ABSTRACT
Colonic drug delivery offers numerous pharmaceutical opportunities, including direct access to local therapeutic targets and drug bioavailability benefits arising from the colonic epithelium's reduced abundance of cytochrome P450 enzymes and particular efflux transporters. Current workflows for developing colonic drug delivery systems involve time-consuming, low throughput in vitro and in vivo screening methods, which hinder the identification of suitable enabling materials. Polysaccharides are useful materials for colonic targeting, as they can be utilised as dosage form coatings that are selectively digested by the colonic microbiota. However, polysaccharides are a heterogeneous family of molecules with varying suitability for this purpose. To address the need for high-throughput material selection tools for colonic drug delivery, we leveraged machine learning (ML) and publicly accessible experimental data to predict the release of the drug 5-aminosalicylic acid from polysaccharide-based coatings in simulated human, rat, and dog colonic environments. For the first time, Raman spectra alone were used to characterise polysaccharides for input as ML features. Models were validated on 8 unseen drug release profiles from new polysaccharide coatings, demonstrating the generalisability and reliability of the method. Further, model analysis facilitated an understanding of the chemical features that influence a polysaccharide's suitability for colonic drug delivery. This work represents a major step in employing spectral data for forecasting drug release from pharmaceutical formulations and marks a significant advancement in the field of colonic drug delivery. It offers a powerful tool for the efficient, sustainable, and successful development and pre-ranking of colon-targeted formulation coatings, paving the way for future more effective and targeted drug delivery strategies.
ABSTRACT
Form III of linezolid was prepared by heating the commercial form above 150 °C and subsequently analyzed upon cooling down to -160 °C, by low- and high-frequency Raman spectroscopy, differential scanning calorimetry and powder X-ray diffraction (PXRD). It was observed that form III was preserved down to 0 °C. At lower temperatures a soft mode was clearly detected by low-frequency Raman spectroscopy associated with the detection of additional Raman bands distinctive of additional intermolecular H-bond interactions. Raman spectroscopy investigations performed in a wide frequency range revealed a continuous transformation characterized by both displacive and order-disorder signatures. By contrast, PXRD highlighted the absence of symmetry breaking, Bragg peaks being still indexed in the same unit cell from room temperature down to -160 °C. Additionally, a significant broadening of Bragg peaks was observed with decreasing temperature interpreted as being a consequence of a distribution of frozen molecular conformations.
ABSTRACT
The influence of the crystal synthesis method on the crystallographic structure of caffeine-citric acid cocrystals was analyzed thanks to the synthesis of a new polymorphic form of the cocrystal. In order to compare the new form to the already known forms, the crystal structure of the new cocrystal (C8H10N4O2·C6H8O7) was solved by powder X-ray diffraction thanks to synchrotron experiments. The structure determination was performed using `GALLOP', a recently developed hybrid approach based on a local optimization with a particle swarm optimizer, particularly powerful when applied to the structure resolution of materials of pharmaceutical interest, compared to classical Monte-Carlo simulated annealing. The final structure was obtained through Rietveld refinement, and first-principles density functional theory (DFT) calculations were used to locate the H atoms. The symmetry is triclinic with the space group P-1 and contains one molecule of caffeine and one molecule of citric acid per asymmetric unit. The crystallographic structure of this cocrystal involves different hydrogen-bond associations compared to the already known structures. The analysis of these hydrogen bonds indicates that the cocrystal obtained here is less stable than the cocrystals already identified in the literature. This analysis is confirmed by the determination of the melting point of this cocrystal, which is lower than that of the previously known cocrystals.
ABSTRACT
The use of low-frequency Raman spectroscopy (LFRS; ω < 150 cm-1) is booming in the pharmaceutical industry. Specific processing of spectra is required to use the wealth of information contained in this spectral region. Spectra processing and the use of LFRS for analyzing phase transformations in molecular materials are detailed herein from investigations on the devitrification of ibuprofen. LFRS was used to analyze the dehydration mechanism of two hydrates (theophylline and caffeine) of the xanthine family. Two mechanisms of solid-state transformation in theophylline were determined depending on the relative humidity (RH) and temperature. At room temperature and 1% RH, dehydration is driven by the diffusion mechanism, while under high RH (>30%), kinetic laws are typical of nucleation and growth mechanism. By increasing the RH, various metastability driven crystalline forms were obtained mimicking successive intermediate states between hydrate form and anhydrous form achieved under high RH. In contrast, the dehydration kinetics of caffeine hydrate under various RH levels can be described by only one master curve corresponding to a nucleation mechanism. Various metastability driven states were achieved depending on the RH, which can be described as intermediate between forms I and II of anhydrous caffeine.
ABSTRACT
Transdermal administration can be considered as an interesting route to overcome the side-effects inherent to oral intake. Designing topical formulations with maximum drug efficiency requires the optimization of the permeation and the stability of the drug. The present study focuses on the physical stability of amorphous drugs within the formulation. Ibuprofen is commonly used in topical formulations and then was selected as a model drug. Additionally, its low Tg allows easy, unexpected recrystallization at room temperature with negative consequence on skin penetration. In this study, the physical stability of amorphous ibuprofen was investigated in two types of formulations: (i) in terpenes-based deep eutectic solvents (DES) and (ii) in arginine-based co-amorphous blends. The phase diagram of ibuprofen:L-menthol was mainly analyzed by low-frequency Raman spectroscopy, leading to the evidence of ibuprofen recrystallization in a wide range of ibuprofen concentration. By contrast, it was shown that amorphous ibuprofen is stabilized when dissolved in thymol:menthol DES. Forming co-amorphous arginine-ibuprofen blends by melting is another route for stabilizing amorphous ibuprofen, while recrystallization was detected in the same co-amorphous mixtures obtained by cryo-milling. The mechanism of stabilization is discussed from determining Tg and analyzing H-bonding interactions by Raman investigations in the C=O and O-H stretching regions. It was found that recrystallization of ibuprofen was inhibited by the inability to form dimers inherent to the preferential formation of heteromolecular H-bonding, regardless of the glass transition temperatures of the various mixtures. This result should be important for predicting ibuprofen stability within other types of topical formulations.
ABSTRACT
Designing co-crystals can be considered as a commonly used strategy to improve the bioavailability of many low molecular weight drug candidates. The present study has revealed the existence of three pseudo polymorphic forms of theophylline-citric acid (TP-CA) co-crystal obtained via different routes of synthesis. These forms are characterized by different degrees of stability in relation with the strength of intermolecular forces responsible for the co-crystalline cohesion. Combining low- and high-frequency Raman investigations made it possible to identify anhydrous and hydrate forms of theophylline-citric acid co-crystals depending on the preparation method. It was shown that the easiest form to synthesize (form 1'), by milling one hydrate with an anhydrous reactant, is very metastable, and transforms into the anhydrous form 1 upon heating or into the hydrated form 2 when it is exposed to humidity. Raman investigations performed in situ during the co-crystallization of forms 1 and 2 have shown that two different types of H-bonding ensure the co-crystalline cohesion depending on the presence of water. In the hydrated form 2, the cohesive forces are related to strong O-H O H-bonds between water molecules and the reactants. In the anhydrous form 1, the co-crystalline cohesion is ensured by very weak H-bonds between the two anhydrous reactants, interpreted as corresponding to π-H-bonding. The very weak strength of the cohesive forces in form 1 explains the difficulty to directly synthesize the anhydrous co-crystal.
Subject(s)
Citric Acid , Theophylline , Theophylline/chemistry , Crystallization , Water/chemistryABSTRACT
Designing co-amorphous formulations is now recognized as a relevant strategy for improving the bioavailability of low-molecular-weight drugs. In order to determine the most suitable low-molecular-weight excipients for stabilizing the drug in the amorphous state, screening methods were developed mostly using amino acids as co-formers. The present study focused on the analysis of the thermal stability of co-amorphous blends prepared by cryo-milling indomethacin with several amino acids in order to understand the stabilization mechanism of the drug in the amorphous state. Combining low- and mid-frequency Raman investigations has provided information on the relation between the physical properties of the blends and those of the H-bond network of the amorphous drug. This study revealed the surprising capabilities of L-arginine to stiffen the H-bond network in amorphous indomethacin and to drastically improve the stability of its amorphous state. As a consequence, this study suggests that amino acids can be considered as stiffeners of the H-bond network of indomethacin, thereby improving the stability of the amorphous state.
ABSTRACT
Mesoporous silica (MPS) carriers are considered as a promising strategy to increase the solubility of poorly soluble drugs and to stabilize the amorphous drug delivery system. The development by the authors of a solvent-free method (milling-assisted loading, MAL) made it possible to manipulate the physical state of the drug within the pores. The present study focuses on the effects of the milling intensity and the pore architecture (chemical surface) on the physical state of the confined drug and its release profile. Ibuprofen (IBP) and SBA-15 were used as the model drug and the MPS carrier, respectively. It was found that decreasing the milling intensity promotes nanocrystallization of confined IBP. Scanning electron microscopy and low-frequency Raman spectroscopy investigations converged into a bimodal description of the size distribution of particles, by decreasing the milling intensity. The chemical modification of the pore surface with 3-aminopropyltriethoxisylane also significantly promoted nanocrystallization, regardless of the milling intensity. Combined analyses of drug release profiles obtained on composites prepared from unmodified and modified SBA-15 with various milling intensities showed that the particle size of composites has the greatest influence on the drug release profile. Tuning drug concentration, milling intensity, and chemical surface make it possible to easily customize drug delivery.
ABSTRACT
L-Leucine is an essential amino acid which has been focusing a lot of investigations on its phase transition sequence for more than fifty years. Combining Raman spectroscopy and X-ray diffraction experiments provides a new interpretation of the second order phase transition extending between 270 and 360 K as a displacive incommensurate-normal phase transition. A soft mode was clearly detected from low-frequency Raman investigations which exhibits the temperature dependence (A·(TC-T)1/2) typical of the temperature behavior of the amplitudon, an excitation specific to incommensurate phases. Simultaneously to the softening of the amplitudon, several very weakly intense X-ray reflections vanish upon heating at 360 K, and thereby are interpreted as satellite reflections. This incommensurability was described as resulting from the freezing of thermally activated hydrophobic side-chain rotations upon cooling in disordered orientations. Raman investigations were also performed on the isomeric amino acid L-norleucine previously identified as undergoing a normal-incommensurate phase transition around 200 K. Comparison of both studies suggests that the temperature behavior of thermally activated local motions generates lattice instabilities. Loss of periodicity can result from the freezing of rotations of molecular moieties in disordered orientations, or from the enhancement of anharmonicity of these rotations. This could be a general phenomenon in hydrophobic amino acids with direct consequences on their applications in the life science area.
Subject(s)
Amino Acids , Leucine , Phase Transition , X-Ray Diffraction , Hydrophobic and Hydrophilic InteractionsABSTRACT
Raman spectroscopy investigations on L-methionine (L-Met) performed in a large temperature range (170-420 K) and in a wide spectral window (5-3600 cm-1) have revealed an extended disordering mechanism triggered by thermally activated motions of the terminal side-chain atoms, from 250 up to 390 K. This very progressive disordering process is characterized by two thermodynamic features, the first corresponding to a broad endotherm (250 â 310 K) marking the beginning of the process, while the second ending the disordering transformation is a sharp endothermic peak at 390 K. These thermodynamic events are correlated with the softening of lattice vibrations and the increase of the quasielastic scattering, considered as the signatures of displacive phase transitions. The amorphous-like band-shape of the low-frequency Raman spectrum collected above 390 K, resulting from the strong anharmonicity of local motions, is contrasting with the detection of additional Bragg peaks above 390 K by x-ray diffraction, consistent with the Cp jump accompanying the endothermic peak. These observations suggest that L-Met is progressively dynamically disordered adopting additional configurations in the crystalline lattice through rotations of CH3 and the side-chain flexibility not clearly detected by x-ray diffraction. These results should be crucial for considering the stability of dried proteins composed of methionine residues.
ABSTRACT
Using the innovative solid-state loading (milling-assisted loading, MAL) method to confine caffeine to cylindrical pores (SBA-15, ∅ = 6 nm) gives the opportunity to explore the original physical states of caffeine and their subsequent transformation using low-frequency Raman spectroscopy, powder X-ray diffraction and microcalorimetry investigations. It was shown that MAL makes possible the loading of the selected form in the polymorphism of caffeine. While form II has similar structural and dynamics properties in confined and bulk forms, the confined rotator phase (form I) exhibits clear differences with the bulk form inherent to its orientational disorder. Interestingly, the two confined forms of caffeine undergo an exothermic disordering transformation upon heating into a physical state at the border between a nanocrystallized orientationally disordered phase and an amorphous state, not existing in the bulk form. The melting of this new physical state was observed at 150 °C, i.e. 85 degrees below the melting temperature of the bulk form I, thus demonstrating the confinement of caffeine. It was also found that the liquid confined to pores of 6 nm mean diameter recrystallizes upon cooling, which can be explained by the very disordered nature of the recrystallized state.
ABSTRACT
Using the Milling-Assisted Loading (MAL) solid-state method for loading a poorly water-soluble drug (ibuprofen, IBP) within the SBA-15 matrix has given the opportunity to manipulate the physical state of drugs for optimizing bioavailability. The MAL method makes it easy to control and analyze the influence of the degree of loading on the physical state of IBP inside the SBA-15 matrix with an average pore diameter of 9.4 nm. It was found that the density of IBP molecules in an average pore size has a direct influence on both the glass transition and the mechanism of crystallization. Detailed analyzes of the crystallite distribution and melting by Raman mapping, x-ray diffraction, and differential scanning calorimetry have shown that the crystals are localized in the core of the channel and surrounded by a liquid monolayer. The results of these complementary investigations have been used for determining the relevant parameters (related to the SBA-15 matrix and to the IBP molecule) and the nature of the physical state of the confined matter.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemistry , Drug Delivery Systems , Ibuprofen/chemistry , Silicon Dioxide/chemistryABSTRACT
In this paper, we present a kinetic investigation of the polymorphic transformation γ â α of sorbitol under milling in the objective to identify the microscopic mechanisms that govern this type of solid-state transformation. The milling was performed with a high energy planetary mill and the milled material was analysed by DSC, PXRD and Raman spectrometry. The transformation kinetics was found to be sigmoidal with a noticeable incubation time. Moreover, this incubation time was shown to shorten rapidly when seeding the initial form γ with the final form α. The origin of the incubation period and its evolution upon seeding are puzzling as polymorphic transformations induced by milling are not expected to occur through a nucleation and growth process. To explain these puzzling kinetic features, we propose a two-step transformation mechanism involving local amorphisations due to the mechanical impacts, immediately followed by rapid recrystallizations of the amorphized fractions. The key point of the mechanism is that recrystallizations are oriented towards the forms γ or α, depending on the crystalline form of neighbouring crystallites. This mechanism has been validated by numerical simulations which were able to reproduce all the experimental kinetic features of the polymorphic transformation (kinetic law and effects of seeding) upon milling.
Subject(s)
Sorbitol , Calorimetry, Differential Scanning , Crystallization , Kinetics , X-Ray DiffractionABSTRACT
A new method for determining solubility lines of drugs in polymers, based on low-frequency Raman spectroscopy measurements, is described and the results obtained by this method are compared with those obtained using a more classical method based on differential scanning calorimetry investigations. This method was applied to the paracetamol/PVP system using molecular and crystalline dispersions (MCD) rather than usual physical mixtures to reach faster the equilibrium saturated states and make the determination of the solubility line more rapid.
Subject(s)
Acetaminophen/analysis , Polyvinyls/analysis , Pyrrolidines/analysis , Spectrum Analysis, Raman/methods , Acetaminophen/chemistry , Analgesics, Non-Narcotic/analysis , Analgesics, Non-Narcotic/chemistry , Polyvinyls/chemistry , Pyrrolidines/chemistry , Solubility , X-Ray Diffraction/methodsABSTRACT
The devitrification mechanism of d-mannitol was carefully investigated using micro calorimetry experiments and Raman spectroscopy, in order to understand the phase transformation of the undercooled liquid into an apparently amorphous state, called phase X. It was found from micro spectroscopy analyses that the formerly assigned "phase X" observed during the devitrification of undercooled d-mannitol results from a surface crystallization accompanied by a very slow bulk crystallization into the α form. Such a phenomenon can be more easily identified by analyzing microscopic samples obtained upon slow heating runs from the glassy state.
ABSTRACT
The bioprotective properties of 2 disaccharides (sucrose and trehalose) were analyzed during the freeze-drying (FD) process and at the end of the process, to better understand the stabilization mechanisms of proteins in the solid state. In situ Raman investigations, performed during the FD process, have revealed that sucrose was more efficient than trehalose for preserving the secondary structure of lysozyme during FD, especially during the primary drying stage. The lower bioprotective effect of trehalose was interpreted as a consequence of a stronger affinity of this disaccharide to water, responsible for a severe phase separation phenomenon during the freezing stage. Dielectric spectroscopy investigations on the freeze-dried state of protein formulations have shown the capabilities of trehalose assisted by residual water to reduce the molecular mobility of the vitreous matrix, suggesting that trehalose is more efficient to preserve the protein structure during long-term storage.
Subject(s)
Dielectric Spectroscopy , Excipients/chemistry , Muramidase/chemistry , Spectrum Analysis, Raman , Sucrose/chemistry , Trehalose/chemistry , Drug Compounding , Freeze Drying , Ice , Protein Denaturation , Protein Folding , Protein Stability , Protein Structure, Secondary , Time Factors , Water/chemistryABSTRACT
The polymorphism of sulindac was investigated by Raman investigations, mainly in the low-wavenumber region in order to analyze the influence of the amorphization method on recrystallization and crystalline form stability. By devitrification of the quenched liquid, it was found that the undercooled liquid crystallizes into Form I, and a polymorphic transformation by cooling Form I toward Form IV, was clearly revealed. The low-wavenumber spectra of polymorphic forms are direct fingerprints of crystals, indicating a degree of disorder of Form IV intermediate between those of the ordered Form II (commercial form) and the relatively disordered Form I. This study has shown the enantiotropic relationship between Forms I and IV and that both the temperature of crystallization and the physical stability of Form I prepared is dependent on the technique used for preparing amorphous sulindac.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemistry , Sulindac/chemistry , Crystallization , Spectrum Analysis, Raman , VitrificationABSTRACT
The influence of HPßCD on the thermal denaturation of lysozyme was analyzed mainly from microcalorimetry and Raman investigations carried out in the molecular fingerprint and the low-frequency regions. It was shown that Raman spectroscopy investigations performed on a wide spectral range give the opportunity to describe the influence of HPßCD on the mechanism of protein denaturation. Using D2O as solvent allowed us to show that HPßCD mainly destabilizes the tertiary structure of lysozyme by enhancing the protein flexibility and thus inducing the destabilization of the secondary structure. Principal components analysis (PCA) was used for spectra treatment, providing important information about inclusion complex formation between protein hydrophobic residues and CDs molecules. Combining PCA and classical technics (curve fitting) of data analysis allowed a better understanding of the influence of HPßCD on the protein denaturation that seems to be related to the CDs capacity to form inclusion complex. It was observed that these interactions prevent the formation of new strong H-bonds between ß-sheet structures thereby inhibiting protein aggregation. This study reveals that CDs are promising systems for inhibiting protein aggregation without protein denaturation, only if designing derivative CDs is carefully controlled.
Subject(s)
2-Hydroxypropyl-beta-cyclodextrin/chemistry , Muramidase/chemistry , Spectrum Analysis, Raman/methods , beta-Cyclodextrins/chemistry , Animals , Calorimetry/methods , Hydrophobic and Hydrophilic Interactions , Principal Component Analysis , Protein Denaturation , Protein Stability , Protein Structure, Secondary , Solvents/chemistry , TemperatureABSTRACT
Metoprolol tartrate and metoprolol free base loaded pellet starter cores were coated with Eudragit RS, plasticized with 25% triethyl citrate (TEC). The initial drug loading and coating level were varied from 10 to 40 and 0 to 20%, respectively. Drug release was measured in 0.1â¯N HCl and phosphate buffer pH 7.4. The water uptake and swelling kinetics, mechanical properties and TEC leaching of/from coated pellets and/or thin, free films of identical composition as the film coatings were monitored. The following unusual tendencies were observed: (i) the relative drug release rate from coated pellets increased with increasing initial drug content, and (ii) drug release from pellets was much faster for metoprolol free base compared to metoprolol tartrate, despite its much lower solubility (factor >70). These phenomena could be explained by plasticizing effects of the drug for the polymeric film coatings. In particular: 1) Metoprolol free base is a much more potent plasticizer for Eudragit RS than the tartrate, leading to higher film permeability and overcompensating the pronounced differences in drug solubility. Also, Raman imaging revealed that substantial amounts of the free base migrated into the film coatings, whereas this was not the case for the tartrate. 2) The plasticizing effects of the drug for the film coating overcompensated potential increasing limited solubility effects when increasing the initial drug loading from 10 to 40%. In summary, this study clearly demonstrates how important the plasticization of polymeric controlled release film coatings by drugs can be, leading to unexpected formulation effects.
Subject(s)
Acrylic Resins/chemistry , Metoprolol/chemistry , Plasticizers/chemistry , Citrates/chemistry , Drug Liberation , Polymers/chemistry , Solubility , Water/chemistryABSTRACT
Micro-Raman spectroscopy gives the original opportunity to monitor simultaneously the operating process and the protein structure from in situ investigations along the 3 stages of the freeze-drying (FD) process. This opportunity was used for determining how a small amount of glycerol enhances the bioprotective efficiency of trehalose during FD of lysozyme formulations. Three lysozyme formulations were analyzed: lysozyme dissolved in D2O (wt% 1:9), in trehalose-D2O mixture (wt% 1:1:8), and in the trehalose-glycerol-D2O mixture (wt% 1:1:0.17:7.93). Raman mapping performed during each stage of the FD process has provided important information about the preferential interaction between water, trehalose, and lysozyme in relation to the protein stability. It was found that the addition of a small amount of glycerol had a plasticizing effect on the glassy trehalose-water matrix during the primary drying stage and then reduced the bioprotective effect of trehalose. By contrast, during the secondary drying stage, glycerol significantly enhanced the stabilizing effect of trehalose in the same sample, by replacing water-trehalose H-bonds with stronger glycerol-trehalose H-bonds and stiffening the amorphous trehalose matrix. The action of glycerol is also related to its capability to prevent aggregation of trehalose, making the structure of the frozen product more homogeneous, by changing the hydrogen-bond networks in the liquid formulation before the freezing stage.