Effect of the drug-matrix on the stability of enalapril maleate in tablet formulations

The chemical stability of enalapril maleate in tablet dosage forms consisting of different formulation excipients has been studied in this work. The influence of various parameters such as heat, moisture, light and the drug-matrix was investigated. The degradation of enalapril maleate has been followed by using an HPLC method, which was demonstrated to be specific, stability indicating, accurate and precise. The degradation kinetics of enalalpril maleate in phosphate buffer solutions of pH values in the range of 2.2–10.5 were observed to be psuedo first order throughout the whole pH range studied. Enalapril maleate alone showed high stability for temperature under dry and humid conditions, however it became unstable when mixed with the drug-matrix in its tablet formulations and exposed to the same conditions. The pathway of degradation of enalapril maleate was found to be pH dependent. The extent of degradation of two different enalapril maleate tablet formulations (product A of a basic drug-matrix and product B of an acidic drug-matrix) has been investigated. The degree of degradation of the product with acidic matrix was significantly less than that of the basic matrix under same temperature and humidity conditions. Infact, diketopiperazine and enalaprilat degradants were mainly associated with the degradation of the product with the acidic matrix and that with the basic matrix, respectively. Dry enalapril maleate powder showed some photolysis, which was more significant with daylight (3.3%) compared with that under UV light (0.2%). Although the product with the acidic matrix showed some photolysis but the effect was not pronounced and the % recovery of enalapril was almost complete and within the acceptable experimental errors. However, the product with the basic matrix showed almost no response for photolysis.     

高剪切条件下四臣止咳颗粒制备过程中润湿剂的动态分布

目的 研究高剪切条件下制备四臣止咳颗粒过程中润湿剂的动态分布。 方法 以四臣止咳方浸膏粉-可溶性淀粉质量比为1∶2制备混合粉体,将示踪剂荧光素钠加入80%乙醇中作为润湿剂,高速搅拌湿法制粒;检测制粒过程不同时间点、不同粒径颗粒中荧光素钠的量,分析颗粒中润湿剂分布情况。 结果 在制粒初期颗粒粒径出现两极分化,且出现少量团块,主要在大粒径颗粒中检出荧光素钠,而小粒径颗粒中几乎检测不出荧光素钠,说明润湿剂此时主要呈现局部分布的状态;而随着制粒时间推移,颗粒粒径差别逐步缩小,荧光素钠在各粒径颗粒中分布趋向均衡,说明润湿剂此时趋向均匀分布的状态。 结论 高速搅拌湿法制备四臣止咳颗粒过程中,润湿剂分布随时间变化而趋向均匀化。     

The effect of the amount of binder liquid on the granulation mechanisms and structure of microcrystalline cellulose granules prepared by high shear granulation

The structure of granules changes during the high shear granulation process. The purpose of this research was to investigate the effect of the amount of binder liquid on the structure of the granules and the structural changes which occur during the granulation process, using microcrystalline cellulose (MCC) and water as the model system. The structure is the result of the granulation mechanism; therefore, conclusions can be drawn about the latter by studying the former. X-ray microtomography and scanning electron microscopy (SEM) were applied in order to visualise the densification process of granules, which were first freeze dried in order to preserve their structure. Variations in their porosity were quantified by applying image analysis to the tomography results. In order to link the granule mechanical properties to their structural differences, a micromanipulation technique was used to measure granule resistance to deformation. MCC granules granulated with 100% (w/w) water showed increased densification with time, as expected; detailed examination showed that densification is more pronounced in the core of the granule; whereas the outer part remained more porous. Increased densification reduces deformability, so that granules become more resistant to breakage. The lower deformability of the densified granules in the final stages of granulation might result in establishment of equilibrium between attrition and growth, without substantial gross breakage. On the other hand, when more water was used (125%, w/w), densification was hardly observed; the porosity of the granule core was still high even after prolonged granulation times. This may be explained by the fact that higher water content increases the ease of deformation of granules. This increased deformability led to significant granule breakage even during the final phases of the granulation process. Therefore, for these granules a final equilibrium between breakage and coalescence might be established. This also explains why more granules produced with 125% granulation liquid were composed of fragments of irregular shape.

Our results establish the link between the granulation behaviour of MCC in the latter stages and the material structure of these granules, which is determined by their liquid content. The process conditions (amount of liquid) to be chosen depend largely on the final purpose for which the granular material is produced.     

Formulation and evaluation of trimetazidine dihydrochloride extended release tablets by melt congealing method

Trimetazidine dihydrochloride, a cellular antiischemic agent indicated in the management and prophylaxis of angina pectoris is given as 20 mg thrice daily in the conventional dosage regimen. The purpose of the present study was to formulate and evaluate twice a day extended release tablets containing 30 mg trimetazidine dihydrochloride. The method developed to formulate these extended release tablets was melt congealing followed by wet granulation which exhibited uniform sustained release action and overcame the drawbacks of multidosing. The formulation was developed with Methocel^® K100M and stearic acid as release retardant.     

Improving solubility and chemical stability of natural compounds for medicinal use by incorporation into liposomes

Natural bioactive compounds have been studied for a long time for their chemopreventive and therapeutic potential in several chronic inflammatory diseases, including cancer. However, their physicochemical properties generally result in poor chemical stability and lack of in vivo bioavailability. Very few human clinical trials have addressed absorption, distribution, metabolism, and excretion of these compounds in relation to efficacy. This limits the use of these valuable natural compounds in the clinic.In this study, we examined caffeic acid (derivatives), carvacrol (derivatives), thymol, pterostilbene (derivatives), and N-(3-oxo-dodecanoyl)-l-homoserine lactone. These are natural compounds with strong anti-inflammatory properties derived from plants and bacteria. However, these compounds have poor water solubility or are chemically unstable. To overcome these limitations we have prepared liposomal formulations. Our results show that lipophilic 3-oxo-C₁₂-homoserine lactone and stilbene derivatives can be loaded into liposomal lipid bilayer with efficiencies of 50-70%. Thereby, the liposomes solubilize these compounds, allowing intravenous administration without use of solvents. When compounds could not be loaded into the lipid bilayer (carvacrol and thymol) or are rapidly extracted from the liposomes in the presence of serum albumin (3-oxo-C₁₂-homoserine lactone and pterostilbene derivatives), derivatization of the compound into a water-soluble prodrug was shown to improve loading efficiency and encapsulation stability. The phosphate forms of carvacrol and pterostilbene were loaded into the aqueous interior of the liposomes and encapsulation was unaffected by the presence of serum albumin. Chemical instability of resveratrol was improved by liposome-encapsulation, preventing inactivating cis-trans isomerization. For caffeic acid, liposomal encapsulation did not prevent oxidation into a variety of products. Still, by derivatization into a phenyl ester, the compound could be stably encapsulated without chemical degradation.Despite the instability of liposome-association of 3-oxo-C₁₂-homoserine lactone and resveratrol, intravenous administration of these compounds inhibited tumor growth for approximately 70% in a murine tumor model, showing that simple solubilization can have important therapeutic benefits.     

混酸法制取高浓度富过磷酸钙工艺条件的试验研究

介绍采用硫酸、磷酸混合分解磷矿粉制高浓度富过磷酸钙〔w(P2 O5有效)～ 34%〕的试验过程 ,研究混酸用量、混酸浓度、混酸温度、磷酸替代率等工艺条件对磷矿分解率的影响 ,经正交试验 ,确定了制备的最佳工艺条件 :混酸w(H3 PO4+H2 SO4) 6 6 %～ 6 9% ,混酸温度 70～ 80℃ ,磷酸替代率 5 0 %～ 5 4 % ,混酸用量为理论酸用量的 93%～ 97%。并对影响料浆固化及成品质量的有关因素展开了讨论     

Melt extrusion with poorly soluble drugs – An integrated review

Over the last few decades, hot melt extrusion (HME) has emerged as a successful technology for a broad spectrum of applications in the pharmaceutical industry. As indicated by multiple publications and patents, HME is mainly used for the enhancement of solubility and bioavailability of poorly soluble drugs. This review is focused on the recent reports on the solubility enhancement via HME and provides an update for the manufacturing/scaling up aspects of melt extrusion. In addition, drug characterization methods and dissolution studies are discussed. The application of process analytical technology (PAT) tools and use of HME as a continuous manufacturing process may shorten the drug development process; as a result, the latter is becoming the most widely utilized technique in the pharmaceutical industry. The advantages, disadvantages, and practical applications of various PAT tools such as near and mid-infrared, ultraviolet/visible, fluorescence, and Raman spectroscopies are summarized, and the characteristics of other techniques are briefly discussed. Overall, this review also provides an outline for the currently marketed products and analyzes the strengths, weaknesses, opportunities and threats of HME application in the pharmaceutical industry.