Thermal,mechanical and drug release characteristics of an acrylic film using active pharmaceutical ingredient as non-traditional plasticizer

Abstract

The objective of this study was to investigate thermal and mechanical properties as well as in vitro drug release of Eudragit® RL (ERL) film using chlorpheniramine maleate (CPM) as either active pharmaceutical ingredient or non-traditional plasticizer. Differential scanning calorimeter was used to measure the glass transition temperature (T_g) of 0–100% w/w CPM in ERL physical mixture. Instron testing machine was used to investigate Young’s modulus, tensile stress and tensile strain (%) of ERL film containing 20–60% w/w CPM. Finally, a Franz diffusion cell was used to study drug release from ERL films obtained from four formulations, i.e. CRHP0/0, CRHP0/5, CRHP2/0 and CRHP2/5. The T_g of ERL was decreased when the weight percentage of CPM increased. The reduction of the T_g could be described by Kwei equation, indicating the interaction between CPM and ERL. Modulus and tensile stress decreased whereas tensile strain (%) increased when weight percentage of CPM increased. The change of mechanical properties was associated with the reduction of the T_g when weight percentage of CPM increased. ERL films obtained from four formulations could release the drug in no less than 10?h. Cumulative amount of drug release per unit area of ERL film containing only CPM (CRHP0/0) was lower than those obtained from the formulations containing traditional plasticizer (CRHP0/5), surfactant (CRHP2/0) or both of them (CRHP2/5). The increase of drug release was a result of the increase of drug permeability through ERL film and drug solubility based on traditional plasticizer and surfactant, respectively.     

Evaluating the efficacy of a group of nontraditional plasticizers on the glass transition temperature of ethyl cellulose polymer

Objective: The aim of this study was to investigate the efficiency of a homologous series of esters of dicarboxylic acid on ethyl cellulose polymer in terms of their glass transition temperatures (T_g). Methods: Ethyl cellulose polymer was plasticized with succinates (C-2), glutarates (C-5), adipates (C-6), pimelates (C-7), suberates (C-8), and sebacates (C-10) at different concentration levels. The film formation and physical state of plasticizers within the polymer were investigated and incompatibility of plasticizers was determined by nonhomogeneous system. Results: A decrease in T_g of the plasticized polymer was used as an indicator of plasticizing efficiency. Experimental T_g values were correlated with the theoretical ones predicted by Gordon–Taylor equation. Most of the experimental T_g values did not fit with the predicted ones. For all plasticizers (except succinates) the measured T_g was lower than calculated indicating negative deviation from the ideal behavior. Anti-plasticization was obtained with lower plasticizers concentration. Fourier transform infrared spectroscopy was used to determine the interactions between the polymer and plasticizers on T_g values in predicting the efficiency. Conclusions: The correlation between experimental and calculated T_g values verifies that physiochemical properties are the primary factors influencing the plasticization efficiency. However, further studies are needed to establish the plasticization efficiency.     

The Potential of Small-Scale Fusion Experiments and the Gordon-Taylor Equation to Predict the Suitability of Drug/Polymer Blends for Melt Extrusion

The aim of this study was to investigate the use of small-scale fusion experiments and the Gordon-Taylor (GT) equation to predict whether melt extrusion of a drug with an amorphous polymer produces a stable amorphous dispersion with increased drug dissolution. Indomethacin, lacidipine, nifedipine, piroxicam, and tolbutamide were used as poorly soluble drugs. Drug/polyvinylpyrrolidone (PVP) blends were prepared at a 1:1 mass ratio. Small-scale fusion experiments were performed in a differential scanning calorimeter (DSC) and in stainless steel beakers. Extrusion was performed in a Brabender Plasti-corder. The glass transition temperatures T_g were determined by DSC. Taking an average T_g from the DSC melt, beaker melt, and GT equation accurately predicted the extrudate T_g. Physical stability of beaker melt and extrudate samples was tested by X-ray powder diffraction (XRPD) and DSC after storage at 30°C (beaker melt) or 25°C (extrudate) and less than 10%, 60%, and 75% relative humidity (RH). Beaker melts were amorphous, apart from some residual crystallinity. Extrudates were amorphous after preparation. Except for indomethacin/PVP, which remained amorphous, the crystallinity of beaker melts and extrudates increased only at 75% RH. Recrystallization occurred even when the T_g of the sample was well above the storage temperature. Chemical stability of the beaker melts and extrudates was tested by capillary electrophoresis and high-performance liquid chromatography (HPLC). Stability was slightly improved in the extrudate compared to the beaker melt. In general, the order for rate of dissolution was crystalline drug was less than the physical mixture, which was less than the drug/PVP beaker melt, which was approximately equal to the extrudate. The use of beaker melts allows a conservative estimate of the potential to melt extrude a drug. To predict physical stability, analysis of the T_g must be combined with physical stability experiments.     

Aqueous film coating to reduce recrystallization of guaifenesin from hot-melt extruded acrylic matrices

Objectives: This study investigated the effect of aqueous film coating on the recrystallization of guaifenesin from acrylic, hot-melt extruded matrix tablets. Methods: After hot-melt extrusion, matrix tablets were film-coated with either hypromellose or ethylcellulose. The effects of the coating polymer, curing and storage conditions, polymer weight gain, and core guaifenesin concentration on guaifenesin recrystallization were investigated. Results: The presence of either film coating on the guaifenesin-containing tablets was found to prolong the onset time of drug crystallization. The coating polymer was the most important factor determining the delay in the onset of crystallization, with the more hydrophilic polymer, hypromellose, having a higher solubilization potential for the guaifenesin and delaying crystallization for longer period (3 or 6 months in tablets stored at 40°C or 25°C, respectively) than the more hydrophobic ethylcellulose, which displayed a lower solubilization potential for guaifenesin (crystal growth on tablets cured for 2 hours at 60°C occurred within 3 weeks, whereas uncoated tablets displayed surface crystal growth after 30 minutes). Crystal morphology was also affected by the film coating. Elevated temperatures during both curing and storage, incomplete film coalescence, and high core drug concentrations all contributed to an earlier onset of crystal growth.     

A dynamic mechanical thermal analysis study of the viscoelastic properties and glass transition temperature behaviour of bioresorbable polymer matrix nanocomposites

The application of bioresorbable polymer nanocomposites in orthopaedics offer the potential to address several of the limitations associated with the use of metallic implants. Their enhanced biological performance has been demonstrated recently, but until now relatively little work has been reported on their mechanical properties. To this end, the viscoelastic properties and T_g of bioresorbable polylactide-co-glycolide/α-tricalcium phosphate nanocomposites were investigated by dynamic mechanical thermal analysis. At room temperature of approximately 20°C, the storage moduli of the nanocomposites were generally higher than the storage modulus of the unfilled polymer due to the stiffening effect of the nano-particles. However at physiological temperature of approximately 37°C, the storage moduli of the nanocomposites decreased from 6.2 to 15.4% v/v nano-particle loadings. Similarly the T_g of the nanocomposites also decreased from 6.2 to 15.4% v/v nano-particle loadings. These effects were thought to be due to weak interfacial bonding between the nano-particles and polymer matrix. The storage moduli at 37°C and T_g increased from the minimum value when the particle loading was raised to 25.7 and 34.2% v/v loadings. SEM and particle size distribution histograms showed that at these loadings, there was a broad particle size distribution consisting of nano-particles and micro-particles and that some particle agglomeration was present. The consequent reduction in the interfacial area and the number of weak interfaces presumably accounts for the rise in the storage modulus at 37°C and the T_g.     

Stabilization of fenofibrate in low molecular weight hydroxypropylcellulose matrices produced by hot-melt extrusion

Abstract

The objective of this study was to improve the dissolution rate and to enhance the stability of a poorly water-soluble and low glass-trasition temperature (T_g) model drug, fenofibrate, in low molecular weight grades of hydroxypropylcellulose matrices produced by hot-melt extrusion (HME). Percent drug loading had a significant effect on the extrudability of the formulations. Dissolution rate of fenofibrate from melt extruded pellets was faster than that of the pure drug (p < 0.05). Incorporation of sugars within the formulation further increased the fenofibrate release rates. Differential scanning calorimetry results revealed that the crystalline drug was converted into an amorphous form during the HME process. Fenofibrate is prone to recrystallization due to its low T_g. Various polymers were evaluated as stabilizing agents among which polyvinylpyrrolidone 17PF and amino methacrylate copolymer exhibited a significant inhibitory effect on fenofibrate recrystallization in the hot-melt extrudates. Subsequently immediate-release fenofibrate tablets were successfully developed and complete drug release was achieved within 5 min. The dissolution profile was comparable to that of a currently marketed formulation. The hot-melt extruded fenofibrate tablets were stable, and exhibited an unchanged drug release profile after 3-month storage at 40°C/75% RH.     

Storage modulus and glass transition behaviour of CdS/PMMA nanocomposites

The storage modulus and glass transition temperature (T _g) of CdS/PMMA nanocomposites have been evaluated as a function of concentration of CdS nanoparticles. CdS particles have been synthesised via chemical route using cadmium acetate, thiourea and dimethylformamide. The solution-based processing has been used to prepare PMMA composites with CdS nanoparticles at different filler concentration. Size and shape of CdS nanoparticles in PMMA have been determined with the help of small angle X-ray scattering and transmission electron microscope measurements. Dynamical mechanical analysis was carried out on the CdS/PMMA nanocomposites to study storage modulus and tan?δ. It is observed that CdS nanoparticles enhance the storage modulus and T _g for composites. The storage modulus and T _g show the maximum value of 6?wt.% of CdS nanoparticles embedded PMMA composite. The results indicate that the 6?wt.% of CdS nanoparticles in PMMA matrix provides more stability to the composite over the other composites.     

Development of a HPMC-based controlled release formulation with hot melt extrusion (HME)

The objective of this study was to develop hydroxypropyl methylcellulose (HPMC) based controlled release (CR) formulations via hot melt extrusion (HME) with a highly soluble crystalline active pharmaceutical ingredient (API) embedded In the polymer phase. HPMC is considered a challenging CR polymer for extrusion due to its high glass transition temperature (T_g), low degradation temperature, and high viscosity. These problems were partially overcome by plasticizing the HPMC with up to 40% propylene glycol (PG). Theophylline was selected as the model API. By using differential scanning calorimetry (DSC), thermal gravimetric analysis (TGA), dynamic mechanical analysis (DMA), and X-ray powder diffraction (XRPD), the physical properties of the formulations were systematically characterized. Five grades of HPMC (Methocel^®) – E6, K100LV, K4M, K15M, and K100M – were tested. The extrusion trials were conducted on a 16?mm twIn screw extruder with HPMC/PG placebo and formulations containing theophylline/HPMC/PG (30:42:28, w/w/w). The dissolution results showed sustained release profiles without burst release for the HPMC K4M, K15M, and K100M formulations. The extrudates have good dissolution stability after being stressed for 2 weeks under 40°C/75% RH open dish conditions and the crystalline API form did not change upon storage. Overall, the processing windows were established for the HPMC based HME-CR formulations.     

Mechanical study of poly(vinylidene fluoride)-poly(methyl methacrylate) amorphous blends

Amorphous films of poly(vinylidene fluoride)-poly (methyl methacrylate) were prepared by initial precipitation from a solvent and rapid solidification at ≈ 15 °C from the molten state. The PVDF/PMMA compositions studied were 25/75, 45/55, 50/50, 55/45, 60/40 and 75/25. X-ray scattering analysis suggests that mixture of the two components throughout the composition range studied occurs at a molecular level. The parallel decrease of the microhardness, which obeys a simple expression:H _blend =H _PMMA (1−φ) (φ being the PVDF concentration) and the glass transition temperature,T _g, following the predictions, of Gordon and Taylor, reveals that the depression of microhardness is caused by the shift ofT _g towards lower temperatures. It is pointed out that the effect of PVDF molecules is to act as a softening agent within the PMMA component.     

Enhanced Dissolution of Ibuprofen Using Solid Dispersion with Polyethylene Glycol 20000

To improve its dissolution, ibuprofen solid dispersions (SDs) were prepared in a relatively easy and simple manner, characterized by scanning electron microscopy (SEM), differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FTIR), and evaluated for solubility and in vitro drug release. Loss of individual surface properties during melting and re-solidification as revealed by SEM micrographs indicated the formation of effective SDs. Absence or shifting toward the lower melting temperature of the drug peak in SDs in DSC study indicated the possibilities of drug–polymer interactions. FTIR spectra showed the presence of drug crystalline in SDs. The effect of improved dissolution on the oral absorption of ibuprofen in rats was also studied. Quicker release of ibuprofen from SDs in rat intestine resulted in a significant increase in AUC and C_max, and a significant decrease in T_max over pure ibuprofen. Preliminary results from this study suggested that the preparation of fast dissolving ibuprofen SDs by low-temperature melting method using polyethylene glycol 20000 as a meltable hydrophilic polymer carrier could be a promising approach to improve solubility, dissolution, and absorption rate of ibuprofen.     

In vitro release of ketoprofen from hydrophilic matrix tablets containing cellulose polymer mixtures

The effect of cellulose ether polymer mixtures, containing both hydroxypropylcellulose (HPC) and hydroxypropylmethylcellulose (HPMC K15M or K100M), on ketoprofen (KTP) release from matrix tablets was investigated. In order to evaluate the compatibility between the matrix components, Raman spectroscopy, scanning electron microscopy (SEM), and X-ray powder diffraction (XRPD) experiments were performed. The results evidence the absence of significant intermolecular interactions that could eventually lead to an incompatibility between the drug and the different excipients. Formulations containing mixtures of polymers with both low and high viscosity grades were prepared by a direct compression method, by varying the polymer/polymer (w/w) ratio while keeping the drug amount incorporated in the solid dispersion constant (200?mg). The hardness values of different matrices were found within the range 113.8 to 154.9 N. HPLC analysis showed a drug content recovery between 99.3 and 102.1%, indicating that no KTP degradation occurred during the preparation process. All formulations attained a high hydration degree after the first hour, which is essential to allow the gel layer formation prior to tablet dissolution. Independent-model dissolution parameters such as t_10% and t_50% dissolution times, dissolution efficiency (DE), mean dissolution time (MDT), and area under curve (AUC) were calculated for all formulations. Zero-order, first-order, Higuchi, and Korsmeyer–Peppas kinetic models were employed to interpret the dissolution profiles: a predominantly Fickian diffusion release mechanism was obtained – with Korsmeyer–Peppas exponent values ranging from 0.216 to 0.555. The incorporation of HPC was thus found to play an essential role as a release modifier from HPMC containing tablets.     

Preparation and pharmacokinetics study on gastro-floating sustained-release tablets of troxipide

The purpose of this research aimed at preparing gastro-floating sustained-release tablets of troxipide and a further study on in vitro release and in vivo bioavailability. Under the circumstances of direct powder compression, the floating tablets were successfully prepared with HPMC as main matrix material, Carbopol as assistant matrix material, octadecanol as floating agent and sodium bicarbonate as foaming agent to float by gas-forming. The floating time and accumulative release amount as evaluation indexes were utilized to perform pre-experiment screening and single-factor test, respectively, while central composite design response surface method was applied for formulation optimization, followed by in vivo pharmacokinetic study in beagles after oral administration for floating tablets and commercial tablets used as the control. The results indicated that the floating sustained-release tablets held a better capability for floating and drug release and more satisfactory pharmacokinetic parameters, such as a lower C_max, a prolonged T_max, but an equivalent bioavailability calculated by AUC_0–24 compared to commercial tablets. So a conclusion was finally drawn that the floating sustained-release tablets possessing a good release property could be suitable for demands of design.     

Effect of aluminum nitride on thermomechanical properties of high performance PEEK

High performance polymer matrix composites based on poly(ether–ether–ketone) (PEEK) as matrix and aluminum nitride particle (AlN_p) as filler were prepared. The effect of AlN_p on the storage modulus, loss modulus, mechanical loss factor, and glass transition were investigated. The AlN_p reinforcement is more pronounced above glass transition temperature (T_g). Composite containing 70 wt.% AlN_p exhibit about 100% increase in storage modulus at 50 °C and about 500% increase at 250 °C, and 19 °C increase in glass transition temperature as compared to pure PEEK. Peak height of tan δ for composites was decreased to one sixth of the pure PEEK. It is probably due to improved crystallinity of PEEK and strong interaction between the AlN_p and PEEK matrix. SEM reveals excellent distribution of AlN_p in PEEK matrix and good interaction between AlN_p and PEEK matrix.     

Synthesis and mechanical properties of cardanol-formaldehyde (CF) resins and CF-poly(methylmethacrylate) semi-interpenetrating polymer networks

Cardanol-formaldehyde (CF) resins (both novolac and resol) and CF-poly(methylmethacrylate) (PMMA) semi-interpenetrating polymer networks were synthesized and their mechanical properties and thermal transitions were evaluated. The lower tensile strength of CF resins compared to phenol-formaldehyde (PF) resins may be understood on the basis of the structure of the C₁₅ side chain imparting steric hindrance and reduction in intermolecular interactions. Interpenetration of CF with PMMA increased the mechanical properties only marginally. Scanning electron micrographs of the semi-IPNs showed two distinct phases. Thermomechanical analysis gave two glass transition temperatures,T _g, for the IPNs, the lowerT _g corresponding to the PMMA phase and the higherT _g to the CF phase. However, the unusual increase inT _g of the CF from 128°C to 144°C suggests restrictions in the segmental motion of the CF phase brought about by mixing with another rigid polymer such as PMMA.     

Spray-dried O-carboxymethyl chitosan as potential hydrophilic matrix tablet for sustained release of drug

Objective: The aim of the present investigation was to evaluate the use of spray-dried O-carboxymethyl chitosan (OCMCS) as potential hydrophilic matrix excipient for sustained release of drug.

Methods: The polymer was synthesized from chitosan, then spray-dried and characterized. Tablets with different OCMCS concentrations (80, 50, 30, 5 and 2% w/w), containing diltiazem (DTZ) as model drug, were prepared for direct compression (DC) and after the wet granulation method (WG).

Results: The spray-dried OCMCS powder was spherical, with a smooth surface and an average size of 2.2?µm. The tablets prepared for WG disintegrated in time less than 30?min. The tablets obtained for DC presented high retention of the drug, with zero order or Higuchi release kinetic. There was a direct relationship between the OCMCS concentration and the release ratio, swelling degree and water uptake behavior. DC tablets containing 80% OCMCS presented behavior as an effective swelling-control system. The DC tablets with 5% OCMCS showed a similar release profile at formulations with 30% HPMC.

Conclusion: Spray-dried OCMCS showed great potential as hydrophilic matrices for drug-sustained release.     

Application of hot melt extrusion for improving bioavailability of artemisinin a thermolabile drug

Hot melt extrusion has been used to produce a solid dispersion of the thermolabile drug artemisinin. Formulation and process conditions were optimized prior to evaluation of dissolution and biopharmaceutical performance. Soluplus^®, a low T_g amphiphilic polymer especially designed for solid dispersions enabled melt extrusion at 110?°C although some drug-polymer incompatibility was observed. Addition of 5% citric acid as a pH modifier was found to suppress the degradation. The area under plasma concentration time curve (AUC_0–24h) and peak plasma concentration (C_max) were four times higher for the modified solid dispersion compared to that of pure artemisinin.     

Enthalpy relaxation studies of two structurally related amorphous drugs and their binary dispersions

Objective: The purpose of the current study was to evaluate the enthalpy relaxation behavior of valdecoxib (VLB) and etoricoxib (ETB) and their binary dispersions to derive relaxation constants and to understand their molecular mobilities. Methods: Solid dispersions of VLB and ETB were prepared with 1%, 2%, 5%, 10%, 15%, and 20% (w/w) concentrations of polyvinylpyrrolidone (PVP) in situ using differential scanning calorimetry (DSC). Enthalpy relaxation studies were carried out with isothermal storage periods of 1, 2, 4, 6, 16, and 24 hours at 40°C and 0% relative humidity (RH). Results: PVP increased the glass transition temperature (T_g) and decreased the enthalpy relaxation. Significant differences between two drugs were observed with respect to their relaxation behavior which may be due to differences in intermolecular interactions as predicted by Couchman–Karasz equation and molecular mobility. Kohlrausch–Williams–Watts equation was found to be inadequate in describing complex molecular relaxations in binary dispersions. The enthalpy relaxation behavior of VLB and ETB was found to be significantly different. PVP stabilized VLB significantly; however, its effect on ETB was negligible. The extent of enthalpy relaxation was found to correlate with hydrogen bonding tendency of the drug molecules. Conclusion: The outcome can help in rational designing of amorphous systems with optimal performance.     

Nifedipine di-matrix depot tablets prepared by compression coating for obtaining zero-order release

Compression coating is a possible process for obtaining zero-order release. Nifedipine compression-coated (CC) di-matrix depot tablets were prepared from a single punch tablet press with low viscosity hydroxypropyl cellulose (HPC-L) as the inner polymer, and with middle viscosity hydroxypropyl cellulose (HPC-M), HPC-L and Eudragit RSPO as outer polymers. The release behavior and mechanisms in vitro of the final tablets were investigated, and gravimetric analysis was used to study the release mechanism. The fast release of the core depot and slow release of the outer depot with time formed total zero-order release. The results showed that the formulation presented ideal zero-order release at the weight ratio of nifedipine 3:5 (core: layer), the combination of HPC-L and HPC-M (56:25) in the outer depot, and with the core depot placed in the center. The CC tablets released to more than 95% in 24?h and fitted a zero-order model with the equation M_t/M^∞?=?0.038t (R²?=?0.98555). In conclusion, zero-order release of nifedipine over 24?h could be achieved by applying polymer HPC-L and HPC-M with the compression coating technique.     

Remarks on Single and Multiparameter Free Volume Calculations in Physical Aging of Poly(vinyl acetate) in the T g-Region

Free volume plays an important role in the analysis of physical aging,both experimentally and theoretically. In this work, the Doolittle freevolume equation and the KAHR model are used to predict isothermal responsesfollowing temperature down- and up-jumps for poly(vinyl acetate), PVAc, inthe T _g-region. The constant B of the Doolittleequation is less than unity when the equation is combined with the Kovacsdifferential equation for free volume collapse for isothermal contractionpredictions. Using B values in the range 0.3 to 0.5 allows goodprediction of the isothermal contraction. It is shown that the equationyields aging rates approaching realistic values only for temperatures muchbelow T _g. Isothermal expansion could not be predicted. Volumerelaxation kinetics is analysed based on the Doolittle equation and comparedwith stress relaxation kinetics near T _g, where the slope ofthe inflexion region is calculated. The transient response of PVAc in thesame aging experiments is obtained using the KAHR model.     

Fine tuning of glass transition temperature in monolithic organic photorefractive material

In order to study the effect of T_g on the photorefractivity in organic monolithic system, we designed and synthesized photorefractive homopolymer (PCzBO) and organic glass (EHCzBO), consisting of the same monolithic chromophore. Photorefractive polymer composites were prepared by blending them. T_g of PCzBO and EHCzBO were 106 and 29 °C, respectively. T_g of polymer composite could be controlled precisely by the compositional ratio of PCzBO and EHCzBO in the range from 29 to 40 °C. Since both the polymer and the organic glass contained the same chromophore structure, all the samples had nearly the same chromophore concentration even though compositional ratios of them were different, as was confirmed by UV–visible spectroscopy. Frequency-dependent ellipsometric technique showed that the birefringence contribution through the orientation enhancement effect was dominant in the refractive index modulation of our low T_g composites. It was found that the reorientation of chromophore according to the modulated voltage was more limited for the higher T_g composite, which consequently reduced the birefringence contribution. The diffraction efficiency and two beam coupling coefficient were decreased with the increase of T_g.