Crystal Polymorphism Research Articles

Controlling orientation, polymorphism, and crystallinity in thin films of poly(lactic‐acid) homopolymer and stereocomplex aligned by high temperature rubbing

AbstractHigh temperature rubbing is a fast and low‐cost method that can align semi‐crystalline polymers such as poly(lactic acid) (PLA) by application of a shear‐force via a rotating cylinder covered with a microfiber cloth on a thin film maintained at high temperature. A multi technique approach uncovers the role of rubbing temperature and film thickness on the PLA thin film structure. Both poly(l‐lactic acid) (PLLA) and the stereo‐complex (SC‐PLA) can be readily aligned by high temperature rubbing. The rubbing temperature TR and the film thickness are the key parameters that control polymorphism, in‐plane orientation, crystallinity and contact plane of the polymer crystals. Rubbing PLLA films in the range 80–140°C affords different aligned polymorphs (mesophase, α′, α′ + α mixtures and pure α phase) depending on the rubbing temperature. Pure α form of PLLA with 53% crystallinity is obtained at TR = 140°C whereas pure oriented crystalline SC‐PLA films are obtained by rubbing at 200°C.

A rod- and tessellation-based comparative analysis of polymorphic and structurally-invariant molecular crystals: application to sulfathiazole and 2-benzyl-5-benzylidenecyclopentanones.

A rationalization of the alternative crystal structures adopted by a given molecular compound or by a set of substitutionally related molecular compounds is provided by reference to the five known polymorphs of sulfathiazole and 16 substituted 2-benzyl-5-benzylidene cyclopentanones (BBCPs), respectively. Two-dimensional (2D) packing fractions (ϕ2D) take space-group symmetry into account, with a clear demarcation of closed-packed zones (CPZ) and molecular junction zones (JZ) in all Z' = 1 structures. Representation of the molecules as two linked rods allows a concise treatment of conformation and rapid visualization of crystal packing. Combined with calculations of intermolecular potential energies, the rod method provides insight into the stabilization mechanisms of alternative polymorphs. In sulfathiazole, the primary factor is to obtain satisfactory hydrogen bonding, with close packing a secondary consideration. In BBCP derivatives, by comparison, close packing is the primary mechanism of stabilization. Whereas the 2D structures arising in CPZ can be analysed as tessellations of molecular-based cells, a method based on 2D Dirichlet cells is required for the JZ. These are calculated from the centroids of the molecular envelopes in high-symmetry planes. It is shown that these centroid coordinates, when combined with space-group symmetry and unit cell coordinates, provide a concise parameterization of all structures containing JZ. It is anticipated that this parameterization may be exploited to predict such crystal structures from powder diffraction data.

Hydrated polymorphs of 2,3,4,5,6-pentachlorobenzoic acid: Crystallographical and computational analyses of disordered hydrogen-bonding networks

The title compound, 2,3,4,5,6-pentachlorobenzoic acid (PCBAH), was found to have two crystal polymorphs, I and II. In this work, novel two hydrated polymorphs, polymorph III and IV, were reported. An asymmetric unit of the polymorph III is comprised of one PCBAH and a water molecule. They align alternatively along the a axis, forming C22(6) hydrogen-bonding. The water molecule makes another hydrogen bond with a water molecule in an inversion symmetry to give two-legged ladder hydrogen-bonding network. In polymorph IV, there are two PCBAHs, 2,3,4,5,6-pentachlorobenzate (PCBA) and H3O+ in an asymmetric unit. H3O+ molecule makes hydrogen-bonding with two PCBA anions, forming C22(6) hydrogen-bonding along the 21 axis. Two PCBAH molecule make hydrogen bonds with both H3O+ and PCBA. In both hydrated polymorphs, hydrogen atoms of water molecules are disordered. The positions of hydrogen atoms of the water molecules were determined with assistance of computational calculations under the crystalline environment.

DEVELOPMENT AND CHARACTERIZATION OF LAURIC ACID OLEOGELS

Bu çalışmada laurik asit (LA) oleojelatörü Span 60 ve Pluronic F68 (%10 poloksamer 188) emülgatörleriyle birlikte kullanılarak ayçiçek yağı oleojelleri geliştirilmiştir. Geliştirilen oleojellerin fizikokimyasal, termal, yapısal ve reolojik özellikleri belirlenmiştir. Sadece LA içeren (%20) oleojellerin jel oluşum zamanının %15 LA ve %5 emülgatör içeren oleojellerden daha kısa olduğu, LA konsantrasyonundaki artışın jel yapı oluşum zamanını kısalttığı gözlenmiştir. LA konsantrasyonu ve emülgatör çeşidine bağlı olarak oleojellerin renk değerlerinde farklılıklar görülürken tüm oleojel örneklerinin yağ bağlama kapasitelerinin yüksek olduğu belirlenmiştir. Polarize ışık mikroskobu görüntülerinde oleojellerin ince kristal yapılar oluşturduğu gözlenirken, X-ışını kırınım deseni β ve β՛ polimorf kristallerinin varlığını kanıtlamıştır. Reolojik analizlerle geliştirilen oleojellerinin yapısal geri dönüşüm yeteneğinin olduğu belirlenmiştir. Emülgatör ilavesinin daha düşük konsantrasyonlarda LA ile oleojel oluşumuna olanak sunduğu, aynı zamanda daha dayanıklı jel yapı oluşturabildiği reolojik testlerle tespit edilmiştir.

Crystal polymorphism in fragment-based lead discovery of ligands of the catalytic domain of UGGT, the glycoprotein folding quality control checkpoint.

None of the current data processing pipelines for X-ray crystallography fragment-based lead discovery (FBLD) consults all the information available when deciding on the lattice and symmetry (i.e., the polymorph) of each soaked crystal. Often, X-ray crystallography FBLD pipelines either choose the polymorph based on cell volume and point-group symmetry of the X-ray diffraction data or leave polymorph attribution to manual intervention on the part of the user. Thus, when the FBLD crystals belong to more than one crystal polymorph, the discovery pipeline can be plagued by space group ambiguity, especially if the polymorphs at hand are variations of the same lattice and, therefore, difficult to tell apart from their morphology and/or their apparent crystal lattices and point groups. In the course of a fragment-based lead discovery effort aimed at finding ligands of the catalytic domain of UDP-glucose glycoprotein glucosyltransferase (UGGT), we encountered a mixture of trigonal crystals and pseudotrigonal triclinic crystals-with the two lattices closely related. In order to resolve that polymorphism ambiguity, we have written and described here a series of Unix shell scripts called CoALLA (crystal polymorph and ligand likelihood-based assignment). The CoALLA scripts are written in Unix shell and use autoPROC for data processing, CCP4-Dimple/REFMAC5 and BUSTER for refinement, and RHOFIT for ligand docking. The choice of the polymorph is effected by carrying out (in each of the known polymorphs) the tasks of diffraction data indexing, integration, scaling, and structural refinement. The most likely polymorph is then chosen as the one with the best structure refinement Rfree statistic. The CoALLA scripts further implement a likelihood-based ligand assignment strategy, starting with macromolecular refinement and automated water addition, followed by removal of the water molecules that appear to be fitting ligand density, and a final round of refinement after random perturbation of the refined macromolecular model, in order to obtain unbiased difference density maps for automated ligand placement. We illustrate the use of CoALLA to discriminate between H3 and P1 crystals used for an FBLD effort to find fragments binding to the catalytic domain of Chaetomium thermophilum UGGT.

Ultrafast magic angle spinning NMR characterization of pharmaceutical solid polymorphism: A posaconazole example

Protons represent the most NMR-sensitive nucleus in pharmaceutical compounds. Therefore, proton-detected solid-state NMR techniques under fast magic angle spinning are among the few solutions to overcome the challenge of low sensitivity to analyze natural abundant drug substances and products. In this study, we report the structural characterization of crystal polymorphs of a commercial drug molecule, posaconazole, with a relatively large molecular weight of 700.8 g·mol−1 and at the natural abundance. The enhanced sensitivity and resolution at 100 kHz MAS enables the exploration of the distinct intermolecular packing in posaconazole forms I, III, and γ. These results demonstrate that proton-detected homo- and heteronuclear correlation methods can probe the structural details of pharmaceutical polymorphism.

Crystal Polymorphism Induced by Surface Tension.

We use classical density functional theory (cDFT) to calculate fluid-solid surface tensions for fcc and bcc crystals formed by hard spheres and Lennard-Jones (LJ) particles. For hard spheres, our results show that the recently introduced "explicitly stable" functionals perform as well as the state of the art, and for both interaction potentials, our results compare well to simulation. We use the resulting bulk and interfacial energies for LJ to parametrize a capillary model for the free energy of small solid clusters and thereby determine the relative stability of bcc and fcc LJ clusters. We show a crossover from bcc to fcc stability as cluster size increases, thus providing insight into long-standing tension between simulation results and theoretical expectations. We also confirm that the bcc phase in contact with a vapor is unstable, thus extending earlier zero-temperature results. Our Letter demonstrates the potential of cDFT as an important tool in understanding crystallization and polymorphism.

Flow-induced crystallization effect on polypropylene with respect to nucleating agents

To study FIC on the laboratory scale, we used a parallel plate rheometer (PPR), which imparts shear rates of some order of magnitude. Applying shear in undercooling temperature (151 °C) conditions to induced crystallization, which was monitored by the increase in viscosity in the PPR following an established protocol that was stetted up to assess the conditions of the experiments. After annealing samples at 230 °C for 10 min to remove the melt memory effect, it was cooled to crystallization temperature (1510C) at the rate of -1.5 °C/min to undertake FIC and finally the sample was quenched by a cryo-freezer aerosol below 0 °C before being removed for characterization study. FIC involves the formation of the time and temperature-dependent relative crystallinity of a series of isotactic polypropylene (iPP) homopolymers. In this study, I selected iPP as a typical sample due to its simple formation conditions of polymorphic crystals and its unique properties of melting curves and crystalline morphology. In this research, the influence of some nucleating agents on the crystallization behavior of (iPP) Homopolymer has been investigated by OM (Optical Microscopy) and Transmission Electron Microscope (TEM) after undergoing FIC crystallization. The study of crystallization kinetics of iPP Homopolymer nucleated with (Talc, Na-Benzoate) and neat melt (Not nucleated-used as control) helped us to control the final morphologies and mechanical properties of semi-crystalline polymers. From the measured onset time of crystallization, it was possible to conclude that iPP containing Na- Benzoate as the nucleating agent was faster in crystallization.

Phase control of two-dimensional tin sulfide compounds deposited via atomic layer deposition

Two-dimensional (2D) semiconductor materials are emerging as potential candidates for emerging electronic device applications due to their excellent electrical properties and unique properties such as flexibility and transparency. Among the various potential 2D semiconductor materials, tin sulfide compounds can form polymorphs of different 2D crystals: 2D layered-SnS2 with hexagonal symmetry and 2D layered SnS with orthorhombic symmetry. In addition, since they each have different electrical and optical properties, their controlled growth is important for appropriate target applications. Therefore, we investigated the phase control of tin sulfide compounds deposited via atomic layer deposition according to their deposition temperature and post-annealing conditions. A strategy for controlling the growth of SnS2 or SnS was proposed by investigating phase transition tendencies according to deposition temperature and annealing conditions (temperature, pressure, atmosphere). As a result, it was possible to selectively deposit SnS2 and SnS thin films based on a phase transition study; it was confirmed that SnS2 and SnS thin films exhibited n-type and p-type semiconductor characteristics, respectively.

Complex Additive‐Assisted Crystal Growth and Phase Stabilization of α‐FAPbI3 Film for Highly Efficient, Air‐Stable Perovskite Photovoltaics

AbstractSolution‐processed formamidinium lead iodide (FAPbI3) perovskite is entropically metastable, and it exhibits condition‐induced crystal polymorphism. Under an ambient atmosphere, the photoactive black α‐FAPbI3 converts easily to photoinactive yellow δ‐FAPbI3. This α → δ phase degradation is further accelerated upon exposure to high temperature/humidity, directly threatening the performance and stability of perovskite solar cells (PSCs). Herein, cesium iodide‐lead iodide:dimethyl sulfoxide (CsI‐PbI2:DMSO) complex is introduced as a phase stabilizer to modulate the crystallization of α‐FAPbI3 perovskite from δ‐FAPbI3 precursor and simultaneously, serve as a defect passivator to suppress trap states formation. Theoretical simulations and experimental results reveal the pivotal role of complex additive in optimizing the energy band alignment and optoelectronic properties of α‐FAPbI3 perovskite and most importantly, hindering the α → δ phase transition. The best PSC device based on the additive‐engineered perovskite film achieves an efficiency of ≈21.9%, which is ≈11% higher than that of its pristine counterpart (≈19.8%). In addition, the incorporation of CsI‐PbI2:DMSO complex remarkably enhances the long‐term stability and photostability of the PSCs by inhibiting ion migrations and preserving the α‐phase in FAPbI3 perovskite. The additive engineering presented herein offers a route to produce FAPbI3‐based PSCs with improved performance, stability, and reproducibility.

Surface-enhanced crystal nucleation and polymorph selection in amorphous posaconazole.

Molecules at a liquid/vapor interface have different organizations and mobilities from those in the bulk. These differences potentially influence the rate of crystal nucleation, but the effect remains imperfectly understood. We have measured the crystal nucleation rates at the surface and in the bulk of amorphous poscaconazole, a rod-like molecule known to have a preferred interfacial orientation. We find that surface nucleation is vastly enhanced over bulk nucleation, by ∼9 orders of magnitude, and selects a different polymorph (II) from bulk nucleation (I). This phenomenon mirrors the recently reported case of D-arabitol and stems from the similarity of anisotropic surface molecular packing to the structure of the surface-nucleating polymorph. In contrast to these two systems, the surface enhancement of nucleation is weaker (though still significant) in acetaminophen and in water and does not select a different polymorph. Together, the systems investigated to date all feature surface enhancement, not suppression, of crystal nucleation, and those showing a polymorphic change feature (1) structural reconstruction at the surface relative to the bulk and (2) existence of a different polymorph that can take advantage of the surface environment to nucleate. These results help predict the effect of a liquid/vapor interface on crystal nucleation and polymorph selection, especially in systems with a large surface/volume ratio, such as atmospheric water and amorphous particles.

Solution-mediated phase transition of pharmaceutical compounds: Case studies of acetaminophen and aspirin

Polymorphism is crucial in organic solid-state chemistry because different polymorphs exhibit different physical properties. Thus, the control of crystal polymorphism is a long-standing issue. We have been engaged in crystal polymorph control research, mainly targeting pharmaceutical compounds. Three processes to control the polymorphism must be considered: nucleation, crystal growth, and phase transition. Finding a metastable phase by nucleation control techniques is the first step. The next crucial step is controlling phase transition and keeping the metastable phase as long as possible. Understanding the phase transition from metastable to stable phase is essential, especially to realize the high stability metastable phase. Herein we will show the phase transition processes of acetaminophen and aspirin as model materials.

Selective formation of crystal polymorphs in Er3+-doped Bi2O3 thin films and their photoluminescence properties

The process conditions for selectively forming crystal polymorphs in Er3+-doped Bi2O3 films deposited on Si, SiO2, and C-plane sapphire substrates were systematically investigated. Bi2O3:Er films were deposited at either room temperature or 300 °C and subsequently post annealed to promote crystallization. The critical factor controlling the crystal polymorphs was Er content. When the Er content was less than 1.5 at.%, only α-Bi2O3 phase nucleated upon post annealing. Deposition at 300 °C somewhat lowered the oxidization state, under which β-Bi2O3 structure appeared at lower temperatures and α-Bi2O3 structure appeared at higher temperatures. When the films were doped with over 2 at.% Er3+ ions, the excess Er2O3 stabilized the δ-Bi2O3 structure as the lowest temperature phase. The universal phase transition scheme with increasing annealing temperature was δ-Bi2O3 → β-Bi2O3 → α-Bi2O3. The δ → β transition proceeded through splitting each diffraction peak of δ-Bi2O3 into two components of β-Bi2O3, indicating a correlation between the structures of β-Bi2O3 and δ-Bi2O3. The γ-Bi2O3 phase appeared only in films on Si(100) substrates and after vacuum annealing, suggesting the formation of sillenite (Bi12SiO20). Deposition on C-plane sapphire by using H2O as the oxygen source gas produced a highly (111)-oriented δ-Bi2O3 structure, whereas deposition with O2 yielded a randomly oriented δ-Bi2O3 structure. At Er content exceeding 4 at.%, δ-Bi2O3 was the primary phase in the films on SiO2. The photoluminescence (PL) activity of dopant Er3+ under excitation at a wavelength of 532 nm strongly depended on the crystal polymorphs. α-Bi2O3:Er exhibited intense and stable PL spectra consisting of eight Stark splitting lines. PL from γ-Bi2O3:Er exhibited much weaker two emission lines. δ-Bi2O3:Er and β-Bi2O3:Er films were not emission-active at all. However, δ-Bi2O3:Er film on SiO2 with an Er content of 4 at.% exhibited an intense and broad emission at 1530 and 1560 nm.

Unsupervised Pharmaceutical Polymorph Identification and Multicomponent Particle Mapping of ToF-SIMS Data by Non-Negative Matrix Factorization.

Crystal polymorphism of pharmaceutical compounds directly impacts resulting physicochemical characteristics, a critical aspect in active pharmaceutical ingredient (API) production. Tools to characterize and chemically map these polymorphs at the single particle scale remain important to advancing directed manufacture of targeted polymorphs. Here, time-of-flight secondary ion mass spectrometry (ToF-SIMS) was employed for chemically imaging inkjet printed acetaminophen samples. ToF-SIMS generates large data sets of high spatial resolution images. Extracting relevant data and peaks of interest can be laborious for, and biased by, users. Advances in machine learning approaches have introduced many supervised and unsupervised methods for data analysis. In this study, we apply non-negative matrix factorization (NMF) for the unsupervised analysis of ToF-SIMS chemical image data. More specifically, an expanded variant of NMF, NMFk, was employed to determine the data set's latent dimensionality. NMFk combines the spectral unmixing of traditional NMF with k-means clustering of the resulting factors and an optimization of the reconstruction and clustering. The method was used to identify the number of polymorph phases-and their representative mass spectra-generated from inkjet printed acetaminophen samples. Amorphous, crystalline form I, and crystalline form II polymorphs were observed. The learned polymorph mass spectra were then used to map the learned polymorphs onto subsequent particle samples of acetaminophen. Finally, NMFk also enabled the decomposition of mixed particle samples (i.e., migraine medicine), learning the number of compounds and their composition. The extracted constituent phase mass spectra-representing single compounds-were searched against mass spectral libraries for identification.

Polymorphic Crystallization Behavior of a Poly(butylene adipate) Midblock within a Poly(L-lactide-butylene adipate-L-lactide) Triblock Copolymer.

New biodegradable aliphatic PLLA-PBA-PLLA copolymers with soft poly(butylene adipate) (PBA) and hard poly(l-lactide) (PLLA) building blocks were synthesized via ring-opening polymerization (ROP). Proton nuclear magnetic resonance (1HNMR) was utilized to confirm the volume fraction of PBA (fPBA) within PLLA-PBA-PLLA. It was found that a PBA midblock (PBA-mid) within PLLA-PBA-PLLA-s (PLLA-PBA-PLLA triblock copolymer with a short PLLA block length) might display lamellar domain structure. However, PBA-mid within PLLA-PBA-PLLA-l (PLLA-PBA-PLLA triblock copolymer with a long PLLA block length) might locate itself as a nanoscale cylindrical domain surrounded by a PLLA continuous phase. Polymorphic crystals of PBA-mid within the PLLA-PBA-PLLA copolymers were formed after melt crystallization at the given temperatures, which were studied by differential scanning calorimetry (DSC) and wide-angle X-ray diffraction (WAXD) analysis. According to the WAXD and DSC analyses, it was interesting to find that the α-type crystal of PBA-mid was favorable to develop in the lower temperature region regardless of the state (crystallization or amorphous) of the PLLA component. Additionally, when the PLLA component was held in its amorphous state, it was easier for PBA-mid within the PLLA-PBA-PLLA copolymers to transform from the metastable β-form crystal to the stable α-form crystal. Furthermore, polarized optical microscopy (POM) photos provided direct evidence of the polymorphic crystals of PBA-mid within PLLA-PBA-PLLAs.

Controlled crystallization of metastable polymorphic pharmaceutical: Comparative study of batchwise and continuous tubular crystallizers

The deliberate and reproducible crystallization of metastable polymorphs of active pharmaceutical ingredients (APIs) from solution remains difficult and is still far from trivial. The main challenge is to prevent cross nucleation of the stable form. The traditional cooling experiments in a batch crystallizer cannot repeatably produce aripiprazole (APZ) metastable Form III within selected initial concentrations and cooling rates. The computational fluid dynamics simulations confirmed that fluctuations in temperature and solution concentration in the batch crystallizer would induce the nucleation of stable crystal forms and accelerate solvent-mediated phase transformation. This work presents, for the first time, ultrasonic- and slug-assisted tubular crystallizers for the continuous and controllable preparation of pure metastable crystal Form III of APZ. The ultrasound-assisted air segmented plug flow tubular crystallizer provides an efficient configuration to produce high purity metastable polymorphism pharmaceuticals, which also offers a facile approach for the continuous manufacturing of drug substances.

Stereocomplexed Materials of Chiral Polymers Tuned by Crystallization: A Case Study on Poly(lactic acid)

ConspectusWidespread in chemistry and biochemistry, chirality strongly affects the biological, chemical, material, and physical properties. As a downstream derivative, the enantiopure polymers of opposite chirality can cocrystallize in the stereocomplex (SC) in their enantiomeric blends or block copolymers, which endows the materials with improved physical properties and specific functions such as enhanced melting temperature, thermal stability, crystallizability, and hydrolytic resistance. A well-studied stereocomplexable polymer is poly(lactic acid) (PLA); both of its two enantiomers, poly(l-lactic acid) and poly(d-lactic acid), are biobased and biodegradable. SC crystallization is a simple and practical approach to improve the essential properties and functions of chiral polymers, which advances existing polymer applications and paves a new way to develop a variety of novel materials. However, it is noteworthy that not all of the enantiomeric blends of l- and d-polymers can exclusively crystallize into SC crystals in a typical crystallization process, which is usually accompanied by the homocrystallization of each individual enantiomer. Developing stereocomplexed materials with controlled crystalline structure, physical properties, and functions is still challenging. Consequently, studying and discussing the stereocomplexed materials developed by harnessing SC crystallization are of fundamental importance not only to obtain novel functional materials but also to promote the advancement of material researches.In this Account, we concisely summarize and analyze our recent progresses in SC crystallization and stereocomplexed materials of PLA, which initializes a conceptual methodology to study and develop the stereocomplexed materials from chiral polymers. We first introduce various approaches for controlling the polymorphic crystallization structure, in order to promote the SC crystallization of high-molecular-weight PLA and to prepare the stereocomplexed materials. Then, we present our efforts on the preparation of novel stereocomplexed materials such as micelles, physical hydrogels, and elastomers by harnessing SC crystallization. These stereocomplexed materials show good physical properties (e.g., thermomechanical property and thermal resistance) and can further be functionalized toward shape memory, drug release, and thermoresponsive materials. These works have established a practical platform to unveil the relationships between crystalline structure, physical properties, and functions of stereocomplexed materials. At the end of the Account, we offer a brief summary and outlooks in this field. Even though a case study on PLA is focused in this Account, a similar methodology can be generalizable to other chiral polymer systems. We hope that this Account will evoke new inspirations and innovative work in the field of stereocomplexed materials of chiral polymers in the near future.

Correcting π-delocalisation errors in conformational energies using density-corrected DFT, with application to crystal polymorphs

We consider several molecules characterised by π-electron conjugation whose extent changes along a flexible torsional coordinate, and which represent the monomer units of polymorphic molecular crystals. Delocalisation error in density functional theory (DFT) adversely impacts conformational energies in these species, overstabilising the conformation that maximises conjugation length and leading to incorrect relative energies for the corresponding crystal polymorphs. We demonstrate that density-corrected (DC-)DFT, in which a DFT exchange-correlation functional is evaluated using a Hartree–Fock density, significantly reduces these conformational energy errors. When DC-DFT monomer energies are used as a low-cost intramolecular correction to a periodic DFT calculation of the molecular crystal, the resulting relative polymorph energies are within 1 kJ/mol of benchmark results.

Polymorphism and Perfection in Crystallization of Hard Sphere Polymers

We present results on polymorphism and perfection, as observed in the spontaneous crystallization of freely jointed polymers of hard spheres, obtained in an unprecedentedly long Monte Carlo (MC) simulation on a system of 54 chains of 1000 monomers. Starting from a purely amorphous configuration, after an initial dominance of the hexagonal closed packed (HCP) polymorph and a transitory random hexagonal close packed (rHCP) morphology, the system crystallizes in a final, stable, face centered cubic (FCC) crystal of very high perfection. An analysis of chain conformational characteristics, of the spatial distribution of monomers and of the volume accessible to them shows that the phase transition is caused by an increase in translational entropy that is larger than the loss of conformational entropy of the chains in the crystal, compared to the amorphous state. In spite of the significant local re-arrangements, as reflected in the bending and torsion angle distributions, the average chain size remains unaltered during crystallization. Polymers in the crystal adopt ideal random walk statistics as their great length renders local conformational details, imposed by the geometry of the FCC crystal, irrelevant.

Polymorphism of Purpurin and Low-level Detection of the Noncentrosymmetric form by Second Harmonic Generation Microscopy

Nonlinear optical imaging based on second harmonic generation (SHG) provides rapid and highly selective detection of polar crystals. Purpurin (PUR) is a natural product with multiple pharmacological activities. Two polymorphs of PUR show distinct crystal packing and structural symmetry, where form I crystallizes in a polar space group and form II crystallizes in a centrosymmetric crystal structure. The two polymorphs are monotropically related, with form I being the thermodynamically stable form, as suggested by slurry experiments, in-situ Raman spectroscopy and crystal structure prediction (CSP). The specificity of SHG to the polar crystals of form I allows rapid polymorphism detection at the limit of individual crystals. SHG is also able to detect low levels of form I in a tablet matrix dominated by amorphous excipients. This study shows that SHG microscopy can achieve the rapid and sensitive detection of noncentrosymmetric crystals in solid dosage forms, which is especially helpful for the early detection of unwanted polymorphic conversion or crystallization of amorphous drugs in formulations and final products.