decreased when plasticizers were present.     

Characterization of thermal and rheological properties of zidovudine, lamivudine and plasticizer blends with ethyl cellulose to assess their suitability for hot melt extrusion

The influence of antiretroviral drugs and plasticizers on the rheological and thermal characteristics of ethyl cellulose formulations intended for hot melt extrusion has been investigated. Antiretroviral drugs used were zidovudine and lamivudine, whilst plasticizers included triethylcitrate (TEC) and polyethylene glycol (PEG-6000). Physical mixtures containing ethyl cellulose with varying concentrations of drugs and plasticizers were characterized using differential scanning calorimetry (DSC) and parallel plate oscillatory rheometry. The viscosity of physical mixtures containing both drugs was lower than observed for pure ethyl cellulose, indicating that the drugs had a plasticizing effect. This was confirmed by lowering of the glass transition temperature (Tg) of ethyl cellulose. At the highest loading of 40% by weight, lamivudine appeared to become saturated within the polymer, causing an increase in viscosity and showing evidence of recrystallization upon cooling. Both TEC and PEG-6000 were found to lower the Tg of ethyl cellulose, although PEG-6000 recrystallized upon cooling which makes it unsuitable for use in the proposed controlled release formulations. Both plasticizers were also shown to reduce the viscosity of ethyl cellulose, more significantly so for TEC. The results indicate that ethyl cellulose formulations containing up to 40% by weight of zidovudine, not more than 30% by weight of lamivudine, with 5-10% by weight of TEC as the plasticizer are suitable for processing by hot melt extrusion.     

Characterization of physico-mechanical properties of indomethacin and polymers to assess their suitability for hot-melt extrusion processs as a means to manufacture solid dispersion/solution

The objective of the study was to characterize the physical and viscoelastic properties of binary mixtures of drug and selected polymers to assess their suitability for use in the hot-melt extrusion (HME) process as a means to improve solubility by manufacturing either solid dispersion or solid solution. Indomethacin (INM) was selected as a model drug. Based on comparable solubility parameters, the selected polymers were Eudragit EPO (EPO), polyvinylpyrrolidone/vinyl acetate copolymer (PVP-VA), polyvinylpyrrolidone K30 (PVPK30), and poloxamer 188 (P188). The various drug and polymer systems were characterized for thermal and rheological properties as a function of drug concentration to provide an insight into miscibility and processibility of these systems. From the thermal analysis studies, a single T(g) was observed for the binary mixtures of INM/EPO, INM/PVP-VA, and INM/PVPK30, indicating miscibility of drug and polymer in the given ratios. In the case of mixtures of INM/P188, two melting endotherms were observed with decreasing drug melting point as a function of polymer concentration indicating partial miscibility of drug in polymer. As part of the rheological evaluation, zero rate viscosity (eta(o)) and activation energy (E(a)) was determined for the various systems using torque rheometer at varying shear rates and temperatures. The eta(o) for binary mixtures of drug and EPO, PVP-VA and PVPK30 were found to be significantly lower as compared to pure polymer, indicating disruption of the polymer structure due to miscibility of the drug. On the other hand, INM/P188 mixtures showed a higher eta(o) compared to pure polymer indicating partial miscibility of drug and polymer. With respect to E(a), the mixtures of INM/EPO showed an increase in E(a) with increasing drug concentration, suggesting antiplasticization effect of the drug. These findings corroborate the thermal analysis results showing increase T(g) for the various binary mixtures. The mixtures of INM/PVP-VA showed a decrease in the E(a) with the increasing drug concentration suggesting a plasticization effect of the drug. The understanding of thermal and rheological properties of the various drug/polymer mixtures help established the processing conditions for hotmelt extrusion (such as extrusion temperatures and motor load) as well as provided insight into the properties of the final extrudates. Using the actual hot-melt processing, a model was developed correlating the zero rate viscosity to the motor load determined by rheological evaluation.     

Structural and thermal characterization of glyceryl behenate by X-ray diffraction coupled to differential calorimetry and infrared spectroscopy

Physical and thermal properties of glyceryl behenate (Compritol 888 ATO) used as sustained-release matrix in pharmaceutical applications are studied by coupled time-resolved synchrotron X-ray diffraction and Differential Scanning Calorimetry combined with Infrared Spectroscopy. With these techniques, all polymorphs formed in glyceryl behenate, analyzed as received and after various thermal treatments from quenching to slow crystallization, are characterized. By using different well-controlled mixtures of mono-, di- and tribehenate, we identify each lamellar phase observed in the glyceryl behenate. Finally the influence of the crystallization rate on the formation of preferential conformations was also analyzed in order to bring insights into the polymorphism of glyceryl behenate. By changing the crystallization rate of the sample, it was shown that one can favor the formation of preferential polymorphs in the sample. In particular the crystallization at 10 degrees C/min seems to be well adapted for producing a single lamellar phase with a period of 60.9 A while a crystallization rate of 0.4 degrees C/min produces three different lamellar phases.     

The influence of povidone K17 on the storage stability of solid dispersions of nimodipine and polyethylene glycol.

Previous studies revealed that solid dispersions containing nimodipine and polyethylene glycol 2000 can be effectively prevented from recrystallization by adding povidone K17. These systems are characterized by a high dissolution rate and a remarkable supersaturation of the drug in the dissolution media. It is still unknown if these characteristics are achievable with all polyethylene glycol and povidone mixtures. The objective of the present study is to find out, whether povidone K17 has to be dissolved in melted polyethylene glycol during the preparation process of solid dispersions by the melting method in order to avoid recrystallization of the drug and to ensure storage stability. Solid dispersions consisting of 20% (m/m) nimodipine, 16% (m/m) povidone K17 and 64% (m/m) of six different mixtures of polyethylene glycol 2000 and 8000 were prepared by the melting method and investigated by dissolution testing, thermal analysis and X-ray diffraction. As the solubility of povidone K17 in polyethylene glycol 2000 is about 70% at 65 degrees C and decreases with increasing molecular weight of the polyethylene glycol, mixtures containing different amounts of dissolved povidone K17 are obtained by varying the mixing ratio of polyethylene glycol 2000 and 8000. Recrystallization is inhibited in the formulations, containing mainly polyethylene glycol 2000 whereas recrystallization occurs in systems consisting predominantly of polyethylene glycol 8000. These results show clearly that dissolution of povidone in melted polyethylene glycol is a prerequisite in order to prevent recrystallization.     

Formulation development and process analysis of drug-loaded filaments manufactured via hot-melt extrusion for 3D-printing of medicines

Abstract

Three dimensional(3D)-printing via fused deposition modeling (FDM) allows the production of individualized solid dosage forms. However, for bringing this benefit to the patient, active pharmaceutical ingredient (API)-loaded filaments of pharmaceutical grade excipients are necessary as feedstock and have to be produced industrially. As large-scale production of API-loaded filaments has not been described in literature, this study presents a development of 3D-printable filaments, which can continuously be produced via hot-melt extrusion. Further, a combination of testing methods for mechanical resilience of filaments was applied to improve the prediction of their printability. Eudragit RL was chosen as a sustained release polymer and theophylline (30%) as thermally stable model drug. Stearic acid (7%) and polyethylene glycol 4000 (10%), were evaluated as suitable plasticizers for producing 3D-printable filaments. The two formulations were printed into solid dosage forms and analyzed regarding their dissolution profiles. This revealed that stearic acid maintained sustained release properties of the matrix whereas polyethylene glycol 4000 did not. Analysis of the continuous extrusion process was done using a design of experiments. It showed that powder feed rate and speed of the stretching device used after extrusion predominantly determine the diameter of the filament and thereby the mechanical resilience of a filament.     

The Effect of Plasticizers on Compatibility,Mechanical Properties,and Adhesion Strength of Drug-Free Eudragit E Films

The use of plasticizers to affect the properties of drug-free, self-adhesive Eudragit E-100 films with higher transparency was tested for possible transdermal drug delivery. Triacetin was found to be an effective first plasticizer for Eudragit E-100 polymer. In order to improve the flexibility and adhesiveness of Eudragit E-100 film plasticized with triacetin, a more flexible and adhesive, secondary plasticizer was added. Plasticizer–polymer compatibility was evaluated by measuring transparency, surface topography, and solubility. Secondary plasticizers with a low molecular weight and a solubility parameter similar to that of Eudragit E-100 polymer and triacetin were compatible. Further, a lower molecular weight or higher concentration of the secondary plasticizers might lead to greater plasticizing action, reduce tensile strength, and increase film elongation, independent of the hydrophilicity of the plasticizer. The adhesive strength of Eudragit E-100 film under a 180° peel test was also affected by the molecular weight and solubility parameter of the secondary plasticizers used. The results indicate that PEG 200, propylene glycol, diethyl phthalate, and oleic acid can serve as a secondary plasticizer to improve the transparency, flexibility, and adhesion of Eudragit E-100 film.     

Determination of acetaminophen's solubility in poly(ethylene oxide) by rheological, thermal and microscopic methods

A drug's solubility in a polymeric excipient is an important parameter that dictates the process window of hot-melt extrusion (HME) and product stability during storage. However, it is rather challenging to experimentally determine the solubility and there is very few published work in this field. In this study, the solubility of a model drug acetaminophen (APAP) in a pharmaceutical grade polymer poly(ethylene oxide) (PEO) at HME processing temperature was measured utilizing rheological analysis, hot-stage microscopy and differential scanning calorimetry (DSC). The results from three methods were consistent and the solubility was found to increase from 14% at 80°C to 41% at 140°C. The apparent drug solubility at room temperature was estimated to be less than 10% through glass transition temperature (T(g)) measurement using DSC and dynamic mechanical thermal analysis (DMTA). A "phase diagram" was constructed based on the experimental data and could be explored to design the HME process and formulation. Very few assumptions were made in the experimental study and result analysis, and the methods described here can be applied to investigate other drug-polymer systems to obtain the important thermodynamic data.     

Plasticized Drug‐Loaded Melt Electrospun Polymer Mats: Characterization,Thermal Degradation,and Release Kinetics

Melt electrospinning (MES) was used to prepare fast dissolving fibrous drug delivery systems in the presence of plasticizers. This new method was found promising in the field of pharmaceutical formulation because it combines the advantages of melt extrusion and solvent‐based electrospinning. Lowering of the process temperature was performed using plasticizers in order to avoid undesired thermal degradation. Carvedilol (CAR), a poorly water‐soluble and thermal‐sensitive model drug, was introduced into an amorphous methacrylate terpolymer matrix, Eudragit® E, suitable for fiber formation. Three plasticizers (triacetin, Tween® 80, and polyethylene glycol 1500) were tested, all of which lowered the process temperature effectively. Scanning electron microscopy, X‐ray diffraction, differential scanning calorimetry, and Raman microspectrometry investigations showed that crystalline CAR turned into an amorphous form during processing and preserved it for longer time. In vitro dissolution studies revealed ultrafast drug dissolution of the fibrous samples. According to the HPLC impurity tests, the reduced stability of CAR under conditions applied without plasticizer could be avoided using plasticizers, whereas storage tests also indicated the importance of optimizing the process parameters during MES. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:1278–1287, 2014     

Comparative study of the lubricant performance of Compritol HD5 ATO and Compritol 888 ATO: effect of polyethylene glycol behenate on lubricant capacity

The aim of this paper is to study the lubricant capacity of Compritol HD5 ATO, a glyceryl and polyethylene glycol dibehenate, obtained by atomization. This material is compared to Compritol 888 ATO, constituted only by glyceryl dibehenate. First, this study verifies that Compritol HD5 ATO and Compritol 888 ATO present the same granular characteristics and that their mixes with Lactopress present no structural differences. Secondly, in term of compressibility and cohesiveness, the use of Compritol 888 ATO or Compritol HD5 ATO with Lactopress does not involve any significant modification. Finally, the minor difference of lubricant capacity between Compritol HD5 ATO and Compritol 888 ATO has no consequence in compression practice. The presence of polyethylene glycol behenate does not decrease the glyceryl dibehenate compression functionality. This study concludes that Compritol HD5 ATO could be a very interesting excipient because it associates the glyceryl dibehenate lubricant capacity with the polyethylene glycol behenate-specific capacity in terms of dissolution enhancement.     

Plasticizers and their effects on microencapsulation process by spray-drying in an aqueous system.

Microencapsulated theophylline particles were prepared by an aqueous spray-drying process using hydroxypropylmethylcellulose. The effect of different plasticizers, triethylcitrate, polyethylene glycol, propylene glycol, glycerin and citric acid, was investigated. Triethylcitrate, a water-insoluble plasticizer, produced a porous honeycomb-like microcapsule wall resulting in rapid drug release. The presence of the plasticizers also influenced crystallization of the drug. The formation of a solid drug dispersion was observed with the addition of citric acid or glycerin. Changes in the pH of liquid feed caused by the plasticizer had an effect on the product dissolution profile, but this was not a major factor. Formation of pores due to leaching of plasticizers during dissolution enhanced drug release. Flow property measurements indicated that the plasticizers also affect the cohesiveness of the spray-dried products. Compared to the microcapsules formed without any plasticizers, propylene glycol, glycerin and citric acid appeared to be beneficial to the microcapsule wall formation, with microcapsules containing citric acid having the slowest drug release.     

Plasticization of cellulose ethers used in the film coating of tablets

Plasticizer/polymer interactions have been studied by measuring the intrinsic viscosities of both ethyl cellulose and hydroxypropyl methylcellulose in a series of dialkyl phthalates and in a series of liquid glycols respectively. A correlation was found between the intrinsic viscosity of the polymer/plasticizer solutions and the tensile strength, elongation at rupture and work done in stressing to failure of cast films—the mechanical properties being at a minimum when the intrinsic viscosity was at a maximum. This correlation held only within a homologous series of plasticizers and none was found for plasticizers of different structures. A relationship was found between the lowering of a calculated glass transition temperature of hydroxypropyl methylcellulose in the presence of the plasticizers propylene glycol, polyethylene glycol 200 and glycerol and the intrinsic viscosity of the corresponding solutions—the higher the viscosity the greater the lowering of the transition temperature.     

Development and evaluation of glyceryl behenate based solid lipid nanoparticles (SLNs) using hot self-nanoemulsification (SNE) technique

The purpose of this research was to improve oral bioavailability of poorly aqueous soluble drug lopinavir using solid lipid nanoparticles (SLNs). Glyceryl behenate based SLNs of lopinavir were prepared using hot self-nanoemulsification (SNE) technique. The hot isotropic mixture of glyceryl behenate, Poloxamer 407 and polyethylene glycol 4000 was spontaneously self-nanoemulsify in hot water (80 °C) and SLNs were subsequently formed with rapid cooling. Hot SNE ability of isotropic mixture was visually assessed by ternary phase diagram study. Optimized SLNs were having particle size of 214.5 ± 4.07 nm, entrapment efficiency of 81.6 ± 2.3 % and zeta potential of ?12.7 ± 0.87 mV. SLNs were evaluated by transmission electron microscopy and atomic force microscopy for morphological details. Further, differential scanning calorimetry and x-ray diffraction were also performed for solid state characterization of SLNs. Higher oral bioavailability (3.56-fold) was found for lopinavir loaded SLNs in comparison to bulk lopinavir due to higher lymphatic drug transport (p < 0.05). Results indicate that SLNs of glyceryl behenate can be successfully prepared by hot SNE technique.     

Plasticization of cellulose ethers used in the film coating of tablets.

Plasticizer/polymer interactions have been studied by measuring the intrinsic viscosities of both ethyl cellulose and hydroxypropyl methylcellulose in a series of dialkyl phthalates and in a series of liquid glycols respectively. A correlation was found between the intrinsic viscosity of the polymer/plasticizer solutions and the tensile strength, elongation at rupture and work done in stressing to failure of cast films--the mechanical properties being at a minimum when the intrinsic viscosity was at a maximum. This correlation held only within a homologous series of plasticizers and none was found for plasticizers of different structures. A relationship was found between the lowering of a calculated glass transition temperature of hydroxypropyl methylcellulose in the presence of the plasticizers propylene glycol, polyethylene glycol 200 and glycerol and the intrinsic viscosity of the corresponding solutions--the higher the viscosity the greater the lowering of the transition temperature.     

Physicochemical stability of solid dispersions of enantiomeric or racemic ibuprofen in stearic acid

The aim of this study was to investigate the solid dispersion phase behavior of s- or rs-ibuprofen in stearic acid. By means of thermal analysis, we have demonstrated the total immiscibility, in solid state, of the corresponding binary mixtures. This indicates that no specific interactions exist between the chosen excipient and active pharmaceutical ingredient (API) that lead to eutectic systems. Furthermore, based on calorimetric and X-ray diffraction experiments, we have showed that upon cooling of the molten state, only stearic acid recrystallizes in the presence of s-ibuprofen, whereas a quaternary phase mixture is obtained for the racemic ibuprofen/stearic acid preparation. The solubility of stearic acid in s-ibuprofen liquid in all proportions was also determined. Overall, the results presented here offer an approach for the study of API/excipient interactions.     

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. The solubility of CA MH in extruded tablets was studied by means of modulated differential scanning calorimetry (MDSC) and powder X-ray diffraction (PXRD). Films were cast from organic solutions to demonstrate the plasticizing effect of CA MH as a change in physico-mechanical properties (tensile strength, elastic modulus and elongation). The CA release from extruded tablets was studied over 12 h. The monohydrate form was found to distinctly facilitate the extrusion of Eudragit RS PO, whereas the addition of anhydrous CA to the polymer powder was less effective. This divergent behaviour in plasticization of Eudragit RS PO was attributed to the higher solubility of the monohydrate in the acrylic polymer. The plasticizing effect of the CA MH reached a plateau at 25% during hot-melt extrusion, which coincided with the solubility limit of the organic acid in the polymer as shown by MDSC and PXRD results. The CA MH increased the flexibility of Eudragit RS PO films, as demonstrated by a decrease in tensile strength and elastic modulus and an increase in elongation as a function of CA MH concentration. The dissolution of CA from the matrix tablets followed an extended-release profile, with CA MH exhibiting a faster dissolution rate than the anhydrous form. In conclusion, CA MH was found to be an effective plasticizer for Eudragit RS PO that facilitates the production of controlled-release matrix systems by hot-melt extrusion.     

Investigating critical effects of variegated lubricants,glidants and hydrophilic additives on lag time of press coated ethylcellulose tablets

The research envisaged focuses on vital impacts of variegated lubricants, glidants and hydrophilic additives on lag time of press coated ethylcellulose (EC) tablets using prednisone as a model drug. Several lubricants and glidants such as magnesium stearate, colloidal SiO₂, sodium stearyl fumarate, talc, stearic acid, polyethylene glycol (6000) and glyceryl behenate were investigated to understand their effects on lag time by changing their concentrations in outer coat. Further, the effects of hydrophilic additives on lag time were examined for hydroxypropylmethylcellulose (E5), hydroxypropylcellulose (EF and SSL), povidone (K30), copovidone, polyethylene glycol (4000), lactose and mannitol. In vitro drug release testing revealed that each selected lubricant/glidant, if present even at concentration of 0.25% w/w, significantly reduced the lag time of press coated tablets. Specifically, colloidal SiO₂ and/or magnesium stearate were detrimental while other lubricants/glidants were relatively less injurious. Among hydrophilic additives, freely water soluble fillers had utmost influence in lag time, whereas, comparatively less impact was observed with polymeric binders. Concisely, glidant and lubricant should be chosen to have minimal impact on lag time and further judicious selection of hydrophilic additives should be exercised for modulating lag time of pulsatile release formulations.     

Enhanced Dissolution of a Porous Carrier–Containing Ternary Amorphous Solid Dispersion System Prepared by a Hot Melt Method

The focus of our study was to employ a solvent-free, thermal process to evaluate the use of a porous carrier in a drug-polymer-porous carrier ternary formulation containing a high drug load (e.g., ≥50% w/w). The purpose of the study was to improve the dissolution properties of the biopharmaceutical classification system class II drug, indomethacin, in the ternary formulation. The effect that the selected polymer has on properties of the formulation was studied, and the formulation characteristics of hypromellose (AF15), copovidone (VA64), and polyvinyl alcohol-polyethylene glycol graft copolymer was evaluated to understand differences in dissolution rates and drug adsorption onto the porous carrier. The ternary formulations were manufactured using a thermal technique that relied on heating and mixing, without the necessity of mechanical shear. All thermally processed granules that employed the porous carrier exhibited immediate release compared with crystalline indomethacin and physical mixtures. In addition, the ternary formulations maintained supersaturation compared with the binary formulations without polymer. The results of this study indicated that the thermally processed ternary formulations containing a porous carrier demonstrated a much improved dissolution profile in nonsink conditions.     

Application of TPX polymer membranes for the controlled release of triprolidine.

Oral administration of triprolidine, antihistamines, may cause many adverse effects such as dry mouth, sedation, dizziness and transdermal drug delivery was considered. Poly(4-methyl-1-pentene) (TPX) membrane, which has good mechanical strength was fabricated by the casting method. TPX membranes was a little brittle and the plasticizers was added for preparing the membranes. The present study was carried out to evaluate the possibility of using the polymer TPX membrane as a controlling membrane and further develop a TPX matrix system for transdermal delivery of triprolidine. The effects of molecular weights of TPX, plasticizers, polyethylene glycol (PEG) 400, drug concentration, and temperature on drug release were studied. The solubility of triprolidine increased exponentially as the increased volume fraction of PEG 400 in saline, and the rate of permeation through TPX membrane was proportional to PEG 400 volume fraction. The release rate of drug from the TPX matrix increased with increased temperature and drug concentration. Among the plasticizers used such as alkyl citrates, phthalates and sebacate, tetra ethyl citrate (TEC) showed the best enhancing effects. Enhancement factor of TEC was 3.76 from TPX matrix at 37 degrees C. The transdermal controlled release of triprolidine system could be developed using the TPX polymer including the plasticizer.