Structure of solid dispersions
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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.
- Klíčová slova
- Drug-polymer interaction, Inverse gas chromatography, Molecular dispersion, Raman mapping, Structure of solid dispersions, Surface free energy,
- MeSH
- chromatografie plynová MeSH
- polymery * chemie MeSH
- povidon * chemie MeSH
- rozpustnost MeSH
- tadalafil chemie MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- polymery * MeSH
- povidon * MeSH
- tadalafil MeSH
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 quantum mechanics-aided COSMO-SAC activity coefficient model is applied and systematically examined for predicting the thermodynamic compatibility of drugs and polymers. The drug-polymer compatibility is a key aspect in the rational selection of optimal polymeric carriers for pharmaceutical amorphous solid dispersions (ASD) that enhance drug bioavailability. The drug-polymer compatibility is evaluated in terms of both solubility and miscibility, calculated using standard thermodynamic equilibrium relations based on the activity coefficients predicted by COSMO-SAC. As inherent to COSMO-SAC, our approach relies only on quantum-mechanically derived σ-profiles of the considered molecular species and involves no parameter fitting to experimental data. All σ-profiles used were determined in this work, with those of the polymers being derived from their shorter oligomers by replicating the properties of their central monomer unit(s). Quantitatively, COSMO-SAC achieved an overall average absolute deviation of 13% in weight fraction drug solubility predictions compared to experimental data. Qualitatively, COSMO-SAC correctly categorized different polymer types in terms of their compatibility with drugs and provided meaningful estimations of the amorphous-amorphous phase separation. Furthermore, we analyzed the sensitivity of the COSMO-SAC results for ASD to different model configurations and σ-profiles of polymers. In general, while the free volume and dispersion terms exerted a limited effect on predictions, the structures of oligomers used to produce σ-profiles of polymers appeared to be more important, especially in the case of strongly interacting polymers. Explanations for these observations are provided. COSMO-SAC proved to be an efficient method for compatibility prediction and polymer screening in ASD, particularly in terms of its performance-cost ratio, as it relies only on first-principles calculations for the considered molecular species. The open-source nature of both COSMO-SAC and the Python-based tool COSMOPharm, developed in this work for predicting the API-polymer thermodynamic compatibility, invites interested readers to explore and utilize this method for further research or assistance in the design of pharmaceutical formulations.
- Klíčová slova
- COSMO-SAC, amorphous solid dispersions (ASD), drug−polymer thermodynamic compatibility, miscibility, prediction, quantum mechanics, solubility,
- MeSH
- farmaceutická chemie metody MeSH
- léčivé přípravky chemie MeSH
- nosiče léků chemie MeSH
- polymery * chemie MeSH
- rozpustnost * MeSH
- termodynamika * MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- léčivé přípravky MeSH
- nosiče léků MeSH
- polymery * 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.
- Klíčová slova
- Dissolution rate, FT-IR spectroscopy, Magnetic resonance imaging, Solid dispersion, Spray drying, Water penetration,
- MeSH
- aprepitant 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
- Názvy látek
- aprepitant MeSH
- morfoliny MeSH
- polymery MeSH
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.
- Klíčová slova
- Fluorescence, Pharmaceuticals, Raman spectroscopy, Simvastatin, Solid dispersions, Solid-state NMR,
- 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
- Názvy látek
- Duxon MeSH Prohlížeč
- kyseliny polymethakrylové MeSH
- simvastatin MeSH
- voda 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.
- Klíčová slova
- Acetaminophen, Inverse gas chromatography, Pharmaceutical polymers, Physical mixture, Solid dispersion, Surface energy,
- MeSH
- farmaceutická chemie MeSH
- paracetamol chemie MeSH
- polyethylenglykoly chemie MeSH
- polymery MeSH
- polyvinyly chemie MeSH
- povidon chemie MeSH
- rozpustnost MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- paracetamol MeSH
- polyethylenglykoly MeSH
- polymery MeSH
- polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer MeSH Prohlížeč
- polyvinyly MeSH
- povidon MeSH
In this contribution the ability of (19)F MAS NMR spectroscopy to probe structural variability of poorly water-soluble drugs formulated as solid dispersions in polymer matrices is discussed. The application potentiality of the proposed approach is demonstrated on a moderately sized active pharmaceutical ingredient (API, Atorvastatin) exhibiting extensive polymorphism. In this respect, a range of model systems with the API incorporated in the matrix of polvinylpyrrolidone (PVP) was prepared. The extent of mixing of both components was determined by T(1)((1)H) and T(1ρ)((1)H) relaxation experiments, and it was found that the API forms nanosized domains. Subsequently it was found out that the polymer matrix induces two kinds of changes in (19)F MAS NMR spectra. At first, this is a high-frequency shift reaching 2-3 ppm which is independent on molecular structure of the API and which results from the long-range polarization of the electron cloud around (19)F nucleus induced by electrostatic fields of the polymer matrix. At second, this is broadening of the signals and formation of shoulders reflecting changes in molecular arrangement of the API. To avoid misleading in the interpretation of the recorded (19)F MAS NMR spectra, because both the contributions act simultaneously, we applied chemometric approach based on multivariate analysis. It is demonstrated that factor analysis of the recorded spectra can separate both these spectral contributions, and the subtle structural differences in the molecular arrangement of the API in the nanosized domains can be traced. In this way (19)F MAS NMR spectra of both pure APIs and APIs in solid dispersions can be directly compared. The proposed strategy thus provides a powerful tool for the analysis of new formulations of fluorinated pharmaceutical substances in polymer matrices.
- MeSH
- atorvastatin MeSH
- časové faktory MeSH
- faktorová analýza statistická MeSH
- fluor chemie MeSH
- krystalizace MeSH
- kyseliny heptylové chemie MeSH
- léčivé přípravky chemie MeSH
- magnetická rezonanční spektroskopie MeSH
- povidon chemie MeSH
- pyrroly chemie MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- atorvastatin MeSH
- fluor MeSH
- kyseliny heptylové MeSH
- léčivé přípravky MeSH
- povidon MeSH
- pyrroly 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.
- Klíčová slova
- active pharmaceutical ingredients, amorphous dispersion, glass transition, molecular dynamics,
- 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.
- Klíčová slova
- PEO, ciclopirox olamine, mucoadhesive buccal films, polymer−drug interactions, polymorphism, solid state NMR,
- MeSH
- adheziva chemie metabolismus MeSH
- biologická dostupnost MeSH
- ciklopirox 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
- Názvy látek
- adheziva MeSH
- ciklopirox MeSH
- ethylenoxid MeSH
- polyethylenglykoly MeSH
- polymery MeSH
- pyridony MeSH
A new method for the preparation of polyaniline (PANI) films that have a 2D structure and can record high active mass loading (up to 30 mg cm-2) via acid-assisted polymerization in the presence of concentrated formic acid was developed. This new approach represents a simple reaction pathway that proceeds quickly at room temperature in quantitative isolated yield with the absence of any byproducts and leads to the formation of a stable suspension that can be stored for a prolonged time without sedimentation. The observed stability was explained by two factors: (a) the small size of the obtained rod-like particles (50 nm) and (b) the change of the surface of colloidal PANI particles to a positively charged form by protonation with concentrated formic acid. The films cast from the concentrated suspension were composed of amorphous PANI chains assembled into 2D structures with nanofibrillar morphology. Such PANI films demonstrated fast and efficient diffusion of the ions in liquid electrolyte and showed a pair of revisable oxidation and reduction peaks in cyclic voltammetry. Furthermore, owing to the high mass loading, specific morphology, and porosity, the synthesized polyaniline film was impregnated by a single-ion conducting polyelectrolyte-poly(LiMn-r-PEGMm) and characterized as a novel lightweight all-polymeric cathode material for solid-state Li batteries by cyclic voltammetry and electrochemical impedance spectroscopy techniques.
- Klíčová slova
- 2D material, acid-assisted synthesis, all-solid-state L batteries, cathode material, poly(ionic liquid), polyaniline, single-ion conductor,
- Publikační typ
- časopisecké články MeSH
