A Comparative Study on the Melt Crystallization of Biodegradable Poly(butylene succinate-co-terephthalate) and Poly(butylene adipate-co-terephthalate) Copolyesters.

As an important biodegradable and partially biobased copolyester, poly(butylene succinate-co-terephthalate) (PBST) possesses comparable thermal and mechanical properties and superior gas barrier performance when compared with poly(butylene adipate-co-terephthalate) (PBAT), but it was found to display poorer melt processability during pelletizing and injection molding. To make clear its melt crystallization behavior under rapid cooling, PBST48 and PBST44 were synthesized, and their melt crystallization was investigated comparatively with PBAT48. PBST48 showed a PBAT48-comparable melt crystallization performance at a cooling rate of 10 °C/min or at isothermal conditions, but it showed a melt crystallization ability at a cooling rate of 40 °C/min which was clearly poorer. PBST44, which has the same mass composition as PBAT48, completely lost its melt crystallization ability under the rapid cooling. The weaker chain mobility of PBST, resulting from its shorter succinate moiety, is responsible for its inferior melt crystallization ability and processability. In comparison with PBAT48, PBST48 displayed higher tensile modulus, and both PBST48 and PBST44 showed higher light transmittance. The findings in this study deepen the understanding of PBST's properties and will be of guiding significance for improving PBST's processability and application development.

Eco-friendly zinc-metal-organic framework as a nucleating agent for poly (lactic acid).

Eco-friendly poly(L-lactic acid) (PLA) can be made more versatile, and its crystallization rate is accelerated by adding Zinc-based metal-organic framework (Zn-MOF) particles. Using differential scanning calorimetry (DSC), the non-isothermal melt crystallization behavior of biodegradable PLA nucleated by 0.3 to 3 wt% of Zn-MOF was examined. The non-isothermal melt crystallization kinetics parameters were determined using a modified Avrami model and Mo approach. Zn-MOF dramatically accelerated the crystallization process, as evidenced by several non-isothermal crystallization metrics, including the crystallization half-time and crystallization rate constant. The melt crystallization temperatures of the PLA-Zn-MOF composites, with contents of 0.7 and 1 wt%, were increased by 21 °C compared to the neat PLA. Using the Friedman isoconversional kinetic method, the neat PLA and PLA-Zn-MOF composites' effective activation energy values, ∆E, were determined. The ∆E values of PLA-Zn-MOF from 0.3 to 1 wt% Zn-MOF composites were lower than that of neat PLA. Moreover, polarized optical microscopy revealed the formation of numerous small-sized PLA spherulites upon Zn-MOF addition. The results indicate that the Zn-MOF (at concentrations of 0.7 to 1.0 wt%) can be used as an efficient nucleating agent for PLA, where it increases the melt crystallization temperature, nucleation density, and crystallinity without changing the crystalline structure, while also significantly reduces the effective activation energy and the size of spherulites. Additionally, scanning electron microscopy confirms good dispersion of Zn-MOF (0.3 to 1 wt%) within the PLA matrix.

Molecular insights into the formation of drug-polymer inclusion complex.

Drug-polymer inclusion complex (IC) has been viewed as a novel solid form of drugs for property modification. Nonetheless, our understanding of the formation mechanism remains limited. This work aims to provide insight into the molecular processes governing the structural construction of carbamazepine (CBZ) and griseofulvin (GSF) channel-type ICs in the presence of guest polymers. Leveraging microdroplet melt crystallization, we successfully unveiled the single-crystal structures of these ICs, enabling structural analysis, density functional theory calculations, and molecular dynamics simulations. The results collectively elucidate the disparity between CBZ and GSF channels in terms of their autonomy in the absence of guest polymers. CBZ molecules can spontaneously assemble into stable channel structures independently, capitalizing on their unique mortise-tenon architecture and robust π…π interactions. Conversely, GSF channels lack sufficient support from weak Cl…O and C-H…π intermolecular interactions and necessitate the insertion of guest molecules to stabilize their structures. We further calculated the eleven structurally determined drug-polymer ICs and found that their channel sizes consistently fall within a narrow range of 3.81-5.18 Å although they adopt diverse approaches to construct channel structures. We anticipate that these findings will inspire continued exploration of this novel solid form, facilitating theoretical predictions and practical applications in pharmaceutical development.

Ritonavir Revisited: Melt Crystallization Can Easily Find the Late-Appearing Polymorph II and Unexpectedly Discover a New Polymorph III.

Identification of a thermodynamically stable polymorph is an important step in the early stage of drug development. Ritonavir (RIT) is a well-known case where the most stable polymorph II emerged after being marketed, leading to a loss of $250 million. Herein, we report the findings that routine melt crystallization can reveal the late-appearing polymorph II of RIT at small supercooling, but the probability of nucleation is very low. The addition of 30-50% polyethylene glycol (PEG) promotes the crystallization of Form II as the only phase at low supercooling, making it easier to detect in polymorphism screening. During the course of our research, a new polymorph, denoted Form III, was unexpectedly discovered, crystallizing as the major phase from neat RIT melts. Single crystals of Form III were grown from melt microdroplets. Benefiting from the ability of synchrotron radiation to detect weak diffraction signals that cannot be accessible by a laboratory diffractometer, a reasonable structure of Form III was solved with slight disorder relative to thiazole groups (P1 space group and Z' = 4). The thermodynamic stability ranking of the three true polymorphs is Form II > Form I > Form III, as opposed to the order of solubility. The capacity to efficiently reveal rich polymorphs, especially the kinetically hindered polymorph, and rapidly grow single crystals of a new phase for structure determination together highlights the necessity of incorporating melt crystallization into routine methods for pharmaceutical polymorphism screening.

In Search of a Double Perovskite in the Phase Triangle of Bromides CsBr-CuBr-InBr3.

New bromide compounds A2BIBIIIBr6 with a double perovskite structure provide variety and flexibility of optoelectronic properties, and some of them are of poor toxicity in comparison with such popular lead halides. The promising compound with a double perovskite structure was proposed recently for the ternary system of CsBr-CuBr-InBr3. Analysis of phase equilibria in the CsBr-CuBr-InBr3 ternary system showed stability of the quasi-binary section of CsCu2Br3-Cs3In2Br9. Formation of the estimated phase Cs2CuInBr6 by melt crystallization or solid-state sintering was not observed, most likely, as a result of higher thermodynamic stability of binary bromides CsCu2Br3 and Cs3In2Br9. The existence of three quasi-binary sections was observed, while no ternary bromide compounds were found.

Melt blending crystallization regulating balanced nanodomains in efficient and scalable coating processed organic solar cells.

The miscibility between active layer donors (D) and acceptors (A) is a key factor impeding the development of organic photovoltaics (OPVs) toward higher performance and large-area production. In this study, melt blending crystallization (MBC) was used to accomplish molecular-level blending and highly oriented crystallization in bulk heterojunction (BHJ) films realized by a scalable blade coating process, which increased the D/A contact area and provided sufficient exciton diffusion and dissociation. At the same time, the highly organized and balanced crystalline nanodomain structures permitted dissociated carriers to be efficiently transmitted and collected, resulting in significantly enhanced short-circuit current density, fill factor, and efficiency of the device by means of optimum melting temperature and quenching rates. The method can be simply incorporated into current efficient OPV material systems and achieve a device performance comparable to the best values. The blade-coating-processed PM6/IT-4F MBC devices achieved an efficiency of 13.86% in a small-area device and 11.48% in a large-area device. A power conversion efficiency (PCE) of 17.17% was obtained in PM6:BTP-BO-4F devices, and a PCE of 16.14% was acquired in PM6:Y6 devices.

Melt Crystallization of Celecoxib-Carbamazepine Cocrystals with the Synchronized Release of Drugs.

PURPOSE: The fixed-dose combination drug products have been increasingly used to treat some complex diseases. A cocrystal containing two therapeutic components, named as a drug-drug cocrystal, is an ideal solid form to formulate as a fixed-dose combination product. The aim of the study is to prepare celecoxib-carbamazepine (CEL-CBZ) cocrystals by melt crystallization to achieve the synchronized release of drugs. METHOD: The crystal structure of the CEL-CBZ cocrystal was determined from the cocrystals harvested from melt by single crystal X-ray diffraction. The binary phase diagram and crystal growth kinetics of the CEL-CBZ cocrystal from melt were studied to optimize the process parameters of hot-melt extrusion for manufacturing large-scale cocrystals. The intrinsic dissolution rate studies were conducted to compare the dissolution profiles of drugs in the cocrystal and their individual forms. RESULT: The CEL-CBZ cocrystal crystallized in the triclinic space group with one CEL and one CBZ molecule in the asymmetric unit. The crystallization of CEL-CBZ cocrystals were observed both in the supercooled liquid and glassy state. The formation of drug-drug cocrystals significantly alter the intrinsic dissolution rates of the parent drugs to favor the synchronized release. CONCLUSION: Melt crystallization is an alternative, efficient and eco-friendly approach for preparing drug-drug cocrystals on a large scale. The synchronized drug release by drug-drug cocrystals can be used to modulate the release profiles of parent drugs in the fixed-dose combination products.

Ritonavir Form III: A New Polymorph After 24 Years.

Polymorphism occurs widely in pharmaceutical solids, and must be thoroughly studied during product development. Twenty-four years after ritonavir (RTV) Form II materialized, we report a new polymorph, Form III, discovered via melt crystallization. Form III has a unique PXRD pattern, Raman spectrum, lower melting point and heat of fusion, compared to the known polymorphs, Form I and Form II. It is the least stable form, monotropically, among the three polymorphs. Form III differs from Form I and Form II in molecular conformation and hydrogen bonding motifs in crystal lattice. Nucleation from RTV supercooled liquid is slow, and selected Form III exclusively. The discovery of RTV Form III demonstrates the importance of crystal nucleation studies. Crystallization from supercooled liquids should be incorporated as part of polymorph screening workflow.

Melt-Crystallizations of α and γ Forms of Isotactic Polypropylene in Propene-Butene Copolymers.

Random isotactic propene-butene copolymers (iPPC4) of different stereoregularity have been synthesized with three different homogeneous single center metallocene catalysts having different stereoselectivity. All samples crystallize from the polymerization solution in mixtures of α and γ forms, and the relative amount of γ form increases with increasing concentrations of butene and of rr stereodefects. All samples crystallize from the melt in mixtures of α and γ forms and the fraction of γ form increases with decreasing cooling rate. At high cooling rates, the crystallization of the α form is always favored, even for samples that contain high total concentration of defects that should crystallize in the γ form. The results demonstrate that in iPPs containing significant concentrations of defects, such as stereodefects and comonomeric units, the γ form is the thermodynamically stable form of iPP and crystallizes in selective conditions of very slow crystallization, whereas the α form is the kinetically favored form and crystallizes in conditions of fast crystallization.

Inclusion/Exclusion Behaviors of Small Molecules during Crystallization of Polymers in Miscible PLLA/TAIC Blend.

In this work, PLLA/TAIC has been taken as a model system to investigate the inclusion and exclusion of small molecules during the crystallization of polymers in their miscible blend. Our results indicate that it is the growth rate and diameter of PLLA spherulites that dominate the localization of TAIC. On the one hand, crystallization temperature plays an important role. Crystallization at higher temperature corresponds to higher growth rates and a greater diameter of PLLA spherulites. The former improves the ability of PLLA crystals to trap TAIC while the latter leads to a lower volume fraction of space among neighboring PLLA spherulites. The combination of the two contributes to the enhanced inclusion behaviors. On the other hand, when compared to melt crystallization, cold crystallization results in much smaller spherulites (from higher nucleation density) and sufficient space among spherulites, which accounts for the enrichment of TAIC in interspherulitic regions and for its enhanced exclusion. In the adopted polymer-small molecule blend, TAIC can enrich in interspherulitic regions even in its miscible blend with PLLA, which can be attributed to its stronger diffusion ability.

Indomethacin Polymorph δ Revealed To Be Two Plastically Bendable Crystal Forms by 3D Electron Diffraction: Correcting a 47-Year-Old Misunderstanding.

Indomethacin is a clinically classical non-steroidal anti-inflammatory drug that has been marketed since 1965. The third polymorph, Form δ, was discovered by both melt and solution crystallization in 1974. δ-indomethacin cannot be cultivated as large single crystals suitable for X-ray crystallography and, therefore, its crystal structure has not yet been determined. Here, we report the structure elucidation of δ-indomethacin by 3D electron diffraction and reveal the truth that melt-crystallized and solution-crystallized δ-indomethacin are in fact two polymorphs with different crystal structures. We propose to keep the solution-crystallized polymorph as Form δ and name the melt-crystallized polymorph as Form θ. Intriguingly, both structures display plastic flexibility based on a slippage mechanism, making indomethacin the first drug to have two plastic polymorphs. This discovery and correction of a 47-year-old misunderstanding signify that 3D electron diffraction has become a powerful tool for polymorphic structural studies.

Melt Crystallization Behavior and Crystalline Morphology of Polylactide/Poly(ε-caprolactone) Blends Compatibilized by Lactide-Caprolactone Copolymer.

Lactide-Caprolactone copolymer (LACL) was added to a Polylactide/Poly(ε-caprolactone) (PLA/PCL) blend as a compatibilizer through solution mixing and the casting method. The melt crystallization behavior and crystalline morphology of PLA, PLA/PCL, and PLA/PCL/LACL were investigated using differential scanning calorimeter (DSC) and polarized optical microscopy (POM), respectively. The temperature of the shortest crystallization time for the samples was observed at 105 °C. The overall isothermal melt crystallization kinetics of the three samples were further studied using the Avrami theory. Neat PLA showed a higher half-time of crystallization than that of the PLA/PCL and PLA/PCL/LACL blends, whereas the half-time of crystallization of PLA/PCL and PLA/PCL/LACL showed no significant difference. The addition of PCL decreased the spherulite size of crystallized PLA, and the nuclei density in the PLA/PCL/LACL blend was much higher than that of the PLA and PLA/PCL samples, indicating that LACL had a compatibilization effect on the immiscible PLA/PCL blend, thereby promoting the nucleation of PLA. The spherulites in the PLA/PCL and PLA/PCL/LACL blend exhibited a smeared and rough morphology, which can be attributed to the fact that PCL molecules migrated to the PLA spherulitic surface during the crystallization of PLA.

Continuous Preparation of 1:1 Haloperidol-Maleic Acid Salt by a Novel Solvent-Free Method Using a Twin Screw Melt Extruder.

Salts are generally prepared by acid-base reaction in relatively large volumes of organic solvents, followed by crystallization. In this study, the potential for preparing a pharmaceutical salt between haloperidol and maleic acid by a novel solvent-free method using a twin-screw melt extruder was investigated. The pH-solubility relationship between haloperidol and maleic acid in aqueous medium was first determined, which demonstrated that 1:1 salt formation between them was feasible (pHmax 4.8; salt solubility 4.7 mg/mL). Extrusion of a 1:1 mixture of haloperidol and maleic acid at the extruder barrel temperature of 60 °C resulted in the formation of a highly crystalline salt. The effects of operating temperature and screw configuration on salt formation were also investigated, and those two were identified as key processing parameters. Salts were also prepared by solution crystallization from ethyl acetate, liquid-assisted grinding, and heat-assisted grinding and compared with those obtained by melt extrusion by using DSC, PXRD, TGA, and optical microscopy. While similar salts were obtained by all methods, both melt extrusion and solution crystallization yielded highly crystalline materials with identical enthalpies of melting. During the pH-solubility study, a salt hydrate form was also identified, which, upon heating, converted to anhydrate similar to that obtained by other methods. There were previous reports of the formation of cocrystals, but not salts, by melt extrusion. 1H NMR and single-crystal X-ray diffraction confirmed that a salt was indeed formed in the present study. The haloperidol-maleic acid salt obtained was nonhygroscopic in the moisture sorption study and converted to the hydrate form only upon mixing with water. Thus, we are reporting for the first time a relatively simple and solvent-free twin-screw melt extrusion method for the preparation of a pharmaceutical salt that provides material comparable to that obtained by solution crystallization and is amenable to continuous manufacturing and easy scale up.

Crystallization kinetics of orthorhombic paracetamol from supercooled melts studied by non-isothermal DSC.

A simple and highly reproducible procedure was established for the study of orthorhombic paracetamol crystallization kinetics, comprising melting, quench-cooling of the melt and scanning the formed glass by DSC at different heating rates. Results were analyzed on the basis of the mean as well as local values of the Avrami exponent, n, the energy of activation, as well as the Sesták-Berggren two-parameter autocatalytic kinetic model. The mean value of the Avrami kinetic exponent, n, ranged between 3 and 5, indicating deviation from the nucleation and growth mechanism underlying the Johnson-Mehl, Avrami-Kolmogorov (JMAK) model. To verify the extent of the deviation, local values of the Avrami exponent as a function of the volume fraction transformed were calculated. Inspection of the local exponent values indicates that the crystallization mechanism changes over time, possibly reflecting the uncertainty of crystallization onset, instability of nucleation due to an autocatalytic effect of the crystalline phase, and growth anisotropy due to impingement of spherulites in the last stages of crystallization. The apparent energy of activation, Ea, has a rather low mean value, close to 81 kJ/mol, which is in agreement with the observed instability of glassy-state paracetamol. Isoconversional methods revealed that Ea tends to decrease with the volume fraction transformed, possibly because of the different energy demands of nucleation and growth. The exponents of the Sesták-Berggren two-parameter model showed that the crystallized fraction influences the process, confirming the complexity of the crystallization mechanism.

Acemetacin cocrystals and salts: structure solution from powder X-ray data and form selection of the piperazine salt.

Acemetacin (ACM) is a non-steroidal anti-inflammatory drug (NSAID), which causes reduced gastric damage compared with indomethacin. However, acemetacin has a tendency to form a less soluble hydrate in the aqueous medium. We noted difficulties in the preparation of cocrystals and salts of acemetacin by mechanochemical methods, because this drug tends to form a hydrate during any kind of solution-based processing. With the objective to discover a solid form of acemetacin that is stable in the aqueous medium, binary adducts were prepared by the melt method to avoid hydration. The coformers/salt formers reported are pyridine carboxamides [nicotinamide (NAM), isonicotinamide (INA), and picolinamide (PAM)], caprolactam (CPR), p-aminobenzoic acid (PABA), and piperazine (PPZ). The structures of an ACM-INA cocrystal and a binary adduct ACM-PABA were solved using single-crystal X-ray diffraction. Other ACM cocrystals, ACM-PAM and ACM-CPR, and the piperazine salt ACM-PPZ were solved from high-resolution powder X-ray diffraction data. The ACM-INA cocrystal is sustained by the acid⋯pyridine heterosynthon and N-H⋯O catemer hydrogen bonds involving the amide group. The acid⋯amide heterosynthon is present in the ACM-PAM cocrystal, while ACM-CPR contains carboxamide dimers of caprolactam along with acid-carbonyl (ACM) hydrogen bonds. The cocrystals ACM-INA, ACM-PAM and ACM-CPR are three-dimensional isostructural. The carboxyl⋯carboxyl synthon in ACM-PABA posed difficulty in assigning the position of the H atom, which may indicate proton disorder. In terms of stability, the salts were found to be relatively stable in pH 7 buffer medium over 24 h, but the cocrystals dissociated to give ACM hydrate during the same time period. The ACM-PPZ salt and ACM-nicotinamide cocrystal dissolve five times faster than the stable hydrate form, whereas the ACM-PABA adduct has 2.5 times faster dissolution rate. The pharmaceutically acceptable piperazine salt of acemetacin exhibits superior stability, faster dissolution rate and is able to overcome the hydration tendency of the reference drug.