Interaction between polyethylene films and bromhexine HCl in solid dosage forms. I. Effects of moisture contents in the solid dosage forms on the sorption of the drug

The decrease of bromhexine HCl contents in granules and tablets was determined when the preparations were stored in polyethylene film package. Effects of temperature, contact area with film, excipients and moisture contents in the preparation on the remaining amount of bromhexin HCl were studied in order to investigate the interaction mechanism between bromhexine HCl and polyethylene film. It was observed that the decrease of bromhexine HCl was due to the sorption to the polyethylene film. The results indicated that the moisture contents of the dosage forms determined the rate of sorption predominantly, and that removal of adsorbed water from dosage forms was effective to prevent bromhexine HCl content decrease.     

固体制剂干法包衣工艺的研究进展

目的对近年来国内外固体制剂的非溶剂包衣工艺进行介绍。方法通过查阅文献,综述了目前比较常用的几种包衣方式,包括静电干粉包衣、增塑剂干法包衣、增塑剂静电干粉包衣、热溶包衣、压制包衣和光固化包衣,以及各种包衣工艺的原理、过程与特点。结果干法包衣工艺可以避免水性或有机溶剂的使用。结论干法包衣工艺具有很大潜力,可用于固体制剂包衣的工业化生产。     

速释固体制剂主要辅料的流动性和吸水性测定

目的：了解速释固体制剂所用辅料的流动性和吸水特性，为粉末直接压片方法提供工艺参数。方法：采用粉末基础物性测定仪和吸水装置测定稀释剂的休止角、抹角、稀释剂的流动性指数和崩解剂的吸水速率常数。结果：国产微晶纤维素凝聚现象较强，流动性指数最小；进口微晶纤维素几乎没有凝聚现象，流动性指数最高。交联聚乙烯吡咯烷酮(PVPP XL)的吸水量最小，而吸水速率最快。结论：Avicel PH102微晶纤维素和40～80目乳糖作为主要稀释剂可用于粉末直接压片工艺。PVPP XL是一种优良的超级崩解剂。     

Compatibility study between ketoprofen and pharmaceutical excipients used in solid dosage forms

Thermogravimetry/derivative thermogravimetry (TG/DTG) and differential scanning calorimetry (DSC) techniques were used for assessing the compatibility between ketoprofen (KT) and several excipients as: corn starch, microcrystalline cellulose (PH 101 and PH 102), colloidal silicon dioxide, lactose (monohydrate and anhydre), polyvinylpyrrolidone K30, magnesium stearate and talc, commonly used in the pharmaceutical form.In order to investigate the possible interactions between the components, the thermal curves of KT and each selected excipients were compared with those of their 1:1 (w/w) physical mixtures.For KT, the DSC curves have shown a sharp endothermic peak at 96.8 °C which corresponds to the melting process (literature value: 94-97 °C), respectively the TG curves demonstrated a simple stage of mass loss in the temperature range of 235-400 °C.FT-IR spectroscopy and X-ray powder diffraction (XRPD) were used as complementary techniques to adequately implement and assist in interpretation of the DSC results.On the basis of thermal results, a possible interaction was found between the KT with polyvinylpyrrolidone K30 and magnesium stearate, which could influence the stability of the KT in the binary mixtures. These possible incompatibilities were confirmed by FT-IR and X-ray analysis.     

Compatibility studies between piroxicam and pharmaceutical excipients used in solid dosage forms

Differential scanning calorimetry (DSC) with the support of Fourier transform infrared spectroscopy (FT-IR) was used as a screening technique for testing the compatibility of piroxicam (4-hydroxy-2-methyl-N-(2-pyridyl)-2H-1,2-benzothiazine-3carboxamide-1,1-dioxide) with various pharmaceutical excipients for solid dosage forms. Based on the results, magnesium stearate, stearic acid, and mannitol were found to show interaction with piroxicam. In conclusion, tools of DSC and FT-IR were successfully employed to evaluate the compatibility of piroxicam and selected excipients.     

Physicochemical interactions in solid dosage forms

Complete characterization and mechanistic understanding of physicochemical interactions in solid dosage forms are not only important for consistent manufacturability, stability, and bioavailability of the drug product, but are also expected under the quality-by-design paradigm of drug development. Lack of this understanding can impact successful and timely development, scale-up, and commercial manufacture of dosage forms. This article highlights the stability and bioavailability implications of physicochemical interactions in dosage forms citing a couple of examples where such interactions necessitated the recall of commercial drug products.     

Taste-masking possibilities in solid dosage forms

Increasing number of new, innovative pharmaceutical products are in the generic market. One of the important dosage forms is the group of orally disintegrating products. The feature of these products is that they disintegrate rapidly in the mouth upon contact with the saliva; therefore the dissolution of the water-soluble components begins in the mouth. Since a large part of the drug molecules is characterised by a more or less bitter taste, even a small amount of the dissolved drug can cause an unpleasant taste in the mouth. Manufacturers apply different techniques to mask the bitter taste of these products, depending on the characteristics of the dosage form and the bioavailability requirements. In this study, we reviewed the most widespread taste-masking methods based on the scientific literature and different patents and the characteristics of some important excipients, and outline an instrumental technique used for bitterness measurements.     

Microenvironmental pH modulation in solid dosage forms

There are many reports in the literature referring to the effect of microenvironmental pH on solid dosage form performance, particularly stability and dissolution profiles. Several techniques have been proposed for the measurement of the microenvironmental pH. Those techniques use certain assumptions and approximations and many of them employ a solution calibration curve of a probe to predict hydrogen ion activity in a substantially dry solid. Despite the limitation of the methodology, it is clear from the literature that microenvironmental pH has a significant impact on stability of compounds which demonstrate pH dependent stability in solution. Degradation kinetics of such compounds, and in some cases degradation profile as well, are dependent on the microenvironmental pH of the solid. Modulation of the microenvironmental pH through the use of pH modifiers can hence prove to be a very effective tool in maximizing solid dosage form stability. Judicial selection of the appropriate pH modifier, its concentration and the manufacturing process used to incorporate the pH modifier is necessary to enhance stability. Control of microenvironmental pH to maximize stability can be achieved without the use of pH modifier in some cases if an appropriate counter ion is used to provide an inherently optimal pH for the salt. Microenvironmental pH modulation was also shown to control the dissolution profile of both immediate and controlled release dosage forms of compounds with pH dependent solubility. The pH modifiers have been used in conjunction with high energy or salt forms in immediate release formulations to minimize the precipitation of the less soluble free form during initial dissolution. Additionally, pH modifiers were utilized in controlled release dosage forms of weakly basic drugs which exhibit diminished release in dissolution media with high pH. The incorporation of acidic pH modifiers in the controlled release formulation increases the solubility of the basic drug even as the high pH dissolution medium enters into the dosage form hence increasing drug release rate.     

Analysis of coating structures and interfaces in solid oral dosage forms by three dimensional terahertz pulsed imaging

Three dimensional terahertz pulsed imaging (TPI) was evaluated as a novel tool for the nondestructive characterization of different solid oral dosage forms. The time-domain reflection signal of coherent pulsed light in the far infrared was used to investigate film-coated tablets, sugar-coated tablets, multilayered controlled release tablets, and soft gelatin capsules. It is possible to determine the spatial and statistical distribution of coating thickness in single and multiple coated products using 3D TPI. The measurements are nondestructive even for layers buried underneath other coating structures. The internal structure of coating materials can be analyzed. As the terahertz signal penetrates up to 3 mm into the dosage form interfaces between layers in multilayered tablets can be investigated. In soft gelatin capsules it is possible to measure the thickness of the gelatin layer and to characterize the seal between the gelatin layers for quality control. TPI is a unique approach for the nondestructive characterization and quality control of solid dosage forms. The measurements are fast and fully automated with the potential for much wider application of the technique in the process analytical technology scheme.     

丙烯酸树脂系列辅料在药物新剂型中的应用

本文对丙烯酸树脂系列辅料在缓解微丸，缓释骨架片，固体分散体，微球和微囊，口服结肠定位给药系统及透皮给药系统等药物新剂中的应用进行了综述。认为：随着新型丙烯酸树脂的研究开发，其在药物新剂型的应用更加广泛。     

Gastric acid inactivation of erythromycin stearate in solid dosage forms.

The effect of hydrochloric acid at pH 1.2-3.2 ON ERYTHROMYCIN STEARATE AND COMMERCIAL DOSAGE FORMS OF ERYTHROMYCIN STEARATE WAS STUDIED. Under all conditions examined, erythromycin was readily dissolved from the stearate as hydrochloride, and rapidly lost its biological activity in solution. The inclusion of pepsin in the test systems did not affect the results. Although formulation differences somewhat affected the rate of destruction, acid lability was exhibited by all products examined, except enteric-coated tablets. Amounts of acid considered to be normal in the fasting stomach contents of adults during the time likely for a dose to remain in the stomach caused 70-90% destruction within 15 min after the shells started to rupture. Amounts of hydrochloric acid appreciably less than 1 mEq, representing abnormally small quantities even in the fasting state, caused destruction ranging from 30 to 70% of the doses in 15 min. These results are not reconcilable with published statements that the sensitivity of erythromycin to gastric acid is overcome by providing the antibiotic in the form of stearate salt.     

Stability of dry coated solid dosage forms

The dry coating process was evaluated in terms of storage stability investigating drug release and agglomeration tendency of the different coated oral dosage forms; hydroxypropyl methylcellulose acetate succinate (HPMCAS) was used with triethylcitrate (TEC) as plasticizer and acetylated monoglyceride (Myvacet^®) as wetting agent. Talc or colloidal silicon dioxide (Aerosil^®) was used as anti-tacking agents. In contrast to coating formulations consisting of HPMCAS and Myvacet^® all formulations containing TEC showed enteric resistance and no agglomeration tendency after preparation. After storage at 10% RH?±?5% enteric resistance is increased slightly. This increase is more pronounced at 60% RH?±?5%. The formulations without anti-tacking agents showed higher drug releases after 12 and 24 months due to the damage of the film’s integrity during sample preparation caused by the high tackiness of the film. Tackiness is not affected by storing if samples are stored at low relative humidity. At high relative humidity tackiness increases upon storage especially for formulations without anti-tacking agents. The sieving results of the agglomeration measurements after storage can be confirmed by ring shear measurements performed immediately after preparation and approved to be a tool, which is able to predict the agglomeration during storage.     

Near infrared spectroscopy in the development of solid dosage forms

The use of near infrared (NIR) spectroscopy has rapidly grown partly due to demands of process analytical applications in the pharmaceutical industry. Furthermore, newest regulatory guidelines have advanced the increase of the use of NIR technologies. The non-destructive and non-invasive nature of measurements makes NIR a powerful tool in characterization of pharmaceutical solids. These benefits among others often make NIR advantageous over traditional analytical methods. However, in addition to NIR, a wide variety of other tools are naturally also available for analysis in pharmaceutical development and manufacturing, and those can often be more suitable for a given application. The versatility and rapidness of NIR will ensure its contribution to increased process understanding, better process control and improved quality of drug products. This review concentrates on the use of NIR spectroscopy from a process research perspective and highlights recent applications in the field.     

Imaging and behaviour of solid oral dosage forms in vivo

The kinetics of the hydrolysis of methyl, ethyl and n-propyl 4-hydroxybenzoate esters and a subsequent decarboxylation of 4-hydroxybenzoic acid have been studied at pH 1.26–10.59 and the sterilizing temperature of 130.5°C. Enthalpies (ΔH1) and entropies (ΔS1) of activation are reported for k_obs and the derived rate constants. The decarboxylation reaction showed a maximum rate near the mid-pH region where the esters were more susceptible to hydrolysis. The overall pathway for the degradation of the esters was accounted for by a consecutive reaction sequence:

where A represents ester, B, 4-hydroxybenzoic acid and C, phenol. Interference with the spectrophotometric assay by the subsequent oxidation of phenol, made necessary the exhaustive de-oxygenation of solutions for the kinetic runs where phenol was formed. The esters were found to be sufficiently stable to withstand a heat sterilization process within the pH range 3–6. The rate of phenol formation by decarboxylation of the acid was greater in the pH range where the esters are frequently used commercially, as preservatives.