Machine learning of Raman spectra predicts drug release from polysaccharide coatings for targeted colonic delivery.

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.

Description of an original molecular ordering process into a disordered crystalline form: the atypical low-temperature transformation of the disordered form III of linezolid.

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.

Relationship between synthesis method-crystal structure-melting properties in cocrystals: the case of caffeine-citric acid.

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 (CHNO·CHO) 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.

Low-Frequency Raman Spectroscopy: An Exceptional Tool for Exploring Metastability Driven States Induced by Dehydration.

The use of low-frequency Raman spectroscopy (LFRS; ω < 150 cm) 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.

Co-Amorphous Versus Deep Eutectic Solvents Formulations for Transdermal Administration.

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.

Milling-Assisted Loading of Drugs into Mesoporous Silica Carriers: A Green and Simple Method for Obtaining Tunable Customized Drug Delivery.

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.

Mechanism for Stabilizing an Amorphous Drug Using Amino Acids within Co-Amorphous Blends.

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.

Analysis of Co-Crystallization Mechanism of Theophylline and Citric Acid from Raman Investigations in Pseudo Polymorphic Forms Obtained by Different Synthesis Methods.

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.

Identification of incommensurability in L-leucine: can lattice instabilities be considered as general phenomena in hydrophobic amino acids?

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 (·(-)) typical of the temperature behavior of the amplitudon, an excitation specific to incommensurate phases.

Confinement of molecular materials using a solid-state loading method: a route for exploring new physical states and their subsequent transformation highlighted by caffeine confined to SBA-15 pores.

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.

Revisiting the phase transition sequence in L-methionine: Description of the disordering mechanism in an essential amino acid.

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) 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 → 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.

Manipulating the physical states of confined ibuprofen in SBA-15 based drug delivery systems obtained by solid-state loading: Impact of the loading degree.

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.

Kinetics and mechanism of polymorphic transformation of sorbitol under mechanical milling.

In this paper, we present a kinetic investigation of the polymorphic transformation γ → 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.

Contribution of low-frequency Raman spectroscopy to determine the solubility curves of drugs in polymers: The case of paracetamol/PVP.

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.

A detailed description of the devitrification mechanism of d-mannitol.

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.

Trehalose or Sucrose: Which of the Two Should be Used for Stabilizing Proteins in the Solid State? A Dilemma Investigated by In Situ Micro-Raman and Dielectric Relaxation Spectroscopies During and After Freeze-Drying.

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.

Polymorphism versus devitrification mechanism: Low-wavenumber Raman investigations in sulindac.

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.

Using Milling to Explore Physical States: The Amorphous and Polymorphic Forms of Sulindac.

This article shows how milling can be used to explore the phase diagram of pharmaceuticals. This process has been applied to sulindac. A short milling has been found to trigger a polymorphic transformation between form II and form I upon heating which is not seen in the nonmilled material.

A detailed analysis of the influence of β-cyclodextrin derivates on the thermal denaturation of lysozyme.

The influence of HPβCD 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 HPβCD on the mechanism of protein denaturation. Using DO as solvent allowed us to show that HPβCD mainly destabilizes the tertiary structure of lysozyme by enhancing the protein flexibility and thus inducing the destabilization of the secondary structure.

Storage of Micellar Casein Powders with and without Lactose: Consequences on Color, Solubility, and Chemical Modifications.

During storage, a series of changes occur for dairy powders, such as protein lactosylation and the formation of Maillard reaction products (MRPs), leading to powder browning and an increase of insoluble matter. The kinetics of protein lactosylation and MRP formation are influenced by the lactose content of the dairy powder. However, the influence of lactose in the formation of insoluble matter and its role in the underlying mechanisms is still a subject of speculation.

When drugs plasticize film coatings: Unusual formulation effects observed with metoprolol and Eudragit RS.

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.

Investigation of secondary structure evolution of micellar casein powder upon aging by FTIR and SRCD: consequences on solubility.

Background: Synchrotron radiation circular dichroism (SRCD) and Fourier transform infrared (FTIR) spectroscopy were used to examine the conformation evolution of micellar casein (MC) powder during storage and to determine whether the spectral changes could be related to their solubility evolution.

Results: A loss in intensity of SRCD spectra as a function of storage time has been observed. Quantification of secondary structures revealed losses of α-helix content during storage.

Influence of a Small Amount of Glycerol on the Trehalose Bioprotective Action Analyzed In Situ During Freeze-Drying of Lyzozyme Formulations by Micro-Raman Spectroscopy.

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 DO (wt% 1:9), in trehalose-DO mixture (wt% 1:1:8), and in the trehalose-glycerol-DO mixture (wt% 1:1:0.

Structural description of the marketed form of valsartan: A crystalline mesophase characterized by nanocrystals and conformational disorder.

Valsartan is an antihypertensive drug, recognized to be marketed in an amorphous state, different from that obtained by quenching the liquid state below T. This is an unusual and very original situation, given that the amorphous state is unstable. Low-wavenumber Raman spectroscopy and X-ray diffraction investigations were carried out on the various solid-state forms of valsartan.

Low-Frequency Dynamics of BSA Complementarily Studied by Raman and Inelastic Neutron Spectroscopy.

The present study focuses on protein motions on the picosecond time scale, generally characterized by the overlapping of vibrational and relaxational dynamics in disordered molecular systems. Recently, it has been demonstrated that a dry protein, bovine serum albumin (BSA), shows a glass-like transition in the temperature range between 240 and 260 K. Here, we present the results of combined low-frequency Raman and inelastic neutron scattering studies of dry BSA under conditions similar to those of this glass-like transition.