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.     

Itraconazole formulation studies of the melt-extrusion process with mixture design

Itraconazole is a poorly water soluble compound. One method to increase the aqueous solubility of itraconazole is through formation of a solid dispersion. The purpose of this study is to develop a 40% w/w itraconazole formulation through solid dispersion formation, using hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and hydroxypropylmethyl-cellulose (HPMC) as mixture components. The solid dispersion was obtained by melt-extrusion using a twin-screw corotating melt extruder. A D-optimal mixture design was applied for the development of the optimal itraconazole formulation. The itraconazole fraction varied between 20% w/w and 50% w/w in the mixture design and the HPMC and HP-beta-CD fractions varied between 10% w/w and 60% w/w. The itraconazole formulation was optimized by producing clear extrudates, minimizing the torque, and maximizing the glass transition temperature and the apparent itraconazole solubility in 0.1 N HCl. Regression models were developed for the torque, glass transition temperature, and apparent solubility of itraconazole. High itraconazole fraction in the mixture promoted a better melt processing (minimizes torque). High HPMC fraction (>33% w/w) resulted in clear extrudates, indicating a solid dispersion and resulted in high glass transition temperature of the melt. High HP-beta-CD fraction resulted in increased apparent itraconazole solubility in 0.1 N HCl. The optimal itraconazole formulation consisted of 45% w/w HPMC and 15% HP-beta-CD w/w.     

Size effect and dielectric properties of NH4H2PO4 — porous glass composites

NH₄H₂PO₄ nano-composite antiferroelectric materials in porous glass have been studied by means of dielectric and dilatometric investigations. Dielectric spectroscopy measurements in a wide frequency range are reported here for the first time, for both the antiferro- and paraelectric phases of ammonium dihydrogen phosphate (ADP) embedded in a porous matrix. Low frequency relaxation processes above the phase transition temperature were shown to occur. An investigation of the thermal expansion revealed a negative volume jump at the phase transition point. It was found that the phase transition temperature in ADP crystals embedded in porous glass decreased with the decrease of the mean pore size. The experimentally observed shift of the phase transition temperature is caused by a combination of size and pressure effects.     

Part II: Bioavailability in Beagle Dogs of Nimodipine Solid Dispersions Prepared by Hot-Melt Extrusion

ABSTRACT

The aim of the present work was to investigate the in vitro dissolution properties and oral bioavailability of three solid dispersions of nimodipine. The solid dispersions were compared with pure nimodipine, their physical mixtures, and the marketed drug product Nimotop®. Nimodipine solid dispersions were prepared by a hot-melt extrusion process with hydroxypropyl methylcellulose (HPMC, Methocel E5), polyvinylpyrrolidone/vinyl acetate copolymer (PVP/VA, Plasdone S630®), and ethyl acrylate, methyl methacrylate polymer (Eudragit® EPO). Previous studies of XRPD and DSC data showed that the crystallinity was not observed in hot-melt extrudates, two T_gs were observed in the 30% and 50% NMD-HPMC samples, indicating phase separation. The weakening and shift of the N–H stretching vibration of the secondary amine groups of nimodipine as determined by FT-IR proved hydrogen bonding between the drug and polymers in the solid dispersion. The dissolution profiles of the three dispersion systems showed that the release was improved compared with the unmanipulated drug. Drug plasma concentrations were determined by HPLC, and pharmacokinetic parameters were calculated after orally administering each preparation containing 60 mg of nimodipine. The mean bioavailability of nimodipine was comparable after administration of the Eudragit® EPO solid dispersion and Nimotop®, but the HPMC and PVP/VA dispersions exhibited much lower bioavailability. However, the AUC_{0–12 hr} values of all three solid dispersions were significantly higher than physical mixtures with the same carriers and nimodipine powder.     

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.     

偶联剂对玻璃纤维增强淀粉/聚乳酸复合材料性能的影响

分别以马来酸酐、KH550、KH560和KH570为偶联剂对玻璃纤维进行预处理,再与淀粉、聚乳酸(PLA)复合,通过熔融挤出法制备玻璃纤维增强淀粉/PLA复合材料。研究了偶联剂种类对玻璃纤维增强复合材料熔融指数、力学性能、热性能和熔融流变性能的影响。实验发现马来酸酐、KH550、KH570、KH560处理玻璃纤维增强淀粉/PLA复合材料的熔融指数和力学性能都依次增大,表明KH560处理玻璃纤维增强淀粉/PLA复合材料的界面黏结作用最强。对热性能进行表征发现,马来酸酐、KH550、KH570、KH560处理玻璃纤维增强淀粉/PLA复合材料玻璃化转变温度、重结晶温度、结晶度和热稳定性均依次提高。受玻璃纤维与淀粉/PLA基体界面黏结效果的影响,马来酸酐、KH550、KH570、KH560处理玻璃纤维增强淀粉/PLA体系的储能模量和复数黏度依次增大。     

Part II: bioavailability in beagle dogs of nimodipine solid dispersions prepared by hot-melt extrusion

The aim of the present work was to investigate the in vitro dissolution properties and oral bioavailability of three solid dispersions of nimodipine. The solid dispersions were compared with pure nimodipine, their physical mixtures, and the marketed drug product Nimotop. Nimodipine solid dispersions were prepared by a hot-melt extrusion process with hydroxypropyl methylcellulose (HPMC, Methocel E5), polyvinylpyrrolidone/vinyl acetate copolymer (PVP/VA, Plasdone S630), and ethyl acrylate, methyl methacrylate polymer (Eudragit EPO). Previous studies of XRPD and DSC data showed that the crystallinity was not observed in hot-melt extrudates, two T(g)s were observed in the 30% and 50% NMD-HPMC samples, indicating phase separation. The weakening and shift of the N-H stretching vibration of the secondary amine groups of nimodipine as determined by FT-IR proved hydrogen bonding between the drug and polymers in the solid dispersion. The dissolution profiles of the three dispersion systems showed that the release was improved compared with the unmanipulated drug. Drug plasma concentrations were determined by HPLC, and pharmacokinetic parameters were calculated after orally administering each preparation containing 60 mg of nimodipine. The mean bioavailability of nimodipine was comparable after administration of the Eudragit EPO solid dispersion and Nimotop, but the HPMC and PVP/VA dispersions exhibited much lower bioavailability. However, the AUC(0-12 hr) values of all three solid dispersions were significantly higher than physical mixtures with the same carriers and nimodipine powder.     

A preliminary assessment of the impact of hot-melt extrusion on the physico-mechanical properties of a tablet

Objectives: This research aimed at investigating the difference between the powders prior to and after hot melt extrusion. A preliminary assessment was also conducted to gain a better mechanistic understanding of the impact of hot melt extrusion on tabletability.

Materials and methods: Kollidon® VA 64 and mannitol were sieved into different particles sizes and used as is or after drying for 24?h. Hot melt extrusion was used to manufacture an amorphous solid dispersion of Kollidon® VA 64 and mannitol. The extrudates were milled and sieved into different particles sizes. Tablets were manufactured from the different powders and their tabletability, compressibility and compactibility determined.

Results and discussions: It was shown that the as received tablets gave higher tabletability compared with the tablets manufactured from the dried or hot melt extruded (HME) powder. Differences in the tabletability between the as received. dried and HME material could be related back to changes in the bonding area and bonding strength as a result of the hot melt extrusion process and/or a loss of moisture because of the high processing temperature.

Conclusions: The reduced tabletability of the HME tablets appeared to be a function of multiple factors. Both the hot melt extrusion process and the moisture content may play significant roles in determining this phenomenon.     

Electrical and dielectric analysis of phosphate based glasses doped with alkali oxides

In this work, new phosphate glasses with the molar composition 20.7P₂O₅–17.2Nb₂O₅–13.8WO₃–34.5A₂O–13.8B₂O₃ where A = Li, Na and K were prepared using the melt quenching technique. These types of glasses have potential to absorb hydrogen in its structure, which makes them promising materials to be used as electrolytes in intermediate temperature fuel cells. Additionally, niobium phosphate glasses can also have applications such as glass fibers, optical lenses, hermetic sealing and electrodes. The structure of the obtained samples was analyzed using Differential Thermal Analysis (DTA), X-ray powder diffraction (XRD), and Raman spectroscopy and the morphology by Scanning Electron Microscopy (SEM). The DTA measurements revealed values of glass transition temperature around 415 °C, and the Raman analysis showed that the amount of alkali and niobium oxides included on the studied compositions, successfully disrupted the P–O–P chains characteristic of the phosphate glasses. Dc (σ_dc) and ac (σ_ac) conductivities and dielectric spectroscopy measurements were performed as function of the temperature (200–370 K) which presented conductivity predominantly ionic (σ_electronic/σ_ionic of about 10^− 4). The dielectric spectroscopy was measured in the frequency range 100–1 MHz.     

Effect of Zr on dielectric, ferroelectric and impedance properties of BaTiO3 ceramic

A polycrystalline sample of Zr-doped barium titanate (BaTiO₃) was prepared by conventional solid state reaction method. The effect of Zr (0·15) on the structural and microstructural properties of BaTiO₃ was investigated by XRD and SEM. The electrical properties (dielectric, ferroelectric and impedance spectroscopy) were measured in wide range of frequency and temperature. With substitutions of Zr, the structure of BaTiO₃ changes from tetragonal to rhombohedral. Lattice parameters were found to increase with substitution. The room temperature dielectric constant increases from ～ 1675 to ～ 10586 and peak dielectric constant value increases from ～ 13626 to ～ 21023 with diffuse phase transition. Impedance spectroscopy reveals the formation of grain and grain boundary in the material and found to decrease with increase in temperature.     

Development of a fast,lean and agile direct pelletization process using experimental design techniques

A novel hot melt direct pelletization method was developed, characterized and optimized, using statistical thinking and experimental design tools. Mixtures of carnauba wax (CW) and HPMC K100M were spheronized using melted gelucire 50–13 as a binding material (BM). Experimentation was performed sequentially; a fractional factorial design was set up initially to screen the factors affecting the process, namely spray rate, quantity of BM, rotor speed, type of rotor disk, lubricant–glidant presence, additional spheronization time, powder feeding rate and quantity. From the eight factors assessed, three were further studied during process optimization (spray rate, quantity of BM and powder feeding rate), at different ratios of the solid mixture of CW and HPMC K100M. The study demonstrated that the novel hot melt process is fast, efficient, reproducible and predictable. Therefore, it can be adopted in a lean and agile manufacturing setting for the production of flexible pellet dosage forms with various release rates easily customized between immediate and modified delivery.     

Dissolution rate enhancement,in vitro evaluation and investigation of drug release kinetics of chloramphenicol and sulphamethoxazole solid dispersions

Formulation of solid dispersions is one of the effective methods to increase the rate of solubilization and dissolution of poorly soluble drugs. Solid dispersions of chloramphenicol (CP) and sulphamethoxazole (SX) as model drugs were prepared by melt fusion method using polyethylene glycol 8000 (PEG 8000) as an inert carrier. The dissolution rate of CP and SX were rapid from solid dispersions with low drug and high polymer content. Characterization was performed using fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and scanning electron microscopy (SEM). FTIR analysis for the solid dispersions of CP and SX showed that there was no interaction between PEG 8000 and the drugs. Hyper-DSC studies revealed that CP and SX were converted into an amorphous form when formulated as solid dispersion in PEG 8000. Mathematical analysis of the release kinetics demonstrated that drug release from the various formulations followed different mechanisms. Permeability studies demonstrated that both CP and SX when formulated as solid dispersions showed enhanced permeability across Caco-2 cells and CP can be classified as well-absorbed compound when formulated as solid dispersions.     

Applications of low frequency dielectric spectroscopy to the pharmaceutical sciences

Low frequency dielectric spectroscopy (LFDS) is an analytical technique which has found considerable application in the study of pharmaceutical systems. In this article, an outline of the theoretical and practical aspects of the method will be given, as well as a discussion of the advantages and disadvantages of the technique. Examples will be given of how LFDS may be used in the analysis of pharmaceutical systems, including studies on solid dispersions, inter-batch variation, liposome suspensions and cyclodextrins.     

Carbamazepine/betaCD/HPMC solid dispersions. I. Influence of the spray-drying process and betaCD/HPMC on the drug dissolution profile

The aim of this study was to compare carbamazepine (CBZ) solid dispersions prepared by spray-drying of aqueous dispersions with the corresponding physical mixtures. The influence of the association of β-cyclodextrin (βCD) and hydroxypropyl methylcellulose (HPMC) on the CBZ dissolution profile of the preparations was investigated. Results demonstrated that CBZ release from solid dispersions is dependent on the ratio of βCD and HPMC. The spray-drying process confers better homogeneity to CBZ polymeric dispersions than the physical mixture process. In summary, we demonstrated the feasibility of obtaining a homogeneous polymeric solid dispersion of CBZ from an aqueous media by spray-drying and a clear influence of the βCD:HPMC ratio on the release profile of CBZ.     

Effect of melt heat treatment on the solid/liquid interface morphology of directional solidification

A set of quadral-electrode DC input voltage measure equipment was built up to detect the electrical resistance of Sb–Bi single-phase alloy. The results suggest that Sb–5%wt Bi undergoes structural transition in the temperature range of 730–750°C. By overheating the melt to different temperatures and then cooling to 690°C after a period of time, the samples are directionally solidified in a Bridgeman-type furnace. It is found for the first time that after heat treatment of the melt, the solid/liquid interface morphology shows significant variation depending on the speciic heat treatment. Also, in Ag–Cu, Al–Cu systems, bicrystal growth with different orientation is found to have different interface morphologies after heat treatment. It is believed that the evolution of the cluster size distribution in the melt contributes to these phenomena.     

Effect of melt heat treatment on the solid/liquid interface morphology of directional solidification

A set of quadral-electrode DC input voltage measure equipment was built up to detect the electrical resistance of Sb–Bi single-phase alloy. The results suggest that Sb–5%wt Bi undergoes structural transition in the temperature range of 730–750°C. By overheating the melt to different temperatures and then cooling to 690°C after a period of time, the samples are directionally solidified in a Bridgeman-type furnace. It is found for the first time that after heat treatment of the melt, the solid/liquid interface morphology shows significant variation depending on the specific heat treatment. Also, in Ag–Cu, Al–Cu systems, bicrystal growth with different orientation is found to have different interface morphologies after heat treatment. It is believed that the evolution of the cluster size distribution in the melt contributes to these phenomena.     

Hot melt extrusion versus spray drying: hot melt extrusion degrades albendazole

Abstract

The purpose of this study was to enhance the dissolution properties of albendazole (ABZ) by the use of amorphous solid dispersions. Phase diagrams of ABZ–polymer binary mixtures generated from Flory–Huggins theory were used to assess miscibility and processability. Forced degradation studies showed that ABZ degraded upon exposure to hydrogen peroxide and 1 N NaOH at 80?°C for 5?min, and the degradants were albendazole sulfoxide (ABZSX), and ABZ impurity A, respectively. ABZ was chemically stable following exposure to 1 N HCl at 80?°C for one hour. Thermal degradation profiles show that ABZ, with and without Kollidon^® VA 64, degraded at 180?°C and 140?°C, respectively, which indicated that ABZ could likely be processed by thermal processing. Following hot melt extrusion, ABZ degraded up to 97.4%, while the amorphous ABZ solid dispersion was successfully prepared by spray drying. Spray-dried ABZ formulations using various types of acids (methanesulfonic acid, sulfuric acid and hydrochloric acid) and polymers (Kollidon^® VA 64, Soluplus^® and Eudragit^® E PO) were studied. The spray-dried ABZ with methanesulfonic acid and Kollidon^® VA 64 substantially improved non-sink dissolution in acidic media as compared to bulk ABZ (8-fold), physical mixture of ABZ:Kollidon^® VA 64 (5.6-fold) and ABZ mesylate salt (1.6-fold). No degradation was observed in the spray-dried product for up to six months and less than 5% after one-year storage. In conclusion, amorphous ABZ solid dispersions in combination with an acid and polymer can be prepared by spray drying to enhance dissolution and shelf-stability, whereas those made by melt extrusion are degraded.     

Applications of low frequency dielectric spectroscopy to the pharmaceutical sciences

Abstract

Low frequency dielectric spectroscopy (LFDS) is an analytical technique which has found considerable application in the study of pharmaceutical systems. In this article, an outline of the theoretical and practical aspects of the method will be given, as well as a discussion of the advantages and disadvantages of the technique. Examples will be given of how LFDS may be used in the analysis of pharmaceutical systems, including studies on solid dispersions, inter-batch variation, liposome suspensions and cyclodextrins.     

Tailoring the Release Rates of Fluconazole Using Solid Dispersions in Polymer Blends

Formulations of the drug Fluconazole with different release characteristics were prepared by dispersing the active pharmaceutical ingredient (API) in various polymeric carriers, and especially in polymer blends. Fluconazole was tested as a model drug with low solubility in water. First solid dispersions in pure polymers were studied. Use of pure polyvinylpyrrolidone (PVP) as carrier even for high drug load (30 wt%) resulted in rapid release. The drug release rates decreased by increasing the API content. The dissolution rate enhancement was attributed to drug amorphization, particle size reduction, and possible improvement of the drug wetting characteristics. Hydroxypropyl methylcellulose (HPMC) gave solid dispersions, from which the release rates of the drug varied from immediate to sustaining. As the drug amount increased, the rates became higher. Similar behavior also was found when Chitosan was used as carrier, with much more controlled rates close to those for sustained release. These differences were mainly attributed to the limited solubility and swelling of HPMC and Chitosan in aquatic media. To study the effectiveness of polymer blends in adjusting the release rates of the drug, solid dispersions in PVP/HPMC and PVP/Chitosan miscible blends were studied. The release rates of Fluconazole were adequately adjusted by differentiating the weight ratio of the polymers in the blends. PVP/HPMC blends with high PVP content can be used for immediate release formulations but PVP/Chitosan blends are inappropriate for such formulations and can only be used for controlled release.     

Tailoring the release rates of fluconazole using solid dispersions in polymer blends

Formulations of the drug Fluconazole with different release characteristics were prepared by dispersing the active pharmaceutical ingredient (API) in various polymeric carriers, and especially in polymer blends. Fluconazole was tested as a model drug with low solubility in water. First solid dispersions in pure polymers were studied. Use of pure polyvinylpyrrolidone (PVP) as carrier even for high drug load (30 wt%) resulted in rapid release. The drug release rates decreased by increasing the API content. The dissolution rate enhancement was attributed to drug amorphization, particle size reduction, and possible improvement of the drug wetting characteristics. Hydroxypropyl methylcellulose (HPMC) gave solid dispersions, from which the release rates of the drug varied from immediate to sustaining. As the drug amount increased, the rates became higher. Similar behavior also was found when Chitosan was used as carrier, with much more controlled rates close to those for sustained release. These differences were mainly attributed to the limited solubility and swelling of HPMC and Chitosan in aquatic media. To study the effectiveness of polymer blends in adjusting the release rates of the drug, solid dispersions in PVP/HPMC and PVP/Chitosan miscible blends were studied. The release rates of Fluconazole were adequately adjusted by differentiating the weight ratio of the polymers in the blends. PVP/HPMC blends with high PVP content can be used for immediate release formulations but PVP/Chitosan blends are inappropriate for such formulations and can only be used for controlled release.