超临界流体过程与药物的超细化

用超临界流体过程制备微米和纳米级微粒,是近年来发展的一种粉体超细化处理的新技术,特别适用于具有热敏性和生物活性等特殊性能材料的超细化处理,在制药行业具有广阔的应用前景.介绍了超临界溶液快速膨胀过程和超临界反溶过程的原理、特点及其在药物微粒和微胶囊制备中的应用.     

Continuous processes for the production of pharmaceutical intermediates and active pharmaceutical ingredients

Continuous processing can be applied to the production of pharmaceutical intermediates and active pharmaceutical ingredients. Relatively small, well-designed continuous reactors offer enhanced heat and mass transfer rates, shorter inventories of hazardous materials and precise control of reaction and quench times compared with batch processing. These factors have a significant impact on the safety, quality and economics of a process. Continuous processing, a mainstay of the chemical industry, remains a novelty within the pharmaceutical industry; however, there has been renewed interest in the application of continuous processing to organic synthesis in the pharmaceutical industry in recent years, and this review discusses the opportunities for reaction engineering of low-molecular-weight compounds.     

Scalable enantioselective processes for chiral pharmaceutical intermediates

The importance and practicality of asymmetric synthesis to obtain enantiomerically pure drug substances has been fully recognized by process chemists of the pharmaceutical industry. Catalytic enantioselective processes would be particularly advantageous, compared to processes requiring stoichiometric amounts of chiral initiators, and would also be of interest from an environmental perspective. Since the commercialization of the Monsanto process for the manufacturing of L-DOPA in the early 1970s, catalytic asymmetric reactions have often been utilized in the commercial production of active pharmaceutical ingredients. This review will focus on recent advances in the development of scalable enantioselective processes for chiral pharmaceutical intermediates.     

The influence of crystal form on the radial stress transmission characteristics of pharmaceutical materials.

Various crystal forms of sulphathiazole, barbitone and aspirin were compressed in a single-punch tablet machine instrumented to monitor axially applied and radially transmitted forces, and upper punch movement. The changes in radial stress during the compression cycle depended upon the polymorphic form of the compressed material. The results were rationalized in terms of the degree of plastic flow/crushing that occurred with each material, and the degree to which the final compact underwent elastic compression. It is postulated that the reduction in the transition temperature of polymorphic forms of sulphathiazole and barbitone and the polymorphic transition of sulphathiazole Form II was due to the production of dislocations in the crystal and the crystals at crystal boundaries formed in the compressed materials.     

Aging processes in pharmaceutical polymers

In the practical field of solid pharmaceutical formulations, studies of the physical aging of polymers and the stability of dosage forms are of great importance. Polymers are the additives used to convert pharmacologically active compounds into pharmaceutical dosage forms suitable for administration to patients, and thus a knowledge of the physical aging effects on the stability of final products is essential. In this review, the author attempts to elucidate the fundamental concepts of physical aging in polymers, and correlate the effects of physical aging on the properties with changes in solid dosage form stability.     

A quality evaluation strategy for multi-sourced active pharmaceutical ingredient (API) starting materials

Establishing appropriate impurity specifications for active pharmaceutical ingredient (API) starting materials is an important component of the commercialization and registration of an API. Multiple sources and routes of manufacture of starting materials and the capability of the API synthetic process for tolerating impurities introduced with starting materials must be understood. A strategy for purity method development and use test evaluation of starting materials to aid in establishing quality requirements is described. Phenyl methyl amino propanol (PMAP), a starting material that may be used for fluoxetine hydrochloride and atomoxetine hydrochloride, is used to illustrate the quality evaluation strategy. Knowledge of actual and potential synthetic routes was used to predict potential impurities and guide purity method development. Multiple analytical methods that were semi-orthogonal in the nature of impurity retention (ion-pairing, ion interaction and hydrophilic interaction chromatographic modes) along with use tests were investigated.     

Amorphous form in pharmaceutical technological research

Detecting and analysing of the amorphous phase are increasingly important in pharmaceutical technology. The amorphous or glassy state has a several advantages and disadvantages. The amorphous form can be applied in deliberate amorphization, when active pharmaceutical ingredient (API) is formulated in glassy state, or this form can appear accidentally during formulation or storage. The aim of this study was to characterize glass-forming properties of 13 different materials. Differential Scanning Calorimetry (DSC) was used as an analytical technique and T(g) and T(m) values were determined. The equation of T(g)/T(m) (K/K) was applied to determine the glass-forming tendencies. We made 2 groups of investigated substances. The first group was that we could not amorphized: tenoxicam, mannitol, niflumic acid, theophyllin and lidocain. The second group contains materials, which could be prepared in glassy form. This group can be divided into 2 sub-groups: poor-glass formers and good-glass formers. Poor-glass formers are following: meloxicam, ibuprofen and piroxicam. Good-glass formers are lacidipine, gemfibrosil, sorbitol, loratadine, chlorhexidine and clopidogrel hydrogensulfate.     

无菌制剂的灭菌方法和灭菌工艺的验证

无菌制剂应具有无菌、无微生物污染的特性。无菌制剂主要包括注射剂、眼用制剂、植入剂、用于伤口或手术后切口的冲洗液和透析液等。因为它们直接与身体内易发生感染的体液或组织接触,故这些制剂中无菌是最重要的质量指标。无菌制剂的制备工艺过程中最重要的步骤就是灭菌。常用     

儿童用药制剂现状及剂型设计

本文从儿童用药的临床使用现状、政策、制剂设计、安全性评价等方面,综述了儿童用药的现状及研究进展.     

Nondimensional scaling laws for controlling pharmaceutical spray uniformity: understanding and scale-up

Spatially resolved drop size, drop velocity, and spray volume flux measurements for sprays produced by a commonly used pharmaceutical coating nozzle were performed in this study. Results showed three distinctive spray patterns: Gaussian, homogeneous, and dumbbell shaped. We found that transition from a dumbbell-shaped to a homogeneous pattern is related to the shaping air-induced breakup of already formed drops: depending on the drop size upstream of the location where the shaping air flows meet (i.e., the "junction" point), the drop viscosity, and the magnitude of the shaping air velocity, the shaping air can either pinch the spray or cause additional drop breakup. When the former outweighs the latter, the dumbbell-shaped pattern occurs; the homogeneous pattern is present when the opposite occurs. A corollary to this experimental interpretation is that whether additional drop breakup homogenizes the sprays or pinches, it is related to a Weber number (We) that is calculated using drop sizes upstream of the junction point, drop viscosity and surface tension, and the shaping air velocity at the junction point. With this idea in mind, we propose a We-based scaling method for optimizing the uniformity of air-assist spray patterns.     

Pelletization processes for pharmaceutical applications: a patent review

Pellets exhibit major therapeutic and technical advantages which have established them as an exceptionally useful dosage form. A plethora of processes and materials is available for the production of pellets, which practically allows inexhaustible configurations contributing to the flexibility and versatility of pellets as drug delivery systems. The scope of this review is to summarize the recent literature on pelletization processes for pharmaceutical applications, focusing on the awarded and pending patents in this technical field. The first part of the article provides an overview of innovation in pelletization processes, while the second part evaluates their novel applications.     

仿制原料药研究开发流程及技术要求

本文针对国家食品药品监督管理局对仿制原料药研究开发出台的一些新法规和技术指导原则,研究确定了仿制药研发流程及技术要求,以期对仿制原料药的研发具有一定的指导意义。     

One-phase crystal disorder in pharmaceutical solids and its implication for solid-state stability

Solid-state disorders of active pharmaceutical ingredients have been characterized by means of X-ray diffraction techniques and solid-state nuclear magnetic resonance spectroscopy. The results determined that the pleuromutilin-derivative, I, displays a unique continuous conformational disorder while retaining its long-range crystalline structure. The propionic acid (PA) version of this compound displayed partial crystalline order and site disorder of PA, depending on the quantity of PA incorporated in the structure. Thus, I is a unique example of one-phase crystalline–amorphous model. Physical and chemical stability data was acquired on these disordered systems and discussed in relation with the characterized disorder present in the crystal systems. Analysis of the results showed that in contrast to phase-separated amorphous, restrained disorders do not influence the stability.     

Stable isotopic composition of the active pharmaceutical ingredient (API) naproxen

A survey of the multi-stable isotopic composition of an active pharmaceutical ingredient (API), naproxen, was performed to assess the potential of Isotope Ratio Mass Spectrometry (IRMS) to distinguish the provenance of APIs. Twenty-six lots of naproxen from six manufacturers representing four countries (Italy, India, Ireland, and the USA) were analyzed for three isotope ratios (13C/12C, 18O/16O, and D/H). The samples were analyzed by either Elemental Analyzer/Isotope Ratio Mass Spectrometry (EA/IRMS: carbon (delta13C)) or by Thermal Conversion-EA/IRMS (TCEA/IRMS: hydrogen (deltaD) and oxygen (delta18O)). Bivariate and trivariate isotope ratio graphs for naproxen show marked clustering of the data for five out of the six naproxen manufacturers, suggesting that IRMS may be a plausible means to screen for manufacturer of given APIs.     

Microbiological assay for the determination of meropenem in pharmaceutical dosage form

Meropenem is a highly active carbapenem antibiotic used in the treatment of a wide range of serious infections. The present work reports a microbiological assay, applying the cylinder-plate method, for the determination of meropenem in powder for injection. The validation method yielded good results and included linearity, precision, accuracy and specificity. The assay is based on the inhibitory effect of meropenem upon the strain of Micrococcus luteus ATCC 9341 used as the test microorganism. The results of assay were treated statistically by analysis of variance (ANOVA) and were found to be linear (r=0.9999) in the range of 1.5-6.0 microg ml(-1), precise (intra-assay: R.S.D.=0.29; inter-assay: R.S.D.=0.94) and accurate. A preliminary stability study of meropenem was performed to show that the microbiological assay is specific for the determination of meropenem in the presence of its degradation products. The degraded samples were also analysed by the HPLC method. The proposed method allows the quantitation of meropenem in pharmaceutical dosage form and can be used for the drug analysis in routine quality control.     

The computational prediction of pharmaceutical crystal structures and polymorphism

A computational method of predicting all the polymorphs of an organic molecule would be a valuable complement to polymorph screening in the developmental phase. Such a computational method is in its early stages of development, and the current methodologies, which are based on searches for the most stable lattice structure, are critically reviewed. This crude thermodynamic approach generally overestimates the propensity for polymorphism, at least for most of the molecules studied so far, showing the need to model kinetic effects as well as to refine the thermodynamic models. Although the ultimate goal of these studies is still far off, computational predictions of crystal structures have proved useful in aiding the characterisation of polymorphs from powder X-ray data, and in providing insights into the range of types of packing that may be adopted by a given molecule. Thus, computational studies already have the potential to be a valuable tool in pharmaceutical solid state science.