Adenilson O. dos Santos

A PAT approach for the on-line monitoring of pharmaceutical co-crystals formation with near infrared spectroscopy.

Cocrystals represent a class of crystalline solids consisting of two or more molecular species usually held together by non-covalent bonds. Pharmaceutical cocrystals can alter the physicochemical properties of the active pharmaceutical ingredient to improve solubility, dissolution rate, particle properties and stability. This work presents a process analytical technology (PAT) approach to monitor on-line the cocrystallization of furosemide and adenine by solvent evaporation using near infrared spectroscopy (NIRS). Furosemide and adenine were added to a small volume of methanol in a beaker and stirred on an orbital stirring table during 8h at room temperature. The on-line monitoring was performed with a FT-NIR spectrometer fitted with a reflectance fiber optic probe. Monitoring was performed with the probe tip placed 1cm above the cocrystallization medium to avoid interference with the cocrystallization process. Cocrystals were vacuum dried to remove residual solvent and characterized off-line by NIRS, MIRS, DSC and XRPD. Results demonstrate that it was possible to follow the main cocrystallization events on-line.

Batch Statistical Process Monitoring Approach to a Cocrystallization Process

Cocrystals are defined as crystalline structures composed of two or more compounds that are solid at room temperature held together by noncovalent bonds. Their main advantages are the increase of solubility, bioavailability, permeability, stability, and at the same time retaining active pharmaceutical ingredient bioactivity. The cocrystallization between furosemide and nicotinamide by solvent evaporation was monitored on-line using near-infrared spectroscopy (NIRS) as a process analytical technology tool. The near-infrared spectra were analyzed using principal component analysis. Batch statistical process monitoring was used to create control charts to perceive the process trajectory and define control limits. Normal and non-normal operating condition batches were performed and monitored with NIRS. The use of NIRS associated with batch statistical process models allowed the detection of abnormal variations in critical process parameters, like the amount of solvent or amount of initial components present in the cocrystallization.

Lattice strain distribution resolved by X‐ray Bragg‐surface diffraction in an Si matrix distorted by embedded FeSi2 nanoparticles

Out-of-plane and primarily in-plane lattice strain distributions, along the two perpendicular crystallographic directions on the subsurface of a silicon layer with embedded FeSi2 nanoparticles, were analyzed and resolved as a function of the synchrotron X-ray beam energy by using ω:φ mappings of the ({\overline 1}11) and (111) Bragg-surface diffraction peaks. The nanoparticles, synthesized by ion-beam-induced epitaxial crystallization of Fe+-implanted Si(001), were observed to have different orientations and morphologies (sphere- and plate-like nanoparticles) within the implanted/recrystallized region. The results show that the shape of the synthesized material singularly affects the surrounding Si lattice. The lattice strain distribution elucidated by the nonconventional X-ray Bragg-surface diffraction technique clearly exhibits an anisotropic effect, predominantly caused by plate-shaped nanoparticles. This type of refined detection reflects a key application of the method, which could be used to allow discrimination of strains in distorted semiconductor substrate layers.

X-ray phase measurements as a probe of small structural changes in doped nonlinear optical crystals

X-ray multiple diffraction experiments with synchrotron radiation were carried out on pure and doped nonlinear optical crystals: NH4H2PO4 and KH2PO4 doped with Ni and Mn, respectively. Variations in the intensity profiles were observed from pure to doped samples, and these variations correlated with shifts in the structure factor phases, also known as triplet phases. This result demonstrates the potential of X-ray phase measurements to study doping in this type of single crystal. Different methodologies for probing structural changes were developed. Dynamical diffraction simulations and curve fitting procedures were also necessary for accurate phase determination. Structural changes causing the observed phase shifts are discussed.

Synthesis of a Glibenclamide Cocrystal: Full Spectroscopic and Thermal Characterization

A cocrystal of glibenclamide, an antidiabetic drug classified as type II compound according to the Biopharmaceutics Classification System, has been synthesized using tromethamine as coformer in 1:1 molar ratio, by slow solvent evaporation cocrystalization. The cocrystal obtained was characterized by X-ray powder diffraction, differential scanning calorimetry, Raman, mid infrared, and near-infrared spectroscopy. The results consistently show the formation of a cocrystal between active pharmaceutical ingredients and conformer with the synthons corresponding to hydrogen bonding between hydrogen in amines of tromethamine and carbonyl and sulfonyl groups in glibenclamide.

Statistical process control of cocrystallization processes: A comparison between OPLS and PLS

Orthogonal partial least squares regression (OPLS) is being increasingly adopted as an alternative to partial least squares (PLS) regression due to the better generalization that can be achieved. Particularly in multivariate batch statistical process control (BSPC), the use of OPLS for estimating nominal trajectories is advantageous. In OPLS, the nominal process trajectories are expected to be captured in a single predictive principal component while uncorrelated variations are filtered out to orthogonal principal components. In theory, OPLS will yield a better estimation of the Hotellings T2 statistic and corresponding control limits thus lowering the number of false positives and false negatives when assessing the process disturbances. Although OPLS advantages have been demonstrated in the context of regression, its use on BSPC was seldom reported. This study proposes an OPLS-based approach for BSPC of a cocrystallization process between hydrochlorothiazide and p-aminobenzoic acid monitored on-line with near infrared spectroscopy and compares the fault detection performance with the same approach based on PLS. A series of cocrystallization batches with imposed disturbances were used to test the ability to detect abnormal situations by OPLS and PLS-based BSPC methods. Results demonstrated that OPLS was generally superior in terms of sensibility and specificity in most situations. In some abnormal batches, it was found that the imposed disturbances were only detected with OPLS.

On the effect of Au2+ ion irradiation in an amorphous Fe–Si thin layer synthesized by ion implantation: a high resolution X-ray diffraction study

High resolution X-ray diffraction and synchrotron radiation multiple diffraction were used to investigate the structural effects induced by 5 MeV Au2+ ion irradiation into amorphous Fe–Si thin layers synthesized by Fe+ ion implantation in a Si(001) substrate. The concentration–depth profile and damage distribution induced by the Fe and Au ions were estimated by Monte-Carlo calculations (TRIM code) and were used to support the obtained experimental results. Grazing incidence X-ray diffraction and reflectivity measurements show the amorphous feature and interface quality of the as-implanted and Au-irradiated samples. Matrix and a distinct Si-distorted region contributions were detected by high resolution (004) rocking curves, as well as by Si(113) asymmetrical reciprocal space mapping patterns, for just the Au-irradiated samples. They have also shown defect distribution on the Si-distorted region interface plane. The exact multiple diffraction condition of the (1)(13) four-beam case was tailored and showed in a single ω:phi mapping, through the (1-13) coherent hybrid reflection, all previously detected effects of the Au-irradiation in the Si lattice. It is the first observation of this kind of hybrid reflection in an ion implanted and irradiated Si substrate. From the incidence (ω) and azimuthal (ϕ) angular positions measured, the Si-distorted region lattice parameters were determined along the in-plane and out-of-plane directions.