ABSTRACT
The method of homogeneity evaluation for active pharmaceutical ingredient (API) spatial distribution in lyophilized product was investigated for the first time with confocal micro-Raman spectroscopy mapping, using pemetrexed disodium for injection as a model drug. Certain areas of the lyophilized product were scanned to obtain Raman spectra. The classical method ("peak clipping" method) was employed for mapping with characteristic Raman peaks of the API and the excipient. Due to the API being finely dispersed in the excipient in lyophilized products, the classical method cannot discriminate between the two ingredients making the distribution homogeneity difficult to evaluate. The "ratio of characteristic peak intensities" method was then utilized. Using this method, the relative intensity of the characteristic Raman peaks of the API to the excipient was applied for mapping and the relative content of API to excipient was calculated for a homogeneity evaluation of the drug distribution. The validation of this method showed a good linear relationship between the relative intensity and the relative content of API to excipient (r2 > 0.99), and the precision and recovery were adequate for homogeneity evaluation of API by Raman spectroscopy mapping. Five products of pemetrexed disodium for injection from different manufacturers were tested through Raman maps applying this method and the histograms of relative Raman intensity were also plotted by frequency to help the homogeneity evaluation of drug distribution. The results showed that there were obvious differences in the drug distribution homogeneity from different products, where a more homogeneous API distribution was found in the brand product. This research provides a reliable method for the homogeneity evaluation of API distribution, which facilitates quality evaluation and process optimization of lyophilized products.
ABSTRACT
Pulmonary administration route has been extensively exploited for the treatment of local lung diseases such as asthma, chronic obstructive pulmonary diseases and respiratory infections, and systemic diseases such as diabetes. Most inhaled medicines could be cleared rapidly from the lungs and their therapeutic effects are transit. The inhaled medicines with extended pulmonary exposure may not only improve the patient compliance by reducing the frequency of drug administration, but also enhance the clinical benefits to the patients with improved therapeutic outcomes. This article systematically reviews the physical and chemical strategies to extend the pulmonary exposure of the inhaled medicines. It starts with an introduction of various physiological and pathophysiological barriers for designing inhaled medicines with extended lung exposure, which is followed by recent advances in various strategies to overcome these barriers. Finally, the applications of the inhaled medicines with extended lung exposure for the treatment of various diseases and the safety concerns associated to various strategies to extend the pulmonary exposure of the inhaled medicines are summarized.
ABSTRACT
The determination and characterization of solid drug form polymorphisms plays an important role in drug quality control, selection of the production process and clinical efficacy evaluation. Vibrational spectroscopy is a powerful method for the characterization of drug polymorphisms. In this paper we review recent research and application advances in the polymorphic characterization of active pharmaceutical ingredients (APIs) and drug cocrystals/salts by using Fourier transform infrared (FTIR) and Raman spectroscopy to elucidate the characteristics of APIs and drug complexes. This may provide theoretical support for structural analysis during the development process for drugs.
ABSTRACT
Drug-drug complexes play important roles in improving the physicochemical properties of drugs including the solubility, dissolution rate and stability of the active pharmaceutical ingredients (APIs). In this paper, the design, synthesis, characterization, changes in physicochemical and pharmacologic properties, structural polymorphisms and the research and development pipelines of a variety of drug-drug cocrystals/salts synthesized based on the crystal engineering design are reviewed. This may provide theoretical support for the development of the new solid-state combinational drugs.
ABSTRACT
We have developed a new method using HPLC-CAD (charged aerosol detector) for the quantitative analysis of cyclovirobuxine D and related substances in the API of Huangyangning tablets. The related substances were further studied by HPLC-Q-Exactive coupled with hybrid quadrupole-orbitrap mass spectrometry. A HILIC column of XBridge Amide (4.6 mm×250 mm, 5 μm) was used, and the mobile phase was composed of acetonitrile and 100 mmol·L-1 ammonium formate (85∶15), which was adjusted to pH 2.8 with formic acid. Isocratic mode elution was adopted at a flow rate of 1.1 mL·min-1. The column temperature was set at 30 ℃. For CAD, the temperature of atomization and gas pressure were respectively set at 35 ℃ and 62.2 psi. This method detected and quantified five related substances to cyclovirobuxine D. The results showed that the LOD and LOQ of cyclovirobuxine D was 12.588 ng and 28.323 ng, respectively with an average recovery of 95.74% (RSD = 1.79%, n = 6). The content of cyclovirobuxine D in 12 batches of API samples provided by three manufacturers was from 79.94% to 88.49%, with an average value of 82.20%. The total content of the five related substances was from 15.99% to 22.15% with an average value of 20.10%, using an external standard method with cyclovirobuxine D as the reference and according to the CAD uniform response to non-volatile substances. The newly developed HPLC-CAD method has advantages in terms of the comprehensiveness of signals from Buxus alkaloids without UV absorption and with high sensitivity to its trace-related substances; the method yields good separation between the components and is compatible with mass spectrometry. It is applicable for the accurate quantitative analysis of main components and related substances in the API of Huangyangning tablets.
ABSTRACT
Ionic liquids are not limited to the traditional use of solvents because of their high permeability and excellent physicochemical and unique biological properties. Nowadays, with the deep understanding of their toxicity and biocompatibility, ionic liquids have been tailored as novel solutions to address potential problems of marketed drugs. Based on the research and development of modified new drugs, ionic liquids have been incorporated into drug synthesis and emerged as attractive environmental-friendly reaction media with milder reaction conditions, higher yields and easier reaction workups and drug delivery systems. In addition, they have been designed for effective drug carriers removing undesirable properties of solid drugs. Further, ionic liquids forming active pharmaceutical ingredients dedicated to the liquefaction of drugs for promising clinical applications.
ABSTRACT
In recent years, the coamorphous drug delivery system has been established as a promising formulation approach for delivering poorly water-soluble drugs. The coamorphous solid is a single-phase system containing an active pharmaceutical ingredient (API) and other low molecular weight molecules that might be pharmacologically relevant APIs or excipients. These formulations exhibit considerable advantages over neat crystalline or amorphous material, including improved physical stability, dissolution profiles, and potentially enhanced therapeutic efficacy. This review provides a comprehensive overview of coamorphous drug delivery systems from the perspectives of preparation, physicochemical characteristics, physical stability, and performance. Furthermore, the challenges and strategies in developing robust coamorphous drug products of high quality and performance are briefly discussed.
ABSTRACT
Pharmaceutical cocrystals are a promising technology that can be used to improve the solubility of poor aqueous compounds. The objective of this study was to systematically investigate the solubility of myricetin (MYR) cocrystals, including their kinetic solubility, thermodynamic solubility, and intrinsic dissolution rate (IDR). The effects of pH, surfactant, ion concentration, and coformers on the cocrystal solubility were evaluated. Furthermore, single crystal structures of MYR, myricetin-isonicotinamide (MYR-INM) and myricetin-caffeine (MYR-CAF) cocrystals were analyzed to discuss the possible reasons for the enhancement of cocrystal solubility from the perspective of the spatial structure. The results indicated that the kinetic solubility of MYR cocrystals was modulated by pH and cocrystal coformer (CCF) ionization in buffer solution, while it primarily depended on the CCF solubility in pure water. In addition, the solubility of MYR cocrystals was increased in a concentration dependent fashion by the surfactant or ion concentration. The thermodynamic solubility of MYR-INM (1:3) cocrystals decreased with the increases of the pH value of the dissolution media. The IDR of MYR cocrystals was faster than that of MYR in the same medium and extremely fast in pH 4.5 buffer. The improved solubility of MYR cocrystals was probably related to the alternate arrangements of MYR and INM/CAF molecules and increased intermolecular distance. The present study provides some references to investigate the solubility behavior of pharmaceutical cocrystals.
ABSTRACT
To establish a HPLC-MS/MS method for simultaneous determination and active ingredients screening of pseudoginsenoside RT5, 20(S)-ginsenoside Rh1 and 20(S)-ginsenoside Rh2 by cell membrane chromatography (CMC) in secondary ginsenoside H dripping pills (SGHDP). Methods The samples were separated on Century SIL BDS C18 column (250 mm × 4.6 mm, 5 μm) eluted with 0.2% formic acid aqueous solution-acetonitrile in a gradient mode, and the target compounds were analyzed by positive ion multiple reaction monitoring (MRM) mode, and active ingredients of SGHDP obtained in solid-phase of biomembrane by CMC technology were determined at the same time. Results The linear ranges of pseudoginsenoside RT5, 20(S)-ginsenoside Rh1, and 20(S)-ginsenoside Rh2 were 0.095-0.235, 0.042-0.168, and 0.105-0.419 mg/mL; the extraction recoveries were 99.95%, 100.12%, and 100.06%; and RSD were 1.06%, 0.96%, and 0.91%, respectively. The contents of pseudoginsenoside RT5, 20(S)-ginsenoside Rh1, and 20(S)-ginsenoside Rh2 in SGHDP were 21.24%, 21.42%, and 29.70%, respectively. 20(S)-Ginsenoside Rh2 was the active ingredient obtained by biomembrane using as a new quality control maker for SGHDP. Conclusion The developed method is accurate and reliable for the determination of three ginsenosides in SGHDP, and provides a new reference for quality control of SGHDP. 20(S)-Ginsenoside Rh2 is a immobilization component of red cell membrane, speculated to be the active ingredient of SGHDP, which is in consistent with previous studies on antitumor and antidepression.
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Oral drug absorption is a process influenced by the physicochemical and biopharmaceutical properties of the drug and its inter-relationship with the gastrointestinal tract. Drug solubility, dissolution and permeability across intestinal barrier are the key parameters controlling absorption. This review provides an overview of the factors that affect drug absorption and the classification of a drug on the basis of solubility and permeability. The biopharmaceutical classification system (BCS) was introduced in early 90׳s and is a regulatory tool used to predict bioavailability problems associated with a new entity, thereby helping in the development of a drug product. Strategies to combat solubility and permeability issues are also discussed.
ABSTRACT
Dry powder inhalers (DPIs) offer distinct advantages as a means of pulmonary drug delivery and have attracted much attention in the field of pharmaceutical science. DPIs commonly contain micronized drug particles which, because of their cohesiveness and strong propensity to aggregate, have poor aerosolization performance. Thus carriers with a larger particle size are added to address this problem. However, the performance of DPIs is profoundly influenced by the physical properties of the carrier, particularly their particle size, morphology/shape and surface roughness. Because these factors are interdependent, it is difficult to completely understand how they individually influence DPI performance. The purpose of this review is to summarize and illuminate how these factors affect drug-carrier interaction and influence the performance of DPIs.
ABSTRACT
A rapid detection method of active pharmaceutical ingredients( API) in weak API signal drugs by surface enhanced Raman scattering ( SERS) technology combined with paper substrate was established in this work. By soaking the filter paper in silver nanoparticles solution ( Ag NPs) to synthesize Ag NPs-paper as the substrate, and then the sample solution was dropping on the substrate with SERS detection. On the basis of strengthen ability of Ag NPs-paper, result of SERS detection and optimal preparation conditions, the fast identification method of weak API signal drugs was established. In this case, the SERS spectra of weak API signal drugs and their standards SERS spectra were obtained, where the correlation coefficient of weak API signal drug SERS spectra and its standard was more than 0. 9. The result showed that by this method, the low content API in weak API signal drugs could be well investigated, and the deficiencies of the normal Raman spectroscopy efficiently was also overcome. In conclusion, the synthesize method of Ag NPs-paper was simple, and the strengthen effect of this Ag NPs-paper on the intensity was obviously observed. Paper substrate-SERS method was simple, rapid and sensitive, and could be used to detect weak API signal drugs, presenting broad application prospects in the rapid detection of weak API signal drugs.
ABSTRACT
A Fourier transform infrared derivative spectroscopy (FTIR-DS) method has been developed for determining furosemide (FUR) in pharmaceutical solid dosage form. The method involves the extraction of FUR from tablets with N,N-dimethylformamide by sonication and direct measurement in liquid phase mode using a reduced path length cell. In general, the spectra were measured in transmission mode and the equipment was configured to collect a spectrum at 4 cm(-1) resolution and a 13 s collection time (10 scans co-added). The spectra were collected between 1400 cm(-1) and 450 cm(-1). Derivative spectroscopy was used for data processing and quantitative measurement using the peak area of the second order spectrum of the major spectral band found at 1165 cm(-1) (SO2 stretching of FUR) with baseline correction. The method fulfilled most validation requirements in the 2 mg/mL and 20 mg/mL range, with a 0.9998 coefficient of determination obtained by simple calibration model, and a general coefficient of variation <2%. The mean recovery for the proposed assay method resulted within the (100±3)% over the 80%-120% range of the target concentration. The results agree with a pharmacopoeial method and, therefore, could be considered interchangeable.
ABSTRACT
A high performance liquid chromatographic (HPLC) method for the analysis of ketorolac tromethamine and its associated impurities was examined with the aim of reducing analysis times while maintaining good efficiency. The separation was carried out using a waters X-bridge – C8 (3mm x75mm, 2.5μm particle size) column with a mobile phase of tetrahydrofuran – ammonium dihydrogen phosphate (0.05M, pH3, 28:72 v/v) at a flow rate of 1.7mL/min and UV detection at 313nm. The method was validated according to ICH (international conference on harmonisation) guidelines with respect to precision, accuracy, linearity, specificity, robustness and limits of detection and quantification. All parameters examined were found to be well within the stated guidelines. Naturally aged samples were also tested to determine sample stability. A profile of sample and impurity breakdown was presented. A three-fold reduction in analysis time was achieved in comparison with the current approved EP (european pharmacopeia) method and the method can be immediately used for routine assay and related substance determination.
ABSTRACT
OBJECTIVE: To compare the stability between imported branded and domestic entecavir active pharmaceutical ingredient(API) and among four Entecavir products (A for the original brand product and B-D for the domestic generic agents) and to provide references for clinical use. METHODS: The influencing factor tests and accelerated tests of the API and the four products were carried out. The stability of the imported and domestic API was studied. The stability of the product was studied by comparing the appearance, weight of tablets, API content, related substance and dissolution. RESULTS: The influence of illumination on the stability was the least, while high temperature and high humidity had the most significant influence. In the accelerated tests, product A was the most stable one while products B-D changed with varying degrees, which showed up in appearance, the API content, the related substances and the dissolution. CONCLUSION: The stability of the API from different sources appeared to be similar, while that of the four products showed differences. The stability of the original product was noticeably superior to the domestic generic agents. Copyright 2012 by the Chinese Pharmaceutical Association.
ABSTRACT
The objective of the study was to develop UPLC method for the determination of purity of Cefditoren Pivoxil in API and its validation. UPLC is a better technique than HPLC in terms of performance and speed, so it was selected. The method was developed using Acetonitrile and Ammonium Acetate buffer (pH 6.7) and Kromacil column C18 (50×2.1mm, 3.5μ) as a stationary phase at a flow rate of 0.25ml/min. Validation was done by linearity, precision, and robustness studies. The precision was found to be within the limits. The linearity studies indicated the drug obeys Beer’s law and revealed the specified range of linearity for drug was between 80μg/ml and 120μg/ml. The robustness was observed from the insignificant variation in the analysis by changes in flow rate, mobile phase ratio, wavelength, column oven temperature and pH. Forced Degradation study revealed the drug degraded initially by the influence of acid, alkali, and peroxide. Solution stability study showed the drug was not stable for more than 2 h at 25˚C but stable at 5˚C. It can be concluded that the proposed method was simple, precise, and robust and can be useful for determination of purity of Cefditoren Pivoxil in API by using UPLC.
ABSTRACT
There are a number of challenges during tablet dosage form development like excipient selection, poor powder flow, poor tableting, lack of hardness, high friability, elevated disintegration time, low dissolution rate etc. Most of them are significantly influenced by the mechanical properties (like elasticity, plasticity, brittleness, powder compressibility, tensile strength, etc.) of the active pharmaceutical ingredient (API). Assessment of these properties of the pure actives is not always easy. Absence of lubrication may induce a lot of friction, causing capping, lamination or sticking or in many cases, combination of them, damaging the test tablet when taken out. Different approaches were studied to overcome this problem and a solution was found by compaction of a tablet of Sodium Starch Glycolate-Magnesium Stearate in a ratio of 2.75:1 before compressing each tablet of pure API.