Mechanistic Basis of Cocrystal Dissolution Advantage

Current interest in cocrystal development resides in the advantages that the cocrystal may have in solubility and dissolution compared with the parent drug. This work provides a mechanistic analysis and comparison of the dissolution behavior of carbamazepine (CBZ) and its 2 cocrystals, carbamazepine-saccharin (CBZ-SAC) and carbamazepine-salicylic acid (CBZ-SLC) under the influence of pH and micellar solubilization. A simple mathematical equation is derived based on the mass transport analyses to describe the dissolution advantage of cocrystals. The dissolution advantage is the ratio of the cocrystal flux to drug flux and is defined as the solubility advantage (cocrystal to drug solubility ratio) times the diffusivity advantage (cocrystal to drug diffusivity ratio). In this work, the effective diffusivity of CBZ in the presence of surfactant was determined to be different and less than those of the cocrystals. The higher effective diffusivity of drug from the dissolved cocrystals, the diffusivity advantage, can impart a dissolution advantage to cocrystals with lower solubility than the parent drug while still maintaining thermodynamic stability. Dissolution conditions where cocrystals can display both thermodynamic stability and a dissolution advantage can be obtained from the mass transport models, and this information is useful for both cocrystal selection and formulation development.     

Transformation Pathways of Cocrystal Hydrates When Coformer Modulates Water Activity

An important attribute of cocrystals is that their properties can be tailored to meet required solubility and stability specifications. But before such practical uses can be realized, a better understanding of the factors that dictate cocrystal behavior is needed. This study attempts to explain the phase behavior of anhydrous/hydrated cocrystals when the coformer modulates both water activity and cocrystal solubility. Stability dependence on solution composition and water activity was studied for theophylline-citric acid (THP–CTA) anhydrous and hydrated cocrystals by both suspension and vapor equilibration methods. Eutectic points and associated water activities were measured by suspension equilibration methods to determine stability regions and phase diagrams. The critical water activity for the anhydrous-hydrate cocrystal was found to be 0.8. It is shown that (a) both water and coformer activities determine phase stability, and (b) excipients that alter water activity can profoundly affect the hydrate/ anhydrous eutectic points and phase stability. Vapor phase stability studies demonstrate that cocrystals of highly water soluble coformers, such as citric acid, are predisposed to conversions due to moisture uptake and deliquescence of the coformer. The presence of such coformers as trace level impurities with cocrystal will alter hygroscopic behavior and stability.     

Investigation of the Effect of Hydroxypropyl Methylcellulose on the Phase Transformation and Release Profiles of Carbamazepine-Nicotinamide Cocrystal

Purpose

The aim of this work was to investigate the influence of hydroxypropyl methylcellulose (HPMC) on the phase transformation and release profile of carbamazepine-nicotinamide (CBZ-NIC) cocrystal in solution and in sustained release matrix tablets.

Methods

The polymorphic transitions of the CBZ-NIC cocrystal and its crystalline properties were examined by differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), Raman spectroscopy, and scanning electron microscopy (SEM).

Results

The apparent CBZ solubility and dissolution rate of CBZ-NIC cocrystal were constant in different concentrations of HPMC solutions. In a lower percentage of HPMC in the matrix tablets, the CBZ release profile of the CBZ-NIC cocrystal was nonlinear and declined over time. With an increased HPMC content in the tablets, the CBZ-NIC cocrystal formulation showed a significantly higher CBZ release rate in comparison with the other two formulations of CBZ III and the physical mixture.

Conclusions

Because of a significantly improved dissolution rate of the CBZ-NIC cocrystal, the rate of CBZ entering into solution is significantly faster than the rate of formation of the CBZ-HPMC soluble complex in solution, leading to a higher supersaturation level of CBZ and subsequently precipitation of CBZ dihydrate.     

Mechanistic Analysis of Cocrystal Dissolution,Surface pH,and Dissolution Advantage as a Guide for Rational Selection

The dissolution behavior of a dibasic drug ketoconazole under the influence of pH has been evaluated and compared to its three 1:1 cocrystals with diacidic coformers, fumaric acid, succinic acid (SUC), and adipic acid. Mass transport models were developed by applying Fick's law of diffusion to dissolution with simultaneous chemical reactions in the hydrodynamic boundary layer adjacent to the dissolving surface to predict the interfacial pH and flux of the parent drug and cocrystals. All 3 cocrystals have the ability to modulate the interfacial pH to different extents compared to the parent drug due to the acidity of the coformers. Dissolution pH dependence of ketoconazole is significantly reduced by the cocrystallization with acidic coformers. Due to the different dissolution pH dependence, there exists a transition pH where the flux of the cocrystal is the same as the parent drug. Below this transition pH, the drug flux is higher, but above it, the cocrystal flux is higher. The development of these mass transport models provide a mechanistic understanding of the dissolution behavior and help identify cocrystalline solids with optimal dissolution characteristics.     

共无定形盐酸鲁拉西酮-莽草酸的稳定性研究

目的 建立盐酸鲁拉西酮的含量测定方法,并对盐酸鲁拉西酮-莽草酸共无定形体系的稳定性进行研究.方法 采用溶剂法(真空减压旋转蒸发法)制备得到3种摩尔比为1∶1,1∶2及2∶1的共无定形盐酸鲁拉西酮-莽草酸,采用熔点仪、偏光显微镜、HPLC、PXRD等方法对共无定形盐酸鲁拉西酮-莽草酸进行了理化性质的考察.结果 制备的3种...     

Mechanistic Study of the Oxidative Degradation of the Triazole Antifungal Agent CS-758 in an Amorphous Form

In this study, the degradates generated from a pharmaceutical solid were characterized, and a mechanistic pathway underlying their formation was proposed. The chemical stability of a novel triazole antifungal drug, CS‐758, deteriorated significantly when the crystal was disordered, and characteristic degradates were generated. A total of eight degradates in solution and nine degradates in a solid state were isolated by preparative liquid chromatography. Degradates were characterized using high‐performance liquid chromatography–photodiode array, mass spectrometry, and nuclear magnetic resonance. Radical‐mediated oxidation is proposed as the main degradation pathway in the solid state. The initiation step of this pathway is hydrogen atom abstraction from a methine carbon that is adjacent to a dien moiety and the formation of a delocalized vinylic radical intermediate. Molecular oxygen is then added to the radical position to form hydroperoxides. There are three potential oxidation routes based on the proposed autoxidation pathway that lead to the generation of the dioxane ring‐opening hydroxyl form, the 9,10‐epoxide form, or the 11,12‐epoxide form, depending on the substituted position of the added molecular oxygen. The epimer compound generated via the vinylic radical intermediate and sulfoxides was characterized. This degradation mechanism provides the scientific foundation for an oxidative stressing system currently under investigation.     

乙水杨胺-草酸共晶的制备、表征及溶解性研究

目的 以乙水杨胺为药物活性成分,草酸为共晶形成物,制备乙水杨胺-草酸共晶,研究乙酸杨胺-共晶在磷酸盐缓冲溶液(PBS)以及模拟胃液(SGF)中的溶解度。方法 采用溶液结晶法制备了由两分子乙水杨胺和一分子草酸组成的乙水杨胺-草酸共晶。将乙水杨胺和草酸加热溶于乙酸乙酯,缓慢降温至室温、析晶、抽滤干燥,即获得乙水杨胺-草酸共晶。应用单晶X射线衍射(SCXRD)、X射线粉末衍射(XRPD)、差示扫描量热法(DSC)对乙水杨胺-草酸共晶进行了结构表征,测试溶解度。结果 共晶在磷酸盐缓冲溶液以及模拟胃液中的溶解度分别为乙水杨胺的2.0倍和2.5倍。     

Effect of Polymer Additives on the Transformation of BMS-566394 Anhydrate to the Dihydrate Form

Purpose To investigate the effect of polymer additives on the transformation of BMS-566394 anhydrate to the dihydrate form and to propose the possible mechanisms for inhibition of conversion of the anhydrate to the dihydrate form. Materials and methods The conversion of anhydrate to dihydrate was monitored using differential scanning calorimetry, powder X-ray diffraction and polarized light microscopy. Solubility and intrinsic dissolution studies were performed on anhydrate and dihydrate. IR and NMR spectroscopy were used to probe the molecular interactions between BMS-566394 and cellulose ether polymers. Results The anhydrate form of BMS-566394 was readily transformed into the more stable dihydrate form in aqueous suspension. The kinetic solubility and intrinsic dissolution rate of the anhydrate were ca. fourfold that of the dihydrate. Addition of cellulose ether polymers (HPC, HPMC, MC) inhibited anhydrate to dihydrate transformation in aqueous suspensions. Hydrogen bonding interaction between the polar groups of the drug and polymers was inferred from infrared spectroscopy. Solution NMR also indicated a hydrophobic interaction between the drug and polymer backbone. Conclusions The anhydrate form of BMS-566394 is stabilized in the presence of cellulose ether polymers. Spectroscopic evidence is offered to postulate a molecular interaction between drug and polymers.     

In Situ Monitoring and Modeling of the Solution-Mediated Polymorphic Transformation of Rifampicin: From Form II to Form I

In this article, the solution-mediated polymorphic transformation of rifampicin was investigated and simulated in 3 solvents at 30°C. The solid-state form I and form II of rifampicin was characterized by powder X-ray diffraction, scanning electron microscopy, thermogravimetric analysis, Raman spectroscopy, and Fourier transform infrared spectroscopy (FTIR). To explore the relative stability, solubility data of form I and form II of rifampicin in butan-1-ol were determined using a dynamical method. In addition, Raman spectroscopy and focused beam reflectance measurement were used to in situ monitor the transformation of rifampicin from form II to form I. The liquid state concentration of rifampicin was measured by UV spectroscopic method. To investigate the effect of solvent on transformation, the transformation experiments were carried out in 3 solvents. Furthermore, a mathematical model was built to describe the kinetics of dissolution, nucleation, and growth processes during transformation by using experimental data. By combination of experimental and simulation results, it was found that the transformation process of rifampicin is controlled by dissolution of form II in heptane, whereas the transformation in hexane and octane was firstly controlled by dissolution of solid-state form and then controlled by growth of form I.     

Exploring the Formation Mechanism of Coamorphous Andrographolide-Oxymatrine Based on Molecular Dynamics and Spectroscopy

Coamorphous drug delivery systems have shown great potential in improving the solubility and bioavailability of poorly water-soluble drugs. However, the coamorphous formation mechanism remains unclear. In this study, coamorphous andrographolide (AP) - oxymatrine (OMT) was successfully prepared by solvent evaporation and characterized by PXRD and DSC. The potential groups of intermolecular interactions in coamorphous binary systems were predicted by the molecular electrostatic potential (ESP) in the density functional theory (DFT) and the HOMO and LUMO in the molecular frontier orbitals, which had been confirmed by FTIR, FT-NIR, and Raman spectroscopy. Molecular dynamics (MD) was used to explore the mechanism of coamorphous formation. The results of the solvent-state radial distribution function (RDF) showed that the hydrogen bonds between AP and OMT molecules were irregular and intermittent in the solvent system of AP-OMT-methanol (MeOH) until MeOH was completely volatilized to form a stable coamorphous AP-OMT system, which has been preliminarily verified by solvent-state FT-NIR and solvent-state Raman spectroscopy. In addition, the solubility of coamorphous AP-OMT was significantly higher than that of crystalline AP. The results of intrinsic dissolution experiments showed that the intrinsic dissolution rate (IDR) of coamorphous AP-OMT was 2.5 times that of crystalline AP, although recrystallization occurred during dissolution. In conclusion, the results of the experimental solvent-state RDF, solvent-state FT-NIR, and solvent-state Raman spectroscopy can be used to better understand the coamorphous formation process and to guide the preparation of coamorphous AP-OMT.     

Mechanistic Fluid Transport Model to Estimate Gastrointestinal Fluid Volume and Its Dynamic Change Over Time

Gastrointestinal (GI) fluid volume and its dynamic change are integral to study drug disintegration, dissolution, transit, and absorption. However, key questions regarding the local volume and its absorption, secretion, and transit remain unanswered. The dynamic fluid compartment absorption and transit (DFCAT) model is proposed to estimate in vivo GI volume and GI fluid transport based on magnetic resonance imaging (MRI) quantified fluid volume. The model was validated using GI local concentration of phenol red in human GI tract, which was directly measured by human GI intubation study after oral dosing of non-absorbable phenol red. The measured local GI concentration of phenol red ranged from 0.05 to 168 μg/mL (stomach), to 563 μg/mL (duodenum), to 202 μg/mL (proximal jejunum), and to 478 μg/mL (distal jejunum). The DFCAT model characterized observed MRI fluid volume and its dynamic changes from 275 to 46.5 mL in stomach (from 0 to 30 min) with mucus layer volume of 40 mL. The volumes of the 30 small intestine compartments were characterized by a max of 14.98 mL to a min of 0.26 mL (0–120 min) and a mucus layer volume of 5 mL per compartment. Regional fluid volumes over 0 to 120 min ranged from 5.6 to 20.38 mL in the proximal small intestine, 36.4 to 44.08 mL in distal small intestine, and from 42 to 64.46 mL in total small intestine. The DFCAT model can be applied to predict drug dissolution and absorption in the human GI tract with future improvements.     

Mechanistic Study of the Azithromycin Dosage-Form-Dependent Food Effect

Purpose  

Azithromycin capsules are known to exhibit a negative food effect, manifest as a decrease in azithromycin bioavailability in the fed state. Azithromycin tablets are known to be bioequivalent to capsules in the fasted state, but do not exhibit a food effect. In the present study, the involvement of gastric degradation of azithromycin to des-cladinose azithromycin (DCA) has been investigated as a possible mechanism for the observed capsule food effect.     

Detection of Cocrystal Formation Based on Binary Phase Diagrams Using Thermal Analysis

Purpose

Although a number of studies have reported that cocrystals can form by heating a physical mixture of two components, details surrounding heat-induced cocrystal formation remain unclear. Here, we attempted to clarify the thermal behavior of a physical mixture and cocrystal formation in reference to a binary phase diagram.

Methods

Physical mixtures prepared using an agate mortar were heated at rates of 2, 5, 10, and 30°C/min using differential scanning calorimetry (DSC). Some mixtures were further analyzed using X-ray DSC and polarization microscopy.

Results

When a physical mixture consisting of two components which was capable of cocrystal formation was heated using DSC, an exothermic peak associated with cocrystal formation was detected immediately after an endothermic peak. In some combinations, several endothermic peaks were detected and associated with metastable eutectic melting, eutectic melting, and cocrystal melting. In contrast, when a physical mixture of two components which is incapable of cocrystal formation was heated using DSC, only a single endothermic peak associated with eutectic melting was detected.

Conclusion

These experimental observations demonstrated how the thermal events were attributed to phase transitions occurring in a binary mixture and clarified the relationship between exothermic peaks and cocrystal formation.     

缩宫素受体主要存在形式的研究

目的 研究缩宫素受体(oxytocin receptor,OTR)在体外培养细胞中及动物组织中的主要存在形式,为进一步研究OTR多聚化的部位及多聚化在OTR功能调节中的作用提供依据.方法 取体外培养的中国仓鼠(CHO)细胞中表达的OTR及大鼠不同的组织,分别用anti-OTR抗体进行免疫沉淀及免疫印迹,观察得到的OTR...     

缩宫素受体主要存在形式的研究

目的 研究缩宫素受体(oxytocin receptor,OTR)在体外培养细胞中及动物组织中的主要存在形式,为进一步研究OTR多聚化的部位及多聚化在OTR功能调节中的作用提供依据.方法 取体外培养的中国仓鼠(CHO)细胞中表达的OTR及大鼠不同的组织,分别用anti-OTR抗体进行免疫沉淀及免疫印迹,观察得到的OTR条带的情况;分别在样品中加入还原剂DTT,再进行免疫印迹,观察得到OTR条带的大小与数量.结果 在体外培养的细胞中检测到OTR的多聚体,在大鼠的组织中同样也检测到OTR的多聚体.表明在动物体内,OTR也是以多聚体形式存在,跟体外细胞表达的OTR形成的多聚体不同的是,在动物体内的OTR多聚体主要以四聚体为主,而二聚体、三聚体量很少,特别是三聚体,几乎没有.OTR的多聚体可被还原剂DTT还原为单体形式.结论 OTR形成的多聚体是一种同源多聚体,此种多聚体中的单体是由共价键连接,而这种共价键最常见的是半胱氨酸残基间形成的二硫键,因此推测半胱氨酸残基是OTR多聚体形成的关键残基.     

Mechanistic Study of Belinostat Oral Absorption From Spray-Dried Dispersions

Spray-dried dispersions (SDDs) are an important technology for enhancing the oral bioavailability of poorly water-soluble drugs. To design an effective oral SDD formulation, the key rate-determining step(s) for oral drug absorption must be understood. This work combined in vivo and in vitro tests with in silico modeling to identify the rate-determining steps for oral absorption of belinostat SDDs made with 3 different polymers (PVP K30, PVP VA64, and HPMCAS-M). The goal was developing a belinostat SDD formulation that maximizes oral bioavailability (ideally matching the performance of a belinostat oral solution) and defining critical performance attributes for formulation optimization. The in vivo pharmacokinetic study with beagle dogs demonstrated that 1 of the 3 SDDs (PVP K30 SDD) matched the performance of the oral solution. In vitro data coupled with in silico modeling elucidated differences among the SDDs and supported the hypothesis that absorption of belinostat in the small intestine from the other 2 SDDs (PVP VA64 and HPMCAS-M) may be limited by dissolution rate or reduced drug activity (maximum concentration) in the presence of polymer. It was concluded that drug concentration in the stomach before emptying into the proximal intestine is a key factor for maximizing in vivo performance.     

Mechanistic studies on chloral toxicity: relationship to trichloroethylene carcinogenesis

Chloral (trichloroacetaldehyde), the major metabolite of trichloroethylene (TCE), was investigated for its potential to form DNA-protein cross-links (DPX), a lesion produced by other aldehydes. Chloral did not form DPX in rat liver nuclei at concentrations up to 250 mM for 30 min at 37 degrees C, while chloroacetaldehyde (47 mM) and acetaldehyde (200 mM) did form cross-links. Experiments with the aldehyde-trapping reagents thiosemicarbazide and semicarbazide showed that chloral did not react, in contrast with aldehydes that form DPX. This indicates a very strong hydration of chloral. Mice given 800 mg/kg [14C]chloral after pretreatment with 1500 mg/kg TCE for 10 days had no detectable covalent binding of 14C to DNA in the liver. These results do not support a genotoxic theory of carcinogenesis for TCE mediated through chloral.     

论药师职责转型的时代使命与其必然性

目的:探讨药师的职责转型与其必然性。方法:回顾药师基本职责的转变历程,阐述我国药师队伍的发展现状,分析其职责转型的必然。结果与结论:我国药师职责转型是时代的要求,只有尽快加强药学人才的培养与学科建设,注重药学信息化建设、信息的发掘与利用,开展药学科研、新技术、新方法的应用,加强药品物流链的管理及尽快建立《药师法》等,才能提供全程的药学服务。     

Use of a Glutaric Acid Cocrystal to Improve Oral Bioavailability of a Low Solubility API

Purpose The bioavailability of a development candidate active pharmaceutical ingredient (API) was very low after oral dosing in dogs. In order to improve bioavailability, we sought to increase the dissolution rate of the solid form of the API. When traditional methods of forming salts and amorphous material failed to produce a viable solid form for continued development, we turned to the non-traditional approach of cocrystallization.Methods A crystal engineering approach was used to design and execute a cocrystal screen of the API. Hydrogen bonding between the API and pharmaceutically acceptable carboxylic acids was identified as a viable synthon for associating multiple components in the solid state. A number of carboxylic acid guest molecules were tested for cocrystal formation with the API.Results A cocrystal containing the API and glutaric acid in a 1:1 molecular ratio was identified and the single crystal structure is reported. Physical characterization of the cocrystal showed that it is unique regarding thermal, spectroscopic, X-ray, and dissolution properties. The cocrystal solid is nonhygroscopic, and chemically and physically stable to thermal stress. Use of the cocrystal increased the aqueous dissolution rate by 18 times as compared to the homomeric crystalline form of the drug. Single dose dog exposure studies confirmed that the cocrystal increased plasma AUC values by three times at two different dose levels.Conclusions APIs that are non-ionizable or demonstrate poor salt forming ability traditionally present few opportunities for creating crystalline solid forms with desired physical properties. Cocrystals are an additional class of crystalline solid that can provide options for improved properties. In this case, a crystalline molecular complex of glutaric acid and an API was identified and used to demonstrate an improvement in the oral bioavailability of the API in dogs.