In vitro assessment of lidocaine release from aqueous and oil solutions and from preformed and in situ formed aqueous and oil suspensions. Parenteral depots for intra-articular administration

In vitro drug release rates from aqueous and oil solutions as well as preformed and in situ formed aqueous and oil suspensions intended for intra-articular delivery have been investigated using the rotating dialysis cell model. Using lidocaine as a model drug substance the release kinetics from aqueous and oil suspensions have been compared and the sustained release properties from such suspensions formed in situ has been evaluated. The appearance of lidocaine in the acceptor phase after instillation of preformed and in situ formed aqueous and oil suspensions into the small aqueous donor compartment applied to zero-order kinetics as long sufficient amounts of solid lidocaine remained in the donor cell. The obtained data indicate that oil solutions and oil suspensions of lidocaine possess prolonged release properties equal to or better than those of aqueous counterparts. Also the release properties of preformed aqueous and oil suspensions are identical to such suspension types formed in situ. The present in vitro model appears useful in quality control and formulation development in the field of parenteral depots.     

Dissolution and crystal growth in aqueous suspensions of cortisone acetate

The change in particle size distribution of cortisone acetate in aqueous (saline) suspensions has been examined using the Coulter Counter. Rate of growth under standardized conditions was calculated as increase of diameter per unit time. Solubility of a water-unstable crystal form has been shown to be greater than that of the stable form. Discussion of the results reveals that crystal growth is mainly initiated by polymorphic transformation. Lattice energies, heats of wetting and solution of the different crystal forms are thought to be the rate controlling factors.     

Improvement of the wettability and dissolution of fenofibrate compacts by plasma treatment

The goal of this study was to investigate the effect of plasma treatment on the wettability and dissolution of fenofibrate compacts. Contact angle measurements and intrinsic dissolution rate studies of untreated and plasma-treated fenofibrate compacts were conducted. The contact angle data clearly show that the wettability of the tablet surface increased with the duration of plasma treatment.Analyses of stability revealed that the surfaces which were plasma-treated for more than 1 min regained some degree of hydrophobicity after storage in air. Since their hydrophobic recovery finally reached the level observed with 1 min plasma-treated fenofibrate compacts it was deduced that permanent incorporation of hydrophilic groups had already attained saturation upon plasma irradiation for 1 min.Dissolution studies revealed the advantages of the hydrophilized surface of plasma-treated fenofibrate compacts. Due to the improved wettability of plasma-treated fenofibrate its intrinsic dissolution rate was vastly increased compared to untreated fenofibrate. This study thus demonstrates the potential of plasma treatment to enhance the wettability and dissolution behavior of poorly water-soluble drugs.     

Cylindrical tube and surface tension viscous flow models in the assessment of capillary flow and liquid contact angles in pharmaceutical powders

The validity of the cylindrical tube (CT) model for the estimation of contact angles of irregular porous media using liquid penetration data is based on the linearity of l vs t^1/2 plots which assumes the same geometric contribution for liquids exhibiting different contact angles in the same medium. In recent criticisms it was observed that conformation of penetration data to t^1/2 dependence has also been predicted for systems other than cylindrical tubes, and a method for obtaining contact angles based on surface tension viscous flow (STVF) model and scaling concepts was proposed. To assess the validity of these proposals, the rates of liquid penetration of a homologous series of alkanes, alcohol and carboxylic acids into fifteen pharmaceutical powders (Avicel PH101, Starch 1500, magnesium stearate, calcium carbonate, calcium phosphate, calcium formate, calcium acetate, calcium lactate, calcium gluconate, calcium stearate, p-hydroxybenzoic acid, methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, propyl p-hydroxybenzoate and butyl p-hydroxybenzoate) were determined. Contact angles were obtained according to the CT model. Plots of l vs t^1/2 were linear as predicted by the CT model. Plots of reduced distance travelled as a function of reduced time, based on the STVF scaling concepts, did not superimpose on a single curve, an indication that the systems studied were in dissimilar states, exhibiting differing contact angles. On the other hand, contact angles obtained from STVF scaling concepts were similar, thus indicating that the systems are in similar states. This contradicts the results from plots of reduced distance vs time. The inability of both approaches to reach the same conclusion questions the validity of the universal application of the STVF model. The STVF model does not adequately describe liquid-powder systems which display finite and differing contact angles when different liquids are used on the same powder. This may be due to the differences in wettability and surface energetics inherent in such systems and not necessarily because of geometric factors.     

头孢克洛颗粒及干混悬剂溶出度的研究

目的研究测定头孢克洛颗粒以及干混悬剂溶出度的方法。方法采用浆法,以水为溶出介质,转速为50r/min,紫外-可见分光光度法264nm波长处测定吸光度。结果头孢克洛颗粒和干混悬剂在5min的溶出量均不少于80%。结论方法准确可靠,能满足质量控制要求。     

Effect of lubricant on spreading of coating liquid on surface of tablets containing pancreatin

The objective of this study was to evaluate the spreading of the coating liquid on different tablets containing pancreatin and microcrystalline cellulose. The effects of the ratio of the components, the presence of magnesium stearate and the blending circumstances were investigated. The contact angle of the liquids on the different tablets did not change linearly. For the mixture containing 50% pancreatin, the deviation of the measured value from the predicted one was more than 25%. This deterioration was also detected for mixtures containing 1% lubricant, but the extent was lower and was not modified by change of the mixing circumstances. This phenomenon was explained by the special microstructure of the surface of the tablet. This was predicted from the spreading coefficient, calculated from the surface free energy. The enrichment of pancreatin on the surface was preferred in binary mixtures. The spreading of magnesium stearate was most preferred for the powder mixture, and thus prediction of the properties of the tablet was easier for these mixtures. The extent of the effect of this excipient on the surface properties was very wide-ranging. The change in the spreading of the coating liquid was significant; however, the change in the work of friction was negligible.     

乙醇-水混合溶剂中妥布霉素晶体生长机理研究

利用激光法试验测定了296.15～312.15K的温度范围内妥布霉素在乙醇-水混合溶剂中的结晶诱导期,并考察了温度、溶剂组成等因素对结晶诱导期的影响.结合经典成核理论,利用试验测定的诱导期计算出了妥布霉素在乙醇-水混合溶剂中的固液表面张力、表面熵因子.利用表面熵辨识了妥布霉素在乙醇-水混合溶剂中晶体的生长模式为连续生长模式,晶体表面粗糙,此结果与试验结果完全吻合.     

Study on formability of solid nanosuspensions during nanodispersion and solidification: I. Novel role of stabilizer/drug property

Few or no attempts have been made so far to understand the feasibility of solid nanosuspension formulation during nanodispersion and solidification in terms of drug properties and stabilizer characterizations. In order to establish a knowledge base about the effect of physicochemical property of drug compounds and stabilizers on solid nanosuspension production during nanodispersion and solidification, a comparative study was firstly performed on 10 different stabilizers at 3 concentrations for 8 structurally different drug compounds. Synthetic polymers (HPMC, PVP K30, CMS-Na and MC) displayed a poor stabilizing performance (10% success rate on average) during nanodispersion, but polymers showed better potential when higher concentrations was applied during freezing and lyophilization. Meanwhile, an effect for the surfactants group was even more pronounced during nanodispersion. However, the solid nanosuspension stabilized by surfactants showed the worst formability potential when be applied in setted concentrations during freezing and lyophilization. From the point of view of drug property, it was found that the surface hydrophobicity and cohesive energy of drug, were responsible for the formability of the solid nanosuspension during nanodispersion and solidification. Wetting index (k) and ΔE were concluded to have a direct correlation on the feasibility of formation of a stable solid nanosuspension, which can give a formulation design strategy from where candidate drugs and stabilizers with a set of properties.     

钛及钛合金种植体的两种表面处理对细菌黏附能力的影响

目的研究两种表面处理(等离子渗氮和物理气相沉积TiN涂层)对钛、钛合金表面的组织结构、性能及对变形链球菌黏附的影响。方法将相同规格的钛、钛合金片经逐级抛光后分别随机分成3组,每组3片,依次为抛光组,渗氮表面处理组,TiN涂层表面处理组。以抛光钛、钛合金组作为对照。测量所有试件表面的粗糙度值,并采用扫描电镜、Axiovert 25CA光学图像分析仪及GDA750对钛、钛合金表面渗镀层的表面形态进行分析;将材料接种于变形链球菌悬液,在荧光显微镜下计数黏附细菌的数量。结果两种表面处理仅使原有表面粗糙度略微增加;扫描电镜显示两种表面处理后材料表面的原始划痕消失;GDS检测分析结果表明:钛、钛合金两种表面处理后,表面主要由氮化钛化合物组成。经两种处理后,钛、钛合金黏附细菌的量显著减少,而两种表面处理差异无统计学意义。结论钛、钛合金经两种表面处理后形成了稳定的改性层,且能减少细菌的黏附。相对于有涂层脱落之忧的物理气相沉积TiN涂层技术,等离子渗氮技术有望作为种植体穿龈部和种植体基台部的表面处理技术。     

Effect of crystal form, cortisone alcohol and agitation on crystal growth of cortisone acetate in aqueous suspensions

Particle size distribution in aqueous suspensions of stable and unstable crystal forms of cortisone acetate under conditions of agitation and different degrees of saturation with cortisone alcohol is described. Agitation accelerated the diffusion-controlled processes of dissolution and crystallization, leading to the formation of a high proportion of large particles. Cortisone alcohol inhibited the polymorphic transformation necessary for the crystal growth and formation of the water-stable form. The mechanism of action is discussed.     

Stability of fenbendazole suspensions for veterinary use: Correlation between zeta potential and sedimentation

In this paper we have carried out a detailed investigation of the stability and redispersibility characteristics of fenbendazole aqueous suspensions, through a thermodynamic and electrokinetic characterization, considering the effect of both pH and ionic strength. The hydrophobic character of the drug, and the surface charge and electrical double-layer thickness play an essential role in the stability of the system, hence the need for a full characterization of fenbendazole. It was found that the drug suspensions displays "delayed" or "hindered" sedimentation, determined by their hydrophobic character and their low zeta potential (indicating a small electrokinetic charge on the particles). The electrostatic repulsion between the particles is responsible for the low sedimentation volume and poor redispersibility of the drug. However, only low concentrations of AlCl(3) induced a significant effect on both the zeta potential and stability of the drug, leading to a "free-layered" sedimentation and a very easy redispersion which could be of great interest in the design of an oral pharmaceutical dosage form for veterinary.     

Predicting the quality of powders for inhalation from surface energy and area

Purpose. To correlate the surface energy of active and carrier components in an aerosol powder to in vitro performance of a passive dry powder inhaler. Methods. Inverse gas chromatography (IGC) was used to assess the surface energy of active (albuterol and ipratropium bromide) and carrier (lactose monohydrate, trehalose dihydrate and mannitol) components of a dry powder inhaler formulation. Blends (1%w/w) of drug and carrier were prepared and evaluated for dry powder inhaler performance by cascade impaction. The formulations were tested with either of two passive dry powder inhalers, Rotahaler^® (GlaxoSmithKline) or Handihaler^® (Boehringer Ingelheim). Results. In vitro performance of the powder blends was strongly correlated to surface energy interaction between active and carrier components. Plotting fine particle fraction vs. surface energy interaction yielded an R² value of 0.9283. Increasing surface energy interaction between drug and carrier resulted in greater fine particle fraction of drug. Conclusions. A convincing relationship, potentially useful for rapid formulation design and screening, was found between the surface energy and area parameters derived from IGC and dry powder inhaler performance.     

Evaluation of surface and microstructure of differently plasticized chitosan films

Surface and structural investigations of natural biopolymer (chitosan) films containing various conventionally applied hydrophilic plasticizers (glycerol and poly(ethylene glycol) 400) were performed and the results were compared, with the aim of acquiring new information concerning the formation of these plasticized films. The surface tests revealed that the water uptake, the water-binding properties (moisture content) and the polarity were higher for the film containing glycerol as plasticizer. Positronium lifetime measurements and NMR studies performed to evaluate the effects of the plasticizer on the polymer structure demonstrated relevant differences in the effects of the plasticizers. The influence of glycerol on the structure of the film formed was more intensive than that of PEG 400. It can be concluded that the surface properties of the films, which are very important for their storage and application, cannot be established exactly by means of structural tests. Both surface and structural tests must be performed before the formulation of this type of plasticized mucoadhesive films.     

Investigation into the influence of polymeric stabilizing excipients on inter-particulate forces in pressurised metered dose inhalers

Colloid probe atomic force microscopy (AFM) was utilised to quantify the cohesive forces of salbutamol sulphate in a model non-pressurised fluorinated liquid (mHFA), in the presence of increasing concentrations of poly(ethylene glycol) (PEG; molecular weight (MW) 200, 400 and 600). In addition, samples of PEG 400 (0.05–0.5%, v/w), were analysed in the presence of 0.001% (w/w) of poly(vinyl pyrrolidone) (PVP). In the absence of any stabilizing agents, strong attractive forces were present between particles. Increasing the concentration of the different MW PEG solutions in the mHFA system (up to 0.5%, v/w), significantly decreased the force of interaction (ANOVA, p < 0.05). The decrease in cohesion was particularly evident at very low concentrations of PEG (0.05–0.1%, v/w). Further data analysis (p < 0.05) suggested that the reduction in the force of cohesion was dependent on the concentration and molecular weight of PEG. The addition of low concentration of PVP to the PEG 400-mHFA system had the most significant influence on drug particle cohesion. In the presence of PVP, increasing addition of PEG 400 (0.05–0.5%, v/w) to the mHFA, resulted in no significant reduction in the force of cohesion (p > 0.05). Clearly, an understanding of the conformation of polymer molecules at interfaces is of vital importance when controlling the stability/flocculation behaviour of sterically stabilized pMDI suspensions. In this context, the use of the colloid probe AFM technique has provided a quantitative insight into the interactions of these complex systems and may be an invaluable asset during the early phase of formulation product development.     

Impact of Polysorbate 80 Grade on the Interfacial Properties and Interfacial Stress Induced Subvisible Particle Formation in Monoclonal Antibodies

Polysorbate 80 is a nonionic surfactant that is added to therapeutic protein formulations to mitigate protein particle formation when subjected to various mechanical stresses. Variations in the PS80 grade has recently sparked questions surrounding the effect of oleic acid content (OAC) on surfactant's ability to mitigate interface-induced protein particle formation when stressed. In this work, a Langmuir trough was used to apply interfacial dilatational stress to two IgG molecules (mAb1 and mAb2) in formulations containing Chinese pharmacopeia (CP) and multicompendial (MC) grades of PS80. The interfacial properties of these mAb formulations, with and without interfacial dilatational stresses, were correlated with subvisible particle count and particle size/morphology distributions as measured by Micro-flow imaging (MFI). Overall, differences in interfacial properties correlated well with protein particle formation for both molecules in the two PS80 formulations. Further, the impact of grade of PS80 on the interfacial properties and interfacial stress-induced protein particle formation depends on the adsorption kinetics of the IgG molecules as well as the concentration of the surfactant used. This study demonstrates that measuring the interfacial properties of mAb formulations can be a useful tool to predict interfacial stress induced protein particle formation in the presence of different excipients of varying quality.     

Effects of sugar ester and hydroxypropyl methylcellulose on the physicochemical stability of amorphous cefditoren pivoxil in aqueous suspension

The improvement in physicochemical stability of amorphous cefditoren pivoxil (CDTR-PI) in aqueous suspensions by addition of sugar ester (SE) and hydroxypropyl methylcellulose (HPMC) was explained by prolonging the induction period prior to crystallization and the reduction in crystal peak intensity. Furthermore, the stabilizing effect of these additives in a multiple additive system was greater than in a single additive system. To determine the mechanism, by which these additives stabilized the amorphous CDTR-PI, we evaluated the surface states of CDTR-PI in suspension by measuring Raman spectra and zeta potential. The change in Raman spectra demonstrated that SE and HPMC interacted with CDTR-PI at the same interaction sites on CDTR-PI. The zeta potential reflected the adsorption phenomena of the additives and indicated that both SE and HPMC adsorbed onto particles of CDTR-PI with no apparent competitive interaction and the response was complementary. It was considered, based on this study, that HPMC and SE would stabilize amorphous CDTR-PI by different mechanisms; HPMC would mainly inhibit crystal growth by small amount of adsorption and SE would inhibit both crystal growth and nucleation by large amount of adsorption. This was considered to result in the hybrid effect in the multiple additive system.     

Electrostatic characterisation of inhaled powders: Effect of contact surface and relative humidity

Electrostatic charge accumulation on drug and excipient powders arising from interparticulate collisions or contacts between particles and other solid surfaces often leads to agglomeration and adhesion problems during the manufacture and use of dry powder inhaler (DPI) formulations. The aim of this work was to investigate the role of triboelectrification in particle interactions between micronised drug (salbutamol sulphate or ipratropium bromide monohydrate) and excipient (alpha-lactose monohydrate, 63-90 microm) during mixing in cylindrical vessels constructed from stainless steel, polypropylene and acetal under selected relative humidity (rh) conditions (0-86%). The charge was found to depend on both the nature of the powders and the mixing vessel surface. In addition, coating the vessels with drug or excipient removed the influence of the vessel material on charge generation, thus providing a technique to investigate interactions between the drug and excipient substances. A triboelectric series of all materials used, placed ipratropium at the positive end and polypropylene at the negative end. Micronised drug profoundly altered the charging properties of lactose in drug (1.46%, w/w)/lactose DPI formulations. An increase in rh in the range 0-86% produced a corresponding decrease in charge and adhesion values for each drug, lactose and DPI formulation during triboelectrification with each mixing vessel surface. The results provide increased knowledge of the role of electrostatics in DPI technology.     

Surface energy changes and their relationship with the dispersibility of salmeterol xinafoate powders for inhalation after storage at high RH

This study investigated the relationship between surface energy of micronized lactose, coarse lactose and salmeterol xinafoate and dispersibility from a mixture after storage at 75% RH. Surface energies, dispersibility, morphology, and the presence of amorphous domains were determined by inverse gas chromatography, twin stage impinger, scanning electron microscope and dynamic vapour sorption, respectively. The fine particle fraction of mixture decreased significantly in 4 weeks (P < 0.05), reaching a static level in 3 months. Amorphous content was not detected in the micronized lactose, coarse lactose and salmeterol xinafoate. After conditioning stored samples at 75% RH for 2 h, dispersive surface energy of both micronized and coarse lactose significantly decreased (P < 0.05), while the polar surface energy of all significantly increased (P < 0.05) resulting in significant increase in total surface energy after storage. After conditioning stored samples at 0% RH for 2 h, no significant difference was observed in any surface energy parameter. This study concluded that the total surface energy increased during storage at high RH due to the adhered surface moisture. The mechanism of decreased dispersibility was related to increased capillary/solid bridging interactions and to possible increased interaction of contiguous particles due to increased polar surface energy.     

Changes in surface properties by granulation and physicochemical stability of granulated amorphous cefditoren pivoxil with additives

The evaluation of the physicochemical stability of granules of amorphous cefditoren pivoxil (CDTR-PI), alone or with polymers, demonstrated that granulated amorphous CDTR-PI with hydroxypropyl methylcellulose was the most stable. We measured glass transition temperature by differential scanning calorimetry (DSC). The molecular mobility of the whole granules did not change, and it was not consistent with the results of the evaluation of physicochemical stability. Peak shifts were observed in IR spectra of amorphous CDTR-PI with polymers after granulation, and the shifts were similar to those observed for spray-dried samples. Furthermore, the shifts were not observed after the granules were ground. Acid–base parameters, which were also measured by inverse gas chromatography (IGC), changed after granulation. These results suggested that on the surface of the granules, CDTR-PI and the polymers would be mixed monomolecularly, as in the spray-dried samples. The changes in the molecular state of a drug when mixed monomolecularly with a polymer on the surface of granules were successfully confirmed by IGC and IR.