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). [26]. ICH stability testing of new drug substances and products (Q1AR2) , International Conference on Harmonization, IFPMA, Geneva, 2003 . [27

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Abstract  

The properties of the solid-state of drug substances are critical factors that determine the choice of an appropriate salt form for the development of the pharmaceutical formulation. The most relevant properties may affect the therapeutic efficacy, toxicity, bioavailability, pharmaceutical processing and stability. The salt form must fulfil the needs of the targeted formulation, be suitable for full-scale production and its solid-state properties maintained batchwise as well as over time. Comparison of the solid-state properties of different salt candidates may be quite complicated if each salt candidate exist as different solid phases: polymorphs, solvates or amorphous forms. Thermal analysis, microcalorimetry and combined techniques, X-ray diffraction, solubility, intrinsic dissolution, sorption-desorption and stability studies are basic techniques for the characterisation of the salt candidates. Some examples show the role of the salt form as well as the polymorphic form in the characteristics of the solid-state. Thermal analysis and combined techniques are efficient for the detection of unexpected phase transitions and for the comparison of the suitability of the salt candidates prepared for salt selection.

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Acta Microbiologica et Immunologica Hungarica
Authors: F. Kerek, G. Szegli, Lidia Cremer, Andreea-Roxana Lupu, Steliana Durbaca, Ana Calugaru, Aurora Herold and D. Radu

Influence of the novel arthritis drug-substance MCS-18 on the antibody (Ab) production against tetanus toxoid (TT) and diphtheria toxoid (DT) antigens was tested in vivo . Possible involvement of MCS-18 in Toll-like receptor (TLR) signalling pathway was further considered.Materials and methods: Immunization of male CD1 mice was done with subcutaneous injection of TT emulsified in Freund’s Complete (FCA) or Incomplete Adjuvant (FIA) and mixed diversly with MCS-18 and different test substances. To investigate the influence of TLR activation Pam3Cys and lipopolysaccharide (LPS) emulsified in FIA were tested in combinations with MCS-18. Antibody production was analysed in vivo by tetanus-or diphtheria-toxin neutralization test.Results: Immunogenicity of TT was significantly enhanced if administered together with FCA or TLR agonists Pam3Cys or LPS emulsified in FIA. It was shown that MCS-18 attenuated strongly the production of anti-TT Ab if administered together with the Ab elicitor FCA or TLR agonists in various combinations. MCS-18 was also active via oral administration.Discussion: These findings suggest that MCS-18 could be a potent, non-toxic antagonist or a down-regulator of TLR signalling pathway. Investigations on further models are needed to establish if MCS-18 may influence particularly the production of RA-specific auto-antibodies, too.

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An OPLC purity test suitable for routine analysis of norethisterone bulk drug substance and in tablets has been developed. Separation was performed on a fine-particle silica gel adsorbent layer by continuous development with n -hexane and butyl acetate-chloroform, 85 + 15 ( v/v ), as mobile phases. Visualization of the chromatogram by use of sulfuric acid enables detection of less than 0.05% of possible impurities by use of long-wave UV illumination. The selectivity and efficiency of this OPLC method were compared with those of the pharmacopeial TLC methods and those of HPLC method.

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Use of sub-ambient DSC to complement conventional DSC and TG

The study of water adsorption of drug substances and excipients

Journal of Thermal Analysis and Calorimetry
Authors: D. Giron and C. Goldbronn

Abstract  

Several drug substances or excipients are hygroscopic. The uptake or loss of water of such substances is generally difficult to control during processing or storage of drug products. DSC instruments with sub-ambient temperature equipment allow the determination of the amount of freezable water by measuring the corresponding melting enthalpy. The determination of freezable water adds valuable information complementary to TG analysis for understanding the processing and storage of raw materials and drug products. Several substances were tested as is, without treatment, after storage at 92% r.h. and after equilibration with water. The results of these experiments showed that it was possible to demonstrate defined hydrate formation, to determine the upper level of binding of water in amorphous substances and to confirm reversible hydrate formations demonstrated by temperature resolved X-ray diffraction.

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Abstract  

The polymorphic stability of a drug substance is a very important topic in the pharmaceutical industry. Differential scanning calorimetry, thermogravimetric analysis with the support of X-ray powder diffraction and infrared spectroscopy were used as screening techniques for testing structural changes of zolpidem tartrate hydrate stored under different conditions. Obtained data suggested that first structural changes occurred at the temperature of 25C after 2 months of storage. DSC analysis showed that there was a two-step process of water elimination and lack of a phase transition in the temperature range from 130 to 170C in comparison with an initial sample.

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Abstract  

Modern thermal analysis, microcalorimetry and new emerging combined techniques which deliver calorimetric, microscopic and spectroscopic data offer a powerful analytical battery for the study of pharmaceuticals. These techniques are very useful in all steps of development of new drug products as well as methods for quality control in production. The characterization of raw materials enables to understand the relationships between polymorphs, solvates and hydrates and to choose the proper development of new drug products with very small amount of material in a very short time. Information on stability, purity is valuable for new entities as well as for marketed drug substances from different suppliers. Excipients which vary from single organic or inorganic entity to complexes matrixes or polymers need to be characterized and properly controlled. The thermodynamic phase-diagrams are the basis of the studies of drug-excipients interactions. They are very useful for the development of new delivery systems. A great number of new formulations need proper knowledge of the behaviour of the glass transition temperature of the components. Semi-liquid systems, interactions in aqueous media are also successfully studied by these techniques.

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processes) or a more complex assembly of unit operations or steps. Continuous manufacturing implies yet another degree of integration where the entire sequence of unit operations is linked in a continuous train to deliver the drug substance (DS) or drug

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. [10]. ICH International Conference on Harmonization, Impurities in New Drug Substances Q3A(R2) , Geneva , 1996 . [11]. C. Li

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Introduction The problem, which is of particular interest and also plays an important role in the process of evaluation of the quality and safety of application of drug substances and medicinal products, is their chemical

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