Rheological Characterization of Molten Polymer-Drug Dispersions as a Predictive Tool for Pharmaceutical Hot-Melt Extrusion Processability

Purpose

The aim of this study was to investigate (i) the influence of drug solid-state (crystalline or dissolved in the polymer matrix) on the melt viscosity and (ii) the influence of the drug concentration, temperature and shear rate on polymer crystallization using rheological tests.

Methods

Poly (ethylene oxide) (PEO) (100.000 g/mol) and physical mixtures (PM) containing 10–20–30–40% (w/w) ketoprofen or 10% (w/w) theophylline in PEO were rheologically characterized. Rheological tests were performed (frequency and temperature sweeps in oscillatory shear as well as shear-induced crystallization experiments) to obtain a thorough understanding of the flow behaviour and crystallization of PEO-drug dispersions.

Results

Theophylline did not dissolve in PEO as the complex viscosity (η*) of the drug-polymer mixture increased as compared to that of neat PEO. In contrast, ketoprofen dissolved in PEO and acted as a plasticizer, decreasing η*. Acting as a nucleating agent, theophylline induced the crystallization of PEO upon cooling from the melt. On the other hand, ketoprofen inhibited crystallization upon cooling. Moreover, higher concentrations of ketoprofen in the drug-polymer mixture increasingly inhibited polymer crystallization. However, shear-induced crystallization was observed for all tested mixtures containing ketoprofen.

Conclusion

The obtained rheological results are relevant for understanding and predicting HME processability (e.g., barrel temperature selection) and downstream processing such as injection moulding (e.g., mold temperature selection).

     

Characterization of a Hot-Melt Fluid Bed Coating Process for Fine Granules

The equipment modifications and process changes necessary to perform hot-melt particle coating in a fluid bed granulator are reviewed. A specific case is presented in which partially hydrogenated cottonseed oil is coated onto fine granules (mean particle size, 77 µm; range, 10–150 µm; one standard deviation is 10 µm) composed of a hydrophobic drug and sucrose. The major variables were product bed temperature, temperature of the wax, spray rate, and atomization air pressure. The product bed temperature was selected to give the optimum congealing rate, and the latter three variables were varied in a statistically designed experiment. The physical properties of wax-coated granules fabricated using combinations of process variables were examined. Response surface analysis was used to determine the optimum process settings in terms of dissolution, particle size, and density of the coated product. This system proved quite adequate for the production of uniformly coated granules, with the best product being obtained at the optimized conditions using 120°C atomization air and molten coating temperature, 30 g/min as the spray rate, and an atomization air pressure of 5 bar.     

Matrix-Assisted Cocrystallization (MAC) Simultaneous Production and Formulation of Pharmaceutical Cocrystals by Hot-Melt Extrusion

A novel method for the simultaneous production and formulation of pharmaceutical cocrystals, matrix-assisted cocrystallization (MAC), is presented. Hot-melt extrusion (HME) is used to create cocrystals by coprocessing the drug and coformer in the presence of a matrix material. Carbamazepine (CBZ), nicotinamide (NCT), and Soluplus® were used as a model drug, coformer, and matrix, respectively. The MAC product containing 80:20 (w/w) cocrystal:matrix was characterized by differential scanning calorimetry, Fourier transform infrared spectroscopy, and powder X-ray diffraction. A partial least squares (PLS) regression model was developed for quantifying the efficiency of cocrystal formation. The MAC product was estimated to be 78% (w/w) cocrystal (theoretical 80%), with approximately 0.3% mixture of free (unreacted) CBZ and NCT, and 21.6% Soluplus (theoretical 20%) with the PLS model. A physical mixture (PM) of a reference cocrystal (RCC), prepared by precipitation from solution, and Soluplus resulted in faster dissolution relative to the pure RCC. However, the MAC product with the exact same composition resulted in considerably faster dissolution and higher maximum concentration (∼five-fold) than those of the PM. The MAC product consists of high-quality cocrystals embedded in a matrix. The processing aspect of MAC plays a major role on the faster dissolution observed. The MAC approach offers a scalable process, suitable for the continuous manufacturing and formulation of pharmaceutical cocrystals. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:2904–2910, 2014     

Physicochemical Characterization of Felodipine-Kollidon VA64 Amorphous Solid Dispersions Prepared by Hot-Melt Extrusion

To improve the dissolution and hence the oral bioavailability, amorphous felodipine (FEL) solid dispersions (SDs) with Kollidon® VA 64 (PVP/VA) were prepared. Hot-melt extrusion was employed with an extruding temperature below the melting point (T_m) of FEL. X-ray powder diffraction (XRPD) and ¹³C CP/MAS nuclear magnetic resonance (NMR) measurements show that the extrudates are amorphous. The intermolecular interaction between FEL and PVP/VA in SDs was investigated by Fourier transform infrared spectroscopy, ¹⁵N CP/MAS NMR, and ¹H high-resolution MAS NMR. Furthermore, a single glass transition temperature (T_g) was detected by differential scanning calorimetry in addition to a single ¹H T₁ or T_1rho relaxation time detected by ¹³C NMR signals. These results confirm that the extru-dates contain FEL dispersed into the polymer matrix at a molecular level with no detectable phase separation. This molecular-scale mixing results in a significantly faster dissolution rate compared with the pure crystalline FEL. Additionally, the molecular-scale mixing prevents the amorphous drug from recrystallizing even after being stored at 40°C/75% Relative Humidity for 2 months.     

Physical Characterization of Pharmaceutical Solids

A general review of the methods available for the physical characterization of pharmaceutical solids is presented. The techniques are classified as being on the molecular level (properties capable of being detected in an ensemble of individual molecules), the particulate level (properties which can be detected through the analysis of an ensemble of particles), and the bulk level (properties which can be measured only using a relatively large amount of material). The molecular-level properties discussed are infrared spectroscopy and nuclear magnetic resonance spectrometry, the particulate-level properties discussed are particle morphology, particle size distribution, powder X-ray diffraction, and thermal methods of analysis, and the bulk-level properties discussed are surface area, porosity and pore size distribution, and powder flow characteristics. Full physical characterization of three modifications of lactose (hydrous, anhydrous, and Fast-Flo) is presented to illustrate the type of information which can be obtained using each of the techniques discussed.     

兰索拉唑脂质体的制备及其药剂学性质考察

目的:研究兰索拉唑阳离子脂质体的制备方法并考察其药剂学性质。方法:采用正交设计筛选处方,乙醇注入法制备兰索拉唑脂质体;超滤法测定其包封率;用透射电镜观察脂质体的外观形态,并用粒径分析仪和Zeta电位仪分别测定脂质体的粒径和Zeta电位;进一步考察脂质体的释放规律。结果:所得脂质体包封率约为(80±1.23)%;形态为粒径均匀的球形和类球形,粒径为(184±21)nm,Zeta电位为(36.1±5)mV;脂质体的体外释放符合一级方程;具有较好的稳定性。结论:优选得到的脂质体处方和制备工艺合理、稳定,其体外释放具有缓释特点。     

Hyaluronan: Pharmaceutical Characterization and Drug Delivery

Hyaluronic acid (HA), is a polyanionic polysaccharide that consists of N-acetyl-D-glucosamine and β-glucoronic acid. It is most frequently referred to as hyaluronan because it exists in vivo as a polyanion and not in the protonated acid form. HA is distributed widely in vertebrates and presents as a component of the cell coat of many strains of bacteria. Initially the main functions of HA were believed to be mechanical as it has a protective, structure stabilizing and shock-absorbing role in the body. However, more recently the role of HA in the mediation of physiological functions via interaction with binding proteins and cell surface receptors including morphogenesis, regeneration, wound healing, and tumor invasion, as well as in the dynamic regulation of such interactions on cell signaling and behavior has been documented. The unique viscoelastic nature of hyaluronan along with its biocompatibility and nonimmunogenicity has led to its use in a number of cosmetic, medical, and pharmaceutical applications. More recently, HA has been investigated as a drug delivery agent for ophthalmic, nasal, pulmonary, parenteral, and dermal routes. The purpose of our review is to describe the physical, chemical, and biological properties of native HA together with how it can be produced and assayed along with a detailed analysis of its medical and pharmaceutical applications.     

Preparation of Gelatin Nanocapsules and Their Pharmaceutical Characterization

A production process is described that yields nanocapsules instead of nanoparticles. The process allows the encapsulation of lipophilic drugs such as triamcinolone acetonide with an O/W emulsion system. The capsular structure of the products was confirmed by transmission and scanning electron microscopy. The nanocapsules displayed a mean size of 141 ± 47 nm to 523 ± 340 nm (mean ± S.D.) and a drug content of 7 % to 15.4 % w/w. Drug release experiments showed that the encapsulated triamcinolone acetonide was released more slowly than micronized drug crystals. A more pronounced retarded release could be achieved by raising the pH during the hardening reaction or by encapsulating cholesterol into the nanocapsules.     

Spheronization of Small Extrudates Containing κ-Carrageenan

Spheronization of extrudates of around 500 µm diameter needs improvement of the Schlueter spheronizer conditions with regard to moisture content of the extrudates. The extrudates were obtained by a twin-screw extruder and contained κ-carrageenan as pelletization aid. The influences of spheronization speed, residence time, temperature of the spheronizer wall and loading on the responses aspect ratio, pellet size and yield, were studied with a central composite circumscribed design. The Schlueter spheronizer was compared with a Nica spheronizer. Further, additional spheronizer process variables such as temperature of the spheronizer wall and inlet air pressure were also investigated. The results were evaluated in a full factorial (mixed) design. The micropellets in general showed a pellet size between 500 and 700 µm. A twisted-rope movement during the spheronization process was not observed and adhesion to the spheronizer wall resulted in suboptimal micropellets. However, at suitable moisture content, less loading in the spheronizer, higher spheronization speed and longer residence time micropellets with an aspect ratio below 1.1 were obtained. In addition the adhesion to the spheronizer wall was reduced. Spheronizer wall temperature and inlet air pressure were negligible variables. Significant differences between the two spheronizers could not be established. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:3776–3787, 2009     

Rational Development of Solid Dispersions via Hot-Melt Extrusion Using Screening,Material Characterization,and Numeric Simulation Tools

Effective and predictive small-scale selection tools are inevitable during the development of a solubility enhanced drug product. For hot-melt extrusion, this selection process can start with a microscale performance evaluation on a hot-stage microscope (HSM). A batch size of 400 mg can provide sufficient materials to assess the drug product attributes such as solid-state properties, solubility enhancement, and physical stability as well as process related attributes such as processing temperature in a twin-screw extruder (TSE). Prototype formulations will then be fed into a 5 mm TSE (～1–2 g) to confirm performance from the HSM under additional shear stress. Small stress stability testing might be performed with these samples or a larger batch (20–40 g) made by 9 or 12 mm TSE. Simultaneously, numeric process simulations are performed using process data as well as rheological and thermal properties of the formulations. Further scale up work to 16 and 18 mm TSE confirmed and refined the simulation model. Thus, at the end of the laboratory-scale development, not only the clinical trial supply could be manufactured, but also one can form a sound risk assessment to support further scale up even without decades of process experience. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:2297–2310, 2013     

Preformulation-Assisted Design and Characterization of Modified Release Gastroretentive Floating Extrudates Towards Improved Bioavailability and Minimized Side Effects of Baclofen

Baclofen immediate release mode of administration exhibit sharp plasma peaking that results in the emergence of side effects like hypotension. This research employs preformulation studies to design an optimum dosage form for baclofen to enhance therapeutic outcomes. These studies include partition coefficient and ex-vivo permeation studies. Partition coefficient was found to be 1.27 at pH 7.4. Permeation studies confirmed the presence of specialized transport mechanism through the GIT. It was concluded that an ideal formulation of baclofen should provide slow-release of the drug to avoid sharp peaking. Modified-release floating extrudates of baclofen were prepared using Carbopol 934 and HPMC with different gas-forming agents. Different release-retarding materials (Eudragit L100, Eudragit RS100 and Cetyl alcohol) were used as ingredients in the binder solutions. The prepared extrudates were assessed for their drug content, floating ability, friability properties and in vitro release properties. The prepared extrudates recorded buoyance characteristics for 24 h with a floating lag time varying from 0 to 73.34 s. The optimized extrudates manifested extended baclofen release for up to 8 h compared to 0.2 h for marketed baclofen tablets. This approach was found efficient to provide greater bioavailability and minimize hypotension associated with commercial baclofen tablets.     

Additional Transporter Characterization May Lead to New Pharmaceutical Opportunities

Pharmaceutical Research -     

A Simplified Model Structure for Compression Characterization of Pharmaceutical Tablets

Despite -or maybe because- many shortcomings, Heckel's equation is by far the most investigated compressibility model for decades. The somewhat overlooked Gurnham equation is proposed as a more stable and better fitting compressibility model. Combining this equation with a linear model for the strength/pressure relation provides a composite function identical with the often-used Ryshkewitch equation for the relation between strength and porosity. It is thus questioned whether the three-dimensional compression characterization presented in USP monograph <1062> is correct. Substantial errors in computed parameters are revealed with consequences for reproducibility or inter-lab assessments. Elastic recovery is proposed as a more interesting and relevant characteristic in relation to pharmaceutical tablet formulation.     

Acoustic Testing and Characterization Techniques for Pharmaceutical Solid Dosage Forms

The mechanical state of a drug tablet is an important factor in its physical form and therapeutic function. In recent years, a strong need for new technologies for faster and more reliable quality assurance has often been voiced by both regulators and manufacturers. In the current study, a novel air-coupled acoustic technique is demonstrated as a noncontact/nondestructive method for mechanical characterization and coating thickness determination of tablets. For verification purposes, a contact ultrasonic scheme is employed. Applications of the technique in solid dosage form characterization and process monitoring applications and its role as a potential PAT tool are discussed.     

无定形药物固相表征技术的研究进展及应用

无定形药物在提高难溶性药物溶解度、改善其溶出及生物利用度方面具有显著优势,故而广泛应用于药物制剂领域。但无定形药物处于能量较高的非稳态,易发生结晶,从而失去其在溶解度和溶出速率等方面的优势。因此,在无定形药物制剂的制备和储存过程中,为控制质量需要对其进行相应表征。目前,已有包括光学技术、热分析技术、光谱学技术等在内的多种技术被广泛用于无定形药物制剂的研究领域。本文简述无定形药物制剂的多种新发展的表征技术,包括偏光显微镜-控温热台联用、表面光栅衰减、X射线粉末衍射-同步辐射光源技术联用、热分析技术、宽频介电谱、纳米红外光谱分析、拉曼光谱成像、固态核磁共振、荧光分析、X射线光电子能谱等技术,并重点介绍近几年该领域的研究进展及其应用,以期为无定形药物制剂研究和开发提供借鉴。     

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

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

微生物鉴定分型技术应用于医药企业微生物污染调查

采用平板沉降法收集制药企业车间生产现场环境微生物,以了解药品生产环境微生物的污染程度和潜在风险.经过API生化鉴定方法、全自动微生物鉴定仪和16S rRNA基因序列分析技术,对分离到的微生物进行鉴定.本次共收集沉降微生物106株,分为16个属19个种.其中,16S rRNA基因序列鉴定结果显示,属的准确率为100%(19/19),有68.4%(13/19)的微生物菌株可直接鉴定到种.根据细菌16S rRNA基因同源性,初步判断在工厂万级环境中,从应隔离的配料间和洗瓶间的采样点监测到的藤黄微球菌同源性较高,分析该工厂十万级环境可能随人流或物流受到同一株微生物交叉污染.     

药用辅料羧甲基纤维素钠物理表征参数研究

目的：对不同来源的羧甲基纤维素钠物理质量属性进行评价。方法：借鉴中药化学指纹图谱的概念,由松密度、振实密度、粒径＜50 μm百分比、粉体粒度分布宽度、粉体粒度分布范围、豪斯纳比、 休止角、颗粒间空隙率、卡尔指数、干燥失重、吸湿性11个指标作为羧甲基纤维素钠的物理表征参数, 并对其进行评价;构建了可压性参数(参数指数、参数轮廓指数和良好可压性指数),预测辅料的压缩特性。结果：不同来源或同一型号不同批次的羧甲基纤维素钠粉体学性质存在明显差异,可压性差异不大。结论：建立的羧甲基纤维素钠物理参数表征方法,可以用于评价不同来源粉体的质量一致性,为药用辅料质量评价和口服固体制剂处方开发及工艺控制提供新的思路。     

Compression of Controlled-Release Pellets Produced by a Hot-Melt Extrusion and Spheronization Process

The purpose of this study was to investigate the physicomechanical and dissolution properties of tablets containing controlled-release pellets prepared by a hot-melt extrusion and spheronization process. A powder blend of anhydrous theophylline, Eudragit® Preparation 4135 F, and functional excipients was melt-extruded, pelletized, and then spheronized. The pellets were compressed into tablets using forces of 5, 10, 15, and 20 kN. Tablet diluents included microcrystalline cellulose, a mixture of spray-dried lactose and microcrystalline cellulose, modified food starch, and soy polysaccharides. The effective porosity of the compressed pellets was measured using mercury porosimetry and helium pycnometry, while the surface area was determined using Brunauer, Emmett, and Teller (BET) analysis. The disintegration time, hardness, and friability of compacts were determined. Drug release studies were performed according to USP 27 Apparatus 3 guidelines in 250 mL of medium (pH 1.0, 3.0, 5.0, 6.8, and 7.4) 37°C and 20 dpm. Samples were analyzed by high pressure-liquid chromatography (HPLC). Effective porosity and surface area determinations of the melt-extruded pellets were not influenced by compression. The percent of theophylline released from rapidly disintegrating tablets was not affected by compression force or excipient selection, but tablets with prolonged disintegration times exhibited delayed drug release in acidic media. However, dissolution profiles of uncompressed pellets and all compacts were identical after transition from 0.1 N HCl to media increasing in pH from 3.0 to 7.4. Furthermore, pellet to filler excipient ratio and filler excipient selection did not influence the rate of drug release from compacts.