Polymorphic Forms Research Articles

Structural Specificity of Polymorphic Forms of α-Synuclein Amyloid.

The structural transformation producing amyloids is a phenomenon that sheds new light on the protein folding problem. The analysis of the polymorphic structures of the α-synuclein amyloid available in the PDB database allows analysis of the amyloid-oriented structural transformation itself, but also the protein folding process as such. The polymorphic amyloid structures of α-synuclein analyzed employing the hydrophobicity distribution (fuzzy oil drop model) reveal a differentiation with a dominant distribution consistent with the micelle-like system (hydrophobic core with polar shell). This type of ordering of the hydrophobicity distribution covers the entire spectrum from the example with all three structural units (single chain, proto-fibril, super-fibril) exhibiting micelle-like form, through gradually emerging examples of local disorder, to structures with an extremely different structuring pattern. The water environment directing protein structures towards the generation of ribbon micelle-like structures (concentration of hydrophobic residues in the center of the molecule forming a hydrophobic core with the exposure of polar residues on the surface) also plays a role in the amyloid forms of α-synuclein. The polymorphic forms of α-synuclein reveal local structural differentiation with a common tendency to accept the micelle-like structuralization in certain common fragments of the polypeptide chain of this protein.

Characterization of Thermal Properties of Ruby Chocolate Using DSC, PDSC and TGA Methods

Barely explored in the prior literature, ruby chocolate was investigated in this study to explore its thermal properties. The fatty acid composition of ruby chocolate (RC) fat was determined using gas chromatography. Differential scanning calorimetry (DSC) was successfully used to determine the melting behavior and polymorphic forms of the cocoa fat and milk fat present in the RC. The oxidative stability of the fat extracted from the RC was studied with the use of pressurized differential scanning calorimetry (PDSC). The thermal behavior of the chocolate and the fat were investigated using thermogravimetry (TGA). The thermal profile and characteristics of the RC showed how the parameters compared with those of dark and milk chocolate. The melting temperature of the RC obtained by DSC was more similar to that of milk chocolate than to that of dark chocolate. Regression analysis of the PDSC data for the fat extracted from the RC was characterized by very high correlation coefficients (>0.99). It was noticed there was no statistically significant difference between the values of the activation energy (Ea) of the oxidation process for the fat extracted from the RC, obtained by the means of maximum temperature (dynamic mode) and maximum induction time (isothermal mode).

Computational investigation of the impact of potential AT2R polymorphism on small molecule binding

For more than a century, the renin-angiotensin system (RAS) has been acknowledged for playing a crucial part in the physiological control of arterial pressure, as well as sodium and fluid balance. It is now generally acknowledged that one of the receptor of RAS system i.e. angiotensin type 2 receptor (AT2R) functions as a repair system during pathophysiologic circumstances and performs a significant protective role. Efforts have been made previously to design suitable agonist and antagonist molecules to potentially modulate AT2R. One of the agonists and antagonists, named C21 and EMA401, has been studied in a number of pathological conditions. Additionally, a wide panel of single nucleotide polymorphisms (SNPs) has been reported for AT2R, which might potentially affect the efficacy of these molecules. Therefore, computational investigations have been carried out to analyze all the SNPs (1151) reported in NCBI to find potential SNPs affecting the active site of AT2R, as this domain is still unexplored. Structures of these polymorphic forms were modeled, and in silico drug interaction studies with C21 and EMA401 were carried out. The two mutants (rs868939201 and rs1042852794) that significantly affect the binding affinity as that of the wild type were subjected to molecular dynamics simulations. Our analysis of native and mutant AT2R and their complexes with C21 and EMA401 indicated that the occurrence of these mutations affects the conformation of the protein and has affected the binding of these ligand molecules. The study’s findings will aid in the development of better, more versatile medications in the near future, and also in vitro and in vivo studies might be planned in accordance with recent findings. Communicated by Ramaswamy H. Sarma

Combined novel approach to enhance the solubility and Intestinal absorption: A recent review

For oral pharmaceutical products to achieve high bioavailability and minimal variability, the API must dissolve and be stable in the GI media as well as sufficiently absorb at pertinent sites in the large intestine and small intestine. The possibility for API absorption from any dosage form is determined by an important biopharmaceutical parameter known as regional intestine effective permeability. For effective estimation of the manufacturing potential of a dosage form, it is especially crucial to understand the quantity of drug absorption from the human large intestine. Drug development is difficult because enhancing a drug's solubility, dissolution, and bioavailability is challenging. Among the four classes of the biopharmaceutical classification system (BCS) major work has been done on the low soluble drugs. In recent years poor solubility has been a major challenge for pharmaceutical scientists and a lot of experimental works are ongoing. Changing polymorphic forms by different new approaches and increase in the surface area is a widely used and comparatively simple method for increasing solubility and making the drug more bioavailable. For achieving the desired effects, permeability (intestinal absorption) is also playing an important role like solubility, but the focus of scientists is less on the permeability enhancement of low permeable drugs in respect of solubility. Sometimes it has been tried but with very limited success. The objective of this paper to provide a comprehensive review on improving solubility, release and intestinal absorption of low soluble and low permeable drugs with a combined novel approach of solubility and absorption enhancement. The ability to produce high soluble and high permeable drugs will grow significantly in the coming years and this will help to grow the revenue of the innovators as well as generic pharmaceutical companies. Keywords: Absorption, Bioavailability, Dissolution, Duodenum, Gastrointestinal tract, Gastrointestinal transit time, Gastroretention, Milling, Permeability, Poorly water-soluble drug(s), Polymer(s), Solvent evaporation, Spray drying

13C CPMAS NMR as an Alternative Method to Verify the Quality of Dietary Supplements Containing Curcumin.

Turmeric is a traditional Indian spice that has recently become very popular worldwide because it contains a powerful ingredient called curcumin, which has strong anti-inflammatory properties. Hence, dietary supplements containing extracts rich in curcumin have gained great popularity. The main problems related to curcumin-containing dietary supplements are poor water solubility and the fact that they are often faked by using synthetic curcumin instead of the plant extract. In this article, we propose the use of the 13C CPMAS NMR method to control the quality of dietary supplements. The analysis of 13C CPMAS NMR spectra supported by GIPAW computations allowed us to identify a polymorphic form present in dietary supplements (which affected the solubility of curcumin) and to point out a dietary supplement that could be faked by using synthetic curcumin. Further PXRD and HPLC investigations confirmed that the examined supplement contained synthetic curcumin instead of the genuine extract. Our method can be used for routine control, especially because the investigation is performed directly from the capsule/tablet content and does not require any special sample preparation.

Mesoporous Drug Delivery System: From Physical Properties of Drug in Solid State to Controlled Release.

Mesoporous materials, which exhibit great potential in the control of polymorphs and delivery of poorly water-soluble drugs, have obtained considerable attention in the field of pharmaceutical science. The physical properties and release behaviors of amorphous or crystalline drugs may be affected by formulating them into mesoporous drug delivery systems. In the past few decades, an increasing amount of papers have been written about mesoporous drug delivery systems, which play a crucial role in improving the properties of drugs. Herein, mesoporous drug delivery systems are comprehensively reviewed in terms of their physicochemical characteristics, control of polymorphic forms, physical stability, in vitro performance, and in vivo performance. Moreover, the challenges and strategies of developing robust mesoporous drug delivery systems are also discussed.

Structural Characterization of Pharmaceutical Cocrystals with the Use of Laboratory X-ray Powder Diffraction Patterns

X-ray powder diffraction is a vital analytical tool that is used in pharmaceutical science. It is increasingly used to establish the crystal structure of a new pharmaceutical substance, in particular, cocrystal or its polymorphic forms. This review begins with a brief discussion of the reliability of the structural parameters retrieved from powder patterns. Recent examples of the successful determination of crystal structures of pharmaceutical cocrystals and salts from powder diffraction data are discussed. These examples show the increased capabilities of laboratory X-ray powder diffractometers and modern software in solving actual problems of pharmaceutical science.

POLYMORPHIC STABILITY EVALUATION OF DARUNAVIR AND RITONAVIR IN FIXED DOSE DRUG COMBINATION PRODUCT BY X-RAY DIFFRACTION AND DIFFERENTIAL SCANNING CALORIMETRY TECHNIQUES

Evaluation of polymorphism for active ingredients and its stability during manufacturing and storage is a critical task for pharmaceutical firms. For solubility enhancement of ritonavir, hot melt extrusion process was selected through conversion of commercially available crystalline form to amorphous. XRD method (with normal and slow scan) and DSC method was considered for polymorphic evaluation in tablet formulation comprising darunavir 800 mg and ritonavir 100 mg. Specificity and precision of XRD method was justified by no interference of placebo and 5.6% RSD, respectively. The observed correlation coefficient of 0.9991 and average recovery of 98.7% (range 91.5 to 105.1) depicts linearity and recovery power of developed method. Studied DSC method shows exotherm for ritonavir crystalline form II at 127.4 °C and darunavir ethanolate at 105.7 °C, which were specific and sensitive to assess polymorphic form of available drug substances in ritonavir blend as well as in tablet formulation during release and stability period.

Relative Stability of Pyrazinamide Polymorphs Revisited: A Computational Study of Bending and Brittle Forms Phase Transitions in a Broad Temperature Range

Pyrazinamide may exist in at least four known polymorphic forms, which were obtained experimentally. One of these polymorphs, (α), shows outstanding mechanical properties, demonstrating a significant anisotropic plasticity in a three-point bending test, while the δ form was brittle. Despite a δ → α transition as well as β and γ behavior being experimentally studied, the relative stability of pyrazinamide polymorphs remains unclear and even controversial. In this work we provide a pure computational study of the thermodynamic relationships between all four polymorphs as a function of temperature using periodic DFT calculations. It was shown that the β but not the δ form is the most stable at low temperatures. Moreover, the relative stability of the δ form in comparison to α is questioned, showing that the “brittle to bending” δ → α transition was kinetically hindered in the experiments. We show that α and γ polymorphs were stabilized at higher temperatures due to an entropy term. Finally, the calculated stability of the bending α form of pyrazinamide at room temperature was in perfect agreement with previous experiments, which showed a transformation of all other forms to α during six month storage or grinding.

Polymorphism of Pradofloxacin: Crystal Structure Analysis, Stability Study, and Phase Transformation Behavior.

Pradofloxacin is an important antibiotic with poor physical stability. At present, there is no systematic study on its polymorphic form. The purpose of this study is to develop new crystal forms to improve the stability of Pradofloxacin and systematically study the crystal transformation relationships to guide industrial production. In this work, three solvent-free forms (Form A, Form B and Form C), a new dimethyl sulfoxide solvate (Form PL-DMSO) and a new hydrate (Form PL-H) were successfully obtained and the single crystal data of Form A, Form B and Form PL-DMSO were solved for the first time. Various solid state analysis techniques and slurry experiments have been used to evaluate the stability and determine phase transformation relationships of five crystal forms, the analysis of crystal structure provided theoretical support for the results. The water vapor adsorption and desorption experiences of Forms A, B, C and Form PL-H were studied, and the results show that the new hydrate has good hygroscopic stability and certain development potential. The thermal stability of different forms was determined by thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) and the crystal structure shows that there are more hydrogen bonds and C - H···π interactions in form B, which is the reason why Form B is more stable than form A. Finally, the phase transformation relationships of the five crystal forms were systematically studied and discussed. These results are helpful to provide guiding methods in the production and storage of pradofloxacin.

The world of exotic crystals: Raman spectro-microscopy for probing local structure

In this article, we review briefly the recent progress on mechanically responsive molecular crystals which defy the common perception that “crystals are rigid”. Crystals which respond to different external stimuli are emerging fast and may find applications in miniature technologies, sensors, flexible devices, and soft-robotics. Here, we present some early examples of molecular crystals from our group, along with other examples of our choice, to emphasize on the use of Raman spectromicroscopy technique for characterizing crystals, polymorphic forms and strained crystals in the context of structure- property correlation and crystal engineering.

Polymorphism of Butyl Ester of Oleanolic Acid—The Dominance of Dispersive Interactions over Electrostatic

Oleanolic (OA) and glycyrrhetinic acids (GE), as well as their derivatives, show a variety of pharmacological properties. Their crystal structures provide valuable information related to the assembly modes of these biologically active compounds. In the known-to-date crystals of OA esters, their 11-oxo derivatives, and GE ester crystals, triterpenes associate, forming different types of ribbons and layers whose construction is based mainly on van der Waals forces and weak C-H···O interactions. New crystal structures of 11-oxo OA methyl ester and the polymorph of OA butyl ester reveal an alternative aggregation mode. Supramolecular architectures consist of helical chains which are stabilized by hydrogen bonds of O-H···O type. It was found that two polymorphic forms of butyl OA ester (layered and helical) are related monotropically. In a structure of metastable form, O-H···O hydrogen bonds occur, while the thermodynamically preferred phase is governed mainly by van der Waals interactions. The intermolecular interaction energies calculated using CrystalExplorer, PIXEL, and Psi4 programs showed that even in motifs formed through O-H···O hydrogen bonds, the dispersive forces have a significant impact.

Structure–energy relationship of food materials using differential scanning calorimetry

AbstractThe use of differential scanning calorimetry (DSC) in the food authentication and process‐chain traceability has raised significant amelioration in terms of structure and stability of some structured foods. In this review article DSC is used to raise other quantitative energy parameters related to structural reconformation and variation in the intra‐molecular dimension of studied materials. These properties are explained by the respective energy models involving (1) quantum energy, (2) quantum mass, and (3) quantum velocity. These models parameters are explored as well as on from enthalpy, entropy, heat capacity, and Gibbs free energy of transition in determining the nucleation energy relevant to crystallization and polymorphic transformation of some studied food‐materials.Practical ApplicationDifferential scanning calorimetry is remaining the powerful thermoanalytical tool used in studying the mechanism of crystallization, polymorphism, and structural reconformation of biological matters. The expression of energetic parameters on from enthalpy, entropy, heat capacity, and Gibbs free energy of transition help in determining the nucleation energy whether is stable or in the meta‐static forms. In addition these energy parameters are the key elements in understanding whether the food materials undergoing denaturation, unfolding or reversible folding, meaning that DSC is able in determining the status of food materials whether is stable or instable as well as the texture whether is soft, grainy, or coarse and also the polymorphic forms of the crystals and stability of the emulsions. Thus, gathering information on the thermal analysis using DSC helped in establishing some model correlation between energy and structure in association with the chemical composition changes of some model of oils and fats.

Synthesis and crystal structure of two novel polymorphs of (NaCl)[Cu(HSeO3)2]: a further contribution to the family of layered copper hydrogen selenites

Abstract Crystals of two new polymorphic forms of the known compound (NaCl)[Cu(HSeO3)2], which we term polymorphs II and III, were formed after a ca. one-year dwelling of a crystalline precipitate under mother liquor and upon crystallization in the presence of K+, respectively. Both structures belong to the “layered copper hydroselenite” family. The polymorph II is a structural analog of (KCl)[Cu(HSeO3)2] with a fully ordered Na+ site; the main difference concerns the environment of Cu2+ which is more regular in (NaCl)[Cu(HSeO3)2]-II. In contrast to some expectations, crystallization from solutions containing KCl. NaCl, CuCl2, and H2SeO3 upon evaporation does not result in formation of mixed (Na1−x K x Cl)[Cu(HSeO3)2] crystals, but rather in a separate crystallization of (KCl)[Cu(HSeO3)2] and (NaCl)[Cu(HSeO3)2]-III which exhibits a complex structure with four ordered and one disordered Na+ sites. It is possible that longer crystallization times enhance formation of ordered structures.

Carbonization of Class G well cement containing metakaolin under supercritical and saturated environments

A well-cement alteration in a CO2-rich environment can affect the well integrity, and, consequently, compromise the overall safety of an external ecosystem. The objective of this study was to evaluate the carbonization of Class G well cement and metakaolin modified Class G cement samples exposed to CO2 at 323 K and 15 MPa under supercritical state and in the saturated solution. Cement alternation was more rapid and extensive under a CO2 saturated solution than under supercritical CO2. Metakaolin amended Class G cement samples showed improved mechanical properties, while their carbonation resistance was impaired and reduced. X-ray Powder Diffraction confirmed that CaCO3 polymorphs were present in greater proportions in the metakaolin-modified samples and when exposed to a CO2-saturated salt solution. Moreover, samples containing metakaolin have a larger specific surface area, and, consequently, can absorb more CO2. The micrographs showed that the cement samples exposed to a CO2-rich environment have rough and porous surfaces containing CaCO3 polymorphic crystalline forms.

Assessment of Solid-State Behaviour and in vitro Release of Artemether from Liquisolid Compact Using Mesoporous Material as an Excipient

Abstract: Background: Artemether is a potent antimalarial drug used in the first-line treatment of multi-drug-resistant malaria. It belongs to BCS II, exist in different polymorphic forms, and exhibits incomplete absorption and low oral bioavailability owing to poor dissolution. Aim: The present study evaluates the effect of different mesoporous materials in the liquisolid compact for the augmentation of dissolution of the drug, and polymorphic stability. Materials and Methods: In the liquisolid compact Tween 80 was used as a non-volatile solvent for the dispersion of the drug, microcrystalline cellulose as carrier, and Syloid244FP and SyloidXDP as coating materials at different coating and carrier ratios. Eight such formulations were prepared. The formulated liquisolid compact was evaluated for precompression parameters, followed by direct compression process. The tablets thus prepared were assessed for hardness, friability, wetting time, in-vitro dissolution, and stability studies. Physico-chemical characterization was done to study drug excipient interaction, thermal behaviour, and surface characteristics. Results and Discussion: The study revealed that an increasing quantity of mesoporous material exhibited a better release profile compared to the pure drug. Good compressibility and tablet ability were observed at a carrier and coating materials ratio of 1:5. Compatibility between the drug and excipients was established from the FTIR study. Noteworthy findings of PXRD and DSC suggested the presence of artemether in metastable β form in the formulations. Short-term stability of the formulations was established. Conclusion: Hence, the approach of liquisolid compact using mesoporous silicas at a suitable excipient ratio could be an optimistic approach for the enhancement of dissolution and stability of artemether. Keywords: Artemether, Liquisolid compact, Solid-state behaviour, Dissolution, Mesoporous silica.

Control of the Crystal Morphology and Polymorphic Form of a Dithiadiazolyl Radical Using Co-sublimation

Crystals of the elusive α-polymorph of the dithiadiazolyl radical p-NCC6F4CNSSN• (1) have been isolated from co-sublimations of 1 with a second radical, 2,6-C6H4F2CNSSN• (2). Co-sublimation of 1 and 2 also results in control of the morphology of crystals of the β-polymorph of 1, yielding blocks of 1β instead of the long needles more commonly obtained. An analysis of the intermolecular interaction strengths in the two polymorphs gives insight into a proposed mechanism for polymorph control.

A QBD WITH THE FRACTIONAL FACTORIAL DESIGN WAS USED TO MATCH THE SIMILARITY BETWEEN RANOLAZINE EXTENDED-RELEASE TABLETS 500 MG AND 1000 MG

Objective: Formulation and development of Ranolazine extended-release Tablets 500 mg and 1000 mg by using QBD with Fractional factorial design to match the similarity with Branded formulation (RANEXA®). Methods: Ranolazine extended-release tablets were developed by using various polymers, Polyquid PA100 and ETHOCEL TMstandard 7 premium and Hypromellose with a wet granulation process. QBD (Quality by Design) approach was used to identify the formulation and process variables that may affect the CQAs (critical quality attributes). Excipient compatibility studies were conducted to identify the interaction between API (active pharmaceutical ingredient) and selected excipients. Additionally, using a two-level, fractional factorial (22+3) design, the DOE (design of experiments) was employed to confirm the impacts of key process factors (fluid uptake and kneading time) on the formulation's ability to match the dissolution (f2) compared to RLD (reference listed drug) and establish a stable formulation. Results: Initial risk assessment was carried out to identify the various attributes such as API flow properties, solubility, PSD, Hygroscopicity, formulation, and process variables to impact the quality of the drug product. Flow properties of API indicate poor flow. Drug and excipients compatible study results indicate that excipients used in the compatibility study are considered compatible with the active ingredient. As per the saturation solubility studies and sink conditions, dissolution media was selected. Significant differences were found among the drug release profile by examining the various levels of polymers and binders. Using a two-level, fractional factorial (22+3) design, optimum process parameters were identified with selected formulation to match the dissolution (f2) similarity with the reference listed drug (RLD); finally, XRD (X-ray diffraction) studies confirm that the crystalline polymorphic forms (Form 1) peaks in optimum formulation (F07) comparable to the reference listed drug. Conclusion: Optimized formulation and process were established with QbD (quality by design) that provides the consistent drug release to match the f2 similarities with the extended-release tablets of RANEXA®(Ranolazine) 500 mg and 1000 mg.

Approach for Detecting Junctions in Roundabout Using Map Data

In logical terms, a 2D map is a polymorphic form of linear objects made from practical features like roads, cartos (geometrical representation of a collection of buildings or specific features), roundabouts, highways, and many more. As autonomous vehicle disrupts transportation and navigation, there is a need to detect and identify map features at a granular level with no human intervention. This paper focuses on one of the practical problems, i.e. determining whether a junction is part of roundabouts using the Map domain, which is a novel approach to the best of the knowledge of an author. In a roundabout, the junction is the node having entry or exit of roads in or away from it. Closed loops in roads are extracted by traversing each link and checking for the common junctions using a deterministic algorithm. Loops can be formed not only by roundabouts it can be present at any intersection of roads, from all the universal sets of junctions; identifying the pattern and finding the right junctions of a roundabout is a very challenging and exciting problem. The authors have solved this problem in two parts; data extraction is done by collecting all the roads of America and Europe and then features are extracted, which depend on logical and domain knowledge. Finally, for the fuzzy part of features, a machine model that provides an efficient accuracy of 81% is created as it reduces lots of manual effort for verifying and correcting junctions. This applied methodology is easy to implement.

Baking using oleogels

Baking using oleogels