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1.
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.
This revised version was published online in July 2006 with corrections to the Cover Date. 相似文献
2.
Giron D. Goldbronn Ch. Mutz M. Pfeffer S. Piechon Ph. Schwab Ph. 《Journal of Thermal Analysis and Calorimetry》2002,68(2):453-465
Manufacturing processes may involve the presence of water in the crystallization of the drug substance or in manufacturing
or in the composition of the drug product through excipients. Dehydration steps may occur in drying, milling, mixing and tabletting
processes. Furthermore, drug substances and drug products are submitted to different temperatures and relative humidities,
due to various climatic conditions giving rise to unexpected hydration or dehydration aging phenomena. Therefore the manufacture
and the characterization of hydrates is part of the study of the physical properties of drug substances.
Several hydrates and even polymorphic forms thereof can be encountered. Upon dehydration crystal hydrates may retain more
or less their original crystal structure, they can lose crystallinity and give anamorphous phase, they can transform to crystalline
less hydrated forms or to crystalline anhydrous forms.
The proper understanding of the complex polyphasic systemhydrates–polymorphs–amorphous state needs several analytical methods.
The use of techniques such as DSC-TG, TG-MS, sorption-desorption isotherms, sub-ambient experiments, X-ray diffraction combined
with temperature or moisture changes as well as crystal structure and crystal modelling in addition to solubilities and dissolution
experiments make interpretation and quantitation easier as demonstrated with some typical examples.
This revised version was published online in August 2006 with corrections to the Cover Date. 相似文献
3.
S. Shantikumar G. Sreekanth K. V. SurendraNath S. JaferValli N. Satheeshkumar 《Journal of Thermal Analysis and Calorimetry》2014,115(3):2423-2428
Differential scanning calorimetry (DSC) is a primary technique for measuring the thermal properties of materials, which reflects the physico-chemical properties of drug substances. In the present study, it is used as a screening technique for assessing the compatibility of sitagliptin with some currently employed pharmaceutical excipients. The influence of processing conditions and their effects (simple blending, co-grinding or kneading) on drug stability was evaluated. Sitagliptin showed a sharp endothermic peak at 212.1 °C with an enthalpy change of 131.5 J g?1 indicating melting of drug. Facile transformation of dehydrated sitagliptin to monohydrate form was observed in some mixtures, disappearance of sharp melting endothermic peak of sitagliptin was observed in some mixtures. On the basis of DSC results, sitagliptin was found to be compatible with micro crystalline cellulose, croscarmellose, and pregelatinized starch. Some excipient interaction was observed with magnesium stearate, ascorbic acid, and citric acid. X-ray diffractometry and FT-IR were used as supportive tools in interpreting the DSC results. Overall, the excipients selected were compatible with the API and the mixtures are stable within the tested conditions. These results would be useful for formulation development of the film coated tablets of sitaglitptin. 相似文献
4.
Pfeffer-Hennig S. Piechon P. Bellus M. Goldbronn C. Tedesco E. 《Journal of Thermal Analysis and Calorimetry》2004,77(2):663-679
The physico-chemical properties and polymorphism of a new active pharmaceutical ingredient entity has been analyzed and the
gain of knowledge during the chemical development of the substance is described. Initial crystallization revealed an anhydrous
crystal form with good crystallinity and a single, sharp DSC melting peak at 171°C and a straightforward development of this
crystal form seemed possible. However, during polymorphism screening, new crystalline forms were detected that were often
analyzed as mixtures of crystal forms. The process of characterization and identification of the different crystalline forms
and its thermodynamical relationship has been supported by a combination of experimental and computational work including
determination of the three-dimensional structures of the crystal forms. The crystal structure of one polymorphic form was
solved by single crystal X-ray structure analysis. Unfortunately, Mod B resisted in formation of suitable single crystals,
but its structure could be solved by high resolution powder diffraction data analysis using synchrotron radiation. Calculation
of the theoretical X-ray powder diffraction pattern from three dimensional crystal coordinates allowed an unambiguous identification
of the different crystalline forms. Two polymorphic crystal forms of the API-CG3, named Mod A and Mod B, are enantiotropic
whereas Mod B is the most stable polymorph at room temperature up to about 50°C and Mod A at temperatures above 50°C. The
mechanism of the solid-solid transition can be explained by analyzing the molecular packing information gained from the single
crystal structures. A third crystalline form with the highest melting peak turned out to be not a polymorphic or pseudopolymorphic
crystal modification of our API-CG3 but a chemically different substance.
This revised version was published online in July 2006 with corrections to the Cover Date. 相似文献
5.
Andrea Sala Zakiena Hoossen Alessia Bacchi Mino R. Caira 《Molecules (Basel, Switzerland)》2021,26(15)
Inclusion complexes between cyclodextrins (CDs) and active pharmaceutical ingredients (APIs) have potential for pharmaceutical formulation. Since crystallization of a given complex may result in the isolation of multiple crystal forms, it is essential to characterize these forms with respect to their structures and physicochemical properties to optimize pharmaceutical candidate selection. Here, we report the preparation and characterization of two crystallographically distinct hydrated forms of an inclusion complex between β-cyclodextrin (β-CD) and the antifungal API fluconazole (FLU) as well as temperature–concentration conditions required for their individual isolation. Determination of crystal water contents was achieved using thermoanalytical methods. X-ray analyses revealed distinct structural differences between the triclinic (TBCDFLU, space group P1) and monoclinic (MBCDFLU, space group C2) crystal forms. Removal of the crystals from their mother liquors led to rapid dehydration of the MBCDFLU crystal, while the TBCDFLU crystal was stable, a result that could be reconciled with the distinct packing arrangements in the respective crystals. This study highlights (a) the importance of identifying possible multiple forms of a cyclodextrin API complex and controlling the crystallization conditions, and (b) the need to characterize such crystal forms to determine the extent to which their physicochemical properties may differ. 相似文献
6.
M. I. Yoshida M. A. Oliveira E. C. L. Gomes W. N. Mussel W. V. Castro C. D. V. Soares 《Journal of Thermal Analysis and Calorimetry》2011,106(3):657-664
Thermogravimetry (TG) and differential scanning calorimetry (DSC) are useful techniques that have been successfully applied
in the pharmaceutical industry to reveal important information regarding the physicochemical properties of drug and excipient
molecules such as polymorphism, stability, purity, and formulation compatibility among others. In this study, lovastatin was
studied by TG, DSC, and other techniques such as Fourier transform infrared spectroscopy, optical microscopy, X-ray diffraction,
chromatography, and mass spectrometry. Lovastatin showed melting point at 445 K and thermal stability up to 535 K. It presented
morphological polymorphism, which in the drug has the same unit cell, but with different crystal habits. Preservative excipient
butylhydroxyanisole (BHA) causes amorphization of lovastatin crystallites and, therefore is incompatible with lovastatin.
Degradation by hydrolysis was observed under neutral, acid, and basic conditions. The active degradation product, lovastatin
hydroxyacid, was obtained after neutral and basic hydrolysis. 相似文献
7.
Monica Felts de La Roca Soares José Lamartine Soares-Sobrinho Keyla Emanuelle Ramos da Silva Lariza Darlene Santos Alves Pablo Queiroz Lopes Lidiane Pinto Correia Fábio Santos de Souza Rui Oliveira Macêdo Pedro José Rolim-Neto 《Journal of Thermal Analysis and Calorimetry》2011,104(1):307-313
The ornidazole drug substance presents melt at approximately 90 °C (∆T = 85–98 °C), which is critical for its use on pharmaceutical manufacturing process. This work aimed the thermal characterization
of ornidazole raw-material synthesized by three different manufacturers from India, China, and Italy, using the thermoanalytical
techniques of DTA, DSC, and TG, besides the verification of its stability and compatibility as a solid pharmaceutical product
by the analysis of its binary mixtures (BM) with excipients and a tablet formulation. The characterization includes the thermal
decomposition kinetic investigation by Ozawa model using Arrhenius equation and drug purity determination by Van’t Hoff equation.
The DSC purity determination and precision were compared with results from UV–Vis spectrophotometric and liquid chromatography,
showing an adequate correlation before being recommended as a general method for purity assay. The drug raw-materials presented
similar quality and zero-order kinetic behavior, besides showing differences on thermal stability. The drug presented compatibility
with the tested excipients since the BM studied presented melting at the same temperature range as the drug and a decomposition
temperature similar to the drug for two of the BM, and at a higher temperature for the others three of the BM evaluated, which
presented excipients with higher molecular structure, capable of spatial coating on the small drug molecule promoting a physical
interaction pharmaceutical acceptable. The tablet was processed by wet granulation and compressed under normal conditions
of pressure and temperature, maintaining the physical properties of solid drug approving the manufacturing process used. In
this study, the thermal analysis was used with success as an alternative method to characterize, quantify, and perform a preformulation
study. 相似文献
8.
Yu. N. Morozov S. P. Mikhalev V. P. Shabatin P. N. Kolotilov G. B. Sergeev 《Moscow University Chemistry Bulletin》2010,65(4):237-243
Cryochemical modification is a method of micronization and changing of the crystalline structure of organic substances that
in application with drug substances may lead to the improvement of their biopharmacological properties. This method was successfully
developed for a chemically labile compound named gabapentin [1-(aminomethyl)-cyclohexaneacetic acid]. According to the data
obtained by X-ray diffraction, FTIR spectroscopy, and differential scanning calorimetry (DSC), the formation of two kinetically
stable polymorphic modifications of gabapentin (forms with melting points of 157°C and 163°C), which are different from the
initial commercial one (with a melting point of 153°C) was observed. These two forms are well known, but the advantage of
this work is in developing a new method of their production that excludes the use of any solvents, which is very important
for environmental safety. 相似文献
9.
Polymorphic crystals and complex multiple melting behavior in an aliphatic biodegradable polyester, poly(butylene adipate) (PBA), were thoroughly examined by wide‐angle X‐ray diffraction (WAXD) and differential scanning calorimetry (DSC). Further clarification on mechanisms of multiple melting peaks related to polymorphic crystal forms in PBA was attempted. More stable α‐form crystal is normally favored for crystallization from melt at higher temperatures (31–35 °C), or upon slow cooling from the melt; while the β‐form is the favored species for crystallization at low temperatures (25–28 °C). We further proved that PBA crystallization could also result in all α‐form even at low temperatures (25–28 °C) if it crystallized with the presence of prior α‐form nuclei. PBA packed with both crystal forms could display as many as four melting peaks (P1 ? P4, in ascending temperature order). However, PBA initially containing only the α‐crystal exhibited dual melting peaks of P1 and P3, which are attributed to dual lamellar distributions of the α‐crystal. By contrast, PBA initially containing only the β‐crystal could also exhibit dual melting peaks (P2 and P4) upon scanning. While P2 is clearly associated with melting of the initial β‐crystal, the fourth melting peak (P4), appearing rather broad, was determined to be associated with superimposed thermal events of crystal transformation from β‐ to α‐crystal and final re‐melting of the new re‐organized α‐crystal. Crystal transformation from one to the other or vice versa, lamellae thickening, annealing at molten state, and influence on crystal polymorphism in PBA were analyzed. Relationships and mechanisms of dual peaks for isolate α‐ or β‐crystals in PBA are discussed. © 2005 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 43: 1662–1672, 2005 相似文献
10.
Examples of the use of subambient DSC for characterizing excipients which have the melting range within ambient or subambient temperatures as well as liquid and semiliquid dosage forms are presented in the following paper.Influences of the quality, polymorphism, storage of excipients used for dosage forms and changes in the composition on the melting behaviour and quality of dosage forms were investigated.Changes of the melting behaviour of dosage forms determined with subambient DSC have shown to correlate with the quality of the dosage form, the quality of excipients used or structural changes (due to various influences) in the dosage form. DSC for use in the range of subambient and ambient temperatures represents an alternative analytical method for development and quality assurance in pharmaceutical industry for liquid and semiliquid preparations. 相似文献
11.
During preformulation studies of pharmaceutical solid dosage forms, thermal analysis techniques are very useful to detect
physical or chemical incompatibilities between the drug and adjuvants of interest that might interfere with efficacy and safety
of the final drug product. Differential scanning calorimetry (DSC) and thermogravimetry (TG) are useful tools for this purpose.
The aim of this study was to investigate the thermoanalytical behavior of olanzapine (OLZ) when mixed with several excipients
commonly used in solid dosage forms such as microcrystalline cellulose, croscarmellose, dicalcium phosphate dihydrate (DCPD),
lactose, magnesium stearate, and povidone. Following DSC and TG analyses, powder X-ray diffraction tests were carried out.
Thermoanalytical methods showed evidence of interaction between OLZ and magnesium stearate, lactose, and povidone. These results
can be useful during the selection of excipients for pharmaceutical formulation development. 相似文献
12.
J. D. Menczel M. Jaffe C. K. Saw T. P. Bruno 《Journal of Thermal Analysis and Calorimetry》1996,46(3-4):753-771
Poly(2-methylpentamethylene terephthalamide) (Nylon M5T) is a new high temperature aromatic polyamide developed by Hoechst Celanese. In this paper thermal properties of Nylon M5T chips, as well as as-spun and drawn fibers were studied by DSC, DMA, hot stage microscopy and WAXS.T
g of the fully amorphous Nylon M5T is 143°C when measured by DSC;T
g increases with crystallinity to 151°C. The temperature dependence of the solid and melt specific heat capacities has also been determined. The heat capacity increase at the glass transition of the amorphous polymer is 103.9 J °C–1 mol–1.T
g by DMA for the as-spun fiber is 155°C, for a drawn fiber is 180°C. Three secondary transitions were observed by DMA in addition to the glass transition. These correspond to a local mode relaxation of the methylene groups at –120°C, onset of rotation of the amide-groups at –65°C and the onset of the rotation of the phenylenegroups (at 63°C). The crystallinity of Nylon M5T strongly depends on the rate of cooling from the melt. The isothermal crystallization data are melt temperature dependent: two-dimensional crystallization takes place when the samples are crystallized from higher melt temperatures, and this phase changes into a spherulitic structure during cooling to room temperature. Spherulitic crystallization occurs when lower melt temperatures are used. This polymer has three crystal forms as indicated by DSC, DMA and WAXS data. The crystal to crystal transitions are clearly visible when amorphous samples are heated in the DSC, or the DMA curves of as-spun fibers are recorded. It is experimentally shown that a considerable melting of the lower temperature crystal forms takes place during the crystal to crystal transitions. The equilibrium melting point as measured by the Hoffman-Weeks method, has been determined to be 339°C.Dedicated to Professor Bernhard Wunderlich on the occasion of his 65th birthday 相似文献
13.
Marti E. Kaisersberger E. Emmerich W.-D. 《Journal of Thermal Analysis and Calorimetry》2004,77(3):905-934
The definitions of the temperature resolution, the so-called resolution of DSC instruments given in literature are discussed.
A new definition of the resolution for DSC instruments is presented and outlined. The main characteristic introduced in this
new definition is a minimum between two caloric events as a prerequisite of an existing resolution. Possible candidates of
test substances have been evaluated. The oligomer n-hexatriacontane is revealing an interesting phenomenon, namely a lambda
transition which is in the peak temperature only 2 K lower than the melting temperature of 76°C. The substance was selected
as an ideal test substance for the quantification of the resolution of DSC instruments. The lambda transition is a second
order process which may reach under certain conditions the saturation of the occurring molecular dislocation within 0.2 K,
and after saturation the heat flow rate drops sharply down. Investigations concerning the main characteristics of n-hexatriacontane
in respect to the temperatures of transition (lambda transition and melting), to the involved enthalpies, and to the resolution
factors were performed as functions of the sample mass and the heating rate. The importance of relevant evaluation procedures
increasing the resolution factors of DSC curves are discussed and these procedures are integrated into the testing of the
resolution. The necessity for widening the experimental scope from instruments to evaluation procedures is forced by the existence
of instruments with built-in signal treatments based on electronic devices and software procedures. A comparison with literature
data is outlined for all of the mentioned characteristic values of n-hexatriacontane.
This revised version was published online in August 2006 with corrections to the Cover Date. 相似文献
14.
Perlovich G. L. Hansen L. Kr. Bauer-Brandl A. 《Journal of Thermal Analysis and Calorimetry》2003,73(3):715-725
Single crystals of the N,N-dimethylformamide (DMF) solvate (1:1) of flurbiprofen (FBP) were grown for the first time and characterised
by X-ray diffraction, IR spectrophotometry, DSC and solution calorimetric methods. The structure may be characterised as a
layer-structure, where DMF double-sheets are arranged between FBP double-sheets. The FBP and DMF molecules are linked to each
other by a hydrogen bond, which is formed between the hydroxyl group of FBP and the carbonyl group of DMF. The conformation
of FBP molecules in the DMF solvate differs from analogous enantiomers in the unsolvated form. The differences are discussed
from the point of view of the influence of the nature of the solvent on selective crystallisation of the enantiomers. A peculiarity
of the solvate is its low melting point, 37.3±0.2°C, with respect to the unsolvated phase, 113.5±0.2°C. Based on solution
enthalpies of the solvated and unsolvated phases dissolved in DMF, the difference in crystal lattice energies, 9.8 kJ mol-1, was calculated and the difference in entropies, 33 J mol-1 K-1 estimated. A possible mechanism explaining the low melting point of the solvate is discussed.
This revised version was published online in August 2006 with corrections to the Cover Date. 相似文献
15.
The evolution of crystal engineering into a form of supramolecular synthesis is discussed in the context of problems and opportunities in the pharmaceutical industry. Specifically, it has become clear that a wide array of multiple component pharmaceutical phases, so called pharmaceutical co-crystals, can be rationally designed using crystal engineering, and the strategy affords new intellectual property and enhanced properties for pharmaceutical substances. 相似文献
16.
Thiele J Windbergs M Abate AR Trebbin M Shum HC Förster S Weitz DA 《Lab on a chip》2011,11(14):2362-2368
Early development drug formulation is exacerbated by increasingly poor bioavailability of potential candidates. Prevention of attrition due to formulation problems necessitates physicochemical analysis and formulation studies at a very early stage during development, where the availability of a new substance is limited to small quantities, thus impeding extensive experiments. Miniaturization of common formulation processes is a strategy to overcome those limitations. We present a versatile technique for fabricating drug nanoformulations using a microfluidic spray dryer. Nanoparticles are formed by evaporative precipitation of the drug-loaded spray in air at room temperature. Using danazol as a model drug, amorphous nanoparticles of 20-60 nm in diameter are prepared with a narrow size distribution. We design the device with a geometry that allows the injection of two separate solvent streams, thus enabling co-spray drying of two substances for the production of drug co-precipitates with tailor-made composition for optimization of therapeutic efficiency. 相似文献
17.
DSC purity analysis is based on thermodynamic phase diagrams for substances (purity ≥98%) which undergo a melting point. Impurities which have eutectic behaviour with the analyte are determined together. DSC purity analysis obtained from a single melting event of a 1–2 mg sample is, therefore, extremely attractive for the global assessment of eutectic impurities. The main advantages in early development lie in the very small amount of material necessary and the very fast analysis time. However, the DSC purity analysis cannot replace chromatographic methods which deliver specific individual levels of impurities. Furthermore, a complete validation of a DSC purity method is difficult and time consuming. Despite these limitations, DSC is the best support for the development of chromatographic methods, for purity profile and stability assessment during pharmaceutical development. Parameters of purity determination and validation aspects are discussed. Examples of use in pharmaceutical development are given. 相似文献
18.
Luz Z Poupko R Wachtel EJ Zheng H Friedman N Cao X Freedman TB Nafie LA Zimmermann H 《The journal of physical chemistry. A》2007,111(42):10507-10516
The paper concerns the structural and optical isomers of nonamethoxy-tribenzocyclononene (compound 1). In the first part of the paper it is shown that 1 exists in two structural isomers: a rigid crown (c-1) with C3 symmetry and a flexible saddle (s-1) with C1 symmetry. The latter, not previously known, can be prepared from the as-synthesized c-1 by quenching a hot solution (or the melt) followed by HPLC separation. The crown/saddle equilibrium, isomerization kinetics, and associated thermodynamic parameters in various organic solvents are reported. Carbon-13 MAS NMR, X-ray diffraction, and differential scanning calorimetry (DSC) of polycrystalline c-1 and s-1 racemates are also reported. The different melting points of the isomers and their rapid isomerization in the melt result in unconventional DSC thermograms involving multiple endothermic and exothermic transitions. The second part of the paper concerns the chiral properties of 1. Both the saddle and crown isomers are structurally chiral, but due to the fast pseudorotation of s-1 in solution, it cannot be separated into its enantiomers. Those of c-1 were separated by HPLC using a chiral column. Their X-ray structure and melting points differ considerably from those of the racemate. This and their fast racemization in the melt lead to complex DSC thermograms with multiple transitions. Solutions of the neat enantiomers exhibit a relatively small specific optical rotation. In the UV they show circular dichroism for the B1u and B2u transitions, with the latter exhibiting a clear couplet structure. Infrared and vibrational circular dichroism spectra of the enantiomers in solution are reported. Comparison of these spectra with quantum mechanical simulations provides unambiguous identification of the enantiomers. 相似文献
19.
Stefani Fertaki Georgios Bagourakis Malvina Orkoula Christos Kontoyannis 《Molecules (Basel, Switzerland)》2022,27(8)
The assessment of active pharmaceutical ingredient (API) particle size and morphology is of great importance for the pharmaceutical industry since it is expected to significantly affect physicochemical properties. However, very few methods are published for the determination of API morphology and particle size of film-coated (FC) tablets. In the current study we provide a methodology for the measurement of API particle size and morphology which could be applied in several final products. Bismuth Oxide 120 mg FC Tabs were used for our method development, which contain bismuth oxide (as tripotassium dicitratobismuthate (bismuth subcitrate)) as the active substance. The sample preparation consists of partial excipient dissolution in different solvents. Following this procedure, the API particles were successfully extracted from the granules. Particle size and morphology identification in Bismuth Oxide 120 mg FC Tabs was conducted using micro-Raman mapping spectroscopy and ImageJ software. The proposed methodology was repeated for the raw API material and against a reference listed drug (RLD) for comparative purposes. The API particle size was found to have decreased compared to the raw API, while the API morphology was also affected from the formulation manufacturing process. Comparison with the RLD product also revealed differences, mainly in the API particle size and secondarily in the crystal morphology. 相似文献
20.
Lemmerer A Bernstein J Griesser UJ Kahlenberg V Többens DM Lapidus SH Stephens PW Esterhuysen C 《Chemistry (Weinheim an der Bergstrasse, Germany)》2011,17(48):13445-13460
A co-crystal of two polymorphic active pharmaceutical ingredients (APIs), first reported and patented in 1937, has been prepared and thoroughly characterised, including crystal structure analysis. The existence of four crystal forms of one of the APIs, the sedative and hypnotic active pharmaceutical ingredient 3,3-diethyl-2,4(1H,3H)-pyridinedione, pyrithyldione (PYR), and of three crystal forms of the co-crystal-forming second API, the non-steroidal anti-inflammatory drug 1,2-dihydro-1,5-dimethyl-4-(1-methylethyl)-2-phenyl-3H-pyrazol-3-one, propyphenazone (PROP), has been reported previously, but they have only been partly characterised. For both compounds, none of the metastable forms exist at room temperature. DSC, hot-stage microscopy, X-ray diffraction and powder synchrotron X-ray diffraction were employed to characterise the polymorphic forms and to determine the crystal structures of forms I-III of PYR and forms I and II of PROP. 相似文献