Establishment of cocrystal cocktail grinding method for rational screening of pharmaceutical cocrystals

Cocrystals (CCs) used in the pharmaceutical industry are defined as complex crystals formed by reaction between an API and a cocrystal former (CCF); unlike salts, CCs do not show proton transfer. Recently, pharmaceutical CCs have been used to improve the drug-likeness of APIs, such as solubility and stability. Grinding is more effective for CC synthesis than crystallization from solution because in the former case, the API can predominantly interact with the CCF without being affected by solvents. However, this method is tedious because the API is ground with only one CCF at a time. We developed a cocktail cocrystal grinding (CCG) method, in which a mixture of CCFs having the same functional group was used. No false negatives/positives were observed in CCG when carbamazepine was used as the model compound. This method could be used to obtain CCs of piroxicam and spironolactone. False negatives were observed for only one compound from among three model compounds, indicating that CCG facilitates efficient CC detection and that it has higher throughput than does the conventional method. Further, CCG is fast and suitable for rational CC screening, and it helps identify the partial structure of CCFs that forms synthons with an API.     

Coformer selection in pharmaceutical cocrystal development: a case study of a meloxicam aspirin cocrystal that exhibits enhanced solubility and pharmacokinetics

Meloxicam is a nonsteroidal anti-inflammatory drug with low aqueous solubility and high permeability. Because of its low solubility under acidic conditions (e.g., pH 1-5), it can take more than 2 h for meloxicam to reach its therapeutic concentration in humans. Although the slow onset of meloxicam does not necessarily impact the current label indications, the slow onset does prevent meloxicam from its potential application for the relief of mild-to-medium-level acute pain. Pharmaceutical cocrystallization of meloxicam, which represents a promising approach to generate diverse novel crystal forms, could be used to improve the aqueous solubility and accelerate the onset of action. In this contribution, we describe how a novel method can be used for coformer selection to enable the efficient and effective development of a pharmaceutical cocrystal with desired physicochemical and pharmacokinetic properties. Aspirin was selected as the coformer for meloxicam based upon this alternative route, which combines the supramolecular synthon approach with findings in the previous pharmacological and toxicological studies of meloxicam. The resulting cocrystal of meloxicam and aspirin exhibited superior kinetic solubility and possessed the potential to significantly decrease the time required to reach the human therapeutic concentration compared with the parent drug, meloxicam.     

两亲性PCL-PVP聚合物水凝胶负载布洛芬-精氨酸药物共晶制备及体外释放研究

目的：制备两亲性聚己内酯-聚乙烯吡咯烷酮（PCL-PVP）聚合物水凝胶用于负载布洛芬-精氨酸药物共晶并考察其体外释放行为。方法：采用溶剂挥发法制备物质的量比1：1布洛芬-精氨酸药物共晶;通过自由基溶液聚合法制备PCL-PVP聚合物凝胶。将布洛芬-精氨酸共晶负载于PCL-PVP聚合物凝胶上,考察不同亲疏水比例载药物共晶凝胶（PCL：PVP=1：9,3：7,5：5）在pH 5.8,7.4的PBS中的体外释放行为。结果：在pH 5.8 PBS中,布洛芬释放速率及释放量受载药凝胶亲疏水比例影响较大,释放72 h后, PCL：PVP=3：7的载药凝胶累积释放量达到约80%,为3组凝胶中的最大值。在pH 7.4 PBS中,不同亲疏水比例的载药凝胶的释放速率差别不大,布洛芬的释放速率较pH 5.8 PBS中的释放速率明显增大,在释放开始12 h后三者累积释放率均已接近或超过80%。结论：药物共晶的体外释放受多种因素影响,两亲性PCL-PVP聚合物凝胶可用于布洛芬-精氨酸药物共晶的载体,具有一定控释作用。     

A novel method for deriving true density of pharmaceutical solids including hydrates and water-containing powders

True density is commonly measured using helium pycnometry. However, most water-containing powders, for example, hydrates, amorphous drugs and excipients, and most tablet formulations, release water when exposed to a dry helium atmosphere. Because released water brings significant errors to the measured true density and drying alters the nature of water-containing solids, the helium pycnometry is not suitable for those substances. To overcome this problem, a novel method has been developed to accurately calculate powder true density from compaction data. No drying treatment of powder samples is required. Consequently, the true density thus obtained is relevant to tableting characterization studies because no alteration to the solid is induced by drying. This method involves nonlinear regression of compaction pressure-tablet density data based on a modified Heckel equation. When true density values of water-free powders derived by this novel method were plotted against values measured using pycnometry, a regression line with slope close to unity and intercept close to zero was obtained. Thus, the validity of this method was supported. Using this new method, it was further demonstrated that helium pycnometry always overestimates true densities of water containing powders, for example, hydrates, microcrystalline cellulose (MCC), and tablet formulations. The calculated true densities of powders were the same for different particle shapes and sizes of each material. This further suggests that true density values calculated using this novel method are characteristic of given materials and independent of particulate properties.     

Discovery of Ligands for ADP-Ribosyltransferases via Docking-Based Virtual Screening

The diphtheria toxin-like ADP-ribosyltransferases (ARTDs) are an enzyme family that catalyzes the transfer of ADP-ribose units onto substrate proteins by using nicotinamide adenine dinucleotide (NAD(+)) as a cosubstrate. They have a documented role in chromatin remodelling and DNA repair, and inhibitors of ARTD1 and 2 (PARP1 and 2) are currently in clinical trials for the treatment of cancer. The detailed function of most other ARTDs is still unknown. By using virtual screening, we identified small ligands of ARTD7 (PARP15/BAL3) and ARTD8 (PARP14/BAL2). Thermal-shift assays confirmed that 16 compounds, belonging to eight structural classes, bound to ARTD7/ARTD8. Affinity measurements with isothermal titration calorimetry for two isomers of the most promising hit compound confirmed binding in the low micromolar range to ARTD8. Crystal structures showed anchoring of the hits in the nicotinamide pocket. These results form a starting point in the development of chemical tools for the study of the role and function of ARTD7 and ARTD8.     

晚期恶性肿瘤患者厌食-恶病质综合征筛查和药学干预

目的探讨晚期恶性肿瘤厌食-恶病质综合征的筛查和干预策略,为其个体化治疗提供科学依据。方法将210例入选患者随机分为对照组和试验组,采用主观全面营养评估法(PG-SGA)和Edmonton症状评估表(ESAS)筛查出具有厌食-恶病质综合征患者,对照组行常规治疗,试验组则行药学干预。2周后再次对两组患者进行厌食恶病质评估,分析药学干预的效果。结果与药学干预前相比,干预后试验组厌食恶病质状态明显改善,两者差异有统计学意义(P0.05)。结论对晚期恶性肿瘤患者进行厌食-恶病质综合征评估,并针对性的给予药学干预可显著改善患者的营养状况,提高患者的生存质量,应该成为肿瘤综合治疗的一个重要组成部分。     

Evaluation of degradation pathways for plasmid DNA in pharmaceutical formulations via accelerated stability studies

The stability of highly purified supercoiled plasmid DNA formulated in simple phosphate or Tris-buffered saline solutions has been characterized to establish the overall degradation processes that occur during storage in aqueous solution. Plasmid DNA stability was monitored during accelerated stability studies (at 50 degrees C) by measurements of supercoiled, open-circle, and linear DNA content, as well as the accumulation of apurinic sites and 8-hydroxydeoxyguanosine residues over time. The effects of formulation pH, demetalation, metal ion chelators, and ethanol (hydroxyl radical scavenger) on the supercoiled content of plasmid DNA during storage at 50 degrees C were also determined. The results indicate that free radical oxidation may be a major degradative process for plasmid DNA in pharmaceutical formulations unless specific measures are taken to control it by the addition of free radical scavengers, specific metal ion chelators, or both. The generation of hydroxyl radicals in phosphate-buffered saline was confirmed by examining the hydroxylation of phenylalanine over time by reverse phase high-performance liquid chromatography. Ethanol was found to enhance plasmid DNA stability and to inhibit the hydroxylation of phenylalanine; both observations are consistent with the known ability of ethanol to serve as a hydroxyl radical scavenger. Moreover, the combination of ethylenediamine tetraacetic acid (EDTA) and ethanol had a synergistic enhancing effect on DNA stability. However, the metal ion chelator diethylenetriaminepentaacetic acid (DTPA) was as potent as the combination of EDTA and ethanol for enhancing the stability of plasmid DNA. By controlling free radical oxidation with EDTA and ethanol, the rate constants of plasmid DNA degradation by means of depurination and beta-elimination were then determined, allowing accurate predictions of DNA storage stability as a function of formulation pH and temperature. The ability to predict plasmid DNA storage stability in the absence of free radical oxidation should prove to be a valuable tool for the design of stable pharmaceutical formulations of plasmid DNA.     

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.     

Environmental sustainability analysis of chitosan microbeads production for pharmaceutical applications via computer-aided simulation,WAR and TRACI assessments

In recent decades, pharmaceutical uses of chitosan microbeads have been identified owing to their low toxicity, biocompatibility and biodegradability. However, many contributions have limited such microbeads preparation to lab-scale and there are no works reported in the literature about the scaling-up of chitosan microbeads production. To fill the knowledge gap, this research attempts to simulate and evaluate the environmental performance of large-scale production of chitosan microbeads under sustainability concept using computer-aided process engineering (CAPE). The extended energy and mass balances were provided by process simulation using the commercial software Aspen Plus ®. The environmental assessment was performed through two computer-aided tools: waste reduction (WAR) algorithm and Tool for the Reduction and Assessment of Chemical and other Environmental Impacts (TRACI). Results reported negatives values for total generation rate of Potential Environmental Impacts (PEI) (?1.16 × 10⁺², ?9.25 × 10⁺¹, ?1.00 × 10⁺² and ?7.66 × 10⁺¹ PEI/hr) and highest total output rate of PEI for cases 4 and 3 (considering energy flows contributions). For TRACI tool, potential environmental impacts were low, however, the freshwater ecotoxicity potential for freshwater emissions was higher (6.03E+02 CTUeco/hr) than for natural soil emissions (1.55E+02 CTUeco/hr). These results showed good environmental performance of the process and can be used as a benchmark in the production of more environmental-friendly chitosan microbeads at large-scale.     

Hydrogels for pharmaceutical and biomedical applications

Hydrogels are crosslinked hydrophilic polymer structures that can imbibe large amounts of water or biological fluids. Hydrogels are one of the upcoming classes of polymer-based systems that embrace numerous biomedical and pharmaceutical applications. This review discusses various parameters of hydrogels such as surface properties, water content and swelling behavior, effect of nature of polymer, ionic content, and thermodynamics, all of which can influence the biomedical usage of hydrogels. Meanwhile, intelligent or environment-sensitive hydrogels and bioadhesive hydrogels continue to be important materials for medical applications; therefore, a part of this review is devoted to some of their important classes. Hydrogels are extensively used for various biomedical applications--tissue engineering, molecular imprinting, wound dressings materials, immunoisolation, drug delivery, etc. Thus, this review aims to throw light on the numerous applications that hydrogels have in the biomedical arena.     

Solid-state characterization of novel active pharmaceutical ingredients: cocrystal of a salbutamol hemiadipate salt with adipic acid (2:1:1) and salbutamol hemisuccinate salt

The production of salt or cocrystalline forms is a common approach to alter the physicochemical properties of pharmaceutical compounds. The goal of this work was to evaluate the impact of anion choice (succinate, adipate, and sulfate) on the physicochemical characteristics of salbutamol forms. Novel crystals of salbutamol were produced by solvent evaporation: a cocrystal of salbutamol hemiadipate with adipic acid (salbutamol adipate, SA), salbutamol hemisuccinate tetramethanolate (SSU.MeOH), and its desolvated form (SSU). The crystalline materials obtained were characterized using thermal, X-ray, nuclear magnetic resonance, Fourier transform infrared spectroscopy, dynamic vapor sorption (DVS), and elemental analysis. The crystal forms of SA and SSU.MeOH were determined to be triclinic, (Pī), and monoclinic, (P2(1) /n), respectively. DVS analysis confirmed that SSU and SA do not undergo hydration under increased relative humidity. Both thermal and elemental analyses confirmed the stoichiometry of the salt forms. The aqueous solubilities of SA and SSU were measured to be 82 ± 2 mg/mL (pH 4.5 ± 0.1) and 334 ± 13 mg/mL (pH 6.6 ± 0.1), respectively. Measured values corresponded well with the calculated pH solubility profiles. The intrinsic dissolution rate of cocrystallized SA was approximately four times lower than that of SSU, suggesting its use as an alternative to more rapidly dissolving salbutamol sulfate.     

Analytical methods for determination of neat and microencapsulated trichloroethylene in dosing vehicles and whole blood

Gas chromatographic methodologies were developed for the analysis of microencapsulated trichloroethylene (TRI) in corn oil and feed dosage formulations as well as neat TRI in corn oil and whole blood. Recovery, precision, linearity, and the appropriateness of a linear regression model were evaluated for each method. In all cases recovery was greater than 96% and linearity of the standard curves was confirmed. Good precision and chromatographic resolution were obtained for all samples analyzed.     

PEGylated nanoparticles for biological and pharmaceutical applications

The utility of polymeric micelles formed through the multimolecular assembly of block copolymer was comprehensively described as novel core–shell typed colloidal carriers for drug and gene targeting. Particularly, novel approaches for the formation of functionalized poly(ethylene glycol) (PEG) layers as hydrophilic outer shell were focused to attain receptor-mediated drug and gene delivery through PEG-conjugated ligands with a minimal non-specific interaction with other proteins. Surface organization of block copolymer micelles with cross-linking core was also described from a standpoint of the preparation of a new functional surface-coating with a unique macromolecular architecture. The micelle-attached surface and the thin hydrogel layer made by layered micelles exhibited nonfouling properties and worked as the reservoir for hydrophobic reagents. Furthermore, the potential utility of multimolecular assembly derived from heterobifunctional PEGs and block copolymers were explored to systematically modify the properties of metal and semiconductor nanostructures by controlling their structure and their surface properties, making them extremely attractive for use in biological and biomedical applications.     

PEGylated nanoparticles for biological and pharmaceutical applications

The utility of polymeric micelles formed through the multimolecular assembly of block copolymer was comprehensively described as novel core-shell typed colloidal carriers for drug and gene targeting. Particularly, novel approaches for the formation of functionalized poly(ethylene glycol) (PEG) layers as hydrophilic outer shell were focused to attain receptor-mediated drug and gene delivery through PEG-conjugated ligands with a minimal non-specific interaction with other proteins. Surface organization of block copolymer micelles with cross-linking core was also described from a standpoint of the preparation of a new functional surface-coating with a unique macromolecular architecture. The micelle-attached surface and the thin hydrogel layer made by layered micelles exhibited nonfouling properties and worked as the reservoir for hydrophobic reagents. Furthermore, the potential utility of multimolecular assembly derived from heterobifunctional PEGs and block copolymers were explored to systematically modify the properties of metal and semiconductor nanostructures by controlling their structure and their surface properties, making them extremely attractive for use in biological and biomedical applications.     

Cyclodextrin-based nanogels for pharmaceutical and biomedical applications

Hydrophilic nanogels combine the advantages of hydrogels with certain advantages that are inherent in their nanoscale size. Similar to macrogels, nanogels can contain and protect drugs and regulate their release by incorporating high-affinity functional groups, stimuli-responsive conformations and biodegradable bonds into the polymer network. Similar to nanoparticles, nanogels can easily be administered in liquid form for parenteral drug delivery. The nanoscale size of nanogels gives them a high specific surface area that is available for further bioconjugation of active targeting agents. Biodistribution and drug release can be modulated through size adjustments. The incorporation of hydrophilic cyclodextrin (CD) moieties into the polymeric network of the nanogels provides them with a drug loading and release mechanism that is based on the formation of inclusion complexes without decreasing the hydrophilicity of the network. The covalent attachment of CD molecules to the chemically crosslinked networks may enable the CDs to display fully their ability to form complexes, while simultaneously preventing drug release upon media dilution. The preparation, characterization and advantages for pharmaceutical and biomedical applications of CD-based nanogels are reviewed in this article.     

肺炎的治疗原则与药学监护

目的：探索肺炎患者治疗过程的药学监护方式。方法：通过笔者的实践,结合肺炎的治疗原则及抗菌药物的特点进行分析总结。结果：药学监护可提高肺炎患者的用药安全性及治疗效果。结论：药学监护工作体现出其在临床工作中的重要意义。     

阿考替胺原料药粒径筛选与阿考替胺片体外溶出行为一致性评价

目的筛选原料药阿考替胺粒径并制备阿考替胺片剂,将自制品与原研上市品溶出行为进行一致性评价。方法研究原料药粒径对阿考替胺溶出速率的影响,筛选适宜的原料药粒径及合适的溶出介质,建立体外溶出度测定方法,对比自制品与原研上市品溶出曲线。结果合适的阿考替胺的粒径为D90≤20μm,用该粒径原料制备的阿考替胺片剂与原研上市品在四种溶出介质中溶出相似因子f2均大于50。结论用该方法制备的阿考替胺片剂与原研上市品体外溶出行为相似。