Control of the Iron State in Pharmaceuticals Used for Treatment and Prevention of Iron Deficiency Using Mössbauer Spectroscopy.

Various iron-containing medicaments, vitamins and dietary supplements are used or developed for treatment and prevention of the iron deficiency anemia which is very dangerous for human and may cause various disorders. From the other hand, blood losses, iron poor diet, microelements (co-factors) deficiency, metabolic failures, absorption problems, etc. can change the iron status and affect the health. These pharmaceuticals contain iron compounds in the ferrous and ferric states. It is known that ferrous salts are more suitable for the intestinal intake than ferric ones. On the other hand, pharmaceutically important ferritin analogues contain ferric hydrous oxides and appear to be effective for both injections and peroral administration. 57Fe Mössbauer spectroscopy is a unique physical technique which allows one to study various iron-containing materials including pharmaceuticals. Therefore, this technique was applied to study iron-containing pharmaceuticals for the analysis of the iron state, identification of ferric and ferrous compounds, revealing some structural peculiarities and for detection of aging processes in relation to the iron compounds. This review considers the main results of a long experience in the study of iron-containing pharmaceuticals by Mössbauer spectroscopy with critical analysis that may be useful for pharmacists, biochemists, biophysicists, and physicians.

A Rational Hierarchy to Capture Raw Material Attribute Variability in the Pharmaceutical Drug Product Development and Manufacturing Lifecycle.

Assessing the robustness of a drug product formulation and manufacturing process to variations in raw material (RM) properties is an essential aspect of pharmaceutical product development. Motivated by the need to demonstrate understanding of attribute-performance relationships at the time of new product registration and for subsequent process maintenance, we review practices to explore RM variations. We describe limitations that can arise when active ingredients and excipients invariably undergo changes during a drug product lifecycle. Historical approaches, such as Quality-by-Design (QbD) experiments, are useful for initial evaluations but can be inefficient and cumbersome to maintain once commercial manufacturing commences. The relatively miniscule data sets accessible in product development - used to predict response to a hypothetical risk of variation - become less relevant as real-world experience of actual variability in the commercial landscape grows. Based on our observations of development and manufacturing, we instead propose a holistic framework exploiting a hierarchy of RM variability, and challenge this with common failure modes. By explicitly incorporating higher ranking RM variations as perturbations, material-conserving experiments are shown to provide powerful and enduring robustness data. Case studies illustrate how correctly contextualizing such data in formulation and process development can avoid the traps of historical QbD approaches and become valuable for evaluating changes occurring later in the drug product lifecycle.

[Research progress and maturity assessment of continuous manufacturing of traditional Chinese medicine].

The pharmaceutical manufacturing model is gradually changing from intermittent manufacturing to continuous manufacturing and intelligent manufacturing. This paper briefly reviewed the supervision and research progress in continuous pharmaceutical manufacturing in China and abroad and described the definition and advantages of continuous pharmaceutical manufacturing. The continuous manufacturing of traditional Chinese medicine(TCM) at the current stage was summarized in the following three terms: the enhancement of the continuity of intermittent manufacturing operations, the integration of continuous equipment to improve physical continuity between units, and the application of advanced process control strategies to improve process continuity. To achieve continuous manufacturing of TCM, the corresponding key technologies, such as material property characterization, process modeling and simulation, process analysis technology, and system integration, were analyzed from the process and equipment, respectively. It was proposed that the continuous manufacturing equipment system should have the characteristics of high speed, high response, and high reliability, "three high(H~3)" for short. Considering the characteristics and current situation of TCM manufacturing, based on the two dimensions of product quality control and production efficiency, a maturity assessment model for continuous manufacturing of TCM, consisting of operation continuity, equipment continuity, process continuity, and quality control continuity, was proposed to provide references for the application of continuous manufacturing technology for TCM. The implementation of continuous manufacturing or the application of key continuous manufacturing technologies in TCM can help to systematically integrate advanced pharmaceutical technology elements and promote the uniformity of TCM quality and the improvement of production efficiency.

Research progress and maturity assessment of continuous manufacturing of traditional Chinese medicine / 中国中药杂志

The pharmaceutical manufacturing model is gradually changing from intermittent manufacturing to continuous manufacturing and intelligent manufacturing. This paper briefly reviewed the supervision and research progress in continuous pharmaceutical manufacturing in China and abroad and described the definition and advantages of continuous pharmaceutical manufacturing. The continuous manufacturing of traditional Chinese medicine(TCM) at the current stage was summarized in the following three terms: the enhancement of the continuity of intermittent manufacturing operations, the integration of continuous equipment to improve physical continuity between units, and the application of advanced process control strategies to improve process continuity. To achieve continuous manufacturing of TCM, the corresponding key technologies, such as material property characterization, process modeling and simulation, process analysis technology, and system integration, were analyzed from the process and equipment, respectively. It was proposed that the continuous manufacturing equipment system should have the characteristics of high speed, high response, and high reliability, "three high(H~3)" for short. Considering the characteristics and current situation of TCM manufacturing, based on the two dimensions of product quality control and production efficiency, a maturity assessment model for continuous manufacturing of TCM, consisting of operation continuity, equipment continuity, process continuity, and quality control continuity, was proposed to provide references for the application of continuous manufacturing technology for TCM. The implementation of continuous manufacturing or the application of key continuous manufacturing technologies in TCM can help to systematically integrate advanced pharmaceutical technology elements and promote the uniformity of TCM quality and the improvement of production efficiency.

[Research on batch-to-batch quality control of compound Danshen extract based on physical characterization and multivariate statistical analysis].

Physical attributes of Chinese herbal extracts are determined by their chemical components, and the physical and chemical attributes jointly affect the preparation process performance and the final product quality. Therefore, in order to improve the quality control of Chinese herbal extracts, we should comprehensively study the batch-to-batch consistency of physical and chemical attributes as well as the correlations between them. This paper first explored the physical attributes affecting the preparation process performance of the compound Danshen extract and developed a method for characterizing the texture attributes. With such main chemical components as water, phenolic acids, saponins, and saccharides and texture, rheology, and other physical attributes taken into consideration, the batch-to-batch quality fluctuation of products from different production lines and time was analyzed by principal components analysis(PCA). Finally, the correlation and partial least squares(PLS) analysis was conducted, and the regression equation was established. The fitting result of the PLS model for dynamic viscosity was satisfying(R~2Y=0.857, Q~2=0.793), suggesting that the chemical components could be adjusted by the component transfer rate in the extraction process, the impurity removal rate in the alcohol precipitation process, and the water retention rate of the concentration process to meet the control of the extract dynamic viscosity. This study clarified the correlations between physical and chemical attributes of the compound Danshen extract and established a method for controlling its physical attributes based on process regulation, which would provide reference for improving the quality control of Chinese herbal extracts.

Isolation, characterization and in vitro antioxidant activity screening of pure compound from black pepper (Piper nigrum).

The present study's aims of isolation, characterization and in vitro antioxidant activity screening of pure compound from Black pepper (Piper nigrum) were investigated. Nowadays, scientific exploration of medicinal plants from natural sources has become the prime concern globally. All the crude drugs that have been isolated from natural plant origin (herbs, root, stem, bark, fruit and flower) have great significance in drug discovery as well as a lead compound to demonstrate great synergistic effect on pharmacology. For this research work, methanol was selected as a mother solvent, and the crude methanolic extract of black pepper was partitioned in between the solvent chloroform and di-ethyl-ether. A crystal fraction has been eradicated from the chloroform extract of black pepper (Piper nigrum). The crystal compound (C1) was isolated and purified by using thin layer chromatography (TLC) and recrystallization technique. The purified crystal compound (C1) isolated from black pepper possesses a strong in vitro antioxidant activity. The IC50 value of crystal compound (C1) was 4.1 µg/ml where the standard one had 3.2 µg/ml. Physical, phytochemical and chromatographical characterization of pure crystal compound (C1) has been explored, and from the analysis of all characteristics, it was found that, crystal compound (C1) might have resembling features of the standard Piperine of black pepper. The overall research work was really remarkable and introduced a convenient way of isolating pure compound from the natural source which will be a great referential resource in isolating crude drugs for future analysis.

Research on batch-to-batch quality control of compound Danshen extract based on physical characterization and multivariate statistical analysis / 中国中药杂志

Physical attributes of Chinese herbal extracts are determined by their chemical components, and the physical and chemical attributes jointly affect the preparation process performance and the final product quality. Therefore, in order to improve the quality control of Chinese herbal extracts, we should comprehensively study the batch-to-batch consistency of physical and chemical attributes as well as the correlations between them. This paper first explored the physical attributes affecting the preparation process performance of the compound Danshen extract and developed a method for characterizing the texture attributes. With such main chemical components as water, phenolic acids, saponins, and saccharides and texture, rheology, and other physical attributes taken into consideration, the batch-to-batch quality fluctuation of products from different production lines and time was analyzed by principal components analysis(PCA). Finally, the correlation and partial least squares(PLS) analysis was conducted, and the regression equation was established. The fitting result of the PLS model for dynamic viscosity was satisfying(R~2Y=0.857, Q~2=0.793), suggesting that the chemical components could be adjusted by the component transfer rate in the extraction process, the impurity removal rate in the alcohol precipitation process, and the water retention rate of the concentration process to meet the control of the extract dynamic viscosity. This study clarified the correlations between physical and chemical attributes of the compound Danshen extract and established a method for controlling its physical attributes based on process regulation, which would provide reference for improving the quality control of Chinese herbal extracts.

Spray Drying in Research of Traditional Chinese Medicine Powders： A Review / 中国实验方剂学杂志

After more than 100 years of development， spray drying technology has become more mature and widely used， and it is of great importance in the field of traditional Chinese medicine （TCM）. TCM powders prepared by spray drying is the raw material of dispensing granules， and the powder properties have an important influence on subsequent molding process and product quality. As a new form of TCM， dispensing granules have been included in the management category of TCM decoction pieces， indicating a broader application market， and a consensus has also been reached on the importance of TCM powder research. Based on this， the author summarized the application progress of spray drying in the study of TCM powders， including the factors affecting spray drying process， such as liquid properties， process parameters and equipment factors， as well as the application of computational fluid dynamics （CFD） and thermodynamic model in spray drying process simulation. Moreover， some commonly used pharmaceutical excipients for the modification of TCM powders were also introduced such as maltodextrin， microcrystalline cellulose and povidone. In addition， spray drying technology can also be used as a preparation technology for new drug delivery systems such as microcapsules and solid dispersions. Through the summary of this paper， the author suggests that the future research direction of spray drying of TCM can be carried out from the aspects of application rule of the coprocessing auxiliary materials based on the "unification of medicines and excipients"， the "structure-property" relationship of spray-dried powders and the application of computer simulation and design， so as to further enrich the application of spray drying in the field of TCM powders.

[Mechanism of "unification of drugs and excipients" for Chinese medicine semi-extract based on powder compression behavior analysis].

In this paper, five representative Chinese herbal decoction pieces of Scutellariae Radix, Paeoniae Radix Alba, vinegar-processed Corydalis Rhizoma, Polygoni Multiflori Radix Praeparata and Lonicerae Japonicae Flos were selected to prepare the corresponding fine powder of pieces, extract powder, semi-extract powder and physical mixed powder. The physical properties of 20 kinds of powders, such as related parameters of particle size, density, stability and flowability, were evaluated comprehensively. The compression curves of powder porosity and tensile strength changing with pressure were plotted, and the Heckel equation and the Kawakita equation were used to describe the powder compression behavior. The results showed that compared with the fine powder of pieces, the compressibility of the semi-extract powder and the extract powder was significantly improved. Compared with the extract powder, the particle size and relative uniformity of the semi-extract powder were increased, indicating that the uniformity of the powder was improved. Besides, the semi-extract powder could reduce the hygroscopicity of the powder. Particularly, the semi-extract powder of Scutellariae Radix, Paeoniae Radix Alba and vinegar-processed Corydalis Rhizoma could maintain the porous structure of the tablet even under a high tableting pressure, which was beneficial to tablet disintegration. For some traditional Chinese medicines(such as Lonicerae Japonicae Flos), the semi-extract powder could reduce the viscosity, which avoided the sticking in the die compression. The semi-extract powder and the physical mixture powder prepared by the same Chinese herbal decoction pieces had similar physical properties and compression behaviors. Principal component analysis(PCA) was carried out on the 17 physical attributes and 5 compression parameters of the powder. It was found that the first principal component mainly reflected the differences among the material sources, while the second principal component could reflect the differences among fine powder of pieces, extract powder, semi-extract powder and physical mixed powder originating from the same Chinese herbal decoction pieces. In this paper, the mechanism of "unification of drugs and excipients" of Chinese medicine semi-extract powder was explained in terms of physical properties and compression behavior of powders, which provided reference for the formulation design and process development of Chinese medicine tablets.

Detection and Sizing of Submicron Particles in Biologics With Interferometric Scattering Microscopy.

We demonstrate the application of interferometric scattering microscopy (IFS) for characterizing submicron particles in stir-stressed monoclonal antibody. IFS uses a layered silicon sensor and modified optical microscope to rapidly visualize and determine the particle size distribution (PSD) of submicron particles based on their scattering intensity, which is directly proportional to particle mass. Limits for particle size and optimal solution concentration were established for IFS characterization of submicron particles. We critically compare IFS data with dynamic light scattering (DLS) and nanoparticle tracking analysis (NTA) and find IFS is superior to NTA and DLS for determining the realistic shape of the number-based PSD, whereas NTA and DLS provide superior information about absolute particle size. Together, IFS, NTA, and DLS provide complementary information on submicron particles and enable quantitative characterization of the PSD of submicron aggregates. Finally, we explore quantifying particle size with IFS by developing a calibration curve for particle scattering intensity based on correlative scanning electron microscopy imaging. We found that only a subset of isotropic-shaped particles followed the expected proportionality between IFS intensity and particle mass. Overall, this study demonstrates IFS is a simple approach for detecting and quantifying submicron aggregate PSD in protein-based therapeutics.

Quantitative X-Ray Microcomputed Tomography Assessment of Internal Tablet Defects.

Physical tablet defects are related to internal structural defects that are not easily assessed by the traditional methods, such as dusting, laminating, or fracturing during appearance, friability, or hardness testing. Also, these methods do not allow objective and quantitative investigation of the role of formulation and process variables, which is essential for quality-by-design drug product development. In this study, an X-ray microcomputed tomography (XµCT) method to analyze internal tablet defects is developed using tablets from a quality-by-design design-of-experiment study. The design of experiment investigated the effect of roller compaction roll force, filler composition, and the amount of magnesium stearate on tablet quality attributes. Average contiguous void volume by optical image processing and fracture size distribution and direction by artificial intelligence-based image processing quantified the internal tablet fracture severity. XµCT increased formulation and process knowledge in support of scale-up manufacturing. We demonstrated how XµCT can be incorporated as a part of a holistic approach to quantitatively identify and mechanistically assess the risks of internal tablet defects. Furthermore, expanding the use of XµCT with an artificial intelligence-based quantitative analysis can deepen our tableting knowledge from an empirical understanding to a mechanistic understanding of compaction phenomenon.

Physical and Biochemical Characterization of Chemically Treated Pollen Shells for Potential Use in Oral Delivery of Therapeutics.

Allergen-free pollen shells obtained from natural pollen grains have recently attracted attention as microcapsules for oral therapeutic delivery. We have recently developed a chemical treatment method that enables successful retrieval of hollow pollen shells from diverse species. A comprehensive characterization is critical to characterize the effects of chemical treatment which will not only benchmark the pollen treatment process but can also lay the foundation of quality control procedures to check allergen-removal efficiency during pollen treatment. Therefore, in this study, we followed the effects of chemical treatment on 4 different pollen species using electron microscopy, elemental analysis, gel electrophoresis, confocal microscopy, Fourier-transform infrared spectroscopy, and thermogravimetric analysis. These analyses revealed that acetone treatment removed lipids from the pollen surface. Phosphoric acid treatment removed proteins and nucleic acids from the pollen core and transformed esters into carboxylic acids. Potassium hydroxide hydrolysis changed carbohydrate composition of the pollen wall. Chemically treated pollen shells exhibited hydroxyl and carboxyl functional groups on their surface. Overall, we propose that confocal microscopy could be used as a rapid scanning technique to visualize the removal of biomolecules, whereas Fourier-transform infrared combined with gel electrophoresis could be used as a more objective approach for analysis and benchmarking.

Comprehensive Evaluation of Powdered Chinese Herbal Medicines-An Exemplification of Isatidis Radix / 中草药·英文版

Objective Currently, powdered Chinese herbal medicines (CHMs) were mainly evaluated through physical property, chemical dissolution, and bioactivity independently. It could not reflect the quality comprehensively. This paper was to explore and establish a comprehensive evaluation method for powdered CHMs. Methods Isatidis Radix was chosen as an exemple. Firstly, powdered Isatidis Radix in different particle size was prepared. Then, their physical properties were characterized. The dissolution of index component epigoitrin was determined, and their antiviral activities were evaluated by neuraminidase-based bioassay. Results As the particle size decreased, powder distribution tended to be uniform, and the dissolution of epigoitrin increased, antiviral activity enhanced. According to cluster analysis of above results, the sequence of evaluation consequence was ultrafine powder S2 (D90: 32.80 ± 0.29) > ultrafine powder S1 (D90: 52.08 ± 0.53) > fine powder S0 (D90: 118.16 ± 0.76) (from the superior to the inferior). Conclusion Overall, the comprehensive evaluation for powdered CHMs based on the physical characterization, chemical dissolution, and bioassay could not only be used to evaluate powdered herbs, but also guide the screening and optimization of the particle size of powder.

Physical, antioxidant and structural characterization of blend films based on hsian-tsao gum (HG) and casein (CAS).

The effects of hsian-tsao gum (HG) addition on the physical properties, antioxidant activities and structure of casein (CAS) film have been investigated. It has been observed that HG addition provided CAS film with better mechanical properties and resistant to moisture, stronger barrier properties against light and higher antioxidant activities than pure CAS film. Fourier transformation infrared (FTIR) data indicated that hydrogen bonding interactions and Maillard reactions occurred between CAS and HG, giving rise to a more compact structure than CAS film. The results of X-ray diffraction and differential scanning calorimetry (DSC) indicated that CAS and HG were compatible, and addition of HG destroyed the original crystalline domains of CAS film, and the blend films exhibited higher glass transition temperatures than CAS film. Moreover, nuclear magnetic resonance (NMR) analysis showed that HG addition significantly changed the mobility of water molecule in CAS film. Especially, ratio of the high mobility water of CAS/HG films significantly decreased as compared to CAS film.

Investigation of the Sedimentation Behavior of Aluminum Phosphate: Influence of pH, Ionic Strength, and Model Antigens.

Evaluation of the physical characteristics of vaccines formulated in the presence of adjuvants, such as aluminum salts (Alum), is an important step in the development of vaccines. Depending on the formulation conditions and the associated electrostatic interactions of the adjuvant particles, the vaccine suspension may transition between flocculated and deflocculated states. The impact of practical formulation parameters, including pH, ionic strength, and the presence of model antigens, has been correlated to the sedimentation behavior of aluminum phosphate suspensions. A novel approach for the characterization of suspension properties of Alum has been developed to predict the flocculated state of the system using a sedimentation analysis-based tool (Turbiscan®). Two sedimentation parameters, the settling onset time (Sonset) and the sedimentation volume ratio (SVR) can be determined simultaneously in a single measurement. The results demonstrate the suspension characteristics to be significantly altered by solution conditions (pH and ionic strength) and the charge state of bound antigens. Formulation conditions that promote the flocculated state of the suspension are characterized by faster Sonset and higher SVR, and are generally easy to resuspend. The Turbiscan® method described herein is a useful tool for the characterization of aluminum-containing suspensions and may be adapted for screening and optimization of suspension-based vaccine formulations in general.

Excipient variability and its impact on dosage form functionality.

Pharmaceutical excipients are essential components of most modern dosage forms. Although defined as pharmacologically inert, excipients can be thought of as the true enablers of drug product performance. Unintentional variability in the properties of the excipients may be unavoidable, albeit minimizable. The variability may originate from the source, the excipient-manufacturing process, or during the manufacturing of dosage forms. Excipient variability may have a range of influences on their functionality and performance in the dosage form. A better understanding of these influences on the critical quality attributes of the final product is of prime importance. Modern analytical tools provide a significant assistance in characterizing excipient variability to achieve this understanding. The principles and concepts of Quality-by-Design, process analytical technology, and design space, provide a holistic risk-based approach toward manufacture and application of excipients in pharmaceutical formulations. The International Pharmaceutical Excipients Council (IPEC) has developed guidelines for proper selection, use, and evaluation of excipients in pharmaceutical products.

Shear effects on aluminum phosphate adjuvant particle properties in vaccine drug products.

Adjuvant-containing drug products can be exposed to high levels of interfacial shear during manufacture. This may affect the integrity of the adjuvant, alter its interaction with the drug substance or change the physical characteristics of the drug product. In this study, a solid-liquid interfacial shear device was used to investigate the shear response of aluminum phosphate adjuvant alone and two adjuvant containing vaccine drug products (DP1 and DP2). The relationship between the shear sensitivity of each and its resuspension properties was determined. Changes in the particle dimensions of the bulk adjuvant were minimal at shear strain rates of 10,900 s(-1) . However, at 25,500 s(-1) , the median particle diameter was reduced from 6.2 to 3.5 µm and was marked by the presence of sub-micron fines. A formulation without drug substance and DP2 produced similar shear responses but with less impact on particle diameter. The behavior of DP1 was less predictable. Sheared DP1 was characterized by prolonged sedimentation because of the presence of fine particulates and required in excess of 300 rotations to resuspend after extended storage. The study confirms that the solid-liquid interfacial shear device may be applied to understand product shear sensitivity associated with vaccine manufacturing.

Enhanced mucosal immune responses against tetanus toxoid using novel delivery system comprised of chitosan-functionalized gold nanoparticles and botanical adjuvant: characterization, immunogenicity, and stability assessment.

Approaches based on combined use of delivery systems and adjuvants are being favored to maximize efficient mucosal delivery of antigens. Here, we describe a novel delivery system comprised of chitosan-functionalized gold nanoparticles (CsAuNPs) and saponin-containing botanical adjuvant; Asparagus racemosus extract (ARE) for oral delivery of tetanus toxoid (TT). A significant increase in TT-specific IgG (34.53-fold) and IgA (43.75-fold) was observed when TT-CsAuNPs were formulated with ARE (TT-ARE-CsAuNPs). The local IgA immune responses for TT also showed a significant increase (106.5-fold in intestine washes and 99.74-fold in feces) with ARE-based formulations as compared with plain TT group. No effect of ARE was observed on size, charge, and loading properties of CsAuNPs. Additionally, no effect of ARE and CsAuNPs was observed on antigenicity and secondary structure of TT as determined by fluorescence, circular dichroism, and Fourier transform infrared spectroscopy. The stability studies demonstrated excellent stability profile of formulation at recommended storage conditions. The study establishes the possible role of immunomodulatory adjuvants in particulate delivery systems for mucosal delivery of vaccines.

Physical characterization of drug:polymer dispersion behavior in polyethylene glycol 4000 solid dispersions using a suite of complementary analytical techniques.

Fifteen model drugs were quenched from 3:1 (w/w) mixtures with polyethylene glycol 4000 (PEG4000). The resulting solids were characterized using powder X-ray diffraction (PXRD), analysis of pair distribution function-transformed PXRD data (where appropriate), hot-stage polarized light microscopy, and differential scanning calorimetry (DSC). Drug/polymer dispersion behavior was classified using the data from each technique, independent of the others, and limitations to single-method characterization of PEG-based systems are highlighted. The data from all characterization techniques were collectively used to classify dispersion behavior, which was compared with single-technique characterization. Of the 15 combinations, only six resulted in solids whose dispersion behavior was consistently described using each standalone technique. The other nine were misclassified using at least one standalone technique, mainly because the phase behavior was ambiguously interpreted when only the data from one technique were considered. The data indicated that a suite of complementary techniques provided better classifications of the phase behavior. Of all the quenched solids, only cimetidine was fully dispersed in PEG4000, suggesting that it solidified from a completely miscible mixture of molten drug and polymer that did not phase separate upon cooling. In contrast, ibuprofen and PEG4000 completely recrystallized during preparation, whereas the remaining 13 drugs were partially dispersed in PEG4000 at this composition.