Spherical crystallization of benzoic acid

Transungual transport is hindered by the inherent small effective pore size of the nail even when it is fully hydrated. The objectives of this study were to determine the effects of chemical enhancers thioglycolic acid (TGA), glycolic acid (GA), and urea (UR) on transungual transport and iontophoresis efficiency. In vitro passive and iontophoretic transport experiments of model permeants mannitol (MA), UR, and tetraethylammonium (TEA) ion across the fully hydrated, enhancer-treated and untreated human nail plates were performed in phosphate-buffered saline. The transport experiments consisted of several stages, alternating between passive and anodal iontophoretic transport at 0.1 mA. Nail water uptake experiments were conducted to determine the water content of the enhancer-treated nails. The effects of the enhancers on transungual electroosmosis were also evaluated. Nails treated with GA and UR did not show any transport enhancement. Treatment with TGA at 0.5 M enhanced passive and iontophoretic transungual transport of MA, UR, and TEA. Increasing the TGA concentration to 1.8 M did not further increase TEA iontophoresis efficiency. The effect of TGA on the nail plates was irreversible. The present study shows the possibility of using a chemical enhancer to reduce transport hindrance in the nail plate and thus enhance passive and iontophoretic transungual transport.     

Spherical crystallization of mebendazole to improve processability

Spherical crystallization technique combines crystallization and agglomeration directly to generate spherical crystals with improved micromeretic properties, thus obviating need for further processing by granulation and agglomeration. The present study was focused on spherical crystallization of an antihelmentic drug - Mebendazole (MBZ) - using spherical agglomeration technique. Apart from being poorly water-soluble, MBZ exhibits poor flow and compressibility owing to its needle shaped crystal habit and electrostatic charge. Spherical agglomeration was carried out in the presence of different bridging liquids (hexane, octanol, toluene, dichloromethane) and polymers (polyethylene glycol, cross-povidone, starch, cross carmellose sodium, hydroxyl propyl methyl cellulose (HPMC), hydroxyl propyl cellulose (HPC), ethyl cellulose (EC), Eudragit S100, Eudragit RLPO, Eudragit RD100, Eudragit E), by employing different crystallization conditions such as variation of polymer type, polymer concentration, and rate of stirring. The final parameters were optimized to obtain crystals with an aspect ratio in the range of 1-2 compared to a value of 12 for untreated MBZ. These agglomerates retained form C of MBZ, and exhibited good flow properties, high bulk density and improved compressibility. Lower elastic:plastic energy (EE/PE) ratio for spherical crystals generated in the presence of Eudragit-S100 and Hydroxypropylcellulose (HPC) indicated better compressibilty of spherical crystals.     

Spherical agglomerates of water-insoluble drugs

Spherical pellets of poorly soluble drugs (micronized griseofulvin, ibuprofen, indomethacin, sulfadiazine, or tolbutamide) were prepared by dispersing each drug in solutions of the ionic polysaccharides chitosan or sodium alginate, and then dropping these dispersions into solutions of the respective counterions tripolyphosphate or calcium chloride (CaCl2). The droplets instantaneously formed gelled spheres by inotropic gelation. Strong spherical beads with a narrow particle size distribution and low friability could be prepared with high yield and a drug content approaching 98%. The flow properties of micronized or needle-like drug crystals were significantly improved by this agglomeration technique when compared with nonagglomerated drug crystals. The ionic character of the polymers resulted in pH-dependent disintegration of the beads. Chitosan beads disintegrated in 0.1M HCl, while calcium alginate beads stayed intact in 0.1M HCl but rapidly disintegrated in simulated intestinal fluids. In addition to scanning electron microscopy, dissolution and disintegration tests were used to characterize the drug pellets.     

Spherical crystallization of ezetimibe for improvement in physicochemical and micromeritic properties

Spherical agglomerates of ezetimibe (EZT) were prepared with hydrophilic polymers; polyvinyl pyrrolidone K30 (PVP) and/or poloxamer 188 (poloxamer) at drug to polymer ratios of 1:1 (w/w) by spherical crystallization technique, in order to improve its physicochemical and micromeritic properties. Three different bridging liquids; chloroform, dichloromethane and/or ethyl acetate along with good solvent acetone and poor solvent water were used to form six batches of agglomerates. Initial characterization of all batches in terms of micromeritic and physicochemical properties resulted in optimization of (A3, EZT:PVP:ethyl acetate) and (B3, EZT:poloxamer:ethyl acetate) batches and hence further investigated for drug–polymer interaction, crystallinity and morphology using FTIR, XRPD, DSC and SEM techniques. The results indicated presence of hydrogen bonding, crystallinity and spherical shape in agglomerates. Therefore, the optimized agglomerates (B3) were directly compressed into tablet. Unfortunately, drug release from the tablet was not satisfactory, suggesting a need of disintegrant from dissolution point of view. Therefore, these agglomerates were recompressed incorporating certain excipients and evaluated as per pharmacopoeia. The dissolution rate of prepared tablet was similar to that of marketed tablet (p > 0.05). It could be concluded that spherical crystallization could be one of the effective and alternative approaches for improved performance of EZT and its tablet formulation.     

Micronization of anti-inflammatory drugs for pulmonary delivery by a controlled crystallization process

Jet-milling as the common way for micronization of drugs shows several disadvantages. Drug powder properties are decisive for pulmonary use because, besides a small particle size, a good deagglomeration behavior is required. In this study, several anti-inflammatory drugs [beclomethasone-17,21-dipropionate (BDP), betamethasone-17-valerate (BV), triamcinolone acetonide, ECU-R2, budesonide, and prednisolone] were micronized by controlled crystallization without any milling processes. First the drug is dissolved in an organic solvent (BDP/BV: 4%; ECU-R2: 1% in acetone) and precipitated by a solvent change method in the presence of a cellulose ether (hydroxypropylmethylcellulose) as stabilizing hydrocolloid. By rapid pouring the solution of hydroxypropylmethylcellulose in water (BDP/BV: 0.005%; ECU-R2: 0.025%) into the drug solution under stirring in a relationship (v/v) of 1:16 (BDP/BV), 1:4 (ECU-R2), the previously molecularly dispersed drug was associated to small particles and stabilized against crystal growth simultaneously. This dispersion was spray-dried, resulting in a drug powder with a uniform particle-size distribution and a drug load of up to 98% (BDP, BV). The mean particle size of the drug was lower than 5 microm in most cases and consequently in the respirable range. Whereas the fine particle fraction (<5 microm, measured without excipients and without an inhalation device) of jet-milled drugs is 9.5 (BDP) or 13.1 (ECU-R2), fine particle fractions of 25.6% (BDP) resp. 78.2% (ECU-R2) are obtained with the spray-dried powders. As the formation of the small crystals requires a rapid solvent change process, the affinity of the hydrocolloid, and a high difference between the solubility in the solvent and nonsolvent, the drug's partition coefficient limits the method as drugs which are more hydrophilic form larger particles.     

球晶造粒技术制备药用可直压微粒的研究进展

球晶造粒技术使微粒晶型在结晶或反应过程中直接转变为球形聚集体,从而改善微粒的第二性质,如流动性和可压性,使其可以直接用于压片。本文介绍球晶造粒技术制备药用可直压微粒的研究进展情况。     

Matching pH values for antibody stabilization and crystallization suggest rationale for accelerated development of biotherapeutic drugs

Monoclonal antibodies (mAbs) are currently leading products in the global biopharmaceutical market. Multiple mAbs are in clinical development and novel biotherapeutic protein scaffolds, based on the canonical immunoglobulin G (IgG) fold, are emerging as treatment options for various medical conditions. However, fast approvals for biotherapeutics are challenging to achieve, because of difficult scientific development procedures and complex regulatory processes. Selecting molecular entities with superior physicochemical properties that proceed into clinical trials and the identification of stable formulations are crucial developability aspects. It is widely accepted that the solution pH has critical influences on both the protein's colloidal stability and its crystallization behavior. Furthermore, proteins usually crystallize best at solution conditions that enable high protein solubility, purity, stability, and monodispersity. Therefore, we hypothesize that the solution pH value is a central parameter that is linking together protein formulation, protein crystallization, and thermal protein stability. In order to experimentally test this hypothesis, we have investigated the effect of the solution pH on the thermal stabilities and crystallizabilities for three different mAbs. Combining biophysical measurements with high throughput protein (HTP) crystallization trials we observed a correlation in the buffer pH values for eminent mAb stability and successful crystallization. Specifically, differential scanning fluorimetry (DSF) was used to determine pH values that exert highest thermal mAb stabilities and additionally led to the identification of unfolding temperatures of individual mAb domains. Independently performed crystallization trials with the same mAbs resulted in their successful crystallization at pH values that displayed highest thermal stabilities. In summary, the presented results suggest a strategy how protein crystallization could be used as a screening method for the development of biotherapeutic protein formulations with improved in vitro stabilities.     

In-process crystallization of acidic drugs in acrylic microparticle systems: influence of physical factors and drug-polymer interactions

Emulsion-solvent evaporation is an established method to fabricate amorphous drug-loaded microparticles. In some cases, however, the encapsulated drug is present in its crystalline form, which can affect drug release and negatively impact on other characteristics of the final product. This work aimed to investigate the factors that are responsible for the formation (and inhibition) of drug crystals in modified-release microparticles. Five acidic drugs were encapsulated into Eudragit S or Eudragit L microparticles. Drug crystallinity was observed when indometacin and naproxen were encapsulated, while crystallization was not observed in the case of ketoprofen, salicylic acid, or paracetamol (acetaminophen). All drug-loaded microparticles had single glass transition temperature (T(g) ) intermediate between the T(g) of the drug and that of the polymer. The drop in T(g) in the case of the paracetamol-loaded particles was higher than predicted from the Gordon-Taylor equation, indicating that paracetamol was acting as a plasticizer in this system. After melt quenching in the presence of the Eudragit polymers, the crystallization of paracetamol was inhibited. The ratio of drug to polymer in the microparticles was the major determinant of drug crystallization, as was the solubility of the drug in the processing solvent. This work confirms that drug crystallization is a complex phenomenon, and that drug-polymer molecular interactions play a role in the inhibition of drug crystallization.     

Comparative study of crystallization processes in case of glycine crystallization

In our work, the effect of crystallization methods and their parameters on the particle size, particle size-distribution and roundness were investigated in case of glycine crystallization. Three types of crystallization methods were applied according to the solubility results of the substance. In case of cooling crystallization, the effect of cooling and stirring rates were investigated. The feeding and stirring rates were changed in the feeding crystallization. In the antisolvent technique, the effect of cycle and amplitude of the sonification were studied on the particle size. A 3(2) full factorial design was applied for investigation of the effect of crystallization parameters. The results were analyzed by statistical software. The particle size distribution and roundness were measured by laser diffraction and light microscopic image analysis systems. The polymorph type of products was investigated by XRPD. The crystallized product morphology was examined using scanning electron microscopy. We found that the crystallization methods and certain parameters have significant effect on the particle size, particle size distribution. In spite of the modified particle size, morphology, roundness, the polymorph type of the product was the same with the original material.     

Polymer-directed crystallization of atorvastatin

Living organisms secrete minerals composed of peptides and proteins, resulting in "mesocrystals" of three-dimensional-assembled composite structures. Recently, this biomimetic polymer-directed crystallization technique has been widely applied to inorganic materials, although it has seldom been used with drugs. In this study, the technique was applied to the drowning-out crystallization of atorvastatin using various polymers. Nucleation and growth at optimized conditions successfully produced composite crystals with significant polymer contents and unusual characteristics. Atorvastatin composite crystals containing polyethylene glycol, polyacrylic acid, polyethylene imine, and chitosan showed a markedly decreased melting point and heat of fusion, improved stability, and sustained-release patterns. The use of hydroxypropyl cellulose yielded a unique combination of enhanced in vitro release and improved drug stability under a forced degradation condition. The formation hypothesis of unique mesocrystal structures was strongly supported by an X-ray diffraction pattern and substantial melting point reduction. This polymer-directed crystallization technique offers a novel and effective way, different from the solid dispersion approach, to engineer the release, stability, and processability of drug crystals.     

吲哚美辛微观结晶机制及纳米包衣的影响

药物的无定形状态比晶态具有更大的溶解度,可以促进吸收,提高口服生物利用度,但是稳定性差,易转变为晶体状态。本文采用偏光显微镜、扫描电子显微镜、差示扫描量热法、X-射线衍射法和拉曼光谱法等研究无定形吲哚美辛的微观结晶机制,并对药物表面进行喷金包衣,厚度为10 nm,研究结晶行为变化。结果发现,无定形吲哚美辛自由表面的结晶速率远大于其内部,金包衣可显著抑制自由表面的结晶。这提示,自由表面的结晶是影响无定形药物稳定性的关键因素,纳米包衣可用于增强无定形药物的稳定性。     

Water-catalyzed crystallization of amorphous acadesine

Lyophilized, amorphous acadesine crystallizes when exposed to water vapor. Isothermal calorimetry of samples held at constant humidity showed crystallization always occured within 1.5 h at relative humidities above about 50%, but was never observed at humidities below about 40%. The crystalline phase is anhydrous. Crystallization must proceed through an intermediate, metastable hydrate that immediately decomposes to the anhydrous crystal, a mechanism not commonly considered. The various possible mechanisms of water-catalyzed crystallization of amorphous materials can be distinguished by the dependence of the initiation time on the partial pressure of water vapor.     

普鲁卡因青霉素的溶液微粒结晶Ⅲ.结晶工艺优化

通过实验研究各操作参数对普鲁卡因青霉素结晶产品粒度的影响,来考察混合对普鲁卡因青霉素溶液微粒结晶过程的影响,从而得到了最佳结晶工艺,并应用于工业生产中。     

舒巴坦钠结晶工艺的优化研究

目的 优化舒巴坦钠结晶工艺,降低产品比容。方法 以舒巴坦钠的比容为指标,采用单因素试验考察舒巴坦酸滴加方式、舒巴坦酸预加量、搅拌速度和晶种重量对产品比容的影响;选取舒巴坦酸预加量、搅拌速度和晶种重量为考察因素,通过正交试验优选最佳舒巴坦钠结晶工艺条件。通过30批大生产试验验证优化工艺,并选取前3批产品进行稳定性考察。结果 舒巴坦钠结晶的优化工艺为舒巴坦酸预加量50L、搅拌速度40r/min、晶种重量18kg。30批验证试验比容均值为2.38mL/g,较优化前降低32%,产品质量均符合中国药典质量标准。稳定性考察的各考察项目均符合中国药典(ChP2015)标准规定,质量稳定。结论 优化工艺稳定可行,可以有效降低产品比容,产生可观的经济效益。     

Spherical Crystallization of Mebendazole to Improve Processability

Spherical crystallization technique combines crystallization and agglomeration directly to generate spherical crystals with improved micromeretic properties, thus obviating need for further processing by granulation and agglomeration. The present study was focused on spherical crystallization of an antihelmentic drug – Mebendazole (MBZ) – using spherical agglomeration technique. Apart from being poorly water-soluble, MBZ exhibits poor flow and compressibility owing to its needle shaped crystal habit and electrostatic charge. Spherical agglomeration was carried out in the presence of different bridging liquids (hexane, octanol, toluene, dichloromethane) and polymers (polyethylene glycol, cross-povidone, starch, cross carmellose sodium, hydroxyl propyl methyl cellulose (HPMC), hydroxyl propyl cellulose (HPC), ethyl cellulose (EC), Eudragit®S100, Eudragit®RLPO, Eudragit®RD100, Eudragit®E), by employing different crystallization conditions such as variation of polymer type, polymer concentration, and rate of stirring. The final parameters were optimized to obtain crystals with an aspect ratio in the range of 1–2 compared to a value of 12 for untreated MBZ. These agglomerates retained form C of MBZ, and exhibited good flow properties, high bulk density and improved compressibility. Lower elastic:plastic energy (EE/PE) ratio for spherical crystals generated in the presence of Eudragit®-S100 and Hydroxypropylcellulose (HPC) indicated better compressibilty of spherical crystals.     

Avoiding crystallization of lorazepam during infusion

Lorazepam is a strong sedative for intensive care patients and a commonly used method of administering it to the patient is by infusion of a freshly prepared lorazepam solution. During lorazepam infusion often unwanted lorazepam crystallization occurs, resulting in line obstruction and reduced lorazepam concentrations. With the aid of solubility measurements a solid-liquid phase diagram for lorazepam in mixtures of a commercially available lorazepam solution and an aqueous glucose solution was determined. This confirmed that the glucose solution acts as an anti-solvent, greatly reducing the lorazepam solubility in the infusion solution. Three approaches are proposed to obtain stable lorazepam solutions upon mixing both solutions and thus to prevent crystallization during infusion: (1) using a high lorazepam concentration, and thus a lower glucose solution volume fraction, in the mixed solution; (2) using an elevated temperature during solution preparation and administration; (3) reducing the lorazepam concentration in the commercial lorazepam solution.     

Surface crystallization of indomethacin below Tg

Purpose To study the surface crystallization of indomethacin (IMC) below T _g and its effects on the kinetics of overall crystallization.Methods Crystal growth rates in liquid layers formed between microscope cover glasses were measured with the top cover glass in place and removed. Polymorphs were identified by powder X-ray diffraction, Raman microscopy, and melting-point determination by hot-stage microscopy. Surface crystals were identified by scratching the sample surface, by cutting the sample to expose its interior, and by analyzing the intensity of X-ray diffraction. Amorphous IMC particles of different sizes were stored at 40°C (T _g−2°C) and analyzed at different times by differential scanning calorimetry to obtain the kinetics of crystallization.Results Crystal growth of IMC below T _g at the free surface was approximately two orders of magnitude faster than that in the bulk, resulting in a surface layer of crystals around a slower-crystallizing interior. Surface crystallization yielded mainly the γ polymorph. Amorphous IMC powders showed rapid initial crystallization at 40°C, but the crystallization abruptly slowed down at “saturation levels” below 100%; the larger the particles, the lower the “saturation level.”Conclusion The faster surface crystallization of IMC than the bulk crystallization leads to unusual crystallization kinetics wherein a rapid initial increase of crystallinity is followed by an abrupt slowdown of crystallization. Surface crystallization should be distinguished from bulk crystallization in modeling and controlling the crystallization of amorphous solids.     

The crystallization of aspirin from ethanol

The rate of growth of aspirin crystals has been examined in a circulatory crystallizer in which the crystals are held in suspension as a fluidized bed. The deposition rate was measured, as a function of both the degree of supersaturation and the solution temperature, by observing the rate of weight increase and the change in particle size distribution of the crystals. The dependence of the mass transfer coefficient for the process upon the temperature was of the Arrhenius type, the activation energy being 21·8 kcal/mole. This indicates that the surface reaction step is rate-controlling, diffusional transport to the crystal surface being rapid. The density of aspirin solutions in alcohol has also been measured as a function of temperature and concentration.