Structure of solid dispersions
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Solid dispersions of active pharmaceutical ingredients are of increasing interest due to their versatile use. In the present study polyvinylpyrrolidone (PVP), poly[N-(2-hydroxypropyl)-metacrylamide] (pHPMA), poly(2-ethyl-2-oxazoline) (PEOx), and polyethylene glycol (PEG), each in three Mw, were used to demonstrate structural diversity of solid dispersions. Acetylsalicylic acid (ASA) was used as a model drug. Four distinct types of the solid dispersions of ASA were created using a freeze-drying method: (i) crystalline solid dispersions containing nanocrystalline ASA in a crystalline PEG matrix; (ii) amorphous glass suspensions with large ASA crystallites embedded in amorphous pHPMA; (iii) solid solutions with molecularly dispersed ASA in rigid amorphous PVP; and (iv) nanoheterogeneous solid solutions/suspensions containing nanosized ASA clusters dispersed in a semiflexible matrix of PEOx. The obtained structural data confirmed that the type of solid dispersion can be primarily controlled by the chemical constitutions of the applied polymers, while the molecular weight of the polymers had no detectable impact. The molecular structure of the prepared dispersions was characterized using solid-state NMR, wide-angle X-ray scattering (WAXS), and differential scanning calorimetry (DSC). By applying various (1)H-(13)C and (1)H-(1)H correlation experiments combined with T1((1)H) and T1ρ((1)H) relaxation data, the extent of the molecular mixing was determined over a wide range of distances, from intimate intermolecular contacts (0.1-0.5 nm) up to the phase-separated nanodomains reaching ca. 500 nm. Hydrogen-bond interactions between ASA and polymers were probed by the analysis of (13)C and (15)N CP/MAS NMR spectra combined with the measurements of (1)H-(15)N dipolar profiles. Overall potentialities and limitations of individual experimental techniques were thoroughly evaluated.
The aim of this study was to investigate the molecular structures of tadalafil solid dispersions prepared by different techniques and further to relate them to surface free energy information indicating the final amorphousness of the product. Thus, we tried to complement the existing knowledge of solid dispersion formation. Poorly water-soluble tadalafil was combined with different polymers, i.e. Kollidon® 12 PF, Kollidon® VA 64 and Soluplus®, to form model systems. To assess the extent of drug-polymer miscibility, we studied model solid dispersion surface energy using inverse gas chromatography and phase micro-structure using confocal Raman microscopy. The selection of the preparation method was found to play a crucial role in the molecular arrangement of the incorporated drug and the polymer in resulting solid dispersion. Our results showed that a lower surface free energy indicated the formation of a more homogeneous solid dispersion. Conversely, a higher surface free energy corresponded to the heterogeneous systems containing tadalafil amorphous clusters that were captured by Raman mapping. Thus, we successfully introduced a novel evaluation approach of the drug molecular arrangement in solid dispersions that is especially useful for examining the miscibility of the components when the conventional characterizing techniques are inconclusive or yield variable results.
- MeSH
- chromatografie plynová MeSH
- polymery * chemie MeSH
- povidon * chemie MeSH
- rozpustnost MeSH
- tadalafil chemie MeSH
- Publikační typ
- časopisecké články MeSH
The dissolution mechanism of a poorly aqueous soluble drug from amorphous solid dispersions was investigated using a combination of two imaging methods: attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopic imaging and magnetic resonance imaging (MRI). The rates of elementary processes such as water penetration, polymer swelling, growth and erosion of gel layer, and the diffusion, release and in some cases precipitation of drug were evaluated by image analysis. The results from the imaging methods were compared with drug release profiles obtained by classical dissolution tests. The study was conducted using three polymeric excipients (soluplus, polyvinylpyrrolidone - PVP K30, hydroxypropylmethyl cellulose - HPMC 100M) alone and in combination with a poorly soluble drug, aprepitant. The imaging methods were complementary: ATR-FTIR imaging enabled a qualitative observation of all three components during the dissolution experiments, water, polymer and drug, including identifying structural changes from the amorphous form of drug to the crystalline form. The comparison of quantitative MRI data with drug release profiles enabled the different processes during dissolution to be established and the rate-limiting step to be identified, which - for the drug-polymer combinations investigated in this work - was the drug diffusion through the gel layer rather than water penetration into the tablet.
- MeSH
- časové faktory MeSH
- magnetická rezonanční tomografie * přístrojové vybavení MeSH
- molekulární struktura MeSH
- morfoliny chemie MeSH
- polymery chemie MeSH
- spektroskopie infračervená s Fourierovou transformací přístrojové vybavení MeSH
- uvolňování léčiv MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Many newly developed active pharmaceutical ingredients (APIs) have very low solubility in aqueous media. The preparation of solid dispersions (SDs) is one way of avoiding this problem. However, compound wettability and thus solubility are influenced by surface energy. In this study, we used inverse gas chromatography (IGC) to evaluate the surface energies of prepared SDs, and compared them with those obtained for physical mixtures (PMs). SDs containing different weight ratios of crystalline acetaminophen and one of three polymers (Kollidon®12 PF, Kollidon®VA 64 or Soluplus®) were prepared by the melt-quenching of corresponding PMs. In all cases, as the polymer content increased, the surface energy decreased significantly. For the SDs and PMs containing Soluplus®, this decrease in surface energy showed the same non-linear trend. In the cases of Kollidon®12 PF and Kollidon®VA 64, the trend was linear, with the SDs showing a steeper decrease in surface energy than the corresponding PMs. Typically, such decreases are ascribed to the dissolution of the crystalline structure of an API. Our results suggest that in the case of the Kollidons, the steeper decrease is caused by another mechanism, namely, strong API-Kollidon interaction leading to the less wettable surface of SDs.
New drug formulations are sought for poorly water-soluble substances because there is a risk of compromised bioavailability if such substances are administered orally. Such active pharmaceutical ingredients can be reformulated as solid dispersions with suitable water-soluble polymers. In this contribution, formulation of a novel and physically stable dispersion of Simvastatin in poly(2-hydroxypropyl) methacrylamide (pHPMA) is demonstrated. Due to the limited water sorption of pHPMA and a high Tg, the prepared dispersion is more suited for oral administration and storage compared with neat amorphous Simvastatin. Surprisingly, the rate of global reorientation and the internal motion of Simvastatin molecules were enhanced and exhibited dynamical heterogeneities when incorporated into the pHPMA matrix. As revealed by solid-state nuclear magnetic resonance combined with Raman spectroscopy exploiting the fluorescence phenomenon the mobility of the ester and lactone components increased considerably, whereas the naphthalene ring remained rigid. Furthermore, the solid dispersion was found to be nano-heterogeneous with nanometer-sized Simvastatin domains. The presence of these clusters had no impact on the dynamics of the rigid pHPMA chains. Thus, the diffusion of Simvastatin molecules through the glassy pHPMA walls and the subsequent transformation of the clusters into larger crystallites were prevented. No crystallization was detected for more than two years.
- MeSH
- adsorpce MeSH
- diferenciální skenovací kalorimetrie MeSH
- kyseliny polymethakrylové chemie MeSH
- magnetická rezonanční spektroskopie MeSH
- molekulární struktura MeSH
- Ramanova spektroskopie MeSH
- simvastatin chemie MeSH
- stabilita léku MeSH
- voda chemie MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Glass transition temperature (Tg) is an important material property, which predetermines the kinetic stability of amorphous solids. In the context of active pharmaceutical ingredients (API), there is motivation to maximize their Tg by forming amorphous mixtures with other chemicals, labeled excipients. Molecular dynamics simulations are a natural computational tool to investigate the relationships between structure, dynamics, and cohesion of amorphous materials with an all-atom resolution. This work presents a computational study, addressing primarily the predictions of the glass transition temperatures of four selected API (carbamazepine, racemic ibuprofen, indomethacin, and naproxen) with two nucleobases (adenine and cytosine). Since the classical non-polarizable simulations fail to reach the quantitative accuracy of the predicted Tg, analyses of internal dynamics, hydrogen bonding, and cohesive forces in bulk phases of pure API and their mixtures with the nucleobases are performed to interpret the predicted trends. This manuscript reveals the method for a systematic search of beneficial pairs of API and excipients (with maximum Tg when mixed). Monitoring of transport and cohesive properties of API-excipients systems via molecular simulation will enable the design of such API formulations more efficiently in the future.
- Publikační typ
- časopisecké články MeSH
Mucoadhesive buccal films (MBFs) provide an innovative way to facilitate the efficient site-specific delivery of active compounds while simultaneously separating the lesions from the environment of the oral cavity. The structural diversity of these complex multicomponent and mostly multiphase systems as well as an experimental strategy for their structural characterization at molecular scale with atomic resolution were demonstrated using MBFs of ciclopirox olamine (CPX) in a poly(ethylene oxide) (PEO) matrix as a case study. A detailed description of each component of the CPX/PEO films was followed by an analysis of the relationships between each component and the physicochemical properties of the MBFs. Two distinct MBFs were identified by solid-state NMR spectroscopy: (i) at low API (active pharmaceutical ingredient) loading, a nanoheterogeneous solid solution of CPX molecularly dispersed in an amorphous PEO matrix was created; and (ii) at high API loading, a pseudoco-crystalline system containing CPX-2-aminoethanol nanocrystals incorporated into the interlamellar space of a crystalline PEO matrix was revealed. These structural differences were found to be closely related to the mechanical and physicochemical properties of the prepared MBFs. At low API loading, the polymer chains of PEO provided sufficient quantities of binding sites to stabilize the CPX that was molecularly dispersed in the highly amorphous semiflexible polymer matrix. Consequently, the resulting MBFs were soft, with low tensile strength, plasticity, and swelling index, supporting rapid drug release. At high CPX content, however, the active compounds and the polymer chains simultaneously cocrystallized, leaving the CPX to form nanocrystals grown directly inside the spherulites of PEO. Interfacial polymer-drug interactions were thus responsible not only for the considerably enhanced plasticity of the system but also for the exclusive crystallization of CPX in the thermodynamically most stable polymorphic form, Form I, which exhibited reduced dissolution kinetics. The bioavailability of CPX olamine formulated as PEO-based MBFs can thus be effectively controlled by inducing the complete dispersion and/or microsegregation and nanocrystallization of CPX olamine in the polymer matrix. Solid-state NMR spectroscopy is an efficient tool for exploring structure-property relationships in these complex pharmaceutical solids.
- MeSH
- adheziva chemie metabolismus MeSH
- biologická dostupnost MeSH
- ethylenoxid chemie MeSH
- farmaceutická chemie metody MeSH
- krystalizace metody MeSH
- magnetická rezonanční spektroskopie metody MeSH
- nanočástice chemie MeSH
- orální absorpce fyziologie MeSH
- polyethylenglykoly chemie metabolismus MeSH
- polymery chemie MeSH
- pyridony chemie MeSH
- rozpustnost MeSH
- ústní sliznice metabolismus MeSH
- uvolňování léčiv fyziologie MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Autoři popisují cytologický a histologický obraz u případu solidního a papilárního epiteliálního tumoru pankreatu u 341eté ženy. V materiálu získaném tenkojehlovou aspirační cytologií dominovaly pseudopapilárně utvářené fragmenty s jemným fibrovaskulárním stromatem obklopeným jednou či více vrstvami nádorových buněk se světlou cytoplazmou. Přítomny byly též acinární, rozetovité struktury a nádorové buňky volně rozptýlené na pozadí. Nádorové elementy měly drobná, kulatá až oválná jádra s jemným chromatinem a nenápadným jadérkem. Ojediněle byly zastiženy i intranukleární zářezy. Mitózy nebyly přítomny. Histologický šlo o opouzdřený, převážně solidně uspořádaný nádor, ložiskově s tvorbou drobných pseudocyst, pseudopapilárních struktur a granulomů z cizích těles, tvořený drobnými uniformními buňkami se světlou cytoplazmou, prakticky bez mitotické aktivity. Imunohistochemícky nádorové buňky difuzně exprimovaly vimentin, fokálně byla prokázána pozitivita α1-antitrypsinu a CD68. Negativní byl průkaz chromograninu, synaptofyzinu, cytokeratinů, HMB 45, estrogenových a progesteronových receptorů. ^diferenciálně diagnosticky je nutno odlišit zejména mucinózní tumory pankreatu, mikrocystický adenom a pseudocysty, ale též endokrinní nádory pankreatu, karcinom z acinámích buněk, světlobvměčný karcinom ledviny, kôrový adenom nadledvinky či primární extrapulmonální sugar tumor.
Cytologic and histologic features in a case of solid and papillary epithelial neoplasm (SPEN) of the pancreas in a 34-year-old female are presented. In the fine-needle aspiration material, there was a predominance of pseudopapillary fragments with delicate fibrovascular core lined with one or more layers of uniform tumor cells with clear cytoplasm. There were also acinar-Iike or rosette-like structures and dispersed tumor cells. Tumor cells had small, round to oval nuclei, with finely granular chromatin and inconspicuous nucleolus. Rarely, nuclear grooves were present. Mitoses were not seen. Histologically, the encapsulated tumor was predominantly solid, with focal pseudocystic and pseudopapillary areas; foreign body granulomas were focally present. Tumor ceUs were small and uniform with clear cytoplasm. Mitoses were extremely rare. Immunohistochemically, the tumor cells revealed diffuse positivity of vimentin, and focal positivity for α1-antitrypsin and CD68. No immunoreactivity for chromogranin, synaptophysin, cytokeratin, HMB 45, estrogen and progesteron receptors was found. In differential diagnosis, it is important to distinguish SPEN mainly from mucinous tumors of the pancreas, microcystic adenoma and pseudocysts, but also from endocrine tumors of the pancreas, acinic cell carcinoma, renal cell carcinoma, adrenal cortical adenoma and primary extrapulmonary sugar tumor.
A sustained effort to maximize the therapeutic effect of newly discovered active pharmaceutical ingredients (APIs) leads to the search for and development of advanced drug formulations. In this regard, a range of multicomponent and nanostructured systems that often combine the properties of solid and liquid materials have been developed. Besides the sophisticated supramolecular synthesis the development of these systems also requires in-depth view into their local architecture at atomic-resolution level. As these materials naturally exist at the borderline between the solid and liquid phases, the high-quality diffraction data are inherently unavailable. Therefore the structural description of these materials requires development of novel and highly efficient strategies. The aim of all this process is formulation of computation-experimental procedures allowing for precise characterization of the complex pharmaceutical systems including composite solids, nanocrystalline systems as well as partially ordered materials. In this regard, NMR crystallography belongs among the most successful approaches. In this contribution we report our recent achievements in characterizing atomic-resolution structure of complex pharmaceutical solids such as peptide derivatives of boronic acid, hybrid organic-inorganic liquisolid drug delivery systems, polymer-drug solid dispersions and mucoadhesive buccal films.
- Klíčová slova
- krystalové struktury,
- MeSH
- algináty chemie MeSH
- Aspirin chemie MeSH
- ciklopirox chemie MeSH
- farmaceutická technologie klasifikace MeSH
- krystalografie * metody MeSH
- léčivé přípravky MeSH
- magnetická rezonanční spektroskopie * metody MeSH
- nanomedicína dějiny metody MeSH
- polymery aplikace a dávkování chemie MeSH
- sloučeniny boru chemie MeSH
- Publikační typ
- práce podpořená grantem MeSH
... STRUCTURE OF MATTER 7 -- 1.1 Particles and force interactions 7 -- 1.2 Energy 9 -- 1.3 Quantum effects ... ... Quantum numbers 12 -- 1.4 Hydrogen atom 14 -- 1.4.1 Spectrum of hydrogen atom 15 -- 1.5 Electron structure ... ... Theorem of the equipartition of energy 31 -- 2.2.1.4 Real gases 31 -- 2.2.2 Liquid phase 32 -- 2.2.3 Solids ... ... of phases 32 -- 2.3.1 Phase diagram 33 -- 2.3.2 Gibbs law of phases 33 -- 2.4 Classification of dispersion ... ... system 34 -- 2.4.1 Analytical dispersions 35 -- 2.4.2 Colloidal dispersions 36 -- 2.4.2.1 Electric double-layer ...
Učební texty Univerzity Karlovy v Praze
2nd ed. 132 s. : il. ; 30 cm
- MeSH
- biofyzika záření MeSH
- biofyzika MeSH
- elektrofyziologie MeSH
- molekulární struktura MeSH
- spektrální analýza MeSH
- termodynamika MeSH
- Publikační typ
- učebnice MeSH
- Konspekt
- Biochemie. Molekulární biologie. Biofyzika
- NLK Obory
- fyzika, biofyzika
