Spherical crystals of celecoxib to improve solubility, dissolution rate and micromeritic properties

Celecoxib spherical agglomerates were prepared with polyvinylpyrrolidone (PVP) using acetone, water and chloroform as solvent, non-solvent and bridging liquid, respectively. The agglomerates were characterized by differential scanning calorimetry (DSC), X-ray diffraction (XRD), IR spectroscopic studies and scanning electron microscopy (SEM). The IR spectroscopy and DSC results indicated the absence of any interactions between drug and additives. XRD studies showed a decrease in crystallinity in agglomerates. The crystals exhibited significantly improved micromeritic properties compared to pure drug. The loading efficiency (% or mg drug per 100 mg crystals) was in the range of 93.9 +/- 2.3 and 97.3 +/- 1.3% (n = 3) with all formulations. The aqueous solubility and dissolution rate of the drug from crystals was significantly (p < 0.05) increased (nearly two times). The solubility and in vitro drug release rates increased with an increase in PVP concentration (from 2.5 to 10%). The SEM studies showed that the crystal posseses a good spherical shape with smooth and regular surface.     

Preparation of amorphous carvedilol polymeric microparticles for improvement of physicochemical properties

The aim of the present study was to enhance the physicochemical properties of poorly aqueous soluble carvedilol (CRV) by preparing its microparticles in presence and/or in absence of a hydrophilic carrier. The polymeric microparticles of CRV were prepared with polyvinylpyrrolidone K30 with or without addition of adsorbents like Aerosil^?200 and/or Sylysia^?350 by using spray drying technique. The dissolution profiles revealed that the drug and polymer ratio and colloidal silica both played critical role in solubility enhancement. The spray dried microparticles and drug alone were characterized by differential scanning calorimetry (DSC), X-ray powder diffraction, Fourier transformation infrared spectroscopy (FTIR), particle size analysis and scanning electron microscopy (SEM). DSC analysis showed that CRV transformed from the crystalline state to amorphous state by spray drying, confirmed by disappearance of its melting peak. The results of the X-ray analysis were in agreement with the thermal analysis data. It did not show characteristic crystalline drug peaks which confirmed that the amorphous form of CRV was present in the CRV loaded microparticles. FTIR analysis demonstrated hydrogen bonding interaction with an absence of significant chemical interaction between CRV and polymer. Spherical microparticles were yielded with smooth surfaces as observed by SEM. All in all, this work reveals that spray drying is a suitable technique for preparation of microparticles with improved physicochemical properties of CRV.     

Spherical crystallization of drugs

Spherical crystallization of drugs is the process of obtaining larger particles by agglomeration during crystallization. The most common techniques used to obtain such particles are spherical agglomeration and quasi-emulsion solvent diffusion. Ammonia diffusion systems and crystallo-co-agglomeration are extensions of these techniques. By controlling process parameters during crystallization, such as temperature, stirring rate, type and amount of solvents, or excipient selection, it is possible to control the formation of agglomerates and obtain spherical particles of the desired size, porosity, or hardness. Researchers have reported that the particles produced have improved micromeritic, physical, and mechanical properties, which make them suitable for direct compression. In some cases, when additional excipients are incorporated during spherical crystallization, biopharmaceutical parameters including the bioavailability of drugs can also be tailored.     

Relations between crystallisation conditions and micromeritic properties of ibuprofen

The effects of solvent, cooling rate and type of methacrylic polymer (Eudragit(R)) on the micromeritic properties (size, elongation ratio, roundness and fullness ratio), the temperature change in the crystallisation liquid, the crystal yield and the extent of agglomeration of ibuprofen crystals have been compared. Twenty batches of crystals were prepared and Latin square experimental design was applied with four levels for each factor. It was found that crystal yield (Y) is related to the extrapolated point of maximum rate of temperature-deviation (T(d)) with a logarithmic-type equation [Y=34.45lnT(d)-28.00] and to the area under the curve of temperature-deviation versus time (AUC) with a polynomial equation including cooling rate [Y=19.95AUC-1.57AUC/CR+63.00]. Crystal size is affected by the cooling rate and analysis of variance (ANOVA) showed that elongation ratio and fullness ratio of single crystals (P=0.05 and 0.05), as well as roundness and fullness ratio of agglomerates (P=0.05 and 0.1), are affected by the solvent. Post hoc statistical analysis of the solvent effects on the shape of crystals and agglomerates (Tukey's HSD multiple pairwise comparison test of means) indicated that their significance lies in the different polarity and may be attributed to interactions of solvent (acetone) with the growing crystal faces. Extent of crystal agglomeration was found to be inversely proportional to the ratio of elongation ratio/circle equivalent diameter of the single crystals.     

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.     

Parameters determining the agglomeration behaviour and the micromeritic properties of spherically agglomerated crystals prepared by the spherical crystallization technique with miscible solvent systems

The parameters determining the agglomeration behaviour and micromeritic properties of spherically agglomerated crystals of acebutolol hydrochloride prepared by the spherical crystallization technique with a two- or three-miscible-solvent system (i.e., bridging liquid, good solvent, poor solvent) were investigated. With decreasing amount of water (= bridging liquid) in the three-solvent system, the median diameter of agglomerated crystals increased, having a wider size distribution. When the composition of the system approached that of phase separation (= saturation with water), smaller sized agglomerates with a narrower size distribution were produced. The median diameter of agglomerates decreased with increasing content of ethanol (= good solvent) in the formulation. Spherically agglomerated crystals were produced evenly with the two-solvent system, i.e., water and isopropyl acetate (= poor solvent), in which the water played both the roles of bridging liquid and good solvent. The median diameter of agglomerates decreased with increasing agitation speed of the system.     

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.     

疏水型二氧化硅对馨月舒喷雾干燥粉药剂学性质的影响

目的:考察疏水型二氧化硅AEROSIL R972对馨月舒喷雾干燥粉的粉体学及体外溶出等药剂学性质的影响。方法:研究加入不同比例AEROSIL R972对馨月舒喷雾干燥粉吸湿性、流动性、压缩成形性、阿魏酸体外溶出度的影响。结果:加入5%AEROSIL R972能显著改善馨月舒喷雾干燥粉的吸湿性和流动性;对粉体的压缩成形性和阿魏酸体外溶出度无明显影响。结论:疏水型二氧化硅在中药喷雾干燥粉体中的应用值得进一步研究。     

An improvement in physicochemical properties of carvedilol through spherically agglomerated solid dispersions with PVP K30

Spherically agglomerated solid dispersions of carvedilol (CAR) were prepared with polyvinyl-pyrrolidone (PVP) using acetone, water and dichloromethane as solvent, non-solvent and bridging liquid, respectively. The prepared agglomerates were evaluated for its percentage yield, drug content, morphology, thermal behavior, micromeritic properties, aqueous solubility and in vitro drug release. Differential scanning calorimetric and powder X-ray diffraction studies confirm that formulation process altered the crystalline nature of carvedilol. The recrystallized agglomerates exhibited significant increase (p < 0.05) in micromeritic properties than untreated carvedilol. Solubility and in vitro drug release studies indicated that the spherical agglomerates showed significant increase (p < 0.05) in solubility and dissolution rate than pure carvedilol alone.     

依折麦布片HPLC含量测定方法学研究

目的建立依折麦布含量测定方法。方法采用高效液相色谱祛,以Agilent SB-C18（5μm,150mm×4．6mm）为色谱柱,以0．05mol／L磷酸二氢钾溶液-乙腈-四氢呋喃（65：25：10）为流动相;检测波长为232nm,柱温为25℃,流速为1．0mL／min。结果含量测定方法学研究表明,该方法专属性好;依折麦布在40．23-402．30μg／mL的浓度范围内与其峰响应值呈良好的线性关系,平均回收率为98．8％（RSD=0.3％）。结论本方法测定结果准确,精密度高,耐用性良好,可以作为依折麦布的含量测定方法。     

Importance of pharmacological and physicochemical properties for tolerance of antimuscarinic drugs in the treatment of detrusor instability and detrusor hyperreflexia--chances for improvement of therapy.

BACKGROUND: Antimuscarinic side-effects are relatively frequent problems in oral pharmacotherapy of detrusor instability and neurogenic dysfunction of the urinary bladder. Results of recent clinical trials demonstrate differences in tolerance between antimuscarinic drugs. It is the purpose of this paper to relate the available clinical data to the pharmacological and physicochemical properties of the different antimuscarinic drugs, in order to discuss the reasons for this enhanced tolerance and to make possible modes for improvement of antimuscarinic therapy plainly visible. METHODS: Therefore, we reviewed the available literature using among others the computerized library systems Medline (National Library of Medicine, Bethesda, Maryland, USA) and Embase (Excerpta Medica, Amsterdam, the Netherlands). Differences in tolerance of oral antimuscarinic drugs may result from muscarine-receptor selectivity, organ selectivity, and pharmacokinetic as well as physicochemical properties. While the roles of m-receptor and organ selectivity need more detailed clarification, influences of differences in bioavailability and physicochemical properties on the tolerance of antimuscarinic drugs are more sufficiently investigated. RESULTS: Generally, tolerance as well as efficacy of antimuscarinic drugs seem to be a complex result of a combination of various pharmacological properties distinguishing the individual substances. The enhancement of tolerance of propiverine hydrochloride, tolterodine tartrate and trospium chloride compared to oxybutynin chloride seems to be reached by different modes, from which the molecular structure -- propiverine and tolterodine are tertiary amines, trospium chloride possesses a quarternary ammonium structure -- may be of great importance. First investigations with alternative transdermal and intravesical application routes show interesting possibilities for further improvement of antimuscarinic therapy in urological indications. CONCLUSION: In conclusion, from pharmacological and clinical data it becomes obvious that there are significant differences between antimuscarinic drugs, which are of clinical relevance and include possible starting points for the development of new drugs and application forms.     

Effect of formulation variables on in vitro drug release and micromeritic properties of modified release ibuprofen microspheres

Modified release microspheres of the non-steroidal anti-inflammatory drug, ibuprofen, were formulated and prepared using the emulsion solvent diffusion technique. The contribution of various dispersed phase and continuous phase formulation factors on in vitro drug release and micromeritic characteristics of microspheres was examined. The results demonstrated that the use of Eudragit RS 100 and Eudragit RL 100 as embedding polymers modified the drug release properties as a function of polymer type and concentration. Eudragit RS 100 retarded ibuprofen release from the microspheres to a greater extent than Eudragit RL 100. The drug/polymer concentration of the dispersed phase influenced the particle size and drug release properties of the formed microspheres. It was found that the presence of emulsifier was essential for microsphere formation. Increasing the concentration of emulsifier, sucrose fatty acid ester F-70, decreased the particle size which contributed to increased drug release properties. Scanning electron microscopy revealed profound distortion in both the shape and surface morphology of the microspheres with the use of magnesium stearate as added emulsifier. The application of an additional Eudragit RS 100 coat onto formed microspheres using fluid bed technology was successful and modulated the drug release properties of the coated microspheres.     

提高抗生素溶析结晶产品质量的途径探讨

针对目前抗生素溶析结晶产品普遍存在的主粒度小、相对标准差大等问题，研究了提高溶析结晶产品质量的途径，即在溶析结晶物系中施加超声波快速制备高质量的晶种，建立沉淀剂流加的最佳操作程序     

Impact of process variables on the micromeritic and physicochemical properties of spray‐dried microparticles – Part II. Physicochemical characterisation of spray‐dried materials

Objectives In this work we investigated the residual organic solvent content and physicochemical properties of spray‐dried chlorothiazide sodium (CTZNa) and potassium (CTZK) salts. Methods The powders were characterised by thermal, X‐ray diffraction, infrared and dynamic vapour sorption (DVS) analyses. Solvent levels were investigated by Karl–Fischer titration and gas chromatography. Key findings Spray‐drying from water, methanol (MeOH) and mixes of MeOH and butyl acetate (BA) resulted in amorphous microparticles. The glass transition temperatures of CTZNa and CTZK were ～192 and ～159°C, respectively. These materials retained their amorphous nature when stored at 25°C in dry conditions for at least 6 months with no chemical decomposition observed. DVS determined the critical relative humidity of recrystallisation of CTZNa and CTZK to be 57% RH and 58% RH, respectively. The inlet temperature dependant oxidation of MeOH to formaldehyde was observed; the formaldehyde was seen to deposit within the amorphous matrix of spray‐dried product. Spray‐drying in the open blowing mode coupled with secondary drying resulted in a three‐fold reduction in residual BA (below pharmacopoeial permitted daily exposure limit) compared to spray‐drying in the closed mode. Conclusions Experiments showed that recirculation of recovered drying gas increases the risk of deposition of residual solvents in the spray‐dried product.     

Analysis of physicochemical properties for drugs from nature

The chemical structure of a compound has a direct influence on its physical, chemical, and biological properties. The present study describes data pertaining to calculations and statistical analysis of the physicochemical parameters of drugs obtained directly or indirectly from nature. The study projects various physiochemical parameters required for their druggability. The study reveals that most of these drugs fall close to Lipinski’s rule of five. Among the reported physicochemical parameters, the number of aromatic rings is most interesting. Illustrations regarding the same are reported, along with their statistical trends.     

油用牡丹籽蛋白质的制备及理化性质研究

目的对油用牡丹籽蛋白质的制备工艺以及理化性质进行初步研究。方法在单因素实验基础上,采用碱提酸沉的方法进行提取并以正交试验优化牡丹籽蛋白质的提取工艺。结果牡丹籽蛋白质提取的最佳工艺条件为pH 10.5,提取40 min,液料比25∶1(ml/g),提取温度40℃。牡丹籽蛋白质的分子量主要集中在66.2~18.4 kDa。结论采用碱提酸沉的方法对牡丹籽蛋白质进行提取方便快速,可为牡丹籽蛋白质的开发与利用提供基础。     

The physicochemical properties of oestradiol

The spectral, solubility and related physicochemical characteristics of the ovarian hormone are presented. A review of its crystal properties indicates that the common crystalline form of the steroid is the hemihydrate.     

The physicochemical properties of digoxin

In a study of variations in the physicochemical properties of digoxin powder from several commercial sources, recrystallizations of digoxin were performed under several conditions. Polymorphs were not obtained whereas a pure amorphous form was formed under certain conditions. The amorphous form was more soluble and more stable under compression than was the crystalline form; nevertheless in contact with water it crystallized quickly. Traces of the crystalline form reduced the dissolution rate and stability of the amorphous form. Variations in the thermal behaviour of commercial samples can be explained by the presence of variable proportions of the amorphous form and also by thermal decomposition that varies from one sample to another and generally occurs at 160 degrees C and above.